Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. 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. A Trial in Progress: Gestational Diabetes Placental transfer of rosiglitazone in the first trimester of human pregnancy. Metformin treatment in pregnant women with polycystic ovary syndrome--is reduced complication rate mediated by changes in the uteroplacental circulation? Perfusion studies of glyburide transfer across the human placenta: implications for fetal safety. A comparison of glyburide and insulin in women with gestational diabetes mellitus. Managing Preexisting Diabetes for Pregnancy
BACKGROUND Investigation of a possible effect of metformin on and rogen levels in pregnant women with polycystic ovary syndrome ( PCOS ) . METHODS A prospect i ve , r and omized , double-blind , placebo-controlled pilot study was conducted . Forty pregnant women with PCOS received diet and lifestyle counselling  and were r and omized to either metformin 850 mg twice daily or placebo . Primary outcome measures were changes in serum levels of dehydroepi and rosterone sulphate , and rostenedione , testosterone , sex hormone-binding globulin , and free testosterone index . Secondary outcome measures were pregnancy complications and outcome . Two-tailed t-tests and chi2-tests were used . RESULTS Maternal and rogen levels were unaffected by metformin treatment in pregnant women with PCOS . While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication , seven of the 22 ( 32 % ) women experienced severe complications in the placebo group ( P = 0.01 ) . CONCLUSIONS Metformin treatment did not reduce maternal and rogen levels in pregnant women with PCOS . In the metformin-treated group we observed a reduction of severe , pregnancy and post-partum complications .  Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period Background . Women with polycystic ovary syndrome have elevated homocysteine levels . Elevated homocysteine levels associate with pregnancy complications . Women with polycystic ovary syndrome are often treated with metformin , a drug that may increase homocysteine levels . Hence , we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome . Methods . Two prospect i ve r and omized placebo‐controlled studies included women with polycystic ovary syndrome in a university hospital setting . Sixty‐three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy . All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice , and oral folate and vitamin B12 substitution , and a daily oral multivitamin tablet . The main outcome measures were serum levels of homocysteine , folate , and vitamin B12 . Results . Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome . However , in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment . At inclusion in nonpregnant women , serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index . No such associations were seen in pregnant women . Conclusions . Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state BACKGROUND Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus ( NIDDM ) in the United States . Recently , however , metformin has been approved for the treatment of NIDDM . METHODS We performed two large , r and omized , parallel-group , double-blind , controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet ( protocol 1 : metformin vs. placebo ; 289 patients ) , or diet plus glyburide ( protocol 2 :  metformin and glyburide vs. metformin vs. glyburide  ; 632 patients ) . To determine efficacy we measured plasma glucose ( while the patients were fasting and after the oral administration of glucose ) , lactate , lipids , insulin , and glycosylated hemoglobin before , during , and at the end of the study . RESULTS In protocol 1 , at the end of the study the 143 patients in the metformin group , as compared with the 146 patients in the placebo group , had lower mean ( + /- SE ) fasting plasma glucose concentrations ( 189 + /- 5 vs. 244 + /- 6 mg per deciliter [ 10.6 + /- 0.3 vs. 13.7 + /- 0.3 mmol per liter ] , P < 0.001 ) and glycosylated hemoglobin values ( 7.1 + /- 0.1 percent vs. 8.6 + /- 0.2 percent , P < 0.001 ) . In protocol 2 , the 213 patients given metformin and glyburide , as compared with the 210 patients treated with glyburide alone , had lower mean fasting plasma glucose concentrations ( 187 + /- 4 vs. 261 + /- 4 mg per deciliter [ 10.5 + /- 0.2 vs. 14.6 + /- 0.2 mmol per liter ] , P < 0.001 ) and glycosylated hemoglobin values ( 7.1 + /- 0.1 percent vs. 8.7 + /- 0.1 percent , P < 0.001 ) . The effect of metformin alone was similar to that of glyburide alone . Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia , as compared with 3 percent in the glyburide group and 2 percent in the metformin group . In both protocol s the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations , whereas the values in the respective control groups did not change . There were no significant changes in fasting plasma lactate concentrations in any of the groups . CONCLUSIONS Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone OBJECTIVE To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus ( GDM ) treated with metformin vs. insulin . STUDY DESIGN Women with GDM not controlled with diet and exercise were r and omized to metformin ( n = 32 ) or insulin ( n = 31 ) . The levels of glycemic control as well as maternal/neonatal complications were evaluated . RESULTS The mean ( + /- SD ) fasting and 2-hour postpr and ial blood glucose did not differ statistically