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:

• https://wellroundedmama.blogspot.com/2011/12/fourth-annual-turkey-awards-leaps-of.html
• https://wellroundedmama.blogspot.com/2015/10/metformin-does-not-lower-birthweight.html
• https://wellroundedmama.blogspot.com/2016/03/once-again-metformin-does-not-reduce.html

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.  

Induction: Don't Break The Waters Early

Amnihooks, which are used to artificially break a woman's waters

New research (Pasko 2018) suggests that when care providers induce high BMI women, they should NOT break the waters in early labor (early amniotomy), especially in first-time mothers.

Breaking the waters early is commonly done to speed up labor. Sometimes it is done to place an internal monitor to monitor the baby more easily, but usually it is used to intensify contractions and shorten labor. Caregivers assume that this will help obese women avoid a cesarean.

However, the results from this new study suggest that early amniotomy actually increases the risk for a cesarean instead.

Study Details

In this retrospective cohort study, women with Class III "obesity" (body mass index ≥40 kg/m2) who were being induced  (n=285) were placed into two groups.

The first group (n=107) received early amniotomy before 4 cm dilation, and the other group (n=178) received late amniotomy.

The group who received early amniotomy had double the cesarean risk of those who did received later amniotomy.

In first-time (nulliparous) mothers, the risk for cesarean was tripled with early amniotomy. 

The length of labor was not shortened in either group. So the whole justification for using early amniotomy (shorter labor, fewer cesareans) for obese women was irrelevant.

An older study (Sheiner 2000) which examined induction by early amniotomy concluded:

In order to decrease the CS rates, induction should probably start with cervical ripening techniques in order to improve the Bishop scores.

Bishop Scores are a measure of how ripe and ready for labor the cervix is. Inductions on an unripe cervix are more likely to fail and result in cesarean, especially in first-time moms. Bishop scores tend to be lower at the start of inductions in women of size, which is probably an important factor in higher weight women's induction failures. 

Women of size also tend to have longer labors and generally take longer in latent (early) labor before reaching active labor. Yet despite this, research shows that early amniotomy is used more often in higher weight women. This needs to change.

How can early amniotomy (also known as Artificial Rupture of Membranes or early AROM) affect labor? When the water is broken, the cushioning around the baby is removed. Labor becomes much more painful, and there is risk for infection. The baby may be more likely to experience an abnormal heart rate (distress). If the baby is not well-positioned when AROM occurs, then the baby can become stuck in that position and have difficult getting out (labor dystocia). These factors can add up and result in a cesarean.

The take-home message from this study on high BMI women is obvious: Avoid having your waters broken before active labor begins (now defined as at least 6 cm dilation). This is especially important if you are a first-time mother. 

Of course, parents have to remain flexible in labor; plans may need to change. For example, if baby may be in trouble and external monitoring is not working well, then breaking the water sooner to place an internal monitor may make sense. But most of the time, amniotomy should not be done early in labor, especially in obese first-time mothers.

Induction Hints

It is best to await spontaneous labor whenever possible, so always question whether an induction is truly necessary. However, it's a hard truth that sometimes induction of labor does become medically necessary. If so, there are some lessons from research that may lessen your risk for cesarean. Most apply to women of all sizes but may be particularly relevant for higher weight women.

Ask your provider about your Bishop Score; if your cervix isn't ripe (Bishop score <5), ask if the induction can be delayed. If it cannot be delayed, ask for techniques to help ripen the cervix before pitocin is started and realize that you may need more time to reach active labor. Some research suggests that Foley catheter or prostaglandin (PGE2) inductions may be more effective in women of size than misoprostol (Cytotec).

Women of size may also need a larger dose of pitocin to keep an induced labor going strong, but this must be done cautiously because too much pitocin can send the baby into fetal distress. Wait and see how you and baby respond before increasing the dosage and go slowly with any adjustments.

