The FDA Office of Women’s Health (OWH) awards research grants to support FDA regulatory decision-making and advance the science of women’s health. OWH has funded research projects that address health issues affecting women across their lifespan. This page highlights OWH-funded research related to pregnancy.
Development of an artificially intelligent virtual pregnant woman modeling suite to support regulatory decisions - Annie Lumen, PhD/NCTR (19)
Efficacy and safety testing remains a challenge in pregnant women as deliberate experimentation for every compound of regulatory interest is not feasible or ethical. This hinders regulatory agencies from providing authoritative guidance for the use of a range of products such as drugs and vaccines that could promote or protect pregnant women’s health. Computational models, which have the unique ability to assimilate available information (e.g. animal model findings) and make appropriate inferences in humans are invaluable tools to guide regulatory decisions for pregnant women.
Such models are developed on a case-by-case basis and can be a time- and labor-intensive process driven by the expertise of an individual modeler. No unified computational tool exists to support regulatory evaluations in pregnant women that is accessible by both modeling experts and novices and adaptable for any products to be tested. This presents an unmet need for a scientific methodology across the agency limiting the widespread use of modeling and simulations; i.e., to do the best available science to protect pregnant women’s health. Our project’s goal is to address this need.
We, a team of modelers and regulators across the FDA Centers in global collaboration with computer programmers from academia and research institutes, propose to develop a prototype for a virtual pregnant woman modeling suite. The novel aspect of this suite is that it will be developed to be ‘artificially intelligent’. The time- and labor-intensive part of model development process will be pre-built in the suite using advanced computer algorithms. Such that the suite interactively gathers available data from the end-user and the type of regulatory question to be addressed as input and automatically generates the most appropriate computational model for testing. Such a flexible tool will increase the overall regulatory capacity of the FDA to efficiently evaluate products for pregnant women.
Evaluation of women’s-targeted dietary supplements for labeling compliance and potential contamination, containing live microbes in the U.S. market with special emphasis on pregnant and lactating women, and infants - Carmen Tartera/CFSAN (19)
Many products available to the consumer, such as dietary supplements and foods contain intentionally added live microorganisms that may provide a human health benefit. This has led to an increased production of these commodities to meet the demand for these new health related supplements. However, identification and characterization of the microbes in these products is lacking and pre-market requirements are limited to general safety concerns. Consumers rely on product labels, that report identity and viability, to be accurate and true. However, species are often misclassified or absent, and products are occasionally contaminated, in some instances with a pathogen. Our interest focuses on dietary supplements that target women at various stages of life, especially pregnancy and lactation, as well as infants. Products designed for women contain microbes associated with support of vaginal, urinary tract, breast and gut health, among others. Newborns, especially those prematurely born, are considered at-risk populations due to their underdeveloped immune system. They can be particularly susceptible to contaminants and pathogenic microorganism that may be present in the final product through the manufacturing and handling processes. High-throughput next generation sequencing (NGS) can support metagenomic investigations as a feasible means to analyze these products and eliminate any bias of culture-based sampling, or the inability to isolate all microbes present in foods. The challenge remains to identify microbes present in low amounts in the presence of predominantly beneficial microbes. The aim of this project is to create an analytical pipeline that will incorporate the use of specific phages and antibodies to reduce the product’s indigenous microorganisms and allow detection of low level microbial constituents and contaminants by metagenomics. This approach will provide a better understanding of the content and purity of dietary supplements available to women and infants in the U.S. market.
Utilizing Model-Informed Drug Development to Facilitate Antimalaria Dosing in Pregnant Women - Luning Zhuang/CDER (19)
Malaria infection during pregnancy, particularly Plasmodium falciparum (P. falciparum) malaria, has been linked to increased morbidity and mortality. It is vital for pregnant women infected with malaria to receive prompt and effective treatment. However, current dosing strategies of antimalarial drugs in pregnant women are not guided by physiologic changes during pregnancy and are typically the same as those for non-pregnant adults. The objective of the current project is to evaluate the recommended dosing of approved antimalarial drugs and proposed dosing of investigational antimalarial drugs in pregnant women infected with malaria. Model-informed drug development (MIDD) approaches will be used to characterize physiologic changes during pregnancy and the potential effect of those changes on efficacy and safety. The results of this project will support regulatory decision making on dose recommendations for approved and investigational antimalarial drugs in pregnant women and provide guidance for clinical study design to expedite antimalarial drug development in this population.
