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Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery

Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery
Authors:
Men-Jean Lee, MD
Debra Guinn, MD, FACOG
Section Editors:
Charles J Lockwood, MD, MHCM
Richard Martin, MD
Deputy Editor:
Vanessa A Barss, MD, FACOG
Literature review current through: Jul 2022. | This topic last updated: Jul 07, 2022.

INTRODUCTION — Over two dozen randomized trials have confirmed that a course of antenatal corticosteroid therapy (ACS) administered to women at risk for preterm delivery reduced the incidence and severity of respiratory distress syndrome (RDS) and mortality in offspring [1]. Subsequent trials have shown that ACS also improves circulatory stability in preterm neonates, resulting in lower rates of intraventricular hemorrhage and necrotizing enterocolitis compared with unexposed preterm neonates.

This topic will review evidence supporting the use of ACS to improve neonatal outcomes in women at risk for preterm delivery, pharmacologic issues, and clinical concerns about administration of this therapy. Postnatal interventions to prevent and treat RDS and its sequelae are reviewed separately. (See "Management of respiratory distress syndrome in preterm infants".)

MECHANISM OF ACTION — ACS accelerates development of type 1 and type 2 pneumocytes, leading to structural and biochemical changes that improve both lung mechanics and gas exchange (eg, surfactant production) [2-7]. Other effects include induction of pulmonary beta-receptors, which play a role in surfactant release and absorption of alveolar fluid when stimulated [4]; induction of fetal lung antioxidant enzymes [8]; and upregulation of genes for mediators of pulmonary epithelial sodium and liquid absorption, which are important for postnatal absorption of lung fluid [9,10]. For these changes to occur, however, the lungs need to have reached a stage of development that is biologically responsive to corticosteroids. (See 'Candidates for a first ACS course by gestational age' below.)

TIMING BEFORE DELIVERY — Ideally, ACS is timed so that maximum efficacy is achieved before delivery, and this window is two to seven days after administration of the first dose [11]. Efficacy is incomplete <24 hours from administration of the first dose and appears to decline after seven days [12-15]. Observational data suggest neonatal benefits begin to accrue within a few hours of ACS administration [16,17]. Infants who received one dose of betamethasone in utero, but delivered before the second dose was given, had better outcomes than infants who did not receive any ACS [16,17]. Laboratory data also support an early physiologic effect as early as 6 hours following the first injection [18,19]. In cell culture models, biochemical stimulation of surfactant production was limited to seven to eight days [20].

However, predicting when a patient is two to seven days before delivery is often highly imprecise. Some examples of pregnancies with a high probability of imminent delivery include patients who present with signs of spontaneous preterm labor with cervical change ≥3 cm, patients who present with spontaneous preterm prelabor rupture of membranes, or patients with a pregnancy complication (eg, preeclampsia with severe features, bleeding placenta previa) warranting planned delivery (eg, induction, cesarean) within 48 hours to improve maternal and/or neonatal outcomes. Administration of ACS for preterm contractions alone will result in overtreatment and its consequences: A meta-analysis reported that 53 percent of patients with threatened preterm labor were undelivered seven days after diagnosis and 40 percent delivered at term [21].

CHOICE OF DRUG, DOSING, AND SIDE EFFECTS

Betamethasone or dexamethasone? — Either betamethasone or dexamethasone administered parenterally is acceptable; both drugs were effective for accelerating fetal maturity in randomized trials [1,22,23]. These steroids are preferred over other steroids because they are less extensively metabolized by the placental enzyme 11 beta-hydroxysteroid dehydrogenase type 2, so they have maximum fetal impact. When both drugs are available, some of the contributors to this topic prefer betamethasone because, in randomized trials where each drug was compared with placebo, betamethasone showed a clear reduction in intraventricular hemorrhage (IVH; risk ratio [RR] 0.48, 95% CI 0.34-0.68) whereas confidence intervals were wide for dexamethasone (RR 0.78, 95% CI 0.54-1.13), but no direct comparisons of the drugs have been performed and the test for subgroup differences in the meta-analysis did not suggest a difference in effect on IVH between different types of ACS [1].

Alternatives — Hydrocortisone is extensively metabolized by placental enzymes, so relatively little active drug crosses into the fetal compartment; therefore, beneficial fetal effects may not occur. However, if both betamethasone and dexamethasone are unavailable due to drug shortages, hydrocortisone 500 mg intravenously every 12 hours for four doses has been proposed as a last resort [24,25].

In women incidentally receiving high-dose hydrocortisone for treatment of a medical disorder, a standard course of betamethasone or dexamethasone, when indicated for fetal lung maturation, is recommended.

Dosing and pharmacology — A course of therapy consists of the following:

Betamethasone two doses of 12 mg intramuscularly 24 hours apart.

One milliliter of the betamethasone suspension commonly used in clinical practice is a combination of 3 mg of betamethasone sodium phosphate and 3 mg of betamethasone acetate. Betamethasone sodium phosphate is soluble, so it is rapidly absorbed, while betamethasone acetate is only slightly soluble and, therefore, provides sustained activity.

