Definition/Introduction
In recent decades, a profound understanding has emerged regarding the potential adverse effects of drugs on fetal physical development when administered to pregnant women. A prime example is thalidomide, an ostensibly innocuous over-the-counter remedy for morning sickness, which can lead to grave consequences for the fetus, including miscarriages and physical deformities.[1] Since 2015, the US Food and Drug Administration (FDA) has enhanced drug safety categorization through the implementation of the Pregnancy and Lactation Labelling Rule (PLLR), replacing the previous "A, B, C, D, X" pregnancy labeling categories.[2] The pivotal factor in determining the nature of these potential defects lies in the gestational age of the embryo at the time of exposure. Consequently, the first trimester, the crucial period of organogenesis, is particularly susceptible to significant malformations.[3] Understanding the mechanisms, risks, and consequences of teratogenic drugs is crucial for healthcare professionals. This activity aims to elucidate the most significant teratogenic medications, shed light on their mechanisms of action, and emphasize the importance of vigilance in the realm of maternal and fetal health.
Issues of Concern
Neurological Medications
Medications for neurologic conditions are among the drugs with the highest teratogenic potential. One of the most commonly prescribed drug categories in pregnant women is antiepileptic drugs (AEDs), used primarily to prevent seizures but also for neuropathic pain, migraines, and psychiatric disorders. AEDs in low doses can cause cognitive defects and, in higher doses, cause structural malformations.[4]
At a molecular level, phenobarbital, an inducer of CYP450 2B and 3A genes, produces free radicals and causes DNA base transversion while macroscopically, resulting in impaired growth, motor development, and fetal mortality.[5][6]
Valproate poses a higher teratogenic threat than the other AEDs and potentially can distort the development of the fetus. It can lead to cardiac anomalies, neural tube defects, dominantly spina bifida, and developmental delay.[7] It may also cause fetal valproate syndrome, a rare clinical condition consisting of characteristic facial dysmorphisms linked to valproate exposure, limb abnormalities, lip/cleft palate, and urinary tract defects.[8][9] The teratogenicity of valproic acid is exerted via the inhibitory actions of folate and histone deacetylase through increased accumulation in embryonic circulation and by the production of reactive oxygen species (ROS).[10][11]
Carbamazepine is useful for the treatment of epilepsy and bipolar disorder during pregnancy. Carbamazepine is metabolized into carbamazepine-10,11-epoxide, damages DNA, and can be associated with craniofacial defects, abnormal IQ, and growth retardation.[9][12]
Lamotrigine, a newer antiepileptic medication, has been established as the safest mood stabilizer during pregnancy, although it carries an increased risk for facial malformations in fetuses, especially facial cleft.[13][14]
When the fetus suffers exposure in utero to phenytoin, it increases the risk of developing fetal phenytoin syndrome (FHS), characterized by growth deficiency, mental retardation, epicanthic folds, hypertelorism, and a short nose with anteverted nostrils.[15] Phenytoin gets bioactivated by embryonic prostaglandin H synthase to a free radical, resulting in DNA oxidative damage.[16]
Topiramate is a drug used for epilepsy and migraines. It has been linked to hypospadias and oral clefts in newborns, especially in those whose pregnant mothers received higher doses.[17][18]
Antimicrobial Medications
Antimicrobials are among the most generously prescribed medications during pregnancy and lactation.[19] Clinicians should pay careful attention to the dose and type of drug administered to pregnant women due to pharmacokinetic alterations during this period and the potential harm posed to the fetus.
Chloramphenicol is a bacteriostatic drug that binds to the 50s subunit of prokaryotic ribosomes and, thus, interferes with bacterial protein synthesis. According to the available data regarding the toxicity of chloramphenicol to fetuses and newborns, there is a potential danger of bone marrow suppression in direct proportion to the dose. Also, chloramphenicol may lead to the development of gray baby syndrome, a syndrome characterized by abdominal dilatation, vomiting, hypothermia, cyanosis, and the gray color of the baby’s skin.[19] This syndrome has a high prevalence among premature infants because of their reduced ability for renal and liver metabolism (primarily glucuronidation) of chloramphenicol.[20]
Tetracyclines and fluoroquinolones are drug categories that should be avoided during pregnancy. Quinolones and fluoroquinolones, a very effective group of bactericidal antimicrobials, act by inhibiting the bacterial DNA gyrase and the topoisomerase IV enzyme. They are associated with renal, cardiac, and central nervous system toxicity.[21] Fluoroquinolones inhibit DNA synthesis, possibly leading to organ agenesis or even carcinogenesis in fetuses. Animal studies have shown that they induce articular cartilage damage. In further studies conducted on fetal embryonic tissues, in vitro, fluoroquinolones caused impairment of limb development that was dose-dependent and antimicrobial-dependent.[22]
Tetracyclines, a bacteriostatic group of antimicrobials that bind to the 30S ribosomal subunit, are contraindicated in pregnancy due to liver necrosis and bone and teeth defects.[23] Tetracyclines can penetrate several tissues and cross the placenta but do not accumulate within the fetus. They can form a complex with calcium and the organic matrix without affecting the crystal of hydroxyapatite and can result in discoloration of bones and teeth. In high doses, tetracyclines suppress skeletal bone growth and cause hypoplasia of tooth enamel.[24]
The aminoglycoside streptomycin has been shown to cause irreversible bilateral congenital deafness in children born to mothers who were treated with streptomycin during the first trimester of pregnancy, and thus, it should be avoided during pregnancy.[21] Other aminoglycosides, eg, tobramycin, gentamicin, and amikacin, could be used for a short course of therapy if carefully monitored, and the benefits outweigh the risks.
