No Evidence of Birth Defects With Antipsychotics in Pregnancy

Fran Lowry

August 17, 2016

Evidence from a study of more than 1.3 million women suggests that use of antipsychotics (APs) early in pregnancy does not confer a heightened risk for cardiac or other congenital malformations.

The results, published online August 17 in JAMA Psychiatry, should allay the concerns of women who must take APs while they are pregnant, lead author Krista F. Huybrechts, PhD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"Based on our findings, there is no evidence that use of antipsychotics early in pregnancy increases the risk of congenital malformations overall or cardiac malformations in specific, with the possible exception of risperidone," Dr Huybrechts said.

Dr Krista Huybrechts

"For women with indications such as schizophrenia, bipolar disorder, or major depressive disorder, for whom avoiding medication during pregnancy is often not possible, this should be reassuring," she said.

But Dr Huybrechts added a caveat: "Our results should be reassuring but only with respect to congenital malformations. We did not look at any other potential maternal or fetal adverse outcomes. But at least with respect to this outcome, which is typically of great concern because of the severity, the findings should be reassuring," Dr Huybrechts said.

Such a caveat notwithstanding, Katherine L. Wisner, MD, Norman and Helen Asher Professor of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology at Northwestern University Feinberg School of Medicine, Chicago, Illinois, called it a "landmark study" from a "stellar group" of researchers. Dr Wisner coauthored an editorial that accompanies the article.

Dr Katherine Wisner

"This is now the second large-scale article they have published, using very sophisticated methodology to do what is so difficult to do in this area of research. We do not have randomization as a tool, because you can't randomize pregnant women to drug or not. You have to do these big observational studies," Dr Wisner told Medscape Medical News.

"Of course, you only give the drug because it is being used to treat a disease, but when the disease and the drug affect the same outcome potential, it is very hard to separate the two, but this is what they do very well in a very large sample of American women," she added.

The use of antipsychotics in pregnancy has increased substantially in the past decade, but information as to their safety has been limited, Dr Huybrechts said.

"There were a couple of registry studies, but they were very small, and then there were two epidemiological studies that again were small, with less than 600 exposed women in total. The evidence from all of these studies were mixed. Some suggested no association, others suggested that there might be an association, so we felt it was very important, given the increasing use of these medications during pregnancy, to look at the issue in a study that was large enough to have enough statistical power to draw meaningful conclusions, and also be able to carefully look at the role of potential confounding variables," she said.

For their analyses, Dr Huybrechts and her team used a nationwide Medicaid database comprising data from 1,360,101 pregnant women from January 1, 2000, to December 31, 2010.

In this study sample, there were 1,341,715 pregnancies; the mean age of the women was 24 years (standard deviation [SD], 5.88 years), 9258 (0.69%) women filled at least one prescription for an atypical AP, and 733 (0.05%) women filled at least one prescription for a typical AP during the first trimester.

The most frequently used atypical antipsychotic was quetiapine, followed by aripiprazole, risperidone, olanzapine, and ziprasidone.

Women taking APs during the first trimester were older, more likely to be white, and more likely to deliver prematurely. They also had more comorbid illnesses and more psychiatric and neurologic conditions, and they were generally in poorer health than women who did not take APs.

The main outcomes were overall and cardiac malformations identified during the first 90 days after delivery.

Overall, congenital malformations were diagnosed in 32.7 (95% confidence interval [CI], 32.4 - 33.0) per 1000 births that were not exposed to APs compared with 44.5 (95% CI, 40.5 - 48.9) per 1000 births that were exposed to atypical APs and 38.2 (95% CI, 26.6 - 54.7) per 1000 births exposed to typical APs.

The unadjusted analyses suggested a 36% increased risk for malformations overall for atypical APs (relative risk [RR], 1.36; 95% CI, 1.24 - 1.50), but not for typical APs (RR, 1.17; 95% CI, 0.81 - 1.68).

In the adjusted analyses, which took into account more than 50 potential confounding variables, the RR was reduced to 1.05 (95% CI, 0.96 - 1.16) for atypical APs and 0.90 (95% CI, 0.62 - 1.31) for typical APs.

Similar results were seen for cardiac malformations.

An increased risk, albeit small, was seen with only one AP, risperidone. This risk was independent of measured confounders.

For risperidone, there was a 26% increased risk in overall malformations (RR, 1.26; 95% CI, 1.02 - 1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88 - 1.81).

Dr Huybrechts noted that the increase in risk associated with risperidone should be interpreted with caution.

"We did a whole range of additional sensitivity analyses to try and exclude the possibility that this finding with risperidone was residual confounding. We tried to think what the biological mechanism could be, and there is no mechanism that would readily explain this outcome for risperidone and not for the other antipsychotics. At this point, we are interpreting the finding as an initial signal that will be very important in future studies, using different data, to see whether we can replicate it or not," Dr Huybrechts said.

"This is the best paper that has been published to date to examine whether the risk of cardiac and general birth defects is higher when women are exposed to antipsychotics," said Dr Wisner.

"The study leaves our field hungry for more information," she added. "How do the babies do immediately after birth? How do they do mentally? Is there a higher risk for preterm birth? There are a whole set of other outcomes that we need to know. Of course, all the studies focus on birth defects, because that is the thing we all worry about and we want to establish that risk first.

"So, if there is not a risk for birth defects, which this study shows quite convincingly with the exception of the one drug, risperidone, we can now move on to finding answers about the offspring's development and those kinds of questions," Dr Wisner said.

This study was supported by the National Institute of Mental Health. Dr Huybrechts reports no relevant financial relationships. Dr Wisner reports that the Department of Psychiatry at Northwestern University received contractual fees for her consultation to Quinn Emanuel Urquhart & Sullivan, LLP (New York City), who represented Pfizer Pharmaceutical Company, in 2015.

JAMA Psychiatry. Published online August 17, 2016. Abstract, Editorial

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