Obesity, gestational diabetes and pregnancy outcome

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Summary

The prevalence of both obesity and gestational diabetes mellitus (GDM) is rising worldwide. The complications of diabetes affecting the mother and fetus are well known. Maternal complications include preterm labor, pre-eclampsia, nephropathy, birth trauma, cesarean section, and postoperative wound complications, among others. Fetal complications include fetal wastage from early pregnancy loss or congenital anomalies, macrosomia, shoulder dystocia, stillbirth, growth restriction, and hypoglycemia, among others. The presence of obesity among diabetic patients compounds these complications. The above-mentioned short-term complications can be mediated by achieving the desired level of glycemic control during pregnancy. However, GDM during pregnancy is associated with increased risk of early obesity, type 2 diabetes during adolescence and the development of metabolic syndrome in early childhood. Additionally, GDM is a marker for the development of overt type 2 diabetes and metabolic syndrome for the mother in the early future.

Introduction

Established diabetes mellitus, either type 1 or 2, is the most common pre-existing medical condition in pregnant women. According to the United States Centers for Disease Control (CDC), its frequency is 2–5 per 1000 pregnancies.1 Nevertheless, this calculation was published in 1990 and has most likely increased by 40% in view of the present epidemic of worldwide obesity.

The World Health Organization (WHO) estimated in the year 2000 that as many as 300 million people worldwide were clinically obese. European countries are now following the health-compromising trends found in the USA with as many as 30% of adults classified as overweight and obese.2 Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. As a rule, women have more body fat than men, and it is widely agreed that men with >30% body fat and women with >25% body fat are obese. The WHO and the National Institutes of Health define: underweight as a body mass index (BMI; kg/m2) ≤18.5, normal weight as a BMI of 18.5–24.9, overweight as a BMI of 25–29.9, and obesity as a BMI of ≥30. Obesity is further characterized by BMI into class I (30–34.9), class II (35–39.9), and class III (>40).3 The WHO's latest reports indicate that in 2005 ∼1.6 billion adults (aged  15 years) were overweight and at least 400 million adults were obese. This international agency also projects that by 2015, ∼2.3 billion adults will be overweight and more than 700 million will be obese. Results from the latest 2003–2004 United States National Health and Nutrition Examination Survey (NHANES) indicate that 66.3% of adults are overweight (BMI  25), and 32.2% are obese (BMI  30). The prevalence of overweight and obesity among adults aged 20–74 years in the USA has increased from 47.0% (in the 1976–1980 survey) to 66.3% (in the 2003–2004 survey). Over the same period, the prevalence of obesity has doubled among women from 16.5% to 33.2%.4, 5

The complications of diabetes affecting the mother and fetus are well known. Maternal complications include preterm labor, pre-eclampsia, nephropathy, birth trauma, cesarean section, and postoperative wound complications, among others. Fetal complications include fetal wastage from early pregnancy loss or congenital anomalies, macrosomia, shoulder dystocia, stillbirth, growth restriction, and hypoglycemia, among others. The presence of obesity among diabetic patients compounds these complications. The nature and type of diabetes-related pregnancy complications were such that the international medical community (WHO and International Diabetes Federation) set forth the St Vincent's declaration of 1989, with one of its aims to achieve similar pregnancy outcomes in diabetic and non-diabetic women.6

This review addresses issues concerning pre-gravid obesity and weight gain during pregnancy and their implications on gestational diabetes and pregnancy outcome.

