966 Medical and Surgical Complications

20
Controls (BMI < 30) (n = 3752)
Obese (BMI 30–35) (n = 1473)
SECTION 12

15 Morbidly obese (BMI > 35) (n = 877)

Incidence (percent)

14.6
13.3
12.3
10
10.2
9.5
8.3

5 6.3 6.3
4.8
3.0 2.6
2.3 2.1 1.0 2.1
0
Gestational Gestational Preeclampsia Birthweight Birthweight
diabetes hypertension > 4000 g > 4500 g
FIGURE 48-5 Incidence of selected pregnancy outcomes in 16,102 women enrolled in the FASTER (First- and Second-Trimester Evalua-
tion of Risk) trial according to body mass index (BMI) status. (Data from Weiss, 2004.)

Although not as magnified as in the obese cohort, almost all after delivery (Catalano, 2007; National Research Council and
complications are significantly increased in overweight women Institute of Medicine, 2007; Rode, 2005). Finally, there is evi-
compared with those whose BMI is normal. dence that quality-of-life measures are negatively affected by
Obesity is detrimental to the accuracy of obstetrical ultra- obesity during pregnancy (Amador, 2008). LaCoursiere and
sound examination (Weichert, 2011). Other morbidity includes Varner (2009) found that postpartum depression was signifi-
a higher incidence of failed trial of labor with a prior cesar- cantly increased in obese women in relation to the degree of
ean delivery (Bujold, 2005; Goodall, 2005; Hibbard, 2006; obesity—class 1, 23 percent; class 2, 32 percent; and class 3,
Robinson, 2005). Obesity and hypertension are common 40 percent.
cofactors in causing peripartum heart failure (Cunningham,
Gestational Diabetes
1986, 2012). And, obese women present anesthesia challenges
that include difficult epidural and spinal analgesia placement Obesity and gestational diabetes are inextricably linked. Their
and complications from failed or difficult intubations (Hood, coexistence with and adverse effects on pregnancy outcomes are
1993; Mace, 2011). Second-trimester dilatation and evacuation discussed in Chapter 57 (p. 1139).
was reported to take longer and be more difficult in women Preeclampsia
whose BMI was 30 kg/m2 or greater (Dark, 2002).
There is no doubt that obesity is a consistent risk factor for pre-
Obese women are less likely to breast feed than normal-weight
eclampsia (see Fig. 48-6). In a review of studies that included
women (Li, 2003). They also have greater weight retention 1 year
more than 1.4 million women, O’Brien and associates (2003)
found that the preeclampsia risk doubled with each 5 to 7 kg/m2
increase in prepregnancy BMI. In The Hyperglycemia and
30 30.4 Adverse Pregnancy Outcome (HAPO) study (2010), the inci-
dence of preeclampsia increased almost geometrically with each
23.4 BMI category. Obesity and the metabolic syndrome discussed
Incidence (percent)

on page 962 are characterized by insulin resistance causing

20
low-grade inflammation and endothelial activation (Catalano,
2010). These have a central and integral role in development
12.1 of preeclampsia as discussed in Chapter 40 (p. 733). Wolf and
10 8.2 colleagues (2001) linked these two conditions, and Ramsay and
coworkers (2002) confirmed that obese pregnant women had
4.8
2.1 2.9 significantly elevated serum levels of IL-6 and C-reactive pro-
tein and impaired endothelial function. Obese gravidas were
0 found to have significantly higher levels of triglycerides, very-
6
.2

44

low-density lipoprotein cholesterol, insulin, and leptin com-

7

4
3.
6.

0.

8.

–4
23

–3

>
–2

–3

–3

.4

pared with normal-weight pregnant woman.

≤

.6
.3

.8

.7

38
30
23

26

33

Body mass index (kg/m2) Contraception

FIGURE 48-6 Frequency of preeclampsia according to body mass Most studies report that oral contraceptive failure is more likely
index. (Data from the Hyperglycemia and Adverse Pregnancy Out- in overweight women. This is discussed in detail in Chapter 38
come [HAPO] Study Cooperative Research Group, 2010.) (p. 695).
 Obesity 967

■ Perinatal Mortality women in pregnancy—47 percent—rather than the 4 percent

Stillbirths are more prevalent as the degree of obesity increases (see of pregnant women with diabetes. More recently, Edlow and
Table 48-3). Indeed, in a review of almost 100 population-based associates (2013) have shown that genes expressed in the adult

CHAPTER 48
studies, Flenady and associates (2011) found that obesity was metabolic syndrome may be initiated in the fetus.
the highest ranking modifiable risk factor for stillbirth. Chronic
Morbidity in Children Born to Obese Women
hypertension with superimposed preeclampsia associated with
obesity is one cause of excessive stillbirths. An increased inci- It appears that obese women beget obese children, who them-
dence of otherwise inexplicable late-pregnancy stillbirths and selves become obese adults. Whitaker (2004) studied low-income
early neonatal deaths is also associated with obesity (Cnattingius, children in the Special Supplemental Food Program for Women,
1998; Stephansson, 2001; Waldenström, 2014; Yao, 2014). In Infants, and Children (WIC) and found a linear association
one metaanalysis, there was a 1.5-fold increased risk for stillbirth between early pregnancy maternal BMI and prevalence of over-
in overweight and a 2.1-fold risk in obese women (Chu, 2007). weight children at 2, 3, and 4 years. Schack-Nielson and associates
A Scottish study of more than 186,000 nulliparas described an (2005) reported a direct association between maternal, newborn,
almost fourfold increased stillbirth rate in women with a BMI ≥ and childhood BMI. This association strengthened as offspring
35 kg/m2 compared with women of normal size (Denison, 2008). progressed to adulthood. Catalano and coworkers (2005) studied
Increased prepregnancy weight was the factor most strongly offspring at a median age of 7 years and found a direct associa-
associated with unexplained fetal deaths even after adjusting for tion with maternal prepregnancy obesity and childhood obesity.
maternal age and excluding women with diabetes and hyperten- They also reported associations with central obesity, elevated sys-
sive disorders (Huang, 2000; Nohr, 2005; Ovesen, 2011). tolic blood pressure, increased insulin resistance, and decreased
high-density lipoprotein (HDL) cholesterol levels—all elements
of the metabolic syndrome. In their analysis of 28,540 women,
■ Perinatal Morbidity Reynolds and associates (2013) found increased rates of cardiovas-
Both fetal and neonatal complications are increased in obese cular disease and all-cause mortality in offspring of overweight and
women. The Atlantic Birth Defects Risk Factor Surveillance obese mothers. Boney and colleagues (2005) studied offspring of
Study found a two- to threefold increased incidence in various women with or without gestational diabetes. They observed that
anomalies in obese women (Watkins, 2003). Rasmussen and children who were large for gestational age at birth and whose
coworkers (2008) performed a metaanalysis and found 1.2-, 1.7-, mothers were either obese or had gestational diabetes had signifi-
and 3.1-fold increased risks for neural-tube defects in overweight, cantly increased risks for developing metabolic syndrome.
obese, and severely obese women, respectively. Another meta- It also appears that excessive maternal weight gain in
analysis found that maternal obesity was significantly associated pregnancy may predict adulthood obesity in their offspring.
with an increased risk of a wide range of anomalies (Stothard, Schack-Nielsen and associates (2005) found a linear associa-
2009). The National Birth Defect Prevention Study reported a tion of maternal weight gain with the subsequent BMI in their
correlation between BMI and congenital heart defects (Gilboa, children. Analyzing data from Project Viva, Oken (2006) con-
2010). According to Biggio and colleagues (2010), however, this firmed this. However, not all studies concur. In their analysis
may be related to diabetes as a cofactor. Already mentioned is of children in the WIC program cited above, Whitaker and
concern for unreliable fetal anatomy sonographic screening in associates (2004) found no obvious linear association between
obese women (Dashe, 2009; Thornburg, 2009; Weichert, 2011). gestational weight gain and childhood obesity. This is also dis-
Two important and interrelated cofactors that contribute to cussed in some detail in Chapter 44 (p. 876).
excessive rates of perinatal morbidity are chronic hypertension
and diabetes mellitus, both of which are associated with obe- Fetal Programming and Childhood Morbidity
sity. Affected women have increased rates of preterm delivery Epidemiological studies have addressed the association of child-
and fetal-growth restriction (McDonald, 2010; Waldenström, hood, adolescent, and even adult adverse health outcomes in
2014; Wang, 2011). As discussed above, pregestational diabetes relation to the fetal environment. Adverse outcomes include
increases the birth defect rate, and gestational diabetes is com- obesity, diabetes, hypertension, and the metabolic syndrome.
plicated by excessive numbers of large-for-gestational age and Variables studied have included maternal prepregnancy BMI,
macrosomic fetuses (Chap. 44, p. 884). obesity, gestational weight gain, and pregestational or ges-
Even without diabetes, the prevalence of macrosomic tational diabetes. The most robust evidence suggests a direct
newborns is increased in obese women (Cedergren, 2004; association between children born to women who had prepreg-
Ovesen, 2011). The group from MetroHealth Medical Center nancy obesity or gestational diabetes and being overweight in
in Cleveland has conducted studies of prepregnancy obesity, childhood and adulthood.
gestational weight gain, and prepregnancy and gestational dia- The potential biological causes and mechanisms of these
betes and their relationship to newborn weight and fat mass associations are not clear. Elucidation is limited by insufficient
(Catalano, 2005, 2007; Ehrenberg, 2004; Sewell, 2006). data on potential maternal and genetic predisposing factors and
Although each of these variables was found to be associated on the environment of the infant and child in relation to diet
with larger and more corpulent newborns, prepregnancy BMI and activity. The science of epigeneticss has provided some sup-
had the strongest influence on the prevalence of macrosomic port for the possibility that perturbations of the maternal-fetal
neonates. They attributed this increased prevalence of macro- environment can adversely alter postdelivery events (Aagard-
somic infants to the marked frequency of overweight or obese Tillery, 2006). Perhaps more likely are contributions of the
 968 Medical and Surgical Complications

maternal-child environment subsequent to birth (Gluck,

2009). These and other factors regarding fetal programming
are discussed in Chapter 44 (p. 876).
SECTION 12

■ Antepartum Management
Dietary Intervention in Pregnancy
Weight reduction is not advisable during pregnancy (Catalano,
2013). As noted, recommended weight gain in obese women
is 11 to 20 pounds, and several dietary interventions to limit
weight gain to these targets have been reported. These include
lifestyle interventions and physical activity (Petrella, 2013).
Reviews by Quinlivan (2011) and Tanentsapf (2011) found
that randomized trials generally reported successful results with
intervention. On the other hand, in many other studies, either
these have been unsuccessful or the results were insufficient to
permit a conclusion (Campbell, 2011; Dodd, 2010; Guelinckx,
2010; Nascimento, 2011; Ronnberg, 2010). Special attention
to psychological aspects of pregnancy has been recommended
by some (Skouteris, 2010).

Prenatal Care
Close prenatal surveillance detects most early signs of diabetes A
or hypertension. Standard screening tests for fetal anomalies
are sufficient, while being mindful of sonographic limitations
for detection of fetal anomalies. Accurate assessment of fetal
growth usually requires serial sonography. Antepartum and
intrapartum external fetal heart rate monitoring are likewise
more difficult, and sometimes these are even impossible.

■ Surgical and Anesthetic Concerns

Evaluation by the anesthesia team is performed at a prenatal visit
or on arrival at the labor unit (American College of Obstetricians
and Gynecologists, 2013b). Anesthetic risks and complications
faced by obese women are discussed in Chapter 25 (p. 505).
Special attention is given to complications that might arise dur- B
ing labor and delivery. Vricella and coworkers (2010) reported FIGURE 48-7 Abdominal incision for the obese woman. A. Fron-
the following frequencies of anesthetic complications in 142 tal view. The dotted line indicates an appropriate skin incision
morbidly obese women at cesarean delivery. These included for abdominal entry relative to the panniculus. As shown by the
technical problems with regional analgesia—up to 6 percent; uterus in the background, selection of this periumbilical site per-
mits access to the lower uterine segment. B. Sagittal view.
use of general anesthesia—6 percent; hypotension—3 percent;
and overall anesthetic complications of 8.4 percent.
For cesarean delivery, forethought is given to optimal place- of subcutaneous closure in 887 women undergoing cesarean
ment and type of abdominal incision to allow access to the fetus delivery whose wound thickness was greater than 2 centime-
and to effect the best wound closure with the least intervening tis- ters. Subcutaneous closure resulted in a modest but signifi-
sue (Alexander, 2006). One technique is shown in Figure 48-7. cant 6-percent decrease in wound disruption. The frequency
Others prefer a transverse abdominal incision (Alanis, 2010). of abdominal wound infections is directly related to BMI
Individual differences in maternal body habitus preclude nam- (Norman, 2013). Comorbid diabetes apparently increases this
ing any one approach as superior (Gilstrap, 2002; McLean, risk (Leth, 2011). Several reports describe a wound complica-
2012). Although some have reported similar wound complica- tion rate of 15 to 45 percent. Alanis and colleagues (2010)
tions with either incision, others reported a fourfold wound com- reported a 30-percent rate in 194 women whose BMI was
plication rate when a vertical abdominal incision was compared > 50 kg/m2. Of these, 90-percent were wound disruptions to
with a transverse incision—31 versus 8 percent (Houston, 2000; the fascia, but there was only one evisceration. As indicated
Thornburg, 2012; Wall, 2003). Finally, a mid-abdomen trans- above, the transverse abdominal incision had fewer complica-
verse incision has been advocated by some (Tixier, 2009). tions. Walsh and coworkers (2009) have reviewed the preven-
Attention to closure of the subcutaneous layer is impor- tion and management of surgical site infections in morbidly
tant. Chelmow and associates (2004) performed a metaanalysis obese women.
 Obesity 969

To lower thromboembolic complications, graduated com-

TABLE 48-4. Pregnancy Outcomes Following Gastric
pression stockings, hydration, and early mobilization after
Banding Surgery and Roux-en-Y
cesarean delivery in obese women are recommended by the
Gastric Bypass

CHAPTER 48
American College of Obstetricians and Gynecologists (2013a).
Some also recommend “mini-dose” heparin prophylaxis, but Gastric Roux-en-Y
we do not routinely use this (Chap. 52, p. 1044). Bandingb Gastric Bypassc
Outcomea (n = 258) (n = 236)
Hypertension 8% 6%
■ Bariatric Surgery Gestational diabetes 12% 4%
Several surgical procedures have been designed to treat morbid Cesarean delivery 25% 23%
obesity either by decreasing gastric volume—restrictive, or by Mean birthweight 3000 g 3300 g
bypassing gastrointestinal absorption—restrictive malabsorptive Small for gestational age 10% 17%
(Adams, 2007; Kushner, 2012). In nonpregnant patients, these Stillbirth 4/1000 6/1000
procedures have been shown to improve or resolve diabetes,
a
hyperlipidemia, hypertension, and obstructive sleep apnea Data not reported identically—frequencies are approxi-
(Buchwald, 2007; Mingrone, 2012; Schauer, 2012). mations.
b
Data from Bar-Zohar, 2006; Dixon, 2001; Ducarme,
Pregnancy 2013; Martin, 2000; Skull, 2004.
c
Because of these successes, bariatric surgery currently has become From review by Abodeely, 2008.
popular, and many women are becoming pregnant following
weight-reduction surgery (Abodeely, 2008). Several observa-
tional studies have reported improved fertility rates and reduced Reported complications have been few and include exces-
risks of obstetrical complications in women following bariatric sive nausea and vomiting that abated with band adjustment
surgery and compared with morbidly obese controls (Alatishe, (Martin, 2000). Rarely, women may have band slippage asso-
2013; Guelinckx, 2009; Kjaer, 2013a; Lesko, 2012; Tan, 2012). ciated with hyperemesis or with advancing gestation (Pilone,
The largest of these studies is from the Swedish Birth Register, 2012; Suffee, 2012). One newborn died after fetal cerebral
which included 681 women with a pregnancy following bariat- hemorrhage developed from vitamin K deficiency associated
ric surgery (Josefsson, 2011). Despite surgical treatments, half with band slippage (Van Mieghem, 2008).
of these women were still obese by the time of their first preg-
nancy following bypass, however, the proportion with morbid Restrictive Malabsorptive Procedures
obesity was smaller. The frequency of large-for-gestational age There are three procedures to accomplish gastric restriction
infants decreased from 9.1 to 3.2 percent and that of small-for- and selective malabsorption. The most commonly used is the
gestational age neonates increasedd from 2.1 to 5.6 percent. In laparoscopically performed Roux-en-Y gastric bypasss and bilio-
a recent systematic review, Kjaer and Nilas (2013b) reported a pancreatic diversion with duodenal switch. With the Roux-en-Y
decreased risk after bariatric surgery for diabetes, preeclampsia, procedure, the proximal stomach is completely transected
and large-for-gestational age infants. Most studies confirmed a to leave a 30-mL pouch. A gastroenterotomy is then created
higher risk for small-for-gestational age fetuses. by connecting the proximal end of the distal jejunum to the
pouch. A Roux-en-Y enteroenterostomy is also completed
Restrictive Procedures 60 cm distal to this gastrojejunostomy to allow drainage of the
The prototypical vertical banded gastroplasty has been largely unused stomach and proximal small intestine.
replaced by the laparoscopic adjustable silicone gastric band- As with other bariatric procedures, pregnancy outcomes are
ing (LASGB) operation. With the two approved LASGB changed remarkably following Roux-en-Y bypass (Wittgrove,
procedures—LAPBAND D and REALIZE, an adjustable band is 1998). As shown in Table 48-4, rates of hypertension, gesta-
placed 2 cm below the gastroesophageal junction to create a tional diabetes, and fetal macrosomia are reduced. Serious com-
small pouch. The pouch size is controlled by a saline reservoir plications are uncommon. Intussusception and small bowel
in the band. Salutary effects on pregnancy outcomes involve obstruction develop from internal herniation, and maternal
before-and-after cohorts as well as pregnancies in postsurgical deaths from herniation and obstruction have been reported
women compared with obese, nonsurgical controls (Vrebosch, (Kakarla, 2005; Moore, 2004; Renault, 2012; Wax, 2007).
2012). In a report by Dixon and colleagues (2005), pregnancy Bowel obstruction is notoriously difficult to diagnose, and Wax
outcomes were compared with their preprocedural outcomes and associates (2013) caution for a high index of suspicion.
and with a matched cohort of obese women. Following band-
ing, the incidences of gestational hypertension—10 versus 45 Recommendations
percent—and gestational diabetes—6 versus 15 percent—were The American College of Obstetricians and Gynecologists
significantly lower compared with their preprocedural pregnan- (2013a) recommends that women who have undergone bariat-
cies. Incidences in banded patients were also significantly lower ric surgery be assessed for vitamin and nutritional sufficiency.
than those in the obese cohort, whose rates for hypertension When indicated, vitamin B12 and D, folic acid, and calcium
were 38 percent, and for diabetes, 19 percent. The results from supplementation are given. Vitamin A deficiency has also been
these and other studies are shown in Table 48-4. reported (Chagas, 2013). Women with a gastric band should
 973

CHAPTER 49

Cardiovascular Disorders

PHYSIOLOGICAL CONSIDERATIONS IN PREGNANCY . . . 973 Cardiovascular diseases also account for significant maternal
morbidity and are a leading cause of obstetrical intensive care
DIAGNOSIS OF HEART DISEASE . . . . . . . . . . . . . . . . . . . 974 unit admissions (Small, 2012).
PERIPARTUM MANAGEMENT CONSIDERATIONS . . . . . . 977 The increasing prevalence of cardiovascular diseases compli-
cating pregnancy is likely due to a number of causes, includ-
SURGICALLY CORRECTED HEART DISEASE . . . . . . . . . . . 979 ing higher rates of obesity, hypertension, and diabetes. Indeed,
according to the United States National Center for Health
VALVULAR HEART DISEASE . . . . . . . . . . . . . . . . . . . . . . 981 Statistics, almost half of adults aged 20 and older have at least
CONGENITAL HEART DISEASE . . . . . . . . . . . . . . . . . . . . 984 one risk factor for cardiovascular disease (Fryar, 2012). And
as shown in Figure 49-1, the prevalence of these risk factors
PULMONARY HYPERTENSION . . . . . . . . . . . . . . . . . . . . 986 among reproductive-aged women is dramatic. Other related
factors include delayed childbearing. From 1970 to 2006 the
CARDIOMYOPATHIES . . . . . . . . . . . . . . . . . . . . . . . . . . 988 proportion of first births to women aged 35 years or older
HEART FAILURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990 increased nearly eightfold (Mathews, 2009). Finally, as dis-
cussed subsequently, an increasing number of patients with
INFECTIVE ENDOCARDITIS . . . . . . . . . . . . . . . . . . . . . . . 990 congenital heart disease are now becoming pregnant.

ARRHYTHMIAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991

DISEASES OF THE AORTA . . . . . . . . . . . . . . . . . . . . . . . 992 PHYSIOLOGICAL CONSIDERATIONS

IN PREGNANCY
ISCHEMIC HEART DISEASE . . . . . . . . . . . . . . . . . . . . . . . 994
■ Cardiovascular Physiology
The marked pregnancy-induced anatomical and functional
changes in cardiac physiology can have a profound effect
Heart disease complicates more than 1 percent of all pregnan- on underlying heart disease (Chap. 4, p. 58). Some of these
cies and is now the leading cause of indirect maternal deaths— changes are listed in Table 49-1. Importantly, cardiac out-
accounting for 20 percent of all cases (Simpson, 2012). In an put increases approximately 40 percent during pregnancy.
analysis of maternal mortality in the United States between Almost half of this total increase takes place by 8 weeks and
1987 and 2005, the causes previously responsible for most is maximal by midpregnancy (Capeless, 1989). The early
maternal deaths—hemorrhage and hypertensive disorders— increase stems from augmented stroke volume that results
had progressively decreased rates, whereas deaths attributable from decreased vascular resistance. Later in pregnancy, rest-
to cardiovascular diseases had the greatest percentage increase ing pulse and stroke volume increase even more because of
(Berg, 2010). Similarly, in the United Kingdom, the rate of increased end-diastolic ventricular volume that results from
maternal mortality due to cardiac disease increased from pregnancy hypervolemia. This along with an increase in heart
1.65 to 2.31 per 100,000 births between 1997–1999 and rate translates to increased cardiac output that continues to
2006–2008 (Centre for Maternal and Child Enquiries, 2011). rise across pregnancy to average 40 percent higher at term.
 974 Medical and Surgical Complications

50 common obstetrical conditions add undue cardiac burdens.

Some of these include preeclampsia, hemorrhage and anemia,
40 and sepsis syndrome. In a report of 542 women with heart dis-
Percentage

ease, eight of 10 maternal deaths were during the puerperium

SECTION 12

30 (Etheridge, 1977).
20
■ Ventricular Function in Pregnancy
10
Ventricular volumes increase to accommodate pregnancy-
0 induced hypervolemia. This is reflected by increasing end-
Inactivity Obesity Smoking High Pre-DM systolic as well as end-diastolic dimensions. At the same time,
cholesterol however, there is no change in septal thickness or in ejec-
FIGURE 49-1 Prevalence of risk factors for cardiovascular disease tion fraction. This is because these changes are accompanied
among reproductive-aged women. DM = diabetes mellitus. by substantive ventricular remodeling—plasticity—
— —which is
(From Centers for Disease Control and Prevention, 2011.) characterized by eccentric expansion of left-ventricular mass
that averages 30 to 35 percent near term. All of these adap-
tations return to prepregnancy values within a few months
These changes are even more profound in multifetal preg- postpartum.
nancy (Kametas, 2003; Kuleva, 2011). Certainly for clinical purposes, ventricular function dur-
An important study by Clark and colleagues (1989) con- ing pregnancy is normal as estimated by the Braunwald ven-
tributed greatly to the understanding of cardiovascular physiol- tricular function graph depicted in Figure 4-9 (p. 59). For
ogy during pregnancy. Using right-sided heart catheterization, given filling pressures, there is appropriate cardiac output
hemodynamic function was measured in 10 healthy primi- so that cardiac function during pregnancy is eudynamic.
gravid volunteers, and pregnancy values were compared with Despite these findings, it remains controversial whether myo-
those measured again at 12 weeks postpartum. As shown in cardial function per se is normal, enhanced, or depressed.
Table 49-1, the cardiac output near term in the lateral recum- Myocardial performance is measured by preload, afterload,
bent position increased 43 percent. Systemic and pulmonary contractility, and heart rate. Because these depend on ven-
vascular resistances were concomitantly decreased. Importantly, tricular geometry, they can only be measured indirectly
intrinsic left ventricular contractility did not change. Thus, (Savu, 2012). In nonpregnant subjects with a normal heart
normal left ventricular function is maintained during preg- who sustain a high-output state, the left ventricle undergoes
nancy, that is, pregnancy is not characterized by hyperdynamic longitudinal remodeling, and echocardiographic functional
function or a high cardiac-output state. indices of its deformation provide normal values. In preg-
Women with underlying cardiac disease may not always nancy, there instead appears to be spherical remodeling, g and
accommodate these changes, and ventricular dysfunction these calculated indices that measure longitudinal deforma-
leads to cardiogenic heart failure. A few women with severe tion are depressed. Thus, these normal indices are likely
cardiac dysfunction may experience evidence of heart failure inaccurate when used to assess function in pregnant women
before midpregnancy. In others, heart failure may develop after because they do not take into account the spherical eccentric
28 weeks when pregnancy-induced hypervolemia and cardiac hypertrophy characteristic of normal pregnancy.
output reach their maximum. In most, however, heart failure
develops peripartum when labor, delivery, and a number of
DIAGNOSIS OF HEART DISEASE
The physiological adaptations of normal pregnancy can induce
TABLE 49-1. Hemodynamic Changes in 10 Normal symptoms and alter clinical findings that may confound the
Pregnant Women at Term Compared diagnosis of heart disease. For example, in normal pregnancy,
with Repeat Values Obtained 12 Weeks functional systolic heart murmurs are common; respiratory
Postpartum effort is accentuated and at times suggests dyspnea; edema
in the lower extremities after midpregnancy is common; and
Parameter Change (%)
fatigue and exercise intolerance develop in most women. Some
Cardiac output +43 systolic flow murmurs may be loud, and normal changes in
Heart rate +17 the various heart sounds depicted in Figure 49-2 may suggest
Left ventricular stroke work index +17 cardiac disease.
Vascular resistance Clinical findings that may suggest heart disease are listed
Systemic −21 in Table 49-2. Pregnant women with none of these rarely
Pulmonary −34 have serious heart disease. As an interesting aside, Melchiorre
Mean arterial pressure +4 and associates (2011) found that the prevalence of previously
Colloid osmotic pressure −14 undiagnosed maternal cardiac structural abnormalities is sig-
nificantly increased in women with high midtrimester uterine
Data from Clark, 1989.
artery Doppler resistance indices (Chap. 17, p. 345).
 Cardiovascular Disorders 975

External jugular vein

CHAPTER 49
Aorta
t unk
Pulmonaryy tr
Pulmonic val
alve
al
Aortic valve
Miitr
Mitr
t al valve

Tricuspid valve
Tri
Tr

Mammary souffle

Jugular venous
S2 P increased; S2 split Occasional S3
distention
S1 M increased and widely Aortic or pulmonary
Venous hum
split flow murmurs
FIGURE 49-2 Normal cardiac examination findings in the pregnant woman. S1 = first sound; M1 = mitral first sound; S2 = second sound;
P2 = pulmonary second sound. (From Gei, 2001; Hytten, 1991.)

■ Diagnostic Studies
In most women, noninvasive cardiovascular studies such as
TABLE 49-2. Clinical Indicators of Heart Disease electrocardiography, chest radiography, and echocardiog-
During Pregnancy raphy will provide data necessary for evaluation. In some
Symptoms situations, such as complex congenital heart disease, trans-
Progressive dyspnea or orthopnea esophageal echocardiography may be useful. Albumin or red
Nocturnal cough cells tagged with technicium-99m are rarely needed during
Hemoptysis pregnancy to evaluate ventricular function. That said, the esti-
Syncope mated fetal radiation exposure from nuclear medicine stud-
Chest pain ies of myocardial perfusion are calculated to range between
5 and 17 mGy depending on the technique employed
Clinical Findings
(Colletti, 2013). If indicated, cardiac catheterization can be
Cyanosis
performed with limited fluoroscopy time. During coronary
Clubbing of fingers
angiography, the mean radiation exposure to the unshielded
Persistent neck vein distention
abdomen is 1.5 mGy, and less than 20 percent of this reaches
Systolic murmur grade 3/6 or greater
the fetus because of tissue attenuation (European Society of
Diastolic murmur
Cardiology, 2011). Shielding the fetus from direct radiation
Cardiomegaly
and shortening the fluoroscopic time help to minimize radia-
Persistent arrhythmia
tion exposure. In women with clear indications, any mini-
Persistent split second sound
mal theoretical fetal risk is outweighed by maternal benefits
Criteria for pulmonary hypertension
(Chap. 46, p. 932).
 976 Medical and Surgical Complications

Electrocardiography stroke; (2) baseline NYHA class III or IV or cyanosis; (3) left-
As the diaphragm is elevated in advancing pregnancy, there is sided obstruction defined as mitral valve area < 2 cm2, aortic
an average 15-degree left-axis deviation in the electrocardio- valve area < 1.5 cm2, or peak left ventricular outflow tract gra-
dient > 30 mm Hg by echocardiography; (4) ejection fraction
SECTION 12

gram (ECG), and mild ST changes may be seen in the inferior

leads. Atrial and ventricular premature contractions are rela- less than 40 percent. The risk of pulmonary edema, sustained
tively frequent (Carruth, 1981). Pregnancy does not alter volt- arrhythmia, stroke, cardiac arrest, or cardiac death was substan-
age findings. tially increased with one of these factors and even more so with
two or more.
Chest Radiography At least two studies have been conducted using these
Anteroposterior (AP) and lateral chest radiographs are useful, latter risk criteria. Khairy and colleagues (2006) reviewed
and when a lead apron shield is used, fetal radiation exposure 90 pregnancies in 53 women with congenital heart disease
is minimal (Chap. 46, p. 931). Gross cardiomegaly can usually at Brigham and Women’s Hospital. There were no mater-
be excluded, but slight heart enlargement cannot be detected nal deaths, and heart failure and symptomatic arrhythmias
accurately because the heart silhouette normally is larger in developed in 16.7 and 2.8 percent of the women, respec-
pregnancy. This is accentuated further with a portable AP chest tively. Similar to the Canadian study cited above, the most
radiograph. important predictors of complications were prior congestive
heart failure, depressed ejection fraction, and smoking. In a
Echocardiography German study that also used these predefined risk predic-
Widespread use of echocardiography has allowed accurate tors, they were found to be accurate in assessing most cardiac
diagnosis of most heart diseases during pregnancy. It allows outcomes (Stangl, 2008).
noninvasive evaluation of structural and functional cardiac
factors. Some normal pregnancy-induced changes include
■ Preconceptional Counseling
slightly but significantly increased tricuspid regurgitation, left
atrial end-diastolic dimension, and left ventricular mass. Savu Women with severe heart disease will benefit immensely from
(2012) and Vitarelli (2011) and their coworkers have pro- counseling before undertaking pregnancy, and they usually are
vided normal morphological and functional echocardiographic referred for maternal-fetal medicine or cardiology consultation
parameters for pregnancy, which are listed in the Appendix (Clark, 2012; Seshadri, 2012).
(p. 1293). Maternal mortality rates generally vary directly with func-
tional classification, and this relationship may change as preg-
nancy progresses. In the Canadian study, Siu and colleagues
■ Classification of Functional Heart Disease (2001b) observed significant worsening of NYHA class in
There is no clinically applicable test for accurately measuring 4.4 percent of 579 pregnancies in which the baseline class was
functional cardiac capacity. The clinical classification of the I or II. Their experiences, however, as well as those of McFaul
New York Heart Association (NYHA) was first published in and coworkers (1988), were that there were no maternal deaths
1928, and it was revised for the eighth time in 1979. This clas- in 1041 women with class I or II disease. As described later,
sification is based on past and present disability and is uninflu- some women have life-threatening cardiac abnormalities that
enced by physical signs: can be reversed by corrective surgery, and subsequent preg-
nancy becomes less dangerous. In other cases, such as women
• Class I. Uncompromised—no limitation of physical activity:
with mechanical valves taking warfarin, fetal considerations
These women do not have symptoms of cardiac insufficiency
predominate.
or experience anginal pain.
The World Health Organization Risk Classification of
• Class II. Slight limitation of physical activity: These women
Cardiovascular Disease and Pregnancy is useful for assessing
are comfortable at rest, but if ordinary physical activity is
maternal risk associated with various cardiovascular conditions
undertaken, discomfort in the form of excessive fatigue,
and for preconceptional counseling and planning (Thorne,
palpitation, dyspnea, or anginal pain results.
2006). Maternal risk is divided among four progressively wors-
• Class III. Marked limitation of physical activity: These women
ening classes as shown in Table 49-3. Its use has been recom-
are comfortable at rest, but less than ordinary activity causes
mended by the European Society of Cardiology (2011).
excessive fatigue, palpitation, dyspnea, or anginal pain.
• Class IV. Severely compromised—inability to perform any phys-
ical activity without discomfort: Symptoms of cardiac insuf- f ■ Congenital Heart Disease in Offspring
ficiency or angina may develop even at rest. If any physical
Many congenital heart lesions appear to be inherited as poly-
activity is undertaken, discomfort is increased.
genic characteristics, which are discussed in Chapter 13
Siu and associates (2001b) expanded the NYHA classifi- (p. 274). Because of this, some women with congenital heart
cation and developed a scoring system for predicting cardiac lesions give birth to similarly affected infants, the risk of which
complications during pregnancy. The system is based on a pro- varies widely as shown in Table 49-4. Environmental factors are
spective analysis of 562 consecutive pregnant women with heart also important. One example is a study from Tibet in which the
disease during 617 pregnancies in 13 Canadian teaching hospi- prevalence of fetal heart disease was increased among women
tals. Predictors of cardiac complications included the following: living at higher altitudes (> 3600 meters) and was presumably
(1) prior heart failure, transient ischemic attack, arrhythmia, or due to lower oxygen concentrations (Chen, 2008).
 Cardiovascular Disorders 977

TABLE 49-3. World Health Organization (WHO) Risk Classification of Cardiovascular Disease and Pregnancy
Risk Category Associated Conditions

CHAPTER 49
WHO 1—Risk no higher than general Uncomplicated, small, or mild:
population Pulmonary stenosis
Ventricular septal defect
Patent ductus arteriosus
Mitral valve prolapse with no more than trivial mitral regurgitation
Successfully repaired simple lesions:
Ostium secundum atrial septal defect
Ventricular septal defect
Patent ductus arteriosus
Total anomalous pulmonary venous drainage
Isolated ventricular extrasystoles and atrial ectopic beats
WHO 2—Small increase in risk of maternal If otherwise uncomplicated:
mortality and morbidity Unoperated atrial septal defect
Repaired Fallot tetralogy
Most arrhythmias
WHO 2 or 3—depends on individual case Mild left ventricular impairment
Hypertrophic cardiomyopathy
Native or tissue valvular heart disease not considered WHO 4
Marfan syndrome without aortic dilation
Heart transplantation
WHO 3—Significantly increased risk of Mechanical valve
maternal mortality or expert cardiac and Systemic right ventricle—congenitally corrected transposition, simple
obstetrical care required transposition post-Mustard or -Senning repair
Post-Fontan operation
Cyanotic heart disease
Other complex congenital heart disease
WHO 4—Very high risk of maternal Pulmonary arterial hypertension
mortality or severe morbidity; pregnancy Severe systemic ventricular dysfunction (NYHA III-IV or LVEF < 30%)
contraindicated and termination Previous peripartum cardiomyopathy with any residual impairment of left
discussed ventricular function
Severe left heart obstruction
Marfan syndrome with aorta dilated > 40 mm

Modified from Thorne, 2006.

TABLE 49-4. Risks for Fetal Heart Lesions Related to

Affected Family Members PERIPARTUM MANAGEMENT CONSIDERATIONS
Congenital Heart Disease in In most instances, management involves a team approach with
Fetus (%) an obstetrician, cardiologist, anesthesiologist, and other spe-
cialists as needed. With complex lesions or with women who
Previous
are especially at risk, evaluation by a multidisciplinary team is
Sibling Father Mother
recommended early in pregnancy. During consultation, cardio-
Cardiac Lesion Affected Affected Affected
vascular changes likely to be poorly tolerated by an individual
NS 50 50 woman are identified, and plans are formulated to minimize
Aortic stenosis 2 3 15–18 these. In some, pregnancy termination may be advisable.
Pulmonary stenosis 2 2 6–7 Maxwell (2010) has provided an in-depth checklist that consid-
Ventricular septal defect 3 2 10–16 ers detailed management options. The four changes that affect
Atrial septal defect 2.5 1.5 5–11 management that are emphasized by the American College
Patent ductus arteriosus 3 2.5 4 of Obstetricians and Gynecologists (1992) include decreased
Coarctation of the aorta NS NS 14 vascular resistance, increased blood volume and cardiac out-
Fallot tetralogy 2.5 1.5 2–3 put and their fluctuations peripartum, and hypercoagulability.
Within this framework, both prognosis and management are
NS = not stated.
influenced by the type and severity of the specific lesion and by
Data from Lupton, 2002.
the patient’s functional classification.
 978 Medical and Surgical Complications

With rare exceptions, women in NYHA class I and most in suggest impending ventricular failure. If there is any evidence
class II negotiate pregnancy without morbidity. Special atten- of cardiac decompensation, intensive medical management
tion should be directed toward both prevention and early rec- must be instituted immediately. It is essential to remember that
ognition of heart failure as discussed on page 990. Infection delivery itself does not necessarily improve the maternal condi-
SECTION 12

with sepsis syndrome is an important factor in precipitating tion and in fact, may worsen it. Moreover, emergency operative
cardiac failure. Moreover, bacterial endocarditis is a deadly delivery may be particularly hazardous. Clearly, both maternal
complication of valvular heart disease (p. 990). Each woman and fetal status must be considered in the decision to hasten
should receive instructions to avoid contact with persons who delivery under these circumstances.
have respiratory infections, including the common cold, and to
report at once any evidence for infection. Pneumococcal and Analgesia and Anesthesia
influenza vaccines are recommended. Relief from pain and apprehension is important. Although
Cigarette smoking is prohibited, because of both its car- intravenous analgesics provide satisfactory pain relief for some
diac effects and its propensity to cause upper respiratory infec- women, continuous epidural analgesia is recommended for
tions. Illicit drug use may be particularly harmful, an example most. The major problem with conduction analgesia is mater-
being the cardiovascular effects of cocaine or amphetamines. nal hypotension (Chap. 25, p. 514). This is especially danger-
In addition, intravenous drug use increases the risk of infective ous in women with intracardiac shunts in whom flow may be
endocarditis. reversed. Blood passes from right to left within the heart or
Fortunately, cases of NYHA class III and IV are uncommon aorta and thereby bypasses the lungs. Hypotension can also
today. In the Canadian study, only 3 percent of approximately be life-threatening if there is pulmonary arterial hypertension
600 pregnancies were complicated by NYHA class III heart dis- or aortic stenosis because ventricular output is dependent on
ease, and no women had class IV when first seen (Siu, 2001b). adequate preload. In women with these conditions, narcotic
In a Turkish study, 8 percent of pregnancies in women with conduction analgesia or general anesthesia may be preferable.
cardiac diseases were NYHA class III or IV (Madazli, 2010). For vaginal delivery in women with only mild cardiovascular
An important question in these women is whether pregnancy compromise, epidural analgesia given with intravenous sedation
should be undertaken. If women make that choice, they must often suffices. This has been shown to minimize intrapartum car-
understand the risks, and they are encouraged to be compliant diac output fluctuations and allows forceps or vacuum-assisted
with planned care. In some, prolonged hospitalization or bed delivery. Subarachnoid blockade is not generally recommended
rest is often necessary with continued pregnancy. in women with significant heart disease. For cesarean delivery,
epidural analgesia is preferred by most clinicians with cave-
ats for its use with pulmonary arterial hypertension (p. 987).
■ Labor and Delivery Finally, general endotracheal anesthesia with thiopental, suc-
In general, vaginal delivery is preferred, and labor induction cinylcholine, nitrous oxide, and at least 30-percent oxygen has
is usually safe (Oron, 2004). Cesarean delivery is limited to also proved satisfactory.
obstetrical indications, and considerations are given for the
specific cardiac lesion, overall maternal condition, and avail- Intrapartum Heart Failure
ability of experienced anesthesia personnel and general support Cardiovascular decompensation during labor may manifest as
facilities. Some of these women tolerate major surgical proce- pulmonary edema with hypoxia or as hypotension, or both. The
dures poorly and are best delivered in a unit experienced with proper therapeutic approach depends on the specific hemody-
management of complicated cardiac disease. In some women, namic status and the underlying cardiac lesion. For example,
pulmonary artery catheterization may be indicated for hemo- decompensated mitral stenosis with pulmonary edema due to
dynamic monitoring (Chap. 47, p. 941). In our experiences, fluid overload is often best approached with aggressive diure-
however, invasive monitoring is rarely indicated. sis. If precipitated by tachycardia, heart rate control with
Based on her review, Simpson (2012) recommends cesarean β-blocking agents is preferred. Conversely, the same treatment
delivery for women with the following: (1) dilated aortic root > in a woman suffering decompensation and hypotension due to
4 cm or aortic aneurysm; (2) acute severe congestive heart fail- aortic stenosis could prove fatal. Unless the underlying patho-
ure; (3) recent myocardial infarction; (4) severe symptomatic physiology is understood and the cause of the decompensation
aortic stenosis; (5) warfarin administration within 2 weeks of is clear, empirical therapy may be hazardous. Heart failure is
delivery; and (6) need for emergency valve replacement imme- discussed in more detail on page 990.
diately after delivery. Although we agree with most of these, we
have some caveats. For example, we prefer aggressive medical
stabilization of pulmonary edema followed by vaginal delivery ■ Puerperium
if possible. Also, warfarin anticoagulation can be reversed with Women who have shown little or no evidence of cardiac
vitamin K, plasma, or prothrombin concentrates. compromise during pregnancy, labor, or delivery may still
During labor, the mother with significant heart disease decompensate postpartum when fluid mobilization into the
should be kept in a semirecumbent position with lateral tilt. intravascular compartment and reduction of peripheral vas-
Vital signs are taken frequently between contractions. Increases cular resistance place higher demands on myocardial per-
in pulse rate much above 100 bpm or respiratory rate above formance. Therefore, it is important that meticulous care be
24 per minute, particularly when associated with dyspnea, may continued into the puerperium (Keizer, 2006; Zeeman, 2006).
 Cardiovascular Disorders 979

Postpartum hemorrhage, anemia, infection, and thromboem-

TABLE 49-5. Outcomes Reported Since 1990
bolism are much more serious complications with heart dis-
in Pregnancies Complicated by a
ease. Indeed, these factors often act in concert to precipitate
Heart-Valve Replacement

CHAPTER 49
postpartum heart failure (Cunningham, 1986). In addition
to increased cardiac work, many of these—for example, sepsis Type of Complicationsa
and severe preeclampsia—cause or worsen pulmonary edema Valve Total Maternal Perinatal
because of endothelial activation and capillary-alveolar leakage b
Mechanical 567 38 thromboses 107 miscarriages/
(Chap. 47, p. 947).
17 emboli abortions
19 hemorrhages 37 stillbirths
■ Sterilization and Contraception 14 deaths
If indicated, tubal sterilization is performed at cesarean deliv- Porcine 265c 32 valve failures 9 abortions
ery. If it is to be performed after vaginal delivery, the pro- or deterioration 3 stillbirths
cedure can be delayed up to several days to ensure that the a
Numbers estimated in some because definitions are not
mother has become hemodynamically near normal and that
consistent.
she is afebrile, not anemic, and ambulating normally. Other b
Data from Cotrufo, 2002; Hanania, 1994; Kawamata,
women are given detailed contraceptive advice. Special con-
2007; Nassar, 2004; Sadler, 2000; Sbarouni, 1994; Suri,
siderations for contraception in women with various cardiac
1999, 2011.
disorders are discussed in some of the following sections and c
Data from Hanania, 1994; Lee, 1994; Sadler, 2000;
in Table 38-3 (p. 698).
Sbarouni, 1994.

SURGICALLY CORRECTED HEART DISEASE

Anticoagulation
Most clinically significant congenital heart lesions are repaired This is critical for women with mechanical prosthetic valves.
during childhood. Examples of those frequently not diagnosed Unfortunately, warfarin is the most effective anticoagulant for
until adulthood include atrial septal defects, pulmonic stenosis, preventing maternal thromboembolic complications but causes
bicuspid aortic valve, and aortic coarctation (Brickner, 2000). significant fetal morbidity and mortality. Anticoagulation
In some cases, the defect is mild and surgery is not required. with heparin is less hazardous for the fetus, however, the risk
In others, a significant structural anomaly is amenable to surgi- of maternal thromboembolic complications is much higher
cal correction. With successful repair, many women attempt (McLintock, 2011).
pregnancy. In some instances, surgical corrections have been As noted, warfarin, despite its effective anticoagulation, is
performed during pregnancy. teratogenic and causes miscarriage, stillbirths, and fetal mal-
formations (Chap. 12, p. 252). In one study of 71 pregnancies
in women given warfarin throughout pregnancy, the rates of
■ Valve Replacement before Pregnancy
miscarriage were 32 percent; stillbirth, 7 percent; and embry-
Numerous reports describe subsequent pregnancy outcomes in opathy, 6 percent (Cotrufo, 2002). The risk was highest when
women who have a prosthetic mitral or aortic valve. The type the mean daily dose of warfarin exceeded 5 mg. From a sys-
of valve is paramount, and pregnancy is undertaken only after tematic review, Chan and coworkers (2000) concluded that the
serious consideration in women with a prosthetic mechani- best maternal outcomes were achieved with warfarin anticoagu-
cal valve. This is because anticoagulation is requisite, and at lation but with a 6.4-percent embryopathy rate. And although
least when not pregnant, warfarin is necessary. As shown in heparin substituted before 12 weeks’ gestation eliminated
Table 49-5, a number of serious complications can develop embryopathy, thromboembolic complications during that time
with mechanical valves. Both thromboembolisms involving the were increased significantly.
prosthesis and hemorrhage from anticoagulation are of extreme In examining heparin, anticoagulation for mechanical valves
concern. This is in addition to deterioration in cardiac func- using low-dose unfractionated heparin is definitely inadequate
tion. Overall, the maternal mortality rate is 3 to 4 percent with and has a high associated maternal mortality rate (Chan, 2000;
mechanical valves, and fetal loss is common. Iturbe-Alessio, 1986). Even fulll anticoagulation with either
Porcine tissue valves are much safer during pregnancy, pri- unfractionated heparin (UFH) or one of the low-molecular-
marily because thrombosis is rare and anticoagulation is not weight heparins (LMWH) is associated with valvular thrombo-
required (see Table 49-5). Despite this, valvular dysfunction sis (Leyh, 2002, 2003; Rowan, 2001). Thus, many authorities
with cardiac deterioration or failure is common and develops recommend warfarin. However, the American College of Chest
in 5 to 25 percent of involved pregnancies. Another drawback Physicians has recommended use of any of several regimens
is that bioprostheses are not as durable as mechanical ones, and that include adjusted-dose UFH or LMWH heparin given
valve replacement longevity averages 10 to 15 years. Based on throughout pregnancy as subsequently discussed (Bates, 2012).
their longitudinal study of 100 reproductive-aged women with
a biological heart valve prosthesis, Cleuziou and colleagues Recommendations for Anticoagulation. A number of
(2010) concluded that pregnancy does not accelerate the risk different treatment options—none of which are completely
for replacement. ideal—have been proposed and are principally based on
 980 Medical and Surgical Complications

TABLE 49-6. American College of Chest Physicians Guidelines for Anticoagulation of Pregnant Women with
Mechanical Prosthetic Valves
Any one of the following anticoagulant regimens is recommended:
SECTION 12

Adjusted-dose LMWH twice daily throughout pregnancy. The doses should be adjusted to achieve the manufacturer’s
peak anti-Xa level 4 hours after subcutaneous injection
Adjusted-dose UFH administered every 12 hours throughout pregnancy. The doses should be adjusted to keep the
midinterval aPTT at least twice control or attain an anti-Xa level of 0.35 to 0.70 U/mL
LMWH or UFH as above until 13 weeks’ gestation, then warfarin substitution until close to delivery when LMWH or UFH is
resumed
In women judged to be at very high risk of thromboembolism and in whom concerns exist about the efficacy and safety
of LMWH or UFH as dosed above—some examples include older-generation prosthesis in the mitral position or history
of thromboembolism—warfarin treatment is suggested throughout pregnancy with replacement by UFH or LMWH
(as above) close to delivery. In addition, low-dose aspirin—75 to 100 mg daily—should be orally administered

aPTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.
Adapted from Bates, 2012.

consensus opinion. For this reason, they differ and allow more associates (2005) found that maternal mortality rates with car-
than one scheme. For example, and as shown in Table 49-6, diopulmonary bypass are between 1.5 and 5 percent. Although
the most recent guidelines of the American College of Chest these are similar to those for nonpregnant women, the fetal
Physicians for the management of pregnant women with mortality rate approaches 20 percent. In a longitudinal study
mechanical prosthetic valves offer several different treatment from the Mayo Clinic, John and coworkers (2011) reported
options. the outcomes of 21 pregnant women who underwent cardio-
Heparin is discontinued just before delivery. If delivery thoracic surgery requiring cardiopulmonary bypass between
supervenes while the anticoagulant is still effective, and exten- 1976 and 2009. The procedures included eight aortic valve
sive bleeding is encountered, then protamine sulfate is given replacements, six mitral valve repairs or replacements, two
intravenously. Anticoagulant therapy with warfarin or heparin myxoma excisions, two aortic aneurysm repairs, one patent
may be restarted 6 hours following vaginal delivery, usually foramen ovale closure, one prosthetic aortic valve thrombec-
with no problems. Following cesarean delivery, full anticoagu- tomy, and one septal myectomy. Median cardiopulmonary
lation is withheld, but the duration is not exactly known. The bypass time was 53 minutes, with a range of 16 to 185 min-
American College of Obstetricians and Gynecologists (2011b) utes. One woman died two days after surgery, and three other
advises resuming unfractionated or low-molecular-weight hep- deaths occurred 2, 10, and 19 years postoperatively. Three
arin 6 to 12 hours after cesarean delivery. It is our practice, fetuses died, and 52 percent delivered before 36 weeks. To
however, to wait at least 24 hours, and preferably 48 hours, optimize outcomes, Chandrasekhar and coworkers (2009) rec-
following a major surgical procedure. ommend the following: surgery done electively when possible,
Because warfarin, low-molecular-weight heparin, and unfrac- pump flow rate maintained > 2.5 L/min/m2, normothermic
tionated heparin do not accumulate in breast milk, they do not perfusion pressure > 70 mm Hg, pulsatile flow used, and
induce an anticoagulant effect in the infant. Therefore, these hematocrit kept > 28 percent.
anticoagulants are compatible with breast feeding (American
College of Obstetricians and Gynecologists, 2011b). Mitral Valvotomy During Pregnancy
Tight mitral stenosis that requires intervention during preg-
Contraception nancy was previously treated by closed mitral valvotomy
Because of their possible thrombogenic action, estrogen- (Pavankumar, 1988). More recently, however, percutaneous
progestin oral contraceptives are relatively contraindicated in transcatheter balloon dilatation of the mitral valve has largely
women with prosthetic valves. Because these women are gener- replaced surgical valvotomy during pregnancy (Fawzy, 2007).
ally fully anticoagulated, however, any increased risk is specu- Rahimtoola (2006) summarized outcomes of 36 women—25
lative. Contraceptive options are discussed in Chapters 38 and of whom were NYHA class III or IV—who underwent balloon
39. Sterilization should be considered because of the serious commissurotomy at an average gestational age of 26 weeks.
pregnancy risks faced by women with significant heart disease. Surgery was successful in 35 women, and left atrial and pulmo-
nary artery pressures were reduced as the mitral valve area was
increased from 0.74 to 1.59 cm2. Esteves and associates (2006)
■ Cardiac Surgery During Pregnancy described similarly good outcomes in 71 pregnant women with
Although usually postponed until after delivery, valve replace- tight mitral stenosis and heart failure who underwent percuta-
ment or other cardiac surgery during pregnancy may be lifesav- neous valvuloplasty. At delivery, 98 percent were either NYHA
ing. Several reviews confirm that such surgery is associated with class I or II. At a mean of 44 months, the total event-free
major maternal and fetal morbidity and mortality. Sutton and maternal survival rate was 54 percent, however, eight women
 Cardiovascular Disorders 981

required another surgical intervention. The 66 infants who evolution of nonrheumatogenic streptococcal strains. Still,
were delivered at term all had normal growth and development. it remains the chief cause of serious mitral valvular disease
(Roeder, 2011).

