Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography–tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman’s correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (>30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value < 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes.

Neutralizing Antibody Activity Against SARS-CoV-2 Variants in Gestational Age-Matched Mother-Infant Dyads

Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines were matched with 30 naturally infected women by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type or Alpha variant Spike, these nAbs were less effective against the Kappa, Delta, and Mu Spike variants. Vaccination during the third trimester induced higher nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure. Vaccine induced neutralizing activity was reduced against the Delta, Mu, and Kappa variants.Graphic abstract

In-Utero Exposure to Cigarette Smoking on Child Long-Term Risk of Obesity: Concordance of Self-Report, Maternal and Cord Blood Biomarkers

Most studies on the association of in utero exposure to cigarette smoking and childhood overweight or obesity (OWO) were based on maternal self-reported smoking data and few were based on objective biomarkers. In this study, we evaluated the associations between self-reported and biomarkers of in utero exposure to cigarette smoking with risk of childhood OWO. We analyzed data from 2351 mother-child pairs in the Boston Birth Cohort, a US low-income minority cohort that enrolled children at birth and followed prospectively up to age 18 years. In utero smoking exposure was measured by maternal self-report and by maternal and cord plasma cotinine and hydroxycotinine metabolites. We assessed the individual and joint associations of each smoking exposure measure and maternal OWO with childhood OWO using multinomial logistic regressions. We used nested logistic regressions to investigate the childhood OWO prediction performance when adding maternal and cord plasma biomarkers as input covariates on top of self-reported data. Our results demonstrated that in utero cigarette smoking exposure defined by self-report and by maternal or cord metabolites were consistently associated with increased risk of long-term child OWO. Adding maternal and cord plasma biomarker information to self-reported data improved the prediction accuracy of long-term child OWO risk.

Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways

Oxidative stress mechanisms may explain associations between perinatal acetaminophen exposure and childhood attention-deficit hyperactivity disorder (ADHD). We investigated whether the changes in umbilical cord plasma amino acids needed to synthesize the antioxidant glutathione and in the oxidative stress biomarker 8-hydroxy-deoxyguanosine may explain the association between cord plasma acetaminophen and ADHD in the Boston Birth Cohort (BBC). Mother–child dyads were followed at the Boston Medical Center between 1998 and 2018. Cord plasma analytes were measured from archived samples collected at birth. Physician diagnoses of childhood ADHD were obtained from medical records. The final sample consisted of 568 participants (child mean age [SD]: 9.3 [3.5] years, 315 (52.8%) male, 248 (43.7%) ADHD, 320 (56.3%) neurotypical development). Cord unmetabolized acetaminophen was positively correlated with methionine (R = 0.33, p < 0.001), serine (R = 0.30, p < 0.001), glycine (R = 0.34, p < 0.001), and glutamate (R = 0.16, p < 0.001). Children with cord acetaminophen levels >50th percentile appeared to have higher risk of ADHD for each increase in cord 8-hydroxy-deoxyguanosine level. Adjusting for covariates, increasing cord methionine, glycine, serine, and 8-hydroxy-deoxyguanosine were associated with significantly higher odds for childhood ADHD. Cord methionine statistically mediated 22.1% (natural indirect effect logOR = 0.167, SE = 0.071, p = 0.019) and glycine mediated 22.0% (natural indirect effect logOR = 0.166, SE = 0.078, p = 0.032) of the association between cord acetaminophen >50th percentile with ADHD. Our findings provide some clues, but additional investigation into oxidative stress pathways and the association of acetaminophen exposure and childhood ADHD is warranted.

Sex Dimorphic Associations of Gestational Diabetes Mellitus With Cord Plasma Fatty Acid Binding Protein 4 and Estradiol

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P&gt;0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

Association Between Neonatal Thyroid Function and Anogenital Distance from Birth to 48 Months of Age

BackgroundEvidence from animal studies has indicated that neonatal thyroid function is vital for the reproductive development. Anogenital distance (AGD), a sensitive biomarker of the fetal hormonal milieu, can be used to predict adult reproductive disorders. However, few human studies have examined the association between neonatal thyroid function and AGD. We aimed to explore their associations in a birth cohort study.MethodsConcentrations of thyroid stimulating hormone (TSH) and thyroid hormones (THs), including total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) were measured in cord plasma in the Shanghai-Minhang Birth Cohort. The offspring AGD (AGDAP [anus–penis] and AGDAS [anus–scrotum] for boys and AGDAC [anus–clitoris] and AGDAF [anus–fourchette] for girls), body weight and anogenital index (AGI = AGD/weight [mm/kg]) were obtained at each follow-up visit. In total, 344 children (194 boys and 150 girls) with cord plasma concentrations of THs and TSH and at least one AGD measurement at birth and at 6, 12, and 48 months of age were included. Multiple linear regression and generalized estimating equation (GEE) models were used to examine the associations of cord plasma concentrations of THs and TSH with AGI.ResultsMultiple linear regression models showed inverse associations of TT4, FT3, and FT4 with female AGI, although statistical significance was only reached at birth, 6 and 48 months of age. These associations were also found in GEE models: higher TT4 and FT4 concentrations were associated with lower AGIAC (TT4: β = -0.27, 95% CI: -0.50, -0.03 for middle vs. lowest tertile; FT4: β = -0.38, 95% CI: -0.61, -0.16 for middle and β = -0.30, 95% CI: -0.55, -0.04 for highest vs. lowest tertile). Besides, girls with the highest tertile of FT3 concentrations had lower AGIAF than those with the lowest tertile (the highest vs. lowest tertile: β = -0.22, 95% CI: -0.36, -0.08). Positive associations between TSH and AGI at birth and at 12 months of age were observed in boys.ConclusionsThis study provides further evidence on the effects of neonatal thyroid function on reproductive development at an early life stage.

