Treatment for Mild Chronic Hypertension during Pregnancy.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

FGF2 is secreted in extracellular vesicles from lung cells.

The 18-kDa isoform of basic fibroblast growth factor (bFGF/FGF2) lacks a conventional signal peptide sequence and is exported by a novel membrane-associated transport pathway. Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in the lung, and our prior work demonstrates that EVs carry cargo that contributes to hyperoxic lung injury and are biomarkers for bronchopulmonary dysplasia. We used primary human bronchial epithelial (HBE), pulmonary artery endothelial (HPAE), and fibroblast (HNF) cells to determine whether FGF2 was secreted in EVs. EVs were isolated by ultracentrifugation from HBE, HPAE, and HNF exposed to either normoxia or hyperoxia, followed by nanoparticle tracking analysis and electron microscopy. Hyperoxia exposure increased the total EV number. All three cell types released FGF2-18kDa both directly into the extracellular environment (secretome), as well as in EVs. HBE released more FGF2-18kDa in EVs during hyperoxia, and these were internalized and localized to both nuclei and cytoplasm of recipient cells. By co-immunoprecipitation, we identified potential binding partners of FGF2-18kDa in the nuclei, including histone 1.2 (H1.2) binding protein, that may mediate downstream effects that do not involve FGF2 binding to cell surface receptors. FGF2-18kDa interaction with H1.2 binding protein may indicate a mechanism by which FGF2 secreted in EVs modulates cellular processes. FGF2 was also found to increase angiogenesis by Matrigel assay. Further studies are necessary to determine the biological relevance of FGF2 in EVs as modulators of lung injury and disease.NEW & NOTEWORTHY We found that multiple lung cell types release basic fibroblast growth factor (FGF2)-18kDa both directly into the extracellular environment (secretome), as well as in extracellular vesicles (EVs). Bronchial epithelial cells released more FGF2-18kDa in EVs during hyperoxia, which could be internalized rapidly by recipient cells. We also identified potential binding partners of FGF2-18kDa in nuclei that may mediate downstream effects that do not involve FGF2 binding to cell surface receptors. We also confirmed a potential angiogenic role for FGF2-18kDa.

Risk Assessment of Cognitive Impairment at 2 Years of Age in Infants Born Extremely Preterm Using the INTERGROWTH-21st Growth Standards.

OBJECTIVE: To assess the risk of cognitive impairment among infants born extremely preterm using the INTERGROWTH-21st standards. STUDY DESIGN: We analyzed anthropometric data at birth and 36 weeks postmenstrual age (PMA) from infants born extremely preterm (24-26 weeks of gestation) admitted to US neonatal units between 2008 and 2018. To determine INTERGROWTH-21st z-score values that indicate an increased risk of cognitive impairment at 2 years of age (Bayley cognitive score <85), we employed classification and regression trees and redefined growth failure (weight, length, and head circumference z-scores at 36 weeks PMA) and growth faltering (weight, length, and head circumference z-score declines from birth to 36 weeks PMA). RESULTS: Among 5393 infants with a mean gestational age of 25 weeks, growth failure defined as a weight z-score of -1.8 or below at 36 weeks PMA and growth faltering defined as a weight z-score decline of 1.1 or greater from birth to 36 weeks PMA indicated a higher likelihood of cognitive impairment. A length z-score less than -1 at 36 weeks PMA had the highest sensitivity to detect cognitive impairment at 2 years (80%). A head circumference z-score decline of 2.43 or greater from birth to 36 weeks PMA had the highest specificity (86%). Standard definitions had fair to low sensitivity and specificity for risk detection of cognitive impairment. CONCLUSIONS: Length and head circumference z-scores had the highest sensitivity and specificity for risk detection of cognitive impairment. Monitoring these growth parameters could guide earlier individualized interventions with potential to reduce cognitive impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID Generic Database: NCT00063063.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Blood pressure control in pregnant patients with chronic hypertension and diabetes: should <130/80 be the target?

