The impact of betamethasone on fetal pulmonary, umbilical and middle cerebral artery Doppler velocimetry and its relationship with neonatal respiratory distress syndrome.

BACKGROUND: Prenatal corticosteroid administration is known to be an effective strategy in improving fetal pulmonary maturity. This study aimed to evaluate the impact of maternal betamethasone administration on fetal pulmonary and other arteries Doppler velocity and the correlation between RDS development and Doppler indices results. METHODS: Fifty one singleton pregnancies between 26 and 34 gestational weeks with a diagnosis of preterm labor were included in the exposed group and received betamethasone. Fifty one uncomplicated pregnancies were included in the non-exposed group. Fetal pulmonary, umbilical and middle cerebral arteries Doppler parameters were evaluated before and 24 to 48 h after steroid administration in the exposed group and two times at same intervals in the non-exposed group. Maternal records were matched to neonatal charts if delivery happened, and demographic and outcome data were abstracted. RESULTS: When compared with the nonexposed group, fetuses treated with corticosteroids demonstrated significantly decreased umbilical artery Pulsatility index (PI) and significantly increased the middle cerebral artery PI, pulmonary artery Acceleration time (AT) and pulmonary artery AT/ET (Ejection time), while all other indices remained similar. We found significantly decreased pulmonary artery AT in the fetuses with respiratory distress syndrome (RDS) compared to those that did not. CONCLUSIONS: The results of our study showed that maternal antenatal betamethasone administration caused significant changes in the fetus blood velocity waveforms and also affected the blood flow in the pulmonary artery which led to an increase in the pulmonary artery AT and AT/ET. Among those fetuses with RDS, we found a significant decrease in the pulmonary artery AT, but we did not observe any pulmonary artery AT/ET differences.

Antenatal corticosteroids and short-term neonatal outcomes in term and near-term infants of diabetic mothers. Analysis of the Qatar PEARL-peristat registry.

OBJECTIVES: A recent discussion surrounding the extension of antenatal corticosteroid (ACS) use beyond 34 weeks of gestation did not include the subgroup of infants of diabetic mothers (IDM). We aimed to examine the association between ACS exposure and outcomes in neonates born at term and at near-term gestation in a large cohort of IDMs. METHODS: We selected 13976 eligible near-term and term infants who were included in the PEARL-Peristat Perinatal Registry Study (PPS). We assessed the association of ACS exposure with neonatal outcomes in a multivariate regression model that controlled for diabetes mellitus (DM) and other perinatal variables. RESULTS: The incidence of DM was 28% (3,895 of 13,976) in the cohort. Caesarean section was performed in one-third of the study population. The incidence of ACS exposure was low (1.8%) and typically occurred>2 weeks before delivery. The incidence rates of respiratory distress syndrome (RDS)/ transient tachypnoea of newborns (TTN), all-cause neonatal intensive care unit (NICU) admissions, NICU admissions for hypoglycaemia, and low 5-min Apgar scores were 3.5, 8.8, 1.3, and 0.1%, respectively. In a multivariate regression model, ACS was associated with a slight increase in NICU admissions (OR: 1.44; 95% CI: 1.04-2.03; p=0.028), but not with RDS/TTN. CONCLUSIONS: Although the low exposure rate was a limitation, ACS administration did not reduce respiratory morbidity in near-term or term IDMs. It was independently associated with an increase in NICU admissions. Randomized controlled trials are required to assess the efficacy and safety of ACS administration in diabetic mothers at late gestation.

Antenatal corticosteroids: a reappraisal of the drug formulation and dose.

We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials. The treatment used in the United States is two intramuscular doses of a mixture of 6 mg betamethasone phosphate (Beta P) and 6 mg betamethasone acetate (Beta Ac). To optimize outcomes with ACS, the goal should be to minimize fetal drug exposure. We have determined that the minimum exposure needed for fetal lung maturation in sheep, monkeys, and humans (based on published cord blood corticosteroid concentrations) is about 1 ng/ml for a 48-h continuous exposure, far lower than the concentration reached by the current dosing. Because the slowly released Beta Ac results in prolonged fetal exposure, a drug containing Beta Ac is not ideal for ACS use. IMPACT: Using sheep and monkey models, we have defined the minimum corticosteroid exposure for a fetal lung maturation. These results should generate new clinical trials of antenatal corticosteroids (ACS) at much lower fetal exposures to ACS, possibly given orally, with fewer risks for the fetus.