Plasma Concentrations and Maternal-Umbilical Cord Plasma Ratios of the Six Most Prevalent Carotenoids across Five Groups of Birth Gestational Age

Carotenoids are antioxidant nutrients with the potential to provide protection against oxidative stress. Plasma carotenoid concentrations are lower in newborn infants compared to their mothers; however, limited information is available regarding how concentrations differ by gestational age. The objective of this research is to assess maternal and umbilical cord plasma carotenoid concentrations and maternal-umbilical cord plasma ratios across five groups of birth gestational age. Mother-infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood. Plasma carotenoids were analyzed by HPLC and LC-MS/MS. Birth gestational age was categorized into five groups, and the Kruskal–Wallis test compared carotenoid concentrations and maternal-umbilical cord plasma ratios between these groups. A p-value of < 0.05 was considered statistically significant. 370 mother-infant dyads were included, with most infants delivered at early term (20.3%) or term (64.6%). Though maternal plasma concentrations increased with birth gestational age, we observed less variability in umbilical cord plasma concentrations, thus the maternal-umbilical cord plasma ratio also increased with birth CGA groups for lutein + zeaxanthin (p = 0.008), β-cryptoxanthin (p = 0.027), α-carotene (p = 0.030); β-carotene approached significance (p = 0.056). Additional research is needed to determine if carotenoid concentrations were physiologic to varying gestational ages or if they were impacted by factors associated with preterm birth.

Maternal Plasma Metabolic Profile Demarcates a Role for Neuroinflammation in Non-Typical Development of Children

Maternal and cord plasma metabolomics were used to elucidate biological pathways associated with increased diagnosis risk for autism spectrum disorders (ASD). Metabolome-wide associations were assessed in both maternal and umbilical cord plasma in relation to diagnoses of ASD and other non-typical development (Non-TD) compared to typical development (TD) in the Markers of Autism risk in Babies: Learning Early Signs (MARBLES) cohort study of children born to mothers who already have at least one child with ASD. Analyses were stratified by sample matrix type, machine mode, and annotation confidence level. Dimensionality reduction techniques were used [i.e, principal component analysis (PCA) and random subset weighted quantile sum regression (WQSRS)] to minimize the high multiple comparison burden. With WQSRS, a metabolite mixture obtained from the negative mode of maternal plasma decreased the odds of Non-TD compared to TD. These metabolites, all related to the prostaglandin pathway, underscored the relevance of neuroinflammation status. No other significant findings were observed. Dimensionality reduction strategies provided confirming evidence that a set of maternal plasma metabolites are important in distinguishing Non-TD compared to TD diagnosis. A lower risk for Non-TD was linked to anti-inflammatory elements, thereby linking neuroinflammation to detrimental brain function consistent with studies ranging from neurodevelopment to neurodegeneration.

The Choline Metabolite TMAO Inhibits NETosis and Promotes Placental Development in GDM of Humans and Mice

Choline metabolite Trimethylamine N-oxide (TMAO) has been recognized as a risk factor of gestational diabetes mellitus (GDM), but its exact role in GDM has not been reported. In this study, we focused on the placenta development to reveal the role of TMAO in GDM. We found the TMAO levels in peripheral and cord plasma were increased in women with GDM, and TMAO levels were positively correlated with newborn weight and placental thickness. Neutrophil extracellular traps (NETs) in the peripheral and cord plasma and the myeloperoxidase expression in the placenta of women with GDM also increased. NETs could inhibit the proliferation, migration, invasion and angiogenesis of HTR-8/Svneo cells. However, TMAO could not only inhibit the formation of NETs, but also enhance the biological function of HTR-8/Svneo cells. By inducing GDM models in NETs deficient PAD4^-/- and wild-type mice, the placental weight of PAD4^-/- mice increased significantly. TMAO feeding also inhibited the formation of NETs and further increased the weight of the placenta and fetuses, and this increase did not affect the placental structure. Our data indicated that higher TMAO levels and the formation of abnormal NETs were associated with GDM. TMAO could not only promote the development of the placenta and fetuses, but also inhibit the formation of NETs.