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      Antenatal dietary supplementation with myo‐inositol in women during pregnancy for preventing gestational diabetes

      systematic-review

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          Abstract

          Background

          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.

          Objectives

          To assess if antenatal dietary supplementation with myo‐inositol is safe and effective, for the mother and fetus, in preventing gestational diabetes.

          Search methods

          We searched the Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, WHO ICTRP (2 November 2015) and reference lists of retrieved studies.

          Selection criteria

          We sought published and unpublished randomised controlled trials, including conference abstracts, assessing the effects of myo‐inositol for the prevention of gestational diabetes mellitus (GDM).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.

          Data collection and analysis

          Two review authors independently assessed trials for inclusion, risk of bias and extracted the data. Data were checked for accuracy.

          Main results

          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.

          Authors' conclusions

          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.

          Taking myo‐inositol as a dietary supplement during pregnancy to prevent the development of gestational diabetes

          What is the issue?

          This review aimed to investigate if myo‐inositol is an effective antenatal dietary supplement for preventing gestational diabetes in pregnant women. Women who develop gestational diabetes have a higher risk of experiencing complications during pregnancy and birth, as well as developing diabetes later on in life. The babies of mothers who have gestational diabetes can be larger than they should be potentially causing injuries to the babies at birth. These babies are at risk of diabetes even as young children or young adults.

          Why is this important?

          The number of women being diagnosed with gestational diabetes is increasing around the world so finding simple and cost‐effective ways to prevent women developing gestational diabetes is important. Myo‐inositol is a naturally occurring sugar found in cereals, corn, green vegetables and meat that has a role in the body's sensitivity to insulin.

          What evidence did we find?

          We searched for studies on 2 November 2015 and included four small randomised controlled trials involving a total of 567 women who were less than 11 weeks' to 24 weeks' pregnant at the start of the trials. The quality of the evidence was assessed as low or very low and the overall risk of bias was unclear.

          Myo‐inositol was associated with a reduction in the rate of gestational diabetes ( low quality evidence), reducing the incidence from 28% in women who did not take the supplement, to between 8% and 18% in the women who took it. There was no difference between groups in terms of the number of women who had hypertensive disorders of pregnancy (including pre‐eclampsia, eclampsia and abnormally high blood pressure during pregnancy) ( very low quality evidence). The trials did not provide any information about the number of babies that died (either before being born or shortly afterwards) or babies that were large‐for‐gestational age. There were no maternal adverse effects of therapy in the two trials that reported on this outcome (the other two trials did not mention this).

          This review did not find any impact on other outcomes such as the risk of having a caesarean section ( low quality evidence), a large baby, obstructed labour when the baby's shoulder becomes stuck (shoulder dystocia) or a baby with low blood glucose levels. This may be due to the trials being too small to detect differences in these outcomes and the outcomes not being reported by all trials. All four trials were from Italy.

          The included trials did not report on a large number of other mother and baby outcomes listed in this review and nor were there any data relating to longer‐term outcomes for the mother or the infant, or the cost of health services.

          What does this mean?

          Myo‐inositol as a dietary supplement during pregnancy shows promise in preventing gestational diabetes but there is not enough evidence at this stage to support its routine use. Further large, well‐designed, randomised controlled trials are required to assess the effectiveness of myo‐inositol in preventing gestational diabetes and improving other health outcomes for mothers and their babies.

          Ideally, future studies should consider involving women from different ethnicities and with differing risk factors for gestational diabetes. It would be useful for future studies to consider the ways that myo‐inositol can be used (different doses, frequency and when to take it) and compare the intervention with a placebo control, diet and exercise or pharmacological interventions. We recommend that future studies utilise the outcomes listed in this review and that potential harms, including adverse effects are included.

          Related collections

          Most cited references22

          • Record: found
          • Abstract: found
          • Article: not found

          Gestational diabetes and the incidence of type 2 diabetes: a systematic review.

