Nonexposed Infants Research Articles

Investigating the impact of severe maternal SARS-CoV-2 infection on infant DNA methylation and neurodevelopment.

Maternal infections during pregnancy can increase the risk to offspring of developing a neurodevelopmental disorder. Given the global prevalence and severity of infection with Severe Acute Respiratory Syndrome related Coronavirus 2 (SARS-CoV-2), the objective of this study was to determine if in utero exposure to severe maternal SARS-CoV-2 infection alters infant neurodevelopmental outcomes at 12 months and to identify potential biological markers of adverse infant outcomes. Mother-infant dyads exposed to severe SARS-CoV-2 infection (requiring hospitalization) during pregnancy and age and sociodemographic matched control dyads were recruited from Monash Medical Centre, Australia in 2021/22 and prospectively assessed over 12 months. Maternal serum cytokine levels and Edinburgh Postnatal Depression Scale (EPDS) scores were assessed at birth. DNA methylation was assessed from infant buccal swabs at birth (Illumina EPIC BeadChip). Infant neurodevelopmental outcomes at 12 months were assessed using the Ages and Stages Questionnaire (ASQ-3). Mothers exposed to severe SARS-CoV-2 exhibited elevated serum IL-6 and IL-17A and higher EPDS scores than controls at birth. Infants exposed to severe SARS-CoV-2 in utero demonstrated over 3000 significant differentially methylated sites within their genomes compared to non-exposed (adjusted p-value < 0.05), including genes highly relevant to ASD and synaptic pathways. At 12 months, severe SARS-CoV-2 exposed infants scored lower on the ASQ-3 than non-exposed infants, and communication and problem-solving scores negatively correlated with maternal IL-6 levels at birth. DNA methylation changes therefore unveil potential mechanisms linking infection exposure to delayed neurodevelopment and maternal serum IL-6 levels may be a potential biomarker of child developmental delay. Mothers exposed to severe SARS-CoV-2 infections show elevated pro-inflammatory cytokines. Infants exposed in utero to severe SARS-CoV-2 infection show altered DNA methylation at birth and delayed development at 12 months of age. Created in Biorender.com.

Illicit Fentanyl in the Prenatal Period: A Significant Emerging Risk for Neonatal Opioid Withdrawal Syndrome

Objective This study aimed to evaluate the impact of in-utero illicit fentanyl exposure on neonatal outcomes, including neonatal opioid withdrawal syndrome (NOWS), length of stay (LOS), and treatment requirements. Study Design This study was conducted from March 2020 to December 2022, and focused on neonates born to mothers with opioid use or opioid use disorder (OUD). Maternal opioid use was identified through self-report or umbilical cord tissue (UCT) testing. Severe NOWS was defined as cases requiring pharmacological treatment. Statistical analyses included univariate comparisons, logistic regression, and generalized linear models to assess the associations between fentanyl exposure and neonatal outcomes. Results Forty-seven percent (75/159) of infants had in-utero fentanyl exposure. Fentanyl-positive mothers were older, 31 ± 5 years, compared to non-fentanyl mothers, 29 ± 5, p = 0.01. They were also less likely to receive prenatal care (p &lt; 0.01) and had a higher number of polysubstance used, 5 ± 1 compared to non-fentanyl mothers, 3 ± 1, p &lt; 0.01. Overall, infants exposed to fentanyl had a higher incidence of severe NOWS (odds ratio = 5.8, 95% confidence interval [CI]: 2.49–12.95, p &lt; 0.01) and required earlier NOWS treatment initiation, 1 ± 1 day compared to non-exposed infants 3 ± 2 days, p &lt; 0.01. In adjusted analysis, fentanyl exposure was associated with a nearly three-fold increased risk of NOWS (Mantel–Haenszel combined relative risk = 2.98, 95% CI: 1.94–4.57). Furthermore, fentanyl exposure led to longer LOS, with a 40% increase for preterm neonates (p &lt; 0.01) and a 63% increase for full-term neonates (p &lt; 0.01). Additionally, there was a significant correlation between log fentanyl concentration in umbilical cord tissue and cumulative morphine dose required for NOWS treatment, p = 0.001. Conclusion Prenatal illicit fentanyl exposure is an independent and strong risk factor for severe NOWS presentation in newborns requiring extended hospital stays. Key Points

