Just as an added note: Around Sept. 23/24, 2002, a discussion was held on obgyn-l (for professionals only) at OBGYN.NET. Note that only professionals can post on the list, however the archives are searchable. Please review the following posts using the Gyn:PCO subject line.
On March 19, 2002, I got some information from Robert W. Rossi, R.Ph., C.D.E., a Clinical Pharmacist Consultant, in regards to glyburide during pregnancy as an alternative to Metformin. There is some question as to whether or not this is safer than Metformin. Apparently the newer version of these types of drugs do not cross the placenta barrier. Dr. Langer is doing research on this. Those resources will be listed at the end of this page.11, 12, 13, 14, 15, 16, 17. As of April 8, 2002, I believe I have the paper Maria Iuorno's paper in here (a Dr. Nestler colleague at MCV in Richmond, Va.), presented at the Endocrine Society. It was posted on one of the forums, and I'm trying to look up the person who sent it. Its in the Journal of Clinical Endocrinology & Metabolism, Effects of Metformin on Early Pregnancy Loss in the Polycystic Ovary Syndrome, Daniela J. Jakubowicz, Maria J. Iuorno, Salomon Jakubowicz, Katherine A. Roberts and John E. Nestler. Hospital de Clinicas Caracas and Central University of Venezuela (D.J.J., S.J.), Caracas 1040, Venezuela; and Departments of Medicine (M.J.I., K.A.R., J.E.N.) and Obstetrics and Gynecology (J.E.N.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0111. A retrospective study of all PCOS women seen in an academic endocrinology clinic within the past 4.5 yr and who became pregnant during that time were studied. 65 women got Metformin and 31 did not. The early pregnancy loss rate with Metformin was 8.8% (6 of 68 pregnancies), compared with 41.9% (13 of 31 pregnancies) for non Metformin takers. In each group of women, those who had a prior history of miscarriage, the loss rate was 11.1% (4 of 36 pregnancies) for those taking Metformin, 58.3% (7 of 12 pregnancies) without. Metformin administration during pregnancy reduces first-trimester pregnancy loss in women with the polycystic ovary syndrome. There has been a lot of controversy regarding the use of Metformin during pregnancy. The protocol varies on the doctor: remove you off Metformin after a positive pregnancy test, once a heartbeat is seen on ultrasound, at the end of the first trimester, or during the whole pregnancy. This article lists researched pros and cons to help you make a decision on the subject, along with some thoughts and future articles to look out for on the subject. Starting with the "pro" side of using Metformin throughout pregnancy, Dr. Charles Glueck has been at the forefront. His website, lists his studies and articles. He also has a note on his website that he is setting up a worldwide registry of pregnancy in women with PCOS, both with and without Metformin use. Dr. Glueck published an article in Fertility and Sterility, one of the most well known and respected publications for infertility physicians, this year for a pilot study involving continuing Metformin throughout pregnancy (1). He stated that 19 women taking Metformin (1500 to 2550 mg a day) have had no bad maternal side effects and no birth defects. 9 had normal term births, 2 delivered early, 6 have normal pregnancies past the first trimester (no congenital defects seen on monitoring), and 2 had miscarriages. He spoke at the Experimental Biology 2000 conference in San Diego, Ca. in April, 2000 on: "Pregnancy failure and preservation in women with Polycystic Ovary Syndrome: Safety and efficacy of Metformin therapy continued through pregnancy". 118 women with PCOS had 239 pregnancies with 94 miscarriages for a 39% miscarriage rate. PAI-Fx, the protein plasminogen activator inhibitor, appears to cause the miscarriage rate, and metformin lowers PAI-Fx. The women were on Metformin for an avg. of 5 months and he states that it lowered the first trimester miscarriage rate from 45% to 9%. Another article listed on his site from the Journal of Investigative Medicine 2000;48:188A (Abstract) is entitled, "Metformin throughout pregnancy in women with Polycystic Ovary Syndrome reduces first trimester miscarriage from 39%-58% TO 5%-11%.". He refered to his recent study of 43 women in the Metabolism 1999 and retrospectively studied the pregnancy outcomes of 41 women with at least 1 pregnancy who conceived without Metformin. He used stepwise logistic regression to calculate his statistics that PAI-Fx was a "predominant" risk factor for miscarriage in women with PCOS. Dr. Glueck frequently quotes Dr. Coetzee, from South Africa. Dr. Coetzee used calorie-restricted diets, along with Metformin and Glibenclamide between June 1974 and December 1983 to manage 423 new diabetics (2). Side-effects of the drugs were "rare and mild", and he noted that any babies' hypoglycemia is preventable by using continuous insulin infusion during delivery. Dr. Coetzee also studied 171 pregnant women with diabetes for 5 1/2-years (3). 