Friday, October 23, 2015

Metformin Does NOT Lower Birthweight Among Non-Diabetic Obese Mothers

Although most higher-BMI women have average-sized babies, larger women have a higher percentage of big babies. This is one of the biggest reasons care providers intervene in the pregnancies of women of size.

Although most big babies do just fine, bigger babies do have higher rates of issues like shoulder dystocia, cesarean birth, and low blood sugar after birth. So care providers have long searched for ways to lower the rate of big babies among women of size.

Whether that's justified or not is a debate for another day. The point is that many care providers are willing to go to extreme lengths for this goal.

A few years ago there was a large public campaign pushing the prescription of metformin (brand name: Glucophage) for reducing birthweights among non-diabetic "obese" mothers.

We've written about this before. The study was called EMPOWaR and was a randomized, controlled study at 15 different U.K. hospitals.

The theory was that insulin resistance and/or borderline blood sugars were probably at the root of a higher incidence of large infants among high-BMI women, and that lowering blood sugar and insulin resistance even in non-diabetic obese mothers might improve outcomes.

While the publicity campaign noted that they were just investigating this possibility ─ really! ─ the publicity push around a study that hadn't even been done yet suggests that the investigators really had ulterior motives.

Pushing Unproven Agendas Through Publicity 

This is one of my pet peeves about research on obesity in pregnancy; it is often publicized now before the study is even done. One suspects that the researchers are trying to promote unproven high-intervention protocols for this group, trying to raise their own public profiles, or maybe even create a new market for certain medications or programs.

Why else would researchers publicize a study not yet even done?

Publicizing a research trial before it's done creates an expectation in the reading public, including other doctors, that a particular protocol or medication is THE way to manage a particular population or problem. It does an end run around the usual research procedures and starts promoting protocol changes in the minds of the public without having to wait for any pesky results.

We've seen it before in a Kaiser study that promoted zero weight gain in obese pregnant women before the study had even been done. Best guess is that it was part of a push from some doctors to lower prenatal weight gain guidelines because they didn't think the 2009 guidelines (11-20 lbs. for obese women) were low enough.

Certainly, doctors can campaign for changes to national guidelines because of strongly-held beliefs that a particular approach might improve outcomes. However, a pet theory is not enough; any changes need to be supported by actual evidence.

It is medically unethical for doctors to be promoting changes to policy without having clear data that shows a need for such changes and conclusive proof of a lack of harm of such changes.

And guess what? There is good reason for demanding such proof of lack of harm before guideline changes. Turns out that there IS harm in minuscule weight gains.

recent meta-analysis of 18 cohort studies concluded that "gestational weight gain below the guidelines cannot be routinely recommended" in obese women because of an increase in too-small infants and premature births.

THAT is why you need to show proof of a lack of harm of proposed changes and why no one should be publicizing studies before they are done. Doctors all over the country ─ outside of the research trials ─ took that publicity push seriously and are currently promoting minuscule gains, zero gain, and even weight loss in obese pregnant women. How many premature babies and too-small babies have been the result?

Promote healthy eating and lifestyle? Absolutely. And some larger women naturally gain very little in pregnancy, even with normal eating. That's okay; those women generally do okay. But to deliberately manipulate the diet so that weight gains are minuscule or non-existent? Unwise.

Too many care providers have jumped on the minuscule weight gain bandwagon because of the publicity push promoting it before these protocols were examined adequately for harm.

The Metformin Study

A similar questionable publicity campaign surrounded the British study using metformin to hopefully lower birth weights in babies of obese women. Some publicity articles used scare tactics and hyperbole about pregnancy risks in obese women to justify using this medication experimentally and implied that taking metformin would keep "overweight" women from having "overweight" babies. Basically, it was implied that obese women would be irresponsible if they didn't comply with this experiment.

The study had other issues; it used birthweight as a surrogate marker for the future ill-health of obese mothers' offspring. To me this is a very questionable assumption, since it is difficult to untangle cause and effect of metabolic issues like PCOS, lipedema, thyroid disturbances, and genetic contributions to a child's health vs. birthweight alone. In addition, big babies don't automatically become unhealthy adults, and there is plenty of evidence that too-small babies have more health problems than bigger ones.