Section snippets

The influence of obesity on pregnancy outcome in the non-diabetic patient

As the prevalence of obesity is increasing, so is the number of women in the reproductive age who are overweight and obese. The average BMI is increasing among all age categories, and women enter pregnancy at higher weights. Women are also more likely to retain gestational weight with each pregnancy. Approximately one-third of women of reproductive age in the USA are obese, with no appreciable increase from 1999.7, 8

Human pregnancy is an insulin-resistant condition by itself. There is a 40–50%

Fertility

Several studies have shown an increased risk of anovulatory infertility in obese women [odds ratio (OR): 2–3] by mechanisms of hyperandrogenism and polycystic ovarian syndrome, which share several pathophysiological characteristics, namely insulin resistance.11, 12, 13, 14, 15 Although some controversy still exists regarding the effect of obesity in patients who undergo in-vitro fertilization (IVF), three large population- based retrospective studies have shown lower pregnancy rates in obese

Miscarriage

Although the relationship between obesity and first trimester miscarriage has been investigated extensively, the results are far from conclusive and require further research. Whereas several studies suggest that obesity may increase the risk of miscarriage19, 20, 21, 22, 23 due to adverse influences on the embryo, the endometrium or both,20 others found no association between miscarriage and obesity.24, *25, 26, 27 These studies lack consistency, however, mainly because of the use of different

Thromboembolic complications

Pregnancy itself is a prothrombotic state with increases in the plasma concentration of coagulation factors I, VII, VllI and X, a decrease in protein S and inhibition of fibrinolysis, resulting in a 5-fold increased risk for venous thrombosis.28, 29 Other factors likely to be important in the etiology of pregnancy-associated vein thromboembolisem (VTE) are advanced maternal age, high parity, operative delivery, pre-eclampsia and obesity. Abdollahi et al.30 evaluated in a case-controlled study,

Hypertension disorders

Arterial blood pressure, haemoconcentration and cardiac function are all altered by the hemodynamic changes brought about by obesity. Authors have suggested a 10-fold higher rate of chronic hypertension in obese patients compared to normal weight women.31, 32, 33, 34, *35 The risk of pregnancy-induced hypertension or pre-eclampsia are significantly greater if the mother is overweight as assessed by BMI in early pregnancy.36, *37 Studies suggest a 2–3-fold increased risk for pre-eclampsia at BMI

Stillbirth and fetal death

Stillbirth remains a serious reproductive failure, with a frequency of 2–5 per 1000 births, and constitutes more than half of all perinatal deaths.43, 44 Pre-pregnancy BMI and fetal death were examined in the Danish National Birth Cohort among 54 505 pregnant women. They reported a 5-fold increase in risk of stillbirth in obese women. Pre-pregnancy obesity correlated with an increased risk of both late spontaneous abortion and stillbirth expressed as hazard ratio (HR) and CI: before week 14:

Preterm delivery

Most investigators report both low pre-pregnancy weight and poor weight gain in low BMI women as risk factors for preterm birth.48, 49, 50 Regarding obese women, reports are inconclusive. Current evidence suggests that obesity may be associated with induced preterm delivery, but not spontaneous preterm birth. Smith et al.51 reported that among nulliparous women, the risk of spontaneous preterm labor decreased with increasing BMI, whereas the risk of requiring an elective preterm delivery

Cesarean section

Studies report a nearly 2-fold increased risk of cesarean delivery in women who are obese even after controlling for other factors. Why obesity increases the risk for cesarean section with an even greater risk among morbidly obese women needs further study. The increased risk of cesarean delivery in obese women should not be taken lightly. Apart from the immediate operative risk, the increased cesarean rate in overweight and obese women is also associated with an increase in postoperative

Birth defects

Apart from the increase in failure to detect birth defects in obese women due to difficult interpretation of serum markers (changes in the volume of distribution) and suboptimal visualization of fetal anatomy by ultrasound examination, several studies report a factual increase in birth defects among obese women. Waller et al.61 in 1994 first suggested that offspring of obese women were at increased risk of neural tube defects (OR: 1.8; 95% CI: 1.1–3.0), especially spina bifida (2.6; 1.5–4.5).

