Clinical Opinion
Antenatal corticosteroids: an assessment of anticipated benefits and potential risks

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Antenatal corticosteroids are standard of care for pregnancies at risk of preterm delivery between 24-34 weeks’ gestational age. Recent trials demonstrate modest benefits from antenatal corticosteroids for late preterm and elective cesarean deliveries, and antenatal corticosteroids for periviable deliveries should be considered with family discussion. However, many women with threatened preterm deliveries receive antenatal corticosteroids but do not deliver until >34 weeks or at term. The net effect is that a substantial fraction of the delivery population will be exposed to antenatal corticosteroids. There are gaps in accurate assessments of benefits of antenatal corticosteroids because the randomized controlled trials were performed prior to about 1990 in pregnancies generally >28 weeks. The care practices for the mother and infant survival were different than today. The randomized controlled trial data also do not strongly support the optimal interval from antenatal corticosteroid treatment to delivery of 1-7 days. Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies treated with antenatal corticosteroids probably overestimate the benefits of antenatal corticosteroids. Although most of the prematurity-associated mortality is in low-resource environments, the efficacy and safety of antenatal corticosteroids in those environments remain to be evaluated. The short-term benefits of antenatal corticosteroids for high-risk pregnancies in high-resource environments certainly justify antenatal corticosteroids as few risks have been identified over many years. However, cardiovascular and metabolic abnormalities have been identified in large animal models and cohorts of children exposed to antenatal corticosteroids that are consistent with fetal programming for adult diseases. These late effects of antenatal corticosteroids suggest caution for the expanded use of antenatal corticosteroids beyond at-risk pregnancies at 24-34 weeks. A way forward is to develop noninvasive fetal assessments to identify pregnancies across a wider gestational age that could benefit from antenatal corticosteroids.

Section snippets

Standard of care for ACS

Since the 1994 Consensus Conference recommendations,1 the standard of care for the use of ACS in the United States and, with small variations, in the rest of the high medical–resource world has been the treatment of virtually all 24-34 weeks’ gestation pregnancies at risk of preterm delivery within 1-7 days after initiation of treatment.2 A single course of two 12-mg doses of a 1:1 mixture of betamethasone (Beta)-phosphate (P) and Beta-acetate (Ac) separated by 24 hours or four 6-mg doses of

ACS for 24-28 weeks’ pregnancies

During studies of the mechanisms of labor in sheep, Liggins7 recognized that fetal subjects exposed to ACS caused early lung maturation in 1969. Liggins and Howie8 completed the RCT report in 1972 demonstrating the benefits of ACS. The logo of the Cochrane Systematic Reviews is a forest plot of 7 RCTs from the initial meta-analysis by Crowley4 in 1995. In all, 21 RCTs of 4269 infants were included in the 2006 meta-analysis.5 The majority of the trials were completed prior to 1990, and only

Interval from treatment to benefit

Liggins and Howie8 reported in 1972 that ACS did not decrease RDS for deliveries <24 or 48 hours after initiation of treatment or for a treatment to delivery interval >7 days. While many subsequent trials did not evaluate the treatment to delivery interval for benefit, information from 9 trials was compiled in the Roberts and Dalziel5 2006 meta-analysis to support a 24-hour to 7-day benefit interval for decreased RDS. A secondary analysis of the same trials by the WHO in 2015 identified that

Expanding use of ACS: periviable pregnancies

Routine use of ACS for pregnancies at risk of preterm delivery for gestations between 24-34 weeks is being expanded by new clinical trials that potentially could include a majority of deliveries. A NICHD workshop in 2004 evaluated the possible benefits of ACS for periviable pregnancies at risk for delivery >20-week gestations.27 The Obstetric Care Consensus no. 6 for 2017 defined periviable as 200-256 weeks and recommended consideration of ACS in discussion with the family.28 The reality on the

Expanding use of ACS: 34- to 37-week gestation

Concurrently with the 1994 National Institutes of Health (NIH) Consensus Conference, Sinclair32 demonstrated with RCT data that ACS probably decreased RDS for late preterm gestations but with a number needed to treat of about 94 at 34 weeks’ gestational age. Based on the limited information available at the time the upper gestational age for use of ACS was proposed as 32 or 34 weeks. However, the incidence of both RDS and transient tachypnea increase as gestational age at deliveries decrease

