Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life.

OBJECTIVE: To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes. STUDY DESIGN: This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34 weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors. RESULTS: Infants with PPHN (n = 7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n = 3 974 536), and infants with only mild PPHN (n = 2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome. CONCLUSIONS: The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents.

Initial Metabolic Profiles Are Associated with 7-Day Survival among Infants Born at 22-25 Weeks of Gestation.

OBJECTIVE: To evaluate the association between early metabolic profiles combined with infant characteristics and survival past 7 days of age in infants born at 22-25 weeks of gestation. STUDY DESIGN: This nested case-control consisted of 465 singleton live births in California from 2005 to 2011 at 22-25 weeks of gestation. All infants had newborn metabolic screening data available. Data included linked birth certificate and mother and infant hospital discharge records. Mortality was derived from linked death certificates and death discharge information. Each death within 7 days was matched to 4 surviving controls by gestational age and birth weight z score category, leaving 93 cases and 372 controls. The association between explanatory variables and 7-day survival was modeled via stepwise logistic regression. Infant characteristics, 42 metabolites, and 12 metabolite ratios were considered for model inclusion. Model performance was assessed via area under the curve. RESULTS: The final model included 1 characteristic and 11 metabolites. The model demonstrated a strong association between metabolic patterns and infant survival (area under the curve [AUC] 0.885, 95% CI 0.851-0.920). Furthermore, a model with just the selected metabolites performed better (AUC 0.879, 95% CI 0.841-0.916) than a model with multiple clinical characteristics (AUC 0.685, 95% CI 0.627-0.742). CONCLUSIONS: Use of metabolomics significantly strengthens the association with 7-day survival in infants born extremely premature. Physicians may be able to use metabolic profiles at birth to refine mortality risks and inform postnatal counseling for infants born at <26 weeks of gestation.

Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature.

OBJECTIVE: To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm. STUDY DESIGN: A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009. RESULTS: Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930). CONCLUSIONS: Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

Polymorphisms in NR5A2, gene encoding liver receptor homolog-1 are associated with preterm birth.

BACKGROUND: Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidence of genetic susceptibility. Objective of this study was to identify genetic variants contributing to PTB. METHODS: Genotyping was performed for 24 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NR5A2, FSHR, FOXP3, and SERPINH1). Genotyping was completed on 728 maternal triads (mother and maternal grandparents of a preterm infant). Data were analyzed with Family Based Association Test. RESULTS: For all maternal triads rs2737667 of NR5A2 showed significant association at P = 0.02. When stratifying by gestational age three SNPs in NR5A2 had P values <0.05 in the <32-wk gestational age group (rs12131233, P = 0.007; rs2737667, P = 0.04; rs2816949, P = 0.02). When preterm premature rupture of membranes cases were excluded rs2737667 of NR5A2 showed the strongest association with a P value <0.0002. This association remained significant after correction for multiple testing. CONCLUSION: This study suggests a potential association between intronic SNPs in the NR5A2 gene and PTB. NR5A2 gene encodes for the liver receptor homolog-1 protein, which plays a critical role in regulation of cholesterol metabolism, steroidogenesis, and progesterone synthesis. These findings suggest that NR5A2 may be important in the pathophysiology of PTB and exploring noncoding regulators of NR5A2 is warranted.

Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study.

BACKGROUND: Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. METHODS: To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. RESULTS: Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case-control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. CONCLUSIONS: Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

Replication of a genome-wide association study of birth weight in preterm neonates.

OBJECTIVE: To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al. STUDY DESIGN: A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis. RESULTS: Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples. CONCLUSIONS: These results indicate the potential importance of this marker on birth weight regardless of gestational age.