The biologic half-life is 35 to 54 hours [26]. The onset and duration of action are affected by the vascularity at the injection site. Drug concentrations in cord blood are approximately 20 percent of maternal levels one hour following maternal injection [27].

or

Dexamethasone sodium phosphate four doses of 6 mg intramuscularly 12 hours apart.

Dexamethasone has a more rapid onset and shorter duration of action than betamethasone; therefore, the dosing interval is shorter and more doses are required.

Use of oral dexamethasone should be avoided, except in the context of a randomized trial or unavailability of parenteral ACS therapy, as it has been associated with an increased risk for some adverse outcomes [28-30]. The dose is 6 mg orally every 6 hours for 48 hours.

Optimal dosing studies have not been performed. At the above doses, 75 to 80 percent of available corticosteroid receptors are occupied, which should provide near-maximal induction of corticosteroid receptor-mediated response in fetal target tissues [27]. These doses result in cord blood glucocorticoid levels in the range seen with physiologic stress in the preterm neonate.

There is no convincing evidence that the beneficial fetal effects of standard doses of ACS are significantly reduced in overweight or obese women (body mass index [BMI] ≥25 kg/m2), but further study is needed [31]. In a randomized trial, maternal and cord blood betamethasone levels were similar for obese (BMI ≥30 kg/m2) and nonobese women; however, this trial did not evaluate clinical outcomes [32].

Nonstandard dosing regimens — There is no convincing evidence of the safety and efficacy of increasing the ACS dose [33], maternal weight-based dosing, accelerating the interval between doses [34,35], or using an intravenous or oral route of administration [28].

Maternal side effects — Most pregnant women tolerate a single course of ACS without difficulty. In a 2020 systematic review of randomized trials, treatment probably did not increase the risk of chorioamnionitis or endometritis [1]. Case reports have described pulmonary edema, primarily associated with combination treatment with tocolytics, especially in the setting of chorioamnionitis, fluid overload, or multiple gestation [36-38]. Betamethasone and dexamethasone have low mineralocorticoid activity compared with other corticosteroids; therefore, hypertension is not a contraindication to therapy [39].

Transient hyperglycemia occurs in many women; the steroid effect begins approximately 12 hours after the first dose and may last for five days. Screening for gestational diabetes, if indicated, should be performed either before ACS administration or at least five days after the first dose [40,41]. In women with diabetes, hyperglycemia can be severe if not closely monitored and treated. (See "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management", section on 'Antenatal glucocorticoids in patients at risk for preterm birth'.)

The total leukocyte count increases by approximately 30 percent within 24 hours after ACS injection, and the lymphocyte count significantly decreases [42,43]. These changes return to baseline within three days but may complicate the diagnosis of infection.

Uterine activity may increase slightly after betamethasone administration, particularly in multiple gestations and especially with increasing duration of pregnancy [44,45]. The mechanism is not known.

Fetal side effects

Fetal heart rate (FHR) and biophysical parameters – ACS may be associated with transient FHR and behavioral changes that typically return to baseline by four to seven days after treatment [46,47]. Because steroids are generally administered in high-risk obstetric situations where the likelihood of a true positive nonreassuring antenatal test is more likely, any changes in fetal testing should be evaluated according to the clinician's best judgment. (See "Nonstress test and contraction stress test" and "Biophysical profile test for antepartum fetal assessment".)

The most consistent FHR finding is a decrease in variability on days 2 and 3 after administration, which alone is not an indication for delivery [48-52]. Reduced fetal breathing and body movements can result in a lower biophysical profile score or nonreactive nonstress test [52-55]; however, decreased fetal movement is not a consistent finding [56].

FHR and behavioral changes may reflect a direct physiologic response of the brain to ACS, or they may be an indirect result of a transient increase in fetal vascular resistance and blood pressure, which has been demonstrated in some animal studies [57-61].

Doppler flow studies – A transient improvement in umbilical artery end-diastolic flow (EDF) after ACS administration has been described in 63 to 71 percent of patients participating in three studies [62-64]. The improvement began approximately eight hours after the first dose of ACS and lasted a median of three days (range 1 to 10 days). However, other studies have not observed effects on fetal blood flow velocity waveform patterns in the umbilical artery, middle cerebral artery, or ductus venosus [54,65].

Preterm fetuses with severe early-onset growth restriction and absent or reversed EDF do not have a consistent cardiovascular response to ACS. Some exhibit transient improvement of EDF while others do not. The latter group appears to be at higher risk of severe acidosis or death. Because these observations were based on a small number of events in two studies, they need to be confirmed before a change in management of this subgroup of fetuses is considered [64,66]. Abnormal umbilical cord Dopplers or the fear of causing worsening Dopplers should not preclude administration of steroids to pregnancies with growth restriction. (See "Doppler ultrasound of the umbilical artery for fetal surveillance in singleton pregnancies".)