Expanding use of ACS: elective cesarean delivery at term

Infants born by cesarean delivery without labor have more respiratory symptoms and neonatal adaptation problems than infants born vaginally or with labor prior to cesarean delivery.40 Stutchfield et al41 hypothesized that ACS initiated 48 hours before elective cesarean delivery could decrease these neonatal transition abnormalities. They demonstrated that ACS decreased neonatal intensive care unit admission and qualitatively decreased respiratory findings, effects that decreased as gestation at

Deliveries after the treatment to benefit interval

The (presumed) window of efficacy for ACS exposures is 1-7 days. Deliveries >7 days after ACS may not benefit and may be at increased risk. We define these deliveries >7 days as off-target. Deliveries at <24 hours after treatment may benefit from ACS and should not be considered off-target. For previable pregnancies identified as being at risk, many deliveries may occur weeks beyond the previable window and thus ACS treatments will be off-target. The successful application of standard of care

ACS in low-resource environments

In contrast to the effective use of ACS for at-risk pregnancies in high medical–resource environments, their use is extremely variable in low- and middle-income countries. Generally, the therapy is only available in the few medical facilities that can provide higher levels of care.50 Nevertheless, the promotion of ACS use is the number 1 of 10 recommendations by the WHO to decrease the prematurity-related mortality and morbidity in low-resource environments.3 Prematurity-related mortality is

Benefits of ACS

The primary benefits of ACS historically were a decrease in RDS and mortality. But the pleotropic effects of ACS on the developing fetus also decreased other severe pathologies in premature infants, including IVH, necrotizing enterocolitis, and postnatal sepsis. The magnitudes of the benefits were well calibrated for the populations included in the RCT trials prior to 1994.5 However, the target treatment population of 24-to 34-week gestation pregnancies at risk now include more extremely

Risks of ACS

Concerns about ACS can be divided into short-term adverse effects, early childhood effects, and very long-term fetal/neonatal programming within the context of the developmental origins of health and disease. For late preterm pregnancies, ACS increase the risk of hypoglycemia in newborns.34 Further, women with a low BMI given ACS have more severe and more prolonged hyperglycemia than women with a high BMI.54 Infants born in low-resource environments from women with low BMI may be at substantial

Repeat ACS treatments

An initial ACS treatment decreased RDS by about 35%, but many patients thought to be at risk for delivery within 7 days of treatment do not deliver and are considered to be still at risk of delivery <34 weeks’ gestational age. With concerns of increased respiratory morbidity for deliveries >7 days, the controversial practice of retreatment ≥1 times at 7- to 14-day intervals became common practice resulting in a second NIH-sponsored consensus conference in 2000 to assess repeated treatments.101

Drugs, doses, and treatment interval

Most trials have evaluated the mixture of 2 prodrugs: Beta-P, which is soluble and rapidly dephosphorylated to Beta; and the milled form of Beta-Ac, which is slowly deacetylated to Beta. Beta is the drug that crosses the placenta to produce fetal effects. Dosing has been as 12 mg of Beta-P + Beta-Ac given at recognition of a risk of preterm delivery and a second 12-mg dose 24 hours later. This treatment has been the most tested drug in RCTs of single doses and was used exclusively for RCTs of

The knowns and unknowns about ACS

Our perspective on the benefits of ACS is tempered by the current trends to view ACS as both safe and effective for more low-risk pregnancies. In the extreme, the pregnant population that would not receive ACS would be only term nonelective cesarean deliveries and term normal vaginal deliveries not associated with abnormalities earlier in pregnancy (Table 2). Kaempf and Suresh38 recently used the framework of the knowns and unknowns for a discussion of the benefits and risks of ACS (Figure 2).

Ways forward for ACS

We must accept that clinical decision making for ACS is imperfect because risks to benefits change with gestational age and the potential for the life-changing risks from programming are essentially unknown in the human. High-risk patients certainly benefit and the accepted gestational age for treatment are for deliveries at 24-34 weeks. Treatments at earlier or later gestations are less secure as to benefits or risks, and parents need to be aware of the uncertainties. Better targeting of

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    Dr Jobe was supported in part by the Bill and Melinda Gates Foundation.

    The authors report no conflict of interest.

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