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OBJECTIVES: To describe the typical clinical course of reversible persistent pulmonary hypertension of the newborn (PPHN) from perinatal etiologies and compare that with the clinical course of PPHN due to underlying fetal developmental etiologies. STUDY DESIGN: This was a single-center, retrospective cohort study of liveborn newborns either born or transferred to our facility for higher level of care between 2015 and 2020 with gestational age ≥35 weeks and a clinical diagnosis of PPHN in the electronic health record. Newborns with complex congenital heart disease and congenital diaphragmatic hernia were excluded. Using all data available at time of collection, newborns were stratified into 2 groups by PPHN etiology - perinatal and fetal developmental causes. Primary outcomes were age at initiation, discontinuation, and total duration of extracorporeal life support, mechanical ventilation, supplemental oxygen, inhaled nitric oxide, inotropic support, and prostaglandin E1. Our secondary outcome was age at echocardiographic resolution of pulmonary hypertension. Groups were compared by t-test. Time-to-event Kaplan Meier curves described and compared (log-rank test) discontinuation of each therapy. RESULTS: Sixty-four (72%) newborns had perinatal etiologies whereas 24 (28%) had fetal developmental etiologies. The resolution of perinatal PPHN was more rapid compared with fetal developmental PPHN. By 10 days of age, more neonates were off inotropes (98% vs 29%, P < .01), decannulated from extracorporeal life support (100% vs 0%, P < .01), extubated (75% vs 37%, P < .01), and had echocardiographic resolution of PH (35% vs 7%, P = .02). CONCLUSIONS: An atypical PPHN course, characterized by persistent targeted therapies in the second week of life, warrants further work-up for fetal developmental causes.

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OBJECTIVE: To determine whether differential exposure to an adverse maternal fetal environment partially explains disparate outcomes in infants with major congenital heart disease (CHD). STUDY DESIGN: Retrospective cohort study utilizing a population-based administrative California database (2011-2017). Primary exposure: Race/ethnicity. Primary mediator: Adverse maternal fetal environment (evidence of maternal metabolic syndrome and/or maternal placental syndrome). OUTCOMES: Composite of 1-year mortality or severe morbidity and days alive out of hospital in the first year of life (DAOOH). Mediation analyses determined the percent contributions of mediators on pathways between race/ethnicity and outcomes after adjusting for CHD severity. RESULTS: Included were 2747 non-Hispanic White infants (reference group), 5244 Hispanic, and 625 non-Hispanic Black infants. Hispanic and non-Hispanic Black infants had a higher risk for composite outcome (crude OR: 1.18; crude OR: 1.25, respectively) and fewer DAOOH (-6 & -12 days, respectively). Compared with the reference group, Hispanic infants had higher maternal metabolic syndrome exposure (43% vs 28%, OR: 1.89), and non-Hispanic Black infants had higher maternal metabolic syndrome (44% vs 28%; OR: 1.97) and maternal placental syndrome exposure (18% vs 12%; OR, 1.66). Both maternal metabolic syndrome exposure (OR: 1.21) and maternal placental syndrome exposure (OR: 1.56) were related to composite outcome and fewer DAOOH (-25 & -16 days, respectively). Adverse maternal fetal environment explained 25% of the disparate relationship between non-Hispanic Black race and composite outcome and 18% of the disparate relationship between Hispanic ethnicity and composite outcome. Adverse maternal fetal environment explained 16% (non-Hispanic Black race) and 21% (Hispanic ethnicity) of the association with DAOOH. CONCLUSIONS: Increased exposure to adverse maternal fetal environment contributes to racial and ethnic disparities in major CHD outcomes.

