Bronchopulmonary dysplasia and neurobehavioural outcomes at birth and 2 years in infants born before 30 weeks
Martin M, Smith L, Hofheimer JA, McGowan EC, O'Shea TM, Pastyrnak S, Carter BS, Helderman J, Check J, Neal C, Roberts MB, Dansereau LM, Della Grotta SA, Lester BM.
Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):142-148. doi: 10.1136/archdischild-2021-323405. Epub 2022 Aug 23. PMID: 35999044; PMCID: PMC9947192.
Abstract
Objective: To identify neurobehavioural risks in preterm infants with bronchopulmonary dysplasia (BPD) prior to hospital discharge.
Design and patients: Longitudinal study of 676 newborns born before 30 weeks of gestation.
Setting: Nine university NICUs affiliated with six universities. All were Vermont Oxford Network (VON) participants.
Patients and interventions: Infants were enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study from April 2014 to June 2016. Prospective medical record reviews, VON definitions and criteria, and maternal interviews were used to collect maternal and neonatal medical variables and socioenvironmental data.
Main outcome measures: NICU Network Neurobehavioral Scale (NNNS) at the time of hospital discharge; Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and Gross Motor Function Classification System at 2 years’ corrected age.
Results: Infants with moderate/severe BPD were less attentive (Wald χ2 9.68, p=0.008), more lethargic (Wald χ2 9.91, p=0.007), with increased non-optimal reflexes (Wald χ2 7.37, p=0.025). Infants with moderate/severe BPD were more likely to have Bayley-III language and motor scores <85 (adjusted OR (aOR) 1.74, 95% CI 1.06 to 2.85, and aOR 2.06, 95% CI 1.10 to 3.85). Infants with both moderate/severe and mild BPD were more likely to have a cerebral palsy diagnosis (aOR 2.96, 95% CI 1.34 to 6.54, and aOR 2.81, 95% CI 1.32 to 5.99).
Conclusions: BPD severity presents risks for poor neurodevelopment at NICU discharge and at age 2 years. Early identification of poorly regulated behaviour can provide critical information for early preventive and targeted interventions with potential to improve long-term outcomes.
Metal mixtures modeling identifies birth weight-associated gene networks in the placentas of children born extremely preterm
Eaves LA, Bulka CM, Rager JR, Galusha AL, Parson PJ, O’Shea TM, Fry RC
Chemosphere 2023 Feb;313:137469. doi: 10.1016/j.chemosphere.2022.137469. Epub 2022 Dec 6
Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program
Camerota M, McGowan EC, Aschner J, Stroustrup A, Karagas MR, Conradt E, Crowell SE, Brennan PA, Carter BS, Check J, Dansereau LM, DellaGrotta SA, Everson TM, Helderman JB, Hofheimer JA, Kuiper JR, Loncar CM, Marsit CJ, Neal CR, O'Shea TM, Pastyrnak SL, Sheinkopf SJ, Smith LM, Zhang X, Lester BM.
Pediatr Res. 2023 Feb 25. doi: 10.1038/s41390-023-02540-2. Epub ahead of print. PMID: 36841884.
Background: Single-cohort studies have identified distinct neurobehavioral profiles that are associated with prenatal and neonatal factors based on the NICU Network Neurobehavioral Scale (NNNS). We examined socioeconomic, medical, and substance use variables as predictors of NNNS profiles in a multi-cohort study of preterm and term-born infants with different perinatal exposures.
Methods: We studied 1112 infants with a neonatal NNNS exam from the Environmental influences on Child Health Outcomes (ECHO) consortium. We used latent profile analysis to characterize infant neurobehavioral profiles and generalized estimating equations to determine predictors of NNNS profiles.
Results: Six distinct neonatal neurobehavioral profiles were identified, including two dysregulated profiles: a hypo-aroused profile (16%) characterized by lethargy, hypotonicity, and nonoptimal reflexes; and a hyper-aroused profile (6%) characterized by high arousal, excitability, and stress, with low regulation and poor movement quality. Infants in the hypo-aroused profile were more likely to be male, have younger mothers, and have mothers who were depressed prenatally. Infants in the hyper-aroused profile were more likely to be Hispanic/Latino and have mothers who were depressed or used tobacco prenatally.
Conclusions: We identified two dysregulated neurobehavioral profiles with distinct perinatal antecedents. Further understanding of their etiology could inform targeted interventions to promote positive developmental outcomes.
Impact: Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings. In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated. Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents. Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.
Analysis of Pregnancy Complications and Epigenetic Gestational Age of Newborns
Ladd-Acosta C, Vang E, Barrett ES, Bulka CM, Bush NR, Cardenas A, Dabelea D, Dunlop AL, Fry RC, Gao X, Goodrich JM, Herbstman J, Hivert MF, Kahn LG, Karagas MR, Kennedy EM, Knight AK, Mohazzab-Hosseinian S, Morin A, Niu Z, O'Shea TM, Palmore M, Ruden D, Schmidt RJ, Smith AK, Song A, Spindel ER, Trasande L, Volk H, Weisenberger DJ, Breton CV; Environmental Influences on Child Health Outcomes Program.
JAMA Netw Open. 2023 Feb 1. doi: 10.1001/jamanetworkopen.2023.0672. PMID: 36826815; PMCID: PMC9958528.
Importance: Preeclampsia, gestational hypertension, and gestational diabetes, the most common pregnancy complications, are associated with substantial morbidity and mortality in mothers and children. Little is known about the biological processes that link the occurrence of these pregnancy complications with adverse child outcomes; altered biological aging of the growing fetus up to birth is one molecular pathway of increasing interest.
