Trends in the early care of infants with myelomeningocele in the United States 2012-2018.

PURPOSE: The early care of children with spina bifida has changed with the increasing availability of fetal surgery and evidence that fetal repair improves the long-term outcomes of children with myelomeningocele. We sought to determine current trends in the prevalence and early care of children with myelomeningocele using a national administrative database. METHODS: This is a retrospective, cross-sectional cohort study of infants with spina bifida admitted within the first 28 days of life using the 2012-2018 Healthcare Cost and Utilization Project National Inpatient Database. Patients with spina bifida were identified by ICD code and stratified into a cohort with a coded neonatal repair of the defect and those without a coded repair. This database had no identifier specific for fetal surgery, but it is likely that a substantial number of infants without a coded repair had fetal surgery. RESULTS: We identified 5,090 patients with a coded repair and 5,715 without a coded repair. The overall prevalence of spina bifida was 3.94 per 10,000 live births. The percentage of patients without neonatal repair increased during the study period compared to those with repair (p = 0.0002). The cohort without neonatal repair had a higher risk of death (p < 0.001), prematurity (p < 0.001), and low birth weight (p < 0.001). More shunts were placed in patients who underwent neonatal repair (p < 0.001). Patients without neonatal repair were less likely to have public insurance (p = 0.0052) and more likely to reside in zip codes within the highest income quartile (p = 0.0002). CONCLUSIONS: The prevalence of spina bifida from 2012 to 2018 was 3.94 per 10,000 live births, with an increasing number of patients without neonatal repair of the defect, suggesting increased utilization of fetal surgery. Patients without neonatal repair had a higher risk of death, prematurity, and low birth weight but were more likely to have commercial insurance and reside in high-income zip codes.

Code Blue Events in the Neonatal and Pediatric Intensive Care Units at a Tertiary Care Children's Hospital.

OBJECTIVE: The authors aim to compare all code blue events, regardless of the need for chest compressions, in the neonatal intensive care unit (NICU) versus the pediatric intensive care unit (PICU). We hypothesize that code events in the two units differ, reflecting different disease processes. STUDY DESIGN: This is a retrospective analysis of 107 code events using the code narrator, which is an electronic medical record of real-time code documentation, from April 2018 to March 2019. Events were divided into two groups, NICU and PICU. Neonatal resuscitation program algorithm was used for NICU events and a pediatric advanced life-support algorithm was used for PICU events. Events and outcomes were compared using univariate analysis. The Mann-Whitney test and linear regressions were done to compare the total code duration, time from the start of code to airway insertion, and time from airway insertion to end of code event. RESULTS: In the PICU, there were almost four times more code blue events per month and more likely to involve patients with seizures and no chronic condition. NICU events more often involved ventilated patients and those under 2 months of age. The median code duration for NICU events was 2.5 times shorter than for PICU events (11.5 vs. 29 minutes), even when adjusted for patient characteristics. Survival to discharge was not different in the two groups. CONCLUSION: Our study suggests that NICU code events as compared with PICU code events are more likely to be driven by airway problems, involve patients <2 months of age, and resolve quickly once airway is taken care of. This supports the use of a ventilation-focused neonatal resuscitation program for patients in the NICU. KEY POINTS: · Code blue events are four times more common in PICU.. · NICU code events are 2.5 times shorter in duration compared with PICU events.. · NICU code events are more likely to be attributed to a problem with an airway..

Neonatal Birth Trauma: Analysis of Yearly Trends, Risk Factors, and Outcomes.

