Duloxetine Exposure During Pregnancy and the Risk of Offspring Being Born Small for Gestational Age or Prematurely: A Nationwide Danish and Swedish Safety Study

Abstract

Background: Depression or depressive symptoms are common among pregnant women. The use of antidepressants during pregnancy has grown steadily. The risk of offspring being born small for gestational age or prematurely when exposed to duloxetine during pregnancy is not established.

Objective: We aimed to investigate the association between duloxetine exposure during pregnancy and offspring being born small for gestational age or prematurely.

Methods: We conducted an observational study including live births in Sweden and Denmark (2004-2016). Duloxetine exposure during early (0-140 days) or late (141 to delivery) pregnancy compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, venlafaxine-exposed, and duloxetine discontinuers.

Results: In total, 2,083,467 pregnancies were identified, where 1589 and 450 were duloxetine exposed in early and late pregnancy, respectively. For small for gestational age, no increased risk was seen for duloxetine across comparators. In the early and late exposure windows, propensity score-matched odds ratios for small for gestational age ranged between 0.64 (95% confidence interval 0.44-0.95) and 1.48 (95% confidence interval 0.85-2.57). For preterm birth, the findings differed across comparators and exposure-time windows, but trended towards an increased risk for duloxetine-exposed when compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, and duloxetine discontinuers in both early exposure and late exposure. The odds ratios ranged between 1.17 and 2.04, of which some did not reach statistical significance. No clear association was observed when compared with venlafaxine exposed, 0.91 (95% confidence interval 0.73-1.14) for early exposure and 1.26 (95% confidence interval 0.86-1.86) for late exposure. Most preterm births (79.2%) occurred in weeks 33-36 of gestation.

Conclusions: Duloxetine exposure during pregnancy is unlikely to increase the risk of small for gestational age. Although not consequently statistically significant across comparisons, a trend towards an increased risk of preterm birth was observed for duloxetine exposed. Therefore, an increased risk of preterm birth cannot be excluded, especially for women exposed to duloxetine throughout pregnancy.

Fig. 1

Flow chart of the population. All registered births in Sweden and Denmark. Exposure-time windows: early: from last menstrual period (LMP) to 140 days post-LMP; late: from 141 days post-LMP to the date of delivery. The same cohort is used for the analyses of small for gestational age and preterm delivery

Fig. 2

Small for gestational age (SGA), early-exposure window: duloxetine versus four comparators. Exposure definition: one or more redeemed prescription. Early-exposure window: from last menstrual period to 140 days post-last menstrual period. Adjusted and propensity score (PS)-matched analyses based on conditional logistic regression models were based on covariates covering comorbidity, comedication, hospital contacts, education, and income. For the complete list of the individual analyses, see Table S4 of the ESM. N number of observations in analyses, CI Wald 95% confidence intervals, SSRI selective serotonin reuptake inhibitor

Fig. 3

Small for gestational age (SGA), late-exposure window: duloxetine versus four comparators. Exposure definition: one or more redeemed prescription. Late-exposure window: from 141 days post-last menstrual period to the date of delivery. Adjusted and propensity score (PS)-matched analyses based on conditional logistic regression models were based on covariates covering comorbidity, comedication, hospital contacts, education, and income. For the complete list of the individual analyses, see Table S4 of the ESM. N number of observations in analyses, CI Wald 95% confidence intervals, SSRI selective serotonin reuptake inhibitor

Fig. 4

Preterm birth, early-exposure window: duloxetine versus four comparators. Exposure definition: oen or more redeemed prescription. Early-exposure window: from last menstrual period to 140 days post-last menstrual period. Adjusted and propensity score (PS)-matched analyses based on conditional logistic regression models were based on covariates covering comorbidity, comedication, hospital contacts, education, and income. For the complete list of the individual analyses, see Table S4 of the ESM. N number of observations in analyses, CI Wald 95% confidence intervals, SSRI selective serotonin reuptake inhibitor

Fig. 5

Preterm birth, late-exposure window. Duloxetine versus four comparators. Exposure definition: one or more redeemed prescription. Late-exposure window: from 141 days post-last menstrual period to the date of delivery. Adjusted and propensity score (PS)-matched analyses based on conditional logistic regression models were based on covariates covering comorbidity, comedication, hospital contacts, education, and income. For the complete list of the individual analyses, see Table S4 of the ESM. N number of observations in analyses, CI Wald 95% confidence intervals, SSRI selective serotonin reuptake inhibitor