Racial and Ethnic Disparities in Human Milk Intake at Neonatal Intensive Care Unit Discharge among Very Low Birth Weight Infants in California.

OBJECTIVES: To examine how infant and maternal factors, hospital factors, and neighborhood-level factors impact or modify racial/ethnic disparities in human milk intake at hospital discharge among very low birth weight infants. STUDY DESIGN: We studied 14 422 infants from 119 California Perinatal Quality Care Collaborative neonatal intensive care units born from 2008 to 2011. Maternal addresses were linked to 2010 census tract data, representing neighborhoods. We tested for associations with receiving no human milk at discharge, using multilevel cross-classified models. RESULTS: Compared with non-Hispanic whites, the adjusted odds of no human milk at discharge was higher among non-Hispanic blacks (aOR 1.33 [1.16-1.53]) and lower among Hispanics (aOR 0.83 [0.74-0.93]). Compared with infants of more educated white mothers, infants of less educated white, black, and Asian mothers had higher odds of no human milk at discharge, and infants of Hispanic mothers of all educational levels had similar odds as infants of more educated white mothers. Country of birth and neighborhood socioeconomic was also associated with disparities in human milk intake at discharge. CONCLUSIONS: Non-Hispanic blacks had the highest and Hispanic infants the lowest odds of no human milk at discharge. Maternal education and country of birth were the biggest drivers of disparities in human milk intake, suggesting the need for targeted approaches of breastfeeding support.

Fetal de novo mutations and preterm birth.

Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.

A Genome-Wide Analysis of Clinical Chorioamnionitis among Preterm Infants.

OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with clinical chorioamnionitis among preterm infants. STUDY DESIGN: We reanalyzed a genome-wide association study (GWAS) from preterm newborns at less than 30 weeks' gestation. Cases and control definitions were determined using administrative records. There were 213 clinical chorioamnionitis cases and 707 clinically uninfected controls. We compared demographic and clinical outcomes of cases and controls. We performed a GWAS and compared the distribution of SNPs from the background genes and from the immunome genes. We used a Wilcoxon's rank-sum test to compare the SNPs normalized odds ratio and used odds ratios and p-values to determine candidate genes. RESULTS: Infants affected by clinical chorioamnionitis were more likely to have periventricular leukomalacia, high-grade retinopathy, and high-grade intraventricular hemorrhage (IVH). Although a GWAS did not identify SNPs associated with clinical chorioamnionitis at the genome-wide significance level, a direct test on the exonic variants in the human immunome revealed their significant increase of risk in clinical chorioamnionitis. CONCLUSION: Among very preterm infants, clinical chorioamnionitis was associated with periventricular leukomalacia, high-grade retinopathy, and IVH. Our analysis of variants in the human immunome indicates an association with clinical chorioamnionitis in very preterm pregnancies.

Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth.

OBJECTIVE: To examine linkages between mitochondrial genetics and preterm birth by assessing the risk for preterm birth associated with the inheritance of nuclear haplotypes that are ancestrally distinct from mitochondrial haplogroup. STUDY DESIGN: Genome-wide genotyping studies of cohorts of preterm and term individuals were evaluated. We determined the mitochondrial haplogroup and nuclear ancestry for individuals and developed a scoring for the degree to which mitochondrial ancestry is divergent from nuclear ancestry. RESULTS: Infants with higher degrees of divergent mitochondrial ancestry were at increased risk for preterm birth (0.124 for preterm vs 0.105 for term infants; P< .05). This finding was validated in 1 of 2 replication cohorts. We also observed that greater degrees of divergent ancestry correlated with earlier delivery within the primary study population, but this finding was not replicated in secondary cohorts born preterm. CONCLUSIONS: Individuals with divergent patterns of mitochondrial and nuclear ancestry are at increased risk for preterm birth. These findings may in part explain the higher rates of preterm birth in African Americans and in individuals with a matrilineal family history of preterm birth.

Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis. OBJECTIVES: Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease. METHODS: We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes. MEASUREMENTS AND MAIN RESULTS: We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD. CONCLUSIONS: Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.

Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of α-fetoprotein, human chorionic gonadotropin, and unconjugated estriol.

INTRODUCTION: Although maternal serum α-fetoprotein (AFP), human chorionic gonandotropin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship with the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors. RESULTS: We found that these serum biomarkers were associated with an increased risk of BPD. Risks were especially high when AFP and/or hCG levels were above the 95th percentile and/or when unconjugated estriol (uE3) levels were below the 5th percentile (relative risks (RRs) 3.1-6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9-75.9). DISCUSSION: Data suggested that pregnancies that had a biomarker risk and yielded an offspring with BPD were more likely to have other factors present that suggested early intrauterine fetal adaptation to stress, including maternal hypertension and asymmetric growth restriction. METHODS: The objective of this population-based study was to examine whether second-trimester levels of AFP, hCG, and uE3 were associated with an increased risk of BPD.

