Dr Fergus McCarthy takes a monthly look at articles just published in the area of hypertension & pre-eclampsia…

In their work, published in Circulation this month, Zadora et al examine whether disturbances in gene imprinting contribute to the pathophysiology of pre-eclampsia.¹  The authors firstly generated and analysed genome-wide molecular data on well-characterised patient material. They then performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with pre-eclampsia. This allowed them to identify differentially expressed genes in pre-eclamptic placentas which were then intersected with the list of human imprinted genes allowing them to predict biological processes affected in pre-eclampsia. They then established an in vitro invasion-differentiation trophoblast model. Their comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis.

They demonstrated disturbed placental imprinting in pre-eclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status. These candidates had no prior association with pre-eclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of pre-eclamptic placentas. DLX5 is expressed in human but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of pre-eclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation.

This exciting body of work provides evidence of an association among disturbed imprinting, gene expression, and pre-eclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation.

In contrast to this genetic basic science work, Bellizzi et al examined the potential associations between hypertensive disorders of pregnancy and congenital malformations.² The authors estimated the country incidence of congenital malformations estimated using data on the 310,401 livebirths of the WHO Multicountry Survey which reported information from 359 facilities across 29 countries. A random-effect logistic regression model was utilised to explore the associations between six broad categories of congenital malformations and the four maternal hypertensive disorders “Chronic Hypertension”, “Pre-eclampsia” and “Eclampsia” and “Chronic hypertension with superimposed pre-eclampsia”.

The authors demonstrated that the occupied territories of Palestine presented the highest rates in all groups of malformation except for the “Lip/Cleft/Palate” category. Newborns of women with chronic maternal hypertension were associated with a 3.7 (95 % CI 1.3-10.7), 3.9 (95 % CI 1.7-9.0) and 4.2 (95 % CI 1.5-11.6) times increase in odds of renal, limb and lip/cleft/palate malformations respectively. Chronic hypertension with superimposed pre-eclampsia was associated with a 4.3 (95 % CI 1.3-14.4), 8.7 (95 % CI 2.5-30.2), 7.1 (95 % CI 2.1-23.5) and 8.2 (95 % CI 2.0-34.3) times increase in odds of neural tube/central nervous system, renal, limb and Lip/Cleft/Palate malformations.

This study demonstrated that chronic hypertension in the maternal period exposes newborns to a significant risk of developing renal, limb and lip/cleft/palate congenital malformations, and the risk is further exacerbated by superimposing pre-eclampsia. Additional research is needed to identify shared pathways of maternal hypertensive disorders and congenital malformations and to examine ethnic disparities.

Finally, Bergman et al examined the long term neurological sequelae following pregnancy complicated by pre-eclampsia. Levels of the cerebral biomarkers neuron-specific enolase (NSE) and S100B have previously been shown to be elevated during pregnancy in women developing pre-eclampsia. This study compared levels of S100B and NSE during pregnancy and 1 year postpartum in women who have had pre-eclampsia to women with normal pregnancies.³

The authors conducted a case control study which longitudinally studied cases (n = 53) with pre-eclampsia and controls (n = 58) consisted of normal pregnant women in matched gestational weeks. Plasma samples were collected at inclusion during pregnancy and 1 year postpartum. Plasma samples were analysed for levels of S100B and NSE by enzyme-linked immunosorbent assays kits.

Levels of NSE and S100B in women with pre-eclampsia were higher during pregnancy than in women with normal pregnancies. One year postpartum, women who have had pre-eclampsia still had a higher median level of both NSE (5.07 vs. 4.28 µg/l, P < 0.05) and S100B (0.07 vs. 0.06 µg/l, P < 0.05) compared to women with previous normal pregnancies. High levels of NSE and S100B postpartum remained associated with previous pre-eclampsia after adjustment for confounding factors. Levels of NSE correlated to S100B during pregnancy and postpartum.

The implications clinically of these findings regarding long term maternal health remains unclear. Nonetheless, this study provides interesting evidence supporting acute and chronic cerebral involvement in pre-eclampsia.

 

References

1. Zadora J, Singh M, Herse F, et al. Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. Circulation. 2017;136(19):1824-1839.
2. Bellizzi S, Ali MM, Abalos E, et al. Are hypertensive disorders in pregnancy associated with congenital malformations in offspring? Evidence from the WHO Multicountry cross sectional survey on maternal and newborn health. BMC pregnancy and childbirth. 2016;16(1):198.
3. Bergman L, Akerud H, Wikstrom AK, Larsson M, Naessen T, Akhter T. Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum. Am J Hypertens. 2016;29(12):1374-1379.