Metformin

 Risk Factor: BM
 Class: HORMONES / Antidiabetic Agents

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Metformin is an oral, biguanide, antihyperglycemic agent that is chemically and pharmacologically unrelated to the sulfonylureas. Its mechanism of action is thought to include decreased hepatic glucose production, decreased intestinal absorption of glucose, and increased peripheral uptake and utilization of glucose (1,2). The latter two mechanisms result in improved insulin sensitivity (i.e., decreased insulin requirements) (1,2).

Reproduction studies found no evidence of impaired fertility in male and female rats and no evidence of teratogenicity in rats and rabbits at doses up to 600 mg/kg/day, approximately 2 times the maximum recommended human dose on a mg/m2 basis (1). A partial placental barrier to metformin was observed, however, based on fetal concentrations (1).

Shepard (3) and Schardein (4) cited a study in rats that observed teratogenesis (neural tube closure defects and edema) in rat fetuses exposed to metformin. The drug did not appear to be a major teratogen because less than 0.5% of the rat fetuses in mothers fed 5001000 mg/kg developed anophthalmia and anencephaly (3). Higher doses in this study were embryotoxic (5).

A 1994 abstract described the teratogenic effects of high metformin concentrations on early somite mouse embryos exposed in vitro (6). At levels much higher than those obtained clinically, metformin produced neural tube defects and malformations of the heart and eye. In contrast, a study that also appeared in 1994 observed no major malformations in mouse embryos exposed in culture to similar concentrations of metformin (7). About 10% of the embryos, however, demonstrated a transient delay in closure of cranial neuropores.

In an experiment using the human single-cotyledon model with placentas obtained from diabetic patients and normal controls, researchers measured the effect of metformin on the uptake and transport of glucose in both the maternal-to-fetal and fetal-to-maternal directions (8). A second publication described only the results of the experiments studying the effect of metformin on the maternal-to-fetal direction of glucose (9). Compared with controls, metformin had no effect on the movement of glucose in either direction (8,9).

Among 26 women undergoing treatment for polycystic ovary syndrome with metformin, 1.5 g/day for 8 weeks, 3 became pregnant during treatment (10). The women were involved in a study to determine whether metformin was effective in normalizing the condition that is characterized by insulin resistance and hyperandrogenism. One of the pregnancies aborted after 2 months, and the outcomes of the other two were not mentioned.

A number of References have described the use of metformin during all stages of gestation for the control of maternal diabetes (11,12,13,14,15,16,17,18 and 19). A 1979 Reference described the therapy of gestational diabetes that included the use of metformin alone (N=15), glyburide alone (N=9), or metformin plus glyburide (N=6) in women who were not controlled on diet alone and did not require insulin (13). None of the newborns developed symptomatic hypoglycemia, and only one infant had a congenital defect (ventricular septal defect). Although the treatment group was not specified, ventricular septal defects are commonly associated with poorly controlled diabetes occurring early in gestation (19).

A 1979 Reference described the pregnancy outcomes of 60 obese women who received metformin in the 2nd and the 3rd trimester for diabetes (preexisting [N=39] or gestational [N=21]) that was not controlled by diet alone (14). The drug was not effective in 21 (54%) and 6 (29%) of the patients, respectively. The pregnancy outcomes, in terms of hyperbilirubinemia, polycythemia, necrotizing enterocolitis, and major congenital abnormalities, were not better than those observed in another group of insulin-dependent and noninsulin-dependent diabetic women treated by the investigators, except for perinatal mortality. None of the newborns had symptoms of hypoglycemia. The three infants with congenital malformations had defects (two heart defects and one sacral agenesis) that were most likely caused by poorly controlled diabetes occurring early in gestation.

In another report, metformin in combination with diet (N=22) and glyburide (N=45) was used during pregnancy for the treatment of preexisting diabetes (15). No cases of lactic acidosis or neonatal hypoglycemia were observed with metformin and diet alone, but the latter complication did occur when glyburide was added. Neonatal hypoglycemia is a well-known complication of sulfonylurea agents if they are ingested too close to delivery (see Glyburide). In an earlier Reference, a total of 56 patients had received metformin up to 24 hours of delivery without adverse effects in the newborns (12).