OBJECTIVE: To evaluate the trends, proportions, risk factors, resource utilization, and outcomes of neonatal birth trauma in the US. STUDY DESIGN: This cross-sectional study of in-hospital births used the Nationwide Inpatient Sample for 2006-2014. We divided the cases by type of birth trauma: scalp injuries and major birth trauma. Linear regression for yearly trends and logistic regression were used for risk factors and outcomes. A generalized linear model was used, with a Poisson distribution for the length of stay and a gamma distribution for total spending charges. RESULTS: A total of 982 033 weighted records with neonatal birth trauma were found. The prevalence rate increased by 23% from (from 25.3 to 31.1 per 1000 hospital births). Scalp injuries composed 80% of all birth traumas and increased yearly from 19.87 to 26.46 per 1000 hospital births. Major birth trauma decreased from 5.44 to 4.67 per 1000 hospital births due to decreased clavicular fractures, brachial plexus injuries, and intracranial hemorrhage. There were significant differences in demographics and risk factors between the 2 groups. Compared with scalp injuries, major birth trauma was associated with higher odds of hypoxic-ischemic encephalopathy, seizures, need for mechanical ventilation, meconium aspiration, and sepsis. Length of stay was increased by 56%, and total charges were almost doubled for major birth trauma. CONCLUSIONS: Neonatal birth trauma increased over the study period secondary to scalp injuries. Major birth trauma constitutes a significant health burden. Scalp injuries are also associated with increased morbidity and might be markers of brain injury in some cases.

Improved Maternal and Infant Outcomes with Serial, Self-Reported Early Prenatal Substance Use Screening.

INTRODUCTION: Most screening tools identifying women with substance use are not validated, used once in pregnancy, and are not reflective of continued substance use. We hypothesized that serial early prenatal substance screening leads to decreased substance use by the end of pregnancy and improved outcomes. METHODS: This is a retrospective cohort study of mothers and their infants between 1/2015 and 12/2017. A self-reported substance screening tool was administered on the first prenatal visit and subsequent visits until delivery. For analysis, mothers were divided into three groups based on the trimester of their first screen and adjusted for demographics and risk factors. RESULTS: Early first trimester screening resulted in 52% of mothers having ≥ 3 screens throughout pregnancy vs. 6% of mothers with late third trimester screens (p < 0.001). Compared to third trimester screening, there was a five-fold decrease of any substance use at second trimester, a seven-fold decrease at first trimester, and a nine-fold decrease for marijuana at first trimester. Compared to third trimester screening, there was a significant five-fold increase of negative maternal urine drug screen, 3 ½ -fold increase in well newborn diagnosis, and a five-fold increase of no infant morphine treatment at first trimester. DISCUSSION: We identified improved maternal and infant outcomes with serial early prenatal substance use screening. Early maternal substance use identification is crucial for immediate referral for prevention and treatment, and for social and community services. Further research is needed on universal serial early prenatal screenings.

Outcome of neonates with gastroschisis at different gestational ages using a national database.

BACKGROUND/PURPOSE: The optimal time for delivery of neonates with a prenatal diagnosis of gastroschisis (GS) is controversial. We compared the outcomes for GS at three different gestational ages (GAs), 33-34 weeks, 35-36 weeks, and ≥ 37 weeks. METHODS: We analyze hospital discharge data of neonates with GS using the 2006, 2009 and 2012 Healthcare Cost and Utilization Project Kids' Inpatient Database (HCUPKIDS). Multivariable analysis was used to compare the association between GS outcomes and the three GAs. RESULTS: Significantly higher number of 33-34 week infants had coexisting morbidities like respiratory distress syndrome, bronchopulmonary dysplasia, small bowel atresia, stenosis, or stricture, large bowel atresia and/or stenosis, malrotation, and atrial septal defect. In multivariable logistic regression, 33-34 week infants had higher NEC (p value = 0.002, 95% CI1.64-10.32), small bowel resection (0.024, 1.12-5.25) and pRBCs transfusion (0.024, 1.05-2.11). No differences were found between 35-36 weeks and ≥37 weeks gest infants for NEC, malabsorption, small bowel resection, TPN cholestasis, sepsis, CLABSI, number of pRBCs transfusion, length of stay and total charges. CONCLUSION: We did not show benefit for delivering early and in the absence of data, delivery at ≥37 weeks was noninferior to 35-36 weeks. We suggest that waiting for spontaneous onset of labor may be a better approach to balance the effects of prematurity and possible ongoing in utero bowel damage/stillbirth. LEVELS OF EVIDENCE: Level 3 (Retrospective comparative study).

