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.
The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 250–296/7 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.
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.
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.
genome-wide association study (GWAS); chronic lung disease; genetic predisposition to disease; premature; very low birth weight infant
To examine the extent to which performance assessment methodologies affect the percent of neonatal intensive care units (NICUs) and very low birth weight (VLBW) infants included in performance assessments, distribution of NICU performance ratings, and level of agreement in those ratings.
Cross-sectional study based on risk-adjusted nosocomial infection rates.
NICUs belonging to the California Perinatal Quality Care Collaborative 2007–2008.
126 California NICUs and 10,487 VLBW infants.
Three performance assessment choices: 1. Excluding “low-volume” NICUs (those caring for < 30 VLBW infants in a year) vs. a criterion based on confidence intervals, 2. Using Bayesian vs. frequentist hierarchical models, and 3. Pooling data across one vs. two years.
Main Outcome Measures
Proportion of NICUs and patients included in quality assessment, distribution of ratings for NICUs, and agreement between methods using the kappa statistic.
Depending on the methods applied, between 51% and 85% of NICUs were included in performance assessment, the percent of VLBW infants included in performance assessment ranged from 72% to 96%, between 76–87% NICUs were considered “average,” and the level of agreement between NICU ratings ranged from 0.26 to 0.89.
The percent of NICUs included in performance assessment and their ratings can shift dramatically depending on performance measurement methodology. Physicians, payers, and policymakers should continue to closely examine which existing performance assessment methodologies are most appropriate for evaluating pediatric care quality.
Quality; quality improvement; performance incentives; pay-for-performance; public reporting; neonatal intensive care units; Very Low Birth Weight infants; Nosocomial infections
To examine the relationship between typically measured prenatal screening biomarkers and early preterm birth in euploid pregnancies.
Included were 345 early preterm cases (< 30 weeks) and 1,725 controls drawn from a population-based sample of California pregnancies that all had both first and second trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and controls and to develop predictive models. Replicability of the biomarker-early preterm relationships revealed by the models was evaluated by examining the frequency and associated adjusted relative risks (RRsadj) for early preterm birth and for preterm birth in general (< 37 weeks) in pregnancies with identified abnormal markers compared to those without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).
The final model for early preterm birth included first trimester pregnancy-associated plasma protein A (PAPP-A) ≤ the 5th percentile, second trimester alpha-fetoprotein (AFP) ≥ the 95th percentile, and second trimester inhibin (INH) ≥ the 95th percentile (odds ratios 2.3 to 3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern found to be associated with early preterm delivery in the first sample were at an increased risk for early preterm birth and preterm birth in general (< 37 weeks) (RRsadj 1.6 to 27.4). Pregnancies with two or more biomarker abnormalities were at particularly increased risk (RRsadj 3.6 to 27.4).
When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early preterm birth.
Preterm Birth; Prenatal Screening; Biomarkers
To develop a length of stay (LOS) model for extremely low birth weight (ELBW) infants.
We included infants from the California Perinatal Quality Care Collaborative with birth weight 401–1,000 grams who were discharged to home. Exclusion criteria were congenital anomalies, surgery, and death. LOS was defined as days from admission to discharge. As patients who died or were transferred to lower level of care were excluded, we assessed correlation of hospital mortality rates and transfers torisk adjusted LOS.
There were 2,012 infants with median LOS 79 days (range 23–219). Lower birth weight, lack of antenatal steroids, and lower Apgar score were associated with longer LOS. There was negligiblecorrelation between risk-adjusted LOS and hospital mortality rates (r = 0.0207) and transfer-out rates (r = 0.121).
Particularly because ELBW infants have extended hospital stays, identification of unbiased and informative risk-adjusted LOS for these infants is an important step in benchmarking best practice and improving efficiency in care.
Length of stay; Extremely low birth weight
This study examined the ability of social, demographic, environmental and health-related factors to explain geographic variability in preterm delivery among black and white women in the US and whether these factors explain black-white disparities in preterm delivery.
We examined county-level prevalence of preterm delivery (20–31 or 32–36 weeks gestation) among singletons born 1998–2002. We conducted multivariable linear regression analysis to estimate the association of selected variables with preterm delivery separately for each preterm/race-ethnicity group.