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

BACKGROUND: Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Despite early evidence indicating a beneficial effect of antenatal corticosteroids on fetal lung maturation and widespread recommendations to use this treatment in women at risk of preterm delivery, some uncertainty remains about their effectiveness particularly with regard to their use in lower-resource settings, different gestational ages and high-risk obstetric groups such as women with hypertension or multiple pregnancies. This updated review (which supersedes an earlier review Crowley 1996) was first published in 2006 and subsequently updated in 2017. OBJECTIVES: To assess the effects of administering a course of corticosteroids to women prior to anticipated preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 September 2020), ClinicalTrials.gov, the databases that contribute to the WHO International Clinical Trials Registry Platform (ICTRP) (3 September 2020), and reference lists of the retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of antenatal corticosteroid administration with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following rupture of membranes or spontaneous labour), regardless of other co-morbidity, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness based on predefined criteria developed by Cochrane Pregnancy and Childbirth, extracted data and checked them for accuracy, and assessed the certainty of the evidence using the GRADE approach. Primary outcomes included perinatal death, neonatal death, RDS, intraventricular haemorrhage (IVH), birthweight, developmental delay in childhood and maternal death. MAIN RESULTS: We included 27 studies (11,272 randomised women and 11,925 neonates) from 20 countries. Ten trials (4422 randomised women) took place in lower- or middle-resource settings. We removed six trials from the analysis that were included in the previous version of the review; this review only includes trials that meet our pre-defined trustworthiness criteria. In 19 trials the women received a single course of steroids. In the remaining eight trials repeated courses may have been prescribed. Fifteen trials were judged to be at low risk of bias, two had a high risk of bias in two or more domains and we ten trials had a high risk of bias due to lack of blinding (placebo was not used in the control arm. Overall, the certainty of evidence was moderate to high, but it was downgraded for IVH due to indirectness; for developmental delay due to risk of bias and for maternal adverse outcomes (death, chorioamnionitis and endometritis) due to imprecision. Neonatal/child outcomes Antenatal corticosteroids reduce the risk of: - perinatal death (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; 9833 infants; 14 studies; high-certainty evidence; 2.3% fewer, 95% CI 1.1% to 3.6% fewer), - neonatal death (RR 0.78, 95% CI 0.70 to 0.87; 10,609 infants; 22 studies; high-certainty evidence; 2.6% fewer, 95% CI 1.5% to 3.6% fewer), - respiratory distress syndrome (RR 0.71, 95% CI 0.65 to 0.78; 11,183 infants; studies = 26; high-certainty evidence; 4.3% fewer, 95% CI 3.2% to 5.2% fewer). Antenatal corticosteroids probably reduce the risk of IVH (RR 0.58, 95% CI 0.45 to 0.75; 8475 infants; 12 studies; moderate-certainty evidence; 1.4% fewer, 95% CI 0.8% to1.8% fewer), and probably have little to no effect on birthweight (mean difference (MD) -14.02 g, 95% CI -33.79 to 5.76; 9551 infants; 19 studies; high-certainty evidence). Antenatal corticosteroids probably lead to a reduction in developmental delay in childhood (RR 0.51, 95% CI 0.27 to 0.97; 600 children; 3 studies; moderate-certainty evidence; 3.8% fewer, 95% CI 0.2% to 5.7% fewer). Maternal outcomes Antenatal corticosteroids probably result in little to no difference in maternal death (RR 1.19, 95% CI 0.36 to 3.89; 6244 women; 6 studies; moderate-certainty evidence; 0.0% fewer, 95% CI 0.1% fewer to 0.5% more), chorioamnionitis (RR 0.86, 95% CI 0.69 to 1.08; 8374 women; 15 studies; moderate-certainty evidence; 0.5% fewer, 95% CI 1.1% fewer to 0.3% more), and endometritis (RR 1.14, 95% CI 0.82 to 1.58; 6764 women; 10 studies; moderate-certainty; 0.3% more, 95% CI 0.3% fewer to 1.1% more) The wide 95% CIs in all of these outcomes include possible benefit and possible harm. AUTHORS' CONCLUSIONS: Evidence from this updated review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and RDS and probably reduces the risk of IVH. This evidence is robust, regardless of resource setting (high, middle or low). Further research should focus on variations in the treatment regimen, effectiveness of the intervention in specific understudied subgroups such as multiple pregnancies and other high-risk obstetric groups, and the risks and benefits in the very early or very late preterm periods. Additionally, outcomes from existing trials with follow-up into childhood and adulthood are needed in order to investigate any longer-term effects of antenatal corticosteroids. We encourage authors of previous studies to provide further information which may answer any remaining questions about the use of antenatal corticosteroids without the need for further randomised controlled trials. Individual patient data meta-analyses from published trials are likely to provide answers for most of the remaining clinical uncertainties.

