Betamethasone treatment-to-delivery interval, retreatment, and severe intraventricular hemorrhage in infants <28 weeks' gestation.

BACKGROUND: Antenatal corticosteroids decrease the incidence of severe intraventricular hemorrhage (grades 3, 4) in preterm infants. It is unclear whether their beneficial effects on intraventricular hemorrhage wane with time (as occurs in neonatal respiratory distress) and if repeat courses can restore this effect. Previous randomized controlled trials of betamethasone retreatment found no benefit on severe intraventricular hemorrhage rates. However, the trials may have included an insufficient number of infants at risk for intraventricular hemorrhage to be able to adequately address this question. Severe intraventricular hemorrhages occur almost exclusively in infants born at <28 weeks' gestation, whereas only 7% (0%-16%) of the retreatment trials' populations were <28 weeks' gestation. OBJECTIVE: This study aimed to determine if the risk for severe intraventricular hemorrhage in infants delivered at <28 weeks' gestation increases when the betamethasone treatment-to-delivery interval increases beyond 9 days and to determine if betamethasone retreatment before delivery decreases the rate of hemorrhage. STUDY DESIGN: This was an observational study that examined the incidence of intraventricular hemorrhage before (epoch 1) and after (epoch 2) a practice change that encouraged obstetricians to retreat pregnant women still at high risk for delivery before 28 weeks' gestation when >9 days elapsed from the first dose of betamethasone. Multivariable analyses with logistic regression using generalized estimating equation techniques were conducted to examine the rates of intraventricular hemorrhage among 410 infants <28 weeks' gestation who were either delivered between 1 to 9 days (n=290) after the first 2-dose betamethasone course or ≥10 days (and eligible for retreatment) after the first course (n=120). RESULTS: After adjusting for potential confounding variables, infants who were delivered ≥10 days after a single betamethasone course had an increased risk for either severe intraventricular hemorrhage alone or the combined outcome severe intraventricular hemorrhage or death before 4 days (odds ratio, 2.8; 95% confidence interval, 1.2-6.6) when compared with infants who were delivered between 1 and 9 days after betamethasone. Among the 120 infants who were delivered ≥10 days after the first dose of betamethasone, 64 (53%) received a second or retreatment course of antenatal betamethasone. The severe intraventricular hemorrhage rate in infants whose mothers received a second or retreatment course of betamethasone was similar to the rate among infants who delivered within 1 to 9 days and significantly lower than among those who delivered ≥10 days without retreatment (odds ratio, 0.10; 95% confidence interval, 0.02-0.65). Following the change in guidelines, the rate of retreatment in infants who were delivered ≥10 days after the first betamethasone course (and before 28 weeks) increased from epoch 1 to epoch 2 (25% to 87%; P<.001) and the rate of severe intraventricular hemorrhage decreased from 22% to 0% (P<.001). In contrast, the rate of severe intraventricular hemorrhage among infants who were delivered 1 to 9 days after the initial betamethasone dose (who were not eligible for retreatment) did not change between epochs 1 and 2 (12% and 11%, respectively). CONCLUSION: Although betamethasone's benefits on severe intraventricular hemorrhage appear to wane after the first dose, retreatment with a second course seems to restore its beneficial effects. Encouraging earlier retreatment of women at high risk for delivery before 28 weeks was associated with a lower rate of severe intraventricular hemorrhages among infants delivered at <28 weeks' gestation.

Resource and Service Use after Discharge Among Infants 22-25 Weeks Estimated Gestational Age at the First High-Risk Infant Follow-Up Visit in California.

OBJECTIVE: To examine resource and service use after discharge among infants born extraordinarily preterm in California who attended high-risk infant follow-up (HRIF) clinic by 12 months corrected age. STUDY DESIGN: We included infants born 2010-2017 between 22 + 0/7 and 25 + 6/7 weeks' gestational age in the California Perinatal Quality Care Collaborative and California Perinatal Quality Care Collaborative-California Children's Services HRIF databases. We evaluated rates of hospitalization, surgeries, medications, equipment, medical service and special service use, and referrals. We examined factors associated with receiving ≥ 2 medical services, and ≥ 1 special service. RESULTS: A total of 3941 of 5284 infants received a HRIF visit by 12 months corrected age. Infants born at earlier gestational ages used more medications, equipment, medical services, and special services and had higher rates of referral to medical and special services at the first HRIF visit. Infants with major morbidity, surgery, caregiver concerns, and mothers with more years of education had higher odds of receiving ≥ 2 medical services. Infants with Black maternal race, younger maternal age, female sex, and discharge from lower level neonatal intensive care units (NICUs) had lower odds of receiving ≥ 2 medical services. Infants with more educated mothers, multiple gestation, major morbidity, surgery, caregiver concerns, and discharge from lower level NICUs had increased odds of receiving a special service. CONCLUSIONS: Infants born extraordinarily preterm have substantial resource use after discharge. High resource utilization was associated with maternal/sociodemographic factors and expected clinical factors. Early functional and service use information is valuable to parents and underscores the need for NICU providers to appropriately prepare and refer families.