78 women got oral hypoglycaemic drugs during the 1st trimester (although it does not state which drugs they were, more than just Metformin from the report) and 93 did not. There were only two major congenital anomalies were seen in the tablet-taking group and 4 miscarriages. The perinatal mortality rate was initially high after large doses of Metformin had been given during the 1st trimester, but he states that was due to loss of diabetic control later on in pregnancy. Only 4% of the last 50 of the 75 babies who made it to term with the drugs in early pregnancy were miscarried. Dr. Coetzee also did a 4 year study (4) involving 104 women. He said that 67 patients were well controlled on diet alone with no loss of babies. The rest got Glibenclamide or Metformin, where the loss of babies went to 1%. There was little problem with hypoglycemia and 79% of the babies' birth weights were fine. Dr. Coetzee studied 171 pregnant women (5) who had diabetes before pregnancy for 5 1/2 years. Eleven were excluded for getting in late. The other 160 patients were managed primarily by diet; when that failed, they used Metformin or Glibenclamide, then insulin. There was no split between how many got Metformin and how many got Glibenclamide. 25% of people were controlled with diet with only 1 baby dying. Glibenclamide and Metformin had death rates of 7.8% versus 36.4% in those that weren't treated. Only 18 of the babies were overweight (> 4,000 g), and Glibenclamide was the drug that was related to hypoglycemia. This can be ameloriated by giving a low dose insulin IV 24 hrs. before delivering. He did note that major abnormalities was at least 2 times that of non-diabetic mothers. Dr. Coetzee studied (6) 60 pregnant women, having diabetes before pregnancy, were given Metformin during the 2nd and 3rd trimester. Metformin failed to work for 27 of these women and were given other therapy. 33 patients received Metformin up till delivery, with only 2 deaths and a high incidence of jaundice that needed therapy. 3 babies with congenital abnormalities had received Metformin only during the last trimester of their pregnancy. The American Journal of Obstetrics and Gynecology's March 1997 article (176(3):527-30) says that the placenta's glucose uptake and transport do not show any change using Metformin. A group of doctors at the Central University of Venezuela (7) believe that hyperinsulinemia contributes to early pregnancy loss by decreasing serum glycodelin, a marker of how well your endometrium functions. 48 PCOS women were studied: 26 were given 500 mg Metformin three times a day; 22 got a placebo. Metformin increased follicular and luteal phase serum glycodelin, insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow. The newest articles I have as of June 2002 are the following on the pro side of Metformin:
Metformin Therapy Throughout Pregnancy Reduces GD Metformin Helps Prevent Gestational Diabetes Metformin Shows Promise in Preventing Miscarriage Hope they help. There was another article/study in Fertility and Sterility in March 2002 by Dr. Glueck showing a very significant reduction in gestational diabetes when metformin is continued during pregnancy. I am currently researching the specific article and where it was found. Since these findings go directly against what the next paper says, lets move on to the "con" side. On the "con" side of using Metformin, The Juliane Marie Centre in Copenhagen, Denmark published a paper that tested a sulphonylurea, Metformin, and insulin during pregnancy on diabetic women (8) at a university hospital: 50 women got metformin, 68 women got a sulphonylurea and the control group of 42 women used insulin. Significantly higher rates of pre-eclampsia was seen in the group of metformin women compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%), plus the perinatal mortality was higher. The Metformin group, treated in the third trimester, had perinatal mortality significantly increased compared to women not treated with metformin (11.6 vs. 1.3%). There was no difference in neonatal morbidity between the orally treated and insulin-treated group and no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. Although this study (9) wasn't on humans, it seems that mouse embryos exposed to Metformin produced no problems growing or malformations, but 10% of the embryos exposed at any dose showed open areas at the brain site. However, this was apparently due to a delay in closure of the brain, versus any kind of defect. Using umbilical and endothelial cells, sulphonylureas and Metformin did produce changes in endothelial cells (10). Another factor that you may want to consider in your decision is that drugs such as DES were given to pregnant women for over 20 years, to