Fetal brain biometry and cortical development after maternal SARS-CoV-2 infection in pregnancy: A prospective case-control study.

OBJECTIVES: To assess cerebral growth and the development of fetal cortex using neurosonography in fetuses from pregnancies experiencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to infection timing. METHODS: Pregnancies with by SARS-CoV-2 during first and second trimesters were prospectively studied and matched with unaffected controls. Enclosed women underwent neurosonography at 30-34 weeks of gestation and corpus callosum (CC) and cerebellar vermis (CV) lengths measured. Further Sylvian fissure (SF), insula. Parieto-occipital fissure (POF), and calcarine sulci fissures (CSF) depths were obtained. The ultrasonographic variables considered were normalized with fetal head size. RESULTS: One hundred and seventy four consecutive pregnancies experiencing SARS COV 2 infection (81 before 14 weeks and 93 later) and 131 not affected pregnancies were considered. General and pregnancy characteristics were similar between the three groups of women. No significant differences existed in CC and CV lengths across groups. Similarly, insula, SF, POF And CSF depth did not result changed in fetuses of affected mothers. CONCLUSIONS: SARS-CoV-2 infection does nor resulted associate with differential fetal cortical development or brain growth in mildly symptomatic pregnant women. This information may be useful to reassure infected mothers on the health of their fetuses.

Impact of COVID-19 Related Maternal Stress on Fetal Brain Development: A Multimodal MRI Study.

BACKGROUND: Disruptions in perinatal care and support due to the COVID-19 pandemic was an unprecedented but significant stressor among pregnant women. Various neurostructural differences have been re-ported among fetuses and infants born during the pandemic compared to pre-pandemic counterparts. The relationship between maternal stress due to pandemic related disruptions and fetal brain is yet unexamined. METHODS: Pregnant participants with healthy pregnancies were prospectively recruited in 2020-2022 in the greater Los Angeles Area. Participants completed multiple self-report assessments for experiences of pandemic related disruptions, perceived stress, and coping behaviors and underwent fetal MRI. Maternal perceived stress exposures were correlated with quantitative multimodal MRI measures of fetal brain development using multivariate models. RESULTS: Increased maternal perception of pandemic related stress positively correlated with normalized fetal brainstem volume (suggesting accelerated brainstem maturation). In contrast, increased maternal perception of pandemic related stress correlated with reduced global fetal brain temporal functional variance (suggesting reduced functional connectivity). CONCLUSIONS: We report alterations in fetal brainstem structure and global functional fetal brain activity associated with increased maternal stress due to pandemic related disruptions, suggesting altered fetal programming. Long term follow-up studies are required to better understand the sequalae of these early multi-modal brain disruptions among infants born during the COVID-19 pandemic.

Fetal Brain Damage during Maternal COVID-19: Emerging Hypothesis, Mechanism, and Possible Mitigation through Maternal-Targeted Nutritional Supplementation.

The recent outbreak of the novel Coronavirus (SARS-CoV-2 or CoV-2) pandemic in 2019 and the risk of CoV-2 infection during pregnancy led the scientific community to investigate the potential negative effects of Coronavirus infection on pregnancy outcomes and fetal development. In particular, as CoV-2 neurotropism has been demonstrated in adults, recent studies suggested a possible risk of fetal brain damage and fetal brain development impairment, with consequent psychiatric manifestations in offspring of mothers affected by COronaVIrus Disease (COVID) during pregnancy. Through the understanding of CoV-2's pathogenesis and the pathways responsible for cell damage, along with the available data about neurotropic virus attitudes, different strategies have been suggested to lower the risk of neurologic disease in newborns. In this regard, the role of nutrition in mitigating fetal damages related to oxidative stress and the inflammatory environment during viral infection has been investigated, and arginine, n3PUFA, vitamins B1 and B9, choline, and flavonoids were found to be promising in and out of pregnancy. The aim of this review is to provide an overview of the current knowledge on the mechanism of fetal brain damage and the impact of nutrition in reducing inflammation related to worse neurological outcomes in the context of CoV-2 infections during pregnancy.

COVID-19 in pregnancy: implications for fetal brain development.