The prevalence of preterm delivery varied two- to three-fold across U.S. counties, and the distributions were strikingly distinct for blacks and whites. Among births to blacks, regression models explained 46% of the variability in county-level risk of delivery at 20–31 weeks and 55% for delivery at 32–36 weeks (based on R-squared values). Respective percentages for whites were 67% and 71%. Models included socio-environmental/demographic and health-related variables and explained similar amounts of variability overall.
Much of the geographic variability in preterm delivery in the US can be explained by socioeconomic, demographic and health-related characteristics of the population, but less so for blacks than whites.
To assess the level of agreement when selecting quality measures for inclusion in a composite index of neonatal intensive care quality (Baby-MONITOR) between two panels: one comprised of academic researchers (Delphi) and another comprised of academic and clinical neonatologists (Clinician).
In a modified Delphi process, a panel rated twenty eight quality measures. We assessed clinician agreement with the Delphi panel by surveying a sample of forty eight neonatal intensive care practitioners. We asked the clinician group to indicate their level of agreement with the Delphi panel for each measure using a five- point scale (much too high, slightly too high, reasonable, slightly too low, and much too low). In addition, we asked clinicians to select measures for inclusion in the Baby-MONITOR based on a yes or no vote and a pre-specified two-thirds majority for inclusion.
Twenty three (47.9%) of the clinicians responded to the survey. We found high levels of agreement between the Delphi and clinician panels, particularly across measures selected for the Baby-MONITOR. Clinicians selected the same nine measures for inclusion in the composite as the Delphi panel. For these nine measures, 74% of clinicians indicated that the Delphi panel rating was ‘reasonable’.
Practicing clinicians agree with an expert panel on the measures that should be included in the Baby-MONITOR, enhancing face validity.
infant; newborn; quality of health care; measurement; composite indicator
To investigate the relationship between breastmilk feeding in very low birth weight infants in the neonatal intensive care unit and breastmilk feeding rates for all newborns by hospital.
This was a cross-sectional study of 111 California hospitals in 2007 and 2008. Correlation coefficients were calculated between overall hospital breastfeeding rates and very low birth weight infant breastmilk feeding rates. Hospitals were categorized in quartiles by crude and adjusted very low birth weight infant rates to compare rankings between measures.
Correlation between very low birth weight infants and overall breastfeeding rates varied by neonatal intensive care unit level of care, from 0.13 for intermediate hospitals to 0.48 for regional hospitals. For hospitals categorized in the top quartile according to overall breastfeeding rate, only (46%) were in the top quartile for both crude and adjusted very low birth weight infant rates. On the other hand, when considering the lowest quartile for overall breastfeeding hospitals, 3 of 27 (11%) actually were performing in the top quartile of performance for very low birth weight infant rates.
Reporting hospital overall breastfeeding rates and neonatal intensive care unit breastmilk provision rates separately may give an incomplete picture of quality of care.
Preterm infants; Neonatal intensive care; Breastmilk; Breastfeeding; Quality improvement
To measure the influence of varying mortality time frames on performance rankings among regional NICUs in a large state.
We carried out cross-sectional data analysis of VLBW infants cared for at 24 level 3 NICUs. We tested the effect of four definitions of mortality: (1) deaths between admission and end of birth hospitalization or up to 366 days; (2) deaths between 12 hours of age and end of birth hospitalization or up to 366 days; (3) deaths between admission and 28 days; and (4) deaths between 12 hours of age and 28 days. NICUs were ranked by quantifying their deviation from risk-adjusted expected mortality and splitting them into three tiers: top six, bottom six, and in-between.
There was wide inter-institutional variation in risk-adjusted mortality for each definition (observed minus expected Z-score range, -6.08 to 3.75). However, mortality-rate-based NICU rankings, and their classification into performance tiers, were very similar for all institutions for each of our time frames. Among all four definitions, NICU rank correlations were high (>0.91). Few NICUs changed relative to a neighboring tier with changes in definitions, and none changed by more than one tier.
The time frame used to ascertain mortality had little effect on comparative NICU performance.
Infant; newborn; quality of care; performance measurement; mortality
To determine the incidence and risk factors for maternal morbidity during childbirth hospitalization.
