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.

References

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.

Most Babies Suspected to be Large Actually Aren't

So many mothers get the "big baby" fear card handed to them during pregnancy. This often leads to pressure for interventions such as induction of labor, or scaring women into a planned cesarean.

In this survey, one-third of women surveyed were told their babies were getting "quite large." Yet only one in five of these women actually went on to have large babies (around 9 lbs. or more).

Although the survey doesn't have information specifically about women of size, I would bet that the rate of big baby fear cards is even higher in our care. There is some justification for this; on average, we do tend to have somewhat larger babies. But even so, most high-BMI women have average-sized babies. And even if they do have a bigger baby, most of these can be born just fine with a little care and patience, especially if they have full mobility during labor.

But the fear of big babies from big mothers is so exaggerated these days that many care providers act as if every high-BMI woman will have a Godzilla Baby. Sadly, a great deal of the increased interventions we experience is likely tied to that fear of big babies.


Reference

Matern Child Health J. 2015 Dec;19(12):2578-86. doi: 10.1007/s10995-015-1776-0. Labor and Delivery Experiences of Mothers with Suspected Large Babies. Cheng ER1, Declercq ER2, Belanoff C3, Stotland NE4, Iverson RE5. PMID: 26140835

OBJECTIVE: To characterize the prevalence of and factors associated with clinicians' prenatal suspicion of a large baby; and to determine whether communicating fetal size concerns to patients was associated with labor and delivery interventions and outcomes. METHODS: We examined data from women without a prior cesarean who responded to Listening to Mothers III, a nationally representative survey of women who had given birth between July 2011 and June 2012 (n = 1960). We estimated the effect of having a suspected large baby (SLB) on the odds of six labor and delivery outcomes. RESULTS: Nearly one-third (31.2%) of women were told by their maternity care providers that their babies might be getting "quite large"; however, only 9.9% delivered a baby weighing ≥4000 g (19.7% among mothers with SLBs, 5.5% without). Women with SLBs had increased adjusted odds of medically-induced labor (AOR 1.9; 95% CI 1.4-2.6), attempted self-induced labor (AOR 1.9; 95% CI 1.4-2.7), and use of epidural analgesics (AOR 2.0; 95% CI 1.4-2.9). No differences were noted for overall cesarean rates, although women with SLBs were more likely to ask for (AOR 4.6; 95% CI 2.8-7.6) and have planned (AOR 1.8; 95% CI 1.0-4.5) cesarean deliveries. These associations were not affected by adjustment for gestational age and birthweight. CONCLUSIONS FOR PRACTICE: Only one in five US women who were told that their babies might be getting quite large actually delivered infants weighing ≥4000 g. However, the suspicion of a large baby was associated with an increase in perinatal interventions, regardless of actual fetal size.

Once Again, Metformin Does Not Reduce Birthweight

One of the risks of "obesity" and pregnancy that care providers get most concerned about is big babies.

Although most high-BMI women have average-sized babies, they do have an increased rate of big babies on average and this tends to panic many providers.

Why all the concern? Most of the time, big babies have normal outcomes, but research is clear that they are more at risk for shoulder dystocia (shoulders getting stuck), as well as low blood sugar at birth and perhaps also cesarean section.

Because doctors frequently get sued for nerve damage caused by shoulder dystocia, they understandably are concerned when they suspect a woman might have a large baby. And because larger women tend to have larger babies on average, many care providers want to intervene in the pregnancies of women of size to try and prevent big babies.

Prophylactic metformin is just the latest intervention that care providers are using to try and reduce fetal size among high-BMI women.

Interventions for Big Babies

Traditionally, the most common intervention if a big baby is suspected is a planned cesarean or an induction "before the baby gets too big," even though most research does not support improved outcomes from either of these interventions. Indeed, there is substantial research to suggest poorer outcomes. Thus care providers have looked for other alternatives to reduce birthweight in the infants of high-BMI women.

The most popular intervention these days is to strictly limit the mother's prenatal weight gain. A high weight gain has been shown to be associated with more Large-for-Gestational-Age (LGA) babies, so it does make sense for women to be careful about what they eat and try to avoid large gains.

On the other hand, too-small gains are associated with increased risks of prematurity and Small-for-Gestational-Age (SGA) babies. Some research also suggests that very small gains and weight loss during pregnancy are associated with infant death, so it's important that care providers not go too far in limiting prenatal weight gain.

Many care providers try to reduce the number of large babies by pressuring women to lose weight before pregnancy. However, research clearly shows that few people lose weight long-term, and that even when weight is lost long-term, it is usually only a very small percentage of their weight. Rarely does a woman completely normalize her weight before pregnancy and keep it off successfully. So this tactic also has limited use, leading care providers to look for other possibilities.

Metformin to Reduce Birthweight

The most recent trendy "fix" for big babies has been to put high-BMI women, even those with normal glucose tolerance, on metformin (Glucophage). The theory is that many high-BMI women have blood sugar or insulin levels that are elevated but not high enough to be diagnosed with gestational diabetes. These "pre-diabetic" blood sugar levels and/or high insulin levels are thought to be what is causing the baby to grow larger.