CHAPTER 49
■ Pregnancy after Heart Transplantation
The first successful pregnancy in a heart-transplant recipient was ■ Mitral Stenosis
reported 25 years ago by Löwenstein and associates (1988). Since Rheumatic endocarditis causes most mitral stenosis lesions.
that time, more than 50 pregnancies in heart-transplant recipients The normal mitral valve surface area is 4.0 cm2, and when
have been described. Key (1989) and Kim (1996) and their col- stenosis narrows this to < 2.5 cm2, symptoms usually develop
leagues provide detailed data to show that the transplanted heart (Desai, 2000). The contracted valve impedes blood flow from
responds normally to pregnancy-induced changes. Despite this, the left atrium to the ventricle. The most prominent complaint
complications are common during pregnancy (Dashe, 1998). is dyspnea due to pulmonary venous hypertension and edema.
Armenti (2002) from the National Transplantation Pregnancy Fatigue, palpitations, cough, and hemoptysis are also common.
Registry and Miniero (2004), each with their coworkers, With more severe stenosis, the left atrium dilates, left atrial
described outcomes of 53 pregnancies in 37 heart recipients. pressure is chronically elevated, and significant passive pulmo-
Almost half developed hypertension, and 22 percent suffered nary hypertension develops (Table 49-7). These women have a
at least one rejection episode during pregnancy. They were relatively fixed cardiac output, and thus the increased preload of
delivered—usually by cesarean—at a mean of 37 to 38 weeks. normal pregnancy, as well as other factors that increase cardiac
Three fourths of infants were liveborn. At follow-up, at least output, may cause ventricular failure and pulmonary edema.
five women had died more than 2 years postpartum. From Indeed, a fourth of women with mitral stenosis have cardiac
Scandinavia, Estensen and associates (2011) detailed the out- failure for the first time during pregnancy (Caulin-Glaser,
comes of 19 women who had received a heart transplant and six 1999). Because the murmur may not be heard in some women,
who received both a heart and lung transplant. These 25 women this clinical picture at term may be confused with idiopathic
had 42 pregnancies, and there were no maternal deaths. Major peripartum cardiomyopathy (Cunningham, 1986, 2012).
complications included two rejections during the early puerpe- Also with significant stenosis, tachycardia shortens ventricu-
rium, two cases of renal failure, and 11 spontaneous abortions. lar diastolic filling time and increases the mitral gradient. This
Five women died 2 to 12 years after delivery. Ethical consid- raises left atrial as well as pulmonary venous and capillary pres-
erations of counseling and caring for such women related to sures and may result in pulmonary edema. Thus, sinus tachy-
pregnancy were summarized by Ross (2006). cardia is often treated prophylactically with β-blocking agents.
Atrial tachyarrhythmias, including fibrillation, are common in
VALVULAR HEART DISEASE mitral stenosis and are treated aggressively. Atrial fibrillation
also predisposes to mural thrombus formation and cerebrovas-
Rheumatic fever is uncommon in the United States because cular embolization that can cause stroke (Chap. 60, p. 1192).
of less crowded living conditions, availability of penicillin, and Atrial thrombosis can develop despite a sinus rhythm, and

TABLE 49-7. Major Cardiac Valve Disorders

Type Cause Pathophysiology Pregnancy
Mitral stenosis Rheumatic valvulitis LA dilation and passive Heart failure from fluid overload,
pulmonary hypertension tachycardia
Atrial fibrillation
Mitral insufficiency Rheumatic valvulitis LV dilatation and eccentric Ventricular function improves with
Mitral-valve prolapse hypertrophy afterload decrease
LV dilatation
Aortic stenosis Congenital bicuspid valve LV concentric hypertrophy, Moderate stenosis is tolerated; severe
decreased cardiac output is life-threatening with decreased
preload, e.g., obstetrical hemorrhage
or regional analgesia
Aortic insufficiency Rheumatic valvulitis LV hypertrophy and Ventricular function improves with
Connective-tissue disease dilatation afterload decrease
Congenital
Pulmonary stenosis Rheumatic valvulitis Severe stenosis associated Mild stenosis usually well tolerated;
Congenital with RA and RV severe stenosis associated with right
enlargement heart failure and atrial arrhythmias

LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.

 982 Medical and Surgical Complications

Hameed (2005) reported three such women. One suffered an

Pulmonary capillary wedge pressure

25
embolic stroke, and another had pulmonary edema causing
maternal hypoxemia leading to fetal encephalopathy.
20
SECTION 12

Pregnancy Outcomes

(mm Hg)
In general, complications are directly associated with the degree 15
of valvular stenosis. Recall that investigators from the large
Canadian study found that women with a mitral-valve area 10
< 2 cm2 were at greatest risk. In another study, Hameed (2001) A B C
described 46 pregnant women with mitral stenosis—43 percent D E
5
developed heart failure and 20 percent developed arrhythmias.
Fetal-growth restriction was more common in those women
with a mitral valve area < 1.0 cm2. 0
A B C D E
Prognosis is also related to maternal functional capac-
ity. Among 486 pregnancies complicated by rheumatic heart Time-arbitrary units
disease—predominantly mitral stenosis—Sawhney (2003) FIGURE 49-3 Mean pulmonary capillary wedge pressure measure-
reported that eight of 10 maternal deaths were in women in ments (red graph line) in eight women with mitral valve stenosis.
NYHA classes III or IV. Shaded yellow and blue boxes are mean (± 1 SD) pressures in
nonlaboring normal women at term. A. First-stage labor. B. Second-
Management stage labor 15 to 30 minutes before delivery. C. Postpartum 5 to
15 minutes. D. Postpartum 4 to 6 hours. E. Postpartum 18 to
Limited physical activity is generally recommended in women 24 hours. (Data from Clark, 1985, 1989.)
with mitral stenosis. If symptoms of pulmonary congestion
develop, activity is further reduced, dietary sodium is restricted,
and diuretics are given (Siva, 2005). A β-blocker drug is usu- mitral regurgitation may develop. This is eventually followed by
ally given to slow the ventricular response to activity (Maxwell, left ventricular dilatation and eccentric hypertrophy (see Table
2010). If new-onset atrial fibrillation develops, intravenous 49-7). Chronic mitral regurgitation has a number of causes,
verapamil, 5 to 10 mg, is given, or electrocardioversion is including rheumatic fever, mitral valve prolapse, or left ventric-
performed. For chronic fibrillation, digoxin, a β-blocker, or a ular dilatation of any etiology—for example, dilated cardiomy-
calcium-channel blocker is given to slow ventricular response. opathy. Less common causes include a calcified mitral annulus,
Therapeutic anticoagulation with heparin is indicated with per- possibly some appetite suppressants, and in older women,
sistent fibrillation. Some recommend heparin anticoagulation ischemic heart disease. Mitral valve vegetations—Libman-Sacks
for those with severe stenosis even if there is a sinus rhythm endocarditis—are relatively common in women with antiphos-
(Hameed, 2005). pholipid antibodies (Roldan, 1996; Shroff, 2012). These some-
Labor and delivery are particularly stressful for women with times coexist with systemic lupus erythematosus (Chap. 59,
symptomatic mitral stenosis. Uterine contractions increase car- p. 1170). In contrast, acute mitral insufficiency is caused by
diac output by increasing circulating blood volume. Pain, exer- chordae tendineae rupture, papillary muscle infarction, or leaf-f
tion, and anxiety cause tachycardia with possible rate-related let perforation from infective endocarditis.
heart failure. Epidural analgesia for labor is ideal, but with strict In nonpregnant patients, symptoms from mitral valve
attention to avoid fluid overload. Abrupt increases in preload incompetence are rare, and valve replacement is seldom indi-
may increase pulmonary capillary wedge pressure and cause cated unless infective endocarditis develops. Likewise, mitral
pulmonary edema. The effects of labor on pulmonary pres- regurgitation is well tolerated during pregnancy, probably
sures in women with mitral stenosis are shown in Figure 49-3. because decreased systemic vascular resistance results in less
Wedge pressures increase most immediately postpartum. Clark regurgitation. Heart failure only rarely develops during preg-
and colleagues (1985) hypothesize that this is likely due to nancy, and occasionally tachyarrhythmias require treatment.
loss of the low-resistance placental circulation along with the
venous “autotransfusion” from a now-empty uterus and from Mitral Valve Prolapse
the lower extremities and pelvis. This diagnosis implies the presence of a pathological connec-
Most consider vaginal delivery to be preferable in women tive tissue disorder—often termed myxomatous degeneration—
with mitral stenosis. Elective induction is reasonable so that which may involve the valve leaflets themselves, the annulus, or
labor and delivery are attended by a scheduled, experienced the chordae tendineae. Mitral insufficiency may develop. Most
team. With severe stenosis and chronic heart failure, insertion women with mitral valve prolapse are asymptomatic and are
of a pulmonary artery catheter may help guide management. diagnosed by routine examination or while undergoing echo-
cardiography. The small percentage of women with symptoms
have anxiety, palpitations, atypical chest pain, dyspnea with
■ Mitral Insufficiency exertion, and syncope (Guy, 2012).
A trivial degree of mitral insufficiency is found in most nor- Pregnant women with mitral valve prolapse rarely have
mal patients (Maxwell, 2010). But if there is improper coapta- cardiac complications. Hypervolemia may even improve align-
tion of mitral valve leaflets during systole, abnormal degrees of ment of the mitral valve, and women without pathological
 Cardiovascular Disorders 983

myxomatous change generally have excellent pregnancy out- rupture, aortic valve insufficiency, and death (Reich, 2004). In
comes (Leśniak-Sobelga, 2004; Rayburn, 1987). In a study of rare cases, it may be preferable to perform valve replacement
3100 women in the Taiwanese Birth Registry with mitral valve during pregnancy (Datt, 2010).

CHAPTER 49
prolapse, however, the preterm birth rate was 1.2 times higher For women with critical aortic stenosis, intensive monitor-
than among controls (Chen, 2011). ing during labor is important. Pulmonary artery catheteriza-
For women who are symptomatic, β-blocking drugs are tion may be helpful because of the narrow margin separating
given to decrease sympathetic tone, relieve chest pain and fluid overload from hypovolemia. Women with aortic steno-
palpitations, and reduce the risk of life-threatening arrhyth- sis are dependent on adequate end-diastolic ventricular filling
mias. According to the American College of Obstetricians and pressures to maintain cardiac output and systemic perfusion.
Gynecologists (2011a), mitral valve prolapse is not considered Abrupt decreases in end-diastolic volume may result in hypo-
an indication for infective endocarditis prophylaxis. tension, syncope, myocardial infarction, and sudden death.
Thus, the management key is avoidance of decreased ventricular
preload and the maintenance of cardiac output. During labor
■ Aortic Stenosis and delivery, such women should be managed on the “wet”
Usually a disease of aging, aortic stenosis in women younger side, maintaining a margin of safety in intravascular volume in
than 30 years is most likely due to a congenital lesion. This anticipation of possible hemorrhage. In women with a compe-
stenosis is less common since the decline in incidences of rheu- tent mitral valve, pulmonary edema is rare, even with moderate
matic diseases, and the most frequent cause in this country is a volume overload.
bicuspid valve (Friedman, 2008). A normal aortic valve has an During labor, narcotic epidural analgesia seems ideal, thus
area of 3 to 4 cm2, with a pressure gradient of less than 5 mm avoiding potentially hazardous hypotension, which may be
Hg. If the valve area is < 1 cm2, there is severe obstruction to encountered with standard conduction analgesia techniques.
flow and a progressive pressure overload on the left ventricle Easterling and coworkers (1988) studied the effects of epidural
(Carabello, 2002; Roeder, 2011). Concentric left ventricu- analgesia in five women with severe stenosis and demonstrated
lar hypertrophy follows, and if severe, end-diastolic pressures immediate and profound effects of decreased filling pressures.
become elevated, ejection fraction declines, and cardiac output Xia and associates (2006) emphasize slow administration of
is reduced (see Table 49-7). Characteristic clinical manifesta- dilute local anesthetic agents into the epidural space. Forceps
tions develop late and include chest pain, syncope, heart failure, or vacuum delivery is used for standard obstetrical indications
and sudden death from arrhythmias. Life expectancy averages in hemodynamically stable women. Late cardiac events include
only 5 years after exertional chest pain develops, and valve pulmonary edema, arrhythmias, cardiac interventions, and
replacement is indicated for symptomatic patients. death, which were identified within 1 year of delivery in 70
pregnancies (Tzemos, 2009).
Pregnancy
Clinically significant aortic stenosis is infrequent during preg-
nancy. Mild to moderate degrees of stenosis are well toler- ■ Aortic Insufficiency
ated, however, severe disease is life threatening. The principal Aortic valve regurgitation or insufficiency allows diastolic
underlying hemodynamic problem is the fixed cardiac output flow of blood from the aorta back into the left ventricle.
associated with severe stenosis. During pregnancy, a number Frequent causes of abnormal insufficiency are rheumatic fever,
of events acutely decrease preload further and thus aggravate connective-tissue abnormalities, and congenital lesions. With
the fixed cardiac output. These include vena caval occlusion, Marfan syndrome, the aortic root may dilate, resulting in
regional analgesia, and hemorrhage. Importantly, these also regurgitation. Acute insufficiency may develop with bacterial
decrease cardiac, cerebral, and uterine perfusion. It follows that endocarditis or aortic dissection. Aortic and mitral valve insuf-
f
severe aortic stenosis may be extremely dangerous during preg- ficiency have been linked to the appetite suppressants fenflura-
nancy. From the large Canadian multicenter study cited above, mine and dexfenfluramine and to the ergot-derived dopamine
there were increased complications if the aortic valve area was agonists cabergoline and pergolide (Gardin, 2000; Schade,
< 1.5 cm2 (Siu, 2001b). And in the report by Hameed and 2007; Zanettini, 2007). With chronic insufficiency, left ven-
associates (2001) described earlier, the maternal mortality rate tricular hypertrophy and dilatation develop and are followed by
with aortic stenosis was 8 percent. Women with valve gradients slow-onset fatigue, dyspnea, and edema, although rapid dete-
exceeding 100 mm Hg appear to be at greatest risk. rioration usually follows (see Table 49-7).
Aortic insufficiency is generally well tolerated during preg-
Management nancy. Like mitral valve incompetence, diminished vascular
For the asymptomatic woman with aortic stenosis, no treat- resistance is thought to improve hemodynamic function. If
ment except close observation is required. Management of the symptoms of heart failure develop, diuretics are given and bed
symptomatic woman includes strict limitation of activity and rest is encouraged.
prompt treatment of infections. If symptoms persist despite
bed rest, valve replacement or valvotomy using cardiopulmo-
nary bypass must be considered. In general, balloon valvotomy ■ Pulmonic Stenosis
for aortic valve disease is avoided because of serious complica- The pulmonary valve is affected by rheumatic fever far less often
tions, which exceed 10 percent. These include stroke, aortic than the other valves. Instead, pulmonic stenosis is usually
 984 Medical and Surgical Complications

congenital and also may be associated with Fallot tetralogy or With the potential to shunt blood from right to left, a para-
Noonan syndrome. The clinical diagnosis is typically identified doxical embolism, that is, entry of a venous thrombus through
by auscultating a systolic ejection murmur over the pulmonary the septal defect and into the systemic arterial circulation, is
area that is louder during inspiration. possible and may cause an embolic stroke (Chap. 60, p. 1192).
SECTION 12

Increased hemodynamic burdens of pregnancy can precipi- Erkut and associates (2006) described a woman who developed
tate right-sided heart failure or atrial arrhythmias in women with an entrapped thrombus in a patent foramen ovale postpartum.
severe stenosis. Surgical correction ideally is done before preg- In asymptomatic women, thromboembolism prophylaxis is
nancy, but if symptoms progress, a balloon angioplasty may be problematic, and recommendations include either observation
necessary antepartum (Maxwell, 2010; Siu, 2001a). In a study or antiplatelet therapy such as low-dose aspirin (Kizer, 2005;
of 81 pregnancies in 51 Dutch women with pulmonic steno- Maxwell, 2010). Compression stockings and prophylactic hep-
sis, cardiac complications were infrequent (Drenthen, 2006). arin for a pregnant woman with a septal defect and concurrent
NYHA classification worsened in two women, and nine expe- immobility or other risk factors for thromboembolism have
rienced palpitations or arrhythmias. No changes in pulmonary also been recommended (Head, 2005).
valvular function or other adverse cardiac events were reported.
However, noncardiac complications were increased—17 per- Ventricular Septal Defects
cent had preterm delivery; 15 percent had hypertension; and 4 These lesions close spontaneously during childhood in 90 per-
percent developed thromboembolism. Interestingly, two of the cent of cases. Most defects are paramembranous, and physi-
offspring were diagnosed with pulmonic stenosis, and another ological derangements are related to lesion size. In general, if
had complete transposition and anencephaly. the defect is less than 1.25 cm2, pulmonary hypertension and
heart failure do not develop. If the effective defect size exceeds
that of the aortic valve orifice, symptoms rapidly develop. For
CONGENITAL HEART DISEASE these reasons, most children undergo surgical repair before pul-
The incidence of congenital heart disease in the United States monary hypertension develops. Adults with unrepaired large
is approximately 8 per 1000 liveborn infants. Approximately defects develop left ventricular failure and pulmonary hyper-
a third of these have critical disease that requires cardiac cath- tension and have a high incidence of bacterial endocarditis
eterization or surgery during the first year of life. Others require (Brickner, 2000; Maxwell, 2010).
surgery in childhood, and it is currently estimated that there are Pregnancy is well tolerated with small to moderate left-to-
nearly 1 million adults in this country with congenital heart right shunts. If pulmonary arterial pressures reach systemic
disease (Bashore, 2007). levels, however, there is reversal or bidirectional flow—
According to an analysis from the Nationwide Inpatient Eisenmenger syndromee (p. 985). When this develops, the
Sample discharge database, more than 30,000 women admit- maternal mortality rate is significantly increased, and thus,
ted for delivery between 1998 and 2007 had congenital heart pregnancy is not generally advisable. Bacterial endocarditis
disease—a rate of 71.6 per 100,000 deliveries (Opotowsky, is more common with unrepaired defects, and antimicrobial
2012). After statistical adjustments, women with congenital prophylaxis is often required (p. 991). As shown in Table
heart disease were found to be eight times more likely to sustain 49-4, up to 15 percent of offspring born to these women also
an adverse cardiovascular event that included death, heart fail- have a ventricular septal defect.
ure, arrhythmia, and cerebrovascular or embolic event. Of these,
Atrioventricular Septal Defects
arrhythmia was the most common, and the rate of maternal
death was approximately 1.5 per 1000. Thompson and coworkers These account for approximately 3 percent of all congenital car-
(2014) found similar risks. diac malformations and are distinct from isolated atrial or ven-
tricular septal defects. An atrioventricular (AV) septal defect is
characterized by a common, ovoid AV junction. This defect is
■ Septal Defects associated with aneuploidy, Eisenmenger syndrome, and other
malformations, but still, some of these women become preg-
Atrial Septal Defects nant. Compared with simple septal defects, complications are
After bicuspid aortic valve, these are the most frequently more frequent during pregnancy. In a review of 48 pregnancies
encountered adult congenital cardiac lesions. Indeed, a fourth in 29 such women, complications included persistent deteriora-
of all adults have a patent foramen ovale (Kizer, 2005). tion of NYHA class in 23 percent, significant arrhythmias in
Most are asymptomatic until the third or fourth decade. The 19 percent, and heart failure in 2 percent (Drenthen, 2005b).
secundum-type defect accounts for 70 percent, and associ- Congenital heart disease was identified in 15 percent of the
ated mitral valve myxomatous abnormalities with prolapse are offspring.
common. Most recommend repair if discovered in adulthood.
Pregnancy is well tolerated unless pulmonary hypertension
has developed, but this is uncommon (Maxwell, 2010; Zuber, ■ Persistent (Patent) Ductus Arteriosus
1999). Treatment is indicated for congestive heart failure or The ductus connects the proximal left pulmonary artery
an arrhythmia. Based on their review, Aliaga and associates to the descending aorta just distal to the left subclavian
(2003) concluded that the risk of endocarditis with an atrial artery. Functional closure of the ductus from vasoconstric-
septal defect is negligible. tion occurs shortly after term birth (Akintunde, 2011). The
 Cardiovascular Disorders 985

physiological consequences of persistence of this structure events including new onset or worsening of arrhythmias and
are related to its size. Most significant lesions are repaired in heart failure. For women with a pulmonary valve replacement,
childhood, but for individuals who do not undergo repair, Oosterhof and coworkers (2006) reported that pregnancy did

CHAPTER 49
the mortality rate is high after the fifth decade (Brickner, not adversely affect graft function.
2000). In some younger women with an unrepaired ductus
during pregnancy, however, pulmonary hypertension, heart Transposition of the Great Vessels. Pregnancy following sur-
failure, or cyanosis will develop if systemic blood pressure gical correction of transposition also has risks. Canobbio (2006)
falls and leads to shunt reversal of blood from the pulmonary and Drenthen (2005a), each with their colleagues, described
artery into the aorta (Maxwell, 2010). A sudden blood pres- outcomes of 119 pregnancies in 68 women—90 percent had
sure decline at delivery—such as with conduction analgesia a Mustard procedure and 10 percent a Senning procedure.
or hemorrhage—may lead to fatal collapse. Therefore, hypo- During pregnancy, a fourth had arrhythmias. Twelve percent
tension should be avoided whenever possible and treated vig- developed heart failure, and one of these patients subsequently
orously if it develops. Prophylaxis for bacterial endocarditis required cardiac transplantation. One woman died suddenly a
may be indicated at delivery for unrepaired defects (p. 991). month after delivery, and another died 4 years later. A third of
As shown in Table 49-4, the incidence of inheritance is the newborns were delivered preterm, but no infant had heart
approximately 4 percent. disease. In a more recent study, Metz and associates (2011)
reported that five of 14 pregnancies resulting in live births
were complicated by symptomatic intracardiac baffle obstruc-
■ Cyanotic Heart Disease tion, which required postpartum stenting. In review, baffles
When congenital heart lesions are associated with right-to- are surgically constructed conduits that redirect anomalous
left shunting of blood past the pulmonary capillary bed, cya- cardiac blood flow and are integral to initial transposition
nosis develops. The classic and most commonly encountered correction.
lesion in adults and during pregnancy is the Fallot tetralogy Successful—although eventful—pregnancies in women
(Maxwell, 2010). It is characterized by a large ventricular sep- with previously repaired truncus arteriosuss and double-outlet
tal defect, pulmonary stenosis, right ventricular hypertrophy, right ventriclee have also been described (Drenthen, 2008;
and an overriding aorta that receives blood from both the Hoendermis, 2008).
right and left ventricles. The magnitude of the shunt varies
inversely with systemic vascular resistance. Hence, during Single Functional Ventricle. Feinstein and associates
pregnancy, when peripheral resistance decreases, the shunt (2012) recently reviewed the remarkably improved treat-
increases and cyanosis worsens. Women who have undergone ments for patients with hypoplastic left heart syndrome. Almost
repair and who do not have a recurrence of cyanosis do well 70 percent of these women are now expected to survive into
in pregnancy. adulthood and frequently become pregnant. Those who have
Some women with Ebstein anomalyy with a malpositioned, undergone a Fontan repairr are at particularly high risk for
malformed tricuspid valve may reach reproductive age. Right complications, which include atrial arrhythmias and peripar-
ventricular failure from volume overload and appearance or wors- tum heart failure (Nitsche, 2009). In a report of four preg-
ening of cyanosis are common during pregnancy. In the absence nancies post-Fontan repair, there were no maternal deaths,
of cyanosis, these women usually tolerate pregnancy well. but complications were frequent (Hoare, 2001). All were
Women with cyanotic heart disease generally do poorly dur- delivered preterm, two had supraventricular arrhythmias,
ing pregnancy. With uncorrected Fallot tetralogy, for example, and two developed ventricular failure. Similarly high com-
maternal mortality rates approach 10 percent. Moreover, any plication rates were described by Jain and coworkers (2011)
disease complicated by severe maternal hypoxemia is likely in 15 women with a systemic right ventricle, that is, one in
to lead to miscarriage, preterm delivery, or fetal death. There which the right ventricle rather than the left pumps blood to
is a relationship between chronic hypoxemia, polycythemia, the support systemic circulation.
and pregnancy outcome. When hypoxemia is intense enough
to stimulate a rise in hematocrit above 65 percent, pregnancy Eisenmenger Syndrome
wastage is virtually 100 percent. This describes secondary pulmonary hypertension that devel-
ops from any cardiac lesion. The syndrome develops when
Pregnancy after Surgical Repair pulmonary vascular resistance exceeds systemic resistance
Some of the more complex lesions cannot be successfully and leads to concomitant right-to-left shunting. The most
repaired. But with satisfactory surgical correction of cyanotic common underlying defects are atrial or ventricular septal
lesions before pregnancy, maternal and fetal outcomes are defects and persistent ductus arteriosus (Fig. 49-4). Patients
much improved (Maxwell, 2010). are asymptomatic for years, but eventually pulmonary hyper-
tension becomes severe enough to cause right-to-left shunt-
Fallot Tetralogy. Balci (2011) and Kamiya (2012) and their ing, and few persons survive into the fifth decade (Makaryus,
associates described a total of 197 pregnancies in 99 women 2006; Maxwell, 2010).
with surgically corrected Fallot tetralogy. Pregnancy was usually The prognosis for pregnancy depends on the severity of
well tolerated, and there were no maternal deaths. Still, almost pulmonary hypertension but survival has improved during the
9 percent of pregnancies were complicated by adverse cardiac past 50 years. Women with Eisenmenger syndrome tolerate
 986 Medical and Surgical Complications

Initial left-to-right shunt Ultimate right-to-left shunt

SECTION 12

Pu
P ulm
lmon onary
ar y
ar Pu
P ullm
mon
onar
ar y
ary
arr te
a ter y ar te
ar ter
er y
Pulmonary
arteriole
Left
atrium Left
atrium
Right Right
atrium atrium

Left Left
ventricle ventricle
Right ventricle
Right
hypertrophy
ventricle
Narrowed pulmonary
arterioles result and
lead to pulmonary
A hypertension B
FIGURE 49-4 Eisenmenger syndrome due to a ventricular septal defect (VSD). A. Substantial left-to-right shunting through the VSD leads
to morphological changes in the smaller pulmonary arteries and arterioles. Specifically, medial hypertrophy, intimal cellular proliferations,
and fibrosis lead to narrowing or closure of the vessel lumen. These vascular changes create pulmonary hypertension and a resultant
reversal of the intracardiac shunt (B). With sustained pulmonary hypertension, extensive atherosclerosis and calcification often develop
in the large pulmonary arteries. Although a VSD is shown here, Eisenmenger syndrome may also develop in association with a large
atrial septal defect or patent ductus arteriosus.

hypotension poorly, and the cause of death usually is right other groups. Group I indicates that a specific disease affects
ventricular failure with cardiogenic shock. Management is dis- pulmonary arterioles. It includes idiopathic or primary pulmo-
cussed subsequently. In a review of 44 cases through 1978, nary arterial hypertension as well as those cases secondary to a
maternal and perinatal mortality rates approximated 50 per- known cause such as connective-tissue disease. Approximately
cent (Gleicher, 1979). In a later review of 73 pregnancies, a third of women with scleroderma and 10 percent with sys-
Weiss and coworkers (1998) cited a 36-percent maternal death temic lupus erythematosus have pulmonary hypertension
rate. Three of 26 deaths were antepartum, and the remainder (Rich, 2005). Other causes in young women are sickle-cell
died intrapartum or within a month of delivery. In a more disease and thyrotoxicosis (Sheffield, 2004). Another is plexo-
recent study of 13 pregnant women, there was one mater- genic pulmonary arteriopathy associated with cirrhosis and
nal death 17 days after delivery, and there were five perinatal portal hypertension, and this has been reported to cause a
deaths (Wang, 2011). maternal death (Sigel, 2007).
Group II disorders are the most commonly encountered in
pregnant women. These are secondary to pulmonary venous
PULMONARY HYPERTENSION hypertension caused by left-sided atrial, ventricular, or valvular
disorders. A typical example is mitral stenosis discussed on page
Normal resting mean pulmonary artery pressure is 12 to 981. In contrast, groups III through V are seen infrequently in
16 mm Hg. In the study by Clark and colleagues (1989), pul- young otherwise healthy women.
monary vascular resistance in late pregnancy was approximately
80 dyn/sec/cm−5, which was 34-percent less than the nonpreg-
nant value of 120 dyne/sec/cm−5. Pulmonary hypertension is a ■ Diagnosis
hemodynamic observation and not a diagnosis and is defined Symptoms may be vague, and dyspnea with exertion is the
in nonpregnant individuals as a mean pulmonary pressure most common. With group II disorders, orthopnea and noc-
> 25 mm Hg. turnal dyspnea are also usually present. Angina and syncope
The World Health Organization classification shown in occur when right ventricular output is fixed, and they suggest
Table 49-8 has been adopted by the American College of advanced disease. Chest radiography commonly shows enlarged
Cardiology and the American Heart Association (McLaughlin, pulmonary hilar arteries and attenuated peripheral markings.
2009). There are important prognostic and therapeutic dis- It also may disclose parenchymal causes of hypertension.
tinctions between group I pulmonary hypertension and the Although cardiac catheterization remains the standard criterion
 Cardiovascular Disorders 987

were frequently poor distinctions in identifying both causes

TABLE 49-8. World Health Organization Classification of
and severity of hypertension. Thus, although most severe cases
Some Causes of Pulmonary Hypertension
of idiopathic pulmonary arterial hypertension had the worst

CHAPTER 49
I Pulmonary arterial hypertension prognosis, it was erroneously assumed that all types of pulmo-
Idiopathic—previously “primary” pulmonary nary hypertension were equally dangerous. With widespread
hypertension use of echocardiography, less-severe lesions with a better prog-
Familial—chromosome 2 gene in TGF superfamily nosis are now separable. Curry (2012) and Weiss (1998) and
Associated with: collagen-vascular disorders, their colleagues reviewed 36 cases of pulmonary hypertension
congenital left-to-right cardiac shunts, in pregnancy and found an approximate 30-percent mortality
HIV infection, thyrotoxicosis, sickle rate. Bédard and coworkers (2009) reported that mortality sta-
hemoglobinopathies, antiphospholipid antibody tistics improved during the decade ending in 2007 compared
syndrome, diet drugs, portal hypertension with those for the decade ending in 1996. Mortality rates were
Persistent pulmonary hypertension of the newborn 25 and 38 percent, respectively. Importantly, almost 80 percent
Other of the deaths were during the first month postpartum.
II Pulmonary hypertension with left-sided heart Pregnancy is contraindicated with severe disease, especially
disease those with pulmonary arterial changes—most cases in group
Left-sided atrial or ventricular disease I. With milder disease from other causes—group II being
Left-sided valvular disease the most common—the prognosis is much better. With the
III Pulmonary hypertension associated with lung more frequent use of echocardiography and pulmonary artery
disease catheterization in young women with heart disease, we have
Chronic obstructive pulmonary disease identified women with mild to moderate pulmonary hyper-
Interstitial lung disease tension who tolerate pregnancy, labor, and delivery well. One
Other example described by Sheffield and Cunningham (2004) is that
IV Pulmonary hypertension due to chronic of pulmonary hypertension that develops with thyrotoxicosis
thromboembolic disease but is reversible with treatment (Chap. 58, p. 1151). Similarly,
V Miscellaneous Boggess and colleagues (1995) described nine women with
interstitial and restrictive lung disease with varying degrees of
HIV = human immunodeficiency virus; TGF = transforming pulmonary hypertension, and all tolerated pregnancy reason-
growth factor. ably well.
Adapted from Simmoneau, 2004.
Management
Treatment of symptomatic pregnant women includes activity
limitation and avoidance of the supine position in late preg-
for the measurement of pulmonary artery pressures, noninva-
nancy. Diuretics, supplemental oxygen, and vasodilator drugs
sive echocardiography is often used to provide an estimate. In
are standard therapy for symptoms. Some recommend antico-
33 pregnant women who underwent both echocardiography
agulation (Hsu, 2011; Larson, 2010). In addition, there are
and cardiac catheterization, pulmonary artery pressures were
many reports describing the successful use of intravenous pul-
significantly overestimated by echocardiography in a third of
monary artery vasodilators in both singleton and twin gesta-
cases (Penning, 2001).
tions (Badalian, 2000; Easterling, 1999; Garabedian, 2010).
Prostacyclin analogues that can be administered parenter-
■ Prognosis ally include epoprostenol and treprostinil, whereas iloprost is
Longevity depends on the severity and cause of pulmonary inhaled. There are reports of successful use of each in pregnant
hypertension at discovery. For example, although invariably women, but data are insufficient to prefer one over another.
fatal, idiopathic pulmonary hypertension has a 3-year survival Inhaled nitric oxide is also an option that has been employed in
rate of 60 percent, whereas that due to collagen-vascular diseases cases of acute cardiopulmonary decompensation during preg-
has only a 35-percent rate (McLaughlin, 2004). Some disorders nancy or the puerperium (Lane, 2011).
respond to pulmonary vasodilators, calcium-channel blockers,
Labor and Delivery
prostacyclin analogues, or endothelin-receptor blockers, all
which may improve quality of life. The prostacyclin analogues These women are at greatest risk during labor and delivery
epoprostenol and treprostinil significantly lower pulmonary when there is diminished venous return and decreased right
vascular resistance but must be given parenterally (Humbert, ventricular filling—both associated with most maternal deaths.
2004; Roeleveld, 2004). Preconceptional counseling is impera- To avoid hypotension, assiduous attention is given to epidural
tive as emphasized by Easterling and associates (1999). analgesia induction and to blood loss prevention and treatment
at delivery. Parneix and coworkers (2009) describe low-dose
spinal-epidural analgesia for cesarean delivery. Women with
■ Pulmonary Hypertension and Pregnancy group I severe hypertension have been delivered successfully
The maternal mortality rate is appreciable, but this is especially while using either inhaled nitric oxide or iloprost (Lam, 2001;
so with idiopathic pulmonary hypertension. In the past, there Weiss, 2000).
 1125

CHAPTER 57

Diabetes Mellitus

TYPES OF DIABETES . . . . . . . . . . . . . . . . . . . . . . . . . . 1125 example, in utero exposure to maternal hyperglycemia leads

to fetal hyperinsulinemia, causing an increase in fetal fat cells.
PREGESTATIONAL DIABETES . . . . . . . . . . . . . . . . . . . . 1127 This leads to obesity and insulin resistance in childhood (Feig,
DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127 2002). This in turn leads to impaired glucose tolerance and
diabetes in adulthood. This cycle of fetal exposure to diabetes
FETAL EFFECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128 leading to childhood obesity and glucose intolerance has been
reported in Pima Indians and a heterogeneous Chicago popula-
MATERNAL EFFECTS . . . . . . . . . . . . . . . . . . . . . . . . . . 1131 tion (Silverman, 1995).
MANAGEMENT OF DIABETES IN PREGNANCY . . . . . . . 1134

GESTATIONAL DIABETES . . . . . . . . . . . . . . . . . . . . . . . 1136 TYPES OF DIABETES

SCREENING AND DIAGNOSIS . . . . . . . . . . . . . . . . . . . 1136 In nonpregnant individuals, the type of diabetes is based on its
presumed etiopathogenesis and its pathophysiological mani-
MATERNAL AND FETAL EFFECTS . . . . . . . . . . . . . . . . . 1139 festations. Absolute insulin deficiency characterizes type 1 dia-
betes. In contrast, defective insulin secretion, insulin resistance,
MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1140
or increased glucose production characterizes type 2 diabetes
(Table 57-1). Both types are generally preceded by a period of
abnormal glucose homeostasis. The terms insulin-dependent
diabetes mellitus (IDDM) and noninsulin-dependent diabe-
According to the National Center for Health Statistics (2013), tes mellitus (NIDDM) are now obsolete. Pancreatic β-cell
the number of adults diagnosed with diabetes in the United destruction can begin at any age, but type 1 diabetes is clini-
States has tripled from 6.9 million in 1991 to 20.9 million cally apparent most often before age 30. Type 2 diabetes usu-
in 2011. Astoundingly, the Centers for Disease Control ally develops with advancing age but is increasingly identified
and Prevention (2010) have estimated that the number of in younger obese adolescents.
Americans with diabetes will range from 1 in 3 to 1 in 5 by
2050. Reasons for this rise include an aging population more
likely to develop type 2 diabetes, increases in minority groups ■ Classification During Pregnancy
at particular risk for type 2 diabetes, and dramatic increases Diabetes is the most common medical complication of preg-
in obesity—also referred to as diabesity. This term reflects the nancy. Women can be separated into those who were known
strong relationship of diabetes with the current obesity epi- l or overt,
to have diabetes before pregnancy—pregestational
— t
demic in the United States and underlines the critical need and those diagnosed during pregnancy—gestational
— diabetes.
for diet and lifestyle interventions to change the trajectory The incidence of diabetes complicating pregnancy increased
of both. approximately 40 percent between 1989 and 2004 (Getahun,
There is keen interest in events that precede diabetes, and 2008). In 2006, slightly more than 179,000—4.2 percent—
this includes the uterine environment, where early imprint- of American women had pregnancies coexistent with some
ing is believed to have effects later in life (Saudek, 2002). For form of diabetes (Martin, 2009). African American, Native
 1126 Medical and Surgical Complications

TABLE 57-1. Etiological Classification of Diabetes Mellitus 10

Type 1: β-Cell destruction, usually absolute insulin 9 < 25 years

deficiency
SECTION 12

25–34 years
8
Immune-mediated ≥ 35 years
Idiopathic

Incidence (percent)
7
Type 2: Ranges from predominantly insulin resistance to
6
predominantly an insulin secretory defect with insulin
resistance 5
Other types 4
Genetic mutations of β-cell function—MODY 1–6, others
Genetic defects in insulin action 3
Genetic syndromes—Down, Klinefelter, Turner
2
Diseases of the exocrine pancreas—pancreatitis, cystic
fibrosis 1
Endocrinopathies—Cushing syndrome,
pheochromocytoma, others 0
1993–94 1997–98 2001–02 2002–04
Drug or chemical induced—glucocorticosteroids,
thiazides, β-adrenergic agonists, others Period (years)
Infections—congenital rubella, cytomegalovirus, FIGURE 57-1 Age-specific incidence of gestational diabetes from
coxsackievirus National Hospital Discharge Survey Data of nearly 59 million
Gestational diabetes births in the United States from 1989 to 2004. (Redrawn from
Getahun, 2008.)
MODY = maturity-onset diabetes of the young.
Modified from Powers, 2012.

American, Asian, and Hispanic women are at higher risk for role remains important. And because most currently cited liter-
gestational diabetes compared with white women (Ferrara, ature contains data from these older classifications, the one pre-
2007). The increasing incidence of gestational diabetes during viously recommended by the American College of Obstetricians
the past 15 years, shown in Figure 57-1, is reminiscent of simi- and Gynecologists (1986) is provided in Table 57-2.
lar statistics for obesity (Chap. 48, p. 961). Beginning several years ago, the American College of
Obstetricians and Gynecologists (2012, 2013) no longer rec-
ommended the White classification. Instead, the current focus
■ White Classification in Pregnancy is whether diabetes antedates pregnancy or is first diagnosed
Until the mid-1990s, the classification by Priscilla White for during pregnancy. Many now recommend adoption of the
diabetic pregnant women was the linchpin of management. classification proposed by the American Diabetes Association
Today, the White classification is used less frequently, but its (ADA), as shown in Table 57-3.

TABLE 57-2. Classification Scheme Used from 1986 through 1994 for Diabetes
Complicating Pregnancy
Plasma Glucose Level
Class Onset Fasting 2-Hour Postprandial Therapy
A1 Gestational < 105 mg/dL < 120 mg/dL Diet
A2 Gestational > 105 mg/dL > 120 mg/dL Insulin
Class Age of Onset (yr) Duration (yr) Vascular Disease Therapy
B Over 20 < 10 None Insulin
C 10 to 19 10 to 19 None Insulin
D Before 10 > 20 Benign retinopathy Insulin
F Any Any Nephropathya Insulin
R Any Any Proliferative retinopathy Insulin
H Any Any Heart Insulin
a
When diagnosed during pregnancy: proteinuria ≥ 500 mg/24 hr before 20 weeks’
gestation.
 Diabetes Mellitus 1127

TABLE 57-3. Proposed Classification System for Diabetes in Pregnancy

Gestational diabetes: diabetes diagnosed during pregnancy that is not clearly overt (type 1 or type 2) diabetes

CHAPTER 57
Type 1 Diabetes: Type 2 Diabetes:
Diabetes resulting from β-cell destruction, usually leading Diabetes from inadequate insulin secretion in the face of
to absolute insulin deficiency increased insulin resistance
a. Without vascular complications a. Without vascular complications
b. With vascular complications (specify which) b. With vascular complications (specify which)
Other types of diabetes: genetic in origin, associated with pancreatic disease, drug-induced, or chemically induced

Data from American Diabetes Association, 2012.

PREGESTATIONAL DIABETES in pregnancy, The International Association of Diabetes and

Pregnancy Study Groups (IADPSG) Consensus Panel (2010)
The increasing prevalence of type 2 diabetes in general, and in recommends threshold values for fasting or random plasma glu-
younger people in particular, has led to an increasing number cose and glycosylated hemoglobin (A1c) levels at prenatal care
of affected pregnancies (Ferrara, 2007). In Los Angeles County, initiation (Table 57-4). There was no consensus on whether
Baraban and coworkers (2008) reported that the age-adjusted such testing should be universal or limited to those women clas-
prevalence tripled from 14.5 cases per 1000 women in 1991 sified as high risk. Regardless, the tentative diagnosis of overt
to 47.9 cases per 1000 in 2003. Thus, the number of pregnant diabetes during pregnancy based on these thresholds should be
women with diabetes that was undiagnosed before pregnancy confirmed postpartum. Risk factors for impaired carbohydrate
is increasing. Many women found to have gestational diabetes metabolism in pregnant women include a strong familial his-
are likely to have type 2 diabetes that has previously gone undi- tory of diabetes, prior delivery of a large newborn, persistent
agnosed (Feig, 2002). In fact, 5 to 10 percent of women with glucosuria, or unexplained fetal losses.
gestational diabetes are found to have diabetes immediately after
pregnancy.
■ Impact on Pregnancy
With pregestational—or overt—diabetes, the embryo, fetus,
■ Diagnosis and mother frequently experience serious complications
Women with high plasma glucose levels, glucosuria, and keto- directly attributable to diabetes. The likelihood of successful
acidosis present no problem in diagnosis. Similarly, women outcomes with overt diabetes is related somewhat to the degree
with a random plasma glucose level > 200 mg/dL plus classic of glycemic control, but more importantly, to the degree of
signs and symptoms such as polydipsia, polyuria, and unex- underlying cardiovascular or renal disease. Thus, advanc-
plained weight loss or those with a fasting glucose level exceed- ing stages of the White classification, seen in Table 57-2,
ing 125 mg/dL are considered by the ADA (2012) to have overt are inversely related to favorable pregnancy outcomes. As an
diabetes. Women with only minimal metabolic derangement example shown in Table 57-5, data from Yang and associates
may be more difficult to identify. To diagnose overt diabetes (2006) chronicles the deleterious pregnancy outcomes of overt

TABLE 57-4. Diagnosis of Overt Diabetes in Pregnancya TABLE 57-5. Pregnancy Outcomes of Births in Nova
Measure of Glycemia Threshold Scotia from 1988 to 2002 in Women with
and without Pregestational Diabetes
Fasting plasma glucose At least 7.0 mmol/L (126 mg/dL)
Hemoglobin A1c At least 6.5% Diabetic Nondiabetic
Random plasma At least 11.1 mmol/L (200 mg/dL) (n = 516) (n = 150,598) p
glucose plus confirmation Factor % % value
Gestational 28 9 < .001
a
Apply to women without known diabetes antedating hypertension
pregnancy. The decision to perform blood testing for Preterm birth 28 5 < .001
evaluation of glycemia on all pregnant women or only Macrosomia 45 13 < .001
on women with characteristics indicating a high risk for Fetal-growth 5 10 < .001
diabetes is based on the background frequency of abnor- restriction
mal glucose metabolism in the population and on local Stillbirth 1.0 0.4 .06
circumstances. Perinatal death 1.7 0.6 .004
Modified from International Association of Diabetes and
Pregnancy Study Groups Consensus Panel, 2010. Adapted from Yang, 2006.
 1128 Medical and Surgical Complications

diabetes. These maternal and fetal complications are described 30

in the following sections.
25
Fetal Effects
SECTION 12

20
Spontaneous Abortion. Several studies have shown that

Percent
15.8
early miscarriage is associated with poor glycemic control. In 15
215 women with type 1 diabetes enrolled for prenatal care 11.7
before 9 weeks’ gestation, 24 percent had an early pregnancy 10
loss (Rosenn, 1994). Only those whose initial glycohemoglo- 3/19
5 2/17
bin A1c concentrations were > 12 percent or whose preprandial 5 2.8
glucose concentrations were persistently > 120 mg/dL were 2/40
1/35
0
at increased risk. In another analysis of 127 Spanish women <6 6–6.9 7–7.9 ≥8
with pregestational diabetes, poor glycemic control, defined by
glycohemoglobin A1c concentrations > 7 percent, was associ- FIGURE 57-2 The frequency of major congenital malformations
ated with a threefold increase in the spontaneous abortion rate in newborns of women with pregestational diabetes stratified by
hemoglobin A1c levels at first prenatal visit. (Data from Galindo,
(Galindo, 2006).
2006.)
Preterm Delivery. Overt diabetes is an undisputed risk fac-
tor for preterm birth. Eidem and associates (2011) analyzed
1307 births in women with pregestational type 1 diabetes from sequence is a rare malformation frequently associated with mater-
the Norwegian Medical Birth Registry. More than 26 percent nal diabetes (Garne, 2012).
were delivered preterm compared with 6.8 percent in the gen- Poorly controlled diabetes, both preconceptionally and
eral obstetrical population. Moreover, almost 60 percent were early in pregnancy, is thought to underlie this increased
indicated preterm births, that is, due to obstetrical or medical severe-malformation risk. As shown in Figure 57-2, Galindo
complications. In the Canadian study shown in Table 57-5, the and colleagues (2006) demonstrated a clear correlation between
incidence of preterm birth was 28 percent—a fivefold increase increased maternal glycohemoglobin A1c at first prenatal visit
compared with that of their normal population. and major malformations. Eriksson (2009) concluded that the
Malformations. The incidence of major malformations in etiology was multifactorial. At least three interrelated molecu-
women with type 1 diabetes is doubled and approximates 5 per- lar chain reactions have been linked to maternal hyperglycemia
cent (Eidem, 2010; Sheffield, 2002). These account for almost
half of perinatal deaths in diabetic pregnancies. A twofold
increased risk of major congenital defects in Norwegian women
with pregestational type 1 diabetes included cardiovascular mal-
formations that accounted for more than half of the anomalies
(Table 57-6). In the National Birth Defects Prevention Study,
the risk of an isolated cardiac defect was fourfold higher in women
with pregestational diabetes compared with the twofold increased
risk of noncardiac defects (Correa, 2008). The caudal regression

TABLE 57-6. Congenital Anomalies in Fetuses of 91

Women with Type 1 Diabetes between
1999 and 2004 in Norway
Babies Affected
Organ System n (%)
Cardiovascular 47 (52)
Musculoskeletal 11 (12)
Urogenital 8 (9)
CNS 4 (4)
Gastrointestinal 2 (2)
Chromosomal 3 (3)
Others 9 (10)
Multiorgan 7 (8)

CNS = central nervous system.