Fetal behavior and gestational serotonin reuptake inhibitor exposure: relationships between behavior, drug dosage, plasma drug level, and a measure of drug bioeffect

Determination of the relationships between drug dosage, maternal and infant (cord blood) plasma drug concentrations, and serotonin reuptake inhibitor (SRI) bioeffect on offspring neurobehavior is crucial to assessing the effects of gestational SRI exposure. Measurement of maternal and cord blood platelet serotonin (5-HT) provides an index of inhibitory bioeffect at the 5-HT transporter and complements other measures of drug exposure. Three groups of mother-infant pairs were evaluated: (1) mothers with depression untreated with SRIs (DEP, n = 17), (2) mothers treated for depression with SRIs (DEP + SRI, n = 17), and (3) mothers who were not depressed and untreated (ND, n = 29). Fetal movement was assessed using a standardized ultrasound imaging and rating protocol. Maternal and cord blood platelet 5-HT levels were obtained from all participants. For the SRI + DEP group, maternal and infant plasma drug concentrations and an estimate of third-trimester maternal SRI drug exposure were obtained. As expected, substantially lower median platelet 5-HT levels were observed in the DEP + SRI group than in the non-exposed, combined ND and DEP groups. In non-exposed mothers and infants, platelet 5-HT levels were not affected by the presence of maternal depression. Lower maternal and infant platelet 5-HT levels were associated with more immature fetal movement quality. Although these data are limited by small sample size, the bioeffect index of in vivo platelet 5-HT transporter inhibition appears to provide a valuable approach for elucidating and possibly predicting the effects of gestational SRI exposure on fetal and perinatal neurobehavior.

DNA methylation patterns in umbilical cord blood from infants of methadone maintained opioid dependent mothers

Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference > + 2, < − 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.

Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life.

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12-182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire-Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG (β = -0.116) and longitudinal changes in ORC (β = 0.266) and NEG (β = -0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression.

Excess prenatal loss and respiratory illnesses of infant macaques living outdoors and exposed to wildfire smoke.

Global climate change has transformed predictions of fire seasons in the near future, and record-breaking wildfire events have had catastrophic consequences in recent years. In September 2020, multiple wildfires subjected Oregon to hazardous air quality for several days. In this retrospective cohort study, we aimed to examine prenatal loss, morbidity, and mortality of rhesus (Macaca mulatta) and Japanese macaques (Macaca fuscata) exposed to poor air quality from the nearby wildfires. Detailed medical records from 2014 to 2020 of 580 macaques housed outdoors at a research facility in Beaverton, Oregonwere used to evaluate the association between these health outcomes and wildfire smoke exposure. Logistic regression models estimated excess prenatal loss, hospitalization rates, respiratory problems, and mortality during and following the wildfire event, and Kruskal-Wallis statistics were used to determine if infant growth was affected by wildfire smoke exposure. Risk of pregnancy loss (relative risk = 4.1; p < 0.001) and odds of diagnosis with a respiratory problem (odds ratio = 4.47; p = 0.003) were higher in exposed infant macaques compared to nonexposed infants. Infant growth was not affected by poor air quality exposure. Our findings suggest wildfire smoke exposure poses a risk to the health of infants and pregnant individuals and should be monitored more closely in the future.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm

Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Any platelet transfusion during neonatal intensive care unit hospitalization. The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Prenatal tobacco smoke exposure and risk for cognitive delays in infants born very premature

