Publications

Prenatal exposure to toxic metals is linked to numerous adverse birth and later-in-life outcomes. These outcomes are tied to disrupted biological processes in fetal-derived tissues including the placenta and umbilical cord yet the precise pathways are understudied in these target tissues. We set out to examine the relationship between metal concentrations in umbilical cord and altered gene expression networks in placental tissue. These novel relationships were investigated in a subset of the Extremely Low Gestational Age Newborn (ELGAN) cohort (n = 226). Prenatal exposure to 11 metals/metalloids was measured using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS) in cord tissue, ensuring passage through the placental barrier. RNA-sequencing was used to quantify >37,000 mRNA transcripts. Differentially expressed genes (DEGs) were identified with respect to each metal. Weighted gene co-expression analysis identified gene networks modulated by metals. Two innovative mixtures modeling techniques, namely principal components analysis and quantile-based g-computation, were employed to identify genes/gene networks associated with multi-metal exposure. Individually, lead was associated with the strongest genomic response of 191 DEGs. Joint lead and cadmium exposure was related to 657 DEGs, including DNA Methyl Transferase 1 (DNMT1). These genes were enriched for the Eukaryotic Initiation Factor 2 (EIF2) pathway. Four gene networks, each containing genes within a Nuclear Factor kappa-light-chain-enhancer of Activated B Cells (NF-kB)-mediated network, were significantly increased in average expression level in relation to increases in all metal concentrations. All four of these metal mixture-associated gene networks were negatively correlated with important predictors of neonatal health including birth weight, placenta weight, and fetal growth. Bringing together novel methodologies from epidemiological mixtures analyses and toxicogenomics, applied to a unique cohort of extremely preterm children, the present study highlighted critical genes and pathways in the placenta dysregulated by prenatal metal mixtures. These represent potential mechanisms underlying the developmental origins of metal-induced disease.

Background: To analyze the relationship of child behavioral and communication disorders, and adverse family events, to later-in-life child health and cognitive function among youth born extremely preterm.

Methods: The study participants were 694 children enrolled in the Extremely Low Gestational Age Newborn Study. At ages 2 and 10, we assessed internalizing and externalizing behaviors, and at age 10, we assessed adverse life events within the family. Associations were evaluated between these child and family factors and positive child health at age 10 years, and global health and cognitive function at age 15 years.

Results: Lower T-scores for internalizing or externalizing behaviors at age 2 were associated with more positive health at age 10. The absence of internalizing behaviors at age 10 was associated with better global child health and better cognitive function at age 15. The absence of communication deficits at age 10 was associated with better cognitive function at age 15. The absence of parent job loss was associated with better global child health at age 15.

Conclusion: Among individuals born extremely preterm, child health and cognitive outcomes might be improved by timely interventions to address child behavioral symptoms and the impact of adverse life events in the family.

Impact: The absence of child behavioral and communication disorders, and adverse family events, were associated with more positive health, higher global health, and better cognitive function among youth born extremely preterm. Interventions to address behavioral disorders in early childhood, and to reduce the impact of adverse life events on the family, might promote improved health and developmental outcomes for adolescents born extremely preterm.

Objective: To evaluate associations between changes in weight, length, and weight/length ratio during infancy and outcomes later in life among individuals born extremely preterm.

Study design: Among participants in the Extremely Low Gestational Age Newborn (ELGAN) study, we measured weight and length at discharge from the neonatal intensive care unit (NICU) and at age 2 years and evaluated neurocognitive, psychiatric, and health outcomes at age 10 years and 15 years. Using multivariable logistic regression, we estimated associations between gains in weight, length, and weight/length ratio z-scores between discharge and 2 years and outcomes at 10 and 15 years. High gain was defined as the top quintile of change; low gain, as the bottom quintile of change.

Results: High gains in weight and weight/length were associated with greater odds of obesity at 10 years, but not at 15 years. These associations were found only for females. High gain in length z-score was associated with lower odds of obesity at 15 years. The only association found between high gains in growth measures and more favorable neurocognitive or psychiatric outcomes was between high gain in weight/length and lower odds of cognitive impairment at age 10 years.

Conclusions: During the 2 years after NICU discharge, females born extremely preterm with high gains in weight/length or weight have greater odds of obesity at 10 years, but not at 15 years. Infants with high growth gains in the 2 years after NICU discharge have neurocognitive and psychiatric outcomes in middle childhood and adolescence similar to those of infants with lower gains in weight and weight/length.

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age <12 months) enrolled in one of the 53 prospective cohort studies in the ECHO Program during 2001−2021. The exposure was bronchiolitis hospitalization during infancy. The outcome was a diagnosis of asthma by a physician by age 12 years. We examined their longitudinal association and determined the potential effect modifications of major demographic factors. Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24−3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74−5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60−3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77−2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups.

