Gestational Diabetes During and After Pregnancy

23. Emerging Science: Interventions in Women at Risk of GDM During Pregnancy

Lisa Chasan-Taber 

(1)

Department of Public Health, University of Massachusetts, Amherst, 405 Arnold House, 715 North Pleasant Street, Amherst, MA 01003, USA

Lisa Chasan-Taber

Email: LCT@schoolph.umass.edu

Abstract

As the prevalence of diabetes continues to rise worldwide, it is increasingly important to identify high-risk populations and to implement strategies to delay or prevent diabetes onset. Women diagnosed with gestational diabetes mellitus (GDM) are at substantially increased risk of developing type 2 diabetes and obesity, both currently epidemic in the United States. Diagnosis of GDM, therefore, provides an excellent opportunity to intervene years before the development of this disorder. Indeed, women may be more likely to adopt healthy lifestyle habits during pregnancy and maintain these habits into the postpartum period. This chapter will summarize interventions which rely on lifestyle modifications to prevent GDM or mitigate the effects of GDM during pregnancy. These include changes in diet, as well as physical activity, both of which are established risk factors in the prevention and treatment of type 2 diabetes. The chapter concludes with recommendations for future intervention studies.

23.1 Introduction

As the prevalence of diabetes continues to rise worldwide,1 it is increasingly important to identify high risk populations and to implement strategies to delay or prevent diabetes onset.23 Women diagnosed with gestational diabetes mellitus (GDM) are at substantially increased risk of developing type 2 diabetes and obesity, both currently epidemic in the United States. Furthermore, there is evidence that the incidence of GDM and of postpartum type 2 diabetes following a diagnosis of GDM may both be increasing.46 It has been estimated that, in some populations, women with a history of GDM may account for up to one-third of diabetes cases among parous women.7 They are also more likely to display features of the insulin resistance syndrome which are linked to cardiovascular disease.8 In the long term, their children are at increased risk of obesity and glucose intolerance.911 GDM, therefore, identifies a population of women at high risk of developing type 2 diabetes and thus provides an excellent opportunity to intervene years before the development of this disorder.

The rapidly changing context of pregnancy brings opportunities for women to adopt and maintain healthy new behaviors which may be incorporated as lifestyle habits in the postpartum period. This chapter will summarize interventions which rely on lifestyle modifications to prevent GDM or mitigate the effects of GDM during pregnancy. Such modifications include changes in diet as well as physical activity, already established factors in the prevention and treatment of type 2 diabetes. The chapter concludes with recommendations for future intervention studies.

23.2 Interventions to Prevent GDM

Established GDM risk factors include race/ethnicity, elevated body mass index (BMI), history of GDM in a past pregnancy, >25 years of age, family history of diabetes mellitus, history of abnormal glucose metabolism, and history of poor obstetric outcome.12 Maternal weight gain and diet are also likely to be important factors.12 However, recognized risk factors for GDM are absent in up to half of affected women.13 In addition, many of these factors, such as age and family history, are nonmodifiable. In the light of these facts, as well as the increasing prevalence of GDM, the need to assess strategies to prevent its onset is critical.

23.2.1 Exercise Interventions Designed to Prevent GDM

The hormonal changes of pregnancy reduce insulin sensitivity and glucose tolerance, which can result in the clinical presentation of GDM.14 By increasing insulin sensitivity and improving glucose tolerance via several mechanisms, physical activity has a beneficial effect on many aspects of insulin resistance syndromes.1517 During physical activity, glucose uptake and utilization by working muscle are increased in direct proportion to the intensity of the exercise.16 After physical activity, glucose tolerance is improved for 48–72 h by increasing cellular sensitivity to circulating insulin.18,19 Although the exact mechanism is still contentious, prior physical activity clearly upregulates the translocation of insulin-sensitive glucose transporters to the cell surface, facilitating glucose uptake from the blood.20Longer-term, even relatively modest increases in habitual physical activity induce adaptations that can have profound effects on glucose tolerance18 and potentially reduce the risk for GDM.

