JOURNAL OF WOMENS HEALTH Volume 20, Number 10, 2011 Mary Ann Liebert, Inc. DOI: 10.1089/jwh.2010.

2703

Interventions for Preventing Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis
1 1,2 Nicolette Oostdam, M.Sc., Mireille N.M. van Poppel, Ph.D., 3 1,2 Maurice G.A.J. Wouters, Ph.D., M.D., and Willem van Mechelen, M.D.

Abstract

Background: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM is associated with increased risks for mother and child during pregnancy and in later life. The aim of this article is to systematically review literature on the effectiveness of interventions to prevent GDM. Methods: Controlled trials found in PubMed, EMBASE, or CENTRAL were selected. The primary outcome was GDM, and relevant secondary outcomes were maternal fasting blood glucose and large-for-gestational age (LGA) or macrosomia. Data were combined in meta-analyses, and the quality of evidence for the effectiveness of the interventions was assessed in a GRADE approach. Results: Nineteen studies evaluating six types of interventions were included. Dietary counseling signicantly reduced GDM incidence compared to standard care. None of the interventions was effective in lowering maternal fasting blood glucose. Low glycemic index (LGI) diet advice and an exercise program signicantly reduced the risk of macrosomia. The quality of evidence for these outcomes was low. Conclusions: The results indicate that there may be some benets of dietary counseling, an LGI diet advice, or an exercise program. However, better-designed studies are required to generate higher quality evidence. At the moment, no strong conclusions can be drawn with regard to the best intervention for prevention of GDM.

Introduction he prevalence of gestational diabetes mellitus (GDM) is increasing worldwide,1 parallel to the increase in type 2 diabetes (T2D).2 Until recently, GDM was dened as glucose intolerance that begins, or is rst detected during pregnancy,3,4 usually between 24 and 28 weeks. In 2010, the need to diagnose women with likely prepregnancy diabetes was recognized, and testing for overt diabetes at the rst visit for prenatal care was recommended.5 Approximately 1% 14% of pregnant women will have a blood glucose level above normal, depending on the population and the diagnostic procedure applied.3 Risk factors for GDM include advanced maternal age, obesity, ethnicity, family history of T2D, history of a macrosomic baby, and a previous history of GDM.3,6 GDM is a risk factor for pregnancy-related maternal and perinatal morbidity, and mother and offspring have an in-

creased risk for developing T2D.7 The cause of GDM is the inability to meet the demand for increased insulin production to counteract the increased insulin resistance caused by hormones produced in pregnancy. Because of the overlap in risk factors for GDM and T2D and the similarities in the underlying pathophysiology, it is likely that strategies that are effective in the prevention of T2D might be successful in the prevention of GDM.810 These interventions involve reducing overweight and obesity, limiting gestational weight gain, improving diet and physical activity behavior, and various drug therapies with glucose-lowering agents.810 It is important to identify interventions that might prevent the development of glucose intolerance in pregnancy. Therefore, our aim was to systematically review the literature on (quasi) randomized controlled trials (RCTs) focusing on interventions to prevent GDM. The primary outcome of interest was the incidence of GDM, and secondary outcomes were blood glucose levels and macrosomia.

1 Department of Public and Occupational Health, EMGO + Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands. 2 Body@Work, Research Centre Physical Activity, Work and Health, TNO-VU University Medical Centre, Amsterdam and Hoofddorp, The Netherlands. 3 Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, The Netherlands.

1551

1552 Methods of Study Selection Search strategy The databases PubMed, EMBASE, and CENTRAL (Cochrane Central Register of controlled trials) were searched from January 1980 until March 2011 for relevant studies. The search strategy focused on four elements: (1) a population consisting of pregnant women in general (e.g., pregnancy, pregnancy complications), (2) outcomes related to GDM (e.g., gestational diabetes, maternal blood glucose, maternal body weight, embryonic and fetal development), (3) possible interventions to prevent or treat (gestational) diabetes (e.g., diet, exercise, drugs, supplements), and (4) clinical trials (adapted lter from Robinson and Dickersin11). These terms were used as MESH terms and as free text words, adjusted to each database. The search was limited to publications in the following languages: English, German, Danish, Dutch, Finnish, Norwegian, and Swedish. After inclusion of the articles that met the selection criteria, we searched the reference lists of the included studies and of relevant review articles for other eligible studies. Selection of studies Two reviewers (N.O. and M.v.P.) evaluated the studies identied with the search strategy. They independently reviewed the titles and the abstracts of every study to determine if the study met the inclusion criteria. When needed, the full text of the article was also retrieved. The articles were blinded for author, institution, and journal. Any differences in opinion with regard to the inclusion or exclusion of a study were resolved by consensus. Inclusion criteria were (1) study sample consisting of pregnant women, (2) (quasi) RCT, (3) the study evaluated an intervention that could prevent GDM, and (4) the outcome measures included GDM incidence and maternal fasting blood glucose level. Exclusion criteria were women with GDM or preexisting diabetes mellitus type I or type II. To evaluate the incidence of GDM, a large sample size is required; most RCTs had not enough power to evaluate GDM. Therefore, we also chose to look at effects on a secondary outcome measure, maternal fasting blood glucose, as a surrogate outcome for GDM. In addition, macrosomia, macrosomial (birth weight above 4000 gram) or LGA (above goth percentile [pgo] for gotationalage) was chosen as a secondary outcome in this review because it is the most important infant outcome associated with GDM. Methodologic quality and quality of evidence The two reviewers independently determined the methodologic quality of the selected studies. The quality was scored according to a quality assessment list for RCTs.12 The list consists of 10 items on sequence generation, allocation concealment, blinding, and other biases. All items were scored as 1 (yes), 0 (no), or ? (not or insufciently described). A consensus meeting was organized to discuss any differences between the scores of the two reviewers. For the criteria scored?, the authors of the original publication were contacted for additional information. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to determine the overall quality of evidence for each type of intervention.13 The quality of the evidence was assessed for ve domains: limitations of the study, consistency of