Coronavirus and birth in Italy: results of a national population-based cohort study.

INTRODUCTION: The study was implemented to provide guidance to decision-makers and clinicians by describing hospital care offered to women who gave birth with confirmed SARS-CoV-2 infection. MATERIALS AND METHODS: National population-based prospective cohort study involving all women with confirmed SARS-CoV-2 infection who gave birth between February 25 and April 22, 2020 in any Italian hospital. RESULTS: The incidence rate of confirmed SARS-CoV-2 infection in women who gave birth was 2.1 per 1000 maternities at a national level and 6.9/1000 in the Lombardy Region. Overall one third of the women developed a pneumonia and 49.7% assumed at least one drug against SARS-CoV-2 infection. Caesarean rate was 32.9%, no mothers nor newborns died. Six percent of the infants tested positive for SARS-CoV-2 at birth. CONCLUSIONS: Clinical features and outcomes of COVID-19 in women who gave birth are similar to those described for the general population, most women developing mild to moderate illness.

Corticosteroids in the Management of Pregnant Patients With Coronavirus Disease (COVID-19).

Recent evidence supports the use of an early, short course of glucocorticoids in patients with COVID-19 who require mechanical ventilation or oxygen support. As the number of coronavirus disease 2019 (COVID-19) cases continues to increase, the number of pregnant women with the disease is very likely to increase as well. Because pregnant women are at increased risk for hospitalization, intensive care unit admission, and mechanical ventilation support, obstetricians will be facing the dilemma of initiating maternal corticosteroid therapy while weighing its potential adverse effects on the fetus (or neonate if the patient is postpartum and breastfeeding). Our objective is to summarize the current evidence supporting steroid therapy in the management of patients with acute respiratory distress syndrome and COVID-19 and to elaborate on key modifications for the pregnant patient.

Variability in the efficacy of a standardized antenatal steroid treatment was independent of maternal or fetal plasma drug levels: evidence from a sheep model of pregnancy.

BACKGROUND: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%. In some cases, antenatal steroid use is associated with limited benefit and potential harm. OBJECTIVE: We hypothesized that individual differences in maternofetal steroid exposure would contribute to observed variability in antenatal steroid treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between maternofetal steroid exposure and antenatal steroid treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. STUDY DESIGN: Ewes carrying a single fetus underwent surgery to catheterize a fetal and maternal jugular vein at 119 days' gestation. Animals recovered for 24 hours before being randomized to either (1) a single maternal intramuscular injection of 2 mL saline (negative control group, n=10) or (2) a single maternal intramuscular injection of 0.25 mg/kg betamethasone phosphate plus acetate (antenatal steroid group, n=20). Serial maternal and fetal plasma samples were collected from each animal after 48 hours before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. RESULTS: One animal from the control group and one animal from the antenatal steroid group did not complete their treatment protocol and were removed from analyses. Animals in the antenatal steroid group were divided into a responder subgroup (n=12/19) and a nonresponder subgroup (n=7/19) using a cutoff of partial pressure of arterial CO2 at 30-minute ventilation within 2 standard deviations of the mean value from saline-treated negative control group animals. Although antenatal steroid improved fetal lung maturation in the undivided antenatal steroid group and in the responder subgroup both physiologically (blood gas- and ventilation-related data) and biochemically (messenger ribonucleic acid expression related to fetal lung maturation), these values did not improve relative to saline-treated control group animals in the antenatal steroid nonresponder subgroup. No differences in betamethasone distribution, clearance, or protein binding were identified between the antenatal steroid responder and nonresponder subgroups. CONCLUSION: This study correlated individual maternofetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation that was not significantly different to saline-treated control group animals. These nonresponsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of antenatal steroid therapy is not solely determined by maternofetal drug levels and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid signaling.

