COCHRANE CONCISE
Metformin treatment before and during in vitro fertilization or intracytoplasmic sperm injection in women with polycystic ovary syndrome: summary of a Cochrane review Leopoldo O. Tso, M.D.,a Michael F. Costello, M.B.B.S.,b Luiz Eduardo T. Albuquerque, M.D.,c gis B. Andriolo, Ph.D.,d Jane Marjoribanks, M.P.H.,e and Cristiane R. Macedo, Ph.D.f Re a ~o Paulo, Sa ~ o Paulo, Brazil; b Division of Obstetrics & Gynaecology, Department of Gynecology, Federal University of Sa School of Women's and Children's Health, University of New South Wales and Royal Hospital for Women and IVF Australia, Sydney, New South Wales, Australia; c Human Reproduction Center, Fertivitro Center for Human State, Bele m, Brazil; ~ o Paulo, Brazil; d Department of Public Health, University of Para Reproduction Humana, Sa e Cochrane Office, University of Auckland, Auckland, New Zealand; and f Brazilian Cochrane Centre, Centre for Evidence ~ o Paulo, Brazil Based Health Studies and Health Technology Evaluation, Sa
In women with polycystic ovary syndrome, metformin treatment before or during assisted reproductive technology cycles increases clinical pregnancy rates and decreases the risk of ovarian hyperstimulation syndrome. However, there is no conclusive evidence of a benefit in live birth rates. (Fertil SterilÒ 2015;-:-–-. Use your smartphone Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Metformin, polycystic ovary syndrome, assisted reproductive techniques, in vitro and connect to the fertilization, intracytoplasmic sperm injection Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/tsol-metformin-pcos-ivf-icsi/
M
etformin is an insulinsensitizing agent that reduces hyperinsulinemia and suppresses the excessive ovarian production of androgens in women with polycystic ovary syndrome (PCOS). It has been suggested that metformin could improve pregnancy and live birth rates, and
reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing assisted reproductive techniques (ART).
MATERIALS AND METHODS We included all randomized controlled trials (RCTs) that compared metformin
Received May 6, 2015; accepted May 29, 2015. L.O.T. has nothing to disclose. M.F.C. has nothing to disclose. L.E.T.A. has nothing to disclose. R.B.A. has nothing to disclose. J.M. has nothing to disclose. C.R.M. has nothing to disclose. This is a summary of a systematic review published on the Cochrane Library: Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2014, Issue 11. Reprint requests: Jane Marjoribanks, M.P.H., Cochrane Office, University of Auckland, Private Bag 92019, Auckland 1020, New Zealand (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.05.038 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
treatment with placebo, or with no treatment, in women with PCOS undergoing in vitro fertilization or intracytoplasmic sperm injection. Two review authors independently selected trials, extracted the data, and assessed study risk of bias. Our primary outcomes were live birth, clinical pregnancy, and OHSS. Secondary outcomes included side effects. Studies were pooled when appropriate, to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We used a random effects model, assuming a distribution of effect sizes rather than a single true effect size. Statistical heterogeneity was assessed using the I2 statistic. The quality of the evidence for each comparison was assessed using GRADE 1
COCHRANE CONCISE
FIGURE 1
Forest plot for live birth. Tso. Metformin to treat PCOS with IVF or ICSI. Fertil Steril 2015.
(Grades of Recommendation, Assessment, Development, and Evaluation) methods. Institutional review board approval was not required, because this work is secondary research.