OOSTDAM ET AL. the results, directness (generalizability), precision, and publication bias.13 The overall quality of evidence was considered to be high if multiple RCTs with a low risk of bias provided consistent and generalizable ndings, direct and precise data, and no known or suspected publication bias.13 From this starting point, the quality of evidence was downgraded one level per domain that was not met. Thus, the GRADE approach results in four levels of evidence: high, moderate, low, and very low. GRADE proler software (version 3.2.2) was used. Data analysis Meta-analyses were performed among studies with the same kind of intervention that reported on the same outcome. For the dichotomous measures GDM and macrosomia, we calculated relative risk (RR) or risk difference (RD) with 95% condence intervals (CIs). For the continuous measure, maternal fasting glucose, we calculated weighted mean differences (WMD) with 95% CIs when it was measured in the same way in trials. Fixed-effect meta-analysis was applied to combine data in the absence of signicant heterogeneity between trials. Statistical heterogeneity was assessed with the Cochrans Q test and by calculating I2 values. I2 values of 25%, 50%, and 75% can be interpreted as low, substantial, and considerable heterogeneity. The random effect model for meta-analysis was used when I2 values exceeded 50%. Methodologic explanations for substantial heterogeneity were described in sensitivity analyses. The effect of outliers or of the largest trial on the overall outcome estimates was assessed in sensitivity analyses by recalculating the pooled outcome proportions with these studies removed one by one and all others included. Statistical analyses were performed using Review Manager 5.0 software. Results Selection of studies The literature search found 8416 potentially relevant studies. Fifty-one articles that were identied as potentially relevant were retrieved in full text (Fig. 1). Thirty-three studies were nally excluded from the review. The most important reasons for exclusion were that the study was not a controlled trial and the absence of GDM or maternal fasting glucose as an outcome measure. Eighteen articles met the inclusion criteria.1431 Reference checking found one extra relevant publication.32 Of the 19 studies included in the review, 13 evaluated the effects of a dietary intervention, 3 evaluated an intervention with metformin, and 3 evaluated an exercise training program. Table 1 provides detailed information about the included studies. Three studies were described in other articles and provided additional information for data extraction. Piirainen et al.33 and Luoto et al.34 provided additional information about the Laitinen et al. intervention22; Clapp35,36 provided additional information for the earlier article17; and Fougner et al.37 provided additional information for the Vanky et al. article.24 Methodologic quality Table 2 shows the scores for the methodologic quality of the included studies. For criteria that were scored ?, the authors were contacted for more information, and 11 authors responded to our request.1521,23,24,27,28 The nal quality scores are shown in Table 2, based on the additional information

SYSTEMATIC REVIEW OF PREVENTING GDM

1553

FIG. 1.

Flow chart of selection process. dices were comparable. However, the studies differed with regard to treatment in the preconception period and also with regard to co-interventions. All participants in the Clapp study17 received an LGI diet before conception until 8 weeks of pregnancy, and they also took part in an exercise program before and after pregnancy. Three trials (114 participants) showed no statistical difference in maternal fasting glucose (WMD - 0.13, 95% CI - 0.3 mmol/L-0.04 mmol/L) between pregnant women who received LGI diet advice and those who received HGI diet advice, but evidence was of low quality. Clapp17,35 and Rhodes et al.30 did not report GDM screening in the study sample. Moses et al.32 diagnosed only 1 woman with GDM, and she was allocated to the HGI group. Three trials showed that an LGI diet is more effective than an HGI diet in reducing a womans risk of having an LGA infant, with an RR of 0.14 (95% CI 0.050.41), but evidence was of low quality. There was low heterogeneity between the studies for maternal fasting glucose (I2 = 40%) and for LGA (I2 = 43%). Any dietary counseling vs. usual care. Nine studies16,18,19,21,22,25,26,27,31 compared any form of dietary counseling with usual care in a total of 836 participants. Fraser et al.,18 Hui et al.,21 Asbee et al.,26 Polley et al.,27 and Thornton et al.31 described usual care as providing a standard advice on diet during pregnancy. Bevier et al.,16 Guelinckx et al.,19 Laitinen et al.,22 and Wolff et al.25 described usual care as no special diet or no consultations. The Guelinckx et al. study19 had two intervention groups; a passive group received a brochure on diet and physical activity, and the active group received active counseling. The active intervention group corresponded most closely with the intervention groups in the other studies and was used for the pooling. Laitinen et al.22 also had two intervention groups: diet/placebo and diet/ probiotics. Both intervention groups were combined into one single intervention group for the pooling. Not all studies reported data on all three outcomes. Asbee et al.26 included the measures of birth weight and GDM but did not publish

