Recent History of Drug Development and Research During Pregnancy

There has been an increase in the prevalence of preexisting and chronic conditions (ie, asthma, diabetes, hypertension, heart disease, and substance use disorders) among women of childbearing age in recent years, which require them to continue taking medications during their pregnancy, the postpartum period, and lactation. Between 40% to 60% of pregnant women take 1 or more prescription medications for their preexisting or pregnancy-induced conditions during their pregnancy. More than 70% of women who breastfeed or pump their milk take some form of medication during lactation. However, the majority of medications prescribed to pregnant and lactating women are used “off-label” because more than 90% of clinically-approved medications do not have appropriate drug labeling information for pregnant and lactating women ( Figure ). Medications that have never been tested in pregnant and lactating women may have potential risks for adverse effects in pregnant and lactating women as well as lead to harmful effects to their developing fetus, neonates, and infants. This may contribute to increased maternal and perinatal morbidity.

Most women take 1 or more medications during pregnancy and lactation

Most of the medications lack appropriate labeling information for pregnant women and lactating women.

Ren. Drug development research in pregnant and lactating women. Am J Obstet Gynecol 2021.

Historically, pregnant women largely have been excluded from clinical drug research and new drug development processes primarily because of legal and ethical concerns. This exclusion led to the use of drugs in clinical practice that had not undergone rigorous evaluation for use during pregnancy; this, unfortunately, led women to take drugs that had significant adverse effects. One example was the use of diethylstilbestrol (DES) in pregnant women to protect against miscarriages and other pregnancy-related complications from the 1940s to the 1960s. It was later identified that exposure to DES in utero caused vaginal clear-cell adenocarcinoma in female offspring ^, and congenital anomalies in female reproductive tracts such as hypoplastic cervix and Mullerian duct abnormalities. ^, Another example is thalidomide. Thalidomide is a sedative drug that was widely used among pregnant women to relieve pregnancy-induced nausea and vomiting in the late 1950s and early 1960s. The lack of human data on the safety and efficacy of the drug during pregnancy led to the prescription of thalidomide to pregnant women; unfortunately, thousands of babies were born with severe upper and lower limb malformations caused by the teratogenic effects of thalidomide. In addition, a wide variety of internal defects such as patent ductus arteriosus, pulmonary stenosis, duodenal atresia, etc were associated with prenatal exposure to thalidomide. The drug was taken off the market in 1961.

In the wake of the worldwide thalidomide tragedy, the US Food and Drug Administration (FDA) increased its regulations on drug approvals for use in pregnant women and released new guidelines in 1977 (General Considerations for the Clinical Evaluation of Drugs), which prevented pregnant women from participating in phase I and early phase II clinical trials. In 1979, the FDA implemented a pregnancy category labeling system that required sponsors to include information on the safety of medications in pregnancy that was largely based on data from animal studies. The FDA labeling rule classified pregnant women as a “vulnerable” population that require special protection in research. Owing to the lack of incentives to conduct research in such a “high-risk,” “vulnerable” population and the fears of potential harmful effects to the developing fetus, pharmaceutical companies have been very reluctant to include pregnant and lactating women in drug development research and clinical trials.

To date, the drug safety and efficacy data for pregnant and lactating women for most FDA-approved drugs have been collected from the postmarketing surveillance pregnancy registries. However, over the past several decades, attitudes concerning the inclusion of women in clinical research and trials have changed dramatically. The National Institutes of Health Revitalization Act in 1993, which required the inclusion of women in clinical research and trials, led to considerable changes in research design and practice and led to more women being included in clinical research and trials. Despite these considerable changes, however, the inclusion of pregnant women in drug development research and clinical trials was still limited. In fact, the concern for pregnant women as a result of being categorized as a “vulnerable” population with regards to clinical research and trials remained until a recent revision of the “Common Rule” (the “Common Rule” is a short name for “The Federal Policy for the Protection of Human Subjects” and was adopted by a number of federal agencies in 1991. URL: https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html ) that removed the classification of pregnant women as a “vulnerable” population.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Approaches in Obstetrical-Fetal Pharmacology Research

The importance and necessity of creating a systematic framework and infrastructure in which to study medications used in pregnant women was recognized in the early 2000s by the scientific community and federal agencies. A multicenter collaborative research network—the Obstetric-Fetal Pharmacology Research Units (OPRU) Network––was thus established by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in 2004 as a follow-up on a workshop about drug use during pregnancy hosted by the NICHD in September 2000. The OPRU Network was changed to the Obstetric-Fetal Pharmacology Research Centers (OPRCs) after re-competition in 2015.

