Mortality reduction in preterm births in low resource settings – What is the place of antenatal corticosteroid therapy?

Introduction

Worldwide, almost 10% of births are preterm, causing more than a third of all neonatal deaths per year, in total almost one million.¹ Prevention of preterm birth is difficult, and emphasis is put on premature baby care and management of premature labour. Antenatal corticosteroid therapy for foetal pulmonary maturation could have a significant impact on neonatal survival by reducing complications of prematurity. Labour is postponed for two days while maternally administered corticosteroids trigger foetal lung maturation. In the most recent systematic review, there was a 34% reduction of respiratory distress syndrome, a 46% reduction of intraventricular haemorrhage and a 31% reduction in neonatal mortality.² The use of corticosteroids is incorporated in many guidelines worldwide, but most studies have been done in a high-resource setting.

A review of the use of antenatal corticosteroids in several middle-income countries showed a neonatal mortality reduction of 53%, and the effect in low-income countries might be even greater.³ However, some doubts have been voiced regarding the effectiveness of corticosteroid therapy in a low-resource setting, and these doubts were strengthened when in 2015 the results of an antenatal corticosteroid trial was published in The Lancet by Althabe et al.⁴ This population-based, multi-country study did not show a positive effect in the preterm infants group, even though nearly half of them received therapy. The results prompted the World Health Organization (WHO) to recommend that the following four conditions be met before antenatal corticosteroid administration is considered for women at risk of preterm delivery between 24-34 weeks of gestation: (a) gestastional age is accurately assessed, (b) preterm birth is imminent, (c) there is no evidence of infection, and (d) adequate childbirth care and care for the preterm neonate are available.⁵

In this review, we will discus what factors can explain the above findings and what place there might be for corticosteroid therapy in a low-resource setting.

Possible reasons for differences in effect between high- and low-income countries

The clinical trial reported by Althabe et al. does not identify the reason for the adverse effects of antenatal corticosteroids. However, three different reasons for increased risk and lower effectiveness of antenatal corticosteroids in low-income countries can be assumed.⁶,⁷,⁸

(1) Suboptimal administration of antenatal corticosteroids. Uncertainty about gestational age is the main challenge in selecting patients for therapy. In a setting of late booking, unreliable history of last menstrual period and absence of ultrasound facilities, it is difficult to identify women who are at risk for preterm delivery and eligible for corticosteroid administration. In the trial, only 16% of pregnant women who received corticosteroids delivered a preterm infant (using birth weight as a proxy for gestational age). Not only will this dilute any positive effects of therapy, but women and babies are also exposed to the risk of corticosteroids without the benefits.

In low-resource settings, it can also be more difficult to identify women with imminent preterm birth, as few women present with preterm labour. Without symptoms of preterm labour, women might deliver at home or arrive in the hospital too late to start tocolytics. In the large trial, the most common indication (77%) for corticosteroid therapy was preterm labour, and 70% of women completed the therapy.⁴ Ultimately, more than half of the women who received treatment delivered at term. Since few women present at hospitals with premature labour, antenatal corticosteroids are mostly given to women with severe maternal disease requiring preterm termination of pregnancy, almost always severe hypertensive disorder. Although in Western countries the evidence and benefits for this type of treatment are clear, the considerations may be different in a low resource setting, since the risks are different. Antenatal corticosteroid therapy requires postponing delivery, but women with severe diseases who are at risk cannot always be monitored and treated adequately.

(2) Increased risk of corticosteroids use. As an unintended side-effect, corticosteroids increase the susceptibility to infection and decrease the immune function.⁹ This can explain the higher rate of suspected infection in the trial by Althabe et al. In low-income countries, the infectious disease burden is higher and the level of antisepsis lower. Sepsis is one of the main causes of foetal and maternal mortality, and therefore administering corticosteroids is potentially dangerous.

(3) Limited possibility for adequate preterm birth care and postnatal care. In settings with overburdened and understaffed labour wards and limited possibilities for maternal and foetal monitoring, infection and foetal distress can go undetected. Keeping the foetus in this situation without the ability to check its condition can lead to undetected foetal distress and eventually death. Causes of neonatal mortality of preterm infants in resource-limited settings include hypothermia, hypoglycaemia, birth asphyxia, infection and respiratory issues. Addressing only the latter cause when the others can not be managed adequately has been called ‘useless’.¹⁰

The trial by Althabe et al. is not necessarily applicable to all hospitals. The WHO has issued general precautions that would need to be considered before starting antenatal corticosteroid treatment. These seem logical in view of the considerations above, but the preconditions are not very specific and the relative importance of each precondition is not known. Corticosteroids have the potential of reducing neonatal morbidity and mortality when used properly. Further studies can hopefully make it clear under which circumstances antenatal corticosteroid therapy can be used in low-income countries.

Conclusion

Adverse effects of antenatel corticosteroid therapy are more prominent in low-income countries. Reliability of gestational age estimation, epidemiology of preterm birth, exposure to infections, foetal monitoring and quality of neonatal care are likely to influence the effect of corticosteroids, but it is unclear what the exact preconditions are for corticosteroid therapy to be effective and safe. Further studies and audits are needed to determine in which settings and under which circumstances corticosteroids are safe for both mothers and their unborn babies. Until then, the WHO precautions seem reasonable.

References

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