RESULTS We included 9 RCTs (n ¼ 816 women). They compared metformin with placebo (7 RCTs) and with no treatment (2 RCTs). Eight studies used a long protocol gonadotropinreleasing hormone agonist (GnRH-a), and 1 study used a short protocol GnRH antagonist. When metformin was compared with placebo, no statistically significant difference was found between the groups in live birth rates (OR 1.39, 95% CI 0.81–2.40; 5 RCTs; 551
women; I2 ¼ 52%; low-quality evidence; Figure 1 and Table 1). If the chance of live birth without use of metformin is assumed to be 32%, the corresponding chance with use of metformin is estimated to be between 28% and 53% (95% CI). When metformin was compared with placebo or no treatment, clinical pregnancy rates were significantly higher in the metformin group (OR 1.52, 95% CI 1.07–2.15; 8 RCTs; 775 women; I2 ¼ 18%; moderate-quality evidence). If the chance of clinical pregnancy without use of metformin is assumed to be 31%, the corresponding chance with use of metformin is estimated to be between 32% and 49% (95% CI). When metformin was compared with placebo or no treatment, the risk of OHSS was significantly lower in the metformin group (OR 0.29, 95% CI 0.18–0.49; 8 RCTs; 798 women; I2 ¼ 11%;
TABLE 1 Summary of findings. Illustrative comparative ratesa (95% CI)
Outcome
Assumed rate: placebo or no treatment
Corresponding rate: metformin treatment
Relative effect (95% CI)
No. of participants (studies)
Live birth
320 per 1,000
395 per 1,000 (276 to 530)
OR 1.39 (0.81–2.40)
551 (5)
Clinical pregnancy OHSS
307 per 1000
403 per 1000 (322 to 488)
OR 1.52 (1.07–2.15)
775 (8)
270 per 1,000
97 per 1,000 (62 to 153)
OR 0.29 (0.18–0.49)
798 (8)
Side effects
106 per 1,000
347 per 1,000 (182 to 559)
OR 4.49 (1.88–10.72)
431 (4)
Quality of the evidence (GRADE) 4422 Lowb,c,d 4442 Moderatec,d 4442 Moderatec 4422 Lowb,e
Note: GRADE Working Group grades of evidence are as follows: High quality: Further research is very unlikely to change our confidence in the effect estimate. Moderate quality: Further research is likely to have an important impact on our confidence in the effect estimate and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the effect estimate and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a The basis for the assumed rate is the median control group rate across studies. The corresponding rate (and its 95% CI) is based on the assumed rate in the comparison group and the relative effect of the intervention (and its 95% CI). b Inconsistency: unexplained heterogeneity (I2 ¼ 52%). c Imprecision: total number of events is
Metformin treatment before and during in vitro fertilization or intracytoplasmic sperm injection in women with polycystic ovary syndrome: summary of a Cochrane review Leopoldo O. Tso, M.D.,a Michael F. Costello, M.B.B.S.,b Luiz Eduardo T. Albuquerque, M.D.,c gis B. Andriolo, Ph.D.,d Jane Marjoribanks, M.P.H.,e and Cristiane R. Macedo, Ph.D.f Re a ~o Paulo, Sa ~ o Paulo, Brazil; b Division of Obstetrics & Gynaecology, Department of Gynecology, Federal University of Sa School of Women's and Children's Health, University of New South Wales and Royal Hospital for Women and IVF Australia, Sydney, New South Wales, Australia; c Human Reproduction Center, Fertivitro Center for Human State, Bele m, Brazil; ~ o Paulo, Brazil; d Department of Public Health, University of Para Reproduction Humana, Sa e Cochrane Office, University of Auckland, Auckland, New Zealand; and f Brazilian Cochrane Centre, Centre for Evidence ~ o Paulo, Brazil Based Health Studies and Health Technology Evaluation, Sa
In women with polycystic ovary syndrome, metformin treatment before or during assisted reproductive technology cycles increases clinical pregnancy rates and decreases the risk of ovarian hyperstimulation syndrome. However, there is no conclusive evidence of a benefit in live birth rates. (Fertil SterilÒ 2015;-:-–-. Use your smartphone Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Metformin, polycystic ovary syndrome, assisted reproductive techniques, in vitro and connect to the fertilization, intracytoplasmic sperm injection Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/tsol-metformin-pcos-ivf-icsi/
M
etformin is an insulinsensitizing agent that reduces hyperinsulinemia and suppresses the excessive ovarian production of androgens in women with polycystic ovary syndrome (PCOS). It has been suggested that metformin could improve pregnancy and live birth rates, and
reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing assisted reproductive techniques (ART).
