Advertisement

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

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

Keywords

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

Notes

Acknowledgments

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.

Funding

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

228_2017_2385_MOESM1_ESM.docx (15 kb)
Suppl. Table 1 (DOCX 14 kb)
228_2017_2385_MOESM2_ESM.docx (15 kb)
Suppl. Table 2 (DOCX 14 kb)
228_2017_2385_MOESM3_ESM.docx (17 kb)
Suppl. Table 3 (DOCX 16 kb)
228_2017_2385_Fig1_ESM.jpg (30 kb)
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)

228_2017_2385_MOESM4_ESM.tif (1.9 mb)
High resolution image (TIFF 1901 kb)
228_2017_2385_Fig2_ESM.jpg (49 kb)
Suppl. Fig. 2

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

228_2017_2385_MOESM5_ESM.tiff (561 kb)
High resolution image (TIFF 560 kb)
228_2017_2385_Fig3_ESM.jpg (136 kb)
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)

References

  1. 1.
    Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343(21):1520–1528.  https://doi.org/10.1056/NEJM200011233432103 CrossRefPubMedGoogle Scholar
  2. 2.
    Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352(11):1092–1102CrossRefPubMedGoogle Scholar
  3. 3.
    Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352(11):1071–1080CrossRefPubMedGoogle Scholar
  4. 4.
    van der Heijden BJ, Carlus C, Narcy F, Bavoux F, Delezoide AL, Gubler MC (1994) Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin. Am J Obstet Gynecol 171(3):617–623.  https://doi.org/10.1016/0002-9378(94)90073-6 CrossRefPubMedGoogle Scholar
  5. 5.
    Torloni MR, Cordioli E, Zamith MM, Hisaba WJ, Nardozza LM, Santana RM, Moron AF (2006) Reversible constriction of the fetal ductus arteriosus after maternal use of topical diclofenac and methyl salicylate. Ultrasound Obstet Gynecol 27(2):227–229.  https://doi.org/10.1002/uog.2647 CrossRefPubMedGoogle Scholar
  6. 6.
    Groom KM, Shennan AH, Jones BA, Seed P, Bennett PR (2005) TOCOX—a randomised, double-blind, placebo-controlled trial of rofecoxib (a COX-2-specific prostaglandin inhibitor) for the prevention of preterm delivery in women at high risk. BJOG 112(6):725–730.  https://doi.org/10.1111/j.1471-0528.2005.00539.x CrossRefPubMedGoogle Scholar
  7. 7.
    Stika CS, Gross GA, Leguizamon G, Gerber S, Levy R, Mathur A, Bernhard LM, Nelson DM, Sadovsky Y (2002) A prospective randomized safety trial of celecoxib for treatment of preterm labor. Am J Obstet Gynecol 187(3):653–660.  https://doi.org/10.1067/mob.2002.125281 CrossRefPubMedGoogle Scholar
  8. 8.
    Daniel S, Matok I, Gorodischer R, Koren G, Uziel E, Wiznitzer A, Levy A (2012) Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy. J Rheumatol 39(11):2163–2169.  https://doi.org/10.3899/jrheum120453 CrossRefPubMedGoogle Scholar
  9. 9.
    Ofori B, Oraichi D, Blais L, Rey E, Berard A (2006) Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol 77(4):268–279.  https://doi.org/10.1002/bdrb.20085 CrossRefPubMedGoogle Scholar
  10. 10.
    European Surveillance of congenital anomalies (version 20/12/2016) Complete EUROCAT Guide 1.4 and Reference Documents, http://www.eurocat-network.eu/aboutus/datacollection/guidelinesforregistration/guide1_4
  11. 11.
    Meister R, Schaefer C (2008) Statistical methods for estimating the probability of spontaneous abortion in observational studies—analyzing pregnancies exposed to coumarin derivatives. Reprod Toxicol 26(1):31–35.  https://doi.org/10.1016/j.reprotox.2008.1006.1006 CrossRefPubMedGoogle Scholar
  12. 12.
    Matok I, Azoulay L, Yin H, Suissa S (2014) Immortal time bias in observational studies of drug effects in pregnancy. Birth Defects Res A Clin Mol Teratol 100(9):658–662.  https://doi.org/10.1002/bdra.23271 CrossRefPubMedGoogle Scholar
  13. 13.
    Suissa S (2007) Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 16(3):241–249.  https://doi.org/10.1002/pds.1357 CrossRefPubMedGoogle Scholar
  14. 14.
    D'Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17(19):2265–2281.  https://doi.org/10.1002/(SICI)1097-0258(19981015)17:19<2265::AID-SIM918>3.0.CO;2-B CrossRefPubMedGoogle Scholar
  15. 15.
