Wednesday, March 30, 2016

Can Inositol Prevent Gestational Diabetes?

We have written before about the use of inositol (either myo-inositol or d-chiro-inositol) to reduce insulin resistance in women with Polycystic Ovarian Syndrome (PCOS). It's a promising therapy, one that deserves far more research attention than it is getting so far.

But one of the pressing questions so far is whether or not it can reduce a woman's chance for raised blood sugar during pregnancy (Gestational Diabetes, or GD). Several recent studies from Italy have addressed this question.

How Inositol Works

Inositols are a group of carbohydrate compounds that exist in nine chemical orientations called stereoisomers; the two most important ones are myo-inositol and d-chiro-inositol. Your body uses bacteria from the gut to convert the phytic acid found in found in fruits, vegetables, legumes, whole grains, nuts, and other foods into inositols. They then play an important role inside the cell in insulin signaling.

In PCOS, this pathway does not seem to function properly. While most people can get the inositol they need from foods, women with PCOS may have difficulty converting naturally-occurring inositols into d-chiro-inositol (DCI). Or they may convert it reasonably well but excrete it too quickly and therefore do not have enough in the body to help utilize its insulin properly. Supplementing with exogenous (outside the body) sources of inositol is thought to help restore proper signaling function.

So, basically, the idea is that women with PCOS are not able to utilize the natural forms of inositol in their food and this causes insulin metabolism to be inefficient. This leads to a build-up of insulin in the body, which leads to the hormone imbalances of PCOS. And in pregnancy, it may lead to an increased risk for gestational diabetes. The hope is that treatment with inositol may help reduce these problems. 

Inositol and GD

During pregnancy, a temporary state of increased insulin resistance occurs because diabetogenic hormones are produced by the placenta in order to provide the fetus with more energy in case of famine or nutritional challenges. This happens in all women.

In normal pregnancies, the mother's insulin levels are able to respond enough to keep her blood sugar in the normal range, but in some women, the pancreas can't respond with enough insulin (or the body becomes too resistant to the insulin) to keep the blood sugar normal. These women are at high risk for getting GD in pregnancy, which in turn may lead to a higher rate of big babies, pre-eclampsia, and other problems. The women most at risk for GD include those with PCOS, those with a strong family history of diabetes, and high-BMI women.

As a result, a number of researchers have proposed using insulin-sensitizing medications routinely during pregnancy in these groups to reduce the risk of GD and other problems.

Or course, some insulin-sensitizing drugs cannot be used because they cross the placenta and can cause birth defects or low blood sugar in the newborn. Metformin is the usual drug of choice in recent years and seems relatively safe, but its performance has been mixed. So now researchers are proposing using inositols (usually myo-inositol) to reduce the risk for GD.

And indeed, some research has shown that women who develop GD in pregnancy tend to excrete high levels of inositol in their urine, suggesting their bodies are unable to convert/utilize it properly. And there is at least one small study that suggests that some women with already-diagnosed cases of GD can be effectively treated with inositols.

So might prophylactic treatment with inositol help prevent GD in women at high risk for the condition?

Studies on Inositol for GD Prevention

So far, the studies on using inositol to prevent or lower the incidence of GD are promising.

An April 2013 study found that myo-inositol lowered the rate of GD in non-obese women with a history of Type 2 diabetes in a close relative. The GD rate was 15.3% in the placebo group vs. 6% in the myo-inositol group.

A July 2013 study found that administering myo-inositol to women who had elevated fasting glucose levels in early pregnancy also lowered the rate of the development of GD.

A December 2015 study found that myo-inositol lowered the rate of GD in a population of "overweight" (BMI 25-30) women. The GD rate was 27.4% in the placebo group vs. 11.6% in the myo-inositol group.

An August 2015 study found that myo-inositol cut the rate of GD incidence in obese women (BMI 30 and over) in half; the GD incidence was 33% in the placebo group vs. 14% in the myo-inositol group.

Most significant of all, a small June 2012 study found that myo-inositol dramatically lowered the rate of GD in women with PCOS. The control group (treated with metformin until conception was confirmed, when it was stopped) had a 54% GD rate, whereas the myo-inositol group (treated before and throughout the entire pregnancy) had a 17.4% rate.

