Association of Persistent Pulmonary Hypertension in Infants With the Timing and Type of Antidepressants In Utero

Antidepressant exposure during pregnancy has been linked to increased risk of persistent pulmonary hypertension of the newborn (PPHN).¹ Risks of PPHN have been explored for different types of selective serotonin reuptake inhibitors (SSRIs). However, risks after non-SSRI exposure and risks with timing of exposure in pregnancy across type of antidepressants have been insufficiently quantified or evidence remains conflicting.^2,3 Given that PPHN is a potentially lethal complication, more detailed information on trimester- and antidepressant type–specific risk is essential.

In this population-based cohort study, we identified 1 246 347 live-born singleton children born to 707 026 mothers from January 1, 1997, to December 31, 2016. Antidepressant use during pregnancy was ascertained from recorded prescriptions of antidepressants (anatomic therapeutic chemical [ATC] code N06A) dispensed on any date between 1 month before pregnancy and delivery.⁴ We investigated the association by timing of antidepressant exposure as follows: early pregnancy (defined as ≤20 weeks’ gestation) and late pregnancy (defined as >20 weeks’ gestation), and treatment was categorized into SSRI (ATC code N06AB) and non-SSRI (ATC code N06A excluding N06AB) antidepressants (Table 1). Information on race and ethnicity was not available for the present study. A newborn was categorized as having PPHN through a hospital contact with International Statistical Classficiation of Diseases, Tenth Revision codes of P29.3 or I27.0 within 7 days of birth identified from the patient registry.⁵ The Danish Data Protection agency gave permission for the study to be conducted, and no informed consent is required for register-based studies based on deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Data were analyzed from March 1 to July 31, 2021. We estimated adjusted odds ratios (ORs) and absolute risk differences of PPHN by antidepressant exposure status using random-effects logistic regression with robust SE and mothers’ identification number as a cluster to account for the dependence between siblings. A detailed description of methods and potential confounders can be found in the eMethods in the Supplement. We also calculated the number of women who would need to be treated with antidepressants to cause 1 additional PPHN case as the inverse of the adjusted absolute risk reduction. A 2-sided significance threshold of P = .05 was used for the calculations. Data were analyzed in Stata, version 15.0 (StataCorp LLC).

Among the 1 246 347 live-born singleton children born to 707 026 mothers, the mean (SD) age of the mothers was 30.5 (4.9) years, and 44.9% were primiparous. Of 29 822 live-born singleton children born to mothers who used antidepressants, PPHN was identified among 79 children (2.6 per 1000 live births), in contrast to 1637 children (1.3 per 1000 live births) among the unexposed children (Table 2). The adjusted OR for PPHN after antidepressant exposure at any time during pregnancy was 1.29 (95% CI, 0.95-1.74). Of note, detailed results showed differences in risk by exposure early vs late in pregnancy; at 20 weeks’ gestation or less: OR, 0.80; 95% CI, 0.51-1.25; at more than 20 weeks’ gestation: OR, 2.01; 95% CI, 1.32-3.05. The absolute risk difference for the development of PPHN after exposure to antidepressants in late pregnancy was 1.3 per 1000 infants (95% CI, 0.2-2.4), suggesting that between 417 and 5000 women would need to be treated with antidepressants in late pregnancy to result in 1 additional PPHN case. Further, in late pregnancy, a more pronounced risk was observed with non-SSRI exposure (OR, 2.56; 95% CI, 1.54-4.25) than with SSRI exposure (OR, 1.36; 95% CI, 0.95-1.95) (P = .046).

The results of this population-based study suggest an association between antidepressant exposure in late pregnancy and increased risk of PPHN. However, we note that the absolute risk of PPHN was low and the number of mothers needed to be treated with antidepressants to result in 1 additional PPHN case varied substantially based on our analyses (from 417 to 5000 women). In contrast, there was no evidence of increased risk for exposure at or before 20 weeks’ gestation. Limitations of the study include potential exposure misclassification and a lack of power to study individual antidepressants. This study’s findings provide reassuring clinical information for a substantial proportion of women who stop or taper antidepressant use shortly after they become pregnant.

Accepted for Publication: October 5, 2021.

Published: December 1, 2021. doi:10.1001/jamanetworkopen.2021.36639

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Munk-Olsen T et al. JAMA Network Open.

Corresponding Author: Trine Munk-Olsen, PhD, Department of Clinical Research, University of Southern Denmark, J. B. Winsløws Vej 19, 3. sal, 5000 Odense C, Denmark (tmun@sdu.dk).

Author Contributions: Dr Liu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Munk-Olsen, Bergink, Rommel, Liu.

Acquisition, analysis, or interpretation of data: Munk-Olsen, Rommel, Momen, Liu.

Drafting of the manuscript: Munk-Olsen, Bergink, Rommel.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Liu.

Obtained funding: Munk-Olsen, Rommel.

Administrative, technical, or material support: Munk-Olsen.

Supervision: Munk-Olsen, Bergink.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by grants R313-2019-569 from The Lundbeck Foundation, AUFF-E 2016-9-25 from AUFF NOVA, and from Fabrikant Vilhelm Pedersen og Hustrus Legat (Dr Munk-Olsen); by grant R01MH122869 from the National Institute of Mental Health (Dr Munk-Olsen and Prof Bergink); and by Marie Sklodowska-Curie grant 891079 from the European Union’s Horizon 2020 research and innovation program (Dr Liu).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.