Maternal morbidities were determined using ICD9-CM and vital records codes from linked hospital discharge and vital records data for 1,572,909 singleton births in California, 2005-2007. Sociodemographic, obstetric, and hospital volume risk factors were estimated using mixed effects logistic regression models.
The maternal morbidity rate was 241/1000 births. The most common morbidities were episiotomy, pelvic trauma, maternal infection, postpartum hemorrhage, and severe laceration. Preeclampsia (Adjusted Odds Ratio [AOR] 2.96; 95% CI 2.8,3.13), maternal age over 35 years, (AOR 1.92; 1.79,2.06), vaginal birth after cesarean, (AOR 1.81; 1.47,2.23), and repeat cesarean birth (AOR 1.99; 1.87,2.12) conferred the highest odds of severe morbidity. Non-white women were more likely to suffer morbidity.
Nearly one in four California women experienced complications during childbirth hospitalization. Significant health disparities in maternal childbirth outcomes persist in the United States.
Childbirth hospitalization; maternal morbidity; risk factors
To evaluate ROP screening rates in a population-based cohort; To identify characteristics of patients that were missed.
We used the California Perinatal Quality Care Collaborative data from 2005-2007 for a cross sectional study. Using eligibility criteria, screening rates were calculated for each hospital. Multivariable regression was used to assess associations between patient clinical and socio-demographic factors and the odds of missing screening.
Overall rates of missed ROP screening decreased from 18.6% in 2005 to 12.8% in 2007. Higher gestational age (odds ratio [OR] 1.25 for increase of one week, 95% confidence interval [CI] 1.21-1.29), higher birth weight (OR 1.13, 95% CI 1.10-1.15), and singleton birth (OR 1.2, 95% CI 1.07-1.34) were associated with higher probability of missing screening. Level II NICUs and NICUs with lower volume were more likely to miss screenings.
Although ROP screening rates improved over time, larger and older infants are at risk for not receiving screening. Furthermore, large variations in screening rates exist among hospitals in California. Identification of gaps in quality of care creates an opportunity to improve ROP screening rates and prevent impaired vision in this vulnerable population.
Retinopathy of Prematurity; Premature; Quality of Care; Neonatal
To investigate the incidence and risk factors associated with uncomplicated maternal sepsis and progression to severe sepsis in a large population-based birth cohort.
This retrospective cohort study used linked hospital discharge and vital statistics records data for 1,622,474 live births in California during 2005–2007. Demographic and clinical factors were adjusted using multivariable logistic regression with robust standard errors.
1598 mothers developed sepsis; incidence of all sepsis was 10 per 10,000 live births (95% CI = 9.4–10.3). Women had significantly increased adjusted odds (aOR) of developing sepsis if they were older (25–34 years: aOR = 1.29; ≥35 years: aOR = 1.41), had ≤high-school education (aOR = 1.63), public/no-insurance (aOR = 1.22) or a cesarean section (primary: aOR = 1.99; repeat: aOR = 1.25). 791 women progressed to severe sepsis; incidence of severe sepsis was 4.9 per 10,000 live births (95% CI = 4.5–5.2). Women had significantly increased adjusted odds of progressing to severe sepsis if they were Black (aOR = 2.09), Asian (aOR = 1.59), Hispanic (aOR = 1.42), had public/no-insurance (aOR = 1.52), delivered in hospitals with <1,000 births/year (aOR = 1.93), were primiparous (aOR = 2.03), had a multiple birth (aOR = 3.5), diabetes (aOR = 1.47), or chronic hypertension (aOR = 8.51). Preeclampsia and postpartum hemorrhage were also significantly associated with progression to severe sepsis (aOR = 3.72; aOR = 4.18). For every cumulative factor, risk of uncomplicated sepsis increased by 25% (95% CI = 17.4–32.3) and risk of progression to severe sepsis/septic shock increased by 57% (95% CI = 40.8–74.4).
The rate of severe sepsis was approximately twice the 1991–2003 national estimate. Risk factors identified are relevant to obstetric practice given their cumulative risk effect and the apparent increase in severe sepsis incidence.
Using a statewide population-based data source, we describe current neonatal follow-up referral practices for high-risk infants with developmental delays throughout California.