Population-based computational framework for assessing xenobiotic disposition and interaction effects in pregnant women- Annie Lumen, PhD/NCTR (17)
Women are sensitive to thyroid disturbances during crucial life-stages, such as pregnancy, which can lead to pregnancy-related complications. Pregnant women are normally excluded from clinical trials because of ethical concerns. Given the lack of available data, there is a need for better approaches to characterize the dose-response relationships for drugs and chemicals in pregnant women to guide regulatory decisions. Recently, we developed a first-of-its-kind computational model to evaluate the effects of iodide deficiency and exposure to a single dietary contaminant, perchlorate, on the thyroid function of an ‘average’ pregnant woman1. In a pilot study, the average model was extended to a population-based model to capture successfully the dose-response relationship for perchlorate in a population of pregnant women. Our work also highlighted the prevalence of iodine inadequacy among late-gestation pregnant women in the U.S., which will further predispose women to thyroid disruption. Current efforts aim to continue the expansion of this generalized computational pregnancy modeling framework for addressing the issue of co-exposure to mixtures of thyroid-active chemicals that reflects better real world exposure scenarios. Specifically, thiocyanate, a thyroid-disruptor, predominantly found in food and to which pregnant women are exposed at high levels is being evaluated in our ongoing work as a constituent of a ternary mixture. The complete population-based risk assessment framework, including model components addressing the issue of chemical mixtures, will provide regulatory agencies with a valuable and robust tool for the quantitative assessment of health risks of exposure to thyroid-active chemicals by a population of pregnant women. Such computational tools have high regulatory relevance in line with the FDA’s strategic plan for modernizing toxicology and advancing regulatory science. In addition, the development and implementation of such computational approaches to evaluate women’s health outcomes and address emerging public health concerns contributes directly to the Office of Women’s Health mission.
Assessment of Placental Transmission of Zika Virus Glycoprotein E Immunogen (Special Funding)- Evi Struble, PhD/CBER (16)
Zika virus infection has reached epidemic proportions in Latin America. Based on the geographical distribution of its mosquito carriers, it is likely that Zika virus will spread to the U.S. Zika infections during pregnancy have been associated with increased number of severe neurologic birth defects in newborn babies. Treatment with human antibodies against Zika virus may become a likely treatment option during pregnancy. Given the limited scientific data on Zika disease and treatment during pregnancy, it is very important to collect and analyze safety and efficacy data for this potential medical intervention. Toward this goal, we propose to use our expertise on placental transfer studies to investigate whether circulating non-neutralizing ZIKV antibody complexes contribute to fetal infection and the potential for interaction with pre-existing immunity to other flaviviruses.
We will use monoclonal antibodies and antibodies from individuals that have recovered from the Zika infection in complex with the virus envelope protein E, the viral component that mediates both viral infection of human cells and the host immune response to the Zika virus. Experiments will be performed to evaluate whether Zika protein E/antibody complexes are required for the passage of E protein across a laboratory model of the placental barrier. In addition, we will determine if differences in antibodies produced by different recovered individuals or individuals with antibodies against other mosquito borne viruses can have an effect in the placental transfer of Zika. Our study should provide critical information on what constitutes an efficacious and safe immunoglobulin therapy during pregnancy to benefit the mother and her baby.
