The Relationship Between Obesity And Adverse Pregnancy Outcomes And Its Mechanisms Involved

Overweight and obesity have become a public health concern in the world. The epidemic of obesity in women of childbearing age has also become increasingly prominent. Overweight or obesity has a negative impact on the outcome of pregnancy and presents an increased risk of maternal and neonatal complications, such as gestational hypertension, preeclampsia, gestational diabetes, prematurity, macrosomia, shoulder dystocia, and premature rupture of membranes. These complications can seriously undermine the health of mothers and infants. There is a paucity of information about prepregnancy BMI, gestational weight gain and their effects on maternal and fetal complications from developing countries. Therefore, it is important to conduct the present study.Obesity and excessive weight gain during pregnancy is often excessive accumulation of body fat tissue. Bioactive mediators such as leptin, adiponectin, resistin, retinol binding protein-4 (RBP-4) released by adipose tissue were called adipocytokines. Adipocytokines modulate a variety of obesity-related complications, including type 2 diabetes, hypertension, atherosclerosis and so on through autocrine, paracrine and endocrine manner. However we found that obese pregnant women are not always developing GDM and GDM pregnant women are not always obese patients. We therefore speculate serum levels of adipocytokines in GDM pregnant women with obesity or not obesity, obesity pregnant women and non-obese healthy pregnant women may be different and assess the relationship between adipocytokines and metabolic factors.GDM is a complex disorder with inherited and environmental factors influencing its occurrence. Adiponectin is synthesized and secreted by the fat cells and it plays an important role in the regulation of energy stability and insulin sensitivity. Decreased circulation adiponectin levels are associated with insulin resistance. Adiponectin gene polymorphism has been associated with obesity, insulin resistance, type 2 diabetes and other metabolic diseases. In view of GDM and type 2 diabetes have many similarities, we hypothesized that adiponectin gene polymorphisms may be associated with the incidence of GDM and metabolic indicators.Materlals and methods1. A retrospective cohort study was conducted. We categorized 2586 women into four BMI groups according to the Chinese adult BMI classification (underweight, BMI <18.5 kg/m2; normal weight, BMI 18.5-23.9 kg/m2; overweight, BMI 24-27.9 kg/m2; obesity, BMI≥28 kg/m2). We then classified gestational weight gain into four catagories based on their average weekly weight gain during pregnancy for these women (less than 0.41kg/wk,0.41-0.49kg/wk,0.50-0.58kg/wk, and more than 0.59kg/wk). Multiple logistic regression analysis was performed to examine the correlations between prepregnancy BMI and gestational weight gain with adverse pregnancy complications.2. Fasting serum RBP-4 levels, APN, TNF-αwere measured by Enzyme-Linked Immuno Sorbent Assay(ELISA)in 19 cases of GDM with obesity,23 cases of GDM with normal weight,18 cases of obesity pregnant women without pregnancy complications and 18 cases of normal weight pregnant women. Meanwhile, FINS, FPG, TC, TG, HDL-C, LDL-C were measured. Insulin resistance was estimated using the homeostatic model assessment-insulin resistance (HOMA-IR) index, calculated as (FPG*FINS)/22.5. The changes of serum adipocytokines levels in subjects with different groups and the correlation between adipocytokines levels and metabolic indicators were analyzed.3. Adiponectin gene promoter region-11426A＞G, - 11377C＞G and 2 exons +45 T> G polymorphisms were detected by MALDI-TOFMS technique among 103 cases of GDM pregnant women and 97 normal pregnant women. Meanwhile, FINS, FPG, TC, TG, HDL-C, LDL-C, APN were measured among 40 cases of GDM women without any treatment.Results1. Prepregnancy body mass index, gestational weight gain and pregnancy outcomes(1) Among the 2586 women studied, prepregnancy BMI classified 408 cases as underweight (15.8%),1744 normal weight (67.4%),341 overweight (13.2%), and 93 as obesity (3.6%).(2) Prepregnancy BMI and maternal age was positively correlated (F= 9.651, P < 0.001). The proportion of overweight or obesity was lower among women with the higher education level than those with less than 12 years of education (x2= 73.42, P< 0.001). The prevanlence of overweight and obesity was higher for unemployed women (x2=23.59, P< 0.001) and for those who were multiparas (x2= 28.12, P< 0.001). As prepregnancy BMI increased, the amount of weekly weight gain decreased (F=15.27, P <0.001).(3) Prepregnancy overweight and obesity increased the risks of gestational hypertension, preeclampsia, gestational diabetes and preterm premature rupture of membranes (P<0.05). Being underweight before pregnancy was protective against gestational hypertension, GDM, and fetal macrosomia.