Scott P. Oltman

Gestational Age and Outcomes in Critical Congenital Heart Disease

Population-based cohort study to assess impact of GA on morbidity and mortality in preterm and term infants with CCHD. BACKGROUND AND OBJECTIVES: It is unknown how gestational age (GA) impacts neonatal morbidities in infants with critical congenital heart disease (CCHD). We aim to quantify GA-specific mortality and neonatal morbidity in infants with CCHD. METHODS: Cohort study using a database linking birth certificate, infant hospital discharge, readmission, and death records, including infants 22 to 42 weeks’ GA without chromosomal anomalies (2005–2012, 2 988 925 live births). The International Classification of Diseases, Ninth Revision diagnostic and procedure codes were used to define CCHD and neonatal morbidities (intraventricular hemorrhage, retinopathy, periventricular leukomalacia, chronic lung disease, necrotizing enterocolitis). Adjusted absolute risk differences (ARDs) with 95% confidence intervals (CIs) were calculated. RESULTS: We identified 6903 out of 2 968 566 (0.23%) infants with CCHD. The incidence of CCHD was highest at 29 to 31 weeks’ GA (0.9%) and lowest at 39 to 42 weeks (0.2%). Combined neonatal morbidity or mortality in infants with and without CCHD was 82.8% and 57.9% at <29 weeks and declined to 10.9% and 0.1% at 39 to 42 weeks’ GA. In infants with CCHD, being born at 34 to 36 weeks was associated with a higher risk of death or morbidity than being born at 37 to 38 weeks (adjusted ARD 9.1%, 95% CI 5.5% to 12.7%), and being born at 37 to 38 weeks was associated with a higher risk of death or morbidity than 39 to 42 weeks (adjusted ARD 3.2%, 95% CI 1.6% to 4.9%). CONCLUSIONS: Infants born with CCHD are at high risk of neonatal morbidity. Morbidity remains increased across all GA groups in comparison with infants born at 39 to 42 weeks. This substantial risk of neonatal morbidity is important to consider when caring for this patient population.

Risk of preterm birth by maternal age at first and second pregnancy and race/ethnicity

Abstract We examined the risk of preterm birth (PTB, <37 weeks’ gestation) in a second pregnancy and analyzed the extent to which this risk varies by maternal age and race/ethnicity. The sample included nulligravida mothers in California who delivered two singletons between 2005 and 2011. Logistic regression was used to calculate the odds of PTB in the second pregnancy. Within each race/ethnicity stratum, women delivering term infants in their first pregnancy and between 25 and 34 years old for both pregnancies served as the referent group. There were 2,90,834 women included in the study. Among women who delivered their first infant at term, the odds of delivering their second infant early differed by race and age. Hispanic, Black and Asian non-Hispanic women who were <18 years for both pregnancies were at higher odds of having a PTB in their second pregnancy (adjusted odds ratios 1.7, 3.3 and 2.9, respectively). Asian non-Hispanic women who were <18 years for their first delivery at term and between 18 and 24 years for their second delivery, or were >34 years for both, were also at higher odds of delivering their second baby prematurely (adjusted odds ratios 1.9 and 1.3, respectively). Women who deliver their first infant at <37 weeks of gestation are at 3 to 7 times higher odds of delivering their second infant preterm. Providers should consider including information about these risks in counseling their patients.

Racial and Ethnic Disparities in Preterm Infant Mortality and Severe Morbidity: A Population-Based Study

Background: Disparities exist in the rates of preterm birth and infant mortality across different racial/ethnic groups. However, only a few studies have examined the impact of race/ethnicity on the outcomes of premature infants. Objective: To report the rates of mortality and severe neonatal morbidity among multiple gestational age (GA) groups stratified by race/ethnicity. Methods: A retrospective cohort study utilizing linked birth certificate, hospital discharge, readmission, and death records up to 1 year of life. Live-born infants ≤36 weeks born in the period 2007-2012 were included. Maternal self-identified race/ethnicity, as recorded on the birth certificate, was used. ICD-9 diagnostic and procedure codes captured neonatal morbidities (intraventricular hemorrhage, retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis). Multiple logistic regression was performed to evaluate the impact of race/ethnicity on mortality and morbidity, adjusting for GA, birth weight, sex, and multiple gestation. Results: Our cohort totaled 245,242 preterm infants; 26% were white, 46% Hispanic, 8% black, and 12% Asian. At 22-25 weeks, black infants were less likely to die than white infants (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.62-0.94). However, black infants born at 32-34 weeks (OR 1.64; 95% CI 1.15-2.32) or 35-36 weeks (OR 1.57; 95% CI 1.00-2.24) were more likely to die. Hispanic infants born at 35-36 weeks were less likely to die than white infants (OR 0.66; 95% CI 0.50-0.87). Racial disparities at different GAs were also detected for severe morbidities. Conclusions: The impact of race/ethnicity on mortality and severe morbidity varied across GA categories in preterm infants. Disparities persisted even after adjusting for important potential confounders.

