Acta Clin Croat 2016; 55:309-315 Professional Paper

doi: 10.20471/acc.2016.55.02.19

THE ROLE OF LOW MOLECULAR WEIGHT HEPARIN

IN WOMEN WITH HEREDITARY THROMBOPHILIA
FOR GOOD PERINATAL OUTCOME
Vesna Sokol1, Marina Ivanišević1,2, Mislav Herman1 and Josip Đelmiš2

1
Clinical Department of Gynecology and Obstetrics, Zagreb University Hospital Center;
2
University of Zagreb, School of Medicine, Zagreb, Croatia

SUMMARY – The aim of the study was to establish the importance of low molecular weight
heparin (LMWH) treatment for good pregnancy outcome in patients with hereditary thrombophilia.
This retrospective study included 70 patients with inherited thrombophilia who gave birth at Zagreb
University Hospital Center in the period from January 2014 to January 2015. Fifty-seven women
were treated and 13 women were not treated with LMWH. Perinatal outcome was significantly better
in women with hereditary thrombophilia who were treated with heparin during pregnancy as com-
pared with women without LMWH (p=0.006). Regardless of heparin therapy, patients with heredi-
tary thrombophilia alone had a significantly better perinatal outcome as compared with women who,
along with hereditary thrombophilia, had a history of habitual abortions (p=0.035) or intrauterine
fetal death (p=0.033). Women treated with heparin had better perinatal outcome if they were without
a history of recurrent or non-recurrent fetal loss (p=0.088). In the group without LMWH, perinatal
outcome was significantly better in women with no history of habitual abortions as compared with
women with recurrent miscarriages (p=0.047). Administration of LMWH is justified in women with
hereditary thrombophilia and a history of adverse perinatal outcome.
Key words: Thrombophilia, hereditary; Pregnancy; Heparin, low-molecular-weight; Pregnancy outcome

Introduction ized by the presence of antiphospholipid antibodies.

Antiphospholipid syndrome can be either primary or
Thrombophilias are inherited or acquired condi- secondary to another autoimmune disease. The overall
tions that create a hypercoagulable state which predis- impact of inherited and acquired thrombophilias is
poses the individual to thromboembolism1-3. Inherited low in non-pregnant population and the majority of
defects related to thrombosis include the G1691A patients never experience a thrombotic event. During
mutation in the factor V gene, the G20210A mutation
pregnancy, however, the thrombogenic potential of
in the prothrombin gene, the C677T mutation and the
these disorders is enhanced because of the hypercoag-
A1298C mutation in the methylenetetrahydrofolate
ulable state produced by normal pregnancy-associated
reductase (MTHFR) gene, antithrombin III, protein
changes with which the mother’s body adjusts to preg-
C and protein S deficiency4. The most entrenched ac-
nancy and later on to childbirth. Such changes occur
quired thrombophilia is the antiphospolipid syndrome,
in the blood flow, vascular wall and coagulation factors
a non-inflammatory autoimmune disease character-
(increased levels of factors VII, VII, X and von Wille-
brand’s factor, decreased activity levels of protein C
Correspondence to: Vesna Sokol, MD, Clinical Department of Gy- and protein S, and increased activity level of fibrino-
necology and Obstetrics, Zagreb University Hospital Center,
lytic inhibitors)4.
Petrova 13, HR-10000 Zagreb, Croatia
E-mail: vesnasokol83@[Link] Whereas in recent years numerous studies have es-
Received January 13, 2016, accepted February 25, 2016 tablished the association between acquired thrombo-

Acta Clin Croat, Vol. 55, No. 2, 2016 309

Vesna Sokol et al. Heparin effect on perinatal outcome in women with hereditary thrombophilia

