Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden.

Importance: Neonatal hyperbilirubinemia can cause lifelong neurodevelopmental impairment (kernicterus) even in high-resource settings. A better understanding of the incidence and processes leading to kernicterus may help in the design of preventive measures. Objectives: To determine incidence rates of hazardous hyperbilirubinemia and kernicterus among near-term to term newborns and to evaluate health care professional adherence to best practices. Design, Setting, and Participants: This population-based nationwide cohort study used prospectively collected data on the highest serum bilirubin level for all infants born alive at 35 weeks' gestation or longer and admitted to neonatal care at all 46 delivery and 37 neonatal units in Sweden from 2008 to 2016. Medical records for newborns with hazardous hyperbilirubinemia were evaluated for best neonatal practices and for a diagnosis of kernicterus up to 2 years of age. Data analyses were performed between September 2017 and February 2018. Exposures: Extreme (serum bilirubin levels, 25.0-29.9 mg/dL [425-509 µmol/L]) and hazardous (serum bilirubin levels, ≥30.0 mg/dL [≥510 µmol/L]) neonatal hyperbilirubinemia. Main Outcomes and Measures: The primary outcome was kernicterus, defined as hazardous neonatal hyperbilirubinemia followed by cerebral palsy, sensorineural hearing loss, gaze paralysis, or neurodevelopmental retardation. Secondary outcomes were health care professional adherence to national guidelines using a predefined protocol with 10 key performance indicators for diagnosis and treatment as well as assessment of whether bilirubin-associated brain damage might have been avoidable. Results: Among 992 378 live-born infants (958 051 term births and 34 327 near-term births), 494 (320 boys; mean [SD] birth weight, 3505 [527] g) developed extreme hyperbilirubinemia (50 per 100 000 infants), 6.8 per 100 000 infants developed hazardous hyperbilirubinemia, and 1.3 per 100 000 infants developed kernicterus. Among 13 children developing kernicterus, brain injury was assessed as potentially avoidable for 11 children based on the presence of 1 or several of the following possible causes: untimely or lack of predischarge bilirubin screening (n = 6), misinterpretation of bilirubin values (n = 2), untimely or delayed initiation of treatment with intensive phototherapy (n = 1), untimely or no treatment with exchange transfusion (n = 6), or lack of repeated exchange transfusions despite indication (n = 1). Conclusions and Relevance: Hazardous hyperbilirubinemia in near-term or term newborns still occurs in Sweden and was associated with disabling brain damage in 13 per million births. For most of these cases, health care professional noncompliance with best practices was identified, suggesting that a substantial proportion of these cases might have been avoided.

Lower cognitive test scores at age 7 in children born with marginally low birth weight.

BackgroundBeing born with very low birth weight (<1500 g) is associated with poorer neurocognition later in life. The aim of this study was to explore neurodevelopmental functions in those born with marginally LBW (2000-2500 g).MethodsThis was originally a randomized controlled trial investigating the effects of early iron supplementation in 285 marginally LBW children. Herein, we explored the combined marginally LBW group and compared their results to 95 normal birth weight (NBW; 2501-4500 g) controls in an observational design. At 7 years, a pediatric psychologist tested the children using Wechsler Intelligence Scale for Children (WISC IV), Beery-Buktenica developmental test of Visual-Motor Integration (Beery VMI), and Test of Everyday Attention for Children (TEA-Ch).ResultsThe marginally LBW children had lower verbal comprehension intelligence quotient (IQ) (104 vs. 107, P=0.004), lower VMI scores (96.5 vs. 100, P=0.028), and lower total mean TEA-Ch scores (8.5 vs. 9.7, P=0.006), compared to controls. Also, the marginally LBW children group had a higher proportion of children below -1 SD for VMI and TEA-Ch.ConclusionsMarginally LBW children had lower verbal comprehension IQ, lower visual-motor integration, and lower attention performance than NBW children, suggesting an increased risk of cognitive difficulties in early school age.

Effects of iron supplementation of low-birth-weight infants on cognition and behavior at 7 years: a randomized controlled trial.