Bayesian demographic subgroup analyses for pregnant women- Judy X. Li, PhD/CBER (15)
This project is a statistical study of the effects of pre-eclampsia therapies in subgroups of pregnant women. Pre-eclampsia (PE) affects pregnant women in different subgroups, e.g., different ages and ethnic groups. Therefore, it is important to be able to make accurate safety and efficacy assessments of pre-eclampsia therapies among different demographic subgroups. Standard statistical analysis could yield inaccurate results if these nonhomogeneous populations were simply combined and treated as a single population. On the other hand, individual standard statistical analysis of each small, diverse population could yield erroneous results because some or all of the sample sizes might be too small, that is, they might have low statistical power. To solve the problem of having too few individuals in subgroups, this project will use Bayesian statistics to analyze clinical trial data, which enables borrowing information across data from different subgroups. This approach will enable FDA regulators to make more informed regulatory assessments about the safety and effectiveness of new treatments based on data from clinical trials that are composed of different subgroups that might each respond somewhat differently to the treatment. This project will help healthcare providers and patients make more informed treatment decisions.
Treating the pregnant patient: pharmacokinetic and mechanistic studies of antiviral IGIV preparations at different stages of gestation in an animal model of pregnancy- Evi Struble, PhD/CBER (15)
Pregnant women are at high risk for infection by pathogens. Vertical transmission of infectious agents, such as hepatitis B (HBV), hepatitis C (HCV), and cytomegalovirus (CMV) during pregnancy remains a public health problem, associated with dire outcomes for the neonate. Thus, a safe prophylactic and therapeutic approach for protecting the mother and the neonate from infection remains a high priority. This project is focused on ensuring the safety and efficacy of hyperimmune preparations of immune globulin intravenous (IGIV) when used to combat infectious diseases during pregnancy. The results of previous studies using the guinea pig model suggested that transplacental transfer of human antibodies given at the end of pregnancy contributes to lower half life and faster clearance of antibody biologics, compared to non-pregnant age-matched controls. In addition, it was demonstrated that transplacental transfer in guinea pigs increases exponentially with gestation age. This study aims to investigate 1) the pharmacokinetics of IGIV preparations in different stages of pregnancy; 2) how the differences in transplacental transfer at different gestation ages correlate to the differences in antibody pharmacokinetics in pregnancy; 3) mechanism for these differences, especially regarding placenta structure and IgG receptor (FcRn) expression. Data from this study will provide information that can inform dosing decisions during pregnancy that are efficacious for the pregnant woman and her baby.
Effect of pro-coagulant impurity on coagulation in plasma from pregnant women- Mikhail Ovanesov PhD/CBER (15)
This project will study the mechanisms of thrombotic adverse events (TAE) in pregnant women who receive treatment with immune globulin (IG) products. This study is important because IGs are often used to prevent recurrent pregnancy loss and for other indications in pregnant women, despite evidence that some IG products cause thrombotic complications due to the presence of a procoagulant impurity, activated coagulation Factor XI (FXIa). Researchers hypothesized that pregnant women are at increased risk for thrombosis after IG because: 1) they are at up to 50x higher risk than non-pregnant women even in the absence of IG; 2) TAE risk is further elevated under most known procoagulant conditions, such as surgery, history of thrombotic events, or genetic anticoagulant deficiency. In the absence of results from human studies, researchers have investigated increased thrombogenicity of IG products in pregnant mice using vascular injury, ex vivo pharmacodynamics, and pharmacokinetics approaches. This study used the findings and methodology of the animal study to design a study on human plasma from pregnant women spiked with procoagulant impurities in vitro. This study will help to bridge the gap between animal and human studies. The results of this study will enhance the FDA regulatory science base in facilitating the product review.
Modulatory effects of progesterone on maternal immunity and their implications in pregnancy-associated Susceptibility to avian influenza infections- Hang Xie, PhD/ CBER (15)
This study will use a mouse model to investigate how female hormones modulate maternal immune responses to avian influenza viruses. The epidemiological data suggest that pregnant women are highly susceptible to severe influenza infections, including the highly pathogenic avian influenza (HPAI) H5N1 viruses. Babies born to women with severe influenza illness are at higher risk for premature birth and low birth weight. However, many pregnant women are reluctant to get vaccinated because they are unaware of the potentially severe complications of influenza infections and have misconceptions about the safety of vaccines. Furthermore, research in this area is lagging because: 1) HPAI H5N1 viruses and associated biological materials are strictly controlled by federal regulations; 2) Pregnant women have been traditionally excluded from clinical investigations studying human disease pathogenesis and new drug and vaccine development because of the concerns about fetal safety. To fill this gap, this project will develop a mouse model to mimic responses of pregnant women to H5N1 infections. Using this model, this project aims to elucidate how female hormones, particularly progesterone, affect maternal immunity during H5N1 infections. The study will help us to better understand the susceptibility of pregnant women to H5N1 infections.