Corticosteroid Guidance for Pregnancy during COVID-19 Pandemic.

The novel coronavirus disease 2019 (COVID-19) pandemic is causing a necessary, rapid adjustment within the field of obstetrics. Corticosteroid use is a mainstay of therapy for those women delivering prematurely. Unfortunately, corticosteroid use has been associated with worse outcomes in COVID-19 positive patients. Given this information, it is necessary that obstetricians adjust practice to carefully weigh the fetal benefits with maternal risks. Therefore, our institution has examined the risks and benefits and altered our corticosteroid recommendations. KEY POINTS: · Corticosteroid use is an important part of prematurity treatment because it provides benefit to the fetus.. · Corticosteroid use may be related with increased morbidity and mortality in novel coronavirus disease 2019 (COVID-19).. · Therefore, during the COVID-19 pandemic, an alteration in current corticosteroid practices is necessary to uniquely weigh the maternal risks and fetal benefits..

The duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation.

BACKGROUND: Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. Antenatal corticosteroid dosing remains nonoptimized, and there is little understanding of how different treatment-to-delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with antenatal corticosteroids do not deliver within the widely accepted 1- to 7-day window of treatment efficacy. OBJECTIVE: We used a sheep model to test the duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. MATERIALS AND METHODS: For infusion studies, ewes with single fetuses were randomized to receive an intravenous bolus and maintenance infusion of betamethasone phosphate to target 1-4 ng/mL fetal plasma betamethasone for 36 hours, with delivery at 2, 4 ,or 7 days posttreatment or sterile saline solution as control. Animals receiving the clinical treatment were randomised to receive either a single injection of 0.25 mg/kg with a 1:1 mixture of betamethasone phosphate + betamethasone acetate with delivery at either 1 or 7 days posttreatment, or 2 treatments of 0.25 mg/kg betamethasone phosphate + betamethasone acetate spaced at 24 hours (giving ∼48 hours of fetal steroid exposure) with delivery at 2, 5, 7, or 10 days posttreatment. Negative control animals were treated with saline solution. All lambs were delivered at 121 ± 3 days gestational age and ventilated for 30 minutes to assess lung function. RESULTS: Preterm lambs delivered at 1 or 2 days post-antenatal corticosteroid treatment had significant improvements in lung maturation for both intravenous and single-dose intramuscular treatments. After 2 days, the efficacy of 36-hour betamethasone phosphate infusions was lost. The single dose of 1:1 betamethasone phosphate + betamethasone acetate also was ineffective at 7 days. In contrast, animals treated with 2 doses had significant improvements in lung maturation at 2, 5, and 7 days, with treatment efficacy reduced by 10 days. CONCLUSION: In preterm lambs, the durability of antenatal corticosteroids treatment depends on the duration of fetal exposure and is independent of the intravenous or intramuscular maternal route of administration. For acute 24- to 48-hour posttreatment deliveries, a 24-hour fetal antenatal corticosteroids exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single-dose ACS treatment should be sufficient for women delivering within <48 hours of antenatal corticosteroids treatment.

Severe antepartum hypertension and associated peripartum morbidity among pregnant women in an urban tertiary care medical center.

