Objective: Although metformin crosses the placenta, there is no current evidence whether the use of metformin in pregnancy is associated with increased risk of fetal and maternal complications. The aim of this present study is to investigate the attitudes of Turkish physicians in different specialties in terms of metformin use in pregnancy.
Materials and Methods: Current opinions were assessed by a questionnaire. Nine hundred forty physicians were invited to join the study; however, completely fulfilled questionnaires could be obtained from a total of 407 physicians (170 family physicians, 139 internists and 98 obstetricians).
Results: One hundred fifty-one physicians (37.1%) stated that they recommended metformin use in pregnancy for any of the indications (pregnant women with PCOS, type-2 diabetes or gestational diabetes). Obstetricians were more likely to suggest metformin use in pregnancy rather than other physicians. Metformin use in pregnancy was seldom recommended by internists. The rationales of physicians for the metformin use were: lower risk for abortion, decreased prevalence of maternal and neonatal complications, improvement in insulin resistance, prevention of excess weight gain, better glycemic control in diabetics and decreased insulin need in diabetics taking insulin.
Conclusions: Despite limited data on metformin use in pregnancy, significant number of physicians in Turkey supported the metformin use. Obstetricians were the ones most likely to recommend metformin treatment in pregnancy. Turk Jem 2009; 13: 25-8
Key words: Metformin, pregnancy, diabetes, polycystic ovary syndrome, physicians
Amaç: Metformin plasentayı geçse de günümüzde gebelikte metformin kullanımının artmış fötal ve maternal komplikasyonlar ile ilişkili olduğuna dair bir kanıt yoktur. Bu çalışmanın amacı farklı branşlardaki Türk doktorlarının gebelikte metformin kullanımı konusundaki davranışlarının araştırılmasıdır.
Gereç ve Yöntemler: Güncel görüşler bir anket formu ile değerlendirildi. Çalışmaya 940 doktor davet edildi ancak tam olarak doldurulmuş formlar toplam 407 doktordan elde edilebildi (170 aile hekimi, 139 iç hastalıkları uzmanı ve 98 kadın hastalıkları ve doğum uzmanı).
Bulgular: Yüz elli bir doktor (%37.1) gebelikte endikasyonların (PCOSlu gebe, tip-2 diyabet veya gestasyonel diyabet) herhangi biri nedeniyle metformin kullanımını önerdiklerini belirttiler. Kadın hastalıkları ve doğum uzmanları gebelikte metformin kullanımını diğer doktorlardan daha çok desteklediler. Gebelikte metformin kullanımı iç hastalıkları uzmanlarınca nadiren önerildi. Doktorların metformin kullanımı için rasyonelleri daha düşük abortus riski, maternal ve neonatal komplikasyonların azalmış prevalansı, insülin direncinin iyileşmesi, fazla kilo alımının önlenmesi, diyabetiklerde daha iyi glisemik kontrol ve insülin kullanan diyabetiklerde azalmış insülin ihtiyacı olarak tespit edildi.
Sonuç: Gebelikte metformin kullanımı ile ilgili kısıtlı veri olmasına rağmen Türkiyede önemli sayıda doktor metformin kullanımını desteklemektedir. Kadın hastalıkları ve doğum uzmanları gebelikte metformin tedavisini daha sıklıkla önermektedir. Türk Jem 2009; 13: 25-8
Anahtar kelimeler: Metformin, gebelik, diyabet, polikistik over sendromu, doktorlar
Metformin is a biguanide that is currently approved for treatment of type 2 diabetes. Metformin inhibits hepatic gluconeogenesis and increases the action of insulin in certain target organs and improves insulin sensitivity and hyperglycemia (1). Metformin use is associated with weight loss, improved lipid profile, and a small reduction in blood pressure (2,3). It is also useful in the treatment of insulin resistance and constitutes an increasingly popular treatment for polycystic ovarian syndrome (PCOS). Metformin facilitates conception in women who have oligomenorrhoea and PCOS (4).
