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Info RE Metformin & Pregnancy: Given by my OB
I promised a while back that I would ask my dr. about the articles he mentioned when telling me why he thought metformin during pregnancy was safe and a good idea. Also, he said that the largest group of perinatologists in Denver uses metformin in pregnancy for their PCOS patients. This is a group of I don't know how many doctors, but HUGE and they deal with high risk patients every day and do their homework.
Also, for those that don't know, my OB is this practice's in-house expert on PCOS and really seems to do his homework.
Attached please find:
Metformin may block gestational diabetes - Polycystic Ovary Syndrome
"Miscarriage rate in PCOS falls to 12% with Metformin"
NOW. Below is the *BIG* article. The one he first mentioned. I can't link to it online, because they'll want to charge you to view it if you haven't joined some membership. But, the doctor gave me the article. Here it is.
Metformin in Obstetric and Gynecologic Practice: A Review
McCarthy, Elizabeth A. MB BS, FRANZCOG*; Walker, Susan P. MD, FRANZCOG‟; McLachlan, Kylie MB BS, FRACP‡; Boyle, Jacqui MPHTM, FRANZCOG§; Permezel, Michael MD, FRANZCOG¶
*Lecturer, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, East Melbourne, Australia; ‟Senior Lecturer, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, East Melbourne, Australia; ‡Research Fellow, Department of Endocrinology and Diabetes, St Vincent's Hospital, Melbourne, Australia; §Consultant Obstetrician-Gynaecologist, Royal Darwin Hospital, Darwin, Australia; and ¶Professor, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, East Melbourne, Australia
Reprint requests to: Elizabeth A. McCarthy, MB BS, FRANZCOG, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, 126 Clarendon Street, East Melbourne 3002, Australia. E-mail: eamcca@unimelb.edu.au
The authors have disclosed no significant financial or other relationship with any commercial entity. The authors disclose that metformin has not been approved by the U.S. Food and Drug Administration for use during pregnancy.
Article Outline
Abstract
PHARMACODYNAMICS AND PHARMACOKINETICS
MECHANISMS OF ACTION
Gastrointestinal Effects
Hepatic Effects
Skeletal Muscle
Adipose Tissue
Vascular Effects
CLINICAL APPLICATIONS OF METFORMIN
Gynecology
Metformin and Insulin Resistance
Hyperandrogenism
Anovulation and Infertility
Early Pregnancy Loss
Obstetrics
Metformin and the Placenta
Clinical Experience With Metformin in Pregnancy
Diabetes in Pregnancy
Hypertension in Pregnancy
Adverse Effects
Maternal
Adverse Effects
Fetal-Neonatal
CONCLUSIONS
REFERENCES
Citing Articles
Abstract TOP
Metformin is a common treatment for women who have insulin resistance manifesting as type 2 diabetes or polycystic ovarian syndrome (PCOS). With an increasing number of these patients conceiving, it is expected that the use of metformin in and around the time of pregnancy will increase. This article reassesses the mechanisms, safety, and clinical experience of metformin use in obstetrics and gynecology. Metformin is an attractive therapeutic option because administration is simple, hypoglycemia rare, and weight loss promoted. There is a large volume of research supporting the use of metformin treatment in diabetes mellitus, androgenization, anovulation, infertility, and recurrent miscarriage. Although metformin is known to cross the placenta, there is, as yet, no evidence of teratogenicity. Metformin has an array of complex actions, accounting for the varied clinical roles, many of which are still to be fully evaluated. Much research is still needed.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to explain the pharmacokinetics of metformin, to describe the mechanisms of action of metformin, to list the potential applications of metformin use, and to outline the potential adverse effects of metformin.
There is a clinical impression that metformin use during and around the time of pregnancy is increasing. A survey by the Australasian Society for Diabetes in Pregnancy found that 25% to 50% of members would consider oral hypoglycemic agents in this setting (1). These Australasian clinicians favored metformin over glyburide or glibenclamide as alternatives to or additional treatment with insulin (1). This is despite arguably higher-grade evidence for the safety of glyburide than metformin (2, 3).
Given the clinical impression of increasing metformin use in pregnancy, a Medline search for English language papers using the terms metformin and pregnancy published between 1971 and December 2002 was conducted. Sixty publications were obtained, supplemented with articles from the reference lists of these 60 publications and papers in the authors' personal libraries. Readers are also advised to consult the product information before prescribing.
