PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene.

BACKGROUND: Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains controversial even though previous randomized trials have examined this. METHODS: A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome. Women with high body mass index (BMI) > 32 kg/m(2) received placebo ('standard care') or metformin; women with BMI < or = 32 kg/m(2) received CC ('standard care'), metformin or both. Treatment continued for 6 months or until pregnancy was confirmed. Primary outcomes were clinical pregnancy and live birth. RESULTS: For women with BMI > 32 kg/m(2), clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15% (5/33) and 6% (2/33) with placebo. For women with BMI < or = 32 kg/m(2), clinical pregnancy and live birth rates were 40% (14/35) and 29% (10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC. CONCLUSIONS: There is no evidence that adding metformin to 'standard care' is beneficial. Pregnancy and live birth rates are low in women with BMI > 32 kg/m(2) whatever treatment is used, with no evidence of benefit of metformin over placebo. For women with BMI < or = 32 kg/m(2) there is no evidence of significant differences in outcomes whether treated with metformin, CC or both. ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol 2006;46:141-145.

A critical assessment of the role of antiphospholipid antibodies in infertility.

Antiphospholipid antibodies (aPL) are a family of autoantibodies that are associated with pregnancy complications including stillbirth and recurrent miscarriage. Infertile women, and those with recurrent IVF implantation failure, have an increased incidence of aPL (22% and 30%, respectively) compared with a healthy, fertile population (1-3%). Despite this increased incidence, aPL are not predictive of an adverse outcome from IVF. In this review we critically assess the literature in this field, which we believe to be awash with poorly designed studies. Our main criticism is that studies have not examined the fertility outcomes for individual aPL, but rather have examined outcomes for women with between one and eight different aPL. The wide range of antibodies tested and collectively analyzed means that any clinically relevant effects of a specific antibody would be undetectable, if such effects exist. It is also difficult to envisage how aPL present in the maternal blood might damage zygotes or embryos in order to induce infertility. We review the experimental data, looking at possible mechanisms by which aPL might induce infertility. Despite the multiplicity of studies we demonstrate in this review that the question of whether aPL are associated with, or cause, reduced fertility remains unanswered. We also demonstrate that there is no evidence that supposedly aPL-induced infertility or implantation failure after IVF can be treated with pharmacological interventions.

Antiphospholipid antibodies in serum and follicular fluid--is there a correlation with IVF implantation failure?

BACKGROUND: Antiphospholipid antibodies (aPLs) are associated with infertility, but the mechanism underlying this statistical association is currently obscure. We aimed to investigate the finding that aPLs are concentrated in follicular fluid and to establish if this is associated with a poorer outcome from IVF. METHODS AND RESULTS: In 19.2% of 99 women undergoing IVF, at least one aPL was detected in their serum and/or follicular fluids, but the antibody levels in follicular fluid were not higher than in serum. Women with aPLs had a lower implantation rate (14%) than women without these antibodies (24.1%), but this difference was not significant (P=0.127). There was also a non-significant reduction in the live birth rate for women with aPLs. In a parallel investigation, 10 sheep immunized with beta2 glycoprotein I (beta2GPI) or irrelevant control antigens showed strong immune responses, but there were no significant differences between the levels of antibodies in the follicular fluid or serum from beta2GPI or control immunized sheep. CONCLUSION: aPLs do not appear to be selectively concentrated in follicular fluids and, when present, do not adversely affect the reproductive outcome of women undergoing IVF.