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OBJECTIVE: To investigate the trends of 1-year mortality and neonatal morbidities in preterm infants with serious congenital heart disease (CHD). STUDY DESIGN: This cohort study used a population-based administrative dataset of all liveborn infants of 26-36 weeks gestational age with serious CHD born in California between 2011 and 2017. We assessed 1-year mortality and major neonatal morbidities (ie, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage grade >2, and periventricular leukomalacia) across the study period and compared these outcomes with those in infants without CHD. RESULTS: We identified 1921 preterm infants with serious CHD. The relative risk (RR) of death decreased by 10.6% for each year of the study period (RR, 0.89; 95% CI, 0.84-0.95), and the RR of major neonatal morbidity increased by 8.3% for each year (RR, 1.08; 95% CI, 1.02-1.15). Compared with preterm neonates without any CHD (n = 234 522), the adjusted risk difference (ARD) for mortality was highest at 32 weeks of gestational age (9.7%; 95% CI, 8.3%-11.2%), that for major neonatal morbidity was highest at 28 weeks (21.9%; 95% CI, 17.0%-26.9%), and that for the combined outcome was highest at 30 weeks (26.7%; 95% CI, 23.3%-30.1%). CONCLUSIONS: Mortality in preterm neonates with serious CHD decreased over the last decade, whereas major neonatal morbidities increased. Preterm infants with a gestational age of 28-32 weeks have the highest mortality or morbidity compared with their peers without CHD. These results support the need for specialized and focused medical neonatal care in preterm neonates with serious CHD.

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OBJECTIVE: To compare mortality and early respiratory outcomes of very preterm infants conceived via assisted reproductive technology (ART) vs spontaneously. STUDY DESIGN: We identified inborn infants (July 2014-July 2019) with gestational age <32 weeks (n = 439); 54 cases were ART conceived. Spontaneously conceived controls (n = 103) were matched by multiple gestation status and gestational age. Primary outcome was 1-year mortality. Secondary outcomes were receipt of respiratory support and supplemental oxygen at 7 and 28 days and 36 weeks of postmenstrual age. We evaluated the association between conception method and outcomes by logistic regression, with adjustment for sociodemographic status. RESULTS: Women who conceived via ART had increased rates of prepregnancy and gestational diabetes, and no differences in rates of hypertensive disorders. Infant 1-year mortality was not different by mode of conception (ART 11.8% vs spontaneous 7.1%, P = .49). Infants conceived by ART were less likely to receive respiratory support or supplemental oxygen at all time points, but this relationship only reached significance for receipt of oxygen at 28 days (ART 20.8% vs spontaneous 39.0%, P = .03); this remained true after adjustment for race/ethnicity and socioeconomic index. CONCLUSIONS: When controlling for gestational age and multiple gestation status, very preterm infants conceived following ART had similar outcomes as those conceived spontaneously.

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OBJECTIVE: To evaluate B-type natriuretic peptide (BNP) as a longitudinal biomarker of clinical outcome in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective study of 49 infants with CDH, classifying the cohort by respiratory status at 56 days, based on a proposed definition of bronchopulmonary dysplasia for infants ≥32 weeks' gestation: good outcome (alive with no respiratory support) and poor outcome (ongoing respiratory support or death). BNP levels were available at age 1-5 weeks. Longitudinal BNP trends were assessed using mixed-effects modeling. Receiver operating characteristic curves were generated to identify BNP cutoffs maximizing correct outcome classification at each time point. The time to reach BNP cutoff by outcome was assessed using Kaplan-Meier curves for weeks 3-5. RESULTS: Twenty-nine infants (59%) had a poor outcome. Infants with a poor outcome were more likely than those with a good outcome to have liver herniated into the thorax (90% vs 50%; P = .002) and to undergo nonprimary repair (93% vs 35%; P < .001). Mixed-effects modeling demonstrated a differing decline in BNP over time by outcome group (P = .003 for interaction). BNP accurately predicted outcome at 3-5 weeks (area under the curve, 0.81-0.82). BNP cutoffs that maximized correct outcome classification decreased over time from 285 pg/mL at 3 weeks to 100 pg/mL at 4 weeks and 48 pg/mL at 5 weeks. Time to reach the cutoffs of 100 pg/mL and 48 pg/mL were longer in the poor outcome group (log-rank P = .006 and <.0001, respectively). CONCLUSIONS: Elevated BNP accurately predicts poor outcome in infants with CDH at age 3-5 weeks, with declining cutoffs over 3-5 weeks of age.

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OBJECTIVE: To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes. STUDY DESIGN: This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34 weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors. RESULTS: Infants with PPHN (n = 7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n = 3 974 536), and infants with only mild PPHN (n = 2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome. CONCLUSIONS: The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents.