The validity of hospital diagnostic and procedure codes reflecting morbidity in preterm neonates born <32 weeks gestation.

OBJECTIVE: To determine the validity of diagnostic hospital billing codes for complications of prematurity in neonates <32 weeks gestation. STUDY DESIGN: Retrospective cohort data from discharge summaries and clinical notes (n = 160) were reviewed by trained, blinded abstractors for the presence of intraventricular hemorrhage (IVH) grades 3 or 4, periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), stage 3 or higher, retinopathy of prematurity (ROP), and surgery for NEC or ROP. Data were compared to diagnostic billing codes from the neonatal electronic health record. RESULTS: IVH, PVL, ROP and ROP surgery had strong positive predictive values (PPV > 75%) and excellent negative predictive values (NPV > 95%). The PPVs for NEC (66.7%) and NEC surgery (37.1%) were low. CONCLUSION: Diagnostic hospital billing codes were observed to be a valid metric to evaluate preterm neonatal morbidities and surgeries except in the instance of more ambiguous diagnoses such as NEC and NEC surgery.

Predicting the risk of 7-day readmission in late preterm infants in California: A population-based cohort study.

Background and aims: The American Academy of Pediatrics describes late preterm infants, born at 34 to 36 completed weeks' gestation, as at-risk for rehospitalization and severe morbidity as compared to term infants. While there are prediction models that focus on specific morbidities, there is limited research on risk prediction for early readmission in late preterm infants. The aim of this study is to derive and validate a model to predict 7-day readmission. Methods: This is a population-based retrospective cohort study of liveborn infants in California between January 2007 to December 2011. Birth certificates, maintained by California Vital Statistics, were linked to a hospital discharge, emergency department, and ambulatory surgery records maintained by the California Office of Statewide Health Planning and Development. Random forest and logistic regression were used to identify maternal and infant variables of importance, test for association, and develop and validate a predictive model. The predictive model was evaluated for discrimination and calibration. Results: We restricted the sample to healthy late preterm infants (n = 122,014), of which 4.1% were readmitted to hospital within 7-day after birth discharge. The random forest model with 24 variables had better predictive ability than the 8 variable logistic model with c-statistic of 0.644 (95% confidence interval 0.629, 0.659) in the validation data set and Brier score of 0.0408. The eight predictors of importance length of stay, delivery method, parity, gestational age, birthweight, race/ethnicity, phototherapy at birth hospitalization, and pre-existing or gestational diabetes were used to drive individual risk scores. The risk stratification had the ability to identify an estimated 19% of infants at greatest risk of readmission. Conclusions: Our 7-day readmission predictive model had moderate performance in differentiating at risk late preterm infants. Future studies might benefit from inclusion of more variables and focus on hospital practices that minimize risk.

Racial disparities in emergency mental healthcare utilization among birthing people with preterm infants.