stop miscarriages, with outcomes that weren't discovered until years later. Rezulin was hailed as a breakthrough drug, but has been pulled off the market due to liver failure. In addition, when going to your doctor with research, there might be several reasons why he or she may not accept it. Some of these could be: that it is extremely new research; lack of followup data or long term testing to see outcomes of the participants; too few participants in the study to be significant; lack of double blind placebo testing (where the doctor nor you know whether or not you will receive a placebo or the real drug) or lack of enough data in the mind of the doctor to be convincing. Here is another problem: Doctors face quandary in prescribing to mothers-to-be. I know of 2 doctors who are publishing in regards to this topic. Dr. John Nestler, Department Chair of The Division of Endocrinology and Metabolism at the Medical College of Virginia, will be having a paper come out sometime in 2001/2002 regarding continuing Metformin during pregnancy. Dr. Michael Heard of Baylor presented at the Society of Gynecologic Investigation a paper where he continued metformin uncontrolled and found miscarriage rates similiar to historically high rates for women with PCOS. At this point, it is up to you and your doctor to investigate all and weigh all possibilities and both sides of the issue. References
1 Fertility and Sterility, 2001 Jan;75(1):46-52, "Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study" by Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. The Cholesterol Center, Jewish Hospital, Cincinnati, Ohio 45229, USA. 2 Diabetes Res Clin Pract 1985-86 Feb;1(5):281-7, "The management of non-insulin-dependent diabetes during pregnancy" by Coetzee EJ, Jackson WP.3 S Afr Med J 1984 Apr 21;65(16):635-7, "Oral hypoglycaemics in the first trimester and fetal outcome" by Coetzee EJ, Jackson WP.4 S Afr Med J 1979 Sep 1;56(12):467-75, "Diabetes newly diagnosed during pregnancy: A 4-year study at Groote Schuur Hospital" by Coetzee EJ, Jackson WP.5 S Afr Med J 1980 Nov 15;58(20):795-802, "Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital" by Coetzee EJ, Jackson WP.6 Diabetologia 1979 Apr;16(4):241-5, "Metformin in management of pregnant insulin-independent diabetics" by Coetzee EJ, Jackson WP.7 J Clin Endocrinol Metab 2001 Mar;86(3):1126-33, "Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome" by Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, Koistinen R, Nestler JE. Hospital Clinicas Caracas and Central University of Venezuela, 1050 Caracas, Venezuela.8 Diabet Med 2000 Jul;17(7):507-11, "Oral hypoglycaemic agents in 118 diabetic pregnancies" by Hellmuth E, Damm P, Molsted-Pedersen L. Department of Obstetrics and Gynaecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Denmark.9 Teratology 1994 Apr;49(4):260-6, "Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis" by Denno KM, Sadler TW. Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill 27599.10 Diabet Med 1992 Jan-Feb;9(1):30-7, "The influence of hypoglycaemic agents on the growth and metabolism of human endothelial cells" by Petty RG, Pearson JD. Section of Vascular Biology, M.R.C. Clinical Research Centre, Harrow, UK.11 Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol 2001 May-Jun;15(3):227-9 (ISSN: 0890-6238) Koren G he Motherisk Program, Division of Clinical Pharmacology and Toxicology,
The Research Institute, The Hospital for Sick Children and the University of Toronto, 555 University Avenue, M5G 1X8, Toronto, Ontario, Canada., gkoren@sickkids.on.ca.12 Oral hypoglycemic drugs for gestational diabetes. N Engl J Med 2000 Oct 19;343(16):1178-9 (ISSN: 0028-4793) Greene MF Comment On: Comment On: RefSource:N Engl J Med. 2000 Oct. 19; 343(16):1134-813 A comparison of glyburide and insulin in women with gestational diabetes
mellitus. N Engl J Med 2000 Oct 19;343(16):1134-8 (ISSN: 0028-4793) Langer O; Conway DL; Berkus MD; Xenakis EM; Gonzales O
Department of Obstetrics and Gynecology, St. Luke's-Roosevelt Hospital Center, New York 10019, USA. olanger@slrhc.org.14 The use of glyburide in gestational diabetes--an ideal example of "bench to
bedside" Pediatr Res 2001 Jun;49(6):734 (ISSN: 0031-3998) Koren G The Motherisk Program, The Hospital for Sick Children, Toronto, ON, Canada.15 A comparison of glyburide and insulin in women with gestational diabetes mellitus. Diabet Med 2001 May;Suppl 3:12-4 (ISSN: 0742-3071) Dornhorst A Metabolic Medicine, Imperial College at Hammersmith Campus, London, UK.16 Critical appraisal of published research evidence: treatment of gestational
diabetes. Diabet Med 2001 May;Suppl 3:1-5 (ISSN: 0742-3071) Dornan T; Hollis S17 Gestational diabetes: an alternative to insulin therapy?] [Diabete gestationnel: une alternative a l'insulinotherapie.] Presse Med 2001 Feb 3;30(4):169-70 (ISSN: 0755-4982) Letonturier P