Hum. Reprod. Advance Access originally published online on October 23, 2006
Human Reproduction 2007 22(2):623-624; doi:10.1093/humrep/del387
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Letters to the editor |
Reply: Polycystic ovary-related miscarriage—should metformin be proposed to such frustrated women?
1 Department of Obstetrics and Gynecology, UCL, Chenies Mews 2 Department of Obstetrics and Gynecology, Liverpool Women’s Hospital, Liverpool, UK 3 Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark and 4 Spaarne Ziekenhuis Haarlem, Department of Obstetrics and Gynaecology, the Netherlands
5 To whom correspondence should be addressed at: Spaarne Ziekenhuis Haarlem, Department of Obstetrics and Gynaecology, PO Box 1644, Haarlem 2003 BR, the Netherlands. E-mail: exalto{at}gyn.nl
Sir,
We appreciate the interest of Dr Manno, Dr Tomei and Dr Marchesan in our ESHRE (SIGEP) publication on ‘Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage’ (Jauniaux et al., 2006
). We are aware of several publications suggesting a possible beneficial effect of metformin in polycystic ovary syndrome (PCOS) patients.
PCOS is associated with a higher miscarriage risk in spontaneous pregnancies as well as in pregnancies after surgical treatment or induced ovulation with or without ovarian suppression. This is primarily related to obesity (Fedorcsak et al., 2001) and maybe due to high LH and androgen levels but not due to the existence of polycystic ovary (PCO) as such (Rai et al., 2000).
Glueck et al. (2001, 2002) claimed a reduction of first-trimester miscarriage in observational studies comparing pregnancy outcome in metformin-treated pregnancies with the patient’s own previous obstetrical histories. The beneficial effect of metformin in the retrospective observational study (n = 188) of Thatcher and Jackson (2006) was also based on a reduction of early pregnancy loss (67 versus 36%) comparing pregnancy outcome before and after therapy. The method of comparing post-treatment outcome with pretreatment outcome in the same patients is considered statistically invalid (Christiansen et al., 2005), and even placebo treatment can be shown to be highly efficient using this method (Christiansen, 1996).
The study of Jakubowicz et al. (2002) is retrospective, and the results are therefore subject to selection bias. Their claim that metformin reduces the miscarriage risk is based on a high miscarriage risk in the small control group (13/31; 41.9%) in comparison with the treatment group (6/68; 8.8%). Furthermore, the studies by Glueck et al. (2001, 2002) and Thatcher and Jackson (2006) include several metformin-treated pregnancies from some of the patients—this is also a statistically flawed method.
The study of Palomba et al. (2005a) is a prospective randomized controlled trial comparing clomiphene citrate and metformin for ovulation induction in non-obese anovulatory women with PCOS and primary infertility. In the metformin group, a higher pregnancy rate was observed in this study despite a comparable ovulation rate. The miscarriage rate was lower in the metformin group (3/31; 9.7%) as compared with the clomiphene group (6/16; 37.5%; P = 0.045). This is an interesting finding based on small numbers in a non-obese population of women with no previous miscarriages, which prospectively is expected to exhibit a low risk of miscarriage. More interesting is the suggestion of the same group that plasminogen activator inhibitor-1 (PAI-1) might be involved in the mode of action (Palomba et al., 2005b).
Unfortunately, none of the mentioned studies meets the proper criteria for a well-designed randomized controlled trial (Carrington et al., 2005; Christiansen et al., 2005) and more importantly did not include patients with recurrent miscarriage. We therefore did not mention metformin treatment in our evidence-based guidelines.
We do not agree with the statement that low-risk metformin administration may be more justified than no treatment. Reducing the helplessness sensation of both physicians and patients is not an answer to a patient’s questions about the underlying cause. The ESHRE Guideline was developed to help clinicians and patients approaching the difficult clinical problem of recurrent miscarriage scientifically and in a robust framework.
Metformin treatment deserves a well-designed prospective randomized controlled trial first. Until then, speculation remains that metformin will be added to despairing treatment schedules using a combination of prednisone, aspirin, folate and progesterone as published recently (Tempfer et al., 2006).
References
Carrington B, Sacks G, Regan L. (2005) Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 17:591–597.[ISI][Medline]
Christiansen OB. (1996) Transabdominal cervicoisthmic cerclage in the management of recurrent second trimester miscarriage and preterm delivery. Br J Obstet Gynaecol 103:595–596.[ISI][Medline]
Christiansen OB, Nybo Andersen AM, Bosch E, Daya S, Delves PJ, Hviid TV, Kutteh WH, Laird SM, Li TC, et al. (2005) Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 83:821–839.[CrossRef][ISI][Medline]
Fedorcsak P, Dale PO, Storeng R, Tanbo T, Abyholm T. (2001) The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod 16:1086–1091.
Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. (2001) Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 75:46–52.[CrossRef][ISI][Medline]
Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. (2002) Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 17:2858–2864.
Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. (2002) Effects of metformin on early pregnancy loss in polycystic ovary syndrome. J Clin Endocrinol Metab 87:524–529.
Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21:92216–2222 [Epub 17 May 2006].
Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. (2005a) Prospective parallel randomized, double blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:4068–4074.
Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F. (2005b) Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome. Fertil Steril 84:761–765.[CrossRef][ISI][Medline]
Rai R, Backtos M, Rushworth F, Regan L. (2000) Polycystic ovaries and recurrent miscarriage: a reappraisal. Hum Reprod 15:612–615.
Tempfer CB, Kurz C, Bentz EK, Unfried G, Walch K, Czizek U, Huber JC. (2006) A combination treatment of prednisone, aspirin, folate and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril 86:145–148.[CrossRef][ISI][Medline]
Thatcher SS and Jackson EM. (2006) Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 85:1002–1009.[CrossRef][ISI][Medline]
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