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Background: Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term., Methods: In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status., Results: Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm [β 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3] than those born term (β 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002., Conclusion: We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Early-life exposures have been associated with an increased risk of eosinophilic esophagitis (EoE); however, most studies to date have been conducted at referral centers and are subject to recall bias. By contrast, we conducted a nationwide, population-based and registry-based case-control study of prenatal, intrapartum, and neonatal exposures, using data collected prospectively through population-based Danish health and administrative registries., Methods: We ascertained all EoE cases in Denmark (birth years 1997-2018). Cases were sex and age matched to controls (1:10) using risk-set sampling. We obtained data on prenatal, intrapartum, and neonatal factors, i.e., pregnancy complications, mode of delivery, gestational age at delivery, birthweight (expressed as a z-score), and neonatal intensive care unit (NICU) admission. We used conditional logistic regression to compute the crude and adjusted odds ratios (aOR) of EoE in relation to each prenatal, intrapartum, and neonatal factor, thus providing an estimate of incidence density ratios with 95% confidence intervals (CI)., Results: In the 393 cases and 3,659 population controls included (median age at index date, 11 years [interquartile range, 6-15]; 69% male), we observed an association between gestational age and EoE, peaking at 33 vs 40 weeks (aOR 3.6 [95% CI 1.8-7.4]), and between NICU admission and EoE (aOR 2.8 [95% CI 1.2-6.6], for a NICU hospitalization of 2-3 weeks vs no admission). In interaction analyses, we observed a stronger association between NICU admission and EoE in infants born at term than in preterm infants (aOR 2.0 [95% CI 1.4-2.9] for term infants and aOR 1.0 [95% CI 0.5-2.0] for preterm infants). We also observed an association between pregnancy complications and EoE (aOR 1.4 [95% CI 1.0-1.9]). Infants who were very growth restricted at birth had an increased rate of EoE (aOR 1.4 [95% CI: 1.0-1.9] for a z-score of -1.5 vs a z-score of 0). Mode of delivery was not associated with EoE., Discussion: Prenatal, intrapartum, and neonatal factors, particularly preterm birth and NICU admission, were associated with development of EoE. Further research is needed to elucidate the mechanisms underlying the observed associations., (Copyright © 2023 by The American College of Gastroenterology.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (β = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (β = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Elevated serum uric acid increases the risk of hypertension, and individuals born preterm have higher blood pressure (BP) and uric acid, but the mechanisms remain unclear. Preclinical studies demonstrate uric acid increases BP via increased renin-angiotensin system (RAS) expression, especially angiotensin (Ang) II, but the association of uric acid with Ang-(1-7) is unknown. Ang-(1-7), an alternative RAS product, counteracts Ang II by stimulating sodium excretion, vasodilation, and nitric oxide, thus contributing to lower BP. Plasma Ang-(1-7) is lower in preterm-born adolescents. We hypothesized uric acid is associated with a higher ratio of Ang II to Ang-(1-7) in plasma, especially in preterm-born adolescents. We measured BP, serum uric acid, and plasma RAS components in a cross-sectional analysis of 163 14-year olds (120 preterm, 43 term). We estimated the associations between uric acid and the RAS using generalized linear models adjusted for sex, obesity, sodium intake, and fat intake, stratified by birth status. Uric acid was positively associated with Ang II/Ang-(1-7) (adjusted β (aβ): 0.88 mg/dl, 95% CI 0.17-1.58), plasma renin activity (aβ: 0.32 mg/dl, 95% CI 0.07-0.56), and aldosterone (aβ: 1.26 mg/dl, 95% CI 0.18-2.35), and inversely with Ang-(1-7) (aβ: -1.11 mg/dl, 95% CI -2.39 to 0.18); preterm birth did not modify these associations. Higher Ang II/Ang-(1-7) was associated with higher uric acid in adolescents. As preterm birth is associated with higher BP and uric acid, but lower Ang-(1-7), the imbalance between uric acid and Ang-(1-7) may be an important mechanism for the development of hypertension.

Early-life factors including preterm birth and VLBW increase the risk of hypertension, but the mechanisms remain poorly understood. Reductions in the anti-aging protein α-klotho are associated with hypertension, possibly due to angiotensin (Ang) II activation, but the mechanisms are incompletely understood and clinical evidence is lacking. The association of α-klotho with the alternative Ang-(1-7) pathway, which counteracts Ang II to lower BP, is undescribed. We hypothesized that lower urinary α-klotho is associated with higher BP and lower urinary Ang-(1-7) in preterm-born VLBW young adults. In a cross-sectional analysis of data from a prospective cohort of 141 preterm-born VLBW young adults, we assessed the associations among urinary α-klotho/creatinine, Ang II/creatinine, Ang-(1-7)/creatinine, Ang II/Ang-(1-7), and BP using generalized linear models adjusted for age and hypertensive pregnancy and conducted a sensitivity analysis in 32 term-born young adults. Among those born preterm, lower α-klotho/creatinine was associated with higher systolic BP (adjusted β (aβ): -2.58 mm Hg, 95% CI -4.99 to -0.17), lower Ang-(1-7)/creatinine (ln aβ: 0.1, 0.04-0.16), and higher Ang II/Ang-(1-7) (ln aβ: -0.14, -0.21 to -0.07). In term-born participants, α-klotho/creatinine was inversely associated with Ang II/creatinine (ln aβ: -0.15, -0.27 to -0.03) and Ang II/Ang-(1-7) (ln aβ: -0.15, -0.27 to -0.03). In preterm-born young adults with VLBW, lower urinary α-klotho/creatinine was associated with higher SBP, lower urinary Ang-(1-7)/creatinine, and higher urinary Ang II/Ang-(1-7). Reduced renal α-klotho expression could lead to renal Ang-(1-7) suppression as a novel mechanism for the development of hypertension among individuals born preterm with VLBW., (© 2020 Wiley Periodicals LLC.)