BACKGROUND: The Chronic Hypertension and Pregnancy Study demonstrated that a target blood pressure of <140/90 mm Hg during pregnancy is associated with improved perinatal outcomes. Outside of pregnancy, pharmacologic therapy for patients with diabetes and hypertension is adjusted to a target blood pressure of <130/80 mm Hg. During pregnancy, patients with both diabetes and chronic hypertension may also benefit from tighter control with a target blood pressure <130/80 mm Hg. OBJECTIVE: We compared perinatal outcomes in patients with hypertension and diabetes who achieved blood pressure <130/80 vs 130 to 139/80 to 89 mm Hg. STUDY DESIGN: This was a secondary analysis of a multcenter randomized controlled trial. Participants were included in this secondary analysis if they had diabetes diagnosed prior to pregnancy or at <20 weeks of gestation and at least 2 recorded blood pressure measurements prior to delivery. Average systolic and diastolic blood pressure were calculated using ambulatory antenatal blood pressures. The primary composite outcome was preeclampsia with severe features, indicated preterm birth <35 weeks, or placental abruption. Secondary outcomes were components of the primary outcome, cesarean delivery, fetal or neonatal death, neonatal intensive care unit admission, and small for gestational age. Comparisons were made between those with an average systolic blood pressure <130 mm Hg and average diastolic blood pressure <80 mm Hg and those with an average systolic blood pressure 130 to 139 mm Hg or diastolic blood pressure 80 to 89 mm Hg using Student's t test and chi-squared tests. Multivariable log-binomial regression models were used to evaluate risk ratios between blood pressure groups for dichotomous outcomes while accounting for baseline covariates. RESULTS: Of 434 participants included, 150 (34.6%) had an average blood pressure less than 130/80 mm Hg. Participants with an average blood pressure less than 130/80 were more likely to be on antihypertensive medications at the start of pregnancy and more likely to have newly diagnosed diabetes mellitus prior to 20 weeks. Participants with an average blood pressure less than 130/80 mm Hg were less likely to have the primary adverse perinatal outcome (19.3% vs 46.5%, adjusted relative risk 0.43, 95% confidence interval 0.30-0.61, P<.01), with decreased risks specifically of preeclampsia with severe features (adjusted relative risk 0.35, 95% confidence interval 0.23-0.54) and indicated preterm birth prior to 35 weeks (adjusted relative risk 0.44, 95% confidence interval 0.24-0.79). The risk of neonatal intensive care unit admission was lower in the lower blood pressure group (adjusted relative risk 0.74, 95% confidence interval 0.59-0.94). No differences were noted in cesarean delivery (adjusted relative risk 1.04, 95% confidence interval 0.90-1.20), fetal or neonatal death (adjusted relative risk 0.59, 95% confidence interval 0.12-2.92). Small for gestational age less than the 10th percentile was lower in the lower blood pressure group (adjusted relative risk 0.37, 95% confidence interval 0.14-0.96). CONCLUSION: In those with chronic hypertension and diabetes prior to 20 weeks, achieving an average goal blood pressure of <130/80 mm Hg may be associated with improved perinatal outcomes.

Control of breathing in preterm infants on incubator oxygen or nasal cannula oxygen.

BACKGROUND: Incubator oxygen may improve respiratory stability in preterm infants compared with nasal cannula oxygen. METHODS: Single center randomized trial of infants <29 weeks' gestation on supplemental oxygen at ≥32 weeks' postmenstrual age. Infants were crossed-over every 24 hours for 96 hours between incubator oxygen and nasal cannula ≤1.0 L/kg/min. We measured episodes of intermittent hypoxemia (oxygen saturations (SpO2) < 85% ≥10 seconds), bradycardia, cerebral and abdominal hypoxemia, and end-tidal carbon dioxide. RESULTS: We enrolled 25 infants with a gestational age of 26 weeks 4 days±15 days (mean ± SD) and birth weight 805 ± 202 grams. There were no differences in episodes of intermittent hypoxemia, bradycardia, or cerebral hypoxemia between groups. There were fewer episodes of abdominal hypoxemia <40% ≥10 seconds with incubator oxygen compared with nasal cannula (132 ± 130 versus 158 ± 125; p < 0.01). Time with SpO2 < 85% and abdominal hypoxemia was lower among infants on incubator oxygen. Carbon dioxide values were higher while on incubator oxygen (41 ± 11 versus 36 ± 10 mmHg; p < 0.02). CONCLUSION: There was no difference in intermittent hypoxemia between incubator and nasal cannula oxygen among preterm infants on supplemental oxygen. Infants had higher levels of carbon dioxide while on incubator oxygen, which may have improved some measures of respiratory stability. CLINCALTRIALS. GOV IDENTIFIERS: NCT03333174 and NCT03174301. IMPACT STATEMENT: In this randomized cross-over trial of preterm infants on supplemental oxygen, incubator oxygen did not decrease episodes of intermittent hypoxemia compared with nasal cannula oxygen. Incubator oxygen reduced time with oxygen saturations less than 85%, reduced abdominal hypoxemia, and increased carbon dioxide levels. Differences in measures of respiratory stability on incubator oxygen may be partly due to higher carbon dioxide levels compared with nasal cannula oxygen. The mode of supplemental oxygen administration may impact control of breathing in preterm infants through its effect on hypopharyngeal oxygen stability and carbon dioxide levels.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