CANDIDATES FOR A FIRST ACS COURSE BY GESTATIONAL AGE — The benefits of ACS do not appear to be affected by fetal sex or race [67]. Pregnancies <22+0 weeks are generally not considered candidates for ACS as there are only a few primitive alveoli at this gestational age on which the drug can exert an effect [68].

22+0 to 22+6 weeks — After thorough counseling between the patient and maternal-fetal medicine and neonatology specialists, ACS can be considered at 22+0 to 22+6 weeks of gestation for a patient in whom delivery in the next seven days is anticipated and if the patient is requesting aggressive neonatal intervention [69].

A key concept at this gestational age is that ACS may provide a survival benefit, but the risk of major long-term morbidity in survivors is high. For example, in the Vermont-Oxford database of children born in the 22nd week of gestation and given postnatal life support, survival in the ACS-exposed and unexposed cohorts was 38.5 versus 17.7 percent, and survival without major morbidities was 4.4 versus 1.0 percent [70]. Major morbidities included severe intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis, culture-confirmed infection, severe retinopathy of prematurity, and chronic lung disease.

23+0 to 33+6 weeks — In agreement with virtually all guidelines, we recommend administration of ACS for all pregnant patients at 23+0 to 33+6 weeks of gestation who are at increased risk of preterm delivery within the next seven days. At this gestational age, ACS improves neonatal survival and reduces major short-term morbidity, although long-term neurodevelopmental issues remain a concern. Selection of such pregnancies is a clinical judgment based on a high probability of induction/cesarean for obstetric or medical indications or a high probability of spontaneous preterm labor and delivery (eg, preterm prelabor rupture of membranes, tocolysis for active preterm labor).

34+0 or more weeks — In contrast to pregnancies at 23+0 to 33+6 weeks, where consensus exists about ACS administration, the use of ACS at ≥34+0 weeks is controversial given the absence of a survival benefit, less absolute respiratory benefit due to the lower risk of serious respiratory problems at this gestational age, and greater concern about potential long-term harm.

Our approach is more cautious compared with recommendations of some organizations (see 'Recommendations of selected national organizations' below). We have concerns that the short-term benefit of keeping the neonate out of the neonatal intensive care unit because of transient tachypnea of the newborn (TTN), which is a transient and treatable problem, may be outweighed by the potential risk for adverse long-term neuropsychiatric outcomes. Therefore:

For patients scheduled within seven days for cesarean delivery at ≥34 weeks, it is our opinion that ACS is best restricted to participants enrolled in randomized trials powered and funded to evaluate both short-term and long-term outcomes, particularly neuropsychiatric outcomes. However, we do discuss with patients the limited available data regarding the uncertain benefits described in a meta-analysis of ACS administration 48 hours before planned cesarean delivery at ≥37 weeks of gestation [71] and the benefits in the Antenatal Late Preterm Steroids (ALPS) trial of ACS administration at 34+0 to 36+5 weeks of gestation in patients at high risk for late preterm birth. The potential harms of late preterm steroids, particularly long-term neuropsychiatric effects, are also presented. These data are reviewed separately below (see 'Evidence of efficacy' below and 'Evidence of potential harms' below). After this discussion, some patients may choose to receive ACS before their scheduled cesarean delivery as part of shared decision making.

For patients in whom vaginal delivery at 34+0 to 34+6 weeks is expected within seven days (eg, planned induction, preterm labor with substantial cervical change, preterm prelabor rupture of membranes), we suggest not administering ACS as the neonatal respiratory problems described in the ALPS trial are less common after labor and vaginal birth than after planned cesarean [72-74]. In addition, overall rates of respiratory distress syndrome (RDS) and mechanical ventilation were not reduced in ALPS, and we are concerned about the potential long-term risk of harm to short-term benefit ratio. However, we discuss with patients the available data regarding the benefits described in the ALPS trial and the potential harms (see 'Evidence of efficacy' below), particularly long-term neuropsychiatric effects, which are reviewed separately below (see 'Evidence of potential harms' below). After this discussion, some patients may choose to receive a course of steroids as part of shared decision making.

For patients at 34+0 to 36+6 weeks in whom there is only a low risk of delivery within seven days (eg, threatened preterm labor with no or minimal cervical change), we believe a course of ACS should not be administered because there is potential for long-term harm with no benefit if the patient does not deliver preterm. Importantly, a large proportion of patients with threatened preterm labor (up to 84 percent in some studies [21]) do not deliver within seven days, when the favorable effects of steroid administration are most likely to occur. (See 'Evidence of potential harms' below.)

Recommendations of selected national organizations — Based on the evidence of benefit at 34+0 to 36+6 weeks discussed below (see '34+0 to 36+5 weeks and ≥37 weeks' below):

The Society for Maternal-Fetal Medicine (SMFM) recommends a two-dose course of ACS for women at 34+0 to 36+6 weeks of gestation at high risk for preterm birth within seven days, with the following caveats [75]:

For women with symptoms of preterm labor, cervical dilation should be ≥3 cm or effacement ≥75 percent before treatment, and tocolysis should not be used to delay delivery for completion of the course of steroids.

