Altered placental phenotype and increased risk of placental pathology in fetal spina bifida: a matched case-control study

Abstract

Open spina bifida (SB) remains one of the most common congenital anomalies and associates with significant comorbidities in the fetus, which may, in part, be driven by placental maldevelopment. We hypothesised that placental pathologies and maldevelopment would be more prevalent in fetuses with SB compared to fetuses without congenital anomalies. Placental histopathology (H&E-stained slides) and transcriptome (Clariom DTM microarray) were evaluated for fetuses with isolated open SB undergoing either pregnancy terminations or term deliveries (cases; n=12) and control fetuses without congenital anomalies having term or preterm births (n=22). Associations between study group and placental histopathology were adjusted for fetal sex and gestational age [GA] at delivery. Relationships between placental histopathology and select placental gene expression signatures were also evaluated. Case placentae had lower placental weight than controls (median [IQR]: 263g [175, 370] vs. 455 [378, 560], p=0.001). Placental villi structural phenotype was different in cases, who had a higher proportion of immature intermediate villi than controls (32.5% [6.3, 56.3] vs. 10% [5, 13.8], p=0.01), but similar proportions of mature intermediate (10% [5, 10] vs. 10% [8.75, 11.25]) and terminal villi (22.5% [11.3, 43.8] vs. 30 [20, 36.3]), and similar odds of having many syncytial knots (adjusted odds ratio [aOR]=6 [0.2, 369]) as full-term born controls. Cellular phenotypic differences in case placentae included higher odds of having many Hofbauer cells (aOR=16.2 [1.4, 580], p=0.02) and a thick syncytial membrane (aOR=146 [3, 3.46e5], p=0.007). Expression in gene pathways related to immune/inflammatory processes, spinal cord injury, and Hedgehog and Wnt signaling were associated with placental maturity in cases. This study is the first to characterize placental histopathology in a contemporary cohort of fetuses with SB. Improved knowledge on placental histopathological and genetic phenotypes in spina bifida increases our understanding of mechanisms that may drive comorbidities to ultimately reduce offspring morbidity and mortality.

Altered placental immune cell composition and gene expression with isolated fetal spina bifida

“…As immune dysregulation is one known contributor to the pathogenesis of NTDs, and in particular, folate‐resistant NTDs, 37 we hypothesized that HBC proliferation in cases may be a placental marker for an altered immune phenotype in the uterine environment. Indeed, the increase in HBC number in cases is consistent with findings from placental histopathology assessments in this cohort 17 and a historical cohort, 12 and appears to be driven by a largely CD80 – HBC population, which play important regulatory roles in placental immunomodulation 33,38 . Cases also had increased FRβ expression by HBCs, which may be an adaptive response to a villous microenvironment that is more “competitive” for folate resources, due to the high number of HBCs, or be required for an increase in HBC function.…”

“…Folate transporter expression in the placental syncytium was not altered in fetuses with SB, in a contemporary cohort from a region where folate deficiency is rare 36 . Collectively, our findings suggest that fetal SB may associate with an increase in HBC proliferation and function, which could be a mechanism contributing to placental villous maldevelopment observed in these fetuses 12,17 and provide further evidence in support of a role for immune dysregulation in NTDs 37 …”

“…21 Given that HBCs regulate placental angiogenesis, and changes in HBC number or polarization may alter angiogenesis, 33 an altered HBC phenotype may contribute to placental villous maldevelopment observed in these cases. 17 Future studies should consider a deeper phenotyping of the role of regulatory (M2) HBC subtypes (M2a, M2b, M2c, and M2d 38 ) in placental physiology in both healthy fetuses, and those with isolated SB, to better delineate how HBC composition may relate to placental villous maldevelopment in fetuses with isolated NTDs.…”

“…Importantly, as HBCs express FRβ , it is possible that beginning early in pregnancy, HBC level and function could be sensitive to changes in local folate bioavailability and/or metabolism. In assessments of placental histopathology from both historical (pre‐folic acid fortification/supplementation) and contemporary cohorts, 12,17 we have shown that fetuses with NTDs have increased HBC abundance. However, how HBC phenotype may be altered in fetuses with NTDs remains unknown.…”

“…It is plausible that a uterine environment permissive of NTDs may influence HBC phenotype and function, and that these changes could contribute to placental villous maldevelopment, as observed in these cases. 12,17 Folates are also actively transported to the fetus to support fetal growth and development through transmembrane transporters. 18 Folate uptake and transport across the placental syncytium is coordinated by folate receptor-α (FRα), proton coupled folate receptor (PCFT/heme carrier protein 1 [HCP1]), and reduced folate carrier (RFC).…”