Skip to main content
SpringerLink
Log in

Diclofenac/misoprostol during early pregnancy and the risk of miscarriage: a Danish nationwide cohort study

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Introduction

Misoprostol can be used in the prevention of gastric ulcer in treatment with diclofenac and is used in rheumatic diseases. Since misoprostol causes contractions of the uterus, it can also be used to induce abortions when administrated vaginally. The aim of the study was to investigate if early pregnancy exposure to oral diclofenac/misoprostol was associated with miscarriage.

Method

We conducted a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2011. All births were identified using the Medical Birth Registry, and all records of induced abortion and miscarriage were from the National Hospital Register. Data on drug use were from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed to diclofenac/misoprostol in early pregnancy.

Result

We identified 1,338,824 pregnancies (970,491 births, 142,147 miscarriages, 226,145 induced abortions). One hundred sixty-six were exposed to diclofenac/misoprostol in the early pregnancy of which 28.3 % (47) ended up in a miscarriage compared to 10.6 % among unexposed. The adjusted hazard ratio of having a miscarriage after exposure to diclofenac/misoprostol in the first trimester was 3.6 (CI 95 % 2.6–4.9).

Conclusion

We found an increased risk of miscarriage after exposure to diclofenac/misoprostol during the early pregnancy. Women in the fertile age should not be treated with the combination of diclofenac/misoprostol if other options were available.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dajani EZ (1987) Perspective on the gastric antisecretory effects of misoprostol in man. Prostaglandins 33:68–77

    Article  CAS  PubMed  Google Scholar 

  2. Graham DY, Agrawal NM, Roth SH (1988) Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 2:1277–1280

    Article  CAS  PubMed  Google Scholar 

  3. Tang OS, Gemzell-Danielsson K, Ho PC (2007) Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 99(Suppl 2):S160–S167

  4. Tang J, Kapp N, Dragoman M, de Souza JP (2013) WHO recommendations for misoprostol use for obstetric and gynecologic indications. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 121:186–189

  5. El-Refaey H, Rajasekar D, Abdalla M, Calder L, Templeton A (1995) Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med 332:983–987

    Article  CAS  PubMed  Google Scholar 

  6. Tanha FD, Golgachi T, Niroomand N, Ghajarzadeh M, Nasr R (2013) Sublingual versus vaginal misoprostol for second trimester termination: a randomized clinical trial. Arch Gynecol Obstet 287:65–69

    Article  CAS  PubMed  Google Scholar 

  7. Dahiya K, Ahuja K, Dhingra A, Duhan N, Nanda S (2011) Efficacy and safety of mifepristone and buccal misoprostol versus buccal misoprostol alone for medical abortion. Arch Gynecol Obstet 285:1055–1058

    Article  PubMed  Google Scholar 

  8. Pfizer Limited (2013) Summary of product characteristics arthrotec 50 tablets. https://www.medicines.org.uk/emc/medicine/10673. Accessed 26 Nov 2013

  9. Pastuszak AL et al (1998) Use of misoprostol during pregnancy and Möbius’ syndrome in infants. N Engl J Med 338:1881–1885

    Article  CAS  PubMed  Google Scholar 

  10. Orioli IM, Castilla EE (2000) Epidemiological assessment of misoprostol teratogenicity. BJOG Int J Obstet Gynaecol 107:519–523

    Article  CAS  Google Scholar 

  11. Vargas FR et al (2000) Prenatal exposure to misoprostol and vascular disruption defects: a case-control study. Am J Med Genet 95:302–306

    Article  CAS  PubMed  Google Scholar 

  12. Schüler L et al (1999) Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study. Reprod Toxicol Elmsford N 13:147–151

    Article  Google Scholar 

  13. Norman JE, Thong KJ, Baird DT (1991) Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 338:1233–1236

    Article  CAS  PubMed  Google Scholar 

  14. Vauzelle C, Beghin D, Cournot M-P, Elefant E (2013) Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study. Reprod Toxicol Elmsford N 36:98–103

    Article  CAS  Google Scholar 

  15. Watzer B, Lusthof KJ, Schweer H (2014) Abortion after deliberate Arthrotec® addition to food. Mass spectrometric detection of diclofenac, misoprostol acid, and their urinary metabolites. Int J Legal Med 129:759–769

