Abstract
Maternal mortality and morbidity continue to rise in the United States. Despite these trends there are limited novel interventions to investigate and improve these metrics, partly due to research protocol limitations which restrict participation of pregnant women. Inclusion of pregnant women in research studies is integral to the process of obtaining important information regarding the safety and efficacy of therapeutics or interventions to improve maternal health and pregnancy outcomes. While significant changes in research practices have resulted in an increase of female participants, there remains a paucity of research trials directly targeting pregnant and lactating women. This article provides an overview of issues surrounding inclusion of pregnant or breastfeeding women in research studies, and includes historical perspectives, navigating concerns over safety profile, considerations for appropriate development, and future perspectives.
Similar content being viewed by others
References
Gonzalez D, Boggess KA, Cohen-Wolkowiez M (2015) Lessons learned in pediatric clinical research to evaluate safe and effective use of drugs in pregnancy. Obstet Gynecol 125(4):953–958
Illamola SM, Bucci-Rechtweg C, Costantine MM, Tsilou E, Sherwin CM, Zajicek A (2018) Inclusion of pregnant and breastfeeding women in research: efforts and initiatives. Br J Clin Pharmacol 84(2):215–222
Gynecologists ACoOa (2015) Ethical considerations for including women as research participants. Committee Opinion No. 646. Obstet Gynaecol. 126:e100–107
Shanks N, Greek R, Greek J (2009) Are animal models predictive for humans? Philos Ethics Humanit Med 4:2
Hoover RN, Hyer M, Pfeiffer RM et al (2011) Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365(14):1304–1314
Vargesson N (2015) Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today 105(2):140–156
Food US, Drug A (1993) Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs; notice. Fed Regist 58(139):39406–39416
Food and Drug Administration (1979) Labeling and prescription drug advertising: content and format for labeling for human prescription drugs. Fed Reg 44:37434–37467
Prescription drug products; patient labeling requirements proposed rule. Fed Regist 44(131 Pt 2):40015–40041
Doering PL, Boothby LA, Cheok M (2002) Review of pregnancy labeling of prescription drugs: is the current system adequate to inform of risks? Am J Obstet Gynecol 187(2):333–339
National Institutes of Health Revitalization Act 1993; Science and Technology. Vol. Public Law, pp. 103–143
Cleary KL, Roney K, Costantine M (2014) Challenges of studying drugs in pregnancy for off-label indications: pravastatin for preeclampsia prevention. Semin Perinatol 38(8):523–527
Administration USFaD (2006) Requirements on content and format of labeling for human prescription drug and biological products Proposed rule. Fed Regist 2006(71):3921–3997
Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling. Fed Regist.233:72064–72103.
Ayad M, Costantine MM (2015) Epidemiology of medications use in pregnancy. Semin Perinatol 39(7):508–511
McCormack SA, Best BM (2014) Obstetric pharmacokinetic dosing studies are urgently needed. Front Pediatr 2:9
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use arD.
Saint-Raymond A, de Vries CS (2016) Medicine safety in pregnancy and ambitions for the EU medicine regulatory framework. Clin Pharmacol Ther 100(1):21–23
Lupattelli A, Spigset O, Twigg MJ et al (2014) Medication use in pregnancy: a cross-sectional, multinational web-based study. BMJ Open 4(2):e004365
Mitchell AA, Gilboa SM, Werler MM et al (2011) Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol. 205(1):51
Glover DD, Amonkar M, Rybeck BF, Tracy TS (2003) Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population. Am J Obstet Gynecol 188(4):1039–1045
Centers for Disease Controls & Prevention. Use of Medication in Pregnancy. 2016. https://www.cdc.gov/pregnancy/meds/treatingfortwo/data.html.
Adam MP, Polifka JE, Friedman JM (2011) Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet 157C(3):175–182
Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van den Anker JN (2014) Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 211(6):690
Marwick C (1997) Thalidomide back–under strict control. JAMA 278(14):1135–1137
Sheffield JS, Siegel D, Mirochnick M et al (2014) Designing drug trials: considerations for pregnant women. Clin Infect Dis 59(Suppl 7):S437–444
Schwenzer KJ (2008) Protecting vulnerable subjects in clinical research: children, pregnant women, prisoners, and employees. Respir Care 53(10):1342–1349
Zimmerman K, Gonzalez D, Swamy GK, Cohen-Wolkowiez M (2015) Pharmacologic studies in vulnerable populations: using the pediatric experience. Semin Perinatol 39(7):532–536
Costantine MM, Cleary K, Hebert MF et al (2016) Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 214(6):720
Dallmann A, Mian P, Van den Anker J, Allegaert K (2019) Clinical pharmacokinetic studies in pregnant women and the relevance of pharmacometric tools. Curr Pharm Des 25(5):483–495
PRGLAC Report to HHS Secretary and Congress. Eunice Kennedy Shriver National Institute of Child Health and Human Development. https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf (accessed March 20, 2020).