Patent Ductus Arteriosus and Development of Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. Objective: To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. Methods: We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. Measurements and Main Results: A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 (P < 0.001) and 0.45 (P < 0.001), respectively. Conclusions: In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.

Intermittent Hypoxemia and Bronchopulmonary Dysplasia with Pulmonary Hypertension in Preterm Infants.

Rationale: Bedside biomarkers that allow early identification of infants with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) are critically important, given the higher risk of death in these infants. Objectives: We hypothesized that infants with BPD-PH have patterns of intermittent hypoxemia (IH) that differ from infants with BPD without PH. Methods: We conducted a matched case-control study of extremely preterm infants from 22 weeks 0 days to 28 weeks 6 days born between 2018 and 2020 at the University of Alabama at Birmingham. BPD-PH status was determined using echocardiographic data performed after postnatal Day 28. Physiologic data were compared between infants with BPD-PH (cases) and BPD alone (control subjects). Receiver operating characteristic (ROC) analysis estimated the predictive ability of cumulative hypoxemia, desaturation frequency, and duration of intermittent hypoxemic events in the week preceding echocardiography to discriminate between cases and control subjects. Measurements and Main Results: Forty infants with BPD-PH were compared with 40 infants with BPD alone. Infants with and without PH had a similar frequency of IH events, but infants with PH had more prolonged hypoxemic events for desaturations below 80% (7 s vs. 6 s; P = 0.03) and 70% (105 s vs. 58 s; P = 0.008). Among infants with BPD-PH, infants who died had longer hypoxemic events below 70% (145 s vs. 72 s; P = 0.01). Using the duration of hypoxemic events below 70%, the areas under the ROC curves for diagnosis of BPD-PH and death in BPD-PH infants were 0.71 and 0.77, respectively. Conclusions: Longer duration of intermittent hypoxemic events was associated both with a diagnosis of BPD-PH and with death among infants with BPD-PH.

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Psychological distress among postpartum women who took opioids during pregnancy: the role of perceived stigma in healthcare settings.

This study examined the relationship between perceived stigma in healthcare settings during pregnancy and psychological distress and well-being in the postpartum period among individuals who took opioids while pregnant. Analyses included 134 birth mothers of opioid-exposed infants. At 0-1 months postpartum, perceived stigma and psychological distress were measured using the Prenatal Opioid use Perceived Stigma scale and measures from the Patient-Reported Outcome Measurement Information System (PROMIS). Food insecurity, housing instability, and Adverse Childhood Experiences (ACEs) were also assessed. Linear and generalized linear mixed-effect models were conducted to compare PROMIS scale scores and unmet needs by stigma, adjusting for site/location, age, race/ethnicity, marital status, education, public insurance, and parity. More than half of participants (54%) perceived stigma in healthcare settings. Individuals reporting stigma had higher depression, anxiety, and anger scores (p < 0.001) indicating greater psychological distress in the postpartum period compared to those reporting no stigma, after controlling for demographic characteristics. In addition, they scored significantly lower on the PROMIS meaning and purpose scale, an indicator of well-being (p = 0.002). Those reporting stigma were more likely to have food insecurity (p = 0.003), three or more ACEs (p = 0.040), verbal or physical abuse during pregnancy (p < 0.001), and less emotional support (p = 0.006) than those who did not. An association was observed between perceived stigma in the prenatal period and psychological distress in the postpartum period, providing support for stigma reduction interventions and education for healthcare providers on trauma-informed care.