philias and adverse pregnancy outcome5-7, inherited All the variables collected were statistically analyzed
thrombophilia and related complications in pregnancy and presented descriptively. Inferential statistical anal-
still remain debatable8,9. Available evidence does not ysis aimed to investigate the relationship between the
support an association between inherited thrombo- use of LMWH in women with thrombophilic muta-
philia and preeclampsia, fetal growth restriction, or tions and their perinatal outcome. The level of statisti-
abruption, and, in turn, it does not support prophy- cal significance was set at p<0.05.
lactic anticoagulation to prevent the possible adverse
pregnancy outcomes in patients with hereditary
Results
thrombophilias10. However, adverse medical and ob-
stetric history in patients with inherited thrombophil- A total of 70 women with inherited thrombophilia
ia requires special caution for good outcome of the who gave birth at the Zagreb University Hospital
current pregnancy. Center were recruited during the study period. The
The aim of the study was to establish the role of mean age of study patients was 34.2±4 years, range 20-
low molecular weight heparin (LMWH) in patients 45 years. The mean body mass index was 25.7 (range
with inherited thrombophilia for good pregnancy out- 18-35). The minimum number of pregnancies was 1
come, with special emphasis on the women with ad-
verse obstetric history, and to identify the common Table 1. Demographic characteristics of patients
types of mutation in the study group. with hereditary thrombophilia
Characteristic Patients with HT
Patients and Methods
Age
34.2±4.40 (20.0-45.0)
This retrospective epidemiological study was con- (years; mean ± SD and range)
ducted at the State Referral Center for Diabetes in BMI
25.7±5.21 (18.0-35.0)
Pregnancy, Zagreb University Hospital Center, Za- (kg/m²; mean ± SD and range)
greb, Croatia, during the period from January 2014 to Gravidity
2.9±1.51 (1.0-9.0)
January 2015. The study included 70 patients diag- (n; mean ± SD and range)
nosed with hereditary thrombophilia. All enrolled pa- Parity
0.7±0.74 (0.0-2.0)
tients delivered in our hospital but the majority of (n; mean ± SD and range)
them had their regular examinations and treatment Abortion
1.3±1.36 (0.0-7.0)
provided by their physicians in primary or secondary (n; mean ± SD and range)
health care centers. Patients were classified into two HT = hereditary thrombophilia; BMI = body mass index; SD =
groups: 57 women with hereditary thrombophilia that standard deviation; n = number
were treated with LMWH and 13 women not treated
with LMWH despite the diagnosis of inherited Table 2. History of comorbidity in patients
thrombophilia. Patient characteristics including de- with hereditary thrombophilia
mographics, obstetric and medical history were ob-
History of comorbidity n (%)
tained from patients at the hospital visit and entered in
Primary or secondary infertility 9 (12.5)
the database. Data on pregnancy outcomes were ob-
- IVF in current pregnancy 6 (6.6)
tained from the delivery suite database.
Hypertensive disorders 6 (8.5)
- PIH 3 (50)
Statistical analysis
- PE 3 (50)
All statistical analyses were performed using the GDM 8 (11.4)
SPSS for Windows, release 17 (SPSS Inc., Chicago, T1D 1 (1.4)
IL, USA). For quantitative measurements (continu- T2D 1 (1.4)
ous), the mean and standard deviation was calculated.
For qualitative measurements, absolute frequency was n = number; IVF = in vitro fertilization; PIH = pregnancy induced
hypertension; PE = preeclampsia; GDM = gestational diabetes
calculated and prevalence was expressed as percentage. mellitus; T1D = diabetes mellitus type 1; T2D = diabetes mellitus
The c2-test was used on comparison of qualitative data. type 2

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Vesna Sokol et al. Heparin effect on perinatal outcome in women with hereditary thrombophilia

Table 3. Type of mutation for hereditary thrombophilia in the study group

Mutation n %
PAI 1 homozygous 12 10.8
MTHFR heterozygous (C677T), PAI1 (4G/5G) homozygous 11 9.9
PAI1 heterozygous 10 9.0
PAI1 homozygous, MTHFR homozygous 6 5.4
FVL heterozygous, PAI1 heterozygous 5 4.5
PAI1 heterozygous, MTFHFR heterozygous 5 4.5
FII heterozygous, PAI1 homozygous, MTHFR homozygous 4 3.6
MTHFR homozygous, PAI1 heterozygous 3 2.7
FVL heterozygous 2 1.8
FII heterozygous 2 1.8
PAI1 homozygous, protein S deficiency 1 0.9
MTHFR homozygous, FVL heterozygous 1 0.9
MTHFR homozygous, PAI1 heterozygous, FVL heterozygous 1 0.9
MTHFR heterozygous, PAI1 homozygous, protein S deficiency 1 0.9
MTHFR heterozygous 1 0.9
PAI1 heterozygous, MTHFR heterozygous, FVL heterozygous 1 0.9
FVL homozygous, PAI1 heterozygous 1 0.9
FII homozygous, FVL heterozygous, PAI1 homozygous, MTHFR heterozygous 1 0.9
MTHFR heterozygous, PAI1 heterozygous, protein C and protein S deficiency 1 0.9
Antithrombin III deficiency, PAI1 heterozygous 1 0.9