Racial/ethnic disparities in maternal morbidities: a statewide study of labor and delivery hospitalizations in Wisconsin.

We examined racial/ethnic disparities in maternal morbidities (MM) and the number of MM during labor and delivery among hospital discharges in Wisconsin. We conducted a retrospective cohort study of hospital discharge data for 206,428 pregnant women aged 13-53 years using 2005-2007 Healthcare Cost and Utilization Project State Inpatient Dataset (HCUP-SID) for Wisconsin. After adjustments for covariates, MM (preterm labor, antepartum and postpartum hemorrhage, hypertension in pregnancy, gestational diabetes, membrane-related disorders, infections and 3rd and 4th perineal lacerations) were examined using logistic regression models, and number of MM (0, 1, 2, >2 MM) were examined using multivariable ordered logistic regressions with partial proportional odds models. African-Americans had significantly higher likelihood of infections (OR = 1.74; 95% CI 1.60-1.89), preterm labor (OR = 1.42; 1.33-1.50), antepartum hemorrhage (OR = 1.63; 1.44-1.83), and hypertension complicating pregnancy (OR = 1.39; 1.31-1.48) compared to Whites. Hispanics, Asian/Pacific Islanders, and Native Americans had significantly higher likelihood of infections, postpartum hemorrhage, and gestational diabetes than Whites. Major perineal lacerations were significantly higher among Asian/Pacific Islanders (OR = 1.53; 1.34-1.75). All minority racial/ethnic groups, except Asians, had significantly higher likelihood of having 0 versus 1, 2 or >2 MM, 0 or 1 versus 2 or >2 MM, and 0, 1 or 2 versus >2 MM than white women. Findings show significant racial/ethnic disparities in MM, and suggest the need for better screening, management, and timely referral of these conditions, particularly among racial/ethnic women. Disparities in MM may be contributing to the high infant mortality and adverse birth outcomes among different racial/ethnic groups in Wisconsin.

Novel CYP2C9 promoter variants and assessment of their impact on gene expression.

There are a considerable number of reports identifying and characterizing genetic variants within the CYP2C9 coding region. Much less is known about polymorphic promoter sequences that also might contribute to interindividual differences in CYP2C9 expression. To address this problem, approximately 10,000 base pairs of CYP2C9 upstream information were resequenced using 24 DNA samples from the Coriell Polymorphism Discovery Resource. Thirty-one single-nucleotide polymorphisms (SNPs) were identified; nine SNPs were novel, whereas 22 were reported previously. Using both sequencing and multiplex single-base extension, individual SNP frequencies were determined in 193 DNA samples obtained from unrelated, self-reported Hispanic Americans of Mexican descent, and they were compared with similar data obtained from a non-Latino white cohort. Significant interethnic differences were observed in several SNP frequencies, some of which seemed unique to the Hispanic population. Analysis using PHASE 2.1 inferred nine common (>1%) variant haplotypes, two of which included the g.3608C>T (R144C) CYP2C9(*)2 and two the g.42614A>C (I359L) CYP2C9(*)3 SNPs. Haplotype variants were introduced into a CYP2C9/luciferase reporter plasmid using site-directed mutagenesis, and the impact of the variants on promoter activity assessed by transient expression in HepG2 cells. Both constitutive and pregnane X receptor-mediated inducible activities were measured. Haplotypes 1B, 3A, and 3B each exhibited a 65% decrease in constitutive promoter activity relative to the reference haplotype. Haplotypes 1D and 3B exhibited a 50% decrease and a 40% increase in induced promoter activity, respectively. These data suggest that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype both within and among different populations.

Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics.

