Dr Fergus McCarthy takes a look at the news this month……

Falco et al performed a systematic review and meta-analysis examining placental histopathology associated with pre-eclampsia with the aim of quantifying the prevalence of placental histopathological lesions in pregnancies complicated by pre-eclampsia.¹ The authors searched MEDLINE, EMBASE and CINAHL and included prospective and retrospective case-control studies including ≥ 100 pregnancies. The incidence of each type of histological lesion according to the Perinatal Section of the Society for Pediatric Pathology classification in pre-eclamptic and normal pregnancies was identified, and lesions were categorized into two main groups: villous lesions and vascular lesions.

A total of eight studies (four blinded and four non-blinded) were included in the review. In unblinded studies, the pooled prevalence of villous lesions was 11.6% and 48.2% in normal and pre-eclamptic pregnancies, respectively, giving a pooled odds ratio (OR) of 7.59. In blinded studies, the pooled prevalence of villous lesions was 18.5% and 42.0% in normal and pre-eclamptic pregnancies, respectively, giving a pooled OR of 4.28. In unblinded studies, the pooled prevalence of vascular lesions was 8.1% and 37.3% in normal and pre-eclamptic pregnancies, respectively, giving a pooled OR of 20.34. In blinded studies, the pooled prevalence of vascular lesions was 9.8% and 38.9%, in normal and pre-eclamptic pregnancies, respectively, giving a pooled OR of 7.08.

Overall, in blinded studies, the incidence of both placental villous and vascular histopathological lesions was four- to seven-fold higher in pre-eclamptic than in normal pregnancies. Despite the higher probability (point prevalence) of finding abnormal placental pathology in pregnancies with pre-eclampsia, the placental lesions were not specific to the diagnosis of pre-eclampsia.

Stougaard et al presented their results from the D-tect study examining the association between extra vitamin D from fortification and the risk of pre-eclampsia.² The objective of the study was to examine if exposure to extra vitamin D from food fortification was associated with a decrease in the risk of pre-eclampsia.

The study was based on data from a natural experiment exploring the effect of the abolition of the Danish mandatory vitamin D fortification of margarine in 1985.

The effect of the extra vitamin D (1.25μg vitamin D/100 g margarine) was examined by comparing pre-eclampsia risk in women who have been exposed or unexposed to extra vitamin D from the fortified margarine during pregnancy, and who gave birth in the period from June 1983 to August 1988. The authors used data from the Danish National Patient Registry, which identified 73,237 women who gave birth during 1983-1988.

No association between exposure to vitamin D fortification during pregnancy and the risk of any of the pregnancy-related hypertensive disorders, including pre-eclampsia was demonstrated. The odds ratios (OR, 95%) for all hypertensive pregnancy-related disorders among exposed compared with unexposed women was (OR 1.04, 95%CI: 0.98,1.10). In conclusion, the extra vitamin D from the mandatory vitamin D fortification did not influence the risk of subsequently developing pre-eclampsia.

Finally this month, Kaitu’u-Lino et al examined the effects of combining metformin and esomeprazole on sFlt-1 secretion endothelial dysfunction.³ The anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury.

The authors examined whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (versus drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro.

Metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants, and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression.

Combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and esomeprazole may provide a more effective treatment or prevention for pre-eclampsia compared to either as single agents.

 

References

1. Falco ML, Sivanathan J, Laoreti A, Thilaganathan B, Khalil A. Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2017;50(3):295-301.
2. Stougaard M, Damm P, Frederiksen P, Jacobsen R, Heitmann BL. Extra vitamin D from fortification and the risk of preeclampsia: The D-tect Study. PloS one. 2018;13(1):e0191288.
3. Kaitu’u-Lino TJ, Brownfoot FC, Beard S, et al. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction – implications for treating preeclampsia. PloS one. 2018;13(2):e0188845.