PHARMACODYNAMICS AND PHARMACOKINETICS TOP
Metformin is a dimethylbiguanide. The 2 methyl groups render the drug readily soluble in water and the amine groups make it a weak base. Metformin is somewhat lipophilic and able to bind to cell membranes where its cationic residues can interfere with extracellular cations such as Ca2+ and Na+, which are involved in membrane excitation (4, 5). Plausible membrane targets include the external cell membrane, internal and internalized membranes such as vesicles containing the glucose transporter proteins, and mitochondria (5-7). Abnormal membrane fluidity caused by glycosylation can be rectified by metformin (6).
Peak venous serum concentrations of metformin are observed approximately 2 hours after oral administration, with acute changes in glucose and insulin seen over a number of hours (6). Two to 9 months are required to observe putative clinical manifestations of improved insulin sensitivity such as return of ovulation, conception, amelioration of hirsutism, or optimization of body weight and composition (8).
MECHANISMS OF ACTION TOP
Many effects of metformin require the presence of insulin. The diversity of metformin effects suggests a point of action high up in the cascade of postreceptor events (9). Metformin increases tyrosine kinase activity of the beta-subunit of the insulin receptor in an animal model (10). Postreceptor phenomena attributable to metformin include activation of AMP-activated protein kinases involved in fatty acid and glucose metabolism, elevated inositol-3,4,5-triphosphate (IP3), increased intracellular free Ca2+, and increased phosphorylation of insulin receptor substrates (IRS) (6). Insulin-stimulated flux of glucose into cells depends on IP3-increasing activity and cycling of GLUT4 glucose-transporting protein (11). Metformin augments insulin-dependent (GLUT4) and insulin-independent (GLUT1- and GLUT3-mediated) cellular uptake of glucose (6). For an overview of insulin receptor and postreceptor functions as they relate to human pregnancy, the reader is referred to a recent review by Yama****a and colleagues (11).
Proposed mechanisms by which metformin lowers glucose in the presence of insulin include increased peripheral cellular glucose uptake, reduced hepatic gluconeogenesis, and reduced absorption. These effects on glucose, as well as other metabolic effects on lipids and vascular function, are discussed subsequently.
Gastrointestinal Effects TOP
It could be that the gastrointestinal effects of metformin are the most potent for the control of serum glucose. Concentrations of orally administered metformin vary quite markedly from tissue to tissue, but extremely high concentrations have been measured in jejunal and ileal walls (up to 3 μmol/L). This is 10 times higher than at the liver and 60 times as high as muscle or fat concentrations (measured as 0.05 μmol/L) (6).
Metformin causes a degree of anorexia resulting in reduced food intake. Nausea and diarrhea are estimated to make treatment with metformin intolerable in 5% of nonpregnant patients (12). These could be the result of local or systemic effects. Serotonin (5HT), Ca2+ flux, lactate, and nitric oxide have all been implicated in gastrointestinal side effects. There is evidence for local serosal release of 5HT and other neurotransmitters (5). Malabsorption can occur as a result of a Ca2+ channel effect (5). High concentrations of metformin in the intestinal wall can stimulate anaerobic metabolism of glucose with lactate release into the portal vein (12). Central and/or peripheral nitric oxide release in the hypothalamus and/or brown fat can also account for changed feeding behavior and gastrointestinal side effects (13). Pregnant women could be especially sensitive to gastrointestinal side effects of medications such as metformin given a high background rate of morning sickness, dyspepsia, and other symptoms in normal pregnancy (14).
Vitamin B12 deficiency has been recorded in 10% to 30% of nonpregnant patients treated with metformin for 3 months (5). Deficiencies of vitamin B12, folic acid, and other micronutrients could have serious perinatal effects (15, 16). Despite the fact that most patients who take metformin are obese and thus grossly overnourished, micronutrient deficiencies can occur with important implications for pregnancy.
Hepatic Effects TOP
Wiernsperger and Bailey (6) propose several types of metformin action at the liver to lower serum glucose, including:
1. Increased hepatic sensitivity to insulin; insulin more effectively suppresses glucagon production and gluconeogenesis in the presence of metformin;
2. Reduced glycogenolysis; and
3. Reduced fatty acid oxidation, which would be expected to enhance glucose oxidation through the glucose fatty acid (Randle) cycle (6).
