Antenatal administration of corticosteroids for women at risk of preterm birth
The administration of certain corticosteroids to women at risk of preterm birth causes a considerable reduction in the risks of complications of prematurity such as respiratory distress syndrome, intraventricular haemorrhage and perinatal death. Corticosteroid therapy should be incorporated into comprehensive maternal health care services and official guidelines for maternity care.
RHL Commentary by Hofmeyr GJ
Preterm birth is a leading cause of perinatal death and disability and is an important public health problem globally (1). Preterm birth occurs most commonly in economically disadvantaged communities and those with high rates of urinary and genital tract infection. The problem of preterm birth in under-resourced settings is compounded by a lack of neonatal health-care facilities and access to expensive interventions such as surfactant therapy. Information on the effectiveness of antenatal corticosteroids, a comparatively inexpensive intervention, is thus particularly relevant for these settings. This commentary covers three Cochrane reviews that sought to: (i) "assess the effects on fetal and neonatal morbidity and mortality, on maternal mortality and morbidity, and on the child in later life of administering corticosteroids to the mother before anticipated preterm birth" (2); "assess the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids" (3); and "assess the effects of different corticosteroid regimens for women at risk of preterm birth" (4).
All three Cochrane reviews used appropriate, standard Cochrane methodology, including a comprehensive search for trials, inclusion of trials according to predefined quality criteria, transparent data extraction and pre-specified analyses.
3.1 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth
This Cochrane review was updated in 2006, with the inclusion of 21 studies involving 3885 women and 4269 infants. The review found that the administration of certain corticosteroids to women at risk of preterm delivery produces a considerable reduction in the risks of complications of prematurity such as combined fetal and neonatal death, respiratory distress syndrome, cerebroventricular haemorrhage, necrotizing enterocolitis, systemic infections and childhood developmental delay. Benefits were found when treatment was commenced between 26 and 35 weeks of gestation, and for babies born 1–7 days after commencing treatment, and also for subsets of women with premature rupture of the membranes and with hypertensive disorders. Combined fetal and neonatal deaths were reduced even in infants born less than 24 hours after administration of the first dose.
No benefits were demonstrated for treatment commenced, or infants born, before 26 weeks of gestation, nor for those born more than seven days after treatment. For babies born after 36 weeks there was a trend to increase combined fetal and neonatal death.
Birth weight was reduced in infants born 1–7 days, and more than seven days after the first treatment. One trial that had recruited women with severe pre-eclampsia suggested that the treated women were at increased risk of gestational diabetes.
Evidence from epidemiological and animal studies suggests that there may be long-term adverse effects of prenatal corticosteroid exposure, including impaired glucose tolerance and hypertension. Animal studies have also suggested impairment of brain growth.
Follow-up of the offspring of one trial at age 30 years found an increase in insulin release in response to a 75-g glucose load, but no other morbidity.
Corticosteroid regimens shown to be effective include: betamethasone 12 mg intramuscularly, 2 doses 24 hours apart; or dexamethasone 6 mg intramuscularly 4 doses 12 hourly. Studies using methyl-prednisolone were excluded because this steroid has been shown to have altered placental transfer. The review found indirect evidence suggesting a greater reduction of respiratory distress syndrome with betamethasone than with dexamethasone treatment, and dexamethasone significantly increased the risk of puerperal sepsis (see iii below).
3.2 Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease
This review includes five trials involving 2028 women. In all five trials, which were of high methodological quality, repeat corticosteroid therapy was given to women who had received a single course of corticosteroids seven or more days previously. Four trials used two doses of betamethasone 12 mg and one used single doses, all repeated weekly. One or more repeat courses of corticosteroids were associated with reduced severe lung disease [relative risk (RR) 0.60; 95% confidence interval (CI) 0.48–0.75]; serious infant morbidity (RR 0.79; 95% CI 0.67–0.93). On the other hand, in one trial there was a reduction in birth weight Z score (RR −0.13, 95% CI −0.26–0.00) and in two trials there was an increased risk of being small for gestational age at birth (RR 1.63, 95% CI 1.12–2.37) No other outcomes were statistically significant. However, available data from the studies did not give the review sufficient statistical power to assess important rare outcomes such as perinatal/infant death (RR 0.53; 95% CI: 0.18–1.57). In one trial, in 160 women with preterm premature rupture of the membranes, there was no significant reduction in respiratory distress, and maternal chorioamnionitis was increased (RR 1.56, 95% CI 1.05–2.31). One trial reported data on a subgroup of women who receive four or more repeat courses of corticosteroids: birth weight was significantly reduced (WMD -161, 95% CI −291–−31). Benefits in terms of respiratory distress and evidence of growth impairment were seen both in trials with a single dose and those with two doses, all repeated weekly.
