Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated. OBJECTIVE: This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes. STUDY DESIGN: We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia. RESULTS: After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial. CONCLUSION: In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings.

Prenatal diagnosis of fetal bradyarrhythmia and postnatal outcome.

INTRODUCTION: Prenatal diagnosis of Fetal bradyarrhythmia leads to parental and care provider anxiety as data on outcome is scarce. We aimed to correlate the prenatal presentation of fetal bradyarrhythmia with postnatal outcome. METHODS: Retrospective analysis of case records from 2017 to 2021. All fetuses with sustained bradyarrhythmia beyond 11 weeks were included in the study. RESULTS: Twenty fetuses were identified: mean gestational age at diagnosis was 23 weeks 2 days. The type of bradyarrhythmia was as follows: Complete atrioventricular block 10 (50 %), Sinus Bradycardia 7 (35 %), second degree atrioventricular block 2 (10 %), and Unclassified 1 (5 %). In 10 fetuses, cardiac and extracardiac anatomy were normal; 8 fetuses (40 %) had cardiac anomalies,1 fetus had intraventricular hemorrhage and 1 had nuchal cystic hygroma. Among the fetuses with associated anomalies, there were 5 terminations of pregnancy (TOP), 1 intrauterine fetal demise (IUD), 3 neonatal demise (NND) and 1 livebirth. Among fetuses with normal anatomy, there were 2 TOP and 8 livebirths; five of the 10 mothers (50 %) tested positive for Anti Ro/La antibodies. All the 6 liveborn fetuses with complete atrioventricular block are on conservative management: 2 on metaproterenol and 4 on clinical follow up. Nine out of the 10 cases that had a postnatal paediatric cardiology assessment had a correct prenatal diagnosis. CONCLUSION: Correct prenatal identification of fetal bradyarrhythmia is feasible in about 90 % of cases. The risk of postnatal pacemaker requirement appears to be low irrespective of maternal Anti Ro/La status.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

Timing of antenatal steroid administration for imminent preterm birth: results of a prospective observational study in Germany.

PURPOSE: To evaluate the timing of antenatal steroid administration and associated medical interventions in women with imminent preterm birth. METHODS: We performed a prospective observational study at a single tertiary center in Germany from September 2018 to August 2019. We included pregnant women who received antenatal steroids for imminent preterm birth and evaluated the interval from administration to birth. 120 women with antenatal steroid application were included into our analysis. Descriptive statistics were performed to analyze factors influencing the timing of antenatal steroids and to evaluate additional medical interventions which women with imminent preterm birth experience. RESULTS: Of the 120 women included into our study, 35.8% gave birth before 34/0 weeks and 64.2% before 37/0 weeks of gestation. Only 25/120 women (20.8%) delivered within the optimal time window of 1-7 days after antenatal steroid application. 5/120 women (4.2%) only received one dose of antenatal steroids before birth and 3/120 (2.5%) gave birth within 8 to 14 days after antenatal steroids. Most women gave birth more than 14 days after steroid application (72.5%, 87/120). Women with preeclampsia (60%), PPROM (31%), and FGR (30%) had the highest rates of delivery within the optimal time window. Women of all timing groups received additional interventions and medications like antibiotics, tocolytics, or anticoagulation. CONCLUSION: Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially for women with symptoms of preterm labor and bleeding placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly (P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Antenatal Risk Factors Associated with Spontaneous Intestinal Perforation in Preterm Infants Receiving Postnatal Indomethacin.

OBJECTIVE: To determine if antenatal variables affect the risk of spontaneous intestinal perforation (SIP) among preterm infants when prophylactic indomethacin is used. STUDY DESIGN: Retrospective case-control study of infants <29 weeks of gestational age between January 2010 and June 2018 at one hospital. SIP was defined as acute abdominal distension and pneumoperitoneum without signs of necrotizing enterocolitis at <14 days of life. Each case (n = 57) was matched with 2 controls (n = 114) for gestational age and birth year. Maternal and infant data were abstracted until the SIP or equivalent day for controls. Univariate analyses were followed by adjusted conditional logistic regressions and reported as OR and 95% CI. RESULTS: Mothers of cases were younger, more often delivering multiples (31% vs 14%, P = .007), and less abruptions (15% vs 29%, P = .045) but did not differ in intra-partum betamethasone, magnesium, or indomethacin use. Prophylactic indomethacin was given on day 1 to 99% of infants. SIP was associated with a shorter interval from last betamethasone dose to delivery (46 hours vs 96 hours, P = .01). Dopamine use (14% vs 4%, P = .02), volume expansion (23% vs 8%, P = .003), and high grade intraventricular hemorrhage (28% vs 8%, P = .0008) were related postnatal factors. The adjusted odds of SIP increased by 1% for each hour decrease between the last dose of betamethasone and delivery (OR 1.01, 95% CI 1.002-1.019) and with multiple births (OR 2.66, 95% CI 1.05-6.77). CONCLUSIONS: Antenatal betamethasone given shortly before delivery is associated with an increased risk of SIP. Potential interaction with medications such as postnatal indomethacin needs study.