These are all very significant findings and some researchers are getting very excited about the use of inositols in pregnancy. We will undoubtedly see many more studies on this in the future.

Weaknesses of the Studies

However, some cautions are warranted in looking at these studies. One prominent GD researcher wrote a mostly-positive editorial on the use of myo-inositol for preventing GD, but noted a number of problems with the studies, echoing the reservations that I had as I reviewed the abstracts.

Generally, the study groups are pretty small. You need much larger studies to be sure there is a true benefit happening. Also, most serious complications are rare in pregnancy; you need really large study groups to confidently rule out potential safety issues like birth defects or perinatal mortality.

Also, the studies are all done in Italy; most of the inositol research these days is being done there. When all the research on a substance is being done in one particular area or by one set of doctors, that raises the question of bias. It will be very important to see this work replicated in other places and other populations.

The Italian hospitals have also concentrated mostly on myo-inositol. I'd also like to see researchers compare myo-inositol and d-chiro-inositol to see which has greater efficacy.

And of course, the potential for harm in pregnancy is always high because there is a baby involved. Since inositol is a substance your own body produces from food, you would think the risk should be low, but even nutrients that are beneficial in small doses (like vitamin A) can be harmful to fetuses in large doses. More research is needed to look for any possible neonatal effects, as well as to clarify optimal and safe dosages.

Furthermore we need to clarify when usage of inositols is safe. In most of these studies, myo-inositol was only given after the first trimester, so we don't really know if it has any effect on the development of babies early in the first trimester. In the study on obese women, myo-inositol was started in the first trimester but likely this occurred after organogenesis. People in the PCOS study took it throughout the whole pregnancy; no harm was found, but the study was quite small and much larger studies would be needed to see possible impact on rare outcomes.

Some animal models have suggested that large doses of myo-inositol can trigger uterine contractions, so that is another concern that must be addressed. No increase in prematurity was noted in the PCOS pregnancy study, but again, that study was too small to be definitive. Obviously, research that looks specifically at premature labor is needed.

One intriguing finding has been that inositol use (especially d-chiro-inositol) has lowered the risk for Neural Tube Defects (NTDs) in folate-resistant mouse models. A defect in insulin-signaling pathways might be a plausible explanation for why obese women have a somewhat higher risk for neural tube defects than other women. Although no research on obese women has been done, preliminary research on inositol supplementation in women who are at high risk for a NTD because of a prior NTD-affected fetus has been promising. On the other hand, because NTDs are rare, it will probably be a very long time before we know for sure whether inositol use lowers the risk of NTDs in obese women. 

In addition, as a Cochrane Review noted, studies were inconsistent in reporting neonatal outcomes, and the overall quality of studies were judged to be of low or very low quality. The review found the preliminary GD results quite favorable, but strongly encouraged larger, more diverse, and better-designed research.
So while the initial results from these inositol in pregnancy studies are quite promising, there is definitely room for reservations too.

Final Thoughts

Personally, I am very intrigued by the potentials of inositol use. I find the research around the use of inositols outside of pregnancy to be very promising so far, and I'm intrigued by the anecdotal benefits many women with PCOS have reported. To me the mechanism of action seems quite plausible and it is logical that inositol supplementation might be useful. Since myo-inositol is very inexpensive and easy to find, inositols have tremendous potential as a therapy ─ if they are effective and safe.

However, I'm always a little bit leery when researchers start experimenting with interventions during pregnancy. History is littered with examples of things we thought were a good idea in pregnancy, were adopted without adequate research, and which actually turned out to be ineffective or even harmful.

I also have mixed feelings about the fact that doctors are pushing this treatment with high-BMI women regardless of glycemic status or PCOS diagnosis. Some researchers have pushed the envelope of ethical behavior at times to try to reduce possible complications in obese women, and I'm deeply concerned doctors will start pushing these treatments before they are truly proven to be effective and without harm.

On the other hand, high-BMI women clearly do have increased risks for some complications, including gestational diabetes. If a way to prevent GD could be found, that might improve outcomes in some women. As long as this is treated as experimental research, done with proper protocols and truly informed consent, it is important that these studies go forward ─ but it's equally important that women have the right to opt out of them without penalty if they decide they are uncomfortable with the potential risks. Nor should inositols be incorporated into routine care at this point.

