Search

OBJECTIVE: To evaluate the outcomes of extremely premature infants who received inhaled nitric oxide(iNO) for hypoxic respiratory failure(HRF). STUDY DESIGN: Retrospective analysis of 107 infants born 22–26 weeks gestation who received iNO for HRF at a single institution. Infants were categorized as positive, negative, or no responders based on change in FiO(2) or OI. Underlying physiology was determined using Echocardiography/Radiography/Biochemistry. RESULTS: 63% of infants had a positive response; they received iNO earlier and were more likely to have acute pulmonary hypertension(PH). Positive response correlated with decreased incidence of death or grade 3 BPD at 36 weeks postmenstrual age, as compared to a negative response. CONCLUSIONS: Extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of HRF prior to iNO initiation.

Background DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed of preterm infants with European genetic ancestry but not in more genetically diverse populations. Goal To determine if the effects of TFAP2B and PTGIS polymorphisms on ductus arteriosus (DA) gene expression differ based on genetic ancestry. Methods DA from 273 human second trimester fetuses were genotyped for TFAP2B and PTGIS polymorphisms and for polymorphisms distributing along genetic ancestry lines. RT-PCR was used to measure the RNA expression of 49 candidate genes involved with DA closure. Results Seventeen percent of the DA analyzed were of European ancestry. In multivariable regression analyses we found consistent associations between four PDA-related TFAP2B polymorphisms (rs2817399(A), rs987237(G), rs760900(C), and rs2817416(C)) and expression of the following genes: EPAS1, CACNB2, ECE1, KCNA2, ATP2A3, EDNRA, EDNRB, BMP9, and BMP10, and between the PTGIS haplotype rs493694(G)/rs693649(A) and PTGIS and NOS3. These changes only occurred in DA with European ancestry. No consistent positive or negative associations were found among DA samples unless an interaction between the polymorphisms and genetic ancestry was taken into account. Conclusion PTGIS and TFAP2B polymorphisms were associated with consistent changes in DA gene expression when present in fetuses with European ancestry. Impact DNA polymorphisms in PTGIS and TFAP2B have been identified as risk factors for patent ductus arteriosus (PDA) in a population composed primarily of preterm infants with European genetic ancestry but not in more genetically diverse populations. The same PTGIS and TFAP2B polymorphisms are associated with changes in ductus gene expression when present in ductus from fetuses with European genetic ancestry. No consistent associations with gene expression can be found unless an interaction between the polymorphisms and genetic ancestry is taken into account.

Background Identifying preterm infants at risk for mortality or major morbidity traditionally relies on gestational age, birth weight, and other clinical characteristics that offer underwhelming utility. We sought to determine whether a newborn metabolic vulnerability profile at birth can be used to evaluate risk for neonatal mortality and major morbidity in preterm infants. Methods This was a population-based retrospective cohort study of preterm infants born between 2005 and 2011 in California. We created a newborn metabolic vulnerability profile wherein maternal/infant characteristics along with routine newborn screening metabolites were evaluated for their association with neonatal mortality or major morbidity. Results Nine thousand six hundred and thirty-nine (9.2%) preterm infants experienced mortality or at least one complication. Six characteristics and 19 metabolites were included in the final metabolic vulnerability model. The model demonstrated exceptional performance for the composite outcome of mortality or any major morbidity (AUC 0.923 (95% CI: 0.917-0.929). Performance was maintained across mortality and morbidity subgroups (AUCs 0.893-0.979). Conclusions Metabolites measured as part of routine newborn screening can be used to create a metabolic vulnerability profile. These findings lay the foundation for targeted clinical monitoring and further investigation of biological pathways that may increase the risk of neonatal death or major complications in infants born preterm. Impact We built a newborn metabolic vulnerability profile that could identify preterm infants at risk for major morbidity and mortality. Identifying high-risk infants by this method is novel to the field and outperforms models currently in use that rely primarily on infant characteristics. Utilizing the newborn metabolic vulnerability profile for precision clinical monitoring and targeted investigation of etiologic pathways could lead to reductions in the incidence and severity of major morbidities associated with preterm birth.