The authors conclude that, while there was evidence of short-term respiratory benefits from repeated courses of corticosteroids, there was insufficient evidence regarding the potential risks and long-term effects to justify the use of repeated doses of corticosteroids in clinical practice, and that further results were needed (several trials are continuing long-term follow-up).
3.3 Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth
This review, published in 2008, includes ten trials involving 1089 women and 1161 infants. The review found that dexamethasone decreased the incidence of intraventricular haemorrhage compared with betamethasone (RR 0.44, 95% CI 0.21–0.92; four trials, 549 infants). No statistically significant differences were seen for other primary outcomes, including respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular haemorrhage, periventricular leukomalacia, perinatal death, or mean birth weight. Results for biophysical parameters were inconsistent, but mostly no important differences were seen for those or any other secondary outcome except that, in one trial of 105 infants, significantly more infants in the dexamethasone group were admitted to a neonatal intensive care unit compared with the betamethasone group (RR 3.83, 95% CI 1.24–11.87).
Oral dexamethasone compared with intramuscular dexamethasone increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11–64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported. In one small trial of 69 infants, which had compared betamethasone acetate and phosphate with betamethasone phosphate, no differences were seen for any of the outcomes reported.
4.1. APPLICABILITY OF THE RESULTS
Most of the studies reviewed were conducted in industrialized countries. The risk of respiratory distress syndrome at specific gestational ages may differ in different settings. It may thus be necessary to use local data to identify gestational ages at which babies are at risk of respiratory distress syndrome or periventricular haemorrhage. There is no biological reason to expect that corticosteroid therapy will not be equally effective in all settings in improving the outcome for fetuses identified as at risk of respiratory distress and other complications of premature birth in different populations (personal opinion).
4.2. IMPLEMENTATION OF THE INTERVENTION
Corticosteroid therapy is relatively inexpensive. It is feasible to implement corticosteroid therapy at primary health-care level provided skilled health-care providers are available to identify women at risk of preterm birth and administer intramuscular injections. Given a reasonable health service infrastructure, no specific organizational changes are needed. Corticosteroid therapy should be incorporated into comprehensive maternal health-care services, and included in official guidelines for maternity care. Dexamethasone or betamethasone should be available in all maternity facilities and should be included in national essential drugs lists. Our experience in South Africa is that health-care providers have readily taken up the use of antenatal corticosteroid therapy, as is the case in other low-income countries such as Thailand (5).
The major barrier to implementation of corticosteroid therapy is the difficulty of identifying women at risk of preterm delivery in time to administer corticosteroids. This requires an effective and well-utilized antenatal service. Successful implementation of this intervention would involve: education of health-care providers regarding the effectiveness and implementation of corticosteroid therapy; introduction of protocols for its use; identification of women at risk, including effective antenatal screening for hypertension and proteinuria, as pre-eclampsia is an important cause of preterm delivery in low-income countries; and providing information to pregnant women. The information to pregnant women would need to focus on early reporting to a health facility at the first signs of pregnancy complications such as preterm uterine contractions, preterm rupture of membranes and symptoms of pre-eclampsia.
Current evidence supports the use of dexamethasone as the first choice of treatment: four 6-mg doses given 12-hourly. However, if dexamethosone is not available, betamethasone may be used: two 12- mg doses given 24-hourly.
4.3. IMPLICATIONS FOR RESEARCH
Further trials on the effectiveness of antenatal corticosteroid treatment are not justified. Research should instead be directed towards methods of achieving effective implementation of the intervention in different settings. Further research is also needed on the benefits and risks of repeated courses of corticosteroid therapy, and the optimal drug, dose and route of administration.
Sources of support: Eastern Cape Department of Health, Universities of the Witwatersrand and Fort Hare, South Africa; WHO Long-term Institutional Development Grant.
- Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. The Lancet 2007;371(9608):261–9.
- Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006; Issue 3. Art. No.: CD004454; DOI: 10.1002/14651858.CD004454.pub2.
- Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database of Systematic Reviews 2007; Issue 3. Art. No.: CD003935; DOI: 10.1002/14651858.CD003935.pub2.
- Brownfoot FC, Crowther CA, Middleton P. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2008; Issue 4. Art. No.: CD006764; DOI: 10.1002/14651858.CD006764.pub2.
- Saengwaree P, Liabsuetrakul T. Changing practice on corticosteroids. Journal of the Medical Association of Thailand 2005;88:307–13.
This document should be cited as: Hofmeyr GJ. Antenatal corticosteroids for women at risk of preterm birth: RHL commentary (last revised: 2 February 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.