The Impact of Hospital Delivery Volumes of Newborns Born Very Preterm on Mortality and Morbidity.

OBJECTIVE: To examine if the annual patient volume of infants born very preterm (VPT, gestational age <32 weeks) at a hospital is associated with neonatal mortality and morbidity. STUDY DESIGN: We performed an observational, secondary data analysis using a 20-year panel of birth certificates linked to hospital discharge abstracts, including transfers in California, Michigan, Missouri, Oregon, Pennsylvania, and South Carolina from 1996 through 2015. The study included all in-hospital VPT deliveries (n = 208 261). Study outcomes were in-hospital mortality or serious morbidity (intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, or bronchopulmonary dysplasia), attributed to the hospital of birth. Poisson regression models estimated the risk-adjusted relative risk (RR) for mortality and serious morbidity across different patient volume categories within a given hospital using hospital fixed effects. RESULTS: The risk of mortality and serious morbidity for VPT infants increased as the number of infants born VPT at a hospital decreased. Compared with VPT delivery volumes >100 infants per year, the risk of mortality increased when a given hospital had VPT delivery volumes < 60 per year, ranging from a RR of 1.13 (95% C.I. 1.02-1.25) for volumes between 50 to 59 and 1.39 (1.19-1.62) for VPT volumes <10, and the risk of mortality or serious morbidity increased when a given hospital had VPT volumes <100, ranging from a RR of 1.05 (1.02-1.08) for volumes between 90 to 99 and 1.27 (1.19-1.36) for VPT volumes <10. CONCLUSIONS: These results suggest that, for VPT infants, the risk of both mortality and mortality or serious morbidity is increased as the VPT volume within a given hospital declines.

County-Level Structural Vulnerabilities in Maternal Health and Geographic Variation in Infant Mortality.

OBJECTIVE: To evaluate whether community factors that differentially affect the health of pregnant people contribute to geographic differences in infant mortality across the US. STUDY DESIGN: This retrospective cohort study sought to characterize the association of a novel composite measure of county-level maternal structural vulnerabilities, the Maternal Vulnerability Index (MVI), with risk of infant death. We evaluated 11 456 232 singleton infants born at 22 0 of 7 through 44 6 of 7 weeks' gestation from 2012 to 2014. Using county-level MVI, which ranges from 0 to 100, multivariable mixed effects logistic regression models quantified associations per 20-point increment in MVI, with odds of death clustered at the county level and adjusted for state, maternal, and infant covariates. Secondary analyses stratified by the social, physical, and health exposures that comprise the overall MVI score. Outcome was also stratified by cause of death. RESULTS: Rates of death were higher among infants from counties with the greatest maternal vulnerability (0.62% in highest quintile vs 0.32% in lowest quintile, [P < .001]). Odds of death increased 6% per 20-point increment in MVI (aOR: 1.06, 95% CI 1.04, 1.07). The effect estimate was highest with theme of Mental Health and Substance Abse (aOR 1.08; 95% CI 1.06, 1.09). Increasing vulnerability was associated with 6 of 7 causes of death. CONCLUSIONS: Community-level social, physical, and healthcare determinants indicative of maternal vulnerability may explain some of the geographic variation in infant death, regardless of cause of death. Interventions targeted to county-specific maternal vulnerabilities may reduce infant mortality.

The association of maternal country/region of origin and nativity with infant mortality rate among Hispanic preterm infants.

OBJECTIVES: Among US-born preterm infants of Hispanic mothers, we analyzed the unadjusted and adjusted infant mortality rate (IMR) by country/region of origin and maternal nativity status. STUDY DESIGN: Using linked national US birth and death certificate data (2005-2014), we examined preterm infants of Hispanic mothers by subgroup and nativity. Clinical and sociodemographic covariates were included and the main outcome was death in the first year of life. RESULTS: In our cohort of 891,216 preterm Hispanic infants, we demonstrated different rates of infant mortality by country and region of origin, but no difference between infants of Hispanic mothers who were US vs. foreign-born. CONCLUSION: These findings highlight the need to disaggregate the heterogenous Hispanic birthing population into regional and national origin groups to better understand unique factors associated with adverse perinatal outcomes in order to develop more targeted interventions for these subgroups.

Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration. STUDY DESIGN: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time. RESULTS: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001). CONCLUSIONS: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed.