Skeletal Muscle TOP
Metformin increases glucose disposal, which is believed to be mainly the result of increased uptake in skeletal muscle (12). Proposed mechanisms with some laboratory support include increased glucose-mediated-glucose-disposal, enhanced insulin-stimulated glucose uptake, and enhanced insulin sensitivity as a result of other positive metabolic changes such as reduced free fatty acids and triglyceride levels (12).
Adipose Tissue TOP
Most studies, but not all, report that metformin improves insulin-mediated glucose uptake into adipose tissue (6). Several studies have shown metformin reduces circulating levels of free fatty acid (FFA) (12) and decreases fatty acid oxidation (17, 18). Triglyceride levels are also reduced by metformin; hepatic synthesis is reduced (19) and clearance of very low-density lipoproteins (VLDL) is increased (6).
Vascular Effects TOP
Hyperinsulinemia has been associated with hypertension. This association has prompted investigation into the role of metformin in hypertension. Tonically elevated insulin levels can increase blood pressure by some or all of 4 mechanisms (20, 21). Hyperinsulinemia can increase the sensitivity of vascular smooth muscle to calcium fluxes, promote renal tubular reabsorption of sodium and water, induce vascular smooth muscle hypertrophy, and/or directly stimulate the sympathetic nervous system.
At least 2 clinical trials in nonpregnant humans confirm improved vasodilatation in the presence of metformin. Mather demonstrated improved endothelium-dependent vasodilatation (acetylcholine stimulated) (22) and Marfella showed enhanced nitric oxide-mediated vasodilatation with metformin treatment (23).
A series of studies of metformin in normotensive and hypertensive, insulin-sensitive and insulin-resistant rats confirm that metformin tends to lower high blood pressure with minimal effect in normotensive subjects (20, 24-28). The majority of these laboratory studies favor a mechanism involving the sympathetic nervous system (24, 26, 28), possibly at a central nervous system level (26, 28). Calcium blockade has also been investigated with some investigators favoring this mechanism (24, 27).
As well as influencing vascular smooth muscle and endothelial function, chemokines originating in extravascular tissues could affect vascular function. For example, reduced production of the chemokine interleukin-8 (IL-8) has been observed in adipocytes exposed to metformin (29). Metformin effects on low-density lipoprotein (LDL) size, oxidative stress, and inflammation could also affect vascular smooth muscle and increase vasodilatation (22).
CLINICAL APPLICATIONS OF METFORMIN TOP
Gynecology TOP
Metformin and Insulin Resistance TOP
Insulin resistance is linked to Reaven's Syndrome X in both men and women, a major contributor to the burden of cardiovascular disease in our community (30). Insulin-resistant women are also at risk for polycystic ovarian syndrome (31, 32), gestational diabetes (33) and pregnancy-induced hypertension (34, 35). Ovarian and endometrial cancers occur more commonly in women diagnosed with polycystic ovarian syndrome than in women with normal ovarian function (31). There are thus many public health reasons to reduce the incidence and severity of insulin resistance in women (36).
Insulin resistance is multifactorial in origin (21). Even within the same individual, tissue insulin resistance varies between organs. Insulin receptor abnormalities have been demonstrated in fibroblasts from women with polycystic ovary syndrome (PCOS) such that glucose handling is abnormal but the mitogenic properties of insulin are preserved (37). Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins has been reported in women with PCOS (38). Given such polymorphism of the insulin receptor, it is quite probable that the response to metformin will vary between individuals.
Three randomized, placebo-controlled trials and 6 observational studies conclude that metformin improves insulin sensitivity in women who do not have diabetes (39-47). The gastrointestinal side effect profile of metformin means that associated weight loss could compliment its metabolic effects, but the degree to which insulin sensitivity is increased is greater than that which would be expected from weight loss alone (43).
Three studies failed to show an improvement in insulin resistance in nondiabetic patients. Two studies could have lacked sufficient power to demonstrate an effect (48, 49), whereas another study investigated extremely obese women who could have been relatively underdosed (50).
Hyperandrogenism TOP
High serum levels of insulin are believed to increase biologically active androgens by a combination of ovarian, adrenal, and hepatic effects. Insulin acts synergistically with luteinizing hormone (LH) in stimulating ovarian androgen production (51, 52). Insulin reduces hepatic sex hormone binding globulin (SHBG) production, increasing free androgen levels in the circulation (53, 54). Metformin treatment has been offered to women with symptomatic androgenization in the hope that lowering insulin levels will normalize androgen levels. Both clinical (hirsutism, acne) and biochemical (serum testosterone, dehydroepinandrostenedione sulfate [DHEAS], and SHBG) end points have been examined.
