Does maternal asthma contribute to racial/ethnic disparities in obstetrical and neonatal complications?

PURPOSE: To examine whether maternal asthma contributes to racial/ethnic differences in obstetrical and neonatal complications. METHODS: Data on white (n = 110,603), black (n = 50,284), and Hispanic (n = 38,831) singleton deliveries came from the Consortium on Safe Labor. Multilevel logistic regression models, with an interaction term for asthma and race/ethnicity, estimated within-group adjusted odds ratios (aORs) for gestational diabetes, gestational hypertension, pre-eclampsia, placental abruption, premature rupture of membranes, preterm delivery, maternal hemorrhage, neonatal intensive care unit admissions, small for gestational age, apnea, respiratory distress syndrome, transient tachypnea of the newborn, anemia, and hyperbilirubinemia after adjustment for clinical and demographic confounders. Nonasthmatics of the same racial/ethnic group were the reference group. RESULTS: Compared with nonasthmatics, white asthmatics had increased odds of pre-eclampsia (aOR, 1.28; 95% confidence interval [CI], 1.15-1.43) and maternal hemorrhage (aOR, 1.14; 95% CI, 1.04-1.23). White and Hispanic infants were more likely to have neonatal intensive care unit admissions (aOR, 1.19; 95% CI, 1.11-1.28; aOR, 1.16; 95% CI, 1.02-1.32, respectively) and be small for gestational age (aOR, 1.11; 95% CI, 1.02-1.20; aOR, 1.26; 95% CI, 1.10-1.44, respectively), and Hispanic infants were more likely to have apnea (aOR, 1.32; 95% CI, 1.02-1.69). CONCLUSIONS: Maternal asthma did not affect most obstetrical and neonatal complication risks within racial/ethnic groups. Despite their increased risk for both asthma and many complications, our findings for black women were null. Asthma did not contribute to racial/ethnic disparities in complications.

Late-preterm birth and neonatal morbidities: population-level and within-family estimates.

PURPOSE: The objective of this study was to compare two salient neonatal outcomes-respiratory disorders and hyperbilirubinemia-between late-preterm (34-36 weeks) and full-term (37-41 weeks) singleton infants both at the population level and within families. METHODS: Analyses were based on natality data on all births in the state of New Jersey from 1996 to 2006 linked to newborn hospital discharge records. For population-level models, logistic regression analyses were conducted to estimate unadjusted and adjusted differences in outcomes by gestational age. For within-family analyses, unadjusted and adjusted logistic fixed-effects models were estimated with the latter including factors that differed across births to the same mother. RESULTS: Late-preterm birth increased the odds of a neonatal respiratory condition by more than fourfold (odds ratio, 4.08-4.53) and of neonatal hyperbilirubinemia by more than fivefold (odds ratio, 5.11-5.93) even when comparing births to the same mother and controlling for demographic and economic, behavioral, and obstetric factors that may have changed across pregnancies. CONCLUSIONS: Based on population-level and within-family models, this study provides the strongest evidence to date that late-preterm birth is an important risk factor for adverse neonatal outcomes that other studies have found are associated with cognitive and behavioral disorders in childhood.

Synonymous ABCA3 variants do not increase risk for neonatal respiratory distress syndrome.

OBJECTIVE: To determine whether synonymous variants in the adenosine triphosphate-binding cassette A3 transporter (ABCA3) gene increase the risk for neonatal respiratory distress syndrome (RDS) in term and late preterm infants of European and African descent. STUDY DESIGN: Using next-generation pooled sequencing of race-stratified DNA samples from infants of European and African descent at ≥34 weeks gestation with and without RDS (n = 503), we scanned all exons of ABCA3, validated each synonymous variant with an independent genotyping platform, and evaluated race-stratified disease risk associated with common synonymous variants and collapsed frequencies of rare synonymous variants. RESULTS: The synonymous ABCA3 variant frequency spectrum differs between infants of European descent and those of African descent. Using in silico prediction programs and statistical strategies, we found no potentially disruptive synonymous ABCA3 variants or evidence of selection pressure. Individual common synonymous variants and collapsed frequencies of rare synonymous variants did not increase disease risk in term and late-preterm infants of European or African descent. CONCLUSION: In contrast to rare, nonsynonymous ABCA3 mutations, synonymous ABCA3 variants do not increase the risk for neonatal RDS among term and late-preterm infants of European or African descent.