Genomic Differences between Spontaneous versus Indicated Extreme Preterm Birth.

OBJECTIVE: Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth (PTB) may result from spontaneous preterm labor or preterm premature rupture of membranes or may be indicated due to preeclampsia, eclampsia, hypertension, or other causes. Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme PTB using the neonatal genome. STUDY DESIGN: We evaluated 523 spontaneous births and 134 indicated births weighing 401 to 1,000 g at birth from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Genomics dataset by genome-wide association study (GWAS) and pathway analysis. The TOLSURF cohort was used to replicate the results. RESULTS: In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p = 1.03E-07) along with many other modest peaks at p = 1-9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being "GO_mf:go_low_density_lipoprotein_particle_receptor_activity" at p = 1.14E-06. However, these results could not be replicated in the TOLSURF cohort. CONCLUSION: Genomic differences are seen between infants born by spontaneous versus indicated extreme PTB. Due to the limited sample size, there is a need for larger studies. KEY POINTS: · Genomic differences are seen between infants born by spontaneous versus indicated very PTB.. · Future studies with large sample sizes evaluating extreme PTB are necessary.. · Spontaneous PTB is more common than indicated extreme PTB..

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Microbial-induced Redox Imbalance in the Neonatal Lung Is Ameliorated by Live Biotherapeutics.

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants. Hyperoxia exposure and microbial dysbiosis are contributors to BPD development. However, the mechanisms linking pulmonary microbial dysbiosis to worsening lung injury are unknown. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates oxidative stress responses and modulates hyperoxia-induced lung injury. We hypothesized that airway dysbiosis would attenuate Nrf2-dependent antioxidant function, resulting in a more severe phenotype of BPD. Here, we show that preterm infants with a Gammaproteobacteria-predominant dysbiosis have increased endotoxin in tracheal aspirates, and mice monocolonized with the representative Gammaproteobacteria Escherichia coli show increased tissue damage compared with germ-free (GF) control mice. Furthermore, we show Nrf2-deficient mice have worse lung structure and function after exposure to hyperoxia when the airway microbiome is augmented with E. coli. To confirm the disease-initiating potential of airway dysbiosis, we developed a novel humanized mouse model by colonizing GF mice with tracheal aspirates from human infants with or without severe BPD, producing gnotobiotic mice with BPD-associated and non-BPD-associated lung microbiomes. After hyperoxia exposure, BPD-associated mice demonstrated a more severe BPD phenotype and increased expression of Nrf2-regulated genes, compared with GF and non-BPD-associated mice. Furthermore, augmenting Nrf2-mediated antioxidant activity by supporting colonization with Lactobacillus species improved dysbiotic-augmented lung injury. Our results demonstrate that a lack of protective pulmonary microbiome signature attenuates an Nrf2-mediated antioxidant response, which is augmented by a respiratory probiotic blend. We anticipate antioxidant pathways will be major targets of future microbiome-based therapeutics for respiratory disease.

Pediatric ventilation liberation: evaluating the role of endotracheal secretions in an extubation readiness bundle.