Data from Eidem, 2010. FIGURE 57-3 This 6050-g macrosomic infant was born to a
woman with diabetes.
 Diabetes Mellitus 1129

and can potentially explain the mechanism behind poor glyce- in 145 control women. The abdominal circumference evolved
mic control and increased risk for major malformations (Reece, differently in the diabetic groups. Analysis of head circumfer-
2012). These include alterations in cellular lipid metabolism, ence/abdominal circumference (HC/AC) ratios shows that this

CHAPTER 57
excess production of toxic superoxide radicals, and activation disproportionate growth occurs mainly in diabetic pregnancies
of programmed cell death. For example, Morgan and associ- that ultimately yield macrosomic newborns (Fig. 57-5). These
ates (2008) demonstrated that hyperglycemia-induced oxida- findings comport with the observation that virtually all neo-
tive stress inhibited migration of cardiac neural-crest cells in nates of diabetic mothers are growth promoted. Ben-Haroush
embryos of diabetic mice. and associates (2007) analyzed fetal sonographic measurements
Altered Fetal Growth. Diminished growth may result from between 29 and 34 weeks’ gestation in 423 diabetic pregnancies
congenital malformations or from substrate deprivation due to and found that accelerated fetal growth was particularly evident
advanced maternal vascular disease. However, fetal overgrowth in women with poor glycemic control.
is more typical of pregestational diabetes. Maternal hypergly- Unexplained Fetal Demise. The risk of fetal death is three
cemia prompts fetal hyperinsulinemia, particularly during to four times higher in women with type 1 diabetes compared
the second half of gestation. This in turn stimulates excessive with that of the general obstetrical population (Eidem, 2011).
somatic growth or macrosomia. Except for the brain, most fetal Stillbirth without an identifiable cause is a phenomenon rela-
organs are affected by the macrosomia that characterizes the tively limited to pregnancies complicated by overt diabetes.
fetus of a diabetic woman. Such infants are described as being These stillbirths are “unexplained” because common factors
anthropometrically different from other large-for-gestational such as obvious placental insufficiency, abruption, fetal-growth
age (LGA) infants (Durnwald, 2004; McFarland, 2000). restriction, or oligohydramnios are not identified. These infants
Specifically, those whose mothers are diabetic have excessive are typically LGA and die before labor, usually after 35 weeks’
fat deposition on the shoulders and trunk, which predisposes gestation or later (Garner, 1995).
to shoulder dystocia or cesarean delivery (Fig. 57-3).
The incidence of macrosomia rises significantly when mean
maternal blood glucose concentrations chronically exceed
130 mg/dL (Hay, 2012). Hammoud and coworkers (2013)
Abdominal circumference (mm)

reported that the macrosomia rates for Nordic women with 400 DM, Type 1
type 1, type 2, or gestational diabetes were 35 percent, 28 per- 350 DM, Type 2
cent, and 24 percent, respectively. As shown in Figure 57-4, the Gestational DM
birthweight distribution of neonates of diabetic mothers is skewed 300 Controls
toward consistently heavier birthweights compared with that of 250
normal pregnancies.
In the study by Hammoud and colleagues (2013), fetal 200
growth profiles from 897 sonographic examinations in 244 150
women with diabetes were compared with 843 examinations
100
100 120 140 160 180 200 220 240 260 280
A Gestational age (days)

27 700 1.25
24 1.20
600
21 1.15
HC/AC ratio

500 1.10
No. of diabetic patients

18 Controls
No. of controls

Normal Diabetic 1.05 DM1, no macrosomia

15 400
1.00 DM1, macrosomia
DM2, no macrosomia
12 300 0.95 DM2, macrosomia
GDM, no macrosomia
9 0.90
200 GDM, macrosomia
6 0.85
100 120 140 160 180 200 220 240 260 280
100 B Gestational age (days)
3

0 0 FIGURE 57-5 Comparison of sonographic fetal anatomic mea-

surements by gestational age and subdivided according to pres-
⫺4 ⫺3 ⫺2 ⫺1 0 1 2 3 4 5 6
ence or absence of macrosomia among women with various
Birthweight (standard deviations)
types of diabetes types and controls. A. Abdominal circumfer-
FIGURE 57-4 Distribution of birthweight standard deviation ence measurements. B. Head circumference (HC)/Abdominal
from the normal mean for gestational age in 280 infants of circumference (AC) ratio. DM = diabetes mellitus; GDM = gesta-
diabetic mothers and in 3959 infants of nondiabetic mothers. tional diabetes mellitus. (Redrawn from Hammoud, 2013, with
(From Bradley, 1988, with permission.) permission.)
 1130 Medical and Surgical Complications

These unexplained stillbirths are associated with poor glyce- observations challenged this concept, and gestational age rather
mic control. Lauenborg and coworkers (2003) identified sub- than overt diabetes is likely the most significant factor associ-
optimal glycemic control in two thirds of unexplained stillbirths ated with respiratory distress syndrome. Indeed, in their analy-
between 1990 and 2000. Also, fetuses of diabetic mothers often sis of 19,399 very-low-birthweight neonates delivered between
SECTION 12

have elevated lactic acid levels. Salvesen and colleagues (1992, 24 and 33 weeks’ gestation, Bental and colleagues (2011) were
1993) analyzed fetal blood samples and reported that mean unable to demonstrate an increased rate of respiratory distress
umbilical venous blood pH was lower in diabetic pregnancies syndrome in newborns of diabetic mothers. This is discussed
and was significantly related to fetal insulin levels. Such find- further in Chapter 33 (p. 637).
ings support the hypothesis that hyperglycemia-mediated
chronic aberrations in oxygen and fetal metabolite transport Hypoglycemia. Newborns of a diabetic mother experience
may underlie these unexplained fetal deaths (Pedersen, 1977). a rapid drop in plasma glucose concentration after delivery.
However, the exact mechanisms by which uncontrolled hyper- This is attributed to hyperplasia of the fetal β-islet cells induced
glycemia leads to elevated lactic acid levels and fetal acidosis by chronic maternal hyperglycemia. Low glucose concentra-
remain unclear. tions—defined as < 45 mg/dL—are particularly common in
Explicable stillbirths due to placental insufficiency also occur newborns of women with unstable glucose concentrations
with increased frequency in women with overt diabetes, usu- during labor (Persson, 2009). In a recent analysis of pre-
ally in association with severe preeclampsia. In a retrospective natal outcomes during a 20-year period in Finnish women
analysis of more than 500,000 singleton deliveries, Yanit and with type 1 diabetes, the incidence of neonatal hypoglycemia
associates (2012) found that the fetal death risk was sevenfold declined significantly over time (Klemetti, 2012). The authors
higher in women with hypertension and pregestational diabetes attributed this to frequent blood glucose measurements and
compared with the threefold increased risk associated with dia- active early feeding practices in such neonates. Prompt recog-
betes alone. Stillbirth is also increased in women with advanced nition and treatment of the hypoglycemic newborn minimizes
diabetes and vascular complications. Maternal ketoacidosis can adverse sequelae.
also cause fetal death.
Hypocalcemia. Defined as a total serum calcium concen-
tration < 8 mg/dL in term newborns, hypocalcemia is one of
Hydramnios. Diabetic pregnancies are often complicated the potential metabolic derangements in neonates of diabetic
by excess amnionic fluid. According to Idris and coworkers mothers. Its cause has not been explained. Theories include
(2010), 18 percent of 314 women with pregestational diabe- aberrations in magnesium–calcium economy, asphyxia, and
tes were identified with hydramnios, defined as an amnionic preterm birth. In a randomized study by DeMarini and associ-
fluid index (AFI) greater than 24 cm in the third trimester. ates (1994), 137 pregnant women with type 1 diabetes were
A likely—albeit unproven—explanation is that fetal hypergly- managed with strict versus customary glucose control. Almost
cemia causes polyuria (Chap. 11, p. 234). In a study from a third of neonates in the customary control group developed
Parkland Hospital, Dashe and colleagues (2000) found that hypocalcemia compared with only 18 percent of those in the
the AFI parallels the amnionic fluid glucose level among strict control group.
women with diabetes. This finding suggests that the hydram-
nios associated with diabetes is a result of increased amnionic Hyperbilirubinemia and Polycythemia. The pathogen-
fluid glucose concentration. Further support for this hypoth- esis of hyperbilirubinemia in neonates of diabetic mothers is
esis was provided by Vink and associates (2006), who linked uncertain. A major contributing factor is newborn polycythe-
poor maternal glucose control to macrosomia and hydramnios. mia, which increases the bilirubin load (Chap. 33, p. 643).
In their retrospective analysis of diabetic pregnancies, Idris and Polycythemia is thought to be a fetal response to relative
coworkers (2010) also found that women with elevated glyco- hypoxia. According to Hay (2012), the sources of this fetal
hemoglobin A1c values in the third trimester were more likely hypoxia are hyperglycemia-mediated increases in maternal
to have hydramnios. affinity for oxygen and fetal oxygen consumption. Together
with insulin-like growth factors, this hypoxia leads to increased
Neonatal Effects. Before tests of fetal health and maturity fetal erythropoietin levels and red cell production. Venous
became available, delivery before term was deliberately selected hematocrits of 65 to 70 volume percent have been observed
for women with diabetes to avoid unexplained fetal death. in up to 40 percent of these newborns (Salvesen, 1992). Renal
Although this practice has been abandoned, there is still an vein thrombosis is reported to result from polycythemia.
increased frequency of preterm delivery in women with dia-
betes. Most are due to advanced diabetes with superimposed Cardiomyopathy. Infants of diabetic pregnancies may
preeclampsia. Thankfully, modern neonatal care has largely have hypertrophic cardiomyopathy that primarily affects
eliminated neonatal deaths due to immaturity. Conversely, the interventricular septum (Rolo, 2011). In severe cases,
neonatal morbidityy due to preterm birth continues to be a seri- this cardiomyopathy may lead to obstructive cardiac failure.
ous consequence. Russell and coworkers (2008) performed serial echocardio-
grams on fetuses of 26 women with pregestational diabetes.
Respiratory Distress Syndrome. Historically, newborns In the first trimester, fetal diastolic dysfunction was evident
of diabetic mothers were thought to be at increased risk for compared with that of nondiabetic controls. In the third tri-
respiratory distress from delayed lung maturation. Subsequent mester, the fetal interventricular septum and right ventricular
 Diabetes Mellitus 1131

wall were thicker in fetuses of diabetic mothers. The authors 17 women with coronary artery disease—class H diabetes—
concluded that cardiac dysfunction precedes these structural and reported that only half survived pregnancy.
changes. Fortunately, most affected newborns are asymp-
Preeclampsia. Hypertension that is induced or exacerbated

CHAPTER 57
tomatic following birth, and hypertrophy resolves in the
months after delivery. Relief from maternal hyperglycemia by pregnancy is the complication that most often forces pre-
is presumed to promote this resolution (Hornberger, 2006). term delivery in diabetic women. The incidence of chronic
Conversely, fetal cardiomyopathy may progress to adult car- and gestational hypertension—and especially preeclampsia—is
diac disease. remarkably increased in diabetic mothers. In the study cited
earlier by Yanit and colleagues (2012), preeclampsia developed
Long-Term Cognitive Development. Intrauterine meta- three to four times more often in women with overt diabetes.
bolic conditions have long been linked to neurodevelopment Moreover, those diabetics with coexistent chronic hyperten-
in offspring. This may also be true in children of diabetic moth- sion were almost 12 times more likely to develop preeclampsia.
ers. Despite rigorous antepartum management, Rizzo and col- Special risk factors for preeclampsia include any vascular com-
leagues (1995) found numerous correlations between maternal plication and preexisting proteinuria, with or without chronic
glycemia and intellectual performance in children up to age 11 hypertension. As shown in Figure 57-6, women with type 1
years in 139 offspring of diabetic women. In a study of more diabetes who are in more advanced White classes of overt dia-
than 700,000 Swedish-born men, the intelligence quotient of betes increasingly developed preeclampsia. This increasing risk
those whose mothers had diabetes during pregnancy averaged 1 with duration of diabetes may be related to oxidative stress,
to 2 points lower (Fraser, 2014). DeBoer and associates (2005) which plays a key role in the pathogenesis of diabetic complica-
demonstrated impaired memory performance in infants of dia- tions and preeclampsia. With this in mind, the Diabetes and
betic mothers at age 1 year. Finally, results from the Childhood Preeclampsia Intervention Trial (DAPIT) randomly assigned
Autism Risks from Genetics and the Environment (CHARGE) 762 women with type 1 diabetes to antioxidant vitamin C and
study indicated that autism spectrum disorders or developmen- E supplementation or placebo in the first half of pregnancy
tal delay were more common in children of diabetic women (McCance, 2010). There were no differences in preeclampsia
(Krakowiak, 2012). Although interpreting effects of the intra- rates except in a few women with a low antioxidant status at
uterine environment on neurodevelopment is certainly con- baseline. Temple and coworkers (2006) prospectively studied
founded by postnatal events, emerging data at least support a hemoglobin A1c levels at 24 weeks’ gestation in 290 women
link between maternal diabetes, glycemic control, and neuro- with type 1 diabetes and found that preeclampsia was related
cognitive outcome. to glucose control. Management of preeclampsia is discussed in
Chapter 40 (p. 749).
Inheritance of Diabetes. The risk of developing type 1 Diabetic Nephropathy. Diabetes is the leading cause of end-
diabetes if either parent is affected is 3 to 4 percent. Type 2 stage renal disease in the United States (Chap. 53, p. 1060).
diabetes has a much stronger genetic component. If both par- Clinically detectable nephropathy begins with microalbumin-
ents have type 2 diabetes, the risk of developing it approaches uria—30 to 300 mg/24 hours. This may manifest as early as
40 percent. McKinney and coworkers (1999) studied 196 5 years after diabetes onset. Macroalbuminuria—more than
children with type 1 diabetes and found that older maternal 300 mg/24 hours—develops in patients destined to have end-
age and maternal type 1 diabetes are important risk factors. stage renal disease. Hypertension almost invariably develops
Plagemann and colleagues (2002) have implicated breast feed- during this period, and renal failure ensues typically in the
ing by diabetic mothers in the genesis of childhood diabetes. next 5 to 10 years. The incidence of overt proteinuria is nearly
Conversely, breast feeding has also been associated with a 30 percent in individuals with type 1 diabetes and ranges
reduced risk of type 2 diabetes (Owen, 2006). The Trial to
Reduce Insulin-dependent Diabetes Mellitus in the Genetically
At Risk (TRIGR) was designed to analyze hydrolyzed formula 60
use, rather than breast milk, to reduce rates of type 1 diabetes Swedena
Preeclampsia incidence

in at-risk children by age 10. This study will be complete in United Statesb
2017 (Knip, 2011). 45
(percent)

Maternal Effects 30
Diabetes and pregnancy interact significantly such that mater-
nal welfare can be seriously jeopardized. With the possible
exception of diabetic retinopathy, however, the long-term 15
course of diabetes is not affected by pregnancy.
Maternal death is uncommon, but rates in women with diabetes
are still increased. In an analysis of 972 women with type 1 diabe- Diabetic class B C D F T
Total
tes, Leinonen and associates (2001) reported a maternal mortality (n =164) (n=129) (n =172) (n = 26) (n =491)
rate of 0.5 percent. Deaths resulted from diabetic ketoacidosis, FIGURE 57-6 Incidence of preeclampsia in 491 type 1 diabetic
hypoglycemia, hypertension, and infection. Especially morbid is women in Sweden and the United States. (Data from Hansona,
ischemic heart disease. Pombar and coworkers (1995) reviewed 1993; Sibaib, 2000.)
 1132 Medical and Surgical Complications

from 4 to 20 percent in those with type 2 diabetes (Reutens,

2013). Progression from microalbuminuria is not inexorable,
and regression is common. Presumably from improved glu-
cose control, the incidence of nephropathy in individuals
SECTION 12

with type 1 diabetes has declined in the past few decades.

Investigators for the Diabetes Control and Complications
Trial (2002) reported that there was a 25-percent decrease
in the rate of nephropathy for each 10-percent decrease in
hemoglobin A1c levels.
Approximately 5 percent of pregnant women with diabe-
tes already have renal involvement. Approximately 40 percent
of these will develop preeclampsia (Vidaeff, 2008). High rates
are also illustrated in Figure 57-6. However, this may not be
the case with microproteinuria. In one analysis of 460 women, A
How and colleagues (2004) found no association between
preeclampsia and microproteinuria. Nevertheless, they found
that chronic hypertension with overt diabetic nephropathy
increased the risk of preeclampsia to 60 percent.
In general, pregnancy does not appear to worsen diabetic
nephropathy. In their prospective study of 43 women with
diabetes, Young and associates (2012) could not demonstrate
diabetic nephropathy progression through 12 months after
delivery. Most of these women had only mild renal impair-
ment. Conversely, pregnancy in women with moderate to
severe renal impairment may accelerate progression of their
disease (Vidaeff, 2008). As in women with glomerulopathies,
hypertension or substantial proteinuria before or during preg-
nancy is a major predictive factor for progression to renal fail-
ure in women with diabetic nephropathy (Chap. 53, p. 1062). B

Diabetic Retinopathy. Retinal vasculopathy is a highly FIGURE 57-7 Retinal photographs from a 30-year-old diabetic
specific complication of both type 1 and type 2 diabetes. In woman. A. Optic nerve head showing severe proliferative reti-
nopathy characterized by extensive networks of new vessels
the United States, diabetic retinopathy is the most impor- surrounding the optic disc. B. A portion of the acute photocoagu-
tant cause of visual impairment in persons younger than age lation full “scatter” pattern following argon laser treatment. (From
60 years (Frank, 2004). The first and most common visible Elman, 1990, with permission.)
lesions are small microaneurysms followed by blot hemorrhages
that form when erythrocytes escape from the aneurysms. These to be a rare example of a long-term adverse effect of preg-
areas leak serous fluid that creates hard exudates. Such features nancy. However, in a prospective postpartum 5-year surveil-
are termed benign or backgroundd or nonproliferative retinopa- lance of 59 type 1 diabetic women, Arun and Taylor (2008)
thy. With increasingly severe retinopathy, the abnormal vessels found that baseline retinopathy was the only independent risk
of background eye disease become occluded, leading to retinal factor for progression.
ischemia and infarctions that appear as cotton wool exudates. Other risk factors that have been associated with progres-
These are considered preproliferative retinopathy. In response sion of retinopathy include hypertension, higher levels of
to ischemia, there is neovascularization on the retinal surface insulin-like growth factor-I, and macular edema identified in
and out into the vitreous cavity. Vision is obscured when there early pregnancy (Bargiota, 2011; Mathiesen, 2012; Ringholm,
is hemorrhage. Laser photocoagulation before hemorrhage, as 2011; Vestgaard, 2010). The National Institute for Health and
shown in Figure 57-7, reduces the rate of visual loss progres- Clinical Excellence (2008) established guidelines recommend-
sion and blindness by half. The procedure is performed during ing that pregnant women with preexisting diabetes should rou-
pregnancy when indicated. tinely be offered retinal assessment after the first prenatal visit.
Vestgaard and coworkers (2010) reported that almost two Currently, most agree that laser photocoagulation and good
thirds of 102 pregnant women with type 1 diabetes examined glycemic control during pregnancy minimize the potential for
by 8 weeks’ gestation had background retinal changes, pro- deleterious effects of pregnancy.
liferative retinopathy, or macular edema. A fourth of these Ironically, “acute” rigorous metabolic control during preg-
women developed progression of retinopathy in at least one nancy has been linked to acute worsening of retinopathy. In
eye. The same group of investigators evaluated 80 type 2 dia- a study of 201 women with retinopathy, McElvy and associ-
betics and identified retinopathy, mostly mild, in 14 percent ates (2001) found that almost 30 percent suffered eye disease
during early pregnancy. Progression was identified in only progression during pregnancy despite intensive glucose con-
14 percent (Rasmussen, 2010). This complication is believed trol. That said, Wang and coworkers (1993) have observed that
 Diabetes Mellitus 1133

retinopathy worsened during the critical months of rigorous glu- gluconeogenesis and ketone body formation. The ketone body
cose control, but long term, deterioration of eye disease slowed. β-hydroxybutyrate is synthesized at a much greater rate than
In their study mentioned above, Arun and Taylor (2008) found acetoacetate, which is preferentially detected by commonly

CHAPTER 57
that only four women required laser photocoagulation during used ketosis detection methodologies. Therefore, serum or
pregnancy, and none required laser in the next 5 years. plasma assays for β-hydroxybutyrate more accurately reflect
true ketone body levels.
Diabetic Neuropathy. Peripheral symmetrical sensorimotor The incidence of fetal loss can be as high as 20 percent with
diabetic neuropathy is uncommon in pregnant women. But DKA. Noncompliance is a prominent factor, and this and keto-
a form of this, known as diabetic gastropathy, is troublesome acidosis were historically considered prognostically bad signs in
during pregnancy. It causes nausea and vomiting, nutritional pregnancy (Pedersen, 1974). Pregnant women usually develop
problems, and difficulty with glucose control. Women with ketoacidosis at lower blood glucose thresholds than when non-
gastroparesis should be advised that this complication is associ- pregnant. In a study from China, the mean glucose level for
ated with a high risk of morbidity and poor perinatal outcome pregnant women with DKA was 293 mg/dL compared with
(Kitzmiller, 2008). Treatment with metoclopramide and H2- 495 mg/dL for nonpregnant women (Guo, 2008). Chico and
receptor antagonists is sometimes successful. Hyperemesis gravi- associates (2008) reported ketoacidosis in a pregnant woman
darum is further discussed in Chapter 54 (p. 1070). whose plasma glucose was only 87 mg/dL.
One management protocol for diabetic ketoacidosis is
Diabetic Ketoacidosis. This serious complication develops shown in Table 57-7. An important cornerstone of manage-
in approximately 1 percent of diabetic pregnancies (Hawthorne, ment is vigorous rehydration with crystalloid solutions of nor-
2011). It is most often encountered in women with type 1 mal saline or Ringer lactate.
diabetes. It is increasingly being reported in women with
type 2 or even those with gestational diabetes (Sibai, 2014). Infections. Almost all types of infections are increased in
Diabetic ketoacidosis (DKA) may develop with hyperemesis diabetic pregnancies. Stamler and coworkers (1990) reported
gravidarum, β-mimetic drugs given for tocolysis, infection, and that almost 80 percent of women with type 1 diabetes develop
corticosteroids given to induce fetal lung maturation. DKA at least one infection during pregnancy compared with only
results from an insulin deficiency combined with an excess in 25 percent in those without diabetes. Common infections
counter-regulatory hormones such as glucagon. This leads to include Candidaa vulvovaginitis, urinary and respiratory tract

TABLE 57-7. Protocol Recommended by the American College of Obstetricians

and Gynecologists (2012) for Management of Diabetic Ketoacidosis
During Pregnancy
Laboratory assessment
Obtain arterial blood gases to document degree of acidosis present; measure glucose,
ketones, and electrolyte levels at 1- to 2-hour intervals
Insulin
Low-dose, intravenous
Loading dose: 0.2–0.4 U/kg
Maintenance: 2–10 U/hr
Fluids
Isotonic sodium chloride
Total replacement in first 12 hours of 4–6 L
1 L in first hour
500–1000 mL/hr for 2–4 hours
250 mL/hr until 80 percent replaced
Glucose
Begin 5-percent dextrose in normal saline when glucose plasma level reaches
250 mg/dL (14 mmol/L)
Potassium
If initially normal or reduced, an infusion rate up to 15–20 mEq/hr may be required;
if elevated, wait until levels decrease into the normal range, then add to
intravenous solution in a concentration of 20–30 mEq/L
Bicarbonate
Add one ampule (44 mEq) to 1 L of 0.45 normal saline if pH is < 7.1

From Landon, 2007, with permission.

 1134 Medical and Surgical Complications

infections, and puerperal pelvic sepsis. In their population-

TABLE 57-8. Action Profiles of Commonly Used Insulins
based study of almost 200,000 pregnancies, Sheiner and col-
leagues (2009) found a twofold increased risk of asymptomatic Peak Duration
bacteruria in women with diabetes. Similarly, Alvarez and Insulin Type Onset (hr) (hr)
SECTION 12

associates (2010) reported positive urine cultures in a fourth Short-acting (SC)

of diabetic women compared with 10 percent of nondiabetic Lispro < 15 min 0.5–1.5 3–4
pregnant women. In a 2-year analysis of pyelonephritis at Glulisine < 15 min 0.5–1.5 3–4
Parkland Hospital, 5 percent of women with diabetes devel- Aspart < 15 min 0.5–1.5 3–4
oped pyelonephritis compared with 1.3 percent of the non- Regular 30–60 min 2–3 4–6
diabetic population (Hill, 2005). Fortunately, these latter Long-acting (SC)
infections can be minimized by screening and eradication of Detemir 1–4 hr Minimala Up to 24
asymptomatic bacteriuria (Chap. 53, p. 1053). Takoudes and Glargine 1–4 hr Minimala Up to 24
colleagues (2004) found that pregestational diabetes is associ- NPH 1–4 hr 6–10 10–16
ated with a two- to threefold increase in wound complications
after cesarean delivery. a
Minimal peak activity.
NPH = neutral protamine Hagedorn; SC = subcutaneous.
Modified from Powers, 2012.
■ Management of Diabetes in Pregnancy
Because of the relationship between pregnancy complications
and maternal glycemic control, efforts to achieve glucose targets
are typically more aggressive during pregnancy. Management to assess the extent of diabetic vascular complications and pre-
preferably should begin before pregnancy and include specific cisely establish gestational age.
goals during each trimester.
Insulin Treatment
Preconceptional Care The overtly diabetic pregnant woman is best treated with
To minimize early pregnancy loss and congenital malforma- insulin. Although oral hypoglycemic agents have been used
tions in offspring of diabetic mothers, optimal medical care successfully for gestational diabetes (p. 1141), these agents
and education are recommended before conception (Chap. 8, are not currently recommended for overt diabetes except
p. 157). Unfortunately, nearly half of pregnancies in the United for limited and individualized use (American College of
States are unplanned, and many diabetic women frequently Obstetricians and Gynecologists, 2012). Maternal glycemic
begin pregnancy with suboptimal glucose control (Finer, 2011; control can usually be achieved with multiple daily insulin
Kim, 2005). injections and adjustment of dietary intake. The action pro-
The ADA has defined optimal preconceptional glucose con- files of commonly used short- and long-term insulins are
trol using insulin to include self-monitored preprandial glucose shown in Table 57-8.
levels of 70 to 100 mg/dL, peak postprandial values of 100 to Subcutaneous insulin infusion by a calibrated pump may
129 mg/dL, and mean daily glucose concentrations < 110 mg/ be used during pregnancy. However, as demonstrated in a
dL (Kitzmiller, 2008). Glycosylated hemoglobin measurement, Cochrane Database review by Farrar and associates (2007),
which reflects an average of circulating glucose for the past 4 to there is scarce robust evidence for specific salutary pregnancy
8 weeks, is useful to assess early metabolic control. The ADA effects. In a metaanalysis of six small randomized trials compar-
(2012) defines optimal values to be < 7 percent. In their pro- ing insulin pumps to multiple daily injections of insulin, there
spective population-based study of 933 pregnant women with were no significant differences in LGA birthweight, maternal
type 1 diabetes, Jensen and colleagues (2010) found the risk of hypoglycemia, or retinopathy progression (Mukhopadhyay,
congenital malformations was not demonstrably higher with 2007). Notably, more women using insulin pumps developed
glycosylated hemoglobin levels < 6.9 percent compared with ketoacidosis. Roeder and colleagues (2012) noted with insulin
that in more than 70,000 nondiabetic controls. They also iden- pump use in women with type 1 diabetes that total daily doses
tified a substantial fourfold increased risk for malformations at declined in the first trimester but later increased by more than
levels > 10 percent. threefold. Postprandial glucose excursions accounted for most
If indicated, evaluation and treatment for diabetic com- increases. Women who use an insulin pump must be highly
plications such as retinopathy or nephropathy should also be motivated and compliant to minimize the risk of nocturnal
instituted before pregnancy. Finally, folate, 400 μg/day orally hypoglycemia (Gabbe, 2003).
is given periconceptionally and during early pregnancy to
decrease the risk of neural-tube defects. Monitoring. Self-monitoring of capillary glucose levels
using a glucometer is recommended because this involves the
First Trimester woman in her own care. Glucose goals recommended during
Careful monitoring of glucose control is essential. For this rea- pregnancy are shown in Table 57-9. Advances in noninvasive
son, many clinicians hospitalize overtly diabetic women during glucose monitoring will undoubtedly render intermittent cap-
early pregnancy to initiate an individualized glucose control illary glucose monitoring obsolete. Subcutaneous continuous
program and offer education. It also provides an opportunity glucose monitoring devices reveal that pregnant women with
 Diabetes Mellitus 1135

similar glucose values delayed and slowed diabetic retinopa-

TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals
thy, nephropathy, and neuropathy. Thus, women with overt
Specimen Level (mg/dL) diabetes who have glucose values considerably above those
≤ 95

CHAPTER 57
Fasting defined as normal both during and after pregnancy can expect
Premeal ≤ 100 good outcomes.
1-hr postprandial ≤ 140
2-hr postprandial ≤ 120 Second Trimester
0200–0600 ≥ 60
Maternal serum alpha-fetoprotein determination at 16 to 20
Mean (average) 100
weeks’ gestation is used in association with targeted sono-
Hemoglobin A1c ≤ 6%
graphic examination at 18 to 20 weeks to detect neural-tube
defects and other anomalies (Chap. 14, p. 284). Maternal
alpha-fetoprotein levels may be lower in diabetic pregnancies,
diabetes experience significant periods of daytime hyperglyce- and interpretation is altered accordingly. Because the incidence
mia and nocturnal hypoglycemia that are undetected by tra- of congenital cardiac anomalies is five times greater in moth-
ditional monitoring (Combs, 2012). In one randomized trial ers with diabetes, fetal echocardiography is an important part
of 71 women, those with periodic supplemental access to con- of second-trimester sonographic evaluation (Fouda, 2013).
tinuous glucose data had lower glycosylated hemoglobin lev- Despite advances in ultrasound technology, however, Dashe
els—5.8 versus 6.4 percent—and delivered fewer overgrown and associates (2009) cautioned that detection of fetal anoma-
newborns (Murphy, 2008). To date however, there have been lies in obese diabetic women is more difficult than in similarly
no trials evaluating the impact of personall continuous monitor- sized women without diabetes.
ing devices that give immediate feedback to pregnant women. Regarding second-trimester glucose control, euglycemia
Such glucose monitoring systems, coupled with a continuous with self-monitoring continues to be the goal in management.
insulin pump, offer the potential of an “artificial pancreas” to After the first-trimester instability, a stable period ensues. This
avoid undetected hypo- or hyperglycemia during pregnancy. is followed by an increased insulin requirement. Recall that
Roeder and coworkers (2012) identified a threefold increase
Diet. Nutritional planning includes appropriate weight gain in total daily insulin after the first trimester in women using
through carbohydrate and caloric modifications based on an insulin pump. This is due to the increased peripheral resis-
height, weight, and degree of glucose intolerance (American tance to insulin described in Chapter 4 (p. 53).
Diabetes Association, 2012; Bantle, 2008). The mix of car-
bohydrate, protein, and fat is adjusted to meet the metabolic
Third Trimester and Delivery
goals and individual patient preferences, but a 175-g minimum
of carbohydrate per day should be provided. Carbohydrate During the last several decades, the threat of late-pregnancy
should be distributed throughout the day in three small- to fetal death in women with diabetes has prompted recommen-
moderate-sized meals and two to four snacks (Bantle, 2008). dations for various fetal surveillance programs beginning in the
Weight loss is not recommended, but modest caloric restric- third trimester. Such protocols include fetal movement count-
tion may be appropriate for overweight or obese women. An ing, periodic fetal heart rate monitoring, intermittent biophysi-
ideal dietary composition is 55 percent carbohydrate, 20 per- cal profile evaluation, and contraction stress testing (Chap.
cent protein, and 25 percent fat, of which < 10 percent is 17, p. 335). None of these techniques has been subjected to
saturated fat. prospective randomized clinical trials, and their primary value
seems related to their low false-negative rates. The American
Hypoglycemia. Diabetes tends to be unstable in the first College of Obstetricians and Gynecologists (2012) suggests ini-
trimester. Hellmuth and associates (2000) reported that 37 tiating such testing at 32 to 34 weeks’ gestation.
percent of 43 women with type 1 diabetes had maternal hypo- At Parkland Hospital, women with diabetes are seen in a spe-
glycemia during the first trimester, and the average duration cialized obstetrical complications clinic every 2 weeks. During
was more than 2 hours. Similarly, Chen and coworkers (2007) these visits, glycemic control is evaluated and insulin adjusted.
identified hypoglycemic events—blood glucose < 40 mg/dL— They are routinely instructed to perform fetal kick counts
in 37 of 60 women with type 1 diabetes. A fourth of these beginning early in the third trimester. At 34 weeks, admission
were considered severe because the women were unable to treat is offered to all insulin-treated women. While in the hospital,
their own symptoms. Rosenn and colleagues (1994) noted they continue daily fetal movement counts and undergo fetal
that maternal hypoglycemia had a peak incidence between heart rate monitoring three times a week. Delivery is planned
10 and 15 weeks’ gestation. Caution is recommended when for 38 weeks.
attempting euglycemia in women with recurrent episodes of Labor induction may be attempted when the fetus is not
hypoglycemia. excessively large and the cervix is considered favorable (Chap.
We have reported that good pregnancy outcomes can be 26, p. 523). Cesarean delivery at or near term has frequently
achieved in women with mean preprandial plasma glucose been used to avoid traumatic birth of a large infant in a woman
values up to 143 mg/dL (Leveno, 1979). In women with with diabetes. In women with more advanced diabetes, especially
diabetes who are not pregnant, the Diabetes Control and those with vascular disease, the reduced likelihood of successful
Complications Trial Research Group (1993) found that labor induction remote from term has also contributed to an
 1136 Medical and Surgical Complications

TABLE 57-10. Insulin Management During Labor and Delivery

• Usual dose of intermediate-acting insulin is given at bedtime.
• Morning dose of insulin is withheld.
SECTION 12

• Intravenous infusion of normal saline is begun.

• Once active labor begins or glucose levels decrease to < 70 mg/dL, the infusion is changed from saline to 5-percent dextrose
and delivered at a rate of 100–150 mL/hr (2.5 mg/kg/min) to achieve a glucose level of approximately 100 mg/dL.
• Glucose levels are checked hourly using a bedside meter allowing for adjustment in the insulin or glucose infusion rate.
• Regular (short-acting) insulin is administered by intravenous infusion at a rate of 1.25 U/hr if glucose levels exceed
100 mg/dL.

Data from Coustan DR. Delivery: timing, mode, and management. In: Reece EA, Coustan DR, Gabbe SG, editors. Diabetes
in women: adolescence, pregnancy, and menopause. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004; and
Jovanovic L, Peterson CM. Management of the pregnant, insulin-dependent diabetic woman. Diabetes Care 1980;3:63–8.
From Pregestational diabetes mellitus. ACOG Practice Bulletin No. 60. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2005;105:675–85; reaffirmed 2012.

increased cesarean delivery rate. In a nested case-control study of race, ethnicity, age, and body composition and by screening and
209 women with type 1 diabetes, Lepercq and colleagues (2010) diagnostic criteria. There continue to be several controversies
reported a 70-percent cesarean delivery rate overall. Two thirds pertaining to the diagnosis and treatment of gestational diabetes.
of these were delivered without labor. Both maternal body mass Accordingly, a National Institutes of Health (NIH) Consensus
index (BMI) > 25 kg/m2 and low Bishop score were indepen- Development Conference (2013) was convened. Coincidental
dently associated with cesarean delivery for those in labor. In with publication of the Conference findings, the American
another study, a glycohemoglobin level > 6.4 percent at delivery College of Obstetricians and Gynecologists (2013) also updated
was independently associated with urgent cesarean delivery. This its recommendations. These two authoritative sources provide
suggests that tighter glycemic control during the third trimester an up-to-date analysis of the issues surrounding this diagnosis
might reduce late fetal compromise and cesarean delivery for and bolster the approach to identifying and treating women
fetal indications (Miailhe, 2013). The cesarean delivery rate for with gestational diabetes, as described subsequently.
women with overt diabetes has remained at approximately 80 The word gestationall implies that diabetes is induced by preg-
percent for the past 35 years at Parkland Hospital. nancy—ostensibly because of exaggerated physiological changes
Reducing or withholding the dose of long-acting insulin given in glucose metabolism (Chap. 4, p. 53). Gestational diabetes
on the day of delivery is recommended. Regular insulin should be is defined as carbohydrate intolerance of variable severity with
used to meet most or all of the insulin needs of the mother during onset or first recognition during pregnancy (American College of
this time, because insulin requirements typically drop markedly Obstetricians and Gynecologists, 2013). This definition applies
after delivery. We have found that continuous insulin infusion by whether or not insulin is used for treatment and undoubtedly
calibrated intravenous pump is most satisfactory (Table 57-10). includes some women with previously unrecognized overt dia-
Throughout labor and after delivery, the woman should be ade- betes. In their analysis of more than 1500 nonpregnant adults
quately hydrated intravenously and given glucose in sufficient as part of National Health and Nutrition Examinations Survey
amounts to maintain normoglycemia. Capillary or plasma glucose (NHANES) IV, Karve and Hayward (2010) estimated that only
levels should be checked frequently, especially during active labor, 4.8 percent of individuals with impaired fasting glucose or glu-
and regular insulin should be administered accordingly. cose intolerance were aware of their diagnosis.
Use of the term gestational diabetess has been encouraged to
Puerperium communicate the need for increased surveillance and to stimu-
Often, women may require virtually no insulin for the first 24 late women to seek further testing postpartum. The most impor-
hours or so postpartum. Subsequently, insulin requirements tant perinatal correlate is excessive fetal growth, which may
may fluctuate markedly during the next few days. Infection result in both maternal and fetal birth trauma. The likelihood of
must be promptly detected and treated. fetal death with appropriately treated gestational diabetes is not
Counseling in the puerperium should include a discussion different from that in the general population. Importantly, more
of birth control. Available options are discussed in Chapter 38 than half of women with gestational diabetes ultimately develop
(p. 695). Effective contraception is especially important in overt diabetes in the ensuing 20 years. And, as discussed on page
women with overt diabetes to allow optimal glucose control 1125, evidence is mounting for long-range complications that
before subsequent conceptions. include obesity and diabetes in their offspring.

■ Screening and Diagnosis

GESTATIONAL DIABETES
Despite more than 40 years of research, there is still no agree-
In the United States, 5 to 6 percent of pregnancies—almost ment regarding optimal gestational diabetes screening. The dif-
f
250,000 women—are affected annually by various forms of ges- ficulty in achieving consensus is underscored by the controversy
tational diabetes. Worldwide, its prevalence differs according to following publication of the single-step approach espoused by
 Diabetes Mellitus 1137

Consensus Development Conference in 2013 concluded that

TABLE 57-11. Threshold Values for Diagnosis of
evidence is insufficient to adopt a one-step approach.
Gestational Diabetes
The recommended two-step approach begins with either uni-
Glucose Concentration

CHAPTER 57
Above Threshold versal or risk-based selective screening using a 50-g, 1-hour oral
Plasma Thresholda (%) glucose challenge test. Participants in the Fifth International
Glucose mmol/L mg/dL Cumulative Workshop Conferences on Gestational Diabetes endorsed use
of selective screeningg criteria shown in Table 57-12. Universal
5.1 92 8.3
screeningg is also acceptable. Gabbe and associates (2004) sur-
1-hr OGTT 10.0 180 14.0
veyed practicing obstetricians and reported that 96 percent used
2-hr OGTT 8.5 153 16.1b
universal screening. Screening should be performed between 24
a
One or more of these values from a 75-g OGTT must and 28 weeks’ gestation in those women not known to have
be equaled or exceeded for the diagnosis of gestational glucose intolerance earlier in pregnancy. This 50-g screening test
diabetes. is followed by a diagnostic 100-g, 3-hour oral glucose tolerance
b
In addition, 1.7% of participants in the initial cohort test (OGTT) if screening results meet or exceed a predeter-
were unblinded because of fasting plasma glucose mined plasma glucose concentration.
levels > 5.8 mmol/L (105 mg/dL) or 2-hr OGTT values For the 50-g screen, the plasma glucose level is measured
> 11.1 mmol/L (200 mg/dL), bringing the total to 17.8%. 1 hour after a 50-g oral glucose load without regard to the
OGTT = oral glucose tolerance test. time of day or time of last meal. In a recent review, the pooled
sensitivity for a threshold of 140 mg/dL ranged from 74 to
83 percent depending on 100-g thresholds used for diagnosis
the IADPSG Consensus Panel (2010) (Table 57-11). This (van Leeuwen, 2012). Sensitivity estimates for a 50-g screen
strategy was greatly influenced by results of the Hypoglycemia threshold of 135 mg/dL improved only slightly to 78 to 85
and Pregnancy Outcomes (HAPO) Study described later. percent. Importantly, specificity dropped from a range of 72 to
Although the ADA adopted this new scheme, the American 85 percent for 140 mg/dL to 65 to 81 percent for a threshold of
College of Obstetricians and Gynecologists (2013) declined to 135 mg/dL. That said, the American College of Obstetricians
endorse the single 75-gram oral glucose tolerance test. Instead, and Gynecologists (2013) recommends using either 135 or
the College continues to recommend a two-step approach to 140 mg/dL as the 50-g screen threshold. At Parkland Hospital,
screen and diagnose gestational diabetes. Similarly, the NIH we continue to use 140 mg/dL.

TABLE 57-12. Fifth International Workshop-Conference on Gestational Diabetes:

Recommended Screening Strategy Based on Risk Assessment for
Detecting Gestational Diabetes (GDM)
GDM risk assessment: should be ascertained at the first prenatal visit
Low Risk: Blood glucose testing not routinely required if all the following are present:
Member of an ethnic group with a low prevalence of GDM
No known diabetes in first-degree relatives
Age < 25 years
Weight normal before pregnancy
Weight normal at birth
No history of abnormal glucose metabolism
No history of poor obstetrical outcome
Average Risk: Perform blood glucose testing at 24 to 28 weeks using either:
Two-step procedure: 50-g oral glucose challenge test (GCT), followed by a diagnostic
100-g OGTT for those meeting the threshold value in the GCT
One-step procedure: diagnostic 100-g OGTT performed on all subjects
High Risk: Perform blood glucose testing as soon as feasible, using the procedures
described above, if one or more of these are present:
Severe obesity
Strong family history of type 2 diabetes
Previous history of GDM, impaired glucose metabolism, or glucosuria
If GDM is not diagnosed, blood glucose testing should be repeated at 24 to
28 weeks’ gestation or at any time symptoms or signs suggest hyperglycemia

OGTT = oral glucose tolerance test.

Modified from Metzger, 2007.
 1138 Medical and Surgical Complications

TABLE 57-13. Fifth International Workshop Conference on Gestational Diabetes:

Diagnostic Criteria of Gestational Diabetes by Oral Glucose
Tolerance Testing
SECTION 12

Oral Glucose Loada

Time 100-g Glucoseb 75-g Glucoseb
95 mg/dL 5.3 mmol/L 95 mg/dL 5.3 mmol/L
1-hr 180 mg/dL 10.0 mmol/L 180 mg/dL 10.0 mmol/L
2-hr 155 mg/dL 8.6 mmol/L 155 mg/dL 8.6 mmol/L
3-hr 140 mg/dL 7.8 mmol/L — —
a
The test should be performed in the morning after an overnight fast of at least 8 hr
but not more than 14 hr and after at least 3 days of unrestricted diet (≥ 150 g/d)
and physical activity. The subject should remain seated and should not smoke during
the test.
b
Two or more of the venous plasma glucose concentrations listed must be met or
exceeded for a positive diagnosis.
Data from Metzger, 2007.

Justification for screening and treatment of women with tional diabetes. The World Health Organization (1998) and
gestational diabetes was strengthened by the study by Crowther now the American Diabetes Association (2013) recommend
and coworkers (2005). They assigned 1000 women with gesta- the 75-g 2-hour oral glucose tolerance test. In the United
tional diabetes between 24 and 34 weeks’ gestation to receive States, however, the 100-g, 3-hour OGTT test performed after
dietary advice with blood glucose monitoring plus insulin ther- an overnight fast is recommended by the American College of
apy—the intervention group—or to undergo routine prenatal Obstetricians and Gynecologists (2013). Criteria for interpreta-
care. Women were diagnosed as having gestational diabetes if tion of the 100-g diagnostic glucose tolerance test are shown in
their blood glucose was < 100 mg/dL after an overnight fast Table 57-13. Also shown are the criteria for the 75-g test most
and was between 140 and 198 mg/dL 2 hours after ingesting a often used outside the United States.
75-g glucose solution. Women in the intervention group had a
significantly reduced risk of a composite adverse outcome that The Hyperglycemia and Adverse Pregnancy
included perinatal death, shoulder dystocia, fetal bone frac- Outcome (HAPO) Study
ture, and fetal nerve palsy. Macrosomia defined by birthweight This was a 7-year international epidemiological study of 23,325
≥ 4000 g complicated 10 percent of deliveries in the interven- pregnant women at 15 centers in nine countries (HAPO Study
tion group compared with 21 percent in the routine prenatal Cooperative Research Group, 2008). The investigation ana-
care group. Cesarean delivery rates were almost identical in the lyzed the association of various levels of glucose intolerance
two study groups. during the third trimester with adverse infant outcomes in
Slightly different results were reported by the Maternal- women with gestational diabetes. Between 24 and 32 weeks’
Fetal Medicine Units Network randomized trial of 958 women gestation, the general population of pregnant women under-
(Landon, 2009). Dietary counseling plus glucose monitoring went 75-g oral glucose tolerance testing after overnight fast-
was compared with standard obstetrical care in women with ing. Blood glucose levels were measured fasting and then 1 and
mild gestational diabetes to reduce perinatal morbidity rates. 2 hours after glucose ingestion. Caregivers were blinded to
Mild gestational diabetes was identified in women with fast- results except for women whose glucose levels exceeded values
ing glucose levels < 95 mg/dL. They reported no differences in that required treatment and removal from the study. Glucose
rates of composite morbidity that included stillbirth; neonatal values at each of these three time posts were stratified into
hypoglycemia, hyperinsulinemia, and hyperbilirubinemia; and seven categories (Fig. 57-8). Values were then correlated with
birth trauma. Importantly, secondary analyses demonstrated a rates for birthweight > 90th percentile (LGA), primary cesar-
50-percent reduction in macrosomia, fewer cesarean deliveries, ean delivery, clinical neonatal hypoglycemia, and cord-serum
and a significant decrease in shoulder dystocia rates—1.5 versus C-peptide levels > 90th percentile. C-peptide is a measur-
4 percent—in treated versus control women. able by-product created during insulin production. Odds of
Based largely on these two studies, the U.S. Preventive each outcome were calculated using the lowest category—for
Services Task Force (2013) now recommends universal screen- example, fasting plasma glucose < 75 mg/dL—as the referent
ing in low-risk women after 24 weeks’ gestation. However, the group. Their findings in general supported the supposition that
Task Force concluded that evidence is insufficient to assess the increasing plasma glucose levels at each epoch were associated
balance of benefits versus harms of screening before 24 weeks. with increasing adverse outcomes.
From the foregoing, there obviously is not international agree- In an editorial accompanying publication of the HAPO
ment as to the optimal glucose tolerance test to identify gesta- trial, Ecker and Greene (2008) posed the question: “Given
 Diabetes Mellitus 1139

30 adopting this new approach based on

benefits inferred from trials in women
25 identified using a two-step approach
LGA Frequency (percent)

CHAPTER 57
described on page 1138 (Crowther,
2005; Landon, 2009).
20
National Institutes of Health
15 Consensus Development
Conference on Diagnosing
10 Gestational Diabetes Mellitus
Prompted by the IADPSG recommen-
5 dations (2010) and their adoption by
the ADA (2013), an NIH Consensus
Development Conference (2013) was
Glucose levels convened. This conference included
Fasting ≤ 75 75–79 80–84 85–89 90–94 95–99 ≥ 100 input from a multidisciplinary planning
1 hour ≤ 105 106–132 133–155 156–171 172–193 174–211 ≥ 212
committee, a systematic evidence review
by the Agency for Healthcare Research
2 hour ≤ 90 91–108 109–125 126–139 140–157 158–177 ≥ 178
and Quality (AHRQ) Evidence-Based
FIGURE 57-8 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The Practice Center, expert testimony,
frequency of newborn birthweight ≥ 90th percentile for gestational age plotted against and a nonbiased panel to produce the
glucose levels (mg/dL) fasting and at 1- and 2-hr intervals following a 75-g oral glucose overall report. The panel concluded
load. LGA = large for gestational age. (Adapted from The HAPO Study Cooperative
Research Group, 2008.)
that there were potential benefits to
worldwide standardization. However,
it found insufficient evidence to adopt
the results of the HAPO study, should we lower our threshold a one-step diagnostic process such as the one proposed by the
for the diagnosis and treatment of gestational diabetes?” It was IADPSG. Moreover, as mentioned previously, after consider-
adjudged that it will be difficult to show that treating lesser ation of these findings, the American College of Obstetricians
degrees of carbohydrate intolerance—as suggested in the HAPO and Gynecologists (2013) continues to recommend a two-
study—would provide any meaningful improvements in clini- step screening and diagnostic approach to gestational diabetes
cal outcomes. Thus Ecker and Greene (2008) concluded, and diagnosis. It noted no significant improvements in maternal
we agree, that changes in criteria are not justified until clinical or perinatal outcomes that would offset the tripling of gesta-
trials prove benefits. Most recently, this position was endorsed tional diabetes incidence that would derive from the one-step
by the 2013 NIH Consensus Development Conference. approach. We applaud this decision.