The publicity campaign fanned the anti-obesity hysteria in the U.K., created a climate where women in the study probably felt they had little choice about taking such drugs (even though their use in this context was experimental), and created an expectation among care providers that metformin was the standard of care even in the pregnancies of non-diabetic obese women.

So I didn't love the premise of the study or the means by which they pressured women into it, even though I thought it would be interesting to see if metformin had an effect on birthweight.

Well, the study results are in, and metformin did NOT reduce birthweight among obese mothers. Birthweights were similar between the metformin and placebo groups. The ponderal index (a measure of length and weight, kind of like a BMI for babies) was similar between groups as well. In other words, metformin not only didn't lower average birthweight, it didn't make the babies any skinnier for their lengths either.

Nor did metformin improve other outcomes of pregnancy in obese women. The metformin group did not have lower prenatal weight gains, nor did they have fewer cesareans.

Basically, the researchers could not show any meaningful improvements in outcome from taking metformin.

There were a few minor differences between groups that did not rise to statistical significance. The metformin group did develop fewer cases of gestational diabetes, but only marginally. There were some small improvements in blood sugar and insulin in the metformin group at 28 weeks, but not at 36 weeks. Some inflammatory markers were lessened but the significance of this is unclear and didn't seem to have any bearing on immediate outcomes.

The metformin group did develop more pregnancy-induced hypertension, pre-eclampsia, and pre-term birth, but again only marginally. The difference did not rise to statistical significance.

Interestingly, there was a stronger tendency towards more poor outcomes (miscarriage, termination, stillbirth, or neonatal death) among the metformin group (3% vs. 1%), but the confidence interval crossed 1.0 and these results could have been mere coincidence rather than a real result of metformin. Given the rarity of such poor outcomes, the study group probably was not large enough to determine whether a real relationship between metformin and poor outcomes in non-diabetic mothers exists. In the study's defense, the description of the poor outcomes does not seem to indicate that they were due to metformin. The bottom line is that the study did not find a statistically significant increase in poor outcomes among those taking metformin.

It IS important to note that metformin is probably a relatively safe drug to use in pregnancy and is used with significant benefit in some diabetic mothers and women with PCOS, but its safety and efficacy in other mothers is less established.

Now we know that it really doesn't lower the birthweight of babies nor improve other outcomes in non-diabetic high BMI mothers. That led the study authors to conclude:
Metformin should not be used to improve pregnancy outcomes in obese women without diabetes.
Further Details

The fact that the study found no real benefit from metformin use in non-diabetic obese women disproved the authors' hypothesis that metformin would improve outcomes. However, the study's authors speculate that an impact on birthweight was not seen because of several possibilities.

First, the medication was not started until 12-16 weeks, rather than early in pregnancy or pre-conception. They theorized that perhaps the programming of fetal size takes place so early that starting it at 12-16 weeks was too late. However, since most women aren't seen in pregnancy until the end of the first trimester, it is unlikely most obese pregnant women would be able to be started earlier anyhow.

Second, they wondered if the doses may not have been high enough to be effective. They started at 500 mg per day and slowly increased the dosage until the "maximum tolerable dose" was reached ─ i.e., until woman experienced too many side effects like nausea, vomiting, diarrhea to tolerate continuing to increase the dose. Still, about 2/3 of the metformin arm received 2000 mg, very near the maximum dosage of 2500 mg, so the argument that the dose wasn't high enough is weak. This was an adequate test.

Third, the authors speculate that the real benefits of taking metformin during the fetal period would likely show in other ways as the child grew up instead of affecting birthweight. They cite an animal study that suggests less visceral fat in the offspring of mothers that received metformin during gestation. As a result, they are planning a follow-up study to monitor metformin-exposed children and see if they have less obesity and/or metabolic issues as they grow up.