Metformin was used during the 1st trimester in 21 pregnancies described in a 1984 report (16). A minor abnormality (polydactyly) was observed in a newborn whose mother had taken metformin and glyburide. Based on this and previous experience, these investigators proposed a treatment regimen for the management of women with noninsulin-dependent diabetes mellitus (NIDDM) (i.e., type II diabetes mellitus) who become pregnant consisting of diet and treatment with metformin and glyburide as necessary (17). If this regimen did not provide control of the blood glucose, a change to insulin therapy was recommended (17). These investigators concluded that the drug therapy was not teratogenic and did not cause ketosis and that neonatal hypoglycemia was preventable if the therapy was changed to insulin before delivery.

A 1990 Reference addressed the problem of treating diabetes in tropical countries where the availability of medical support and facilities is poor (18). The author recommended that gestational diabetes, not responding to diet alone, be treated with sulfonylurea agents or metformin or both because the initiation of insulin therapy in developing countries was difficult.

The fetal effects of oral hypoglycemic agents on the fetuses of women attending a diabetes and pregnancy clinic were reported in 1991 (19). All of the women (N=21) had NIDDM and were treated during organogenesis with oral agents (1 with metformin, 2 with phenformin, 17 with sulfonylureas, and 1 with an unknown agent), with a duration of exposure of 328 weeks. A control group (N=40) of similar women with NIDDM who were also attending the clinic, matched for age, race, parity, and glycemic control, was used for comparison. Both groups of patients were changed to insulin therapy at the first prenatal visit. From the study group, 11 infants (52%) had congenital malformations, compared with 6 (15%) from the controls (p<0.002). Moreover, six of the newborns from the study group (none in the control group) had ear defects, a malformation that is observed, albeit uncommonly, in diabetic embryopathy (19). No defects were seen in the one infant exposed to metformin. Sixteen live births occurred in the exposed group, compared with 36 in controls. The groups did not differ in the incidence of hypoglycemia at birth (53% vs. 53%), but three of the exposed newborns had severe hypoglycemia lasting 2, 4, and 7 days, respectively, even though the mothers had not used the oral agents close to delivery. In one of these cases, the mother had been taking metformin 1500 mg daily for 28 weeks. Hyperbilirubinemia was noted in 10 (67%) of 15 exposed liveborn infants, compared with 13 (36%) of the controls (p<0.04), and polycythemia and hyperviscosity requiring partial exchange transfusions were observed in 4 (27%) of 15 exposed vs. 1 (3.0%) control (p<0.03) (one exposed infant was not included in these data because the child presented after completion of the study).

In summary, although the use of metformin may be beneficial for decreasing the incidence of fetal and/or newborn morbidity and mortality in developing countries where the proper use of insulin is problematic, insulin is still the treatment of choice for this disease. Moreover, insulin, unlike metformin, does not cross the placenta and, thus, eliminates the additional concern that the drug therapy itself is adversely affecting the fetus. Carefully prescribed insulin therapy will provide better control of the mother's blood glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as may occur in diabetes mellitus, are closely associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, most experts, including the American College of Obstetricians and Gynecologists, recommend that insulin be used for types I and II diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (20,21).

Breast Feeding Summary

No reports describing the use of metformin during human lactation or measuring the amount excreted in milk have been located. Metformin is excreted in the milk of lactating rats, obtaining levels comparable to those in the plasma (1). Because of its low molecular weight (about 166), the passage of metformin into human milk should be anticipated. The effect on the nursing infant from exposure to this agent via the milk is unknown.