International Association of Diabetes and

Pregnancy Study Group ■ Maternal and Fetal Effects
The IADPSG sponsored a workshop conference on the diag- Adverse consequences of gestational diabetes differ from
nosis and classification of gestational diabetes in 2008. After those of pregestational diabetes. Unlike in women with overt
reviewing the results of the HAPO study, a panel was appointed diabetes, rates of fetal anomalies do not appear to be sub-
to develop recommendations for the diagnosis and classifica- stantially increased (Sheffield, 2002). In a study of more than
tion of hyperglycemia during pregnancy. This panel allowed 1 million women from the Swedish Medical Birth Registry,
for the diagnosis of overt diabetes during pregnancy as shown major malformation rates were marginally increased—2.3
in Table 57-4. It also recommended a single-step approach to versus 1.8 percent (Fadl, 2010). The stillbirth rate was
the diagnosis of gestational diabetes using the 75-g, 2-hour not increased in this study or in an analysis of 130 peri-
OGTT. Thresholds for fasting, 1-, and 2-hour values based natal deaths in the HAPO study (2008). In contrast, and
on mean glucose concentrations from the entire HAPO study not unexpectedly, women with elevatedd fasting glucose lev-
cohort were considered. These thresholds were derived using an els have increased rates of unexplained stillbirths similar to
arbitrary 1.75 odds ratio of outcomes such as LGA birthweight women with overt diabetes. The ADA (2003) concluded that
and cord serum C-peptide levels > 90th percentile. Only one of fasting hyperglycemia > 105 mg/dL may be associated with
these thresholds would need to be met or exceeded to make the an increased risk of fetal death during the final 4 to 8 weeks.
diagnosis of gestational diabetes (see Table 57-11). This increasing risk with progressive maternal hyperglycemia
It is estimated that implementation of these recommendations prompted the IADPSG (2010) to emphasize the importance
would increase the prevalence of gestational diabetes in the United of identifying women with evidence of preexisting diabetes
States to 17.8 percent! Said another way, the number of women early in pregnancy (see Table 57-4). Similar to women with
with mild gestational diabetes would increase almost threefold overt diabetes, adverse maternal effects associated with gesta-
with no evidence of treatment benefit (Cundy, 2012). Despite tional diabetes include an increased frequency of hyperten-
these significant drawbacks, the ADA (2013) recommended sion and cesarean delivery.
 1140 Medical and Surgical Complications

Fetal Macrosomia cord-blood insulin levels are related to maternal glucose con-
The primary effect attributed to gestational diabetes is excessive trol (Leipold, 2004).
fetal size or macrosomia that is variably defined and discussed Maternal Obesity
SECTION 12

further in Chapter 44 (p. 884). Maternal hyperglycemia prompts

fetal hyperinsulinemia, particularly during the second half of In women with gestational diabetes, maternal BMI is an inde-
pregnancy. This in turn stimulates excessive somatic growth. The pendent and more substantial risk factor for fetal macrosomia
perinatal goal is to avoid difficult delivery from macrosomia and than is glucose intolerance (Ehrenberg, 2004; Mission, 2013).
concomitant birth trauma associated with shoulder dystocia. In Stuebe and colleagues (2012) completed a secondary analysis
a retrospective analysis of more than 80,000 vaginal deliveries of women with either untreated mild gestational diabetes or
in Chinese women, Cheng and associates (2013) calculated a normal glucose tolerance testing results. They found that higher
76-fold increased risk for shoulder dystocia in newborns weigh- BMI levels were associated with increasing birthweight, regard-
ing ≥ 4200 g compared with the risk in those weighing < 3500 less of glucose levels. Also, maternal obesity is an important
g. Importantly, however, the odds ratio for shoulder dystocia confounding factor in the diagnosis of gestational diabetes. In
in women with diabetes was less than 2. Although gestational their metaanalysis, Torloni and coworkers (2009) estimated that
diabetes is certainly a risk factor, it accounts for only a small the gestational diabetes prevalence increases by approximately
number of pregnancies complicated by shoulder dystocia. 1 percent for every 1 kg/m2 increase in BMI. Weight distri-
The excessive shoulder and trunk fat that commonly char- bution also seems to play a role because the risk of gestational
acterizes the macrosomic infant of a diabetic mother theoreti- diabetes is increased with truncal obesity. Suresh and colleagues
cally predisposes such infants to shoulder dystocia or cesarean (2012) verified that increased maternal abdominal subcutane-
delivery (Durnwald, 2004; McFarland, 2000). Landon and col- ous fat thickness as measured by sonography at 18 to 22 weeks’
leagues (2011) identified shoulder dystocia in approximately gestation correlated with BMI and was a better predictor of ges-
4 percent of women with mild gestational diabetes compared tational diabetes. Martin and associates (2009) reported similar
with < 1 percent of women with a 50-g glucose screen result findings for sonographically measured maternal visceral adipose
< 120 mg/dL. In a prospective study of fetal adipose measure- depth. Importantly, excessive gestational weight gain is com-
ments, however, Buhling and coworkers (2012) demonstrated monly identified in women with gestational diabetes and also
no differences between measurements in 630 offspring of confers an additive risk for fetal macrosomia (Egan, 2014).
women with gestational diabetes and 142 without diabetes. The
authors attributed this negative finding to successful treatment ■ Management
of gestational diabetes.
Women with gestational diabetes can be divided into two
There is extensive evidence that insulin-like growth factors
functional classes using fasting glucose levels. Pharmacological
also play a role fetal-growth regulation (Chap. 44, p. 872).
methods are usually recommended if diet modification
These proinsulin-like polypeptides are produced by virtually
does not consistently maintain the fasting plasma glucose
all fetal organs and are potent stimulators of cell differentiation
levels < 95 mg/dL or the 2-hour postprandial plasma glu-
and division. Luo and coworkers (2012) reported that insulin-
cose < 120 mg/dL (American College of Obstetricians and
like growth factor-I strongly correlated with birthweight. The
Gynecologists, 2013). Whether pharmacological treatment
HAPO study investigators also reported dramatic increases of
should be used in women with lesser degrees of fasting hyper-
cord-serum C-peptide levels with increasing maternal glucose
glycemia—105 mg/dL or less before dietary intervention—is
levels following a 75-g OGTT. C-peptide levels > 90th per-
unclear. There have been no controlled trials to identify ideal
centile were found in almost a third of newborns in the high-
glucose targets for fetal risk prevention. On the other hand,
est glucose categories. Other factors implicated in macrosomia
the HAPO study (2008) did demonstrate increased fetal
include epidermal growth factor, fibroblast growth factor,
risk at glucose levels below the threshold used for diagnosis
platelet-derived growth factor, leptin, and adiponectin (Grissa,
of diabetes. The Fifth International Workshop Conference
2011; Loukovaara, 2004; Mazaki-Tovi, 2005).
recommended that fasting capillary glucose levels be kept
≤ 95 mg/dL (Metzger, 2007).
Neonatal Hypoglycemia In a systematic review, Hartling and colleagues (2013) con-
Neonatal hyperinsulinemia may provoke hypoglycemia cluded that treating gestational diabetes resulted in a significantly
within minutes of birth. The incidence varies depending on lower incidence of preeclampsia, shoulder dystocia, and macro-
the threshold definition. Cornblath and associates (2000) somia. For example, the calculated risk ratio for delivering an
established a threshold of 35 mg/dL in term newborns. An infant > 4000 g after treatment was 0.50. These investigators cau-
NIH workshop conference on neonatal hypoglycemia sup- tion that the attributed risk for these outcomes is low, especially
ported use of such operational thresholds but cautioned that when glucose values are only moderately elevated. Importantly,
these are not strictly evidence-based (Hay, 2009). Newborns they were unable to demonstrate an effect on neonatal hypogly-
described by the HAPO study (2008) had an incidence of cemia or future metabolic outcomes in the offspring.
clinical neonatal hypoglycemia that increased with increasing
maternal OGTT values defined in Figure 57-8. The frequency Diabetic Diet
varied from 1 to 2 percent, but it was as high as 4.6 percent As discussed previously, reports by Crowther (2005) and
in women with fasting glucose levels ≥ 100 mg/dL. Likewise, Landon (2009) and their colleagues describe the benefits
 Diabetes Mellitus 1141

of dietary counseling and monitoring in women with gesta- Postprandial surveillance for gestational diabetes has been
tional diabetes. The ADA recommends individualized nutri- shown to be superior to preprandial surveillance. DeVeciana
tional counseling based on height and weight (Bantle, 2008). and coworkers (1995) studied 66 pregnant women with ges-

CHAPTER 57
Nutritional instructions generally include a carbohydrate- tational diabetes in whom insulin was initiated for fasting
controlled diet sufficient to maintain normoglycemia and avoid hyperglycemia. The women were randomly assigned to glucose
ketosis. On average, this includes a daily caloric intake of 30 to surveillance using either preprandial or 1-hour postprandial
35 kcal/kg. Moreno-Castilla and associates (2013) randomly capillary blood-glucose concentrations. Postprandial surveil-
assigned 152 women with gestational diabetes to either a 40- or lance was shown to be superior in that blood-glucose con-
a 55-percent daily carbohydrate diet and found no difference in trol was significantly improved and was associated with fewer
insulin levels and pregnancy outcomes. The American College cases of neonatal hypoglycemia—3 versus 21 percent; less
of Obstetricians and Gynecologists (2013) suggests that carbo- macrosomia—12 versus 42 percent; and fewer cesarean deliv-
hydrate intake be limited to 40 percent of total calories. The eries for dystocia—24 versus 39 percent. At Parkland Hospital,
remaining calories are apportioned to give 20 percent as protein we were unable to demonstrate similar findings when we
and 40 percent as fat. reviewed the impact of changing to postprandial monitoring in
Although the most appropriate diet for women with gesta- women with diet-treated gestational diabetes. We did, however,
tional diabetes has not been established, the ADA (2003) has demonstrate a significant reduction in maternal weight gain
suggested that obese women with a BMI > 30 kg/m2 may ben- per week—0.63 lb/week to 0.45 lb/week—in women managed
efit from a 30-percent caloric restriction, which approximates with a postprandial monitoring schema. The American College
25 kcal/kg/d. This should be monitored with weekly assessment of Obstetricians and Gynecologists (2013) recommends four-
for ketonuria, which has been linked with impaired psycho- times daily glucose monitoring performed fasting and either 1
motor development in offspring (Rizzo, 1995; Scholte, 2012). or 2 hours after each meal.
That said, Most and Langer (2012) found that insulin was nec-
essary to reduce excess birthweight in offspring of obese women Insulin Treatment
with gestational diabetes. Historically, insulin has been considered standard therapy
in women with gestational diabetes when target glucose lev-
Exercise els cannot be consistently achieved through nutrition and
The American College of Obstetricians and Gynecologists exercise. It does not cross the placenta, and tight glycemic
(2009) reviewed three randomized trials of exercise in women control can typically be achieved. In a report prepared for
with gestational diabetes (Avery, 1997; Bung, 1993; Jovanovic- the AHRQ, Nicholson and associates (2009) were unable to
Peterson, 1989). The results suggest that exercise improved car- determine a threshold above which insulin should be initi-
diorespiratory fitness without improving pregnancy outcome. ated. Pharmacological therapy—in this case insulin—is typi-
Importantly, these trials were small and had limited power cally added if fasting levels persistently exceed 95 mg/dL in
to show improvement in outcomes. Dempsey and coworkers women with gestational diabetes. The American College of
(2004) found that physical activity during pregnancy reduced Obstetricians and Gynecologists (2013) also recommends that
the risk of gestational diabetes. Brankston and associates (2004) insulin be considered in women with 1-hour postprandial lev-
reported that resistance exercise diminished the need for insu- els that persistently exceed 140 mg/dL or those with 2-hour
lin therapy in overweight women with gestational diabetes. levels above 120 mg/dL. Importantly, all of these thresholds
Conversely, Stafne and colleagues (2012), in a randomized are extrapolated from recommendations for managing women
controlled trial in 855 women, observed that a 1-week exercise with overt diabetes.
program during the second half of pregnancy did not prevent If insulin is initiated, the starting dose is typically 0.7–
gestational diabetes or improve insulin resistance. Importantly, 1.0 units/kg/day given in divided doses (American College of
the average BMI at enrollment was 24.8 ± 3.2. The American Obstetricians and Gynecologists, 2013). A combination of
College of Obstetricians and Gynecologists (2013) recom- intermediate-acting and short-acting insulin may be used, and
mends a moderate exercise program as part of the treatment dose adjustments are based on glucose levels at particular times
plan for women with gestational diabetes. of the day. At Parkland Hospital, insulin instruction for these
women is accomplished either in a specialized outpatient clinic
Glucose Monitoring or during a short hospital stay. As shown in Table 57-8, insu-
Hawkins and colleagues (2008) compared outcomes in 315 lin analogues such as insulin aspart and insulin lispro have a
women with diet-treated gestational diabetes who used per- more rapid onset of action than regular insulin and theoreti-
sonal glucose monitors with those of 615 gestational diabetics cally could be helpful in postprandial glucose management.
who were also diet-treated but who underwent intermittent Experience with these analogues with gestational diabetes is
fasting glucose evaluation during semi-weekly obstetrical limited, and Singh and coworkers (2008) were unable to dem-
visits. Women using daily blood-glucose self-monitoring onstrate a benefit compared with conventional insulins.
had significantly fewer macrosomic infants and gained less
weight after diagnosis than women evaluated during clinic Oral Hypoglycemic Agents
visits only. These findings support the common practice of Several studies have attested to the safety and efficacy of ges-
blood-glucose self-monitors for women with diet-treated ges- tational diabetes treatment with either glyburide (Micronase)
tational diabetes. or metformin (Glucophage) (Langer, 2000; Nicholson, 2009;
 1142 Medical and Surgical Complications

Rowan, 2008). In one study, Langer and colleagues (2000, of antepartum fetal testing. It is typically reserved for women
2005) randomly assigned 404 women to insulin or glyburide with pregestational diabetes because of the increased stillbirth
therapy. Near normoglycemic levels were achieved with either risk. The American College of Obstetricians and Gynecologists
regimen, and there were no apparent neonatal complications (2013) endorses fetal surveillance in women with gestational
SECTION 12

attributable to glyburide. In a follow-up study, Conway and diabetes and poor glycemic control. At Parkland Hospital,
coworkers (2004) reported that women with fasting glucose women with gestational diabetes are routinely instructed to
levels > 110 mg/dL did not adequately respond to glyburide perform daily fetal kick counts in the third trimester (Chap.
therapy. Similar results were reported by Chmait (2004) and 17, p. 335). Insulin-treated women are offered inpatient admis-
Kahn (2006) and their associates. At one time, glyburide was sion after 34 weeks’ gestation, and fetal heart rate monitoring is
thought not to cross the placenta. However, Hebert and col- performed three times each week.
leagues (2008, 2009) sampled 20 paired maternal-cord speci- Women with gestational diabetes and adequate glycemic
mens and found the latter to have glyburide concentrations control are managed expectantly. Elective labor induction to
approximately half that of maternal levels. prevent shoulder dystocia compared with spontaneous labor
Metformin treatment for polycystic ovarian disease through- remains controversial. One randomized trial evaluated induc-
out pregnancy reduced the incidence of gestational diabetes tion at 38 weeks in 200 women with insulin-treated diabetes—
(Glueck, 2004). Because metformin crosses to the fetus, there 187 of whom had gestational diabetes. Investigators reported a
was reticence to use it in pregnant women (Harborne, 2003). significantly lower proportion of newborns with a birthweight
Subsequent studies have helped allay these concerns. Rowan > 90th percentile in the active induction group—10 versus
and associates (2008) randomly assigned 751 women with 23 percent (Kjos, 1993). However, there were no differences
gestational diabetes to metformin or insulin treatment. The in rates of cesarean delivery or shoulder dystocia or in neonatal
primary outcome was a composite of neonatal hypoglycemia, outcomes. Witkop and colleagues (2009) performed a system-
respiratory distress syndrome, phototherapy, birth trauma, atic review and concluded that, in the aggregate, a reduction
5-minute Apgar score ≤ 7, and preterm birth. Similarities in the in fetal macrosomia is likely in women with gestational dia-
composite outcome between metformin and insulin led inves- betes who undergo an elective labor induction at term. They
tigators to conclude that metformin was not associated with also found a limited ability to draw definite conclusions based
adverse perinatal outcomes. It is noteworthy that 46 percent of on available evidence. The American College of Obstetricians
women in the metformin trial required supplemental insulin and Gynecologists (2013) also has concluded that no evidence-
compared with only 4 percent of women treated with glyburide based recommendation can be made regarding delivery timing
(Langer, 2000). in women with gestational diabetes. To study this, a large mul-
In their systematic review and metaanalysis of oral hypogly- ticenter trial (NCT01058772) expected to enroll 1760 women
cemic agents for gestational diabetes, Nicholson and coworkers with gestational diabetes is currently recruiting participants
(2009) found no evidence of increased adverse maternal or neo- (Maso, 2011).
natal outcomes with glyburide or metformin compared with Elective cesarean delivery to avoid brachial plexus injuries
insulin. Moore and associates (2010) randomly assigned 149 in overgrown fetuses is also an important issue. The American
women with gestational diabetes who did not achieve glycemic College of Obstetricians and Gynecologists (2013) has sug-
control on diet therapy to either glyburide or metformin treat- gested that cesarean delivery should be considered in women
ment. More than a third of women in the metformin group with gestational diabetes whose fetuses have a sonographically
required supplemental insulin compared with 16 percent of estimated weight ≥ 4500 g. From their systematic review,
those treated with glyburide. Garabedian and coworkers (2010) estimated that as many as
Oral hypoglycemic agents are being increasingly used for 588 cesarean deliveries in women with gestational diabetes and
gestational diabetes, although they have not been approved by an estimated fetal weight of ≥ 4500 g would be necessary to
the Food and Drug Administration for this indication. A survey avoid one case of permanent brachial plexus palsy. Effects of
of almost 1400 fellows of the American College of Obstetricians such a policy were retrospectively analyzed by Gonen and asso-
and Gynecologists found that 13 percent of respondents were ciates (2000) in a general obstetrical population of more than
using glyburide as first-line therapy for diet failure in women 16,000 women. Elective cesarean delivery had no significant
with gestational diabetes (Gabbe, 2004). The American College effect on the incidence of brachial plexus injury.
of Obstetricians and Gynecologists (2013) acknowledges that
both glyburide and metformin are appropriate, as is insulin, for
first-line glycemic control in women with gestational diabetes. ■ Postpartum Evaluation
Because long-term outcomes have not been studied, the com- Recommendations for postpartum evaluation are based on
mittee recommends appropriate counseling when hypoglyce- the 50-percent likelihood of women with gestational diabetes
mic agents are used. developing overt diabetes within 20 years (O’Sullivan, 1982).
The Fifth International Workshop Conference on Gestational
Diabetes recommended that women diagnosed with gestational
■ Obstetrical Management diabetes undergo evaluation with a 75-g oral glucose tolerance
In general, for women with gestational diabetes who do not test at 6 to 12 weeks postpartum and other intervals thereaf-
f
require insulin, early delivery or other interventions are seldom ter (Metzger, 2007). These recommendations are shown in
required. There is no consensus regarding the value or timing Table 57-14 along with the classification scheme of the ADA
 Diabetes Mellitus 1143

TABLE 57-14. Fifth International Workshop-Conference: Metabolic Assessments Recommended after Pregnancy with
Gestational Diabetes
Time Test Purpose

CHAPTER 57
Postdelivery (1–3 d) Fasting or random plasma glucose Detect persistent, overt diabetes
Early postpartum (6–12 wk) 75-g, 2-hr OGTT Postpartum classification of glucose metabolism
1-yr postpartum 75-g, 2-hr OGTT Assess glucose metabolism
Annually Fasting plasma glucose Assess glucose metabolism
Triannually 75-g, 2-hr OGTT Assess glucose metabolism
Prepregnancy 75-g, 2-hr OGTT Classify glucose metabolism
Classification of the American Diabetes Association (2013)
Impaired Fasting Glucose or
Normal Values Impaired Glucose Tolerance Diabetes Mellitus
Fasting < 100 mg/dL 100–125 mg/dL ≥ 126 mg/dL
2 hr < 140 mg/dL 2 hr ≥ 140–199 mg/dL 2 hr ≥ 200 mg/dL
Hemoglobin A1c < 5.7% 5.7–6.4% ≥ 6.5%

OGTT = oral glucose tolerance test.

From American Diabetes Association, 2013; Metzger, 2007.

(2013). Hunt and colleagues (2010) reviewed performance out gestational diabetes in their first pregnancy were diagnosed
rates of postpartum glucose screening and found that anywhere with gestational diabetes when screened in a second pregnancy.
between 23 and 58 percent of women actually undergo 75-g This compared with 41.3 percent in women with a history of
glucose testing. The American College of Obstetricians and gestational diabetes.
Gynecologists (2013) recommends either a fasting glucose or
the 75-g, 2-hour OGTT for the diagnosis of overt diabetes.
The ADA (2011) recommends testing at least every 3 years in ■ Contraception
women with a history of gestational diabetes but normal post- Low-dose hormonal contraceptives may be used safely by
partum glucose screening. women with recent gestational diabetes (Chap. 38, p. 709).
Women with a history of gestational diabetes are also at The rate of subsequent diabetes in oral contraceptive users is
risk for cardiovascular complications associated with dyslip- not significantly different from that in those who did not use
idemia, hypertension, and abdominal obesity—the metabolic hormonal contraception (Kerlan, 2010). Importantly, comor-
syndromee (Chap. 48, p. 962). In a study of 47,909 parous bid obesity, hypertension, or dyslipidemia should direct the
women, Kessous and coworkers (2013) evaluated subsequent choice for contraception toward a method without potential
hospitalizations due to cardiovascular morbidity. They found cardiovascular consequences. In these instances, the intrauter-
that almost 5000 women with gestational diabetes were 2.6 ine device is a good alternative.
times more likely to be hospitalized for cardiovascular mor-
bidity. Shah and coworkers (2008) also documented excessive REFERENCES
cardiovascular disease by 10 years in women with gestational
diabetes. Akinci and associates (2009) reported that a fasting Akinci B, Celtik A, Yener S, et al: Prediction of developing metabolic syndrome
glucose level ≥ 100 mg/dL in the index OGTT was an inde- after gestational diabetes mellitus. Fertil Steril 93(4):1248, 2010
Alvarez JR, Fechner AJ, Williams SF, et al: Asymptomatic bacteriuria in pre-
pendent predictor of the metabolic syndrome. gestational diabetic pregnancies and the role of group B streptococcus. Am
J Perinat 27(3):231, 2010
American College of Obstetricians and Gynecologists: Management of diabetes
■ Recurrent Gestational Diabetes mellitus in pregnancy. Technical Bulletin No. 92, May 1986
American College of Obstetricians and Gynecologists: Exercise during preg-
In subsequent pregnancies, recurrence was documented in 40 nancy and the postpartum period. Committee Opinion No. 267, January
percent of 344 primiparous women with gestational diabe- 2009
tes (Holmes, 2010). Obese women were more likely to have American College of Obstetricians and Gynecologists: Pregestational diabetes
mellitus. Practice Bulletin No. 60, 2005, Reaffirmed 2012
impaired glucose tolerance in subsequent pregnancies. Thus, American College of Obstetricians and Gynecologists: Gestational diabetes
lifestyle behavioral changes, including weight control and exer- mellitus. Practice Bulletin No. 137, August 2013
cise between pregnancies, likely would prevent gestational dia- American Diabetes Association: Gestational diabetes mellitus. Diabetes Care
26:S103, 2003
betes recurrence (Kim, 2008). Ehrlich and colleagues (2011) American Diabetes Association: Standards of medical care in diabetes—2011.
found that the loss of at least two BMI units was associated Diabetes Care 34(1 Suppl):S11, 2011
with a lower risk of gestational diabetes in women who were American Diabetes Association: Standards of medical care in diabetes—2012.
Diabetes Care 35(1 Suppl):S11, 2012
overweight or obese in the first pregnancy. Getahun and American Diabetes Association: Standards of medical care in diabetes—2013.
coworkers (2010) found that only 4.2 percent of women with- Diabetes Care 36(suppl 1):S11, 2013
 1147

CHAPTER 58

Endocrine Disorders

THYROID PHYSIOLOGY AND PREGNANCY . . . . . . . . . . 1147 THYROID DISORDERS

HYPERTHYROIDISM. . . . . . . . . . . . . . . . . . . . . . . . . . . 1148 Taken in aggregate, these are common in young women and
HYPOTHYROIDISM . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152 thus frequently managed in pregnancy. There is an intimate
relationship between maternal and fetal thyroid function,
SUBCLINICAL HYPOTHYROIDISM . . . . . . . . . . . . . . . . . 1154 and drugs that affect the maternal thyroid also affect the fetal
gland. Moreover, thyroid autoantibodies have been associated
IODINE DEFICIENCY . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155 with increased early pregnancy wastage, and uncontrolled thy-
CONGENITAL HYPOTHYROIDISM . . . . . . . . . . . . . . . . . 1156 rotoxicosis and untreated hypothyroidism are both associated
with adverse pregnancy outcomes. Finally, there is evidence
POSTPARTUM THYROIDITIS. . . . . . . . . . . . . . . . . . . . . 1156 that autoimmune thyroid disorder severity may be ameliorated
during pregnancy, only to be exacerbated postpartum.
NODULAR THYROID DISEASE . . . . . . . . . . . . . . . . . . . 1157

PARATHYROID DISEASES . . . . . . . . . . . . . . . . . . . . . . 1157

■ Thyroid Physiology and Pregnancy
ADRENAL GLAND DISORDERS . . . . . . . . . . . . . . . . . . . 1159 Maternal thyroid changes are substantial, and normally
PITUITARY DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . 1162 altered gland structure and function are sometimes confused
with thyroid abnormalities. These alterations are discussed
in detail in Chapter 4 (p. 68), and normal hormone level
values are found in the Appendix (p. 1290). First, mater-
There are no endocrine disorders that are unique to pregnancy. nal serum concentrations of thyroid-binding globulin are
However, endocrinopathies seem particularly closely related increased concomitantly with total or bound thyroid hor-
to pregnancy due to their proclivity for hormone secretion. mone levels (Fig. 4-17, p. 69). Second, thyrotropin, also
Indeed, some hormones are secreted in prodigious quantities. called thyroid-stimulating hormone (TSH), currently plays a
This is probably best illustrated by placental lactogen in diabe- central role in screening and diagnosis of many thyroid dis-
tes, the most common endocrinopathy encountered in preg- orders. Serum TSH levels in early pregnancy decline because
nancy (Chap. 57, p. 1125). Pregnancy is also interrelated with of weak TSH-receptor stimulation from massive quantities of
some endocrinopathies that are at least partially due to autoim- human chorionic gonadotropin (hCG) secreted by placental
mune dysregulation. Clinical manifestations of this result from trophoblast. Because TSH does not cross the placenta, it has
complex interplay among genetic, environmental, and endog- no direct fetal effects. During the first 12 weeks of gesta-
enous factors that activate the immune system against targeted tion, when hCG serum levels are maximal, thyroid hormone
cells within endocrine organs. An extraordinary example of secretion is stimulated. The resulting increased serum free
these interactions comes from studies that implicate maternal thyroxine levels act to suppress hypothalamic thyrotropin-
organ engraftment by fetal cells that were transferred during releasing hormone (TRH) and in turn limit pituitary TSH
pregnancy. These cells later provoke antibody production, tis- secretion (Fig. 58-1). Accordingly, TRH is undetectable in
sue destruction, and autoimmune endocrinopathies. maternal serum. Conversely, beginning at midpregnancy,
 1148 Medical and Surgical Complications

6 2.0 70

5 61%
60

Antithyroid peroxidase antibodies

1.5

Free T 4 (ng/dL)
SECTION 12

4
TSH (mU/L)

(percent > 50 kIU/mL)

50
3 1.0
40
2
0.5 31%
1 30

0 0.0 20
0 10 20 30 40
Gestational age (weeks)
10
FIGURE 58-1 Gestational age-specific values for serum thyroid- 4% 5%
stimulating hormone (TSH) levels (black lines) and free thyroxine
(T4) levels (blue lines). Data were derived from 17,298 women Normal IMH SCH Overt
tested during pregnancy. For each color, the dark solid lines rep-
resent the 50th percentile, whereas the upper and lower light FIGURE 58-2 Incidence in percent of antithyroid peroxidase
lines represent the 2.5th and 97.5th percentiles, respectively. antibodies in 16,407 women who are normal or euthyroid, in
(Data from Casey, 2005; Dashe, 2005.) 233 with isolated maternal hypothyroxinemia (IMH), in 598
with subclinical hypothyroidism (SCH), and in 134 with overt
hypothyroidism. (Data from Casey, 2007).

TRH becomes detectable in fetal serum, but levels are static 2011). Conversely, in a study with more than 1000 TPO
and do not increase with advancing gestation. antibody-positive pregnant women, there was no increased
Throughout pregnancy, maternal thyroxine is transferred risk for preterm birth, however, there was an increased risk for
to the fetus (Calvo, 2002). Maternal thyroxine is impor- placental abruption (Abbassi-Ghanavati, 2010). These women
tant for normal fetal brain development, especially before are also at high risk for postpartum thyroid dysfunction and
development of fetal thyroid gland function (Bernal, 2007). at lifelong risk for permanent thyroid failure (Premawardhana,
And even though the fetal gland begins concentrating iodine 2000; Stagnaro-Green, 2011b).
and synthesizing thyroid hormone after 12 weeks’ gesta-
tion, maternal thyroxine contribution remains important. In Fetal Microchimerism
fact, maternal sources account for 30 percent of thyroxine in Autoimmune thyroid disease is much more common in women
fetal serum at term (Thorpe-Beeston, 1991; Vulsma, 1989). than in men. One intriguing explanation for this disparity is
Developmental risks associated with maternal hypothyroid- fetal-to-maternal cell trafficking (Greer, 2011). When fetal
ism after midpregnancy, however, remain poorly understood lymphocytes enter the maternal circulation, they can live for
(Morreale de Escobar, 2004). more than 20 years. Stem cell interchange also occurs with
engraftment in several maternal tissues including the thyroid
(Bianchi, 2003; Khosrotehrani, 2004). A high prevalence of
■ Autoimmunity and Thyroid Disease Y-chromosome-positive cells has been identified using fluores-
Most thyroid disorders are inextricably linked to autoantibod- cence in situ hybridization (FISH) in thyroid glands of women
ies against various cell components. Several of these antibodies with Hashimoto thyroiditis—60 percent, or Graves disease—40
variably stimulate thyroid function, block function, or cause percent (Renné, 2004). In another study of women giving birth
thyroid inflammation that may lead to follicular cell destruc- to a male fetus, Lepez and colleagues (2011) identified signifi-
tion. Often, these effects overlap or even coexist. cantly more circulating male mononuclear cells in those with
Thyroid-stimulating autoantibodies, also called thyroid-stimu- Hashimoto thyroiditis.
lating immunoglobulins (TSIs), bind to the TSH receptor and
activate it, causing thyroid hyperfunction and growth. Although
these antibodies are identified in most patients with classic ■ Hyperthyroidism
Graves disease, simultaneous production of thyroid-stimulating The incidence of thyrotoxicosis or hyperthyroidism in preg-
blocking antibodiess may blunt this effect (Weetman, 2000). nancy is varied and complicates between 2 and 17 per 1000
Thyroid peroxidase (TPO) is a thyroid gland enzyme that nor- births when gestational-age appropriate TSH threshold values
mally functions in the production of thyroid hormones. Thyroid are used (Table 58-1). Because normal pregnancy simulates
peroxidase antibodies, previously called thyroid microsomal auto- some clinical findings similar to thyroxine (T4) excess, clinically
antibodies, are directed against TPO and have been identified mild thyrotoxicosis may be difficult to diagnose. Suggestive
in 5 to 15 percent of all pregnant women (Fig. 58-2) (Abbassi- findings include tachycardia that exceeds that usually seen with
Ghanavati, 2010; Kuijpens, 2001). These antibodies have been normal pregnancy, thyromegaly, exophthalmos, and failure to
associated in some studies with early pregnancy loss and pre- gain weight despite adequate food intake. Laboratory confirma-
term birth (Abramson, 2001; Negro, 2006; Thangaratinam, tion is by a markedly depressed TSH level along with an elevated
 Endocrine Disorders 1149

lead to poorly controlled thyroid function. Accordingly, at

TABLE 58-1. Incidence of Overt Hyperthyroidism in
Parkland Hospital we continue to prescribe PTU treatment
Pregnancy
throughout pregnancy.
Study Country Overt Hypothyroidism

CHAPTER 58
Transient leukopenia can be documented in up to 10 percent
a
Wang (2011) China 1% of women taking antithyroid drugs, but this does not require
Vaidya (2007)a United Kingdom 0.7% therapy cessation. In 0.3 to 0.4 percent, however, agranulocy-
Lazarus (2007)b United Kingdom 1.7% tosiss develops suddenly and mandates drug discontinuance. It
Casey (2006b)c United States 0.4% is not dose related, and because of its acute onset, serial leu-
kocyte counts during therapy are not helpful. Thus, if fever
a
Screened in the first trimester. or sore throat develops, women are instructed to discontinue
b
Screened at 9–15 weeks. medication immediately and report for a complete blood count
c
Screened at < 20 weeks. (Brent, 2008).
As mentioned above, hepatotoxicity is another potentially
serious side effect that develops in 0.1 to 0.2 percent. Serial
serum free T4 (fT4) level. Rarely, hyperthyroidism is caused measurement of hepatic enzymes has not been shown to prevent
by abnormally high serum triiodothyronine (T3) levels—so- fulminant PTU-related hepatotoxicity. Also, approximately 20
called T3-toxicosis. percent of patients treated with PTU develop antineutrophil
cytoplasmic antibodies (ANCA
( A). However, only a small percent-
Thyrotoxicosis and Pregnancy age of these subsequently develop serious vasculitis (Helfgott,
The overwhelming cause of thyrotoxicosis in pregnancy is 2002; Kimura, 2013). Finally, although thionamides have
Graves disease, an organ-specific autoimmune process associated the potential to cause fetal complications, these are uncom-
with thyroid-stimulating TSH-receptor antibodies as previ- mon. In some cases, thionamides may even be therapeutic,
ously discussed. Because these antibodies are specific to Graves because TSH-receptor antibodies cross the placenta and can
hyperthyroidism, such assays have been proposed for diagno- stimulate the fetal thyroid gland to cause thyrotoxicosis and
sis, management, and prognosis in pregnancies complicated goiter.
by hyperthyroidism (Barbesino, 2013). At Parkland Hospital, The initial thionamide dose is empirical. For nonpregnant
these receptor antibody assays are generally reserved for cases patients, the American Thyroid Association recommends that
in which fetal thyrotoxicosis is suspected. With Graves disease, methimazole be used at an initial higher daily dose of 10 to 20
during the course of pregnancy, hyperthyroid symptoms may mg orally followed by a lower maintenance dose of 5 to 10 mg.
initially worsen because of chorionic gonadotropin stimula- If PTU is selected, a dose of 50 to 150 mg orally three times
tion, but then subsequently diminish with decreases in recep- daily may be initiated depending on clinical severity (Bahn,
tor antibody titers in the second half of pregnancy (Mestman, 2011). At Parkland Hospital, we usually initially give 300
2012; Stagnaro-Green, 2011a). Amino and coworkers (2003) or 450 mg of PTU daily in three divided doses for pregnant
have found that levels of blocking antibodies are also decreased women. Occasionally, daily doses of 600 mg are necessary. As
during pregnancy. discussed, we generally do not transition women to methima-
zole during the second trimester. The goal is treatment with the
Treatment. Thyrotoxicosis during pregnancy can nearly lowest possible thionamide dose to maintain thyroid hormone
always be controlled by thionamide drugs. Propylthiouracil levels slightly above or in the high normal range while TSH
(PTU) has been historically preferred because it partially levels remains suppressed (Bahn, 2011). Serum free T4 concen-
inhibits the conversion of T4 to T3 and crosses the placenta trations are measured every 4 to 6 weeks (National Academy of
less readily than methimazole. The latter has also been associ- Clinical Biochemistry, 2002).
ated with a rare methimazole embryopathy characterized by Subtotal thyroidectomyy can be performed after thyrotoxicosis
esophageall or choanal atresiaa as well as aplasia cutis, a congeni- is medically controlled. This seldom is done during pregnancy
tal skin defect. Yoshihara and associates (2012) analyzed more but may be appropriate for the very few women who cannot
than 5000 Japanese women with first-trimester hyperthyroid- adhere to medical treatment or in whom drug therapy proves
ism and found a twofold increased risk of major fetal mal- toxic (Davison, 2001; Stagnaro-Green, 2012a). Surgery is best
formations in pregnancies exposed to methimazole compared accomplished in the second trimester. Potential drawbacks of
with the risk from PTU. Specifically, seven of nine cases with thyroidectomy during pregnancy include inadvertent resec-
aplasia cutis and the only case of esophageal atresia were in the tion of parathyroid glands and injury to the recurrent laryngeal
group of methimazole-exposed infants. nerve (Fitzpatrick, 2010).
Until recently, PTU has been the preferred thionamide Thyroid ablation with therapeutic radioactive iodine is contra-
in the United States (Brent, 2008). In 2009, however, the indicated during pregnancy. These doses may also cause fetal thy-
Food and Drug Administration issued a safety alert on PTU- roid gland destruction. Thus, when given unintentionally, many
associated hepatotoxicity. This warning prompted the American clinicians recommend abortion. Any exposed fetus must be
Thyroid Association and the American Association of Clinical carefully evaluated, and the incidence of fetal hypothyroidism
Endocrinologists (2011) to recommend PTU therapy during depends on gestational age and radioiodine dose (Berlin, 2001).
the first trimester followed by methimazole beginning in the Tran and colleagues (2010) describe a case in which a relatively
second trimester. The obvious disadvantage is that this might high dose (19.8 mCi) of radioiodine early in the first trimester
 1150 Medical and Surgical Complications

resulted in a normal euthyroid male infant assessed at 6 months.

The authors hypothesized that the exposure occurred well before
thyroid embryogenesis. There is no evidence that radioiodine
given before pregnancy causes fetal anomalies if enough time has
SECTION 12

passed to allow radiation effects to dissipate and if the woman

is euthyroid (Ayala, 1998). The International Commission on
Radiological Protection has recommended that women avoid
pregnancy for 6 months after radioablative therapy (Brent,
2008). Moreover, during lactation, the breast also concentrates a
substantial amount of iodide. This may pose neonatal risk due to
131
I-containing milk ingestion and maternal risk from significant
breast irradiation. To limit maternal exposure and her cancer
risks, a delay of 3 months between lactation and ablation will
more reliably ensure complete breast involution (Sisson, 2011).

Pregnancy Outcome. Women with thyrotoxicosis have

pregnancy outcomes that largely depend on whether met-
abolic control is achieved. For example, as discussed in
Chapter 18 (p. 353), excess thyroxine may cause miscar-
riage (Anselmo, 2004). In untreated women or in those who FIGURE 58-3 Term neonate delivered of a woman with a 3-year
history of thyrotoxicosis that recurred at 26 weeks’ gestation.
remain hyperthyroid despite therapy, there is a higher inci-
The mother was given methimazole 30 mg orally daily and was
dence of preeclampsia, heart failure, and adverse perinatal euthyroid at delivery. Laboratory studies showed that the infant
outcomes (Table 58-2). A prospective cohort study from was hypothyroid.
China reported that women with clinical hyperthyroidism
had a 12-fold increased risk of delivering an infant with hear-
ing loss (Su, 2011). Perinatal mortality rates varied from 6 to sonographically measured thyroid volume (Gietka-Czernel,
12 percent in several studies. 2012; Ranzini, 2001).
The fetus or neonate who was exposed to excessive maternal
Fetal and Neonatal Effects thyroxine may have any of several clinical presentations. First,
In most cases, the perinate is euthyroid. In some, however, goitrous thyrotoxicosiss is caused by placental transfer of thyroid-
hyper- or hypothyroidism can develop with or without a goi- stimulating immunoglobulins. Nonimmune hydropss and fetal
ter (Fig. 58-3). Clinical hyperthyroidism develops in approxi- demise have been reported with fetal thyrotoxicosis (Nachum,
mately 1 percent of neonates born to women with Graves 2003; Stulberg, 2000). The best predictor of perinatal thyro-
disease (Barbesino, 2013; Fitzpatrick, 2010; Luton, 2005). If toxicosis is presence of thyroid-stimulating TSH-receptor anti-
fetal thyroid disease is suspected, nomograms are available for bodies in women with Graves disease. This is especially true if
their levels are more than threefold higher than the upper nor-
mal limit (Barbesino, 2013). In a study of 72 pregnant women
with Graves disease, Luton and associates (2005) reported that
TABLE 58-2. Pregnancy Outcomes in 239 Women with none of the fetuses in 31 low-risk mothers had a goiter, and all
Overt Thyrotoxicosis were euthyroid at delivery. Low risk was defined by no anti-
Treated and Uncontrolled thyroid medications during the third trimester or absence of
Euthyroida Thyrotoxicosisa antithyroid antibodies. Conversely, in a group of 41 women
Factor n = 149 n = 90 who either were taking antithyroid medication at delivery or
had thyroid receptor antibodies, 11 fetuses—27 percent—had
Maternal outcome
sonographic evidence of a goiter at 32 weeks’ gestation. Seven
Preeclampsia 17 (11%) 15 (17%)
of these 11 were determined to be hypothyroid, and the remain-
Heart failure 1 7 (8%)
ing fetuses were hyperthyroid. In response to such results, the
Death 0 1
American Thyroid Association and American Association of
Perinatal outcome Clinical Endocrinologists (2011) recommend routine evalu-
Preterm delivery 12 (8%) 29 (32%) ation of TSH-receptor antibodies between 22 and 26 weeks’
Growth restriction 11 (7%) 15 (17%) gestation in women with Graves disease. The American College
Stillbirth 0/59 6/33 (18%) of Obstetricians and Gynecologists (2013), however, does not
Thyrotoxicosis 1 2 recommend such testing because management is rarely changed
Hypothyroidism 4 0 by the results. If the fetus is thyrotoxic, treatment is by adjust-
Goiter 2 0 ment of maternal thionamide drugs even though maternal thy-
a roid function may be within the targeted range (Duncombe,
Data presented as n (%).
2001; Mestman, 2012). Occasionally, neonatal thyrotoxicosis
Data from Davis, 1989; Kriplani, 1994; Millar, 1994.
may also require short-course antithyroid drug treatment.
 Endocrine Disorders 1151

A second presentation is goitrous hypothyroidism caused by Management. Treatment for thyroid storm or heart failure
fetal exposure to maternally administered thionamides (see is similar and should be carried out in an intensive care area
Fig. 58-3). Although there are theoretical neurological impli- that may include special-care units within labor and delivery
(Fitzpatrick, 2010; Zeeman, 2003). Shown in Figure 58-4

CHAPTER 58
cations, reports of adverse fetal effects seem to have been
exaggerated. Available data indicate that thionamides carry is our stepwise approach to medical management of thyroid
an extremely small risk for causing neonatal hypothyroidism storm or thyrotoxic heart failure. An hour or two after initial
(Momotani, 1997; O’Doherty, 1999). For example, of the 239 thionamide administration, iodide is given to inhibit thyroidal
treated thyrotoxic women shown in Table 58-1, there was evi- release of T3 and T4. It can be given intravenously as sodium
dence of hypothyroidism in only four infants despite relatively iodide or orally as either saturated solution of potassium iodide
high maternal PTU doses. Furthermore, at least four long-term (SSKI) or Lugol solution. With a history of iodine-induced
studies report no abnormal intellectual and physical develop- anaphylaxis, lithium carbonate, 300 mg every 6 hours, is
ment of these children (Mestman, 1998). If hypothyroidism given instead. Most authorities recommend dexamethasone,
is identified, the fetus can be treated by a reduced maternal 2 mg intravenously every 6 hours for four doses, to further
antithyroid medication dose and injection of intraamnionic block peripheral conversion of T4 to T3. If a β-blocker drug is
thyroxine if necessary. given to control tachycardia, its effect on heart failure must be
A third presentation, nongoitrous hypothyroidism, may considered. Propranolol, labetalol, and esmolol have all been
develop from transplacental passage of maternal TSH-receptor used successfully. Coexisting severe preeclampsia, infection,
blocking antibodies (Fitzpatrick, 2010; Gallagher, 2001). And or anemia should be aggressively managed before delivery is
finally, fetal thyrotoxicosiss after maternal thyroid gland ablation, considered.
usually with 131I radioiodine, may result from transplacental
thyroid-stimulating antibodies. In the previously described case Hyperemesis Gravidarum and Gestational
of early fetal exposure to radioiodine, neonatal thyroid studies Transient Thyrotoxicosis
indicated transient hyperthyroidism from maternal transfer of Transient biochemical features of hyperthyroidism may be
stimulating antibodies (Tran, 2010). observed in 2 to 15 percent of women in early pregnancy
(Fitzpatrick, 2010). Many women with hyperemesis gravi-
Fetal Diagnosis. Evaluation of fetal thyroid function is some- darum have abnormally high serum thyroxine levels and low
what controversial. Although fetal thyroid sonographic assess- TSH levels (Chap. 54, p. 1070). This results from TSH-
ment has been reported in women taking thionamide drugs receptor stimulation from massive—but normal for preg-
or those with thyroid-stimulating antibodies, most investiga- nancy—concentrations of hCG. This transient condition is
tors do not currently recommend this routinely (Cohen, 2003; also termed gestational transient thyrotoxicosis. Even if associ-
Luton, 2005). Kilpatrick (2003) recommends umbilical blood ated with hyperemesis, antithyroid drugs are not warranted
sampling and fetal antibody testing only if the mother has pre- (American College of Obstetricians and Gynecologists, 2013).
viously undergone radioiodine ablation. Because fetal hyper- or Serum thyroxine and TSH values become more normal by
hypothyroidism may cause hydrops, growth restriction, goi- midpregnancy (Fitzpatrick, 2010).
ter, or tachycardia, fetal blood sampling may be appropriate
if these are identified (Brand, 2005). The Endocrine Society Thyrotoxicosis and Gestational
Clinical Practice Guidelines recommend umbilical blood sam- Trophoblastic Disease
pling only when the diagnosis of fetal thyroid disease cannot be The prevalence of increased thyroxine levels in women with
reasonably ascertained based on clinical and sonographic data molar pregnancy has been reported to be between 25 and
(Garber, 2012). Diagnosis and treatment are considered further 65 percent (Hershman, 2004). As discussed, abnormally high
in Chapter 16 (p. 324). hCG levels lead to overstimulation of the TSH receptor.
Because these tumors are now usually diagnosed early, clini-
Thyroid Storm and Heart Failure cally apparent hyperthyroidism has become less common. With
Both are acute and life-threatening in pregnancy. Thyroid definitive treatment, serum free-T4 levels usually normalize rap-
storm is a hypermetabolic state and is rare in pregnancy. In idly in parallel with the decline in hCG concentrations. This is
contrast, pulmonary hypertension and heart failure from car- discussed further in Chapter 20 (p. 399).
diomyopathy caused by the profound myocardial effects of
thyroxine is common in pregnant women (Sheffield, 2004). As
shown in Table 58-2, heart failure developed in 8 percent of ■ Subclinical Hyperthyroidism
90 women with uncontrolled thyrotoxicosis. In these women, Third-generation TSH assays with an analytical sensitivity of
cardiomyopathy is characterized by a high-output state, which 0.002 mU/mL permit identification of subclinical thyroid
may lead to a dilated cardiomyopathy (Fadel, 2000; Klein, disorders. These biochemically defined extremes usually rep-
1998). The pregnant woman with thyrotoxicosis has minimal resent normal biological variations but may herald the earli-
cardiac reserve, and decompensation is usually precipitated est stages of thyroid dysfunction. Subclinical hyperthyroidism
by preeclampsia, anemia, sepsis, or a combination of these. is characterized by an abnormally low serum TSH concen-
Fortunately, thyroxine-induced cardiomyopathy and pulmo- tration in concert with thyroxine hormone levels within the
nary hypertension are frequently reversible (Sheffield, 2004; normal reference range (Surks, 2004). Long-term effects of
Siu, 2007; Vydt, 2006). persistent subclinical thyrotoxicosis include osteoporosis,
 1152 Medical and Surgical Complications

Start thionamides and consider heart rate control

SECTION 12

Thionamides:
PTU 1000 mg PO/NGT load Heart rate control (if necessary):
then Propranolol 10–40 mg PO every 4–6 hr
200 mg every 6 hr PO/NGT

After 1–2 hours of thionamide therapy start iodine:

Sodium iodide 500–1000 mg IV every 8 hr
or
Potassium iodide 5 gtt PO every 8 hr
or
Lugol solution 10 gtt PO every 8 hr
or
if iodine anaphylaxis history,
Lithium carbonate 300 mg PO every 6 hr

Consider corticosteroid therapy for 24 hours:

Dexamethasone 2 mg IV every 6 hr
or
Hydrocortisone 100 mg IV every 8 hr

FIGURE 58-4 One management method for thyroid storm or thyrotoxic heart failure. gtt = drops; NGT = nasogastric tube; PO = orally.

cardiovascular morbidity, and progression to overt thyrotoxi- ■ Hypothyroidism

cosis or thyroid failure. Casey and Leveno (2006b) identi- Overt or symptomatic hypothyroidism, as shown in
fied subclinical hyperthyroidism in 1.7 percent of pregnant Table 58-3, has been reported to complicate between 2 and
women. Importantly, these investigators showed that sub- 10 pregnancies per 1000. It is characterized by insidious
clinical hyperthyroidism was not associated with adverse nonspecific clinical findings that include fatigue, constipa-
pregnancy outcomes. In separate retrospective analyses of tion, cold intolerance, muscle cramps, and weight gain. A
almost 25,000 women who underwent thyroid screening pathologically enlarged thyroid gland depends on the etiology
throughout pregnancy, Wilson and colleagues (2012) and
Tudela and coworkers (2012) confirmed no relationship
between subclinical hyperthyroidism and preeclampsia or
gestational diabetes. TABLE 58-3. Frequency of Overt Hypothyroidism
The American Thyroid Association and American Association in Pregnancy
of Clinical Endocrinologists guidelines recommend consider-
Overt
ation for treatment of subclinical hyperthyroidism in individu-
Study Country Hypothyroidism
als 65 years or older and in postmenopausal women to improve
cardiovascular health and bone mineral density. There is, how- Wang (2011)a China 0.3%
ever, no convincing evidence that subclinical hyperthyroidism Cleary-Goldman United States 0.3%
should be treated in younger nonpregnant individuals. Thus, (2008)a
treatment seems especially unwarranted in pregnancy because Vaidya (2007)a United Kingdom 1.0%
antithyroid drugs may affect the fetus. Women identified Casey (2005)b United States 0.2%
with subclinical hyperthyroidism may benefit from periodic a
Screened during first trimester.
surveillance, and approximately half eventually have normal b
Screened at < 20 weeks’ gestation.
TSH concentrations.
 Endocrine Disorders 1153

of hypothyroidism and is more likely in women in areas of

TABLE 58-4. Pregnancy Complications in 440 Women
endemic iodine deficiency or those with Hashimoto thyroid-
with Hypothyroidism
itis. Other findings include edema, dry skin, hair loss, and
Hypothyroidism (%)

CHAPTER 58
prolonged relaxation phase of deep tendon reflexes. Clinical
or overt hypothyroidism is confirmed when an abnormally Overt Subclinical
high serum TSH level is accompanied by an abnormally low Complications n = 112 n = 328
thyroxine level. Subclinical hypothyroidism is defined by an
32 8
elevated serum TSH level and normall serum thyroxine con-
Placental abruption 8 1
centration (Surks, 2004). Included in the spectrum of sub-
Cardiac dysfunction 3 2
clinical thyroid disease are asymptomatic individuals with
Birthweight < 2000 ga,b 33 32
measurable antithyroid peroxidase or antithyroglobulin anti-
Stillbirthsc 9 3c
bodies. Euthyroid autoimmune thyroid disease represents a
new investigative frontier in screening and treatment of thy- a
Preterm or term deliveries were the only outcomes
roid dysfunction during pregnancy. reported by Abalovich, 2002.
b
Low birthweight and stillbirth were outcomes reported
Overt Hypothyroidism and Pregnancy by Su, 2011.
The most common cause of hypothyroidism in pregnancy is c
One infant died from syphilis.
Hashimoto thyroiditis, characterized by glandular destruction Data from Abalovich, 2002; Davis, 1988; Leung, 1993;
from autoantibodies, particularly antithyroid peroxidase anti- Männistö, 2009; Su, 2011.
bodies. Clinical identification of hypothyroidism is especially
difficult during pregnancy because many of the signs or symp-
toms are also common to pregnancy itself. Thyroid analyte test-
ing should be performed on symptomatic women or those with (Alexander, 2004; Loh, 2009; Rotondi, 2004). Anticipatory
a history of thyroid disease (American College of Obstetricians 25-percent increases in thyroxine replacement at pregnancy
and Gynecologists, 2013). As discussed in Chapter 18 (p. 353), confirmation will reduce this likelihood. All other women
severe hypothyroidism during pregnancy is uncommon, probably with hypothyroidism should undergo TSH testing at initia-
because it is often associated with infertility and increased spon- tion of prenatal care.
taneous abortion rates (Abalovich, 2002; De Groot, 2012).
Even women with treated hypothyroidism undergoing in vitro Pregnancy Outcome with Overt Hypothyroidism.
fertilization have a significantly decreased chance of achieving Observational studies, although limited, indicate that there are
pregnancy (Scoccia, 2012). excessive adverse perinatal outcomes associated with overt thy-
roxine deficiency (Table 58-4). With appropriate replacement
Treatment. The American Thyroid Association and American therapy, however, adverse effects are not increased in most
Association of Clinical Endocrinologists (2011) recommend reports (Matalon, 2006; Tan, 2006; Wolfberg, 2005). In one
replacement therapy for hypothyroidism beginning with dissenting study, however, there was an increased risk for some
levothyroxine in doses of 1 to 2 μg/kg/day or approximately pregnancy complications even in women taking replacement
100 μg daily. Women who are athyreotic after thyroidectomy therapy (Wikner, 2008). Most experts agree that adequate
or radioiodine therapy may require higher doses. Surveillance hormone replacement during pregnancy minimizes the risk of
is with TSH levels measured at 4- to 6-week intervals, and the adverse outcomes and most complications (Abalovich, 2002;
thyroxine dose is adjusted by 25- to 50-μg increments until Fitzpatrick, 2010).
TSH values become normal. Pregnancy is associated with an
increased thyroxine requirement in approximately a third of Fetal and Neonatal Effects. There is no doubt that mater-
supplemented women (Abalovich, 2010; Alexander, 2004). nal and fetal thyroid abnormalities are related. In both, thyroid
Because a similar increased requirement is seen in women with function is dependent on adequate iodide intake, and its defi-
postmenopausal hypothyroidism after estrogen replacement, ciency early in pregnancy can cause both maternal and fetal
the increased demand in pregnancy is believed to be related to hypothyroidism. And as discussed, maternal TSH-receptor-
increased estrogen production (Arafah, 2001). blocking antibodies can cross the placenta and cause fetal thy-
Increased thyroxine requirements begin as early as 5 weeks. roid dysfunction. Rovelli and colleagues (2010) evaluated 129
In a randomized trial that provided an increased levothyrox- neonates born to women with autoimmune thyroiditis. They
ine dose at pregnancy confirmation in 60 mothers, Yassa and found that 28 percent had an elevated TSH level on the third or
coworkers (2010) found that a 29- to 43-percent increase in fourth day of life, and 47 percent of these had TPO antibodies
the weekly dose maintained serum TSH values < 5.0 mU/L on day 15. Still, autoantibodies were undetectable at 6 months
during the first trimester in all women. Importantly, how- of age. It seems paradoxical that despite these transient labora-
ever, this increase caused TSH suppression in more than a tory findings in the neonate, TPO and antithyroglobulin (TG)
third of women. Significant hypothyroidism may develop antibodies have little or no effect on fetall thyroid function
early in women without thyroid reserve such as those with (Fisher, 1997). Indeed, prevalence of fetal hypothyroidism in
a previous thyroidectomy, those with prior radioiodine abla- women with Hashimoto thyroiditis is estimated to be only 1 in
tion, or those undergoing assisted reproductive techniques 180,000 neonates (Brown, 1996).
 1154 Medical and Surgical Complications

■ Subclinical Hypothyroidism likely associated with some adverse pregnancy outcomes. In

This thyroid condition is common in women, but its inci- 1999, interest was heightened by two studies that suggested
dence can be variable depending on age, race, dietary iodine that undiagnosed maternal thyroid hypofunction may impair
fetal neuropsychological development. In one study, Pop and
SECTION 12

intake, and serum TSH thresholds used to establish the diag-

nosis (Cooper, 2012). According to Fitzpatrick and Russell associates (1999) described 22 women who had free T4 lev-
(2010), its prevalence in pregnancy has been estimated to be els < 10th percentile in early pregnancy whose offspring were
between 2 and 5 percent. In two large studies totaling more at increased risk for impaired psychomotor development. In
than 25,000 pregnant women screened in the first half of the other study, Haddow and coworkers (1999) retrospectively
pregnancy, subclinical hypothyroidism was identified in 2.3 evaluated children born to 48 untreated women whose serum
percent of women (Casey, 2005; Cleary-Goldman, 2008). TSH values were > 98th percentile. Some had diminished
The rate of progression to overt thyroid failure is affected by school performance, reading recognition, and intelligent quo-
TSH level, age, other disorders such as diabetes, and presence tient (IQ) scores. Although described as “subclinically hypothy-
and concentration of antithyroid antibodies. Diez and Iglesias roid,” these women had an abnormally low mean serum free
(2004) prospectively followed 93 nonpregnant women with thyroxine level, and thus, many had overt hypothyroidism.
subclinical hypothyroidism for 5 years and reported that in To further evaluate any adverse effects, Casey and colleagues
a third, TSH values became normal. In the other two thirds, (2005) identified subclinical hypothyroidism in 2.3 percent of
those women whose TSH levels were 10 to 15 mU/L devel- 17,298 women screened before midpregnancy. As shown in
oped overt disease at a rate of 19 per 100 patient-years. Those Table 58-5, these women had higher incidences of preterm
women whose TSH levels were < 10 mU/L developed overt birth, placental abruption, and admission of infants to the
hypothyroidism at a rate of 2 per 100 patient-years. The U.S. intensive care nursery compared with euthyroid women. In the
Preventative Services Task Force on screening for subclini- study of 10,990 participants in the First- and Second-Trimester
cal hypothyroidism also reported that nearly all patients who Evaluation of Risk (FASTER) Trial, Cleary-Goldman and asso-
develop overt hypothyroidism within 5 years have an initial ciates (2008) did not find such a link with these adverse obstet-
TSH level > 10 mU/L (Helfand, 2004; Karmisholt, 2008). In rical outcomes.
a 20-year follow-up study of 5805 women who were screened In a study of 24,883 women screened throughout preg-
in early pregnancy, only 3 percent developed thyroid disease. nancy, Wilson and coworkers (2012) found that women iden-
Of the 224 women identified with subclinical hypothyroid- tified with subclinical hypothyroidism had an almost twofold
ism during pregnancy, 36 (17 percent) developed thyroid increased risk of severe preeclampsia. The authors hypothesized
disease in the next 20 years, and most of these had either that this was related to endothelial cell dysfunction that has
TPO or TG antibodies during pregnancy (Männistö, 2010). been linked to subclinical hypothyroidism in older patients.
Consequently, the likelihood of progression to overt hypothy- In their analysis of the same cohort, Tudela and associates
roidism duringg pregnancy in otherwise healthy women with (2012) identified a consistent relationship between increasing
subclinical hypothyroidism seems unlikely. TSH level and risk for gestational diabetes. More specifically,
6.3 percent of women with subclinical hypothyroidism were
diagnosed with gestational diabetes compared with 4.2 percent
Subclinical Hypothyroidism and Pregnancy in euthyroid women. Nelson and colleagues (2014) evaluated
Observational studies spanning almost 25 years and shown 230 women diagnosed with subclinical hypothyroidism dur-
in Table 58-4 suggest that subclinical hypothyroidism is ing a prior pregnancy. These women were at increased risk for

TABLE 58-5. Pregnancy Outcomes in Women with Untreated Subclinical Hypothyroidism and Isolated Maternal
Hypothyroxinemia Compared with Euthyroid Pregnant Women
Subclinical Isolated
Euthyroid Hypothyroidism Hypothyroxinemia
Outcome n = 16,011 n = 598 p value n = 233 p value
Hypertension (%) 9 9 0.68 11 0.53
Placental abruption (%) 0.3 1.0 0.03 0.4 0.75
Gestational age delivered (%)
≤ 36 weeks 6.0 7.0 0.09 6.0 0.84
≤ 34 weeks 2.5 4.3 0.005 2.0 0.44
≤ 32 weeks 1.0 2.2 0.13 1.0 0.47
RDS/ventilator (%) 1.5 2.5 0.05 1.3 0.78
Neonatal intensive care (%) 2.2 4.0 0.005 1.3 0.32

RDS = respiratory distress syndrome.

