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. The C-VIPER and the PIPER are international, non-interventional, real-world cohort studies. Participants receiving a COVID-19 vaccine during pregnancy will be matched in the analyses by country and gestational age at enrollment to unvaccinated individuals. Self-enrolled and self-consented participants complete online questionnaires at enrollment, during pregnancy, and for 12 months after the delivery of a live infant. Where possible, outcomes are verified by medical records. The study aims to recruit at least 500 pregnancies for each approved or authorized vaccine and will last for 5 years for each product. By collecting data for each vaccine brand, the C-VIPER will be able to determine individual safety profiles. The study design allows for analysis of the effects of exposure to COVID-19 vaccines during specific etiologically relevant periods of gestation. Although the sample size may be too small to detect associations with rare outcomes, the study will be used to generate hypotheses for future research. Ultimately, the C-VIPER should provide data that will allow pregnant people and their healthcare providers to make informed decisions about COVID-19 vaccination. ClinicalTrials.gov NCT04705116. Registered on 12 January, 2021. EU PAS EUPAS39096. Registered on 20 January, 2021.

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. To address this issue, the Clinical Trials Transformation Initiative convened content experts and stakeholders to develop recommendations for pregnancy testing in clinical research based on currently available evidence. Recommendations included: 1) the study protocol should clearly state the rationale for pregnancy testing and the plan for handling positive and indeterminate tests; 2) protocols should include an assessment of the pregnancy testing plan advantages (reduced risk of embryo/fetal exposure) versus the burdens (participant burden, study team workload, costs); 3) protocols should assess the participant burdens regarding the likelihood of false negative and false positive results; 4) participant administered home pregnancy testing should be avoided in clinical trials; and 5) the consent process should describe the extent of knowledge about the study intervention’s potential risk to the embryo/fetus and the limitations and consequences of pregnancy testing. CTTI has also developed an online tool to help implement these recommendations.

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. A key goal of the new label is to assist physicians and patients as they weigh the risks and benefits of medications vs the risks of pregnancy in a woman with a chronic, untreated illness. As such, each label now includes a section outlining the pregnancy risks of the diseases that the medication treats. This review includes a historical perspective on the label change and a guide to the interpretation of the new label. It also includes an assessment of the baseline risk of pregnancy in women with SLE and RA, to help balance the consideration of medication risks and benefits in pregnancy.

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 72 h, and whole genome transcriptional profiles were determined. The results indicate a track of differentiation was identified as mESCs differentiate. Biological processes that were associated with differentiation related genes included embryonic development and, specifically, skeletal system development. Cadmium sulfate inhibited mESC differentiation at all three time points. Functional pathway analysis indicated biological pathways affected included those related to skeletal development, renal and reproductive function. In summary, our results suggest that transcriptional profiles are a sensitive indicator of early mESC differentiation. Transcriptomics may improve the predictivity of the mEST by suggesting possible modes of action for tested chemicals.

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. We assessed the prevalence of antiemetic use by trimester, calendar year, and formulation.RESULTS:In over 2.3 million pregnancies, the prevalence of ondansetron, promethazine, metoclopramide, or doxylamine/pyridoxine use anytime in pregnancy was 15.2, 10.3, 4.0, and 0.4%, respectively. Ondansetron use increased from <1% of pregnancies in 2001 to 22.2% in 2014, with much of the increase attributable to oral ondansetron beginning in 2006. Promethazine and metoclopramide use increased modestly between 2001 (13.8%, 3.2%) and 2006 (16.0%, 6.0%) but decreased annually through 2014 (8.0%, 3.2%). Doxylamine/pyridoxine, approved for management of nausea and vomiting in pregnancy in 2013, was used in 1.8% of pregnancies in 2014. For all antiemetics, use was highest in the first trimester.CONCLUSIONS:We observed a marked increase in ondansetron use by study year, prescribed to nearly one-quarter of insured pregnant women in 2014, occurring in conjunction with decreased use of promethazine and metoclopramide. Given the widespread use of ondansetron in pregnancy, data establishing product efficacy and methodologically rigorous evaluation of post-marketing safety are needed. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants.

On 30 June 2015, the US Food and Drug Administration Pregnancy and Lactation Labeling Rule (PLLR) took effect. This rule sets new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy and lactation. The new labeling requirements have important implications for clinical pharmacology as there is a subheading that is dedicated to inclusion of clinical pharmacology information that inform dosing during pregnancy and the postpartum period, if available.

Details of embryo-fetal development (EFD) studies were compiled from published FDA approval documents for 43 small molecule drugs (2014–2015) and 37 monoclonal antibodies (mAbs, 2002–2015). Anti-cancer agents were analyzed separately. Rats and rabbits were the species used for EFD studies on 93% of small molecule drugs. Overall, the rat and rabbit were equally sensitive to maternal and fetal toxicity (including teratogenicity). Dosages equivalent to more than 50-times the human exposure (or 10-times for mAbs) were frequently used, but were unnecessary for 90% of drugs. EFD studies were not required for several recently approved mAbs owing to pre-existing scientific knowledge. The cynomolgus monkey was used for developmental toxicity testing of 75% of mAbs, frequently using an ePPND study design. Studies in pregnant rodents using homologous murine antibodies supplemented or replaced monkey studies under some circumstances. Most anti-cancer small molecules and mAbs were tested for developmental toxicity in at least one species.

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.CONCLUSION:The Pregnancy and Lactation Labeling Rule will set new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy; the National Birth Defects Prevention Study, along with other data sources, will be critical for providing safety data to inform product labeling.