For women with potential medical/obstetric indications for early delivery, ACS should not be administered until a definite plan for delivery has been made.

Women with multiple gestations, those who had previously been treated with betamethasone prior to 34 weeks, those with pregestational diabetes, and those with scheduled cesarean deliveries at ≥37 weeks of gestation were excluded from the ALPS trial; therefore, the above recommendation should not be applied to these women outside of research or quality improvement. (See '34+0 to 36+5 weeks and ≥37 weeks' below.)

The American College of Obstetricians and Gynecologists (ACOG) states administration of ACS is recommended for women with a singleton pregnancy at 34+0 to 36+6 weeks of gestation at imminent risk of preterm birth within seven days, with the following caveats [12,76]:

ACS administration should not be administered to patients with chorioamnionitis.

Tocolysis should not be used to delay delivery in women with symptoms of preterm labor to allow administration of ACS. Medically/obstetrically indicated preterm delivery should not be postponed for ACS administration.

ACS should not be administered if the patient has already received a course.

Newborns should be monitored for hypoglycemia.

The National Institute for Health and Care Excellence (NICE) guideline (NG25) on preterm labor and birth recommends considering ACS for women between 34+0 and 35+6 weeks of gestation who are in suspected, diagnosed, or established preterm labor; are having a planned preterm birth; or have preterm prelabor rupture of membranes [77].

The Royal College of Obstetricians and Gynaecologists (RCOG) recommends offering ACS up to 34+6 weeks of gestation for patients in whom imminent preterm birth is anticipated [78].

Others have cautioned against universal adoption of ACS for pregnancies at risk of preterm birth at 34+0 to 36+6 weeks of gestation because it is unclear whether the short-term benefits (reduction in TTN) clearly outweigh the risks (neonatal hypoglycemia, unknowns about long-term neurodevelopmental outcome and metabolic risks) [79]. As an example, European Guidelines for the Management of RDS recommend ACS only up to 34 weeks [80].

EVIDENCE OF EFFICACY — The gestational age recommendations discussed above are based on data from randomized trials in meta-analyses and the Antenatal Late Preterm Steroids (ALPS) trial [1,81] (see '34+0 to 36+5 weeks and ≥37 weeks' below). Some of these benefits derive from the favorable effect on respiratory morbidity; however, maturational effects in numerous tissues due to corticosteroid stimulation of developmentally regulated genes and physiologic functions suggest an independent effect as well [26,82-88]. The composite of multiple maturational effects is likely to have a salutary effect on the fetus's transition to extrauterine life.

24+0 to 36+6 weeks

In a 2020 systematic review of randomized trials comparing ACS versus placebo/no treatment in patients at risk for preterm birth at a wide range of preterm gestational ages, ACS resulted in reductions in [1]:

Neonatal mortality (9.3 versus 11.9 percent, relative risk [RR] 0.78, 95% CI 0.70-0.87, 22 trials, >10,600 infants).

Perinatal death (stillbirths and deaths in the first 28 days of life: 13.3 versus 15.6 percent, RR 0.85, 95% CI 0.77-0.93, 14 trials, >9800 infants).

Respiratory distress syndrome (RDS; 10.5 versus 14.8 percent, RR 0.71, 95% CI 0.65-0.78, 26 trials, >11,000 infants). Moderate to severe RDS was also reduced (RR 0.70, 95% CI 0.59-0.83), but it is unclear whether chronic lung disease was reduced (RR 0.86, 95% CI 0.41-1.79).

Need for mechanical ventilation/continuous positive pressure (RR 0.75, 95% CI 0.66-0.84, 11 trials, >4500 infants).

Intraventricular hemorrhage (IVH; 1.9 versus 3.3 percent, RR 0.58, 95% CI 0.45-0.75, 12 trials, >8400 infants).

Necrotizing enterocolitis (NEC; RR 0.50, 95% CI 0.32-0.78, 10 trials, 4702 infants).

Evidence of ACS efficacy very early in gestation was provided by a 2018 meta-analysis of randomized trials that established efficacy at 22, 23, and 24 weeks of gestation [89]:

Reduction in mortality at 24 weeks (odds ratio [OR] 0.46, 95% CI 0.34-0.62), 23 weeks (OR 0.49, 95% CI 0.43-0.56), and 22 weeks (OR 0.58, 95% CI 0.38-0.89).

Reduction in IVH (stage III and IV) or periventricular leukomalacia at 23 and 24 weeks but not at 22 weeks.

No statistical reductions for NEC greater than stage II or chronic lung disease.