          To examine factors associated with variation in the risk for type 2 diabetes in women with prior gestational diabetes mellitus (GDM). We conducted a systematic literature review of articles published between January 1965 and August 2001, in which subjects underwent testing for GDM and then testing for type 2 diabetes after delivery. We abstracted diagnostic criteria for GDM and type 2 diabetes, cumulative incidence of type 2 diabetes, and factors that predicted incidence of type 2 diabetes. A total of 28 studies were examined. After the index pregnancy, the cumulative incidence of diabetes ranged from 2.6% to over 70% in studies that examined women 6 weeks postpartum to 28 years postpartum. Differences in rates of progression between ethnic groups was reduced by adjustment for various lengths of follow-up and testing rates, so that women appeared to progress to type 2 diabetes at similar rates after a diagnosis of GDM. Cumulative incidence of type 2 diabetes increased markedly in the first 5 years after delivery and appeared to plateau after 10 years. An elevated fasting glucose level during pregnancy was the risk factor most commonly associated with future risk of type 2 diabetes. Conversion of GDM to type 2 diabetes varies with the length of follow-up and cohort retention. Adjustment for these differences reveals rapid increases in the cumulative incidence occurring in the first 5 years after delivery for different racial groups. Targeting women with elevated fasting glucose levels during pregnancy may prove to have the greatest effect for the effort required.
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            • Record: found
            • Abstract: found
            • Article: not found

            Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy.

            We studied the relation in Pima Indians between obesity in children and diabetes during pregnancy in their mothers. Sixty-eight children of 49 women who had had diabetes during pregnancy had a higher prevalence of obesity than 541 children of 134 women who subsequently had diabetes (prediabetics) or than 1326 children of 446 women who remained nondiabetic. At 15 to 19 years of age, 58 per cent of the offspring of diabetics weighed 140 per cent or more of their desirable weight, as compared with 17 per cent of the offspring of nondiabetics and 25 per cent of those of prediabetics (P less than 0.001). Obesity in the offspring was directly related to maternal diabetes, since the association was not substantially confounded by maternal obesity. The findings strongly suggest that the prenatal environment of the offspring of diabetic women results in the development of obesity in childhood and early adulthood.
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              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial

              Summary Background Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes. Methods We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m2 or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30–39 vs ≥40 kg/m2). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843. Findings Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference −0·029, 95% CI −0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74–17·50; p=0·11). Interpretation Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes. Funding The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.
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                Author and article information

                Contributors
                j.brown@auckland.ac.nz
                Journal
                Cochrane Database Syst Rev
                Cochrane Database Syst Rev
                14651858
                10.1002/14651858
                The Cochrane Database of Systematic Reviews
                John Wiley & Sons, Ltd (Chichester, UK )
                1469-493X
                17 December 2015
                December 2015
                17 December 2015
                : 2015
                : 12
                : CD011507
                Affiliations
                The University of Auckland deptLiggins Institute 85 Park RoadGrafton Auckland New Zealand 1023
                The University of Adelaide deptARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology Women's and Children's Hospital72 King William Road Adelaide Australia 5006
                Auckland Hospital deptNeonatal Intensive Care Unit Park Rd. Auckland New Zealand
                Author notes

                Editorial Group: Cochrane Pregnancy and Childbirth Group.

                Article
                PMC6599829 PMC6599829 6599829 CD011507 CD011507.pub2
                10.1002/14651858.CD011507.pub2
                6599829
                26678256
                2097af3c-620f-4231-859d-4b44eb6ebab2
                Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
                History
                : 04 February 2015
                Categories
                Medicine General & Introductory Medical Sciences

                Randomized Controlled Trials as Topic,Isomerism,Inositol/therapeutic use,Inositol/chemistry,Inositol/adverse effects,Inositol,Incidence,Diabetes, Gestational/prevention & control,Diabetes, Gestational/epidemiology,Diabetes, Gestational,Prenatal Care,Pregnancy,Humans,Female

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