Prior epidemiologic studies have suggested that prepregnancy physical activity may have a protective role in the development of GDM.2127 Studies examining activity during pregnancy have been less consistent with one case–control study21 and one small cohort study28 observing a significant protective effect and others supporting this trend, but not significantly so.22232627

Engaging in 30 min of moderate intensity physical activity (e.g., brisk walking) during most days of the week has been adopted by the American College of Obstetricians and Gynecologists as a recommendation for pregnant women without medical or obstetrical complications.29 This approach, which emphasizes the accumulation of physical activity (e.g., through 10-min sessions) may be more acceptable to pregnant women than traditional exercise recommendations. Individually-tailored, motivationally-matched exercise interventions have been found to be an effective, low-cost approach for enhancing physical activity participation among nonpregnant women in the community but have not been adequately evaluated among pregnant women.3032 Furthermore, the majority of pregnant women in the United States are inactive,33 with minority women reporting lower levels of recreational physical activity during pregnancy as compared with nonminority women.34

To date, few primary prevention studies have intervened to test whether making a change in physical activity reduces risk of developing GDM among women at risk of this disorder. In one of the first studies, Dyck et al. examined the feasibility of early pregnancy exercise (<21 weeks gestation) in Aboriginal women in Saskatchewan with a prior history of GDM.35 Participants were asked to exercise for 45 min, 3 times per week, at 70% of age predicted maximum. Failure to achieve targeted recruitment goals (n = 10) was attributed to lack of community-based participatory research techniques.

Mottola et al. conducted a pilot study, the Nutrition and Exercise Lifestyle Intervention Program (NELIP), among 23 overweight women (prepregnancy BMI ≥ 25 kg/m2) at 16–20 weeks gestation. The intervention consisted of a mild walking program (30% of peak VO2, 3–4 times/week) combined with nutritional control (8,350 kJ/day; 200 g carbohydrate/ day).36 None of the participants developed GDM, and oral glucose tolerance (OGTT) values at 34–36 weeks gestation were significantly lower than reference values for women diagnosed with GDM (p < 0.05). HbA1c values and insulin areas under the curve remained within the normal range at 34–36 weeks. While provocative, this study was limited by lack of a control group.

The Behaviors Affecting Baby and You (BABY) Study is an ongoing intervention study in Western Massachusetts designed to investigate the effects of a motivationally-targeted, individually tailored physical activity intervention on risk of GDM among women at high risk of the disorder.37 The B.A.B.Y. study was initiated in 2007 and plans to recruit a total of 364 women (49% will be from minority groups). Primary outcomes include GDM, serum biomarkers associated with insulin resistance (i.e., glucose, insulin, leptin, tumor necrosis factor alpha, resistin, C-reactive protein, and adiponectin), and the adoption and maintenance of exercise during pregnancy. Secondary goals are to investigate the impact of the intervention on gestational weight gain and selected birth outcomes (i.e., accelerated fetal growth, Apgar score).

Women are recruited in early pregnancy and randomized to either an exercise intervention or a comparison health and wellness intervention. Both interventions consist of 12-week programs ending at routine GDM screen (24–28 weeks gestation) with approximately 14 weeks of follow-up (ending at birth). The overall goal of the exercise intervention is to encourage pregnant women to achieve American College of Obstetricians and Gynecologists (ACOG) guidelines for physical activity during pregnancy (30 min or more of moderate-intensity activity on most days of the week) through increased walking and developing a more active lifestyle in one daily session or accumulated through 10-min sessions.29 The health and wellness group receives high-quality, low-cost, self-help general health and wellness during pregnancy material, which is currently available to the public.

For both intervention groups, a baseline face-to-face session with individualized counseling is followed by weekly and biweekly mailed, print-based materials as well as telephone booster calls to provide motivationally-based individualized feedback. The face-to-face session takes place at the hospital or at the participant’s home, according to the participant’s preference. Physical activity is assessed via three 24-h recalls, 7-days of accelerometer monitoring, and the Pregnancy Physical Activity Questionnaire (PPAQ).38 Dietary recalls are conducted in mid pregnancy and serum biomarkers are collected at baseline and at 24–28 weeks gestation. The intervention protocol can readily be translated into clinical practice in underserved and minority populations.

