With increased emphasis on disease prevention, gestational diabetes (GDM) is worthy of more attention. The incidence of GDM is on the rise not only in the United States (U.S.) but worldwide.1,2 Complications of GDM such as preeclampsia, cesarean delivery, neonatal hypoglycemia, macrosomia, and birth trauma negatively impact maternal and fetal health. And result in a heavy economic burden. An estimated $1.3 billion — that’s billion with a “b” — was spent on GDM-associated problems in the U.S. in 2012.3 The long-term consequences of GDM do not stop once the baby is delivered. Women with GDM are at 7-times greater risk of developing type 2 diabetes in their lifetime.4 A safe, effective, practical, and inexpensive strategy to prevent GDM would be welcomed. Is a readily available, non-prescription dietary supplement the answer?
Current approaches to GDM emphasize early recognition and screening. Risk factors for GDM include previous history of GDM, ethnicity (Latino, Native American, African American, Asian American, and Pacific Islander), advanced age (> 30 years old), first-degree relative with diabetes, obesity, polycystic ovary syndrome (PCOS), and corticosteroid use.5 To clearly differentiate unrecognized pre-existing diabetes from GDM with an onset in the second or third trimester of pregnancy, the American Diabetes Association (ADA) recommends screening all women with risk factors for diabetes at their first prenatal visit.6 Screening for GDM then occurs between 24 and 28 weeks gestation. Early recognition allows for aggressive glucose control through lifestyle interventions, and for some, the administration of insulin or oral antidiabetic medications.1,2 Although treatment for GDM is associated with fewer fetal and maternal complications, the opportunity to prevent GDM is appealing from both clinical and financial perspectives. Unfortunately, prevention strategies such as increased physical activity, dietary interventions, probiotics, and vitamin D supplementation have all yielded underwhelming results.7,8
Myo-inositol, an isomer of inositol that serves as an intracellular mediator of insulin action, originally gained attention for its effects on insulin resistance in women with PCOS.9 More recent investigations examined the use of myo-inositol for GDM prevention, with positive results in small trials of non-obese women at risk for GDM due to a family history of type 2 diabetes or elevated fasting glucose during the first trimester.10,11 Because obesity is a primary contributor to insulin resistance and GDM, D’Anna performed a randomized, controlled, open-label study of myo-inositol supplementation specifically in obese pregnant women recruited from two hospitals in Italy.12
The researchers enrolled 220 pregnant women with a pregestational body mass index (BMI) of 30 kg/m2 or greater and singleton gestation. Subjects were divided equally between the treatment group (myo-inositol 2 grams plus 200 mcg folic acid twice daily) and the control group (200 mcg folic acid twice daily). Women with prior GDM, existing pregestational diabetes, or evidence of diabetes in the first trimester were excluded, as were women with hypertension, renal or hepatic disease, and those requiring corticosteroids. There were 107 evaluable cases in each group for the intention to treat analysis. However, fewer women in the treatment group completed the study, primarily due to dropouts by “patient decision” (n=8). A total of 97 women completed the study in the treatment group and 104 in the control group. Baseline characteristics (table 1) were similar except for a statistically significant higher incidence of parental type 2 diabetes in the control group.
Table 1: Select Baseline Demographics
Characteristic |
Myo-inositol (n=110) |
Control (n=110) |
Maternal age (yr) |
30.9 (18-44) |
31.7 (19-43) |
Prepregnancy BMI (kg/m2) |
33.8 (30-46.9) |
33.8 (30-46) |
Nulliparous |
52 (47.3%) |
47 (42.7%) |
Fasting plasma glucose (mg/dL) |
83.1 ± 8.5 |
82.3 ± 10.6 |
Non-Caucasian |
10 (9.1%) |
14 (12.7%) |
Parent with type 2 DM* |
22 (20%) |
41 (37.3%) |
*p=0.004
The primary outcome measures were occurrence of GDM, as defined by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommendations, and the change in insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR), calculated as fasting glucose (mg/dL) x insulin (mU/L)/405. Gestational diabetes was diagnosed in 14% of women in the myo-inositol group versus 33.6% in control group (p=0.001), which translates to a number needed to treat of 5 and a 66% lower risk of developing GDM [OR 0.34 (0.17-0.68)]. (See table 2). Adjustments for maternal age, pre-pregnancy BMI, gestational weight gain, parity, ethnicity, and family history of type 2 diabetes yielded a consistent 70% reduction [adjusted OR 0.30 (0.14-0.66)].
Table 2: Select Primary Outcome Measures at 24-28 Weeks Gestation
Outcome |
Myo-inositol (n=107) |
Control (n=107) |
p-value |
Diagnosis of GDM |
15 (14.0%) |
36 (33.6%) |
0.001 |
Fasting glucose OGTT (mg/dL) |
80.6 ± 7.3 |
84.6 ± 10.4 |
0.001 |
1-h glucose OGTT (mg/dL) |
128.5 ± 34.1 |
143.1 ± 31.3 |
0.002 |
2-h glucose OGTT (mg/dL) |
105.1 ± 25.2 |
122.9 ± 30.2 |
<0.001 |
Difference in HOMA-IR* |
-1.0 ± 3.1 |
0.1 ± 1.8 |
0.048 |
* n=99 myo-inositol group and n=107 control group
Secondary outcomes were evaluable in the 97 women in the myo-inositol group and 104 women in the control group who completed the study. Gestational age at delivery, birth weight/macrosomia, shoulder dystocia, cesarean delivery, gestational hypertension, insulin treatment, preterm delivery, neonatal hypoglycemia, and transfer to a neonatal intensive care unit (NICU) were measured. Outcomes were similar between groups but women in the myo-inositol group were less likely to develop gestational hypertension (0% versus 5.8%, p=0.02) and their newborns were less likely to be transferred to the NICU (0% versus 4.8%, p=0.03).
