Drug Safety in Pregnancy: Review of Study Approaches Requested by Regulatory Agencies

  • Andrea V. MargulisEmail author
  • Mary Anthony
  • Elena Rivero-Ferrer
Pharmacoepidemiology (U Haug, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pharmacoepidemiology


Purpose of Review

We reviewed postauthorization pregnancy safety studies requested by regulatory agencies to explore which study approaches have been typically requested and to what extent these have changed over time.

Recent Findings

The most common study approach requested by the US Food and Drug Administration (FDA) is pregnancy exposure registries (observational cohorts with prospective data collection), per the FDA’s Postmarketing Requirements and Commitments (PMR/PMC) database. Since 2017, this requirement has often been paired with a request for a database study (observational study using preexisting electronic health care data), both approaches assessing pregnancy and fetal outcomes. From studies registered in the European Union electronic Register of Post-Authorisation Studies, we observed a similar number of pregnancy exposure registries and database studies, both approaches also assessing pregnancy and fetal outcomes. In requests for drugs approved since 2014, preference appears to have shifted toward studies using preexisting electronic health care databases from multiple countries.


Pregnancy exposure registries have been the most commonly requested study approach on drug safety in pregnancy. Recent regulatory requests and activities denote an increasing interest in other approaches.


Postauthorization safety studies PASS Regulatory requirements Pregnancy pharmacoepidemiology Pregnancy exposure registries Pregnancy registries 



Editorial services were provided by John Forbes and graphic design support was provided by Jason Mathes and Christopher Lovett, all employees of RTI Health Solutions. The authors thank Abenah Harding and Catherine Saltus, also from RTI Health Solutions, for their help in the preparation of this manuscript.


This project was funded by RTI Health Solutions.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

40471_2019_212_MOESM1_ESM.xlsx (54 kb)
ESM 1 (XLSX 54 kb)


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Food and Drug Administration. Guidance for industry - establishing pregnancy exposure registries; 2002.Google Scholar
  2. 2.
    Food and Drug Administration. Procedures and responsibilities for developing postmarketing requirements and commitments - MAPP 6010.9; 2009.Google Scholar
  3. 3.
    • Gelperin K, Hammad H, Leishear K, Bird ST, Taylor L, Hampp C, et al. A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection. Pharmacoepidemiol Drug Saf. 2017;26(2):208–14. Systematic review of existing pregnancy exposure registries focusing on design features that are key to obtaining informative results for drug safety in pregnancy. CrossRefGoogle Scholar
  4. 4.
    • Bird ST, Gelperin K, Taylor L, Sahin L, Hammad H, Andrade SE, et al. Enrollment and retention in 34 United States pregnancy registries contrasted with the manufacturer’s capture of spontaneous reports for exposed pregnancies. Drug Saf. 2018;41(1):87–94. Comparison of number of enrollees in pregnancy exposure registries with number of spontaneous reports of exposed pregnancies for a number of drugs. CrossRefGoogle Scholar
  5. 5.
    Food and Drug Administration. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling (79 FR 72063); 2014.Google Scholar
  6. 6.
    Roldan Munoz S, Rasi V, de Vries C. Evaluating pregnancy registries: opportunities for improving post marketing surveillance methods in pregnancy [abstract]. Pharmacoepidemiol Drug Saf. 2018;27(S2):S240.Google Scholar
  7. 7.
    Food and Drug Administration. Framework for FDA’s real-world evidence program; 2018.Google Scholar
  8. 8.
    Davis RL. Medication exposure in pregnancy risk evaluation program (MEPREP). J Popul Ther Clin Pharmacol. 2010;17(3):e336–40.Google Scholar
  9. 9.
  10. 10.
    Food and Drug Administration. Postapproval pregnancy safety studies - guidance for industry (draft guidance); 2019.Google Scholar
  11. 11.
    Charlton RA, Neville AJ, Jordan S, Pierini A, Damase-Michel C, Klungsoyr K, et al. Healthcare databases in Europe for studying medicine use and safety during pregnancy. Pharmacoepidemiol Drug Saf. 2014;23(6):586–94.CrossRefGoogle Scholar
  12. 12.
    Charlton RA, De Vries C. Systematic overview of data sources for drug safety in pregnancy research consultancy EMA/2010/29/CN; 2012.Google Scholar
  13. 13.
    • Gkori M, Morris J, on behalf of the EUROmediSAFE consortium. EUROmediSAFE INVENTORY. Inventory of available data sources in all 28 EU Member States for potential use when evaluating the long-term risks for children associated with in-utero exposure; 2018. Accessed 2 July 2019. Extensive list of data sources available for research on drug safety in pregnancy in Europe.
  14. 14.
    EMA. Invitation to tender for efficacy and safety studies on medicines (Lot 4: Pharmacoepidemiology research – association studies, including pregnancy and breastfeeding research), 14 December 2017. Accessed 27 Apr 2019.
  15. 15.
    •• Yusuf A, Chia V, Xue F, Mikol DD, Bollinger L, Cangialose C. Use of existing electronic health care databases to evaluate medication safety in pregnancy: triptan exposure in pregnancy as a case study. Pharmacoepidemiol Drug Saf. 2018;27(12):1309–15. Publication comparing two studies that implemented different approaches to assess the same scientific question on drug safety in pregnancy. CrossRefGoogle Scholar
  16. 16.
    Alwan S, Chambers CD, Armenti VT, Sadovnick AD. The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS). Mult Scler Relat Disord. 2015;4(1):6–17.CrossRefGoogle Scholar
  17. 17.
    Pottinger E, Woolf RT, Exton LS, Burden AD, Nelson-Piercy C, Smith CH. Exposure to biological therapies during conception and pregnancy: a systematic review. Br J Dermatol. 2018;178(1):95–102.CrossRefGoogle Scholar
  18. 18.
    Pham-Huy A, Sadarangani M, Huang V, Ostensen M, Castillo E, Troster SM, et al. From mother to baby: antenatal exposure to monoclonal antibody biologics. Expert Rev Clin Immunol. 2019;15(3):221–9.CrossRefGoogle Scholar
  19. 19.
    • Krueger WS, Anthony MS, Saltus CW, Margulis AV, Rivero-Ferrer E, Monz B, et al. Evaluating the safety of medication exposures during pregnancy: a case study of study designs and data sources in multiple sclerosis. Drugs Real World Outcomes. 2017;4(3):139–49. Review of approaches to study drug safety in pregnancy. The focus is on women with multiple sclerosis, but the concepts have a broader application. CrossRefGoogle Scholar
  20. 20.
    Zhang J, Curtis JR. Considerations in using registry and health plan data for studying pregnancy in rheumatic diseases. Curr Opin Rheumatol. 2014;26(3):315–20.CrossRefGoogle Scholar
  21. 21.
    Didden EM, Andrews EB, Hellwig K, Hernandez-Diaz S, Magyari M, Margulis AV, et al. A novel approach for active surveillance of pregnancy safety in multiple sclerosis [abstract]. Pharmacoepidemiol Drug Saf. 2018;27(S2):268.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Andrea V. Margulis
    • 1
    Email author
  • Mary Anthony
    • 2
  • Elena Rivero-Ferrer
    • 1
  1. 1.RTI Health SolutionsBarcelonaSpain
  2. 2.RTI Health SolutionsResearch Triangle ParkUSA

Personalised recommendations