What are two medications with emerging safety concerns or uncertain associations with existing safety issues when used during pregnancy?

From the Guidelines

For your assignment on medicines with emerging safety issues in pregnancy, I recommend focusing on direct oral anticoagulants (DOACs) and myosin inhibitors. DOACs, which are increasingly used for anticoagulation, have insufficient safety data regarding their use in pregnancy, and a recent meta-analysis suggests that they are associated with a higher rate of fetal complications compared with low-molecular-weight heparin or warfarin 1. Myosin inhibitors, on the other hand, may cause fetal toxicity when administered to a pregnant woman, based on unpublished findings in animal studies 1. Both of these medications illustrate the challenges in establishing definitive safety profiles in pregnancy, particularly with the lack of randomized controlled trials in pregnant women, leaving clinicians to rely on observational studies and registries with inherent limitations. Some key points to consider when evaluating the safety of these medications in pregnancy include:

• The potential for fetal complications with DOACs, which may outweigh the benefits of their use in certain cases 1
• The lack of human data on the safety of myosin inhibitors in pregnancy, which makes it difficult to assess their risk-benefit profile 1
• The importance of weighing the potential risks and benefits of these medications on a case-by-case basis, taking into account the individual patient's medical history and circumstances
• The need for close monitoring and follow-up of pregnant women who are taking these medications, to quickly identify and address any potential complications that may arise. In contrast to other medications such as beta blockers, which are generally considered safe to use during pregnancy, although atenolol has some evidence of potential fetal risk 1, or biologic agents like anti-TNF agents, which can be continued during pregnancy to maintain remission without increasing the risk of pregnancy complications 1.

From the FDA Drug Label

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders. Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings. Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.

The emerging safety issue with ondansetron is the potential association with cardiovascular defects and oral clefts in the fetus when used during pregnancy, particularly in the first trimester. However, the current evidence is inconsistent and limited by methodological limitations, making it difficult to draw conclusions about the safety of ondansetron use in pregnancy 2.

• Key findings include:
  • Inconsistent associations between ondansetron exposure and cardiovascular defects
  • Inconsistent associations between ondansetron exposure and oral clefts
  • Important methodological limitations in available studies Given the uncertainty and inconsistency of the evidence, it is essential to exercise caution when using ondansetron in pregnant women.

From the Research

Medicines with Emerging Safety Issues in Pregnancy

Two medicines that have emerging safety issues or uncertainty about their association with existing safety issues are:

• Valproate: an antiepileptic drug with a known risk of neural tube defects, hypospadias, cardiac defects, and oral clefts in infants exposed during pregnancy 3, 4, 5
• Topiramate: an antiepileptic drug associated with an increased risk of cleft lip in infants exposed during pregnancy 3

Safety Concerns with Valproate

Valproate has been linked to various safety concerns, including:

• Neural tube defects: a 1-2% incidence of spina bifida aperta in humans, and exencephaly in mice 5
• Transgenerational adverse effects: potential risk of malformations and neurodevelopmental disorders in children of individuals exposed to valproate in utero 6
• Pharmacogenetic abnormality: suggestion of a pharmacogenetic susceptibility to the teratogenic effects of valproate 4

Comparison with Other Medicines

Compared to other antiepileptic drugs, valproate has a higher risk of major malformations, with a risk ratio of 5.1 compared to lamotrigine 3 Topiramate also has a higher risk of major malformations compared to lamotrigine, with a risk ratio of 2.2 3

Important Considerations

It is essential to inform women of childbearing age about the risks associated with valproate use during pregnancy, particularly the risk of neural tube defects and transgenerational adverse effects 6, 7