Data from Casey, 2007.
 Endocrine Disorders 1155

diabetes and stillbirth in subsequent pregnancies. Although those of euthyroid women (see Table 58-5). And, as shown
these findings are intriguing, there is currently no evidence that in Figure 58-2, unlike subclinical hypothyroidism, these
identification and treatment of subclinical hypothyroidism women had a low prevalence of antithyroid antibodies. The

CHAPTER 58
during pregnancy improves these outcomes. only other finding was from Cleary-Goldman and coworkers
(2008), who reported a twofold incidence of fetal macro-
TSH Level Screening in Pregnancy. Because of the findings somia. Taken together, these findings indicate that isolated
from the 1999 studies cited above, some professional organi- maternal hypothyroxinemia has no apparent serious adverse
zations recommend routine prenatal screening and treatment effects on pregnancy outcome. Finally, the aforementioned
for subclinical hypothyroidism (Gharib, 2005). The American CATS study did not find improved neurodevelopmental
College of Obstetricians and Gynecologists (2013) has reaf- f outcomes in women with isolated hypothyroxinemia who
firmed that although observational data were consistent with were then treated with thyroxine (Lazarus, 2012). Because of
the possibilityy that subclinical hypothyroidism was associated this, routine screening for isolated hypothyroxinemia is not
with adverse neuropsychological development, there have been recommended.
no interventional trials to demonstrate improvement. The
College thus has consistently recommended against implemen-
tation of screening until further studies are done to validate or ■ Euthyroid Autoimmune Thyroid Disease
refute these findings (American College of Obstetricians and Autoantibodies to TPO and TG have been identified in 6
Gynecologists, 2012). to 20 percent of reproductive-aged women (Thangaratinam,
Lazarus and colleagues (2012) reported the findings of 2011). Most who test positive for such antibodies, however,
the international multicenter Controlled Antenatal Thyroid are euthyroid. That said, such women are at a two- to fivefold
Screening (CATS) study of thyroid screening and treatment increased risk for early pregnancy loss (Stagnaro-Green, 2004;
of subclinical hypothyroidism and isolated maternal hypothy- Thangaratinam, 2011). The presence of thyroid antibodies has
roxinemia during pregnancy. The primary outcome was off- ff also been associated with preterm birth (Stagnaro-Green, 2009).
spring IQ scores at 3 years of age. Cognitive function in the In a randomized treatment trial of 115 euthyroid women with
children was not improved with screening and treatment. A TPO antibodies, Negro and coworkers (2006) reported that
second comparable study is being conducted by the Maternal- treatment with levothyroxine astoundingly reduced the preterm
Fetal Medicine Units Network, and the results are anticipated birth rate from 22 to 7 percent. Contrarily, Abbassi-Ghanavati
in 2016. and associates (2010) evaluated pregnancy outcomes in more
Consequent to the Lazarus study, clinical practice guidelines than 1000 untreated women with TPO antibodies and did not
from the Endocrine Society, The American Thyroid Association, find an increased risk for preterm birth compared with the risk
and the American Association of Clinical Endocrinologists in 16,000 euthyroid women without antibodies. These inves-
now uniformly recommend screening only those at increased tigators, however, found a threefold increased risk of placen-
risk during pregnancy (De Groot, 2012; Garber, 2012). tal abruption in these women. As with nonpregnant subjects
Furthermore, previous cost-effectiveness analyses that favored a with TPO antibodies, these women are also at increased risk
universal screening strategy are no longer valid since they were for progression of thyroid disease and postpartum thyroiditis
based on assumptions of improved neurodevelopmental out- (Stagnaro-Green, 2012a).
comes in offspring (Dosiou, 2008; Thung, 2009). This group of euthyroid women with abnormally high
thyroid autoantibody levels represents a new focus of thyroid
research. Dosiou and colleagues (2012) performed a cost-effec-
■ Isolated Maternal Hypothyroxinemia tiveness analysis of universal screening for autoimmune thy-
Women with low serum free T4 values but a normal range TSH roid disease during pregnancy. Their results favored universal
level are considered to have isolated maternal hypothyroxinemia. screening. There is, however, a paucity of studies that show
This was identified by Casey and colleagues (2007) in 1.3 per- benefit to identifying and treating euthyroid women with thy-
cent of more than 17,000 pregnant women screened at Parkland roid autoantibodies. Thus, calls for routine antibody screening
Hospital before 20 weeks. Cleary-Goldman and associates seem premature. Currently, universal screening for the thyroid
(2008) found a 2.1-percent incidence in the FASTER Trial autoantibodies is not recommended by any professional orga-
cohort described earlier. As discussed previously, offspring of nizations (De Groot, 2012; Stagnaro-Green, 2011a, 2012a).
women with isolated hypothyroxinemia have been reported to
have neurodevelopmental difficulties at age 3 weeks, 10 months,
and 2 years (Kooistra, 2006; Pop, 1999, 2003). These find- ■ Iodine Deficiency
ings have not stimulated recommendations for prenatal serum Decreasing iodide fortification of table salt and bread products
thyroxine screening. Importantly, free T4 estimates by currently in the United States during the past 25 years has led to occa-
available immunoassays may not be accurate during pregnancy sional iodide deficiency (Caldwell, 2005; Hollowell, 1998).
because of sensitivity to alterations in binding proteins Importantly, the most recent National Health and Nutrition
(Lee, 2009). Examination survey indicated that, overall, the United States
In a study of 233 women with isolated maternal hypothy- population remains iodine sufficient (Caldwell, 2011). Even
roxinemia, Casey and colleagues (2007) reported that there so, experts agree that iodine nutrition in vulnerable popula-
were no increased adverse perinatal outcomes compared with tions such as pregnant women requires continued monitoring.
 1156 Medical and Surgical Complications

In 2011 the Office of Dietary Supplements of the National ■ Congenital Hypothyroidism

Institutes of Health sponsored a workshop to prioritize iodine Because the clinical diagnosis of hypothyroidism in neo-
research. Participants emphasized the decline in median urinary nates is usually missed, universal newborn screening was
iodine to 125 μg/L in pregnant women and the serious poten-
SECTION 12

introduced in 1974 and is now required by law in all states.

tial impact on the developing fetus (Swanson, 2012). Congenital hypothyroidism develops in approximately 1 in
Dietary iodine requirements are increased during pregnancy 3000 newborns and is one of the most preventable causes of
due to increased thyroid hormone production, increased renal mental retardation (LaFranchi, 2011). Developmental dis-
losses, and fetal iodine requirements. Adequate iodine is req- orders of the thyroid gland such as agenesis and hypoplasia
uisite for fetal neurological development beginning soon after account for 80 to 90 percent of these cases (LaFranchi, 2011;
conception, and abnormalities are dependent on the degree of Topaloglu, 2006). The exact underlying etiology of thyroid
deficiency. The World Health Organization (WHO) has esti- dysgenesis remains unknown. The remaining primary con-
mated that at least 50 million people worldwide have varying genital hypothyroidism cases are caused by hereditary defects
degrees of preventable brain damage due to iodine deficiency in thyroid hormone production. The list of identified gene
(Brundtland, 2002). Although it is doubtful that mild defi- mutations that cause hypothyroidism continues to grow rap-
ciencyy causes intellectual impairment, supplementation does idly (Moreno, 2008).
prevent fetal goiter (Stagnaro-Green, 2012b). Severe deficiency, Early and aggressive thyroxine replacement is critical for
on the other hand, is frequently associated with damage typi- infants with congenital hypothyroidism. Still, some infants
cally encountered with endemic cretinism (Delange, 2001). It is identified by screening programs with severe congenital hypo-
presumed that moderate deficiencyy has intermediate and variable thyroidism who were treated promptly will exhibit cognitive
effects. Berbel and associates (2009) began daily supplementa- deficits into adolescence (Song, 2001). Therefore, in addition
tion in more than 300 pregnant women with moderate defi- to timing of treatment, the severity of congenital hypothyroid-
ciency at three time periods—4 to 6 weeks, 12 to 14 weeks, and ism is an important factor in long-term cognitive outcomes
after delivery. They found improved neurobehavioral develop- (Kempers, 2006). Accordingly, in infants with screening
ment scores in offspring of women supplemented with 200 μg results suggestive of severe hypothyroidism, therapy should be
potassium iodide very early in pregnancy. Similarly, Velasco started immediately without waiting for confirmatory results
and coworkers (2009) found improved Bayley Psychomotor (Abduljabbar, 2012). Olivieri and colleagues (2002) reported
Development scores in offspring of women supplemented with that 8 percent of 1420 infants with congenital hypothyroidism
300 μg of iodide in the first trimester. In contrast, Murcia also had other major congenital malformations.
and colleagues (2011) identified lower psychomotor scores in
1-year-old infants whose mothers reported daily supplementa-
tion of more than 150 μg. There are two ongoing random- ■ Postpartum Thyroiditis
ized controlled trials of iodine supplementation in mildly to Transient autoimmune thyroiditis is consistently found in
moderately iodine-deficient pregnant women in India and approximately 5 to 10 percent of women during the first
Thailand. These studies should provide needed answers as to year after childbirth (Amino, 2000; Stagnaro-Green, 2011b,
whether iodine supplementation in these women is beneficial 2012a). Postpartum thyroid dysfunction with an onset within
(Pearce, 2013). 12 months includes hyperthyroidism, hypothyroidism, or
The Institute of Medicine (2001) recommends daily iodine both. The propensity for thyroiditis antedates pregnancy and is
intake during pregnancy of 220 μg/day, and 290 μg/day for directly related to increasing serum levels of thyroid autoanti-
lactating women (Chap. 9, p. 180). The Endocrine Society bodies. Up to 50 percent of women who are thyroid-antibody
(De Groot, 2012) recommends an average iodine intake of positive in the first trimester will develop postpartum thyroid-
150 μg per day in childbearing-aged women, and this should be itis (Stagnaro-Green, 2012a). In a Dutch study of 82 women
increased to 250 μg during pregnancy and breast feeding. The with type 1 diabetes, postpartum thyroiditis developed in 16
American Thyroid Association has recommended that 150 μg percent and was threefold higher than in the general popula-
of iodine be added to prenatal vitamins to achieve this average tion (Gallas, 2002). Importantly, 46 percent of those identified
daily intake (Becker, 2006). According to Leung and coworkers with overt postpartum thyroiditis had TPO antibodies in the
(2011), however, only 51 percent of the prenatal multivitamins first trimester.
in the United States contain iodine. It has even been suggested
that because most cases of maternal hypothyroxinemia world- Clinical Manifestations
wide are related to relative iodine deficiency, supplementation In clinical practice, postpartum thyroiditis is diagnosed infre-
may obviate the need to consider thyroxine treatment in such quently because it typically develops months after delivery and
women (Gyamfi, 2009). causes vague and nonspecific symptoms that often are thought
On the other hand, experts caution against oversupple- to be stresses of motherhood (Stagnaro-Green, 2004). The clin-
mentation. Teng and associates (2006) contend that exces- ical presentation varies, and classically there are two recognized
sive iodine intake—defined as > 300 μg/day—may lead to clinical phases that may develop in succession. The first and
subclinical hypothyroidism and autoimmune thyroiditis. And earliest is destruction-induced thyrotoxicosiss with symptoms from
the Endocrine Society, in accordance with the WHO, advises excessive release of hormone from glandular disruption. The
against exceeding twice the daily recommended intake of onset is abrupt, and a small, painless goiter is commonly found.
iodine, or 500 μg/day (De Groot, 2012; Leung, 2011). Although there may be many symptoms, only fatigue and
 Endocrine Disorders 1157

palpitations are more frequent in thyrotoxic women compared across pregnancy and did not regress postpartum. Biopsy of
with normal controls. This thyrotoxic phase usually lasts only a those > 5 mm3 that persisted at 3 months usually showed nod-
few months. Thionamides are ineffective, and if symptoms are ular hyperplasia, and none was malignant. In some studies,
severe, a β-blocker agent may be given. The second and usually

CHAPTER 58
however, up to 40 percent of solitary nodules were malignant
later phase is clinical hypothyroidism from thyroiditis between 4 (Doherty, 1995; Rosen, 1986). Even so, most were low-grade
and 8 months postpartum. Thyromegaly and other symptoms neoplasms.
are common and more prominent than during the thyrotoxic Evaluation of thyroid nodules during pregnancy should
phase. Thyroxine replacement with 25 to 75 μg/day is typically be similar to that for nonpregnant patients. As discussed in
given for 6 to 12 months. Chapter 46 (p. 934), most recommend against radioiodine
Stagnaro-Green and associates (2011b) reported postpar- scanningg in pregnancy despite the fact that tracer doses used
tum follow-up from 4562 Italian pregnant women who had are associated with minimal fetal irradiation (Popoveniuc,
been screened for thyroid disease in pregnancy. Serum TSH 2012). Sonographicc examination reliably detects nodules larger
and anti-TPO antibody levels were measured again at 6 and than 0.5 cm, and their solid or cystic structure also is deter-
12 months. Overall, two thirds of 169 women (3.9 percent) mined. According to the American Association of Clinical
with postpartum thyroiditis were identified to have hypothy- Endocrinologists, sonographic characteristics associated with
roidism only. The other third were diagnosed with hyperthy- malignancy include hypoechogenic pattern, irregular margins,
roidism, but only 14 percent of all women demonstrated the and microcalcifications (Gharib, 2005). Fine-needle aspira-
“classic” biphasic progression described above. These find- tion (FNA) is an excellent assessment method, and histologi-
ings are consistent with data compiled from 20 other studies cal tumor markers and immunostaining are reliable to evaluate
between 1982 and 2008 (Stagnaro-Green, 2012a). for malignancy (Bartolazzi, 2001; Hegedüs, 2004). If the FNA
Importantly, women who experience either type of post- biopsy shows a follicular lesion, surgery may be deferred until
partum thyroiditis have an approximately 30-percent risk of after delivery.
eventually developing permanent hypothyroidism, and the Evaluation of thyroid cancer involves a multidisciplinary
annual progression rate is 3.6 percent (Lucas, 2005; Muller, approach (American College of Obstetricians and Gynecol-
2001; Premawardhana, 2000). Women at increased risk for ogists, 2013). Most thyroid carcinomas are well differentiated
developing hypothyroidism are those with higher titers of thy- and pursue an indolent course. When thyroid malignancy
roid antibodies and higher TSH levels during the initial hypo- is diagnosed during the first or second trimester, thyroidec-
thyroid phase. Others may develop subclinical disease, but half tomy may be performed before the third trimester (Chap. 63,
of those with thyroiditis who are positive for TPO antibodies p. 1231). In women without evidence of an aggressive thyroid
develop permanent hypothyroidism by 6 to 7 years (Stagnaro- cancer, or in those diagnosed in the third trimester, surgical
Green, 2012a). treatment can be deferred to the immediate postpartum period
An association between postpartum thyroiditis and post- (Gharib, 2010).
partum depression has been proposed but remains unresolved.
Lucas and coworkers (2001) found a 1.7-percent incidence PARATHYROID DISEASES
of postpartum depression at 6 months in women with thy-
roiditis as well as in controls. Pederson and colleagues (2007) The function of parathyroid hormone (PTH) is to maintain
found a significant correlation between abnormal scores on the extracellular fluid calcium concentration. This 115-amino
Edinburgh Postnatal Depression Scale and total thyroxine val- acid hormone acts directly on bone and kidney and indirectly
ues in the low normal range during pregnancy in 31 women. on small intestine through its effects on synthesis of vitamin
Similarly unsettled is the link between depression and thy- D (1,25[OH2]-D) to increase serum calcium. Secretion is
roid antibodies. Kuijpens and associates (2001) reported that regulated by serum ionized calcium concentration through a
TPO antibodies were a marker for postpartum depression in negative feedback system. Calcitonin is a potent parathyroid
euthyroid women. In a randomized trial, Harris and coworkers hormone that acts as a physiological parathyroid hormone
(2002) reported no difference in postpartum depression in antagonist. The interrelationships between these hormones, cal-
342 women with TPO antibodies who were given either levo- cium metabolism, and PTH-related protein produced by fetal
thyroxine or placebo. tissue are discussed in Chapter 4 (p. 70).
Fetal calcium needs—300 mg/day in late pregnancy and a
total of 30 g—as well as increased renal calcium loss from aug-
■ Nodular Thyroid Disease mented glomerular filtration, substantively increase maternal
Thyroid nodules can be found in 1 to 2 percent of reproductive- calcium demands. Pregnancy is associated with a twofold rise
aged women (Fitzpatrick, 2010). Management of a palpable in serum concentrations of 1,25-dihydroxyvitamin D, which
thyroid nodule during pregnancy depends on gestational age increases gastrointestinal calcium absorption. The effectuating
and mass size. Small nodules detected by sensitive sonographic hormone is probably of placental and decidual origin because
methods are more common during pregnancy in some popu- maternal PTH levels are low normal or decreased during preg-
lations. For example, Kung and associates (2002) used high- nancy (Cooper, 2011; Molitch, 2000). Total serum calcium
resolution sonography and found that 15 percent of Chinese levels decline with serum albumin concentrations, but ionized
women had nodules larger than 2 mm in diameter. Almost calcium levels remain unchanged. Vargas Zapata (2004), and
half were multiple, and the nodules usually enlarged modestly others, have suggested a role for insulin-like growth factor-1
 1158 Medical and Surgical Complications

(IGF-1) in maternal calcium homeostasis and bone turnover, preterm deliveries in pregnancies complicated by hyperpara-
especially in mothers with low calcium intake. thyroidism (Shangold, 1982). More recent reports, however,
described lower rates of stillbirth, neonatal death, and neona-
tal tetany (Kovacs, 2011). Other fetal complications include
SECTION 12

■ Hyperparathyroidism miscarriage, fetal-growth restriction, and low birthweight

Hypercalcemia is caused by hyperparathyroidism or cancer in (Chamarthi, 2011). Schnatz (2005) reported a 25-percent inci-
90 percent of cases. Primary hyperparathyroidism is reported dence of preeclampsia.
most often in women older than 50 (Miller, 2008). Because
many automated laboratory systems include serum calcium Management in Pregnancy. Surgical removal of a symp-
measurement, hyperparathyroidism has changed from being a tomatic parathyroid adenoma is preferable. This should pre-
condition defined by symptoms to one that is discovered on vent fetal and neonatal morbidities, as well as postpartum
routine screening (Pallan, 2012). It has a reported prevalence of parathyroid crises (Kovacs, 2011). Elective neck exploration
2 to 3 per 1000 women, but some have estimated the rate to be during pregnancy is usually well tolerated, even in the third
as high as 14 per 1000 when asymptomatic cases are included trimester (Graham, 1998; Kort, 1999; Schnatz, 2005). In
(Farford, 2007; Schnatz, 2005). Almost 80 percent are caused one woman, a mediastinal adenoma was removed at 23 weeks
by a solitary adenoma, and another 15 percent by hyperfunc- (Rooney, 1998).
tion of all four glands. In the remainder, a malignancy and the None of the three International Workshop Conferences on
cause of increased serum calcium levels are obvious. Of note, Asymptomatic Hyperparathyroidism have addressed its man-
PTH produced by tumors is not identical to the natural hor- agement during pregnancy (Bilezikian, 2009). Medical man-
mone and may not be detected by routine assays. agement may be appropriate in asymptomatic pregnant women
In most patients, the serum calcium level is only elevated to with mild hypercalcemia. If so, patients are carefully monitored
within 1 to 1.5 mg/dL above the upper normal limit. This may in the postpartum period for hypercalcemic crisis (Kovacs,
help to explain why only 20 percent of those who have abnor- 2011). Initial medical management might include calcitonin to
mally elevated levels are symptomatic (Bilezikian, 2004). In a decrease skeletal calcium release, or oral phosphate, 1 to 1.5 g
fourth, however, symptoms become apparent when the serum daily in divided doses to bind excess calcium. For women with
calcium level continues to rise. Hypercalcemic crisiss manifests as dangerously elevated serum calcium levels or those who are
stupor, nausea, vomiting, weakness, fatigue, and dehydration. mentally obtunded with hypercalcemic crisis, emergency treat-
All women with symptomatic hyperparathyroidism should ment is instituted. Diuresis with intravenous normal saline
be surgically treated. Guidelines for management in non- is begun so that urine flow exceeds 150 mL/hr. Furosemidee is
pregnant patients were revised after the Third International given in conventional doses to block tubular calcium reabsorp-
Workshop on the Management of Asymptomatic Primary tion. Importantly, hypokalemia and hypomagnesemia should
Hyperparathyroidism (Bilezikian, 2009). Indications for be prevented. Adjunctive therapy includes mithramycin, which
parathyroidectomy include a serum calcium level 1.0 mg/dL inhibits bone resorption.
above the upper normal range, a calculated creatinine clear-
Neonatal Effects. Normally, cord blood calcium levels are
ance less than 60 mL/min, reduced bone density, or age < 50
higher than maternal levels (Chap. 7, p. 135). With mater-
years. Those not meeting these criteria should undergo annual
nal hyperparathyroidism, abnormally elevated maternal and
calcium and creatinine level measurement and bone density
thence fetal levels further suppress fetal parathyroid func-
assessment every 1 to 2 years (Pallan, 2012).
tion. Because of this, after birth, there is a rapidly decreas-
Hyperparathyroidism in Pregnancy ing newborn calcium level, and 15 to 25 percent of these
infants develop severe hypocalcemia with or without tetany
In their review, Schnatz and Thaxton (2005) found fewer than (Molitch, 2000). Neonatal hypoparathyroidism caused by
200 reported cases complicating pregnancy. As in nonpregnant maternal hyperparathyroidism is usually transient and should
patients, hyperparathyroidism is usually caused by a parathy- be treated with calcium and calcitriol. Calcitriol will not be
roid adenoma. Gravidas with ectopic parathyroid hormone effective in preterm infants, however, because the intestinal
production and rare cases of parathyroid carcinoma have been vitamin D receptor is not sufficiently expressed (Kovacs,
reported (Montoro, 2000). Symptoms include hyperemesis, 2011). Neonatal tetany or seizures should stimulate an evalu-
generalized weakness, renal calculi, and psychiatric disorders. ation for maternal hyperparathyroidism (Beattie, 2000; Ip,
Occasionally, pancreatitis is the presenting finding (Cooper, 2003; Jaafar, 2004).
2011; Dahan, 2001).
Pregnancy theoretically improves hyperparathyroidism
because of significant calcium shunting to the fetus and aug- ■ Hypoparathyroidism
mented renal excretion (Power, 1999). When the “protective The most common cause of hypocalcemia is hypoparathy-
effects” of pregnancy are withdrawn, however, there is sig- roidism that usually follows parathyroid or thyroid surgery.
nificant danger of postpartum hypercalcemic crisis. This life- Hypoparathyroidism is estimated to follow up to 7 percent
threatening complication can be seen with serum calcium levels of total thyroidectomies (Shoback, 2008). It is rare and char-
greater than 14 mg/dL and is characterized by nausea, vomit- acterized by facial muscle spasms, muscle cramps, and pares-
ing, tremors, dehydration, and mental status changes (Malekar- thesias of the lips, tongue, fingers, and feet. This can progress
Raikar, 2011). Early reports described excessive stillbirths and to tetany and seizures. Chronically, hypocalcemic pregnant
 Endocrine Disorders 1159

women may also have a fetus with skeletal demineralization

resulting in multiple bone fractures in the neonatal period
(Alikasifoglu, 2005).

CHAPTER 58
Maternal treatment includes 1,25-dihydroxyvitamin D3
(calcitriol), dihydrotachysterol, or large vitamin D doses of
50,000 to 150,000 U/day; calcium gluconate or calcium lac-
tate in doses of 3 to 5 g/day; and a low-phosphate diet. The
therapeutic challenge in women with known hypoparathyroid-
ism is management of blood calcium levels. The goal during
pregnancy is maintenance of the corrected calcium level in
the low normal range. It is possible that the increased calcium
absorption typical of pregnancy will result in lower calcium
requirements or that the fetal demand for calcium will result
in increased need. Since both scenarios are possible, it is best to
carefully monitor the corrected serum calcium on a frequent, FIGURE 58-5 Anteroposterior plain radiograph with abdominal
perhaps monthly, basis throughout pregnancy (Cooper, 2011; shielding of a 25-year-old patient’s hips at 26-weeks’ gestation.
Kovacs, 2011). The fetal risks from large doses of vitamin D She complained of left hip and knee pain and progressive weak-
have not been established. ness. Her transient osteoporosis of the left femur responded
over 3 months to physical therapy combined with vitamin D and
calcium supplementation.
■ Pregnancy-Associated Osteoporosis
Even with remarkably increased calcium requirements, it
is uncertain whether pregnancy causes osteopenia in most in pregnant women to determine its effect on neonatal bone
women (Kaur, 2003; To, 2003). In one study of 200 pregnant mineral content as assessed by dual-energy x-ray absorptiom-
women in which bone mass was measured using quantita- etry (DEXA) (Harvey, 2012).
tive ultrasonometry of the calcaneus, Kraemer and colleagues
(2011) demonstrated a decline in bone density during preg-
ADRENAL GLAND DISORDERS
nancy. Women who breast fed, carried twin pregnancies, or
had a low body mass index (BMI) were at higher risk of bone Pregnancy has profound effects on adrenal cortical secretion
loss. From their review, Thomas and Weisman (2006) cite a and its control or stimulation. These interrelationships were
3- to 4-percent average reduction in bone-mineral density dur- reviewed by Lekarev and New (2011) and are discussed in
ing pregnancy. Lactation also represents a period of negative detail in Chapter 4 (p. 70).
calcium balance that is corrected through maternal skeletal
resorption. Feigenberg and coworkers (2008) found cortical
bone mass reductions using ultrasound in young primiparas ■ Pheochromocytoma
in the puerperium compared with nulligravid controls. Rarely, These tumors are clinically uncommon and complicate
some women develop idiopathic osteoporosis while pregnant approximately 1 per 10,000 pregnancies. Notably, they are
or lactating. Its incidence is estimated to be 4 per million found in 0.1 percent of hypertensive patients (Abdelmannan,
women (Hellmeyer, 2007). 2011). However, they are more commonly found at autopsy
The most common symptom of osteoporosis is back pain in with infrequent clinical recognition. Pheochromocytomas are
late pregnancy or postpartum. Other symptoms are hip pain, chromaffin tumors that secrete catecholamines and usually are
either unilateral or bilateral, and difficulty in weight bearing located in the adrenal medulla, although 10 percent are located
until nearly immobilized (Maliha, 2012). In more than half in sympathetic ganglia. They are called the 10-percent tumor
of women, no apparent reason for osteopenia is found. Some because approximately 10 percent are bilateral, 10 percent are
known causes include heparin, prolonged bed rest, and cortico- extraadrenal, and 10 percent are malignant. These tumors can
steroid therapy (Cunningham, 2005; von Mandach, 2003). In be associated with medullary thyroid carcinoma and hyperpara-
a few cases, overt hyperparathyroidism or thyrotoxicosis even- thyroidism in some of the autosomally dominant or recessive
tually develops. multiple endocrine neoplasia syndromes, as well as in neurofibro-
Treatment is problematical and includes calcium and vita- matosis and von Hippel-Lindau disease.
min D supplementation as well as standard pain management. Symptoms are usually paroxysmal and manifest as hyperten-
Shown in Figure 58-5 is a hip radiograph from a woman treated sive crisis, seizure disorders, or anxiety attacks. Hypertension is
at Parkland Hospital during the third trimester for transient sustained in 60 percent of patients, but half of these also have
osteoporosis of pregnancy. paroxysmal crises. Other symptoms during paroxysmal attacks
For women with pregnancy-associated osteopenia, long- are headaches, profuse sweating, palpitations, chest pain, nau-
term surveillance indicates that although bone density sea and vomiting, and pallor or flushing.
improves, these women and their offspring may have chronic The standard screening test is quantification of catecholamine
osteopenia (Carbone, 1995). There is an ongoing random- metabolites in a 24-hour urine specimen (Abdelmannan,
ized, placebo-controlled trial of vitamin D supplementation 2011). Diagnosis is established by measurement of a 24-hour
 1160 Medical and Surgical Complications

TABLE 58-6. Outcomes of Pregnancies Complicated by

Pheochromocytoma and Reported in Three
Contiguous Epochs
SECTION 12

Incidence (%)
1980–87 1988–97 1998–2008
Harper Ahlawat Sarathi
(1989) (1999) (2010)
Factor n = 48 n = 42 n = 60
Diagnosis
Antepartum 51 83 70
Postpartum 36 14 23
Autopsy 12 2 7
Maternal death 16 4 12
Fetal wastage 26 11 17

urine collection with at least two of three assays for free cate-
cholamines, metanephrines, or vanillylmandelic acid (VMA).
Determination of plasma catecholamine levels may be accu-
rate but is associated with technical difficulties (Conlin, 2001;
Lenders, 2002). Boyle and colleagues (2007) determined that FIGURE 58-6 Coronal magnetic resonance image taken in a
32-week pregnant woman shows a right-sided pheochromocy-
measurement of urinary free metanephrine was superior to toma (arrow) and its position relative to the liver above it.
assessment of a VMA or urinary or plasma catecholamine
level. In nonpregnant patients, adrenal localization is usu-
ally successful with either computed tomography (CT) or Management
magnetic resonance (MR) imaging. For most cases, preferred Immediate control of hypertension and symptoms with an
treatment is laparoscopic adrenalectomy (Lal, 2003). α-adrenergic blocker such as phenoxybenzaminee is impera-
tive. The dose is 10 to 30 mg, two to four times daily. After
Pheochromocytoma Complicating Pregnancy
α-blockade is achieved, β-blockers may be given for tachycardia.
These tumors are rare but result in dangerous pregnancy In many cases, surgical exploration and tumor removal are per-
complications. Geelhoed (1983) provided an earlier review formed during pregnancy, preferably during the second trimes-
of 89 cases in which 43 mothers died. Maternal death ter (Dong, 2014; Miller, 2005). Successful laparoscopic removal
was much more common if the tumor was not diagnosed of adrenal tumors has become the norm (Junglee, 2007; Kim,
antepartum—58 versus 18 percent. As seen in Table 58-6, 2006; Miller, 2012; Zuluaga-Gómez, 2012). If diagnosed later
maternal mortality rates are now lower but still formidable. in pregnancy, either planned cesarean delivery with tumor exci-
In their review of 60 cases, Sarathi and associates (2010) con- sion or postpartum resection is appropriate.
firmed that antepartum diagnosis is the most important deter- Recurrent tumors are troublesome, and even with good
minant of maternal mortality risk. Maternal death was rare if blood pressure control, dangerous peripartum hypertension
the diagnosis is made antepartum. may develop. We have cared for three women in whom recur-
Diagnosis of pheochromocytoma in pregnancy is similar rent pheochromocytoma was identified during pregnancy.
to that for nonpregnant patients. MR imaging is the pre- Hypertension was managed with phenoxybenzamine in all
ferred imaging technique because it almost always locates three. Two infants were healthy, but a third was stillborn in
adrenal and extraadrenal pheochromocytomas (Fig. 58-6) a mother with a massive tumor burden who was receiving
(Manger, 2005). In many cases, the principal challenge is to phenoxybenzamine, 100 mg daily. In all three women, tumor
differentiate preeclampsia from the hypertensive crisis caused was resected postpartum.
by pheochromocytoma. Desai and coworkers (2009) describe
a woman who was initially treated for severe preeclampsia,
suffered an intrapartum fetal death, and was then treated for ■ Cushing Syndrome
presumed peripartum cardiomyopathy. When she returned This syndrome is rare and has an annual incidence of 2 to 3 per
1 week later with paroxysmal hypertension, pheochromocy- million. The female:male ratio is 3:1 (Steffenson, 2010). Most
toma was diagnosed and her blood pressure and ventricular cases are iatrogenic from long-term corticosteroid treatment.
function returned to normal after tumor resection. Grimbert However, endogenous Cushing syndrome is typically due to
and colleagues (1999) diagnosed two pheochromocytomas Cushing disease, which is bilateral adrenal hyperplasia stimulated
during 56 pregnancies in 30 women with von Hippel-Lindau by corticotropin-producing pituitary adenomas. Most are small
disease. microadenomas < 1 cm, and half measure ≤ 5 mm. Rarely,
 Endocrine Disorders 1161

abnormal secretion of hypothalamic corticotropin-releasing

TABLE 58-7. Maternal and Perinatal Complications
factor may cause corticotropic hyperplasia. Such hyperpla-
in Pregnancies Complicated by Cushing
sia may also be caused by nonendocrine tumors that produce
Syndrome

CHAPTER 58
polypeptides similar to either corticotropin-releasing factor or
corticotropin. Less than a fourth of cases of Cushing syndrome Complication Approximate Incidence (%)
are corticotropin independent, and most of these are caused by Maternal
an adrenal adenoma. Tumors are usually bilateral, and half are Hypertension 68
malignant. Occasionally, associated androgen excess may lead Diabetes 25
to severe virilization (Danilowicz, 2002). Preeclampsia 15
The typical cushingoid body habitus is caused by adipose Osteoporosis/fracture 5
tissue deposition that characteristically results in moon facies, Psychiatric disorders 4
a buffalo hump, and truncal obesity. Fatigability and weakness, Cardiac failure 3
hypertension, hirsutism, and amenorrhea are each encountered Mortality 2
in 75 to 85 percent of nonpregnant patients (Hatipoglu, 2012; Perinatal
Williams, 2001). Personality changes, easy bruisability, and cuta- Fetal-growth restriction 21
neous striae are common. Up to 60 percent may have impaired Preterm delivery 43
glucose tolerance. Diagnosis is verified by elevated plasma cor- Stillbirth 6
tisol levels that cannot be suppressed by dexamethasone or by Neonatal death 2
elevated 24-hour urine free cortisol excretion (Boscaro, 2001).
Neither test is totally accurate, and both are more difficult to Data from Lindsay, 2005.
interpret in obese patients. CT and MR imaging are used to
localize pituitary and adrenal tumors or hyperplasia.
obvious reasons. If necessary, pituitary adenomas can be treated
Cushing Syndrome and Pregnancy
by transsphenoidal resection (Boscaro, 2001; Lindsay, 2005).
Because most women have corticotropin-dependent Cushing Unilateral adrenalectomy has been safely performed in the early
syndrome, associated androgen excess may cause anovulation, third trimester and can also be curative (Abdelmannan, 2011).
and pregnancy is rare. In their review, Lekarev and New (2011)
identified fewer than 140 reported cases of Cushing syndrome in
pregnancy. These differ compared with nonpregnant women in ■ Adrenal Insufficiency—Addison Disease
that half are caused by corticotropin-independent adrenal adeno- Primary adrenocortical insufficiency is rare because more than
mas (Abdelmannan, 2011; Klibanski, 2006). Approximately 30 90 percent of total gland volume must be destroyed for symp-
percent of cases are from a pituitary adenoma, and 10 percent from toms to develop. Autoimmune adrenalitiss is the most common
adrenal carcinomas (Lekarev, 2011; Lindsay, 2005). All reports cause in the developed world, but tuberculosis is a more fre-
stress difficulties in diagnosis because of pregnancy-induced quent etiology in resource-poor countries (Kamoun, 2014).
increases in plasma cortisol, corticotropin, and corticotropin- There is an increased incidence of concurrent Hashimoto thy-
releasing factor levels. Measurement of 24-hour urinary free roiditis, premature ovarian failure, type 1 diabetes, and Graves
cortisol excretion is recommended, with consideration for nor- disease. These polyglandular autoimmune syndromess also include
mal elevation in pregnancy. pernicious anemia, vitiligo, alopecia, nontropical sprue, and
Pregnancy outcomes in women with Cushing syndrome are myasthenia gravis.
listed in Table 58-7. Heart failure is common during pregnancy Untreated adrenal hypofunction frequently causes infertil-
and is a major cause of maternal mortality (Buescher, 1992). ity, but with replacement therapy, ovulation is restored. The
Hypercortisolism in pregnancy may also cause poor wound incidence of primary adrenal insufficiency has been cited as
healing, osteoporotic fracture, and psychiatric complications being as high as 1 in 3000 births in Norway (Lekarev, 2011).
(Kamoun, 2014). If untreated, symptoms often include weakness, fatigue, nau-
Long-term medical therapy for Cushing syndrome usually sea and vomiting, and weight loss (Mestman, 2002). Because
is ineffective, and definitive therapy is resection of the pituitary serum cortisol levels are increased during pregnancy, the finding
or adrenal adenoma or bilateral adrenalectomy for hyperplasia of a low value should prompt an adrenocorticotropic hormone
(Lekarev, 2011; Motivala, 2011). During pregnancy, manage- (ACTH) stimulation test to document the lack of response to
ment of hypertension in mild cases may suffice until delivery. infused corticotropin (Salvatori, 2005).
In their review, Lindsay and associates (2005) described primary In a large Swedish cohort study, 1188 women with Addison
medical therapy in 20 women with Cushing syndrome. Most disease were compared with more than 11,000 age-matched
were successfully treated with metyraponee as an interim treatment controls who delivered between 1973 and 2006. Women diag-
until definitive surgery after delivery. A few cases were treated nosed with adrenal insufficiency within 3 years of delivery were
with oral ketoconazole. However, because this drug also blocks twice as likely to deliver preterm, were three times more likely to
testicular steroidogenesis, treatment during pregnancy with a deliver a low-birthweight infant, and were more likely to undergo
male fetus is worrisome. Mifepristone, the norethindrone deriva- cesarean delivery (Björnsdottir, 2010). Most pregnant women
tive used for abortion and labor induction, has shown promise for with Addison disease are already taking cortisone-like drugs.
treating Cushing disease but should not be used in pregnancy for These should be continued and women observed for evidence of
 1162 Medical and Surgical Complications

either inadequate or excessive corticosteroid replacement. During Symptomatic enlargement of macroadenomas, however, is more
labor, delivery, and postpartum, or after a surgical procedure, frequent and was found in 26 percent of 84 pregnant women
corticosteroid replacement must be increased appreciably to included in this analysis. Schlechte (2007) also reported that
approximate the normal adrenal response—so-called stress doses. 15 to 35 percent of suprasellar macroadenomas have tumor
SECTION 12

Hydrocortisone, 100 mg, is usually given intravenously every enlargement that causes visual disturbances, headaches, and
8 hours. It is important that shock from causes other than adre- diabetes insipidus.
nocortical insufficiency—for example, hemorrhage or sepsis— Gillam and colleagues (2006) recommend that pregnant
be recognized and treated promptly. women with microadenomas be queried regularly for headaches
and visual symptoms. Those with macroadenomas should be fol-
lowed more closely and have visual field testing during each tri-
■ Primary Aldosteronism mester. CT or MR imaging is recommended only if symptoms
Hyperaldosteronism is caused by an adrenal aldosteronoma in develop. Serial serum prolactin levels are of little use because
approximately 75 percent of cases. Idiopathic bilateral adrenal of normal increases during pregnancy (Appendix, p. 1291).
hyperplasia comprise the remainder, except for rare cases of adre- Symptomatic tumor enlargement should be treated immediately
nal carcinoma (Abdelmannan, 2011; Ganguly, 1998). Findings with a dopamine antagonist such as bromocriptine or caber-
include hypertension, hypokalemia, and muscle weakness. High goline. The safety of bromocriptine in pregnancy is well estab-
serum or urine levels of aldosterone confirm the diagnosis. lished. It is less well known for cabergoline, which is increasingly
In normal pregnancy, as discussed in Chapter 4 (p. 61), used in nonpregnant women because it is better tolerated and
progesterone blocks aldosterone action, and thus there are very more effective. It is generally considered safe for use in preg-
high levels of aldosterone (Appendix, p. 1290). Accordingly, nancy (Briggs, 2011). Lebbe and colleagues (2010) described
the diagnosis of hyperaldosteronism during pregnancy can be 100 pregnancies exposed to cabergoline and found no adverse
difficult. Since renin levels are suppressed in pregnant women effects. Similar findings were reported in 85 exposed Japanese
with hyperaldosteronism, a plasma aldosterone-to-renin activ- pregnant women (Ono, 2010). Surgery is recommended for
ity ratio may be helpful for diagnosis (Kamoun, 2014). Medical women with no response, and Gondim and associates (2003)
management includes potassium supplementation and antihy- have described transnasal transseptal endoscopic resection.
pertensive therapy. In many cases, hypertension responds to
spironolactone, but β-blockers or calcium-channel blockers may
■ Acromegaly
be preferred because of the potential fetal antiandrogenic effects
of spironolactone. Mascetti and coworkers (2011) reported suc- This is caused by excessive growth hormone, usually from an
cessful use of amiloridee in a pregnant woman. Use of eplerenone, acidophilic or a chromophobic pituitary adenoma. In normal
a mineralocorticoid receptor antagonist, has also been reported pregnancy, pituitary growth hormone levels decrease as placen-
(Cabassi, 2012). Tumor resection is curative, and laparoscopic tal epitopes are secreted. Diagnosis is confirmed by the failure of
adrenalectomy has been shown to be safe (Kamoun, 2014; an oral glucose tolerance test to suppress pituitary growth hor-
Kosaka, 2006; Miller, 2012). mone (Melmed, 2006). There have been fewer than 100 cases
of acromegaly reported during pregnancy (Motivala, 2011).
Pregnancy is probably rare in women with acromegaly, because
PITUITARY DISORDERS half are hyperprolactinemic and anovulatory. In a recent report
describing 46 pregnant women with acromegaly, Caron and
There is impressive pituitary enlargement during pregnancy, coworkers (2010) concluded that such women were at margin-
predominately from lactotrophic cellular hyperplasia induced ally increased risk for gestational diabetes and hypertension.
by estrogen stimulation (Chap. 4, p. 67). Management is similar to that for prolactinomas, with close
monitoring for symptoms of tumor enlargement. Dopamine
■ Prolactinomas agonist therapy is not as effective as it is for prolactinomas. And
transsphenoidal resection, generally considered first-line treat-
These adenomas are found often in nonpregnant women since
ment outside of pregnancy, may be necessary for symptomatic
the advent of widely available serum prolactin assays. Serum
tumor enlargement during pregnancy (Motivala, 2011). Guven
levels less than 25 pg/mL are considered normal in nonpreg-
and associates (2006) reported a case of pituitary apoplexy
nant women (Motivala, 2011). Adenoma symptoms and
necessitating emergent transsphenoidal adenoma resection and
findings include amenorrhea, galactorrhea, and hyperprolac-
cesarean delivery at 34 weeks. Successful treatment of preg-
tinemia. Tumors are classified arbitrarily by their size measured
nant women with the somatostatin-receptor ligand octreotide
by CT or MR imaging. A microadenoma is ≤ 10 mm, and a
and with the GH analogue pegvisomantt has also been reported
macroadenoma is > 10 mm. Treatment for microadenomas is
(Brian, 2007; Herman-Bonert, 1998; Neal, 2000).
usually with bromocriptine, a dopamine agonist and powerful
prolactin inhibitor, which frequently restores ovulation. For
suprasellar macroadenomas, most recommend surgical resec- ■ Diabetes Insipidus
tion before pregnancy is attempted (Schlechte, 2007). The vasopressin deficiency evident in diabetes insipidus is usu-
In a pooled analysis of more than 500 pregnant women with ally due to a hypothalamic or pituitary stalk disorder rather
prolactinomas, only 1.4 percent with microadenomass developed than to a pituitary lesion (Lamberts, 1998). True diabetes
symptomatic enlargement during pregnancy (Molitch, 2003). insipidus is a rare complication of pregnancy.
 Endocrine Disorders 1163

Therapy for diabetes insipidus is intranasal administration Affected women may have persistent hypotension, tachycardia,
of a synthetic analogue of vasopressin, desmopressin, which is hypoglycemia, and lactation failure. Because deficiencies of
1-deamino-8-d-arginine vasopressin (DDAVP). Ray (1998) some or all pituitary responsive hormones may develop after

CHAPTER 58
reviewed 53 cases in which DDAVP was used during preg- the initial insult, Sheehan syndrome can be heterogenous and
nancy with no adverse sequelae. Most women require increased may not be identified for years (Tessnow, 2010). In one cohort
doses during pregnancy because of an increased metabolic clear- study of 60 women from Costa Rica with Sheehan syndrome,
ance rate stimulated by placental vasopressinase (Lindheimer, the average time to diagnosis was 13 years (Gei-Guardia, 2011).
1994). By this same mechanism, subclinical diabetes insipidus Because adrenal insufficiency is the most life-threatening com-
may become symptomatic or cases of transient diabetes insipi- plication, adrenal function should be immediately assessed in
duss may be encountered during pregnancy (Brewster, 2005; any woman suspected of having Sheehan syndrome. After glu-
Wallia, 2013). The prevalence of vasopressinase-induced dia- cocorticoid replacement, subsequent analyses and replacement
betes insipidus is estimated at 2 to 4 per 100,000 pregnancies of thyroid, gonadal, and growth hormones should be consid-
(Wallia, 2013). ered (Gei-Guardia, 2011; Tessnow, 2010).
In our experiences, as described in Chapter 55 (p. 1086),
transient secondary diabetes insipidus is more likely encoun-
tered with acute fatty liver of pregnancyy (Nelson, 2013). This ■ Lymphocytic Hypophysitis
probably is due to altered vasopressinase clearance because of This autoimmune pituitary disorder is characterized by massive
hepatic dysfunction. infiltration by lymphocytes and plasma cells with parenchymal
destruction of the gland. Most cases are temporally linked to
■ Sheehan Syndrome pregnancy (Caturegli, 2005; Foyouzi, 2011; Madsen, 2000).
There are varying degrees of hypopituitarism or symptoms of
Sheehan (1937) reported that pituitary ischemia and necrosis
mass effect, including headaches and visual field defects. A sel-
associated with obstetrical blood loss could result in hypopi-
lar mass is seen with CT or MR imaging. A mass accompa-
tuitarism. With modern methods of hemorrhagic shock treat-
nied by a modestly elevated serum prolactin level—usually <
ment, Sheehan syndrome is now seldom encountered (Feinberg,
100 pg/mL—suggests lymphocytic hypophysitis. In contrast,
2005; Tessnow, 2010). An example is shown in Figure 58-7.
levels > 200 pg/mL are encountered with a prolactinoma.
The etiology is unknown, but nearly 30 percent have a his-
tory of coexisting autoimmune diseases including Hashimoto
thyroiditis, Addison disease, type 1 diabetes, and pernicious
anemia. Treatment is with hormone replacement and because
the disease may be self-limited, a careful withdrawal of hor-
mone replacement should be attempted after inflammation
resolution (Foyouzi, 2011; Gagneja, 1999). Surgery during
pregnancy is warranted only in cases of severe chiasmal com-
pression unresponsive to corticosteroid therapy (Lee, 2003).