As we have written about before, metformin was thought to be the miracle drug for preventing problems in women with a high potential for insulin resistance. However, more thorough research has shown its usefulness to be mixed.

Metformin has certainly been shown to be useful in managing gestational diabetes once it is diagnosed. And in women with PCOS, a number of small initial studies showed that metformin was helpful in reducing miscarriage, pre-term birth, and perhaps GD and blood pressure issues.

However, a recent randomized study did not show that metformin was useful in preventing GD among women with PCOS, although researchers noted the need for further large studies to confirm this. It should also be noted that metformin does seem to lower the rate of miscarriage pretty consistently, so it still may be a useful drug for PCOS, even if it doesn't prevent GD.

But outside of PCOS and GD treatment, metformin's use in pregnancy is more doubtful. Two recent large studies have found that metformin was not useful in preventing GD or lowering birth weight in babies of high-BMI women with normal glucose tolerance. The authors concluded that metformin should not be be used routinely to prevent complications in obese women.

So there is plenty of precedent for a promising therapy that looked like THE cure-all for prevention of complications associated with insulin resistance in pregnancy. Yet so far, none of these therapies have proven to be useful across the board. Useful under certain conditions, yes, but not for routine use.

Still, the recent research on inositols in pregnancy is very interesting. The inositols are an intriguing, plausible possible treatment, and anecdotally some women with PCOS have achieved great results with them, but this is not the same as having quality research on its use and safety in pregnancy. More research is vitally needed, with larger study groups, more varied populations, and stricter study designs.

Keep your eyes peeled for future developments, as research into the inositols is expanding. Until then, use of the inositols in pregnancy should remain a matter of individual decision-making between a woman and her provider, with full informed consent.


Inositol and High-BMI Pregnant Women

Obstet Gynecol. 2015 Aug;126(2):310-5. doi: 10.1097/AOG.0000000000000958. Myo-inositol Supplementation for Prevention of Gestational Diabetes in Obese Pregnant Women: A Randomized Controlled Trial. DʼAnna R1, Di Benedetto A, Scilipoti A, Santamaria A, Interdonato ML, Petrella E, Neri I, Pintaudi B, Corrado F, Facchinetti F. PMID: 26241420
OBJECTIVE: To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater). We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (α=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. RESULTS: From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo-inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo-inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0±3.1 compared with 0.1±1.8 (P=.048). CONCLUSION: Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance.
J Matern Fetal Neonatal Med. 2015 Dec 23:1-4. [Epub ahead of print] Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized, controlled trial. Santamaria A1, Di Benedetto A2, Petrella E3, Pintaudi B2, Corrado F1, D'Anna R1, Neri I3, Facchinetti F3. PMID: 26698911
OBJECTIVE: To evaluate whether myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) rate in overweight women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 μg folic acid twice a day) or placebo (200 μg folic acid twice a day) was administered from the first trimester to delivery in pregnant overweight non-obese women (pre-pregnancy body mass index ≥ 25 and < 30 kg/m2). The primary outcome was the incidence of GDM. RESULTS: From January 2012 to December 2014, 220 pregnant women were randomized at two Italian University hospitals, 110 to myo-inositol and 110 to placebo. The incidence of GDM was significantly lower in the myo-inositol group compared to the placebo group (11.6% versus 27.4%, respectively, p = 0.004). Myo-inositol treatment was associated with a 67% risk reduction of developing GDM (OR 0.33; 95% CI 0.15-0.70).  CONCLUSIONS: Myo-inositol supplementation, administered since early pregnancy, reduces GDM incidence in overweight non-obese women.
Inositol and Pregnant Women at Strong Risk for Diabetes

