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.

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.

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.

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.

Postural balance in children with cerebral palsy.

Postural control deficits have been suggested to be a major component of gait disorders in cerebral palsy (CP). Standing balance was investigated in 23 ambulatory children and adolescents with spastic diplegic CP, ages 5 to 18 years, and compared with values of 92 children without disability, ages 5 to 18 years, while they stood on a force plate with eyes open or eyes closed. The measurements included center of pressure calculations of path length per second, average radial displacement, mean frequency of sway, and Brownian random motion measures of the short-term diffusion coefficient, and the long-term scaling exponent. In the majority of children with CP (14 of 23) all standing balance values were normal. However, approximately one-third of the children with CP (eight of 23) had abnormal values in at least two of the six center of pressure measures. Thus, mean values for path length, average radial displacement, and diffusion coefficient were higher for participants with CP compared with control individuals with eyes open and closed (p<0.05). Mean values for frequency of sway and the long-term scaling exponent were lower for participants with CP compared with control participants (p<0.05). Increased average radial displacement was the most common (nine of 23) postural control deficit. There was no increase in abnormal values with eyes closed compared with eyes open for participants with CP, indicating that most participants with CP had normal dependence on visual feedback to maintain balance. Identification of those children with impaired standing balance can delineate factors that contribute to the patient's gait disorder and help to guide treatment.