European Journal of Clinical Pharmacology

, Volume 74, Issue 4, pp 489–495 | Cite as

Exposure to cox-2 inhibitors (coxibs) during the first trimester and pregnancy outcome: a prospective observational cohort study

  • Katarina Dathe
  • Stephanie Padberg
  • Stefanie Hultzsch
  • Luisa-Maria Köhler
  • Katja Meixner
  • Anne-Katrin Fietz
  • Tatjana Tissen-Diabaté
  • Reinhard Meister
  • Christof Schaefer
Pharmacoepidemiology and Prescription



Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further data on coxibs and their effects on embryogenesis are needed.


This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January 2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens.


The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI 0.34–3.42; OR adjusted 0.96, 95% CI 0.28–3.26). The cumulative incidence of spontaneous abortions was nonsignificantly lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51–1.58; HR adjusted, 0.87; 95% CI, 0.49–1.56). Elective terminations of pregnancies (ETOP), mainly for ‘social’ reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR, 2.31; 95% CI, 1.26–4.24; HR adjusted 2.12, 95% CI 1.13–3.97).


Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence basis on coxib exposure during pregnancy, well-established alternatives should be preferred.


Cox-2 inhibitors Coxibs Pregnancy outcome Birth defects Spontaneous abortions Pharmacovigilance 



We would like to thank our colleagues from the German Embryotox Pharmacovigilance Institute for counselling patients and their attending physicians. The thorough documentation of each case is an indispensable prerequisite to obtain a high data quality of the study population. This study is part of the thesis of Luisa-Maria Köhler.

Contribution of authors

KD, SP, SH, RM and CS designed the study. KD, SP, LMK and KM validated and analysed the data. AKF and TTD performed the statistical analyses and RM provided expert interpretation of the analyses. KD, SP, SH, CS, AKF, TTD, RM, KD and CS participated in the result interpretation. KD and CS wrote the first draft of the manuscript and all authors critically revised subsequent manuscript drafts and contributed essential discussion points. The listed authors approved the final version of this manuscript and they are responsible for the accuracy of this work.


This work was supported by the German Federal Institute for Drugs and Medical Devices (BfArM). The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval

Ethics approval was obtained from the ethics committee of the Charité Universitätsmedizin Berlin, Germany (no. EA4/029/16). The study was registered in the German Clinical Trials Register (no. DRKS00011140).

Supplementary material

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Suppl. Table 1 (DOCX 14 kb)
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Suppl. Table 2 (DOCX 14 kb)
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Suppl. Table 3 (DOCX 16 kb)
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Suppl. Fig. 1

Flow chart of requests showing inclusion and exclusion criteria for the defined study cohort exposed to coxibs. n, number of requests. *Currently approved and available in Germany. Etoricoxib and Celecoxib, oral medication; Parecoxib, injectable drug, intravenous or intramuscular. #Approval was withdrawn in 2004 (Rofecoxib) and 2005 (Valdecoxib). (JPEG 30 kb)

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High resolution image (TIFF 1901 kb)
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Suppl. Fig. 2

Patterns of missing values in covariates. (JPEG 49 kb)

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High resolution image (TIFF 560 kb)
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Suppl. Fig. 3

Coxib exposure intervals and outcome of pregnancies in the study cohort. The horizontal lines represent the pregnancy courses of the single cases (n = 174). (JPEG 135 kb)

228_2017_2385_MOESM6_ESM.tiff (1.1 mb)
High resolution image (TIFF 1162 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Katarina Dathe
    • 1
  • Stephanie Padberg
    • 1
  • Stefanie Hultzsch
    • 1
  • Luisa-Maria Köhler
    • 1
  • Katja Meixner
    • 1
  • Anne-Katrin Fietz
    • 1
  • Tatjana Tissen-Diabaté
    • 1
  • Reinhard Meister
    • 2
  • Christof Schaefer
    • 1
  1. 1.Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie, Institut für Klinische Pharmakologie und ToxikologieBerlinGermany
  2. 2.Beuth Hochschule für Technik - University of Applied SciencesBerlinGermany

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