Population Improvement Bias Observed in Estimates of the Impact of Antenatal Steroids to Outcomes in Preterm Birth.

OBJECTIVE: To examine the hypothesis that increasing rates and differential uptake of antenatal steroids would bias estimation of impact of antenatal steroids on neonatal death and severe (grade III-IV) intraventricular hemorrhage (IVH). STUDY DESIGN: The study population included infants born between 24 and 28 weeks of gestational age in the California Perinatal Quality Care Collaborative. Outcomes were in-hospital mortality and severe IVH. Mixed multivariable logistic regression models estimated the effect of antenatal steroid exposure, one model accounting for individual risk factors as fixed effects, and a second model incorporating a predicted probability factor estimating overall risk status for each time period. RESULTS: The study cohort included 28 252 infants. Antenatal steroid exposure increased from 80.1% in 2005 to 90.3% in 2016, severe IVH decreased from 14.5% to 9.0%, and mortality decreased from 12.8% to 9.1%. When stratified by group, 3-year observed outcomes improved significantly in infants exposed to antenatal steroids (12.5%-8.6% for IVH, 11.5%-8.8% for death) but not in those not exposed (20.7%-19.1% and 16.6%-15.5%, respectively). Women not receiving antenatal steroids had greater risk profile (such as no prenatal care) and greater predicted probability for severe IVH and mortality. Both outcomes exhibited little change (P > .05) over time for the group without antenatal steroids. In contrast, in women receiving antenatal steroids, observed and adjusted rates for both outcomes decreased (P < .0001). CONCLUSIONS: As the population's proportion of antenatal steroid use increased, the observed positive effect of antenatal steroids also increased. This apparent increase may be designated as the "population improvement bias."

Antenatal betamethasone redistributes central blood flows and preferentially augments right ventricular output and pump function in preterm fetal lambs.

The glucocorticosteroid betamethasone, which is routinely administered prior to anticipated preterm birth to enhance maturation of the lungs and the cardiovascular system, has diverse fetal regional blood flow effects ranging from increased pulmonary flow to decreased cerebral flow. The aim of this study was to test the hypothesis that these diverse effects reflect alterations in major central flow patterns that are associated with complementary shifts in left ventricular (LV) and right ventricular (RV) pumping performance. Studies were performed in anesthetized preterm fetal lambs (gestation = 127 ± 1 days, term = 147 days) with (n = 14) or without (n = 12) preceding betamethasone treatment via maternal intramuscular injection. High-fidelity central arterial blood pressure and flow signals were obtained to calculate LV and RV outputs and total hydraulic power. Betamethasone therapy was accompanied by 1) increased RV, but not LV, output; 2) a greater RV than LV increase in total power; 3) a redistribution of LV output away from the fetal upper body region and toward the lower body and placenta; 4) a greater proportion of RV output passing to the lungs, and a lesser proportion to the lower body and placenta; and 5) a change in the relative contribution of venous streams to ventricular filling, with the LV having increased pulmonary venous and decreased foramen ovale components, and the RV having lesser superior vena caval and greater inferior vena caval portions. Taken together, these findings suggest that antenatal betamethasone produces a widespread redistribution of central arterial and venous flows in the fetus, accompanied by a preferential rise in RV pumping performance.

A new clinical respiratory distress score for surfactant therapy in preterm infants with respiratory distress.

