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Associations between neonatal serum bilirubin and childhood hypertension.

ABSTRACT: Mild hyperbilirubinemia is inversely associated with cardiometabolic diseases in adults. The aim of this study was to evaluate the association between neonatal serum bilirubin levels and childhood hypertension. Data were obtained from the U.S. Collaborative Perinatal Project conducted at 12 U.S. medical centers from 1959 to 1965. This multicenter study recruited participants before phototherapy was routinely used, thereby excluding the influence of phototherapy. In 37,544 newborns (31,819 term and 5,725 preterm births), a generalized linear model and a logistic regression model were used to calculate the linear coefficients and adjusted odds ratios (ORs) of blood pressure and hypertension at 7 years of age based on neonatal serum bilirubin levels. No significant correlation was observed between serum bilirubin at 48 hours after birth and blood pressure at the age of 7 years in the whole study population and in the subgroup of term infants. In preterm infants, a lower total serum bilirubin and unconjugated bilirubin of 3 mg/dl were associated with a higher systolic blood pressure of 62 mmHg (0.38-0.86, p <0.001) and 0.70 mmHg (0.10-1.30, p <0.05) respectively. Relative to a total serum bilirubin level <3 mg/dl among preterm infants, total serum bilirubin levels of 3-6 mg/dl (adjusted OR 1.36; 95% CI: 0.98-1.89), 6-9 mg/dl (adjusted OR 1.35; 95% CI: 0.98-1.85), 9-12 mg/dl (adjusted OR 1.55; 95% CI: 1.10-2.19), and ≥12 mg/dl (adjusted OR 1.42; 95% CI: 1.01-2.00) were associated with higher risks of hypertension. After stratifying for the subtypes of bilirubin, the associations only existed for unconjugated bilirubin. In addition, consistent findings existed when using maximum neonatal serum bilirubin as an exposure factor. Neonatal serum bilirubin levels are positively associated with childhood blood pressure/hypertension in preterm infants. Our findings may shed some light on the role of bilirubin in the prevention of hypertension.

SUBMITTER: Yu H

PROVIDER: S-EPMC6638957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHyperbilirubinemia affects many newborn infants and, if not treated appropriately, can lead to irreversible brain injury.ObjectiveThis study aims to develop predictive models of follow-up total serum bilirubin measurement and to compare their accuracy with that of clinician predictions.MethodsSubjects were patients born between June 2015 and June 2019 at 4 hospitals in Massachusetts. The prediction target was a follow-up total serum bilirubin measurement obtained <72 hours after a previous measurement. Birth before versus after February 2019 was used to generate a training set (27,428 target measurements) and a held-out test set (3320 measurements), respectively. Multiple supervised learning models were trained. To further assess model performance, predictions on the held-out test set were also compared with corresponding predictions from clinicians.ResultsThe best predictive accuracy on the held-out test set was obtained with the multilayer perceptron (ie, neural network, mean absolute error [MAE] 1.05 mg/dL) and Xgboost (MAE 1.04 mg/dL) models. A limited number of predictors were sufficient for constructing models with the best performance and avoiding overfitting: current bilirubin measurement, last rate of rise, proportion of time under phototherapy, time to next measurement, gestational age at birth, current age, and fractional weight change from birth. Clinicians made a total of 210 prospective predictions. The neural network model accuracy on this subset of predictions had an MAE of 1.06 mg/dL compared with clinician predictions with an MAE of 1.38 mg/dL (P<.0001). In babies born at 35 weeks of gestation or later, this approach was also applied to predict the binary outcome of subsequently exceeding consensus guidelines for phototherapy initiation and achieved an area under the receiver operator characteristic curve of 0.94 (95% CI 0.91 to 0.97).ConclusionsThis study developed predictive models for neonatal follow-up total serum bilirubin measurements that outperform clinicians. This may be the first report of models that predict specific bilirubin values, are not limited to near-term patients without risk factors, and take into account the effect of phototherapy.

Project description:Bilirubin is the end product of heme catabolism, mainly produced by the breakdown of mature red blood cells. Due to its anti-inflammatory, antioxidant, antidiabetic, and antilipemic properties, circulating bilirubin concentrations are inversely associated with the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality in adults. Some genetic loci associated with circulating bilirubin concentrations have been identified by genome-wide association studies in adults. We aimed to examine the relationship between circulating bilirubin, cardiometabolic risk factors, and inflammation in children and adolescents and the genetic architecture of plasma bilirubin concentrations. We measured fasting plasma bilirubin, cardiometabolic risk factors, and inflammatory markers in a sample of Danish children and adolescents with overweight or obesity (n = 1530) and in a population-based sample (n = 1820) of Danish children and adolescents. Linear and logistic regression analyses were performed to analyze the associations between bilirubin, cardiometabolic risk factors, and inflammatory markers. A genome-wide association study (GWAS) of fasting plasma concentrations of bilirubin was performed in children and adolescents with overweight or obesity and in a population-based sample. Bilirubin is associated inversely and significantly with a number of cardiometabolic risk factors, including body mass index (BMI) standard deviation scores (SDS), waist circumference, high-sensitivity C-reactive protein (hs-CRP), homeostatic model assessment for insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), triglycerides, and the majority of measured inflammatory markers. In contrast, bilirubin was positively associated with fasting plasma concentrations of alanine transaminase (ALT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SDS), and the inflammatory markers GH, PTX3, THBS2, TNFRSF9, PGF, PAPPA, GT, CCL23, CX3CL1, SCF, and TRANCE. The GWAS showed that two loci were positively associated with plasma bilirubin concentrations at a p-value threshold of <5 × 10-8 (rs76999922: β = -0.65 SD; p = 4.3 × 10-8, and rs887829: β = 0.78 SD; p = 2.9 × 10-247). Approximately 25% of the variance in plasma bilirubin concentration was explained by rs887829. The rs887829 was not significantly associated with any of the mentioned cardiometabolic risk factors except for hs-CRP. Our findings suggest that plasma concentrations of bilirubin non-causally associates with cardiometabolic risk factors in children and adolescents.

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Associations between neonatal serum bilirubin and childhood hypertension.

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