As we have written about before, this is an interesting theory but one that is fraught with concerns. Most women of size don't have big babies; if you put them all on metformin as a preventative, what does this do to the majority who would have normal-sized babies? And does metformin use increase risks for other problems? For example, one meta-analysis shows an increased tendency towards pre-term birth with metformin. And we know that metformin tends to deplete B vitamin levels, especially B12 and folic acid. Could that cause birth defects or cause other problems? These are important questions that need to be answered.

In the meantime, the question of whether metformin "normalizes" fetal birth weights is being answered now. It does not.

One study from England recently found that giving metformin to obese women with normal glucose tolerance did NOT reduce fetal size. 

This new study seems to confirm those findings. Using metformin in women with a BMI over 35 but normal glucose tolerance did not reduce fetal size.

Those who promote scorched-earth intervention policies in the pregnancies of women of size will point out that the metformin use did lower the mother's weight gain. However, the difference was small; only about 5 lbs. or so. Is that really clinically meaningful, especially when it didn't change the baby's birthweight or much of anything else?

The one promising find was that metformin use did lower the rate of pre-eclampsia, from 11% to 3%. Since pre-eclampsia is a very serious complication, that is an interesting finding, and one that echoes a few other studies on metformin use.

However, this is balanced by the fact that most other studies have shown that metformin had little effect on pre-eclampsia rates. Indeed, there have been at least two studies that have found an increased rate of pre-eclampsia when metformin was used. So the question of its efficacy for reducing pre-eclampsia is still up in the air.

Nor did metformin use change the rate of gestational diabetes (GD) in this study, which you might expect it to have done. That casts even more doubt on its utility in non-diabetic obese women.

Another downside is that many women experienced side effects (usually G.I. issues like nausea, vomiting, and diarrhea) while taking metformin. Fifty women dropped out of the trial, presumably because of side effects like these. If taking metformin results in G.I. misery, women are simply not going to take it, so it doesn't really matter how effective it could be (or not). It has to be tolerable for those taking it.

Final Thoughts

This post might make people think I'm opposed to the use of metformin. I'm not.

I think metformin is a pretty amazing drug in many ways. It has an excellent safety profile, and an impressive record of improving health outcomes in people with diabetes. It does cause significant G.I. issues in some people so its utility is limited for those folks, but for those who can tolerate it, it's an extremely useful drug.

Nor am I opposed to the use of metformin in pregnancy─ when it is indicated, such as with GD and/or PCOS (Polycystic Ovarian Syndrome). The research shows it can be quite useful in those situations. 

However, in my opinion, across-the-board use of metformin on all obese women to prevent big babies or other complications is highly questionable. 

That doesn't preclude its use in a carefully monitored research setting, please note. If non-diabetic women of size have been given full informed consent about it and want to participate in a research study on its use, I'm okay with that. They get to decide for themselves whether they think participating in such a study is worthwhile. They should not be pressured or guilted into using it, but if they want to be a test subject then that's their right.

But routine use across the board in all non-diabetic obese women? Pressuring or guilting normoglycemic high BMI women into its use just because they might have a bigger baby? I think the results of these two studies clearly indicate that use is a massive overreach.

The good news is that this study provides further data that use of metformin in pregnancy seems to be reasonably safe. This is great for women with PCOS, type 2 diabetics, and women who develop GD; metformin seems to be clearly helpful in these groups.

The bad news is that it doesn't seem to be very helpful as a way to normalize fetal growth in non-diabetic women.

The bottom line is that care providers need to stop pushing the use of metformin as a way to prevent big babies in high BMI women. 


Reference

N Engl J Med. 2016 Feb 4;374(5):434-43.doi: 10.1056/NEJMoa1509819. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. Syngelaki A1, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. PMID: 26840133

BACKGROUND: Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, -0.71 to 0.92] and 0.17 in the placebo group [interquartile range, -0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.  CONCLUSIONS: Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. 

Weight Loss In Pregnancy Doubles the Risk for Low Birth Weight Babies

Here is yet another study showing that weight loss during the pregnancies of "obese" women increases the risk for low-birth weight babies.

In this study, weight loss during pregnancy doubled the risk for a low-birth-weight baby. 

This is important because low-birth-weight babies are at increased risks for health problems as they get older, including insulin resistance, diabetes, abdominal fatness, metabolic syndrome, and cardiovascular disease. In the rush to "cure" obesity through restricted prenatal weight gain, are care providers increasing the next generation's risk for the very conditions they are trying to prevent?

Nor is this the first study to find an increased risk for small-for-gestational-age babies with gestational weight loss. It is only the latest of quite a few to find this. One recent systematic review concluded that Gestational Weight Loss "should not be advocated in general for obese women."

