METFORMIN
Drugs in Pregnancy and Lactation.
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Name: METFORMIN
Class: Oral Antihyperglycemic
Risk Factor: BM
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 500–1000 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 non–insulin-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 non–insulin-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 3–28 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.
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References
- Product information. Glucophage. Bristol-Myers Squibb, 1997.
- Klepser TB, Kelly MW. Metformin hydrochloride: an antihyperglycemic agent. Am J Health-Syst Pharm 1997;54:893–903.
- Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:270.
- Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York: Marcel Dekker, 1993:417–8.
- Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Volume 2. West Sussex, England: Ellis Horwood Limited, 1984:179.
- Miao J, Smoak IW. In vitro effects of the biguanide, metformin, on early-somite mouse embryos (abstract). Teratology 1994;49:389.
- Denno KM, Sadler TW. Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis. Teratology 1994;49:260–6.
- 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.
- 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;176:527–30.
- 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;43:647–54.
- Brearley BF. The management of pregnancy in diabetes mellitus. Practitioner 1975;215:644–52.
- Jackson WPU, Coetzee EJ. Side-effects of metformin. S Afr Med J 1979;56:1113–4.
- Coetzee EJ, Jackson WPU. Diabetes newly diagnosed during pregnancy. A 4-year study at Groote Schuur Hospital. S Afr Med J 1979;56:467–75.
- Coetzee RJ, Jackson WPU. Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979;16:241–45.
- 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;58:795–802.
- Coetzee EJ, Jackson WPU. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 1984;65:635–7.
- Coetzee EJ, Jackson WPU. The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1986;5:281–7.
- Gill G. Practical management of diabetes in the tropics. Trop Doct 1990;20:4–10.
- Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:866–9.
- American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin No. 200, December 1994.
- Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.
Q&A about Metformin
Has anyone taken metformin to concieve? I have been taking metformin for 2 months. My doctor says that metformin will help me produce an egg so I can become PG. I was just curious what other people may have experienced with this method.
My mother is taking Metformin and the doctor prescribed her with Metformin HCL and we were wondering the difference. We asked but can't remember...I think it is a waterpill added.
The only thing can be the duration of the effect, one acts slower than the other.
After you started metformin did you start taking clomid? Can I started both in the same week? Would it help?
I was wondering if you are taking Metformin if you think its worth taking going through all the side effects it has. I'm taking it once a day before dinner @ 500mg. Now I'm getting headaches, my stomachs upset all the time and I have diarrhea. Are you having any of these symptoms and do you think Metformin is worth taking?
The side effects will lessen with time, and with diet and exercise there may come a time when you no longer need the metformin in your life, but you will still have a life, and your sight, and your feet. :-)
As for the headaches, these are probably happening because the diarrhea is dehydrating you. Supplement with an electrolyte replacement like Gatorade or Pedialyte.
I wish you the best of luck. Diabetes doesn't have to ruin your life, not if you don't let it!
My doctor put me on Metformin 500mg last Friday. I am taking it twice a day for a total of 1000mg a day. Well, I called and spoke to my doctor's nurse today. She said I could switch to taking it three times a day if I felt comfortable. I have not had any major side effects since taking the medication, besides a few days of upset stomach. So my question is, from your own experience, how long should I wait before switching to three times a day?
500mg 1 x daily for 2 weeks
500mg 2 x daily for 2 weeks
1000mg 1 x daily for 2 weeks
1000mg 2 x daily for 2 weeks
My doctor recommended me to use Metformin to try and regulate my periods which would make me ovulate more regularly and hopefully help me get pregnant. But now I'm wondering if it could be doing the total opposite. I'm getting my periods every month, but I haven't been able to get pregnant. I've been on it for about 6 months.
PREGNANCY
While safety during pregnancy has not yet been established, three patients who continued on metformin during their entire pregnancy and one who remained on a glitazone have delivered normal babies. There are no reports of abnormal babies in women who conceived using metformin and all resulting babies were normal. Metformin is a category B medication. This means that insufficient human data is available but no credible animal data suggesting a teratogenic (could produce birth defects) risk. Although to the best of our present knowledge the risk of birth defects would be small, it must also be noted that maternal diabetes has been associated with an increased risk of birth defects and the underlying elevated insulin levels may lead to birth defects if not corrected.
While the most prudent policy may be to avoid the use of these medications during pregnancy until more data on pregnancy outcome is available, the risk of miscarriage may be reduced by continuing metformin during the pregnancy. We ask our PCOS patients taking insulin-lowering medications to monitor their basal body temperatures if pregnancy is a possibility. When the temperature remains elevated for more than 16 days, pregnancy is likely and a home pregnancy test should be performed. If positive, a medical consultation with the physician is scheduled. If the EPT is negative the BBT chart is reviewed by the physician or nurse to determine the appropriate course to follow. Patients should discontinue contact their physician if they are on Avandamet, Actos, or Avandia to receive instructions. Generally, patients taking these medications will be switched to metformin.
