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Literature Review and Implications for Clinical Applications

Eydie L. Moses-Kolko, MD; Debra Bogen, MD; James Perel, PhD; Amy Bregar; Kathleen Uhl, MD; Bob Levin, MD; Katherine L. Wisner, MD, MS

JAMA. 2005;293:2372-2383.

Context  A neonatal behavioral syndrome linked to in utero serotonin reuptake inhibitor (SRI) exposure during the last trimester of pregnancy has been identified. The US Food and Drug Administration (FDA) and drug manufacturers have recently agreed to a class labeling change for SRIs, which include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), to include information about potential adverse events in neonates exposed in utero. Integration of data about the neonatal behavioral syndrome into the management of pregnancy in women who take SRIs is a current challenge for physicians.

Objectives  To review evidence regarding the SRI-related neonatal syndrome and to help clinicians guide their patients in a risk-benefit decision-making process.

Data Sources  We searched MEDLINE (1966–February 2005) and PsycINFO (1974–February 2005). All articles related to neonatal signs after in utero SRI exposure were acquired, as well as unpublished data on this topic from the FDA advisory committee meeting of June 2004. References cited in case reports and studies were reviewed. Foreign-language literature was included and translated to English.

Study Selection and Data Extraction  Studies were included if they had clearly identified maternal SRI exposure for a minimum of the final trimester of pregnancy through delivery and assessed neonatal outcomes. We identified 13 case reports describing a total of 18 cases. Nine cohort studies met criteria. When not included in the published article, relative risks and 95% confidence intervals (CIs) were computed from raw data and summary risk ratios and 95% CIs were determined with Mantel-Haenszel estimates.

Data Synthesis  Compared with early gestational SRI exposure or no exposure, late SRI exposure carries an overall risk ratio of 3.0 (95% CI, 2.0-4.4) for a neonatal behavioral syndrome. The most SRI-related neonatal case reports involved fluoxetine and paroxetine exposures. Neonates primarily display central nervous system, motor, respiratory, and gastrointestinal signs that are usually mild and disappear by 2 weeks of age. Medical management has consisted primarily of supportive care in special care nurseries. A severe syndrome that consists of seizures, dehydration, excessive weight loss, hyperpyrexia, or intubation is rare in term infants (1/313 quantifiable cases). There have been no reported neonatal deaths attributable to neonatal SRI exposure.

Conclusions  Available evidence indicates that in utero exposure to SRIs during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care. The risks and benefits of discontinuing an SRI during pregnancy need to be carefully weighed for each individual patient. Development and validation of assessment methods and clinical management strategies are critical to advancing this research.

Author Affiliations: Departments of Psychiatry (Drs Moses-Kolko, Perel, and Wisner), Pediatrics (Drs Bogen and Wisner), Clinical Pharmacology (Dr Perel), and Obstetrics and Gynecology (Dr Wisner), University of Pittsburgh School of Medicine, Pittsburgh, Pa; Princeton University, Princeton, New Jersey (Ms Bregar); and Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Md (Drs Uhl and Levin).

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