**1. Pathophysiology of pre-eclampsia and gestational diabetes mellitus**

Pre-eclampsia is a multisystem, pregnancy-specific disorder, presenting newonset hypertension and proteinuria after 20 weeks of gestation. It is a leading cause of maternal and foetal morbidity and mortality, with delivery being the only known cure. Pre-eclampsia complicates 2–5% of pregnancies in Europe and America and can reach up to 10% of pregnancies in developing countries [1].

Pre-eclampsia is characterised by a first, asymptomatic stage involving impaired trophoblastic penetration of the decidua (both into the superficial myometrium at 14–16 weeks and into the deep myometrium at 18–20 weeks), limiting the remodelling of the maternal uterine spiral arteries for uteroplacental blood perfusion and producing local placental hypoxia and oxidative stress, which consequently leads to insufficient blood perfusion, inflammation, apoptosis, and structural damage. In the second stage, placental factors released into the maternal circulation from the poorly perfused placenta, together with the aberrant expression of pro-inflammatory, anti-angiogenic, and angiogenic factors, eventually cause the endothelial dysfunction that leads to the main clinical symptoms of pre-eclampsia [1].

This disorder can have an early onset (before 34 weeks of gestation) or a late onset (after 34 weeks of gestation), with the placentas of women with early onset pre-eclampsia presenting hypoplasia (small placental size) and a significantly higher number of placental vascular lesions compared to those with late onset PE, which present hyperplasia (increased placental size) and histological evidence of placental inflammation, with absence of vascular insufficiency, suggesting that pre-eclampsia might be more than a single condition [2].

Gestational diabetes mellitus (GDM) is defined as hyperglycemia that is first diagnosed during pregnancy. This definition of GDM does not preclude the possible existence of unrecognised pre-pregnancy diabetes. The prevalence of GDM ranges from 2 to 10% of all pregnancies in developed countries [3] and is associated with birth complications, including macrosomia and operative delivery. GDM develops from a dysfunction of the pancreatic Beta cells such that the insulin supply is inadequate to meet tissue demands for normal blood glucose regulation. This insulin resistance leads to increased levels of glucose production and free fatty acids, with subsequent increased blood glucose levels [4].

All forms of diabetes (GDM, type 1 diabetes - T1D and type 2 diabetes mellitus - T2DM) increase the risk of pre-eclampsia, with GDM being an independent risk factor for the development of pre-eclampsia [5, 6], and pre-existing diabetes being a risk factor for both early- and late-onset pre-eclampsia [7]. The incidence of preeclampsia increases from 2–7% of pregnancies in non-diabetic women to 15–20% in women with T1D and 10–14% in women with T2DM [8].

Pre-eclampsia and GDM share a number of risk factors, including advanced maternal age, nulliparity, multifetal pregnancies, non-white ethnicity, and prepregnancy obesity [5, 9]. Both pre-eclampsia and GDM also have long-term health implications, with pre-eclampsia increasing the risk of future cardiovascular disease, stroke, kidney disease, ophthalmic disease and development of T2DM (even without GDM), while GDM increases the risk of cardiovascular disease and T2DM for both mother and child [8].

Although the exact pathophysiology is still unknown, it would seem that a combination of maternal risk factors contribute to the similar biochemical dysregulation present in both pre-eclampsia and GDM, compared to healthy pregnancies, including endothelial dysfunction, angiogenic imbalance, insulin resistance, oxidative stress, inflammation and dyslipidemia [8] suggests shared etiological pathways underlying these conditions. Such biochemical changes might result from a common aetiology, have a common trigger (such as insulin resistance during pregnancy [10]) or be similar responses to different underlying disease processes that existed prior to pregnancy [11]. Similarly, genetic and/or environmental factors that contribute to pre-eclampsia could also increase the risk of diabetic complications later in life or it could be just as possible that pre-eclampsia causes lasting damage that leads to diabetic complications years after pregnancy [8].

