Perinatal and maternal research has been a cornerstone of NCTR regulatory science research for more than 40 years. NCTR has typically conducted this work collaboratively with the FDA Product Centers such as the Center for Drug Evaluation and Research (CDER), external partners such as the Mayo Clinic, and academic institutions such as the University of Arkansas for Medical Sciences (UAMS).
NCTR provides the infrastructure to stimulate robust research efforts through faster, less expensive, and more predictive approaches and models, leading the way to improved safety and/or efficacy of FDA-regulated products in susceptible populations, including pregnant women and infants — focusing on the perinatal period (the period-of-time including pregnancy, child birth, and infant/child development). Many drugs and other medical products provided to pregnant women, neonates, and infants are used off-label because of the difficulties in performing clinical trials needed for drug approval in these populations. Therefore, these populations represent a vastly understudied stage of development.
In addition to drugs and devices, environmental exposure through foods represent another area where vast knowledge gaps exist. Infants consume more food per kilogram of body weight than any other age group, resulting in the potential for higher dietary exposures to chemicals. Often there are no available data for humans from which to assess the potential risks associated with these exposures. Thus, safety and risk assessments for foodborne chemicals, and biological- and chemical-threat agents rely upon data obtained from animal models and in vitro cellular-toxicology studies.
In response to the knowledge gaps associated with the perinatal period, Congress directed NCTR to lead efforts to create and manage the FDA virtual Perinatal Health Center of Excellence (PHCE). The PHCE was established in FY 2019 as a collaborative effort with the FDA Product Centers to review and fund research related to perinatal populations on an annual basis. Scientists with PHCE-funded projects are asked to periodically report their research progress and provide annual presentations to the PHCE Leadership Council. The PHCE is just another way NCTR supports perinatal and maternal research at FDA.
The following sections showcase research performed by NCTR to support perinatal and maternal health.
There is limited drug-safety data related to pediatrics, and NCTR scientists are working to bridge the gap in perinatal assessments. Advancements at NCTR’s bio-imaging facility allow FDA to gather new information to help the medical community understand pediatric-anesthetic use and its adverse effects on children. These effects are assessed using minimally invasive imaging technologies, allowing visualization of biological processes in “real time,” with as little interference as possible with life processes. These “translational” imaging technologies, when combined with other methods, allow NCTR scientists to use findings from the laboratory animal to reduce adverse effects in children. For publications describing the use of these technologies, please visit Toxicological Sciences, Journal of Applied Toxicology, and Anesthesiology.
NCTR research results in this area include:
- NCTR researchers demonstrated significant changes and nerve-cell damage in brains of newborn animals exposed to longer duration anesthesia. Publications describing these findings can be found in International Journal of Developmental Neuroscience, Neurotoxicology and Teratology, and Toxicological Sciences. This NCTR research on pediatric anesthetics led to an FDA Drug Safety Communication in 2017. The Safety Communication outlines FDA-approved label changes for the use of general anesthetics and sedation drugs in young children. The changes to the labeling includes a warning about cumulative exposures for long periods of time (multiple surgeries or diagnostic procedures), as well as one-time exposures of more than three hours that may affect the developing brain.
- The effects of pediatric anesthesia are being studied using an NCTR-developed method for assessing brain function in nonhuman primates. This approach provided high-quality experimental data linking prolonged anesthesia exposure to cognitive changes later in life. Publications describing these findings can be found in Neurotoxicology and Teratology and Neurotoxicology.
- NCTR scientists, in collaboration with CDER, have analyzed the microRNA profile in neonatal monkey brain after anesthesia of sevoflurane, given the critical roles of microRNA in brain development and functions. The changes in microRNA expression helped to decipher the mechanisms by which sevoflurane causes neurotoxicity. MicroRNAs are thought to be highly sensitive to toxicants and their expression may change more rapidly than any histological change is observed, making microRNAs a potential marker to predict neurotoxicity. For more information, please visit Neurotoxicology.
- Also, in collaboration with CDER, NCTR scientists demonstrated that xenon, a noble gas with anesthetic properties, protected human neural stem cells from the anesthetic-induced adverse effects of propofol. The protective effects of xenon were at least partially through the amelioration of down-regulated expression of polysialic acid on neurons. In the study, application of human neural stem-cell models allows the findings to be more relevant to the human clinical condition. The neuroprotective properties of xenon highlighted its potential use in pediatric anesthesia. The findings will support FDA’s regulatory roles in pediatric anesthesia. The application of neural stem-cell models to pediatric anesthesia research will also help reduce animal use in future studies. Publications describing these findings can be found in Molecular Neurobiology A and Molecular Neurobiology B.
- NCTR, in collaboration with CDER, continues to generate data on exposure of human induced pluripotent stem cells (iPSCs) to opioids during perinatal development. In fiscal year (FY) 2019 and FY 2020, hydrocodone, codeine, oxycodone, morphine, methadone, buprenorphine, fentanyl, and hydromorphone were evaluated on neural precursor cells. Preliminary results suggest the tested opioids have minimal effect on early growth and development. Experiments in FY 2021 will focus on exposure of stem cells to investigate whether cells at different stages of development have differing sensitivities.
- In another pediatric opioid-related project, Matrix-Assisted Laser Desorption/Ionization (MALDI) imaging will be used to investigate neurotransmitter levels in the brains of fetal mice exposed to morphine or methadone during pregnancy to determine whether differences exist between exposed and non-exposed animals. The study is designed to specifically investigate whether opioid effects are mediated through maternal toxicity or through a direct effect on the fetus. Preliminary study results were presented at the Society for Birth Defects Research and Prevention’s Annual Meeting in June 2020. The study is funded by the PHCE and is being conducted in collaboration with CDER scientists.
The virtual Perinatal Health Center of Excellence (PHCE) is focused on the perinatal period as defined to include: maternal, premature, and neonatal periods, and development throughout childhood. With the support of collaborating product centers, NCTR staff is coordinating the activities of the PHCE to conduct studies that address important regulatory-science needs facing FDA. Broadly speaking, the PHCE-funded research falls into the categories of in silico models, stem cell systems and other in vitro models, laboratory animal studies, translational and clinical studies, mathematical modeling, bioanalytical chemistry, exposure science, and bioinformatics targeting the perinatal period. The highest priority during the selection process is given to projects with a potential for:
- regulatory impact including policy changes and
- industry standards and changing medical practice or research approaches in the areas of perinatal health.
In early FY 2021 the PHCE Leadership Council funded 10 new FY 2021 proposals in addition to the 17 projects that were previously funded or completed. Current PHCE projects have primary investigators representing FDA’s Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), Center for Food Safety and Applied Nutrition (CFSAN), and NCTR. A recently completed PHCE-funded study was a collaboration between CFSAN and NCTR scientists. This study examined polyfluorinated alkyl substance (PFAS)-based compounds and their persistence in various foods. These compounds are found in grease-proofing agents and can be used as stain and waterproof coatings for surfaces. A paper describing this work can be found in Toxicology and Applied Pharmacology.
Other PHCE research topics include, but are not limited to:
- Neonatal immune responses to vaccines
- Computer-based pregnancy models
- COVID-19 effects on pregnancy, prenatal, and postnatal development
- Drug labeling associated with pregnancy