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NIHR Signal Giving obese pregnant women metformin had no effect on baby’s weight at birth

Published on 15 September 2015

doi: 10.3310/signal-000123

A large trial found that giving obese pregnant women the diabetes drug, metformin, to prevent heavier babies, had no effect compared with an inactive dummy tablet. The trial was funded by the NIHR and Medical Research Council, and was the first to give metformin, a diabetes drug that is safe in pregnancy, to pregnant women without type 2 diabetes for this purpose.

There are theoretical reasons why the medication may help in reducing a baby’s birthweight and previous studies had shown links between higher glucose levels in mother’s blood and larger babies. Participants received either standard doses of metformin or the inactive tablet from about 12 weeks of a mother’s pregnancy to a baby’s birth. The researchers now aim to track the children’s weight and health beyond birth to see if there are any other long-term benefits or side-effects. For now, the results show metformin does not work for this purpose.  

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Why was this study needed?

Almost a quarter of women (24%) were obese in 2013 in England. This is up from 16% 20 years earlier. Obese pregnant women are more likely than other women to give birth to heavier babies, and some evidence suggests these babies are more likely to become obese adults. The causes of increased birthweight are not clear, but the mother’s blood sugar control may be a factor. Metformin - a drug taken by mouth – is used to help control the blood sugar of people with type 2 diabetes. This study aimed to find out whether giving metformin to obese pregnant women could prevent their babies being born heavy. Some studies have looked at women who develop diabetes in pregnancy, but this was the first study using metformin in this way in pregnant women without type 2 diabetes.

What did this study do?

This randomised controlled trial took place at 15 NHS antenatal clinics. It included 449 obese pregnant women (BMI greater than or equal to 30 kg per square metre) who had normal blood sugar control when recruited to the trial at 12 to 16 weeks of pregnancy. They were randomly assigned to take either metformin or inactive placebo every day until birth. Birthweight centile, a measure standardised by length of pregnancy, sex, and number of previous babies and derived from weight charts, was used for this study. It is a marker of ill health in later life.

Neither the women nor the treating healthcare staff knew who was being given metformin or placebo. The results for all women were analysed according to the treatment group they had been randomised to, regardless of whether or not they completed the trial. Both points reduce bias and improve the reliability of the results. However, more than a third of women did not take metformin as prescribed. This may hide any positive effect seen in the women who did take it as prescribed.   

What did it find?

  • Metformin had no effect on the birthweight of babies compared with placebo. Average birthweight was very similar in the two groups (3,462 g given metformin vs. 3,463 g given placebo) as was the proportion of babies born overweight or obese.  14% of babies were overweight in the group taking metformin compared to 17% in the placebo group. Taking into account adjustments for length of pregnancy and sex of the baby, these differences were not statistically different.
  • There were no differences in blood sugar levels near the end of pregnancy (36 weeks) between women given metformin or placebo.
  • Two moderate side effects were significantly more common in the metformin group: diarrhoea (42% compared to 19% in the placebo group) and vomiting (32% compared to 22%). There was no significant difference in the number of serious events – such as miscarriage - between the groups.
  • Only two thirds of women recorded taking their medication as prescribed (227 out of 344). Only 260 out of 449 women completed the trial, and the most common reasons given for not taking part were concerns that the study drugs might harm the baby, or not being aware that obesity in pregnancy was a problem.

What does current guidance say on this issue?

Metformin is not currently licensed for use in people with normal blood sugar levels, like the women in this trial. 

NICE guidance from 2010 on weight management in pregnancy recommends a range of healthy lifestyle measures for obese women in pregnancy, such as taking more exercise and eating a balanced diet. NICE guidance published in 2015 on diabetes during pregnancy advises that metformin may be used during pregnancy for women with pre-existing diabetes. It may also be used for women who develop diabetes during pregnancy (gestational diabetes) where blood sugar cannot be controlled with diet and exercise.

What are the implications?

The findings of this trial do not prompt any change to existing guidance or practice. Future trials on metformin for preventing high birthweight would need to allow for a high proportion of trial participants not taking the medication as prescribed.

This trial does not support the use of metformin to improve pregnancy outcomes in obese women without diabetes. The researchers plan to track the children’s weight and health in the future, to see if there are any long term health effects into adulthood.

Citation

Chiswick C, Reynolds RM, Denison F, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015.

This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (project number 08/246/09).

Bibliography

HSCIC. Statistics on obesity, physical activity and diet. England 2015. Leeds: Health and Social Care Information Centre; 2015.

NICE. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. NG3. London: National Institute for Health and Care Excellence; 2015.

NICE. Weight management before, during and after pregnancy. PH27. London: National Institute for Health and Care Excellence; 2010.

NICE. The management of type 2 diabetes. CG87. London: National Institute for Health and Care Excellence; 2009.

Why was this study needed?

Almost a quarter of women (24%) were obese in 2013 in England. This is up from 16% 20 years earlier. Obese pregnant women are more likely than other women to give birth to heavier babies, and some evidence suggests these babies are more likely to become obese adults. The causes of increased birthweight are not clear, but the mother’s blood sugar control may be a factor. Metformin - a drug taken by mouth – is used to help control the blood sugar of people with type 2 diabetes. This study aimed to find out whether giving metformin to obese pregnant women could prevent their babies being born heavy. Some studies have looked at women who develop diabetes in pregnancy, but this was the first study using metformin in this way in pregnant women without type 2 diabetes.