With a core mission to improve the safety and efficacy of medications used by pregnant and lactating women, the NICHD OPRU Network and OPRCs investigators have conducted pharmacokinetic (PK) and pharmacodynamic (PD) studies on a number of medications commonly used during pregnancy and lactation, such as glucose-lowering agents for the treatment of gestational diabetes mellitus (GDM), ^, pravastatin for the prevention of preeclampsia, clonidine and atenolol for the treatment of hypertension, ^, indomethacin for preterm labor, oseltamivir for influenza infection, and others ( Table ). Results from these studies have contributed to the understanding of altered PK processes (drug absorption, distribution, metabolism, and excretion) and PD properties of these medications during pregnancy and lactation. For example, significant changes in the PK parameters (decrease in area under the curve and maximum placenta concentration and increase in apparent oral clearance) of glyburide during pregnancy have suggested that higher dosages of glyburide may be needed in a woman with diabetes during pregnancy than when the patient is not pregnant to achieve comparable glycemic management. The study also found that the umbilical cord plasma glyburide concentration was about 70% of that of the maternal plasma glyburide concentration, which was different from previous reports in which no glyburide was detected in cord blood. ^, These observations provided a pharmacologic basis for altering the glyburide administration regimen in pregnant women to minimize the side effects (both to the mother and the newborn) while maximizing the pregnant woman’s therapeutic response. These study findings have also led to changes in the American College of Obstetricians and Gynecologists Practice Bulletin on GDM and demonstrate how NICHD-sponsored maternal-fetal pharmacology research can have a substantial impact on clinical practice.

Table

Medications studied by the Obstetric-Fetal Pharmacology Research Units Network and Obstetric-Fetal Pharmacology Research Centers

Drug name	Diseases and conditions	Study types	Author, year a
Pravastatin	Preeclampsia	• Phase 1 safety and PK study	• Costantine et al, 2016 Costantine and Ananth, 2016 Cleary et al, 2014 Costantine et al, 2013
		• Transplacental transfer	• Nanovskaya et al, 2013
Glyburide	GDM	• Preclinical studies	• Zhang et al, 2015 Shuster et al, 2014 Naraharisetti et al, 2007
		• PK and PD	• Hebert et al, 2009 Caritis and Hebert, 2013 Shuster et al, 2020
		• Glyburide metabolism	• Zhou et al, 2010 Zhou et al, 2010 Zharikova et al, 2009 Jain et al, 2008 Zharikova et al, 2007
		• Placenta drug transporters	• Hemauer et al, 2010 Nanovskaya et al, 2008
		• Glyburide transporters	• Zhou et al, 2008
Metformin	GDM	• Preclinical study	• Zhang et al, 2015
		• PK and PD	• Eyal et al, 2010 Shuster et al, 2020 Liao et al, 2020 Shuster et al, 2020
		• Placenta drug transporters	• Hemauer et al, 2010
Rosiglitazone	GDM	• Placenta drug transporters	• Hemauer et al, 2010
Oseltamivir	Influenza	• PK	• Beigi et al, 2011 Beigi et al, 2014
		• Transplacental transfer	• Nanovskaya et al, 2012
		• PopPK	• Pillai et al, 2015
Hydralazine, atenolol, clonidine, furosemide, labetalol	Hypertension	• PK and PD of antihypertensive agents	• Buchanan et al, 2009 Eyal et al, 2010 Easterling, 2014 Rothberger et al, 2010 Claessens et al, 2010
17-α hydroxyprogesterone caproate (17-OHPC)	Preterm birth	• PK, PD	• Feghali et al, 2014 Caritis et al, 2014 Caritis et al, 2012
		• Quality assessment of compounded 17-OHPC	• Chang et al, 2014 Caritis et al, 2013
		• Hepatic transporters, metabolism and disposition	• Sharma et al, 2013 Sharma et al, 2010 Sharma et al, 2008 Yan et al, 2008
		• Biotransformation and placental perfusion	• Fokina et al, 2012
		• Assays of drug plasma concentration	• Zhang et al, 2008 Zhang et al, 2007
		• Transplacental transfer	• Hemauer et al, 2008
Telavancin, vancomycin	MRSA infections	• Preclinical PK study of telavancin	• Wang et al, 2014
		• Placental transfer of vancomycin and telavancin	• Nanovskaya et al, 2012
Indomethacin	Preterm birth	• PK	• Rytting et al, 2014
		• Assays of drug plasma concentration	• Wang et al, 2013
Doxorubicin	Cancer	• PK	• Ryu et al, 2014
Tacrolimus	Organ transplant	• Placental drug transfer and drug excretion to breast milk	• Zheng et al, 2013
		• PK	• Hebert et al, 2013 Zheng et al, 2012
Cisplatin	Cervical cancer	• Drug excretion in breast milk	• Hays et al, 2013
Famotidine	Gastroesophageal reflux disease (GERD)	• Assays of drug plasma, urine, and umbilical cord concentration	• Wang et al, 2013
Nifedipine	Preterm birth	• PK and PGx	• Haas et al, 2013 Haas et al, 2012
Metronidazole	Bacterial vaginosis	• PK	• Wang et al, 2011
Triptan	Serotonin syndrome	• Review of FDA Adverse Event Reporting System	• Soldin et al, 2008
Amoxicillin	Anthrax	• PK of drug in pregnancy and postpartum	• Andrew et al, 2007
Antidepressant	Major Depressive Disorder during pregnancy	• Review of antidepressant treatment of depression in pregnant women	• Mesches et al, 2020
Prednisone	Autoimmune disease, asthma, organ transplantation	• PK	• Ryu et al, 2018
Dacarbazine	Hodgkin’s lymphoma	• PK	• Kantrowitz-Gordon et al, 2018

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