Risks and Benefits of Antidepressant Use in Pregnancy

Antidepressant use in pregnancy

Psychiatry Advisor
Michael O'Leary

In a common enough scenario, a pregnant patient being treated for depression or anxiety reads an article that links maternal antidepressant use during pregnancy with birth defects and wonders whether she should stop taking the medication. (published site)

Nearly 20% of women experience depression and anxiety during and after pregnancy1, and the use of antidepressants during pregnancy is rising.  One study found the use of antidepressant medications during pregnancy increased from 5.7% in 1999 to 13.4% in 2003. Selective serotonin reuptake inhibitors (SSRIs) accounted for most of the antidepressants prescribed.2

Many other studies have looked at possible consequences ranging from birth defects, preterm delivery, neonatal syndromes, developmental effects, and even autism and attention deficit/hyperactivity disorder (ADHD). The results have spawned controversy and a long-running debate that has divided researchers into two groups. Some feel antidepressant medications should be considered as a beneficial treatment option for expectant women struggling with depression. Others consider these medications harmful based on evidence from animal models and human studies.

For more than 10 years, Adam Urato, MD, a maternal-fetal medicine obstetrician specializing in high-risk pregnancy at Tufts University School of Medicine, has been an outspoken critic of antidepressant use during pregnancy. He points to the basic science showing that serotonin plays a key role in the formation of organs as the embryo develops into a fetus.

Serotonin's Influence on Embryos “Serotonin is crucial in development,” Urato tells Psychiatry Advisor. “SSRI antidepressants [also] disrupt the serotonin system, and they freely cross the placenta. So what do we expect to see? We expect to see that animal studies will show harm, and they do. “We see birth defects, we see pregnancy loss, and we see abnormalities in development of these rats and mice,” he continues. “Then when we [get to] the human studies, we see further evidence of harm and that evidence continues to grow.”

In a review of 41 studies, published earlier this year in PLoS ONE looking primarily at antidepressant use and risk of preterm delivery, Urato and colleagues found pooled risk odds ratio estimates ranging between 1.16 (95% CI 0.92–1.45) and 1.96 (95% CI 1.62–2.38). The associations were stronger for antidepressant use later in pregnancy. Adjusting for a diagnosis of depression in most cases did not eliminate the effect, although the strength of the observed associations was somewhat lessened.3

“Our review looked at 41 studies of preterm birth, and 39 of the 41 studies showed increased rates of preterm birth. This is not inconsistent. This is not 50/50,” says Urato.

However, Nancy Byatt, DO, MBA, FAPM, a perinatal psychiatrist at the University of Massachusetts Medical School, is among the experts who believe the medication is helpful. Supporters contend that the available data on harm from antidepressant exposure during pregnancy have been inconsistent. Proponents also maintain that it is difficult to tease out whether the harm stems from the medications or the depression itself.

To look at the available human studies, Byatt and colleagues conducted a comprehensive review of almost 160 studies on the risk of first trimester teratogenicity, postnatal adaptation syndrome (PNAS), and persistent pulmonary hypertension (PPHN) with in utero antidepressant exposure.

Risk of Birth Defects With SSRIs Relatively Small

The challenge of achieving consistent results, Byatt says, is partly due to the inability to do randomized comparisons due to ethical concerns, and the difficulty of controlling for maternal illness and severity of illness.

“Pregnancy itself precludes us from using the gold-standard methodology,” Byatt says, “so we're left with other methodologies, and each have their own pros and cons. This makes it very hard to differentiate whether adverse outcomes are associated with underlying illness, the medication, or other unknown factors associated with either or both.”

In summarizing their findings regarding malformations, Byatt says in general they found that paroxetine (Paxil) has been the most controversial because it has been associated with an increased risk of overall major malformations. However, it is also important to note that not all studies support this finding.

“SSRIs remain the most studied antidepressants in pregnancy. Malformations are rare, and the absolute risks appear small,” Byatt says. “No single type of malformation has been consistently observed across studies with any commonly used antidepressant.”

Byatt's team concluded that while some individual studies suggest associations between SSRIs and some specific major malformations, the findings are inconsistently observed and the absolute risks appear small.

With regard to norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion (Wellbutrin), and serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine (Cymbalta), venlafaxine (Effexor XR), and desvenlafaxine (Pristiq), Byatt says that while the limited available data suggest a possible association between bupropion and congenital heart defects, the absolute risk appears low. The limited studies examining SNRIs she says have been reassuring, but further investigation is needed before the risks associated with their use may be fully understood.

