**8. Conclusions**

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

GDM women, independent of other risk factors [122].

by polyphenols that act as antioxidants [123–125].

**6.3 Regulatory microRNAs**

in the maternal plasma [127, 128].

the severity of pre-eclampsia [135].

**7. Insight from metformin**

hypermethylation at methylation variable positions in the placentas of women with pre-eclampsia or GDM, with dysregulation of metabolic pathways, signalling pathways and immune response pathways [112–120]. When interrogating global placental DNA methylation, a preliminary study showed a negative association between the degree of methylation and both pre-eclampsia and GDM [121]. However, a much larger study later found increased placental global DNA hypermethylation in

One driver for DNA hypermethylation in the placenta might be oxidative stress, since both pre-eclampsia and GDM are associated with increased oxidative stress and it has been shown in a T2DM rat model that this condition brings about global DNA hypermethylation in the liver, and that DNA hypermethylation can be reduced

The miRNA expression pattern in the placenta (predominantly in the trophoblast) changes throughout pregnancy due to the involvement of miRNAs in regulating different aspects of trophoblast biology [126]. Such changes are also detectable

A number of studies have identified over 100 differentially expressed miRNAs in the placenta or sera of women with pre-eclampsia compared to normotensive controls. Among these are miRNAs involved in cellular proliferation, cellular migration, inflammation, signal transduction, vascular remodelling and mitochondrial function [126, 129–134]. Increased plasma levels of miR-210 were associated with

The studies focusing on miRNAs in the sera of women with GDM are fewer as are the identified miRNAs (around 50 in total). The processes that seem to be mostly targeted by miRNAs in GDM are insulin/IGF1 signalling (IRS-1, IRS-2, SOS-1, MAPK-1, Insig1, PCK2), adipogenesis, endothelial function, inflammation (TGF-β signalling pathway), and energy balance (EGFR/PI3K/Akt/mTOR signalling pathway) [136–139]. Moreover, 9 miRNAs were found to be shared among T1D, T2DM and GDM, with an additional 19 miRNAs specific to GDM, indicating that GDM leads to changes that differ from those of the other forms of diabetes [140]. Interestingly, the histone methyltransferase enhancer of zester homologue 2

isoform beta (EZH2-β) has been linked to GDM via miRNA control [141].

Metformin (1,1-Dimethylbiguanide) is a small molecule that can readily cross the placental barrier [142]. It is the treatment of choice for GDM due to its efficacy and safety for the unborn child compared to insulin [143]. Metformin acts through the mitochondria, by inhibiting complex I of the electron transport chain, activating AMPK that controls cellular energy homeostasis and thus reduces gluconeogenesis and enhanced insulin suppression of endogenous glucose production by

Metformin was shown to be superior to insulin in reducing the frequency of gestational hypertension and possibly pre-eclampsia [145–147], by reducing ROS production, reducing endothelial dysfunction (by reducing sFlt-1 and sEng secretion regulated through the mitochondria), reducing inflammation (by reducing VCAM-1 mRNA expression induced by TNF–α), enhancing vasodilation and inducing angiogenesis [47, 148]. This suggests that there are similar perturbations in the cellular

energy balance of patients with pre-eclampsia and GDM.

**110**

the liver [144].

Much of the biochemical dysregulation that is common to both GDM and preeclampsia suggests overlapping pathophysiology (**Figure 1**). However, the available data does not clearly outline a common etiologic pathway, mainly due to limited analysis power to compare the different patient groups. Detailed evaluation of pre-pregnancy characteristics and clearer distinction between the different disease

statuses i.e. early- vs. late-onset pre-eclampsia and T1D, pre-existing T2DM, and GDM is required. To achieve this, prospective cohort studies need to be set up in which biochemical data is collected from women at pre-conception, at each trimester during pregnancy and post-partum (ideally with long-term follow-up). Gaining a better understanding of shared and separate pathophysiological pathways would help improve screening and treatment.
