$4 million trial has the power to change the global administration of antenatal corticosteroids during pregnancy

Dr. Kellie Murphy, professor in the Department of Obstetrics and Gynaecology and maternal-fetal medicine subspecialist at Mount Sinai Hospital, has received a Canadian Institutes of Health Research (CIHR) grant for $4,004,776 to fund an international multicentre clinical trial investigating the effects of antenatal corticosteroids (ACS) routinely given to pregnant people when there’s a prediction their baby will be born preterm. The international trial, which was funded in July 2021, is planned to continue until May 2029. 

Globally, each year, 15 million babies are born preterm (before 37 weeks of pregnancy), including 1 in 12 in Canada. The standard care for pregnancies at risk of preterm birth involves two doses of antenatal corticosteroids. The intent of this intervention is to mature fetal lungs and decrease preterm infants’ short-term morbidity and mortality, but there are also risks inherent in this practice.  

“Synthetic glucocorticoids are administered prophylactically to pregnant individuals threatening preterm labour,” said Dr. Ted Brown, professor of obstetrics and gynaecology and expert in reproductive endocrinology. “While these drugs are necessary to promote lung maturation, studies indicate that they can negatively impact the long-term health of the offspring, particularly if the pregnancy is subsequently carried to term.” 

Antenatal corticosteroids were first trialled in 1972 to mature fetal lungs during vulnerable development. Over the last 50 years, 30 randomized controlled trials of ACS use in response to predicted preterm birth have used almost identical doses. 

There are limitations to the ability to accurately predict preterm birth. Of the infants who are exposed to steroids in utero as a precaution, approximately half are born at or close to term.  As a result, a majority of steroid-exposed infants incur risk but receive no benefit. 

“While maternal antenatal corticosteroid treatment can effectively promote lung development in babies born preterm, recent studies have associated corticosteroid exposure in pregnancy with mental and behavioural disorders in children,” said Dr. Stephen Matthews, professor of physiology and obstetrics and gynaecology. “As a scientist focused on the molecular actions of corticosteroids in the developing brain, I believe it critical to find a dose of corticosteroid that maximizes benefit to babies but minimizes potential long-term effects in the brain.” 

Dr. Murphy and co-principal investigator, Dr. Sarah McDonald, professor of obstetrics and gynaecology at McMaster University, aim to determine whether a single dose of antenatal corticosteroids (SNACS) is non-inferior to the standard double dose. This CIHR grant enables an international multi-centre double-blind non-inferiority randomized controlled trial of SNACS in 35 tertiary hospitals in Canada and Australia, with a target of 3,090 participants deemed to be at risk of preterm birth. Following the first dose of ACS, participants will be randomized to receive either a second dose of ACS or a placebo. 

“It is challenging to conduct a large randomized clinical trial as it requires a committed team, extensive time and vast resources, but the results hold the potential for great impact,” said Dr. Murphy. “We are very grateful to CIHR for giving the Canadian and Australian perinatal community the opportunity to answer this important question. SNACS not only has the potential to change our practice patterns nationally, but it is possible that its results will change practice patterns around the globe.”

The clinical trial builds on a previous randomized controlled trial led by Dr. Murphy in 2008, investigating multiple courses of antenatal corticosteroids (MACS) for preterm birth. The trial found that infants exposed to MACS had similar morbidity and mortality to those exposed to a placebo, but were also associated with a decreased weight, length, and head circumference at birth. 

“I am delighted that the visionary leadership of Dr. Murphy and Dr. McDonald, a graduate of our maternal-fetal medicine fellowship, has resulted in the successful CIHR funding and launch of this important trial,” said Dr. John Kingdom, professor and chair of the Department of Obstetrics and Gynaecology. “This collaborative partnership is a leading example of the importance of academic partnerships between the University of Toronto and our closest neighbour, McMaster University.” 

If the outcome of this eight-year study proves that one dose is non-inferior to two, while possibly reducing the unintended consequences of excess steroid exposure before birth, it will greatly simplify a practice that was first developed in the 1970s. This would potentially have an enormous impact on the accepted wisdom for obstetrical care around the world.