The guidelines for surfactant therapy are largely based on studies done in developed coun1tries wherein the facility infrastructure, patient profile, and clinical practices are different from low- and middle-income countries (LMICs). Though SRT is widely practiced in developing countries, there exists variability in clinical practice. Our objective was to identify the factors which would predict the need of surfactant administration and develop a "clinical respiratory distress (RD) score" for surfactant administration in preterm neonates with respiratory distress. A prospective observational study was conducted in 153 preterm infants (260/7 to 346/7 weeks gestation) with respiratory distress who were managed with CPAP and/or surfactant where indicated. Gestation < 32 weeks, no antenatal corticosteroid (ANS), hypothermia at admission, Apgar score < 3 at 1 minute, and Silverman score > 2 at 2 hours were found to be the significant factors in predicting surfactant requirement in multivariate regression analysis. A seven point scale was developed and categorized into two categories as < 4 and ≥ 4. The sensitivity, specificity, PPV, and NPV were 67%, 87%, 86%, and 68%, respectively, with a cutoff score ≥ 4. The positive likelihood ratio was 5.07 (95% CI 2.71-9.48), and negative likelihood ratio was 0.38 (95% CI 0.28-0.52). The observed rate of surfactant administration was found to be around 32% when the composite score was below four, and the rate increased to almost 86% when the composite score was ≥ 4. The predictive accuracy of the model was subsequently evaluated in a cohort of 56 preterm infants with respiratory distress.. Sensitivity, specificity and positive and negative predictive value during the validation phase were 97%, 73%, 85%, and 94%, respectively. With a composite score less than 4, the observed rate of surfactant administration was 6% (95% CI 1%-28%) as against the model predicted rate of 24%, while with composite score ≥ 4, the observed rate was 85% (95% CI 69%-94%) as against the model predicted rate of 90%.Conclusion: "Clinical RD score" is a simple score, which can be utilized for decision-making for early surfactant administration for preterm infants (260/7 to 346/7 weeks gestation) with respiratory distress.Trial Registration: NCT03273764What is Known:• Both CPAP and surfactant therapy are effective in management of preterm infants with RDS.• The efficacy of surfactant replacement therapy is better when it is administered early in the course of disease.What is New:• Many of the known risk factors for RDS do not predict surfactant requirement.• "Composite RD score" comprising of five independent predictors of surfactant requirement with a numeric cutoff may help decide which preterm neonates with respiratory distress need early surfactant administration in low- and middle-income countries.

COVID-19 infection during pregnancy: fetus as a patient deserves more attention.

The novel coronavirus disease 2019 (COVID-19) pandemic is causing concern also for the management and outcome of COVID-19-positive pregnant women and their offspring, as reported cases are rare. Current evidence suggests the association of COVID-19 infection in pregnancy with both severe maternal morbidity requiring intensive care and perinatal complications (preterm birth with consequent neonatal morbidity and even perinatal death). Most of the reported cases focused specifically on the maternal outcomes and possible vertical transmission, but less attention has been paid to fetus as a patient in such pregnancies. The use of antenatal steroids and fetal neuroprotection with magnesium sulfate is clearly underreported. Several recently issued guidelines suggest lowering the upper gestational age for antenatal steroid administration and also advocate extreme caution or even restraining from the use of magnesium sulfate. Also, the rate of cesarean deliveries among COVID-19 women is unacceptably high. Here we provide arguments for NOT changing the existing guidelines and caution against cesarean delivery that was the prevalent delivery mode in the reported cases and case series.

Antenatal betamethasone augments early rise in pulmonary perfusion at birth in preterm lambs: role of ductal shunting and right ventricular outflow distribution.

The glucocorticosteroid betamethasone is routinely administered via maternal intramuscular injection to enhance fetal lung maturation before anticipated preterm birth. Although antenatal betamethasone increases fetal pulmonary arterial (PA) blood flow, whether this agent alters the contribution of 1) right ventricular (RV) output or 2) left-to-right shunting across the ductus arteriosus to rises in PA blood flow after preterm birth is unknown. To address this question, anesthetized control (n = 7) and betamethasone-treated (n = 7) preterm fetal lambs (gestation 127 ± 1 days, means ± SD) were instrumented with aortic, pulmonary, and left atrial catheters as well as ductus arteriosus and left PA flow probes to calculate RV output, with hemodynamics measured for 30 min after cord clamping and mechanical ventilation. Mean PA blood flow was higher in betamethasone-treated than in control lambs over the initial 10 min after birth (P < 0.05). This higher PA flow was accompanied by 1) a greater pulmonary vascular conductance (P ≤ 0.025), 2) a larger proportion of RV output passing to lungs (P ≤ 0.01), despite a fall in this output, and 3) earlier reversal and a greater magnitude (P ≤ 0.025) of net ductal shunting, due to the combination of higher left-to-right (P ≤ 0.025) and lesser right-to-left phasic shunting (P ≤ 0.025). These results suggest that antenatal betamethasone augments the initial rise in PA blood flow after birth in preterm lambs, with this augmented rise supported by the combination of 1) a greater redistribution of RV output toward the lungs and 2) a faster and larger reversal in net ductal shunting underpinned not only by greater left-to-right, but also by lesser right-to-left phasic shunting.