References

1. Product information. Glucophage. Bristol-Myers Squibb, 1997.
2. Klepser TB, Kelly MW. Metformin hydrochloride: an antihyperglycemic agent. Am J Health-Syst Pharm 1997;54:893903.
3. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:270.
4. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York: Marcel Dekker, 1993:4178.
5. Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Volume 2. West Sussex, England: Ellis Horwood Limited, 1984:179.
6. Miao J, Smoak IW. In vitro effects of the biguanide, metformin, on early-somite mouse embryos (abstract). Teratology 1994;49:389.
7. Denno KM, Sadler TW. Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis. Teratology 1994;49:2606.
8. Elliott B, Schuessling F, Langer O. The oral antihyperglycemic agent metformin does not affect glucose uptake and transport in the human diabetic placenta (abstract). Am J Obstet Gynecol 1997;176:S182.
9. Elliott B, Langer O, Schuessling F. Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin. Am J Obstet Gynecol 1997;176:52730.
10. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:64754.
11. Brearley BF. The management of pregnancy in diabetes mellitus. Practitioner 1975;215:64452.
12. Jackson WPU, Coetzee EJ. Side-effects of metformin. S Afr Med J 1979;56:11134.
13. Coetzee EJ, Jackson WPU. Diabetes newly diagnosed during pregnancy. A 4-year study at Groote Schuur Hospital. S Afr Med J 1979;56:46775.
14. Coetzee RJ, Jackson WPU. Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979;16:24145.
15. Coetzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital. S Afr Med J 1980;58:795802.
16. Coetzee EJ, Jackson WPU. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 1984;65:6357.
17. Coetzee EJ, Jackson WPU. The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1986;5:2817.
18. Gill G. Practical management of diabetes in the tropics. Trop Doct 1990;20:410.
19. Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:8669.
20. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin No. 200, December 1994.
21. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:55864.
    
    

Questions and Answers

Trying to get pregnant -Metformin, Clomid and Estradiol?

I have polycystic ovary syndrome (PCOS) and have been on metformin for the past three months to help regulate my hormone levels (I am not diabetic). I am trying to get pregnant, so my doctor has now added clomid and estradiol to the mix. Has anyone heard of these combinations – is it successful for most people? Thanks for your feedbacks.

I don't know the answer, but I am in a great Yahoo group that proably would. I know a few of the girsl are taking that combo. Try joining the yahoo group:
http://health.groups.yahoo.com/group/Get...
Not only can they answer, but they are a great group of girls.
Melissa

How long did it take you to get pregnant on MetFormin w/PCOS?

I have PCOS and was wondering how long it took other woman to get pregnant once on MetFormin. Thanks!

it can take up to 6 months, but if you take clomid and metformin together your chances can increase, talk to your dr. about it
you can also ask doctors online for free, try fertilityties.com
good luck!!!!!!!!!!!

How many have gotten pregnant with only Metformin?

I have PCOS and just started Metformin yesterday. I was wondering if any one has gotten pregnant with just that, not having to use Clomid. How long did it take? My husband and I decided to go to a fertility doctor in the fall, but of course I would like to not have to take Clomid, I have heard there are bad side effects. Thanks!

i also have PCOS and was put on metformin i was on it for 2 months and it had horrible side effects for me i went off of it but i never got pregnant with it. I am now on clomid and the only bad side effect it has is that you get little hot flashes every so offten. Im on my 2nd round of clomid and so far so good. But i have herd of people gettin pregnant with just metformin i hope everything works out for you BABY DUST by the truck loads to you!!

Anyone with PCOS get pregnant on Metformin alone?

I have PCOS and have been TTC for almost 2 years. I started taking Metformin about 2 months ago and just started my third cycle since being on it. Before that I would get a period maybe every 3 months. I did ovulate last cycle too, but unfortunately didn't get pregnant. Even though I was disappointed, it was the first time I ovulated on it, s I know the odds were it wasn't going to happen. Has anyone gotten pregnant just on Metformin? How long did it take?

I personally have not had to take metformin because I do not have PCOS. I have been in groups with lots of women who have taken it and have become pregnant.

I takes a few months though. Metformin is used to treat insulin resistance due to diabetes or pre diabetes. women who have PCOS have really thick egg linings that make it difficult for the sperm to penetrate. Once the medication begins to regulate the sugar the PCOS gets better too. But it takes some time. Good luck'

For women that have PCOS, how long after beginning to take Metformin did you get pregnant?

My fiancee and I have been trying to conceive for a little while now, I have just recently been put on the drug metformin for my PCOS. I am obese, but have been dieting and exercising and have lost 15 pounds so far.

How long did it take you to get pregnant after starting a Metformin regimen?