The primary outcomes in this study are consistent with previous investigations, all performed in Italy using myo-inositol 4 grams daily.10,11 A recent meta-analysis also found a statistically significant reduction in GDM with myo-inositol (RR 0.29; 95% CI, 0.19 – 0.44, p <0.00001).13 Data from four trials evaluating GDM were analyzed, including data from two trials in women with PCOS. The current study was not available for inclusion in the meta-analysis.
A larger sample is necessary to effectively analyze outcomes such as macrosomia, preterm delivery, or cesarean delivery – outcomes that were notably not improved in this study. Preventing GDM alone is not as clinically impactful if it is not also associated with a reduction in related complications. A double-blind study design is also desirable. While it can be argued that objective measurements such as blood glucose or insulin resistance would not be influenced by treatment blinding, the potential bias of an open-label design on a participant’s or clinician’s motivation towards other modifiable risks of GDM such as diet and exercise can not be ruled out.
Several other factors should be considered when applying these data to clinical practice. The use of the IADPSG diagnostic criteria for GDM is consistent with ADA recommendations for the one-step 75 gram OGTT.6 However, a two-step screening using an initial 50 gram glucose load followed by a 100 gram OGTT, if needed, is still supported by expert groups in the U.S.2 The impact of myo-inositol on the primary outcome of GDM diagnosis may differ if these alternate screening methods are used. Additionally, the study was performed in predominantly Caucasian women in Italy, which does not represent ethnicities at highest risk for GDM in the U.S. Thus the results are difficult to generalize to most practice settings in North America. Future investigations should enroll ethnically diverse populations as well as women previously diagnosed with GDM.
The contribution of myo-inositol from food sources should also be considered. Not only is the lack of control for dietary intake of myo-inositol a possible confounder in this study, but the potential to use food sources in place of, or in conjunction with, supplements has not been addressed. A prior investigation estimated up to 1500 mg of myo-inositol per day (in a typical 1800 kcal diet) could be provided through common dietary sources such as fruits, vegetables, beans, and nuts.14
The dosing strategy and formulation, albeit consistent in all myo-inositol GDM studies to date, appears to be based on studies in women with PCOS.9 A purposeful dose ranging trial in women with GDM would assist clinical decision making.
One last concern – safety. Myo-inositol use during pregnancy has not been evaluated as a primary or secondary outcome. Women in this study were assessed for nausea, flatulence, diarrhea, headache, insomnia, uterine contractions, and tiredness at follow-up. The authors state that “no women reported side effects attributable to study medications,” which is consistent with previous studies. While myo-inositol appears well-tolerated, pregnancy outcomes beyond those attributable to GDM (e.g. malformations) should be evaluated before fetal safety is assumed.
Interest in myo-inositol use is gaining momentum. The Cochrane Collaboration published a protocol to analyze myo-inositol for prevention of GDM and ongoing trials in women with GDM, PCOS, and infertility will further inform practice.15 Although the data are positive, the narrowly focused patient populations enrolled in the small studies conducted to date necessitate broader investigations before myo-inositol is ready for prime time. Are you ready to recommend myo-inositol to prevent GDM in high-risk women?
1. American Diabetes Association. Management of diabetes in pregnancy. In: Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl1):S94-98.
2. The American College of Obstetricians and Gynecologists. Practice bulletin: gestational diabetes mellitus. Obstet Gynecol 2013;122:406-16.
3. Dall TM, Yang W, Halder P, et al. The economic burden of elevated blood glucose levels in 2012: diagnosed and undiagnosed diabetes, gestational diabetes mellitus, and prediabetes. Diabetes Care 2014;37:3172-9.
4. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009;373:1773-79.
5. Moyer VA. Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2014;160:414-20.
6. American Diabetes Association. Classification and diagnosis of diabetes. In: Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl1):S13-22.
7. Bain E, Crane M, Tieu J, Han S, Crowther CA, Middleton P. Diet and exercise interventions for preventing gestational diabetes mellitus. Cochrane Database Syst Rev 2015, Issue 4. Art. No. CD010443.
8. Simmons D. Prevention of gestational diabetes mellitus: where are we now? Diabetes Obes Metab 2015;17:824-34.
9. Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol 2012;38(7):509-15.
10. D’Anna R, Scilipoti A, Giordano D, et al. Myo-inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes. Diabetes Care 2013;36:854-7.
11. Matarrelli B, Vitacolonna E, D’angelo M, et al. Effect of dietary myo-inositol supplementation in pregnancy on the incidence of maternal gestational diabetes mellitus and fetal outcomes: a randomized controlled trial. J Matern Fetal Neonatal Med 2013;26:967-72.
12. D’Anna R, Di Benedetto A, Scilipoti A, et al. Myo-inositol supplementation for prevention of gestational diabetes in obese pregnant women. Obstet Gynecol 2015;126:310-5.
13. Zheng X, Liu Z, Zhang Y, et al. Relationship between myo-inositol supplementary and gestational diabetes: a meta-analysis. Medicine 2015;94:e1604.
14. Clements RS, Darnell B. Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J Clin Nutr 1980;33:1954-67.
15. Brown J, Crawford TJ, Alsweiler J, Crowther CA. Myo-inositol for preventing gestational diabetes (protocol). Cochrane Database Syst Rev 2015, Issue 2. Art. No. CD011507.
Thanks!
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