Surfactant protein B deficiency and gene mutations for neonatal respiratory distress syndrome in China Han ethnic population.

OBJECTIVE: To determine whether the SP-B deficiency and gene mutations in exon 4 is associated with neonatal RDS in China Han ethnic population. METHODS: The study population consisted of 40 neonates with RDS and 40 neonates with other diseases as control in China Han ethnic population. We Compared SP-B expression in lung tissue and bronchoalveolar lavage fluid with immunoblotting, and analyzed mutations in the SP-B gene with polymerase chain reaction (PCR) and gene sequencing. RESULTS: In RDS group, low mature Surfactant protein B was found in both lung tissue and bronchoalveolar lavage fluid in 8 neonates. In control group, only 4 neonates with low mature Surfactant protein B in both lung tissue and bronchoalveolar lavage fluid. In RDS group, 20 neonates were found to have mutations in exon 4, 12 homozygous mutations with C/C genotype and 8 heterozygous mutations with C/T genotype in surfactant protein B gene+1580 polymorphism. There were 8 cases mutations in control group, 1 in C/C and 7 in C/T genotype. The frequency of homozygotes with C/C genotype was 0.3 and frequency of heterozygotes with C/T genotype was 0.02 in RDS group. In control group, frequency of homozygotes with C/C genotype was 0.025 and frequency of heterozygote with C/T genotype was 0.175. CONCLUSION: Low mature Surfactant protein B is associated with the pathogenesis of neonatal respiratory distress syndrome (RDS) in China Han ethnic population. Mutations in exon 4 of the surfactant protein B gene demonstrate an association between homozygous mutations with C/C genotype in SP-B gene and neonatal RDS.

Surfactant protein A associated with respiratory distress syndrome in Korean preterm infants: evidence of ethnic difference.

BACKGROUND: Insufficiency of the pulmonary surfactant system is the primary cause of respiratory distress syndrome (RDS) in preterm infants. Genetic factors, including specific single-nucleotide polymorphisms in the genetic components of surfactant protein A (SP-A1 and SP-A2), affect protein structure and function, as well as risk of RDS. OBJECTIVE: We investigated the association between variations in SP-A genotypes and RDS within the genetically homogeneous Korean population. METHODS: We used TaqMan® real-time polymerase chain reaction technology to assess nine single-nucleotide polymorphisms of SP-A in 261 full-term and 152 preterm infants. Among the preterm infants, 76 infants with RDS were matched with 76 control infants with respect to gestation, use of antenatal steroids and gender. RESULTS: The SP-A2 1A(0) variant and the homozygous 1A(0)/1A(0) genotype were associated with protection from RDS (OR 0.31, 95% CI 0.13-0.78). In addition, the 1A(1) carrier genotype (containing one copy of the 1A(1) variant) was associated with increased risk of RDS (OR 2.42, 95% CI 1.06-5.52). The significance of these results is that the association of patterns with RDS was opposite to the findings of previous research with Finnish and North American study populations. CONCLUSIONS: We have identified associations between specific variants of the SP-A genes and RDS risk in the Korean preterm study population. Our data strongly support SP-A as a candidate gene for susceptibility to RDS, and reveal the dissimilarity of the associated risk/protective genetic variants between different ethnic study populations.

Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.

BACKGROUND AND OBJECTIVE: Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability. METHODS: Using next-generation, pooled sequencing of race-stratified DNA samples from infants ≥34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk. RESULTS: Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B. CONCLUSIONS: In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants ≥34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.

Increased risk for respiratory distress among white, male, late preterm and term infants.

OBJECTIVE: To determine whether race/ethnicity and sex independently increase risk of respiratory distress syndrome (RDS) in late preterm and term infants. STUDY DESIGN: Using a cohort design, we studied the risk of RDS associated with race/ethnicity and sex in infants with gestational age (GA) 34 to 42 weeks born between 1 January 2000 and 31 December 2009 (n=286 454) within 12 hospitals in the Northern California Kaiser Permanente Medical Care Program. RESULT: Male sex (adjusted odds ratio (aOR) 1.68; 95% confidence interval 1.45 to 1.93) and White race/ethnicity (vs Asians (aOR 0.57; 95% confidence interval 0.47 to 0.70), Blacks (aOR 0.66; 95% confidence interval 0.50 to 0.87), and Hispanics (aOR 0.76; 95% confidence interval 0.64 to 0.90)) independently increase risk for RDS regardless of GA. A GA <39 weeks, operative delivery, maternal diabetes, and chorioamnionitis also increased RDS risk in this cohort. CONCLUSION: Male sex and White race/ethnicity independently increase risk for RDS in late preterm and term infants. Timing of elective delivery should acknowledge these risks.