    McCaffrey DF, Lockwood JR, Koretz D, Louis TA, Hamilton L (2004) Models for value-added modeling of teacher effects. J Educ Behav Stat 29(1):67–101.  https://doi.org/10.3102/10769986029001067 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Beyersmann J, Allignol A, Schumacher M (2012) Competing risks and multistate models with R. Springer, New York.  https://doi.org/10.1007/978-1-4614-2035-4 CrossRefGoogle Scholar
  17. 17.
    Rubin DB (2004) Multiple imputation for nonresponse in surveys. Wiley, New JerseyGoogle Scholar
  18. 18.
    Therneau TM, Lumley T (published 04/04/2017) Survival analysis, contains the core survival analysis routines, including definition of Surv objects, Kaplan-Meier and Aalen-Johansen (multi-state) curves, Cox models, and parametric accelerated failure time models; version 2.41-3, https://cran.r-project.org/web/packages/survival/index.html. In: ed.
  19. 19.
    van Buuren S, Groothuis-Oudshoorn K (published 12/12/2011) Mice: multivariate imputation by chained equations in R survival analysis, contains the core survival analysis routines, including definition of Surv objects, Kaplan-Meier and Aalen-Johansen (multi-state) curves, Cox models, and parametric accelerated failure time models, https://www.jstatsoft.org/article/view/v045i03. In: ed
  20. 20.
    Malm H, Borisch C (2015) Non-steroidal anti-inflammatory and antirheumatic drugs, chapter 2.1.6. In: Schaefer C, Peters P, Miller RK (Eds.) Drugs during pregnancy and lactation, third edition ed. Elsevier, pp27–58Google Scholar
  21. 21.
    Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, da Silva J, Nelson-Piercy C, Cetin I, Costedoat-Chalumeau N, Dolhain R, Forger F, Khamashta M, Ruiz-Irastorza G, Zink A, Vencovsky J, Cutolo M, Caeyers N, Zumbuhl C, Ostensen M (2016) The EULAR points to consider for use of antirheumatic drugs before pregnancy and during pregnancy and lactation. Ann Rheum Dis 75(5):795–810.  https://doi.org/10.1136/annrheumdis-2015-208840 CrossRefPubMedGoogle Scholar
  22. 22.
    European surveillance of congenital anomalies (2017) EUROCAT Prevalence Data Tables, Cases and prevalence (per 10,000 births) of all congenital anomaly subgroups for all registries, from 2011-2015. https://www.eurocat-network.eu/accessprevalencedata/prevalencetables
  23. 23.
    Ericson A, Kallen BA (2001) Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 15(4):371–375.  https://doi.org/10.1016/S0890-6238(01)00137-X CrossRefPubMedGoogle Scholar
  24. 24.
    van Gelder MM, Roeleveld N, Nordeng H (2011) Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS One 6(7):e22174.  https://doi.org/10.1371/journal.pone.0022174 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nezvalova-Henriksen K, Spigset O, Nordeng H (2013) Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study. BJOG 120(8):948–959.  https://doi.org/10.1111/471-0528.12192
  26. 26.
    Cleves MA, Savell VH, Jr., Raj S, Zhao W, Correa A, Werler MM, et al. (2004) Maternal use of acetaminophen and nonsterodial anti-inflammatory drugs (NSAIDs), and muscular venticular septal defects. Birth Defects Res A Clin Mol Teratol 70(3):107–113 Google Scholar
  27. 27.
    Hernandez RK, Werler MM, Romitti P, Sun L, Anderka M (2012) Nonsteroidal anti-inflammatory drugs use among women and the risk of birth defects. Am J Obstet Gynecol 206(3):228.e1–228.e8.  https://doi.org/10.1016/j.ajog.2011.11.019
  28. 28.
    Li DK, Liu L, Odouli R (2003) Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 327(7411):368–360.  https://doi.org/10.1136/bmj.327.7411.368 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nakhai-Pour HR, Broy P, Sheehy O, Berard A (2011) Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 183(15):1713–1720.  https://doi.org/10.1503/cmaj.110454 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A (2014) Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ 186(5):E177–E182.  https://doi.org/10.1503/cmaj.130605 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Beck E, Lechner A, Schaefer C (2017) Who seeks teratology information service's advice? Assessing the risk of selection bias in observational cohort studies on drug risks in pregnancy. Reprod Toxicol 67:79–84.  https://doi.org/10.1016/j.reprotox.2016.11.019 CrossRefPubMedGoogle Scholar

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

Personalised recommendations