Maternal factors influencing late entry into prenatal care: a stratified analysis by race or ethnicity and insurance status

Abstract Objective: Examine factors influencing late (> sixth month of gestation) entry into prenatal care by race/ethnicity and insurance payer. Methods: The study population was drawn from singleton live births in California from 2007 to 2012 in the birth cohort file maintained by the California Office of Statewide Health Planning and Development, which includes linked birth certificate and mother and infant hospital discharge records. The sample was restricted to infants delivered between 20 and 44 weeks gestation. Logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) for factors influencing late entry into prenatal care. Maternal age, education, smoking, drug or alcohol abuse/dependence, mental illness, participation in the Women, Infants and Children’s program and rural residence were evaluated for women entering prenatal care > sixth month of gestation compared with women entering < fourth month. Backwards stepwise logistic regression was used to create final multivariable models of risk and protective factors for late prenatal care entry for each race or ethnicity and insurance payer. Results: The sample included 2,963,888 women. The percent of women with late entry into prenatal care was consistently higher among women with public versus private insurance. Less than 1% of white non-Hispanic and Asian women with private insurance entered prenatal care late versus more than 4% of white non-Hispanic and black women with public insurance. After stratifying by race or ethnicity and insurance status, women less than 18 years of age were more likely to enter prenatal care late, with young Asian women with private insurance at the highest risk (15.6%; adjusted RR 7.4, 95%CI 5.3–10.5). Among all women with private insurance, > 12-year education or age >34 years at term reduced the likelihood of late prenatal care entry (adjusted RRs 0.5–0.7). Drugs and alcohol abuse/dependence and residing in a rural county were associated with increased risk of late prenatal care across all subgroups (adjusted RRs 1.3–3.8). Participation in the Women, Infants, and Children’s program was associated with decreased risk of late prenatal care for women with public insurance (adjusted RRs 0.6–0.7), but increased risk for women with private insurance (adjusted RRs 1.4–2.1). Conclusions: The percent of women with late entry into prenatal care was consistently higher among women with public insurance. Younger women, women with <12-year education, those who used drugs or alcohol or resided in rural counties were more likely to enter prenatal care late, with Asian women <18 years at especially high risk. Participation in the Women, Infants, and Children’s program and maternal age >34 years at delivery increased the likelihood of late prenatal care for some subgroups of women and decreased the likelihood for others. These findings can inform institutional factors influencing late prenatal care, especially among lower income women, and may assist efforts aimed at encouraging earlier entry into prenatal care. Rationale: Optimal prenatal care includes initiation before the 14th week of gestation. Beginning care in the first trimester provides an opportunity for sonographic pregnancy dating or confirmation with best accuracy, which can later prove critical for management of preterm labor, maternal or fetal complications, or prolonged pregnancy. In order to improve maternal and infant health by increasing the number of women seeking prenatal care in the first trimester, it is important to examine the drivers for late entry. Here, we examine factors influencing late (> sixth month of gestation) entry into prenatal care by race/ethnicity and insurance payer. We found the percent of women with late entry into prenatal care was consistently higher among women with public insurance. Younger women, women with <12-year education, those who used drugs or alcohol or resided in rural counties were more likely to enter prenatal care late, with Asian women <18 years at especially high risk. These findings can inform institutional factors influencing late prenatal care, especially among lower income women, and may assist efforts aimed at encouraging earlier entry into prenatal care.

Initial Metabolic Profiles Are Associated with 7-Day Survival among Infants Born at 22-25 Weeks of Gestation

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.