OBJECTIVES: Hypertensive disorders of pregnancy are a leading cause of maternal morbidity and mortality. Although acute severe hypertension carries with it a poor prognosis, treatment is often delayed and not universal. STUDY DESIGN: A total of 654 patients were assessed for the impact of hypertensive disorders of pregnancies on maternal and fetal morbidity and divided into three groups: normotensive (Group I, N = 306), non-severe hypertension (Group II, N = 248) and severe-range hypertension with blood pressure (BP) episodes ≥160 systolic or ≥105 diastolic (Group III, N = 100). Retrospective demographic and medical information was abstracted from patients' medical records to collect study data. MAIN OUTCOME MEASURES: The main outcomes assessed were composite maternal adverse events,fetal adverse events, and time to treatment. RESULTS: Patients in Group III had higher systolic (182 vs 155 vs 133) and diastolic (106 vs 95 vs 81) BPs compared to patients in Groups II and I. Patients in Group III had a significantly higher incidence of maternal adverse events (26.0% vs 6.5% vs 2.0%, respectively; p < 0.001) and higher neonatal composite adverse events (52.0% vs 17.7% vs 26.1%, respectively; p < 0.001) as compared to patients in Groups II and I. Only 52.2% of patients in Group III were treated within recommended 60 minutes or less. CONCLUSIONS: Patients with severe hypertension antepartum have higher associated maternal and fetal adverse events while treatment is often delayed. Further studies should evaluate the effects of adequate time to treatment for severe hypertension. Steps should also be taken to standardize identification and reporting of severe maternal morbidity.

Oral dosing for antenatal corticosteroids in the Rhesus macaque.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques.

Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) - the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.

Optimizing antenatal corticosteroid therapy.

Treatment with antenatal corticosteroids (ACS) is standard of care for women at risk of preterm birth between 24 and 34 weeks' gestation. ACS are increasingly used for other indications, including threated or indicated late preterm birth, elective cesarean, and in at-risk pregnancies for periviable gestations. However, the various drugs and doses being used worldwide have not been rigorously evaluated to optimize clinical responses and to minimize potential risks. Translational research in animal models indicate that a constant, low concentration fetal exposure to ACS is sufficient for lung maturation, resulting in lower fetal exposures. Clinical trials to develop dosing strategies with inexpensive and widely available drugs could promote greater use in low resource environments.

Antenatal corticosteroids after 34 weeks' gestation: Do we have the evidence?

There is evidence to support the use of antenatal corticosteroids prior to late preterm birth at 35+0 to 36+6 weeks' gestation and for specific 'at-risk' populations, such as planned cesarean section birth and infants of women with diabetes in pregnancy, to reduce short-term neonatal respiratory morbidity. However, the overall size of effect at late preterm and term gestational ages is less than for early and moderate preterm birth and should be countered against the potential harms. Evidence from randomized trials suggest an increase in the incidence of neonatal hypoglycemia after corticosteroid use prior to late preterm birth; any effect of antenatal corticosteroids on neonatal glycemic control after planned cesarean section birth or for infants born to mothers with diabetes in pregnancy is unknown. Accumulating evidence suggests neonatal hypoglycemia may adversely affect childhood development. To date, no trials of antenatal corticosteroids after 34 weeks' gestation have reliably assessed outcomes beyond the neonatal period.

Antenatal corticosteroid therapy: Historical and scientific basis to improve preterm birth management.

OBJECTIVE: The purpose of this review is to describe the historical and scientific basis of antenatal corticosteroids (ACS) therapy, to improve the management of preterm birth and decreasing rates of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis and perinatal mortality in premature infants. STUDY DESIGN: We searched MEDLINE/PubMed electronic database, the Cochrane Library, using medical subheading search words such as "ACS", "corticosteroids", "betamethasone" or "dexamethasone", matching with "preterm birth". RESULTS: This practice was initiated by Liggins and Howie in 1972 and is supported by the initial comprehensive meta-analysis of Crowley, Chambers and Keirse, in 1990, the NIH Consensus Development Conference in 1994, the second Consensus Conference to evaluate repeated courses of corticosteroids in 2000 and the practice recommendations of obstetric societies worldwide. ACS therapy before anticipated preterm birth is one of the most important antenatal therapies and an important evidence-based practice for reducing mortality, and decreasing rates of complications in premature infants. CONCLUSIONS: Today, there is no controversy that women with preterm birth <34 weeks should be ACS treated. Actually, rescue courses are recommended; while multiple, serial, repeated or weekly courses, are not recommended. In any clinical conditions, as preterm premature rupture of membranes, multiple pregnancies, severe preeclampsia/HELLP syndrome and fetal growth restriction; ACS is recommended.