BackgroundLow-birth-weight infants (LBW) are at an increased risk of iron deficiency that has been associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants improves cognitive scores and reduces behavioral problems until school age.MethodsWe randomized 285 marginally LBW (2,000-2,500 g) infants to receive 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 7 years of age, 205 participants were assessed regarding cognition using Wechsler Intelligence Scale for Children (WISC-IV) and behavior using the parental questionnaires Child Behavior Checklist (CBCL) and Five to Fifteen (FTF).ResultsThere were no significant differences between the intervention groups in WISC-IV or FTF. However, the CBCL scores for externalizing problems were significantly different, in favor of supplemented children (P=0.045). When combining the supplemented groups, they had significantly lower scores for externalizing behavior compared with placebo (median (interquartile range): 44 [34;51] vs. 48.5 [41;56] P=0.013), and their risk ratio (95% confidence interval) for a total behavioral score above the cutoff for clinical problems was 0.31 (0.09-1.0), P=0.054.ConclusionLower scores of externalizing behavior in supplemented children support our previous findings at 3 years, and suggest that iron supplementation may have long-lasting effects on behavioral functions.

Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: results from a randomized controlled trial.

Background: Low birth weight (LBW) (≤2500 g) is associated with iron deficiency in infancy and high blood pressure (BP) later in life.Objective: We investigated the effect of iron supplementation that was given to LBW infants on midchildhood BP.Design: The study was a randomized, double-blind, controlled trial that included 285 marginally LBW (2000-2500-g) infants at 2 Swedish centers between May 2004 and November 2007. The infants were randomly assigned to receive a placebo or 1 or 2 mg Fe · kg-1 · d-1 from 6 wk to 6 mo of age. In secondary analyses at the age of 7 y, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the prevalence of children with BP within the hypertensive range (>90th percentile) were compared between the groups.Results: BP was analyzed via intention to treat in 189 children (66%). The mean ± SD SBP was 103 ± 8.1, 101 ± 7.5, and 101 ± 7.8 mm Hg in children who had received the placebo (n = 70), 1 mg Fe · kg-1 · d-1 (n = 54), or 2 mg Fe · kg-1 · d-1 (n = 65), respectively. When the iron-supplemented groups were combined in covariate-adjusted analyses, the mean SBP in LBW children who had received iron supplementation in infancy was 2.2 mm Hg (95% CI: 0.3, 4.2 mm Hg) lower than in those who were unsupplemented (P = 0.026). Multivariate logistic regression showed that iron supplementation in infancy reduced the odds of having an SBP within the hypertensive range at 7 y of age (OR: 0.32; 95% CI: 0.11, 0.96). For DBP, there were no significant differences between the intervention groups.Conclusions: LBW children who receive iron supplementation (1 or 2 mg Fe · kg-1 · d-1) in infancy have lower SBP at 7 y. This (to our knowledge) novel observation suggests that the increased risk of hypertension that is observed in children and adults who are born small might be reduced with early micronutrient interventions. This trial was registered at clinicaltrials.gov as NCT00558454.

Season of birth, neonatal vitamin D status, and cardiovascular disease risk at 35 y of age: a cohort study from Sweden.

BACKGROUND: Lower vitamin D status during gestation may be associated with cardiovascular disease risk later in life. No studies have assessed this hypothesis with a follow-up time reaching beyond childhood. OBJECTIVE: The objective was to assess the link between season of birth, neonatal 25-hydroxyvitamin D3 [25(OH)D3] status, and adult cardiovascular disease risk. DESIGN: Markers of cardiovascular and metabolic disease risk were measured in 284 subjects aged 35 y, born either at the end of the winter or at the end of the summer of 1975. In 275 of these 284 subjects, concentrations of neonatal 25(OH)D3 were measured in dried blood samples by using a highly sensitive liquid chromatography-tandem mass spectroscopy method. RESULTS: Subjects born after the winter had lower neonatal 25(OH)D3 concentrations than did those born after the summer (31.5 compared with 48.5 nmol/L; P < 0.001). In regression analyses adjusted for sex, season of birth, postnatal age at neonatal sample collection, preterm birth, maternal age, education, smoking, fish consumption per week, exercise per week, and current 25-hydroxyvitamin D, higher neonatal 25(OH)D3 (per 50 nmol/L) was associated with 25.8% (95% CI: 1.0%, 58.4%) higher fasting insulin in adult life, 29.6% (5.1%, 58.4%) higher triglycerides, and 4.64 (95% CI: 1.93, 7.36) mmol/L higher serum cholesterol in women. Neonatal 25(OH)D3 (per 1 nmol/L) was directly associated with risk of adult overweight (OR: 1.03; 95% CI: 1.01, 1.05) and with adult obesity in women (OR: 1.09; 95% CI: 1.02, 1.17). Neonatal 25(OH)D3 was not associated with adult aortic pulse wave velocity, blood pressure, fasting glucose, HDL, LDL, or C-reactive protein. Season of birth was not associated with any of the adult outcomes. CONCLUSIONS: Higher neonatal 25(OH)D3 was associated with higher fasting insulin, triglyceride, and cholesterol (in women) concentrations and with a higher risk of overweight at 35 y of age but not with other adult cardiovascular disease risk factors.