REFERENCES
Abalovich M, Alcaraz G, Kleiman-Rubinsztein J, et al: The relationship of
preconception thyrotropin levels to requirements for increasing the levo-
thyroxine dose during pregnancy in women with primary hypothyroidism.
Thyroid 20(10):1175, 2010
Abalovich M, Gutierrez S, Alcaraz G, et al: Overt and subclinical hypothyroid-
ism complicating pregnancy. Thyroid 12:63, 2002
Abbassi-Ghanavati M, Casey B, Spong C, et al: Pregnancy outcomes in women
with thyroid peroxidase antibodies. Obstet Gynecol 116(2, Pt 1):381, 2010
Abdelmannan D, Aron D: Adrenal disorders in pregnancy. Endocrinol Metab
Clin North Am 40:779, 2011
Abduljabbar M, Affi A: Congenital hypothyroidism. J Pediatr Endocrinol
Metab 25(1–2):13, 2012
Abramson J, Stagnaro-Green A: Thyroid antibodies and fetal loss: an evolving
story. Thyroid 11:57, 2001
Ahlawat SK, Jain S, Kumari S, et al: Pheochromocytoma associated with preg-
nancy: case report and review of the literature. Obstet Gynecol Surv 54:728,
1999
FIGURE 58-7 Sheehan syndrome in a 23-year-old primipara who Alexander EK, Marquesee E, Lawrence J, et al: Timing and magnitude of
had major postpartum hemorrhage and hypotension intraopera- increases in levothyroxine requirements during pregnancy in women with
tively during cesarean delivery. Magnetic resonance imaging was hypothyroidism. N Engl J Med 351:241, 2004
obtained because she failed to lactate, and her serum prolactin Alikasifoglu A, Gonc EN, Yalcin E, et al: Neonatal hyperparathyroidism due to
maternal hypoparathyroidism and vitamin D deficiency: a cause of multiple
level was 18 ng/mL. This sagittal magnetic resonance image bone fractures. Clin Pediatr 44:267, 2005
shows a large pituitary gland mass (arrows) consistent with hem- American College of Obstetricians and Gynecologists: Subclinical hypo-
orrhage. Subsequent imaging showed complete hematoma invo- thyroidism in pregnancy. Committee Opinion No. 381, October 2007,
lution, and replacement therapy was not required. Reaffirmed 2012
1168

CHAPTER 59

Connective-Tissue Disorders

IMMUNE-MEDIATED CONNECTIVE-TISSUE DISEASES . . 1168 inflammatory conditions such as SLE, rheumatoid arthritis,
systemic sclerosis (scleroderma), mixed connective-tissue dis-
SYSTEMIC LUPUS ERYTHEMATOSUS. . . . . . . . . . . . . . . 1169 ease, dermatomyositis, polymyositis, and various vasculitis syn-
ANTIPHOSPHOLIPID ANTIBODY SYNDROME . . . . . . . . 1173 dromes. The RF-seronegative spondyloarthropathiess are strongly
associated with expression of the HLA-B27 antigen and include
RHEUMATOID ARTHRITIS . . . . . . . . . . . . . . . . . . . . . . 1176 ankylosing spondylitis, psoriatic arthritis, Reiter disease, and
other arthritis syndromes.
SYSTEMIC SCLEROSIS—SCLERODERMA . . . . . . . . . . . . 1178 Pregnancy may mitigate activity in some of these syndromes
VASCULITIS SYNDROMES . . . . . . . . . . . . . . . . . . . . . . 1179 as a result of the immunosuppression that also allows successful
engraftment of fetal and placental tissues. These changes are
INFLAMMATORY MYOPATHIES . . . . . . . . . . . . . . . . . . 1180 discussed in detail in Chapters 4 and 5 (p. 56). One example
is pregnancy-induced predominance of T2 helper cells com-
HEREDITARY CONNECTIVE-TISSUE DISORDERS . . . . . . 1181 pared with cytokine-producing T1 helper cells (Keeling, 2009).
Pregnancy hormones alter immune cells, for example, estro-
gens upregulate and androgens downregulate T-cell response,
and progesterone is immunosuppressive (Cutolo, 2006; Häupl,
Connective-tissue disorders, which are also termed collagen- 2008a; Robinson, 2012).
vascular disorders, have two basic underlying causes. First are Some immune-mediated diseases may either be caused or acti-
the autoantibody-mediated immune-complex diseasess in which vated as a result of previous pregnancies. To explain, fetal cells and
connective-tissue damage is caused by deposition of immune free fetal DNA are detectable in maternal blood beginning early in
complexes in specific organ(s) or tissue sites. Because these are pregnancy (Simpson, 2013; Sitar, 2005; Waldorf, 2008). Fetal cell
manifest by sterile inflammation—predominately of the skin, microchimerism m is the persistence of fetal cells in the maternal circu-
joints, blood vessels, and kidneys—they are referred to as rheu- lation and organs following pregnancy. These persistent fetal cells
matic diseases. Many of these immune-complex diseases are more may stimulate autoantibodies, or they may become engrafted in
prevalent in women, for example, systemic lupus erythematosus maternal tissues. This raises the possibility that fetal cell microchi-
(SLE), rheumatoid arthritis, and a host of vasculitis syndromes. merism is related to the predilection of autoimmune disorders for
Second are the inherited disorderss of bone, skin, cartilage, blood women (Adams, 2004; Lissauer, 2009). Evidence for this includes
vessels, and basement membranes. Some examples include Marfan findings of fetal stem cells engrafted in maternal tissues in women
syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome. with autoimmune thyroiditis and systemic sclerosis (Jimenez, 2005;
Srivatsa, 2001). Such microchimerism has also been described in
IMMUNE-MEDIATED CONNECTIVE-TISSUE women with SLE and those with rheumatoid arthritis-associated
DISEASES HLA alleles (Johnson, 2001; Lee, 2010; Rak, 2009a). Similarly,
engrafted maternal cells may provoke autoimmune conditions in a
These disorders can be separated into those associated with and woman’s offspring (Ye, 2012). Perhaps related, women with SLE
those without autoantibody formation. So-called rheumatoid have a 0.6 male:female offspring ratio suggesting excessive male
factor (RF) is an autoantibody found in many autoimmune fetal loss in these women (Aggarwal, 2013).
 Connective-Tissue Disorders 1169

TABLE 59-1. Some Autoantibodies Produced in Patients with Systemic Lupus Erythematosus (SLE)
Prevalence
Antibody (%) Clinical Associations

CHAPTER 59
Antinuclear (ANA) 84–98 Best screening test, multiple antibodies; a second negative test makes SLE unlikely
Anti-double-stranded 62–70 High titers SLE-specific; may correlate with disease activity, nephritis, and vasculitis
(ds)-DNA
Anti-Sm (Smith) 25–38 Specific for SLE
Anti-RNP 33–40 Not SLE-specific, high titers associated with rheumatic syndromes
Anti-Ro (SS-A) 30–49 Not SLE-specific; associated with Sjögren syndrome, predisposes to cutaneous lupus,
neonatal lupus with heart block, reduced risk of nephritis
Anti-La (SS-B) 10–35 Associated with anti-Ro; possible decreased nephritis risk
Antihistone 70 Common in drug-induced lupus (95%)
Antiphospholipid 21–50 Lupus anticoagulant and anticardiolipin antibodies associated with thrombosis, fetal
loss, thrombocytopenia, valvular heart disease; false-positive test for syphilis
Anti-erythrocyte 60 Small number develop hemolysis
Antiplatelet 30 Thrombocytopenia in 15%; poor clinical test

Data from Arbuckle, 2003; Hahn, 2012.

■ Systemic Lupus Erythematosus flares, end-organ failure, hypertension, stroke, and cardiovascu-
Lupus is a heterogeneous autoimmune disease with a complex lar disease account for most deaths.
pathogenesis that results in interactions between susceptibility Genetic influences are implicated by a higher concordance
genes and environmental factors (Hahn, 2012; Tsokos, 2011). with monozygotic compared with dizygotic twins—25 versus
Immune system abnormalities include overactive B lympho- 2 percent, respectively. Moreover, there is a 10-percent fre-
cytes that are responsible for autoantibody production. These quency in patients with one affected family member. The rela-
result in tissue and cellular damage when autoantibodies or tive risk of disease is increased if there is inheritance of the
immune complexes are directed at one or more cellular nuclear “autoimmunity gene” on chromosome 16 that predisposes to
components (Tsokos, 2011). In addition, immunosuppres- SLE, rheumatoid arthritis, Crohn disease, and psoriasis (Hahn,
sion is impaired, including regulatory T-cell function (Tower, 2012). Susceptibility genes such as HLA-A1, B8, DR3, DRB1,
2013). Some autoantibodies produced in patients with lupus and TET3 explain only a portion of the genetic heritability
are shown in Table 59-1. (Hom, 2008; Tsokos, 2011; Yang, 2013).
Almost 90 percent of lupus cases are in women, and its prev-
alence in those of childbearing age is approximately 1 in 500 Clinical Manifestations and Diagnosis
(Lockshin, 2000). Accordingly, the disease is encountered rela- Lupus is notoriously variable in its presentation, course, and
tively frequently during pregnancy. The 10-year survival rate is outcome (Table 59-2). Findings may be confined initially
70 to 90 percent (Hahn, 2012; Tsokos, 2011). Infection, lupus to one organ system, and others become involved later. Or,

TABLE 59-2. Clinical Manifestations of Systemic Lupus Erythematosus

Organ System Clinical Manifestations Percent
Systemic Fatigue, malaise, fever, weight loss 95
Musculoskeletal Arthralgias, myalgias, polyarthritis, myopathy 95
Hematological Anemia, hemolysis, leukopenia, thrombocytopenia, 85
lupus anticoagulant, splenomegaly
Cutaneous Malar (butterfly) rash, discoid rash, photosensitivity, oral 80
ulcers, alopecia, skin rashes
Neurological Cognitive dysfunction, mood disorder, headache, seizures 60
Cardiopulmonary Pleuritis, pericarditis, myocarditis, endocarditis, 60
pneumonitis, pulmonary hypertension
Renal Proteinuria, casts, nephrotic syndrome, renal failure 30–50
Gastrointestinal Nausea, pain, diarrhea, abnormal liver enzyme levels 40
Vascular Thrombosis: venous (10%), arterial (5%) 15
Ocular Conjunctivitis 15

Modified from Hahn, 2012.

 1170 Medical and Surgical Complications

the disease may first manifest with multisystem involvement.

TABLE 59-3. Criteria of the American Rheumatism
Common findings are malaise, fever, arthritis, rash, pleuro-
Association for Systemic Lupus
pericarditis, photosensitivity, anemia, and cognitive dysfunc-
Erythematosus (SLE)
tion. At least half of patients have renal involvement. There
SECTION 12

is evidence that lupus is associated with decline in attention, Criteriaa Comments

memory, and reasoning (Kozora, 2008). Although Libman- Malar rash Malar erythema
Sacks endocarditiss was described with lupus, it is likely due to Discoid rash Erythematous patches, scaling, follicular
presence of subsequently discussed anticardiolipin antibodies plugging
(Hojnik, 1996). Photosensitivity Exposure to UV light causes rash
Identification of antinuclear antibodies (ANA) is the best Oral ulcers Usually painless oral and
screening test. However, a positive result is not specific for nasopharyngeal ulcers
lupus. For example, low titers are found in normal individuals, Arthritis Nonerosive involving two or more
other autoimmune diseases, acute viral infections, and chronic peripheral joints with tenderness,
inflammatory processes. Several drugs can also cause a posi- swelling, or effusion
tive reaction. Antibodies to double-stranded DNA (dsDNA) Serositis Pleuritis or pericarditis
and to Smith (Sm) antigens are relatively specific for lupus, Renal Proteinuria greater than 0.5 g/day or
whereas other antibodies are not (see Table 59-1). Although > 3+ dipstick, or cellular casts
hundreds of autoantibodies have been described in SLE, only Neurological Seizures or psychosis without other
a few have been shown to participate in tissue injury (Sherer, cause
2004; Tsokos, 2011). Microarray profiles are being developed Hematological Hemolytic anemia, leukopenia,
for customized and more accurate SLE diagnoses (Lin, 2013; lymphopenia, or thrombocytopenia
Yeste, 2013). Autoantibodies Anti-dsDNA or anti-Sm antibodies,
Anemia develops frequently, and there may be leukopenia or false-positive VDRL, abnormal
and thrombocytopenia. Proteinuria and casts are found in the level of IgM or IgG anticardiolipin
half of patients with glomerular lesions. Lupus nephritis can antibodies, or lupus anticoagulant
also cause renal insufficiency, which is more common if there ANA Abnormally elevated ANA titers
are antiphospholipid antibodies (Moroni, 2004). Other labora-
a
tory findings include false-positive syphilis serology, prolonged If four or more criteria are present at any time during
partial thromboplastin time, and higher rheumatoid factor disease course, SLE can be diagnosed with 75-percent
levels. Elevated serum d-dimer levels often follow a flare or specificity and 95-percent sensitivity.
infection, but unexplained persistent elevations are associated ANA = antinuclear antibodies; dsDNA = double-stranded
with a high risk for thrombosis (Wu, 2008). DNA; Sm = Smith; UV = ultraviolet; VDRL = Venereal
The diagnostic criteria for SLE are listed in Table 59-3. If Disease Research Laboratory.
any four or more of these 11 criteria are present, serially or Modified from Hahn, 2012; Hochberg, 1997; Tan, 1982.
simultaneously, the diagnosis of lupus is made.
Importantly, numerous drugs can induce a lupus-like syn-
drome. These include procainamide, quinidine, hydralazine,
α-methyldopa, phenytoin, and phenobarbital. Drug-induced pregnancy. Women who have confined cutaneous lupus do
lupus is rarely associated with glomerulonephritis and usually not usually have adverse outcomes (Hamed, 2013). Frequent
regresses when the medication is discontinued (Rubin, 1997). complications in a cohort of 13,555 women with SLE during
pregnancy are shown in Table 59-4. The maternal mortality
Lupus and Pregnancy and severe morbidity rate was 325 per 100,000. In a review
Of nearly 16.7 million pregnancies in the United States from of 13 studies with 17 maternal deaths attributable to SLE
2000 to 2003, 13,555 were complicated by lupus—an inci- and lupus nephritis, all occurred in those with active disease
dence of approximately 1 in 1250 pregnancies (Clowse, 2008). (Ritchie, 2012).
During the past several decades, pregnancy outcomes in From the foregoing, it is certain that lupus can be life threat-
women with SLE have improved remarkably. Important fac- ening for both mother and fetus. Generally speaking, pregnancy
tors for pregnancy outcome include whether disease is active outcome is best in those women in whom: (1) lupus activity
at the beginning of pregnancy, age and parity, coexistence of has been quiescent for at least 6 months before conception; (2)
other medical or obstetrical disorders, and whether antiphos- there is no lupus nephritis manifest by proteinuria or renal dys-
pholipid antibodies are detected (p. 1173). There is evidence function; (3) there is no evidence of the antiphospholipid anti-
that newly diagnosed lupus during pregnancy tends to be severe body syndrome or lupus anticoagulant; and (4) superimposed
(Zhao, 2013). preeclampsia does not develop (Peart, 2014; Stojan, 2012).
During pregnancy, lupus improves in a third of women,
remains unchanged in a third, and worsens in the remaining Lupus Nephritis. Active nephritis has been associated with
third. Thus, in any given pregnancy, the clinical condition particularly bad pregnancy outcomes, although these have
can worsen or flaree without warning (Khamashta, 1997). Petri improved remarkably during the past 30 years (Moroni, 2005;
(1998) reported a 7-percent risk of major morbidity during Stojan, 2012). Women with renal disease have a high incidence
 Connective-Tissue Disorders 1171

that this is the time that activation or exacerbations are most

TABLE 59-4. Complications in 13,555 Pregnancies
likely to develop, the evidence is not conclusive.
in Women with Systemic Lupus
Erythematosus Lupus versus Preeclampsia-Eclampsia. Chronic hyper-

CHAPTER 59
Complications Percent tension complicates up to 30 percent of pregnancies in women
Comorbid illness with SLE (Egerman, 2005). And as discussed, preeclampsia is
Pregestational diabetes 5.6 common, and superimposed preeclampsia is encountered even
Thrombophilia 4.0 more often in those with nephritis or antiphospholipid anti-
Hypertension 3.9 bodies (Bertsias, 2008). It may be difficult, if not impossible
Renal failure 0.2 to differentiate lupus nephropathy from severe preeclampsia if
Pulmonary hypertension 0.2 the kidney is the only involved organ (Petri, 2007). Central ner-
vous system involvement with lupus may culminate in convul-
Pregnancy complications
sions similar to those of eclampsia. Thrombocytopenia, with or
Preeclampsia 22.5
without hemolysis, may further confuse the diagnosis because
Preterm labor 20.8
of its similarity to the hemolysis, elevated liver enzymes, low
Fetal-growth restriction 5.6
platelet count (HELLP) syndrome. Management is identical
Eclampsia 0.5
to that for preeclampsia-eclampsia, described in Chapter 40
Medical complications (p. 749).
Anemia 12.6
Thrombocytopenia 4.3 Management During Pregnancy
Thrombotic—stroke, pulmonary 1.7
embolism, deep-vein thrombosis Lupus management consists primarily of monitoring maternal
clinical and laboratory conditions as well as fetal well-being
Infections—pneumonia, sepsis syndrome 2.2
(Lateef, 2012). Pregnancy-induced thrombocytopenia and
Maternal morbidity-mortality rate 325/100,000 proteinuria resemble lupus disease activity, and the identifica-
tion of a lupus flare is confounded by the increase in facial and
Data from Clowse, 2008. palmar erythema of normal pregnancy (Lockshin, 2003). Some
authorities have advocated a number of numerical scales to
emphasize ongoing disease activity. Components are weighted
of gestational hypertension and preeclampsia. However, if for severity, both with the SLE-Pregnancy Disease Activity
their disease remains in remission, they usually have good Index (SLEPDAI) and with the Lupus Activity Index (Buyon,
pregnancy outcomes (Huong, 2001; Moroni, 2002). Of the 1999; Ruiz-Irastorza, 2004). We have not found these to be
125 pregnancies reported by Lockshin (1989), 63 percent of useful.
women with preexisting renal disease developed preeclampsia Lupus activity monitoring and identification of lupus flares
compared with only 14 percent of those without underlying by various laboratory techniques has been recommended. The
renal disease. Moroni and Ponticelli (2005) reviewed results sedimentation rate may be misleading because of pregnancy-
from a total of 309 pregnancies complicated by established induced hyperfibrinogenemia. Serum complement levels are
lupus nephritis. Of these, 30 percent suffered a flare, and 40 also normally increased in pregnancy (Chap. 4, p. 56 and
percent of these had associated renal insufficiency. The maternal Appendix, p. 1291). And, although falling or low levels of
mortality rate was 1.3 percent. complement components C3, C4, and CH50 are more likely
In two studies describing pregnancy outcomes in women with to be associated with active disease, higher levels provide no
lupus nephritis, Wagner and coworkers (2009) compared out- assurance against disease activation. Our experiences, as well
comes of 58 women cared for during 90 pregnancies at the Mayo as those of Varner and colleagues (1983) and Lockshin and
Clinic. Active nephritis was associated with a significantly higher Druzin (1995), are that there is no correlation between clinical
incidence of maternal complications compared with women manifestations of disease and complement levels.
without nephritis—57 versus 11 percent. Quiescent nephritis Serial hematological studies may detect changes in disease
had a nonsignificant effect on preeclampsia rates compared with activity. Hemolysis is characterized by a positive Coombs test,
lupus patients without renal impairment. The fetal death rate anemia, reticulocytosis, and unconjugated hyperbilirubine-
with active maternal nephritis was 35 percent compared with mia. Thrombocytopenia, leukopenia, or both may develop.
9 percent in those with quiescent nephritis. In another study, According to Lockshin and Druzin (1995), chronic thrombo-
Imbasciati and associates (2009) described outcomes in 113 cytopenia in early pregnancy may be due to antiphospholipid
pregnancies in 81 women with known lupus nephritis. During antibodies. Later, thrombocytopenia may indicate preeclampsia.
a third of pregnancies, there was a renal flare. After excluding Serum aminotransferase activity reflects hepatic involve-
nine miscarriages, of the 104 remaining pregnancies, a third ment, as does a rise in serum bilirubin levels. Azathioprine
were delivered preterm, a third of infants weighed < 2500 g, therapy also may induce enzyme elevations. Urine is tested fre-
and the perinatal mortality rate was 6 percent. quently to detect new-onset or worsening proteinuria. Overt
Most recommend continuation of immunosuppressive ther- proteinuria that persists is an ominous sign, even more so if
apy for nephritis during pregnancy. It is not clear whether the accompanied by other evidence of the nephrotic syndrome or
dose should be increased peripartum. Although it is often stated abnormal serum creatinine levels.
 1172 Medical and Surgical Complications

The fetus should be closely observed for adverse effects such fetal-growth restriction, stillbirths, and neonatal lupus syn-
as growth restriction and oligohydramnios. Many recommend drome (Madazli, 2014). Outcomes are worse with a lupus
screening for anti-SS-A (anti-Ro) and anti-SS-B (anti-La) anti- flare, significant proteinuria, or renal impairment, and with
bodies, because of associated fetal complications described sub- chronic hypertension, preeclampsia, or both (Aggarwal, 1999;
SECTION 12

sequently. As discussed in Chapter 17 (p. 335), antepartum Bramham, 2012; Scott, 2002; Wagner, 2009). The observa-
fetal surveillance is done as outlined by the American College tions of Lee and coworkers (2009) are worrisome. In a mouse
of Obstetricians and Gynecologists (2012a). Unless hyper- SLE model, they showed that autoantibodies directed against
tension develops or there is evidence of fetal compromise or the N-methyl-
N d-aspartate neuroreceptor caused fetal neuro-
growth restriction, pregnancy is allowed to progress to term. toxicity. This suggests an underlying etiology for the CNS
Peripartum corticosteroids in “stress doses” are given to women manifestations and learning disorders in children of affected
who are taking these drugs or who recently have done so. mothers. Ongoing work on anti-dsDNA antibodies has iden-
tified peptides that can protect target organs from antibody-
Pharmacological Treatment. There is no cure, and com- mediated damage (Diamond, 2011).
plete remissions are rare. Approximately a fourth of women The reasons at least partially responsible for adverse fetal con-
have mild disease, which is not life threatening, but may be dis- sequences include decidual vasculopathy with placental infarc-
abling because of pain and fatigue. Arthralgia and serositis can tion and decreased perfusion (Hanly, 1988; Lubbe, 1984).
be managed by occasional doses of nonsteroidal antiinflamma- Placental pathology is discussed in more detail in Chapter 6
tory drugs (NSAIDs). However, chronic or large intermittent (p. 119).
dosing is avoided due to pregnancy side effects with these drugs
described in Chapter 12 (p. 247) (Briggs, 2011). Low-dose aspi- Neonatal Lupus Syndrome. This unusual constellation is
rin can be used throughout gestation. Severe disease is managed characterized by newborn skin lesions—lupus dermatitis; a
with corticosteroids such as prednisone, 1 to 2 mg/kg orally per variable number of hematological and systemic derangements;
day. After the disease is controlled, this dose is tapered to a daily and occasionally congenital heart block (Boh, 2004; Lee,
morning dose of 10 to 15 mg. Corticosteroid therapy can result 2009). Although usually associated with anti-SS-A and -SS-B
in the development of gestational diabetes. antibodies, McGeachy and Lam (2009) described an affected
Immunosuppressive agents such as azathioprine are benefi- infant in whom only anti-ribonucleoprotein (RNP) antibod-
cial in controlling active disease (Contreras, 2004; Hahn, 2012). ies were found. Thrombocytopenia and hepatic involvement
In nonpregnant patients, these are usually reserved for lupus are seen in 5 to 10 percent of affected infants. One report
nephritis or disease that is corticosteroid resistant. Azathioprine suggests that neonatal lupus may appear up to 4 weeks after
has a good safety record during pregnancy (Fischer-Betz, 2013; birth (Stirnemann, 2002). Lockshin and colleagues (1988)
Petri, 2007). Its recommended daily oral dose is 2 to 3 mg/kg. prospectively followed 91 infants born to women with lupus.
According to Buhimschi and Weiner (2009), cyclophospha- Eight were possibly affected—four had definite neonatal lupus
mide is teratogenic, and although not usually recommended and four had possible disease. Clinical manifestations, which
during pregnancy, severe disease may be treated after 12 weeks’ include cutaneous lupus, thrombocytopenia, and autoimmune
gestation. As discussed in Chapter 12 (p. 250), medications to hemolysis, are transient and clear within a few months (Lee,
be avoided include mycophenolate mofetil and methotrexate 1984). This may not be so for congenital heart block. In subse-
(Anderka, 2009; Briggs, 2011; Food and Drug Administration, quent offspring, the recurrence risk for neonatal lupus is up to
2008). In some situations, mycophenolate is the only treatment 25 percent (Julkunen, 1993).
that achieves disease stability. In these cases, counseling regard-
ing fetal risks is essential (Bramham, 2012). Congenital Heart Block. Fetal and neonatal heart block
Antimalarials help control skin disease. Although these results from diffuse myocarditis and fibrosis in the region
agents cross the placenta, hydroxychloroquine has not been between the atrioventricular (AV) node and bundle of His.
associated with congenital malformations. Because of the long Buyon and associates (1993) reported that congenital heart
half-life of antimalarials and because discontinuing therapy can block developed almost exclusively in fetuses of women with
precipitate a lupus flare, most recommend their continuation antibodies to the SS-A or SS-B antigens. These antibodies
during pregnancy (Borden, 2001; Harris, 2002). Levy and may also cause otherwise unexplained stillbirths (Ottaviani,
associates (2001) randomly assigned 20 pregnant women to 2004). Even in the presence of such antibodies, however, the
receive hydroxychloroquine or placebo and reported improved incidence of myocarditis is only 2 to 3 percent but increases
SLEPDAI scores with hydroxychloroquine. to 20 percent with a prior affected child (Bramham, 2012;
When severe disease supervenes—usually a lupus flare— Lockshin, 1988). Fetal cardiac monitoring should be per-
high-dose glucocorticoid therapy is given. Petri (2007) recom- formed between 18 and 26 weeks’ gestation in pregnancies
mends pulse therapy consisting of methylprednisolone, 1000 with either of these antibodies. The cardiac lesion is perma-
mg given intravenously over 90 minutes daily for 3 days, then nent, and a pacemaker is generally necessary. Long-term prog-
a return to maintenance doses if possible. nosis is poor. Of 325 infants with cardiac neonatal lupus,
nearly 20 percent died, and of these, a third were stillborn
Perinatal Mortality and Morbidity (Izmirly, 2011).
Adverse perinatal outcomes are increased significantly in preg- Maternal administration of corticosteroids, plasma exchange,
nancies complicated by lupus. These include preterm delivery, or intravenous immunoglobulin have not been found to reduce
1204

CHAPTER 61

Psychiatric Disorders

PSYCHOLOGICAL ADJUSTMENTS TO PREGNANCY . . . . 1204 Suicide is the fifth leading cause of death in the United
States among women during the perinatal period, and major
THE PUERPERIUM . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205 depression is among the strongest predictors of suicidal ide-
PRENATAL EVALUATION . . . . . . . . . . . . . . . . . . . . . . . 1205 ation (Melville, 2010). In both the United Kingdom and
Australia, psychiatric illness is a leading cause of mortality
TREATMENT CONSIDERATIONS . . . . . . . . . . . . . . . . . . 1205 for late maternal deaths—those between 43 and 365 days
postpartum (Austin, 2007). Suicide by violent means was
DEPRESSIVE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . 1206 responsible for 65 percent of these. In a 10-year case-control
BIPOLAR AND RELATED DISORDERS . . . . . . . . . . . . . . 1209 analysis of Washington state hospitalizations, Comtois and
associates (2008) studied 355 women with a postpartum sui-
ANXIETY DISORDERS. . . . . . . . . . . . . . . . . . . . . . . . . . 1210 cide attempt. Significant risk factors and their associated rates
included prior hospitalization for a psychiatric diagnosis—
SCHIZOPHRENIA SPECTRUM DISORDERS . . . . . . . . . . . 1210 27-fold, and for substance abuse—sixfold. These rates were
FEEDING AND EATING DISORDERS . . . . . . . . . . . . . . . 1211 further increased if there were multiple hospitalizations.

PERSONALITY DISORDERS. . . . . . . . . . . . . . . . . . . . . . 1211

PSYCHOLOGICAL ADJUSTMENTS TO PREGNANCY
Biochemical factors—including hormonal effects—and life stress-
ors can markedly influence mental illness. Thus, intuitively,
Pregnancy and the puerperium are at times sufficiently stress- pregnancy exacerbates some coexisting mental disorders.
ful to provoke mental illness. Such illness may represent recur- Indeed, pregnancy-related shifts in sex steroids and monoamine
rence or exacerbation of a preexisting psychiatric disorder, or neurotransmitter levels; dysfunction of the hypothalamic-
may signal the onset of a new disorder. Psychiatric disorders pituitary-adrenal axis; thyroid dysfunction; and alterations in
during pregnancy have been associated with less prenatal immune response are all associated with an increased risk for
care, substance abuse, poor obstetrical and infant outcomes, mood disorders (Yonkers, 2011). These changes, coupled with
and a higher risk of postpartum psychiatric illness (Frieder, evidence of familiality of depression, suggest that there may be
2008). Of pregnant women identified with psychiatric disor- a subgroup of women at risk for developing a unipolar major
ders, Andersson and colleagues (2003) in one Swedish study depressive disorder during pregnancy.
reported that more than 80 percent had a mood disorder. Women respond in a variety of ways to stressors of preg-
According to the Agency for Healthcare Research and Quality, nancy, and some express persistent concerns regarding fetal
the period prevalence of any depressive disorder during preg- health, child care, lifestyle changes, or fear of childbirth pain.
nancy in the United States is 18 percent (Yonkers, 2011). Anxiety, sleep disorders, and functional impairment are com-
Unfortunately, most pregnant women with depressive disor- mon (Morewitz, 2003; Romero, 2014; Vythilingum, 2008).
ders are not treated. In the Swedish study mentioned above, According to Littleton and coworkers (2007), however, anxi-
only 5 percent of women identified with psychiatric disorders ety symptoms in pregnancy are associated with psychosocial
received some form of treatment. variables similar to those for nonpregnant women. The level
 Psychiatric Disorders 1205

of perceived stress is significantly higher for women whose dependence have been associated with an increase in rates of
fetus is at high risk for a malformation, for those with preterm alll mental disorders in pregnancy (Goodwin, 2007). Finally,
labor or delivery, and for those with other medical complica- because eating disorders may be exacerbated by pregnancy,

CHAPTER 61
tions (Alder, 2007; Ross, 2006). Hippman (2009) screened 81 affected women should be followed closely.
women for depression who had an increased risk for a fetus According to the American College of Obstetricians and
with aneuploidy. Half of these women had a positive depres- Gynecologists (2012a), there is currently insufficient evidence
sion screening score, whereas only 2.4 percent of those with a to make a firm recommendation for routine depression screen-
normal pregnancy did so. ing, either during or after pregnancy. At Parkland Hospital,
A number of steps can be taken to diminish psychological all women are asked about depression and domestic violence
stress in the event of a poor obstetrical outcome. For example, at their first prenatal visit. They are also screened again dur-
following a stillbirth, Gold (2007) encouraged parental con- ing their first postpartum visit using the Edinburgh Postnatal
tact with the newborn and provision of photographs and other Depression Scale (EPDS). In an analysis of more than 17,000
infant memorabilia. Addressing associated sleep disorders also of these questionnaires, 6 percent had scores that indicated
seems reasonable (Romero, 2014). either minor or major depressive symptoms. Twelve of these
1106 women also had thoughts of self-harm (Nelson, 2013).
■ The Puerperium
The puerperium is a particularly stressful time and carries as ■ Treatment Considerations
increased risk for mental illness. Up to 15 percent of women A large number of psychotropic medications may be used for
develop a nonpsychotic postpartum depressive disorder within 6 management of the myriad mental disorders encountered in
months of delivery (Tam, 2007; Yonkers, 2011). A few have a pregnancy. For treatment options that include psychosocial
more severe, psychotic illness following delivery, and half of these and psychological interventions, treatment decisions are ide-
have a bipolar disorder (Yonkers, 2011). Depressive disorders ally shared between patients and their health-care providers.
are more likely in women with obstetrical complications such as Women taking psychotropic medication should be informed of
severe preeclampsia or fetal-growth restriction, especially if associ- likely side effects. Many of these drugs are discussed in Chapter
ated with early delivery. However, among women with a history 12 as well as by the American College of Obstetricians and
of bipolar disorder, these factors do not seem to play as great a Gynecologists (2012b). Additionally, these drugs are discussed
role in the development of mania or depression (Yonkers, 2011). subsequently in this chapter. Babbitt (2014) and Pozzi (2014)
and their colleagues have recently reviewed principles of antena-
Maternity Blues tal and intrapartum care of women with major mental disorders.
Also called postpartum blues, this is a time-limited period
of heightened emotional reactivity experienced by half of ■ Pregnancy Outcomes
women within approximately the first week after parturition. There are only a few reports of psychiatric disorders and preg-
Prevalence estimates for the blues range from 26 to 84 percent nancy outcomes. Some, but not all, link maternal psychiatric
depending on criteria used for diagnosis (O’Hara, 2014). This illness with untoward outcomes such as preterm birth, low
emotional state generally peaks on the fourth or fifth post- birthweight, and perinatal mortality (Schneid-Kofman, 2008;
partum day and normalizes by day 10 (O’Keane, 2011). The Steinberg, 2014; Yonkers, 2009). In a population-based cohort
predominant mood is happiness. However, affected mothers of more than 500,000 California births, Kelly and colleagues
are more emotionally labile, and insomnia, weepiness, depres- (2002) assessed the perinatal effects of a psychiatric diagnosis
sion, anxiety, poor concentration, irritability, and affective that included all International Classification of Diseases 9th
lability may be noted. Mothers may be transiently tearful for Edition Clinical Modification (ICD-9-CM) diagnostic codes.
several hours and then recover completely, only to be tear- Women with these diagnoses had up to a threefold increased
ful again the next day. Supportive treatment is indicated, incidence of a very-low- or low-birthweight neonate or preterm
and sufferers can be reassured that the dysphoria is transient delivery. In another study of more than 1100 women enrolled
and most likely due to biochemical changes. They should be in a Healthy Start initiative, women with depression were found
monitored for development of depression and other severe to be 1.5 times more likely to be delivered early compared with
psychiatric disturbances. nondepressed women. Conversely, Littleton and associates
(2007) reviewed 50 studies and concluded that anxiety symp-
■ Prenatal Evaluation toms—a common comorbidity in depression—had no adverse
Screening for mental illness is generally done at the first prenatal effect on outcomes.
visit. Factors include a search for psychiatric disorders, includ-
ing hospitalizations, outpatient care, prior or current use of CLASSIFICATION OF MENTAL DISORDERS
psychoactive medications, and current symptoms. Risk factors
should be evaluated—for example, a prior personal or family The Diagnostic and Statistical Manual-V V is the most recent ver-
history of depression conveys a significant risk for depression. sion by the American Psychiatric Association (2013). Its pur-
Women with a history of sexual, physical, or verbal abuse; sub- pose is to assist in the classification of mental disorders, and it
stance abuse; and personality disorders are also at greater risk specifies criteria for each diagnosis. Shown in Table 61-1 are
for depression (Akman, 2007; Tam, 2007). Smoking and nicotine 12-month prevalences of mental disorders for adults.
 1206 Medical and Surgical Complications

TABLE 61-1. The 12-Month Prevalence of Mental Disorders in Adults in the United States
1-Year Lifetime
Prevalence Adults Prevalence
SECTION 12

Disordera (%) Affectedb (%) Comments

All disorders 26.2 58 million — 1 in 4 adults affected annually
Mood disorders—all 21 million 20.8 Median onset age 30 years
Major depression 6.7 15 million — Leading cause of disability in the United States; high
suicide rate
Dysthymia 1.5 3.3 million — Chronic, mild depression
Bipolar disorder 2.6 5.7 million 3.9 Manic-depressive illness
Suicide — 32,400 — 90% have mental disorder; depression most common
Schizophrenia 1.1 18 million Men = women; onset women 20s or early 30s
Anxiety disorder—all 18 40 million Frequent co-occurrence with depression or
Panic 2.7 substance abuse
Obsessive-compulsive 1
Posttraumatic stress 3.5
Generalized anxiety 3.1
Social phobias 6.8
Eating disorders Adolescent and adult females—85–95%
Anorexia nervosa — 2–3 Mortality rate 0.56% per year
Bulimia nervosa — 2–3
Binge eating—6 months 2–5 —
a
Based on Diagnostic and Statistical Manual-IV-R (DSM-IV-R) of the American Psychiatric Association, 2000b.
b
Based on 2004 census data.
From the National Institute of Mental Health, 2006, 2010.

■ Depressive Disorders
According to the National Institute of Mental Health (2010),
the lifetime prevalence of depressive disorders in the United
States is 21 percent. Women are 50 percent more likely than
men to experience a major mood disorder during their life- TABLE 61-2. Symptoms of Depressive Illnessa
time. Historically, these include major depression—a unipo- Persistent sad, anxious, or “empty” feelings
lar disorder—and manic-depression—a bipolar disorder with Feelings of hopelessness and/or pessimism
both manic and depressive episodes. It also includes dysthymia, Feelings of guilt, worthlessness, and/or helplessness
which is chronic, mild depression. When concurrent with med- Irritability, restlessness
ical complications such as diabetes, heart disease, and asthma, Loss of interest in activities or hobbies once pleasurable,
major mood disorders worsen medical outcomes, and as a including sex
group, contribute to two thirds of all suicides (Yonkers, 2011). Fatigue and decreased energy
Difficulty concentrating, remembering detail, and making
■ Major Depression decisions
This is the most common depressive disorder, and an estimated Insomnia, early-morning wakefulness, or excessive
12 million women each year in the United States are affected sleeping
(Mental Health America, 2013a). The lifetime prevalence is 17 Overeating or appetite loss
percent, but only half ever seek care. The diagnosis is arrived at Thoughts of suicide, suicide attempts
by identifying symptoms listed in Table 61-2. Persistent aches or pains, headaches, cramps, or
Major depression is multifactorial and prompted by digestive problems that do not ease even with
genetic and environmental factors. First-degree relatives have a treatment
25-percent risk, and female relatives are at even higher risk. One a
Not all patients experience the same symptoms, and
genome-wide linkage analysis of more than 1200 mothers sug-
their severity, frequency, and duration will vary among
gests that variation in chromosomes 1 and 9 increases suscepti-
individuals.
bility to postpartum mood symptoms (Mahon, 2009). Families
From the National Institute of Mental Health, 2010.
of affected individuals also often have members with alcohol
 Psychiatric Disorders 1207

abuse and anxiety disorders. Provocative conditions leading episode of “maternity blues” are at inordinately high risk for
to depression include life events that prompt grief reactions, major depression. Indeed, the need for postpartum depression
substance abuse, use of certain medications, and other medical help was the fourth most common challenge identified at 2

CHAPTER 61
disorders. Although life events can trigger depression, genes to 9 months postpartum by the Pregnancy Risk Assessment
influence the response to life events, making the distinction Monitoring System—PRAMS (Kanotra, 2007).
between genetic and environmental factors difficult. Postpartum depression is generally underrecognized and
undertreated. Major depression during pregnancy or after
Pregnancy delivery can have devastating consequences for affected women,
their children, and families. Among new mothers, one of the
It is unquestionable that pregnancy is a major life stressor
most significant contributions to their mortality rate is suicide,
that can precipitate or exacerbate depressive tendencies. In
which is most common among women with mental illness
addition, there are likely various pregnancy-induced effects.
(Koren, 2012; Palladino, 2011). If left untreated, up to 25 per-
Hormones certainly affect mood as evidenced by premen-
cent of women with postpartum depression will be depressed
strual syndrome and menopausal depression. Estrogen has
1 year later. As the duration of depression increases, so too do
been implicated in increased serotonin synthesis, decreased
the number of sequelae and their severity. In addition, maternal
serotonin breakdown, and serotonin receptor modulation
depression during the first weeks and months after delivery can
(Deecher, 2008). Concordantly, women who experience post-
lead to insecure attachment and later behavioral problems in
partum depression often have higher predelivery serum estro-
the child.
gen and progesterone levels and experience a greater decline
postpartum (Ahokas, 1999).
Treatment
Dennis and associates (2007) queried the Cochrane
Database and reported the prevalence of antenatal depression Antidepressant medications, along with some form of psycho-
to average 11 percent. Melville and coworkers (2010) found it therapy, are indicated for severe depression during pregnancy
in nearly 10 percent of more than 1800 women enrolled for or the puerperium (American College of Obstetricians and
prenatal care at a single university obstetrical clinic. Others Gynecologists, 2012b). Shown in Figure 61-1 is one algorithm
have reported the incidence to be much higher (Lee, 2007; regarding initiation of treatment of mood disorders and man-
Westdahl, 2007). In another report, Luke and colleagues agement with a mental health professional. In women with
(2009) found major depressive symptoms in 25 percent of severe depression a selective serotonin-reuptake inhibitor—
pregnant African American women. Hayes and associates SSRI—should be tried initially (Table 61-3). Tricyclic antide-
(2012) reported that 13 percent of pregnant women in the pressants and monoamine oxidase inhibitors are infrequently
Tennessee Medicaid program filled an antidepressant prescrip- used in contemporary practice. If depressive symptoms improve
tion either before or during pregnancy. In another report of during a 6-week trial, the medication should be continued for
almost 119,000 pregnancies in seven health plans, Andrade a minimum of 6 months to prevent relapse (Wisner, 2002). If
and coworkers (2008) found that only 6.6 percent received the response is suboptimal or a relapse occurs, another SSRI is
antidepressants at any time during pregnancy. These findings substituted, or psychiatric referral is considered. Mozurkewich
support to the notion that only half of pregnant women with and associates (2013) reported no salutary effects of docosa-
depression receive treatment. hexaenoic acid (DHA) to prevent perinatal depression.
Postpartum depression—major or minor—develops in 10 Importantly, in a recent metaanalysis by Huang and col-
to 20 percent of parturients (Centers for Disease Control and leagues (2014), women using antidepressants during preg-
Prevention, 2008; Mental Health America, 2013b). Available nancy were found to be at increased risk for preterm birth
data indicate that unipolar major depression may be slightly and low-birthweight neonates. Nevertheless, in their review of
more prevalent during the puerperium than among women in antidepressant medication use in pregnancy, Ray and Stowe
the general population (Yonkers, 2011). In addition to antena- (2014) concluded that the relative reproductive safety data is
tal depression, postpartum depression has been associated with reassuring and that antidepressants remain a viable treatment
young maternal age, unmarried status, smoking or drinking, option.
substance abuse, hyperemesis gravidarum, preterm birth, and Recurrence some time after medication is discontinued develops
high utilization of sick leave during pregnancy (Endres, 2013; in 50 to 85 percent of women with an initial postpartum depres-
Lee, 2007; Marcus, 2009). sive episode. Women with a history of more than one depressive
Depression is frequently recurrent. At least 60 percent of episode are at greater risk (American Psychiatric Association,
women taking antidepressant medication before pregnancy 2000a). Surveillance should include monitoring for thoughts of
have symptoms during pregnancy. According to Hayes and suicide or infanticide, emergence of psychosis, and response to
colleagues (2012), approximately three fourths of women tak- therapy. For some women, the course of illness is severe enough
ing antidepressants before pregnancy stopped taking them to warrant hospitalization.
before or during the first trimester. For those who discontinue
treatment, almost 70 percent have a relapse compared with Fetal Effects of Therapy
25 percent who continue therapy. Up to 70 percent of women Some known and possible fetal and neonatal effects of treat-
with previous postpartum depression have a subsequent episode. ment are listed in Table 61-3. Studies implicating SSRIs with
Women with both prior puerperal depression and a current an increased teratogenic risk for fetal cardiac defects were
 1208 Medical and Surgical Complications

Possible mood disorder

Yes Immediate referral to psychiatrist

SECTION 12

Suicidal/homicidal thoughts
or emergency department
No

Current mania or
bipolar disorder history

No Yes

Psychotic symptoms Psychotic symptoms

No Yes Yes No

Major or minor Consider Rx with typical Rx mood stabilizer: 1st trimester

depressive disorder antipsychotic; co-manage use typical antipsychotic in
lieu of lithium, valproate,
No Yes carbamazepine; co-manage

Routine care Severe

No Yes

Consider psychotherapy; Consider

if no response, consider antidepressant Rx;
antidepressant psychotherapy beneficial

FIGURE 61-1 Treatment algorithm of pregnant women with mood disorders. (Modified from Yonkers, 2011.)

TABLE 61-3. Some Drugs Used for Treatment of Major Mental Disorders in Pregnancy
Indication of Class Examples Comments
Antidepressants
SSRIsa Citalopram, fluoxetine, paroxetine, Possible link with heart defects; neonatal withdrawal
sertraline syndrome; possible persistent pulmonary hypertensiona;
paroxetine use avoided by some
Others Bupropion, duloxetine, nefazodone,
venlafaxine
Tricyclics Amitriptyline, desipramine, doxepin, Not commonly used currently; no evidence of
imipramine, nortriptyline teratogenicity
Antipsychotics
Typical Chlorpromazine, fluphenazine,
haloperidol, thiothixene
Atypical Aripiprazole, clozapine, olanzapine,
risperidone, ziprasidone
Bipolar Disorders
Lithiuma Lithium carbonate Tx manic episodes; teratogen—heart defects,
viz., Ebstein anomaly; few data after 12 wks
Valproic acidb
Carbamazepineb
Antipsychotics See above
a
Chapter 12 (p. 250). bChapter 60 (p. 1190).
SSRI = selective serotonin-reuptake inhibitor; Tx = treat.
Data from American College of Obstetricians and Gynecologists, 2012b; Briggs, 2011; Buhimschi, 2009; Physicians’ Desk
Reference, 2012.
 Psychiatric Disorders 1209

isolated to paroxetine and were most consistent for ventricular compression. Other important preparatory steps include cervi-
septal defects (VSDs). It is estimated that the risk is no greater cal assessment, discontinuation of nonessential anticholinergic
than 1 in 200 exposed infants (Koren, 2012). Nevertheless, the medication, uterine and fetal heart rate monitoring, and intra-

CHAPTER 61
American College of Obstetricians and Gynecologists (2012b) venous hydration. During the procedure, excessive hyperventila-
has recommended that paroxetine be avoided in women who tion should be avoided. In most cases, maternal and fetal heart
are either pregnant or planning pregnancy. Fetal echocardiog- rate and maternal blood pressure and oxygen saturation remain
raphy should be considered in women exposed to paroxetine in normal throughout the procedure.
the first trimester. There have been at least two reviews of ECT outcomes in
In a case-control study, there was a sixfold increased risk of pregnancy. In the earlier one, Miller (1994) found 300 cases
persistent pulmonary hypertension of the newborn (PPHN) and reported complications in 10 percent. These included
in infants exposed to SSRIs after 20 weeks (Chambers, 2006). fetal arrhythmias, vaginal bleeding, abdominal pain, and self-
This translates to an overall risk of pulmonary hypertension limited contractions. Women not adequately prepared had
that would be less than 1 in 100 exposed infants (Koren, increased risks for aspiration, aortocaval compression, and
2012). In contrast, a population-based cohort study of respiratory alkalosis. In the more recent review, Andersen and
1.6 million pregnancies from Nordic countries identified a Ryan (2009) described 339 cases, undoubtedly with some
twofold increased risk in exposed neonates. It was estimated homology with the earlier study. In most cases, ECT therapy
that this yields an attributable risk of 2 per 1000 births (Kieler, was done to treat depression, and it was 78-percent effective.
2012). This marginally increased risk must be weighed against They reported a 5-percent maternal ECT-related complica-
the risk associated with discontinuing or tapering medication tion rate and a 3-percent associated perinatal complication
during pregnancy. rate that included two fetal deaths. For all of these reasons,
Women who abruptly discontinue either serotonin- or we agree with Richards (2007) that ECT in pregnancy is not
norepinephrine-reuptake inhibitor therapy typically experience “low risk” and that it should be reserved for women whose
some form of withdrawal. Not surprisingly, up to 30 percent depression is recalcitrant to intensive pharmacotherapy.
of exposed neonates may also exhibit withdrawal symptoms.
Symptoms are similar to opioid withdrawal, but typically are
less severe. This condition—neonatal behavioral syndrome—is e ■ Bipolar and Related Disorders
self-limited, and the newborn rarely remains in the nursery According to the National Institute of Mental Health
more than 5 days. (Koren, 2009). Currently, convincing evi- (2010), the lifetime prevalence for manic-depression illness
dence of long-term neurobehavioral effects of fetal exposure to is 3.9 percent. There is no difference in the prevalence of bipo-
these medications is lacking (Koren, 2012). lar disorder between pregnant women and nonpregnant repro-
Some psychotropic medications pass into breast milk. ductive-aged women (Yonkers, 2011). It has a strong genetic
However, in most cases, levels are very low or undetectable. component and has been linked to possible mutations on chro-
Importantly, the average amount of drug detected in breast milk mosomes 16 and 8 (Jones, 2007). The risk that monozygotic
is higher with fluoxetine than most other reuptake inhibitors twins are both affected is 40 to 70 percent, and the risk for
(National Library of Medicine, 2012). Adverse effects include first-degree relatives is 5 to 10 percent (Muller-Oerlinghausen,
transient irritability, sleep disturbances, and colic. Agents with 2002). Periods of depression last at least 2 weeks. At other times,
lower excretion into breast milk may therefore be preferred. there are manic episodes, distinct periods during which there
is an abnormally raised, expansive, or irritable mood. Potential
Electroconvulsive Therapy organic causes of mania include substance abuse, hyperthyroid-
This form of depression treatment is occasionally necessary dur- ism, and central nervous system tumors. Importantly, however,
ing pregnancy for women with major mood disorders unre- pregnancy frequently prompts medication discontinuation,
sponsive to pharmacotherapy. With proper preparation, the and this translates to a twofold increased risk for relapse during
risks to both mother and fetus appear to be reasonable (Pinette, pregnancy (Viguera, 2007). Up to 20 percent of patients with
2007). O’Reardon and coworkers (2011) reported a woman manic-depression illness commit suicide.
who underwent 18 electroconvulsive therapy (ECT) sessions Typical therapy for bipolar disorder includes mood stabiliz-
during the second and third trimesters. She was delivered of a ers such as lithium, valproic acid, and carbamazepine, as well
normal child without evidence of developmental delay up to as antipsychotic medications (see Table 61-3). As depicted
18 months of age. That said, adverse maternal and perinatal in Figure 61-1, treatment of bipolar disorder in pregnancy
outcomes have been described from complications of convul- is complex and should be co-managed with a psychiatrist.
sive therapy. Balki and associates (2006) reported a pregnancy Treatment decisions include risks versus benefits of using
in which fetal brain damage likely was caused by sustained mood stabilizers, some of which are teratogenic. For example,
maternal hypotension associated with treatment of status epi- lithium has been linked to Ebstein anomaly in exposed infants
lepticus stimulated by electroshock. (Chap. 12, p. 250). More recent data, however, suggest a
Women undergoing ECT should be fasting for at least lower risk of cardiac malformations than previously indi-
6 hours. They should be given a rapid-acting antacid before the cated (Reprotox, 2012). Nevertheless, fetal echocardiography
procedure, and their airway should be protected to decrease the is recommended by many for exposed fetuses. There is some
likelihood of aspiration. A wedge should be placed under the right limited evidence suggesting that lithium in breast milk can
hip to prevent sudden maternal hypotension from aortocaval adversely affect the infant when its elimination is impaired as
 1210 Medical and Surgical Complications

in dehydration or immaturity (Davanzo, 2011). Lithium use nant and nonpregnant women. One recent analysis of 268
in mothers with a healthy term fetus, however, is considered pregnant women with generalized anxiety disorder demon-
moderately safe. A more detailed discussion of other mood strated that both symptoms and severity of anxiety decrease
stabilizers and antipsychotic medications side effects can be across pregnancy (Buist, 2011). Older studies indicate
SECTION 12

found in Chapter 12 (p. 250). increased risks for adverse pregnancy outcomes with some
of these disorders (American College of Obstetricians and
Postpartum Psychosis Gynecologists, 2012b).
This severe mental disorder is usually a bipolar disorder, but From their review, Ross and McLean (2006) concluded
it may be due to major depression (American Psychiatric that some of the anxiety disorders may have important
Association, 2013). Its incidence is estimated to be 1 in maternal-fetal implications. Some have been linked to pre-
every 1000 deliveries, and it is more common in primipa- term birth and fetal-growth restriction as well as poor neu-
ras, especially those with obstetrical complications (Bergink, robehavioral development (Van den Bergh, 2005). Children
2011; Blackmore, 2006). In most cases, illness manifests with a history of in utero exposure to maternal anxiety are
within 2 weeks of delivery. In a case-control study of post- felt to be at increased risk for a variety of neuropsychiatric
partum women with their first lifetime episode of psychosis, conditions such as attention deficit/hyperactivity disorder
the median onset of psychiatric symptoms was 8 days after (ADHD). Hunter and coworkers (2012) analyzed infants of
delivery, and the median duration of the episode was 40 days 60 mothers with an anxiety disorder and found that auditory
(Bergink, 2011). sensory gating—a reflection of inhibitory neurotransmission—
The most important risk factor for postpartum psychosis was impaired, particularly in offspring of untreated women.
is a history of bipolar disease. These women typically exhibit Conversely, Littleton and associates (2007) found no excessive
symptoms sooner—1 to 2 days after delivery (Heron, 2007, adverse pregnancy outcomes with “anxiety symptoms.” One
2008). Manic symptoms include feeling excited, elated, “high”; important exception is their link with postpartum depression
not needing sleep or unable to sleep; feeling active or energetic; (Vythilingum, 2008).
and feeling “chatty.” Affected women have signs of confu-
sion and disorientation but may also have episodes of lucidity. Treatment
Because those with underlying disease have a 10- to 15-fold Mood and anxiety disorders coexist in more than half of
risk for recurrence postpartum, close monitoring is imperative. women identified with either diagnosis (Frieder, 2008).
Postpartum psychosis has a 50-percent recurrence risk in the Anxiety disorders can be effectively treated during preg-
next pregnancy. As a result, Bergink and colleagues (2012) rec- nancy with psychotherapy, cognitive behavioral therapy, or
ommend initiating lithium therapy immediately postpartum in medications. Antidepressants listed in Table 61-3 are often
women with a history of postpartum psychosis. the first line of pharmacotherapy. Benzodiazepines are also
The clinical course of bipolar illness with postpartum commonly used to treat anxiety or panic disorders before and
psychosis is comparable with that for nonpregnant women. during pregnancy. Earlier case-control studies linked use of
Patients usually require hospitalization, pharmacological treat- these central nervous system depressants to an increased risk
ment, and long-term psychiatric care. Psychotic women may for cleft lip and palate. However, a recent metaanalysis that
have delusions leading to thoughts of self-harm or harm to their included more than 1 million exposed pregnancies did not
infants. Unlike women with nonpsychotic depression, these identify a teratogenic risk (Enato, 2011). Benzodiazepines,
women commit infanticide, albeit uncommonly (Kim, 2008). especially when taken during the third trimester, can cause
In most instances, women with postpartum psychosis ulti- neonatal withdrawal syndrome, which persists for days to
mately develop relapsing, chronic psychotic manic-depression. weeks after delivery.