provided by the authors (indicated by*). The most prevalent shortcomings were found in the items about blinding. Main ndings Figures 2, 3, 4, and 5 show the forest plots of the effect of four different interventions for maternal fasting blood glucose, GDM, and macrosomia in pregnant women. Metformin vs. no metformin. Begum et al.15 and Vanky et al.24,28 studied metformin therapy vs. no metformin in a total of 369 participants with polycystic ovary syndrome (PCOS). Maternal fasting glucose data from these studies could not be pooled because Vanky et al.28 did not yet publish these data and Begum et al.15 did not report maternal fasting glucose in the second or third trimester. Vanky et al.24 found a decrease in maternal fasting glucose in the metformin group that was not statistically signicant. The three trials (348 participants) showed no statistical difference on the risk for GDM (RR 0.80, 95% CI 0.361.78) between pregnant women with PCOS who received metformin and those who received placebo, but evidence was of very low quality. The three trials (369 participants) showed no statistical difference in reducing a womans risk of having a macrosomic infant, with an RR of 0.97 (95% CI 0.631.48) between pregnant women with PCOS who received metformin and those who received placebo, but evidence was of very low quality. There was substantial heterogeneity between the studies for GDM (I2 = 59%), and low heterogeneity for macrosomia (I2 = 18%). Low glycemic index (LGI) diet advice vs. high glycemic index (HGI)/low fat diet advice. Clapp,17 Moses et al.,32 and Rhodes et al.30 compared giving advice on an LGI diet (carbohydrates that break down more slowly during digestion) with advice on an HGI diet (carbohydrates that break down quickly) or low fat diet in a total of 127 participants. In all studies, the participants started the dietary intervention in the rst half of their pregnancy and continued until 36 weeks of gestation. The composition of the diets and the glycemic in-

Table 1. Characteristics of Included Studies Results as reported by authors intervention vs. control group No signicant difference in GDM.

Author Pregnant women I: n = 57, C: n = 43 Routine prenatal care and standard information booklet on diet and exercise.

Study design

Participants sample size

Intervention

Control

Asbee et al., 200926

RCT

Barakat et al., 200914

RCT

Maintain level of activity during study period. Meformin before pregnancy until 6 weeks of pregnancy. No special diet or home glucose monitoring instruction.

GDM, 23.6% vs. 31.4% Macrosomia, 1.4% vs. 10%

Begum et al., 200915

RCT

Bevier et al., 199916

RCT

1554 Healthy women with uncomplicated pregnancy. I: n = 10, C: n = 10

Spanish pregnant women of low-to-medium socioeconomic class. I: n = 72, C: n = 70 Nondiabetic women with PCOS. I: n = 29, C: n = 30 Pregnant women with positive glucose challenge test and negative oral glucose challenge test. I: n = 35, C: n = 48

GDM, OR 12, 95% CI 6.2018.08) LGA, 0% vs. 13.33% Birth weight was signicantly higher in control group.

Clapp, 199717

RCT

Counseling: Information about gestational weight gain guidelines, moderate exercising 35 times/week was recommended, diet advice (40% CHO, 30% fat, 30% protein) by dietitian. Each visit, weight was compared with guidelines and intervention was adapted. Started 616 weeks of pregnancy. Three sessions per week light resistance and toning exercises from 12 weeks of pregnancy until end of pregnancy. Metformin therapy before and during whole pregnancy. Dose of metformin was according to BMI. Weekly dietary counseling by clinic nurse from 24 weeks of pregnancy and home glucose monitoring instruction. Diet calculated using 30 kcal/kg present pregnant weight/24 hours if the woman was 80%120% of ideal body weight, or 24 kcal/kg/24 hours if she was > 120% of ideal body weight (40% fat, 20% protein, 40% CHO). Dietary recalls by dietitian at random times twice weekly during pregnancy (starting in rst trimester of pregnancy). LGI diet with LGI foods (20%25% fat, 17%19% protein, and 55%60% CHO) with total 3545 kcal/kg of lean body mass. Before pregnancy, a weight-maintaining diet. Before and during pregnancy, supervised exercise regimen. Dietary recalls by dietitian at random times twice weekly during pregnancy (starting in rst trimester of pregnancy). HGI diet with HGI foods (20%25% fat, 17%19% protein, and 55%60% CHO) with total 3545 kcal/kg of lean body mass. Before pregnancy, a weight-maintaining diet. Before and during pregnancy, supervised exercise regimen.

All women in HGI had an increase in area under the 3 hour postprandial glucose and insulin responses, those in LGI had no increase. All infants in HGI group were LGA; those in LGI group had normal limits. (continued)

Table 1. (Continued) Results as reported by authors intervention vs. control group Glucose homeostasis was similar in both groups. None of the participants had GDM or macrosomic infants. No signicant differences in neonatal outcome (macrosomia) between groups.

Author Healthy primigravid whose nonpregnant weights were < 110% of ideal for height. I: n = 13, C: n = 12 Standard advice on diet in pregnancy (calorie intake) at 27 weeks of pregnancy, where 2400 calorie intake was suggested (38.5% fat, 17%19% protein, and 43%44% CHO). Routine prenatal care.

Study design

Participants sample size

Intervention

Control

Fraser et al., 198318

RCT

Guelinckx et al., 201019 Obese pregnant women. I1: n = 43, I2: n = 37, C: n = 42

RCT

1555 Healthy nulliparous women. I: n = 47, C: n = 37 Pregnant women. I: n = 24, C: n = 21 Pregnant women I: n = 125, C: n = 111 Computer-assisted food choice map, dietary interviews, and counseling. Personalized plan including recommended changes in food choice, frequency, portion size, and pattern of intake. Weekly group sessions and homebased exercises. Started at 2030 weeks of pregnancy. Self-monitoring gestational weight gain started at 16 weeks of pregnancy.

Hopkins et al., 201020

RCT

Dietitian advice started at 27 weeks of pregnancy and continued for 8 weeks at all antenatal visits. High dietary ber and advice to reduce intake of sucrose and white our while aiming for calorie intake of 2400 (38.5% fat, 17%19% protein, and 43%44% CHO). Intervention 1: Brochure and active counseling by nutritionist in 3 group sessions. Healthy diet and limiting energy-dense foods (30%35% fat, 9%11% protein, and 50%55% CHO) and physical activity advice Intervention 2: Brochure about nutrition and physical activity advice and tips to limit weight gain. Started at 15 weeks of pregnancy. Five sessions per week home-based stationary cycling program from 20 weeks of gestation to delivery. Continue normal daily activities for duration of their pregnancy. Standard care. Information package on diet and activity for healthy pregnancy.