Maternal hyperglycemia is associated with gestational weight gain, postpartum weight retention, and also with altered metabolic supplies from mother to fetus (5,6). Pregnancy is also associated with hyperinsulinemia (7). Although metformin use in pregnancy seems conceivable theoretically, it is still controversial. Despite early reports of adverse effects in those exposed to metformin (8,9), the growing number of data suggests that metformin is a safe choice of treatment in pregnant women with type 2 diabetes, gestational diabetes and PCOS (10-12). Although metformin is currently classified by the Federal Drug Administration (FDA) as a Category B drug for use in pregnancy, there is still no statement of Turkish Ministry of Health regarding the safety of metformin during pregnancy (4). In this study, we aimed to investigate the suggestions of physicians in different specialties in Turkey in terms of metformin use in pregnancy.
Materials and Methods
Current opinions of physicians were assessed by a questionnaire. Physicians were asked to fill in the questionnaire forms at national annual meetings of each specialty between January and December 2007. Questionnaire included four sections. The first section was concerned with the personal data of the physicians including age, sex and experience in current specialty and information about the hospitals they worked at. The second section questioned the opinions of the physicians regarding the use of metformin in pregnancy (in patients with PCOS, gestational diabetes and type 2 diabetes). The third section, which was open-ended, questioned rationales of physicians who approved or disapproved of metformin use in pregnancy. In the last section, physicians were questioned whether they treated pregnant women with PCOS or type 2 or gestational diabetes in daily practice. Physicians were also asked to give themselves a score (1-10) considering their knowledge about PCOS and diabetes.
Nine hundred forty physicians were invited to participate in the study (400 family physicians, 340 internists, 200 obstetricians). However, 421 physicians volunteered to attend the study. Fourteen subjects were excluded, as the questionnaires were not completely fulfilled. Finally, we were able to obtain questionnaires from 407 physicians (170 family physicians, 139 internists and 98 obstetricians). Twenty nine of internists had completed a subspecialty fellowship in endocrinology, or they were being fellows in endocrinology at the time they participated in the study.
Variable distributions were assessed by the Kolmogorov-Smirnov normality test. One way ANOVA or Kruskall-Wallis test were used (considering normality test result) to assess whether there was an overall difference between groups. Afterwards, one-way ANOVA with Bonferroni correction or Mann Whitney U test served as post hoc comparison tools, according to the variable distribution. Categorical variables were compared by the chi-square test. Statistical analysis was performed using Statistical Package of Social Science (SPSS), version 11.0 for Windows. Data were expressed as mean±standard deviation (SD). A p value less than 0.05 was accepted as statistically significant.
Mean age and gender distribution of family physicians, internists and obstetricians are shown in Table 1. Obstetricians were older compared to family physicians and internists. There was no significant difference in gender distribution. Almost all obstetricians stated that they treated people with PCOS and/or diabetes throughout pregnancy. However, internists were less likely than obstetricians to treat pregnant women with PCOS and diabetes. Significant number of family physicians stated that they did not routinely treat pregnant women with PCOS and/or diabetes. The proportion of physicians suggesting the metformin use in pregnancy is shown in Table 1.
Significant number of physicians in each specialty stated that they recommended metformin use in pregnancy. Obstetricians were more likely than other physicians to treat pregnant women with PCOS and diabetes. Metformin use in pregnancy was less common among internists.
One hundred fifty-one physicians (37.1%) stated that they recommended metformin use in pregnancy for any of the indications. Physicians in favor of metformin were older and more experienced when compared to those who did not approved of metformin during pregnancy. There was no significant difference in terms of gender and self-assessment scores of knowledge on PCOS and diabetes. The proportion of physicians regarding their employment region and area was similar (Table 2).
Rationales of physicians supporting the metformin use during pregnancy are shown in Table 3. Significant number of physicians believed that metformin treatment in pregnancy was associated with decreased risk of abortion, lower risk of fetal death, reduced prevalence of maternal and neonatal complications, improvement in insulin resistance, prevention of excess weight gain, better glycemic control in diabetics, and decreased insulin need in diabetics taking insulin.