Table 4. Classification of mutations in the study group disorders such as gestational hypertension and pre-
eclampsia (50% both), and eight (11.4%) women were
Type of mutation n (%)
diagnosed with gestational diabetes (Table 2).
Isolated 27 (38.6)
All study women had DNA blood tests that con-
Combined 43 (61.4)
firmed gene mutations for hereditary thrombophilia.
Total 70 (100.0)
Twenty different combinations of gene mutations were
identified (Table 3).
and maximum 9, with a mean value of 2.9. The mini- Given the high prevalence of different types of mu-
mum number of deliveries was 0 and maximum 2, and tations in the study group, the mutations were classi-
the mean number of abortions was 1.37 (range 0-7) fied as isolated (n=27; 38.6%) and combined (n=43;
(Table 1). 38.7%) (Table 4).
Six (8.5%) women experienced venous thrombo- Analysis of medical records found that treatment
embolism before their pregnancy. These pregnant with heparin was based on obstetric and family history,
women were found to have a family history of venous as well as on the type of mutation for hereditary
thromboembolism, myocardial infarction or stroke in thrombophilia.
first-degree relatives younger than 50. The prevalence Using Pearson’s c2-test, we analyzed perinatal out-
of this history was 15.7% (11 patients). come in all women with hereditary thrombophilia
Nine (12.5%) women with inherited thrombophil- (Table 5), in women with hereditary thrombophilia
ia had a diagnosis of primary or secondary infertility treated with LMWH (Table 6) and in women with
and six (6.6%) of them conceived using in vitro fertil- hereditary thrombophilia not treated with LMWH
ization (IVF). Six (8.5%) patients had hypertensive (Table 7).

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Vesna Sokol et al. Heparin effect on perinatal outcome in women with hereditary thrombophilia

Table 5. Perinatal outcome in women with hereditary thrombophilia (N=70)

Perinatal outcome
Placental
Patients with HT Good IUGR Miscarriage PE
abruption
n % n % n % n % n %
LMWH No 7 53.8% 2 15.4% 0 0.0% 4 30.8% 0 0.0%
treatment Yes 47 82.5% 6 10.5% 2 3.5% 1 1.8% 1 1.8%
Isolated 19 70.4% 4 14.8% 1 3.7% 3 11.1% 0 0.0%
Type of mutation
Combined 35 81.4% 4 9.3% 1 2.3% 2 4.7% 1 2.3%
No 29 76.3% 7 18.4% 1 2.6% 0 0.0% 1 2.6%
Habitual abortion
Yes 25 78.1% 1 3.1% 1 3.1% 5 15.6% 0 0.0%
IUFD in previous No 45 78.9% 6 10.5% 0 0.0% 5 8.8% 1 1.8%
pregnancies Yes 9 69.2% 2 15.4% 2 15.4% 0 0.0% 0 0.0%