Five placebo-controlled, randomized clinical trials (RCTs) have documented statistically significant reductions in free testosterone (39, 41, 55-57). Analysis of published data in 5 positive and 2 negative studies indicate that metformin likely reduces free serum testosterone from approximately 23.6 pmol/L to 15.2 pmol/L (39, 41, 49, 55-58).
Compared with placebo, metformin has minimal effect on total serum testosterone. Only one study has shown a statistically significant effect of metformin compared with placebo (59). Reduction in free testosterone seems mainly to accrue from an increase in SHBG.
The mean SHBG level at entry in 11 placebo-controlled RCTs was 63.4 nmol/L. After metformin treatment, this increased to 88.5 nmol/L compared with 70.5 nmol/L in equivalent placebo control groups (39-41, 49, 55, 56, 58-62). Four individual RCTs showed a statistically significant effect of metformin (41, 55, 56, 58).
Seven others studies did not find a statistically significant effect, but this could be the result of an insufficiently large sample size, a problem that can be addressed in metaanalysis (39, 40, 49, 59-62).
Metformin has less effect on DHEAS than testosterone levels. Despite 2 RCTs showing greater reduction in serum DHEAS in metformin-treated patients compared with placebo-treated patients (55, 56), 10 other RCTs showed no statistically significant difference (39-41, 49, 55-61, 63). The pooled mean DHEAS levels from the 12 RCTs described do suggest a trend to decreased serum levels: the mean DHEAS level at study entry was 7.5 micromol/L compared with 6.9 micromol/L after metformin exposure and 7.3 micromol/L after equivalent duration of placebo exposure.
The RCTs are supplemented by observational studies comprising 85 cases in which reduced androgen levels have been reported after treatment with metformin (43, 45-47). These studies included women of varying ethnicity and age.
Despite apparent biochemical normalization, a clinical improvement in hirsutism has not been reliably observed. Improvement in the hirsutism score was recorded in a series of 10 androgenized adolescent girls treated with metformin (46). However, this study comprised uncontrolled observation only. Although one RCT has shown a greater reduction in hirsutism with metformin treatment compared with placebo treatment (40), another RCT found no difference compared with placebo (62). Metformin was shown to be inferior to ethinyl-estradiol/cyproterone acetate (64) and to flutamide in RCTs investigating treatment of hirsutism (65).
Normalization of weight is known to ameliorate insulin resistance and ovarian dysfunction. To what degree are metformin effects in PCOS attributable to weight loss? Glueck showed that the metformin-induced testosterone decrease and estradiol increase were both independent of weight loss (48). Moghetti's open trial of metformin treatment in PCOS also showed reduced free testosterone in the absence of weight loss (39). This study identified women with higher body mass index as being more likely to respond to metformin.
In contrast, 3 further studies suggest that metformin effects on androgens are not independent of weight loss. A 4-month RCT comparing metformin and placebo demonstrated appropriate weight loss in both patient groups and no attributable extra benefit of metformin in improving androgen levels (61). A single-blind study of metformin versus placebo found that neither group gained or lost weight and no change in androgen level could be confidently ascribed to metformin (66). Erhmann's observational study of a group of very obese women with PCOS also failed to demonstrate changes in androgens after a 12-week course of metformin (50). The authors suggested that very obese patients need higher doses or longer courses of metformin compared with normal-weight women.
Anovulation and Infertility TOP
Metformin promotes normal ovulation in anovulatory women. Sills and colleagues use the term normogonadotropin to describe metformin's effect. Rather than accelerating follicular recruitment or growth, metformin dampens inappropriate cellular signaling arising from tonically elevated insulin levels (67). Inappropriate steroidogenesis in the ovary, adrenal gland, and adipose tissue is ameliorated by normalization of insulin, insulin-like growth factors (IGF-1 and IGF-2), and IGF-binding proteins (IGFBPs).