    Article  PubMed  Google Scholar 

  16. Knudsen LB, Olsen J (1998) The Danish medical birth registry. Dan Med Bull 45:320–323

    CAS  PubMed  Google Scholar 

  17. Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH (1999) The Danish national hospital register. A valuable source of data for modern health sciences. Dan Med Bull 46:263–268

    CAS  PubMed  Google Scholar 

  18. Kristensen J, Langhoff-Roos J, Skovgaard LT, Kristensen FB (1996) Validation of the Danish birth registration. J Clin Epidemiol 49:893–897

    Article  CAS  PubMed  Google Scholar 

  19. The Danish National Board of Health (2004) Project on data quality in the National Hospital Register. The Danish National Board of Health Copenhagen, Denmark

  20. Espersen L (2003) Law amending the Law on the inquest, autopsy and transplantation, etc. and Children Act. https://www.retsinformation.dk/forms/R0710.aspx?id=88046. Accessed 1 Sept 2015

  21. Her Majesty Queen Margrethe II of Denmark (2004) Law amending the Law on the inquest, autopsy and transplantation, etc. and Children Act. https://www.retsinformation.dk/Forms/R0710.aspx?id=1792. Accessed 1 Sept 2015

  22. Kildemoes HW, Sørensen HT, Hallas J (2011) The Danish national prescription registry. Scand J Public Health 39:38–41

    Article  PubMed  Google Scholar 

  23. Sørensen HT, Hansen I, Ejlersen E, Sabroe S, Hamburger H (1996) Identification of patients treated with strong analgesics: an assessment of two Danish information systems with respect to epidemiological research. J Med Syst 20:57–65

    Article  PubMed  Google Scholar 

  24. Baadsgaard M, Quitzau J (2011) Danish registers on personal income and transfer payments. Scand J Public Health 39:103–105

    Article  PubMed  Google Scholar 

  25. Jensen VM, Rasmussen AW (2011) Danish education registers. Scand J Public Health 39:91–94

    Article  PubMed  Google Scholar 

  26. Andersen JT et al (2013) Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based nationwide cohort study. PLoS One 8:e53327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Von Elm E et al (2007) Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 335:806–808

    Article  Google Scholar 

  28. Kalousek DK (1987) Anatomic and chromosome anomalies in specimens of early spontaneous abortion: seven-year experience. Birth Defects Orig Artic Ser 23:153–168

    CAS  PubMed  Google Scholar 

  29. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK (2003) Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 18:1724–1732

    Article  CAS  PubMed  Google Scholar 

  30. Shepard TH (1995) Möbius syndrome after misoprostol: a possible teratogenic mechanism. Lancet 346:780

    Article  CAS  PubMed  Google Scholar 

  31. Gonzalez CH et al (1998) Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy. Lancet 351:1624–1627

    Article  CAS  PubMed  Google Scholar 

  32. Lohse SR et al (2010) Validation of spontaneous abortion diagnoses in the Danish national registry of patients. Clin Epidemiol 2:247–250

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark

    Jon T. Andersen, Morten Petersen, Kasper Broedbaek, Vanja Cejvanovic, Torben K. Nielsen, Henrik E. Poulsen & Espen Jimenez-Solem

  2. Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, USA

    Dimitrios Mastrogiannis

  3. Mental Health Centre Copenhagen, Copenhagen, Denmark

    Nadia L. Andersen

  4. Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

    Jon T. Andersen, Henrik E. Poulsen & Espen Jimenez-Solem

Authors
  1. Jon T. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitrios Mastrogiannis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadia L. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morten Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kasper Broedbaek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vanja Cejvanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Torben K. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Henrik E. Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Espen Jimenez-Solem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon T. Andersen.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Funding

No specific funding has been given to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andersen, J.T., Mastrogiannis, D., Andersen, N.L. et al. Diclofenac/misoprostol during early pregnancy and the risk of miscarriage: a Danish nationwide cohort study. Arch Gynecol Obstet 294, 245–250 (2016). https://doi.org/10.1007/s00404-015-3966-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-015-3966-9

Keywords

Search

Navigation