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on the developing fetal brain is poorly understood. Other antenatal infections such as influenza have been associated with adverse neurodevelopmental outcomes in offspring. Although vertical transmission has been rarely observed in SARS-CoV-2 to date, given the potential for profound maternal immune activation (MIA), impact on the developing fetal brain is likely. Here we review evidence that SARS-CoV-2 and other viral infections during pregnancy can result in maternal, placental, and fetal immune activation, and ultimately in offspring neurodevelopmental morbidity. Finally, we highlight the need for cellular models of fetal brain development to better understand potential short- and long-term impacts of maternal SARS-CoV-2 infection on the next generation.

Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development.

Pathogens comprised of viruses, bacteria, gut microbiome, and parasites are a leading cause of ever-emerging diseases in humans. Studying pathogens for their ability to cause diseases is a topic of critical discussion among scientists and pharmaceutical centers for effective drug development that diagnose, treat, and prevent infection-associated disorders. Pathogens impact health either directly by invading the host or by eliciting an acute inflammatory immune response. This paradigm of inflammatory immune responses is even more consequential in people who may be immunocompromised. In this regard, pregnancy offers an altered immunity scenario, which may allow the onset of severe diseases. Viruses, such as Influenza, HIV, and now SARS-CoV-2, associated with the COVID-19 pandemic, raise new concerns for maternal and fetal/neonatal health. Intrauterine bacterial and parasitic infections are also known to impact pregnancy outcomes and neonatal health. More importantly, viral and bacterial infections during pregnancy have been identified as a common contributor to fetal brain development defects. Infection-mediated inflammatory uterine immune milieu is thought to be the main trigger for causing poor fetal brain development, resulting in long-term cognitive impairments. The concept of in utero programming of childhood and adult disorders has revolutionized the field of neurodevelopment and its associated complications. Recent findings in mice and humans clearly support the idea that uterine immunity during pregnancy controls the health trajectory of the child and considerably influences the cognitive function and mental health. In this review, we focus on the in utero programming of autism spectrum disorders (ASD) and assess the effects of pathogens on the onset of ASD-like symptoms.

Novel Targets of SARS-CoV-2 Spike Protein in Human Fetal Brain Development Suggest Early Pregnancy Vulnerability.

Pregnant women are at greater risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), because of their altered immunity and strained cardiovascular system. Emerging studies of placenta, embryos, and cerebral organoids suggest that fetal organs including brain could also be vulnerable to coronavirus disease 2019 (COVID-19). Additionally, a case study from Paris has reported transient neurological complications in neonates born to pregnant mothers. However, it remains poorly understood whether the fetal brain expresses cellular components that interact with Spike protein (S) of coronaviruses, which facilitates fusion of virus and host cell membrane and is the primary protein in viral entry. To address this question, we analyzed the expression of known (ACE2, TMPRSS2, and FURIN) and novel (ZDHHC5, GOLGA7, and ATP1A1) S protein interactors in publicly available fetal brain bulk and single cell RNA sequencing datasets. Bulk RNA sequencing analysis across multiple regions of fetal brain spanning 8 weeks post conception (wpc)-37wpc indicates that two of the known S protein interactors are expressed at low levels with median normalized gene expression values ranging from 0.08 to 0.06 (ACE2) and 0.01-0.02 (TMPRSS2). However, the third known S protein interactor FURIN is highly expressed (11.1-44.09) in fetal brain. Interestingly, all three novel S protein interactors are abundantly expressed throughout fetal brain development with median normalized gene expression values ranging from 20.38-21.60 (ZDHHC5), 92.47-68.35 (GOLGA7), and 65.45-194.5 (ATP1A1). Moreover, the peaks of expression of novel interactors is around 12-26wpc. Using publicly available single cell RNA sequencing datasets, we further show that novel S protein interactors show higher co-expression with neurons than with neural progenitors and astrocytes. These results suggest that even though two of the known S protein interactors are present at low levels in fetal brain, novel S protein interactors are abundantly present and could play a direct or indirect role in SARS-CoV-2 fetal brain pathogenesis, especially during the 2nd and 3rd trimesters of pregnancy.