Posted by: birdsandsquirrels | April 24, 2009

metformin during pregnancy

I love metformin. I recently commented on Celia’s blog that I intend to take it throughout pregnancy. Now, I understand that doctors are reluctant to prescribe drugs during pregnancy, with good reason. But there have been a number of studies showing that, in women with PCOS, metformin reduces the risk of miscarriage, the risk of developing gestational diabetes, does not cause preeclampsia, and does not cause birth defects. Maybe it hasn’t been studied extensively enough to recommend that all women with PCOS should stay on it during pregnancy, but for me, I’m willing to take whatever low risk there might be if it means I get a real live baby out of this.

I got some requests for links to journal articles on the use of metformin in pregnancy in women with PCOS. Here you go…

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.

Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L.

Cholesterol Center, Jewish Hospital, Cincinnati, Ohio 45229, USA. glueckch@healthall.com

OBJECTIVE: To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS). DESIGN: Prospective and retrospective study. SETTING: Outpatient clinical research center. PATIENT(S): The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy. INTERVENTION(S): Metformin, 2.55 g/d, throughout pregnancy in women with PCOS. MAIN OUTCOME MEASURE(S): Development of gestational diabetes in women with PCOS. RESULT(S): Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was 0.093 (95% CI: 0.011 to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was 0.115 (95% CI: 0.014 to 0.938). CONCLUSION(S): In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic beta-cells by insulin resistance and pregnancy.

Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?

Nawaz FH, Khalid R, Naru T, Rizvi J.

Department of Obstetrics and Gynaecology, Aga Khan University Karachi Pakistan, Karachi, Pakistan. fauzia.nawaz@aku.edu

AIM: Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies in women of reproductive age. It is associated with hyperinsulinemia and insulin resistance which is further aggravated during pregnancy. This mechanism has a pivotal role in the development of various complications during pregnancy. In the past few years, metformin, an insulin sensitizer, has been extensively evaluated for induction of ovulation. Its therapeutic use during pregnancy is, however, a recent strategy and is a debatable issue. At present, evidence is inadequate to support the long-term use of insulin-sensitizing agents during pregnancy. It is a challenge for both clinicians and researchers to provide good evidence of the safety of metformin for long-term use and during pregnancy. This study aimed to evaluate pregnancy outcomes in women with PCOS who conceived while on metformin treatment, and continued the medication for a variable length of time during pregnancy. METHODS: This case-control study was conducted from January 2005 to December 2006 at the antenatal clinics of the Department of Obstetrics and Gynecology, Aga Khan University, Karachi, Pakistan. The sample included 137 infertile women with PCOS; of these, 105 conceived while taking metformin (cases), while 32 conceived spontaneously without metformin (controls). Outcomes were measured in three groups of cases which were formed according to the duration of use of metformin during pregnancy. Comparison was made between these groups and women with PCOS who conceived spontaneously. RESULTS: All 137 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed up during their course of pregnancy; data forms were completed once they had delivered. Cases were divided into three groups: group A, 40 women who stopped metformin between 4-16 weeks of pregnancy; group B, 20 women who received metformin up until 32 weeks of gestation; and group C; 45 women who continued metformin throughout pregnancy. All the groups were matched by age, height and weight. Comparison was in terms of early and late pregnancy complications, intrauterine growth restriction and live birth rates. In groups A, B and C the rate of pregnancy-induced hypertension/pre-eclampsia was 43.7%, 33% and 13.9% respectively (P<0.020). Rates of gestational diabetes requiring insulin treatment in groups A and B were 18.7% and 33.3% compared to 2.5% in group C (P<0.004). The rate of intrauterine growth restriction was significantly low in group C: 2.5% compared to 19.2% and 16.6% in groups A and B respectively (P<0.046). Frequency of preterm labor and live birth rate was significantly better in group C compared to groups A and B. Overall rate of miscarriages was 7.8%. Controls were comparable to group A in terms of early and late pregnancy complications. CONCLUSION: In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction. No congenital anomaly, intrauterine death or stillbirth was reported in this study.

Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review.

Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E.

