**4. Discussion**

The goal of this study was to estimate the levels of adiponectin, leptin, resistin, and visfatin, between 11 and 13 weeks of pregnancy and to see how successful it was to predict PE using first trimester levels of these biomarkers together with maternal factors.

Leptin levels were found to be considerably greater in those who developed PE later on compared to those who did not. This is in line with a previous study that found a rise in leptin levels several weeks before a clinical diagnosis of PE [8]. This observation is also consistent with another study that found an imbalance between adiponectin and leptin in the plasma of women with PE, resulting in raised leptin and decreased adiponectin levels; consequently, these two adipose-derived hormones may play a role in the pathogenesis of PE [64]. Similarly, as compared to normal pregnant controls, leptin levels were found to be 78% higher at 13 weeks of gestation in women who ultimately developed PE [65]. When comparing pregnant women whose first-trimester leptin levels were 25 ng/mL to pregnant women whose first-trimester leptin levels were 25 ng/mL, the risk of PE increased 18.8 fold [66]. Other studies have shown that leptin levels rise before the clinical beginning of the disease, and our findings support that theory [39, 40]. The findings of this study, together with prior research, suggest that leptin is involved in the pathophysiology of PE, rather than a rise in leptin as a result of impaired renal clearance. Hyperleptinemia has been shown to promote sodium reabsorption in the renal tubules, leading to water retention and elevated blood pressure [67]. Furthermore, tumor necrosis factor (TNF)-α and interleukin (IL)-6 upregulate placental leptin mRNA synthesis and increase the formation of endothelin, a vasoconstrictive peptide [68]. The constriction of the blood vessels leads to high blood pressure leading to PE.

Adiponectin levels in the first trimester were considerably lower in women with PE compared to the control group in this study. Other research has found that adiponectin levels are inversely proportional to coronary artery disease but not strongly related to blood pressure levels [69]. In another study, individuals with preeclampsia had lower median maternal high molecular weight and low molecular weight adiponectin concentrations than those with normal pregnancies [70]. Previous reports have demonstrated lower first-trimester adiponectin levels in women who subsequently developed PE compared to their peers [71, 72]. However, this study contradicts a publication that stated that circulation levels of adiponectin were higher in preeclamptic patients than in normal pregnant women [73, 74]. In another study, women with preeclampsia had approximately 50% greater third-trimester adiponectin levels than their normotensive counterparts [75]. In a similar study, women with preeclampsia had higher levels of circulating adiponectin [74]. The compensatory feedback mechanisms to the metabolically altered, anti-angiogenic, and pro-atherogenic condition of severe preeclampsia could explain these increases, which normally occur after the first trimester [74]. Hypoadiponectinemia in the first trimester of pregnant women who later developed PE implies that this adipocytokine is involved in PE etiology [16, 17]. Pregnancy is an inflammatory state associated with elevated plasma TNF-α, which could cause adiponectin levels to drop even further. An increase in TNF-α leads to an increase in endothelin levels [68] which constricts the blood vessels leading to high blood pressure [68]. Adiponectin appears to block the synthesis of angiotensin II, according to available evidence [76]. As adiponectin levels fall, angiotensin II levels rise, resulting in an increase in aldosterone levels. Hypertension results from a rise in aldosterone levels, which causes sodium and water retention.

When comparing pregnancies that resulted in PE to those that did not, this study discovered considerably greater resistin levels in PE pregnancies. A recent study found that preeclamptic pregnancies had higher levels of several adipokines, notably resistin, than healthy pregnant women [25]. Other studies, on the other hand, found no significant difference in resistin levels between preeclampsia patients and healthy pregnant women [77, 78]. Women with PE had significantly lower resistin levels than normotensive women of the same gestational age, according to some studies [46]. The involvement of resistin in the pathophysiology of PE is indicated by the rise in resistin levels months before the clinical diagnosis of PE. Resistin levels in the blood have been associated with coronary artery disease [43]. Resistin levels in the blood have been linked to a number of inflammatory indicators, including C-reactive protein, soluble TNF-α receptor-2, IL-6, and lipoprotein-associated phospholipase A2 [43]. Increased levels of endothelin result from increased TNF-α receptor-2 and IL-6 concentrations, resulting in high blood pressure [68].

Plasma visfatin levels were shown to be considerably higher during PE in our research. Visfatin levels rose during PE from the first trimester onwards, suggesting that visfatin may play a role in the disease's development. Visfatin is widely expressed in adipose tissue, placenta, and fetal membranes [48]. Visfatin concentrations in the second and third trimesters of normal pregnancy have been found to be higher than those in the first trimester [79] indicating that this protein is produced by the placenta and fetal membrane. Thus, it's probable that normal visfatin production is regulated to support the growing baby; yet, in some pregnancies, visfatin's supporting role may be interrupted, resulting in PE. Our findings are consistent with one of similar research which showed greater visfatin levels in the PE compared to normal pregnancy [80]. One study found no significant differences between normal and preeclamptic pregnancies [54] while another found lower levels [53]. Different researchers' reports on visfatin levels during pregnancy could be attributed to variances in sample procedures, ethnic or geographical differences, or the specific test methods used. This study's findings imply that visfatin levels rise before preeclampsia develops.