(4) Gestational weight gain≥0.50 kg/wk was associated with an increased risk of gestational hypertension, preterm premature rupture of membranes and macrosomia (P <0.05). Women with the highest quartile of weight gain (≥0.59 kg/wk) are at higher risk of preeclampsia (P< 0.05).2. The relationgship of pregnancy obesity, gestational diabetes mellitus and serum adipocytokines(1) Triglyceride levels were higher in GDM pregnant women than healthy pregnant women (P=0.021). HDL-C levels were lower in GDM women with obesity than non-GDM women. HDL-C levels were lower in GDM women with nomal weight than healthy pregnant women (P=0.030). FPG levels were the highest in GDM women with obesity. FPG levels in the GDM women with normal weight were higher than healthy pregnant women (P=0.032). FINS levels in GDM pregnant women with obesity were significantly higher than that in the other 3 groups. FINS levels were higher in the obesity pregnant women than the control group (P<0.001). The HOMA-IR in the GDM women with obesity was the highest and that in the control group was the lowest.(2) Serum TNF-αlevels in GDM with obesity were the hightest and that in the health pregnant women were the lowest (P<0.001). Serum APN levels in GDM were lower than ono-GDM group and serum APN levels in obesity pregnant women were lower than health pregnant women (P<0.05).Serum RBP-4 levels in GDM with obesity were higher than others (P<0.05), and serum RBP-4 levels in obese pregnant women was higher than non-obese pregnant women (P<0.05).(3) There was a significant positive correlation between TNF-αlevels and prepregnant BMI, TG, FPG, FINS, RBP-4, and HOMA-IR. Negative correlation was shown between the levels of TNF-αand APN. There was a significant negative correlation between APN levels and age, FPG, FINS, HOMA-IR, TNF-α, and RBP-4. Positive correlation was shown between the levels of APN and HDL-C. There was a significant positive correlation between RBP-4 levels and diastolic blood pressure, prepregnant BMI, FINS, HOMA-IR and TNF-α. There was a significant positive correlation between HOMA-IR levels and age, blood pressure, prepregnant BMI, TG, FPG, FINS, TNF-αand RBP-4. Negative correlation was shown between HOMA-IR and the levels of HDL-C and APN (P<0.05)(4) In a multiple stepwise regression analysis, FINS, FPG, APN and prepregnant BMI were independent variables of HOMA-IR. Prepregnant BMI and TNF-αwere independent variables of RBP4. Age and FINS were independent variables of APN. RBP-4 and FINS were independent variables of TNF-α(P<0.05).3. The study of adiponectin gene polymorphisms and gestational diabetes.(1) The AG, GG genotype frequencies of the SNP -11426 were higher in GDM than in controls (x2=8.822, P=0.012). The Gasssssssss-allele was associated with an increased risk of GDM (x2=10.283, P=0.001). The TG, GG genotype frequencies of the SNP+45 were higher in GDM than in controls (x2=6.722, P=0.035). A higher frequency of the G-allele was observed in the GDM women than that in the control women (x2=7.758, P=0.005).(2) The TG+GG genotype frequency of SNP+45 was higher in the obese GDM women than in the non-obese GDM women (x2=5.068, P=0.024). A higher frequency of the G-allele was observed in the the obese GDM women (x2=6.54, P=0.011)(3) Women carrying the G allele of SNP-11426 showed higher TG (P=0.023), lower APN levels (P=0.024) than those with AA genotype. In +45T>G, carriers of the TG+GG had higher prepregnant BMI, LDL-C, FINS, HOMA-IR than TT genotype (P <0.05).Conclusion1. The issue of overweight and obesity in China is not as serious as that in developed countries. High prepregnancy BMI and excessive gestational weight gain are associated with increased risks of adverse pregnancy outcomes, such as gestational hypertension, gestational diabetes, macrosomia, and preterm premature rupture of membranes..2. There exists glucose and lipid metabolism disorder in GDM women and obese pregnant women.3. GDM is characterized by insulin resistance. Serum levels of TNF-a increased and APN decreased in GDM women. Serum APN levels and pre-pregnancy BMI were independent variables of HOMA-IR.4. Whether or not with GDM, serum RBP4 levels were significantly elevated in obesity pregnant women, and serum RBP-4 levels were closely related with obesity.5. Interactions between these adipokines may be involved in the pathogenesis of obesity or GDM.6. The distributions of genotypes and alleles of the-11426A>G and+45 T>G polymorphisms were different in women with GDM and controls.7. G allele of SNP -11426 was related to GDM possibly. A→G variation was involved in the occurrence of GDM by reducing serum adiponectin levels.8. G allele of SNP+45 was related to GDM possibly. The carriers of the G allele had significant higher BMI relative to non-carriers in GDM women. T→G variation was associated with obesity, insulin resistance, and GDM.