Department of Gynecology and Obstetrics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. wnichol@jhmi.edu

OBJECTIVE: Little is known about the comparative risks and benefits of medical treatments for gestational diabetes mellitus (GDM). We conducted a systematic review of randomized controlled trials and observational studies of maternal and neonatal outcomes in women with GDM treated with oral diabetes agents compared with all types of insulin. DATA SOURCES: We searched four electronic databases from inception through January 2007. Terms for GDM, insulins, and oral hypoglycemic agents were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality. METHOD OF STUDY SELECTION: Articles were excluded if they had no comparison group or did not use a standard diagnosis of GDM (3-hour, 100-g oral glucose tolerance test or 2-hour, 75-g oral glucose tolerance test). Nine studies met our inclusion criteria, four randomized controlled trials (n=1,229 participants) and five observational studies (n=831 participants). Data were abstracted on study characteristics, gestational age at treatment, medication dosage, and length of follow-up. Outcomes included glycemic control, infant birth weight, neonatal hypoglycemia, and congenital anomalies. TABULATION, INTEGRATION, AND RESULTS: Two trials compared insulin to glyburide; one trial compared insulin, glyburide, and acarbose; and one trial compared insulin to metformin. No significant differences were found in maternal glycemic control or cesarean delivery rates between the insulin and glyburide groups. A meta-analysis showed similar infant birth weights between women treated with glyburide and women treated with insulin (mean difference -93 g) (95% confidence interval -191 to 5 g). There was a higher proportion of infants with neonatal hypoglycemia in the insulin group (8.1%) compared with the metformin group (3.3%) (P=.008). The rate of congenital malformations did not differ between pregnancies treated with insulin and those treated with oral agents. Observational studies were limited by selection bias and confounding. CONCLUSION: No substantial maternal or neonatal outcome differences were found with the use of glyburide or metformin compared with use of insulin in women with GDM.

Diabet Med. 2004 Aug;21(8):829-36.

Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome.

Glueck CJ, Bornovali S, Pranikoff J, Goldenberg N, Dharashivkar S, Wang P.

Cholesterol Center, Jewish Hospital, Cincinnati, OH 45229, USA. glueckch@healthall.com

AIMS: Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre-eclampsia, and was it safe for mother and neonate? METHODS: In the current study, pre-eclampsia and other pregnancy outcomes were prospectively studied in 90 women with PCOS who conceived on metformin 1.5-2.55 g/day, and had > or = 1 live birth (97 pregnancies, 100 live births) compared with 252 healthy women (not known to have PCOS) with > or = 1 live birth, consecutively delivered in a community obstetrics practice. RESULTS: Women with PCOS were older than controls (33 +/- 5 vs. 29 +/- 6 years, P < 0.0001), more likely to be > 35 years old at conception (23 vs. 13%, P = 0.028), much heavier (93 +/- 23 vs. 72 +/- 18 kg, P < 0.0001, BMI 33.8 +/- 7.8 kg/m2 vs. 25.6 +/- 5.9, P < 0.0001), and more likely to be Caucasian (97 vs. 90%, P = 0.05), but there were similar numbers with preconception Type 2 diabetes mellitus [2/90 (2.2%) vs. 1/252 (0.4%), P = 0.17]. Pre-eclampsia in PCOS (5/97 pregnancies, 5.2%), did not differ (P = 0.5) from controls (9/252, 3.6%), nor did it differ (P = 1.0) in PCOS vs. control primigravidas [2/45 (4.4%) vs. 4/91 (4.4%)]. Development of gestational diabetes in PCOS did not differ from controls [9/95 pregnancies (9.5%) vs. 40/251 (15.9%), P = 0.12]. Of the 100 live births to 90 women with PCOS, there were no major birth defects. Mean +/- sd birth weight of the 80 live births > or = 37 weeks gestation in women with PCOS (3414 +/- 486 g) did not differ from controls’ 206 live births > or = 37 weeks (3481 +/- 555 g), P = 0.34, nor did the percentage of > or = 37 week gestation neonates > or = 4000 g (12.5 vs. 17.5%, P = 0.3) or > or = 4500 g (1.3 vs. 2.9%, P = 0.7). CONCLUSIONS: Metformin is not associated with pre-eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus. Copyright 2004 Diabetes UK


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Responses

  1. Thanks!!! This post is getting bookmarked, printed, highlighted and annotated (all in good time of course). I was ambivalent when I started on met about continuing it through pregnancy, but now I’m pretty well convinced that it is worth it with low risks. I think the challenge would be to make sure your dr supports you in it and these papers will be helpful in that task (especially since so many obgyns tend to be surprisingly clueless about PCOS).

