One in ten pregnant people are prescribed psychiatric drugs during pregnancy, but searching “is [psychiatric drug] safe to take during pregnancy” on Google or PubMed generally leads to one common result: not enough data. Many researchers, clinicians, and ethicists want to remedy this oversight and provide patients with the data they need to understand any potential risks for them and their fetuses.
Pregnant people are not often included in clinical trials despite efforts to make research more inclusive over the past few decades through legislation by the FDA and United States Department of Health and Human Services. Of the 468 drugs approved by the FDA between 1980 and 2000, the risk of negative effects in pregnant people was undetermined in more than 90% (1). This often leaves clinicians in a tough spot with little data to help navigate the pros and cons of using a particular medication during pregnancy.
“If you don't do [the clinical trials], you're sort of abandoning pregnant women to guesswork and to maybe not taking medicines where the disease is worse for them and potentially their baby than the drugs themselves,” said Margaret Little, an ethicist from the Kennedy Institute of Ethics at Georgetown University. “It's not as hard as many people think to actually do ethically responsible research with pregnant women. Federal regulations allow it; they have some specific guidelines, but they're not that hard to meet.”
Researchers often don’t completely understand how certain medications, particularly psychotropic drugs, work, making it challenging to predict how a drug may affect early development. While experts agree that pregnant people should be included in more clinical trials, studies in pregnant animals, retrospective meta-analyses of electronic health records and small studies, and following the development of children born from parents who did or did not take medication during their pregnancies can provide pregnant patients and their clinicians with clarity.
“There’s a lot of incredibly important clinical research that happens after a drug is approved for use because all that drug development stuff provides just enough evidence for the FDA in the United States to decide whether or not a drug should be sold at all,” said Little.
Finding a balance
In 1977, the FDA excluded pregnant people from phase I and II clinical trials since the efficacy and safety of the drugs in humans is still unknown at that stage. Over time, there was a push to include more women in research, so legislation allowed pregnant people to participate in clinical trials more frequently (2). In 2001, the United States Department of Health and Human Services encouraged inclusion of pregnant people in clinical trials if the study met ten criteria, including preclinical data from pregnant mice or a prospective benefit for the person or the fetus.
Three years ago, the United States Department of Health and Human Services declared that pregnant people were not a “vulnerable” population, meaning that they were not more likely to be coerced than others. Instead, they defined them as “medically complex.” According to Little, the FDA now considers pregnant women “on label,” meaning that when a drug is approved for the general population, that includes pregnant people. However, pregnant women are still often not included in studies.
“Companies may be concerned about liability issues in the event of a poor pregnancy outcome for a pregnant woman who's enrolled in a clinical trial. However, it is important to obtain information about safety of medications in pregnancy and lactating women because we want equitable research,” said Beatrice Chen, an obstetrician and gynecologist and vice chair of the Institutional Review Board at the University of Pittsburgh.
Some experts think that this hesitation stems from infamous historical examples. For example, the prescription of thalidomide to pregnant people for morning sickness in Europe, South America, and Australia in the 1950s resulted in tens of thousands of birth defects, primarily limb malformations, and an immeasurable number of miscarriages. Exactly how this drug mechanistically caused limb malformations was not understood until 2018 (3).
Little said that preclinical testing on pregnant animals examining how the drug affects development are needed to reveal potential toxicity concerns during pregnancy. In fact, testing in pregnant animals recently influenced a decision by the FDA to remove their warning against using statin drugs, which lower cholesterol. These animal studies suggested that statins do not disrupt nervous system development.
In July, The FDA announced that it was “requesting the removal of its strongest warning against using cholesterol-lowering statin medicines in pregnant patients.” The agency cited 15 observational studies examining the outcomes of pregnant patients using statins, especially for controlling conditions like diabetes, that did not find a significant risk for birth defects.
Although the FDA states that “most patients should stop statins once they learn they are pregnant,” they “expect removing the contraindication will enable health care professionals and patients to make individual decisions about benefit and risk.”
“I think the guiding principle still is treat someone with as much as they need, but not more than that. You try to figure out what that right balance is,” said Bradley Gaynes, a psychiatrist and researcher at the University of North Carolina, Chapel Hill School of Medicine.
A case study: psychotropic drugs
Gaynes wants to gather data to help his patients with mental health disorders determine if the benefit of staying on their medication outweighs any risks for them or their fetus’ health. This research could help many patients since ten percent of pregnant people are prescribed psychiatric drugs during pregnancy, and one in eight people develops symptoms of postpartum depression.