Prenatal tobacco smoke exposure (TSE) and prematurity are independent risk factors for abnormal neurodevelopment. The objectives were to compare differences in Bayley-III cognitive, language, and motor scores at 2 years corrected age (CA) in 395 infants born very preterm (≤ 32 weeks gestation) with and without prenatal TSE. We performed multivariable linear regression analyses to examine associations between prenatal TSE and neurodevelopmental outcomes and a mediation analysis to estimate direct effects of prenatal TSE on outcomes and indirect effects through preterm birth. In total, 50 (12.6%) infants had prenatal TSE. Infants with prenatal TSE had lower mean [95% CI] Cognitive score (82.8 [78.6, 87.1]) vs. nonexposed infants (91.7 [90.1, 93.4]). In children with and without prenatal TSE, there were significant differences in mean [95% CI] Language scores (81.7 [76.0, 87.4] vs. 92.4 [90.2, 94.6], respectively) and mean [95% CI] Motor scores (86.5 [82.2, 90.7] vs. 93.4 [91.8, 95.0], respectively); scores remained significant after controlling for confounders. Preterm birth indirectly mediated 9.0% of the total effect of prenatal TSE on Cognitive score (P = NS). However, 91% of the remaining total effect was significant and attributable to TSE’s direct harmful effects on cognitive development (β = − 5.17 [95% CI − 9.97, − 0.38]). The significant association is largely due to TSE’s direct effect on cognitive development and not primarily due to TSE’s indirect effect on preterm birth.

The association between antenatal corticosteroids exposure and postnatal growth in infants born between 23 and 29 weeks of gestation.

To assess the association between antenatal corticosteroids exposure and postnatal growth in infants born at 23-29 weeks' gestation. This retrospective study used data from the Pediatrix Clinical Data Warehouse. Maternal-infant dyads from 2018 to 2020 were included. Inverse propensity weighting (IPW) was applied to balance pre-treatment confounders. Primary outcomes included postnatal weight, length, and head circumference growth trajectory percentiles. The unadjusted cohort consisted of 11,912 dyads. After IPW adjustment, there were 23,231 dyads. Exposed infants showed higher postnatal trajectory percentiles for weight (by 3.4%), length (by 1.8%), and head circumference (by 2.5%) when compared to non-exposed infants. The positive association between antenatal corticosteroids and postnatal growth was only observed in infants not exposed to preeclampsia/eclampsia/HELLP syndrome or without fetal growth restriction. Antenatal corticosteroids exposure is associated with better postnatal growth. The study is limited by its retrospective nature.

Lead contamination in human milk affects infants' language trajectory: results from a prospective cohort study.

Infants growing up in low- and middle-income countries are at increased risk of suffering adverse childhood experiences, including exposure to environmental pollution and lack of cognitive stimulation. In this study, we aimed to examine the levels of metals in the human milk of women living in São Paulo City, Brazil, and determine the effects on infants' neurodevelopment. For such, a total of 185 human milk samples were analyzed for arsenic (As), lead (Pb), mercury (Hg), and cadmium (Cd) using inductively coupled plasma mass spectrometry (ICP-MS). We applied the Bayley scales of infant and toddler development Third Edition (Bayley-III) to assess developmental milestones. In our analysis, we found a mean (standard deviation) concentration of As in human milk equal to 2.76 (4.09) μg L-1, followed by Pb 2.09 (5.36) and Hg 1.96 (6.68). Cd was not detected. We observed that infants exposed to Pb presented language trajectories lower than non-exposed infants (β = -0.413; 95% CI -0.653, -0.173) after adjustment for infant age, maternal education, socioeconomic status, infant sex, and sample weights. Our results report As, Pb, and Hg contamination in human milk, and that infant exposure to Pb decreased infants' language development. These results evidence maternal-child environmental exposure and its detrimental impact on infants' health.

Ultrasound evaluation of brain parenchyma in preterm infants with prenatal opioid exposure.

