Tuesday, 22 January 2019

Metformin Use in Nondiabetic Obese Pregnancy

Article from The Daily Mail, 2011

One of the strongest concerns doctors have about pregnancies in the "obese" is that larger people tend to have larger (macrosomic) babies. Although most macrosomic babies are born just fine, they do have higher rates of shoulder dystocia (babies who get stuck) and related injuries, as well as low blood sugar at birth and more cesareans. So doctors want to do everything they can to prevent abnormally big babies.

Some macrosomia is tied to high blood sugar and high insulin levels. So in hopes of preventing big babies, doctors have been using the diabetes medication, metformin, in those diagnosed with Gestational Diabetes (GD) or Polcystic Ovarian Syndrome (PCOS).

A number of studies have confirmed that metformin use in women with GD does modestly reduce the rate of big babies. It also lowers the rate of early pregnancy loss and prematurity in PCOS. More research is needed but metformin does seem to be a very helpful drug for people with GD or PCOS. No one is questioning this use of metformin.

However, the use of metformin in obese women WITHOUT gestational diabetes or PCOS is a different story. Doctors note that even high BMI people who are not diabetic have larger babies on average. So the working theory has been that these women must be pre-diabetic or have strong insulin resistance that increases fetal size.

So doctors began prescribing metformin to nondiabetic obese women in hopes that lowering insulin levels and borderline blood sugar would cut the odds of a big baby.

The practice was aggressively marketed to the public as a way to prevent "obese babies" before its research was even completed (see headlines quoted here from The Daily Mail 2011 and 2012).

But what does the research say about this use of metformin? Here is a quick summary of the three largest trials.

The Studies on Non-Diabetic High BMI Women

From article in the Daily Mail, 2012
Chiswick 2015

Several years ago, a large study called the EMPOWaR trial (Chiswick 2015) tested this theory in the U.K.

This study involved 15 hospitals and was a large, randomized, double-blind placebo-controlled trial, the gold standard of research. It had n=434 participants with a BMI over 30 for analysis. The maximum metformin dose was 2500 mg.

To authors' great surprise, they found that metformin did NOT lower neonatal size.

Syngelaki 2016

Some common criticisms of the EMPOWaR study were that the metformin dose was too low, the participants weren't fat enough to show any big effect, and they did not take doses strictly enough.

Therefore, in a subsequent study published in the prestigious New England Journal of Medicine (Syngelaki 2016, the MOP trial), n=400 participants were limited to those with a BMI over 35. This study, too, was a randomized, double-blind study with placebo controls and was more racially diverse.

The researchers increased the metformin dose to a maximum of 3000 mg and made sure there was strong adherence to the medication. By limiting the analysis to those with a BMI over 35, increasing the dosage, including more women of color, and making sure metformin was consistently used, the authors hoped to show more of an effect.

To their surprise, results were again similar. While the metformin group had a slightly lower weight gain, fetal size was the same between groups.

Dodd 2019

Researchers just can't leave this theory alone.

Now there is a new study (the GRoW trial) out, also testing the metformin theory (Dodd 2019). This trial was done in Australia and included women with a BMI over 25 (in other words, both "overweight" and "obese"). No previous study had included those in the overweight category.

This also was a gold standard randomized study, n=514 participants. It used doses of up to 2000 mg.

It also found slightly less weight gain in the metformin group but NO difference in birthweight of the babies.

Research Summary

There have been a few other, small studies about metformin use in nondiabetic women, but none have been as large or as strong as these studies. No study so far has found that metformin lowers neonatal birthweight in nondiabetic women. That message is very clear and consistent.

There were other outcomes that weren't as clear. Some, but not all, studies found a mild lowering of prenatal weight gain. Some found decreased incidence of preeclampsia, while others did not. No other outcomes were routinely affected.

At this point, the hypothesis that metformin will "normalize" the size of high BMI women's babies has pretty well been disproven. I'm sure there will be more studies on it because the theory is a favorite of many OBs, but these are strong studies and frankly, I doubt they'll be overturned.