Hui et al., 200621

RCT

No measurable effect of aspects of maternal glucose metabolism. None of the participants had GDM. GDM, 4% vs. 10% Macrosomia 8% vs. 19%

Jeffries et al., 200929

RCT

Standard antenatal care.

GDM, 10.5% vs. 9.0% LGA 6.5% vs. 9.9% (continued)

Table 1. (Continued)

Author Pregnant women. I1: n = 85, I2: n = 86, C: n = 85 Intervention 1: Probiotic capsules and dietary counseling. Control (no counseling) and placebo.

Study design

Participants sample size

Intervention

Control

Results as reported by authors intervention vs. control group Blood glucose concentration was lowest in diet/ probiotics group. GDM intervention 1 = 13% vs. intervention 2 = 36% vs. control = 34% One woman from HGI group diagnosed with GDM. LGA, 3.1% vs. 33.3% No signicant differences in glucose between groups.

Laitinen et al., 200922

RCT

Moses et al., 200632 Healthy pregnant women. I: n = 32, C: n = 30

Quasi-RCT

Ong et al., 200923 Sedentary obese pregnant women. I: n = 6, C: n = 6 Pregnant women I: n = 67, C: n = 43

RCT

Five sessions with dietitian during pregnancy, started in rst half of pregnancy. HGI diet: high bre and low sugar (33% fat, and 55% CHO). Continue usual daily activities.

1556 Pregnant women with BMI between 25 and 45 I: n = 25, C: n = 21 Obese pregnant women I: n = 116, C: n = 116 Prescribed a balanced nutritional regimen based on weight started between 12 and 28 weeks of pregnancy (40% CHO, 30% protein, 30% fat)

Polley et al., 200227

RCT

Standard care and standard nutrition counseling.

GDM, 3.5% vs. 5.7% Macrosomia, 1.75% vs. 0% No signicant differences in glucose between the groups. Macrosomia 8% vs. 5%

Rhodes et al., 201030

RCT

Intervention 2: Dietary counseling. Three counseling sessions with a dietitian focused on amount and type of fat and ber. Started in the rst half of pregnancy. Five sessions with dietitian during pregnancy, started in rst half of pregnancy. LGI diet: LGI foods (33% fat, and 55% CHO). Three sessions per week homebased supervised exercise (upright stationary cycle ergometer) from 18 to 28 weeks of pregnancy. Regularly scheduled clinic visits for education and feedback about healthy diet, weight gain, and exercise. Start before 20 weeks of pregnancy. Counseling sessions by dietitian with 24-week interval from 13 28 till 36 weeks of gestation. Low glycemic load diet: reducing CHO and replacing higher GI CHO with lower GI CHO (45% CHO, 35% fat, 20% protein). Subjects were provided with the majority of their CHO-rich foods.

Thornton et al., 200931

RCT

Counseling sessions by dietitian with 24-week interval from 13 28 till 36 weeks of gestation. Low fat diet: moderately low fat, low fat saturated fat, high complex CHO without considering glycemic index (55% CHO, 25% fat, 20% protein). Subjects were provided with the majority of their CHO-rich foods. Told to eat to appetite following general prenatal dietary guidelines.

GDM, 9.5% vs. 16.4% Macrosomia ( > 4500g), 7.8% vs. 3.4%

(continued)

Table 1. (Continued) Results as reported by authors intervention vs. control group Women diagnosed with GDM did not differ between groups, nor did any other indices of glucose metabolism. GDM, 17.6% vs. 16.9% Macrosomia, 21.5% vs. 20% Placebo identical capsules. In addition 1 mg folate and multivitamin capsules.

Author Women with diagnosis of PCOS before pregnancy. I: n = 22, C: n = 18

Study design

Participants sample size

Intervention

Control Metformin before pregnancy. After conception, placebo identical capsules. In addition 1 mg folate and multivitamin capsules.

Vanky et al., 200424

RCT

Vanky et al., 201028 Pregnant women with PCOS I: n = 136, C: n = 138

RCT

1557 Nondiabetic obese pregnant women. I: n = 23, C: n = 27 Restricted energy diet (30% fat, 15%20% protein, and 50%55% CHO) from 15 weeks of pregnancy to delivery.

Wolff et al., 200825

RCT

Metformin therapy before and during whole pregnancy. Two capsules of 425 mg once daily during rst week and 2 capsules twice daily for rest of study. In addition, 1 mg folate and multivitamin capsules. Metformin therapy during whole pregnancy. Two capsules of 500 mg once daily during rst week and 2 capsules twice daily for rest of study. In addition, 0.8 mg folate and multivitamin capsules. Ten sessions of dietary counseling with dietitian. No consultations.

Reduced fasting blood glucose in intervention group vs. control.

BMI, body mass index; C, control group; CHO, carbohydrate; CI, condence interval; GDM, gestational diabetes mellitus; HGI, high glycemic index; I, intervention group; LGA, large-for-gestational age; LGI, low glycemic index; OR, odds ratio; PCOS, polycystic ovary syndrome; RCT, randomized controlled trial.

1558 Table 2. Scores for Quality of Included Studies

OOSTDAM ET AL.