Objective: To evaluate whether exposure to each of these 3 pregnancy complications (gestational diabetes, gestational hypertension, and preeclampsia) is associated with accelerated or decelerated gestational biological age in children at birth.
Design, setting, and participants: Children included in these analyses were born between 1998 and 2018 and spanned multiple geographic areas of the US. Pregnancy complication information was obtained from maternal self-report and/or medical record data. DNA methylation measures were obtained from blood biospecimens collected from offspring at birth. The study used data from the national Environmental Influences on Child Health Outcomes (ECHO) multisite cohort study collected and recorded as of the August 31, 2021, data lock date. Data analysis was performed from September 2021 to December 2022.
Exposures: Three pregnancy conditions were examined: gestational hypertension, preeclampsia, and gestational diabetes.
Main outcomes and measures: Accelerated or decelerated biological gestational age at birth, estimated using existing epigenetic gestational age clock algorithms.
Results: A total of 1801 child participants (880 male [48.9%]; median [range] chronological gestational age at birth, 39 [30-43] weeks) from 12 ECHO cohorts met the analytic inclusion criteria. Reported races included Asian (49 participants [2.7%]), Black (390 participants [21.7%]), White (1026 participants [57.0%]), and other races (92 participants [5.1%]) (ie, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, and other race not specified). In total, 524 participants (29.0%) reported Hispanic ethnicity. Maternal ages ranged from 16 to 45 years of age with a median of 29 in the analytic sample. A range of maternal education levels, from less than high school (260 participants [14.4%]) to Bachelor’s degree and above (629 participants [34.9%]), were reported. In adjusted regression models, prenatal exposure to maternal gestational diabetes (β, -0.423; 95% CI, -0.709 to -0.138) and preeclampsia (β, -0.513; 95% CI, -0.857 to -0.170), but not gestational hypertension (β, 0.003; 95% CI, -0.338 to 0.344), were associated with decelerated epigenetic aging among exposed neonates vs those who were unexposed. Modification of these associations, by sex, was observed with exposure to preeclampsia (β, -0.700; 95% CI, -1.189 to -0.210) and gestational diabetes (β, -0.636; 95% CI, -1.070 to -0.200), with associations observed among female but not male participants.
Conclusions and relevance: This US cohort study of neonate biological changes related to exposure to maternal pregnancy conditions found evidence that preeclampsia and gestational diabetes delay biological maturity, especially in female offspring.
Child and Family Factors Associated with Positive Outcomes Among Youth Born Extremely Preterm
Emmanuel C, Yi JX, Joseph RM, Kuban KCK, Knafl KA, Docherty SL, Hodges EA, Fry RC, O’Shea TM, Santos HP, Jr
Pediatric Research 2023 Jan 13. doi: 10.1038/s41390-022-02424-x. Epub ahead of print
Comparing Autism Phenotypes in Children Born Extremely Preterm and Children Born at Term
Joseph RM, Lai ER, Bishop S, Bauman ML, Yi J, Frazier JA, Douglas LM, Kuban KKC, Fry RC, O’Shea TM
Autism Research 2023 Jan 3. doi: 10.1002/aur.2885. Epub ahead of print.
Growth During Infancy After Extremely Preterm Birth: Associations with Later Neurodevelopmental and Health Outcomes
O'Shea TM, Register HM, Yi JX, Jensen ET, Joseph RM, Kuban KCK, Frazier JA, Washburn L, Belfort M, South AM, Santos HP Jr, Shenberger J, Perrin EM, Thompson AL, Singh R, Rollins J, Gogcu S, Sanderson K, Wood C, Fry RC; ELGAN-ECHO Pulmonary/Obesity Group.
J Pediatr. 2023 Jan; 252:40-47.e5. doi: 10.1016/j.jpeds.2022.08.015. Epub 2022 Aug 18. PMID: 35987367; PMCID: PMC10242541.
Abstract
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.
Association of Severe Bronchiolitis during Infancy with Childhood Asthma Development: An Analysis of the ECHO Consortium
Nanishi M, Chandran A, Li X, Stanford JB, Alshawabkeh AN, Aschner JL, Dabelea D, Dunlop AL, Elliott AJ, Gern JE, Hartert T, Herbstman J, Hershey GKK, Hipwell AE, Karagas MR, Karr CJ, Leve LD, Litonjua AA, McEvoy CT, Miller RL, Oken E, O'Shea TM, Paneth N, Weiss ST, Wright RO, Wright RJ, Carroll KN, Zhang X, Zhao Q, Zoratti E, Camargo CA Jr, Hasegawa K; Environmental Influences on Child Health Outcomes (ECHO) Investigators.
Biomedicines. 2022 Dec 22;11(1):23. doi: 10.3390/biomedicines11010023. PMID: 36672531; PMCID: PMC9855570.
Abstract
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.
Placental epigenetic gestational aging in relation to maternal sociodemographic factors and smoking among infants born extremely preterm: a descriptive study.
Clark J, Bulka CM, Martin CL, Roell K, Santos HP, O'Shea TM, Smeester L, Fry R, Dhingra R.
Epigenetics. 2022 Dec;17(13):2389-2403. doi: 10.1080/15592294.2022.2125717. Epub 2022 Sep 22. PMID: 36134874; PMCID: PMC9665142.
Abstract
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.
Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation
Vaidya R, Yi JX, O'Shea TM, Jensen ET, Joseph RM, Shenberger J, Gogcu S, Wagner K, Msall ME, Thompson AL, Frazier JA, Fry R, Singh R; ELGAN-ECHO Study Investigators.
2022 Nov 1;150(5):e2022056445. doi: 10.1542/peds.2022-056445. PMID: 36200375; PMCID: PMC9647591.
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.