Placental Progesterone Membrane Receptors in Fetal Growth Restriction

Expression of Progesterone Membrane Receptors in Placentas From Pregnancies Complicated by Intrauterine Growth Restriction: A Prospective Observational Case-Control Study

This prospective observational case-control study aims to compare placental expression levels of progesterone membrane receptors, including PGRMC1, PGRMC2, and PAQR family receptors, among pregnancies affected by impaired fetal growth and appropriately grown control pregnancies. Pregnancies with suspected impaired fetal growth were phenotypically classified before biomarker analyses according to the contemporary Delphi consensus and ISUOG diagnostic criteria into fetal growth restriction (FGR) and small for gestational age (SGA). Placental tissue samples obtained at delivery were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The final study cohort comprised 110 singleton pregnancies, including 48 FGR, 29 SGA, and 33 appropriately grown controls. The study also evaluated the association between progesterone membrane receptor expression and adverse perinatal outcomes.

Intrauterine growth restriction (IUGR) remains one of the leading causes of perinatal morbidity and mortality. Although placental insufficiency is considered the major underlying mechanism, the molecular pathways responsible for impaired fetal growth are not fully understood.

Progesterone is essential for maintaining pregnancy and exerts its biological effects through both classical nuclear receptors and membrane progesterone receptors. Among these, progesterone receptor membrane component-1 (PGRMC1), progesterone receptor membrane component-2 (PGRMC2), and members of the progestin and adipoQ receptor (PAQR) family have recently attracted attention because of their roles in placental development, angiogenesis, immune regulation, and maintenance of placental integrity.

The present study will prospectively recruit women diagnosed with IUGR and healthy pregnant women delivering at the same institution. Placental samples collected immediately after delivery will undergo molecular analysis using quantitative real-time PCR to determine receptor expression levels. Clinical and obstetric characteristics together with neonatal outcomes will be recorded prospectively.

The findings may contribute to a better understanding of the molecular mechanisms underlying placental dysfunction in IUGR and may identify potential biomarkers associated with adverse pregnancy outcomes.

This study was retrospectively registered in ClinicalTrials.gov (NCT07701837). At the time of protocol development, the term intrauterine growth restriction (IUGR) was used to describe pregnancies with suspected impaired fetal growth. Before biomarker analyses, all growth-impaired pregnancies were phenotypically reclassified according to the contemporary Delphi consensus definition and ISUOG Practice Guidelines into fetal growth restriction (FGR) or small for gestational age (SGA). Consecutive participant recruitment continued throughout the approved study period, resulting in a final cohort of 110 singleton pregnancies (48 FGR, 29 SGA, and 33 appropriately grown controls). Comparisons between the FGR and SGA phenotypes were performed as secondary, hypothesis-generating analyses. No changes were made to participant recruitment procedures, biospecimen collection, laboratory methods, or primary biomarker measurements following this phenotypic classification.

Inclusion Criteria:

FGR Group

• Pregnant women aged ≥18 years.
• Singleton pregnancy.
• Gestational age ≥24 weeks.
• Diagnosis of fetal growth restriction according to the Delphi consensus criteria (or your institutional protocol if that is what was used in the study).
• Planned delivery at the participating hospital.
• Written informed consent. SGA Group
• Pregnant women aged ≥18 years.
• Singleton pregnancy.
• Estimated fetal weight or birth weight <10th percentile without evidence of fetal growth restriction.
• Planned delivery at the participating hospital.
• Written informed consent Control Group
• Pregnant women aged ≥18 years.
• Singleton pregnancy.
• Appropriate-for-gestational-age fetus (birth weight between the 10th and 90th percentile).
• No maternal or fetal complications affecting fetal growth.
• Planned delivery at the participating hospital.
• Written informed consent.

Exclusion Criteria:

• Multiple pregnancy.
• Major fetal structural or chromosomal anomalies.
• Congenital fetal infection.
• Known genetic syndromes.
• Intrauterine fetal demise.
• Maternal malignancy.
• Chronic inflammatory or autoimmune disease.
• Refusal or inability to provide informed consent.
• Inadequate maternal blood or placental sample for analysis.