What did this study do?

This randomised controlled trial took place at 15 NHS antenatal clinics. It included 449 obese pregnant women (BMI greater than or equal to 30 kg per square metre) who had normal blood sugar control when recruited to the trial at 12 to 16 weeks of pregnancy. They were randomly assigned to take either metformin or inactive placebo every day until birth. Birthweight centile, a measure standardised by length of pregnancy, sex, and number of previous babies and derived from weight charts, was used for this study. It is a marker of ill health in later life.

Neither the women nor the treating healthcare staff knew who was being given metformin or placebo. The results for all women were analysed according to the treatment group they had been randomised to, regardless of whether or not they completed the trial. Both points reduce bias and improve the reliability of the results. However, more than a third of women did not take metformin as prescribed. This may hide any positive effect seen in the women who did take it as prescribed.   

What did it find?

  • Metformin had no effect on the birthweight of babies compared with placebo. Average birthweight was very similar in the two groups (3,462 g given metformin vs. 3,463 g given placebo) as was the proportion of babies born overweight or obese.  14% of babies were overweight in the group taking metformin compared to 17% in the placebo group. Taking into account adjustments for length of pregnancy and sex of the baby, these differences were not statistically different.
  • There were no differences in blood sugar levels near the end of pregnancy (36 weeks) between women given metformin or placebo.
  • Two moderate side effects were significantly more common in the metformin group: diarrhoea (42% compared to 19% in the placebo group) and vomiting (32% compared to 22%). There was no significant difference in the number of serious events – such as miscarriage - between the groups.
  • Only two thirds of women recorded taking their medication as prescribed (227 out of 344). Only 260 out of 449 women completed the trial, and the most common reasons given for not taking part were concerns that the study drugs might harm the baby, or not being aware that obesity in pregnancy was a problem.

What does current guidance say on this issue?

Metformin is not currently licensed for use in people with normal blood sugar levels, like the women in this trial. 

NICE guidance from 2010 on weight management in pregnancy recommends a range of healthy lifestyle measures for obese women in pregnancy, such as taking more exercise and eating a balanced diet. NICE guidance published in 2015 on diabetes during pregnancy advises that metformin may be used during pregnancy for women with pre-existing diabetes. It may also be used for women who develop diabetes during pregnancy (gestational diabetes) where blood sugar cannot be controlled with diet and exercise.

What are the implications?

The findings of this trial do not prompt any change to existing guidance or practice. Future trials on metformin for preventing high birthweight would need to allow for a high proportion of trial participants not taking the medication as prescribed.

This trial does not support the use of metformin to improve pregnancy outcomes in obese women without diabetes. The researchers plan to track the children’s weight and health in the future, to see if there are any long term health effects into adulthood.

Citation

Chiswick C, Reynolds RM, Denison F, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015.

This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (project number 08/246/09).

Bibliography

HSCIC. Statistics on obesity, physical activity and diet. England 2015. Leeds: Health and Social Care Information Centre; 2015.

NICE. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. NG3. London: National Institute for Health and Care Excellence; 2015.

NICE. Weight management before, during and after pregnancy. PH27. London: National Institute for Health and Care Excellence; 2010.

NICE. The management of type 2 diabetes. CG87. London: National Institute for Health and Care Excellence; 2009.

Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial

Published on 15 July 2015

Chiswick, C.,Reynolds, R. M.,Denison, F.,Drake, A. J.,Forbes, S.,Newby, D. E.,Walker, B. R.,Quenby, S.,Wray, S.,Weeks, A.,Lashen, H.,Rodriguez, A.,Murray, G.,Whyte, S.,Norman, J. E.

Lancet Diabetes Endocrinol , 2015

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/m2 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. Randomisation was stratified by study site and BMI band (30-39 vs >/=40 kg/m2). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843. 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. FUNDING: The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.

Body mass index (BMI) is your weight in kilograms divided by the square of your height measured in metres (kg per square metre). It is a measure of whether you’re a healthy weight for your height.

For adults:

  • The healthy BMI range is from 18.5 to less than 25 kg per square metre.
  • BMI between 25 to less than 30 kg per square metre is classified as overweight
  • Obese is defined as BMI of 30 kg per square metre and over.

For children aged two and over, BMI centile is used. This is a measure of whether the child is a healthy weight for their height, age and sex. Once your child’s BMI centile has been calculated, they will be in one of four categories:

  • underweight: below 2nd BMI centile
  • healthy weight: between the 2nd and 90th BMI centile
  • overweight: between 91st and to 97th BMI centile
  • obese: at or above 98th BMI centile. This BMI centile category is called "very overweight" in letters that are sent by the National Child Measurement Programme.

Author commentary

The purpose of the study was to see if metformin, given to obese pregnant women, would improve the health of the baby in later life. We used (high) birthweight centile as a surrogate marker of later life ill health, as its validity has been shown in large observational studies.

We found that metformin had no significant effect on birthweight percentile in obese pregnant women. We hope to follow-up the babies to see there are any differences in the two groups in the childhood. In the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.

Jane E Norman, Professor of Maternal and Fetal Health,
Director of the Tommy's Centre for Maternal and Fetal Health,
University of Edinburgh MRC Centre for Reproductive Health