The good news is that no babies seem to have been harmed in these studies. However, many of the mothers experienced significant gastrointestinal side effects from the metformin and this some caused drop-outs or scaled-back dosing. If you've ever taken metformin, you know the G.I. effects can be considerable. This certainly affects people's quality of life. As a result, it's not something that should be prescribed lightly.

The take-home message from research: Metformin is a great drug that can be useful for some indications (like GD or PCOS) but in nondiabetic high BMI women it does not lower neonatal birthweight. As the authors of the EMPOWaR study concluded:
... metformin should not be used to improve pregnancy outcomes in obese women without diabetes.
The Fat-Shaming Around These Studies

Illustration from the 2012 Daily Mail article
It has to be pointed out that the U.K. public health campaign around these studies was glaringly fat-shaming.

Look at the caption above. Fat women are accused of letting their babies be "born obese," of passing on their toxic obesity in the womb through their carelessness about their health. They use the classic picture of a fat body with the head cut off, depersonalizing the subject. The person is even holding a roll of fat, pointing out visual blame so the negative message is even clearer. 

The articles were filled with scary summaries of the risks of obesity and pregnancy, without any context for those risks, how often they don't happen, and what can be done about them when they do. It's not unreasonable to inform women of size of the possible risks around weight and pregnancy, but it's another thing to misrepresent those risks to scare or shame women out of pregnancy.

The campaign was attempting to inflame the public about irresponsible fat people, implying that they refuse to be healthy and are costing the NHS huge amounts of money, taking money away from everyone else. The U.K. is a very fat-phobic place and the government is scapegoating fat people for their healthcare budget woes.

The language of the campaign was also offensive. They used the terms "fat babies" or "obese babies" in order to shame the mothers, but a big baby is not necessarily the same as an "obese" baby. They are conflating fetal size caused by diabetic complications with big babies that are simply larger than average.

All big babies are not alike. Some babies are big because of blood sugar issues, and these babies do tend to be abnormally proportioned and have more issues at birth. On the other hand, some babies are just naturally larger without it being pathological. There is a significant difference between a diabetic's baby that is 9 lbs. but only 16 inches long and a 9 lb. baby that is 22 inches long. The first is abnormal and a true concern; the second is proportional and most likely genetic. The first type often has problems being born safely and has many complications; the second type of big baby is proportional and can usually be born vaginally.

Furthermore, the campaign is simplistic and misleading. Not all obese mothers have macrosomic babies; one study found that only 17% of obese women had macrosomic babies while 83% of them did NOT. Subjecting all obese women to metformin "just in case" means medicating many people who wouldn't produce a big baby anyhow. What potential harm might that be doing?

Some people of average size also have macrosomic babies without blood sugar or insulin issues; no one knows why some babies are bigger than others. And many big babies do have vaginal births; Navti 2007 found that 83% of women who had babies around 10 pounds or more were able to have vaginal births. This shows that even very big babies can often be born vaginally, given time, patience, sufficient mobility, and a calm caregiver. We need to stop panicking over babies that are larger than average and save our intervention for those who truly need it.

Researchers: Stop trying to put the baby on a diet before it is even born. Metformin for reducing fetal size does not work in nondiabetics. 

Public Health Campaigns: Stop promoting weight stigma and fat-shaming in your campaigns about obesity and pregnancy. 