■ Anxiety Disorders ■ Schizophrenia Spectrum Disorders

These relatively common disorders–18 percent prevalence This major form of mental illness affects 1.1 percent of adults
overall–include panic attack, panic disorder, social anxiety dis- (see Table 61-1). Schizophrenia spectrum disorders are defined
order, specific phobia, separation anxiety disorder, and gener- by abnormalities in one or more of the following domains:
alized anxiety disorder. All are characterized by irrational fear, delusions, hallucinations, disorganized thinking, grossly disor-
tension, and worry, which are accompanied by physiological ganized or abnormal motor behavior, and negative symptoms.
changes such as trembling, nausea, hot or cold flashes, diz- Brain-scanning techniques such as positron-emission tomogra-
ziness, dyspnea, insomnia, and frequent urination (Schneier, phy (PET) and functional magnetic resonance imaging (fMRI)
2006). They are treated with psychotherapy and medication, have shown that schizophrenia is a degenerative brain disorder.
including selective serotonin-reuptake inhibitors, tricyclic Subtle anatomical abnormalities are present early in life and
antidepressants, monoamine oxide inhibitors, and others. worsen with time.
Schizophrenia has a major genetic component , and there is
Pregnancy a 50-percent concordance in monozygotic twins. If one par-
Despite their relative high prevalence in childbearing-aged ent has schizophrenia, the risk to offspring is 5 to 10 percent.
women as shown in Table 61-1, little specific attention has Some data, including a strong association between schizophre-
been directed to anxiety disorders in pregnancy. Most reports nia and the velocardiofacial syndrome, suggest that associated
conclude that there is no difference in rates in between preg- genes are located on chromosome 22q11 (Murphy, 2002).
 Psychiatric Disorders 1211

But sophisticated gene mapping studies have shown clearly and coworkers (2009) studied pregnancy outcomes in almost
that schizophrenia is not related to a single gene or mutation. 36,000 Norwegian women screened for eating disorders.
Instead, there are multiple DNA variants that likely interact to Approximately 0.1 percent—1 in 1025—had anorexia ner-

CHAPTER 61
lead to schizophrenia (Kukshal, 2012). Other putative risk fac- vosa; 0.85 percent—1 in 120—had bulimia nervosa; and 5.1
tors for subsequent schizophrenia in an exposed fetus include percent reported a binge-eating disorder—a 6-percent preg-
maternal iron deficiency anemia, diabetes, and acute maternal nancy prevalence similar to the 6-month prevalence for non-
stress (Insel, 2008; Malaspina, 2008; Van Lieshout, 2008). pregnant individuals (see Table 61-1). The last subtype had
These remain unproven, as does the association with maternal a higher risk for large-for-gestational age infants with a con-
influenza A (Chap. 64, p. 1241). comitantly increased cesarean delivery rate. All eating disorders
Signs of illness begin approximately at age 20 years, and begin with the desire to be slim, and women with chronic eat-
commonly, work and psychosocial functioning deteriorate over ing disorders may migrate between subtypes (Andersen, 2009).
time. Women have a slightly later onset than men and are less
susceptible to autism and other neurodevelopmental abnormal- Pregnancy
ities. Thus, many investigators theorize that estrogen is protec- As discussed in Chapter 18 (p. 352), there is an increased risk
tive. Affected women may marry and become pregnant before for pregnancy complications with both eating disorders, but
symptoms manifest. With appropriate treatment, patients may especially in women with bulimia nervosa (Andersen, 2009;
experience a decrease or cessation of symptoms. Within 5 years Hoffman, 2011; Sollid, 2004). Generally, eating disorder
from the first signs of illness, 60 percent have social recovery, symptoms improve during pregnancy, and remission rates may
50 percent are employed, 30 percent are mentally handicapped, reach 75 percent. In contrast, what may appear as a typical case
and 10 percent require continued hospitalization (American of hyperemesis gravidarum could actually be a new or relapsing
Psychiatric Association, 2013). case of bulimia nervosa or of anorexia nervosa, binge-purge type
(Torgerson, 2008). As perhaps expected, anorexia is associated
Pregnancy with low-birthweight infants (Micali, 2007). Additional risks
There has been an apparent increase in relative fertility in associated with eating disorders include poor wound healing
schizophrenic women (Solari, 2009). Most studies have not and difficulties with breast feeding (Andersen, 2009). At a min-
found adverse maternal outcomes, although researchers in a imum, closely monitoring gestational weight gain in women
Swedish study noted increased risks of low birthweight, fetal- with a suspected history of an eating disorder seems prudent.
growth restriction, and preterm delivery (Bennedsen, 1999). In
an Australian study of more than 3000 pregnancies in schizo-
phrenic women, Jablensky and colleagues (2005) reported that ■ Personality Disorders
placental abruption was increased threefold and “fetal dis- These disorders are characterized by the chronic use of certain
tress”—vaguely defined—was increased 1.4-fold. coping mechanisms in an inappropriate, stereotyped, and mal-
adaptive manner. They are rigid and unyielding personality
Treatment traits. The American Psychiatric Association (2013) recognizes
Because schizophrenia has a high recurrence if medications are three clusters of personality disorders:
discontinued, it is advisable to continue therapy during preg- 1. Paranoid, schizoid, and schizotypal personality disorders,
nancy. After 40 years of use, there is no evidence that conven- which are characterized by oddness or eccentricity.
tional or “typical” antipsychotic drugs listed in Table 61-3 cause 2. Histrionic, narcissistic, antisocial, and borderline disorders,
adverse fetal or maternal sequelae (McKenna, 2005; Robinson, which are all characterized by dramatic presentations along
2012; Yaeger, 2006). Because less is known about “atypical” with self-centeredness and erratic behavior.
antipsychotics, the American College of Obstetricians and 3. Avoidant, dependent, compulsive, and passive-aggressive
Gynecologists (2012b) recommends against their routine use personalities, which are characterized by underlying fear and
in pregnant and breast-feeding women. In response to adverse anxiety.
event reports, the Food and Drug Administration (2011) issued
a safety communication alerting health-care providers concern- Genetic and environmental factors are important in the
ing some antipsychotic medications. These have been associated genesis of these disorders, whose prevalence may be as high as
with neonatal extrapyramidal and withdrawal symptoms simi- 20 percent. Although management is through psychotherapy,
lar to the neonatal behavioral syndrome seen in those exposed most affected individuals do not recognize their problem, and
to selective serotonin-reuptake inhibitors. thus only 20 percent seek help. In an observational study of
202 women with borderline personality disorder, De Genna
and associates (2012) demonstrated that such women become
■ Feeding and Eating Disorders pregnant during the most severe trajectory of their illness.
These severe disturbances in eating behavior largely affect They are at increased risk for teen and unintended pregnan-
adolescent females and young adults with a lifetime preva- cies, however, it was not a risk factor for elective or spontane-
lence of 2 to 3 percent each (see Table 61-1). They include ous abortion.
anorexia nervosa, in which the patient refuses to maintain
minimally normal body weight. With bulimia nervosa, there Pregnancy
usually is binge eating followed by purging or by excessive Personality disorders during pregnancy are probably no differ-
fasting to maintain normal body weight (Zerbe, 2008). Bulik ent than in nonpregnant women. Management of women with
 1239

CHAPTER 64

Infectious Diseases

MATERNAL AND FETAL IMMUNOLOGY . . . . . . . . . . . . 1239 during pregnancy, although the clinical implications of this sup-
pression are unknown (Jamieson, 2006a; Raghupathy, 2001;
VIRAL INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1240 Svensson-Arvelund, 2014). Importantly, the Th2 humoral
BACTERIAL INFECTIONS . . . . . . . . . . . . . . . . . . . . . . . 1248 immune response remains intact.

PROTOZOAL INFECTIONS . 1254

. . . . . . . . . . . . . . . . . . . . . .
■ Fetal and Newborn Immunology
EMERGING INFECTIONS. . . . . . . . . . . . . . . . . . . . . . . . 1257 The active immunological capacity of the fetus and neonate
is compromised compared with that of older children and
TRAVEL PRECAUTIONS DURING PREGNANCY . . . . . . . 1258
adults. That said, fetal cell-mediated and humoral immunity
BIOTERRORISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1258 begin to develop by 9 to 15 weeks’ gestation (Warner, 2010).
The primary fetal response to infection is immunoglobulin
M (IgM). Passive immunity is provided by IgG transferred
across the placenta. By 16 weeks, this transfer begins to
Infections have historically been a major cause of maternal and increase rapidly, and by 26 weeks, fetal concentrations are
fetal morbidity and mortality worldwide, and they remain so equivalent to those of the mother. After birth, breast feeding
in the 21st century. The unique maternal-fetal vascular con- is protective against some infections, although this protec-
nection in some cases serves to protect the fetus from infec- tion begins to decline at 2 months of age. Current World
tious agents, whereas in other instances it provides a conduit Health Organization (2013) recommendations are to exclu-
for their transmission to the fetus. Maternal serological status, sively breast feed for the first 6 months of life with partial
gestational age at the time infection is acquired, the mode of breast feeding until 2 years of age.
acquisition, and the immunological status of both the mother Vertical transmission refers to passage from the mother to
and her fetus all influence disease outcome. her fetus of an infectious agent through the placenta, dur-
ing labor or delivery, or by breast feeding. Thus, preterm
rupture of membranes, prolonged labor, and obstetrical
MATERNAL AND FETAL IMMUNOLOGY manipulations may increase the risk of neonatal infection.
Those occurring less than 72 hours after delivery are usu-
■ Pregnancy-Induced Immunological Changes ally caused by bacteria acquired in utero or during delivery,
Even after intensive study, many of the maternal immunological whereas infections after that time most likely were acquired
adaptations to pregnancy are not well elucidated. It is known afterward. Table 64-1 details specific infections by mode and
that pregnancy is associated with an increase in CD4-positive timing of acquisition.
T cells secreting Th2-type cytokines—for example interleukins Neonatal infection, especially in its early stages, may be
4, 5, 10, and 13. Th1-type cytokine production—for example, difficult to diagnose because neonates often fail to express
interferon gamma and interleukin 2—appears to be somewhat classic clinical signs. If the fetus was infected in utero, there
suppressed, leading to a Th2 biass in pregnancy. This bias affects may be depression and acidosis at birth for no apparent rea-
the ability to rapidly eliminate certain intracellular pathogens son. The neonate may suck poorly, vomit, or show abdominal
 1240 Medical and Surgical Complications

crust over in 3 to 7 days. Infection tends to be more severe in

TABLE 64-1. Specific Causes of Some Fetal and
adults, and a quarter of varicella deaths are within the 5 per-
Neonatal Infections
cent of nonimmune adults (Centers for Disease Control and
Intrauterine Prevention, 2007).
SECTION 12

Transplacental Mortality is predominately due to varicella pneumonia,

Viruses: varicella-zoster, coxsackie, human which is thought to be more severe during adulthood and par-
parvovirus B19, rubella, cytomegalovirus, HIV ticularly in pregnancy. Between 5 and 20 percent of infected
Bacteria: Listeria, syphilis, Borrelia pregnant women developed pneumonitis (Centers for Disease
Protozoa: toxoplasmosis, malaria Control and Prevention, 2007; Harger, 2002). Risk factors for
Ascending infection VZV pneumonia include smoking and having more than 100
Bacteria: group B streptococcus, coliforms cutaneous lesions. Maternal mortality rates with pneumonia
Viruses: HSV have decreased to 1 to 2 percent (Chandra, 1998). Symptoms
Intrapartum of pneumonia usually appear 3 to 5 days into the course of
Maternal exposure illness. It is characterized by fever, tachypnea, dry cough, dys-
Bacteria: gonorrhea, chlamydia, group B pnea, and pleuritic pain. Nodular infiltrates are similar to other
streptococcus, tuberculosis, mycoplasmas viral pneumonias (Chap. 51, p. 1018). Although resolution of
Viruses: HSV, HPV, HIV, hepatitis B, hepatitis C pneumonitis parallels that of skin lesions, fever and compro-
External contamination mised pulmonary function may persist for weeks.
Bacteria: staphylococcus, coliforms If primary varicella infection is reactivated years later,
Viruses: HSV, varicella zoster it causes herpes zosterr or shingless (Whitley, 2012). This pres-
ents as a unilateral dermatomal vesicular eruption associated
Neonatal
with severe pain. Zoster does not appear to be more frequent
Human transmission: staphylococcus, HSV
or severe in pregnant women. Enders and associates (1994)
Respirators and catheters: staphylococcus, coliforms
reviewed 366 cases during pregnancy and found little evidence
HIV = human immunodeficiency virus; HPV = human that zoster causes congenital malformations. Zoster is conta-
papillomavirus; HSV = herpes simplex virus. gious if blisters are broken, although less so than primary vari-
cella infection.

Fetal and Neonatal Infection

distention. Respiratory insufficiency may develop, which may
present similarly to idiopathic respiratory distress syndrome. In women with chicken pox during the first half of pregnancy,
The neonate may be lethargic or jittery. The response to sepsis the fetus may develop congenital varicella syndrome. Some
may be hypothermia rather than hyperthermia, and the total features include chorioretinitis, microphthalmia, cerebral cor-
leukocyte and neutrophil counts may be depressed. tical atrophy, growth restriction, hydronephrosis, limb hypo-
plasia, and cicatricial skin lesions as shown in Figure 64-1
(Auriti, 2009). Enders and coworkers (1994) evaluated 1373
VIRAL INFECTIONS pregnant women with varicella infection. When maternal
infection developed before 13 weeks, only two of 472 preg-
■ Varicella-Zoster Virus nancies—0.4 percent—had neonates with congenital varicella.
Several viruses that infect the mother can also cause devastat-
ing fetal infections. Varicella-zoster virus (VZV) is a double-
stranded DNA herpes virus acquired predominately during
childhood, and 95 percent of adults have serological evidence
of immunity (Plourd, 2005). The incidence of adult varicella
infections declined by 74 percent after the introduction of
varicella vaccination, probably secondary to herd immunity
(Marin, 2008). This has resulted in a decrease in maternal
and fetal varicella infections (Khandaker, 2011). Primary
infection—varicellaa or chicken pox—is
x transmitted by direct
contact with an infected individual, although respiratory trans-
mission has been reported. The incubation period is 10 to 21
days, and a nonimmune woman has a 60- to 95-percent risk
of becoming infected after exposure (Whitley, 2012). She is
then contagious from 1 day before the onset of the rash until
the lesions are crusted over.

Maternal Infection
FIGURE 64-1 Atrophy of the lower extremity with bony defects
Primary varicella infection presents with a 1- to 2-day flu-like and scarring in a fetus infected during the first trimester by vari-
prodrome, which is followed by pruritic vesicular lesions that cella. (From Paryani, 1986, with permission.)
 Infectious Diseases 1241

The highest risk was between 13 and 20 weeks, during which are recommended for adolescents and adults with no history of
time seven of 351 exposed fetuses—2 percent—had evidence of varicella. This results in 98-percent seroconversion (Centers for
congenital varicella. After 20 weeks’ gestation, the researchers Disease Control and Prevention, 2007). Importantly, vaccine-

CHAPTER 64
found no clinical evidence of congenital infection. Thus, con- induced immunity diminishes over time, and the breakthrough
genital infections, particularly after 20 weeks, are uncommon. infection rate approximates 5 percent at 10 years (Chaves,
Subsequent sporadic reports have described central nervous 2007). The vaccine is not recommended for pregnant women or
system abnormalities and skin lesions in fetuses who developed for those who may become pregnant within a month following
congenital varicella in weeks 21 to 28 of gestation (Lamont, each vaccine dose. That said, a registry of 981 vaccine-exposed
2011b; Marin, 2007). pregnancies reports no cases of congenital varicella syndrome or
If the fetus or neonate is exposed to active infection just other congenital associated malformations (Wilson, 2008). The
before or during delivery, and therefore before maternal anti- attenuated vaccine virus is not secreted in breast milk. Thus,
body has been formed, then there is a serious threat to new- postpartum vaccination should not be delayed because of breast
borns. Attack rates range from 25 to 50 percent, and mortality feeding (American College of Obstetricians and Gynecologists,
rates approach 30 percent. In some instances, neonates develop 2013a; Bohlke, 2003).
disseminated visceral and central nervous system disease, which
is commonly fatal. For this reason, varicella-zoster immune
globulin should be administered to neonates born to mothers ■ Influenza
who have clinical evidence of varicella 5 days before and up to These respiratory infections are caused by members of the fam-
2 days after delivery. ily Orthomyxoviridae. Influenza A and B form one genus of
these RNA viruses, and both cause epidemic human disease.
Diagnosis Influenza A viruses are subclassified further by hemagglutinin
Maternal varicella infection is usually diagnosed clinically. The (H) and neuraminidase (N) surface antigens. Influenza out-
virus may also be isolated by scraping the vesicle base during pri- breaks occur annually, and the most recent epidemic was in
mary infection and performing a Tzanck smear, tissue culture, 2013–2014 caused by an influenza A/H1N1 strain.
or direct fluorescent antibody testing. Also, available nucleic
acid amplification tests (NAATs) are very sensitive. Congenital Maternal and Fetal Infection
varicella may be diagnosed using NAAT analysis of amnionic Maternal influenza is characterized by fever, dry cough, and
fluid, although a positive result does not correlate well with systemic symptoms. Infection usually is not life-threatening
the development of congenital infection (Mendelson, 2006). A in otherwise healthy adults, but pregnant women appear
detailed anatomical sonographic evaluation performed at least to be more susceptible to serious complications, particu-
5 weeks after maternal infection may disclose abnormalities, larly pulmonary involvement (Cox, 2006; Neuzil, 1998;
but the sensitivity is low (Mandelbrot, 2012). Rasmussen, 2012). In early 2003, widespread influenza A
infection affected pregnant women. At Parkland Hospital,
Management more than 100 women were hospitalized for this infection,
Maternal Viral Exposure. There are several aspects of and 12 percent had pulmonary infiltrates seen radiographi-
maternal varicella virus exposure and infection in pregnancy cally (Rogers, 2010).
that affect management. Because most adults are VZV sero- There is no firm evidence that influenza A virus causes
positive, exposed pregnant women with a negative history congenital malformations (Irving, 2000; Saxén, 1990).
for chicken pox should undergo VZV serologic testing. At Conversely, Lynberg and colleagues (1994) reported increased
least 70 percent of these women will be seropositive, and neural-tube defects in neonates born to women with influ-
thus immune. Exposed pregnant women who are susceptible enza early in pregnancy, but this was possibly associated with
should be given VariZIG, a recently approved varicella zoster hyperthermia (Chap. 12, p. 284). Viremia is infrequent, and
immune globulin. Although best given within 96 hours of transplacental passage is rare (Rasmussen, 2012). Stillbirth,
exposure, its use is approved for up to 10 days to prevent or preterm delivery, and first-trimester abortion have all been
attenuate varicella infection (Centers for Disease Control and reported, usually correlated to severity of maternal infection
Prevention, 2012a, 2013h). (Centers for Disease Control and Prevention, 2011; Pierce,
2011; Yates, 2010).
Maternal Infection. Any patient diagnosed with primary vari- Influenza may be detected in nasopharyngeal swabs using
cella infection should be isolated from pregnant women. Because viral antigen rapid detection assays (Table 64-2). Reverse
pneumonia often presents with few symptoms, a chest radio- transcriptase–polymerase chain reaction (RT-PCR) is the
graph is recommended by many. Most women require only more sensitive and specific test, although not commercially
supportive care, but those who require intravenous (IV) flu- available in many hospitals (Dolin, 2012). In contrast, rapid
ids and especially those with pneumonia are hospitalized. influenza diagnostic tests (RIDTs) are least indicative, with
Intravenous acyclovir therapy is given to women requiring sensitivities of 40 to 70 percent. In the Parkland Hospital
hospitalization—500 mg/m2 or 10 to 15 mg/kg every 8 hours. emergency room, immunofluorescent antibody assays are used.
Nasopharyngeal specimens are collected as early as possible
Vaccination. An attenuated live-virus vaccine—Varivax—x after symptom onset to maximize influenza testing sensitivity.
was approved in 1995. Two doses, given 4 to 8 weeks apart, Importantly, decisions to administer antiviral medications for
 1242 Medical and Surgical Complications

asthma, or human immunodeficiency virus (HIV) infection

TABLE 64-2. Outpatient Influenza A and B Virus
(Jamieson, 2012). Inactivated vaccine prevents clinical illness
Testing Methods
in 70 to 90 percent of healthy adults. Importantly, there is
Methoda Test Time no evidence of teratogenicity or other adverse maternal or
SECTION 12

Viral cell culture 3–10 d fetal events (Conlin, 2013; Kharbanda, 2013; Munoz, 2012;
Rapid cell culture 1–3 d Nordin, 2013; Sheffield, 2012). Moreover, several stud-
Direct (DFA) or indirect (IFA) fluorescent 1–4 hr ies have found decreased rates of influenza in infants up to
antibody assay 6 months of age whose mothers were vaccinated during preg-
RT-PCR and other molecular assays 1–6 hr nancy (Steinhoff, 2012; Zaman, 2008). Immunogenicity of
Rapid influenza diagnostic tests < 30 min the trivalent inactivated seasonal influenza vaccine in preg-
nant women is similar to that in the nonpregnant individual
a
Nasopharyngeal or throat swab. (Sperling, 2012). A live attenuated influenza virus vaccine
RT-PCR = reverse transcription-polymerase chain reaction. is available for intranasal use but is not recommended for
Abbreviated from Centers for Disease Control and pregnant women.
Prevention, 2013f.
■ Mumps
This uncommon adult infection is caused by an RNA paramyxo-
virus. Because of childhood immunization, up to 90 percent
influenza treatment or chemoprophylaxis should be based on
of adults are seropositive (Rubin, 2012). The virus primarily
clinical symptoms and epidemiological factors. Moreover, the
infects the salivary glands, and hence its name—mumps—is
start of therapy should not be delayed pending testing results
derived from Latin, “to grimace.” Infection also may involve the
(Centers for Disease Control and Prevention, 2013f).
gonads, meninges, pancreas, and other organs. It is transmitted
Management by direct contact with respiratory secretions, saliva, or through
fomites. Treatment is symptomatic, and mumps during preg-
Two classes of antiviral medications are currently available.
nancy is no more severe than in nonpregnant adults.
Neuraminidase inhibitorss are highly effective for the treat-
Women who develop mumps in the first trimester may
ment of early influenza A and B. These include oseltamivir
have an increased risk of spontaneous abortion. Infection in
(Tamiflu), which is taken orally for treatment and for che-
pregnancy is not associated with congenital malformations, and
moprophylaxis, and zanamivirr (Relenza), which is inhaled for
fetal infection is rare (McLean, 2013).
treatment. Peramivirr is an investigational drug administered
The live attenuated Jeryl-Lynn vaccine strain is part of the
intravenously.
MMR vaccine—measles, mumps, and rubella—and is contra-
The adamantaness include amantadine and rimantadine,
indicated in pregnancy according to the CDC (McLean, 2013).
which were used for years for treatment and chemoprophylaxis
No malformations attributable to MMR vaccination in preg-
of influenza A. In 2005, influenza A resistance to adamantine
nancy have been reported, but pregnancy should be avoided
was reported to be > 90 percent in the United States, and
for 30 days after mumps vaccination. The vaccine may be given
thus, adamantane use is not currently recommended. It is pos-
to susceptible women postpartum, and breast feeding is not a
sible that these drugs may again be effective for subsequently
contraindication.
mutated strains.
There is limited experience with all five of these anti-
viral agents in pregnant women. They are Food and Drug ■ Rubeola (Measles)
Administration category C drugs, used when the potential Measles is caused by a highly contagious RNA virus of the
benefits outweigh the risks. At Parkland Hospital, we recom- family Paramyxoviridae that only infects humans. Annual out-
mend starting oseltamivir treatment within 48 hours of symp- breaks occur in late winter and early spring, transmission is
tom onset—75 mg orally twice daily for 5 days. Prophylaxis primarily by respiratory droplets, and the secondary attack rate
with oseltamivir, 75 mg orally once daily for 10 days, is also among contacts exceeds 90 percent (Moss, 2012). Infection is
recommended for significant exposures. Antibacterial medica- characterized by fever, coryza, conjunctivitis, and cough. The
tions should be added when a secondary bacterial pneumonia characteristic erythematous maculopapular rash develops on
is suspected (Chap. 51, p. 1016). the face and neck and then spreads to the back, trunk, and
extremities. Koplik spotss are small white lesions with surround-
Vaccination ing erythema found within the oral cavity. Diagnosis is most
Effective vaccines are formulated annually. Vaccination commonly performed by serology, although RT-PCR tests are
against influenza throughout the influenza season, but opti- available. Treatment is supportive.
mally in October or November, is recommended by the Pregnant women without evidence of measles immunity
Centers for Disease Control and Prevention (CDC) (2013e) should be administered intravenous immune globulin (IVIG),
and the American College of Obstetricians and Gynecologists 400 mg/kg within 6 days of a measles exposure (McLean,
(2010) for all women who will be pregnant during the influ- 2013). Active vaccination is not performed during pregnancy.
enza season. This is especially important for those affected However, susceptible women can be vaccinated routinely post-
by chronic medical disorders such as diabetes, heart disease, partum, and breast feeding is not contraindicated (Ohji, 2009).
 Infectious Diseases 1243

The virus does not appear to be teratogenic (Siegel, 1973). congenital rubella syndrome includes one or more of the
However, an increased frequency of abortion, preterm delivery, following:
and low-birthweight neonates is noted with maternal measles
• Eye defects—cataracts and congenital glaucoma

CHAPTER 64
(American Academy of Pediatrics, 2006; Siegel, 1966). If a
• Congenital heart defects—patent ductus arteriosus and
woman develops measles shortly before birth, there is consider-
pulmonary artery stenosis
able risk of serious infection developing in the neonate, espe-
• Sensorineural deafness—the most common single defect
cially in a preterm neonate.
• Central nervous system defects—microcephaly, developmen-
tal delay, mental retardation, and meningoencephalitis
■ Rubella—German Measles • Pigmentary retinopathy
• Neonatal purpura
This RNA togavirus typically causes infections of minor
• Hepatosplenomegaly and jaundice
importance in the absence of pregnancy. Rubella infection in
• Radiolucent bone disease
the first trimester, however, poses significant risk for abortion and
severe congenital malformations. Transmission occurs via naso- Neonates born with congenital rubella may shed the virus for
pharyngeal secretions, and the transmission rate is 80 percent many months and thus be a threat to other infants and to suscep-
to susceptible individuals. The peak incidence is late winter tible adults who contact them.
and spring. The extended rubella syndrome, with progressive panencepha-
Maternal rubella infection is usually a mild, febrile illness litis and type 1 diabetes, may not develop clinically until the
with a generalized maculopapular rash beginning on the face second or third decade of life. As many as a third of neonates
and spreading to the trunk and extremities. Other symptoms who are asymptomatic at birth may manifest such developmen-
may include arthralgias or arthritis, head and neck lymph- tal injury (Webster, 1998).
adenopathy, and conjunctivitis. The incubation period is 12
to 23 days. Viremia usually precedes clinical signs by about a Management and Prevention
week, and adults are infectious during viremia and through 5 to There is no specific treatment for rubella. Droplet precautions
7 days of the rash. Up to half of maternal infections are sub- for 7 days after the onset of the rash are recommended. Primary
clinical despite viremia that may cause devastating fetal infec- prevention relies on comprehensive vaccination programs
tion (McLean, 2013; Zimmerman, 2012). (Coonrod, 2008). Although large epidemics of rubella have
virtually disappeared in the United States because of immu-
nization, up to 10 percent of women in the United States are
Diagnosis
susceptible (Zimmerman, 2012). Cluster outbreaks during the
Rubella may be isolated from the urine, blood, nasopharynx, 1990s mainly involved persons born outside the United States,
and cerebrospinal fluid for up to 2 weeks after rash onset. The as congenital rubella is still common in developing nations
diagnosis is usually made, however, with serological analysis. (Banatvala, 2004; Reef, 2002).
Specific IgM antibody can be detected using enzyme-linked To eradicate rubella and prevent congenital rubella syn-
immunoassay from 4 to 5 days after onset of clinical disease, drome completely, a comprehensive approach is recommended
but it can persist for up to 6 weeks after appearance of the for immunizing the adult population (McLean, 2013). MMR
rash (Zimmerman, 2012). Importantly, rubella reinfection can vaccine should be offered to nonpregnant women of childbear-
give rise to transient low levels of IgM. Serum IgG antibody ing age who do not have evidence of immunity whenever they
titers peak 1 to 2 weeks after rash onset. This rapid antibody make contact with the health-care system. Vaccination of all
response may complicate serodiagnosis unless samples are ini- susceptible hospital personnel who might be exposed to patients
tially collected within a few days after the onset of the rash. with rubella or who might have contact with pregnant women
If, for example, the first specimen was obtained 10 days after is important. Rubella vaccination should be avoided 1 month
the rash, detection of IgG antibodies would fail to differenti- before or during pregnancy because the vaccine contains attenu-
ate between very recent disease and preexisting immunity to ated live virus. Although there is a small overall theoretical risk
rubella. IgG avidity testing is performed concomitant with the of up to 2.6 percent, there is no observed evidence that the vac-
serological tests above. High-avidity IgG antibodies indicate cine induces malformations (Badilla, 2007; McLean, 2013).
an infection at least 2 months in the past. MMR vaccination is not an indication for pregnancy termina-
tion. Prenatal serological screening for rubella is indicated for all
Fetal Effects pregnant women. Women found to be nonimmune should be
Rubella is one of the most complete teratogens, and sequelae offered the MMR vaccine postpartum.
of fetal infection are worst during organogenesis (Adams Despite native or vaccine-induced immunity, subclinical
Waldorf, 2013). Pregnant women with rubella infection and rubella maternal reinfection may develop during outbreaks. And
a rash during the first 12 weeks of gestation have a fetus although fetal infection can rarely occur, no adverse fetal effects
with congenital infection in up to 90 percent of cases (Miller, have been described.
1982; Zimmerman, 2012). At 13 to 14 weeks’ gestation, this
incidence was 54 percent, and by the end of the second tri- ■ Respiratory Viruses
mester, it was 25 percent. Defects are rare after 20 weeks More than 200 antigenically distinct respiratory viruses cause the
(Miller, 1982). According to Reef and colleagues (2000), common cold, pharyngitis, laryngitis, bronchitis, and pneumonia.
 1244 Medical and Surgical Complications

Rhinovirus, coronavirus, and adenovirus are major causes of the B—include aseptic meningitis, polio-like illness, hand foot
common cold. The RNA-containing rhinovirus and coronavi- and mouth disease, rashes, respiratory disease, pleuritis, peri-
rus usually produce a trivial, self-limited illness characterized carditis, and myocarditis. No treatment or vaccination is
by rhinorrhea, sneezing, and congestion. The DNA-containing available (Cohen, 2012). Coxsackievirus may be transmitted
SECTION 12

adenovirus is more likely to produce cough and lower respira- by maternal secretions to the fetus at delivery in up to half
tory tract involvement, including pneumonia. of mothers who seroconverted during pregnancy (Modlin,
Teratogenic effects of respiratory viruses are controversial. 1988). Transplacental passage has also been reported (Ornoy,
Women with a common cold had a four- to fivefold increased 2006).
risk of fetal anencephaly in a 393-woman cohort in the Finnish Congenital malformations may be increased slightly in
Register of Congenital Malformations (Kurppa, 1991). In pregnant women who had serological evidence of coxsackie-
another population study, Shaw and coworkers (1998) analyzed virus (Brown, 1972). Viremia can cause fetal hepatitis, skin
California births from 1989 to 1991 and concluded that low lesions, myocarditis, and encephalomyelitis, all of which may
attributable risks for neural-tube defects were associated with be fatal. Koro’lkova and colleagues (1989) have also described
many illnesses in early pregnancy. Recently, amnionic fluid cardiac anomalies. There is evidence of increased low-birth-
viral PCR studies were performed in 1191 women undergoing weight, preterm, and small-for-gestational-age newborns
amniocentesis for fetal karyotyping. Viral PCR was positive in (Chen, 2010). Finally, a rare association between maternal
6.5 percent, with adenovirus being the virus most frequently coxsackievirus infection and insulin-dependent diabetes in
identified. There was an association with fetal-growth restric- offspring has been reported (Dahlquist, 1996; Hyoti, 1995;
tion, nonimmune hydrops, foot/hand abnormalities, and Viskari, 2012).
neural-tube defects (Adams, 2012).
Adenoviral infection is a known cause of childhood myo- Poliovirus
carditis. Towbin (1994) and Forsnes (1998) used PCR tests to Most of these highly contagious but rare infections are sub-
identify and link adenovirus to fetal myocarditis and nonim- clinical or mild. The virus is trophic for the central nervous
mune hydrops. system, and it can cause paralytic poliomyelitis (Cohen,
2012). Siegel (1955) demonstrated that pregnant women
■ Hantaviruses not only were more susceptible to polio but also had a
higher death rate. Perinatal transmission has been observed,
These RNA viruses are members of the family Bunyaviridae.
especially when maternal infection developed in the third
They are associated with a rodent reservoir, and transmission
trimester (Bates, 1955). Inactivated subcutaneous polio vac-
involves inhalation of virus excreted in rodent urine and feces.
cine is recommended for susceptible pregnant women who
An outbreak in the Western United States occurred in 1993
must travel to endemic areas or are placed in other high-risk
due to Sin Nombre virus. The resulting Hantavirus pulmonary
situations. Live oral polio vaccine has been used for mass
syndrome was characterized by severe adult respiratory distress
vaccination during pregnancy without harmful fetal effects
syndrome with a case-fatality rate of 30 to 40 percent (Peters,
(Harjulehto, 1989).
2012). Several outbreaks since then have occurred, the most
recent in 2012.
Hantaviruses are a heterogenous group of viruses with low ■ Parvovirus
and variable rates of transplacental transmission. Howard and Human parvovirus B19 causes erythema infectiosum, or fifth
associates (1999) reported the syndrome to cause maternal disease. The B19 virus is a small, single-stranded DNA virus
death, fetal demise, and preterm birth. They found no evidence that replicates in rapidly proliferating cells such as erythroblast
of vertical transmission of the Sin Nombre virus. However, precursors (Brown, 2012). This can lead to anemia, which is
vertical transmission occurred inconsistently in association its primary fetal effect. Only individuals with the erythrocyte
with hemorrhagic fever and renal syndrome caused by another globoside membrane P antigen are susceptible. In women with
Hantavirus species, the Hantaan virus. severe hemolytic anemia—for example, sickle-cell disease—
parvovirus infection may cause an aplastic crisis.
■ Enteroviruses The main mode of parvovirus transmission is respiratory or
These viruses are a major subgroup of RNA picornaviruses that hand-to-mouth contact, and the infection is common in spring
include poliovirus, coxsackievirus, and echovirus. They are tro- months. The maternal infection rate is highest in women with
phic for intestinal epithelium but can also cause widespread school-aged children and in day-care workers but not usually
maternal, fetal, and neonatal infections that may include the in schoolteachers. Viremia develops 4 to 14 days after exposure.
central nervous system, skin, heart, and lungs. Most maternal By adulthood, only 40 percent of women are susceptible. The
infections are subclinical yet can be fatal to the fetus-neonate annual seroconversion rate is 1 to 2 percent but is greater than
(Goldenberg, 2003; Tassin, 2014). Hepatitis A is an enterovi- 10 percent during epidemic periods (Brown, 2012). Secondary
rus that is discussed in Chapter 55 (p. 1089). attack rates approach 50 percent.

Coxsackievirus Maternal Infection

Infections with coxsackievirus group A and B are usually In 20 to 30 percent of adults, infection is asymptomatic.
asymptomatic. Symptomatic infections—usually with group Fever, headache, and flu-like symptoms may begin in the last
 Infectious Diseases 1245

few days of the viremic phase. Several days later, a bright red Doppler interrogation can also be used to predict fetal anemia
rash with erythroderma affects the face and gives a slapped- (Chap. 10, p. 221). Elevated peak systolic velocity values in
cheek appearance. The rash becomes lacelike and spreads to the fetal MCA accurately predict fetal anemia (Chauvet, 2011;

CHAPTER 64
the trunk and extremities. Adults often have milder rashes Cosmi, 2002; Delle Chiaie, 2001). Fetal blood sampling is war-
and develop symmetrical polyarthralgia that may persist sev- ranted with hydrops to assess the degree of fetal anemia. Fetal
eral weeks. There is no evidence that parvovirus infection is myocarditis may induce hydrops with less severe anemia.
altered by pregnancy (Valeur-Jensen, 1999). With recovery, Depending on gestational age, fetal transfusion for hydrops
there is production of IgM antibody 7 to 10 days postinfec- may improve outcome in some cases (Enders, 2004; Schild,
tion, and this persists for 3 to 4 months. Several days after 1999; von Kaisenberg, 2001). Mortality rates as high as 30
IgM is produced, IgG antibody is detectable and persists for percent have been reported in hydropic fetuses without trans-
life with natural immunity. fusions. With transfusion, 94 percent of hydrops cases resolve
within 6 to 12 weeks, and the overall mortality rate is < 10 per-
Fetal Infection cent. Most fetuses require only one transfusion because hemo-
There is vertical transmission to the fetus in up to a third of poiesis resumes as infection resolves. The technique for fetal
maternal parvovirus infections (Bonvicini, 2011; de Jong, 2011; transfusion is described in Chapter 14 (p. 300).
Lamont, 2011a). Fetal infection has been associated with abor-
tion, nonimmune hydrops, and stillbirth (Enders, 2010; Lassen, Long-Term Prognosis
2012; McClure, 2009). In a review of 1089 cases of mater- Reports describing neurodevelopmental outcomes in fetuses
nal B19 infection from nine studies, Crane (2002) reported transfused for B19 infection-induced anemia are conflicting.
an overall fetal loss rate of 10 percent. It was 15 percent for Nagel and colleagues (2007) reviewed 25 transfusions in 24
infections before 20 weeks but was only 2.3 percent after 20 hydropic fetuses. There was abnormal neurodevelopment in
weeks. Its role in later unexplained stillbirths is unclear because five of 16 survivors—32 percent—at 6 months to 8 years.
most data are from retrospective cohorts with incomplete Outcomes were not related to severity of fetal anemia or aci-
maternal and fetal histological evaluations (Norbeck, 2002; demia, and these investigators hypothesized that the infection
Skjöldebrand-Sparre, 2000; Tolfvenstam, 2001). Currently, itself induced cerebral damage. De Jong (2012) described long-
there are no data to support evaluating asymptomatic mothers term neurodevelopmental outcomes in 28 children treated with
and stillborn fetuses for parvovirus infection. intrauterine transfusion. At a median age of 5 years, 11 percent
Parvovirus is the most frequent infectious cause of nonim- had neurodevelopmental impairment. Conversely, Dembinski
mune hydrops in autopsied fetuses (Rogers, 1999). That said, (2003) followed 20 children for a mean of 52 months after
this complication develops only in approximately 1 percent of transfusion. They found no significant neurodevelopmental
infected women and usually is caused by infection in the first delay despite severe fetal anemia.
half of gestation (Crane, 2002; Enders, 2004; Puccetti, 2012).
Yaegashi (2000) has extensively investigated the development Prevention
and pathophysiology of parvovirus B19 fetal hydrops. At least There is currently no approved vaccine for human parvovirus
85 percent of cases of fetal infection developed within 10 weeks B19, and there is no evidence that antiviral treatment pre-
of maternal infection, and the mean interval was 6 to 7 weeks. vents maternal or fetal infection (Broliden, 2006). Decisions
More than 80 percent of hydrops cases were found in the second to avoid higher-risk work settings are complex and require
trimester, with a mean gestational age of 22 to 23 weeks. The assessment of exposure risks. Pregnant women should be
critical period for maternal infection leading to fetal hydrops counseled that risks for infection approximate 5 percent for
was estimated to be between 13 and 16 weeks—coincidental casual, infrequent contact; 20 percent for intense, prolonged
with the period in which fetal hepatic hemopoiesis is greatest. work exposure such as for teachers; and 50 percent for close,
frequent interaction such as in the home. Workers at day-care
Diagnosis and Management centers and schools need not avoid infected children because
An algorithm for diagnosis of maternal parvoviral infection infectivity is greatest before clinical illness. Finally, infected
is illustrated in Figure 64-2. Diagnosis is generally made by children do not require isolation.
maternal serological testing for specific IgG and IgM antibod-
ies (Bonvicini, 2011; Butchko, 2004; Enders, 2006). Viral
DNA may be detectable by PCR in maternal serum during ■ Cytomegalovirus
the prodrome and persist for months to years after infection. This ubiquitous DNA herpes virus eventually infects most
Fetal infection is diagnosed by detection of B19 viral DNA in humans. Cytomegalovirus (CMV) is the most common peri-
amnionic fluid or IgM antibodies in fetal serum obtained by natal infection in the developed world. Specifically, some
cordocentesis (de Jong, 2011; Weiffenbach, 2012). Fetal and evidence of fetal infection is found in 0.2 to 2.5 percent of
maternal viral loads do not predict fetal morbidity and mortal- all neonates (Kenneson, 2007). The virus is secreted into all
ity (de Haan, 2007). body fluids, and person-to-person contact with viral-laden
Most cases of parvovirus-associated hydrops develop in saliva, semen, urine, blood, and nasopharyngeal and cervi-
the first 10 weeks after infection (Enders, 2004). Thus, serial cal secretions can transmit infection. The fetus may become
sonography every 2 weeks should be performed in women with infected by transplacental viremia, or the neonate is infected
recent infection (see Fig. 64-2). Middle cerebral artery (MCA) at delivery or during breast feeding. Moreover, acquisition
 1246 Medical and Surgical Complications
SECTION 12

FIGURE 64-2 Algorithm for evaluation and management of human parvovirus B19 infection in pregnancy. CBC = complete blood count;
IgG = immunoglobulin G; IgM = immunoglobulin M; MCA = middle cerebral artery; PCR = polymerase chain reaction; RNA = ribonucleic
acid.

continues to accrue. Day-care centers, for example, are a half of women in higher income groups are immune. Following
frequent source, and by 2 to 3 years of age, many children primary CMV infection, and in a manner similar to other
have infected one another and may transmit infection to their herpes virus infections, the virus becomes latent with periodic
parents (Demmler, 1991; Pass, 1991). Revello and coworkers reactivation characterized by viral shedding. This occurs despite
(2008) reported that amniocentesis in women whose blood high serum levels of anti-CMV IgG antibody. These antibodies
is positive for CMV DNA does not result in iatrogenic fetal do not prevent maternal recurrence, reactivation, or reinfection,
transmission. nor do they totally mitigate fetal or neonatal infection.
Up to 85 percent of women from lower socioeconomic back- Women who are seronegative before pregnancy but who
grounds are seropositive by the time of pregnancy, whereas only develop primary CMV infection during pregnancy are at
 Infectious Diseases 1247

CHAPTER 64
A B

FIGURE 64-3 Sagittal (A) and coronal (B) cranial sonograms from a neonate with congenital cytomegalovirus infection. The arrows indi-
cate periventricular calcifications.

greatest risk to have an infected fetus. It is estimated that 25 retinitis, mental and motor retardation, sensorineural defi-
percent of congenital CMV infections in the United States cits, hepatosplenomegaly, jaundice, hemolytic anemia, and
are from primary maternal infection (Wang, 2011). Because thrombocytopenic purpura (Fig. 64-3). The pathogenesis of
most CMV infections are clinically silent, they are detected these outcomes has been reviewed by Cheeran and colleagues
by seroconversion, and this may be as high as 1 to 7 percent (2009). Of the estimated 40,000 infected neonates born each
(Hyde, 2010). year, only 5 to 10 percent demonstrate this syndrome (Fowler,
1992). Thus, most infected infants are asymptomatic at birth,
Maternal Infection but some develop late-onset sequelae. They may include hear-
Pregnancy does not increase the risk or severity of maternal ing loss, neurological deficits, chorioretinitis, psychomotor
CMV infection. Most infections are asymptomatic, but 10 retardation, and learning disabilities.
to 15 percent of infected adults have a mononucleosis-like
syndrome characterized by fever, pharyngitis, lymphade- Prenatal Diagnosis
nopathy, and polyarthritis. Immunocompromised women Routine prenatal CMV serological screening is currently not
may develop myocarditis, pneumonitis, hepatitis, retinitis, recommended. Pregnant women should be tested for CMV if
gastroenteritis, or meningoencephalitis. Nigro and associates they present with a mononucleosis-like illness or if congenital
(2003) reported that most women in a cohort with primary infection is suspected based on abnormal sonographic find-
infection had elevated serum aminotransferases or lymphocy- ings. Primary infection is diagnosed using CMV-specific IgG
tosis. Reactivation disease usually is asymptomatic, although testing of paired acute and convalescent sera. CMV IgM does
viral shedding is common. not accurately reflect timing of seroconversion because IgM
Primary maternal CMV infection is transmitted to the fetus antibody levels may be elevated for more than a year (Stagno,
in approximately 40 percent of cases and can cause severe mor- 1985). Moreover, CMV IgM may be found with reactiva-
bidity (Fowler, 1992; Liesnard, 2000). In contrast, recurrent tion disease or reinfection with a new strain. Thus, specific
maternal infection infects the fetus in only 0.15 to 1 percent CMV IgG avidity testing is valuable in confirming primary
of cases. A review of nine studies of CMV vertical transmission CMV infection (Fig. 64-4). High anti-CMV IgG avidity indi-
rates reported first-trimester transmission in 36 percent, sec- cates primary maternal infection > 6 months before testing
ond-trimester in 40 percent, and third-trimester in 65 percent (Kanengisser-Pines, 2009). Finally, viral culture may be use-
(Picone, 2013). Naturally acquired immunity during preg- ful, although a minimum of 21 days is required before culture
nancy results in a 70-percent risk reduction of congenital CMV findings are considered negative.
infection in future pregnancies (Fowler, 2003). However, as Several fetal abnormalities associated with CMV infection
noted earlier, maternal immunity does not prevent recurrences, may be seen with sonography, computed tomography, or mag-
and maternal antibodies do not prevent fetal infection. Also, netic resonance imaging. In some cases, they are found at the
some seropositive women can be reinfected with a different time of routine prenatal sonographic screening, but in others
viral strain that can cause fetal infection and symptomatic con- they are part of a specific evaluation in women with CMV
genital disease (Ross, 2011). infection. Findings include microcephaly, ventriculomegaly,
and cerebral calcifications; ascites, hepatomegaly, splenomeg-
Fetal Infection aly, and hyperechoic bowel; hydrops; and oligohydramnios
When a newborn has apparent sequelae of in utero-acquired (Malinger, 2003). Abnormal sonographic findings seen in com-
CMV infection, it is referred to as symptomatic CMV infection. bination with positive findings in fetal blood or amnionic fluid
Congenital infection is a syndrome that may include growth are predictive of an approximate 75-percent risk of symptom-
restriction, microcephaly, intracranial calcifications, chorio- atic congenital infection (Enders, 2001).
 1248 Medical and Surgical Complications

Suspected Maternal CMV Infection

SECTION 12

CMV-specific
V IgG and IgM by EIA,
CMV-specific
V IgG avidity by EIA, and
CMV-specific
V IgM by immunoblot
G: negativ
n e
CMV IgM
M: negati
n ve

CMV uninfected;
no further evaluation

CMV IgG: positive CMV IgG: positive Uncertain CMV IgG: positive
IgG avidity index: high or seroconversion serologic IgG avidity index: high
CMV IgM: negative IgG avidity index: low results CMV IgM: positive
CMV IgM: positive

Latent CMV Primary CMV Undefined Recurrent CMV

infection infection CMV infection infection

No further Noninvasive
evaluation follow-up
Invasive
follow-up

FIGURE 64-4 Algorithm for evaluation of suspected maternal primary cytomegalovirus (CMV) infection in pregnancy. EIA = enzyme
immunoassay; IgG = immunoglobulin G; IgM = immunoglobulin M.