Social determinants of health (SDoH) are defined as the conditions in which people are born, grow, live, work, and age. The distribution of these conditions is influenced by underlying structural factors and may be linked to adverse pregnancy outcomes through epigenetic modifications of gestational tissues. A promising modification is epigenetic gestational age (eGA), which captures ‘biological’ age at birth. Measuring eGA in placenta, an organ critical for foetal development, may provide information about how SDoH ‘get under the skin’ during pregnancy to influence birth outcomes and ethnic/racial disparities. We examined relationships of placental eGA with sociodemographic factors, smoking, and two key clinical outcomes: Apgar scores and NICU length of stay. Using the Robust Placental Clock, we estimated eGA for placental samples from the Extremely Low Gestational Age Newborns cohort (N = 408). Regression modelling revealed smoking during pregnancy was associated with placental eGA acceleration (i.e., eGA higher than chronologic gestational age). This association differed by maternal race: among infants born to mothers racialized as Black, we observed greater eGA acceleration (+0.89 week, 95% CI: 0.38, 1.40) as compared to those racialized as white (+0.27 week, 95% CI: -0.06, 0.59). Placental eGA acceleration was also correlated with shorter NICU lengths of stay, but only among infants born to mothers racialized as Black (-0.08 d/week-eGA, 95% CI: -0.12, -0.05). Together, these observed associations suggest that interpretations of epigenetic gestational aging may be tissue-specific.

Importance: Children born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy.

Objective: To assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes.

Design, setting, and participants: The Extremely Low Gestational Age Newborn study was a multicenter, longitudinal cohort study of infants born before 28 weeks’ gestational age between March 22, 2002, and August 31, 2004. The current analyses were performed from September 12, 2020, through September 22, 2022. Of the 1506 infants enrolled, 284 died before discharge and 22 died before 24 months of age. An additional 2 died before age 10 years, leaving 1198 (79.5%) eligible for a visit. Of these, 889 (74%) participated in the visit at age 10. At age 10 years, the association of early-life acid suppressant use with neurocognitive, neurodevelopmental, and psychiatric symptomatology was assessed.

Exposures: Acid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers.

Main outcomes and measures: Neurodevelopmental assessments at age 10 years included the School-Age Differential Ability Scales-II, the Developmental Neuropsychological Assessment-II, the Autism Diagnostic Observation Schedule-2, the Social Responsiveness Scale-2, and the Child Symptom Inventory-4 for attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety.

Results: Of the 889 participants assessed at age 10 years (mean [SD] age, 9.97 [0.67] years; mean [SD] gestational age at birth, 26.1 [1.3] weeks; 455 [51.2%] male), 368 (41.4%) had received acid suppressants by 24 months of age. Associations were observed between acid suppressant use and decreased full-scale IQ z score (adjusted β, -0.29; 95% CI, -0.45 to -0.12), verbal IQ z score (adjusted β, -0.34; 95% CI, -0.52 to -0.15), nonverbal IQ z score (adjusted β, -0.22; 95% CI to -0.39 to -0.05), working memory z score (adjusted β, -0.26; 95% CI to -0.45, -0.08), autism spectrum disorder (adjusted relative risk, 1.84; 95% CI, 1.15-2.95), and epilepsy (adjusted relative risk, 2.07; 95% CI, 1.31 to 3.35). Results were robust to multiple sensitivity analyses. Use of acid suppressants was not associated with inhibitory control, ADHD, anxiety, or depression.

Conclusions and relevance: The results of this cohort study suggest that early-life use of acid suppressants in extremely preterm infants may be associated with poorer neurodevelopmental outcomes and add to evidence indicating caution in use of these agents.

Objectives: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP.

Methods: Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function.

Results: At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted β: -0.75, 95% confidence interval [CI]: -1.25 to -0.25), lower BMI z-score (adjusted β: -0.55, 95% CI: -1.09 to -0.01), and lower height z-score (adjusted β: -0.65, 95% CI: -1.16 to -0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes.

Conclusions: Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.

Cerebral white matter is the most common anatomic location of neonatal brain injury in preterm newborns. Factors that predispose preterm newborns to white matter damage are understudied. In relation to studies of the placenta-brain-axis, dysregulated placental gene expression may play a role in preterm brain damage given its implication in programming early life origins of disease, including neurological disorders. There is a critical need to investigate the relationships between the placental transcriptome and white matter damage in the neonate. In a cohort of extremely low gestational age newborns (ELGANs), we aimed to investigate the relationship between the placental transcriptome and white matter damage as assessed by neonatal cranial ultrasound studies (echolucency and/or ventriculomegaly). We hypothesized that genes involved in inflammatory processes would be more highly expressed in placentas of ELGANs who developed ultrasound-defined indicators of white matter damage. Relative to either form of white matter damage, 659 placental genes displayed altered transcriptional profiles. Of these white matter damage-associated genes, largely distinct patterns of gene expression were observed in the study (n = 415/659 genes). Specifically, 381 genes were unique to echolucency and 34 genes were unique to ventriculomegaly. Pathways involved in hormone disruption and metabolism were identified among the unique echolucency or ventriculomegaly genes. Interestingly, a common set of 244 genes or 37% of all genes was similarly dysregulated in the placenta relative to both echolucency and ventriculomegaly. For this common set of white matter damage-related genes, pathways involved in inflammation, immune response and apoptosis, were enriched. Among the white matter damage-associated genes are genes known to be involved in Autism Spectrum Disorder (ASD) and endocrine system disorders. These data highlight differential mRNA expression patterning in the placenta and provide insight into potential etiologic factors that may predispose preterm newborns to white matter damage. Future studies will build upon this work to include functional measures of neurodevelopment as well as measures of brain volume later in life.