To evaluate whether preterm infants with prenatal opioid exposure had differences in brain size on head ultrasounds (HUS) in comparison to non-exposed infants. Preterm infants ≤34 weeks with prenatal opioid exposure (n = 47) and matched non-exposed infants (n = 62) with early HUSs were examined. Fifteen brain measurements were made and linear regression models performed to evaluate differences. Brain measurements were smaller in the right ventricular index [β = -0.18 mm (95% CI -0.32, -0.03]), left ventricular index [β = -0.04 mm (95% CI -0.08, -0.003)], left basal ganglia insula [β = -0.10 mm (95% CI -0.15, -0.04)], right basal ganglia insula [β = -0.08 mm (95% CI -0.14, -0.03)], corpus callosum fastigium length [β = -0.16 mm (95% CI -0.25, -0.06)], intracranial height index [β = -0.31 mm (95% CI -0.44, -0.18)], and transcerebellar measurements [β = -0.13 (95% CI -0.25, -0.02)] in the opioid-exposed group. Preterm infants with prenatal opioid exposure have smaller brain sizes compared to non-exposed infants, potentially increasing their risk for neurodevelopmental abnormalities.

Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso.

In this study, we investigated how different categories of prenatal malaria exposure (PME) influence levels of maternal antibodies in cord blood samples and the subsequent risk of malaria in early childhood in a birth cohort study (N = 661) nested within the COSMIC clinical trial (NCT01941264) in Burkina Faso. Plasmodium falciparum infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. The levels of maternal IgG and IgG1-4 to 15 P. falciparum antigens were measured in cord blood by quantitative suspension array technology. Results showed a significant variation in the magnitude of maternal antibody levels in cord blood, depending on the PME category, with past placental malaria (PM) more frequently associated with significant increases of IgG and/or subclass levels across three groups of antigens defined as pre-erythrocytic, erythrocytic, and markers of PM, as compared to those from the cord of non-exposed control infants. High levels of antibodies to certain erythrocytic antigens (i.e., IgG to EBA140 and EBA175, IgG1 to EBA175 and MSP142, and IgG3 to EBA140 and MSP5) were independent predictors of protection from clinical malaria during the first year of life. By contrast, high levels of IgG, IgG1, and IgG2 to the VAR2CSA DBL1-2 and IgG4 to DBL3-4 were significantly associated with an increased risk of clinical malaria. These findings indicate that PME categories have different effects on the levels of maternal-derived antibodies to malaria antigens in children at birth, and this might drive heterogeneity to clinical malaria susceptibility in early childhood.

Evaluation of Autism Spectrum Disorder Risk in Infants With Intraventricular Hemorrhage.

Background This study evaluates the long-term risk of autism spectrum disorder (ASD) in infants with intraventricular hemorrhage (IVH) using the Modified Checklist for Autism in Toddlers-Revised with Follow-Up (M-CHAT-R/F) screening tool. Methods This retrospective cohort study compared IVH (exposed) infants across all gestational age groupswith no-IVH(non-exposed)infants admitted to level IV neonatal intensive care unit (NICU). The M-CHAT-R/F screening tool was used to assess the ASD risk at 16-30 months of age. Discharge cranial ultrasound (CUS) findings also determined the ASD risk. Descriptive statistics comprised median and interquartile range for skewed continuous dataand frequencies and percentages for categorical variables. Comparisons for non-ordinal categorical measures in bivariate analysis were carried out using the χ2test or Fisher exact test. Results Of the 334 infants,167had IVH, and 167 had no IVH. High ASD risk (43% vs. 20%, p = 0.044) and cerebral palsy (19% vs. 5%, p = 0.004) were significantly associated with severe IVH. Infants with CUS findings of periventricular leukomalacia had 3.24 odds of developing high ASD risk (odds ratios/OR: 3.24, 95% confidence interval/CI: 0.73-14.34), and those with hydrocephalus needing ventriculoperitoneal (VP) shunt had 4.75 odds of developing high ASD risk (OR: 4.75, 95% CI: 0.73-30.69). Conclusion Severe IVH, but not mild IVH,increased the risk of ASD and cerebral palsy. This study demonstrates the need for timely screening for ASD in high-risk infants. Prompt detection leads to earlier treatment and better outcomes.