Perioperative nutrition in extremely preterm infants undergoing surgical treatment for patent ductus arteriosus is suboptimal.

AIM: To evaluate perioperative nutrition in extremely preterm infants undergoing surgery for patent ductus arteriosus (PDA). METHODS: This is a population-based study of extremely preterm infants born in Sweden during 2004-2007 and operated on for PDA. Data on perioperative nutrition were obtained from hospital records. All enteral and parenteral nutrients and blood products were used to calculate daily nutritional intakes, starting 3 days before and ending 3 days after surgery. Data are mean (95% confidence intervals). RESULTS: Study infants (n = 140) had a mean gestational age (GA) of 24.8 weeks, and mean birth weight was 723 g. Energy and macronutrient intakes were below minimal requirements before, during and after PDA surgery. On the day of surgery, energy intake was 78 (74-81) kcal/kg/day, protein 2.9 (2.7-3.2) g/kg/day, fat 2.5 (2.3-2.7) g/kg/day and carbohydrate intake 10.7 (10.2-11.2) g/kg/day. Nutrition did not vary in relation to GA, but infants operated early (0-6 days after birth) received poorer nutrition than infants operated at older age. Fluid intake was 164 (159-169) mL/kg/day, and it did not vary during the week of surgery. CONCLUSION: Perioperative nutrition in extremely preterm infants undergoing PDA surgery in Sweden is suboptimal and needs to be improved. The significance of malnutrition for outcome after PDA surgery remains unclear and requires further investigation.

Exosomes with immune modulatory features are present in human breast milk.

Breast milk is a complex liquid with immune-competent cells and soluble proteins that provide immunity to the infant and affect the maturation of the infant's immune system. Exosomes are nanovesicles (30-100 nm) with an endosome-derived limiting membrane secreted by a diverse range of cell types. Because exosomes carry immunorelevant structures, they are suggested to participate in directing the immune response. We hypothesized that human breast milk contain exosomes, which may be important for the development of the infant's immune system. We isolated vesicles from the human colostrum and mature breast milk by ultracentrifugations and/or immuno-isolation on paramagnetic beads. We found that the vesicles displayed a typical exosome-like size and morphology as analyzed by electron microscopy. Furthermore, they floated at a density between 1.10 and 1.18 g/ml in a sucrose gradient, corresponding to the known density of exosomes. In addition, MHC classes I and II, CD63, CD81, and CD86 were detected on the vesicles by flow cytometry. Western blot and mass spectrometry further confirmed the presence of several exosome-associated molecules. Functional analysis revealed that the vesicle preparation inhibited anti-CD3-induced IL-2 and IFN-gamma production from allogeneic and autologous PBMC. In addition, an increased number of Foxp3(+)CD4(+)CD25(+) T regulatory cells were observed in PBMC incubated with milk vesicle preparations. We conclude that human breast milk contains exosomes with the capacity to influence immune responses.

Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses.

OBJECTIVE: To investigate whether intrauterine growth retardation (IUGR) and preterm delivery in a poor population of South Asia was associated with altered maternal and fetal levels of folate, vitamin B12, and homocysteine. SUBJECTS AND METHODS: Hundred and twenty-eight pregnant women from a low socio-economic strata in the city of Lahore, Pakistan were followed with ultrasound of fetal growth from the 12th week of pregnancy. Blood samples were drawn from the woman and the cord at delivery. Serum was analyzed by a chemiluminescent immunoassay for folate and vitamin B12 and by fluorescence polarization immunoassay for total homocysteine (tHcy). RESULTS: Fourty-six infants showed IUGR. In term, but not preterm, deliveries with IUGR, maternal and cord blood folate levels were half of those in deliveries of normal birth weight infants (P=0.004 and P=0.005). The risk of IUGR was reduced among women with folate levels in the highest quartile (OR 0.31, 95% CI 0.10--0.84). There was no association between vitamin B12 and IUGR. Total homocysteine levels were higher in women delivering IUGR infants (P=0.02). There was an inverse correlation between cord blood folate and tHcy levels (r=-0.26, P=0.006). We also found increased risks for hypertensive illness (OR 3.5, 95% CI 1.4--8.6) and premature delivery (OR 2.5, 95% CI 1.1--6.2) in women in the highest quartile of tHcy. CONCLUSIONS: The occurrence of IUGR increased with low maternal and cord concentrations of folate and high maternal levels of tHcy. Further studies on the effects of vitamin B supplementation through pregnancy are warranted.