Neurobehavioral Effects of Maternal SSRI Use Linger in Newborns

Megan Brooks

November 11, 2015

Neurobehavioral effects of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) extend beyond the first 7 to 10 days of life, a new study suggests.

The findings also suggest that use of a benzodiazepine plus an SSRI is associated with more significant problems in infant neurologic functioning than use of an SSRI alone. This could be because of the underlying disorder and symptom severity or the neonate's inefficiency in metabolizing multiple drugs, the investigators note.

Importantly, they point out, "in agreement with the current practice guidelines of the American Psychiatric Association and the American College of Obstetricians and Gynecologists, these findings do not support discontinuing SSRI medication in the third trimester of pregnancy for those women who have been successfully managing their depressive symptoms with SSRIs throughout pregnancy."

"We did not find evidence that stopping the medication early changed outcomes, so stopping the medication to prevent infant difficulties is unfounded at this time (and not stopping is the current ACOG/APA recommendation)," first author Amy L. Salisbury, PhD, associate professor, Departments of Pediatrics and Psychiatry and Human Behavior, Alpert Medical School at Brown University, Providence, Rhode Island, told Medscape Medical News.

However, "more consideration may need to be given to women who require the use of a concomitant benzodiazepine," she said.

The study was published online October 30 in the American Journal of Psychiatry.

Direct Effect

The investigators examined the course of infant neurobehavioral functioning during the first month after birth, using a standardized assessment tool. The infants' mothers either were depressed during pregnancy and did not choose to take medication (n = 78); were depressed and chose to take an SSRI (n = 65) or an SSRI and a benzodiazepine (n = 14); or were not depressed and did not take any medication (n = 86).

"Prior studies suggested that 30% of infants have difficulty adapting to withdrawal of SSRI medication after delivery and that this lasts up to 7 to 10 days. Our main findings suggest that the difficulties last at least 14 days and may last through the first month, especially for infants whose mothers also took a benzodiazepine. The difficulties included more startling, tremors, low muscle tone, and high irritability," said Dr Salisbury.

Infants with concomitant benzodiazepine exposure had the "least favorable" neurobehavioral assessment scores and highest number of central nervous system stress signs. Nearly all of the women (90%) who used benzodiazepines reported using them through delivery; 80% used them during the first postpartum month.

The researchers note that limitations of their study include a relatively small sample size of women with concomitant benzodiazepine-SSRI use and heterogeneity in depression characteristics. The study only included full-term, healthy infants across all groups, and therefore the findings may not be generalizable to infants born earlier in gestation or to mothers with more varying health conditions, they add.

"Overall, this study suggests that the difficulties some infants have after prenatal exposure to an SSRI may not be due solely to adaptation or withdrawal but to the more direct effect of the medication on their development. However, the observed effects remain somewhat limited for most infants and do not appear to represent serious risks to the infants," said Dr Salisbury.

She added that although the data suggest a "higher threshold" for recommending the combination of an SSRI and a benzodiazepine in general, "the women in our study who took the additional medications also had the most severe levels of depression and anxiety, which represents high risk for the mother as well as having an impact on infant outcomes. If single-drug treatment can be used to manage symptoms, that would be the first-line choice. More systematic study in larger samples is needed regarding benzodiazepine use during pregnancy."

Clinically Relevant

Commenting on the study for Medscape Medical News, Kimberly A. Yonkers, MD, professor in the Departments of Psychiatry, Obstetrics/Gynecology/Reproductive Sciences, and Epidemiology/Public Health at Yale School of Medicine, in New Haven, Connecticut, described the study as a "very carefully designed study that showed some effects of psychotropic medications that may endure as far out as 1 month. It also shows the additive effects of SSRIs and benzodiazepines. What we don't know is the long-term effects (eg, into late childhood, teenage, adult, etc). There are insults to the brain that are much greater than this, and children are resilient."

Tim Oberlander, MD, FRCP, developmental pediatrician and researcher at the Child and Family Research Institute, University of British Columbia, in Vancouver, Canada, said the findings in this study are clinically relevant and the methodology is strong.

A methodologic strength of the study is the use of different exposure groups, "which are needed to tease apart the effects of depression from the SSRI itself," Dr Oberlander, who was not involved in the research, told Medscape Medical News.

"One of the critical issues is trying to deal with 'confounding by indication,' where the drug is given for a disorder that itself has a similar impact on a newborn's behavior. In this setting, we can't study drug effects with randomized controlled trials, so comparing outcomes between the three groups in this study was a sound methodological approach," he explained.

The study also extends prior observations of neonatal behavior beyond the usual 2-week period, "which offers a new perspective on the extent of SSRI exposure outside of the newborn period," said Dr Oberlander. It is also noteworthy that the researchers used an established structured neurobehavioral assessment, the Neonatal Intensive Care Unit Network Neurobehavioral Scale, "which allowed the investigators to look at very specific behaviors over multiple points during the first month," he said.

Pharmacologically, the findings in this study point to a "drug-drug interaction which might increase the level of an SSRI in the presence of a benzodiazepine. We reported in 2004 probably a similar drug-drug interaction and which appears to be confirmed here," said Dr Oberlander.

At a clinical level, he noted that this study offers findings that "should shape the way we manage infants with prenatal SSRI exposure.

"We have typically thought that neonatal behavioral disturbances in exposed infants during the first 24 hours after birth were just a 'withdrawal' behavior, and these behaviors should disappear by the end of the first month. In this study, we learned that the behavioral disturbance extended beyond the newborn period, perhaps reflecting a more long-term impact on the developing nervous system beyond purely drug withdrawal," Dr Oberlander said.

Findings reported in this study "should help us identify increased behavioral risk and the need for extended observation ― whether during the hospital stay or in the community ― where SSRIs are used in combination with a benzodiazepine," he said.

"No treatment is never an option to managing mood disturbances during pregnancy. Once again, these findings highlight the need to consider all treatment options that help mothers and reduce side effects for their infants," Dr Oberlander added.

The study was supported by the National Institute of Mental Health. The authors, Dr Yonkers, and Dr Oberlander report no relevant financial relationships.

Am J Psychiatry. Published online October 30, 2015. Abstract

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