Antenatal Corticosteroid Use Gets Boost From World Health Organization Study

The inexpensive drugs can be used in preterm labor to support a successful delivery

With Alan H. Jobe MD, PhD

Neonatal

It is estimated that at least 10% of babies born worldwide are premature, that is born before 37 weeks gestation. Preterm delivery along with low-birth weight are the major cause of neonatal deaths. The World Health Organization (WHO) believes that some of these deaths could be prevented by implementing simple steps, such as kangaroo mothering, as well as cord and skin hygiene. Tocolytics, to slow labor, and corticosteroids, to facilitate fetal lung development, are inexpensive drugs that can be used in preterm labor to support a successful delivery. In recent years though, the efficacy and safety of corticosteroids has been questioned.

Last month the New England Journal of Medicine published an article from 121 researchers comprising the WHO ACTION trial collaborators which investigated the use of antenatal corticosteroids (ACS) in pending preterm deliveries. Their primary outcomes were the number of neonatal deaths and frequency of maternal infection rates.

The recent WHO study was motivated by a previous one in 2015, which found an increase in both objects in deliveries during which corticosteroids were used. To be fair, the earlier study compared a multifaceted intervention approach which could have included ACS treatment verses a control approach. The type of approach was randomly assigned to medical clusters, not patients, and was dependent on reliable implementation of the assigned approach. It was not a specific assessment of ACS treatment. However, as these results threw into question the benefit of ACS, the WHO ACTION team initiated a patient-randomized, placebo-controlled study to better characterize the efficacy and safety of ACS treatment during imminent preterm labor.

The 2020 WHO ACS study design

Like the earlier study, this was a multinational trial enrolling mothers in low to mid-income regions. 2852 mothers were recruited across five countries and admitted into 29 different hospitals. The women were randomly assigned in a 1:1 ratio to either placebo or dexamethasone. Treatment followed the WHO criteria for ACS use in which a round of 6mg dexamethasone (IM) could be delivered every 12 hours with four doses max per round. Additional round could be used if labor continued. A standardized process of care was available to all patients, which included access to ultrasonography, CPAP machines, pulse oximeters, and glucometers.

Inclusion criteria were women with an anticipated delivery within 48 hours and a fetal gestation confirmed via ultrasonography between 26 weeks and under 34 weeks. Exclusion criteria included signs of infection, major fetal abnormalities, and current or recent use of corticosteroids or contraindication for use. The primary outcomes were neonatal death in the first 28 days. Because repeated corticosteroid dosing suppresses adrenal function, women in delivery are at greater risk of infection during this stressful time, thus maternal infection rates were also included. Secondary outcomes were 7-day neonatal death, frequency of respiratory distress syndrome (RDS), and process of care outcomes.  

The 2020 WHO ACS study results

There were 2823 live births which occurred in the course of the study. Neonatal death occurred in 19.6% of infants from the ACS group while 23.5% of infants passed in the placebo group, suggesting a lower relative risk of death in the dexamethasone group (RR= 0.84, CI 0.72-0.99, p=0.03). Maternal infection was also reduced in the dexamethasone group (RR= 0.76, CI 0.56-1.03, p=0.002) with only 4.8% of women showing signs of infection in the treated group compared to 6.3% in the placebo group.

The secondary outcomes continued to support the use of ACS. ACS treatment had fewer early deaths (<7 days post) compared to placebo births (15.4 vs 19.1%, RR= 0.81, CI 0.68-0.96). Incidence of RDS was lower 24 hours post-birth in the ACS group compared to the placebo group (3.0% vs 5.4%; RR= 0.56, CI 0.37-0.85). Major resuscitation and CPAP use was also less frequent in the babies from the ACS treated group (7.3% vs. 10.4% and 18.5% vs. 23.9% treated vs. placebo respectively). Similar results between ACS and placebo groups were found in the use of oxygen therapy (50.8% vs. 53.5%) and mechanical ventilation (6.5% vs. 8.1%).  The percent of infants with APGAR scores less than 7 were also similar (20.3% ACS vs. 21.4% placebo).

The authors concluded that the use of ACS in mothers experiencing imminent preterm-labor significantly reduced neonatal death, maternal infection, and generally had better process of care outcomes. This likely resulted in 4 infants saved per 100 preterm labors.

ACS use in practice

ACS use can vary widely by country. In 2014, a study by Vogel et al. found that only 16% of preterm pregnancies were treated with ACS in Afghanistan and in the Democratic Republic of Congo whereas in Jordan, 91% of preterm labors were given ACS. The use of both tocolytic drugs and ACS was less frequent with a global average use of only 18.1%.

A cross-sectional study from Palestine published in the journal Heliyon earlier this year investigated ACS use and the frequency of RDS in premature infants. Here, 64.1% of mothers in preterm labor were treated with ACS. Mothers treated with ACS were less likely to have their infant develop RDS. However, when gestational age and intrauterine growth restriction were controlled for, the relationship failed to reach significance. The authors concluded that ACS administration was not always compliant with the American College of Obstetricians and Gynecologists, and they suggest that it would be important to understand what factors hinder ACS treatment compliance in the health care setting particularly in variable resource locations.

ACS administration: Oral vs. IM

In the WHO study, and in many field applications, intramuscular injections (IM) of dexamethasone are used. We asked Alan H. Jobe MD, PhD, and Professor of Pediatrics at Cincinnati Children’s Hospital if there were pharmacokinetic (PK) or pharmacodynamics (PD) differences in ACS admintistration. He directed us to a recent publication from his group looking at ACS administration in non-pregnant women. This study compared PK and PD profiles of dexamethasone and betamethasone given IM (6.0 mg) or orally (0.5mg) following guidelines used for ACS.

For IM administration, there were minimal differences between dexamethasone and betamethasone in peak plasma concentrations (Cmax; 65.0 and 67.6 ng/mL respectively) or in time to peak plasma concentration (Tmax; 3.0 hours). In comparison, oral administration of either corticosteroid produced a higher plasma concentration (Cmax; 95.3 and 76.8 ng/mL dexamethasone and betamethasone respectively) in a shorter period of time (Tmax; 1.5 hours both).

The pharmacodynamics of dexamethasone and betamethasone, regardless of administration, produced similar effects on plasma glucose and slight differences on cortisol levels, with betamethasone having a longer suppressive effect (48 hrs vs 24 hrs). All treatments produced similar effects on cell counts of neutrophils, basophils, CD3CD4, and CD3CD8 lymphocytes. Rebound times were shorter for dexamethasone, both oral and IM, than betamethasone.

Taking this down to basics there is little difference in the PK or PD profiles of IM vs. oral drugs. In practice though, Dr. Jobe stated, “The advantages of oral corticosteroids in low resource environments is no injection, cost, stability and product quality.”

We reached out to Emily Willner, MD, Maternal Fetal Medicine Fellow in the Department of Obstetrics and Gynecology at the University of Colorado for her opinion on ACS in pre-mature labor. She told us, “Antenatal corticosteroids have consistently demonstrated improved outcomes in neonates born prematurely, both in resource-poor and resource-rich countries. While the theoretical risk of maternal infection has often limited corticosteroid use, the majority of data suggest maternal infection risk is not actually increased with a short course of corticosteroids for fetal benefit. In most clinical scenarios, the known benefit to the premature neonate of receiving antenatal corticosteroids far outweighs the theoretical risk of maternal infection.”

The authors declare no competing interests in the discussion of this topic.

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