In summary, intervention studies utilizing exercise to prevent GDM are sparse and largely reflect pilot studies or recently initiated trials. Consistent with this finding, evidence-based physical activity prevention programs for GDM with guidelines for frequency, intensity, duration, and type of activity remain to be established.39 Ongoing and future well-controlled intervention studies in this area will inform programs designed to prevent the incidence of GDM in women at risk of this disorder.

23.2.2 Dietary Interventions Designed to Prevent GDM

Dietary factors such as fat, fiber, and glycemic load (GL) have been associated with fasting insulin levels and obesity in adults40 and a small number of prior studies suggest that they may also be related to GDM. In epidemiologic studies, GL prior to pregnancy was associated with the development of GDM in a large prospective cohort study of 21,765 nurses.24 In contrast, GL during early pregnancy was not associated with risk of GDM in a cohort of 1,733 women enrolled in Project Viva.41 High fat diets have been associated with the recurrence of GDM in future pregnancies42 and the development of glucose abnormalities during pregnancy in some studies43 but not in others.41 The findings for fiber have also been inconsistent with some studies supporting a protective effect42,44 while others have not.4145,46

The Cochrane Review recently reviewed randomized and quasi-randomized controlled trials including dietary strategies designed to prevent GDM in pregnant women.47 One study assessed the effect of a high fiber diet48 and two studies compared the impact of high and low glycemic index (GI) diets.49,50 In the first, Fraser et al. randomized 23 nonobese women at 27 weeks gestation to a high fiber diet group or a control group. The high fiber group received advice from a dietician to reduce intake of sucrose and white flour and to make as many high fiber substitutions as possible. The control group was given standard dietary advice. There was no significant difference in mean OGTT results at 35 weeks between the groups (mean difference −0.36, 95% CI −0.90−0.18). However, there was a significant attenuation of postprandial insulin secretion in the high fiber group.

The two studies which evaluated GI randomly assigned a small number of women (ranging from n = 20 to n = 62) to either a low GI or high GI diet in early pregnancy.49,50 In terms of maternal outcomes, the one study that assessed GDM observed only one case in the high GI group and none in the low GI group.50 This study also found an RR of 0.09 for large-for-gestational age (LGA) infants among women in the low GI diet as compared to women on the high GI diet (95% CI 0.01−0.69). For both studies, maternal fasting blood glucose was lower on the low GI diet (weighted mean difference −0.28 mmol/L, 95% CI −0.54 to −0.02) and infants born to women on the low GI diet had better outcomes with respect to birth weight and ponderal index. However, while a low GI diet was beneficial for these selected maternal and child outcomes, results from the review were inconclusive. Neither study reported on other prespecified neonatal outcomes including macrosomia, perinatal mortality, shoulder dystocia, neonatal hypoglycemia, or maternal outcomes such as preeclampsia.

In summary, exercise and diet are promising approaches in the prevention of GDM but intervention studies are sparse. The three studies meeting the Cochrane review criteria included a limited number of outcome variables and included small numbers of participants. Further trials with larger sample sizes and longer follow-up are required to reach more definitive conclusions and to inform clinical practice.

23.3 Interventions to Treat GDM Among Women Diagnosed with GDM

There is controversy regarding the management of GDM and impaired glucose tolerance (IGT) in pregnancy. The majority of women diagnosed with GDM undergo intensive treatment regimens with the goal of preventing pregnancy complications, the most common of which is macrosomia.51 However, other factors such as maternal weight and ethnicity may be more important predictors of birth weight than GDM. Further complicating treatment decisions are recent findings suggesting that there may be a continuum of risk with respect to glucose levels and birth weight.52 In spite of these factors, lifestyle modifications, including physical activity and diet in response to the GDM diagnosis, have potential long-term implications for maternal and fetal health. In addition, such behavioral changes made during pregnancy may also be sustained after pregnancy, thus independently reducing risk of type 2 diabetes.