10. 9. 8. 6. 5. 4. Care 3. Intention- Treated Valid 7. Patient provider Outcome Baseline 1. 2. Randomization Concealment blinded blinded blinded similar Dropouts to-treat equally results Asbee et al.26 Barakat et al.14 Begum et al.15,* Bevier et al.16,* Clapp.17,* Fraser et al.18,* Guelinckx et al.19,* Hopkins et al.20,* Hui et al.21,* Jeffries et al.29 Laitinen et al.22 Moses et al.32 Ong et al.23,* Polley et al.27,* Rhodes et al.30 Thornton et al.31 Vanky et al.24,* Vanky et al.28,* Wolff et al.25 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 0 1 1 0 1 1 1 1 1 1 1 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 1 1 0 0 ? 0 0 1 0 0 0 0 0 0 1 0 1 1 0 1 1 1 0 1 0 0 0 0 0 1 0 0 1 0 0 1 1 0 1 1 ? 1 1 1 1 1 1 1 0 1 1 1 0 1 0 1 1 1 1 1 0 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Rating of criteria: 1 = yes; 0 = no; ? = not or insufciently described. *Indicates that extra information is provided by the authors of the article.

the numbers of macrosomia and numbers of GDM. For this reason, the Asbee study was excluded from the pooling. Three studies16,18,25 reported on maternal fasting glucose in the third trimester of pregnancy. These three trials (98 participants) showed no statistical difference in maternal fasting glucose (WMD - 0.21, 95% CI - 0.45 mmol/L-0.02 mmol/L) between pregnant women who received dietary counseling and those who received usual care, but evidence was of very low quality. Seven studies18,19,21,22,25,27,31 reported on the incidence of GDM. These seven trials (813 participants) showed that dietary counseling is more effective than usual care in reducing the risk of GDM (RD - 0.05, 95% CI - 0.10- - 0.01), but evidence was of very low quality. Five studies16,18,19,21,27 reported on the number of infants with a birth weight > 4000 g (macrosomia). These ve trials (383 participants) showed no statistical difference with regard to having a macrosomic infant with an RD of - 0.04 (95% CI - 0.15-0.06), but evidence was of very low quality. There was no heterogeneity between these trials for maternal fasting glucose (I2 = 0%), low heterogeneity (I2 = 41%) for GDM, and considerable heterogeneity (I2 = 77%) for macrosomia. Probiotics with dietary counseling vs. dietary counseling alone. The Laitinen et al. study22 compared dietary counseling and probiotics with dietary counseling alone. They found a signicant reduction in the incidence of GDM (odds ratio [OR] 0.27, 95% CI 0.11-0.62) but gave no information about glucose levels or the incidence of macrosomia. As there was only one trial (256 participants) that assessed the effect of probiotics, there is very low evidence for the effect of probiotics on the risk for GDM. Self-monitoring weight gain vs. standard care. The Jeffries et al. study29 compared self-monitoring of weight gain with standard care. They found no signicant reduction in the incidence of GDM ( p = 0.83) and the incidence of macrosomia

( p = 0.47). As there was only one trial (257 participants) that assessed the effect of self-monitoring of weight gain, there is very low evidence for the lack of effect of self-monitoring of weight gain on the risk for GDM and macrosomia. Exercise vs. usual care. Three studies14,20,23 with a total of 238 participants compared exercise with usual care (continue usual daily activities). In two of these studies,14,20 the exercise training program started in the second trimester and continued until the end of pregnancy. The Ong et al. study23 continued for 10 weeks. Ong et al.23 and Hopkins et al.20 used a home-based stationary cycling program, and Barakat et al.14 used resistance and toning exercises. Not all studies reported data on all three outcomes. Two trials20,23 (96 participants) showed no statistical difference in maternal fasting glucose (WMD 0.07, 95% CI - 0.08 mmol/L-0.22 mmol/L) between pregnant women who received an exercise training program and those who received usual care, but evidence was of very low quality. Three trials14,20,23 (238 participants) showed no statistical difference in the risk for GDM (RD - 0.05, 95% CI 0.20-0.10) between pregnant women who received an exercise training program and those who received usual care, but evidence was of very low quality. Two trials14,20 (226 participants) showed that an exercise training program is more effective than usual care in reducing a womans risk of having a macrosomic infant, with an RR of 0.36 (95%CI 0.13-0.99), but evidence was of very low quality. There was no heterogeneity among these trials for maternal fasting glucose (I2 = 0%), substantial heterogeneity (I2 = 66%) for GDM, and low heterogeneity (I2 = 38%) for macrosomia. Sensitivity analysis If a study appeared to be an outlier (had results very different from the rest of the studies), its inuence on a metaanalysis was assessed by excluding it. We performed this type

SYSTEMATIC REVIEW OF PREVENTING GDM

1559

Outcome GDM

p p

Outcome macrosomia

p p

FIG. 2. Forest plots of the effect of metformin vs. no metformin for gestational diabetes mellitus (GDM) and macrosomia in pregnant women. (A) Outcome GDM. (B) Outcome macrosomia (birth weight > 4000 g). Data are weighted mean differences, risk ratios (RRs) with 95% condence interval (CI). *Indicates that extra data information was provided by the authors of the article.

of sensitivity analysis, by excluding the studies of Begum et al.,15 Fraser et al.,18 Bevier et al.,16 and Guelinckx et al.19 Excluding Fraser et al. resulted in a signicant effect of dietary counseling on the outcome, maternal fasting blood glucose (WMD - 0.29 mmol/L, 95%CI - 0.55- - 0.03). To determine if a meta-analysis result was being heavily determined by a particular trial, it might be repeated excluding

that trial; for example, the largest trial or the earliest trial could be driving the result. We performed this type of sensitivity analyses by excluding the largest trials of Rhodes et al.30 and Vanky et al.28 Excluding Rhodes et al. gave a signicant result for advice on a low glycemic diet on the outcome, maternal fasting blood glucose (WMD 0.27 mmol/L, 95%CI - 0.51- - 0.03).