Macrosomia

Many variables have been associated with fetal overgrowth or macrosomia. Increasingly, maternal pre-gravid weight and decreased pre-gravid insulin sensitivity have been shown to strongly correlate with fetal growth, especially fat mass at birth.66 Increased maternal insulin resistance may be associated with altered placental function in addition to increased fetoplacental availability of nutrients in late gestation. These nutrients include glucose, but also free fatty acids and amino acids. As

Long-term implications

The implications of maternal obesity far surpass intrauterine life, extending into infancy and even adulthood with severe health repercussions. Both the Barker*71, 72 and fetal insulin hypotheses73 have proposed that impaired adult cardiovascular health is programmed in utero by poor fetal nutrition, or by genetically determined reduction of insulin-mediated fetal growth, resulting in the birth of a small infant. Low birthweight may be a significant variable for the development of the metabolic

Maternal long-term implications

Some pregnancies are associated with excessive maternal weight gain. Mean weight retention after pregnancy ranges between 0.4 and 3.8 kg.83, 84, 85, 86 Weight retention after pregnancy has been attributed to various causative factors, including smoking cessation, changes in activity leading to a more sedentary lifestyle, socioeconomic factors such as low income, etc.

Additionally, increased weight gain during pregnancy remains the strongest factor for weight retention after pregnancy.87, 88 Linnè

Association between maternal obesity and GDM

The association between obesity, hypertension and insulin resistance in type 2 diabetes is well recognized. About 3–15% of women develop GDM during pregnancy. Although many factors are related to this risk, including ethnicity, previous occurrence of GDM, age, parity, family history of diabetes and degree of hyperglycemia in pregnancy, obesity acts as an independent risk for developing GDM, with a risk of about 20%.26, 27 It has been shown that even minor degrees of carbohydrate intolerance are

Level of obesity in GDM and pregnancy outcome

Several studies have suggested a higher rate of morbidity in morbidly obese non-diabetic pregnant women. Yogev and Langer99 found no significant difference between obese and morbidly obese women in pregnancy outcome compromised by diabetes when targeted levels of glycemic control were achieved. However, two-thirds of the morbidly obese patients failed to achieve the desired level of glycemic control and 69% were treated with insulin. In addition to constitutional risk factors such as previous

Obesity, GDM and metabolic syndrome: a vicious cycle

In 1988, Reaven proposed that resistance to insulin-stimulated glucose uptake (insulin resistance, IR) and secondary hyperinsulinemia are involved in the etiology of three major related diseases: cardiovascular disease (CVD), type 2 diabetes and hypertension. He coined the term ‘syndrome X’ that has been modified later to metabolic syndrome (MS) to describe a group of abnormalities that increase the risk for CVD: resistance to insulin-stimulated glucose uptake, glucose intolerance,

GDM and subsequent cardiovascular disease

There are few studies looking at cardiovascular complications in women with GDM. Mestman reported on the incidence of CVD in 58 women with GDM and 31 controls 12–18 years after their pregnancies. Twenty-six (45%) of the GDM women developed hypertension as opposed to one (4%) of the control group. Five GDM women had a cerebrovascular accident and four a myocardial infarction as opposed to none of the control women.105 O'Sullivan106 presented preliminary data showing a significantly higher

GDM as a predictor for subsequent development of the metabolic syndrome

Several studies have investigated the relationship between GDM and subsequent MS. Bo et al. reported on the development of MS in a group of 81 women with prior GDM. Prevalence of the MS and its components was 2–4-fold higher in women with prior gestational hyperglycemia and 10-fold higher if pre-pregnancy obesity coexisted when compared to normoglycemic controls, suggesting that GDM, especially in combination with pre-pregnancy obesity, predicts a subsequent syndrome of high cardiovascular risk.

Conclusion

Obesity has become an epidemic. It is associated with infertility and with many pregnancy complications. Moreover, it is associated with GDM, which increases the risk of these complications. In obese women, modification of risk factors prior to or early in pregnancy is recommended. Infertility treatment should be preceded by weight reduction. The latter may result in spontaneous conception (and prevention of multiple gestations) and in a better outcome of pregnancy.

Treatment options during

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