Hi i'm in the same boat as you. My husband and i have ben trying for a while now, and the other day my doc told to try metformin, he had told me i've lost a bit of weight which is good, and he said that i should find the metformin good to kick start the process, he did say they if i havent had a + by feb to go back into him for some fertility pills, (1 out of 10 do find it hard to conceive just on metformin)...

Good Luck

Can you become pregnant while taking metformin, if so how long did it take you?

Hi, I was wondering if you can become pregnant while taking the Medication Metformin. If so, and if you happened to take the medication how long it took you to become pregnant? I was placed on the medication to treat my PCOS with the hopes of becoming pregnant, I just wanted to know how long it took others to conceive while taking the medication thank you!

I was on it for 2 months before I conceived. Its like a miracle drug. Good luck to you. Sometimes clomid is needed as well. Good luck!!

How long does it take to get pregnant on Metformin?

I have been on it a while, but I dont usually take it consistantly. I have been having my periods again, and had one about two weeks ago I believe. My husband just got back from a deployment two days ago, and we decided not to use any birth control. So, Im just curious as to how long you think it will take me to get pregnant.

That depends entirely on whether you are ovulating, if you actually time your attempts for when you are ovulating and whether your DH's swimmers make it to your egg. I was charting, so I knew exactly when I was ovulating and it still took me six months.

I highly recommend that you relax about it or you're just going to make it harder and more stressful on yourself and your husband. Don't take the fun out of it by getting too technical and worried about making it happen "now".

If you want to know how to chart (it really works), get "Taking Charge of Your Fertility".

Has anyone had any luck in getting pregnant with Metformin?

I have pcos and have been trying to get pregnant for 4 yours now without any luck, Im under a top fertility specialist now and he tryed me on Clomid for 8 months but that didn't work and now he has put me on Metformin. I have heard alot of sucess stories about people getting pregnant with this. Is there anyone out there who has a sucess story and how long did it take to work for you?? Im so desparate for a baby and could use some advice.

Thanks to all of you who answer my question with very caring and heartfelt comments. I appreciate any good advice and yahoo answers makes me feel like im not alone and the only one suffering with this problem.

I too have PCOS...and YES I did get pregnant while on metformin! I have 2 beautiful children and had to have metformin and clomid with both. With my first child it took me only 2 cycles (2 months) but with my second it took almost a whole year. We had actually come to the conclusion that we were only going to have one and then wouldn't you know it.... finally got pregnant. The metformin also had some side effects...some good, some bad. I lost nearly 30lbs in 4 months without even trying, that was good. However, you may find that you will get to know all the restrooms around as your gastrointestinal tract is very active! Keep trying and I do believe that when I relaxed about the whole thing that seemed to be when it happened. Stressing about it can hinder your chances. My specialist told me that there is absolutely no reason that a PCOS woman should not be able to get pregnant...you just need to find the right combination of medications. I wish you all the luck in the world and hope your dream comes true!

I have PCOS and am only taking Metformin to lower hormones, what is the likelyhood of getting pregnant?

My husband and I have been trying to have a baby for 1 1/2 years. I was diagnosed with PCOS and have a testoterone level of 147 (I am not insulin resistant). I have been on Metformin since January and since then my testoterone level has dropped to 123. I have to take provera every 45 days to have a period because I am not producing progesterone to have one on my own. My doctor wants me to have Chlomid treatments, and I tried 1 treatment but it is very costly. Has anyone experienced this situtation before and suceeded in getting pregnant by just taking Metformin? I really need a pick me up, I am starting to feel discouraged.

My husband and I have been TTC for a year and a half also. The doc said I have symptoms of PCOS and have given me Metformin to lower my glucose levels. I've also started this med in January and it has helped me to lose some weight. I'm not obese, just a bit overweight. I weigh 138 lbs at 5 feet 1 inch tall. I've also been taking Clomid since last year. The levels of Clomid have increased to 100mg the past 3 months. We're still hoping and praying to be pregnant this month. We're on our 3rd cycle of IUI and hopefully this will be our lucky month. All of these infertility meds are costly, but it's worth it to have a baby. Thank goodness for insurance. It helps us a lot......hope you also have insurance coverage. Good luck and please don't be discouraged. Think positive because you're not the only one out there. If you need further support, you can email me directly. We're in very similar situations and any support would be helpful to the both of us.