References

Lancet Diabetes Endocrinol. 2019 Jan;7(1):15-24. doi: 10.1016/S2213-8587(18)30310-3. Epub 2018 Dec 4. Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial. Dodd JM, Louise J, Deussen AR, Grivell RM, Dekker G, McPhee AJ, Hague W.  PMID: 30528218
... GRoW was a multicentre, randomised, double-blind, placebo-controlled trial in which pregnant women at 10-20 weeks' gestation with a BMI of 25 kg/m2 or higher were recruited from three public maternity units in Adelaide, SA, Australia. Women were randomly assigned (1:1) via a computer-generated schedule to receive either metformin (to a maximum dose of 2000 mg per day) or matching placebo. Participants, their antenatal care providers, and research staff (including outcome assessors) were masked to treatment allocation...  FINDINGS: Of 524 women who were randomly assigned between May, 28 2013 and April 26, 2016, 514 were included in outcome analyses (256 in the metformin group and 258 in the placebo group). Median gestational age at trial entry was 16·29 weeks (IQR 14·43-18·00) and median BMI was 32·32 kg/m2 (28·90-37·10); 167 (32%) participants were overweight and 347 (68%) were obese. There was no significant difference in the proportion of infants with birthweight greater than 4000 g (40 [16%] with metformin vs 37 [14%] with placebo; adjusted risk ratio [aRR] 0·97, 95% CI 0·65 to 1·47; p=0·899). Women receiving metformin had lower average weekly gestational weight gain (adjusted mean difference -0·08 kg, 95% CI -0·14 to -0·02; p=0·007) and were more likely to have gestational weight gain below recommendations (aRR 1·46, 95% CI 1·10 to 1·94; p=0·008). ... INTERPRETATION: For pregnant women who are overweight or obese, metformin given in addition to dietary and lifestyle advice initiated at 10-20 weeks' gestation does not improve pregnancy and birth outcomes.
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 A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. PMID: 26840133
[kmom summary] Randomized double-blind, placebo controlled trial. Limited to those with BMI over 35 and upped the metformin dosage. Less preeclampsia and less weight gain in metformin group but no difference in birth weight. "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."
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 C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE, Walker BR, Quenby S, Wray S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman JE. PMID: 26165398 Free full text here.
[kmom summary] Randomized placebo-controlled, double-blind study in 15 hospitals in the U.K. on nondiabetic women. Results: "Metformin has no significant effect on birthweight percentile in obese pregnant women."
Previous discussion of these studies and others:
Metformin for Gestational Diabetes or PCOS

J Matern Fetal Neonatal Med. 2018 Nov 20:1-141. doi: 10.1080/14767058.2018.1550480. [Epub ahead of print] Metformin-treated-GDM has lower risk of macrosomia compared to diet-treated GDM- A retrospective cohort study. Bashir M, Aboulfotouh M, Dabbous Z, Mokhtar M, Siddique M, Wahba R, Ibrahim A, Al-Houda Brich S, Konje JC, Abou-Samra AB. PMID: 30458653
...This is a retrospective cohort study that included GDM women compared to normoglycaemic controls between March 2015-December 2016 in the Women's Hospital, Qatar. RESULTS: The study included 2221 women; of which 1420 were normoglycaemic, and 801 were GDM (358 GDM-D and 443 GDM-T)... Women in the GDM-T group had lower GWG/week compared to GDM-D (-0.01 ± 0.7 versus 0.21 ± 0.51 kg/week; p < 0.001). After correcting for age, prepregnancy weight and GWG; GDM-T had higher risk of preterm labour (OR 1.66; 95% CI 1.20-2.22), and C-section (OR 1.37, 95% CI 1.02-1.85) and reduced risk of macrosomia (OR 0.56; 95% CI 0.32-0.96) and neonatal hypoglycaemia (OR 0.49; 95% CI 0.28-0.82). CONCLUSION: ... Treatment with metformin reduces maternal weight gain, the risk of macrosomia and neonatal hypoglycaemia compared to diet alone.
J Clin Endocrinol Metab. 2010 Dec;95(12):E448-55. doi: 10.1210/jc.2010-0853. Epub 2010 Oct 6. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. Vanky E et al.  PMID: 20926533
[kmom summary] n=274 PCOS pregnancies. Randomized controlled trial with placebos. Less prematurity, but more pre-eclampsia in metformin group. Less weight gain in metformin group. No difference in fetal size between groups.  


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