23.3.1 Dietary-Based Treatment Interventions After Diagnosis of GDM

Dietary advice has long been part of a standard regimen of GDM treatment. In 2003, the Cochrane review evaluated randomized controlled trials of alternative management strategies, including diet, for women with GDM and IGT in pregnancy.51 Inclusion criteria were strict and many studies were excluded due to the variation in diagnostic criteria or because they contained an additional screening step that selected from within the population of women with GDM. Trials with GDM as an outcome did not meet the criteria, and only one dietary intervention study with IGT as the primary outcome was included.53In this study, Langer et al. randomized 126 women with IGT to a treated and untreated group. All participants monitored capillary blood glucose 7 times/day. In addition, the treated group was managed according to a protocol which included dietary advice determined by prepregnancy BMI and insulin treatment. The untreated group continued normal eating patterns. There was no difference in the percentage of cesarean sections, NICU admissions, or the gestational age at delivery between the treated and untreated groups. However, the authors observed a lower incidence of neonatal hypoglycemia (RR = 0.13, 95% CI 0.02–0.97) as well as a significant reduction in macrosomia (RR=0.27, 95% CI 0.09–0.76) in the treated group as compared with the untreated group.

While this review failed to show any benefit from dietary intervention in women with GDM, a review of observational and clinical studies conducted from 1995 to 2001 determined that although a number of the studies were of poor quality, findings in general supported the effectiveness of dietary advice as a means of improving maternal hyperglycemia and reducing the risk of accelerated fetal growth.54However, the evidence supporting energy restriction, as well as the optimal balance of dietary carbohydrate and fat intake remain controversial.

Since the publication of these reviews, the Australian Carbohydrate Intolerance Study in Pregnancy (ACHOIS) completed a multicenter, blinded, randomized controlled trial to determine whether treatment of mild GDM, including a dietary strategy, would reduce perinatal complications and improve maternal outcomes, mood, and quality of life ref 72. A total of 1,000 women were enrolled at 14 sites in Australia and four sites in the United Kingdom. Between 24 and 34 weeks gestation, women were randomly assigned to receive individualized dietary advice, blood glucose monitoring, and insulin therapy as required for glycemic control (n = 490); or to routine care (n = 510).

The authors found that the rate of serious perinatal complications was significantly lower among the infants in the intervention group (1% vs. 4%, RR = 0.33; 95% C.I. 0.14–0.75). There were no differences in the rate of cesarean section between groups, however infants of women in the intervention group had higher neonatal intensive care unit admissions and labor induction rates as compared with women in the routine care group. This difference may have been due to physician awareness and response to GDM diagnosis.55 Infants born to mothers in the intervention group were less likely to be LGA as compared with the routine care group. This is important, as infants who are LGA are prone to impaired glucose tolerance or diabetes later in life and have an increased risk of GDM.56,57 This study, therefore, provides critical evidence that GDM treatment, including dietary advice, can reduce the risk of adverse perinatal outcomes.

In summary, while recommendations for GDM management have long included nutritional counseling, areas of continued controversy include defining the appropriate glucose levels to initiate such therapy. Further intervention studies are required to assess the impact of dietary management on pregnancy outcomes in women with GDM, as well as the impact on long-term maternal and fetal outcomes.