Sulfamethoxazole/trimethoprim should be avoided during pregnancy because of the risk of fetal malformations during the first trimester and kernicterus after 32 weeks of gestation because sulfamethoxazole displaces bilirubin from albumin-binding sites.[21]
Nitrofurantoin appears to be safe and effective during pregnancy.[21] However, there seems to be an increased risk of hypoplastic left heart malformations in 3 case-controlled studies and hemolytic anemia in pregnant patients with glucose-6-phosphate dehydrogenase deficiency.
The recommended dosing of rifampin is safe and effective during pregnancy.[21] Higher than recommended doses can increase the risk of fetal malformations. Rifampin may increase the risk of newborn bleeding, which can be treated with vitamin K.
Antifungal agents remain a challenging category of medications prescribed during pregnancy since the understanding of maternal pharmacokinetics has changed.[25] Azoles inhibit the action of C14 demethylase and thus the biosynthesis of ergosterol, a substantial element of fungal cell membranes. Fluconazole, in particular, has been shown to cause clinical manifestations similar to Antley-Bixler syndrome in doses greater than 400 mg per day, with craniosynostosis, trapezoidocephaly, and midfacial hypoplasia.[25]
Anticoagulants
Coumarin derivatives, eg, warfarin, antagonize vitamin K, and inhibit γ-carboxylation of glutamyl residues, reducing protein binding ability with calcium. This inhibition during fetal development can explain the known fetal skeletal abnormalities, stippled calcification of epiphysis, and nasal hypoplasia.[24] Depending on the severity of nasal hypoplasia, choanal atresia or stenosis can also be present, leading to respiratory and feeding problems. Central nervous system malformations may also occur with the administration of coumarin anticoagulation since these medications cross the placenta, inhibit clotting factors, and cause intracranial hemorrhage. The risk of congenital disabilities associated with fetal warfarin syndrome (FWS) is particularly high during gestational weeks 6 through 9.[26][27]
Antithyroid Medications
Maternal hyperthyroidism is still managed with antithyroid drugs during pregnancy. Propylthiouracil (PTU), methimazole (MMI), and carbimazole inhibit the thyroperoxidase (TPO)-mediated iodination of tyrosine residues in thyroglobulin and hinder the synthesis of L-thyroxine/tetraiodothyronine (T4).[28] The administration of these agents has been associated with 2 significant teratogenic effects on fetuses: aplasia cutis and choanal/esophageal atresia. The data remains debatable.[29]
Vitamin A
Vitamin A, in large doses, can also be teratogenic. A pregnant woman may receive excessive vitamin A by eating excess vitamin A-rich food or taking nutritional supplements with vitamin A or drugs containing retinoids.[30] Both the excess and the lack of vitamin A can cause embryonic malformations. Retinoic acid is essential for early embryogenesis and, subsequently, for the maturation and development of tissues and organs. High doses of vitamin A in pregnant rats caused neural tube defects, for instance, exencephaly, spina bifida with meningocele, hydrocephalus, eye malformations, and cleft palate.[31] In humans, high doses of vitamin A can also induce thymic and cardiovascular abnormalities such as hypoplastic aorta and cardiovascular transposition. The pharmacologic action is exerted on the cranial neural crest cells and an unknown central nervous system cellular group. The carboxylate group and the side chain of the molecule give the retinoids their teratogenic potency.[30]
Hormonal Medication
Diethylstilbestrol (DES) is a nonsteroidal estrogen drug that acts by inhibiting the hypothalamic-pituitary-gonadal axis. DES has been prescribed in pregnant women for 3 decades to prevent pregnancy miscarriage. Research later showed that it can potentially be a carcinogen or even a teratogen upon prenatal exposure.[32]
The women exposed in utero to DES developed clear cell adenocarcinoma of the vagina and cervix and structural anomalies in the genital tract. The sons of women who received DES during pregnancy developed several abnormalities of the genital tract. DES has a lower affinity for binding with sex hormone-binding globulin than estradiol, so it can easily cross the placenta. Furthermore, DES undergoes metabolism to reactive intermediates compared to estradiol and does not bind to alpha-fetoprotein.[33]
On the other hand, excessive androgen production or the use of anabolic-androgenic steroids, for example, by female athletes, can cause female fetuses to develop clitoromegaly and labial fusion if administered before the end of the first trimester.[34]
Nursing, Allied Health, and Interprofessional Team Interventions
The responsible and ethical use of teratogenic drugs requires an interprofessional healthcare team that possesses the necessary skills, collaborates effectively, and prioritizes patient-centered care and safety. By integrating these elements, team members, including clinicians, nurses, and pharmacists can minimize risks, maximize patient outcomes, and ensure the well-being of both mother and child when managing teratogenic drugs.
Healthcare professionals need a high level of expertise and knowledge in teratogenic drugs. A complete medication list for the patient is necessary before prescribing a medication to prevent clinically significant drug interactions. Physicians and advanced care practitioners must possess a deep understanding of drug interactions and potential risks to the fetus. Pharmacists can perform medication reconciliation to answer questions or address other healthcare team members' concerns. Nurses, pharmacists, and other healthcare professionals must be skilled in drug administration, monitoring, and patient education.
Developing a comprehensive strategy for managing teratogenic drug use is essential. The interprofessional team should collaborate to create standardized protocols for prescribing, monitoring, and educating patients. These strategies should emphasize the importance of risk assessment.
Team members must discuss with the pregnant patient the potential risks of medication therapy on the developing fetus. Informed consent, patient autonomy, and the best interests of both the mother and the unborn child must be prioritized. Open and honest communication with patients is essential to ensure they make well-informed choices.