The other main area of concern is birth complications. These can include risks of preterm birth, infant-fetal growth, and postnatal syndromes, including PNAS and PPHN. Byatt's group concluded that while the available evidence is conflicting, the overall data suggests that PNAS can occur in neonates exposed to SSRIs and SNRIs, yet have most often been reported after exposure to paroxetine, fluoxetine, and venlafaxine.

With regard to PPHNs, in 2006, the FDA published a Public Health Advisory regarding an increased risk of PPHN associated with the use of SSRIs after week 20 of pregnancy. However, it was rescinded in 2011 after the agency concluded that there was insufficient evidence that antidepressant exposure during pregnancy causes PPHN. Byatt's analysis of the literature concurred and concluded that an association between antidepressant use and PPHN is either small, or non-existent.

Autism and ADHD Links to Antidepressant Use Inconsistent

Studies linking autism spectrum disorders (ASD) and ADHD include a pair of studies published this year: Both found inconsistent associations.

A study done at Johns Hopkins University by Harrington and colleagues found that prenatal exposure to SSRIs was nearly three times as likely in boys with ASD relative to those with typical development. They also found developmental delays were higher with prenatal SSRI exposure.

However, they concluded, “Findings from published studies on SSRIs and ASD continue to be inconsistent. Because maternal depression itself carries risks for the fetus, the benefits of prenatal SSRI use should be carefully weighed against potential harms."4

At Massachusetts General Hospital, Perlis and colleagues analyzed data from a large health system and found antidepressant exposure is associated with a higher risk for ADHD, but not autism.5

In the absence of randomized studies of fetal and newborn exposure to antidepressant medications, clinicians are left with the dilemma of balancing the risks of medications to the fetus and newborn against the risks of not treating or undertreating the mother.

Behavioral Interventions As Alternatives to Antidepressants

Surprisingly, researchers agree about individualized evaluation and treatment for pregnant women with depression and recommend alternatives to medication, including cognitive-behavioral therapy, interpersonal psychotherapy, behavioral activation, mindfulness-based cognitive therapy, and acceptance and commitment therapy. Where they differ significantly is where to place the emphasis in the patient-physician discussion.

Byatt's group advocates for emphasizing the mother's illness. “Clinicians are often understandably concerned about exposure to medicine, and we certainly want to minimize exposure to medicine as much as possible,” she says.  “However, depression itself can have an effect on birth outcomes, baby's health, and later on child health. That must be taken into account because discontinuation of antidepressants may increase the risk of relapse into depression, which carries its own risk.”

“I recommend that providers strongly consider the risk of untreated illness and relapse into depression when making decisions regarding the use of antidepressants during pregnancy.”

Urato strongly disagrees with that approach. “The issue here is that if it's true that depression leads to pregnancy complications and that the antidepressants safely and effectively treat depression, then it clearly follows that when we do studies we should be seeing better outcomes in births of depressed women treated with antidepressants compared to those not treated,” he says.

“But that is never what the studies shows,” Urato adds. “In over 25 years of study, the groups of women on the antidepressants consistently do worse. They have more miscarriages, more birth defects, more preterm births, and their children do worse, so there is something wrong with that helpful drug model.”

Instead, he advocates changing the discussion more temporally and prioritizing nondrug approaches to treating depression long before women become pregnant. By the time women get to their obstetricians, it is too late to have this discussion because many women don't come to their doctors until after the baby's organs have formed, and already have had six to 12 weeks of exposure, Urato notes. It can be very difficult to come off these drugs during pregnancy.

“Depressed pregnant women need good treatment and care. Any discussion of whether these medications are safe or not should not be seen as an argument to ignore depressed pregnant women,” Urato says.

“As a society, however, nonmedical therapies should be first and foremost with women of child-bearing age who are seeing a doctor about symptoms of depression” he continues. “We need to have a discussion about nonmedical as well as medical treatments long before [women] become pregnant.” 

Michael O'Leary is a freelance medical writer based in the greater Seattle Area. This article was medically reviewed by Pat F. Bass III, MD, MS, MPH.

References

1. Byatt N, et al. Antidepressant Use in Pregnancy: A Critical Review Focused on Risks and Controversies. Acta Psychiatr Scand. 2013; 127(2); 94-114.
2. Cooper WO, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol.2007;196: 544.e1-544.e5.
3. Huybrechts, et al. Preterm Birth and Antidepressant Medication Use during Pregnancy: A Systematic Review and Meta-Analysis. PLoS ONE. 2014; 9(3): e92778.
4. Harrington RA, et al. Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics. 2014; 133(5): e1241-8.
5. Perlis RH, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry.2014; doi: 10.1038/mp.2014.90.