The relationship between air pollutants and maternal socioeconomic factors on preterm birth in California urban counties.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality in the U.S. and disparities among racial and ethnic groups persist. While etiologies of preterm birth have not been fully elucidated, it is probable that environmental and social factors play a role. OBJECTIVE: We hypothesized that there is an interactive association between exposure to fine particulate matter (PM2.5) or ozone (O3) and neighborhood socioeconomic factors that increase the risk of preterm birth. METHODS: We conducted a retrospective study using geocoded birth certificate data between 2007 and 2011, daily ambient air quality data on PM2.5 and O3, and American Community Survey (2007-2011 5-year estimates) data to assess census tract-level socioeconomic factors in California urban counties. RESULTS: Our study found a small positive association between maternal exposures to PM2.5 and O3 and preterm birth that varied by gestational exposure period. In mixed-effects models, we found an increase in the risk of preterm birth for a one-unit change in PM2.5 averaged across the entire pregnancy (AOR = 1.02, 95% CI: 1.01, 1.02) and O3 during 3-months pre-pregnancy (AOR = 1.03, 95% CI: 1.02, 1.04). Interaction between census tract-level factors and air pollutants showed an increase in the risk of preterm birth among mothers living in higher socioeconomic areas, though, a fixed cohort bias sensitivity analysis showed these associations were not significant. SIGNIFICANCE: These findings substantiate previous studies that showed associations between air pollution and preterm birth, even as pollution levels have decreased. This study has important implications for policy decisions and may help inform research on potential mechanisms of preterm birth.

Multilevel social factors and NICU quality of care in California.

OBJECTIVE: Our objective was to incorporate social and built environment factors into a compendium of multilevel factors among a cohort of very low birth weight infants to understand their contributions to inequities in NICU quality of care and support providers and NICUs in addressing these inequities via development of a health equity dashboard. STUDY DESIGN: We examined bivariate associations between NICU patient pool and NICU catchment area characteristics and NICU quality of care with data from a cohort of 15,901 infants from 119 NICUs in California, born 2008-2011. RESULT: NICUs with higher proportion of minority racial/ethnic patients and lower SES patients had lower quality scores. NICUs with catchment areas of lower SES, higher composition of minority residents, and more household crowding had lower quality scores. CONCLUSION: Multilevel social factors impact quality of care in the NICU. Their incorporation into a health equity dashboard can inform providers of their patients' potential resource needs.

A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth.

Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births.

We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances.

Factors associated with use of medications with potential to impair cognition or cholinesterase inhibitors among Alzheimer's disease patients.

BACKGROUND: The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer's disease. METHODS: A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer's disease. Concurrent medications were measured, specifically: (1) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis. RESULTS: Fifteen percent of the Alzheimer's disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education. CONCLUSIONS: Determining the patient characteristics associated with the prescription of a medication with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of research.

Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.

Characterization of CFTR mutations in the U.S. Hispanic population is vital to early diagnosis, genetic counseling, patient-specific treatment, and the understanding of cystic fibrosis (CF) pathogenesis. The mutation spectrum in Hispanics, however, remains poorly defined. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. A total of 183 mutations were identified, including 14 different amino acid-changing novel variants. A significant proportion (78/85) of the different mutations identified would not have been detected by the ACMG/ACOG-recommended 25-mutation screening panel. Over one third of the mutations (27/85) occurred with a relative frequency >1%, which illustrates that the identified mutations are not all rare. This is supported by a comparison with other large CFTR studies. These results underscore the disparity in mutation identification between Caucasians and Hispanics and show utility for comprehensive diagnostic CFTR mutation analysis in this population.

Determinants of chronic lung disease severity in the first year of life; A population based study.

OBJECTIVES: First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA). STUDY DESIGN: Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC). RESULTS: We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA.

Unexpectedly high prevalence of posttransplant anemia in pediatric and young adult renal transplant recipients.

BACKGROUND: Although posttransplant anemia (PTA) is recognized as a common problem in adult renal transplant recipients, few pediatric studies have been published. METHODS: In this retrospective cohort study of 162 pediatric renal transplant recipients treated at Stanford University, the authors sought to determine the prevalence, severity, and the predictive factors of PTA. Anemia was defined as a hematocrit (HCT) level greater than 2 SD below published means for age or as erythropoietin dependency to maintain a normal HCT. RESULTS: Sixty-seven percent of pediatric renal transplant recipients were anemic at the time of transplantation. The prevalence of anemia increased to 84.3% in the first month posttransplant. From 6 months to 60 months posttransplant, the prevalence of anemia remained high at 64.2% to 82.2%. Only 4 patients (2.5%) were never anemic. Iron depletion was detected in 19 of 26 and 23 of 23 anemic patients 12 and 60 months posttransplant, respectively. Serum erythropoietin levels were low relative to hematocrit levels in 38 of 56 anemic patients. Logistic regression at 3 months posttransplant showed that discharge hematocrit level (P < 0.0001), calcium (P = 0.0004), and cyclosporine dose (P = 0.0002) correlated with anemia. Creatinine clearance (P = 0.002) and white blood cell count (P = 0.004) correlated with anemia at 12 months posttransplant, but only creatinine clearance (P = 0.011) correlated with anemia 60 months posttransplant. CONCLUSION: Nearly all pediatric renal transplant recipients experience PTA. However, few children less than 2 years of age were anemic during the first year posttransplant. Antirejection therapy, bone disease, iron depletion, and creatinine clearance appear to play pivotal roles in the development of PTA in children.

