INSULIN RESISTANCE SYNDROM IN PREECLAMPSIA – THE INFLUENCE ON THE OFFSPRING

Preeclampsia is a multisystem disorder of unknown cause that is unique to human pregnancy. It is a major cause of perinatal and maternal morbidity and mortality, affecting 5% to 8% of all pregnancies. The clinical findings can manifest as either a maternal syndrome or fetal syndrome. There is increasing data supporting the role of the insulin resistance in preeclampsia, although this evidence has not been seen in all studies. The aim of this research was to determine the influence of the insulin resistance on the offspring in preeclampsia. Sixty preeclamptic pregnancies underwent the research taking the serum insulin of 20uU/ml as the state of insulin resistance’s cut off. Insulin sensitivity was examined by using HOMA and QUICKY indexes. Thirty preeclamptic pregnancies had the insulin resistance syndrome and thirty were the control group. Linear regression analysis and logistic linear analysis were used to examine the influence of the insulin resistance. In the insulin resistance preeclamptic pregnancies, the duration of pregnancy was shorter (2.59; p<0.01) and the placental weight was lower (2.72; p<0.01). This group also had a statistically lower percentage of vaginal birth (9.64; p<0.01) and higher of caesarian sections (4,44; p<0,05). Newborns in the insulin resistance group were shorter (0.108; p<0.001) weighed less (2.81; p<0.01), had a lower Apgar score (3.11; p<0.01) and stayed in the hospital for a longer time (2,48; p<0,05). The insulin resistance syndrome is not present in every preeclamptic pregnancy, but if it is present it affects the offspring in a negative way. Acta Medica Medianae 2016;55(2):19-24.


Introduction
Insulin resistance and inflammation have been reported to contribute to the onset of hypertension and coronary artery disease, as a part of metabolic syndrome, and they may be present in hypertensive disorders of pregnancy (1,2).Normal pregnancy can be considered as a state of insulin resistance.Fasting insulin concentration rising during the pregnancy with a peak in the third trimester, rapidly returns to pre-pregnancy levels after delivery (3).In preeclamptic pregnancies, metabolic changes similar to metabolic syndromeare also present (4).Insulin resistance, present in milder form in late pregnancy, has long been ascribed to rises in cortisol and placental hormones, including human placental lactogen, progesterone, and estrogen.Causes of further enhancement in hypertensive pregnancies remain unknown (5).One explanation could be inflammation, and indeed the rises in some inflammatory markers predict the onset of insulin resistance in pregnant subjects (6,7).Among these candidates, tumor necrosis factor-alfa (TNF-alfa and leptin are known to be produced besides adipose tissue, also in the placenta, and could therefore play a central role in insulin resistance in pregnancy (8).Several studies have suggested that women who develop preeclampsia are at an increased risk of cardiovascular complications later in life (9).Indeed, many risk factors and pathophysiological abnormalities of preeclampsia are similar to those of coronary artery disease.Insulin resistance has been implicated as a common factor.Microvascular dysfunction which is associated with insulin resistance could predispose to both coronary heart disease and preeclampsia (10).

Methods
Sixty pregnant women were eligible to join the study at the University Clinic for Gynecology and Obstetrics, Niš and were admitted to the Department of High Risk Pregnancy Unit with the symptoms of preeclampsia.Preeclampsia was defined as blood pressure >160/110 mmHg and proteinuria occurring after 20 weeks of gestation with no prior history of hypertension or renal disease.Proteinuria was defined as >0.3 g/L per 24h urine collection, with no evidence of urinary tract infection.Thirty preeclamptic pregnancies had the insulin resistance syndrome and thirty were the control group.Serum insulin level of 20 uU/ml was taking as the state of insulin resistance's cut off.Insulin sensitivity was examined by using HOMA and QUICKY indexes.Linear regres-sion analysis and logistic linear analysis were used to examine the influence of the insulin resistance.All subject provided written informed consent.

Discussion
Obesity and insulin resistance may predispose women to preeclampsia, perhaps on the basis of an increased systemic inflammation.It is known that chronic inflammatory activation of the immune system can induce insulin resistance, although its mechanism is not fully elucidated (11).The inflammatory system responds to danger signals which activate a cascade of events that ends with clinically evident preeclampsia.P-IPG is the first molecule that links all major aspects of this syndrome (12) (Figure 1).
The stimulus and its source are still unknown.An excess of circulating anti-angiogenic growth factors (Soluble FMS-like tyrosine kinase 1 and endoglin) have been found in preeclampsia.
They induce a preeclampsia-like syndrome in pregnant rats, but it is still debated whether they are causative of preeclampsia (13).
Dr. David Barker first popularized the concept of fetal origins of adult disease (FOAD).The FOAD hypothesis holds that events during early development have a profound impact on one's risk for development of future adult disease (14).Fetal programming implies that during critical periods of prenatal growth, permanent changes in metabolism or structures result from adverse intrauterine conditions.Low birth weight, a surrogate marker of poor placentation present in preeclampsia, is linked to coronary artery disease, hypertension, obesity, and insulin resistance.Clues originally arose from large 20 th century, European birth registries.Implications of the FOAD extend beyond the low birth weight population and include babies exposed to stress, both nutritional and nonnutritional, during different critical periods of development, which ultimately result in a disease (15).Studies of the Preston records have shown that thinness at birth, measured by a low ponderal index (birth weight/length3), is associated with the "insulin resistance syndrome"-the occurrence of impaired glucose tolerance, raised blood pressure, and disturbed lipid metabolism in adult life (16).Biochemically, the syndrome is characterized by raised serum insulin concentrations, and it leads to coronary heart disease (17).There is evidence that infants who fail to put on weight have become resistant to growth hormone, which takes over control of growth from insulin in late fetal life.Altered settings of hormonal secretion or tissue sensitivity could prove to be one of the important mechanisms, whereby programming leads to pathology (18).Other studies have shown that placental enlargement is also followed by impaired glucose tolerance, disordered blood coagulation, and death from coronary heart disease (19).Insulin resistance and type-2 diabetes have also been found to be independently related to small size at birth in several studies around the world (20).Dietary manipulations in animal models provide further support and mechanistic explana-tions, in particular protein deficiency in pregnant rats, which elevates blood pressure, impairs glucose tolerance, and increases the likelihood of obesity in the progeny (21).Although there are still controversial areas, there is at present sufficient scientific evidence for fetal programming to be regarded as an additional risk factor for chronic disease, in interaction with genetic and lifestyle risk factors.

Conclusion
Many challenges remain regarding the prediction, prevention, and management of preeclampsia as a potential risk condition with deep impact on offspring health.The FOAD hypothesis has expanded greatly during the past decades, and is influential in medicine and epidemiology.Recently, the World Health Organization included low birth weight as a risk factor for cardiovascular disease.The heart of the hypothesis -that environmental influences during gestation have an effect on later development -is a major insight and constitutes a complement to genetic and more proximal factors (such as adult lifestyle) as causes of adult disease.Future research should expand our knowledge of biomarkers for early prediction and management of preeclampsia and aim to reduce the prevalence of disorder that is associated with adverse pregnancy outcome and FOAD.By understanding FOAD, health care professionals and policy makers will make this issue a high healthcare priority and implement preventive measures and treatment for those at higher risk for chronic diseases.The outline of a strategy for developing the fetal origins hypothesis is now in place; it seems reasonable to expect that it will bring rapid advance.

Table 1 .
The course of pregnancy and birth characteristics of women compared to fasting level of serum insulin Graph 1. Mode of delivery by group