Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden

Abstract

Background: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths.

Methods and findings: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates.

Conclusions: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.

Fig 1. Flow chart for the cohorts used to analyze malformations and stillbirth.

The 73 stillbirths identified in the patient registers were all registered as spontaneous abortions after week 22. Exposure time window for malformations: from LMP to 90 days after LMP. Exposure time window for stillbirth: from LMP to end of pregnancy. LMP, last menstrual period; SSRI, selective serotonin reuptake inhibitor.

Fig 2. Risk of major and minor malformation.

Duloxetine vs 4 comparators. Odds ratio for major or minor malformations for duloxetine vs comparator. Exposure definition: ≥1 redeemed prescription. Adjusted and PS-matched models were based on covariates covering comorbidity (up to 5 years prior to LMP), comedication (90 days prior to LMP to end of the relevant exposure time window), hospital contacts, education, and income. For the complete list of covariates for the individual analyses, see Table E in S1 Tables. CI, Wald 95% confidence intervals; LMP, last menstrual period; N, number of observations in analyses; PS-matched, propensity score–matched analyses based on conditional logistic regression; SSRI, selective serotonin reuptake inhibitor.

Fig 3. Risk of stillbirth.

Duloxetine vs 4 comparators. Odds ratio for stillbirth for duloxetine vs comparator. Exposure definition: ≥1 redeemed prescription. PS-matched models were based on covariates covering comorbidity (up to 5 years prior to LMP), comedication (90 days prior to LMP to end of the relevant exposure time window), hospital contacts, education, and income. For the complete list of covariates for the individual analyses, see Table E in S1 Tables. CI, Wald 95% confidence intervals; LMP, last menstrual period; N, number of observations in analyses; PS-matched, propensity score–matched analyses based on conditional logistic regression; SSRI, selective serotonin reuptake inhibitor.