From a cohort analysis of quality improvement data from 66 neonatal follow-up programs in the California Children’s Services and California Perinatal Quality Care Collaborative High-Risk Infant Follow-Up Quality of Care Initiative, 5129 high-risk infants were evaluated at the first visit between 4 and 8 months of age in neonatal follow-up. A total of 1737 high-risk infants were evaluated at the second visit between 12 and 16 months of age. We calculated referral rates in relation to developmental status (high versus low concern) based on standardized developmental testing or screening.
Among infants with low concerns (standard score >70 or passed screen) at the first visit, 6% were referred to early intervention; among infants with high concerns, 28% of infants were referred to early intervention. Even after including referrals to other (private) therapies, 34% infants with high concerns did not receive any referrals. These rates were similar for the second visit.
In spite of the specialization of neonatal follow-up programs to identify high-risk infants with developmental delays, a large proportion of potentially eligible infants were not referred to early intervention.
early intervention; developmental assessment; developmental delay; health service utilization; neonatal follow-up
Although maternal serum alpha-fetoprotein (AFP), human chorionic gonandotrophin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship to the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors. The objective of this population-based study was to examine whether second trimester levels of AFP, hCG, and unconjugated estriol (uE3) were associated with an increased risk of BPD. 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 uE3 levels were below the 5th percentile (relative risks (RRs) 3.1 to 6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9 to 75.9). Data suggested that pregnancies which 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 a stress including maternal hypertension and asymmetric growth restriction.
To estimate trends and risk factors for cesarean delivery for twins in the United States.
This was a cross-sectional study in which we calculated cesarean rates for twins from 1995 to 2008 using National Center for Health Statistics data. We compared cesarean rates by year and for vertex vs. breech presentation. The order of presentation for a given twin pair could not be determined from the available records and therefore analysis was based on individual discrete twin data. Multivariable logistic regression was used to estimate independent risk factors, including year of birth and maternal factors, for cesarean delivery.
Cesarean rates for twin births increased steadily from 53.4% to 75.0% in 2008. Rates rose for the breech twin category (81.5% to 92.1%) and the vertex twin category (45.1% to 68.2%). The relative increase in cesarean rate for preterm and term infants was similar. After risk adjustment, there was an average increase noted in cesarean delivery of 5% each year during the study period (risk ratio 1.05, 95% confidence interval 1.04, 1.05).
Cesarean delivery rates for twin births increased dramatically from 1995 to 2008. This increase is significantly higher than that which could be explained by an increase in cesarean delivery for breech presentation of either the presenting or second twin.
To estimate risk factors for premature infants not receiving antenatal steroids in a population-based cohort and to determine whether the gains of a quality improvement collaborative project on antenatal steroid administration were sustained long-term.
Clinical data for premature infants born in 2005-2007 were obtained from the California Perinatal Quality Care Collaborative, which collects data on more than 90% of neonatal admissions in California. Eligible infants had a birth weight of less than 1500 grams or gestational age less than 34 weeks born at a Collaborative hospital. These data were linked to administrative data from California Vital Statistics. Socio-demographic and medical risk factors for not receiving antenatal steroids were determined. We also examined the effect of birth hospital participation in a prior quality improvement collaborative project. A random effects logistic regression model was used to determine independent risk factors.
Of 15,343 eligible infants, 23.1% did not receive antenatal steroids in 2005-2007. Hispanic mothers (25.6%), mothers younger than age 20 (27.6%), and those without prenatal care (52.2%) were less likely to receive antenatal steroids. Mothers giving birth vaginally (26.8%) and mothers with a diagnosis of “fetal distress” (26.5%) were also less likely to receive antenatal steroids. Rupture of membranes prior to delivery, and multiple gestations were associated with higher likelihood of antenatal steroid administration. Hospitals who participated in a quality improvement collaborative in 1999-2000 had higher rates of antenatal steroid administration (85% vs. 69%, p < 0.0001).
A number of eligible mothers do not receive antenatal steroids. Quality improvement initiatives to improve antenatal steroid administration could target specific high-risk groups.
To evaluate the effectiveness of the California Perinatal Quality Care Collaborative quality-improvement model using a toolkit supplemented by workshops and Web casts in decreasing nosocomial infections in very low birth weight infants.
