Timing of selective serotonin reuptake inhibitor use and risk for preterm birth and related adverse events: with a consideration of the COVID-19 pandemic period

Abstract

Objective

There is uncertainty around the safety of SSRIs for treating depression during pregnancy. Nevertheless, the use of SSRIs has been gradually increasing, especially during the COVID-19 pandemic period. We aimed to (1) characterize maternal depression rate and use of SSRIs in a recent 10-year period, (2) address confounding by indication, as well as socioeconomic and environmental factors, and (3) evaluate associations of the timing of SSRI exposure in pregnancy with risk for preterm birth (PTB), low birthweight (LBW), and small for gestational age (SGA) infants among women with depression before pregnancy.

Methods

We conducted propensity score-adjusted regression to calculate odds ratios (ORs) of PTB, LBW, and SGA. We accounted for maternal/pregnancy characteristics, comorbidity, depression severity, time of delivery, social vulnerability, and rural residence.

Results

There were 50.3% and 40.3% increases in the prevalence rate of prenatal depression and prenatal SSRI prescription rate during the pandemic. We identified women with depression ≤180 days before pregnancy (n = 8406). Women with no SSRI order during pregnancy (n = 3760) constituted the unexposed group. The late SSRI exposure group consisted of women with an SSRI order after the first trimester (n = 3759). The early-only SSRI exposure group consisted of women with SSRI orders only in the first trimester (n = 887). The late SSRI exposure group had an increased risk of PTB of OR = 1.5 ([1.2,1.8]) and LBW of OR = 1.5 ([1.2,2.0]), relative to the unexposed group. Associations between late SSRI exposure and risk of PTB/LBW were similar among a subsample of patients who delivered during the pandemic.

Conclusions

These findings suggest an association between PTB/LBW and SSRI exposure is dependent on exposure timing during pregnancy. Small for gestational age is not associated with SSRI exposure.

Keywords:

• Preterm birth
• infant, low birth weight
• infant, small for gestational age
• serotonin uptake inhibitors
• maternal depression
• COVID-19

Acknowledgements

We thank PSJH for sharing their data engineering expertise and computational resources. We acknowledge SNOMED International for developing and maintaining SNOMED-CT©.

Preliminary results for SGA were orally presented at the 2022 Annual Meeting for Society for Reproductive Investigation, and the abstract was published in the proceedings. This manuscript constitutes one of the chapters of Yeon Mi Hwang’s PhD Dissertation.

Author contributions

Yeon Mi Hwang, Samantha N. Piekos, Mary F. Hebert, Alison G. Paquette, Nathan D. Price, Leroy Hood, and Jennifer J. Hadlock contributed to study conception and design. Yeon Mi Hwang and Ryan T. Roper conducted data cleaning and transformation. Yeon Mi Hwang performed data analyses. Yeon Mi Hwang, Samantha N. Piekos, Daniel A. Enquobahrie, and Mary F. Hebert were involved in data interpretation. Jennifer J. Hadlock supervised study implementation. Yeon Mi Hwang prepared the manuscript with critical revision of the manuscript for important intellectual content provided by Samantha N. Piekos, Daniel A. Enquobahrie, Mary F. Hebert, Alison G. Paquette, Priyanka Baloni, and Jennifer J. Hadlock. All authors reviewed and approved the final version of the manuscript. Funding provided by Nathan D. Price.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. All procedures were reviewed and approved by the Institutional Review Board at the PSJH through expedited review (study number STUDY2020000196).

Consent form

Consent was waived because disclosure of protected health information for the study was determined to involve no more than a minimal risk to the privacy of individuals.

Disclosure statement

YH, RTR, SNP, DAE, MFH, AGP, and PB declare no conflict of interest. JJH has received funding (paid to the Institute for Systems Biology) from Pfizer, Novartis, Janssen, Gilead, and Bristol Myers Squibb for research unrelated to this study or any of its findings. LH and NDP are scientific advisors for Sera Prognostics, a pregnancy diagnostics company, and NDP holds stock options. Sera Prognostics is not associated with this study or any of the findings.

Data availability statement

Results have been aggregated and reported within this paper to the extent possible while maintaining privacy from personal health information as required by law. Data are archived within Providence St. Joseph Health systems in a HIPAA-secure audited compute environment. All clinical logic for data extraction has been shared within the paper and supplemental materials. Code is publicly available at https://github.com/Hadlock-Lab/YH_SSRI_PTB.

Additional information

Funding

This work was supported by the United States National Institute of Child Health and Human Development under Grant HD091527; Eunice Kennedy Shriver National Institute of Child Health and Human Development.