between the 2 treatment groups . No patient failed metformin and required insulin . The majority ( 27/32 ) were easily controlled on the initial dosage ( 500 mg twice a day ) . Gestational age at entry and delivery ( p = 0.077 , 0.412 ) were similar . The difference in the rate of cesarean delivery was not statistically significant between the 2 groups ( p = 0.102 ) . Neonatal statistics were also not different between the metformin and insulin groups : birth weight , Apgar score at 5 minutes , respiratory distress syndrome , hyperbilirubinemia , neonatal hypoglycemia and neonatal intensive care unit admission ( p = 0.144 - 0.373 ) . CONCLUSION Based on these preliminary data , metformin appears to be an effective alternative to insulin in the treatment of GDM OBJECTIVE We sought to investigate the association between glyburide dose , degree of severity in  gestational diabetes mellitus ( GDM ) ,  level of glycemic control , and  pregnancy outcome in insulin- and glyburide-treated patients . STUDY DESIGN In a secondary analysis of our previous r and omized study , 404 women were analyzed . The association among glyburide dose , severity of GDM , and selected maternal and neonatal factors was evaluated . Severity levels of GDM were stratified by fasting plasma glucose ( FPG ) from the oral glucose tolerance test ( OGTT ) . Infants with birth weight at or above the 90th percentile were considered large-for-gestational age ( LGA ) . Macrosomia was defined as birth weight > or = 4000 g. Well-controlled was defined as mean blood glucose < or = 95 mg/dL. The association between glyburide- and insulin-treated patients by severity of GDM and neonatal outcome was evaluated . RESULTS The dose received for the glyburide-treated patients was 2.5 mg-32 % ; 5 mg-23 % ; 10 mg-17 % ; 15 mg-8 % ; and 20 mg-20 % . Patients were grouped into low ( < or = 10 mg ) and high ( > 10 mg ) daily dose of glyburide . A comparison between severity of the disease ( fasting plasma glucose categories ) and highest dose of glyburide revealed a significant difference between the low-95 FPG and the other severity categories ( P = .02 ) . Of patients in the well-controlled glycemic group , only 6 % required the high dose of glyburide ( > 10 mg ) . In patients with poor glycemic control ( mean blood glucose > 95 mg/dL ) , 38 % received the high dose of glyburide ( P = .0001 ) . Comparison between the high glyburide ( > 10 mg ) and the low glyburide dosages ( < or = 10 mg ) revealed that the rate of macrosomia was 16 % vs 5 % and LGA 22 % vs 8 % , ( P = .01 ) , respectively . No significant difference was found in composite outcome , metabolic complications , and Ponderal Index between the 2 dose groups . Stratification by disease severity revealed a significantly lower rate of LGA for both the glyburide- and insulin-treated subjects . No significant difference was found between metabolic , respiratory , and neonatal intensive care unit ( NICU ) for patients within each fasting plasma glucose severity category . CONCLUSION Glyburide and insulin are equally efficient for treatment of GDM in all levels of disease severity . Achieving the established level of glycemic control , not the mode of pharmacologic therapy , is the key to improving the outcome in GDM BACKGROUND We prospect ively assessed growth and motor-social development during the first 18 months of life in 126 live births ( 122 pregnancies ) to 109 women with polycystic ovary syndrome ( PCOS ) who conceived on and continued metformin ( 1.5 - 2.55 g/day ) through pregnancy . METHODS The lengths and weights of PCOS neonates were compared with gender-specific Centers for Disease Control and Prevention ( CDC ) infant data . Gestational diabetes ( GD ) and pre-eclampsia in women with PCOS were compared with 252 healthy women without PCOS who had > or=1 live birth ( 262 live births ) . RESULTS There were 101 out of 126 ( 80 % ) term ( > or=37 gestational weeks ) PCOS births , which was not significantly different ( P = 0.7 ) from controls , 206 out of 252 ( 81.7 % ) . There were two ( 1.6 % ) birth defects . GD occurred in nine out of 119 PCOS pregnancies ( 7.6 % ) versus 40 out of 251 ( 15.9 % ) controls , P = 0.027 . The prevalence of pre-eclampsia did not differ in PCOS versus control pregnancies ( 4.1 versus 3.6 % , P = 0.8 ) . The birth length and weight of the 52 male neonates did not differ ( P > 0.05 ) from those of CDC males ; the 74 female neonates were shorter than CDC females ( 48.9 + /- 5.4 versus 50.6 + /- 2.7 cm , P = 0.006 ) and weighed less ( 3.09 + /- 0.85 versus 3.29 + /- 0.52 kg , P = 0.04 ) . There were no systematic differences in growth between PCOS and CDC infants over 18 months . At 3 , 6 , 9 , 12 and 18 months , of a potential 100 % motor-social development score , scores ( + /-SD ) were 95 + /- 13 , 98 + /- 8 % , 95 + /- 10 , 97 + /- 8 and 94 + /- 16 % ; no infants had motor-social developmental delays . CONCLUSIONS Metformin reduced development of GD , was not teratogenic and did not adversely affect birth length and weight , growth or motor-social development in the first 18 months of life The Metformin in Gestational Diabetes ( MiG ) trial is a prospect i ve r and omized multicenter trial in women with gestational diabetes mellitus ( GDM ) that is testing the hypothesis that metformin treatment , compared with insulin , is associated with similar perinatal outcomes , improved markers of insulin sensitivity in the mother and baby , and improved treatment acceptability . Women with GDM who are at 20–33 weeks ’ gestation in a singleton pregnancy and meet entry criteria are r and omized to insulin or metformin  treatment . The primary outcome is a composite of neonatal morbidity , with 750 recruits required . The trial finished recruiting in October 2006 . Interim data on 200 women ( and subsequently 550 women ) have been review ed by the data safety monitoring committee , which has reported that the trial should answer the hypotheses and no protocol changes are required . Data from 457 women show recruits are a mean age of 33.3 ± 5.3 years ; BMI of 32.1 ± 7.8 kg/m2 ; and ethnicity 47.2 % European/Caucasian , 25.7 % Polynesian , and 24.3 % Indian/Asian .  