[Pulmonary surfactant associated gene variants in mixed ethnic population of Han and Zhuang].

OBJECTIVE: To explore the prevalence of pulmonary surfactant associated pathway genes functional variants in Chinese population. METHOD: Using a cohort of 258 mixed ethnic population of Han and Zhuang, we pooled DNA samples from 146 term male infants and 112 term female infants and then used an Ill umina next generation sequencing platform to perform the complete exonic resequencing in 6 target genes:surfactant protein-B (SFTPB), surfactant protein-C (SFTPC), ATP-binding cassette transporter A3 (ABCA3), lysophospholipid acyltransferase 1 (LPCAT1), choline phosphotransferase 1 (CHPT1), phosphate cytidylyltransferase 1, choline, beta (PCYT1B). Collapsing methods was used to determine the functional allele frequency. RESULT: (1) Altogether, 128 variants were found, including 44 synonymous variants, 66 nonsynonymous variants and 18 insertions-deletions. Of these, 28 variants were predicted to alter protein function. Two of these variants were seen twice, the rest variants were only seen once, for a total of 30 functional alleles; (2) ABCA3 had the most functional variants in both male and female groups with the minor allele frequencies of 0.014 (1.4%) and 0.04 (4%), respectively. The total functional allele frequencies of 6 genes were 0.041 (4.1%) and 0.08 (8%) in the two groups, respectively (P = 0.06). CONCLUSION: (1) Functional variants in pulmonary surfactant associated pathway genes are present in the mixed Han-Zhuang population. (2) ABCA3 contained the most functional variants suggesting that ABCA3 could contribute significantly to neonatal respiratory distress syndrome and other lung disease.

Neurodevelopmental outcome and risk factors for impaired development of African American infants in an underserved urban population: a population-based study.

We aimed 1) to define risk factors for adverse outcome in urban African American patients, 2) to determine whether clinical variables as risk factors are congruent with previously published data, and 3) to identify the proportion of infants with different outcomes. The study included African American infants who were born and participated in neurodevelopmental follow-up. Infants with gestational age range of 23 to 41 weeks, and birth weight (BW) range of 495 to 3,965 g were classified by developmental outcome. Among the smallest infants, BW, gestational age, gender and respiratory distress syndrome were significantly (p<.05) associated with adverse outcome. No significant risk factors were identified for adverse outcome in the two other birth weight categories. Adverse outcomes were seen more frequently in infants with BW ≤1,500 g than in larger infants. The number of infants with severe outcome was found higher than previously reported and may be related to different racial/generational origin.

Maternal ethnicity influences on neonatal respiratory outcomes after antenatal corticosteroid use for anticipated preterm delivery.

OBJECTIVE: To explore the influence of maternal ethnicity on neonatal outcomes after antenatal corticosteroid administration. METHODS: A retrospective review of ethnicity, maternal factors, and neonatal birth outcomes was performed for preterm births at a single institution. Cases were limited to women who received antenatal corticosteroids. The impact of ethnicity on specific neonatal respiratory outcomes and mortality was analyzed by bivariate comparisons and by logistic regression analysis. RESULTS: Complete ethnicity data were obtained for 548 women. Controlling for gestational age at delivery, diabetes, whether the subject completed a course of steroids, and the dosing of the steroids, logistic regression demonstrated that ethnicity was independently associated with respiratory distress syndrome (compared to Caucasians: African-Americans OR 0.49 (95% CI 0.29-0.85); Filipinos OR 0.45 (95% CI 0.21-0.96). CONCLUSIONS: Ethnicity is independently associated with neonatal respiratory outcomes after antenatal corticosteroid use. Perhaps individualized dosing of antenatal corticosteroids is needed to further improve neonatal outcomes.

Do racial disparities persist in infant mortality from respiratory distress syndrome?

