Women face difficult choices when deciding whether or not to continue psychiatric medications during pregnancy.  For many years, we have typically recommended the older antidepressants, including the selective serotonin reuptake inhibitors or SSRIs such as fluoxetine (Prozac), citalopram (Celexa), and sertraline (Zoloft), because we had the most robust data on reproductive safety data for these medications.

Duloxetine (brand name Cymbalta) is increasingly used as a first line treatment for women with major depression, especially if there is comorbid fibromyalgia or neuropathic pain.  Duloxetine is also effective for the treatment of anxiety disorders which are common among women of reproductive age.  Given its efficacy for a broad range of psychiatric disorders, its use has grown considerably since it was released in 2004.

Thus far, there have been several studies which have examined the reproductive safety of duloxetine.  None have documented any concerns regarding risk for malformations in children exposed to duloxetine during pregnancy.  

Lassen et al, 2015:  Meta-analysis of 8 cohort studies including 668 duloxetine exposures, no increase in overall risk for malformations 

Huybrechts et al, 2020: 2532 exposures from the Medicaid Analytic eXtract for 2004-13, no increase in overall risk for malformations. 

Adding to this body of investigation is a population-based observational study analyzing data from birth registers in Sweden and Denmark.  All registered births and stillbirths between 2004 and 2016 were included. Malformation diagnoses were identified up to one year after birth. 

Rates of malformations in duloxetine-exposed pregnancies were compared to rates in the following comparison groups: (1) no duloxetine exposure, (2) SSRI exposure, (3) venlafaxine exposure, and (4) duloxetine before but not during pregnancy.  Exposure was defined as redemption of a prescription during the first trimester and through  pregnancy for the analyses of malformations and stillbirths, respectively. 

No Increase in Risk of Minor or Major Malformations or Stillbirths

From a cohort of more than 2 million births, 1,512 duloxetine-exposed pregnancies were identified. There was no increase in risk for major malformations, minor malformations, or stillbirth in duloxetine-exposed versus comparison groups in adjusted and propensity score-matched analyses. 

Duloxetine-exposed versus duloxetine-nonexposed analyses demonstrated an odds ratio (OR)  of 0.98 (95% confidence interval [CI] 0.74 to 1.30) for major malformations, OR 1.09 (95% CI 0.82 to 1.45) for minor malformation, and 1.18 (95% CI 0.43 to 3.19) for stillbirths. Looking at individual malformations, the analyses were associated with large statistical uncertainty due to the extremely small number of events. 

The Bottom Line

In this study including 1512 pregnancies, duloxetine exposure during the first trimester does not appear to increase the overall risk of major malformations.  This study is consistent with the previous studies of Lassen and Huybrechts.  The literature consists of data from ten different studies and over 4700 exposures.  In general, 700-800 exposures are required to demonstrate a twofold or greater increase in common malformations, so this is well above that threshold.  

This finding will undoubtedly be reassuring to women who have benefited from treatment with duloxetine and would prefer to remain on this medication during the course of pregnancy.

National Pregnancy Registry for Psychiatric Medications

 Women currently taking or planning to take any type of antidepressant (or other medications) during pregnancy may consider participating in the National Pregnancy Registry for Psychiatric Medications.  (This study requires no in-person visits.)

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 for many medications is limited.

 

Ruta Nonacs, MD PhD

 

Ankarfeldt MZ, Petersen J, Andersen JT, Li H, Motsko SP, Fast T, Hede SM, Jimenez-Solem E. Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden. PLoS Med. 2021 Nov 22;18(11):e1003851. doi: 10.1371/journal.pmed.1003851. 

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.  Study reviewed in detail HERE.

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. Study reviewed in detail HERE.

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