Be sure you have a care provider who understands that latent labor tends to take longer in higher weight women and will give you plenty of time. Many cesareans in women of size are done before active labor, and many could probably be prevented if caregivers were more patient and waited longer before moving to a cesarean.

Be sure your baby is in an optimal position for birth before the induction if possible. Chiropractic care may help align the pelvis and maximize the space for an easier birth. If the baby is posterior (facing your front) in labor, ask your caregiver for manual rotation, which clearly reduces the risk for cesarean in several studies.

Maintain your mobility as much as possible and don't get stuck in bed on your back. Make gravity work for you. Upright positions reduce the length of labor and the risk for cesarean. Special positions like hands and knees or an exaggerated Sims position may help malpositioned babies turn more easily. You can read more aboutvarious labor and birth positions here.

As discussed, don't let the caregivers break the waters until you are well into active labor. If possible, let the waters break on their own. Keeping the waters intact as long as possible can help a malpositioned baby turn more easily.

Hire a doula to give professional labor support. One study found a cesarean rate of 13.4% in a group of first-time mothers with doulas, whereas the cesarean rate in the group without doulas was 25%. The difference was even more marked in those whose labors were induced; the group with doulas had a cesarean rate of 12.5%, vs. a 58.8% rate in those without doulas.

These ideas should improve your chances of a normal vaginal birth with an induction. Of course there are no guarantees, but rest assured that with enough time and patience, a reasonably ripe cervix, a well-positioned baby, and good support, many inductions in women of size can result in vaginal births.

Reference

Am J Perinatol. 2018 Nov 5. doi: 10.1055/s-0038-1675331. [Epub ahead of print] Pregnancy Outcomes after Early Amniotomy among Class III Obese Gravidas Undergoing Induction of Labor. Pasko DN, Miller KM, Jauk VC, Subramaniam A.  PMID: 30396229 

OBJECTIVE: We sought to evaluate differences in pregnancy outcomes following early amniotomy in women with class III obesity (body mass index ≥40 kg/m2) undergoing induction of labor. STUDY DESIGN: This is a retrospective cohort study of women with class III obesity undergoing term induction of labor from January 2007 to February 2013. Early amniotomy was defined as artificial membrane rupture at less than 4 cm cervical dilation. The primary outcome was cesarean delivery. Secondary outcomes included length of labor, a maternal morbidity composite, and a neonatal morbidity composite. A subgroup analysis examined the effect of parity. Multivariable logistic regression was used to adjust for covariates. RESULTS: Of 285 women meeting inclusion criteria, 107 (37.5%) underwent early amniotomy and 178 (62.5%) underwent late amniotomy. Early amniotomy was associated with cesarean delivery after multivariable adjustments (adjusted odds ratio [aOR], 2.05; 95% confidence interval [CI], 1.21-3.47). There were no significant differences in length of labor or maternal and neonatal morbidity between groups. When stratified by parity, early amniotomy was associated with increased cesarean delivery (aOR, 3.10; 95% CI, 1.47-6.58) only in nulliparous women. CONCLUSION: Early amniotomy among class III obese women, especially nulliparous women, undergoing labor induction may be associated with an increased risk of cesarean delivery.

Hospitals with Midwives on Staff Have Better Outcomes

Here are two recent studies showing that hospitals with midwives and doctors practicing together ("interprofessional" centers) have better outcomes than hospitals with only doctors. One study is on first-time mothers (nulliparous), and the other study is on women who have given birth before (multiparous), to separate out the possible effects of parity.

In first-time mothers, women were much less likely to be induced or have oxytocin augmentation of labor in interprofessional/collaborative centers. The cesarean rate was 12% lower in interprofessional centers too.

For multiparous mothers (multips), women were again much less likely to be induced or have augmentation of labor in interprofessional centers. The first-time cesarean rate was 36% lower, and the Vaginal Birth After Cesarean (VBAC) rate was 31% higher than in institutions with only doctors. Neonatal outcomes were similar between the two types of centers.

