Fetal effects of mild maternal COVID-19 infection: metabolomic profiling of cord blood.

INTRODUCTION: The impact of maternal coronavirus disease 2019 (COVID-19) infection on fetal health remains to be precisely characterized. OBJECTIVES: Using metabolomic profiling of newborn umbilical cord blood, we aimed to investigate the potential fetal biological consequences of maternal COVID-19 infection. METHODS: Cord blood plasma samples from 23 mild COVID-19 cases (mother infected/newborn negative) and 23 gestational age-matched controls were analyzed using nuclear magnetic spectroscopy and liquid chromatography coupled with mass spectrometry. Metabolite set enrichment analysis (MSEA) was used to evaluate altered biochemical pathways due to COVID-19 intrauterine exposure. Logistic regression models were developed using metabolites to predict intrauterine exposure. RESULTS: Significant concentration differences between groups (p-value < 0.05) were observed in 19 metabolites. Elevated levels of glucocorticoids, pyruvate, lactate, purine metabolites, phenylalanine, and branched-chain amino acids of valine and isoleucine were discovered in cases while ceramide subclasses were decreased. The top metabolite model including cortisol and ceramide (d18:1/23:0) achieved an Area under the Receiver Operating Characteristics curve (95% CI) = 0.841 (0.725-0.957) for detecting fetal exposure to maternal COVID-19 infection. MSEA highlighted steroidogenesis, pyruvate metabolism, gluconeogenesis, and the Warburg effect as the major perturbed metabolic pathways (p-value < 0.05). These changes indicate fetal increased oxidative metabolism, hyperinsulinemia, and inflammatory response. CONCLUSION: We present fetal biochemical changes related to intrauterine inflammation and altered energy metabolism in cases of mild maternal COVID-19 infection despite the absence of viral infection. Elucidation of the long-term consequences of these findings is imperative considering the large number of exposures in the population.

Does Maternal SARS-CoV-2 Infection or SARS-CoV-2 Vaccination Trigger an Inflammatory Response in the Fetus? A Prospective Cohort Study.

OBJECTIVES: SARS-CoV-2 infection triggers a significant maternal inflammatory response. There is a dearth of information regarding whether maternal SARS-CoV-2 infection at admission for delivery or SARS-CoV-2 vaccination triggers an inflammatory response in the fetus. This study aims at evaluating fetal inflammatory response to maternal SARS-CoV-2 infection or SARS-CoV-2 vaccination compared to control group. Design, Participants, Setting, and Methods: A prospective cohort study was performed with a total of 61 pregnant women who presented for delivery at a single medical center (William Beaumont Hospital, Royal Oak, MI). All mothers were tested for SARS-CoV-2 infection using polymerase chain reaction (PCR) on admission to labor and delivery unit. Three groups were evaluated: 22 pregnant with a positive SARS-CoV-2 test (case group), 23 pregnant women with a negative SARS-CoV-2 test (control group), and 16 pregnant women who had recent SAR-CoV-2 vaccination and a negative SARS-CoV-2 test (vaccine group). At delivery, cord blood was collected to determine the levels of IL-6, C-reactive protein (CRP), and SARS-CoV-2 nucleocapsid IgG and IgM antibodies. In all cases, the newborn had a negative PCR test or showed no clinical findings consistent with SARS-CoV-2 infection. RESULTS: Mean (SD) IL-6 level was not significantly different for the three groups: case group 9.00 ± 3.340 pg/mL, control group 5.19 ± 0.759 pg/mL, and vaccine group 7.11 ± 2.468 pg/mL (p value 0.855). Pairwise comparison also revealed no statistical difference for IL-6 concentrations with p values for case versus control, case versus vaccine, and control versus vaccine = 0.57, 0.91, and 0.74, respectively. Similarly, there was no statistically significant difference in the frequency of elevated IL-6 (>11 pg/mL) between groups (p value 0.89). CRP levels across the three groups were not statistically significant different (p value 0.634). Pairwise comparison of CRP levels among the different groups was also not statistically different. SARS-CoV-2 nucleocapsid IgG was positive in 12 out of 22 cord blood samples in the case group, 2 out of 23 of the control group (indicating old resolved maternal infection), and 0 out of 16 of the vaccine group. SARS-CoV-2 nucleocapsid IgM was negative in all cord blood samples of the case group, control group, and vaccine group. LIMITATIONS: A total number of 61 mothers enrolled in the study which represents a relatively small number of patients. Most patients with positive SARS-CoV-2 PCR were mainly asymptomatic. In addition, our vaccine group received the mRNA-based vaccines (mRNA1273 and BNT162b2). We did not study fetal response to other SARS-CoV-2 vaccines. CONCLUSION: In our prospective cohort, neither IL-6 nor CRP indicated increased inflammation in the cord blood of newborns of SARS-CoV-2-infected or vaccinated mothers.