Research has focused on the return of ovulation with metformin alone or in combination with clomiphene or gonadotrophin ovulation induction. Eleven case series describing 265 patients have been published, which describe the development of ovulation in previously anovulatory women after treatment with metformin (43-48, 50, 68-71). A further 8 RCTs have compared metformin with placebo (41, 49, 55-57, 59, 60, 63). Five RCTs have compared metformin or placebo in addition to clomiphene citrate treatment (49, 58, 62, 63, 72). A crossover trial concerned the use of metformin or placebo with gonadotrophin ovulation induction (73). Pooled published RCT data indicate that ovulation occurred in 77 of 184 treated with metformin alone (42%) compared with 38 of 184 cases treated with placebo alone (22%) (49, 55-60, 63). Metformin exposure has been associated with ovulation or surrogate measures such as regular menstrual cycles at rates varying from as high as 90% (58) to as low as 0% (59). The ovulation (or ovulation surrogate) rates in the control groups of these studies ranged from as high as 28% (62) to as low as 0% (39, 59). The addition of clomiphene citrate increased the observed difference in reported ovulation rates: 60 of 91 metformin-treated cases ovulated (66%) compared with 13 of 91 placebo-treated cases (16%) (49, 58, 63, 72). Of the 11 RCTs mentioned here, only 1 did not find a significant improvement in ovulation rates with metformin compared with placebo (62). The entry criteria in this study did not stipulate any other features of polycystic ovarian syndrome apart from chronic clomiphene-resistant anovulation. If the baseline insulin resistance is low, a benefit would not be expected to accrue from an insulin-sensitizing agent such as metformin.
The impact of metformin on gonadotrophin-stimulated ovulation has been investigated in a crossover study. Cycles that included metformin were notable for lower estradiol levels, fewer follicles (>15 mm), and fewer cycles abandoned as a result of risks of ovarian hyperstimulation syndrome (73). The hyperstimulation rate associated with gonadotrophin ovulation induction was reduced from 26.3% to 16.6% while maintaining a pregnancy rate of 16% (73). It has not yet been demonstrated whether metformin reduces the rate of multiple pregnancies after clomiphene- or gonadotrophin-induced ovulation.
To date, pregnancy has not been a commonly used end point in RCTs concerning metformin. Four placebo-controlled RCTs reported 12 conceptions among 94 metformin-treated women (13%) compared with 4 conceptions among 94 (4.2%) placebo-treated women (49, 59, 62, 63). Much higher pregnancy rates, eg, 55% to 65%, have been reported in the RCTs that also used clomiphene citrate with metformin (49, 72, 74).
Early Pregnancy Loss TOP
The prevalence of polycystic ovaries (PCO) identified using pelvic ultrasound criteria is significantly higher among women with recurrent early miscarriage (56%) when compared with the general population (22%) (75). Pregnancy loss in women with PCOS could be the result of some or all of the following: abnormal uteroplacental vascularity, placental bed thrombosis, abnormal decidualization, and abnormal cell adhesion at the maternal-fetal interface. The impact of metformin in each of these areas has been examined.
Uterine vasculature has been observed noninvasively using Doppler ultrasound in infertility patients with PCOS. Treatment with metformin led to lowered vascular resistance in the spiral arteries (55).
Insulin resistance is associated with an increase in plasminogen activator inhibitor 1 (PAI-1) (30). Plasminogen activator inhibitor 1 (PAI-1) is produced by endothelium and decidualized endometrium. PAI-1 is the primary fast inhibitor of fibrinolysis; however, it is also a slow-reacting thrombin inhibitor, thus, although it promotes clot formation at a site of injury, it also limits its extension to produce just the right sized fibrin plug (76). A correlation between reduced insulin levels and reduced PAI-1 after metformin treatment for PCOS has been observed (48, 77). Whereas various thrombophilic states could be associated with placental bed thrombosis (78), research concerning the perinatal consequences of elevated PAI-1 remains speculative (79).
With respect to embryonic implantation, insulin-like growth factor-binding protein-1 is believed to mediate intercellular adhesion at the maternal-fetal interface. Serum glycodelin is a putative biomarker of endometrial function and has been reported to be decreased in women with recurrent pregnancy loss (55). Both follicular- and luteal-phase glycodelin and serum insulin-like-growth factor-binding protein-1 are increased after metformin treatment (55). Normalization of these factors suggests that metformin could have a role in maintaining early pregnancy.
Finally, an adequate decidualized endometrium is required for successful implantation. In a placebo-controlled group of infertile PCOS women undergoing clomiphene citrate ovulation induction, metformin improved ovulation rates, follicular maturation, and also ultrasound assessment of endometrial thickness (63). Improved decidualization is likely to follow normalization of ovarian function.