Yet there are still care providers who are pressuring women of size to lose weight during pregnancy. Care providers need to STOP promoting gestational weight loss as a goal for obese women. 

Side Notes and Cautions

A couple of cautions about the study. 

As we discussed before, there are women of size who naturally lose weight in pregnancy because their metabolism increases during pregnancy. This doesn't automatically mean a bad outcome, and no one should panic if they are losing weight without trying. Some women, especially those with higher BMIs, lose weight without restricting their nutrition and have perfectly fine outcomes. As long as you are eating well and baby seems to be growing adequately, it's not something to panic about. 

But deliberately trying to lose weight during pregnancy is a different story. The care providers who are pressuring women to lose weight during pregnancy by restricting their intake or eliminating food groups are putting babies at risk and this study confirms that. 

Care providers should NOT be counseling women to gain no weight or to lose during pregnancy. Previous research shows that this is particularly risky for women in the "overweight" (BMI 25-30) and "borderline" obese (BMI 30-35) groups. Some gain seems to be helpful, even if the overall gain in higher BMI women is lower than in other weight groups.

On the other hand, it is important to note that excessive weight gain also is associated with increased risks, most notably for a big baby. (It is also associated with higher rates of blood pressure issues in pregnancy, although this could simply be coincidental due to fluid retention.) 

This means that women of size should try to avoid a too-high gain if they can. However, plenty of high-BMI women have had higher gains and still had healthy outcomes. Like weight loss, a higher gain is not something to aim for, but it doesn't have to be something to panic over either, as long as nutrition is normal and healthy and baby seems to be growing along a normal curve.  

Moral of the story: High-BMI women have the best outcomes in pregnancy when they gain modestly...not too much but not losing either. 

However, a modest gain with good nutrition is different from manipulating weight gain deliberately by restricting calories. In my opinion, it's far better to focus on optimal nutrition than on trying to manipulate weight gain to meet arbitrary weight gain guidelines.

My Biggest Quibble

I am always disappointed that I have yet to see a prenatal weight gain study that focuses on the right issue ─ nutrition. Instead they use weight gain as a proxy for good nutrition, which is an erroneous thing to do. 

A person who gains 11-20 lbs. (the amount recommended for obese women by the Institute of Medicine guidelines) while eating a lot of junk food probably has a lot different outcome than one who gains the same amount from healthy proteins, whole grains, and a variety of fruits and vegetables. Both gains are the same, but the nutrition is very different. Instead of looking only at how much weight women gain, I'd rather they did a more qualitative investigation into what the women were consuming and how that influenced outcomes. 

I'd personally be a lot less worried about the woman of size who gains 30 lbs. while eating an excellent diet than one who gains 30 lbs. from eating Twinkies and ice cream. I'd also be a lot less worried about one who loses weight in pregnancy while eating a healthy diet with plenty of calories than one who loses weight by drinking Slim-Fast to limit her weight gain. (Yes, sadly, that's a real recommendation from a real doctor.)

Rather than obsessing over weight gain, care providers would do better to focus on the quality of the mother's nutrition rather than obsessing so much about the numbers on a scale. 

Reference

J Perinatol. 2016 Jan 7. doi: 10.1038/jp.2015.202. [Epub ahead of print] Maternal and neonatal outcomes in obese women who lose weight during pregnancy. Cox Bauer CM1, Bernhard KA2,3, Greer DM2,3, Merrill DC1. PMID: 26741574

OBJECTIVE: To evaluate neonatal and maternal outcomes in obese pregnant women whose weight gain differed from the Institute of Medicine (IOM) recommendations. STUDY DESIGN: Maternal and neonatal outcomes associated with weight change in pregnancy were retrospectively investigated in women with obesity (body mass index (BMI) ⩾30 kg m-2; N=10734) who gave birth at 12 hospitals. Using a 1:1:1:1 design (n=778 matched groups), we matched women with obesity who lost, maintained, gained appropriate (IOM recommended) and gained excessive weight during pregnancy by gestational age at delivery, maternal age, race/ethnicity, prepregnancy BMI, chronic hypertension, pregestational diabetes and smoking status. Regression techniques were used to adjust for confounders and compare outcomes across weight change categories. RESULT: Compared with IOM recommendations, weight loss was associated with twofold greater odds of low birth weight infants and a mean decrease in estimated blood loss of 30 ml; excessive weight gain was associated with doubled odds of gestational hypertension or preeclampsia, fourfold greater odds of macrosomia and a mean decrease in 5-min APGAR of 0.09. From lost to excessively gained weight, the odds of cesarean delivery increased 1.4 times and mean infant birth weight increased by 197 g. In contrast, the odds of small-for-gestational age were 1.8 times greater for women who lost than gained excessive weight. CONCLUSION: Weight loss in obese pregnant women is associated with increased risk for low birth weight neonates but significantly decreased or maintained risk for other maternal and neonatal morbidities, as compared with appropriate or excessive weight gain. This study supports re-evaluation of the current IOM guidelines for women with obesity.