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Meta-Analysis
. 2018 Jul 24;7(7):CD010564.
doi: 10.1002/14651858.CD010564.pub2.

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes

Jodie M Dodd  1 , Rosalie M Grivell, Andrea R Deussen, William M Hague
Affiliations
Meta-Analysis

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes

Jodie M Dodd et al. Cochrane Database Syst Rev. .

Abstract

Background: There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional strategies are required.Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy and reduce the risk of known adverse pregnancy outcomes.

Objectives: To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including adverse effects of treatment and costs.

Search methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (11 October 2017), and reference lists of retrieved studies.

Selection criteria: All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions were eligible for inclusion.

Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the quality of the evidence.

Main results: We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing.All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care.Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence).Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs.

Authors' conclusions: There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment.Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.

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Conflict of interest statement

Jodie Dodd is chief investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy for women with obesity or who are overweight (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is complete. Decisions relating to this trial will be made by third parties not directly involved in the trial.

Rosalie Grivell is an investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy for women with obesity or who are overweight (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is complete. Decisions relating to this trial will be made by third parties not directly involved in the trial.

William Hague is an investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy women with obesity or who are overweight (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is complete. Decisions relating to this trial will be made by third parties not directly involved in the trial. He has received NHMRD MRFF (rare disease) funding for an RCT comparing UDCA with rifampicin in severe early onset Intrahepatic Cholestasis of Pregnancy (Hague et al 2018‐2022) and is an investigator on the MAGDA study on the follow‐up of women with previous GDM, funded by a Partnership grant from NHMRC.

Andrea Deussen is the trial coordinator of a study of a randomised trial evaluating the role of metformin in pregnancy for women who are obese (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is complete. Decisions relating to this trial will be made by third parties not directly involved in the trial.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Metformin versus placebo, Outcome 1 Large‐for‐gestational‐age infant, defined as birthweight ≥ 90th percentile for gestational age and infant sex.
1.2
1.2. Analysis
Comparison 1 Metformin versus placebo, Outcome 2 Gestational weight gain (kg).
1.3
1.3. Analysis
Comparison 1 Metformin versus placebo, Outcome 3 Gestational hypertension.
1.4
1.4. Analysis
Comparison 1 Metformin versus placebo, Outcome 4 Pre‐eclampsia.
1.5
1.5. Analysis
Comparison 1 Metformin versus placebo, Outcome 5 Gestational diabetes.
1.6
1.6. Analysis
Comparison 1 Metformin versus placebo, Outcome 6 Preterm birth (before 37 weeks).
1.7
1.7. Analysis
Comparison 1 Metformin versus placebo, Outcome 7 Preterm premature rupture of membranes.
1.8
1.8. Analysis
Comparison 1 Metformin versus placebo, Outcome 8 Induction of labour.
1.9
1.9. Analysis
Comparison 1 Metformin versus placebo, Outcome 9 Vaginal birth.
1.10
1.10. Analysis
Comparison 1 Metformin versus placebo, Outcome 10 Caesarean birth.
1.11
1.11. Analysis
Comparison 1 Metformin versus placebo, Outcome 11 Shoulder dystocia.
1.12
1.12. Analysis
Comparison 1 Metformin versus placebo, Outcome 12 Third‐ or fourth‐degree perineal tear.
1.13
1.13. Analysis
Comparison 1 Metformin versus placebo, Outcome 13 Adverse effects of the treatment: at least one.
1.14
1.14. Analysis
Comparison 1 Metformin versus placebo, Outcome 14 Adverse effects of the treatment: abdominal pain.
1.15
1.15. Analysis
Comparison 1 Metformin versus placebo, Outcome 15 Adverse effects of the treatment: diarrhoea.
1.16
1.16. Analysis
Comparison 1 Metformin versus placebo, Outcome 16 Adverse effects of the treatment: headache.
1.17
1.17. Analysis
Comparison 1 Metformin versus placebo, Outcome 17 Postpartum haemorrhage.
1.18
1.18. Analysis
Comparison 1 Metformin versus placebo, Outcome 18 Birthweight (g).
1.19
1.19. Analysis
Comparison 1 Metformin versus placebo, Outcome 19 Hypoglycaemia requiring treatment.
1.20
1.20. Analysis
Comparison 1 Metformin versus placebo, Outcome 20 Hyperbilirubinaemia requiring treatment.
1.21
1.21. Analysis
Comparison 1 Metformin versus placebo, Outcome 21 Birth trauma.
1.22
1.22. Analysis
Comparison 1 Metformin versus placebo, Outcome 22 Apgar less than 7 at five minutes.
1.23
1.23. Analysis
Comparison 1 Metformin versus placebo, Outcome 23 NICU/Neonatal unit admission.
1.24
1.24. Analysis
Comparison 1 Metformin versus placebo, Outcome 24 Stillbirth.
1.25
1.25. Analysis
Comparison 1 Metformin versus placebo, Outcome 25 Neonatal death.
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References

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