OBJECTIVE: To examine the subset of the infants who died in 2005 from respiratory distress syndrome to determine if racial disparities persist. DESIGN: A secondary data analysis was performed on the data set of infants who died of respiratory distress syndrome (RDS) in the 2005 period linked birth-infant death data file (N=774). METHODS: Logistic regression was performed to evaluate the contribution of race to RDS-related mortality. RESULTS: When analyzed independently, Black infants were 1.3 times more likely to die of RDS mortality than White infants. After the known predictors of gestation, birth weight, and gender were added to the model, Black race was no longer a significant predictor of RDS. CONCLUSIONS: Despite Black race having been identified as a contributor to RDS mortality in the past, race was not a predictor of RDS mortality in the 2005 cohort. Previous analyses comparing pre- and post-surfactant era mortality assumed that all eligible infants received surfactant, and Black infants did not respond as well as White infants. The 2003 birth certificate revision included surfactant administration, but only 12 states reported that data in the 2005 data set. Only 22% of eligible infants had documentation of surfactant administration. Future research is needed to confirm that eligible infants are receiving surfactant and to evaluate the response of infants by race. If Black infants do not respond to the available surfactant replacement products, genomics research is needed to explore targeted therapies for this group.

Deprivation, ethnicity and prematurity in infant respiratory failure in PICU in the UK.

AIM: To describe the epidemiology of infants admitted to Paediatric Intensive Care (PIC) with acute respiratory failure including bronchiolitis. METHODS: Data from all consecutive admissions from 2004 to 2007 in all 29 designated Paediatric Intensive Care Units (PICUs) in England and Wales were collected. Admission rates, risk-adjusted mortality, length of stay, ventilation status, preterm birth, deprivation and ethnicity were studied. RESULTS: A total of 4641 infants under 1 year of age had an unplanned admission to PIC with acute respiratory failure (ARF), an admission rate of 1.80 per 1000 infants per year. There was a reduced rate of admission with bronchiolitis in South Asian children admitted to PICU, which is not explained by case-mix. Children born preterm had a higher rate of admission and longer stay, but a similar low mortality. Risk-adjusted mortality was higher in South Asian infants and the highest in those with ARF (OR 1.76, 95% CI 1.20-2.57) compared with the rest of the PICU population. CONCLUSION: Acute respiratory failure in infants causes most of the seasonal variation in unplanned admission to intensive care. Socioeconomic deprivation and prematurity are additional risk factors for admission. Fewer South Asian infants are admitted to PICU with a diagnosis of bronchiolitis, but risk-adjusted mortality is higher in South Asian infants overall.

Surfactant use for premature infants with respiratory distress syndrome in three New York city hospitals: discordance of practice from a community clinician consensus standard.

OBJECTIVE: To assess concordance with a locally developed standard of care for premature infants with respiratory distress syndrome (RDS) for whom the standard recommends surfactant treatment within 2 h of birth, and to examine the association between clinical, demographic, and hospital characteristics with discordance from the standard. STUDY DESIGN: Retrospective cohort study of 773 infants weighing < or =1750 g born in any of the three New York City hospitals between 1999 and 2002. RESULT: 227 of the 773 infants (29%) met criteria for treatment according to the standard. Of these, 37% received surfactant by 2 h. By 4 h, 70% of infants who met the standard received surfactant. White infants were more likely to receive surfactant by 4 h (85%) than African American (61%) or Latino infants (67%). Multivariable logistic regression revealed significant odds ratios predicting discordance from the relaxed criteria (4 h) for African American race (4.10, 95% confidence interval: 1.30 to 13.00), 100 g of birth weight (odds ratio: 1.22, 95% confidence interval: 1.10 to 1.34), and hospital of birth. CONCLUSION: Many infants with RDS failed to receive surfactant replacement therapy at 2 and 4 h after birth. African Americans and those born larger were less likely to receive surfactant. If these data can be generalized, there is a large opportunity to reduce infant morbidity from RDS and to reduce racial/ethnic disparities in birth outcomes by increasing the rate and speed with which surfactant is delivered to these infants.

Timing of planned cesarean delivery by racial group.

