Efficacy and safety of antenatal steroids

Abstract

Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

The duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation

“…ACS reduce the risk of serious adverse prematurityassociated outcomes including neonatal death, respiratory distress syndrome and severe intraventricular haemorrhage 6,7 . Despite being used clinically for nearly 50 years, dosing to optimize benefit remains largely unexplored 6,[8][9][10] . A goal for ACS should be to minimize fetal exposure to decrease the potential for long term adverse effects such as growth restriction 11,12 , reduced academic ability 13 , elevated stress responses 14 , altered insulin responsiveness in the adult 15 , and possible epigenetic/ transgenerational effects 16 Using maternal infusions and the maternal intramuscular delayed release (acetate) form of betamethasone, we previously demonstrated in a sheep model that a low fetal plasma exposure in the range of 1-4 ng/mL betamethasone for 26 hours was sufficient to induce lung maturation at 2 days 17,18 .…”

Optimizing antenatal corticosteroid therapy

“…A large experimental literature in animal models from rodents to primates has shown adverse developmental, behavioral, and transgenerational effects of ACS. 10 ACS decrease birth weight by a small amount and may increase the risk of hypoglycemia in late preterm infants. 9 A significant concern with fetal exposure to ACS is the potential for adverse cardiovascular and metabolic effects in later life.…”

“…Since Liggins' original work with corticosteroid infusions in sheep, researchers have utilized multiple animal models to verify the maturational effects of ACS, including rodents, sheep, and primates. 10 Liggins and Howie demonstrated that a continuous fetal exposure of corticosteroids induced lung maturation. 5 However, clinical dosing with betamethasone phosphate (including as a combined preparation of betamethasone phosphate and acetate) or dexamethasone phosphate results in high early maternal blood levels because the drugs are rapidly dephosphorylated to betamethasone or dexamethasone, respectively, which in turn cross the placenta to expose the fetus to high peak drug levels that then decrease over hours to low levels.…”

Antenatal dexamethasone treatment transiently alters diastolic function in the mouse fetal heart

“…A great deal is known about the maturational effects that endogenous as well as exogenous glucocorticoids have on the lungs (Bird et al 2015, Roberts et al 2017). However, the role of glucocorticoids in the maturation of other fetal organs has not been well characterised and concerns have been raised that non-optimal antental glucocorticoid therapy might increase adverse outcomes, including perinatal death (reviewed in Kemp et al 2018). The effects of endogenous glucocorticoids upon fetal heart maturation were, until recently, unclear.…”