Intended for healthcare professionals

  1. Research
  2. Maternal and fetal...
  3. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study
CCBYNC Open access
Research

Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m237 (Published 19 February 2020) Cite this as: BMJ 2020;368:m237
  1. Krista F Huybrechts, associate professor of medicine1,
  2. Brian T Bateman, associate professor of anesthesia1 2,
  3. Ajinkya Pawar, research specialist1,
  4. Lily G Bessette, research assistant1,
  5. Helen Mogun, programmer1,
  6. Raisa Levin, programmer1,
  7. Hu Li, research advisor epidemiology3,
  8. Stephen Motsko, senior director epidemiology3,
  9. Maria Fernanda Scantamburlo Fernandes, medical advisor3,
  10. Himanshu P Upadhyaya, medical fellow3,
  11. Sonia Hernandez-Diaz, professor of epidemiology4
  1. 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  2. 2Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  3. 3Eli Lilly and Company, Indianapolis, IN, USA
  4. 4Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  1. Correspondence to: K F Huybrechts khuybrechts{at}bwh.harvard.edu
  • Accepted 8 January 2020

Abstract

Objective To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine.

Design Cohort study nested in the Medicaid Analytic eXtract for 2004-13.

Setting Publicly insured pregnancies in the United States.

Participants Pregnant women 18 to 55 years of age and their liveborn infants.

Interventions Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy.

Main outcome measures Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage.

Results Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses.

Conclusions On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient.

Trial registration EUPAS 15946.

Footnotes

  • Contributors: KFH conceptualized and designed the study, did the analyses, and drafted the initial manuscript. BTB and SHD conceptualized and designed the study, critically reviewed the results of analyses, and reviewed and revised the manuscript. HM and RL did the analyses and reviewed and revised the manuscript. HL and SM provided input to the study concept and design, critically reviewed the results of analyses, and reviewed and revised the manuscript. AP, LGB, MFSF, and HPU critically reviewed the results of analyses and reviewed and revised the manuscript. All authors approved the final manuscript as submitted. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. KFH is the guarantor.

  • Funding: The study was funded by an unrestricted grant to Brigham and Women’s Hospital from Eli Lilly and Company to provide supplemental evidence to the Cymbalta Pregnancy Registry on the maternal and fetal outcomes of interest specified in the Cymbalta post-marketing requirement. The pre-specified study protocol and full study report are available on the Encepp website. Brigham and Women’s Hospital retained the right to publish this work, without influence from its sponsor.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: the study was funded by an unrestricted grant to Brigham and Women’s Hospital from Eli Lilly and Company; KFH was an investigator on grants from GSK and Pfizer outside the submitted work; BTB was an investigator on grants from Baxalta, Pfizer, GSK, and Pacira outside the submitted work and has received personal fees from Aetion and the Alosa Foundation outside the submitted work; SHD was an investigator on grants from GSK and Pfizer outside the submitted work and has received personal fees from Bayer outside the submitted work; HL, SM, MFSF, and HPU were employees of Eli Lilly during the conduct of the study; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The research was approved by the institutional review board of Brigham and Women’s Hospital, which granted a waiver of informed consent (IRB 2017P001944).

  • Data sharing: No additional data available.

  • Transparency statement: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: Aside from the study protocol and full study report being available on the Encepp website, there are no plans to disseminate the results of the research to study participants or the relevant patient community.

http://creativecommons.org/licenses/by-nc/4.0/

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

View Full Text
Back to top