  2. Hi – you don’t know me, but I’ve enjoyed your blog for a couple weeks now. Congratulations!

    My husband and I are dealing with PCOS and morphology issues, too. We had a miscarriage last March at 12 weeks, so I guess your blog has resonated with me.

    I was wondering why *you* love Metformin. I know it helps some ovulate and helps with sensitizing the body to insulin, but are these the only reasons? How does it affect you?

  3. I have PCOS and strongly believe that metformin has helped tremendously with getting pregnant and keeping the pregnancy. I had been taking several fertility meds with a previous RE and kept telling him I thought I had insulin issues with how I felt after eating different foods, not eating often enough, etc. My new RE immediately ran a series of tests and since i have PCOS they prescribed it and I feel so much better and actually lost weight being on it.

  4. I had my Monthy check up appt yesterday with my OB. I left her office in tears and was so upset, I was ready to call my RE and tell her that I wanted to find a new OB that has an understanding of PCOS because my OB is clearly clueless. She’s the absolute best when it comes to babies, everyone has praised her with her abilities, and I personally asked her to be my OB because I’ve only heard good things. Til yesterday. She actually had the nerve to tell me that if I lost weight, I wouldnt have PCOS and that PCOS is so prevelant now days because so many woman are overweight & obese. I informed her that I was 78 lbs in 7th grade, when all my girlfriends were hitting puberty, I was on the couch with migraines day and night. NOT eating, because I was so nauseated from the headaches, and I gained 125 lbs that summer! I lived with migraines daily for almost 14 years! I didn’t have any relief until I went on birth control and metformin. If I miss a pill or I’m an hr late for a pill, the headaches starts. The only way I could dull the pain was to eat a snickers and a mt dew, with 1000 mg of tylenol and 600 mg of Ibuprofen. Literally several times a day!! You can’t lose weight when you’re eating candybars and laying on the couch with no energy & headaches.

    My OB told me yesterday that I have to stop the Metformin, she was furious with me because I told her that I wasn’t going to stop taking it. She said she couldn’t believe I was taking it still, that SOMEONE should have told me to stop it by 16 weeks. (I’m 24 wks and have had NO complications of any kind thus far). I told her that I could not go without it, or I’d have migraines daily! She said, and I quote, “I dont care about you, my concern is the baby, its not that I dont care about you, but you need to put your babies needs first, metformin doesnt prevent or stop headaches, take a tylenol!” YOUR WRONG, it makes my body use the insulin its producing, so that IT STOPS OVER PRODUCING insulin, the OVER PRODUCTION is what makes the excretion of testosterone & other androgens which CAUSE the headaches! I already stopped taking the spironolactone, because my RE told me that was the only thing besides the birth control (which for obvious reasons) had to be stopped during pregnancy.

    So, after a heated conversation about finding a new OB, she offered to refer to me a HIGH RISK OB Specialist, and get a 2nd opinion. If he says that its safe to continue the Metformin, then she will allow it. The reason I pissed her off is because she wants me to do the glucose tolerance test, and I said, “well isn’t it unneeded since I’m already on Metformin, which helps prevent Gestational Diabetes, and my BG’s are in the 40’s-80s, never ever over 91. If I do end up having it later in the pregnancy, I’m already on metformin, so is it worth it to do the test?” She flipped!! Said I have to stop taking it. If I have GD then I need to start injectable Insulin, and I said, “I wont inject myself with insulin, why would I add more when my body over produces already, and I dont use what I make naturally without the metformin?” I was told I’m obviously not concerned with having a healthy, viable baby, its a shame because I worked so hard to get pregnant (Used fertility drugs) and I’m risking having a still born baby or requiring a c-section because oral meds are not as effective as injectable insulin.

    God, I wish I had printed this out BEFORE the appt! I have an appt with a specialist in 2 weeks. I sure hope he isn’t as ignorant about PCOS as my OB is!

    Thanks for the article, it greatly relieved some doubts that I didn’t have until yesterday. I KNEW I had done my research and that it was safe, I trusted my RE and I was right. My OB is uneducated and needs to open her eyes!

    Thank you,
    Christina 🙂

  5. […] I need your help! I’ve printed off the WebMD article that I linked to above, and also some articles that the blogger Birds and Squirrels linked to in her blog back in April (thanks again to Maybe […]

  6. Excellent phrase

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