Another Source:
There are several possible ways to attempt ovulation induction in women with polycystic ovaries. The easiest and least complicated method is the use of Clomid tablets, also called Serophene, or clomiphene citrate.
Many will be able to get pregnant using clomiphene to induce ovulation. For women that do not ovulate with clomiphene, the "traditional" next step has been to use injectable gonadotropins. About 90% of women that do not ovulate with clomiphene will ovulate with this medication and the majority will get pregnant as well. However, these medications are expensive and there are risks of ovarian hyperstimulation and multiple pregnancy involved. The daily injections and trips to the office for monitoring are also somewhat inconvenient for most women.
A relatively new method of treating ovulation problems in women with polycystic ovarian syndrome is to use an oral medication called metformin (brand name is Glucophage) with or without clomiphene citrate. Metformin has been used in the past as an oral agent to help control diabetes. Recently, it has been found to facilitate ovulation in some women with PCOS. Some women who do not ovulate after taking metformin will be able to ovulate when taking metformin in combination with clomiphene. Therefore using metformin would be a benefit to some women with polycystic ovarian syndrome by allowing them to potentially avoid the injectable FSH medications (if they prefer this approach).
I am a diabetic and recently am unable to afford seeing a doctor. My blood sugar levels are peak at about 500. I am on 1000mg of Metformin. If I double or triple the dosage would this help?
you need to do some serious exercise and diet change! exercise will lower your blood sugar and you will start to lose weight. your blood sugar will continue to go down as you lose weight and you may even be able to decrease your metformin. my husband lost 40 lbs and now takes 500mg metformin with dinner. (He was on 1000 mg twice daily). there are also natural products you can use to lower your glucose. Cinnamon is one.
Does metformin regularize the heavy bleeding that occurs in PCOS?Does the periods get regular and ovulation takes place with metformin?How many days does it tae for the weight to get reduced and heavy bleeding to stop?Which is the best diet for PCOS?Is it safe to have metformin in pregnancy?Is it possible for women with PCOS to become pregnant without much complications?Does anyone have experience of use of metformin in PCOS?Does it affect the child?
To explain what Glucophage does, I need to help you understand what PCOS is. Women with PCOS are almost always insulin resistant, which means that their bodies try to compensate by “overproducing” insulin. (Insulin resistance can be detected by a blood test of fasting serum levels of glucose and insulin.)
High insulin levels produce excess male hormones by increasing androgen production by the ovaries leading to more and more PCOS symptoms. Androgens are male hormones such as testosterone. High insulin levels also increase the production of LH by the pituitary gland. The high LH in turn leads to an even higher level of male hormones. In several recent studies, Glucophage has shown effectiveness in inducing ovulation in some women with PCOS by lowering both LH and male hormone levels.
Now, having said that, note that the major symptom of PCOS is high insulin levels. The goal is to decrease them. And what do carbs do? They raise your insulin level. So, the best diet...one actually created for PCOS sufferers is SugarBusters. It's wonderful and helped me, along with Glucophage, to lose about 20-30lbs.
If you have PCOS you may or may not have trouble getting pregnant. I have two kids and never had a problem getting pregnant. My mother and father only have me and it took them six years. Everyone is different. I would tell you just not to give up.
Yes, it is safe to get pregnant while taking the drug. It's in the FDA pregnancy category B. This means that it is unlikely to harm an unborn baby. However, you should still talk to your doctor if you are pregnant. Also, it does pass to the breast milk, so make sure you talk to your doctor if you are breastfeeding.
Now, the heavy bleeding. The only thing that will stop the heavy bleeding is keeping your insulin levels down month over month so your male hormones decrease and your female hormones increase, thus inducing a monthly period. The bleeding is heavy because when you do have a period, it's likely several periods in one. When I go a few months without a period, my doctor prescribes a hormone pill that I take for a week that starts my period.
The most important thing to do is to take the Glucophage/Metamorphin every single day. When you first start taking it, it can cause some bad cramps and bad poopies, so you might ask about taking the XR/ER version, which is an extended release version. That helps get rid of those symptoms.
Also, it's important to exercise. I found that I need about 240 minutes of cardio every week for it to make a difference. Do your best to get as close to possible as that. And also strength train. Muscle burns more calories than fat.
Hope this helps. Good Luck!
I've been off of my birth control pills since last April and my periods still aren't normal. I went to the doctor and she drew blood and told me I have PCOS. She gave me Metformin 500mg twice a day and I've been taking it for almost two months. I can't get my periods normal, which means I'm not ovulating. When I do have a period it's so light that I wouldn't even have to have a period if I didn't want to. What should I do?
Lately I've been having killer headaches. I'm taking metformin 3 times a day and I'm not sure if it's safe taking them and the aspirin at the same time. Does it affect the performance of the metformin if I take aspirin daily?
Seriously, if the headaches continue, you should talk to your doctor to make sure something else isn't going on.