The main point for drawback was possible risk for congenital malformations. Significant number of physicians stated that they did not recommend metformin use in pregnancy because the Turkish Ministry of Health has not approved its use in pregnancy yet. Other reasons for avoiding metformin use in pregnancy were gastrointestinal side effects, possible risk for increased maternal and neonatal complications, prohibition of physiological weight gain in pregnancy, worse control of hyperglycemia in diabetics, and vitamin B deficiency (Table 4).
Our survey revealed that significant number of Turkish physicians in different specialties supported the metformin use in pregnancy, although the most current product monograph still lists pregnancy as a contraindication to use of metformin. Obstetricians were more likely to treat pregnant women with metformin. Lower risk for abortion, decreased prevalence of maternal and neonatal complications, improvement of insulin resistance, prevention of excess weight gain, better glycemic control in diabetics and decreased insulin need in diabetics taking insulin were brought forward as possible rationales by the physicians suggesting metformin use in pregnancy. The main points for drawback were possible risk for congenital malformations and the disapproval for pregnancy by the Turkish Ministry of Health.
Most of the physicians, who were against metformin use in pregnancy, recommended discontinuation once the pregnancy was confirmed, or before planning pregnancy because of concerns about risks to the fetus (11). Fetal concentrations of metformin in the range of half of maternal concentrations were demonstrated in cord blood of babies whose mothers took metformin during pregnancy, suggesting that significant amount of metformin can cross the placenta (12). Another study showed that cord levels of metformin may exceed maternal levels (13). Animal studies regarding teratogenicity of metformin showed controversial results. One study revealed that biguanides, phenformin and metformin were associated with embryo death, although metformin was observed to be less toxic than phenformin in mouse whole embryo culture (8).
However, another study showed that metformin at doses similar to clinical in vivo levels had no direct toxic effects on mouse embryo development (14). Moreover, it has been reported that metformin induced a low incidence of malformations in rats and there was no evidence of teratogenicity at doses as high as 600 mg/kg daily (15). Human studies have reported no evidence regarding an increase in congenital anomaly rates in women treated with metformin (10,16-18). Two early studies showed lower infant morbidity and mortality rates in pregnant women with type 2 diabetes who were treated with metformin, compared to those who were treated with insulin (19,20). More recent studies also reported no evidence about the teratogenicity of metformin, which was suggested because of the similar risk of developing birth defects, similar fetal loss, prematurity and neonatal hypoglycemia rates and comparable birth weight percentiles (16,18,21). A recent meta-analysis regarding pregnancy outcome after first-trimester exposure to metformin showed a comparable malformation rate with that of the general population. The lower malformation rate in women treated with metformin compared to disease-matched controls raised the question that metformin treatment may prevent congenital malformations when used in the first trimester of pregnancy (11). Continuation of metformin in the first trimester was found not to be associated with an increase in congenital malformations or adverse fetal outcome (22). No difference in growth and motor-social development during the first 18 months of life was observed in children of women with PCOS who conceived while taking metformin, and continued taking it throughout their pregnancy (16).
As most of the experience regarding metformin use in pregnancy has been obtained from studies conducted in women with PCOS and the exposure was restricted to the first trimester, it is not surprising that more physicians supported the metformin use in the first trimester than in the 2nd and 3nd trimesters. Significant number of physicians who supported the metformin use in pregnancy stated that metformin use in the first trimester may be associated with a decreased incidence of miscarriage (21,23,24). On the other hand, studies reported favourable pregnancy outcomes in women who took metformin after the first trimester of pregnancy, or continued it throughout the pregnancy (16-19,25,26). A recent large well-controlled study, the MIG Trial, regarding metformin use in gestational diabetes may encourage physicians to prescribe metformin after the first trimester of pregnancy. Rowan et al. (27) showed that metformin (alone or with supplemental insulin) was not associated with increased perinatal complications as compared with insulin in women with gestational diabetes.