CMV nucleic acid amplification testing of amnionic fluid 6 months and possibly later. Conversely, antiviral chemotherapy
is considered the gold standard for the diagnosis of fetal infec- given antepartum does not avert in utero CMV transmission.
tion. Sensitivities range from 70 to 99 percent and depend on Passive immunization with CMV-specific hyperimmune globu-
amniocentesis timing (Nigro, 2005; Revello, 2004). Sensitivity lin lowers the risk of congenital CMV infection when given
is highest when amniocentesis is performed at least 6 weeks after to pregnant women with primary disease (Nigro, 2005, 2012;
maternal infection and after 21 weeks (Azam, 2001; Guerra, Visentin, 2012). Further clinical trials are necessary before this
2000). A negative amnionic fluid PCR does not exclude fetal becomes standard treatment (McCarthy, 2011).
infection and may need to be repeated if suspicion for fetal There is no CMV vaccine. Prevention of congenital infec-
infection is high. tion relies on avoiding maternal primary infection, especially in
early pregnancy. Basic measures such as good hygiene and hand
Management and Prevention washing have been promoted, particularly for women with tod-
The management of the immunocompetent pregnant woman dlers in day-care settings (Fowler, 2000). Although there may
with primary or recurrent CMV is limited to symptomatic be sexual transmission from infected partners, there are no data
treatment. If recent primary CMV infection is confirmed, on the efficacy of preventive strategies.
amnionic fluid analysis should be offered. Counseling regard-
ing fetal outcome depends on the gestation age during which
primary infection is documented. Even with the high infection BACTERIAL INFECTIONS
rate with primary infection in the first half of pregnancy, most
fetuses develop normally. However, pregnancy termination ■ Group A Streptococcus
may be an option for some. Streptococcus pyogeness are important in preg-
Kimberlin (2003) showed that intravenous ganciclovir nant women. It is the most frequent bacterial cause of acute
administered for 6 weeks to neonates with symptomatic cen- pharyngitis and is associated with several systemic and cutaneous
tral nervous system disease prevents hearing deterioration at infections. S pyogeness produces numerous toxins and enzymes
 Infectious Diseases 1249

responsible for the local and systemic toxicity associated with from respiratory distress syndrome caused by insufficient
this organism. Pyrogenic exotoxin-producing strains are usually surfactant production of the preterm neonate (Chap. 34,
associated with severe disease (Mason, 2012; Wessels, 2012). In p. 653). The mortality rate with early-onset disease has declined

CHAPTER 64
most cases, streptococcal pharyngitis, scarlet fever, and erysipelas to approximately 4 percent, and preterm newborns are dispa-
are not life threatening. Treatment, usually with penicillin, is rately affected.
similar in pregnant and nonpregnant women (Shulman, 2012). Late-onset diseasee caused by GBS is noted in 0.32 per 1000 live
In the United States, Streptococcus pyogeness infrequently births and usually manifests as meningitis 1 week to 3 months
causes puerperal infection. Still, it remains the most com- after birth (Centers for Disease Control and Prevention, 2013a).
mon cause of severe maternal postpartum infection and death The mortality rate, although appreciable, is less for late-onset
worldwide, and the incidence of these infections is increasing meningitis than for early-onset sepsis. Unfortunately, it is not
(Deutscher, 2011; Hamilton, 2013; Mason, 2012; Wessels, uncommon for surviving infants of both early- and late-onset
2012). Puerperal infections are discussed in detail in Chapter disease to exhibit devastating neurological sequelae.
37 (p. 682). The early 1990s saw the rise of streptococcal toxic
shock syndrome, manifested by hypotension, fever, and evi- Prophylaxis for Perinatal Infections
dence of multiorgan failure with associated bacteremia. The As GBS neonatal infections evolved beginning in the 1970s
case-fatality rate approximates 30 percent, and morbidity and and before widespread intrapartum chemoprophylaxis, rates
mortality rates are improved with early recognition. Treatment of early-onset sepsis ranged from 2 to 3 per 1000 live births.
includes clindamycin or penicillin therapy and often surgical In 2002, the Centers for Disease Control and Prevention,
debridement (Hamilton, 2013). No vaccine for group A strep- the American College of Obstetricians and Gynecologists,
tococcus is commercially available. and the American Academy of Pediatrics revised guidelines
for perinatal prevention of GBS disease. They recommended
■ Group B Streptococcus universal rectovaginal culture screening for GBS at 35 to
37 weeks’ gestation followed by intrapartum antibiotic pro-
Streptococcus agalactiaee is a group B organism that can be found phylaxis for women identified to be carriers. Subsequent to
to colonize the gastrointestinal and genitourinary tract in 20 to implementation of these guidelines, the incidence of early-
30 percent of pregnant women. Throughout pregnancy, group
onset GBS neonatal sepsis has decreased to 0.24 cases per
B Streptococcuss (GBS) is isolated in a transient, intermittent, or 1000 live births by 2012 (Centers for Disease Control and
chronic fashion. Although the organism is most likely always Prevention, 2013a). These guidelines were updated for early-
present in these same women, their isolation is not always onset GBS infection in 2010. They expanded laboratory iden-
homologous. tification criteria for GBS; updated algorithms for screening
and intrapartum chemoprophylaxis for women with preterm
Maternal and Perinatal Infection
prematurely ruptured membranes, preterm labor, or penicil-
The spectrum of maternal and fetal GBS ranges from asymp- lin allergy; and described new dosing for penicillin G che-
tomatic colonization to septicemia. Streptococcus agalactiae moprophylaxis.
has been implicated in adverse pregnancy outcomes, includ- Thus, during the past three decades, several strategies have
ing preterm labor, prematurely ruptured membranes, clinical been proposed to prevent perinatal acquisition of GBS infec-
and subclinical chorioamnionitis, and fetal infections. GBS can tions (Ohlsson, 2013). These strategies have not been compared
also cause maternal bacteriuria, pyelonephritis, osteomyelitis, in randomized trials and are either culture-based or risk-based
postpartum mastitis, and puerperal infections. It remains the guidelines as subsequently discussed.
leading infectious cause of morbidity and mortality among
infants in the United States (Centers for Disease Control and Culture-Based Prevention. The 2010 Centers for Disease
Prevention, 2010; Schrag, 2003; Wessels, 2012). Control and Prevention GBS Guidelines recommend a culture-
Neonatal sepsis has received the most attention due to its based approach as shown in Figure 64-5. Such a protocol was
devastating consequences and available effective preventative also adopted by the American College of Obstetricians and
measures. Infection < 7 days after birth is defined as early-onset Gynecologists (2013c). This approach is designed to identify
diseasee and is seen in 0.24/1000 live births (Centers for Disease women who should be given intrapartum antimicrobial pro-
Control and Prevention, 2013a). Many investigators use a phylaxis. Women are screened for GBS colonization at 35 to
threshold of < 72 hours of life as most compatible with intra- 37 weeks’ gestation, and intrapartum antimicrobials are given
partum acquisition of disease (Pulver, 2009; Wendel, 2002). to women with rectovaginal GBS-positive cultures. Selective
We and others have also encountered several unexpected intra- enrichment broth followed by subculture improves detection.
partum stillbirths from GBS infections. Tudela and associates In addition, more rapid techniques such as DNA probes and
(2012) recently reported that newborns with early-onset GBS nucleic acid amplification tests are being developed (Chan,
infection often had clinical evidence of fetal infection during 2006; Helali, 2012). A previous sibling with GBS invasive
labor or at delivery. disease and identification of GBS bacteriuria in the current
In many neonates, septicemia involves signs of serious ill- pregnancy are also considered indications for prophylaxis.
ness that usually develop within 6 to 12 hours of birth. These
include respiratory distress, apnea, and hypotension. At the Risk-Based Prevention. A risk-based approach is recom-
outset, therefore, neonatal infection must be differentiated mended for women in labor and whose GBS culture results
 1250 Medical and Surgical Complications

Vaginal and rectal GBS screening cultures at 35–37 weeks’’ gestation for ALL
V
pregnant women (unless patient had GBS bacteriuria during the current
pregnancy or a previous infant with invasive GBS disease)
SECTION 12

Intrapartum Intrapartum
prophylaxis indicated prophylaxis not indicated

• Previous infant with invasive GBS • Previous pregnancy with a positive

disease GBS screening culture (unless a
culture was also positive during the
• GBS bacteriuria during current current pregnancy)
pregnancy
• Planned cesarean delivery performed
• Positive GBS screening culture in the absence of labor or membrane
during current pregnancy (unless rupture (regardless of maternal GBS
a planned cesarean delivery, in culture status)
the absence of labor or amnionic
membrane rupture, is performed) • Negative vaginal and rectal GBS
screening culture in late gestation
• Unknown GBS status (culture not during the current pregnancy,
done, incomplete, or results regardless of intrapartum risk factors
unknown) and any of the following:

• Delivery at < 37 weeks’’ gestation

• Amnionic membrane rupture

≥ 18 hours

• Intrapartum temperature
≥ 100.4°F (≥ 38.0°C)

• Intrapartum nucleic acid

amplification test (NAAT)
A
positive for GBS

FIGURE 64-5 Indications for intrapartum prophylaxis to prevent perinatal group B streptococcal (GBS) disease under a universal prenatal
screening strategy based on combined vaginal and rectal cultures obtained at 35 to 37 weeks’ gestation. (From Centers for Disease
Control and Prevention, 2010.)

are not known. This approach relies on risk factors associated to 0.4–0.66 per 1000 live births (Wendel, 2002). Non-GBS
with intrapartum GBS transmission. Intrapartum chemopro- early-onset sepsis was identified in 0.24 per 1000 live births,
phylaxis is given to women who have any of the following: and this was stable during the past two decades (Stafford,
delivery < 37 weeks, ruptured membranes ≥ 18 hours, or 2012). Thus, this approach has results similar to those reported
intrapartum temperature ≥ 100.4°F (≥ 38.0°C). Women with by the Centers for Disease Control and Prevention (2010) for
GBS during the current pregnancy and women with a prior culture-based prevention.
infant with invasive early-onset GBS disease are also given
chemoprophylaxis. Intrapartum Antimicrobial Prophylaxis
At Parkland Hospital in 1995—and prior to consensus Prophylaxis administered 4 or more hours before delivery
guidelines—we adopted the risk-based approach for intra- is highly effective (Fairlie, 2013). Regardless of screening
partum treatment of women at high risk. In addition, all method, penicillin remains the first-line agent for prophy-
term neonates who were not given intrapartum prophylaxis laxis, and ampicillin is an acceptable alternative (Table 64-3).
were treated in the delivery room with aqueous penicillin G, Women with a penicillin allergy and no history of anaphylaxis
50,000 to 60,000 units intramuscularly. Rates of early-onset should be given cefazolin. Those at high risk for anaphylaxis
GBS infection and sepsis and of non-GBS sepsis decreased should have antimicrobial susceptibility testing performed to
 Infectious Diseases 1251

TABLE 64-3. Regimens for Intrapartum Antimicrobial Prophylaxis for Perinatal GBS Disease
Regimen Treatment

CHAPTER 64
Recommended Penicillin G, 5 million units IV initial dose, then 2.5 to 3.0 million
units IV every 4 hours until delivery
Alternative Ampicillin, 2 g IV initial dose, then 1 g IV every 4 hours or 2 g
every 6 hours until delivery
Penicillin allergic
Patients not at high risk for anaphylaxis Cefazolin, 2 g IV initial dose, then 1 g IV every 8 hours until delivery
Patients at high risk for anaphylaxis and with GBS Clindamycin, 900 mg IV every 8 hours until delivery
susceptible to clindamycin
Patients at high risk for anaphylaxis and with GBS Vancomycin, 1 g IV every 12 hours until delivery
resistant to clindamycin or susceptibility unknown

GBS = group B Streptococcus; IV = intravenous.

Adapted from the Centers for Disease Control and Prevention, 2010.

exclude clindamycin resistance. Clindamycin-sensitive but chemoprophylaxis, regardless of GBS colonization status or
erythromycin-resistant isolates should have a D-zone test gestational age.
performed to assess for inducible clindamycin resistance. If
clindamycin resistance is confirmed, vancomycin should be
administered. Erythromycin is no longer used for penicillin- ■ Methicillin-Resistant Staphylococcus Aureus
allergic patients. Staphylococcus aureuss is a pyogenic gram-positive organism and
Further recommendations for management of spontane- is considered the most virulent of the staphylococcal species. It
ous preterm labor, threatened preterm delivery, or preterm primarily colonizes the nares, skin, genital tissues, and orophar-
prematurely ruptured membranes are shown in Figure 64-6. ynx. Approximately 20 percent of normal individuals are per-
Women undergoing cesarean delivery before labor onset sistent carriers, 30 to 60 percent are intermittent carriers, and
with intact membranes do not need intrapartum GBS 20 to 50 percent are noncarriers (Gorwitz, 2008). Colonization

Onset of labor or rupture of membranes at < 37 weeks’

gestation with significant risk for imminent preterm delivery

No GBS
BS culture
c GBS positiv
po e GBS negativ
neg e

Obtain vaginal and IV antimicrobials No GBS

GBS
rectal GBS culture for ≥ 48 hours prophylaxis
positive
positive
and initiate IV (during tocolysis)
antimicrobials

No growth
h at 48 hours Repeat vaginal-rectal
GBS culture if patient
reaches 35–37 weeks
and is undelivered
Stop antimicrobials Intrapartum
antimicrobial
prophylaxis at
delivery

FIGURE 64-6 Sample algorithm for prophylaxis for women with group B streptococcal (GBS) disease and threatened preterm delivery.
This algorithm is not an exclusive course of management, and variations that incorporate individual circumstances or institutional
preferences may be appropriate. IV = intravenous. (Adapted from Centers for Disease Control and Prevention, 2010.)
 1252 Medical and Surgical Complications

is considered the greatest risk factor for infection (Sheffield, Uncomplicated superficial infections are managed by drainage
2013). Methicillin-resistant S aureuss (MRSA) colonizes only 2 and local wound care. The benefits of antibiotic treatment in
percent of people but is a significant contributor to the health- this setting are unproven, and most studies have not shown
care burden (Gorwitz, 2008). MRSA infections are associated improved outcomes with the addition of MRSA-appropriate
SECTION 12

with increased cost and higher mortality rates compared with antibiotics (Forcade, 2012; Laibl, 2005). Severe superficial
those by methicillin-sensitive S aureuss (MSSA) (Beigi, 2009; infections, especially those that fail to respond to local care
Butterly, 2010; Klevens, 2007). or those in patients with medical comorbidities, should be
Community-associated MRSA (CA-MRSA) is diagnosed treated with MRSA-appropriate antibiotics. Purulent celluli-
when identified in an outpatient setting or within 48 hours tis should be treated empirically for CA-MRSA until culture
of hospitalization in a person without traditional risk factors. results are available.
The latter include prior MRSA infection, hospitalization, dialy- Most CA-MRSA strains are sensitive to trimethoprim-
sis or surgery within the past year, and indwelling catheters sulfamethoxazole. If clindamycin treatment is considered, inducible
or devices. Hospital-associated MRSA (HA-MRSA) infections resistance must be excluded by a D-zone test for erythromycin-
are nosocomial. Most cases of MRSA in pregnant women are resistant, clindamycin-sensitive isolates. Rifampin rapidly develops
CA-MRSA. resistance and should not be used for monotherapy. Linezolid,
although effective against MRSA, is expensive, and there is little
MRSA and Pregnancy information regarding its use in pregnancy. Doxycycline, mino-
Anovaginal colonization with S aureuss is identified in 10 to 25 cycline, and tetracycline, although effective for MRSA infections,
percent of obstetrical patients (Andrews, 2008; Creech, 2010; should not be used in pregnancy. Vancomycin remains the first-
Top, 2010). MRSA has been isolated in 0.5 to 3.5 percent of line therapy for inpatient MRSA infections.
these women. Skin and soft tissue infections are the most com- The control and prevention of HA-MRSA and CA-MRSA
mon presentation of MRSA in pregnant women (Fig. 64-7). rely on appropriate hand hygiene and prevention of skin-to-skin
Mastitis has been reported in up to a fourth of cases of MRSA contact or contact with wound dressings. Decolonization should
complicating pregnancy (Laibl, 2005; Lee, 2010; Reddy, 2007). be considered only in cases in which a patient develops recur-
Perineal abscesses, wound infections at sites such as abdominal rent superficial infections despite optimal hygiene measures or if
and episiotomy incisions, and chorioamnionitis are also associ- ongoing transmission occurs among household or close contacts
ated with MRSA (Lareau, 2010; Pimentel, 2009; Rotas, 2007; (Liu, 2011). Decolonization measures include nasal treatment
Thurman, 2008). An increase in CA-MRSA infections has been with mupirocin, chlorhexidine gluconate baths, and oral rifampin
reported in neonatal intensive care units and newborn nurs- therapy. Routine decolonization has not been shown to be effec-
eries. In these settings, infection is frequently associated with tive in the obstetrical population. For women with culture-proven
maternal and health-care worker MRSA skin infections and CA-MRSA infection during pregnancy, we add single-dose vanco-
infected breast milk. Vertical transmission appears to be rare mycin to routine β-lactam perioperative prophylaxis for cesarean
(Huang, 2009; Jimenez-Truque, 2012; Pinter, 2009). deliveries and fourth-degree perineal lacerations. Breast feeding in
these women is not prohibited, but optimal hygiene and attention
Management to minor skin breaks is encouraged.
The Infectious Diseases Society of America has published
guidelines for the treatment of MRSA infections (Liu, 2011).
■ Vulvar Abscess
Labia majora infections, which begin as cellulitis, have the poten-
tial for significant expansion and abscess formation. Risk factors
include diabetes, obesity, perineal shaving, and immunosuppres-
sion. For early cellulitis, sitz baths and oral antibiotics are rea-
sonable treatment. If present, a small abscess can be incised and
drained, wound cultures obtained, abscess cavity packed, and sur-
rounding cellulitis treated with oral antibiotics. These infections
are typically polymicrobial, and suitable broad-spectrum anti-
microbials are given along with coverage for MRSA (Thurman,
2008). For severe infections, especially in immunosuppressed or
pregnant patients, hospitalization and intravenous antimicrobial
therapy are often warranted due to increased risks for necrotizing
fasciitis. Large abscesses are best drained in the operating room
with adequate analgesia or anesthesia.
Cysts of the Bartholin gland duct are usually unilateral,
sterile, and need no treatment during pregnancy. If a cyst is
FIGURE 64-7 Typical presentation of a skin lesion caused by sufficiently large to obstruct delivery, then needle aspiration
infection with community-acquired methicillin-resistant Staphylo- is an appropriate temporary measure. With gland duct infec-
coccus aureus (CA-MRSA). Patients often present with what they tion, a localized unilateral vulvar bulge, tenderness, and ery-
describe as an infected spider bite. thema are present. Treatment is given with broad-spectrum
 Infectious Diseases 1253

antimicrobials, and drainage is established. In addition to

obtaining wound cultures, testing is done for Neisseria gonor-
rhoeaee and Chlamydia trachomatis. For a small abscess, incision

CHAPTER 64
and placement of a Word catheter may be suitable. For larger
abscesses with extensive cellulitis, drainage is best performed
in the operating room. In these cases, the incised edges of the
abscess cavity may be marsupialized.
Occasionally, abscesses of the periurethral glands develop.
The largest of these, the Skene gland, may require drainage and
broad-spectrum antimicrobial treatment if there is suppuration.

■ Listeriosis
Listeria monocytogeness is an uncommon but probably underdi-
A
agnosed cause of neonatal sepsis. This facultative intracellular
gram-positive bacillus can be isolated from the feces of 1 to
5 percent of adults. Nearly all cases of listeriosis are thought
to be food-borne (Silk, 2013). Outbreaks have been caused
by raw vegetables, coleslaw, apple cider, melons, milk, fresh
Mexican-style cheese, smoked fish, and processed foods, such
as pâté, hummus, wieners, and sliced deli meats (Cartwright,
2013; Centers for Disease Control and Prevention, 2013i;
Janakiraman, 2008; Varma, 2007; Voetsch, 2007).
Listerial infections are more common in the very old or
young, pregnant women, and immunocompromised patients.
The incidence of such infections appears to be increasing in
several countries worldwide (Allenberger, 2010; Cartwright,
2013; Goulet, 2012). In 1651 cases reported in 2009 to 2011,
the Centers for Disease Control and Prevention found that B
14 percent were in pregnant women (Silk, 2013). And in a
recent review, pregnant women had a significantly higher rate FIGURE 64-8 The pale placenta (A) and stillborn infant
for listeriosis compared with nonpregnant reproductive-aged (B) resulted from maternal listeriosis.
women (Pouillot, 2012). It is unclear why pregnant women
still account for a significant number of these reported cases. infections are similar to GBS sepsis. In a review of 222 cases
One hypothesis is that pregnant women are susceptible by Mylonakis (2002), infection resulted in abortion or stillbirth
because of decreased cell-mediated immunity (Baud, 2011; in 20 percent, and neonatal sepsis developed in 68 percent of
Jamieson, 2006b; Wing, 2002). Another is that placental tro- surviving newborns. Voetsch (2007) detailed similar findings. A
phoblasts are susceptible to invasion by Listeria monocytogenes stillbirth caused by listeriosis is shown in Figure 64-8.
(Le Monnier, 2007). Treatment with ampicillin plus gentamicin is usually rec-
ommended because of synergism against Listeriaa species.
Maternal and Fetal Infection Trimethoprim-sulfamethoxazole can be given to penicillin-
Listeriosis during pregnancy may be asymptomatic or may allergic women. Maternal treatment in most cases is also effec-
cause a febrile illness that is confused with influenza, pyelo- tive for fetal infection (Chan, 2013). No vaccine is available,
nephritis, or meningitis (Centers for Disease Control and and prevention is by washing raw vegetables and cooking all
Prevention, 2013i; Mylonakis, 2002). The diagnosis usually raw food (Goulet, 2012; Silk, 2012). Pregnant women should
is not apparent until blood cultures are reported as positive. also avoid the implicated foods listed previously.
Occult or clinical infection also may stimulate labor (Boucher,
1986). Discolored, brownish, or meconium-stained amnionic ■ Salmonellosis
fluid is common with fetal infection, even preterm gestations. Infections from Salmonellaa species continue to be a major and
In 2011, a listerial outbreak associated with cantaloupes increasing cause of food-borne illness (Peques, 2012). Six sero-
resulted in 147 infected individuals (Centers for Disease types account for most cases in the United States, including
Control and Prevention, 2012b). Seven of these infections were Salmonellaa subtypes typhimurium and enteritidis. Non-typhoid
related to pregnancy—four in pregnant women and three in Salmonellaa gastroenteritis is contracted through contaminated
newborns. Maternal listeriosis causes fetal infection that char- food. Symptoms including nonbloody diarrhea, abdominal
acteristically produces disseminated granulomatous lesions with pain, fever, chills, nausea, and vomiting begin 6 to 48 hours
microabscessess (Topalovski, 1993). Chorioamnionitis is common after exposure. Diagnosis is made by stool studies. Intravenous
with maternal infection, and placental lesions include multiple, crystalloid is given for rehydration. Antimicrobials are not given
well-demarcated macroabscesses. Early- and late-onset neonatal in uncomplicated infections because they do not commonly
 1254 Medical and Surgical Complications

shorten illness and may prolong the convalescent carrier state. migrans, which may be accompanied by a flu-like syndrome
If gastroenteritis is complicated by bacteremia, antimicrobi- and regional adenopathy. If untreated, disseminated infection
als are given as discussed below. Rare case reports have linked follows in days to weeks. Multisystem involvement is frequent,
Salmonellaa bacteremia with abortion (Coughlin, 2002). but skin lesions, arthralgia and myalgia, carditis, and meningitis
SECTION 12

Typhoid fever caused by Salmonella typhii remains a global predominate. If still untreated after several weeks to months,
health problem, although it is uncommon in the United States. late or persistent infection manifests in perhaps half of patients.
Infection is spread by oral ingestion of contaminated food, Native immunity is acquired, and the disease enters a chronic
water, or milk. In pregnant women, the disease is more likely to phase. Although some patients remain asymptomatic, others
be encountered during epidemics or in those with HIV infec- in the chronic phase develop various skin, joint, or neurologi-
tion (Hedriana, 1995). In former years, antepartum typhoid cal manifestations (Wormser, 2006). Although relapses were
fever resulted in abortion, preterm labor, and maternal or fetal initially considered common, recent clinical and epidemio-
death (Dildy, 1990). logical evidence suggests that most cases of recurrent erythema
Fluoroquinolones and third-generation cephalosporins are migrans occurring after appropriate antimicrobial therapy are
the preferred treatment. For enteric (typhoid) fever, antimi- actually new infections (Nadelman, 2012).
crobial susceptibility testing is important because of the devel- Clinical diagnosis is important because serological and PCR
opment of drug-resistant strains (Peques, 2012). Typhoid testing has many pitfalls (Schoen, 2013). IgM and IgG serolog-
vaccines appear to exert no harmful effects when administered ical testing is recommended in early infection and is followed
to pregnant women and should be given in an epidemic or by Western blotting for confirmation. Ideally, acute and conva-
before travel to endemic areas. lescent serological evaluation is completed if possible. The false-
positive and -negative rates are high, and more accurate tests are
being developed (Radolf, 2012; Schoen, 2013; Steere, 2012).
■ Shigellosis
Bacillary dysentery caused by Shigellaa is a relatively common, Treatment and Prevention
highly contagious cause of inflammatory exudative diarrhea in Optimal treatment of Lyme disease was reviewed by Wormser
adults. Shigellosis is more common in children attending day- (2006) for the Infectious Diseases Society of America. For early
care centers and is transmitted via the fecal-oral route. Clinical infection, treatment with doxycycline, amoxicillin, or cefu-
manifestations range from mild diarrhea to severe dysentery, roxime is recommended for 14 days, although doxycycline is
bloody stools, abdominal cramping, tenesmus, fever, and sys- usually avoided in pregnancy. A 14- to 28-day course of IV
temic toxicity. ceftriaxone, cefotaxime, or penicillin G is given for compli-
Although shigellosis may be self-limited, careful attention to cated early infections that include meningitis, carditis, or dis-
treatment of dehydration is essential in severe cases. We have seminated infections. Chronic arthritis and post-Lyme disease
cared for pregnant women in whom secretory diarrhea exceeded syndrome are treated with prolonged oral or IV regimens, how-
10 L/day! Antimicrobial therapy is imperative, and effective treat- ever, symptoms respond poorly to treatment (Steere, 2012).
ment during pregnancy includes fluoroquinolones, ceftriaxone, No vaccine is commercially available. Avoiding areas with
or azithromycin. Antimicrobial resistance is rapidly emerging, endemic Lyme disease and improving tick control in those
and antibiotic susceptibility testing can help guide appropriate areas is the most effective prevention. Self-examination with
therapy (Centers for Disease Control and Prevention, 2013c). removal of unengorged ticks within 36 hours of attachment
reduces infection risk (Hayes, 2003). For tick bites recognized
■ Hansen Disease within 72 hours, a single 200-mg oral dose of doxycycline may
reduce infection development.
Also known as leprosy, this chronic infection is caused by
There are several reports of Lyme disease in pregnancy,
Mycobacterium lepraee and is rare in the United States (United
although large series are lacking. Transplacental transmission
States Department of Health and Human Services, 2011).
has been confirmed, but no congenital effects of maternal
Diagnosis is confirmed by PCR. Multidrug therapy with dapsone,
borreliosis have been conclusively identified (Elliott, 2001;
rifampin, and clofazimine is recommended for treatment and is
Maraspin, 2011; Walsh, 2006). Prompt treatment of mater-
generally safe during pregnancy (Britton, 2004). Duncan (1980)
nal early infection should prevent most adverse pregnancy out-
reported an excessive incidence of low-birthweight newborns
comes (Mylonas, 2011).
among infected women. The placenta is not involved, and neo-
natal infection apparently is acquired from skin-to-skin or drop-
let transmission (Böddinghaus, 2007; Duncan, 1984). Vertical ■ Tuberculosis
transmission is common in untreated mothers (Moschella, 2004). Diagnosis and management of tuberculosis during pregnancy is
discussed in detail in Chapter 51 (p. 1019).
■ Lyme Disease
Caused by the spirochete Borrelia burgdorferi, Lyme disease PROTOZOAL INFECTIONS
is the most commonly reported vector-borne illness in the
United States (Centers for Disease Control and Prevention, ■ Toxoplasmosis
2012c). Lyme borreliosis follows tick bites of the genus Ixodes. The obligate intracellular parasite Toxoplasma gondiii has a life
Early infection causes a distinctive local skin lesion, erythema cycle with two distinct stages (Kim, 2012). The felinee stage takes
 Infectious Diseases 1255

place in the cat—the definitive host—and its prey. Unsporulated 100

Risk of congenital infection (percent)

Risk
oocysts are secreted in feces. In the nonfelinee stage, tissue cysts 95% confidence intervals
containing bradyzoites or oocysts are ingested by the interme- 80

CHAPTER 64
diate host, including humans. Gastric acid digests the cysts to
release bradyzoites, which infect small-intestinal epithelium.
Here, they are transformed into rapidly dividing tachyzoites, 60
which can infect all cells within the host mammal. Humoral
and cell-mediated immune defenses eliminate most of these, 40
but tissue cysts develop. Their lifelong persistence is the chronic
form of toxoplasmosis. 20
Human infection is acquired by eating raw or undercooked
meat infected with tissue cysts or by contact with oocysts from
cat feces in contaminated litter, soil, or water. Prior infection is 0
confirmed by serological testing, and its prevalence depends on 0 4 8 12 16 20 24 28 32 36 40
geographic locale and parasite genotype. In the United States, Gestational age (weeks) at maternal
there is a 5 to 30 percent seroprevalence in persons aged 10 toxoplasmosis seroconversion
to 19 years, and this can exceed 60 percent after age 50 (Kim, FIGURE 64-9 Risk of congenital toxoplasmosis infection by ges-
2012). Thus, a significant segment of pregnant women in this tational age at maternal seroconversion. (From Dunn, 1999, with
country are susceptible to infection. The incidence of prenatal permission.)
infection resulting in birth of a newborn with congenital toxo-
plasmosis has been estimated to vary from 0.8 per 10,000 live
births in the United States to 10 per 10,000 in France (Dubey, triad—chorioretinitis, intracranial calcifications, and hydro-
2000). Between 400 and 4000 cases of congenital toxoplasmo- cephalus—is often accompanied by convulsions. Infected neo-
sis are diagnosed annually in the United States. Globally, it is nates with clinical signs are at risk for long-term complications.
estimated that a third of the population has been exposed to
this parasite (Verma, 2012). Screening and Diagnosis
The American Academy of Pediatrics and the American College
Maternal and Fetal Infection of Obstetricians and Gynecologists (2012) do not recommend
Most acute maternal infections in Europe and North America prenatal screening for toxoplasmosis in areas of low prevalence,
are subclinical and are detected only by prenatal or newborn including the United States. In areas of high toxoplasmosis
serological screening. In some cases, maternal symptoms may prevalence—for example, France and Austria—routine screen-
include fatigue, fever, headache, muscle pain, and sometimes a ing has resulted in diminished congenital disease (Wallon,
maculopapular rash and posterior cervical lymphadenopathy. 2013). With IgG antibody confirmed before pregnancy, there
In immunocompetent adults, initial infection confers immu- is no risk for a congenitally infected fetus (Montoya, 2004).
nity, and prepregnancy infection nearly eliminates any risk Screening should be performed in immunocompromised preg-
of vertical transmission. Infection in immunocompromised nant women, regardless of country of residence.
women, however, may be severe, and reactivation may cause Pregnant women suspected of having toxoplasmosis should
encephalitis, retinochoroiditis, or mass lesions. Maternal infec- be tested. The parasite is rarely detected in tissue or body fluids.
tion is associated with a fourfold increased preterm delivery rate Anti-toxoplasma IgG develops within 2 to 3 weeks after infection,
before 37 weeks (Freeman, 2005). Even so, growth restriction peaks at 1 to 2 months, and usually persists for life—sometimes
is not increased. Toxoplasmosis serotype NE-II is most com- in high titers. Although IgM antibodies appear by 10 days after
monly associated with preterm birth and severe neonatal infec- infection and usually become negative within 3 to 4 months,
tion (McLeod, 2012). they may remain detectable for years. Thus, IgM antibodies
The incidence and severity of fetal toxoplasmosis infection should not be used alone to diagnose acute toxoplasmosis. IgA
depend on gestational age at the time of maternal infection. Risks and IgE antibodies are also useful in diagnosing acute infection.
for fetal infection increase with pregnancy duration (Fig. 64-9). Best results are obtained with the Toxoplasma Serologic Profile
A metaanalysis estimated the risk to be 15 percent at 13 weeks, performed at the Palo Alto Medical Foundation Research Institute
44 percent at 26 weeks, and 71 percent at 36 weeks (SYROCOT ([Link]@[Link]). Toxoplasma IgG avidity increases
Study Group, 2007). Conversely, the severity of fetal infection with time. Thus, if a high-avidity IgG result is found, infection
is much greater in early pregnancy, and these fetuses are much in the preceding 3 to 5 months is excluded. Multiple commercial
more likely to have clinical findings of infection. avidity tests are now available that provide a 100-percent positive-
Importantly, most infected fetuses are born without obvi- predictive value of high avidity confirming latent infection
ous stigmata of toxoplasmosis. Clinically affected neonates (Villard, 2013). PCR testing has a high sensitivity and specificity.
usually have generalized disease expressed as low birthweight, Prenatal diagnosis of toxoplasmosis is performed using
hepatosplenomegaly, jaundice, and anemia. Some primarily DNA amplification techniques and sonographic evaluation.
have neurological disease with intracranial calcifications and PCR of amnionic fluid or fetal blood has improved sensitivity
with hydrocephaly or microcephaly. Many eventually develop compared with standard isolation techniques (Sterkers, 2012).
chorioretinitis and exhibit learning disabilities. This classic The sensitivity varies with gestational age, and it is lowest at
 1256 Medical and Surgical Complications

< 18 weeks (Montoya, 2008). Sonographic evidence of intra-

cranial calcifications, hydrocephaly, liver calcifications, ascites,
placental thickening, hyperechoic bowel, and growth restric-
tion has been used prenatally to help confirm diagnosis.
SECTION 12

Management
No randomized clinical trials have been performed to assess
the benefit and efficacy of treatment to decrease the risk for
congenital infection. A systematic review of data from 1438
treated pregnancies found weak evidence for early treatment
to reduce congenital toxoplasmosis risks (SYROCOT Study
Group, 2007). Treatment has been associated with a reduction
in rates of serious neurological sequelae and neonatal demise A
(Cortina-Borja, 2010).
Prenatal treatment is based on two regimens—spiramycin
alone or a pyrimethamine–sulfonamide combination with
folinic acid. These two regimens have also been used consecu-
tively (Hotop, 2012). Little evidence supports the use of a specific
regimen. That said, most experts will use spiramycin in women
with acute infection early in pregnancy. Pyrimethamine–
sulfadiazine with folinic acid is selected for maternal infection
after 18 weeks or if fetal infection is suspected.

Prevention
There is no vaccine for toxoplasmosis, so avoidance of infection
is necessary if congenital infection is to be prevented. Efforts
include: (1) cooking meat to safe temperatures; (2) peeling or B
thoroughly washing fruits and vegetables; (3) cleaning all food
preparation surfaces and utensils that have contacted raw meat, FIGURE 64-10 Photomicrograph of placental malaria. A. Multiple
infected red blood cells (long black arrow) are seen in the inter-
poultry, seafood, or unwashed fruits and vegetables; (4) wearing villous space of this placenta. Multiple villi cut in cross section are
gloves when changing cat litter, or else delegating this duty; and shown, and three are highlighted (short arrows). B. Increased
(5) avoiding feeding cats raw or undercooked meat and keeping magnification of image (A). Multiple infected erythrocytes are
cats indoors. Although these preventive steps are recommended, seen, and two are identified (arrows).
there are no data to support their effectiveness (Di Mario, 2009).
Vaccine development is actively being pursued (Verma, 2012).
asymptomatic, are said to be more likely to develop traditional
symptoms (Desai, 2007).
■ Malaria Malarial infections during pregnancy—whether symptom-
Malaria remains a global health crisis. In 2010, there were an atic or asymptomatic—are associated with increased rates of
estimated 219 million cases and 655,000 deaths, mainly in perinatal morbidity and mortality (Menéndez, 2007; Nosten,
sub-Saharan Africa (Chico, 2012; World Health Organization, 2007; Rogerson, 2007). Adverse outcomes include stillbirth,
2011). Malaria has been effectively eradicated in Europe and preterm birth, low birthweight, and maternal anemia. The latter
in most of North America, and worldwide mortality rates have two are documented most frequently (Machado Filho, 2014;
fallen more than 25 percent. In the United States, most cases McClure, 2013). Maternal infection is associated with 14 per-
of malaria are imported—some in returning military person- cent of low-birthweight newborns worldwide (Eisele, 2012).
nel (Centers for Disease Control and Prevention, 2013j). These adverse perinatal outcomes correlate with high levels of
Transmitted by infected Anopheless mosquitoes, five species of placental parasitemia (Rogerson, 2007). The latter occurs when
Plasmodium cause human disease—falciparum,
— vivax, ovale, parasitized erythrocytes, monocytes, and macrophages accumu-
malariae, and knowlesii (White, 2012). late in the vascular areas of the placenta (Fig. 64-10). Infections
with P falciparum are the worst, and early infection increases
Maternal and Fetal Infection the risk for abortion (Desai, 2007). The incidence of malaria
Clinical findings are fever, chills, and flu-like symptoms includ- increases significantly in the latter two trimesters and postpar-
ing headaches, myalgia, and malaise, which may occur at tum (Diagne, 2000). Overall, congenital malaria occurs in < 5
intervals. Symptoms are less severe with recurrences. Malaria percent of neonates born to infected mothers.
may be associated with anemia and jaundice, and falciparum
infections may cause kidney failure, coma, and death. That Diagnosis
said, many otherwise healthy but infected adults in endemic Identification of parasites by microscopical evaluation of a thick
areas are asymptomatic. Pregnant women, although often and thin blood smear remains the gold standard for diagnosis.
 Infectious Diseases 1257

In women with low parasite densities, however, the sensitivity women in areas without chloroquine resistance (Cot, 1992).
of microscopy is poor. Malaria-specific antigens are now being For travelers to areas with chloroquine-resistant P falciparum,
used for rapid diagnostic testing. Not only is their sensitivity mefloquine remains the only chemoprophylaxis recommended.

CHAPTER 64
still an issue in pregnancy, but these tests are not routinely Primaquine and doxycycline are contraindicated in pregnancy,
available (Fowkes, 2012; Kashif, 2013; White, 2012). and there are insufficient data on atovaquone/proguanil to
recommend them at this time. Likewise, amodiaquine is used
Management in Africa, but data are limited in pregnant women. The lat-
The most frequently used antimalarial drugs are not contra- est chemoprophylaxis regimens for pregnancy can be obtained
indicated in pregnancy. The World Health Organization from the Centers for Disease Control and Prevention Travelers’
recommends all infected patients living in or traveling from Healthh website at: [Link] The Centers also
endemic areas be treated with an artemisinin-based regimen for publish Health Information for International Travell (The Yellow
uncomplicated falciparum malaria. Little is known about these Book) at: [Link]/yellowbook.
regimens in pregnancy (Mutabinqwa, 2013). The Centers for
Disease Control and Prevention (2013g) recommends using
atovaquone-proguanil or artemether-lumefantrine only if other ■ Amebiasis
treatment options are not available or tolerated. Most persons infected with Entamoeba histolyticaa are asymp-
The Centers for Disease Control and Prevention (2013g) tomatic. Amebic dysentery, however, may take a fulminant
recommends that pregnant women diagnosed with uncom- course during pregnancy, with fever, abdominal pain, and
plicated malaria caused by P vivax, P malariae, P ovale, and bloody stools. Prognosis is worse if complicated by a hepatic
chloroquine-sensitive P falciparum should be treated with abscess. Diagnosis is made by identifying E histolyticaa cysts or
chloroquine or hydroxychloroquine. For women infected trophozoites within a stool sample. Therapy is similar to that
with chloroquine-resistant P falciparum, mefloquine or qui- for the nonpregnant woman, and metronidazole or tinidazole
nine sulfate with clindamycin should be used. Chloroquine- is the preferred drug for amebic colitis and invasive disease.
resistant P vivaxx should be treated with mefloquine. Noninvasive infections may be treated with paromomycin
Chloroquine-sensitive P vivaxx or P ovalee should be treated (Stanley, 2012).
with chloroquine throughout pregnancy and then prima-
quine postpartum. Treatment regimens for uncomplicated
and severe malarial infections in pregnancy are detailed at: MYCOTIC INFECTIONS
[Link]/malaria/diagnosis_treatment/[Link].
The CDC also maintains a malaria hotline for treatment rec- Disseminated fungal infection—usually pneumonitis—during
ommendations (770-488-7788). pregnancy is uncommon with coccidiomycosis, blastomyco-
The World Health Organization (2011) allows for the sis, cryptococcosis, or histoplasmosis. Their identification and
use of intermittent preventative therapy during pregnancy. management are considered in Chapter 51 (p. 1019).
This consists of at least two treatment doses of sulfadoxine-
pyrimethamine in the second and third trimesters. The rationale
is that each dose will clear placental asymptomatic infections EMERGING INFECTIONS
and provide up to 6 weeks of posttreatment prophylaxis. This
These are collectively defined as infectious diseases that have
ideally will decrease the rate of low-birthweight newborns in
newly appeared or increased in incidence or geographic spread
endemic areas (Harrington, 2013). A recent metaanalysis sup-
(Jamieson, 2006a,b; Theiler, 2008). At this time, emerging
ported the use of at least three doses of intermittent preventa-
infections include West Nile virus, coronavirus, and several
tive therapy to improve birthweight and decrease placental and
influenza A strains. They also include many bioterrorism agents.
maternal malarial infection at delivery (Kayentao, 2013).
Resistance to all the antimalarial drugs has been reported,
including the recently added artemisinin. The World Health ■ West Nile Virus
Organization recommends routine monitoring of antimalarial This mosquito-borne RNA flavivirus is a human neuropatho-
drug resistance and tailoring medication regimens. gen. Since 1999, the reported numbers of human and ani-
mal infections have increased, and the geographical range of
Prevention and Chemoprophylaxis disease activity has expanded. The year 2012 was the second
Malaria control and prevention relies on chemoprophylaxis when worst outbreak of total cases in the United States (Centers
traveling to or living in endemic areas. Vector control is also for Disease Control and Prevention, 2013b). West Nile viral
important. Insecticide-treated netting, pyrethroid insecticides, infections are typically acquired through mosquito bites in late
and N,
N N-diethyl-
N m-toluamide (DEET)-based insect repellent summer or perhaps through blood transfusion (Harrington,
decrease malarial rates in endemic areas. These are well tolerated 2003). The incubation period is 2 to 14 days, and most persons
in pregnancy (Menéndez, 2007). If travel is necessary, chemopro- have mild or no symptoms. Fewer than 1 percent of infected
phylaxis is recommended. adults develop meningoencephalitis or acute flaccid paralysis
Chloroquine and hydroxychloroquine prophylaxis is safe (Granwehr, 2004). Presenting symptoms may include fever,
and well tolerated in pregnancy. It decreases placental infec- mental status changes, muscle weakness, and coma (Chapa,
tion from 20 percent to 4 percent in asymptomatic infected 2003; Stewart, 2013).
 1258 Medical and Surgical Complications

Diagnosis of West Nile infection is based on clinical symp- TRAVEL PRECAUTIONS DURING PREGNANCY
toms and the detection of viral IgG and IgM in serum and
IgM in cerebrospinal fluid. There is no known effective anti- Pregnant travelers face obstetrical risks, general medical risks,
viral treatment, and management is supportive. The primary and potentially hazardous destination risks. The International
SECTION 12

strategy for preventing exposure in pregnancy is the use of Society for Tropical Medicines has comprehensive information
insect repellant containing DEET. This is considered safe for available at: [Link] Also, the Centers for Disease
use around pregnant women (Koren, 2003). Avoiding outdoor Control and Prevention have extensive travel information
activity and stagnant water and wearing protective clothing are regarding pregnancy and breast feeding at its websites listed
also recommended. on page 1257.
Adverse effects of West Nile viremia on pregnancy are
unclear. Animal data suggest that embryos are susceptible, and
a case report of human fetal infection at 27 weeks described
BIOTERRORISM
chorioretinitis and severe temporal and occipital lobe leu- Bioterrorism involves the deliberate release of bacteria, viruses,
komalacia (Alpert, 2003; Julander, 2006). Of 77 maternal or other infectious agents to cause illness or death. These natu-
infections initially reported to the West Nile Virus Pregnancy ral agents are often altered to increase their infectivity or their
Registry, there were four miscarriages, two elective abortions, resistance to medical therapy. Clinicians should be alert for
and 72 live births, of which 6 percent were preterm (O’Leary, significant increases in the number of persons with febrile ill-
2006). Three of these 72 newborns were shown to have West nesses accompanied by respiratory symptoms or with rashes not
Nile infection, and it could not be established conclusively easily associated with common illnesses. Clinicians are urged
that infection was acquired congenitally. Of three major mal- to contact their state health department or the Centers for
formations possiblyy associated with viral infection, none was Disease Control and Prevention for contemporary information
definitively confirmed. Similar conclusions were reached by and recommendations. The American College of Obstetricians
Pridjian and colleagues (2014), who analyzed data from the and Gynecologists (2013b) has recently addressed disaster
Centers for Disease Control and Prevention West Nile Virus preparedness for obstetricians. It provides both general consid-
Registry. Transmission of West Nile virus through breast feed- erations and recommendations for hospital preparedness and
ing is rare (Hinckley, 2007). obstetrics-specific recommendations.

■ Coronavirus Infections ■ Smallpox

Coronaviruses are single-stranded RNA viruses that are preva- The variola virus is considered a serious weapon because of high
lent worldwide. They are associated with 10 to 35 percent of transmission and overall 30-percent case-fatality rate. The last
common colds, usually in the fall, winter, and early spring. In case of smallpox in the United States was reported in 1949, and
2002, an especially virulent strain of coronavirus—severe acute worldwide it was reported in Somalia in 1977. Transmission
respiratory syndrome (SARS–CoV) was first noted in China. It occurs with prolonged contact with infected persons, infected
rapidly spread throughout Asia, Europe, and North and South body fluids, or contaminated objects such as clothing. Smallpox
America. Transmission is through droplets or contact with presents with an acute-onset fever that is followed by a rash
infected secretions, fluids, and wastes. The incubation period with firm, deep-seated vesicles or pustules. Nishiura (2006) and
is 2 to 16 days, and there appears to be a triphasic pattern to Suarez and Hankins (2002) have reviewed the severe perinatal
its clinical progression. The first week is characterized by pro- and maternal morbidity and mortality caused by smallpox. The
dromal symptoms of fever, myalgias, headache, and diarrhea. case-fatality rate of smallpox in pregnancy is 61 percent if the
During the second week, patients may suffer recurrent fever, pregnant woman is unvaccinated. There is a significant increase
watery diarrhea, and a dry nonproductive cough with mild in stillbirth, abortion, preterm labor and delivery, and neonatal
dyspnea. These are coincident with IgG seroconversion and a demise in pregnancies complicated by smallpox infection.
declining viral load. Progression at this stage is thought to be Because the smallpox vaccine currently available is made
due to an overexuberant host immune response. The third, and with live vaccinia virus, pregnancy should be delayed for
at times, lethal phase—seen in about 20 percent of patients— 4 weeks in recipients. It is generally not given to pregnant women
is progression to SARS (Christian, 2004; Peiris, 2003a,b). because of the risk of fetal vaccinia, a rare but serious com-
Radiographic lung findings include ground-glass opacities and plication. Inadvertent smallpox vaccination during pregnancy
airspace consolidations that can rapidly progress within 1 to has not, however, been associated with fetal malformations or
2 days. The case-fatality rate approached 10 percent in the non- preterm birth. Moreover, no cases of fetal vaccinia have been
pregnant population and was as high as 25 percent in pregnant reported with second-generation smallpox vaccine exposure
women (Lam, 2004; Wong, 2004). Although there have been (Ryan, 2008a,b). The Smallpox Vaccine in Pregnancy Registry
no confirmed cases since 2004, the Centers for Disease Control remains active, and vaccinated women are still being enrolled.
and Prevention (2013d) now lists SARS-CoV as a “select agent”
that has the potential to pose a severe threat to public health ■ Anthrax
and safety. Another novel coronavirus infecting humans with a Bacillus anthraciss is a gram-positive, spore-forming, aerobic
high case-fatality rate was detected in the Middle East in 2012 bacterium. It can cause three main types of clinical anthrax:
(MERS-CoV). inhalational, cutaneous, and gastrointestinal (Holty, 2006;
 Infectious Diseases 1259

Swartz, 2001; Sweeney, 2011). The bioterrorist anthrax attacks Allenberger F, Wagner M: Listeriosis: a resurgent foodborne infection. Clin
Microbiol Infect 16:16, 2010
of 2001 involved inhalational anthrax (Inglesby, 2002). Spores Alpert SG, Fergerson J, Noël L-P: Intrauterine West Nile virus: ocular and
are inhaled and deposited in the alveoli. They are engulfed by systemic findings. Am J Ophthalmol 136:722, 2003

CHAPTER 64
macrophages and germinate in mediastinal lymph nodes. The American Academy of Pediatrics: Measles. In Pickering IK (ed): Red Book:
2006 Report of the Committee on Infections Diseases, 27th ed. Elk Grove
incubation period is usually less than 1 week but may be as Village, American Academy of Pediatrics, 2006, p 441
long as 2 months. Initial symptoms are nonspecific and include American Academy of Pediatrics and The American College of Obstetricians
low-grade fever, nonproductive cough, malaise, and myalgias. and Gynecologists: Guidelines for Prenatal Care, 7th ed. Washington, 2012,
p 434
Within 1 to 5 days of symptom onset, the second stage is her- American College of Obstetricians and Gynecologists: Management of asymp-
alded by the abrupt onset of severe respiratory distress and high tomatic pregnant or lactating women exposed to anthrax. Committee
fevers. Mediastinitis and hemorrhagic thoracic lymphadenitis Opinion No. 268, February 2002, Reaffirmed 2009
American College of Obstetricians and Gynecologists: Influenza vaccination
are common, and there is a widened mediastinum on chest during pregnancy. Committee Opinion No. 468, October 2010
radiograph. Case-fatality rates with inhalational anthrax are American College of Obstetricians and Gynecologists: Integrating immuniza-
high, even with aggressive antibiotic and supportive therapy tions into practice. Committee Opinion No. 558, April 2013a
American College of Obstetricians and Gynecologists: Hospital disaster pre-
(Dixon, 1999; Holty, 2006). paredness for obstetricians and facilities providing maternity care. Committee
Anthrax affecting pregnant women and its treatment were Opinion No. 555, March 2013b
recently reviewed by Meaney-Delman and coworkers (2012, American College of Obstetricians and Gynecologists: Prevention of early-
onset group B streptococcal disease in newborns. Committee Opinion No.
2013). They reported data on 20 pregnant and postpartum 485, April 2011, Reaffirmed 2013c
women. The overall mortality rate was 80 percent, with a Andrews WW, Schelonka R, Waites K, et al: Genital tract methicillin-resistant
60-percent fetal or neonatal loss rate. Of note, most cases were Staphylococcus aureus. Obstet Gynecol 111:113, 2008
Auriti C, Piersigilli F, De Gasperis MR, et al: Congenital varicella syndrome:
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Regimens for postexposure anthrax prophylaxis are given Azam AZ, Vial Y, Fawer CL, et al: Prenatal diagnosis of congenital cytomega-
for 2 months. The American College of Obstetricians and lovirus infection. Obstet Gynecol 97:443, 2001
Badilla X, Morice A, Avila-Aguero ML, et al: Fetal risk associated with rubella
Gynecologists (2009) and the Centers for Disease Control and vaccination during pregnancy. Pediatr Infect Dis J 26(9):830, 2007
Prevention (Wright, 2010) recommend that asymptomatic Banatvala JE, Brown DW: Rubella. Lancet 363:1127, 2004
pregnant and lactating women with documented exposure to B Bates T: Poliomyelitis in pregnancy, fetus and newborn. Am J Dis Child 90:
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methicillin-resistant Staphylococcus aureuss in obstetrics. Obstet Gynecol
sensitive. In the case of ciprofloxacin allergy and either penicil- 113(5):983, 2009
lin allergy or resistance, doxycycline, 100 mg orally twice daily, Böddinghaus BK, Ludwig RJ, Kaufmann R, et al: Leprosy in a pregnant
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Bohlke K, Galil K, Jackson LA, et al: Postpartum varicella vaccination: is the
risks from doxycycline (Meaney-Delman, 2013). vaccination virus excreted in breast milk? Obstet Gynecol 102:970, 2003
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uct that requires five injections over 18 months. Vaccination is maternal infection: a problem of diagnosis. J Clin Microbiol 49(10):3514,
2011
generally avoided in pregnancy because there are limited safety Boucher M, Yonekura ML: Perinatal listeriosis (early onset): correlation of ante-
data. Reports of inadvertent vaccination of pregnant women natal manifestations and neonatal outcome. Obstet Gynecol 68:593, 1986
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Anthrax vaccine is an essential adjunct to postexposure antimi- Brown GC, Karunas RS: Relationship of congenital anomalies and maternal
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Brown KE: Chapter 184. Parvovirus infections. In Longo DL, Fauci AS,
Kasper DL, et al (eds): Harrison’s Principles of Internal Medicine, 18th ed.
New York, McGraw-Hill, 2012
■ Other Bioterrorism Agents Butchko AR, Jordan JA: Comparison of three commercially available serologic
assays used to detect human parvovirus B19-specific immunoglobulin M
Other category A bioterrorism agents include Francisella tula- (IgM) and IgG antibodies in sera of pregnant women. J Clinic Microbiol
rensis—tularemia, Clostridium botulinum—botulism,
— Yersinia 42:3191, 2004
pestis—plague,
— and viral hemorrhagic fevers—for example, Butterly A, Schmidt U, Wiener-Kronish J: Methicillin-resistant Staphylococcus
aureuss colonization, its relationship to nosocomial infection, and efficacy of
Ebola, Marburg, Lassa, and Machupo. Multiple agents are also control methods. Anesthesiology 113:1453, 2010
listed as category B and C. The guidelines for these biological Cartwright EJ, Jackson KA, Johnson SD, et al: Listeriosis outbreaks and associ-
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Centers for Disease Control and Prevention: Prevention of varicella.
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[Link]/agent/agentlist-category. (ACIP). MMWR 56(4):1, 2007
Centers for Disease Control and Prevention: Prevention of perinatal group B strep-
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Centers for Disease Control and Prevention: Maternal and infant outcomes
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