This last theory is one that a lot of doctors are fixating on. This is the idea of fetal programming, that the window of time during gestation is one in which fat women "program" their babies to be larger and to have poorer long-term health, and therefore we needed to be extremely proactive about intervening in the pregnancies of obese women. One commentator noted:
The bold idea that what we do to the fetus during the short and finite period of pregnancy could change and even improve lifelong outcomes of offspring validates the whole concept of prenatal care. If this concept is true, this tiny window of opportunity should not be wasted.
This is an alarming statement to me. Yes, if we could change things during the fetal period that would improve that child's health long-term, that would be an exciting possibility. However, the potential for abuse here is quite high. I worry that researchers are SO excited about "preventing" obesity that their common sense will go out the window and they will start using even more scorched-earth ─ and unproven ─ tactics.

What if we intervene and change the child's long-term health negatively? I worry that scorched-earth protocols to get smaller babies through gestational weight loss or medications may actually backfire and create ripples those care providers don't anticipate. Where are the safety protocols to ensure lack of harm from such interventions?

The in-utero time is a powerful time, it's true. But that means we must be very VERY careful in how we intervene, if we intervene at all. And we certainly shouldn't be publicizing a particular approach until it has been proven both beneficial and harmless.


Big mothers tend to have bigger babies on average. This leads many care providers to institute major interventions and scorched-earth protocols to lower birth weight.

The most common intervention is to limit prenatal weight gain. While women of size probably need to gain less weight in pregnancy than other women, how much weight they should (or shouldn't) gain is more controversial. Even more controversial is what should be done to try to achieve that lower gain.

Too much weight gain is clearly linked to larger babies, and perhaps to other poor outcomes. As a result, many care providers have pushed to see the 2009 guidelines reduced even further. However, as noted, too-small gains during pregnancy have unacceptable trade-offs in more too-small babies and premature births. The harms are not worth the potential benefits.

Similarly, some care providers have begun to promote the idea of putting non-diabetic obese women on metformin prophylactically to try to prevent big babies. Although this can modestly reduce birthweight in women with gestational diabetes or full-blown diabetes, this study shows that metformin does not reduce birthweight in non-diabetic obese women.

This research effectively disproves the Pederson Hypothesis, which is that big babies are the result of maternal high blood sugar and responding high insulin levels in the baby. Although this feedback loop can cause fetal overgrowth in diabetic women, this study shows that higher birthweights in non-diabetic obese women are NOT because of borderline high blood sugar. There must be something else going on here to cause the bigger babies, which is something I've been saying for years. The authors suspect high lipid levels, but I'm dubious about that one too. Whatever the mechanism is, it's important to go cautiously and avoid jumping to conclusions based only on assumptions about fat people.

This study shows that metformin does not improve outcomes in non-diabetic obese women and should NOT be used for that purpose. Too bad the publicity push around the trial has already created a market for this, and some providers are pushing its use for all their obese patients. Two more trials like this one are already occurring.

Sadly, even though this research was completed and published this past summer, the trial's publicity website has not been updated to show the negative study results or conclusion. Although a bit of publicity about the negative findings has appeared in some medical publications, a large publicity push does not appear to have been done. How many care providers all over the world still have the impression that metformin should be the standard of care of obese women, regardless of blood sugar status?

Researchers, stop promoting a particular approach before the research is even done. A management protocol needs to be proven to be effective and safe in multiple trials before it should be publicized and promoted. Duh.

At least now we know that metformin, while helpful under certain circumstances, is not a cure-all for preventing complications in all high-BMI women or for preventing big babies. Care providers need to restrict its use to situations where it's actually appropriate and needed.


Lancet Diabetes Endocrinol. 2015 Oct;3(10):778-86. doi: 10.1016/S2213-8587(15)00219-3. Epub 2015 Jul 9. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Chiswick C1, Reynolds RM2, Denison F1, Drake AJ2, Forbes S2, Newby DE3, Walker BR2, Quenby S4, Wray S5, Weeks A5, Lashen H6, Rodriguez A7,Murray G7, Whyte S1, Norman JE8. PMID: 26165398  Full text available here.
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/m(2) 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...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

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