**4. Leptin in pathological pregnancy**

### **4.1 Leptin and pre-eclampsia (PE)**

Pre-eclampsia is a multisystem disorder of unknown aetiology characterised by hypertension ≥140/90 mm Hg after 20 weeks of gestation with proteinuria. Preeclampsia complicates around 5% of all pregnancies. The pathophysiology involves defective trophoblastic invasion of maternal spiral arteries leading to reduced placental blood flow and hence hypoxia [23].

Pre-eclamptic pregnancies have higher serum leptin levels (eight folds) specifically in the second half of gestation as compared to normal pregnancy. In PE, plateau of leptin does not occur and leptin levels continue to rise till term, falling only after delivery. The increase in the serum leptin levels are a consequence of placental

### **Figure 2.**

*Schematic diagram representing hyperleptinemia as a consequence of chronic placental hypoxia induced by severe pre-eclampsia [9].*

*Leptin and Female Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.101226*

hypoxia induced stress (**Figure 2**). This rise in leptin levels precedes the clinical onset of disease hence can also be considered as a potential predictive marker of PE. Apart from serum, amniotic fluid also shows a higher concentration of leptin than normotensive pregnancies. Leptin being an angiogenic hormone promotes placental vasculogenesis and trans placental nutrient transfer compensating for the placental insufficiency to some extent [8, 11, 17, 24].

The serum leptin levels rise in linear proportion with the severity of the disease [8, 9]. Studies have also suggested that leptin concentrations are higher in term PE as compared to preterm PE [17].

However the cord blood leptin levels are lower which denote a reduced fetal fat mass often associated with PE [11]. Pre eclamptic pregnancies complicated with FGR have higher maternal leptin levels than those without FGR suggesting a greater degree of placental insufficiency [8].

The data available is conflicting and the modulation of leptin in relation to preeclampsia is a fertile ground for further studies.

### **4.2 Leptin and fetal growth restriction (FGR)**

Fetal growth restriction may be defined as the failure of the fetus to reach its genetically determined growth potential. FGR complicates 5–10% of all pregnancies and is associated with significant perinatal morbidity and mortality [25].

Studies linking the role of leptin in FGR have yielded conflicting results. A recent meta-analysis involving 1734 women showed no difference in the leptin levels between maternal blood of FGR pregnancies and healthy pregnant women [26].

However evidence suggests that the maternal serum leptin levels are higher in pregnancies complicated with FGR and fetal cord blood levels are lower compared with normal pregnancies. The higher maternal levels are a consequence of increased placental production of leptin triggered by placental insufficiency and hypoxia [27]. The lower cord blood levels reflect a lower fetal fat mass seen in FGR and also suggest a plausible role of leptin as a growth factor [28].

### **4.3 Leptin and gestational diabetes mellitus**

Gestational diabetes mellitus (GDM) is one of the most common metabolic complications occurring during pregnancy with a high risk of maternal and perinatal morbidity, also leading to long term sequelae [29]. It may be defined as glucose intolerance of variable severity with its onset or first recognition during pregnancy [30]. Prevalence of GDM is higher in obese women as compared to women with a normal pre-pregnancy BMI [12].

GDM is associated with increased levels of leptin in the placenta and increased expression of placental leptin receptors. The rise in serum leptin levels has been noted in the first trimester of pregnancy itself, illustrating its possible role as a predictive marker for GDM (4.7 fold greater risk of developing GDM). Not only in serum, higher leptin levels have also been measured in the amniotic fluid of women with GDM, each 1 ng/dl rise in amniotic fluid leptin increasing the risk of developing GDM by 4% [31].

It has been observed the higher umbilical cord leptin levels were present in macrosomic foetuses of diabetic mothers correlating with the increased fetal fat mass. Leptin may also contribute to the increased placental size seen in GDM. Moreover, leptin also stimulates placental protein synthesis and transfer of nutrients to the fetus

### **Figure 3.**

*Association of increased leptin production with chronic inflammatory state, insulin resistance and hyperinsulinemia seen in GDM. TNF-*α*, tumour necrosis factor alpha; IL-6, interleukin-6 [30].*

as can be speculated by increased expression of glycerol transporter aquaporin-9 in the placentae of women with GDM [32].

The enhanced placental production of leptin has also been correlated with a higher production of inflammatory cytokines interleukin-6 and tumour necrosis factoralpha and therefore linked with the chronic inflammatory state seen in GDM. IL-6 and TNF-α enhance the placental expression of leptin. Leptin in turn stimulates the monocytes for enhanced production of IL-6 and TNF-α resulting in a vicious cycle [11, 17, 30, 33].

The production of leptin is stimulated by hyperinsulinemia seen in GDM. Therefore, increased leptin levels are also associated with the increased insulin resistance seen in GDM during the second half of pregnancy (**Figure 3**) [33].

Studies evaluating novel bioactive therapeutic agents comprising macro and micronutrients which exert anti-inflammatory actions may be a potential cure for inflammation induced leptin resistance at the level of the hypothalamus seen in GDM. This will lead to improved leptin sensitivity at the centre and decreased insulin resistance at the peripheral level [32].