Altered metabolites in newborns with persistent pulmonary hypertension

BackgroundThere is an emerging evidence that pulmonary hypertension is associated with amino acid, carnitine, and thyroid hormone aberrations. We aimed to characterize metabolic profiles measured by the newborn screen (NBS) in infants with persistent pulmonary hypertension of the newborn (PPHN)MethodsNested case–control study from population-based database. Cases were infants with ICD-9 code for PPHN receiving mechanical ventilation. Controls receiving mechanical ventilation were matched 2:1 for gestational age, sex, birth weight, parenteral nutrition administration, and age at NBS collection. Infants were divided into derivation and validation datasets. A multivariable logistic regression model was derived from candidate metabolites, and the area under the receiver operator characteristic curve (AUROC) was generated from the validation dataset.ResultsWe identified 1076 cases and 2152 controls. Four metabolites remained in the final model. Ornithine (OR 0.32, CI 0.26–0.41), tyrosine (OR 0.48, CI 0.40–0.58), and TSH 0.50 (0.45–0.55) were associated with decreased odds of PPHN; phenylalanine was associated with increased odds of PPHN (OR 4.74, CI 3.25–6.90). The AUROC was 0.772 (CI 0.737–0.807).ConclusionsIn a large, population-based dataset, infants with PPHN have distinct, early metabolic profiles. These data provide insight into the pathophysiology of PPHN, identifying potential therapeutic targets and novel biomarkers to assess the response.

THE EFFECT OF BIRTH WEIGHT ON MORTALITY IN INFANTS WITH CRITICAL CONGENITAL HEART DISEASE

Infants with critical congenital heart disease (CCHD) are more likely to have fetal growth restriction and subsequently be small for gestational age (SGA) at birth. While SGA infants with CCHD are known to have poor postnatal outcomes, birth weight (BW) has only been evaluated as a dichotomous

Second trimester serum cortisol and preterm birth: an analysis by timing and subtype

ObjectiveWe hypothesized second trimester serum cortisol would be higher in spontaneous preterm births compared to provider-initiated (previously termed ‘medically indicated’) preterm births.Study designWe used a nested case-control design with a sample of 993 women with live births. Cortisol was measured from serum samples collected as part of routine prenatal screening. We tested whether mean-adjusted cortisol fold-change differed by gestational age at delivery or preterm birth subtype using multivariable linear regression.ResultAn inverse association between cortisol and gestational age category (trend p = 0.09) was observed. Among deliveries prior to 37 weeks, the mean-adjusted cortisol fold-change values were highest for preterm premature rupture of the membranes (1.10), followed by premature labor (1.03) and provider-initiated preterm birth (1.01), although they did not differ statistically.ConclusionCortisol continues to be of interest as a marker of future preterm birth. Augmentation with additional biomarkers should be explored.

Correction: Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics

Objective:To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia.Study design:Included were 400 women with singleton deliveries in California in 2009–2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15–20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC).Results:Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822–0.959) training; 0.883 (0.804–0.963) testing).Conclusion:Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia.

Newborn Metabolic Profile Associated with Hyperbilirubinemia With and Without Kernicterus

Our objective was to assess the relationship between hyperbilirubinemia with and without kernicterus and metabolic profile at newborn screening. Included were 1,693,658 infants divided into a training or testing subset in a ratio of 3:1. Forty‐two metabolites were analyzed using logistic regression (odds ratios (ORs), area under the receiver operating characteristic curve (AUC), 95% confidence intervals (CIs)). Several metabolite patterns remained consistent across gestational age groups for hyperbilirubinemia without kernicterus. Thyroid stimulating hormone (TSH) and C‐18:2 were decreased, whereas tyrosine and C‐3 were increased in infants across groupings. Increased C‐3 was also observed for kernicterus (OR: 3.17; 95% CI: 1.18–8.53). Thirty‐one metabolites were associated with hyperbilirubinemia without kernicterus in the training set. Phenylalanine (OR: 1.91; 95% CI: 1.85–1.97), ornithine (OR: 0.76; 95% 0.74–0.77), and isoleucine + leucine (OR: 0.63; 95% CI: 0.61–0.65) were the most strongly associated. This study showed that newborn metabolic function is associated with hyperbilirubinemia with and without kernicterus.