A few weeks ago, we published a clinical update for duloxetine (Cymbalta) and pregnancy, stating that there was little new to report since we last covered the topic in 2015.  It is somewhat amusing that Huybrechts and colleagues published a new analysis on the same topic.  So this article is an update of our clinical update, including the new data.  

In a recent cohort study nected in the Medicaid Analytic eXtract for 2004-13, Huybrechts and colleagues assessed the reproductive study of duloxetine in pregnant women (18 to 55 years of age) who had given birth to liveborn infants, looking specifically at the risk for congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage.

The cohort sizes ranged from 1.3 to 4.1 million women, depending on which outcome was being analyzed, including about 2500-3000 women with early pregnancy exposure to duloxetine and 900-950 women for late pregnancy exposure. 

Overall Risk for Malformations

In unexposed children, the risk for congenital malformations overall was 36.6 per 1000 infants (95% confidence interval 36.3 to 36.9) for 3.66%.  The analysis included 2532 infants with first trimester exposure to duloxetine, making this study the largest to date assessing the reproductive safety of duloxetine. In propensity score adjusted analyses the relative risk for major malformations in exposed versus unexposed pregnancies was 1.11 (95% CI 0.93 to 1.33).

Cardiovascular Malformations

In unexposed children, the risk for cardiovascular malformations was 13.7 (CI 13.5 to 13.9) or 1.37%.  In children with first trimester exposure to duloxetine, the relative risk was 1.29 (95% CI 0.99 to 1.68) for cardiovascular malformations.

In this study, exposure was defined as a single dispensing of duloxetine during the first trimester.  When the researchers redefined exposure as two dispensings of duloxetine during the first trimester, the fully adjusted risk estimates were demonstrated a stronger association between duloxetine exposure and risk for cardiovascular malformations: 1.71 (1.21 to 2.41) versus unexposed women, 1.69 (1.11 to 2.56) versus SSRI exposed women, 1.38 (0.90 to 2.11) versus venlafaxine exposed women, and 2.10 (1.14 to 3.85) versus duloxetine discontinuers. 

Several previous studies have suggested an increased risk of certain types of cardiovascular malformations among children exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy.  These findings, however, have been inconsistent. Some have speculated that these findings might reflect differences in methodologies used in the various studies or simply statistical variations.  Some have suggested that other factors – not just exposure to antidepressant – may be involved, such as exposure to tobacco, alcohol, or other drugs.  

Larger studies using data from the Danish medical register, the Medicaid Analytic eXtract in the United States, and the Health Improvement Network primary care database in the UK have failed to support an association between SSRI exposure and cardiovascular malformations.  These studies, however, did not contain adequate numbers of pregnancies with duloxetine exposure; hopefully, future studies will be able to further explore this finding.  

Other Outcomes

For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for women with early exposure to duloxetine and 1.19 (1.04 to 1.37) for women with late exposure. 

For small for gestational age infants the relative risk was 1.14 (0.92 to 1.41) for women with early exposure to duloxetine and 1.20 (0.83 to 1.72) for women with late pregnancy exposure.

For pre-eclampsia the relative risk was 1.12 (0.96 to 1.31) for women with early exposure to duloxetine and 1.04 (0.80 to 1.35) for women with late exposure.

For postpartum hemorrhage, the relative risk was 1.53 (1.08 to 2.18).

The Bottom Line

Duloxetine exposure during the first trimester was not associated with an increased risk for major malformations.  The findings may indicate a small increase risk in risk of cardiac malformations; however, this finding must be interpreted cautiously as there has been considerable inconsistency across studies assessing risk for this type of malformation in antidepressant-exposed pregnancies.

The findings of the current study are consistent with a previous meta-analysis including 668 exposed infants which did not observe an increase in overall risk for malformations.  

This means we have data from over 3000 infants indicating that duloxetine is not a major teratogen.  

Furthermore, duloxetine exposure was not associated with increased risk for preterm birth, small for gestational age infants, or pre-eclampsia.  There was a very small but statistically significant increase in risk for postpartum hemorrhage, a finding which has been observed in previous studies of other serotonergic antidepressants.  

The National Pregnancy Registry for Psychiatric Medications

For women currently taking or planning to take antidepressants (and other medications) during pregnancy, consider participating in the National Pregnancy Registry for Psychiatric Medications.  

The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications such as antidepressants, ADHD medications, and atypical antipsychotics that many women take during pregnancy to treat a wide range of mood, anxiety, executive function, or psychiatric disorders. The goal of this Registry is to gather information on the safety of these medications during pregnancy, as current data is limited.

Ruta Nonacs, MD PhD

Huybrechts KF, Bateman BT, Pawar A, Bessette LG, Mogun H, Levin R, Li H, Motsko S, Scantamburlo Fernandes MF, Upadhyaya HP, Hernandez-Diaz S.  Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study.  BMJ. 2020 Feb 19.   Free Article

Lassen D, Ennis ZN, Damkier P.  First-trimester pregnancy exposure to venlafaxine or duloxetine and risk of major congenital malformations: a systematic review.  Basic Clin Pharmacol Toxicol. 2015 Oct 5.