23.3.2 Exercise-Based Treatment Interventions After Diagnosis of GDM

Although dietary strategies have been the mainstay of therapy for women with GDM, many of these women will experience fasting and/or postprandial hyperglycemia despite dietary interventions. Insulin is typically prescribed for these patients.58 However, insulin corrects the hyperglycemia without affecting the peripheral insulin resistance.58 Thus, physical activity, which affects insulin resistance, may be the preferable intervention in the absence of either medical or obstetric complications. Indeed, exercise has long been accepted as an adjunctive intervention in the management of diabetes in nonpregnant subjects.39

In 1985, Artal et al conducted the first pilot study on the efficacy and safety of an exercise program in 13 insulin-requiring pregnant women with GDM and 42 control women.59 The authors did not observe significant changes in plasma glucose, epinephrine, glucagon, or free-fatty-acid levels with low-level exercise, however plasma norepinephrine significantly increased with exercise. These findings were reflected in the Second International Workshop-Conference on GDM, which recommended that women with an active lifestyle continue a program of moderate exercise under medical supervision during pregnancy.60

In 2006, the Cochrane Review reviewed randomized controlled trials comparing any exercise program to no specific exercise program among pregnant women with GDM.61 A total of four trials met the eligibility criteria.62 - 65In these studies, women were recruited during the third trimester and the exercise intervention was performed for approximately 6 weeks. Programs consisted of exercising 3–4 times weekly on a cycle ergometer at 70% VO2 max for 30 min,64 cycling for 45 min 3 times weekly at 50% VO2 max,63 20 min training on an arm ergometer 3 times/week,62 and 30 min circuit type resistance training 3 times/week.65 The review found no significant differences between the exercise and control groups for all the outcomes evaluated and concluded that there is insufficient evidence to recommend, or advise against, enrolling diabetic pregnant women in exercise programs. However, in combination with other small treatment studies which did not qualify for the review, findings suggest that women receiving an exercise intervention had greater glycemic control, lower fasting and postprandial glucose concentrations, and improved cardiorespiratory fitness as compared with those receiving a standard dietary intervention.66

In one of the most well known randomized trials, Jovanovic-Peterson et al. randomized 19 women to an arm ergometry exercise program in combination with a dietary intervention, or to a standard diet for 6 weeks.62 The exercise program consisted of 20 min of arm ergometry 3 times per week at 50% of VO2 max. The intervention group had greater glycemic control, lower fasting and postprandial glucose concentrations, and improved cardiorespiratory fitness as compared with the control group. However, glycemic levels did not diverge between the groups until week 4 of the intervention.

More recently, Artal et al. conducted an intervention study to assess whether a weight gain restriction regimen with or without exercise would impact glycemic control, pregnancy outcome, and total pregnancy weight gain among obese subjects with GDM.67 A total of 39 subjects were self enrolled in the exercise and diet group and 57 subjects self enrolled in a diet only group according to contraindications or lack of personal preference for exercise. Exercise subjects were prescribed an exercise routine equivalent to 60% of VO2 max. Although glucose control was not reported, weight gain per week was significantly lower in the exercise group (0.1 ± 0.4 kg vs. 0.3 ± 0.4 kg, p< 0.05) as compared to the diet only group; pregnancy and fetal outcomes were similar in both groups. Findings suggest that a diet plus exercise intervention is successful at limiting excessive weight gain in women with GDM as compared to diet alone. However the lack of randomization precludes attributing results to the exercise intervention alone; the two groups may have differed on factors also related to weight change.

Most recently, Davenport et al. conducted a pilot project to determine the effectiveness of a structured low intensity walking protocol on capillary glucose control in women with GDM.68 Women were randomized to conventional management of diet and insulin therapy plus a low intensity walking program (n = 10) or to conventional management alone (n = 20). The walking program consisted of 3–4 exercise sessions per week at 30% of heart rate reserve, increasing gradually from 25 min of walking to 40 min of walking from the time of GDM diagnosis to delivery. The groups were matched on BMI, age, and insulin usage. In the week prior to delivery, the intervention group had significantly lower mean glucose concentrations in the fasted state, and 1-h after meals, achieved with fewer units of insulin per day than the comparison group. Findings suggest an effective role for a practical, structured walking program for women with GDM.