34+0 to 36+5 weeks and ≥37 weeks

≥37 weeks – In a 2021 Cochrane meta-analysis comparing prophylactic ACS (betamethasone or dexamethasone) with placebo or no treatment before planned cesarean birth at ≥37 weeks of gestation (a single randomized trial of 942 pregnancies in 10 hospitals within the United Kingdom [90]), the benefit of ACS was uncertain [71]. Major outcomes in the intervention and control groups were:

RDS (4 versus 11 per 1000; RR 0.34, 95% CI 0.07-1.65; low certainty evidence)

TTN (2.1 versus 4.0 percent; RR 0.52, 95% CI 0.25-1.11; low certainty evidence)

Admission to neonatal special care for respiratory complications (2.3 versus 5.1 percent; RR 0.45, 95% CI 0.22-0.90; moderate certainty evidence)

Need for mechanical ventilation (9 versus 2 per 1000; RR 4.07, 95% CI 0.46-36.27; very low certainty evidence)

No cases of postpartum maternal infection/pyrexia were observed in the first 72 hours. Neonatal hypoglycemia was not reported and longterm outcomes were not assessed. This meta-analysis is a revision of a previous Cochrane meta-analysis that included four trials and reported a statistically significant reduction in RDS and TTN [91], but was challenged because of concerns about the reliability of some of the trials. The single trial in the 2021 analysis was considered at high risk of performance bias as neither participants nor health professionals were blinded to group allocation. The trend toward increased need for mechanical ventilation is puzzling given the trends toward reduction in RDS and transient tachypnea of the newborn (TTN).

34+0 to 36+5 weeks – In ALPS, over 2800 women at 34+0 to 36+5 weeks of gestation at high risk for late preterm birth were randomly assigned to receive a first course of ACS or placebo [81]. No tocolytics were administered, and one-third of patients in each group delivered by cesarean. Major findings were:

The primary outcome was a composite of neonatal respiratory treatment in the first 72 hours (continuous positive airway pressure [CPAP], high-flow nasal cannula for ≥2 hours, supplemental oxygen with fraction of inspired oxygen [FIO2] ≥0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation), stillbirth, or neonatal death within 72 hours of delivery. The primary outcome occurred less often in the treatment group (11.6 versus 14.4 percent, RR 0.80, 95% CI 0.66-0.97) and was primarily driven by reductions in CPAP and high-flow nasal cannula use. There were no stillbirths or neonatal deaths.

TTN occurred less frequently in the treatment group (6.7 versus 9.9 percent, RR 0.67, 95% CI 0.53-0.87).

The rates of RDS and mechanical ventilation were similar in both groups (RDS: 5.5 versus 6.4 percent with placebo, RR 0.87, 95% CI 0.65-1.17; mechanical ventilation: 2.4 versus 3.1 percent with placebo, RR 0.78, 95% CI 0.50-1.21).

Neonatal hypoglycemia occurred more frequently in the treatment group (24 versus 15 percent, RR 1.60, 95% CI 1.37-1.87).

Patients delivered by planned cesarean may have derived a greater reduction in severe respiratory morbidity from steroid administration than those delivered vaginally, but the statistical analysis did not show a definite difference (test for interaction p = 0.05) and there was no significant difference between groups for the primary outcome (test for interaction p = 0.11).

Women with multiple gestations, those who had previously been treated with betamethasone prior to 34 weeks, those with pregestational diabetes, and those with scheduled cesarean deliveries at ≥37 weeks of gestation were excluded from the trial.

EVIDENCE OF POTENTIAL HARMS

Short-term harms — The body of evidence suggests that a single course of ACS does not increase the risk of most fetal/newborn adverse outcomes, such as infection or small for gestational age birth weight [81,89]. However, some studies have observed reduced basal and stress-induced cortisol secretion in these newborns [92-96] and more small for gestational age newborns among term births [97]. An increased risk for neonatal hypoglycemia was noted in two randomized trials of ACS at 34+0 to 36+6 weeks of gestation (22.8 versus 14.2 percent, relative risk [RR] 1.61, 95% CI 1.16-2.12) [98].

In contrast to trials in high-income countries, the Antenatal Corticosteroids Trial (ACT), a large randomized trial of strategies to promote ACS use in low- and middle-income countries, reported the unexpected finding of increased neonatal mortality in steroid-exposed infants (RR 1.12, 95% CI 1.02-1.23) [99]. Suspected maternal infection was also higher in the ACS group (3 versus 2 percent, odds ratio 1.45, 95% CI 1.33-1.58). The reason for increased neonatal mortality was unclear but may have been related to a slightly higher rate of severe neonatal infections in the exposed group, particularly among newborns with birth weight ≥25th percentile [100]. Overtreatment was common: 84 percent of the exposed infants delivered at term, in part because of inaccurate estimates of both gestational age and likelihood of imminent delivery. These findings were concerning and prompted further investigation in similar populations.