ObjectiveOur study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda.Study designForty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda.ResultsThe model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth

OBJECTIVE: To test associations between grades 3 or 4 (severe) intraventricular hemorrhage (IVH) and single nucleotide polymorphisms (SNPs) associated with coagulation, inflammation, angiogenesis, and organ development in an exploratory study. STUDY DESIGN: Extremely low-birthweight (ELBW) infants enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network’s (NRN) Cytokines Study were included if they had cranial ultrasound (CUS) and genotyping data available in the NRN Anonymized DNA Repository and Database. Associations between SNPs and IVH severity were tested with multivariable logistic regression analysis. RESULT: One hundred thirty-nine infants with severe IVH and 687 infants with grade 1 or 0 IVH were included. One thousand two hundred seventy-nine SNPs were genotyped. Thirteen were preliminarily associated with severe IVH including five related to central nervous system (CNS) neuronal and neurovascular development. CONCLUSION: Genetic variants for CNS neuronal and neurovascular development may be associated with severe IVH in premature infants.

The approach to clinical care of infants born at 22 weeks’ gestation must be consistent and well-designed if optimal results are to be expected. Publications from several international centers have demonstrated that, although there may be variance in aspects of care in this vulnerable population, treatment should be neither random nor inconsistent. In designing a standardized approach, careful attention should be paid to the unique anatomy, physiology, and biochemistry of this vulnerable patient population. Emerging evidence, suggesting a link between cardiopulmonary health and longer-term sequela, highlights the importance of understanding the relationship between cardiorespiratory illnesses of the 22-week infant, treatments provided, and subsequent cardiopulmonary development. In this review we will provide an overview to our approach to cardiopulmonary assessment and treatment, with a particular emphasis on the importance of early recognition of atypical phenotypes, timely interventions with evidence-based treatments, and longitudinal monitoring.

Newborn metabolic screening is emerging as a novel method for predicting neonatal morbidity and mortality in neonates born very preterm (

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

OBJECTIVES To compare survival and short-term respiratory outcomes of infants weighing

Objectives Adults born prematurely have an increased risk of early heart failure. The impact of prematurity on left and right ventricular function has been well documented, but little is known about the impact on the systemic vasculature. The goals of this study were to measure aortic stiffness and the blood pressure response to physiological stressors; in particular, normoxic and hypoxic exercise. Methods Preterm participants (n = 10) were recruited from the Newborn Lung Project Cohort and matched with term‐born, age‐matched subjects (n = 12). Aortic pulse wave velocity was derived from the brachial arterial waveform and the heart rate and blood pressure responses to incremental exercise in normoxia (21% O2) or hypoxia (12% O2) were evaluated. Results Aortic pulse wave velocity was higher in the preterm groups. Additionally, heart rate, systolic blood pressure, and pulse pressure were higher throughout the normoxic exercise bout, consistent with higher conduit artery stiffness. Hypoxic exercise caused a decline in diastolic pressure in this group, but not in term‐born controls. Conclusions In this first report of the blood pressure response to exercise in adults born prematurely, we found exercise‐induced hypertension relative to a term‐born control group that is associated with increased large artery stiffness. These experiments performed in hypoxia reveal abnormalities in vascular function in adult survivors of prematurity that may further deteriorate as this population ages., The long-term consequences of prematurity are not well understood. We found that adult survivors of prematurity have increased blood pressure during exercise and evidence of arterial stiffening.

OBJECTIVE: To determine the prevalence of virus in a previously uncharacterized matched maternal-infant preterm cohort and test if viral presence or viral load correlate with histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia. STUDY DESIGN: Using qRT-PCR/qPCR we tested plasma or whole blood samples from 56 matched maternal and premature infant dyads for: adenovirus, anellovirus (alphatorquevirus and betatorquevirus), cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, human herpesvirus 6 (HHV6), parechovirus, and parvovirus B19. RESULT: Viral detection was more common in maternal samples 29/56 (52%) than in cord blood from their infants (4/56 (7%)) (p ≤ .0001). No significant difference in viral load or viral prevalence was identified between pregnancies with and without histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia. CONCLUSION: Despite frequent detection of virus in maternal samples, virus was less frequently detected in the infants. Additionally, there was no association of presence or quantity of virus in maternal blood with histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia in this small, but well-defined cohort. Future studies are necessary to further characterize the role of virus in placental inflammatory states and pregnancy outcomes.

