Comparison of Placental Vitamin D Receptor Target Gene Expression in Idiopathic Foetal Growth Restriction Pregnancy and Gestational Age-matched Healthy Controls: A Case-control Study

Introduction: Foetal Growth Restriction (FGR) is a common pregnancy complication that affects up to 10% of pregnancies and is associated with significant morbidity and mortality in the perinatal period and infancy. Despite extensive investigations, a definite etiology cannot be found in up to 70% of cases of FGR, which are termed idiopathic. One of the causative factors responsible for idiopathic FGR could be altered placental expression of Vitamin D Receptor (VDR) genes. Aim: To estimate placental VDR target gene expression in pregnancies affected by idiopathic FGR and to compare it with gestational age-matched healthy pregnant women. Materials and Methods: A case-control study was conducted in the Department of Obstetrics and Gynaecology, University College of Medical Sciences and GTB Hospital, New Delhi, India, from November 2019 to October 2021. All pregnant women ≥28 weeks gestation with FGR were evaluated to determine the etiology. Those with a negative work-up were defined as having idiopathic FGR (cases, n=30). Gestational age-matched healthy pregnant women were enrolled as controls (n=30). A maternal blood sample for Vitamin D levels was taken before delivery. After delivery, a small portion of the placenta was collected for Ribonucleic Acid (RNA) extraction to study the relative gene expression of VDR and the downstream target gene in the VDR pathway, Transforming Growth Factor Beta 3 (TGFβ3). Statistical tests used in the study included the Independent t-test and Analysis of Variance (ANOVA) for quantitative variables and the Chi-square test or Fisher’s exact test for qualitative variables. The Pearson’s correlation coefficient was used to correlate maternal Vitamin D level (ng/mL) with VDR messenger RNA (mRNA) expression fold change and TGFβ3 mRNA expression fold change. Univariate logistic regression was used to calculate the odds ratio. A p-value of <0.05 was considered significant. The software used for statistical analysis was Statistical Package for Social Sciences (SPSS) software version 21.0. Results: Both groups were comparable in demographic characteristics such as age, socio-economic status, parity and Body Mass Index (BMI). The mean value of maternal Vitamin D levels in idiopathic FGR was 15.73±7.65, compared to 20.01±5.27 in controls. The majority of the patients in our study had Vitamin D deficiency (<20 ng/mL), with 70% of cases and 60% of controls. The mean VDR mRNA Δct value in cases was higher compared to controls (5.09±0.86 vs. 4.53±1.03, p-value=0.027), implying reduced VDR mRNA gene expression in cases. The mean TGFβ3 mRNA Δct value was 8.11±1.81 in cases and 6.73±1.64 in controls (p-value=0.003), suggesting reduced TGFβ3 mRNA gene expression in cases. Maternal Vitamin D levels were not found to have any correlation with VDR mRNA and TGFβ3 mRNA expression (correlation coefficients 0.008 and 0.194, respectively). Conclusion: Women with idiopathic FGR had reduced placental VDR and TGFβ3 mRNA expression. However, no correlation was found with maternal Vitamin D levels, suggesting defects in the placental VDR pathway as an etiological factor in FGR.