Antibiotics in pregnancy influence nasal microbiome and respiratory morbidity in infancy.

The effects of prenatal antibiotic exposure on respiratory morbidity in infancy and the involved mechanisms are still poorly understood. We aimed to examine whether prenatal antibiotic exposure in the third trimester is associated with nasal microbiome and respiratory morbidity in infancy and at school age, and whether this association with respiratory morbidity is mediated by the nasal microbiome. We performed 16S ribosomal RNA gene sequencing (regions V3-V4) on nasal swabs obtained from 296 healthy term infants from the prospective Basel-Bern birth cohort (BILD) at age 4-6 weeks. Information about antibiotic exposure was derived from birth records and standardised interviews. Respiratory symptoms were assessed by weekly telephone interviews in the first year of life and a clinical visit at age 6 years. Structural equation modelling was used to test direct and indirect associations accounting for known risk factors. α-Diversity indices were lower in infants with antibiotic exposure compared to nonexposed infants (e.g. Shannon index p-value 0.006). Prenatal antibiotic exposure was also associated with a higher risk of any, as well as severe, respiratory symptoms in the first year of life (risk ratio 1.38, 95% CI 1.03-1.84; adjusted p-value (padj)=0.032 and risk ratio 1.75, 95% CI 1.02-2.97; padj=0.041, respectively), but not with wheeze or atopy in childhood. However, we found no indirect mediating effect of nasal microbiome explaining these clinical symptoms. Prenatal antibiotic exposure was associated with lower diversity of nasal microbiome in infancy and, independently of microbiome, with respiratory morbidity in infancy, but not with symptoms later in life.

Association of Maternal Gestational Vitamin D Supplementation with Respiratory Health of Young Children.

This study aimed to evaluate the association between maternal gestational Vitamin D3 supplementation and early respiratory health in offspring. This was a population-based record-linkage study which used data from the French National Health Database System. Maternal Vitamin D3 supplementation consisted of a single high oral dose of cholecalciferol, (100,000 IU) from the seventh month of pregnancy, according to national guidelines. In total, 125,756 term-born singleton children were included, of which 37% had respiratory illness defined as hospital admission due to respiratory causes or inhalation treatment up to 24 months of age. Infants prenatally exposed to maternal Vitamin D3 supplementation (n = 54,596) were more likely to have a longer gestational age (GA) at birth (GA 36-38 weeks, 22% vs. 20%, p < 0.001 in exposed vs. non-exposed infants, respectively). After adjusting for the main risk factors (maternal age, socioeconomic level, mode of delivery, obstetrical and neonatal pathology, birth weight appropriateness, sex, and birth season), the risk of RD was found to be 3% lower than their counterparts (aOR [IC 95%], 0.97 [0.95-0.99], p = 0.01). In conclusion, this study provides evidence for the association between maternal gestational Vitamin D3 supplementation and improved early respiratory outcomes in young children.

Neurodevelopmental Outcomes Among Infants Born Preterm Fed With Mother's Own Milk: A Comparison of Singletons and Twins

To examine associations between early exposure to mother's own milk (MOM) and neurodevelopmental outcomes among preterm infants, and to compare these associations between singletons and twins. Retrospective cohort study that included low-risk infants born at <32weeks gestational age. Nutrition was documented over a 3-day period at mean ages of 14 and 28days of life; an average of the 3days was calculated. The Griffiths Mental Development Scales (GMDS) were administered at 12months corrected age. Preterm infants (n=131) with median gestational age of 30.6weeks were included; 56 (42.7%) were singletons. On days 14 and 28 of life, 80.9% and 77.1% were exposed to MOM, respectively. Exposure rate was comparable, but MOM intake (mL/kg/day) was higher among singletons than among twins (P<.05). At both time points, MOM-exposed infants scored higher on personal-social, hearing-language, and total GMDS assessments than nonexposed infants. These differences were significant for the entire cohort and for twins (P<.05). MOM intake correlated with total GMDS score for both singletons and twins. Any exposure to MOM was associated with additional 6-7 points on total GMDS score or 2-3 additional points for every 50mL/kg/day of MOM. The study supports the positive association between early MOM exposure among low-risk preterm infants and neurodevelopmental outcomes at 12months corrected age. The differential effects of MOM exposure on singletons vs twins need further exploration.