Outcome maternal fasting blood glucose

p p

Outcome large-for-gestational age

p p

FIG. 3. Forest plots of the effect of low glycemic index (LGI) diet advice vs. high glycemic index (HGI) diet advice for maternal fasting blood glucose and large-for-gestational age (LGA) in pregnant women. (A) Outcome maternal fasting blood glucose. (B) Outcome large-for-gestational age (LGA). Data are weighted mean differences, RRs with 95% CI. *Indicates that extra data information was provided by the authors of the article.

1560

OOSTDAM ET AL.

Outcome maternal fasting blood glucose

p p

Outcome GDM

p p

Outcome macrosomia

p p

FIG. 4. Forest plots of the effect of dietary counseling vs. usual care for maternal fasting blood glucose, GDM, and macrosomia in pregnant women. (A) Outcome maternal fasting blood glucose. (B) Outcome GDM. (C) Macrosomia (birth weight > 4000 g). Data are weighted mean differences, risk differences (RDs) with 95% CI. *Indicates that extra data information was provided by the authors of the article.

Apart from the sensitivity analyses, we looked at methodologic explanations for heterogeneity (differences in intervention or populations or both) when substantial statistical heterogeneity was found. Substantial heterogeneity was found for metformin on GDM, for dietary counseling on macrosomia, and for exercise on GDM. For the three studies on metformin, no methodologic explanation for heterogeneity could be found, as the intervention and the study populations were very similar. The nine studies on dietary counseling showed much methodologic heterogeneity, such as the start of the counseling (rst or second trimester) and the frequency of the counseling (varying from twice only to weekly during pregnancy). Most importantly, these studies differed because in addition to the variation in dietary counseling, most of the interventions also had a co-intervention, such as home glucose monitoring, exercise, weight gain monitoring, or probiotics. These interventions may have reinforced the effect of the dietary intervention. However, excluding one study at a time did not change the result of nding no effect of dietary

counseling on macrosomia. For exercise, methodologic differences were found in the duration of the intervention and the type of exercise proscribed (cycling vs. strength training). However, excluding studies one at a time did not change the result of nding no effect of exercise on GDM. Conclusions In this systematic review, we identied 19 (quasi) RCTs that evaluated the effects of an intervention for the prevention of GDM. Six types of intervention were included in this review; metformin therapy, LGI diet, dietary counseling, probiotics, self-monitoring of weight gain, and exercise. GDM incidence was signicantly lower among women who received dietary counseling compared with women who received usual care. One study that focused on probiotics reported also a signicant reduction in the incidence of GDM. Furthermore, we identied a signicantly reduced risk for a macrosomic infant among women who received advice on an LGI diet during pregnancy

SYSTEMATIC REVIEW OF PREVENTING GDM

1561

Outcome maternal fasting blood glucose

p p

Outcome GDM

p p

Outcome macrosomia

p p

FIG. 5. Forest plots of the effect of exercise training program vs. usual care for maternal fasting blood glucose, GDM, and macrosomia in pregnant women. (A) Outcome maternal fasting blood glucose. (B) Outcome GDM. (C) Macrosomia (birth weight > 4000 g). Data are weighted mean differences, RRs, RDs with 95% CI. *Indicates that extra data information was provided by the authors of the article. compared with women who received advice on an HGI diet and also among women who received an exercise training program. None of the six interventions caused a signicant difference in maternal fasting glucose. Based on the GRADE approach, we found that the evidence for most of the ndings described is of (very) low quality. The main reasons for the low quality of evidence were limitations in study design (lack of blinding), small sample sizes, and imprecision of the results. Because of the nature of the interventions, in the majority of the studies (advice on diet or exercise), blinding of patients was almost impossible, although greater effort could be put into blinding aspects in future studies. The blinding of outcome assessors and care providers, in particular, should be feasible in most circumstances. The results of the current review have to be interpreted with caution because of the limited number of studies per intervention and per outcome and the heterogeneity in populations, interventions, and diagnostic procedures of GDM. This is underlined in the sensitivity analyses, where excluding outliers or large trials in some instances changed the results. Effect of interventions Metformin is an insulin-sensitizing drug that is used to correct metabolic and endocrine abnormalities15 and can only be used in high-risk populations (PCOS or GDM). Three studies15,24,28 assessed the effects of continuing the use of metformin in pregnancy for the prevention of GDM in women with PCOS. We found no evidence of a signicant difference in maternal fasting glucose or the risk for GDM or macrosomia among women who received metformin therapy. The intervention and the study population were very similar in these studies. In the Begum et al. study,15 women in the control group received nothing, whereas women in the Vanky et al. studies24,28 control group received folate and multivitamin tablets in addition to placebo capsules. Whatever the cause of the discrepancy between the Begum and the Vanky studies, it is clear that more research is needed to evaluate the possible effects of metformin in the prevention of GDM. Three studies compared LGI and HGI dietary advice.17,30,32 The results suggested that women who received advice on an LGI diet had signicantly lower risk of having an LGA infant. An HGI diet is thought to be comparable to the normal diet of many people living in Western industrialized societies.17 Nevertheless, to study the effects of an LGI diet, it might be better to compare it with no dietary advice or standard dietary advice during pregnancy. Although this might decrease the contrast between the study groups somewhat, it would result in a more realistic estimate of the effects that can be obtained with an LGI diet. There were no trials that compared an LGI diet with usual care, however; only other dietary counseling interventions were compared to usual care, and in the nine studies16,18,19,21,22,25,26,27,31 in which this comparison was made, it

