The COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): Protocol and Methodological Considerations.

Introduction: The advent of the coronavirus disease 2019 (COVID-19) pandemic has led to the development of vaccines against severe acute respiratory syndrome coronavirus 2. Prospective evidence regarding safety for pregnant people and their developing fetuses is lacking. The aim of the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) is to estimate the relative risk of obstetric, neonatal, and infant outcomes by comparing participants vaccinated against COVID-19 during pregnancy to a reference group of people enrolled in the Pregistry International Pregnancy Exposure Registry (PIPER) who remained unvaccinated during pregnancy.

Evidence-based pregnancy testing in clinical trials: Recommendations from a multi-stakeholder development process.

Most clinical trials exclude pregnant women in order to avoid the possibility of adverse embryonic and/or fetal effects. Currently, there are no evidence-based guidelines regarding appropriate methods for identifying early pregnancy among research subjects. This lack of guidance results in wide variation in pregnancy testing plans, leading to the potential for inadequate protection against embryonic or fetal exposure in some cases and unnecessary burdens on research participants in others, as well as inefficiencies caused by disagreements among sponsors, investigators, and regulators.

The new FDA labeling rule: impact on prescribing rheumatological medications during pregnancy.

After several decades of deliberation, the US Food and Drug Administration updated the Pregnancy and Lactation Labeling Rule in 2015, eliminating the prior A, B, C, D, X grading system for medication use in pregnancy. Although physicians and patients liked the relative ease of use of this system, it was often misconstrued and not updated to include new data suggesting greater compatibility of medications with pregnancy. The new label is designed to include more clinically relevant data, including data from human studies and registries, and fewer animal data.

Antiemetic use among pregnant women in the United States: the escalating use of ondansetron.

Purpose: To examine ondansetron use in pregnancy in the context of other antiemetic use among a large insured United States population of women delivering live births.

Methods: We assessed ondansetron and other antiemetic use among pregnant women delivering live births between 2001 and 2015 in 15 data partners contributing data to the Mini-Sentinel Distributed Database. We identified live birth pregnancies using a validated algorithm, and all forms of ondansetron and other available antiemetics were identified using National Drug Codes or procedure codes.

Transcriptomics analysis of early embryonic stem cell differentiation under osteoblast culture conditions: Applications for detection of developmental toxicity.

The mouse embryonic stem cell test (mEST) is a promising in vitro assay for predicting developmental toxicity. In the current study, early differentiation of D3 mouse embryonic stem cells (mESCs) under osteoblast culture conditions and embryotoxicity of cadmium sulfate were examined. D3 mESCs were exposed to cadmium sulfate for 24, 48 or 72h, and whole genome transcriptional profiles were determined.

Assessing congenital malformation risk from medications used in pregnancy: The contribution of NBDPS in pregnancy labeling of prescription drug products.

Background: Obtaining human pregnancy data to inform product labeling is important for drug and biological products.

Methods: Collection and analyses of safety data on their use during pregnancy is usually performed after approval.

Results: The Centers for Disease Control National Birth Defects Prevention Study has provided important data on the relationship between drug use in pregnancy and birth defects.

Developing osteoblasts as an endpoint for the mouse embryonic stem cell test.

The mouse Embryonic Stem cell Test (EST) using cardiomyocyte differentiation is a promising in vitro assay for detecting potential embryotoxicity; however, the addition of another differentiation endpoint, such as osteoblasts, may improve the predictive value of the test. A number of variables such as culture conditions and starting cell number were investigated. A 14 day direct plating method of D3 mouse embryonic stem cells (mESCs) was used to test the predictivity of osteoblast differentiation as an endpoint in the EST.

Assessment of health risks resulting from early-life exposures: Are current chemical toxicity testing protocols and risk assessment methods adequate?

Abstract Over the last couple of decades, the awareness of the potential health impacts associated with early-life exposures has increased. Global regulatory approaches to chemical risk assessment are intended to be protective for the diverse human population including all life stages. However, questions persist as to whether the current testing approaches and risk assessment methodologies are adequately protective for infants and children.

Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011.

Purpose: Medication use during pregnancy is common and increasing. Women are also increasingly getting healthcare information from sources other than their physicians.

Methods: This report summarizes an environmental scan that identified 25 active Internet sites that list medications reported to be safe for use in pregnancy and highlights the inadequate evidence base and inconsistent guidance provided by these sites.

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development.

Value of juvenile animal studies.

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development.

Current and future needs for developmental toxicity testing.

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well.

Monitoring for teratogenic signals: pregnancy registries and surveillance methods.

Pregnant women should have access to medications that have been adequately studied for use to facilitate evidence-based risk-benefit discussions with their health care providers. Pregnant women experience acute medical emergencies, have existing conditions that require continued medical treatment or may develop pregnancy-induced conditions, making drug use during pregnancy unavoidable. Drug labeling is the primary source of information about a drug's use.

Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature.

Docosahexanoic acid (DHA) and arachidonic acid (ARA) are long chain essential fatty acids used as supplements in commercial infant formula. DHA/ARA deficient states are associated with adverse neurological outcomes in animals and humans. Preterm infants are at risk for DHA/ARA deficiency.

Juvenile animal studies and pediatric drug development retrospective review: use in regulatory decisions and labeling.

Juvenile animal toxicity studies are conducted to support applications for drugs intended for use in children. They are designed to address specific questions of potential toxicity in the growing animal or provide data about long-term safety effects of drugs that cannot be obtained from clinical trials. Decisions to conduct a juvenile animal study are based on existing data, such as a safety signal already identified in adult studies, or previous knowledge of the drug or chemical class for its potential to impair growth or developmental milestones.

Comparative juvenile safety testing of new therapeutic candidates: relevance of laboratory animal data to children.

Differences in drug response in patients of various ages including children and the elderly are common, often leading to challenges in optimizing dosages and duration of use. For example, developmental changes in renal function can dramatically alter the plasma clearance of compounds with extensive renal elimination and thus can enhance renal and systemic toxicity of these drugs. Preclinical and clinical research of new therapeutics is initially focused on adults, and provides little relevant information for children especially those who are still going through skeletal and organ development.

Timing of implantation and closure of the palatal shelf in New Zealand white and Japanese white rabbits.

Two specific developmental events, namely implantation and palatal shelf closure, are of specific interest because they define, respectively, the beginning and the end of the treatment period in embryo-fetal developmental toxicity studies for pharmaceutical products. Thus, a detailed evaluation of the timing of implantation and closure of the hard palate is necessary to assure use of the proper exposure window in developmental toxicity studies in rabbits, the nonrodent species most commonly evaluated in regulatory developmental toxicology studies. The purpose of this study was to determine the timeline for implantation and closure of the hard palate in the New Zealand White rabbit, and to determine if this timeline differed in the Japanese White rabbit.

Pre- and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague-Dawley rats.

Background: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) developed for the treatment of postmenopausal osteoporosis. The purpose of these studies was to evaluate the effects of lasofoxifene on the postnatal development, behavior, and reproductive performance of offspring of female rats given lasofoxifene during organogenesis and lactation.

Methods: Two range-finding studies were conducted to determine the effects of lasofoxifene at doses from 0.

Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.

Background: Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15-24, 1971).

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case-control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.