Two observational studies suggest that metformin diminishes the risk of miscarriage (77, 80), although a further study did not suggest benefit (71). Further research is awaited.
Obstetrics TOP
Metformin and the Placenta TOP
A partial placental barrier to metformin has been observed based on comparison of fetal and maternal drug concentrations (81). In contrast, sulfonylureas are of larger molecular weight compared with metformin, and the placental barrier is thus more complete (82, 83).
Placental GLUT1 is theoretically a metformin target (6). Insulin-sensitive GLUT4 is not found in placentae to any appreciable degree (84). However, metformin has little effect on transplacental glucose flux in term placentae from nondiabetic pregnancies as evidenced by in vitro studies (82).
Clinical Experience With Metformin in Pregnancy TOP
Metformin is classified as category BM on the basis that animal studies have not shown fetal damage (85). Until recently, clinical experience with metformin has been limited, and the American College of Obstetricians and Gynecologists cautions against metformin use in pregnancy (86).
Despite theoretical concerns, there have been clinical reports of substantial metformin use in pregnancy dating from 1966 (87-90). In more recent times, the use of metformin in early pregnancy is increasing, and some women choose to continue it into later pregnancy (91). Two Australasian studies are in progress comparing insulin with metformin for diabetes in pregnancy (92) (J. Rowan, personal communication, January 2003).
Diabetes in Pregnancy TOP
Catalano has summarized several studies, which indicate that, in some women, insulin resistance in early pregnancy precedes the development of gestational diabetes later in pregnancy (93). Such insulin resistance can, and often does, coexist with normal glucose tolerance before and in early pregnancy. With the development of hepatic, adipose, and skeletal muscle, insulin resistance in later pregnancy, and a failure to mount a sufficiently vigorous beta cell response in later pregnancy, hyperglycemia ensues.
An insulin-sensitizing agent such as metformin would be expected to limit hyperglycemia, although beta cell insufficiency would not be reversed (94).
Insulin is the traditional treatment for gestational hyperglycemia not controlled with diet. Glibenclamide has also been used with success (2). Both insulin and glibenclamide supplement or stimulate underactive pancreatic beta cells. However, neither treatment addresses the problem of hepatic and peripheral insulin resistance.
Potential maternal benefits with metformin treatment include amelioration or prevention of gestational diabetes. Glueck's series included a subgroup of 40 PCOS patients who had been pregnant both with and without metformin. The incidence of gestational diabetes declined from 26% to 4% (95). How much of this decrease can be ascribed to metformin and how much to other factors is yet to be determined.
Hypertension in Pregnancy TOP
Normal pregnancy is characterized by a dominance of vasodilator substances such as prostacyclin and nitric oxide over vasoconstrictors such as thromboxane A2. In preeclampsia, the reverse is true and widespread vasoconstriction ensues (96).
The similarities between preeclampsia and the insulin resistance syndrome have been well summarized in a review article by Innes and Wimsatt (97). They note the association of gestational diabetes with gestational hypertension. Furthermore, gestational diabetes and gestational hypertension commonly precede chronic insulin-resistant conditions in later life, for example, chronic hypertension, diabetes, and ischemic heart disease. Pathophysiological features common to preeclampsia and insulin resistance include lipid, platelet, coagulation/fibrinolysis, prostanoid, and uric acid abnormalities (97). Metformin has been shown to correct a number of these abnormalities in nonpregnant insulin-resistant states, eg, lipid (6), plasminogen activator inhibitor (77), and endothelial abnormalities (22).
The effect of metformin on gestational hypertension has not been systematically studied. However, Hellmuth's historical cohort study recorded no increase or decrease in hypertension in 50 pregnant women with type 2 diabetes who were treated with metformin (90). This group was compared with 68 women who were treated with sulfonylureas (tolbutamide) and 40 who were treated with insulin. Of concern, however, the authors observed an increased incidence of preeclampsia (PET), 32% compared with 10% (P <0.001).
The major limitation of Hellmuth's study is that it was not blinded and treatment was not randomized (90). Patients taking metformin were significantly older and heavier compared with the other 2 groups. Glycosylated hemoglobin was not reported, but possibly the metformin group had more severe diabetes and vascular disease than the groups allocated to sulfonylurea or insulin treatment. There was no significant difference in hypertension, intrauterine growth restriction (IUGR), polyhydramnios, placental abruption, or cesarean section (CS). Although the observed associations of metformin with preeclampsia could have been the result of confounding effects of maternal vascular disease, age, and obesity, the poor outcomes of preeclampsia, neonatal morbidity and mortality demand close attention in any modern study of metformin use in pregnancy.