Efficacy and safety of antenatal steroids.

Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

The Joint Effects of Antenatal Steroids and Gestational Age on Improved Outcomes in Neonates.

OBJECTIVES: Antenatal corticosteroids are standard of care for women at risk of a preterm birth and demonstrated to be protective against poor outcomes in neonates including respiratory disorders, mortality and intraventricular hemorrhage (IVH). Its benefits may vary by gestational age, and accurate estimation is needed in a single-center population to account for practice variation. METHODS: A retrospective cohort of infants admitted to the hospital's neonatal intensive care unit, 1997-2015. Using Poisson regression, we separately modeled the incidence rate ratio of death, grade III or IV intraventricular hemorrhage (IVH), and moderate to severe bronchopulmonary dysplasia (BPD) testing the moderating effects of gestation on antenatal steroids, controlling for potential confounding. RESULTS: Among 5314 infants admitted, death occurred in 298 (6%), severe IVH in 244 (5%), and BPD in 527 (10%). Antenatal steroids were protective of death and BPD in the adjusted analysis, and there was multiplicative interaction where each week increase in gestational age combined with steroid therapy resulted in 13% reduced incidence for each outcome. CONCLUSIONS FOR PRACTICE: Antenatal steroids are protective against severe IVH and moderate to severe BPD, and when combined with gestational age, steroids are associated with greater protective benefits in older neonates. There is likely an ideal window to maximize the benefits of antenatal steroids, and future etiologic research should consider the joint effects with gestational age.

Intra-partum management of women with diabetes.

Management of hyperglycaemia is crucial during labour to improve outcomes both in the newborn and in the mother. This is particularly crucial in mothers with pregestational type 1 diabetes and in all mothers requiring insulin treatment during pregnancy. The use of antenatal steroids in mothers at risk of preterm delivery complicates management of hyperglycaemia in the immediate antepartum period and requires appropriate dosing adjustments of insulin therapy. Mothers are generally asked to be nil per orum during active labour. This requires appropriate fluid, glucose and insulin management in the hours leading on to the delivery of the baby. If the woman undergoes an operative delivery then patients continues to require glucose insulin infusion till patient is able to eat and drink normally. This review focuses on the management of hyperglycaemia during labour and in the immediate post partum period. A dosing schedule for women who receive steroids in the antepartum period is also discussed. The review suggests a practical glucose insulin regimen that can be followed during active labour in women who are nil orally. Lastly the review discusses immediate post partum management in these women as well.

Pulmonary Function at Hospital Discharge in Preterm Infants Randomized to a Single Rescue Course of Antenatal Steroids.

OBJECTIVE: To compare the pulmonary function, measured at birth and at hospital discharge, of infants whose mothers had been randomized to a single rescue course of antenatal steroids versus those whose mothers had been randomized to placebo. STUDY DESIGN: This study involved follow-up at hospital discharge of subjects of a randomized, double-blinded trial. In the original trial, pregnant women at ≥14 days after their initial course of antenatal steroids and <34 weeks' gestation were randomized to rescue antenatal steroids (44 mothers, 56 infants) or placebo (41 mothers, 57 infants). Passive respiratory compliance (Crs), passive respiratory resistance, and functional residual capacity were measured in all infants at birth and again at discharge to evaluate changes in pulmonary mechanics over time. Statistical analyses were based on intention to treat. RESULTS: We previously reported that compared with infants in the placebo group, infants in the rescue antenatal steroids group had a higher mean Crs value measured within 72 hours of birth (1.21 vs 1.01 mL/cm H2O/kg; P < .05). Here we show that the Crs benefit in the antenatal steroids group was sustained until discharge. Infants in the placebo group demonstrated improvement in Crs such that by discharge, there was no difference in mean Crs between the rescue antenatal steroids and placebo groups (1.18 vs 1.22 mL/cm H2O/kg). CONCLUSIONS: Rescue antenatal steroids significantly increased Crs measured within 72 hours of birth, and this increase was sustained until hospital discharge. Preterm infants in the placebo group demonstrated a decreased initial Crs compared with the rescue antenatal steroids group, but achieved a comparable Crs by the time of discharge. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669383.

Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system.

Exposure to glucocorticoids in utero is associated with changes in organ function and structure in the adult. The aims of this study were to characterize the effects of antenatal exposure to glucocorticoids on glucose handling and the role of adipose tissue. Pregnant sheep received betamethasone (Beta, 0.17 mg/kg) or vehicle 24 h apart at 80 days of gestation and allowed to deliver at term. At 9 mo, male and female offspring were fed at either 100% of nutritional allowance (lean) or ad libitum for 3 mo (obese). At 1 yr, they were chronically instrumented under general anesthesia. Glucose tolerance was evaluated using a bolus of glucose (0.25 g/kg). Adipose tissue was harvested after death to determine mRNA expression levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) 1, ACE2, and peroxisome proliferator-activated receptor γ (PPAR-γ). Data are expressed as means ± SE and analyzed by ANOVA. Sex, obesity, and Beta exposure had significant effects on glucose tolerance and mRNA expression. Beta impaired glucose tolerance in lean females but not males. Superimposed obesity worsened the impairment in females and unmasked the defect in males. Beta increased ACE1 mRNA in females and males and AGT in females only (P < 0.05 by three-way ANOVA). Obesity increased AGT in females but had no effect on ACE1 in either males or females. PPAR-γ mRNA exhibited a significant sex (F = 42.8; P < 0.01) and obesity (F = 6.9; P < 0.05) effect and was significantly higher in males (P < 0.01 by three-way ANOVA). We conclude that adipose tissue may play an important role in the sexually dimorphic response to antenatal glucocorticoids.

Assessing the potential impact of extending antenatal steroids to the late preterm period.

BACKGROUND: In 2016, guidance statements were issued by the Society for Maternal-Fetal Medicine and the American Congress of Obstetricians and Gynecologists about extending antenatal steroid use to selected late preterm singleton pregnancies. OBJECTIVE: We sought to review antenatal steroid use prior to the 2016 guidance statements and assess the potential impact of these. STUDY DESIGN: This cohort study used chart-abstracted data from singleton deliveries from Jan. 1, 2012, through March 31, 2016, at 12 centers participating in the Obstetrics Clinical Outcomes Assessment Program, a quality initiative in Washington State. Pregnancies with missing gestation at delivery, fetal anomalies, or antepartum demise were excluded. Antenatal steroid use prior to the 2016 guidance was evaluated based on the percentage of early preterm deliveries (23+0-33+6 weeks) and the percentage of all pregnancies that received antenatal steroids. Newborn complication rates were calculated for late preterm deliveries (34+0+0-36+6 weeks), grouped by whether they would be potentially eligible or ineligible for antenatal steroids based on the 2016 guidance statements. RESULTS: The opportunity for antenatal steroids was missed in 21.8% (226/1034) of early preterm deliveries and of all those who received antenatal steroids, 32.2% (614/1908) delivered at term. Of preterm deliveries, 74% (n = 2942) were in the late preterm period. In all, 80% (n = 2363) of late preterm deliveries were potentially eligible for antenatal steroids and 60% of these (n = 1411) delivered at 36 weeks. The rate of respiratory complications in newborns delivering at 34 and 35 weeks was higher in the group potentially eligible for late preterm antenatal steroids compared to those in the ineligible group. Of those delivering at 36 weeks, no differences were detected in prevalence of respiratory complications by potential eligibility for antenatal steroids; however, compared with the ineligible group, those potentially eligible had a lower risk of neonatal intensive care unit admission (P < .001). More than two thirds (69%; 171/248) of newborn respiratory complications among late preterm deliveries potentially eligible for antenatal steroids occurred in those delivering at 34-35 weeks. The highest rate of respiratory complications was in those ineligible for antenatal steroids due to prepregnancy diabetes or chorioamnionitis, regardless of gestational age at delivery. CONCLUSION: Careful consideration of which pregnancies should receive late preterm antenatal steroids and how to identify these pregnancies is important to optimize benefits and mitigate potential risks of this intervention.

Saving Newborn Babies - The Benefits of Interventions in Neonatal Care in Norway over More Than 40 Years.