Population-based computational framework for assessing xenobiotic disposition and interaction effects in pregnant women (Supplementary Funds) - Annie Lumen, PhD/NCTR (15)
Women are sensitive to thyroid function disturbances during crucial life-stages, such as pregnancy, which can lead to pregnancy-related complications. Pregnant women are normally excluded from clinical trials because of ethical and legal concerns. Given the lack of available data, there is a need for better approaches to characterize the dose-response relationships for drugs and chemicals in pregnant women to guide regulatory decisions. Recently, researchers developed a first-of-its-kind computational model to evaluate the effects of iodide deficiency and exposure to a single dietary contaminant, perchlorate, on the thyroid function in the pregnant women. The model captured the dose-response of an ‘average’ pregnant woman. In a pilot study, the average model was extended to a population-based model and was able to capture successfully the dose-response relationship of a population of pregnant women. Current efforts aim to expand this generalized computational pregnancy modeling framework for addressing the issue of pregnant women’s exposure to mixtures of thyroid-active chemicals that reflects better the real world exposure scenarios. The model developed in this work provides regulatory agencies with a valuable and robust tool for the quantitative assessment of health risks of exposure by pregnant women to thyroid-active chemicals in food.
Publication: Lumen A, McNally K, George N, Fisher JW, and Loizou GD. Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system. Front Pharmacol. 2015; 6: 107. doi: 10.3389/fphar.2015.00107.
Bayesian assessment of safety profiles for pregnant women-From animal study to human clinical trial - Judy X. Li, PhD, CBER (14)
Evaluation of pharmacokinetics of thrombogenic impurity following different routes of immune globulin administration during pregnancy - Mikhail Ovanesov, PhD, CBER (14)
Assessing Passive Prophylaxis of Infection at Different Stages during Gestation in a Pregnant Animal Model - Evi Struble, PhD, CBER (13)
Ma L, Norton MG, Mahmood I, et al. Transplacental Transfer of Hepatitis B Neutralizing Antibody during Pregnancy in an Animal Model: Implications for Newborn and Maternal Health. Hepat Res Treat. 2014;2014:159206. doi:10.1155/2014/159206.
Xu Y, Ma L, Norton MG, et al. Gestation Age Dependent Transfer of Human Immunoglobulins across Placenta in Timed-Pregnant Guinea Pigs. Placenta. 2015 Dec;36(12):1370-7.
Applications of Clinical Pharmacology Principles in Pharcotherapy of Diseases in Pregnancy - Srikanth Nallani, Ph.D CDER (12)
Improving safety of blood products administered during pregnancy - Mikhail Ovanesov, PhD, CBER (12)
Development of a mouse model to mimic the response of female and pregnant human subjects to avian influenza infections and to evaluate the protective efficacy of pandemic H5N1 vaccines against highly pathogenic avian influenza - Zhiping Ye, PhD / Xie Hang, PhD, CBER (12)
A Comparitive Analysis of Adverse Events Between Conventional Tube Ligation and Transcervical Occlusive Devices of the Fallopian Tube for Female Sterilization: A Cohort Study - Colin Anderson-Smits, MPH, CDRH (12)
MRI in pregnant patients: A systematic analysis of Radio-frequency heating with multi-transmit technology - Leonardo Angelone, PhD, CDRH (12)
Prophylaxis of HBV infection with HBIGIV in a pregnant animal model – Pei Zhang, MD, CBER (11)
Publication: Struble EB, Ma L, Zhong L, Lescher A, Beren J, Zhang P. Human antibodies can cross guinea pig placenta and bind its neonatal FC receptor: Implications for studying immune prophylaxis and therapy during pregnancy. Clin Dev Immunol 2012.