Background: Adolescents born preterm have altered hypothalamic-pituitary-adrenal axis function with a blunted cortisol stress response, however, the influences of intrauterine growth restriction and race are unclear., Methods: We measured salivary cortisol before and 20 min after a maximal-exercise stress test and calculated the cortisol stress response. We used linear regression to compare cortisol stress responses between preterm and term groups, adjusting for birth weight z-score and maternal hypertension, and examined effect modification by race and sex., Results: We evaluated 171 adolescents born preterm with very low birth weight and 50 born term. Adolescents born preterm had reduced cortisol stress response compared to term (0.03 vs. 0.08 μg/dL, p = 0.04). This difference was race dependent: non-Black adolescents born preterm had significantly reduced cortisol stress response compared to those born at term (adjusted β: -0.74; 95% CI -1.34, -0.15), while there was no difference in Black adolescents (0.53; -0.16, 1.22). Sex did not modify the relationship., Conclusions: Adolescents born preterm exhibit a reduced salivary cortisol response to exercise stress, suggesting long-term alterations in the hypothalamic-pituitary-adrenal axis. This relationship was evident in non-Black but not in Black adolescents, suggesting that race may modify the influence of preterm birth on stress alterations of the hypothalamic-pituitary-adrenal axis.

Background: Preterm birth increases the risk of hypertension and kidney disease. However, it is unclear when changes in blood pressure (BP) and renal function become apparent and what role obesity and sex play. We hypothesized adolescents born preterm have higher BP and worse kidney function compared to term in an obesity- and sex-dependent manner., Methods: Cross-sectional analysis of 14-year-olds born preterm with very low birth weight (n = 96) compared to term (n = 43). We used generalized linear models to estimate the associations among preterm birth and BP, estimated glomerular filtration rate (eGFR), and ln (x) urinary albumin-to-creatinine ratio (ACR), stratified by overweight/obesity (OWO, body mass index (BMI) ≥ 85th percentile) and sex., Results: Compared to term, preterm-born adolescents had higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) (adjusted β (aβ) 3.5 mmHg, 95% CI - 0.1 to 7.2 and 3.6 mmHg, 95% CI 0.1 to 7.0), lower eGFR (β - 8.2 mL/min/1.73 m 2 , 95% CI - 15.9 to - 0.4), and higher ACR (aβ 0.34, 95% CI - 0.04 to 0.72). OWO modified the preterm-term difference in DBP (BMI < 85th percentile aβ 5.0 mmHg, 95% CI 0.7 to 9.2 vs. OWO 0.2 mmHg, 95% CI - 5.3 to 5.6) and ACR (OWO aβ 0.72, 95% CI 0.15 to 1.29 vs. BMI < 85th percentile 0.17, 95% CI - 0.31 to 0.65). Sex modified the preterm-term ACR difference (female aβ 0.52, 95% CI 0.001 to 1.04 vs. male 0.18, 95% CI - 0.36 to 0.72)., Conclusions: Prematurity was associated with higher BP and reduced renal function that were detectable in adolescence. OWO and sex may modify the strength of these relationships.

Objective: To evaluate whether hormonal contraceptives, used before or in early pregnancy, confer increased risk of preterm birth or reduced fetal growth., Design: Population-based cohort study conducted by the Norwegian Institute of Public Health (Mother and Child Cohort Study, 1998-2008) with linkage to the Norwegian Prescription Registry and to the Medical Birth Registry of Norway., Setting: Norway., Population: Of the 48,615 pregnancies meeting study inclusion criteria, 44,734 pregnancies were included in the complete case analysis., Methods: We characterised hormonal contraception by type (combination oral, progestin-only oral, vaginal ring, transdermal, and injectable) and specific progestin component. We used generalised estimating equations to estimate the odds of adverse outcome according to formulation used. Several sensitivity analyses were conducted., Main Outcome Measures: Preterm birth, small for gestational age., Results: We observed a positive association between use of a combination oral contraceptive and preterm birth for all exposure periods (e.g. adjusted odds ratio 1.21, 95% confidence interval 1.04-1.41 for last use 12 to >4 months before conception); combination contraceptives containing the progestin norethisterone were consistently related to risk. Other types of hormonal contraception were generally not associated with preterm birth; none were related to small for gestational age. Observed associations were robust to sensitivity analyses., Conclusion: Hormonally active agents may exert dose-, agent-, and timing-specific effects on growth and development. We found that the particular progestin component is important when assessing the potential for adverse effects among former users of hormonal contraceptives., (© 2014 Royal College of Obstetricians and Gynaecologists.)