Racial and Ethnic Disparities in Sudden Unexpected Infant Death Among US Infants Born Preterm.

OBJECTIVE: To investigate among US infants born at <37 weeks gestation (a) racial and ethnic disparities in sudden unexpected infant death (SUID) and (b) state variation in SUID rates and non-Hispanic Black (NHB)-non-Hispanic White (NHW) SUID disparity ratio. METHODS: In this retrospective cohort analysis of linked birth and death certificates from 50 states from 2005 to 2014, SUID was defined by the following International Classification of Diseases, 9th or 10th edition, codes listed on death certificates: (7980, R95 or Recode 135; ASSB: E913, W75 or Recode 146; Unknown: 7999 R99 or Recode 134). Multivariable models were used to assess the independent association between maternal race and ethnicity and SUID, adjusting for several maternal and infant characteristics. The NHB-NHW SUID disparity ratios were calculated for each state. RESULTS: Among 4 086 504 preterm infants born during the study period, 8096 infants (0.2% or 2.0 per 1000 live births) experienced SUID. State variation in SUID ranged from the lowest rate of 0.82 per 1000 live births in Vermont to the highest rate of 3.87 per 1000 live births in Mississippi. Unadjusted SUID rates across racial and ethnic groups varied from 0.69 (Asian/Pacific Islander) to 3.51 (NHB) per 1000 live births. In the adjusted analysis, compared with NHW infants, NHB and Alaska Native/American Indian preterm infants had greater odds of SUID (aOR, 1.5;[95% CI, 1.42-1.59] and aOR, 1.44 [95% CI, 1.21-1.72]) with varying magnitude of SUID rates and NHB-NHW disparities across states. CONCLUSIONS: Significant racial and ethnic disparities in SUID among preterm infants exist with variation across US states. Additional research to identify the drivers of these disparities within and across states is needed.

Healthcare Costs of Major Morbidities Associated with Prematurity in US Children's Hospitals.

OBJECTIVE: To evaluate the healthcare costs attributed to major morbidities associated with prematurity, namely, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and nosocomial infections. STUDY DESIGN: This was a retrospective analysis of infants born at 24-30 weeks of gestation, admitted to children's hospitals in the Pediatric Health Information System between 2009 and 2018. Charges were adjusted by geographical price index, converted to costs using cost-to-charge ratios, inflated to 2018 US$, and total costs were accumulated for the initial hospitalization. Quantile regressions, which are less prone to bias from extreme outliers, were used to examine the incremental costs attributed to each morbidity across the entire cost distribution, including the median. RESULTS: There were 19 232 patients from 30 children's hospitals who were eligible. Higher costs were seen in lower gestational age, more severe morbidity, and those with higher number of comorbidities. Patients with surgical NEC, severe ROP, and severe BPD were the costliest with median total costs of $430 860, $413 825, and $399 495, respectively. Quantile regressions showed surgical NEC had the highest adjusted median incremental total cost ($48 621; 95% CI, $39 617-$57 626) followed by severe BPD ($35 773; 95% CI, $32 018-$39 528) and severe ROP ($22 561; 95% CI, $16 699-$28 423). Quantile regressions also revealed that surgical NEC, severe BPD, and severe ROP had increasing incremental costs at higher total cost percentiles, indicating these morbidities have a greater cost impact on the costliest patients. CONCLUSIONS: Severe BPD, surgical NEC, and severe ROP are the costliest morbidities and contribute the most incremental costs especially for the higher costs patients.

Risk of Extreme, Moderate, and Late Preterm Birth by Maternal Race, Ethnicity, and Nativity.

OBJECTIVES: To explore the relative risks of preterm birth-both overall and stratified into 3 groups (late, moderate, and extreme prematurity)-associated with maternal race, ethnicity, and nativity (ie, birthplace) combined. STUDY DESIGN: This was a retrospective cross-sectional cohort study of women delivering a live birth in Pennsylvania from 2011 to 2014 (n = 4 499 259). Log binomial and multinomial regression analyses determined the relative risks of each strata of preterm birth by racial/ethnic/native category, after adjusting for maternal sociodemographic, medical comorbidities, and birth year. RESULTS: Foreign-born women overall had lower relative risks of both overall preterm birth and each strata of prematurity when examined en bloc. However, when considering maternal race, ethnicity, and nativity together, the relative risk of preterm birth for women in different racial/ethnic/nativity groups varied by preterm strata and by race. Being foreign-born appeared protective for late prematurity. However, only foreign-born White women had lower adjusted relative risks of moderate and extreme preterm birth compared with reference groups. All ethnic/native sub-groups of Black women had a significantly increased risk of extreme preterm births compared with US born non-Hispanic White women. CONCLUSIONS: Race, ethnicity, and nativity contribute differently to varying levels of prematurity. Future research involving birth outcome disparities may benefit by taking a more granular approach to the outcome of preterm birth and considering how nativity interacts with race and ethnicity.

Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge.

OBJECTIVES: To measure between-center variation in loop diuretic use in infants developing severe bronchopulmonary dysplasia (BPD) in US children's hospitals, and to compare mortality and age at discharge between infants from low-use centers and infants from high-use centers. STUDY DESIGN: We performed a retrospective cohort study of preterm infants at <32 weeks of gestational age with severe BPD. The primary outcome was cumulative loop diuretic use, defined as the proportion of days with exposure between admission and discharge. Infant characteristics associated with loop diuretic use at P < .10 were included in multivariable models to adjust for center differences in case mix. Hospitals were ranked from lowest to highest in adjusted use and dichotomized into low-use centers and high-use centers. We then compared mortality and postmenstrual age at discharge between the groups through multivariable analyses. RESULTS: We identified 3252 subjects from 43 centers. Significant variation between centers remained despite adjustment for infant characteristics, with use present in an adjusted mean range of 7.3% to 49.4% of days (P < .0001). Mortality did not differ significantly between the 2 groups (aOR, 0.98; 95% CI, 0.62-1.53; P = .92), nor did postmenstrual age at discharge (marginal mean, 47.3 weeks [95% CI, 46.8-47.9 weeks] in the low-use group vs 47.4 weeks [95% CI, 46.9-47.9 weeks] in the high-use group; P = .96). CONCLUSIONS: A marked variation in loop diuretic use for infants developing severe BPD exists among US children's hospitals, without an observed difference in mortality or age at discharge. More research is needed to provide evidence-based guidance for this common exposure.

Impact of Early-Onset Sepsis and Antibiotic Use on Death or Survival with Neurodevelopmental Impairment at 2 Years of Age among Extremely Preterm Infants.

OBJECTIVE: To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI. STUDY DESIGN: Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants. RESULTS: Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort. CONCLUSIONS: Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.

Medication Utilization at School Age for Children Born Preterm.

We explored medication use by children born preterm at 5-8 years of age. Compared with children born at full term, children born preterm had higher medication use that included most therapeutic classifications. Although asthma and chronic lung disease influenced use, prematurity remained an independent risk factor.

Racial and Ethnic Differences Over Time in Outcomes of Infants Born Less Than 30 Weeks' Gestation.

OBJECTIVES: To examine changes in care practices over time by race and ethnicity and whether the decrease in hospital mortality and severe morbidities has benefited infants of minority over infants of white mothers. METHODS: Infants 22 to 29 weeks' gestation born between January 2006 and December 2017 at a Vermont Oxford Network center in the United States were studied. We examined mortality and morbidity rate differences and 95% confidence intervals for African American and Hispanic versus white infants by birth year. We tested temporal differences in mortality and morbidity rates between white and African American or Hispanic infants using a likelihood ratio test on nested binomial regression models. RESULTS: Disparities for certain care practices such as antenatal corticosteroids and for some in-hospital outcomes have narrowed over time for minority infants. Compared with white infants, African American infants had a faster decline for mortality, hypothermia, necrotizing enterocolitis, and late-onset sepsis, whereas Hispanic infants had a faster decline for mortality, respiratory distress syndrome, and pneumothorax. Other morbidities showed a constant rate difference between African American and Hispanic versus white infants over time. Despite the improvements, outcomes including hypothermia, mortality, necrotizing enterocolitis, late-onset sepsis, and severe intraventricular hemorrhage remained elevated by the end of the study period, especially among African American infants. CONCLUSIONS: Racial and ethnic disparities in vital care practices and certain outcomes have decreased. That the quality deficit among minority infants occurred for several care practice measures and potentially modifiable outcomes suggests a critical role for quality improvement initiatives tailored for minority-serving hospitals.

