Researchers at Children’s Hospital of Philadelphia (CHOP) discovered that placental malperfusion (PMP), a condition that disrupts blood flow in the placenta, is common in fetuses with congenital heart disease (CHD) and is linked to poor fetal growth, longer hospital stays and potentially increased mortality. Published today in the Journal of the American College of Cardiology, the study, led by Rebecca Josowitz, MD, PhD, also highlights that genetic changes in key pathways for placental and cardiac development may underlie PMP in CHD.
An adverse maternal-fetal environment, and especially abnormal placental development, is associated with an elevated risk of CHD development and adverse outcomes. Fetuses with CHD often have mothers experiencing higher rates of clinical PMP conditions like preeclampsia. Despite current understanding of the link between PMP and CHD, researchers are delving deeper to better understand how PMP exacerbates negative outcomes in fetuses with CHD and to investigate its mechanisms.
The retrospective study marks the first research paper from the Cardiac Center to utilize data from CHOP’s Birth Defects Biorepository. The Biorepository offers a sustainable resource for research into birth defect causes and outcomes, providing genomic and phenotypic datasets to enhance understanding of long-term outcomes and personalized medicine. It is one of the rare biorepositories to routinely collect and bank placental tissue.
In the study, researchers reviewed data from 299 CHD fetuses, comparing those with PMP to those without the condition. They found PMP in 51% of these fetuses. Non-syndromic fetuses with PMP had lower birth weight, shorter length and smaller head circumference compared to those without PMP.
The findings also revealed that PMP is associated with longer hospitalization and a trend towards increased mortality in CHD. CHD fetuses with PMP more often carry harmful de novo variants – spontaneous genetic changes not inherited from parents – that affect crucial placental and cardiac developmental pathways.
“Our study shows the importance of the prenatal environment in both short- and long-term outcomes in CHD. Understanding the genetic and developmental pathways responsible for the development of PMP could allow us to design therapies to improve placental function, ultimately improving fetal health and outcomes, particularly in cases of CHD,” said Josowitz, who is also an attending physician in the Cardiac Center at CHOP. “This is crucial for early diagnosis, personalized medicine and improved outcomes.”
Research is ongoing to determine which types of CHD might be most susceptible to the effects of PMP, and whether the mechanisms of PMP may differ by CHD type. Dr. Josowitz sees these insights as a foundation for driving research into new therapies to improve the prenatal environment in CHD, enhancing care and improving long-term outcomes.
The work was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001878), National Human Genome Research Institute (R01HG013355) and the National Heart Lung and Blood Institute (T32 HL007915-25).
Josowitz et al. “Placental Malperfusion is Associated with Adverse Outcomes in Congenital Heart Disease and With Genetic Variants in Placental Developmental Pathways.” JACC. November 3, 2025. DOI: 10.1016/j.jacc.2025.07.069.
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Researchers at Children’s Hospital of Philadelphia (CHOP) discovered that placental malperfusion (PMP), a condition that disrupts blood flow in the placenta, is common in fetuses with congenital heart disease (CHD) and is linked to poor fetal growth, longer hospital stays and potentially increased mortality. Published today in the Journal of the American College of Cardiology, the study, led by Rebecca Josowitz, MD, PhD, also highlights that genetic changes in key pathways for placental and cardiac development may underlie PMP in CHD.
An adverse maternal-fetal environment, and especially abnormal placental development, is associated with an elevated risk of CHD development and adverse outcomes. Fetuses with CHD often have mothers experiencing higher rates of clinical PMP conditions like preeclampsia. Despite current understanding of the link between PMP and CHD, researchers are delving deeper to better understand how PMP exacerbates negative outcomes in fetuses with CHD and to investigate its mechanisms.
The retrospective study marks the first research paper from the Cardiac Center to utilize data from CHOP’s Birth Defects Biorepository. The Biorepository offers a sustainable resource for research into birth defect causes and outcomes, providing genomic and phenotypic datasets to enhance understanding of long-term outcomes and personalized medicine. It is one of the rare biorepositories to routinely collect and bank placental tissue.
In the study, researchers reviewed data from 299 CHD fetuses, comparing those with PMP to those without the condition. They found PMP in 51% of these fetuses. Non-syndromic fetuses with PMP had lower birth weight, shorter length and smaller head circumference compared to those without PMP.
The findings also revealed that PMP is associated with longer hospitalization and a trend towards increased mortality in CHD. CHD fetuses with PMP more often carry harmful de novo variants – spontaneous genetic changes not inherited from parents – that affect crucial placental and cardiac developmental pathways.
“Our study shows the importance of the prenatal environment in both short- and long-term outcomes in CHD. Understanding the genetic and developmental pathways responsible for the development of PMP could allow us to design therapies to improve placental function, ultimately improving fetal health and outcomes, particularly in cases of CHD,” said Josowitz, who is also an attending physician in the Cardiac Center at CHOP. “This is crucial for early diagnosis, personalized medicine and improved outcomes.”
Research is ongoing to determine which types of CHD might be most susceptible to the effects of PMP, and whether the mechanisms of PMP may differ by CHD type. Dr. Josowitz sees these insights as a foundation for driving research into new therapies to improve the prenatal environment in CHD, enhancing care and improving long-term outcomes.
The work was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001878), National Human Genome Research Institute (R01HG013355) and the National Heart Lung and Blood Institute (T32 HL007915-25).
Josowitz et al. “Placental Malperfusion is Associated with Adverse Outcomes in Congenital Heart Disease and With Genetic Variants in Placental Developmental Pathways.” JACC. November 3, 2025. DOI: 10.1016/j.jacc.2025.07.069.
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