Image via WikipediaGestational diabetes is a complication in about 5% of pregnancies, is increasing in prevalence, and is associated with complications to the pregnancy and a long-term risk of diabetes in both mother and offspring.1,2,3,4,5 Intervention to change lifestyle and, if maternal hyperglycemia persists, treatment with additional insulin have been shown to improve perinatal outcomes.6,7 Women who begin insulin therapy require education to ensure the safe administration of insulin. Use of insulin is also associated with hypoglycemia and weight gain. The use of safe and effective oral agents may offer advantages over insulin.
Oral metformin is a logical option for women with gestational diabetes mellitus. It improves insulin sensitivity, probably by activating AMP kinase, and is not associated with weight gain or hypoglycemia.8,9 Reported outcomes of its use during pregnancy have been favorable10,11,12,13,14,15,16,17,18,19 except for one small, retrospective cohort study20 that showed increased rates of perinatal loss and preeclampsia as compared with insulin treatment. Metformin crosses the placenta and could affect fetal physiology directly.21 Its use in pregnancy remains controversial; to our knowledge, only two small, randomized trials comparing metformin with insulin have been reported to date.22,23
We designed the Metformin in Gestational Diabetes Trial to rule out a 33% increase in a composite of perinatal complications in infants of women treated with metformin as compared with insulin. Our hypotheses were that perinatal outcomes would be similar for both treatments, that women would consider metformin a more acceptable treatment than insulin, and that metformin would improve markers of insulin sensitivity in the mother and baby.
Discussion
We found no significant increase in a composite measure of neonatal complications among women with gestational diabetes mellitus who were randomly assigned to metformin as compared with those who were assigned to insulin. Rates of neonatal hypoglycemia, one of the components of the composite end point, were similar in the two groups, but severe hypoglycemia (<1.6 mmol of glucose per liter [28.8 mg per deciliter]) occurred significantly less often in infants of women taking metformin. We did not see a reduction in the insulin concentration in umbilical-cord serum in the metformin group, but this finding should be interpreted with caution, since results were available for less than half of the participants.
Prematurity was included as part of the composite outcome. The rationale was that if metformin had any unanticipated adverse effect on fetal growth or well-being, there would be more iatrogenic preterm births. The frequency of preterm birth was higher in the metformin group than in the insulin group, but the difference was associated with a greater frequency of spontaneous (rather than iatrogenic) preterm births that could be due to chance or to an unrecognized effect of metformin on the labor process. The increased rate of preterm birth was not associated with higher rates of other complications, probably because the difference between the two groups in mean gestational age at delivery was clinically insignificant. In a previous cohort of women with gestational diabetes mellitus who were treated with either insulin or glyburide, the rates of preterm delivery were 13% for the insulin group and 12% for the glyburide group, but the causes of preterm birth were not documented.28
In our study, 46.3% of women taking metformin required supplemental insulin. This proportion is likely to vary in other populations, depending on patient characteristics and target levels of glucose.
How do the effects of metformin in women with gestational diabetes mellitus compare with those reported for glyburide? In a randomized trial comparing glyburide and insulin in 404 women with gestational diabetes mellitus, glycemic control and pregnancy outcomes were similar between groups (although the trial was underpowered to address neonatal complications).29 Subsequent experience with glyburide shows that approximately 20% of women change to insulin.30,31 To our knowledge, there are no published trials comparing metformin with glyburide, and comparisons among available data are limited by differences in study populations and glycemic aims.
Although our study was not designed to compare the outcome of combined treatment with that of either treatment alone, the rate of neonatal complications did not differ significantly between women who required supplemental insulin and those who received metformin alone. Moreover, women receiving combined treatment required less insulin and gained less weight than those taking insulin alone.
Strengths of this trial are that it took place within routine clinical practice and included the spectrum of women with a diagnosis of gestational diabetes mellitus. A weakness is that treatment was open-label, since blinding was not considered practical or ethical. A methodologic limitation is that we used a superiority design to assess whether insulin was superior to metformin and have accepted rather than proved the null hypothesis (that there is no difference between treatments). Nonetheless, the 95% confidence interval for the relative risk of the composite measure of neonatal complications suggests that an increase in risk of more than 10% with metformin is implausible. In addition, a post hoc analysis using a noninferiority design and a proposed margin of 1.33 (33% change in complications) supports the conclusion that metformin is not inferior to insulin (relative risk, 1.00; 97.5% CI, 0.89 to 1.12). Finally, the composite outcome included outcomes of differing clinical significance.32 However, data pertaining to the individual components of the composite measure serve to inform clinicians about several relevant effects of metformin.24
Clinicians may remain circumspect about using metformin until follow-up data for offspring are available. The offspring from this trial are being assessed at 2 years of age. Data at 18 months of age from 126 infants of women with polycystic ovarian syndrome who were treated with metformin have provided preliminary reassurance of a lack of effect on growth and on motor and social development.33
In conclusion, our findings suggest that metformin, alone or with supplemental insulin, is an effective and safe treatment option for women with gestational diabetes mellitus who meet the usual criteria for starting insulin, and that metformin is more acceptable to women with gestational diabetes mellitus than is insulin. Further follow-up data are needed to establish long-term safety.
Supported by grants from the Auckland Medical Research Foundation, the National Women's Evelyn Bond Charitable Trust, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia.
Dr. Moore reports receiving speaking fees from Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
We thank all the clinic teams that provided daily support to the researchers and all the women with gestational diabetes mellitus who carefully considered the study and agreed to take part.
* The investigators in the Metformin in Gestational Diabetes (MiG) Trial are listed in the Appendix.
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