A subsequent larger randomized trial conducted by the World Health Organization (WHO) in low-resource countries reported that dexamethasone administration at 26+0 to 33+6 weeks reduced neonatal death (RR 0.84, 95% CI 0.72-0.97) and stillbirth or neonatal death (RR 0.88, 95% CI 0.78-0.99) compared with placebo, with trends toward reduction in severe respiratory distress (RR 0.81, 95% CI 0.64-1.03) and increase in severe intraventricular hemorrhage (RR 1.85, 95% CI 0.46-7.42) [101]. The number needed to treat was 25 to prevent 1 neonatal death. Treatment did not increase maternal or neonatal infection rates. The data and safety monitoring board stopped the trial early because of the mortality benefit and strong evidence of a graded dose-response effect, in the context of existing evidence of benefits of ACS.

The difference between the WHO results and those of ACT may relate to better selection of patients for whom treatment was warranted and more resources for neonatal care. In the WHO trial, 90 percent of the infants who were exposed to dexamethasone were born preterm compared with only 16 percent of those in ACT. In ACT, a minority of ACS-exposed infants delivered at a facility with adequate resources for neonatal care, which secondary analysis suggested was an important factor accounting for the lack of effectiveness of the intervention.

Long-term harms — Most studies of children/adults exposed in utero to a single course of ACS before 34 weeks of gestation have not reported adverse effects on growth; lung function; or psychosexual, motor, cognitive, neurodevelopmental, and ophthalmologic outcomes compared with unexposed controls [3,102,103]. However, data on long-term effects are limited, and fetal programming and its consequences remain a concern. Exposure to excess corticosteroids before birth has been postulated to contribute to development of some adult diseases based on data extrapolated from studies in rodents [104]. Some potentially adverse cardiovascular, renal, and metabolic effects have been reported in epidemiologic studies and require further investigation (eg, increased cortisol reactivity to psychological stress, increased aortic arch stiffness, increased insulin resistance, increased risk of adult hypertension) [103,105-111]. Concerns also remain regarding potential adverse effects on neurodevelopmental outcome, particularly with in utero exposure late in gestation. (See 'Neurologic outcomes' below.)

Neurologic outcomes — A meta-analysis of 30 observational studies published from 2000 to 2021 and including more than 1.25 million children who were at least one year of age when the outcomes were assessed reported the following associations between exposure to a single course of preterm antenatal corticosteroids and neurodevelopmental outcome [112]:

Children with extremely preterm birth – Reduced risk of neurodevelopmental impairment (adjusted odds ratio [aOR] 0.69, 95% CI 0.57-0.84, low certainty)

Children with late-preterm birth – Increased risk of investigation for neurocognitive disorders (adjusted hazard ratio [aHR] 1.12, 95% CI 1.05-1.20, low certainty)

Children with full-term birth – Increased risk of mental or behavioral disorders (aHR 1.47, 95% CI 1.36-1.60, low certainty) and proven or suspected neurocognitive disorders (aHR 1.16, 95% CI 1.10-1.2, low certainty)

The abnormal neurodevelopmental outcomes seen in these studies are biologically plausible [33,113-119] and consistent with animal data [113,120-129]. ACS may cause supraphysiologic activation of glucocorticoid receptors in the fetal brain near term, particularly after 34 weeks when brain growth accelerates [115,116]. Disruption of the normal fetal environment at this critical time may lead to changes in development of the neuroendocrine system; lifelong effects on endocrine, behavioral, emotional, and cognitive function; and increased risks for development of a wide range of metabolic, cardiovascular, and brain disorders in later life [33,117-119].

However, concern regarding an increased risk of adverse neuropsychiatric disorders in children exposed to ACS and born late preterm and at term requires further investigation to assess the contribution of the pregnancy condition leading to ACS administration, which might confound these observations, as well as delineating the developmental period during which ACS exposure occurred (eg, extreme preterm versus late preterm setting), which might represent different neurological vulnerabilities. There are many biases in the assessment of potential long-term harms accruing in ACS in infants who subsequently deliver at term. In particular, normal, uncomplicated pregnancies are not treated with ACS, so the appropriate control group would be those with preterm contractions or other risk factors for preterm birth (eg, preeclampsia, growth restriction, bleeding placenta previa, placenta abruption) who delivered at term and did not receive ACS. It is also important to consider the much greater effect size of benefit in children born very preterm versus the smaller effect size of adverse neurodevelopment close to term. Another important consideration is whether the exposure to ACS in the late preterm setting is exacerbating a critical developmental window for fetal brain maturation that was more quiescent in the very preterm setting.

USE OF RESCUE (SALVAGE, BOOSTER) ACS — The American College of Obstetricians and Gynecologists (ACOG) recommends considering a single repeat course of ACS in patients with all of the following characteristics [12]:

<34+0 weeks of gestation.

At imminent risk of preterm delivery within the next seven days.

A prior course of ACS administered more than 14 days previously. However, rescue ACS can be provided as early as seven days from the prior dose, if indicated by the clinical scenario.

A single repeat dose of betamethasone 12 mg rather than the standard two doses of 12 mg 24 hours apart is reasonable. A single dose may confer all the benefits of rescue treatment while minimizing potential risks based on indirect evidence from the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS), which demonstrated that a single injection of betamethasone was effective after initial standard therapy [130]. However, a two-dose betamethasone or four-dose dexamethasone regimen is also reasonable [131] and commonly used worldwide [132,133].