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*Biochemical Dysregulation of Pre-Eclampsia and Gestational Diabetes Mellitus*

endothelial dysfunction in women with pre-eclampsia [16].

Within the placenta, limited remodelling of the maternal uterine spiral arteries may cause hypoxia [12] or repeated ischemia–reperfusion injury [13], such that the damaged placenta then releases factors into the maternal circulation that contribute to vascular dysfunction [12]. These include the anti-angiogenic proteins soluble vascular endothelial growth factor receptor 1 (sVEGFR-1; or more commonly known as soluble fms-like tyrosine kinase 1 - sFlt-1) and soluble endoglin (sEng) [14, 15]. Excess of these anti-angiogenic proteins contributes to systemic maternal

The sFlt-1 protein is a truncated form of VEGF receptor 1, composed of six immunoglobulin-like domains from the ligand-binding, extracellular domain [1]. Once secreted, sFlt-1 binds to the pro-angiogenic ligands vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), acting as a as a non-signalling decoy, reducing their bio-availability and enhancing endothelial dysfunction [16–18]. The sEng protein is composed of the extracellular domain of Endoglin, following proteolytic cleavage by metalloproteinase (MMP)-14. It binds to Transforming Growth Factor-b1 (TGF-β1), inhibiting binding to Endoglin (a TGF-β1 co-receptor), preventing the activation of endothelial Nitric Oxide Synthase (NOS) and

The levels of sFlt-1 and sEng were found to be proportional to the severity of preeclampsia [19–21], with maternal plasma concentrations of sFlt-1 and sEng increasing before pre-eclampsia was diagnosed, making them potential biomarkers for the disease [1, 22–29]. Concomitantly, the increase of sFlt-1 brings about a decrease in maternal plasma concentration of PlGF [18, 30–32]. However, the relative change in sFlt1 and sEng concentrations between two consecutive visits (first and second trimester) seems more useful as a predictive marker for developing pre-eclampsia among both low- and high-risk women that the absolute concentrations [30, 33]. The relationship between anti-angiogenic factors and pre-eclampsia in women

with GDM has been explored only in a handful of studies. Women with GDM were found to have higher serum sFlt-1, Placental Protein 13 (PP13), Pentraxin 3 (PTX3), myostatin and follistatin levels early in the second trimester, with sFlt-1 and PTX3 having potential predictive value [34]. Quantitative proteomics of syncytiotrophoblasts from women with GDM and pre-eclampsia identified 11 upregulated and 12 downregulated proteins including increased Flt-1 [35]. Moreover, high sEng, high sFlt-1, low PlGF and high sFlt-1/PlGF ratio increased the odds of

developing pre-eclampsia among women with pre-existing diabetes [30].

Further vascular dysfunction results from the inhibition of NOS. Asymmetric dimethylarginine (ADMA) is an analogue of L-arginine and endogenous competitive inhibitor of NOS, resulting in reduced NO synthesis from L-arginine and higher superoxide generation. NO is important in maintaining endothelial homeostasis and elevated ADMA levels are associated with inflammation, insulin resistance, dyslipidemia, obesity, and cardiovascular disease. Numerous studies have measured ADMA levels in women with pre-eclampsia and normotensive women but discrepant findings have been observed. Nevertheless, some reported elevated ADMA levels prior to the development of clinical symptoms of PE, which suggests that ADMA may contribute to the pathophysiology of pre-eclampsia [1, 29]. Poor placentation, oxidative stress, endothelial cell dysfunction and altered glucose metabolism among others generate Damage-Associated Molecular Patterns (DAMPs) including Heat Shock Proteins (HSPs), TNF-α, fetal DNA, hyaluronan, oxidised low-density lipoprotein (LDL) and long pentraxin-3 [36]. HSP70 (and its post-translational modifications) has been shown to be elevated in the placentas and sera of women with PE, reflecting systemic inflammation and oxidative stress, with

*DOI: http://dx.doi.org/10.5772/intechopen.85843*

**2. Endothelial dysfunction**

subsequent vasodilation [15].