OBJECTIVES: Previous work defined two flavin-containing monooxygenase 2 (FMO2) alleles. The major allele, FMO2*2 (g.23,238C>T), encodes truncated inactive protein (p.X472) whereas the minor allele, FMO2*1, present in African- and Hispanic-American populations, encodes active protein (p.Q472). Recently, four common (27 to 51% incidence) FMO2 single nucleotide polymorphisms (SNPs) were detected in African-Americans (N=50); they encode the following protein variants: p.71Ddup, p.V113fs, p.S195L and p.N413 K. Our objectives were to: (1) determine the incidence of these SNPs in 29 Hispanic individuals previously genotyped as g.23,238C (p.Q472) and 124 previously genotyped as homozygous g.23,238 T (p.X472); (2) determine FMO2 haplotypes in this population; and (3) assess the functional impact of SNPs in expressed proteins. METHODS: SNPs were detected via allele-specific oligonucleotide amplification coupled with real-time or electrophoretic product detection, or single strand conformation polymorphism. RESULTS: The g.7,700_7,702dupGAC SNP (p.71Ddup) was absent. The remaining SNPs were present but, except for g.13,732C>T (p.S195L), were less common in the current Hispanic study population versus the previously described African-Americans. Only expressed p.N413 K was as active as p.Q472, as determined by methimazole- and ethylenethiourea-dependent oxidation. Haplotype determination demonstrated that the g.10,951delG (p.V113fs), g.13,732C>T (p.S195L) and g.22,060T>G (p.N413 K) variants segregated with g.23,238C>T (p.X472). CONCLUSIONS: SNPs would not alter FMO2 activity in individuals possessing at least one FMO2*1 allele. It is likely that these SNPs will segregate similarly in African-American populations. Therefore, estimates that 26% of African-Americans and 2-7% of Hispanic-Americans have at least one FMO2*1 allele should closely reflect the percentages producing active FMO2 protein.

Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants.

The flavin-containing monooxygenases (FMOs) are important for xenobiotic metabolism. FMO3, the predominant FMO enzyme in human adult liver, exhibits significant interindividual variation that is poorly understood. This study was designed to identify common FMO3 genetic variants and determine their potential for contributing to interindividual differences in FMO3 expression. FMO3 single nucleotide polymorphism (SNP) discovery was accomplished by resequencing DNA samples from the Coriell Polymorphism Discovery Resource. Population-specific SNP frequencies were determined by multiplexed, single-base extension using DNA from 201 Hispanic American (Mexican descent), 201 African American, and 200 White (northern European descent) subjects. Haplotypes were inferred and population frequencies estimated using PHASE version 2.1. Multiple site-directed mutagenesis was used to introduce inferred upstream haplotypes into an FMO3/luciferase construct for functional analysis in HepG2 cells. Sequence analysis revealed seven FMO3 upstream SNPs, 11 exon SNPs, and 22 intron SNPs. Five of the latter fell within consensus splice sites. A g.72G>T variant (E24D) is predicted to impact the structure of the Rossmann fold involved in FAD binding, whereas a g.11177C>A variant (N61K) is predicted to disrupt the secondary structure of a conserved membrane interaction domain. Seven common (>1%) promoter region haplotypes were inferred in one or more of the study populations that differed in estimated frequency among the groups. Haplotype 2 resulted in an 8-fold increase in promoter activity, whereas haplotypes 8 and 15 exhibited a near complete loss of activity. In conclusion, FMO3 promoter haplotype variants modulate gene function and probably contribute to interindividual differences in FMO3 expression.

Differences in FMO2*1 allelic frequency between Hispanics of Puerto Rican and Mexican descent.