Adverse Effects TOP
Maternal TOP
Maternal as well as fetal risks must be considered before prescribing any drug in pregnancy. With respect to metformin, potential maternal risks include hypoglycemia, lactic acidosis, nausea, vomiting, and potentially malabsorption.
Hypoglycemia resulting from metformin is very rare. This is an advantage compared with insulin or sulfonylurea treatment (98). Recurrent maternal hypoglycemia puts the fetus at increased risk of growth restriction (99).
Biguanides cause lactic acidosis, but this is rare in the absence of chronic renal disease, heart disease, severe trauma, infection, or exposure to certain radiographic contrast agents (12). Liver disease is a contraindication to metformin use because it is metabolized by the liver (100).
Gastrointestinal side effects and possible malabsorption induced by metformin could have more serious consequences in pregnancy than in nonpregnant patients. A pilot study of metformin treatment for gestational diabetes reported that 3 of 16 women withdrew from the trial because of side effects (92). Adequate nutrition is a priority for mother and fetus, even when the mother is obese and hence apparently overnourished. Registries of pregnancy outcome after metformin treatment should document both extremes of fetal growth, macrosomia and growth restriction, and carefully monitor for micronutrient deficiencies in baby and mother, in particular, vitamin B12, folic acid, iron, and calcium.
Adverse Effects TOP
Fetal-Neonatal TOP
There are no data to implicate metformin in teratogenesis over and above the confounding factor of poorly controlled diabetes. Maternal diabetes has been the most common indication for metformin treatment to date (85). Coetzee reported a series of 15 women managed on diet and metformin and 6 women managed on diet, metformin, and glibenclamide when gestational diabetes had been diagnosed on oral glucose tolerance testing prompted by one or more risk factors. They observed one perinatal death among this group and concluded that oral hypoglycemic agents were safe in late pregnancy (88). Similarly, they stated that the perinatal mortality rate was acceptable when metformin alone was used for 33 type 2 diabetics until approximately 24 hours predelivery. There was a 30% incidence of neonatal jaundice requiring phototherapy, 18% of babies were large for gestational age, and 9% had congenital abnormalities. They still concluded that the outcome was better with than without treatment (89).
Hellmuth's historical case series reported increased perinatal death rates in the metformin-treated group compared with the tolbutamide- and insulin-treated groups, 11.6% compared with 1.3% (P <0.02). There was no consistent cause of death. One death was clearly a macrosomic infant and one was severely growth-restricted (90). However, the impact of confounding effects such as maternal vascular disease, age, obesity, and congenital malformations are hard to quantify.
Glueck is following a series of nondiabetic women with PCOS who take metformin before and during pregnancy in the late 1990s and early 21st century. The most recent report included 70 fetuses who survived beyond the first trimester. No fetal abnormalities were detected in 63 babies at birth or in 7 ongoing pregnant women who had undergone a midtrimester fetal anomaly ultrasound scan. There was no obvious excess of growth restriction or macrosomia in this small series (95).
The problem of neonatal hypoglycemia previously noted with chlorpropamide has not been observed with metformin (85).
CONCLUSIONS TOP
Metformin is an appealing therapeutic option in pregnancy as a result of its simplicity of administration and minimal hazard of maternal and neonatal hypoglycemia. Evidence for the safety of metformin in pregnancy is increasing, and clinical applications in anovulation, hyperandrogenism, recurrent miscarriage, and gestational diabetes show substantial promise. Metformin is associated with changes in glucose, lipid, coagulation, and endothelial function, which could lessen the incidence or severity of gestational diabetes and/or hypertension, but large clinical trials are required to verify these clinical applications.
Serious teratogenicity attributable to metformin appears to be unlikely. However, there are concerns about consequences of maternal malabsorption on maternal and fetal nutrition. An excess of preeclampsia and neonatal mortality among women exposed to metformin in the second half of pregnancy in one uncontrolled historical series is concerning (90).
Comprehensive surveillance of deliberate and incidental metformin use in pregnancy should continue and further clinical trials are awaited with interest. Such research will enhance the understanding of the relationship between insulin resistance and reproductive function.
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