Cholesterol biosynthesis is a highly conserved metabolic process. However, genetic variability in cholesterol metabolism contributes to both rare congenital disorders and common chronic conditions. In the post-lanosterol cholesterol biosynthesis pathway, ten enzymes are associated with rare disorders including Greenberg skeletal dysplasia, Pelger–Huet anomaly, CHILD syndrome, Conradi–Hunermann syndrome, lathosterolosis, Smith–Lemli–Opitz syndrome, and desmosterolosis. In addition to these profound dominant and recessive congenital disorders, common genetic variability, in particular, single nucleotide polymorphisms (SNPs), in the genes encoding these enzymes is associated with common chronic diseases such as cancer, diabetes, blood pressure, hepatitis C progression, and Alzheimer’s disease. We will discuss the genetic causes of rare disorders in the post-squalene cholesterol biosynthesis pathway and the chronic disease effects of common genetic variability in this pathway.

Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed.We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment.We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (-2, -2 to -0.5, and-0.5) and PDA surgery following pharmacologic treatment.5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score-2.Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

Background:Patent ductus arteriosus (PDA) treatment is typically pharmacologic, but if unsuccessful, surgical ligation is commonly performed. High-frequency jet ventilation (HFJV) is used at the University of Iowa Stead Family Children’s Hospital for extremely low birth weight infants. Historically, neonates requiring PDA ligation were temporarily transferred to conventional ventilation (CV) prior to surgery.Objective:The objective of this study was to determine whether conversion was necessary.Methods:This retrospective cohort analysis examined outcomes following PDA ligation from 2014 to 2016 at the University of Iowa’s Stead Family Children’s Hospital. Infants who were transferred to CV prior to surgery and returned to HFJV postprocedure are referred to as the CV cohort. The HFJV cohort infants remained on HFJV throughout.Results:We found no significant increases in morbidity or mortality with the use of intraoperative HFJV and potentially show some benefit through greater reduction in serum CO2.Conclusions:Mode of ventilation during PDA ligation does not affect surgical morbidity or mortality or short-term clinical outcomes. Conversion to CV from HFJV is not necessary.

Background: The genetic basis of sepsis susceptibility in preterm infants remains understudied. Herein, we investigated the nucleotide binding-oligomerization domain (NOD)-like receptor (NLR) family of immune receptors as putative loci for preterm sepsis susceptibility. Objective: To determine whether single nucleotide polymorphisms (SNPs) in NLR genes are associated with blood stream infections (BSI) in premature infants. Methods: An international cohort of infants with gestational age (GA) ATG16L1, CARD8, NLRP3, NOD2, and NOD1 genes. χ2 and logistic regression analyses were used to examine relationships between NLR variants and BSI. Results: Among 764 infants, 138 developed BSI, 113 had gram-positive bacterial (GPB) BSI, and 28 had gram-negative bacterial (GNB) BSI. Infants with BSI had a lower birth weight and GA (p < 0.001), but did not differ in gender, race, or chorioamnionitis. NLR variants were not associated with GPB or GNB BSI in the entire cohort. The CC genotype of the NOD1 SNP (rs6958571) was associated with increased GPB BSI in extremely low birth weight (ELBW, birth weight p = 0.003, n = 362) and in Caucasian infants (OR = 2.5, 95% CI: 1.2-5.4, p = 0.016, n = 535). Regression models adjusting for clinical variables identified ELBW status and the NOD1 CC genotype as risk factors for GPB BSI in Caucasian infants. Conclusions: In this study investigating relationships between NLR variants and sepsis in infants with GA NOD1 (rs6958571) SNP was associated with GPB BSI in Caucasian infants and ELBW infants. Replication of our results in an independent cohort would support a role for NLR variants in determining sepsis risk in ELBW infants.

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Objective To assess the outcomes in actively managed extremely preterm infants after admission to a neonatal intensive care unit. Study design Retrospective cohort of 255 infants born at 22-25 weeks of gestation between 2006 and 2015 at a single study institution. Infants were excluded for congenital anomaly, death in delivery room, or parental request for palliation (n = 7). Neurodevelopmental outcomes were analyzed for 169 of 214 survivors (78.9%) at 18-22 months of corrected age. Outcomes were evaluated using the Mann-Whitney U, χ2, or Fisher exact test, where appropriate. In addition, cognitive scores of the Bayley Scales of Infant-Toddler Development (3rd edition) were assessed using generalized estimating equations. Results Seventy infants born at 22-23 weeks of gestation (22 weeks, n = 20; 23 weeks, n = 50) and 178 infants born at 24-25 weeks of gestation (24 weeks, n = 79; 25 weeks, n = 99 infants) were included. Survival to hospital discharge of those surviving to NICU admission was 78% (55/70; 95% CI, 69%-88%) at 22-23 weeks and 89% (159/178; 95% CI, 84%-93% at 24-25 weeks; P = .02). No or mild neurodevelopmental impairment in surviving infants was 64% (29/45; 95% CI, 50%-77%) at 22-23 weeks and 76% (94/124; 95% CI, 68%-83%; P = .16) at 24-25 weeks. Conclusions Although survival was lower in infants born at 22-23 weeks than at 24-25 weeks of gestation, the majority of survivors in both groups had positive outcomes with no or mild neurodevelopmental impairments. Further evaluation of school performance is warranted.