This was a retrospective cohort study of continuous California Perinatal Quality Care Collaborative members' data during the years 2002–2006. The primary dependent variable was nosocomial infection, defined as a late bacterial or coagulase-negative staphylococcal infection diagnosed after the age of 3 days by positive blood/cerebro-spinal fluid culture(s) and clinical criteria. The primary independent variable of interest was voluntary attendance at the toolkit's introductory event, a direct indicator that at least 1 member of an NICU team had been personally exposed to the toolkit's features rather than being only notified of its availability. The intervention's effects were assessed using a multivariable logistic regression model that risk adjusted for selected demographic and clinical factors.
During the study period, 7733 eligible very low birth weight infants were born in 27 quality-improvement participant hospitals and 4512 very low birth weight infants were born in 27 non–quality-improvement participant hospitals. For the entire cohort, the rate of nosocomial infection decreased from 16.9% in 2002 to 14.5% in 2006. For infants admitted to NICUs participating in at least 1 quality-improvement event, there was an associated decreased risk of nosocomial infection (odds ratio: 0.81 [95% confidence interval: 0.68–0.96]) compared with those admitted to nonparticipating hospitals.
The structured intervention approach to quality improvement in the NICU setting, using a toolkit along with attendance at a workshop and/or Web cast, is an effective means by which to improve care outcomes.
central-line–associated bloodstream infection; nosocomial infection; quality improvement; quality-improvement toolkits; quality-improvement evaluation
To investigate the relationship between low Apgar score and neonatal mortality in preterm neonates.
Infant birth and death certificate data from the U.S. National Center for Health Statistics for 2001-2002 were analyzed. Primary outcome was 28 day mortality for 690,933 neonates at gestational ages 24-36 weeks. Mortality rates were calculated for each combination of gestational age and five-minute Apgar score. Relative risks of mortality, by high vs. low Apgar score, were calculated for each age.
Distribution of Apgar scores depended on gestational age, the youngest gestational ages having higher proportions of low Apgar scores. Median Apgar score ranged from 6 at 24 weeks, to 9 at 30-36 weeks gestation. The relative risk of death was significantly higher at Apgar scores 0-3 vs. 7-10, including at the youngest gestational ages, ranging from 3.1 (95% confidence interval 2.9, 3.4) at 24 weeks to 18.5 (95% confidence interval 15.7, 21.8) at 28 weeks.
Low Apgar score was associated with increased mortality in premature neonates, including those at 24 to 28 weeks gestational age, and may be a useful tool for clinicians in assessing prognosis and for researchers as a risk prediction variable.
Apgar score; Neonatal mortality; Prematurity
Pay-for-performance initiatives in medicine are proliferating rapidly. Neonatal intensive care is a likely target for these efforts because of the high cost, available databases, and relative strength of evidence for at least some measures of quality. Pay-for-performance may improve patient care but requires valid measurements of quality to ensure that financial incentives truly support superior performance. Given the existing uncertainty with respect to both the effectiveness of pay-for-performance and the state of quality measurement science, experimentation with pay-for-performance initiatives should proceed with caution and in controlled settings. In this article, we describe approaches to measuring quality and implementing pay-for-performance in the NICU setting.
pay-for-performance programs; quality improvement
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
To determine if cesarean delivery for breech has increased in the United States.
We calculated cesarean rates for term singletons in “breech / malpresentation” from 1997–2003 using National Center for Health Statistics data. We compared rates by socio-demographic groups and state. Multivariable logistic regression models were constructed to see if factors associated with cesarean delivery differed over time.
Breech cesarean rates increased overall from 83.8% to 85.1%. There was a significant increase in rates for most socio-demographic groups. There was little to no increase for mothers < 30 years. There was wide variability in rates by state, 61.6%–94.2% in 1997. Higher breech incidence correlated with lower cesarean rates, suggesting potential state bias in reporting breech.
In the United States, breech infants are predominantly born by cesarean. There was a small increase in this trend from 1998 to 2002. There is wide variability by state, which is not explained by socio-demographic patterns, and may be due to reporting differences.
Cesarean delivery; breech; malpresentation; United States