Some clinicians prefer to withhold rescue steroids if the first ACS course was administered after 28 weeks, but this exception is based on limited evidence.

Evidence — In a 2022 meta-analysis of randomized trials assessing the effectiveness and safety of one or more repeated courses of ACS versus no repeat course for patients who remain at risk of preterm birth ≥7 days after an initial course of therapy (11 trials, 4895 pregnant patients, 5975 newborns), repeated courses resulted in [134]:

For the neonate:

Reduced risk of respiratory distress syndrome (279 versus 340 per 1000 patients treated; relative risk [RR] 0.82, 95% CI 0.74-0.90) and severe lung disease (108 versus 130 per 1000 patients treated; RR 0.83, 95% CI 0.72-0.97).

Reduced risk of composite serious health outcomes (185 versus 211 per 1000 patients treated; RR 0.88, 95% CI 0.80-0.97), as defined by the trial authors.

For the mother:

No significant difference in puerperal sepsis (76 versus 67 per 1000 patients treated; RR 1.13, 95% CI 0.93-1.39).

For children aged 2 to 8 years:

No significant difference in survival free of major neurodevelopmental disability/neurocognitive impairment

These findings are consistent with the results of a 2019 individual patient data meta‐analysis of trials of repeat doses of ACS [135].

Multiple courses of steroids (>1 rescue course) — We and others [96] remain concerned about administering multiple repeat courses of ACS because meta-analyses have not evaluated whether there is an increased risk of harm as the number of repeat courses increased. Individual trials suggest increasing exposure to ACS is associated with increasing risk of adverse effect:

In the Maternal-Fetal Medicine Units Network (MFMU) trial, 63 percent of patients received ≥4 courses of therapy. The percentage of small for gestational age fetuses below the 10th percentile and below the 5th percentile was significantly higher in the repeated ACS group compared with the single course group (10th percentile: 19.3 versus 8.4 percent; 5th percentile: 10.4 versus 4.7 percent) [136]. After 32 weeks of gestation, placental weight was significantly less in the repeat ACS group and was related inversely to the number of courses [137]. Although statistically nonsignificant, repeat courses were associated with an increased incidence of cerebral palsy (one case of cerebral palsy in the control group and five in the weekly steroid group, RR 5.68, 95% CI 0.69-46.7); five of the six children with cerebral palsy were delivered near term or at term and five of the six were exposed to ≥4 courses of ACS [136].

A secondary analysis of data from the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a randomized trial of single versus multiple course ACS, reported a dose-response relationship between the number of ACS courses and a decrease in fetal growth [138]. Multiple courses of therapy were not associated with an increase in the composite outcome of death/survival with a neurodevelopmental disability at five years of age [139].

Other experimental evidence from human and animal studies also supports a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development that may be permanent [113,140-143].

SPECIAL POPULATIONS

Multiple gestation — The same dosing schedule is recommended for singleton and multiple gestations. (See 'Dosing and pharmacology' above.)

A meta-analysis of observational studies of ACS administration in twin pregnancies found that the intervention was associated with lower odds of neonatal mortality (aOR 0.59, 95% CI 0.43-0.80; five studies, over 20,000 neonates) and respiratory distress syndrome (aOR 0.70, 95% CI 0.57-0.86; seven studies, over 20,000 neonates), but results for the other outcomes were inconclusive [144].

Diabetes — ACS should not be withheld from women with diabetes when indicated; however, secondary hyperglycemia must be closely monitored. The steroid effect on glucose levels begins approximately 12 hours after the first dose and may last for five days. Women with diabetes generally have been excluded from randomized trials of ACS because of the adverse effects of steroids on glycemic control; thus, efficacy in this population is inferred [145]. (See "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management", section on 'Antenatal glucocorticoids in patients at risk for preterm birth'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antenatal corticosteroids (glucocorticoids)".)

SUMMARY AND RECOMMENDATIONS

Effects on newborn outcome – Antenatal corticosteroid therapy (ACS) reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and neonatal mortality by approximately 50 percent. These effects are not limited by gender or race; efficacy in multiple gestations is unclear as high-quality data are sparse. (See 'Evidence of efficacy' above and 'Multiple gestation' above.)

Approach to treatment at 23+0 to 33+6 weeks of gestation

Given the benefits of ACS, we recommend administration of ACS to pregnant patients who are at 23+0 to 33+6 weeks of gestation and at increased risk of preterm birth within the next one to seven days (Grade 1A). In our practice, we restrict administration of the first course of ACS to patients who rupture membranes or are receiving tocolysis for active preterm labor, or in whom delivery for maternal or fetal indications is anticipated within the next seven days. Antenatal hospitalization does not necessarily mandate a course of ACS. This approach minimizes the need for salvage (rescue, booster) therapy while allowing most patients to receive a course of ACS prior to preterm delivery.

