A Way Forward? Unknowns and Considerations

The lifesaving benefits of AGT mean this treatment is unlikely to become out of favour with obstetricians, despite the growing evidence for negative effects on the developing heart, brain and other organs and systems. However, it is clear that more basic research is needed to improve understanding of the effects of AGT, and to tailor current clinical practise to minimise the detrimental effects whilst maintaining the clinical benefits. Current estimates suggest that the number needed to treat with AGT to prevent one neonatal death is 798 at 34 weeks gestational age (Travers et al., 2017), hence there is still much room for improvement.

The current dose regimen used in clinical practise is based largely on the original clinical trials and is not adjusted for any maternal or fetal factors (e.g. maternal weight, age, twinning;

Ballard, 1995). Further, if a mother threatened with pre-term labour does not deliver within 7 days of receiving AGT, a repeat course may be given (FIGO committee report, 2019). There is no clear consensus on how many repeat courses should be given to maintain beneficial effects of AGT (Bonanno et al., 2007), and as early as 1996, 58% of responders to a US based survey answered they would give 6 or more courses if pre-term labour had still not occurred (Planer et al., 1996). RDS instance is slightly reduced by multiple courses (Crowther et al., 2015), and a rescue course has been shown to reduce neonatal morbidity (Garite et al., 2009).

However, there is growing concern about the more severe negative effects of repeat doses (Romejko-Wolniewicz et al., 2014). So much so, that in 2003, a second NIH Consensus panel advised against the use of repeated courses of AGT (Crane et al., 2003). There is also evidence from animal studies that significantly lower equivalent doses than those used in clinical

54 practise can achieve similar levels of lung maturation (Jobe et al., 2009). However, some clinical evidence of incomplete course of AGT have shown smaller benefits in preventing RDS when compared to neonates who completed a full course, although the partial course was still effective in reducing IVH and neonatal death (Chien et al., 2002). Further research is therefore clearly needed into the optimal dose, whether it should be adjusted for maternal factors, and how many courses could be given before the potential future detrimental effects outweigh the benefits.

There are also unanswered questions surrounding the correct method of drug administration.

Administering glucocorticoids to the mother rather than directly to the fetus has been reported to cause a more significant growth retardation (Jobe et al., 1998), likely as a result of additional detrimental effects of AGT on placental blood flow and function (Jellyman et al., 2004). However, fetal administration with synthetic glucocorticoids produced smaller improvements in postnatal lung function than with maternal administration despite higher fetal plasma glucocorticoid levels (Jobe & Soll, 2004). Intra-amniotic administration has been shown to be successful in maturing fetal lungs in the sheep and the monkey (Gilbert et al., 2001), but has a high associated morbidity making it potentially unsuitable for clinical use (Moss et al., 2003). Any potential route of fetal administration needs to be investigated thoroughly prior to introduction to clinical practise. It may also be unfeasible in low-income populations, or where obstetric care is less available. Another possibility for route of drug administration is to give AGT orally to the mother. The only clinical trial to use oral dexamethasone as an alternative to standard intra-muscular treatment was ceased after IVH

55 levels were found to be significantly increased in the oral compared to the intra-muscular administration group (Egerman et al., 1998).

Another impending unanswered question as to the optimum clinical treatment is the choice of glucocorticoid for AGT. The synthetic glucocorticoids that are mostly used are Dexamethasone and Betamethasone (Table.1.2; Jobe & Soll, 2004). Both drugs are synthetic analogues of endogenous cortisol, which can readily cross the placenta, with a substantially increased affinity for the GR. They also will not interact with the MR, or with inactivating enzyme 11βHSD2 (Buttgereit et al., 1999). Betamethasone was initially used by Liggins and Howie for the first clinical trials because the acetate formulation of the drug was thought to have a long plasma half-life (Liggins & Howie, 1972). Since then many trials have been conducted using either Dexamethasone or Betamethasone, with few directly comparing the two steroids. A comparison of meta-analyses by Jobe suggests that Betamethasone may be more effective in reducing IVH and death than Dexamethasone (Jobe & Soll, 2004), however this is only based on a small number of studies. Animal studies have also demonstrated that the acetate formulation of Betamethasone may be as effective at stimulating lung maturation as the combined phosphate and acetate formulation used in clinical practise (Jobe et al., 2009;

Schmidt et al., 2019). There clearly needs to be more research into the drug of choice, and formulation of that drug. The WHO currently only lists Dexamethasone as an essential medicine, largely due to it being both cheaper and more widely available than Betamethasone (WHO, 2015). However, the WHO highlighted this as an area in need of further research in their 2015 report on preterm birth outcomes, stating:

‘There is no conclusive evidence on the comparative efficacy of dexamethasone and betamethasone that would support a recommendation of one over the other.’

56 Table 1.2 Comparison of Dexamethasone and Betamethasone dosing regimens for AGT (WHO, 2012).

The lack of a clear consensus surrounding so many aspects of the clinical use of AGT has been reported by several public health bodies. The World Health Organisation (WHO) in 2015 (WHO, 2015) identified the following questions as priority research directions:

• What are the long-term outcomes of all infants exposed to antenatal corticosteroids (including term infants)?

• What are the effects of antenatal corticosteroid at different gestational ages at birth?

• What is the minimum effective dose of corticosteroids to achieve fetal lung maturation and other improved outcomes?

• What is the minimum dose required for repeat courses of antenatal corticosteroids?

• What are the most effective regimen and dose for antenatal corticosteroids?

Drug Dexamethasone Betamethasone

Formulation Phosphate 50:50 Phosphate/Acetate

Route of

Administration

Maternal intra-muscular injection

Maternal intra-muscular injection

Clinical Administration 4x6mg doses, 12hrs apart

2x12mg doses, 24hrs apart

Total Dose 24mg 24mg

MSP

57