BACKGROUND: Birthing people of color are more likely to deliver low birthweight and preterm infants, populations at significant risk of morbidity and mortality. Birthing people of color are also at higher risk for mental health conditions and emergency mental healthcare utilization postpartum. Although this group has been identified as high risk in these contexts, it is not known whether racial and ethnic disparities exist in mental healthcare utilization among birthing people who have delivered preterm. OBJECTIVE: We sought to determine if racial and ethnic disparities exist in postpartum mental healthcare-associated emergency department visits or hospitalizations for birthing people with preterm infants in a large and diverse population. STUDY DESIGN: This population-based historic cohort study used a sample of Californian live-born infants born between 2011 and 2017 with linked birth certificates and emergency department visit and hospital admission records from the California Statewide Health Planning and Development database. The sample was restricted to preterm infants (<37 weeks' gestation). Self-reported race and ethnicity groups included Hispanic, non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, and non-Hispanic others. Mental health diagnoses were identified from the International Classification of Diseases Ninth and Tenth revision codes recorded in emergency department and hospital discharge records. Logistic regression analysis was used to estimate the association between mental health-related emergency department visits and rehospitalizations by race or ethnicity compared with non-Hispanic White birthing people and controlling for the following characteristics and health condition covariates: age, parity, previous preterm birth, body mass index, smoking, alcohol use, hypertension, diabetes, previous mental health diagnosis, and prenatal care. RESULTS: Of 204,539 birthing people who delivered preterm infants in California, 1982 visited the emergency department and 836 were hospitalized in the first year after preterm birth for a mental health-related illness. Black birthing people were more likely to have a mental health-related emergency department visit and hospitalization (risk ratio, 1.8; 95% confidence interval, 1.5-2.0 and risk ratio, 1.9; 95% confidence interval, 1.5-2.3, respectively) within the first postpartum year than White birthing people. Hispanic and Asian birthing people were less likely to have mental health-related emergency department visits (adjusted risk ratio, 0.7; 95% confidence interval, 0.7-0.8 and adjusted risk ratio, 0.2; 95% confidence interval, 0.2-0.3, respectively) and hospitalizations (adjusted risk ratio, 0.6; 95% confidence interval, 0.5-0.7 and adjusted risk ratio, 0.2; 95% confidence interval, 0.1-0.3, respectively). When controlling for birthing people with a previous mental health diagnosis and those without, the disparities remained the same. CONCLUSION: Racial and ethnic disparities exist in emergency mental healthcare escalation among birthing people who have delivered preterm infants. Our findings highlight a need for further investigation into disparate mental health conditions, exacerbations, access to care, and targeted hospital and legislative policies to prevent emergency mental healthcare escalation and reduce disparities.

Metabolic differences among newborns born to mothers with a history of leukemia or lymphoma.

BACKGROUND: Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers. METHODS: A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program. RESULTS: A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (p < .001 - based on Bonferroni correction for multiple testing) higher compared to newborns of mothers without cancer history: C3-DC (mean difference (MD) = 0.006), C5-DC (MD = 0.009), C8:1 (MD = 0.008), C14 (MD = 0.010), and C16:1 (MD = 0.011), whereas citrulline levels were significantly lower (MD = -0.581) among newborns born to mothers with history of leukemia or lymphoma compared to newborns of mothers without a history of cancer. CONCLUSION: The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

Mortality and Major Neonatal Morbidity in Preterm Infants with Serious Congenital Heart Disease.

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.

The association between preterm birth and postpartum mental healthcare utilization among California birthing people.

BACKGROUND: While mental health conditions such as postpartum depression are common, little is known about how mental healthcare utilization varies after term versus preterm delivery. OBJECTIVE: This study aimed to determine whether preterm birth is associated with postpartum inpatient and emergency mental healthcare utilization. STUDY DESIGN: The study sample was obtained from a database of live-born neonates delivered in California between the years of 2011 and 2017. The sample included all people giving birth to singleton infants between the gestational age of 20 and 44 weeks. Preterm birth was defined as <37 weeks' gestation. Emergency department visits and hospitalizations with a mental health diagnosis within 1 year after birth were identified using International Classification of Diseases codes. Logistic regression was used to compare relative risks of healthcare utilization among people giving birth to preterm infants vs term infants, adjusting for the following covariates: age, race or ethnicity, parity, previous preterm birth, body mass index, tobacco use, alcohol or drug use, hypertension, diabetes mellitus, adequacy of prenatal care, education, insurance payer, and the presence of a mental health diagnosis before birth. Results were then stratified by mental health diagnosis before birth to determine whether associations varied based on mental health history. RESULTS: Of our sample of 3,067,069 births, 6.7% were preterm. In fully adjusted models, compared with people giving birth to term infants, people giving birth to preterm infants had a 1.5 times (relative risk; 95% confidence interval, 1.4-1.7) and 1.3 times (relative risk; 95% confidence interval, 1.2-1.4) increased risk of being hospitalized with a mental health diagnosis within 3 months and 1 year after delivery, respectively. People giving birth to preterm infants also had 1.4 times (95% confidence interval, 1.3-1.5) and 1.3 times (95% confidence interval, 1.2-1.4) increased risk of visiting the emergency department for a mental health diagnosis within 3 months and 1 year after birth, respectively. Stratifying by preexisting mental health diagnosis, preterm birth was associated with an elevated risk of mental healthcare utilization for people with and without a previous mental health diagnosis. CONCLUSION: We found that preterm birth is an independent risk factor for postpartum mental healthcare utilization. Our findings suggest that screening for and providing mental health resources to birthing people after delivery are crucial, particularly among people giving birth to preterm infants, regardless of mental health history.