Lifestyle habits and compression of morbidity.

BACKGROUND: There has been much debate regarding the degree to which healthy lifestyles can increase longevity and whether added years will be offset by increased morbidity at older ages. This study was designed to test the compression of morbidity hypothesis, proposing that healthy lifestyles can reduce and compress disability into a shorter period toward the end of life. METHODS: Functional status in 418 deceased members of an aging cohort was observed between 1986 and 1998 in relationship to lifestyle-related risk factors, including cigarette smoking, physical inactivity, and under- or overweight. Three risk groups were created based on the number of these factors at study entry. Disability scores prior to death were modeled for each risk group to compare levels and rates of change, as well as to determine if and when acceleration in functional decline occurred. RESULTS: The risk-factor-free group showed average disability scores near zero 10-12 years before death, rising slowly over time, without evidence of accelerated functional decline. In contrast, those with two or more factors maintained a greater level of disability throughout follow-up and experienced an increase in the rate of decline 1.5 years prior to death. For those at moderate risk, the rate of decline increased significantly only in the last 3 months of life. Other differences between groups provided no alternative explanations for the findings. CONCLUSIONS: These results make a compelling argument for the reduction and postponement of disability with healthier lifestyles as proposed by the compression of morbidity hypothesis.

The accuracy of human senses in the detection of neonatal heart rate during standardized simulated resuscitation: implications for delivery of care, training and technology design.

AIM: Auscultation and palpation are recommended methods of determining heart rate (HR) during neonatal resuscitation. We hypothesized that: (a) detection of HR by auscultation or palpation will vary by more than ± 15BPM from actual HR; and (b) the inability to accurately determine HR will be associated with errors in management of the neonate during simulated resuscitation. SUBJECTS AND METHODS: Using a prospective, randomized, controlled study design, 64 subjects participated in three simulated neonatal resuscitation scenarios. Subjects were randomized to technique used to determine HR (auscultation or palpation) and scenario order. Subjects verbalized their numeric assessment of HR at the onset of the scenario and after any intervention. Accuracy of HR determination and errors in resuscitation were recorded. Errors were classified as errors of omission (lack of appropriate interventions) or errors of commission (inappropriate interventions). Cochran's Q and chi square test were used to compare HR detection by method and across scenarios. RESULTS: Errors in HR determination occurred in 26-48% of initial assessments and 26-52% of subsequent assessments overall. There were neither statistically significant differences in accuracy between the two techniques of HR assessment (auscultation vs palpation) nor across the three scenarios. Of the 90 errors in resuscitation, 43 (48%) occurred in association with errors in HR determination. CONCLUSIONS: Determination of heart rate via auscultation and palpation by experienced healthcare professionals in a neonatal patient simulator with standardized cues is not reliable. Inaccuracy in HR determination is associated with errors of omission and commission. More reliable methods for HR assessment during neonatal resuscitation are required.

A genome-wide association study (GWAS) for bronchopulmonary dysplasia.

OBJECTIVE: Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD. METHODS: The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip. RESULTS: Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative. CONCLUSIONS: We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

Comparison of umbilical venous and intraosseous access during simulated neonatal resuscitation.

OBJECTIVE: Emergent umbilical venous catheter (UVC) placement for persistent bradycardia in the delivery room is a rare occurrence that requires significant skill and involves space constraints. Placement of an intraosseous needle (ION) in neonates has been well described. The ION is already used in the pediatric population and is placed at an anatomic location distant from where chest compressions are performed. In this study we compared time to placement, errors in placement, and perceived ease of use for UVCs and IONs in a simulated delivery room. SUBJECTS AND METHODS: Forty health care providers were recruited. Subjects were shown an instructional video of both techniques and allowed to practice placement. Subjects participated in 2 simulated neonatal resuscitations requiring intravenous epinephrine. In 1 scenario they were required to place a UVC and in the other an ION. Scenarios were recorded for later analysis of placement time and error rate. Subjects were surveyed regarding the perceived level of difficulty of each technique. RESULTS: The average time required for ION placement was 46 seconds faster than for UVC placement (P < .001). There was no significant difference in the number of errors between UVC and ION placement or in perceived ease of use. CONCLUSIONS: In a simulated delivery room setting, ION placement can be performed more quickly than UVC insertion without any difference in technical error rate or perceived ease of use. ION insertion should be considered when rapid intravenous access is required in the neonate at the time of birth, especially by health care professionals who do not routinely place UVCs.