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).
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
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were acquired, as well as unpublished data on this topic from the FDA advisory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
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
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.
Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal Signs After Late In Utero Exposure to Serotonin Reuptake Inhibitors: Literature Review and Implications for Clinical Applications. JAMA. 2005;293(19):2372–2383. doi:10.1001/jama.293.19.2372
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