Maternal lipid profiles are associated with risk for preterm birth (PTB), although the lipid component and effect size are inconsistent between studies. It is also unclear whether these associations are the result of excessive changes in lipid metabolism during pregnancy or genetic variability in genes controlling basal lipid metabolism. This study investigates the association between genetic risk scores (GRS) for four lipid components (high-density lipoprotein [HDL-C], low-density lipoprotein [LDL-C], triacylglycerols [TAG], and total cholesterol [TC]) with risk for PTB. Subjects included 954 pregnant women from California for whom second trimester serum samples were available, of which 479 gave birth preterm and 475 gave birth at term. We genotyped 96 single-nucleotide polymorphisms, which were selected from genome-wide association studies of lipid levels in adult populations. Lipid-specific GRS were constructed for HDL-C, LDL-C, TAG, and TC. The associations between GRS and PTB were analyzed using logistic regression. A higher HDL-C GRS was associated with increased risk for PTB overall and spontaneous PTB. Higher TAG and TC GRS were associated with decreased risk for PTB overall and spontaneous PTB. This study identifies counter-intuitive associations between lipid GRS and spontaneous PTB. Further replication studies are needed to confirm these findings, but they suggest that our current scientific understanding of the relationship between lipid metabolism, PTB, and genetics is incomplete.

OBJECTIVE. Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. STUDY DESIGN. Preterm infants (n=1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables. RESULT. SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p

Objective To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. Study design Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. Results Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. Conclusions MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia–ischemia. Trial registration Clinicaltrials.gov: NCT00614744 .

BackgroundA growing amount of evidence indicates in utero and early life growth has profound, long-term consequences for an individual’s health throughout the life course; however, there is limited data in preterm infants, a vulnerable population at risk for growth abnormalities.ObjectiveTo address the gap in knowledge concerning early growth and its determinants in preterm infants.MethodsA retrospective cohort study was performed using a population of preterm (< 37 weeks gestation) infants obtained from an electronic medical record database. Weight z-scores were acquired from discharge until roughly two years corrected age. Linear mixed effects modeling, with random slopes and intercepts, was employed to estimate growth trajectories.ResultsThirteen variables, including maternal race, hypertension during pregnancy, preeclampsia, first trimester body mass index, multiple status, gestational age, birth weight, birth length, head circumference, year of birth, length of birth hospitalization stay, total parenteral nutrition, and dextrose treatment, were significantly associated with growth rates of preterm infants in univariate analyses. A small percentage (1.32% - 2.07%) of the variation in the growth of preterm infants can be explained in a joint model of these perinatal factors. In extremely preterm infants, additional variation in growth trajectories can be explained by conditions whose risk differs by degree of prematurity. Specifically, infants with periventricular leukomalacia or retinopathy of prematurity experienced decelerated rates of growth compared to infants without such conditions.ConclusionsFactors found to influence growth over time in children born at term also affect growth of preterm infants. The strength of association and the magnitude of the effect varied by gestational age, revealing that significant heterogeneity in growth and its determinants exists within the preterm population.

Reactive oxygen species mediate intestinal injury in necrotizing enterocolitis (NEC), and yet the contribution of antioxidant response (ARE) gene polymorphisms to NEC risk remains unknown. Premature infants recruited in a multicenter study were genotyped for 6 ARE variants. Among 637 infants, 52 had NEC, and 22 developed surgical NEC. Gestational age

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

Objective To implement and evaluate a clinical practice algorithm to identify preterm infants with sodium deficiency and guide sodium supplementation based on urine sodium concentrations. Study Design Urine sodium concentration was measured in infants born at 260/7 to 296/7 weeks' gestation at 2-week intervals. Sodium supplementation was based on the urine sodium algorithm. Growth and respiratory outcomes in this cohort were compared with a matched cohort cared for in our neonatal intensive care unit prior to algorithm implementation (2014–2015 cohort). Results Data were compared for 50 infants in the 2014–2015 cohort and 40 infants in the 2016 cohort. Urine sodium concentration met criteria for supplementation in 75% of the 2016 cohort infants within the first 4 weeks after birth. Average daily sodium intake was greater in the 2016 cohort compared with the 2014–2015 cohort (p Conclusion Institution of a clinical practice algorithm to instruct clinicians on sodium supplementation in preterm infants may improve growth outcomes.