MATERIALS AND METHODS We included all randomized controlled trials (RCTs) that compared metformin
Received May 6, 2015; accepted May 29, 2015. L.O.T. has nothing to disclose. M.F.C. has nothing to disclose. L.E.T.A. has nothing to disclose. R.B.A. has nothing to disclose. J.M. has nothing to disclose. C.R.M. has nothing to disclose. This is a summary of a systematic review published on the Cochrane Library: Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2014, Issue 11. Reprint requests: Jane Marjoribanks, M.P.H., Cochrane Office, University of Auckland, Private Bag 92019, Auckland 1020, New Zealand (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.05.038 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
treatment with placebo, or with no treatment, in women with PCOS undergoing in vitro fertilization or intracytoplasmic sperm injection. Two review authors independently selected trials, extracted the data, and assessed study risk of bias. Our primary outcomes were live birth, clinical pregnancy, and OHSS. Secondary outcomes included side effects. Studies were pooled when appropriate, to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We used a random effects model, assuming a distribution of effect sizes rather than a single true effect size. Statistical heterogeneity was assessed using the I2 statistic. The quality of the evidence for each comparison was assessed using GRADE 1
COCHRANE CONCISE
FIGURE 1
Forest plot for live birth. Tso. Metformin to treat PCOS with IVF or ICSI. Fertil Steril 2015.
(Grades of Recommendation, Assessment, Development, and Evaluation) methods. Institutional review board approval was not required, because this work is secondary research.
RESULTS We included 9 RCTs (n ¼ 816 women). They compared metformin with placebo (7 RCTs) and with no treatment (2 RCTs). Eight studies used a long protocol gonadotropinreleasing hormone agonist (GnRH-a), and 1 study used a short protocol GnRH antagonist. When metformin was compared with placebo, no statistically significant difference was found between the groups in live birth rates (OR 1.39, 95% CI 0.81–2.40; 5 RCTs; 551
women; I2 ¼ 52%; low-quality evidence; Figure 1 and Table 1). If the chance of live birth without use of metformin is assumed to be 32%, the corresponding chance with use of metformin is estimated to be between 28% and 53% (95% CI). When metformin was compared with placebo or no treatment, clinical pregnancy rates were significantly higher in the metformin group (OR 1.52, 95% CI 1.07–2.15; 8 RCTs; 775 women; I2 ¼ 18%; moderate-quality evidence). If the chance of clinical pregnancy without use of metformin is assumed to be 31%, the corresponding chance with use of metformin is estimated to be between 32% and 49% (95% CI). When metformin was compared with placebo or no treatment, the risk of OHSS was significantly lower in the metformin group (OR 0.29, 95% CI 0.18–0.49; 8 RCTs; 798 women; I2 ¼ 11%;
TABLE 1 Summary of findings. Illustrative comparative ratesa (95% CI)
Outcome
Assumed rate: placebo or no treatment
Corresponding rate: metformin treatment
Relative effect (95% CI)
No. of participants (studies)
Live birth
320 per 1,000
395 per 1,000 (276 to 530)
OR 1.39 (0.81–2.40)
551 (5)
Clinical pregnancy OHSS
307 per 1000
403 per 1000 (322 to 488)
OR 1.52 (1.07–2.15)
775 (8)
270 per 1,000
97 per 1,000 (62 to 153)
OR 0.29 (0.18–0.49)
798 (8)
Side effects
106 per 1,000
347 per 1,000 (182 to 559)
OR 4.49 (1.88–10.72)
431 (4)
Quality of the evidence (GRADE) 4422 Lowb,c,d 4442 Moderatec,d 4442 Moderatec 4422 Lowb,e
Note: GRADE Working Group grades of evidence are as follows: High quality: Further research is very unlikely to change our confidence in the effect estimate. Moderate quality: Further research is likely to have an important impact on our confidence in the effect estimate and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the effect estimate and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a The basis for the assumed rate is the median control group rate across studies. The corresponding rate (and its 95% CI) is based on the assumed rate in the comparison group and the relative effect of the intervention (and its 95% CI). b Inconsistency: unexplained heterogeneity (I2 ¼ 52%). c Imprecision: total number of events is