Bronchopulmonary dysplasia precursors influence risk of white matter injury and adverse neurodevelopmental outcome in preterm infants.

BACKGROUND: Cumulative supplemental oxygen (CSO) and cumulative mean airway pressure (CMAP) are associated with bronchopulmonary dysplasia (BPD) in preterm infants, but their relationships to white matter injury (WMI) and neurodevelopment have not been evaluated. METHODS: Preterm infants <32 weeks' gestation were prospectively imaged with 3 T MRI near term. CSO and CMAP were retrospectively summed over the first 14 and 28 days. Neurodevelopment was assessed at 30 months adjusted using the Bayley-III. ROC and linear regression were used to evaluate the relationship between CSO, CMAP, and BPD with WMI and neurodevelopmental performance, respectively. RESULTS: Of the 87 infants, 30 (34.5%) had moderate-severe BPD, which was associated with WMI (OR 5.5, 95% CI 1.1-34.9, p = 0.012). CSO and CMAP predicted WMI as well as BPD (AUC 0.68-0.77). CSO was independently associated with decreased language and cognitive performance (mean difference at 14 days: -11.0, 95% CI -19.8 to -2.2, p = 0.015 and -9.8, 95% CI -18.9 to -0.7, p = 0.035, respectively) at 30 months adjusted. CONCLUSIONS: BPD precursors predict WMI as well as BPD. Cumulative supplemental oxygen over the first 14 days of life is independently associated with lower language and cognitive performances. These data suggest that early respiratory status influences the risk of adverse neurodevelopment in preterm infants. IMPACT: Respiratory precursors to bronchopulmonary dysplasia (BPD), cumulative supplemental oxygen and mean airway pressure, over the first 14-28 days performed as well as BPD for the prediction of white matter injury on MRI in preterm infants. Cumulative supplemental oxygen was independently associated with lower language and cognitive performance on the Bayley-III at 30 months adjusted. These data suggest that early respiratory status may help explain why BPD is independently associated with adverse neurodevelopmental outcomes in the preterm population and highlights the importance of interventions targeting respiratory status as a potential avenue to improve neurodevelopmental outcomes.

Associations between unstable housing, obstetric outcomes, and perinatal health care utilization.

BACKGROUND: While there is a growing interest in addressing social determinants of health in clinical settings, there are limited data on the relationship between unstable housing and both obstetric outcomes and health care utilization. OBJECTIVE: The objective of the study was to investigate the relationship between unstable housing, obstetric outcomes, and health care utilization after birth. STUDY DESIGN: This was a retrospective cohort study. Data were drawn from a database of liveborn neonates linked to their mothers' hospital discharge records (2007-2012) maintained by the California Office of Statewide Health Planning and Development. The analytic sample included singleton pregnancies with both maternal and infant data available, restricted to births between the gestational age of 20 and 44 weeks, who presented at a hospital that documented at least 1 woman as having unstable housing using the International Classification of Diseases, ninth edition, codes (n = 2,898,035). Infants with chromosomal abnormalities and major birth defects were excluded. Women with unstable housing (lack of housing or inadequate housing) were identified using International Classification of Diseases, ninth edition, codes from clinical records. Outcomes of interest included preterm birth (<37 weeks' gestational age), early term birth (37-38 weeks gestational age), preterm labor, preeclampsia, chorioamnionitis, small for gestational age, long birth hospitalization length of stay after delivery (vaginal birth, >2 days; cesarean delivery, >4 days), emergency department visit within 3 months and 1 year after delivery, and readmission within 3 months and 1 year after delivery. We used exact propensity score matching without replacement to select a reference population to compare with the sample of women with unstable housing using a one-to-one ratio, matching for maternal age, race/ethnicity, parity, prior preterm birth, body mass index, tobacco use during pregnancy, drug/alcohol abuse during pregnancy, hypertension, diabetes, mental health condition during pregnancy, adequacy of prenatal care, education, and type of hospital. Odds of an adverse obstetric outcome were estimated using logistic regression. RESULTS: Of 2794 women with unstable housing identified, 83.0% (n = 2318) had an exact propensity score-matched control. Women with an unstable housing code had higher odds of preterm birth (odds ratio, 1.2, 95% confidence interval, 1.0-1.4, P < .05), preterm labor (odds ratio, 1.4, 95% confidence interval, 1.2-1.6, P < .001), long length of stay (odds ratio, 1.6, 95% confidence interval, 1.4-1.8, P < .001), emergency department visits within 3 months (odds ratio, 2.4, 95% confidence interval, 2.1-2.8, P < .001) and 1 year after birth (odds ratio, 2.7, 95% confidence interval, 2.4-3.0, P < .001), and readmission within 3 months (odds ratio, 2.7, 95% confidence interval, 2.2-3.4, P < .0014) and 1 year after birth (odds ratio, 2.6, 95% confidence interval, 2.2-3.0, P < .001). CONCLUSION: Unstable housing documentation is associated with adverse obstetric outcomes and high health care utilization. Housing and supplemental income for pregnant women should be explored as a potential intervention to prevent preterm birth and prevent increased health care utilization.

