Elsevier

The Lancet

Volume 372, Issue 9656, 20 December 2008–2 January 2009, Pages 2143-2151
The Lancet

Articles
Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)61929-7Get rights and content

Summary

Background

One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. Weekly doses given to women who remain undelivered after a single course may have benefits (less respiratory morbidity) or cause harm (reduced growth in utero). We aimed to find out whether multiple courses of antenatal corticosteroids would reduce neonatal morbidity and mortality without adversely affecting fetal growth.

Methods

1858 women at 25–32 weeks' gestation who remained undelivered 14–21 days after an initial course of antenatal corticosteroids and continued to be at high risk of preterm birth were randomly assigned to multiple courses of antenatal corticosteroids (n=937) or placebo (n=921), every 14 days until week 33 or delivery, whichever came first. The primary outcome was a composite of perinatal or neonatal mortality, severe respiratory distress syndrome, intraventricular haemorrhage (grade III or IV), periventricular leucomalacia, bronchopulmonary dysplasia, or necrotising enterocolitis. Analysis was by intention to treat. All patients and caregivers were unaware of the treatment given. This trial is registered as number ISRCTN2654148.

Findings

Infants exposed to multiple courses of antenatal corticosteroids had similar morbidity and mortality to those exposed to placebo (150 [12·9%] vs 143 [12·5%]). Those receiving multiple doses of corticosteroids also weighed less at birth than those exposed to placebo (2216 g vs 2330 g, p=0·0026), were shorter (44·5 cm vs 45·4 cm, p<0·001), and had a smaller head circumference (31·1 cm vs 31·7 cm, p<0·001).

Interpretation

Multiple courses of antenatal corticosteroids, every 14 days, do not improve preterm-birth outcomes, and are associated with a decreased weight, length, and head circumference at birth. Therefore, this treatment schedule is not recommended.

Funding

Canadian Institutes of Health Research.

Introduction

Preterm birth is a worldwide health-care problem contributing greatly to neonatal morbidity and mortality. The administration of one course of antenatal corticosteroids to women who are at high risk of giving birth prematurely reduces the risk of neonatal mortality, respiratory distress syndrome, and intraventricular haemorrhage.1 However, women who receive one course may remain undelivered for weeks afterwards. Basic science and clinical research have suggested that the benefits of one course might diminish over time. Thus, multiple courses of corticosteroids every 7–14 days have been administered even before completion of randomised controlled trials.2, 3, 4, 5

Several trials have investigated the short-term benefits of weekly courses of antenatal corticosteroids versus placebo in women who had already received one course of corticosteroids.6, 7, 8 Overall, initial small trials showed no benefit.6, 8 However, the National Institutes of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units Network trial8 showed a trend towards improved composite outcome for infants who were exposed to weekly courses of antenatal corticosteroids born before 32 weeks' gestation (23% of infants on antenatal corticosteroids vs 39% on placebo, p=0·08). The Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS)7 enrolled 982 women and showed a benefit of weekly courses of antenatal corticosteroids. Fewer infants in the treatment group than in the placebo group had respiratory distress syndrome (33% vs 41%; relative risk [RR] 0·82 [95% CI 0·71–0·95], p=0·01) and severe lung disease (12% vs 20%; 0·60 [0·46–0·79], p=0·0003). A Cochrane systematic review, which included the results of these trials, suggested that weekly courses of antenatal corticosteroids are associated with reduced occurrence [0·82 (0·72–0·93)] and severity [0·60 (0·48–0·75)] of neonatal lung disease, and serious infant morbidity [0·79 (0·67–0·93)].9

However, multiple courses of antenatal corticosteroids may have adverse effects10, 11, 12, 13 such as decreased fetal growth.8, 14, 15 Such treatment might also have long-term adverse effects; indeed, adverse neurological outcomes have been shown in follow-up studies of children given dexamethasone after birth.16

Our aim was to see if a less frequent intervention (a course every 14 days in our trial vs every 7 days in other steroid trials) would show short-term respiratory benefits, and reduce to a minimum the risk of short-term and long-term adverse effects.

Section snippets

Participants

Multiple courses of antenatal corticosteroids for preterm birth study (MACS) is an international, multicentre, double-blind, randomised controlled trial. 1858 women between 25 and 32 weeks of gestation who remained undelivered 14–21 days after an initial course of antenatal corticosteroids (either betamethasone or dexamethasone) and continued to be at high risk of preterm birth (table 1) were enrolled in 80 centres in 20 countries. The study protocol was explained and consenting participants

Results

The figure shows the trial profile. Eight women (five from the antenatal corticosteroid group and 3 from the placebo group), whose one or more fetuses from a multiple gestation died in utero after 13 weeks but before randomisation, were randomly assigned. Live fetuses from these pregnancies were excluded from the analysis (five from the antenatal corticosteroid group and four from the placebo group). After intention-to-treat analysis, data from the eight women were obtained and included in the

Discussion

In MACS, after an initial course of antenatal corticosteroids, infants born to women who received multiple courses of treatment every 14 days had similar risk of morbidity and mortality to those who were born to women receiving placebo. These findings differ from those of the Australian trial ACTORDS7 in which women who received weekly courses of treatment showed short-term neonatal benefits over women receiving placebo. In MACS, the lack of improvement in respiratory morbidity might be due to

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