BACKGROUND: An evidence gap exists regarding the role of endotracheal secretions in pediatric extubation decisions. This study aims to evaluate whether endotracheal secretion burden independently correlates with pediatric extubation failure. METHODS: This is a single-center, prospective cohort study of children aged <19 years requiring intubation. Nurses (RN) and respiratory therapists (RT) independently used a novel secretion assessment score focusing on secretion volume, character, and trend. We hypothesized that the RN and RT secretion scores would not correlate with extubation outcome and inter-rater reliability would be poor. RESULTS: RN secretion character sub-score (OR 3.3, 95% CI 1.1-11.1, p = 0.048) was independently associated with extubation failure. RN and RT inter-rater reliability was poor (correlation 0.385, 95% CI 0.339-0.429, p < 0.001). A failure prediction model incorporating the RN secretion character sub-score as well as indication for mechanical ventilation and spontaneous breathing trial result demonstrated an area under the receiver operating curve of 0.817 (95% CI 0.730-0.904, p < 0.001). CONCLUSIONS: In the general pediatric population, the RN assessment of endotracheal secretion character was independently associated with extubation failure. A model incorporating indication for mechanical ventilation, spontaneous breathing result, and RN assessment of endotracheal secretion character demonstrated reasonable accuracy in predicting failure in those clinically selected for extubation. IMPACT: Development of comprehensive and sensitive extubation readiness bundles are key to balancing the competing risks of prolonged invasive mechanical ventilation duration and extubation failure. Evidence for clinical factors linked to extubation outcomes in children are limited. Endotracheal secretion burden is a common factor considered but has not been studied. This study supports a role for endotracheal secretion burden, as assessed by the bedside nurse, in extubation readiness bundles. Inter-rater reliability with respiratory therapists was poor. A model incorporating other key factors showed good discrimination for extubation outcome and sets the stage for prospective evaluation in the general population and diagnosis-specific subgroups.

Trends in fetal and neonatal outcomes during the COVID-19 pandemic in Alabama.

BACKGROUND: The current study evaluated the hypothesis that the COVID-19 pandemic is associated with higher stillbirth but lower neonatal mortality rates. METHODS: We compared three epochs: baseline (2016-2019, January-December, weeks 1-52, and 2020, January-February, weeks 1-8), initial pandemic (2020, March-December, weeks 9-52, and 2021, January-June, weeks 1-26), and delta pandemic (2021, July-September, weeks 27-39) periods, using Alabama Department of Public Health database including deliveries with stillbirths ≥20 weeks or live births ≥22 weeks gestation. The primary outcomes were stillbirth and neonatal mortality rates. RESULTS: A total of 325,036 deliveries were included (236,481 from baseline, 74,076 from initial pandemic, and 14,479 from delta pandemic period). The neonatal mortality rate was lower in the pandemic periods (4.4 to 3.5 and 3.6/1000 live births, in the baseline, initial, and delta pandemic periods, respectively, p < 0.01), but the stillbirth rate did not differ (9 to 8.5 and 8.6/1000 births, p = 0.41). On interrupted time-series analyses, there were no significant changes in either stillbirth (p = 0.11 for baseline vs. initial pandemic period, and p = 0.67 for baseline vs. delta pandemic period) or neonatal mortality rates (p = 0.28 and 0.89, respectively). CONCLUSIONS: The COVID-19 pandemic periods were not associated with a significant change in stillbirth and neonatal mortality rates compared to the baseline period. IMPACT: The COVID-19 pandemic could have resulted in changes in fetal and neonatal outcomes. However, only a few population-based studies have compared the risk of fetal and neonatal mortality in the pandemic period to the baseline period. This population-based study identifies the changes in fetal and neonatal outcomes during the initial and delta COVID-19 pandemic period as compared to the baseline period. The current study shows that stillbirth and neonatal mortality rates were not significantly different in the initial and delta COVID-19 pandemic periods as compared to the baseline period.

Outcomes of Babies with Opioid Exposure (OBOE): protocol of a prospective longitudinal cohort study.