Amniocentesis compared with antenatal corticosteroids prior to early term scheduled cesarean delivery.

Objective: There are a variety of maternal or fetal conditions that require late preterm or early term delivery. In cases where early delivery is indicated, optimal management is not always clear. Historically, obstetricians used amniocentesis to document fetal lung maturity, but recently, many have transitioned to administration of antenatal corticosteroids (ACS). The objective of this study was to compare neonatal outcomes between women undergoing amniocentesis or receiving ACS prior to scheduled cesarean delivery (CD) less than 39 weeks. Methods: This was a retrospective cohort study of women undergoing scheduled CD by one maternal-fetal medicine practice between 36 and 38 6/7 weeks, from 2005 to 2017. We identified women who underwent amniocentesis or received ACS within 2 weeks prior to delivery. Neonatal outcomes were compared between the two groups, with the primary outcome being neonatal intensive care unit (NICU) admission. Results: A total of 502 women were included, of whom 313 (62.4%) underwent amniocentesis and 189 (37.6%) received ACS. Overall, 55 (11.0%) of neonates were admitted to the NICU. NICU admission was not significantly different between groups (11.8 versus 9.5%, p=.46). This held true after adjusting for gestational age and other differences in baseline characteristics. There were no significant differences between groups for all other neonatal outcomes, including NICU admission for respiratory indications, respiratory support, neonatal greater than maternal length of stay, low Apgar scores, and neonatal death. Rates of hypoglycemia were low and not significantly different between groups (2.2% in the amniocentesis group versus 0.5% in the ACS group, p=.27). Diabetes was the only covariate significantly associated with NICU admission (aOR 3.19, 95% CI 1.35, 7.54). Conclusions: In women undergoing scheduled CD between 36 and 38 6/7 weeks, administration of ACS is associated with similar neonatal outcomes compared to amniocentesis. This supports the current notion that outcomes are similar with ACS compared to amniocentesis for late preterm and early term deliveries. Brief rationale: The objective of this study was to compare neonatal outcomes between women undergoing amniocentesis or receiving antenatal corticosteroids (ACS) prior to scheduled cesarean delivery (CD) less than 39 weeks. We found that in women undergoing scheduled cesarean delivery between 36 and 38 6/7 weeks, administration of antenatal corticosteroids is associated with similar neonatal outcomes compared to amniocentesis.

All-Trans Retinoic Acid Disrupts Development in Ex Vivo Cultured Fetal Rat Testes. I: Altered Seminiferous Cord Maturation and Testicular Cell Fate.

Exposure to excess retinoic acid (RA) disrupts the development of the mammalian testicular seminiferous cord. However, the molecular events surrounding RA-driven loss of cord structure have not previously been examined. To investigate the mechanisms associated with this adverse developmental effect, fetal rat testes were isolated on gestational day 15, after testis determination and the initiation of cord development, and cultured in media containing all-trans RA (ATRA; 10-8 to 10-6 M) or vehicle for 3 days. ATRA exposure resulted in a concentration-dependent decrease in the number of seminiferous cords per testis section and number of germ cells, assessed by histopathology and immunohistochemistry. Following 1 day of culture, genome-wide expression profiling by microarray demonstrated that ATRA exposure altered biological processes related to retinoid metabolism and gonadal sex determination. Real-time RT-PCR analysis confirmed that ATRA enhanced the expression of the key ovarian development gene Wnt4 and the antitestis gene Nr0b1 in a concentration-dependent manner. After 3 days of culture, ATRA-treated testes contained both immunohistochemically DMRT1-positive and FOXL2-positive somatic cells, providing evidence of disrupted testicular cell fate maintenance following ATRA exposure. We conclude that exogenous RA disrupts seminiferous cord development in ex vivo cultured fetal rat testes, resulting in a reduction in seminiferous cord number, and interferes with maintenance of somatic cell fate by enhancing expression of factors that promote ovarian development.