Maternal progesterone therapy may benefit neurodevelopment among fetuses with CHD, reveals JAMA study

In the randomized clinical trial (RCT) of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses indicate heterogeneity of the response to progesterone among congenital heart defect diagnosis and fetal sex.

Congenital heart defects, affecting approximately 1% of newborns globally, pose significant medical challenges, often requiring complex interventions and lifelong management. Beyond the cardiac implications, these defects have been associated with neurodevelopmental delays and disorders, raising concerns about cognitive and behavioral outcomes in affected children.

Neurodevelopmental outcomes for children with CHD have improved minimally over the past 20 years. J. William Gaynor, University of Pennsylvania, Philadelphia, and colleagues aimed to assess the tolerability and feasibility of maternal progesterone therapy and the magnitude of the effect on neurodevelopment for fetuses with CHD.

For this purpose, the researchers conducted a double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD between 2014 and 2021 at a quaternary care children’s hospital.

Participants included maternal-fetal dyads with CHD identification before the fetus' 28 weeks of gestational age and were likely to require surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included an extracardiac anomaly or major genetic than 22q11 deletion syndrome and known contraindication to progesterone.

Participants were block-randomized in a 1:1 ratio to vaginal progesterone or placebo by diagnosis: transposition of the great arteries (TGA), hypoplastic left heart syndrome (HLHS), and other CHD diagnoses. Twice daily treatment was administered between 28 and up to 39 weeks gestational age.

The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes were language and cognitive scales. Exploratory prespecified subgroups included fetal sex, cardiac diagnosis, maternal-fetal environment, and genetic profile.

The study led to the following findings:

• The 102 enrolled fetuses primarily had HLHS (50.9%) and TGA (37.3%), were more frequently male (65.7%), and without genetic anomalies (59.8%).
• The mean motor score differed by 2.5 units for progesterone compared with placebo, a value not statistically different from 0.
• Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis and fetal sex but not genetic profile or maternal-fetal environment.

"We recommend continued study into possible benefits of progesterone for a targeted subset of patients with congenital heart defects," the researchers concluded.

Reference:

Gaynor JW, Moldenhauer JS, Zullo EE, et al. Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(5):e2412291. doi:10.1001/jamanetworkopen.2024.12291