Dose – A course of ACS consists of betamethasone suspension 12 mg intramuscularly every 24 hours for two doses or four doses of 6 mg dexamethasone intramuscularly 12 hours apart. (See 'Choice of drug, dosing, and side effects' above.)

Effect of timing on outcome – Observational data suggest neonatal benefits begin to accrue within a few hours of ACS administration. Maximum efficacy appears to occur when delivery occurs two to seven days after administration of the first dose of ACS. Efficacy is incomplete <24 hours from administration and appears to decline after seven days. (See 'Timing before delivery' above.)

Lower gestational age threshold for administration – We consider approximately 23+0 weeks of gestation as the lower limit for ACS administration since only a few primitive alveoli are present below this gestational age. Earlier administration in the 22nd week is reasonable if aggressive neonatal intervention is planned after thorough counseling about the limit of viability. (See 'Candidates for a first ACS course by gestational age' above and '23+0 to 33+6 weeks' above.)

Approach to treatment at ≥34+0 weeks of gestation – In contemporary obstetric practice in the United States, patients delivered at 34+0 to 38+6 weeks of gestation for an obstetric indication are now delivered without amniocentesis to test for fetal lung maturity. The following approach reflects our concern that widespread use of ACS at ≥34+0 weeks will result in treatment of many pregnancies that will not benefit or will derive only a modest clinical benefit (avoidance of neonatal intensive care unit admission for transient mild respiratory problems) while exposing them to the potential long-term hazards of steroid administration, particularly adverse neurodevelopment outcome in offspring. (See '34+0 or more weeks' above and 'Long-term harms' above.)

Planned cesarean birth at ≥37 weeks – For patients scheduled for cesarean birth at ≥37 weeks, we suggest not administering a course of ACS (Grade 2C). (See '34+0 or more weeks' above and '34+0 to 36+5 weeks and ≥37 weeks' above.)

Planned cesarean birth at 34+0 to 36+6 weeks – For patients scheduled within seven days for cesarean birth at 34+0 to 36+6 weeks, we suggest holding a discussion with the patient regarding the administration of a course of ACS prior to their delivery. There is consensus that repeat courses of steroids are not indicated at this gestational age. For patients who have not received a previous course of steroids, data regarding the potential benefits and long-terms harms of an initial course are discussed using a shared decision-making approach, and some patients may choose to receive a course of steroids before their scheduled cesarean delivery as part of shared decision making. (See '34+0 or more weeks' above and '34+0 to 36+5 weeks and ≥37 weeks' above.)

Vaginal birth at 34+0 to 36+6 weeks

-Imminent vaginal birth uncertain – For patients in whom imminent delivery at 34+0 to 36+6 weeks is uncertain (eg, threatened preterm labor), we recommend not administering a course of steroids (Grade 1C). There is potential for long-term harm with no benefit if the patient does not deliver preterm. Importantly, a large proportion of patients with threatened preterm labor does not deliver within seven days when the effects of steroid administration are most likely to occur. (See '34+0 or more weeks' above and '34+0 to 36+5 weeks and ≥37 weeks' above.)

-Imminent vaginal birth likely – For patients in whom vaginal delivery at 34+0 to 34+6 weeks is expected within seven days (eg, planned induction, preterm labor with substantial cervical change, preterm prelabor rupture of membranes), we suggest not administering ACS as the neonatal respiratory problems described in the ALPS trial are less common after labor and vaginal birth than after planned cesarean (Grade 2C). (See '34+0 or more weeks' above.)

However, this is a controversial area, and some national obstetric organizations have taken a more liberal approach to steroid administration at this gestational age. (See 'Recommendations of selected national organizations' above.)

Use of repeat (rescue or salvage) courses in patients who do not deliver after the first course – The absence of consistent and long-term data precludes making a strong recommendation for the number of courses that are safe for the fetus, the appropriate time interval between courses, the optimal dose for repeated courses of therapy, or the full ramifications of the single course approach to therapy. Given the potential for harm from repeated courses of ACS:

We suggest a course of salvage (rescue, booster) therapy only if the patient is clinically estimated to be at high risk of delivery within the next seven days, more than two weeks have elapsed since the initial course of ACS, and the gestational age at administration of the initial course was ≤28 weeks of gestation (Grade 2C). (See 'Use of rescue (salvage, booster) ACS' above.)

We also suggest that providers who elect to give a course of salvage (rescue, booster) therapy use one rather than two doses of 12 mg betamethasone and limit treatment to this one additional dose (Grade 2C) before 34 weeks of gestation. One dose appears to be effective and may minimize complications related to steroid use; however, a two-dose course is also reasonable. No more than one salvage dose or course is recommended over a single pregnancy. Patients should be informed of potential adverse effects. (See 'Use of rescue (salvage, booster) ACS' above.)

Mechanism of action – ACS leads to improvement in neonatal lung function by enhancing maturational changes in lung architecture and by inducing lung enzymes involved in respiratory function. (See 'Mechanism of action' above.)

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Topic 6796 Version 118.0

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