Treatment of progressive vaccinia in a pregnant immunocompromised mouse model - Dorothy Scott, MD, CBER (10)
An analysis of safety signal detection methods for pregnancy exposure registries - Paul Schuette, PhD, CDER (10)
Applications of clinical pharmacology principles in pharmacotherapy of diseases in pregnancy - Shrikant Nallani, Ph.D, CDER (10)
Ethics roundtable: the ethics of studying drugs and biologics in pregnant women - Karen Feibus, MD, CDER (09)
The Asthma and Allergy Medications in Pregnancy Surveillance System (AAMPSS) Demonstration Project - Sandra Kweder, MD, CDER (08)
Pharmacokinetics and Pharmacodynamics of Selected Antibiotics during Pregnancy - Gloria Sarto, MD, PhD, Univ. of Wisconsin (06)
Research on the Effects of Drug Exposure in Pregnancy - Anne Trontell, MD, MPH, CDER/AHRQ (06)
Drug Use in Pregnancy - Mary Willy, PhD, CDER (06)
Phase I -II Mental Modeling Research of how best to communicate to health care providers about the risks and benefits of prescription drug use for pregnant or Lactating Women with Chronic Conditions - Kara Morgan, PhD, OC (06)
Drug Metabolism in Women - Stephen Hall, PhD, Indiana Univ. (04)
Pharmacokinetics of Atenolol in Lactating Women - Mary Hebert, PharmD, Univ. of Washington (04)
Publication: Hebert MF, Carr DB, Anderson GD, Blough D, Green GE, Brateng DA, Kantor E, Benedetti TJ, Easterling TR. Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin Pharmacol 2005; 45(1):25-33.
Developmental Toxicity of Androstenedione in Rats - Robert Sprando, PhD, CFSAN (04)
Flynn TJ, Sapienza PP, Wiesenfeld PW, Ross IA, Sahu S, Kim CS, O'Donnell MW Jr, Collins TF, Sprando RL. Effects of oral androstenedione on steroid metabolism in liver of pregnant and non-pregnant female rats. Food Chem Toxicol 2005; 43(4):537-542.
Sahu SC, Sapienza PP, Sprando RL, Collins TF, Ross IA, Flynn TJ, Wiesenfeld PL, O'Donnell MW, Kim CS. Hepatotoxicity of androstenedione in pregnant rats. Food Chem Toxicol 2005; 43(2):341-344.
Sprando RL, Collins TF, Black TN, Olejnik N, Sapienza P, Ramos-Valle M, Ruggles DI. EC Maternal exposure to androstenedione does not induce developmental toxicity in the rat. Food Chem Toxicol 2005; 43(4):505-513.
Wiesenfeld PW, Sapienza PP, Flynn TJ, Ford CE, Ross IA, Sahu S, Kim CS, O'donnell MW Jr, Collins TF, Sprando RL. Effects of oral androstenedione on phospholipid fatty acids, ATP, caspase-3, prostaglandin E(2) and C-reactive protein in serum and livers of pregnant and non-pregnant female rats. Food Chem Toxicol 2006; 44:579-587.
Assessment of Maternal Effects & Infant Outcomes Using Large Automated Healthcare Data Systems in Women Exposed to Prescription Medications During Pregnancy - William Cooper, MD MPH, Vanderbilt Univ. (03)
Cooper WO, Hickson GB, Ray WA. Prescriptions for contraindicated category X drugs in pregnancy among women enrolled in TennCare. Pediatric and Perinatal Epidemiology 2004;18:106–111.
Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443-51. (FDA acknowledgement)
Enriquez R, Griffin MR, Carroll KN, Wu P, Cooper WO, Gebretsadik T, Dupont WD, Mitchel EF, Hartert TV. Effect of maternal asthma and asthma control on pregnancy and perinatal outcomes. J Allergy Clin Immunol 2007; 120:625-30.