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.

Bronchopulmonary Dysplasia and Perinatal Characteristics Predict 1-Year Respiratory Outcomes in Newborns Born at Extremely Low Gestational Age: A Prospective Cohort Study.

OBJECTIVE: To assess the utility of clinical predictors of persistent respiratory morbidity in extremely low gestational age newborns (ELGANs). STUDY DESIGN: We enrolled ELGANs (<29 weeks' gestation) at ≤7 postnatal days and collected antenatal and neonatal clinical data through 36 weeks' postmenstrual age. We surveyed caregivers at 3, 6, 9, and 12 months' corrected age to identify postdischarge respiratory morbidity, defined as hospitalization, home support (oxygen, tracheostomy, ventilation), medications, or symptoms (cough/wheeze). Infants were classified as having postprematurity respiratory disease (PRD, the primary study outcome) if respiratory morbidity persisted over ≥2 questionnaires. Infants were classified with severe respiratory morbidity if there were multiple hospitalizations, exposure to systemic steroids or pulmonary vasodilators, home oxygen after 3 months or mechanical ventilation, or symptoms despite inhaled corticosteroids. Mixed-effects models generated with data available at 1 day (perinatal) and 36 weeks' postmenstrual age were assessed for predictive accuracy. RESULTS: Of 724 infants (918 ± 234 g, 26.7 ± 1.4 weeks' gestational age) classified for the primary outcome, 68.6% had PRD; 245 of 704 (34.8%) were classified as severe. Male sex, intrauterine growth restriction, maternal smoking, race/ethnicity, intubation at birth, and public insurance were retained in perinatal and 36-week models for both PRD and respiratory morbidity severity. The perinatal model accurately predicted PRD (c-statistic 0.858). Neither the 36-week model nor the addition of bronchopulmonary dysplasia to the perinatal model improved accuracy (0.856, 0.860); c-statistic for BPD alone was 0.907. CONCLUSION: Both bronchopulmonary dysplasia and perinatal clinical data accurately identify ELGANs at risk for persistent and severe respiratory morbidity at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01435187.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California.

BACKGROUND AND OBJECTIVES: There are limited epidemiologic data on persistent pulmonary hypertension of the newborn (PPHN). We sought to describe the incidence and 1-year mortality of PPHN by its underlying cause, and to identify risk factors for PPHN in a contemporary population-based dataset. METHODS: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharges, readmissions, and birth and death certificates from 1 year before to 1 year after birth. We searched the database (2007-2011) for cases of PPHN (identified by International Classification of Diseases, Ninth Revision codes), including infants ≥34 weeks' gestational age without congenital heart disease. Multivariate Poisson regression was used to identify risk factors associated with PPHN; results are presented as risk ratios, 95% confidence intervals. RESULTS: Incidence of PPHN was 0.18% (3277 cases/1 781 156 live births). Infection was the most common cause (30.0%). One-year mortality was 7.6%; infants with congenital anomalies of the respiratory tract had the highest mortality (32.0%). Risk factors independently associated with PPHN included gestational age <37 weeks, black race, large and small for gestational age, maternal preexisting and gestational diabetes, obesity, and advanced age. Female sex, Hispanic ethnicity, and multiple gestation were protective against PPHN. CONCLUSIONS: This risk factor profile will aid clinicians identifying infants at increased risk for PPHN, as they are at greater risk for rapid clinical deterioration.