The aim of this study was to examine the effect that the introduction of new medical interventions at birth has had on mortality among newborn babies in Norway during the period 1967-2011. During this period, there has been a significant decline in mortality, in particular for low birth weight infants. We identified four interventions that together explained about 50% of the decline in early neonatal and infant mortality: ventilators, antenatal steroids, surfactant and insure. The analyses were performed on a large set of data, encompassing more than 1.6 million deliveries (Medical Birth Registry of Norway). The richness of the data allowed us to perform several robustness tests. Our study indicates that the introduction of new medical interventions has been a very important channel through which the decline in mortality among newborn babies occurred during the second half of the last century. Copyright © 2016 John Wiley & Sons, Ltd.

Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate.

BACKGROUND: Antenatal steroids are standard of care for cases of anticipated preterm labor to improve neonatal outcomes. However, steroids are potent drugs, and their use in pregnancy remains largely unoptimized. OBJECTIVE: The objective of the study was to measure the maternofetal pharmacokinetics of constant, low-dose intravenous betamethasone phosphate infusions and correlate these data with the transcriptional effect exerted by subclinical betamethasone exposures on the ovine fetal lung. STUDY DESIGN: Thirty-two ewes carrying a single fetus had surgery to catheterize fetal and maternal jugular veins at 116 days of gestation (term, 150 days). Animals were recovered for 2 days and then were randomized to receive 2 sequential maternal intravenous infusions of either (n = 4/group) of the following: 1) saline, 0.125, 0.04, or 0.0125 mg/kg betamethasone phosphate over 3 hours; or 2) saline, 0.25, 0.08, or 0.025 mg/kg betamethasone phosphate over 12 hours. Each infusion was separated by 2 days. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction and an ovine-specific microarray. Plasma betamethasone levels from time-course catheter samples were determined by mass spectrometry. Data were assessed for distribution, variance, and tested by an analysis of variance. RESULTS: Betamethasone was detectable (>1 ng/mL) in fetal plasma only in animals randomized to 0.125 mg/kg 3 hour or 0.250 mg/kg 12 hour infusions. Fetal betamethasone half-lives were 1.7-2.8 times greater than maternal values. At maximum concentration, fetal plasma betamethasone levels were approximately 10% of maternal levels. Compared with saline control, all animals, other than those receiving 0.0125 mg/kg 3 hour betamethasone phosphate infusions, had evidence of dose-dependent glucocorticoid transcriptional responses in the fetal lung. CONCLUSION: Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority.

Impact of obstetric interventions on condition at birth in extremely preterm babies: evidence from a national cohort study.

BACKGROUND: To investigate perinatal decision-making and the use of obstetric interventions, we examined the effects of antenatal steroids, tocolysis, and delivery mode on birth in a good condition (defined as presence of an infant heart rate >100 at five minutes of age) and delivery-room (DR) death in extremely preterm deliveries. METHODS: Prospective cohort of all singleton births in England in 2006 at 22-26 weeks of gestation where the fetus was alive at the start of labour monitoring or decision to perform caesarean section. Odds ratios adjusted for potential confounders (aOR) were calculated using logistic regression. RESULTS: One thousand seven hundred twenty two singleton pregnancies were included. 1231 women received antenatal steroids, 437 tocolysis and 356 delivered by Caesarean section. In babies born vaginally, aOR between a partial course of steroids and improved condition at birth was 1.84, 95% CI: 1.20 to 2.82 and, for a complete course, 1.63, 95% CI: 1.08 to 2.47; for DR death, aORs were 0.34 (0.21 to 0.55) and 0.41 (0.26 to 0.64) for partial and complete courses of steroids. No association was seen for steroid use in babies delivered by Caesarean section. Tocolysis was associated with improved condition at birth (aOR 1.45, 95% CI: 1.05 to 2.0) and lower odds of death (aOR 0.48, 95% CI: 0.32 to 0.73). In women without spontaneous labour, Caesarean delivery at ≤24 and 25 weeks was associated with improved condition at birth ((aORs 12.67 (2.79 to 57.60) and 4.94 (1.44 to 16.90), respectively) and lower odds of DR death (aORs 0.03 (0.01 to 0.21) and 0.13 (0.03 to 0.55)). There were no differences at 26 weeks gestation or in women with spontaneous labour. CONCLUSIONS: Antenatal steroids are strongly associated with improved outcomes in babies born vaginally. Tocolysis was associated with improvements in all analyses. Effects persisted after adjustment for perinatal decision-making. However, associations between delivery mode and birth outcomes may be attributable to case selection.