Characterization of the effect of androstenedione exposure on female reproductive health, fertility and the development of the F1 generation - Robert Sprando, PhD, CFSAN (02)
Pharmacokinetics and Pharmacodynamics (PK/PD) of Atenolol in Pregnancy - Mary Hebert, PharmD, Univ. of Washington (02)
Labetalol and Hypertension in Pregnancy: Pharmacokinetics and Pharmacodynamics - James Fischer, PharmD, Univ. of Illinios, Chicago (01)
Fischer JH, Sarto GE, Hardman J, et al. Influence of gestational age and body weight on the pharmacokinetics of labetalol in pregnancy. Clin Pharmacokinet 2014 Apr;53(4):373-83.
JH. Fischer, GE. Sarto, M Habibi, SJ. Kilpatrick, RE. Tuomala, JM. Shier, L Wollett, PA. Fischer, KS. Khorana, KA. Rodvold. Influence of Body Weight, Ethnicity, Oral Contraceptives, and Pregnancy on the Pharmacokinetics of Azithromycin in Women of Childbearing Age. Antimicrob. Agents Chemother 2012; 56(2):715-724.
The PK of Amoxicillin during Pregnancy and Postpartum - Mary Hebert, PharmD, Univ. of Washington (01)
Publication: Andrew MA, Easterling TR, Carr DB, Shen D, Buchanan ML, Rutherford T, Bennett R, Vicini P, Hebert MF. Amoxicillin pharmacokinetics in pregnant women: Modeling and simulations of dosage strategies. Clin Pharmacol Ther 2007; 81(4):547-556.
The effects of Echinacea on cytochrome P450 enzymes and oral contraceptives - Stephan Hall, PhD/ Shiew-Mei Huang PhD, CDER (01)
Use of a Unique Animal Model to Study Placental and Milk Transfer of Enrofloxacin from the Dam to the Offspring During the Perinatal Period - Jurgen von Bredow, PhD, CVM (00)
Focus group testing of labeling for tampons and barrier contraceptives - Robert Navario/S. Lori Brown, CDRH (99)
Determination of antigenic biomarkers of estrogen catechol metabolism for post-market surveillance of oral contraceptives and hormone replacement therapy - Dean W. Roberts, PhD, NCTR (99)
Teratogen Surveillance - Carolyn McCloskey, MD, CDER (98)
Accelerated aging studies of condoms/condom materials - Harvey Rudolf, PhD, CDRH (98)
Pregnancy Labeling Taskforce: Focus Group testing - Kathryn Aiken, PhD, CDER, (98, co-funded by NIH ORWH)
Development and validation of a universal water leak test method for barrier contraceptives - Leslie Kerr (Neunaber), ORA (98)
Molecular and metabolic determinants of maternal risk and progression of Down Syndrome: potential for nutritional intervention - S. Jill James, PhD, NCTR (97)
Optimization of mammography - Robert Jennings, PhD, CDRH, (97)
Screening for nervous system dysfunction in offspring of dams exposed to natural food contaminates during pregnancy - Thomas Sobotka, PhD, CFSAN (96)
Contraceptive efficacy table for uniform contraceptive label-a consumer focus group study-Part I and Part II- Paula G. Silberberg, MD, CDRH (95, 96)
The effect of Thalidomide on the pharmacokinetics of ethinyl estradiol and norethindrone - Carol B. Trapnell, MD, CBER (95)
Thalidomide: Are there gender disparities in treatment outcome and non-teratogenic adverse effects? - Benda Vaughan, MD, CDER (95)
Rapid method for detection and enumeration of Listeria monocytogenes in foods - Mary L. Tortorello, PhD, CFSAN (95)
Profile of drug use in pregnancy - Sheila Weiss, PhD, CDER (95)
An open-label, randomized, crossover, feasibility study to quantify the retention of vaginally administered nonoxynol-9 (N-9) foam in premenopausal women - Carol Trapnell, MD, CDER (94)
FDA-Regulalted Products and Pregnant Women: Workshop, OWH (94)