Effects of intrauterine exposure to SARS-CoV-2 on infants’ development: a rapid review and meta-analysis

Potential medium- and long-term neurodevelopmental sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy have not been ruled out. We aimed to systematically review and summarize the evidence regarding the effects of intrauterine exposure to SARS-CoV-2 on infant development and behavior. Scopus, PubMed, Web of Science, CINAHL, and PsycNet databases were searched for studies published up to February 6, 2023, investigating the effects of gestational SARS-CoV-2 on infant development and behavior. We performed narrative synthesis according to updated protocols. Studies using comparison groups and with the Ages and Stages Questionnaires-Third Edition (ASQ-3) scores available were included in a meta-analysis performed according to Cochrane protocols. We used the Newcastle-Ottawa Quality Assessment Scale to analyze the risk of bias. Heterogeneity was calculated using the I2 statistic. The search identified 2,782 studies. After removing duplicates and applying the eligibility criteria, we performed a narrative synthesis of 10 included studies and a meta-analysis of three. There was no evidence of higher developmental delay rates in infants exposed to SARS-CoV-2 during pregnancy compared to non-exposed infants. However, the exposed infants scored lower than either the non-exposed children or pre-pandemic cohorts in some domains. Pooled results from the random-effects model indicated that SARS-CoV-2-exposed infants had lower scores on fine motor (mean difference [MD] = -4.70, 95% confidence interval [CI]: -8.76; -0.63), and problem-solving (MD = -3.05, 95% CI: -5.88; -0.22) domains than non-exposed infants (heterogeneity: I2 = 69% and 88%, respectively). There was no difference between the exposed and non-exposed infants in the communication, gross motor, and personal-social ASQ-3 domains. Conclusion: We did not find evidence confirming the association between SARS-CoV-2 gestational exposure and neurodevelopmental delays. However, the meta-analysis indicated that gestational exposure negatively affected fine motor and problem-solving skills. Robust evidence on this topic is still incipient, and the available studies present methodological inconsistencies that limit the drawing of clear-cut conclusions. PROSPERO registration: #CRD42022308002; March 14, 2022. What is Known: • COVID-19 is associated with adverse pregnancy outcomes potentially linked to neurodevelopmental delays. • SARS-CoV-2 vertical transmission is rare; however, infections during pregnancy can be deleterious to the fetus, possibly mediated by maternal immune activation and other inflammatory mechanisms. What is New: • No evidence of increased developmental delay rates among SARS-CoV-2 gestational-exposed infants was found. However, a meta-analysis of three studies showed lower scores in fine motor and personal social ASQ-3 domains among exposed infants. • SARS-CoV-2 gestational exposure and the pandemic can affect child development via many mechanisms. Potential neurodevelopmental sequelae of SARS-CoV-2 exposure during gestation have not been ruled out.

Associations between prenatal exposure to second hand smoke and infant self-regulation in a New York city longitudinal prospective birth cohort