#### *Pathophysiology of Preeclampsia: The Role of Adiposity and Serum Adipokines DOI: http://dx.doi.org/10.5772/intechopen.104752*

Visfatin's potential as a marker of preeclampsia, particularly in obese women, will need to be explored further with bigger sample size. Such research will add to the body of knowledge on how to predict this disease and how to start intervention programs to reduce maternal and fetal morbidity and mortality from PE.

The fact that the AUCs and respective sensitivities and specificities did not significantly change after controlling for family history of hypertension (**Table 4**) shows that these biomarkers can predict PE independently regardless of family history of hypertension. When maternal weight was taken into account (**Table 3**), these adipokines were found to be ineffective in predicting PE in women of normal weight (BMI 18.5–24.9 kg/m<sup>2</sup> ). However, the fact that the overweight group (BMI 25–29.9 kg/m<sup>2</sup> ) fared better in terms of predicting these adipokines than the obese group (BMI 30.0 kg/m<sup>2</sup> ) implies a possible negative feedback mechanism that lowers plasma concentrations of these peptides as weight rises. To explain this occurrence, more research with bigger sample size is needed.

This study found that overweight pregnant women are more likely than normalweight pregnant women to get PE during their pregnancy, corroborating an earlier study that found that the likelihood of developing PE increased by two to three times in women with a higher BMI [81] and also similar to another study, which associated higher maternal BMI to a number of pregnancy complications including PE [82]. In addition, this study backs up a recent analysis that showed that advanced maternal age, especially, 35 years or more was a risk factor for preeclampsia [83] as well as a BMI greater than 30 kg/m<sup>2</sup> [84]. Obesity may play a role in the development of PE, according to the findings of this study. Obesity affects nitric oxide production and causes endothelial dysfunction [85] therefore an excessive buildup of fat in a pregnant woman could lead to hypertension during pregnancy which could lead to PE.

With the exception of HDL cholesterol, which was considerably lower in the PE group (**Table 1**) compared to the normotensive group, this investigation found no significant differences in lipids between women who acquired PE and those who remained normotensive during pregnancy. This study contradicts a report by Brazilian researchers who found a substantial difference in TG-rich proteins (VLDL 1) and small dense lipoprotein (LDL III) in women with PE compared to normal pregnant women [86]. Our findings contrast with those published in the Cape Coast region of Ghana, where researchers found substantial dyslipidemia in women with PE compared to women without PE [57]. The variations could be related to the different stages of pregnancy during which the samples were taken. The samples for this study were taken before the commencement of PE, whereas the samples for the other investigations were taken after the disease had begun to manifest. The lack of a significant difference in first trimester lipids between those who got PE and those who did not show that the atherogenic lipid profile commonly seen in pregnant women as reported by other researchers may be insufficient in predicting the chance of getting PE. However, because lower HDL is a substantial risk factor for hypertension, it's probable that the significantly lower HDL seen in individuals who went on to develop PE was linked to the disease's etiology [87]. Adiponectin and resistin were found to be more significant and better predictors of PE than leptin and visfatin after correcting for these potential confounding variables (age, parity, BMI, family history of diabetes, and preeclampsia). Angiotensin II production is reduced by adiponectin [76] while resistin is linked to elevations in TNF-α receptor-2 and IL-6, and so promotes high blood pressure [43], leading to an increased level of endothelin which constricts blood vessels and raises high blood pressure [68]. A family history of PE has been linked to a threefold increase in the chance of developing PE [88, 89] however, we did not detect a significant link

between PE and a family history of hypertension which is likely attributable to the fact that the data obtained from the participants in this study was focused on hypertension in general rather than PE.

According to the findings of this study, obesity may play a role in the development of PE. Obesity induces endothelial dysfunction by reducing nitric oxide production [85], hence if a pregnant woman has an excessive amount of fat on her body, she may develop hypertension and, as a result, PE. Obesity and having four or more children were discovered to be significant PE confounders.

### **4.1 Study limitations**

The study's limitations were limited sample size and insufficient information regarding the individuals' nutritional state. Potassium is abundant in leafy greens like spinach and kale, as well as cherries and red beets. Potassium operates on the kidneys, allowing the salt to be excreted more easily through the kidneys, decreasing blood pressure. Because of the small sample size and lack of nutritional data, conclusions about the association between these adipocytokines and preeclampsia may be difficult to draw, since nutritional status could not be controlled in the multivariate analysis.