BACKGROUND: While the health, social, and economic impacts of opioid addiction on adults and their communities are well known, the impact of maternal opioid use on the fetus exposed in utero is less well understood. METHODS: This paper presents the protocol of the ACT NOW Outcomes of Babies with Opioid Exposure (OBOE) Study, a multi-site prospective longitudinal cohort study of infants with antenatal opioid exposure and unexposed controls. Study objectives are to determine the impact of antenatal opioid exposure on brain development and neurodevelopmental outcomes over the first 2 years of life and explore whether family, home, and community factors modify developmental trajectories during this critical time period. RESULTS: Primary outcomes related to brain development include cortical volumes, deep cerebral gray matter volumes, resting-state functional connectivity measures, and structural connectivity measures using diffusion tensor imaging. Primary neurodevelopmental outcomes include visual abnormalities, cognitive, language, and motor skills measured using the Bayley Scales of Infant Development and social-emotional and behavioral problems and competence measured by the Brief Infant-Toddler Social and Emotional Assessment. CONCLUSIONS: The OBOE study has been designed to overcome challenges of previous studies and will help further understanding of the effects of antenatal opioid exposure on early infant development. IMPACT: This study will integrate MRI findings and comprehensive neurodevelopmental assessments to provide early insights into the functional topography of the brain in this high-risk population and assess MRI as a potential biomarker. Rather than conducting neuroimaging at a single time point, the study will include serial MRI assessments from birth to 2 years, allowing for the examination of trajectories throughout this period of rapid brain development. While previous studies often have had limited information on exposures, this study will use umbilical cord assays to accurately measure amounts of opioids and other substances from 20 weeks of gestation to birth.

Neonatal fluid overload-ignorance is no longer bliss.

Excessive accumulation of fluid may result in interstitial edema and multiorgan dysfunction. Over the past few decades, the detrimental impact of fluid overload has been further defined in adult and pediatric populations. Growing evidence highlights the importance of monitoring, preventing, managing, and treating fluid overload appropriately. Translating this knowledge to neonates is difficult as they have different disease pathophysiologies, and because neonatal physiology changes rapidly postnatally in many of the organ systems (i.e., skin, kidneys, and cardiovascular, pulmonary, and gastrointestinal). Thus, evaluations of the optimal targets for fluid balance need to consider the disease state as well as the gestational and postmenstrual age of the infant. Integration of what is known about neonatal fluid overload with individual alterations in physiology is imperative in clinical management. This comprehensive review will address what is known about the epidemiology and pathophysiology of neonatal fluid overload and highlight the known knowledge gaps. Finally, we provide clinical recommendations for monitoring, prevention, and treatment of fluid overload.

Maternal and Neonatal Outcomes at Periviable Gestation throughout Delivery Admission.

OBJECTIVE: The threshold of viability, as well as cutoffs for delivery interventions and neonatal resuscitation, vary by hospital and involve complex counseling. With improvements in neonatal resuscitation and intensive care, the threshold of viability has been decreasing. Decisions regarding delivery planning and neonatal resuscitation efforts should be based on the best available evidence. Our objective was to characterize survival rates and neonatal outcomes following periviable birth at different milestones beginning with prenatal admission through 1 year of life in a contemporary cohort. STUDY DESIGN: We performed a retrospective cohort study of all inborn infants without major congenital anomalies who delivered at the University of Alabama at Birmingham from 2013 to 2019 at gestational ages 22+0/7 to 25+6/7. Our primary outcome was to compared survival milestones throughout the pre- and postdelivery periods and neonatal complications in surviving newborns through 1 year of life at each gestational age. RESULTS: The survival rate to 1 year of life was 49% (48-56%, 95% confidence interval [CI]) for the entire cohort and varied according to gestational age at delivery (22 weeks 15% [10-23%, 95% CI], 23 weeks 48% [43-58%, 95% CI], 24 weeks 57% [52-67%, 95% CI], 25 weeks 71% [67-82%, 95% CI]). Overall for the entire cohort, the rate of lung disease requiring respiratory support at discharge was 51%, intraventricular hemorrhage was 42%, retinopathy of prematurity was 74%, pulmonary hypertension was 30%, and concerns for cerebral palsy at 1 year of life was 25%. All outcomes improved with advancing gestational age at delivery. Of infants who delivered during the 22nd week of gestation, 50% received antenatal corticosteroids. Infants exposed to antenatal corticosteroids had more interventions, less pulmonary hypertension, and improved survival to 1 year of life. CONCLUSION: Knowledge of maternal complications, longitudinal survival rates, and neonatal outcomes of periviable deliveries according to gestational age throughout the admission enhances obstetric and perinatal counseling after hospital admission. KEY POINTS: · Periviable birth outcomes at different delivery milestones is important for counseling.. · Providing contemporary outcomes for periviable deliveries is critical for accurate counseling.. · Administration of antenatal corticosteroids at 22 weeks' gestation appears beneficial overall..