Description of the condition

The World Health Organization (WHO) defines preterm birth as birth before 37 weeks of gestation (WHO 2015) and this condition is associated with high neonatal morbidity and mortality. Prematurity is the main cause of perinatal mortality and morbidity in high‐income countries (Evans 1993; Goldenberg 2007). In 2013, preterm birth accounted for 16% of all perinatal mortality in Australia (AIHW 2015). Despite advances in medical technology, the primary cause of early neonatal death in preterm infants remains respiratory distress syndrome (RDS) as a consequence of immature lung development and surfactant insufficiency. With increasing gestational age, organ systems are more mature and this increases the survival rate (Doyle 2001; Saigal 2007). Preterm infants who survive the neonatal period are at increased risk of chronic disability, including but not limited to neurological disability and chronic pulmonary disease (Doyle 2001; Evans 1993). As preterm birth is associated with high mortality and long‐term adverse health impact compared with birth at term, this clearly signifies a prominent clinical as well as economic burden on healthcare resources (Goldenberg 2007; WHO 2015).

Description of the intervention

Single (Roberts 2017) or multiple (Crowther 2015) courses of antenatal corticosteroid in women at risk of preterm birth have been shown to reduce the incidence of RDS, as first described by Liggins 1972. Corticosteroid is a steroid hormone that acts by increasing protein and phospholipid synthesis, increasing levels of surfactant in the fetal lung and accelerating maturation of the fetal lung (Ballard 1995; Evans 1993). In addition to reducing the incidence of RDS, antenatal corticosteroid treatment prior to preterm birth has been shown to reduce the risk of perinatal death, neonatal death, intraventricular haemorrhage, infections, intensive care unit admission and developmental delay in childhood (Roberts 2017). These outcomes also depend on the gestational age of the pregnancy. Antenatal corticosteroids have become the standard of care for women at risk of preterm birth in many countries (Antenatal Corticosteroid Guidelines Panel 2015; Haram 2003; Jobe 2004; NIH 1995; WHO 2015).

However, the short‐ and long‐term safety profile of antenatal corticosteroid treatment is still debatable, especially in multiple corticosteroid administrations. Corticosteroids are known to inhibit cell growth and DNA replication. Animal studies have demonstrated that maternal corticosteroid administration at the minimal effective dose inhibits fetal growth, increases fetal blood pressure and perhaps modifies neurodevelopment (Fowden 1996; Jobe 1998; Moss 2003). The severity increases as the dose and number of administrations increase (Moss 2003). The known short‐term effects of antenatal corticosteroids in the fetus are decreased fetal breathing and movements, and a reduction in the amniotic fluid volume (Babovic 2009; Jackson 2003). Exposure to high levels of cortisol in a normally low fetal cortisol environment, in addition to other stress hormones produced with growth restriction, may have lifelong effects, leading to fetal programming for adult diseases, such as hypertension, insulin resistance, diabetes mellitus and metabolic syndrome (Benediktsson 1993; Dalziel 2005; Newnham 1999). Maternal administration of corticosteroid (orally, intramuscularly or intravascularly) not only affects the fetus but has the potential for negative maternal side effects, such as elevation of maternal blood pressure (Babovic 2009) and blood glucose concentrations, increasing susceptibility to sepsis (Evans 1993).

There remains variation in clinical practice on issues regarding the use of antenatal corticosteroids, including the type of corticosteroid to use, the dose and the optimal route of administration (Brownfoot 2013; Jobe 2004). The common route of administration is intramuscularly to the mother, with transplacental transfer to the fetus (Roberts 2017). Animal studies and early studies in pregnant women at risk of preterm birth have reported the use of an alternative route of administration, by direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance, in an attempt to minimise the side‐effect profile. These early studies indicate that direct fetal administration may be feasible in humans but further research still needs to be conducted (Moss 2003).

How the intervention might work

Direct fetal ultrasound‐guided injection of corticosteroid is believed to induce lung maturation of the preterm fetus, with different side‐effect profiles compared to indirect administration. The most important advantages of direct administration could include the avoidance of maternal toxicity and the metabolic side effects, as well as increasing the efficacy of bypassing the placenta and therefore inducing a more rapid fetal lung maturation (Evans 1993; Jobe 1993).

One of the first few animal studies of direct fetal corticosteroid treatment used ultrasound to deliver direct fetal injection of corticosteroid or saline control to 36 pregnant ewes. The preterm lambs were delivered at 128 days gestational age, to assess the postnatal lung function (Jobe 1993). The authors found that relative to the saline control group, corticosteroid given as a single injection 48 hours before birth resulted in a significant improvement in postnatal lung function (Jobe 1993).

Another animal study comparing direct fetal against maternal administration of corticosteroid showed that administration of repeated doses of corticosteroid directly to the fetus did not produce the growth restriction induced by maternal administration (Newnham 1999). There was no reduction in the fetal birthweight or weights of major organs, with the exception of the liver (Newnham 1999).

The first human study (a single‐arm trial) administered direct intramuscular fetal therapy to six women at risk of preterm birth (Ljubic 1999). In five cases, there was an uneventful outcome of fetuses, indicating that direct fetal corticosteroid treatment improved postnatal lung function in preterm fetuses. Another single‐arm trial involving 41 women at risk of preterm birth found that direct intramuscular fetal corticosteroid administration led to an increase in fetal breathing but no change in fetal movement and growth parameters (Babovic 2009).

In an animal study involving direct corticosteroid administration, higher corticosteroid peak concentrations were found in the fetal circulation compared with maternal intramuscular administration of the same dose (Moss 2003). However, the duration of maternal and fetal exposure to corticosteroid has been shown to be shorter after direct fetal injection (Babovic 2009). These differences in corticosteroid concentration and length of exposure are thought to lead to a reduced risk of growth retardation and other maternal and fetal complications (Moss 2003). Neurodevelopmental outcomes and long‐term effects on the risk of hypertension, diabetes and metabolic syndrome in relation to direct corticosteroid treatment are as yet unknown.

As an invasive procedure, direct fetal administration of corticosteroids carries additional risks which are not present with maternal administration. These risks are likely to be similar to those of amniocentesis, which carries a 1:1000 risk of intrauterine infection and 1:100 risk of pregnancy loss (RCOG 2010). In addition, there are potential risks of fetal injury, initiation of preterm labour (Newnham 1999), preterm prelabour rupture of membranes, placental abruption and maternal‐fetal haemorrhage (Gordon 2002).

Why it is important to do this review

Despite the major advances in medical technology, the incidence of preterm birth remains high. This could be due multiple factors such as increasing rates of multiple pregnancies, greater use of reproductive technologies, increases in maternal age and changes in clinical practice (Beck 2010). Preterm birth has significant impacts on maternal health, neonatal and childhood health, families and the economy (Goldenberg 2007; Saigal 2007). The introduction of the use of antenatal corticosteroid administered by intramuscular injection to women at risk of preterm birth has reduced the incidence of RDS and increased the survival rates of preterm infants. However, this intervention also comes with its own risks and side effects. There remains uncertainty about the type of corticosteroid to use and the optimal method of administration (Brownfoot 2013). Direct fetal corticosteroid administration may have benefits over maternal administration in terms of safety and efficacy. This review assesses the effects of direct corticosteroid administration to the preterm fetus, compared with maternal administration, using the best available evidence.