Diabetes Care. 2013 Apr;36(4):854-7. doi: 10.2337/dc12-1371. Epub 2013 Jan 22. myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. D'Anna R1, Scilipoti A, Giordano D, Caruso C, Cannata ML, Interdonato ML, Corrado F, Di Benedetto A. PMID: 23340885
OBJECTIVE: To check the hypothesis that myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) onset in pregnant women with a family history of type 2 diabetes. RESEARCH DESIGN AND METHODS: A 2-year, prospective, randomized, open-label, placebo-controlled study was carried out in pregnant outpatients with a parent with type 2 diabetes who were treated from the end of the first trimester with 2 g myo-inositol plus 200 µg folic acid twice a day (n = 110) and in the placebo group (n = 110), who were only treated with 200 µg folic acid twice a day...RESULTS: Incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group: 6 vs. 15.3%, respectively (P = 0.04). In the myo-inositol group, a reduction of GDM risk occurrence was highlighted (odds ratio 0.35). A statistically significant reduction of fetal macrosomia in the myo-inositol group was also highlighted together with a significant reduction in mean fetal weight at delivery. In the other secondary outcome measures, there were no differences between groups. CONCLUSIONS: myo-Inositol supplementation in pregnant women with a family history of type 2 diabetes may reduce GDM incidence and the delivery of macrosomia fetuses.
J Matern Fetal Neonatal Med. 2013 Jul;26(10):967-72. doi: 10.3109/14767058.2013.766691. Epub 2013 Mar 1. Effect of dietary myo-inositol supplementation in pregnancy on the incidence of maternal gestational diabetes mellitus and fetal outcomes: a randomized controlled trial. Matarrelli B1, Vitacolonna E, D'Angelo M, Pavone G, Mattei PA, Liberati M, Celentano C. PMID: 23327487
OBJECTIVE: To test the hypothesis that dietary myo-inositol may improve insulin resistance and the development of gestational diabetes mellitus (GDM) in women at high risk of this disorder. DESIGN: A prospective, randomized, double-blind, placebo controlled clinical trial, pilot study. PARTICIPANTS: Non-obese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy...RESULTS: Thirty-six women were allocated to receive myo-inositol and 39 placebo. The incidence of GDM in mid-pregnancy was significantly reduced (p = 0.001) in women randomized to receive myo-inositol compared to placebo (relative risk 0.127). Women randomized to receive myo-inositol also required less insulin therapy, delivered at a later gestational age, had significantly smaller babies with fewer episodes of neonatal hypoglycemia. CONCLUSIONS: Myo-inositol supplementation in pregnancy reduced the incidence of GDM in women at high risk of this disorder. The reduction in incidence of GDM in the treatment arm was accompanied by improved outcomes.
Inositol Use in Pregnant Women with PCOS

Gynecol Endocrinol. 2012 Jun;28(6):440-2. doi: 10.3109/09513590.2011.633665. Epub 2011 Nov 28. Myo-inositol may prevent gestational diabetes in PCOS women. D'Anna R1, Di Benedetto V, Rizzo P, Raffone E, Interdonato ML, Corrado F, Di Benedetto A. PMID: 22122627
To evaluate retrospectively the prevalence of gestational diabetes (GD) in pregnancies obtained with myo-inositol administration in women with polycystic ovary syndrome. A total of 98 pregnancies in PCOS women obtained in a 3-year period, either with myo-inositol (n. 54), or with metformin (n. 44) were considered. While myo-inositol was assumed through the whole pregnancy, the group of women treated with metformin stopped the drug assumption after pregnancy diagnosis, and was considered as a control group. After having eliminated cases of miscarriages and twin pregnancies, a definitive number of 46 women in the myo-inositol group and 37 in the control group was taken in account to be retrospectively evaluated. The primary outcome measure was GD occurrence in both groups; whereas secondary outcome measures were pregnancy outcomes: hypertensive disorders, pre-term birth, macrosomia and caesarean section occurrence. Prevalence of GD in the myo-inositol group was 17.4% versus 54% in the control group, with a highly significant difference also after adjusting for covariates. Consequently, in the control group the risk of GD occurrence was more than double compared to the myo-inositol group, with an odds ratio 2.4 (confidence interval 95%, 1.3-4.4). There was no difference between the groups in relation to secondary outcome measures. This study suggests a possible effect of myo-inositol in the primary prevention of GD in PCOS women.
Meta-Analysis on Inositol for Preventing GD

Cochrane Database Syst Rev. 2015 Dec 17;12:CD011507. doi: 10.1002/14651858.CD011507.pub2. Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes. Crawford TJ1, Crowther CA, Alsweiler J, Brown J. PMID: 26678256
BACKGROUND: ...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...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...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 judgments on the quality of the evidence were downgraded to low or very low quality...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.

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