We commend the authors reporting on the Centers for Disease Control and Prevention–sponsored meeting to develop a priority setting, evidence review, and consensus recommendation structure to advance safer medication use during pregnancy.1Broussard C.S. Frey M.T. Hernandez-Dias S. et al.Developing a systematic approach to safer medication use during pregnancy: summary of a Centers for Disease Control and Prevention-convened meeting.Am J Obstet Gynecol. 2014; 211: 208-214Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar However, several key issues received either scant or no mention in their report. The Food and Drug Administration (FDA) classification of drug use in gestation (categories A-D and X) was criticized as a system with which “oversimplification might result in incorrect conclusions.” Indeed, the FDA (itself represented at the meeting) recognized the need for a better approach and proposed major rule changes that would favor more nuanced and informative labeling in 2008. Unfortunately, despite being labeled an “agency priority” to be written and cleared “as efficiently as possible,” no published updates leading to a final rule have appeared since 2011.2US Food and Drug Administration. Pregnancy and lactation labeling final rule. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm; last updated 2/11/2011. Accessed Oct.12, 2014.Google Scholar Is a conclusion anywhere in sight? Further, while systematic reviews are often helpful, a larger concern is that information will be occasionally limited and frequently incomplete. This seems an understatement regarding the still shameful lack of well-designed and adequately powered studies that focus on optimal prescribing, maternal efficacy, and fetal safety of drugs in pregnancy, which is a void that has been recognized for decades.3Barron W.M. Lindheimer M.D. Introduction.in: Barron W.M. Lindheimer M.D. Medical disorders during pregnancy. 3rd ed. Mosby, St. Louis2000: xi-xiiiGoogle Scholar A more explicit plea by the authors for this needed research would have been welcome. Finally, although represented at the meeting, there was no mention of the National Institute of Child Health and Development–supported Obstetric-Fetal Pharmacology Research Units network, whose limited, but much needed, work focuses not on teratogenesis but more broadly on rational pharmacotherapy across the span of pregnancy, which includes safety, efficacy, dosing, and the risks of under-treated maternal disease.4Obstetric-Fetal Pharmacology Research Units Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development Mission statement. Available at: www.nichd.nih.gov/research/supported/Pages/opru_network.aspx. Accessed Oct. 12, 2014.Google Scholar Again, our congratulations to the authors; we all look towards needed progress in this area. Developing a systematic approach to safer medication use during pregnancy: summary of a Centers for Disease Control and Prevention–convened meetingAmerican Journal of Obstetrics & GynecologyVol. 211Issue 3PreviewTo address information gaps that limit informed clinical decisions on medication use in pregnancy, the Centers for Disease Control and Prevention (CDC) solicited expert input on a draft prototype outlining a systematic approach to evaluating the quality and strength of existing evidence for associated risks. The draft prototype outlined a process for the systematic review of available evidence and deliberations by a panel of experts to inform clinical decision making for managing health conditions in pregnancy. Full-Text PDF ReplyAmerican Journal of Obstetrics & GynecologyVol. 213Issue 1PreviewWe thank Drs Umans and Lindheimer for their interest in our meeting summary1 and welcome the opportunity to respond to their concerns. We agree with the authors about the need for more data to inform various aspects of medication treatment during pregnancy; this was evident to all the subject matter experts who attended the Centers for Disease Control and Prevention (CDC) meeting and is likely appreciated by the Journal’s readership. Full-Text PDF

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. Here, we review physiological and developmental differences that may result in differential sensitivity associated with early-life exposures. It is clear that sensitivity to chemical exposures during early-life can be similar, higher, or lower than that of adults, and can change quickly within a short developmental timeframe. Moreover, age-related exposure differences provide an important consideration for overall susceptibility. Differential sensitivity associated with a life stage can reflect the toxicokinetic handling of a xenobiotic exposure, the toxicodynamic response, or both. Each of these is illustrated with chemical-specific examples. The adequacy of current testing protocols, proposed new tools, and risk assessment methods for systemic noncancer endpoints are reviewed in light of the potential for differential risk to infants and young children.

In recent years there has been a heightened interest in developing alternative toxicity testing methods that enhance the current system that relies almost exclusively on whole-animal testing to include in vitro assays focused on defined pathways. The embryonic stem cell test (EST) is one alternative that has been suggested for use in developmental toxicity testing. The EST utilizes the D3 mouse embryonic stem cell line to assess sensitivity of chemicals on differentiating cardiomyocytes. Additionally, a BALB/3T3 line is used to monitor cytotoxicity and compare sensitivities between adult and embryonic cells. We have reevaluated the EST nearly 10 years after formal validation by the European Center for the Validation of Alternative Methods (ECVAM) to test the stability and reliability of the cell lines in predicting developmental toxicity. Eight compounds from the ECVAM validation including the positive control, 5-fluorouracil, and the negative control, penicillin G, were tested. All eight compounds matched the classification reported during validation, indicating comparable responses and transferability of the experimental protocol. However, an increased sensitivity of the cell lines, identified by lower ID50 and IC50 values, was observed for many of the chemicals when compared to the results from the ECVAM validation.

Pediatric clinical outcome assessments (COAs) for use in medical product development are evaluated using the same principles as for adult measures (i.e., content validity, reliability, construct validity, and responsiveness), but additional challenges arise when developing COAs for use in pediatrics. Content validity of any instrument depends upon clear identification of the concept of measurement and is context-specific. Age appropriateness of any instrument intended for pediatric use is essential and determining the appropriateness of self-report among children in the targeted patient population is an inherent consideration. Early planning to meet challenges associated with measurement of treatment benefit in pediatric populations is critical to ensure efficiency in medical product development.