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Progesterone therapy shows mixed results for neurodevelopment in infants with heart defects

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Progesterone therapy shows mixed results for neurodevelopment in infants with heart defects

Scientists at the University of Pennsylvania, USA, have conducted a randomized clinical trial to investigate the impact of maternal progesterone therapy on neurodevelopmental outcomes in infants with congenital heart defects.

A detailed trial report is published in JAMA Network Open.

Study: Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects. Image Credit: adriaticfoto / Shutterstock

Background

Children with congenital heart defects frequently experience substantial neurodevelopmental problems. Brain dysmaturity at birth, characterized by microcephaly, delayed white matter maturation, and simplified cortical folding, is a significant contributor to adverse neurodevelopmental outcomes.

Progesterone is a sex steroid hormone that plays a crucial role in brain development, including white matter maturation. Progesterone and its metabolites promote neural viability and regeneration, increase myelination, and induce maturation of progenitor cells to oligodendrocytes, in addition to exhibiting neuroprotective effects.

Vaginal progesterone therapy in women with preterm birth risk has been found to reduce neonatal mortality and brain injury. A reduced risk of preterm births and neonatal morbidities has also been observed in progesterone-treated women.

In this randomized clinical trial, scientists have assessed the impact of prenatal progesterone therapy on neurodevelopmental outcomes in fetuses with congenital heart defects.

Study design

This randomized controlled clinical trial was conducted at Children’s Hospital of Philadelphia on a total of 102 mothers who were carrying fetuses with congenital heart defects. The participants were randomly categorized into the intervention group and the control group.

The intervention group participants were vaginally administered with progesterone twice daily up to 39 weeks gestational age, starting from 8 weeks gestational age. A placebo drug was administered similarly to the control group participants.  

Infants born to progesterone-treated and placebo-treated mothers underwent neurodevelopmental and genetic evaluations at the age of 18 months. Different types of neurodevelopmental outcomes were assessed, including fine and gross motor abilities, language and cognitive abilities, and receptive and expressive communication abilities.

Important observations

The analysis of baseline characteristics revealed that about 50% of fetuses have hypoplastic left heart syndrome, 37% have transposition of the great arteries, and the rest have other types of congenital heart defects.

Full-term birth occurred in 57.7% of progesterone-exposed fetuses and 44% of placebo-exposed fetuses. About 60% of fetuses were without genetic anomalies.  

Neurodevelopmental evaluations indicated no significant differences in motor, cognitive, and language scores between the progesterone-exposed and placebo-exposed children. A sensitivity analysis considering different types of congenital heart defects and baseline confounders revealed similar neurodevelopmental outcomes.

A subgroup analysis considering cardiac diagnosis, fetal sex, presence of genetic anomalies, and maternal-fetal environment revealed possible heterogeneity of treatment effects for cardiac diagnosis and fetal sex but not for genetic anomalies and maternal-fetal environment.

Progesterone therapy was found to significantly improve motor scores in female children and those with other types of congenital heart defects than hypoplastic left heart syndrome and transposition of the great arteries. A significant improvement in language scores was also observed in progesterone-exposed female children.

Following progesterone treatment in children with hypoplastic left heart syndrome, a small and non-significant improvement in motor and language scores was observed. No positive effect of progesterone treatment on motor and language scores was observed in children with transposition of the great arteries.

In children with genetic anomalies, progesterone treatment was associated with worse cognitive scores compared to placebo treatment. No positive effect of progesterone treatment on male children was observed on cognitive scores. Language scores were worse in progesterone-exposed male children.

Adverse events

The rates of maternal and infant adverse outcomes were similar in both progesterone and placebo groups. Among eight children who died during the study period, seven had hypoplastic left heart syndrome, and one had transposition of the great arteries.

The 18-month mortality rate for hypoplastic left heart syndrome was 7.4% in the progesterone group and 20% in the placebo group.

Study significance

This randomized controlled clinical trial finds no significant beneficial effect of maternal progesterone therapy on neurodevelopmental outcomes in children with congenital heart defects.

A heterogeneity of the response to progesterone has been observed among children with different cardiac diagnoses as well as among male and female children. Overall, no significant adverse events related to vaginal progesterone therapy have been observed in mothers carrying a fetus with congenital heart defects.

Fetal sex determines placental structure and function and outcomes of pregnancy. In-utero adverse environment affects male fetuses more severely than female fetuses, leading to more severe developmental outcomes in male children. Observed benefits of progesterone therapy in female children could be attributed to these factors.        

Given these findings, scientists recommend that future randomized clinical trials should investigate the neuroprotective effects of vaginal progesterone therapy among a targeted subset of patients with congenital heart defects.

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