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OBJECTIVE: To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. STUDY DESIGN: We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. RESULTS: Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. CONCLUSIONS: Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

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OBJECTIVE: To evaluate the association between early metabolic profiles combined with infant characteristics and survival past 7 days of age in infants born at 22-25 weeks of gestation. STUDY DESIGN: This nested case-control consisted of 465 singleton live births in California from 2005 to 2011 at 22-25 weeks of gestation. All infants had newborn metabolic screening data available. Data included linked birth certificate and mother and infant hospital discharge records. Mortality was derived from linked death certificates and death discharge information. Each death within 7 days was matched to 4 surviving controls by gestational age and birth weight z score category, leaving 93 cases and 372 controls. The association between explanatory variables and 7-day survival was modeled via stepwise logistic regression. Infant characteristics, 42 metabolites, and 12 metabolite ratios were considered for model inclusion. Model performance was assessed via area under the curve. RESULTS: The final model included 1 characteristic and 11 metabolites. The model demonstrated a strong association between metabolic patterns and infant survival (area under the curve [AUC] 0.885, 95% CI 0.851-0.920). Furthermore, a model with just the selected metabolites performed better (AUC 0.879, 95% CI 0.841-0.916) than a model with multiple clinical characteristics (AUC 0.685, 95% CI 0.627-0.742). CONCLUSIONS: Use of metabolomics significantly strengthens the association with 7-day survival in infants born extremely premature. Physicians may be able to use metabolic profiles at birth to refine mortality risks and inform postnatal counseling for infants born at <26 weeks of gestation.

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OBJECTIVE: To evaluate the incidence, etiology, and 1-year mortality of nonimmune hydrops fetalis (NIHF) and to identify risk factors for mortality in a contemporary population-based dataset. STUDY DESIGN: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharge, readmissions, and birth and death certificate date from 1 year before to 1 year after birth. We searched the database (2005-2012) for infants with NIHF (identified by the International Classification of Diseases, 9th Revision, Clinical Modification code). Hazard models were used to identify risk factors for mortality in infants with NIHF; results are presented as hazard ratios (HRs, 95% CI). RESULTS: The incidence of NIHF was 2.5 out of 10 000 among live born infants. Neonatal mortality was 35.1% (364 out of 1037) and overall mortality was 43.2% (448 out of 1037) at 1 year of age. Gestational age (GA) was predictive of mortality with a HR of 2.4 (95% CI 1.9-3.2) for preterm compared with term infants. The GA-adjusted HR for mortality was 1.3 (95% CI 1.1-1.6) for polyhydramnios and 1.5 (95% CI 1.2-2.0) for large for gestational age infants compared with appropriate for GA infants. Aneuploid infants with critical congenital heart disease had an adjusted HR of 2.3 (95% CI 1.5-3.6) compared with euploid infants without a structural birth defect. CONCLUSIONS: In this large, population-based study, prematurity, polyhydramnios, and large for gestational age were predictors of increased mortality. Mortality is highly variable among euploid and aneuploid infants with and without structural birth defects and critical congenital heart disease.

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OBJECTIVES: To describe the natural history of pulmonary hypertension (PH) and the risk of death and pulmonary morbidity associated with the persistence of PH through the neonatal hospitalization for these infants. STUDY DESIGN: We performed a retrospective cohort study of infants with congenital diaphragmatic hernia (CDH) cared for at University of California San Francisco (2002-2012). Infants with other major anomalies or syndromes were excluded (n = 43). Clinical echocardiograms were performed weekly for up to 6 weeks or until PH resolved off respiratory support or until hospital discharge. Echocardiograms were re-read by a blinded reviewer and categorized by severity of elevation in estimated pulmonary arterial pressure. PH was defined as ≥2/3 systemic blood pressure. Severity was determined by a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. RESULTS: Of 140 infants with ≥1 echo, 98 resolved their PH prior to death/discharge. Mean time to resolution was 18 days (median 14 days, IQR 8, 21 days). Those with persistence of PH had a higher rate of extracorporeal membrane oxygenation (P < .001) and death (P < .001), and fewer ventilator-free days (P < .001). Persistence of PH at 14 days predicted mortality (area under the receiver operating characteristic curve 0.87) and adverse respiratory outcomes (area under the receiver operating characteristic curve 0.80-0.83). CONCLUSIONS: The majority of infants with CDH resolve PH between 1 and 3 weeks of life. At 2 weeks of age, severity of PH by echocardiogram strongly predicts short-term pulmonary morbidity and death. Further evaluation of physiological alterations during that time may lead to novel therapies for severe CDH.

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