Prematurity as an Independent Risk Factor for the Development of Pulmonary Disease.

OBJECTIVES: To determine if premature infants without bronchopulmonary dysplasia (BPD) are at similar risk for developing pulmonary morbidity as compared with those with BPD and if there are differences in management of care. STUDY DESIGN: We retrospectively abstracted information from our electronic medical record from January 1, 2006, to December 31, 2015, for primary care patients born at <30 weeks of gestation (n = 811). Multivariate models determined the impact of BPD on a diagnosis of respiratory disease, respiratory medications, subspecialty visits, and emergency department use or hospitalizations after adjusting for gestational age, sex, insurance type, and race. RESULTS: Infants with BPD were more likely to be diagnosed with asthma than those without BPD (75% vs 60%; OR, 1.8; 95% CI, 1.27-2.54), but not all respiratory conditions (OR, 1.56; 95% CI, 0.7-3.51), and were more likely to be referred to a pulmonologist (relative risk, 5.98; 95% CI, 4.1-8.74). Infants with BPD were more likely to be hospitalized for respiratory conditions than those without BPD (50% vs 30%; relative risk, 2.44; 95% CI, 1.73-3.45). CONCLUSIONS: Although infants with BPD were more likely to have a diagnosis of asthma and be readmitted for respiratory conditions, 60% of infants without BPD were also diagnosed with asthma and 30% were readmitted. There were significant differences in the management of patients, including time to pulmonary referral and prescription rates for inhaled corticosteroids. Practitioners should consider all patients born prematurely at high risk for respiratory morbidity.

Birth Hospitalization Costs and Days of Care for Mothers and Neonates in California, 2009-2011.

OBJECTIVE: To provide population-based estimates of the hospital-related costs of maternal and newborn care, and how these vary by gestational age and birth weight. STUDY DESIGN: We conducted a retrospective analysis of 2009-2011 California in-hospital deliveries at nonfederal hospitals with the infant and maternal discharge data successfully (96%) linked to birth certificates. Cost-to-charge ratios were used to estimate costs from charges. Physician hospital payments were estimated by mean diagnosis related group-specific reimbursement and costs were adjusted for inflation to December 2017 values. After exclusions for incomplete or missing data, the final sample was 1 265 212. RESULTS: The mean maternal costs for all in-hospital deliveries was $8204, increasing to $13 154 for late preterm (32-36 weeks) and $22 702 for very preterm (<32 weeks) mothers. The mean cost for all newborns was $6389: $2433 for term infants, $22 102 for late preterm, $223 931 for very preterm infants, and $317 982 for extremely preterm infants (<28 weeks). Preterm infants were 8.1% of cases but incurred 60.9% of costs; for very preterm and extremely preterm infants, these shares were 1.0% and 36.5%, and 0.4% and 20.0%, respectively. Overall, mothers incurred 56% of the total costs during the delivery hospitalization. CONCLUSIONS: Both maternal and neonatal costs are skewed, with this being much more pronounced for infants. Preterm birth is much more expensive than term delivery, with the additional costs predominately incurred by the infants. The small share of infants who require extensive stays in neonatal intensive care incur a large share of neonatal costs and these costs have increased over time.

Incidence Trends and Risk Factor Variation in Severe Intraventricular Hemorrhage across a Population Based Cohort.

OBJECTIVE: To quantify the current burden of severe intraventricular hemorrhage (IVH), describe time trends in severe IVH, identify IVH-associated risk factors, and determine the contribution of mediating factors. STUDY DESIGN: The retrospective cohort included infants 220/7-316/7 weeks of gestation without severe congenital anomalies, born at hospitals in the California Perinatal Quality Care Collaborative between 2005 and 2015. The primary study outcome was severe (grade III or IV) IVH. RESULTS: Of 44 028 infants, 3371 (7.7%) had severe IVH. The incidence of severe IVH decreased significantly across California from 9.7% in 2005 to 5.9% in 2015. After stratification by gestational age, antenatal steroid exposure was the only factor associated with a decreased odds of severe IVH for all gestational age subgroups. Other factors, including delivery room intubation, were associated with an increased odds of severe IVH, though significance varied by gestational age. Factors analyzed in the mediation analysis accounted for 45.6% (95% CI 38.7%-71.8%) of the reduction in severe IVH, with increased antenatal steroid administration and decreased delivery room intubation mediating a significant proportion of this decrease, 19.4% (95% CI 13.9%-27.5%) and 27.3% (95% CI 20.3%-39.2%), respectively. The unaccounted proportion varied by gestational age. CONCLUSIONS: The incidence of severe IVH decreased across California, associated with changes in antenatal steroid exposure and delivery room intubation. Maternal, patient, and delivery room factors accounted for less than one-half of the decrease in severe IVH. Study of other factors, specifically neonatal intensive care unit and hospital-level factors, may provide new insights into policies to reduce severe IVH.

