We screened 228 women for eligibility. Three had to be excluded: two had type 2 diabetes and one had raised liver enzyme activity. Baseline characteristics were similar in the two groups apart from the mean total motile sperm count in partners ().
Baseline characteristics of women in study according to allocation to clomifene citrate plus metformin or clomifene citrate plus placebo. Figures are numbers (percentages) of women unless stated otherwise
In the 111 women allocated to metformin, six became pregnant and five dropped out before they started taking the study medication (). Eighty women received 50 mg clomifene citrate, of whom 44 went on to take 100 mg clomifene citrate, and 17 eventually took 150 mg. Twelve women developed resistance to clomifene citrate.
Fig 1 Overview of the clinical trial. Women shown as receiving 50 or 100 mg clomifene citrate received one to six cycles at the noted dose. Ovulatory=women with six ovulatory cycles in total, without pregnancy; temporarily ovulatory=women who ovulated on a (more ...)
In the 114 women allocated to the placebo group, four became pregnant and nine dropped out before they started taking the study medication. Ninety two women received 50 mg clomifene citrate, of whom 54 went on to take 100 mg clomifene citrate, and 23 eventually took 150 mg. Thirteen women developed resistance. In both groups none of the cycles was cancelled and no one developed ovarian hyperstimulation syndrome.
Cumulative rates of ovulation were slightly lower in the metformin group, but this difference was not significant, nor were differences in cumulative pregnancy and spontaneous abortion rates (). There were no significant differences between the two groups when we analysed the data by clomifene citrate dose ().
Rates of ovulation, pregnancy, and spontaneous abortion. Figures are numbers (percentages) of women in each group
Ovulation per dose of clomifene citrate. Figures are numbers (percentages) of women who ovulated out of the total number of women
In the metformin group, 28 women stopped treatment before reaching an end point. Eighteen stopped because of side effects, 10 because of other or unspecified reasons.
In the placebo group, 21 women stopped treatment before reaching an end point. Six stopped because of side effects, 10 because of other or unspecified reasons, and five had a concomitant disease that prevented continuation of the study.
There was a significant difference between the metformin and placebo group in the discontinuation because of side effects (16% v 5%; risk difference 11%, 95% confidence interval 5% to 16%).
As 63 women discontinued study medication, 78 and 84 remained for the per protocol analyses. The results in those who did not withdraw showed no benefit with metformin ().
Rates of ovulation, pregnancy, and spontaneous abortion (per protocol analysis). Figures are numbers (percentages) of women
By the end of follow-up, there were 21 live births without complications in the metformin group, 13 spontaneous abortions, and 14 ongoing singleton pregnancies. There were three premature deliveries (gestational age 36+0, 33+1, and 17+5 weeks). The last pregnancy concerned triplets; none of whom survived. One women developed gestational diabetes but she delivered without further complications. Four women developed hypertension; three delivered without complications, one had a child with Kartagener's syndrome and hypospadias. One woman developed pre-eclampsia and delivered prematurely (32+6 weeks). The child had anal atresia.
In the placebo group there were 30 live births without complications, 1 live twin birth without complications, 12 spontaneous abortions, 9 ongoing singleton pregnancies, and 2 ongoing twin pregnancies. There was one case of intrauterine growth retardation and two premature deliveries (34+1 and 18+0 weeks). The last delivery concerned an anencephalic child who did not survive. Two women developed gestational diabetes and two developed hypertension, all four delivered without further complications. Three women developed pre-eclampsia; two delivered without complications, one delivered prematurely (36+0 weeks).
There were no significant differences in complications of pregnancy, gestational age, complications of delivery, birth weights, or congenital malformations between the two groups. The power for these comparisons, however, was low.