Although significant number of physicians attending this present study recommended the metformin use in pregnancy, it should be noted that we have questioned only their opinions, not prescription practices. Because metformin is still contraindicated in pregnancy according to current product monograph in Turkey, it is possible that physicians might not prescribe metformin, although they suggest its use in pregnancy.
In conclusion, despite increasing number of clinical data demonstrating that metformin treatment is safe in pregnancy, it is still not known whether metformin, which has been shown to cross the placenta, is therapeutic, or deleterious to the fetus. There is limited data on teratogenicity of metformin, but the risk seems to be low. Although Turkish physicians, especially obstetricians, seem to be in favor of using metformin in pregnancy, we believe that further data, also including animal models, are required before metformin becomes commonly prescribed during pregnancy.
Conflict of interest notification: None of the authors have a conflict of interest.
Address for Correspondence: Barış Akıncı, MD, Division of Endocrinology of Metabolism, Department of Internal Medicine, Dokuz Eylül University Medical School, İnciralti, İzmir, Turkey 35340. Phone: +90 232 412 37 44 Fax: +90 232 279 22 67 E-mail: firstname.lastname@example.org Recevied: 01.06.2009 Accepted: 07.07.2009
1. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE: Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 550-4.
2. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996; 334: 574-9.
3. Campbell IW, Howlett HC: Worldwide experience of metformin as an effective glucose-lowering agent: A meta-analysis. Diabetes Metab Rev 1995; 11: 57-62.
4. McCarthy EA, Walker SP, McLachlan K, Boyle J, Permezel M: Metformin in obstetric and gynecologic practice: A review. Obstet Gynecol Surv 2004; 59: 118-27.
5. Scholl TO, Chen X: Insulin and the "Thrifty" Woman: The influence of insulin during pregnancy on gestational weight gain and postpartum weight retention. Matern Child Health J 2002; 6: 255-61.
6. Buchanan TA, Metzger BE, Freinkel N, Bergman RN: Insulin sensitivity and b-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol 1990; 162: 1008-14.
7. Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA: Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991; 165: 1667-72.
8. Denno KM, Sadler TW: Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis. Teratology 1994; 49: 260-6.
9. Hellmuth E, Damm P, Molsted-Pedersen L: Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 2000; 17: 507-11.
10. Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G: The safety of oral hypoglycemic agents in the first trimester of pregnancy: A meta-analysis. Can J Clin Pharmacol 2003; 10: 179-83.
11. Gilbert C, Valois M, Koren G: Pregnancy outcome after first-trimester exposure to metformin: A meta-analysis. Fertil Steril 2006; 86: 658-63.
12. Coustan DR: Pharmacological management of gestational diabetes: An overview. Diabetes Care 2007; 30: 206-8.
13. Vanky E, Zahlsen K, Spigset O, Carlsen SM: Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1575-8.
14. Bedaiwy MA, Miller KF, Goldberg JM, Nelson D, Falcone T: Effect of metformin on mouse embryo development. Fertil Steril 2001; 76: 1078-9.
15. Koren G, Gilbert C, Valois M: Metformin use during the first trimester of pregnancy. Is it safe? Can Fam Physician 2006; 52: 171-2.
16. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P: Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004; 19: 1323-30.
17. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L: Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17: 2858-64.
18. Glueck CJ, Bornovali S, Pranikoff J, Goldenberg N, Dharashivkar S, Wang P: Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome. Diabet Med 2004; 21: 829-36.
19. Coetzee EJ, Jackson WP: Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979; 16: 241-5.
20. Coetzee EJ, Jackson WP: 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.
21. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE: Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 524-9.
22. Bolton S, Cleary B, Walsh J, Dempsey E, Turner MJ: Continuation of metformin in the first trimester of women with polycystic ovarian syndrome is not associated with increased perinatal morbidity. Eur J Pediatr 2008.
23. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P: Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: A pilot study. Fertil Steril 2001; 75: 46-52.
24. Thatcher SS, Jackson EM: Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006; 85: 1002-9.
25. Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A: Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: Prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 2004; 19: 510-21.
26. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L: Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 520-5.
27. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP: Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2003-15.