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns.

OBJECTIVE: To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death. STUDY DESIGN: We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. RESULTS: In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. CONCLUSION: In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Impaired cognitive performance in premature newborns with two or more surgeries prior to term-equivalent age.

BACKGROUND: Anesthesia in early childhood is associated with adverse neurodevelopmental outcome; however, it is not known if age at exposure affects the risk of adverse outcome. Our objective was to evaluate the association of the number and timing of anesthetic exposures for surgery with cognitive outcome in a cohort of premature newborns. METHODS: A cohort study of exposure to anesthesia for surgery in premature newborns (<33 wk gestation) prospectively evaluated with neonatal magnetic resonance imaging (MRI) and neurodevelopmental testing at 3-6 y was employed. Exposure to anesthesia for surgery was classified as before term-equivalent age (TEA, <42 wk postmenstrual age) or after (≥42 wk). Multivariate regression was performed to analyze the association of composite IQ scores with the number of surgeries before and after TEA. RESULTS: Among 137 newborns, 25 (18.2%) had one surgery before TEA and 18 (13.1%) had ≥2 surgeries. Two or more surgeries before TEA were associated with significantly reduced composite IQ scores at 4.6 ± 0.6 y after adjusting for gestational age and illness severity. Neither the number of surgeries after TEA nor sedation for MRI was associated with cognitive outcome. CONCLUSIONS: More than one surgery prior to TEA is independently associated with impaired cognitive performance in premature newborns.

Regulation of growth response to water stress in the soybean primary root. I. Proteomic analysis reveals region-specific regulation of phenylpropanoid metabolism and control of free iron in the elongation zone.

In water-stressed soybean primary roots, elongation was maintained at well-watered rates in the apical 4 mm (region 1), but was progressively inhibited in the 4-8 mm region (region 2), which exhibits maximum elongation in well-watered roots. These responses are similar to previous results for the maize primary root. To understand these responses in soybean, spatial profiles of soluble protein composition were analysed. Among the changes, the results indicate that region-specific regulation of phenylpropanoid metabolism may contribute to the distinct growth responses in the different regions. Several enzymes related to isoflavonoid biosynthesis increased in abundance in region 1, correlating with a substantial increase of isoflavonoid content in this region which could contribute to growth maintenance via various potential mechanisms. In contrast, caffeoyl-CoA O-methyltransferase, which is involved in lignin synthesis, was highly up-regulated in region 2. This response was associated with enhanced accumulation of lignin, which may be related to the inhibition of growth in this region. Several proteins that increased in abundance in both regions of water-stressed roots were related to protection from oxidative damage. In particular, an increase in the abundance of ferritin proteins effectively sequestered more iron and prevented excess free iron in the elongation zone under water stress.

Two MATE proteins play a role in iron efficiency in soybean.

Iron is a necessary but often limiting nutrient for plant growth and development. Soybeans grown on the high-pH calcareous soils are especially prone to developing iron deficiency chlorosis and suffering the resultant yield losses. Once iron is transported into the root, it must be translocated from the root to the shoot where it is needed for photosynthesis and other processes. Previous work has indicated that iron is likely to move through the xylem as ferric citrate. In Arabidopsis thaliana, citrate is effluxed into the xylem by the ferric reductase defective3 (FRD3) protein. Here, we present the identification and characterization of two soybean genes, GmFRD3a and GmFRD3b, with similar sequence and function to AtFRD3. The expression of both GmFRD3a and GmFRD3b is induced by iron deficiency in the iron-efficient reference cultivar Williams 82. GmFRD3b, but not GmFRD3a, is expressed at higher levels in the iron-efficient cultivar Clark than in its iron-inefficient near isogenic line iso-Clark (iso), likely accounting for the higher xylem citrate levels in Clark. Increased xylem citrate levels lead to increased solubility of ferric iron in Clark xylem exudate as compared to iso-Clark exudate. These results support the hypothesis that high xylem citrate levels are needed for efficient root to shoot translocation of iron. Along with efficient ferric chelate reductase activity and root iron uptake activity, high expression levels of FRD3 genes are also proposed as a target for future iron efficiency breeding projects.