Perinatal
Patients with HT
outcome Regardless of LMWH, women without habitual
LMWH c2 14.502 abortions had a significantly better perinatal outcome
treatment Df 4 as compared with women with recurrent miscarriages
P 0.006 (with emphasis on recurrent spontaneous abortion)
Type of mutation c2 2.409 (p=0.035). Nevertheless, women with no history of ad-
Df 4 verse perinatal outcome had a significantly better
P 0.661 pregnancy outcome as compared with women with a
Habitual abortion c2 10.358 history of IUFD (p=0.033). The latter group showed a
Df 4
higher incidence (15.6%) of placental abruption in the
observed pregnancy (Table 5).
P 0.035
In the group of women with hereditary thrombo-
IUFD in previous pregnancies c2 10.486
philia treated with LMWH, we found no association
Df 4
between the type of mutation (isolated or combined)
P 0.033
and perinatal outcome (p=0.636). In the same group,
HT = hereditary thrombophilia; IUGR = intrauterine growth re- there was no significant difference in perinatal out-
striction; PE = preeclampsia; n = number; LMWH = low molecular come between the women with normal pregnancy
weight heparin; IUFD = intrauterine fetal death
outcome and those with habitual abortions in previous
pregnancies (p=0.398). Although there was no signifi-
cant difference in perinatal outcome between women
Adverse perinatal outcome such as intrauterine
with normal pregnancy outcome and those with IUFD
growth restriction (IUGR), intrauterine fetal death
in previous pregnancies (p=0.088), women with IUFD
(IUFD), placental abruption, abortion and preeclamp-
in previous pregnancies had a higher incidence of pla-
sia (PE) was observed.
cental abruption in the observed pregnancy (15.4%)
According to study results, patients with hereditary (Table 6).
thrombophilia that received LMWH had a signifi- In the group of women with hereditary thrombo-
cantly better perinatal outcome as compared with the philia but without LMWH treatment, we found no
group without LMWH (p=0.006). association between the type of mutation (isolated or
The abortion rate was lower in the group with combined) and perinatal outcome (p=0.380). Patients
LMWH; however, this group had a higher incidence with no history of adverse perinatal outcome had a sig-
of placental abruption. There were no significant dif- nificantly better perinatal outcome than women with a
ferences according to the type of mutation (isolated history of recurrent miscarriages (p=0.047). In this
and combined) and perinatal outcome (p=0.661). group, there was no patient with a history of IUFD.

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Vesna Sokol et al. Heparin effect on perinatal outcome in women with hereditary thrombophilia

Table 6. Perinatal outcome in women with hereditary thrombophilia treated with low molecular weight heparin
(N=57)
Perinatal outcome
Patients with HT treated with Placental
Good IUGR Miscarriage PE
LMWH abruption
n % n % n % n % n %
Isolated 18 78.3% 3 13.0% 1 4.3% 1 4.3% 0 0.0%
Type of mutation
Combined 29 85.3% 3 8.8% 1 2.9% 0 0.0% 1 2.9%
No 25 78.1% 5 15.6% 1 3.1% 0 0.0% 1 3.1%
Habitual abortion
Yes 22 88.0% 1 4.0% 1 4.0% 1 4.0% 0 0.0%
IUFD in previous No 38 86.4% 4 9.1% 0 0.0% 1 2.3% 1 2.3%
pregnancies Yes 9 69.2% 2 15.4% 2 15.4% 0 0.0% 0 0.0%

Patients with HT treated with Perinatal

LMWH outcome weeks of gestation, the majority of prospective studies
Type of mutation c2 2.549 deny this causal connection13-15.
Df 4 Our study included a heterogeneous group of
P 0.636 women of different age groups, different family and
Habitual abortion c2 4.060 personal history, and different reasons for genetic test-
ing for hereditary thrombophilia. Different widespread
Df 4
mutations and their combinations found in our geo-
P 0.398
graphical area reflected in our study group, with a pre-
IUFD in previous pregnancies c2 8.095
dominance of so-called ‘mild mutations’ such as PAI1
Df 4 and MTHFR, and a lesser percentage of ‘severe muta-
P 0.088 tions’ such as factor V Leiden and factor II mutations.
HT = hereditary thrombophilia; IUGR = intrauterine growth re- Despite the already inveterate opinion that hereditary
striction; PE = preeclampsia; n = number; LMWH = low molecular thrombophilia has a negligible impact on perinatal
weight heparin; IUFD = intrauterine fetal death
outcome, women in our study that were administered
LMWH had a statistically much better perinatal out-
Unfortunately, the number of cases in this group was come than women that did not receive this therapy,
too small to obtain meaningful data (Table 7). irrespective of the mutation type (p=0.006). Women
treated with heparin experienced a lower percentage of
miscarriages; however, more cases of placental abrup-
Discussion
tion were recorded in this group. Furthermore, an un-
Thrombophilia in mothers, in addition to natural fortunate outcome of previous pregnancies (e.g., recur-
hemostatic changes in every pregnancy, also changes rent miscarriages, IUFD) also led to worse perinatal
placental circulation11,12. Thromboses of maternal pla- outcome of the observed pregnancies. It is important
centa may cause complications such as preeclampsia to highlight that all the observed women with heredi-
and IUGR, as well as more serious complications such tary thrombophilia and recurrent miscarriages that
as miscarriage, placental abruption and IUFD. Nu- were not treated with heparin had a statistically worse
merous studies have evaluated the correlation between perinatal outcome as compared with women who were
thrombophilia and pathologic perinatal outcome. not treated with heparin either but had unremarkable
Even though some retrospective studies argue there is obstetric history.
a link between certain mutations (heterozygous factor This study results supported the Royal College of
V Leiden, heterozygous prothrombin gene, protein C Obstetricians and Gynaecologists Green-top guide-
and S deficiency) and missed abortions after 10 weeks lines, clearly stressing the importance of LMWH for
of gestation, recurrent miscarriages and IUFD after 20 better perinatal outcome in pregnant women with he-

