Maternal COVID-19 Vaccination and Its Potential Impact on Fetal and Neonatal Development

Vaccines have been developed at “warp speed” to combat the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Although they are considered the best approach for preventing mortality, when assessing the safety of these vaccines, pregnant women have not been included in clinical trials. Thus, vaccine safety for this demographic, as well as for the developing fetus and neonate, remains to be determined. A global effort has been underway to encourage pregnant women to get vaccinated despite the uncertain risk posed to them and their offspring. Given this, post-hoc data collection, potentially for years, will be required to determine the outcomes of COVID-19 and vaccination on the next generation. Most COVID-19 vaccine reactions include injection site erythema, pain, swelling, fatigue, headache, fever and lymphadenopathy, which may be sufficient to affect fetal/neonatal development. In this review, we have explored components of the first-generation viral vector and mRNA COVID-19 vaccines that are believed to contribute to adverse reactions and which may negatively impact fetal and neonatal development. We have followed this with a discussion of the potential for using an ovine model to explore the long-term outcomes of COVID-19 vaccination during the prenatal and neonatal periods.

The ALSPAC fetal and neonatal resource: detailed data abstracted from the clinical records of the new-born

In a previous Data Note, we outlined the data obtained from clinical obstetric records concerning many details of the pregnancies resulting in the births of the children in the Avon Longitudinal Study of Parents and Children (ALSPAC). Here we describe the data that have been abstracted from medical records concerning the fetus and neonate. Full details concerning the selection biases regarding the data abstracted are outlined in the previous Data Note. The records that have been abstracted, and described in this Data Note, concern the health of the fetus (measured in relation to the results of fetal monitoring, presentation at various stages of pregnancy, and the method of delivery) as well as the status of the newborn immediately post-delivery. Details of signs, symptoms and treatments of this population of new-born babies, as recorded in the clinical records, are described for the time during which they were in hospital or under the care of a designated midwife. These data add depth to the information collected from elsewhere concerning this period of the child’s life: from the questionnaires completed at the time by the mother; and clinical details from neonatal intensive or special care units which will be detailed in a further Data Note.

Characterization of fluorescent probe substrates to develop an efficient high-throughput assay for neonatal hepatic CYP3A7 inhibition screening

CYP3A7 is a member of the cytochrome P450 (CYP) 3A enzyme sub-family that is expressed in the fetus and neonate. In addition to its role metabolizing retinoic acid and the endogenous steroid dehydroepiandrosterone sulfate (DHEA-S), it also has a critical function in drug metabolism and disposition during the first few weeks of life. Despite this, it is generally ignored in the preclinical testing of new drug candidates. This increases the risk for drug-drug interactions (DDI) and toxicities occurring in the neonate. Therefore, screening drug candidates for CYP3A7 inhibition is essential to identify chemical entities with potential toxicity risks for neonates. Currently, there is no efficient high-throughput screening (HTS) assay to assess CYP3A7 inhibition. Here, we report our testing of various fluorescent probes to assess CYP3A7 activity in a high-throughput manner. We determined that the fluorescent compound dibenzylfluorescein (DBF) is superior to other compounds in meeting the criteria considered for an efficient HTS assay. Furthermore, a preliminary screen of an HIV/HCV antiviral drug mini-library demonstrated the utility of DBF in a HTS assay system. We anticipate that this tool will be of great benefit in screening drugs that may be used in the neonatal population in the future.

Regulatory Considerations for the Mother, Fetus and Neonate in Fetal Pharmacology Modeling

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.

Protective vaccinations during pregnancy - adult Poles knowledge in this area

Background The vaccine is a preparation of biological origin containing antigens that stimulate the body’s immune system to produce acquired immunity. Vaccines can contain killed or “live” (attenuated) microorganisms as well as fragments of these (antigens). Although many vaccines are used routinely in pregnancy to provide a seroprotective immune response for mother, fetus and neonate there is much controversy over their use during this unique time. The aim of the study was to find out about the knowledge of adult Poles on the use of preventive vaccinations during pregnancy. Methods The study involved 700 people (100%) aged 18 to 80 years ($$ \overline{x} $$ x ¯ = 32.16 ± 16.46). Most of the respondents were women (511; 73%). The study consisted of 9 questions about preventive vaccinations of pregnant women and 5 questions about members of the studied group. The aforementioned questions formed the basis of the preparation of the presented article. Results A significant part of respondents (322; 46%) did not have knowledge on the topic of safeness of using preventive vaccinations during pregnancy, 196 (28%) respondents believed that such procedure is not safe. Most of the respondents (371; 53%) did not know about the possibility of using “live” vaccines during pregnancy. 14 (2%) of respondents believed that pregnancy should be terminated in case of administration of a “live” vaccine to a pregnant woman. According to 294 (42%) respondents, vaccinations with “live” vaccines should be completed at least 3 months before the planned pregnancy. The subjects were not aware of the issue of post-exposure vaccination against tetanus and rabies among pregnant women. The respondents’ responses were divided on the issue of the safest trimester of pregnancy for vaccine administration. Almost 1/3 of the respondents (203; 29%) indicated the third trimester as the safest for their performance. Conclusion The knowledge of the surveyed group, the majority of whom were women, about the use of vaccinations before and during pregnancy was unsatisfactory. There is a need to educate the public about the benefits and risks of performing or avoiding preventive vaccinations during pregnancy.

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.