OBJECTIVE: To estimate the incidence of newborn respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN) in relation to gestational age and planned cesarean delivery in white, South Asian, and black women. METHODS: Included in this study were 442,596 white, South Asian, and black women who delivered single live infants at 28 of weeks gestation onwards between 1988 and 2000. Using multiple logistic regression, the gestation-specific patterns of RDS for all deliveries and RDS plus TTN for deliveries by planned cesarean delivery were analyzed by racial group. The predictors of RDS from 37 weeks of gestation onwards were determined. RESULTS: More South Asians (28.2%, 95% confidence interval [CI] 27.8-28.6) and blacks (24.6%, 95% CI 24.0-25.1) delivered spontaneously before 39 weeks than whites (16.9%, 95% CI 16.8-17.1). Respiratory distress syndrome patterns by gestation differed significantly (P<.001). Compared with whites, the gestation-specific crude RDS rate was lower in South Asians up until 40 weeks and after adjusting for confounders; South Asians were most protected against RDS (odds ratio [OR] 0.6, 95% CI 0.5-0.9). The gestation-specific patterns of RDS plus TTN after planned cesarean delivery also differed significantly (P<.001) between racial groups. The lowest rate of TTN plus RDS was at 40 weeks for whites, but in South Asians and blacks, it was lowest at 38 weeks. CONCLUSION: The gestation-specific patterns of RDS differed significantly by racial group from 32 weeks of gestation onwards. Preterm black infants had a lower rate of RDS when compared with whites; also, South Asians had the lowest rate of transient tachypnea until 38 weeks and the lowest rate of RDS until 40 weeks of gestation. The advantages of waiting until 39 weeks to perform planned cesarean delivery for white women are not seen in South Asians or blacks.

Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.

BACKGROUND: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified. METHODS: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut. RESULTS: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 (Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation. CONCLUSION: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

Comprehensive genetic variant discovery in the surfactant protein B gene.

Completely penetrant mutations in the surfactant protein B gene (SFTPB) and >75% reduction of SFTPB expression disrupt pulmonary surfactant function and cause neonatal respiratory distress syndrome. To inform studies of genetic regulation of SFTPB expression, we created a catalogue of SFTPB variants by comprehensive resequencing from an unselected, population-based cohort (n = 1,116). We found an excess of low-frequency variation [81 SNPs and five small insertion/deletions (in/dels)]. Despite its small genomic size (9.7 kb), SFTPB was characterized by weak linkage disequilibrium (LD) and high haplotype diversity. Using the HapMap Yoruban and European populations, we identified a recombination hot spot that spans SFTPB, was not detectable in our focused resequencing data, and accounts for weak LD. Using homology-based software tools, we discovered no definitively damaging exonic variants. We conclude that excess low-frequency variation, intragenic recombination and lack of common disruptive exonic variants favor complete resequencing as the optimal approach for genetic association studies to identify regulatory SFTPB variants that cause neonatal respiratory distress syndrome in genetically diverse populations.

The increasing racial disparity in infant mortality: respiratory distress syndrome and other causes.

Although substantial declines in infant mortality rates have occurred across racial/ethnic groups, there has been a marked increase in relative black-white disparity in the risk of infant death over the past two decades. The objective of our analysis was to gain insight into the reasons for this growing inequality on the basis of data from linked cohort files for 1989-1990 and 1995-1998. We found a nationwide reversal from a survival advantage to a survival disadvantage for blacks with respect to respiratory distress syndrome over this period. The results are consistent with the view that the potential for a widening of the relative racial gap in infant mortality is high when innovations in health care occur in a continuing context of social inequality. As expected, the results for other causes of infant mortality, although similar, are less striking. Models of absolute change demonstrate that among low-weight births, absolute declines in mortality were greater for white infants than for black infants.

Racial differences in leading causes of infant death in the United States.

We used linked birth/infant death records of over 23 million singletons belonging to six birth cohorts (1989-91 and 1995-97) and examined changes in race differentials in the overall and cause-specific infant mortality risks across time in the United States. Results show that infant mortality declined for all races during the time period, with disproportionately greater declines among non-Hispanic American Indians (AIs). Among the leading causes of infant death, declines in mortality from sudden infant death syndrome (SIDS), respiratory distress syndrome (RDS) and congenital anomalies contributed the most to the overall decline in infant mortality in the 1995-97 cohorts, compared with the 1989-91 cohorts. Disproportionately greater reductions in mortality resulting from SIDS and congenital anomalies led to more rapid mortality declines among non-Hispanic AIs than for other races. There are disturbing findings that infants of almost every race experienced increases in mortality from newborn affected by maternal complications of pregnancy (maternal complications) and that none of the race groups experienced a significant decline in mortality from disorders resulting from short gestation/low birthweight.