The length of exposure time to low-dose steroids during pregnancy is key to determining their effectiveness in improving the outcomes of premature babies — a risk factor for cerebral palsy.
The study, “The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: Evidence from a sheep model of pregnancy,” was published in the American Journal of Obstetrics and Gynecology.
It is the result of a longstanding collaborative program based in Western Australia involving scientists from the Women and Infants Research Foundation in Australia, Cincinnati Children’s Hospital in Ohio, and Tohoku University Hospital in Japan.
Perterm births, those occurring before 37 weeks, are considered a risk factor for several conditions, including cerebral palsy.
“The lungs of extreme premature babies are often too structurally and functionally under-developed for the baby to breathe easily, and those born at the earliest gestational ages may suffer from severe and life-long problems such as cerebral palsy, developmental delay, or blindness,” Prof. John Newnham, the study’s author and scientific director of the Women and Infants Research Foundation, said in a press release.
Steroid therapy is among the most important and widely used strategies to improve outcomes for preterm infants but the therapy’s dosing regimens has not been optimized.
“The use of steroid therapy in pregnancy to rapidly mature the fetal lung, making breathing easier and safer for preterm babies, has been responsible for saving the lives of countless thousands of preterm babies,” said Matt Kemp, the study’s first author and an associate professor at the University of Western Australia.
“However, steroid use in pregnancy has never been optimized, meaning that since the 1970s a 50 kg [110 pound] woman early in pregnancy is given the same dose of steroids as a 100 kg [220 pound] woman close to term,” Kemp added.
Because steroids can affect several organs, there is concern that excess exposure may result in potential side effects in both the mother and her unborn baby, Newnham said.
Researchers hypothesized that once exposure to a low concentration of steroids by the mother and fetus is achieved and maintained, the duration of the treatment would determine the therapy’s effectiveness.
They used a sheep model of pregnancy to test their hypothesis and determine the relationship between steroid dose, duration of treatment, and treatment efficacy.
Ewes with single fetuses at 120 days gestation received a steroid dose (called betamethasone phosphate) administered intravenously followed by a maintenance infusion to reach three different concentrations of the steroid in the fetus — 20 ng/mL, 10 ng/mL, and 2 ng/mL — for 12 hours.
A low concentration of 2 ng/mL for an extended period (26 hours) was also studied.
Animals treated with an innocuous saline solution or with two intramuscular injections of 0.25 mg/kg of betamethasone phosphate were used as either negative or positive controls, respectively.
The lung maturation of the fetuses was measured as a readout for the effects of the different steroid regimens.
Lambs born from the 12-hour 2ng/mL betamethasone infusion group had little functional lung maturation, but those who reached the 2 ng/mL betamethasone concentration for 26 hours showed higher lung maturation — equivalent to that of the animals in the positive control group.
These findings suggest that it is the duration of the low-concentration steroid exposure, instead of high peak drug exposure, that determines the effectiveness of the steroid.
“Our study has shown, for the first time ever, that it may be possible to achieve maturation of the preterm lung equivalent to that given by current treatments using approximately 70 percent less drug,” Kemp said.
“Given the strong link between excess fetal steroid exposure and growth restriction, and the global use of this drug, these results have the potential to greatly impact the field of antenatal medicine,” he added.
Researchers also stressed the need to develop “a far-reaching optimized steroid dosing regimen that can improve both the efficacy and safety of antenatal steroid treatment.”
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