Tineke J Crawford, Caroline A Crowther, Jane Alsweiler, Julie Brown

Gestational diabetes, glucose intolerance with onset or first recognition during pregnancy, is a rising problem worldwide. Both non-pharmacological and pharmacological approaches to the prevention of gestational diabetes have been, and continue to be explored. Myo-inositol, an isomer of inositol, is a naturally occurring sugar commonly found in cereals, corn, legumes and meat. It is one of the intracellular mediators of the insulin signal and correlated with insulin sensitivity in type 2 diabetes. The potential beneficial effect on improving insulin sensitivity suggests that myo-inositol may be useful for women in preventing gestational diabetes. To assess if antenatal dietary supplementation with myo-inositol is safe and effective, for the mother and fetus, in preventing gestational diabetes. We searched the Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, WHO ICTRP (2 November 2015) and reference lists of retrieved studies. We sought published and unpublished randomised controlled trials, including conference abstracts, assessing the effects of myo-inositol for the prevention of gestational diabetes mellitus (GDM). Quasi-randomised and cross-over trials were not eligible for inclusion, but cluster designs were eligible. Participants in the trials were pregnant women. Women with pre-existing type 1 or type 2 diabetes were excluded. Trials that compared the administration of any dose of myo-inositol, alone or in a combination preparation were eligible for inclusion. Trials that used no treatment, placebo or another intervention as the comparator were eligible for inclusion. Two review authors independently assessed trials for inclusion, risk of bias and extracted the data. Data were checked for accuracy. We included four randomised controlled trials (all conducted in Italy) reporting on 567 women who were less than 11 weeks' to 24 weeks' pregnant at the start of the trials. The trials had small sample sizes and one trial only reported an interim analysis. Two trials were open-label. The overall risk of bias was unclear.For the mother, supplementation with myo-inositol was associated with a reduction in the incidence of gestational diabetes compared with control (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.29 to 0.64; three trials; n = 502 women). Using GRADE methods this evidence was assessed as low with downgrading due to unclear risk of bias for allocation concealment in two of the included trials and lack of generalisability of findings. For women who received myo-inositol supplementation, the incidence of GDM ranged from 8% to 18%; for women in the control group, the incidence of GDM was 28%, using International Association of Diabetes and Pregnancy Study Groups Consensus Panel 2010 criteria to diagnose GDM.Two trials reported on hypertensive disorders of pregnancy, a primary maternal outcome of this review. There was no clear difference in risk of hypertensive disorders of pregnancy between the myo-inositol and control groups (average RR 0.43, 95% CI 0.02 to 8.41; two trials; n = 398 women; Tau(2) = 3.23; I(2) = 69%). Using GRADE methods, this evidence was assessed as very low, with downgrading due to wide confidence intervals with very low event rates, a small sample size, and lack of blinding and unclear allocation concealment methods, and a lack of generalisability. For women who received myo-inositol the risk of hypertensive disorders of pregnancy ranged from 0% to 33%; for women in the control group the risk was 4%.For the infant, none of the included trials reported on the primary neonatal outcomes of this systematic review (large-for-gestational age, perinatal mortality, mortality or morbidity composite).In terms of this review's secondary outcomes, there was no clear difference in the risk of caesarean section between the myo-inositol and control groups (RR 0.95, 95% CI 0.76 to 1.19; two trials; n = 398 women). Using GRADE methods, this evidence was assessed as low, with downgrading due to unclear risk of bias in one trial and lack of generalisability. For women who received myo-inositol supplementation, the risk of having a caesarean section ranged from 34% to 54%; for women in the control group the was 45%. There were no maternal adverse effects of therapy in the two trials that reported on this outcome (the other two trials did not report this outcome).Two trials found no clear difference in the risk of macrosomia between infants whose mothers received myo-inositol supplementation compared with controls (average RR 0.35, 95% CI 0.02 to 6.37; two trials; n = 398 infants;Tau(2) = 3.33; I(2) = 73%). Similarly, there was no clear difference between groups in terms of neonatal hypoglycaemia (RR 0.36, 95% CI 0.01 to 8.66) or shoulder dystocia (average RR 2.33, 95% CI 0.12 to 44.30, Tau(2) = 3.24; I(2) = 72%).There was a lack of data available for a large number of maternal and neonatal secondary outcomes, and no data for any of the long-term childhood or adulthood outcomes, or for health service cost outcomes. Evidence from four trials of antenatal dietary supplementation with myo-inositol during pregnancy shows a potential benefit for reducing the incidence of gestational diabetes. No data were reported for any of this review's primary neonatal outcomes. There were very little outcome data for the majority of this review's secondary outcomes. There is no clear evidence of a difference for macrosomia when compared with control.The current evidence is based on small trials that are not powered to detect differences in outcomes including perinatal mortality and serious infant morbidity. All of the included studies were conducted in Italy which raises concerns about the lack of generalisability of the evidence to other settings. There is evidence of inconsistency and indirectness and as a result, many of the judgements on the quality of the evidence were downgraded to low or very low quality (GRADEpro Guideline Development Tool).Further trials for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors and use of myo-inositol (different doses, frequency and timing of administration) in comparison with placebo, diet and exercise or pharmacological interventions. Outcomes should include potential harms including adverse effects.