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Vesna Sokol et al. Heparin effect on perinatal outcome in women with hereditary thrombophilia

Table 7. Perinatal outcome in women with hereditary thrombophilia without low molecular weight heparin treatment
(N=13)
Perinatal outcome
Patients with HT without Placental
Good IUGR Miscarriage PE
LMWH treatment abruption
n % n % n % n % n %
Isolated 1 25.0% 1 25.0% 0 0.0% 2 50.0% 0 0.0%
Type of mutation
Combined 6 66.7% 1 11.1% 0 0.0% 2 22.2% 0 0.0%
Habitual No 4 66.7% 2 33.3% 0 0.0% 0 0.0% 0 0.0%
abortion Yes 3 42.9% 0 0.0% 0 0.0% 4 57.1% 0 0.0%
IUFD in previous No 7 53.8% 2 15.4% 0 0.0% 4 30.8% 0 0.0%
pregnancies Yes 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Patients with HT without LMWH Perinatal

treatment outcome of heparin can help the body fight for a better perinatal
Type of mutation c2 1.935 outcome, especially in women who have already lost
the battle in past pregnancies. According to our results,
Df 2
LMWH proved to be the treatment of choice in pa-
P 0.380
tients with adverse pregnancy events in which throm-
Habitual abortion c2 6.102
bophilic mutations were identified.
Df 2
P 0.047
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Sažetak

VAŽNOST PRIMJENE NISKOMOLEKULARNOG HEPARINA

KOD TRUDNICA S NASLJEDNOM TROMBOFILIJOM ZA DOBAR PERINATALNI ISHOD

V. Sokol, M. Ivanišević, M. Herman i J. Đelmiš

Cilj ove studije bio je ustanoviti komplikacije trudnoće i važnost primjene niskomolekularnog heparina za poboljšanje
perinatalnog ishoda kod trudnica s nasljednom trombofilijom. Retrospektivno su analizirani podatci 70 trudnica s dokaza-
nom hereditarnom trombofilijom i urednom ili opterećenom opstetričkom anamnezom koje su porođene u Klinici za ženske
bolesti i porođaje u razdoblju od siječnja 2014. do siječnja 2015. Njih 57 liječeno je niskomolekularnim heparinom, dok kod
ostalih 13 žena nije provedena antikoagulantna terapija. Ispitanice s nasljednom trombofilijom koje su tijekom trudnoće
uzimale heparinsku terapiju imale su statistički značajno bolji perinatalni ishod u odnosu na ispitanice s nasljednom trom-
bofilijom bez antikoagulantne terapije (p=0,006). Ispitanice s hereditarnom trombofilijom i urednom opstetričkom anamne-
zom imale su statistički značajno bolji perinatalni ishod u odnosu na ispitanice s trombofilijom i prethodnim habitualnim
pobačajima (p=0,035) ili intrauterinom smrti čeda (p=0,033). Ispitanice s hereditarnom trombofilijom i urednim prethodnim
trudnoćama koje su liječene heparinom imale su nešto bolji perinatalni ishod u odnosu na skupinu s trombofilijom i prethod-
nim mors fetus in utero kod kojih je također primjenjivana antikoagulantna terapija (p=0,088). U skupini ispitanica s heredi-
tarnom trombofilijom a bez heparinske terapije, ispitanice bez habitualnih pobačaja u anamnezi imale su statistički značajno
bolji perinatalni ishod u odnosu na trudnice s habitualnim pobačajima (p=0,047). Primjena niskomolekularnog heparina za
bolji perinatalni ishod opravdana je kod trudnica s nasljednom trombofilijom i opterećenom opstetričkom anamnezom.
Ključne riječi: Trombofilija, nasljedna; Trudnoća; Heparin, niskomolekularni; Trudnoća, ishod

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