Definition/Introduction

During the last decades, it has become deeply understood that drugs administered to the mothers during pregnancy might have detrimental effects on the physical development of the fetus. Thalidomide is a well-described example of how a seemingly innocent, over-the-counter medication for the morning sickness could exert such a deleterious effect on the fetus, such as miscarriages, and physical deformities.[1] Since 2015, for the better categorization of drug safety, FDA uses the Pregnancy and Lactation Labelling Rule (PLLR), replacing the "A, B, C, D, X" pregnancy labeling categories. The gestational age of the embryo at the time of exposure is the determining factor for the nature of the defect, making the first trimester, the period of organogenesis, the most precarious period for significant malformations.[2] The scope of this article is to present the most important teratogenic medications and their mechanism of action comprehensively.

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. Phenobarbital, an inducer of CYP450 2B and 3A genes, at a molecular level, produces free radicals and causes DNA bases transversion while macroscopically, results in impaired growth, motor development, and fetal mortality.[3][4] Valproate poses a higher teratogenic threat compared to 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.[5] It may also cause the 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.[6][7] The teratogenicity of valproic acid is exerted via the inhibitory actions of folate and histone deacetylase, through increased accumulation in embryonic circulation, as well as by the production of reactive oxygen species (ROS).[8][6][9] Carbamazepine is useful for the treatment of epilepsy and bipolar disorder during pregnancy. Carbamazepine is metabolized into carbamazepine-10, 11-epoxide, damages DNA, and could be associated with craniofacial defects, abnormal IQ, and growth retardation.[7][10] Lamotrigine, a new anti-epileptic 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.[11][12] 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.[13] Phenytoin gets bioactivated by embryonic prostaglandin H synthase to a free radical, resulting in DNA oxidative damage.[14] Topiramate is a drug used for epilepsy and migraines, and it has been interlinked with hypospadias and oral clefts to newborns, especially in pregnant women who received higher doses.[15][16]

Antimicrobial Medications

Antimicrobials are among the most generously prescribed medications during pregnancy and lactation.[17] Hence, clinicians should demonstrate great attention to the dose and type of drug administered to pregnant women, due to pharmacokinetic alterations during this period and the potential harm they could pose to the fetus. Primarily, chloramphenicol is a bacteriostatic drug that binds to the 50s subunit of prokaryotic ribosomes and thus, interferes with 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 dose. Also, it may lead to the development of gray baby syndrome, a syndrome characterized by abdominal dilatation, vomiting, hypothermia, cyanosis, and gray color of the baby’s skin.[17] This syndrome has a high prevalence among premature infants because of their reduced ability for renal and liver metabolism (primarily glucuronidation) of chloramphenicol.[18]

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 or the topoisomerase IV enzyme. They have correlated with renal, cardiac, and central nervous system toxicity.[19] Fluoroquinolones inhibit DNA synthesis and possibly lead 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, dose-dependent, and antimicrobial dependent.[20]Tetracyclines, a bacteriostatic group of antimicrobials that bind to the 30S ribosomal subunit, are contraindicated in pregnancy due to liver necrosis, bone, and teeth defects.[21] 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. Furthermore, in high doses, they suppress skeletal bone growth and cause hypoplasia of tooth enamel.[22]Antifungal agents remain a challenging type of medication to be prescribed during pregnancy since the maternal pharmacokinetics change.[23] 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, in doses greater than 400 mg per day or above, clinical manifestations similar to Antley-Bixler syndrome, with craniosynostosis, trapezoidocephaly, and midfacial hypoplasia.[23]

Anticoagulants

Coumarin derivatives, e.g., warfarin antagonize vitamin K, and inhibit γ-carboxylation of glutamyl residues, reducing protein binding ability with calcium. This inhibition during fetal development could explain the skeletal abnormalities, the stippled calcification of epiphysis, and the nasal hypoplasia.[22] Depending on the severity of nasal hypoplasia, choanal atresia or stenosis could also be present, leading to respiratory and feeding problems. Central nervous system malformations may also occur with the administration of coumarin anticoagulation since they cross the placenta, inhibit clotting factors, and mainly cause intracranial hemorrhage. The risk of congenital disabilities associated with fetal warfarin syndrome (FWS) is particularly high during the 6-9 gestational weeks. Antithyroid Medications

Maternal hyperthyroidism is still managed with antithyroid drugs during pregnancy. Propylthiouracil (PTU), methimazole (MMI), and carbimazole inhibit the TPO-mediated iodination of tyrosine residues in thyroglobulin and thus hinder the synthesis of T4.[24] The administration of these agents has been associated with two significant teratogenic effects on fetus; aplasia cutis and choanal/esophageal atresia, but the data remains debatable.[25]

Vitamin A

Vitamin A, in large doses, can also be teratogenic. A pregnant woman can receive an excessive amount of vitamin A by eating excess food or by taking nutrient supplements with Vitamin A or drugs containing retinoids.[26] Not only the overdose but also the lack of them can cause embryonic malformations. Retinoic acid is essential for early embryogenesis and subsequently for 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.[27] In humans, it can also induce thymic and cardiovascular abnormalities such as hypoplastic aorta and cardiovascular transposition. Their action gets 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.[26]

Hormonal Medication

Diethylstilbestrol (DES) is a nonsteroidal estrogen drug that acts by inhibiting the hypothalamic-pituitary-gonadal axis. DES was being prescribed in pregnant women for three decades, to prevent pregnancy miscarriage. Research later showed that it could potentially be a carcinogen or even a teratogen upon prenatal exposure.[28]The women exposed in utero to DES developed clear cell adenocarcinoma of vagina and cervix and structural anomalies in the genital tract. Besides, 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 in comparison to estradiol, and it does not bind to alpha-fetoprotein.[29] 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.[30]

Clinical Significance

The pharmaceutical management of pregnant women requires special consideration and close collaboration from physicians, to prevent any harmful effects for both the mother and the fetus. Having the disastrous sequelae of thalidomide in mind, clinicians should be quite cautious while prescribing any drug to pregnant women and be aware of the new data about drug safety during pregnancy.

Nursing, Allied Health, and Interprofessional Team Interventions

The healthcare team, i.e., clinicians, nurses, and pharmacists, must work together to make sure that pregnant patients correctly take their medications, and importantly, to discuss any serious drug side effects which they encounter, e.g., muscle pain, jaundice, bleeding, etc. A complete medication list for the patient is necessary before prescribing a medication to prevent clinically significant drug interactions, and a pharmacist can perform medication reconciliation to answer any questions or address concerns other healthcare team members may have. In addition, the healthcare team needs to discuss with the pregnant patient potential risks that medication therapy could have on the developing unborn child especially in the case of patients receiving antiseizure medication treatment.