1562 was found that dietary counseling had a signicant effect on the incidence of GDM. These nine interventions had in common that they advised a reduction in energy intake or reducing weight gain but were considerably heterogeneous in other aspects, as mentioned in the Sensitivity Analysis section. Most importantly, the nine studies differed in the co-interventions, such as home glucose monitoring, exercise, weight gain monitoring, and probiotics. These co-interventions may have reinforced the effect of the dietary intervention. In another review of dietary interventions for the prevention of GDM, carried out in 2008,38 Tieu et al. concluded that an LGI diet lowers maternal fasting glucose levels and results in fewer LGA infants. However, this review did not include the study by Rhodes et al.,30 who found no signicant difference in maternal fasting glucose and LGA infants. Reviews focusing on the prevention of T2D have recommended LGI diets and healthy Mediterranean-style diets39 or interventions aimed at increasing exercise, combined with diet.40 A Cochrane review concluded that the available data suggest that there are benets in following an energycontrolled diet, with an increase in consumption of fresh fruit and vegetables and a decrease in the intake of simple sugars, although more evidence is needed.41 Probiotics were found to be effective in the reduction of GDM in one high-quality trial focusing on this intervention. More research is needed to conrm this nding. Strengths and limitations A strength of this systematic review is that all relevant publications on interventions for the prevention of GDM were systematically identied and evaluated. The search was very extensive to ensure that we included all types of interventions, and by independently scoring all the articles, we maintained objectivity. A possible limitation of this review was that it was restricted to (quasi) RCTs in addition to a language restriction. As in any other review, publication bias might have affected the results. The studies used different methods for screening and diagnosis of GDM; for instance, they used different cutoff points for glucose levels in the diagnosis of GDM. This, in combination with study populations that varied in risk for GDM, will have inuenced the results with regard to the incidence of GDM reported in the articles. However, differences in GDM incidence found between research groups within one study can be attributed to the intervention under study. Another drawback was related to the fact that our analysis was based on the data reported in the publications, some of which did not give a detailed description of the relevant data on outcome measurements. One way in which we tried to solve this problem was to ask all authors individually to provide missing information. Although most of them did, not all authors responded to our request, so not all of the identied studies could be included in the meta-analysis. Implications for future research Given the limited number of studies and the small sample sizes in most of the studies in our review, there is a strong need for additional research on this topic, and not only on the six types of interventions described in our review. When looking at available literature concerning the treatment of GDM and the prevention of T2D, it is plausible that vitamin D could help to decrease the risk of GDM,42,43 but we did not

OOSTDAM ET AL. nd any controlled trials that evaluated this intervention. Furthermore, there is a need for good quality RCTs with adequate sample size to assess the effects of all types of interventions. It would be benecial ifin addition to assessing the effects of the interventions alonesuch trials focused also on the added effects of different interventions and on identifying the interventions that cause the greatest effects with the least costs. Although more evidence is required, the available data suggest that dietary counseling, advice on an LGI diet, or an exercise program could be benecial and that probiotics might be promising. Overall, better designed studies, providing detailed, high-quality data are required before conclusions can be drawn about the best intervention for the prevention of GDM in pregnant women. Acknowledgments We thank the authors of the included trials for their support in providing additional information. We are grateful to Ilse Jansma, medical librarian in the VU University Library/ Medical Library at the VU University Medical Centre, for her support in performing the literature searches for this review. This systematic review is conducted as a part of an RCT that examines the effect of an exercise program on blood glucose during pregnancy. This study was funded by the Netherlands Organisation for Health Research and Development (ZonMw). Disclosure Statement No potential conicts of interest with regard to this article were reported. References
1. Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care 2007;30 (Suppl 2):S141S146. 2. Cheung NW. The management of gestational diabetes. Vasc Health Risk Manag 2009;5:153164. 3. Gestational diabetes mellitus. Diabetes Care 2004;27 (Suppl 1): S88S90. 4. Buchanan TA, Xiang A, Kjos SL, Watanabe R. What is gestational diabetes? Diabetes Care 2007;30 (Suppl 2):S105S111. 5. Metzger BE, Gabbe SG, Persson B, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classication of hyperglycemia in pregnancy. Diabetes Care 2010;33:676682. 6. Teh WT, Teede HJ, Paul E, Harrison CL, Wallace EM, Allan C. Risk factors for gestational diabetes mellitus: Implications for the application of screening guidelines. Aust NZ J Obstet Gynaecol 2011;51:2630. 7. Dempsey JC, Butler CL, Sorensen TK, et al. A case-control study of maternal recreational physical activity and risk of gestational diabetes mellitus. Diabetes Res Clin Pract 2004; 66:203215. 8. Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: Results from a randomized clinical trial. J Am Soc Nephrol 2003;14(Suppl 2): S108S113. 9. American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases. The prevention or delay of type 2 diabetes. Diabetes Care 2002;25:742749.