The implication here is that not only do midwives lower the rates of interventions without endangering outcomes, they also influence the hospital culture in a positive way. Doctors who work with midwives tend to be more flexible about interventions, less likely to push a cesarean without need, and more likely to support VBACs.

If you are considering a hospital birth, try to choose a hospital with both doctors and midwives on staff, one with low overall cesarean rates, and strongly consider hiring a doula for professional labor support. Most women can safely be attended by a midwife, so make that your first choice if you can. If a risk comes up that means that you need to see an OB or high-risk maternal fetal medicine (MFM) specialist, the midwife will refer you to one, probably one that is supportive of the parents' birth wishes whenever conditions allow.



References

Birth. 2018 Nov 11. doi: 10.1111/birt.12407. [Epub ahead of print] Midwifery presence in United States medical centers and labor care and birth outcomes among low-risk nulliparous women: A Consortium on Safe Labor study. Neal JL, Carlson NS, Phillippi JC, Tilden EL, Smith DC, Breman RB, Dietrich MS, Lowe NK. PMID: 30417436

...Our objective was to compare labor processes and outcomes for low-risk nulliparous women birthing in United States medical centers with interprofessional care (midwives and physicians) versus noninterprofessional care (physicians only). METHODS: We conducted a retrospective cohort study using Consortium on Safe Labor data from low-risk nulliparous women who birthed in interprofessional (n = 7393) or noninterprofessional centers (n = 6982). .. women at interprofessional medical centers, compared with women at noninterprofessional centers, were 74% less likely to undergo labor induction (risk ratio [RR] 0.26; 95% CI 0.24-0.29) and 75% less likely to have oxytocin augmentation (RR 0.25; 95% CI 0.22-0.29). The cesarean birth rate was 12% lower at interprofessional centers (RR 0.88; 95% CI 0.79-0.98). Adverse neonatal outcomes occurred in only 0.3% of births and were thus too rare to be modeled. CONCLUSIONS: The care processes and birth outcomes at interprofessional and noninterprofessional medical centers differed significantly. Nulliparous women receiving care at interprofessional centers were less likely to experience induction, oxytocin augmentation, and cesarean than women at noninterprofessional centers. Labor care and birth outcome differences between interprofessional and noninterprofessional centers may be the result of the presence of midwives and interprofessional collaboration, organizational culture, or both.

Birth. 2018 Nov 9. doi: 10.1111/birt.12405. [Epub ahead of print] Influence of midwifery presence in United States centers on labor care and outcomes of low-risk parous women: A Consortium on Safe Labor study. Carlson NS, Neal JL, Tilden EL, Smith DC, Breman RB, Lowe NK, Dietrich MS, Phillippi JC. PMID: 30414200

...We sought to use national United States data to analyze the association between midwifery presence in maternity care teams and the birth processes and outcomes of low-risk parous women. METHODS: We conducted a retrospective cohort study using Consortium on Safe Labor data from low-risk parous women in either interprofessional care (n = 12 125) or noninterprofessional care centers (n = 8996). .. women at interprofessional centers, compared with women at noninterprofessional centers, were 85% less likely to have labor induced (risk ratio [RR] 0.15; 95% CI 0.14-0.17). The risk for primary cesarean birth among low-risk parous women was 36% lower at interprofessional centers (RR 0.64; 95% CI 00.52-0.79), whereas the likelihood of vaginal birth after cesarean for this population was 31% higher (RR 1.31; 95% CI 1.10-1.56). There were no significant differences in neonatal outcomes. CONCLUSIONS: Parous women have significantly higher rates of vaginal birth, including vaginal birth after cesarean, and lower likelihood of labor induction when cared for in centers with midwives. Our findings are consistent with smaller analyses of midwifery practice and support integrated, team-based models of perinatal care to improve maternal outcomes.