GDM is defined as diabetes or impaired glucose tolerance that develops during pregnancy (39). It affects 4-7% of pregnant women (151, 152) and carries considerable perinatal risk including mac-rosomia, hypoglycemia, stillbirth, jaundice and respiratory distress syndrome (153). A randomized controlled trial has shown that rates of serious perinatal complications were reduced, birth weight was lower, and macrosomia was less frequent in patients who were treated intensively for impaired glucose tolerance in pregnancy than in those who received conventional treatment (154). In addition to perinatal risks, women with GDM are at increased risk for birth trauma, cesarean section, pregnancy-induced hypertensive disorders and developing type 2 diabetes mellitus later in life (39, 155).
In normal women, pregnancy is known to increase insulin resistance, which is compensated by hyperinsulinemia; effects are maximal in the third trimester (115, 156). Women with PCOS have greater insulin resistance than normal women and their pancreatic beta cells may be unable to fully compensate for the additional insulin resistance of pregnancy, making them more prone to the development of GDM (157). They are also more likely to be obese and due to the increased rate of infertility in women with PCOS, they frequently conceive at an older age. Both obesity and advanced age increase the risk for GDM (152). Studies have sought to determine if the increased risk for GDM in women with PCOS is due to insulin resistance or other factors that are associated with the syndrome.
Several studies have found an increased prevalence of polycystic ovaries in women with a history of GDM. Holte et al. compared 34 women with GDM 3-5 years prior to 36 controls with uncomplicated pregnancies (158). Women with a history of GDM were more likely to have polycystic ovaries by ultrasound (41% vs. 3%, p < 0.0001), hirsutism, irregular menses and a higher BMI. In a subgroup analysis of the women with previous GDM, those with polycystic ovaries had higher androstenedione and testosterone concentrations, higher LH/FSH ratios, and higher levels of triglycerides and total cholesterol, all independent of age and BMI, despite similar glucose tolerance and prevalence of diabetes. The polycystic ovary group also had lower insulin sensitivity (p < 0.05), independent of BMI, than the group with normal ovaries. Similarly, Anttila et al. found polycystic ovaries to be more common among women with a history of GDM than among age- and BMI-matched controls (159). However, because polycystic ovaries can also be found in normal women, using ultrasound evidence of poly-cystic ovaries is not a definitive surrogate for PCOS and examining rates of polycystic ovaries can overestimate the true prevalence of PCOS in GDM (39).
Several studies have found BMI to be predictive of GDM. In a multiethnic group of women, Kousta et al. found that women with a history of GDM had a higher prevalence of polycystic ovaries, higher fasting glucose, higher BMI, increased waist/hip ratio and lower insulin sensitivity than control women (160). In addition, women with a history of GDM and polycystic ovaries were more likely to have irregular menstrual cycles. Koivunen et al. found that women with a history of GDM were more likely to have polycystic ovaries as well as lower early phase insulin response to glucose and impaired insulin sensitivity (161). However, they were also more likely to be obese and when corrected for waist/hip ratio (but not BMI), the difference in insulin sensitivity was abolished.
Additional studies have sought to further define the association between PCOS and GDM. Urman et al. examined pregnancy outcomes in patients with known PCOS compared with that in healthy controls (162). Women with PCOS had higher rates of GDM than controls (p < 0.05); the difference remained even when lean PCOS patients were compared with lean controls. In a retrospective cohort study, Radon et al. found an increased risk of glucose intolerance among patients with PCOS than among normal controls (OR 22.2, CI 3.8-170) (163). However, there was no comparison performed to determine if obesity or PCOS were independent predictors of GDM.
In a larger retrospective analysis, Mikola et al. found that 20% of PCOS patients developed GDM compared with 8.9% of controls (p < 0.001) (164). After logistic regression analysis, PCOS remained an independent predictor (adjusted OR 1.9, CI 1.0-3.5) but BMI > 25 appeared to be the greatest predictor for GDM (adjusted OR 5.1, CI 3.2-8.3). Similarly, in a retrospective comparison of PCOS patients and controls, Turhan et al. found PCOS to be the main predictor of impaired glucose tolerance (p = 0.01); however, logistic regression analysis revealed that a prepregnancy BMI > 25 was the main predictor of GDM (p = 0.002) (165).
A large population-based study by Lo et al. showed a more than twofold increased odds of GDM (adjusted OR 2.44, CI 2.10-2.83) among women with a documented diagnosis of PCOS, independent of age, race, ethnicity and multiple gestations (152). In addition, they found an intermediate increased risk of GDM (OR 1.40, CI 1.27-1.54) among women with PCOS symptoms by chart review. Unfortunately, the study did not control for obesity rendering it unclear if these results would remain independent of BMI.
Not all studies have found PCOS to be associated with GDM. In a retrospective case-control study comparing age- and weight-matched women, Haakova et al. found no increased incidence in GDM in patients with PCOS when compared with controls (166). While the studies vary in diagnostic criteria and selection of a control group, both the majority of studies and the larger studies support an association between PCOS and GDM. Further support comes from a meta-analysis done by Boomsma et al. comprising 720 women with PCOS who were found to have a significantly higher risk of developing GDM (OR 2.94, CI 1.7-5.08) (167). In addition, a family history of diabetes increases the risk for GDM, and studies have shown that 30-40% of women with PCOS and glucose intolerance have a first degree relative with diabetes (168). Obesity further exacerbates the propensity for developing GDM, again emphasizing the importance of weight loss prior to conception.
Metformin has been investigated for its ability to reduce the incidence of GDM in women with PCOS. Glueck et al. studied development of GDM in nondiabetic women with PCOS who conceived while taking metformin and had live births compared with historical controls who conceived without metformin (144). Development of GDM was 3% in the metformin group vs. 23% in the control group. Of the women in the metformin group with prior pregnancies, 67% had previously developed GDM, suggesting that metformin may also be effective for secondary prevention. The cohorts did not differ in height, weight or insulin resistance. When all live births were combined, the odds ratio for GDM with metformin vs. GDM without metformin was 0.093 (CI 0.011-0.795). No adverse effects were noted on fetal outcomes. An additional study by Glueck et al. found no increase in preeclampsia during pregnancy in women given metformin during pregnancy (169).
Glueck's group further examined the effects of metformin combined with a high-protein diet in preventing GDM and found a similar reduction in rates of GDM in patients taking metformin for both primary and secondary prevention (170). Metformin did not result in any congenital malformations or fetal hypoglycemia. The authors hypothesized that metformin reduces development of GDM by reducing pregnancy-associated insulin resistance and that prevention of GDM with metformin may reduce the subsequent development of type 2 diabetes later in life, although this remains speculative (170). Metformin plus a high-protein, low-carbohydrate diet may also help prevent excessive weight gain during pregnancy, which can also reduce the risk of GDM (170). Nutrition during pregnancy is reviewed in detail in Chap. 14 of this text.
While these results are promising, randomized controlled trials are needed to fully assess the efficacy of metformin in the prevention of GDM. There is limited information regarding the use of other insulin sensitizers in pregnancy. TZDs are pregnancy class C and should be not be taken during pregnancy.
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