Neonatal inflammation and its association with asthma and obesity in late childhood among individuals born extremely preterm.

BACKGROUND: Asthma and obesity are frequent outcomes among individuals born extremely preterm and are associated with decreased lifespan. Neonatal inflammation is associated with chronic neurodevelopmental disorders; however, it is less studied in association with other later childhood chronic disorders in this population. METHODS: Fourteen hospitals in 5 U.S. states enrolled 1506 infants born before 28 weeks of gestation in the Extremely Low Gestational Age Newborn cohort in 2004-2014. Neonatal blood spots were collected on postnatal days 1, 7, 14, 21, and 28, and used to measure 14 inflammation-related proteins. Associations were evaluated between high (top quartile) levels of proteins and two chronic health disorders at ages 10 and 15 years: physician-diagnosed asthma and obesity (body mass index ≥95th percentile). RESULTS: Few associations were found between high levels of 14 inflammation-related proteins, either on a single day or on multiple days, and either asthma or obesity. Similarly, few associations were found in analyses stratified by sex or presence/absence of prenatal inflammation. CONCLUSIONS: In extremely preterm newborns, systemic elevations of inflammation-related proteins during the neonatal period were not associated with childhood asthma and obesity outcomes at 10 or 15 years of age. IMPACT: In the large multi-center Extremely Low Gestational Age Newborn (ELGAN) cohort, sustained elevation of neonatal levels of inflammation-related proteins was not consistently associated with asthma or obesity outcomes at 10 or 15 years of age. This finding contrasts with reported associations of perinatal inflammation with obesity at 2 years and neurodevelopmental disorders at 2-15 years in the ELGANs, suggesting that unlike neurodevelopment, peripubertal obesity and asthma may be driven by later childhood exposures. Future research on perinatal mechanisms of childhood asthma and obesity should account for both fetal and later exposures and pathways in addition to inflammation at birth.

The intergenerational metabolic-cardiovascular life course: maternal body mass index (BMI), offspring BMI, and blood pressure of adolescents born extremely preterm.

BACKGROUND: The aim of this study was to evaluate associations between pre-pregnancy maternal obesity and adolescent blood pressures (BPs) among children born extremely preterm. METHODS: This longitudinal observational cohort study included participants in the multicenter Extremely Low Gestational Age Newborn (ELGAN) study, born before 28 weeks of gestation, recruited at birth between 2002 and 2004, and followed prospectively through late adolescence. Between 2015 and 2022, three oscillometric BPs were obtained from participants (mean age 17.8 years). We used linear regression modeling to evaluate the association between maternal self-reported pre-pregnancy body mass index (BMI) and offspring adolescent systolic BP (SBP). In secondary analyses, we evaluated the association between maternal pre-pregnancy and offspring preadolescent (10-year-old) BMI and between offspring preadolescent BMI and adolescent SBP. RESULTS: The 100 (24%) participants born to a mother with a history of pre-pregnancy obesity (BMI ≥ 30) had a greater mean SBP of 120.5 (± 14.3) mmHg compared to the 324 (76%) of adolescents born to mothers without pre-pregnancy obesity (SBP 115.6 (± 12.0) mmHg). Pre-pregnancy obesity was associated with higher offspring BMI (aß 10.8, 95% CI 2.3, 19.2), and higher offspring BMI was associated with higher adolescent SBP (aß 0.12, 95% CI 0.09,0.16). CONCLUSIONS: For ELGANs, higher maternal pre-pregnancy BMI was associated with higher adolescent SBP. Findings from secondary analyses suggest potential mediation through preadolescent BMI. Future research directions include multi-level interventions to reduce maternal pre-pregnancy obesity, followed by offspring obesity prevention interventions as a way of reducing intergenerational cardiovascular disease in high-risk infants born extremely preterm.

Preoperative Tricuspid Regurgitation Is Associated With Long-Term Mortality and Is Graded More Severe Than Intraoperative Tricuspid Regurgitation.

OBJECTIVES: To determine whether preoperative (preop) tricuspid regurgitation (TR) severity grade was associated with postoperative mortality, to examine the correlation between pre-op and intraoperative (intraop) TR grades, and to understand which TR grade had better prognostic predictability in cardiac surgery patients. DESIGN: Retrospective. SETTING: Single institution. PARTICIPANTS: Patients. INTERVENTIONS: Preop and intraop echocardiography TR grades of 4,232 patients who had undergone cardiac surgeries between 2004 and 2014 were examined. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier curves and Cox proportional hazard models were used to determine the association between TR grades and the primary endpoint of all-cause mortality. The Wilcoxon signed-rank test and Spearman's rank correlation were analyzed to assess the similarity and correlation between preop and intraop-grade pairs. Multivariate logistic regression models of the area under the curve characteristics were compared for prognostic implications. Kaplan-Meier curves demonstrated a strong relationship between preop grades and survival. Multivariate models showed significantly increased mortality starting at mild preop TR (mild TR: hazard ratio [HR] 1.24; 95% CI 1.05-1.46, p = 0.013; moderate TR: HR 1.60; 95% CI 1.05-1.97, p < 0.001; severe TR: HR 2.50; 95% CI 1.74-3.58, p < 0.001). Preop TR grades were mostly higher than intraop grades. Spearman's correlation was 0.55 (p < 0.001). The area under the curves of preop and intraop TR-based models were almost identical (0.704 v 0.702 1-year mortality and 0.704 v 0.700 2-year mortality). CONCLUSIONS: The authors found that echocardiographically-determined preop TR grade at the time of surgical planning was associated with long-term mortality, starting even at a mild grade. Preop grades were higher than intraop grades, with a moderate correlation. Preop and intraop grades exhibited similar prognostic implications.