Maternal lipid profiles during pregnancy are associated with risk for preterm birth. This study investigates the association between maternal dyslipidemia and subsequent preterm birth among pregnant women in the state of California. Births were identified from California birth certificate and hospital discharge records from 2007-2012 (N = 2,865,987). Preterm birth was defined as

In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs. We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants. Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

Persistent Pulmonary Hypertension of the Newborn (PPHN) is characterized by elevated pulmonary vascular resistance with extrapulmonary right to left shunting causing life threatening hypoxemia. Endogenous Nitric Oxide is critical for regulation of pulmonary vascular resistance and the transition of pulmonary circulation at birth. Endothelial cells generate Nitric Oxide from the precursor L …

Rationale Mechanisms contributing to chronic lung disease after preterm birth are incompletely understood. Objectives To identify antenatal risk factors associated with increased risk for bronchopulmonary dysplasia (BPD) and respiratory disease during early childhood after preterm birth, we performed a prospective, longitudinal study of 587 preterm infants with gestational age less than 34 weeks and birth weights between 500 and 1,250 g. Methods Data collected included perinatal information and assessments during the neonatal intensive care unit admission and longitudinal follow-up by questionnaire until 2 years of age. Measurements and main results After adjusting for covariates, we found that maternal smoking prior to preterm birth increased the odds of having an infant with BPD by twofold (P = 0.02). Maternal smoking was associated with prolonged mechanical ventilation and respiratory support during the neonatal intensive care unit admission. Preexisting hypertension was associated with a twofold (P = 0.04) increase in odds for BPD. Lower gestational age and birth weight z-scores were associated with BPD. Preterm infants who were exposed to maternal smoking had higher rates of late respiratory disease during childhood. Twenty-two percent of infants diagnosed with BPD and 34% of preterm infants without BPD had no clinical signs of late respiratory disease during early childhood. Conclusions We conclude that maternal smoking and hypertension increase the odds for developing BPD after preterm birth, and that maternal smoking is strongly associated with increased odds for late respiratory morbidities during early childhood. These findings suggest that in addition to the BPD diagnosis at 36 weeks, other factors modulate late respiratory outcomes during childhood. We speculate that measures to reduce maternal smoking not only will lower the risk for preterm birth but also will improve late respiratory morbidities after preterm birth.

BackgroundPatent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin.MethodsSix SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders.ResultsThe G allele of rs2153628 was associated with increased odds of response to indomethacin in the case-control analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis.ConclusionWe identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.

OBJECTIVE:To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.METHODS:We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs RESULTS:Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs CONCLUSIONS:Center intervention rates explain a portion of the center variation in mortality, especially for infants born at

BACKGROUND Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity. METHODS We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (

Background:The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach.Methods:We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.Results:Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (P = 0.003), IGFBP3 (P = 0.006), DHCR7 (P = 0.009), and TRAF2 (P = 0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.Conclusion:These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.

Background The genetic basis of dysfunctional immune responses in necrotizing enterocolitis (NEC) remains unknown. We hypothesized that variants in Nucleotide binding and Oligomerization Domain (NOD)-Like Receptors (NLRs) and Autophagy (ATG) genes modulate vulnerability to NEC. Methods We genotyped a multi-center cohort of premature infants with and without NEC for NOD1, NOD2, ATG16L1, CARD8 and NLRP3 variants. Chi-square tests and logistic regression were used for statistical analysis. Results In our primary cohort (n=1015), 86 (8.5%) infants developed NEC. The A allele of the ATG16L1 (Thr300Ala) variant was associated with increased NEC (AA vs. AG vs. GG; 11.3% vs. 8.4% vs. 4.8%, p=0.009). In regression models for NEC that adjusted for epidemiological confounders, GA (p=0.033) and the AA genotype (p=0.038) of ATG16L1 variant were associated with NEC. The association between the A allele of the ATG16L1 variant and NEC remained significant among Caucasian infants (p=0.02). In a replication cohort (n=259), NEC rates were highest among infants with the AA genotype but did not reach statistical significance. Conclusion We report a novel association between a hypomorphic variant in an autophagy gene (ATG16L1) and NEC in premature infants. Our data suggest that decreased autophagy arising from genetic variants may confer protection against NEC.