A polymorphism for the phase I drug-metabolizing enzyme, flavin-containing monooxygenase isoform 2 (FMO2), encoding either truncated inactive protein, FMO2X472 (FMO2.2A), or full-length active enzyme, FMO2Q472 (FMO2.1), is known and exhibits significant interethnic differences in allelic frequency. FMO2 is the major or sole FMO isoform expressed in the lung of most mammals, including nonhuman primates. To date, FMO2.1 has been found only in African-American and Hispanic populations, rendering individuals with this allele subject to drug metabolism that is potentially different from that of the general population. Approximately 26% of African-Americans (n = 180) possess the FMO2*1 allele. In preliminary studies, we initially estimated that 5% of Hispanics (n = 40) have the FMO2*1 allele, but access to large cohorts of individuals of defined national origin has allowed us to determine the occurrence among Mexican-American and Puerto Rican-American groups. We used allele-specific genotyping to detect FMO2*1 from 632 Hispanic individuals, including 280 individuals of Mexican origin and 327 individuals of Puerto Rican origin. Statistical analysis indicated that results from Mexican (five sample sources) and Puerto Rican (three sample sources) samples were consistent with the hypothesis of homogeneity within each group from different sources. Data were subsequently pooled across sources to test for evidence of a difference in occurrence of FMO2*1 between ethnic groups. There was strong evidence (p = 0.0066) that FMO2*1 is more common among Puerto Ricans (7%) than among individuals of Mexican descent (2%). The overall occurrence of FMO2*1 among Hispanics of all origins is estimated to be between 2 and 7%.

Genetic variability at the human FMO1 locus: significance of a basal promoter yin yang 1 element polymorphism (FMO1*6).

The flavin-containing monooxygenases (FMOs) are important for the disposition of a variety of toxicants, therapeutics, and dietary components. Although FMO1 is the dominant isoform in fetal liver and adult kidney and intestine and despite up to a 10-fold intersubject variation in expression, a paucity of information is available on FMO1 genetic variability. To address this issue, 24 samples from the Coriell DNA Polymorphism Discovery Resource Panel were sequenced revealing 10 common single nucleotide polymorphisms (SNPs): four located upstream of the structural gene; three within exonic sequences; one within the intron 1 splice donor site; and two with the 3'-untranslated region. Six of these variants are novel. Compared with other FMO loci within the chromosome 1q23-25 cluster, FMO1 seems more highly conserved. Of the identified FMO1 SNPs, only a C>A transversion 9536 base pairs upstream of the exon 2 ATG start codon (g.-9536C>A) would likely affect function, because it lies within the conserved core binding sequence for the yin yang 1 (YY1) transcription factor. Electrophoretic mobility shift assays demonstrated that the g.-9536C>A transversion eliminated YY1 binding. Furthermore, data from transient expression assays in HepG2 cells suggested this SNP could account for a 2- to 3-fold loss of FMO1 promoter activity. Genotype analysis revealed a g.-9,536A allele (FMO1*6) frequency of 13 and 11% in African- and northern European-Americans, respectively, but a significantly higher frequency of 30% in Hispanic-Americans. Thus, the FMO1*6 variant may account for some of the observed interindividual variation in FMO1 expression.

Genotyping and site-directed mutagenesis of a cytochrome P450 meander Pro-X-Arg motif critical to CYP4B1 catalysis.

CYP4B1 isoforms from rodents and other common laboratory animals are involved in the bioactivation of a range of protoxins, including 2-aminofluorene, 4-ipomeanol, and valproic acid. However, an earlier study provided evidence for a human allele encoding a nonfunctional CYP4B1 enzyme due to a Pro427Ser transversion in the meander region of the protein. In the present study, the CYP4B1 gene from several racial groups, Caucasians, African-Americans, and Hispanics, and from six nonhuman primate species was genotyped using a PCR-Hinf1 restriction enzyme fragment length polymorphism assay or by direct sequencing. All human populations examined were found to possess only the Ser allele at codon 427 ((1279)TCT) and all of the nonhuman primate species possessed only the Pro (CCT) allele. Therefore, an inactivating (1279)C-->T mutation in the human CYP4B1 gene likely arose following divergence of the Homo and Pan clades. Amino acid sequence alignments revealed further that this key Pro residue is located two amino acid residues N-terminal to the distal Arg of a Glu-Arg-Arg triad thought to participate in heme binding and/or redox partner interactions. Mutation of the corresponding Arg424 residue in rabbit CYP4B1 to Leu, but not His, resulted in a loss of lauric acid hydroxylase activity and ability to generate a reduced-CO binding spectrum. These data provide additional evidence for the importance of this meander region Pro-X-Arg motif in CYP4B1 heme binding and catalytic function.