BackgroundPrenatal exposure to active or passive maternal smoking –also referred to as second hand smoke (SHS) exposure – are associated with externalizing behaviors, hyperactivity and attention deficit hyperactivity disorder, problems which derive in part from altered self-regulation. ObjectivesDetermine the influence of prenatal SHS on infant self-regulation using direct measures of infant behavior in 99 mothers from the Fair Start birth cohort followed at the Columbia Center for Children's Environmental Health. MethodsSelf-regulation was operationalized with self-contingency, the likelihood of maintaining/changing behavior from second-to-second, measured via split-screen video recordings of mothers playing with their 4-month infants. Mother and infant facial and vocal affect, gaze-on/-off partner, and mother touch were coded on a 1 s time-base. Third trimester prenatal SHS was assessed via self-report of a smoker in the home. Weighted-lag time-series models tested conditional effects of SHS-exposure (vs. non-exposure) on infant self-contingency for eight modality-pairings (e.g., mother gaze-infant gaze). Individual-seconds time-series models and analysis of predicted values at t0 interrogated significant weighted-lag findings. Because prior findings link developmental risk factors with lowered self-contingency, we hypothesized that prenatal SHSSHS would predict lowered infant self-contingency. ResultsRelative to non-exposed infants, those who were prenatally exposed to SHS had lower self-contingency (more variable behavior) in all eight models. Follow-up analyses showed that, given infants were likely to be in the most negative facial or vocal affect, those with prenatal SHS were more likely to make larger behavioral changes, moving into less negative or more positive affect and to alternate between gaze-on and off mother. Mothers who were exposed to SHS during pregnancy (vs. non-exposed) showed a similar, albeit less prevalent, pattern of larger changes out of negative facial affect. ConclusionThese findings extend prior work linking prenatal SHS with youth dysregulated behavior, showing similar effects in infancy, a critically important period that sthe stage for future child development.

Risk of Major Malformations Following First-Trimester Exposure to Olanzapine

Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanzapine during pregnancy compared with a group of nonexposed infants. The National Pregnancy Registry for Psychiatric Medications is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Labor and delivery and pediatric medical records were screened for evidence of major malformations followed by adjudication by a dysmorphologist blinded to medication exposure. Infants with first-trimester exposure to olanzapine were compared with controls without second-generation antipsychotic exposure. As of April 18, 2022, 2619 women have enrolled in the study. At the time of data extraction, 49 olanzapine-exposed infants and 1156 infants in the comparison group were eligible for these analyses. There were no major malformations associated with olanzapine exposure in the first trimester. The absolute risk for major malformations in the exposure group was 0.00% (95% confidence interval, 0.00-7.25) for olanzapine compared with 1.64% (95% confidence interval, 0.99-2.55) in the control group. In this prospective cohort, no major malformations were associated with olanzapine exposure during the first trimester. Although these data are preliminary and cannot rule out more modest effects, they are nonetheless important, adding to the growing reproductive safety data for olanzapine.

Vitamin A Status in Preterm Infants Is Associated with Inflammation and Dexamethasone Exposure.

Vitamin A has a key role in lung development and its deficiency is associated with an increased risk of bronchopulmonary dysplasia. This secondary cohort analysis of the ImNuT trial (Immature, Nutrition Therapy NCT03555019) aimed to (1) explore vitamin A status in preterm infants <29 weeks gestation and (2) assess the influence of inflammation and postnatal dexamethasone exposure on vitamin A concentrations in blood. We report detailed information on vitamin A biochemistry, vitamin A intake, markers of inflammation and dexamethasone exposure. After four weeks of age, infants exposed to dexamethasone (n = 39) showed higher vitamin A concentrations compared to unexposed infants (n = 41); median (IQR) retinol was 1.0 (0.74, 1.5) vs. 0.56 (0.41, 0.74) µmol/L, p < 0.001. Pretreatment retinol concentrations were lower in the dexamethasone group compared to non-exposed infants (p < 0.001); 88% vs. 60% of the infants were considered deficient in vitamin A (retinol < 0.7 µmol/L) at one week of age. Small size for gestational age, mechanical ventilation and elevated levels of interleukin-6 were factors negatively associated with first-week retinol concentrations. In conclusion, preterm infants <29 weeks gestation are at risk of vitamin A deficiency despite intakes that accommodate current recommendations. The presence of inflammation and dexamethasone exposure should be considered when interpreting vitamin A status.