Antidepressants in Pregnancy Linked to Low Absolute Stillbirth Risk

Key Takeaways

• In a multinational cohort from the UK, Norway, and Sweden, antidepressant use during pregnancy was associated with higher odds of stillbirth, preterm delivery, and a low 5-minute Apgar score. The predicted absolute risk of stillbirth was 0.34% in unexposed pregnancies and 0.40% in antidepressant-exposed pregnancies.
• Among mothers with depression or anxiety, the stillbirth association weakened and was no longer statistically clear.
• Sibling analyses were directionally similar but less precise, and paternal antidepressant exposure was largely null for most outcomes, though associations remained for preterm delivery, low Apgar score, and lower post-term delivery.
• Maternal antidepressant use was also linked to a small increase in small for gestational age, while neonatal death and large for gestational age did not show notable differences.

Continuing an antidepressant during pregnancy often forces clinicians and patients to weigh relapse risk against uncertain fetal and neonatal effects. A key challenge is separating risk related to the medication from risk related to underlying depression or anxiety and shared familial factors. Investigators explored that question in a registry and electronic health record cohort spanning the UK, Norway, and Sweden.

In this study published in Pharmacoepidemiology and Drug Safety, investigators evaluated 2,528,916 singleton deliveries reaching at least 22 completed gestational weeks, including 120,209 antidepressant-exposed pregnancies (4.8%). Data came from the UK Clinical Practice Research Datalink (CPRD) GOLD electronic health record (EHR) database, the Norwegian Medical Birth Registry, and the Swedish Medical Birth Register. Maternal exposure was defined as any antidepressant use during pregnancy, identified from prescriptions in the UK and dispensations in Norway and Sweden. Outcomes included stillbirth, neonatal death, preterm and post-term delivery, small for gestational age (SGA), large for gestational age (LGA), and Apgar score below 7 at 5 minutes; adjusted country-specific models were pooled with fixed-effects meta-analysis, and discordant sibling plus paternal negative-control analyses were used to probe residual confounding.

Maternal antidepressant use was associated with stillbirth, with an adjusted odds ratio of 1.16 (95% CI 1.05-1.28), and the predicted absolute stillbirth risk was 0.34% in unexposed pregnancies versus 0.40% in exposed pregnancies. Preterm delivery also remained associated with exposure, with an adjusted odds ratio of 1.26 (95% CI 1.23-1.30), and the odds of a low 5-minute Apgar score were higher as well, with an adjusted odds ratio of 1.83 (95% CI 1.75-1.91). Investigators also observed a small increase in SGA and lower odds of post-term delivery, while neonatal death and LGA did not show notable differences. Sibling analyses were directionally similar but less precise, and paternal exposure signals were largely absent for most outcomes, though associations remained for preterm delivery, low Apgar score, and lower post-term delivery.

Several design features affect interpretation. Exposure was inferred from prescriptions in the UK and dispensations in Norway and Sweden rather than confirmed ingestion, and the primary any-use-during-pregnancy definition did not resolve discontinuation, adherence, or cumulative exposure. Among mothers with depression or anxiety, the stillbirth association attenuated to an adjusted odds ratio of 1.07 (95% CI 0.94-1.21), a pattern that, together with the sibling and paternal analyses, suggested that part of the observed signal may reflect residual confounding related to parental mental health, illness severity, and shared familial factors. The authors also noted that sibling comparisons do not address nonshared time-varying confounders, Sweden lacked primary care diagnosis data for capturing indication, complete-records analysis may introduce selection bias, and restricting the cohort to pregnancies reaching at least 22 weeks leaves competing-event concerns for earlier pregnancy loss.

Clinician Questions

How was antidepressant exposure defined across the UK, Norway, and Sweden in this pregnancy cohort?

Maternal antidepressant exposure meant any antidepressant use during pregnancy, identified from prescriptions written in the UK and dispensations in Norway and Sweden. The investigators also performed trimester-specific analyses, and for preterm-delivery analyses, pregnancies that started antidepressants at 37 weeks or later were counted as unexposed.

Which outcomes remained associated with paternal antidepressant use during pregnancy in the negative-control analysis?

Paternal antidepressant exposure during pregnancy was largely null across outcomes in Norway and Sweden, but associations remained for preterm delivery, low 5-minute Apgar score, and and lower odds of post-term delivery.

What does the 22-week gestation threshold mean for applying these findings to pregnancy outcomes?

The cohort included only singleton pregnancies reaching at least 22 completed gestational weeks, so the reported associations apply to later birth outcomes in pregnancies that survived to that point. The authors noted that this design leaves open the possibility of competing-event or selection effects if antidepressant exposure influences earlier pregnancy loss.