Social determinants of health rather than race impact health-related quality of life in 10-year-old children born extremely preterm.

Background: Reducing healthcare disparities among children is extremely important given the potential impact of these disparities on long-term health-related quality of life (HRQL). Race and parental socioeconomic status (SES) are associated with child HRQL, but these associations have not been studied in infants born extremely preterm (EP), a population at increased risk for physical, cognitive, and psychosocial impairments. Achieving health equity for infants born EP across their life course requires identifying the impact of racism and SES on HRQL. Objective: We aimed to evaluate the association between self-reported maternal race, SES factors, and HRQL among 10-year-old children born EP. Design/methods: Participants were identified from an ongoing multicenter prospective longitudinal study of Extremely Low Gestational Age Newborns (ELGAN Study), born between 2002 and 2004, and evaluated at 10 years of age using the Pediatric quality of life (QoL) Inventory completed by their parent or guardian, assessing physical, emotional, social, school, and total (composite) QoL domains. Multivariable regression models were used to evaluate the relationship between QoL scores and self-identified maternal race, adjusting for SES factors (education level, marital status, and public insurance). Results: Of 1,198 study participants who were alive at 10 years of age, 863 (72.0%) were evaluated at 10 years of age. Differences in mean 10-year QoL scores across racial groups were observed and were significant on univariate analysis. However, these associations attenuated when adjusted for the marital status, public insurance status, and education status of mothers. A comparison of children with English as the primary language spoken at home vs. any other language revealed a significant difference only in school QoL, in which non-English language was associated with more favorable school QoL scores. Conclusions: Among 10-year-old children born EP, differences in parent-reported QoL were associated with maternal SES factors but not with race. Our results suggest that interventions designed to improve the SES of mothers may enhance the QoL of children born EP. Furthermore, these results underscore that race is a social construct, rather than a biological variable, as we work toward greater equity in care provision.

Calcium phosphate deposition, tertiary hyperparathyroidism, and the long-term effect on kidney allografts.

BACKGROUND: Tertiary hyperparathyroidism adversely affects kidney allografts, with calcium phosphate deposition hypothesized to be an underlying cause. We analyzed allograft biopsies to investigate risk factors for calcium phosphate deposition and understand its impact on allograft function. METHODS: We reviewed patients who underwent kidney transplantation from 2017 to 2019. Tertiary hyperparathyroidism was defined as an elevated parathyroid hormone and hypercalcemia beyond 3 months' posttransplant or being prescribed cinacalcet. Allograft failure was defined as needing dialysis posttransplantation or retransplantation beyond 3 months' posttransplant. Three- and 12-month allograft biopsies were reviewed for calcium phosphate deposition. The χ2, t-test, and multivariate regression were used for statistical analysis. RESULTS: Of 159 patients who underwent kidney transplantation, 59 (37.1%) were diagnosed with tertiary hyperparathyroidism. Longer preoperative dialysis vintage (odds ratio, 1.47; confidence interval, 1.22-1.80 P < .001) and preoperative cinacalcet usage (odds ratio, 18.4; confidence interval, 7.24-53.0 P < .001) were associated with tertiary hyperparathyroidism. In total, 36 of 59 (61%) patients with tertiary hyperparathyroidism had calcium phosphate deposition on 3- or 12-month kidney allograft biopsy compared with 23 of 100 (23%) patients without tertiary hyperparathyroidism (P < .001). Tertiary hyperparathyroidism (odds ratio, 6.01; confidence interval, 2.91-13.0 P < .001) was associated with calcium phosphate deposition. Calcium phosphate deposition and tertiary hyperparathyroidism were not associated with worse glomerular filtration rate at 3 years' posttransplantation. Of those with data available at 3 years' posttransplantation, 21 of 49 (42.9%) patients remained on cinacalcet. There were 3 of 159 (2%) patients who had allograft failure, 2 of whom had both tertiary hyperparathyroidism and calcium phosphate deposition. CONCLUSION: Preoperative variables associated with tertiary hyperparathyroidism included longer dialysis vintage and cinacalcet use. Tertiary hyperparathyroidism was the main risk factor for calcium phosphate deposition posttransplantation. In our population, calcium phosphate deposition and tertiary hyperparathyroidism were not significantly associated with lower glomerular filtration rate.

Health-related quality of life at age 10 years in children born extremely preterm.

OBJECTIVE: To evaluate the association between prenatal maternal health and socioeconomic status (SES) and health-related quality of life (QoL) among 10-year-old children born extremely preterm. DESIGN/ METHODS: Retrospective analysis of the Extremely Low Gestational Age Newborns (ELGAN) Study cohort of infants born < 28 weeks gestational age. QoL was assessed at 10 years of age using the Pediatric Quality of Life Inventory. Multivariate regression models were used for analyses. RESULTS: Of 1198 participants who survived until 10 years of age, 889 (72.2%) were evaluated. Lower maternal age, lack of college education; receipt of public insurance and Supplemental Nutrition Assistance Program (SNAP) were associated with lower QoL scores. Specific maternal health factors were also associated with lower child QoL scores. CONCLUSIONS: Specific, potentially modifiable, maternal health and social factors are associated with lower scores on a measure of parent-reported child QoL across multiple domains for children born extremely preterm.

A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm.

Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi-omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro-inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD-associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD-associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi-omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.