Gaynes and Meera Viswanathan, an expert in systemic review methods and director of the RTI International Evidence-based Practice Center at the University of North Carolina, Chapel Hill, recently performed a meta-analysis of 164 studies to analyze the effects of psychiatric drug treatment on pregnant and post-partum people with mental health disorders (4). Their team analyzed reported outcomes, including suicide rates, negative symptoms, and congenital defects.
They found evidence that taking antidepressants and mood stabilizers had positive effects on pregnant people. Two antidepressants, brexanolone and sertraline, relieved depressive symptoms in pregnant women and decreased the number of people who developed postpartum depression. People with bipolar disorder who stopped taking their mood stabilizers experienced more manic and depressive episodes.
The team did not find any significant negative effects on pregnant women taking drugs such as antidepressants across the studies. Gaynes and Viswanthan pointed out that some of the 164 individual studies reported a negative effect by a psychiatric drug, but many of those studies did not exclude confounding factors like disease severity, other medications, drug adherence, and other disorders, making it impossible to delineate if the observed effect resulted from the psychiatric medication in question or something else.
For example, one study concluded that people taking antidepressants during their first trimester had a significantly increased risk for spontaneous abortion (5). However, the disease severity of the control and experimental groups with depression was not accounted for. Viswanthan thinks that more well-designed studies should be conducted to determine both the risks and benefits of using these drugs during pregnancy.
“One of the things that should be a priority is consensus in the field on what outcomes to measure and making sure that those outcomes are actually collected in prospects. In registries, you have that information available on demand, and then you can do a better [study],” said Viswanathan. “If I were to do the next study, it would have the same problem, because there's structural constraints. Fixing these problems requires bigger solutions.”
Based on his review of the available literature, Gaynes recommends that his patients continue antidepressants and mood stabilizers during pregnancy, but suggests drugs where evidence suggests that they pose low risk to the fetus.
“[Antidepressants] are a class that I’m, in general, comfortable prescribing to folks who understand the risks and benefits,” he said. “It gets a little trickier when you are looking at the mood stabilizers to help with bipolar disorder.”
Some valproic acid derivatives such depakote, often used to treat manic episodes, can cause severe neural tube defects, leading to conditions such as spina bifida. But lamotrigine, which moonlights as an anticonvulsant, appears to be safe during pregnancy based on clinical trials in seizure patients (6,7).
Some studies following the children of pregnant people with bipolar disorder who took mood stabilizers did not limit the class of medication, but show low risk for continuing medication during pregnancy. One study followed 197 babies, some with parents with bipolar disorder that did or did not take the medication and some with parents without bipolar disorder, for a year after their birth (8). They tested the babies’ motor and cognitive skills at 12, 26, and 52 weeks after birth, and detected no significant differences between any of the children, although they did see slight differences in neuromotor skills such as posture and reflexes, which was previously reported (9).
Overall, government agencies, researchers, clinicians, and patients want more, high-quality data on the risks of medications for pregnant people because deciding to prescribe a particular medication to pregnant or lactating people without conclusive evidence is, as Little forewarned, “guess work.”
“We want to make sure that any sex and gender related differences are appropriately evaluated. And because pregnant women and postpartum women do develop and oftentimes have medical conditions that may require treatments during pregnancy and postpartum, we want to make sure that we can ensure the safety of therapeutic and preventive options for all people,” said Chen.
- Lo, W.Y. and Friendman, J.M. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol 100, 465-473 (2002).
- Lyerly, A.D. et al. The second wave: Toward responsible inclusion of pregnant women in research. Int J Fem Approaches Bioeth 1, 5-22 (2009).
- Donovan, K.A., et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. eLife 7, e38430 (2018).
- Viswanathan, M., et al. Maternal, fetal, and child outcomes of mental health treatments in women: a meta-analysis of pharmacotherapy. Psychiatric Research and Clinical Practice (2021).
- Almeida, N.D., et al. Risk of miscarriage in women receiving antidepressants in early pregnancy, correcting for induced abortions. Epidemiology 27, 538-546 (2016).
- Meador, K.J., et al. Two-year-old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study. JAMA Neuro (2021).
- Clark, C.T., et al. Lamotrigine dosing for pregnant patients with bipolar disorder. Am J Psychiatry 170, 1240-1247 (2013).
- Santucci, A.K., et al. One-Year Developmental Outcomes for Infants of Mothers With Bipolar Disorder. J Clin Psychiatry 78, 1083-1090 (2017).
- Johnson, K. C., et al. Prenatal Antipsychotic Exposure and Neuromotor Performance During Infancy. Arch Gen Psychiatry 69, 787-794 (2012).