Association between Off-Peak Hour Birth and Neonatal Morbidity and Mortality among Very Low Birth Weight Infants.

OBJECTIVE: To assess the independent association between overnight or "off-peak" hour delivery and 3 neonatal morbidities strongly associated with childhood neurocognitive impairment. STUDY DESIGN: Retrospective population based cohort study of all infants with birth weights of 500-1499 g born without severe congenital anomalies in California or Pennsylvania between 2002 and 2009. Off-peak hour delivery was defined as birth between 12:00 a.m. and 6:59 a.m. The study outcomes were death; bronchopulmonary dysplasia, retinopathy of prematurity, and severe (grade 3 or 4) intraventricular hemorrhage among survivors; the composite of each morbidity or mortality; and the composite of death or 1 or more of the evaluated morbidities. RESULTS: Of 47 617 evaluated infants, 9317 (19.6%) were born during off-peak hours. The frequencies of all study outcomes were higher among infants born during off-peak compared with peak hours. After adjusting for maternal, infant, and hospital characteristics, off-peak hour delivery was associated with increased odds of severe intraventricular hemorrhage among survivors (OR 1.39, 95% CI 1.23-1.57) and the composite outcomes of death or severe intraventricular hemorrhage (OR 1.16, 95% CI 1.07-1.25) and death or major morbidity (OR 1.08, 95% CI 1.02-1.15). There was no evidence of subgroup effects based on delivery mode, birth hospital neonatal intensive care level or annual very low birth weight infant delivery volume, or weekday vs weekend off-peak hour delivery for any study outcome. CONCLUSIONS: Very low birth weight infants born between midnight and 7:00 a.m. are at increased risk for severe intraventricular hemorrhage and death or major neonatal morbidity.

Trends in childbirth before 39 weeks' gestation without medical indication.

BACKGROUND: There is increasing attention to labor induction and cesarean delivery occurring at 37 0/7-38 6/7 weeks' gestation (early-term) without medical indication. OBJECTIVE: To measure prevalence, change over time, patient characteristics, and infant outcomes associated with early-term nonindicated births. RESEARCH DESIGN AND SUBJECTS: Retrospective analysis using linked hospital discharge and birth certificate data for the 7,296,363 uncomplicated births (>37 0/7 wk' gestation) between 1995 and 2009 in 3 states. MEASURES: Early-term nonindicated birth is calculated using diagnosis codes and birth certificate records. Secondary outcomes included infant prolonged length of stay and respiratory distress. RESULTS: Across uncomplicated term births, the early-term nonindicated birth rate was 3.18%. After adjustment, the risk of nonindicated birth before 39 0/7 weeks was 86% higher in 2009 than in 1995 [hazard ratio (HR)=1.86; 95% confidence interval (CI), 1.81-1.90], peaking in 2006 (HR=2.03; P<0.001). Factors independently associated with higher odds included maternal age, higher education levels, private health insurance, and delivering at smaller-volume or nonteaching hospitals. Black women had higher risk of nonindicated cesarean birth (HR=1.29; 95% CI, 1.27-1.32), which was associated with greater odds of prolonged length of stay [adjusted odds ratio (AOR)=1.60; 95% CI, 1.57-1.64] and infant respiratory distress (AOR=2.44; 95% CI, 2.37-2.50) compared with births after 38 6/7 weeks. Early-term nonindicated induction was also associated with comparatively greater odds of prolonged length of stay (AOR=1.20; 95% CI, 1.17-1.23). CONCLUSIONS: Nearly 4% of all uncomplicated births to term infants occurred before 39 0/7 weeks' gestation without medical indication. These births were associated with adverse infant outcomes.