SYSTEMATIC REVIEW OF PREVENTING GDM

10. Reimann M, Bonifacio E, Solimena M, et al. An update on preventive and regenerative therapies in diabetes mellitus. Pharmacol Ther 2009;121:317331. 11. Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol 2002;31:150153. 12. Offringa M, Assendelft WJJ, Scholten RJPM. Inleiding in evidence-based medicine. Klinisch handelen gebaseerd op bewijsmateriaal. Derde herziene druk. ed. Bohn, Staeu, Van Loghum, 2008. 13. Furlan AD, Pennick V, Bombardier C, van Tulder M. 2009 Updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine 2009;34:19291941. 14. Barakat R, Lucia A, Ruiz JR. Resistance exercise training during pregnancy and newborns birth size: A randomised controlled trial. Int J Obes 2009;33:10481057. 15. Begum MR, Khanam NN, Quadir E, et al. Prevention of gestational diabetes mellitus by continuing metformin therapy throughout pregnancy in women with polycystic ovary syndrome. J Obstet Gynaecol Res 2009;35:282286. 16. Bevier WC, Fischer R, Jovanovic L. Treatment of women with an abnormal glucose challenge test (but a normal oral glucose tolerance test) decreases the prevalence of macrosomia. Am J Perinatol 1999;16:269275. 17. Clapp IJF. Diet, exercise, and fetal-placental growth. Arch Gynecol Obstet 1997;260:101108. 18. Fraser RB, Ford FA, Milner RD. A controlled trial of a high dietary bre intake in pregnancyEffects on plasma glucose and insulin levels. Diabetologia 1983;25:238241. 19. Guelinckx I, Devlieger R, Mullie P, Vansant G. Effect of lifestyle intervention on dietary habits, physical activity, and gestational weight gain in obese pregnant women: A randomized controlled trial. Am J Clin Nutr 2010;91:373380. 20. Hopkins SA, Baldi JC, Cuteld WS, McCowan L, Hofman PL. Exercise training in pregnancy reduces offspring size without changes in maternal insulin sensitivity. J Clin Endocrinol Metab 2010;95:20802088. 21. Hui AL, Ludwig SM, Gardiner P, et al. Community-based exercise and dietary intervention during pregnancy: A pilot study. Can J Diabetes 2006;30:169175. 22. Laitinen K, Poussa T, Isolauri E. Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: A randomised controlled trial. Br J Nutr 2009; 101:16791687. 23. Ong MJ, Guel KJ, Hunter T, Wallman KE, Fournier PA, Newnham JP. Supervised home-based exercise may attenuate the decline of glucose tolerance in obese pregnant women. Diabetes Metab 2009;35:418421. 24. Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: Results of a randomized study. Hum Reprod 2004;19:17341740. 25. Wolff S, Legarth J, Vangsgaard K, Toubro S, Astrup A. A randomized trial of the effects of dietary counseling on gestational weight gain and glucose metabolism in obese pregnant women. Int J Obes (Lond) 2008;32:495501. 26. Asbee SM, Jenkins TR, Butler JR, White J, Elliot M, Rutledge A. Preventing excessive weight gain during pregnancy through dietary and lifestyle counseling: A randomized controlled trial. Obstet Gynecol 2009;113:305312. 27. Polley BA, Wing RR, Sims CJ. Randomized controlled trial to prevent excessive weight gain in pregnant women. Int J Obes Relat Metab Disord 2002;26:14941502.

1563
28. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from rst trimester to delivery in polycystic ovary syndrome: A randomized, controlled multicenter study. J Clin Endocrinol Metab 2010;95:E448E455. 29. Jeffries K, Shub A, Walker SP, Hiscock R, Permezel M. Reducing excessive weight gain in pregnancy: A randomised controlled trial. Med J Aust 2009;191:429433. 30. Rhodes ET, Pawlak DB, Takoudes TC, et al. Effects of a lowglycemic load diet in overweight and obese pregnant women: A pilot randomized controlled trial. Am J Clin Nutr 2010;92:13061315. 31. Thornton YS, Smarkola C, Kopacz SM, Ishoof SB. Perinatal outcomes in nutritionally monitored obese pregnant women: A randomized clinical trial. J Natl Med Assoc 2009;101: 569577. 32. Moses RG, Luebcke M, Davis WS, et al. Effect of a lowglycemic-index diet during pregnancy on obstetric outcomes. Am J Clin Nutr 2006;84:807812. 33. Piirainen T, Isolauri E, Lagstrom H, Laitinen K. Impact of dietary counselling on nutrient intake during pregnancy: A prospective cohort study. Br J Nutr 2006;96:10951104. 34. Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: A double-blind, placebo-controlled study. Br J Nutr 2010;103: 17921799. 35. Clapp JF III. Maternal carbohydrate intake and pregnancy outcome. Proc Nutr Soc 2002;61:4550. 36. Clapp JF III. Effect of dietary carbohydrate on the glucose and insulin response to mixed caloric intake and exercise in both nonpregnant and pregnant women. Diabetes Care 1998;21 (Suppl 2):B107B112. 37. Fougner KJ, Vanky E, Carlsen SM. Metformin has no major effects on glucose homeostasis in pregnant women with PCOS: Results of a randomized double-blind study. Scand J Clin Lab Invest 2008;68:771776. 38. Tieu J, Crowther CA, Middleton P. Dietary advice in pregnancy for preventing gestational diabetes mellitus. Cochrane Database Syst Rev 2008;(2):CD006674. 39. Buyken AE, Mitchell P, Ceriello A, Brand-Miller J. Optimal dietary approaches for prevention of type 2 diabetes: A lifecourse perspective. Diabetologia 2010;53:406418. 40. Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roque IF, Richter B, Mauricio D. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev 2008;(3):CD003054. 41. Nield L, Summerbell CD, Hooper L, Whittaker V, Moore H. Dietary advice for the prevention of type 2 diabetes mellitus in adults. Cochrane Database Syst Rev 2008;(3):CD005102. 42. Kayaniyil S, Vieth R, Retnakaran R, et al. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes. Diabetes Care 2010; 33:13791381. 43. Ozrat Z, Chowdhury TA. Vitamin D deciency and type 2 diabetes. Postgrad Med J 2010;86:1825.

Address correspondence to: Mireille N.M. van Poppel, Ph.D. Van der Boechorststraat 7 1081BT Amsterdam The Netherlands E-mail: mnm.vanpoppel@vumc.nl

Copyright of Journal of Women's Health (15409996) is the property of Mary Ann Liebert, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.