List of Recommendations from the Task Force on Research Specific to Pregnant Woman and Lactating Women. Eunice Kennedy Shriver National Institute of Child Health and Human Development. https://www.nichd.nih.gov/about/advisory/PRGLAC/recommendations. Accessed 20 March 2020.
U.S. Department of Health and Human Services PHS, National Institutes of Health, Office of Research on Women’s Health. Bethesda, MD: National Institutes of Health. Enrolling Pregnant Women: Issues in Clinical Research. 2011.
Costantine MM, Cleary K, Eunice Kennedy Shriver National Institute of Child H, Human Development Obstetric-Fetal Pharmacology Research Units N (2013) Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 121:349–353
American College of O, Gynecologists, the Society for Maternal-Fetal M, Kilpatrick SK, Ecker JL (2016) Severe maternal morbidity: screening and review. Am J Obstet Gynecol 215(3):17–22
Marrs CC, Costantine MM (2017) Should we add pravastatin to aspirin for preeclampsia prevention in high-risk women? Clin Obstet Gynecol 60(1):161–168
Edison RJ, Muenke M (2004) Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 131(3):287–298
Kazmin A, Garcia-Bournissen F, Koren G (2007) Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can 29(11):906–908
Ofori B, Rey E, Berard A (2007) Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 64(4):496–509
Taguchi N, Rubin ET, Hosokawa A et al (2008) Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol 26(2):175–177
Bateman BT, Hernandez-Diaz S, Fischer MA et al (2015) Statins and congenital malformations: cohort study. BMJ 350:h1035
Brownfoot FC, Tong S, Hannan NJ et al (2015) Effects of Pravastatin on human placenta, endothelium, and women with severe preeclampsia. Hypertension 66(3):687–697
Kumasawa K, Ikawa M, Kidoya H et al (2011) Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 108(4):1451–1455
Pfeffer MA, Keech A, Sacks FM et al (2002) Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project. Circulation 105(20):2341–2346
Nanovskaya TN, Patrikeeva SL, Paul J, Costantine MM, Hankins GD, Ahmed MS (2013) Transplacental transfer and distribution of pravastatin. Am J Obstet Gynecol. 209(4):373–375
Zarek J, DeGorter MK, Lubetsky A et al (2013) The transfer of pravastatin in the dually perfused human placenta. Placenta 34(8):719–721
Carver AR, Tamayo E, Perez-Polo JR, Saade GR, Hankins GD, Costantine MM (2014) The effect of maternal pravastatin therapy on adverse sensorimotor outcomes of the offspring in a murine model of preeclampsia. Int J Dev Neurosci 33:33–40
Carver AR, Andrikopoulou M, Lei J et al (2014) Maternal pravastatin prevents altered fetal brain development in a preeclamptic CD-1 mouse model. PLoS ONE 9(6):e100873
McDonnold M, Tamayo E, Kechichian T et al (2014) The effect of prenatal pravastatin treatment on altered fetal programming of postnatal growth and metabolic function in a preeclampsia-like murine model. Am J Obstet Gynecol 210(6):542.e541–547
Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G (2016) Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest 126(8):2933–2940
Acknowledgements
MMC is supported by a grant from The Eunice Kennedy Shriver National Institute of Child Health and Human Development (5 UG1 HD027915-29) and the National Heart, Lung, and blood institute (1UG3HL140131-01). This commentary does not necessarily represent the official views of the NICHD, NHLBI, or the National Institute of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None of the authors have any conflicts to disclose
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
McKiever, M., Frey, H. & Costantine, M.M. Challenges in conducting clinical research studies in pregnant women. J Pharmacokinet Pharmacodyn 47, 287–293 (2020). https://doi.org/10.1007/s10928-020-09687-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-020-09687-z