In summary, exercise intervention studies suggest that moderate exercise may be effective in lowering maternal glucose concentrations in women with GDM but are limited by small sample size, lack of well controlled or reported exercise intensity, and differences in the type, intensity, and duration of the training programs.39,69 Despite endorsements by professional organizations,29,7071 exercise for patients with GDM has not been widely prescribed or practiced and exercise remains an adjunctive therapy.39 Additional controlled clinical trials are necessary to determine the effectiveness of structured exercise programs as well as to identify the appropriate type, duration, and intensity of such exercise.39

23.4 Conclusion

Physical inactivity and poor diet are important risk factors for obesity and type 2 diabetes, currently at epidemic rates in the United States. There is substantial evidence that targeting at-risk groups for type 2 diabetes prevention is effective, if lifestyle changes are made. For example, the Diabetes Prevention Program found that intensive lifestyle modification over 4 years with diet and exercise reduced the incidence of type 2 diabetes by more than 50%.19 In light of these observations, the potential for lifestyle interventions integrating appropriate diet and physical activity to reduce such GDM risk factors as overweight, obesity, and excessive maternal weight gain is high. In addition to being a tool for GDM prevention, the bulk of evidence from observational and clinical studies supports a protective role for diet and physical activity in the treatment of GDM. However, to date, randomized controlled clinical trials have been insufficient to conclusively demonstrate that treatment of women with GDM or IGT with diet, physical activity, and/or insulin improves maternal (e.g., preeclampsia) or fetal outcomes (e.g., birthweight, perinatal morbidity, and mortality).

Evidence-based exercise intervention studies should be designed to evaluate the frequency, intensity, duration, and type of physical activity necessary to optimize maternal and fetal outcomes among women with GDM or at risk for GDM. For example, such programs should evaluate the effect of exercise programs of differing intensities as well as active living activities such as walking, gardening, and household activities.39 Further dietary intervention studies are critical to assess the effects of a low GI diet on both GDM prevention as well as GDM treatment. The effectiveness of dietary interventions for overweight or obese women should also be assessed.47 Finally, given that each subsequent pregnancy is associated with greater postpartum weight retention, coupled with the increasing incidence of maternal obesity and GDM, a greater focus should be placed on evaluating the impact of diet and exercise interventions on excessive maternal weight gain.67

To date, randomized trials have not evaluated whether treatment with dietary strategies and/or exercise reduce the long-term risks associated with GDM including obesity and type 2 diabetes in the offspring.55 Such trials would add weight to the ACHOIS findings which supported the use of treatment, including a dietary strategy, in a population similar to the US in terms of ethnicity and obesity.72 The success of these future intervention studies relies, in part, on the achievement of consensus regarding the threshold for diagnosis and treatment of carbohydrate intolerance during pregnancy.

With this purpose in mind, the hyperglycemia and adverse pregnancy outcome (HAPO) study was designed to identify the diagnostic threshold between maternal hyperglycemia and adverse perinatal outcomes (i.e., cesarean section rates, fetal size, neonatal hypoglycemia, and fetal hyperinsulinemia).73 This 7-year prospective observational study enrolled 25,505 nondiabetic pregnant women in nine countries. However, no specific threshold was identified as findings suggested a consistent, continuous increase in risk of adverse pregnancy outcomes over the range of maternal blood glucose levels.

The ongoing Maternal Fetal Medicine Unit (MFMU) trial may also inform the threshold for diagnosis and treatment of carbohydrate intolerance during pregnancy.74,75 This multicenter randomized controlled trial randomizes women in the United States with mild GDM (fasting glucose <95 mg/dL) to formal nutritional counseling and dietary therapy along with insulin as required or to no specific treatment.7475 Perinatal outcomes will be compared between the two groups.

In conclusion, dietary advice and physical activity reinforcement should continue beyond pregnancy. Women should be informed of their risks and empowered to make lifestyle changes. As long-term follow-up studies reveal that a significant proportion of women with GDM go on to develop diabetes outside of pregnancy, especially during the first decade after the index pregnancy, GDM offers an important opportunity for the development, testing, and implementation of clinical strategies for diabetes prevention.76 Pregnant women more readily seek medical care and are highly motivated to make healthy lifestyle changes, making pregnancy a critical opportunity for both short- and long-term behavior modification.

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