The mean fasting glucose at recruitment is 5.3 ± 1.1 mmol/l and A1C is 5.7 ± 0.8 % . Long-term follow-up of children started at age 2 years , with assessment s of body composition , neurodevelopment , diet , and activity levels . The MiG trial will address the efficacy and detailed safety of metformin compared with insulin in women with GDM . Long-term follow-up of offspring will examine whether treatment influences later health ( Australasian Clinical Trials Registry number 12605000311651 ) . GDM is diagnosed in over 4 % of pregnant women ( 1,2 ) . The prevalence is increasing as the pregnancy population becomes older and fatter . Women with GDM have increased rates of pregnancy complications and risks of later type 2 diabetes ( 1,2 ) . The offspring of women with GDM also have increased risks of perinatal complications and long-term risks of obesity and type 2 diabetes ( 1– OBJECTIVE To determine the degree of placental transfer of rosiglitazone in early human pregnancy . DESIGN Prospect i ve observational study . SETTING University teaching hospital . PATIENT(S ) Thirty-one women undergoing surgical termination of pregnancy between 8 and 12 weeks ' gestation . INTERVENTION(S ) Each woman was given two doses of rosiglitazone ( 4 mg ) before the procedure . MAIN OUTCOME MEASURE(S )  Rosiglitazone concentration in fetal tissue and coelomic and amniotic fluids . RESULT ( S ) The mean maternal serum rosiglitazone concentration was 110.3 + /- 47.9 ng/mL. Rosiglitazone was detectable in 19 fetal sample s ( 61.3 % ) . The mean fetal tissue concentration was 52.7 + /- 26.3 ng/g . Rosiglitazone was more likely to be detected in fetal tissue if the gestation at termination was 10 weeks or more compared with earlier gestation . Coelomic fluid was obtained in 22 cases , and rosiglitazone was detected in 13 sample s ( 59.1 % ) . The mean concentration was 22.8 + /- 7.0 ng/mL. Rosiglitazone was detectable in only two of the 31 amniotic fluid sample s , with concentrations of 10.3 and 12.6 ng/mL. CONCLUSION ( S ) The risk of placental transfer of rosiglitazone is much higher at or after 10 weeks of gestation . Absence of detectable rosiglitazone in amniotic fluid despite its presence in fetal tissue suggests that fetuses may have the ability to metabolize rosiglitazone , and little parent drug was excreted unchanged in urine OBJECTIVES To study a possible effect of metformin on the uteroplacental circulation . METHODS Forty pregnant women with polycystic ovary syndrome ( PCOS ) were enrolled in a r and omized , double-blind , placebo-controlled trial of metformin ( 1700 mg/day ) during pregnancy . Doppler ultrasound examinations of the uterine arteries were performed at 12 , 19 , 24 , 32 and 36 gestational weeks and of the umbilical artery at 19 , 24 , 32 and 36 gestational weeks . RESULTS There was a greater mean bilateral uterine artery pulsatility index ( PI ) at 12 weeks ( 1.95 vs. 1.58 , P = 0.02 ) , and a greater reduction in mean PI from 12 to 19 weeks ( P = 0.03 ) in metformin-treated women . There were no differences in mean PI values between groups at 19 , 24 , 32 or 36 gestational weeks . Pregnancy complications , such as preterm delivery before 32 weeks , severe pre-eclampsia or serious postpartum events , occurred only in the placebo group ( 7 of 22 vs. 0 of 18 , P = 0.01 ) . There were no associations between uterine artery Doppler measurements and pregnancy complications . We found no differences between groups in mean umbilical artery PI at 19 , 24 , 32 or 36 gestational weeks . CONCLUSIONS In this small r and omized trial , metformin treatment in pregnancy reduced uterine artery impedance between 12 and 19 weeks of gestation , and this was associated with reduced complication rate . Published by John Wiley & Sons , OBJECTIVE Gestational diabetes affects up to 5 % of women .  Oral hypoglycemics have been avoided because of the assumption that their placental transfer may cause fetal-neonatal hypoglycemia . A recent r and omized trial could not show measurable glyburide levels in umbilical blood despite maternal treatment with regular doses of glyburide . The mechanism underlying this phenomenon is not known . The objective of our study was to document , using a human placenta perfusion model , whether glyburide is actively effluxed from the fetal to the maternal circulation . STUDY DESIGN In vitro perfusion studies of human cotyledon were performed to quantify placental transfer of glyburide . Using close circle experiments and introducing glyburide to both maternal and fetal circulations at 200 ng/mL , we looked for evidence of transport against concentration gradient from the fetus to the mother . In parallel experiments , the P-glycoprotein inhibitor verapamil was used in an attempt to inhibit transplacental glyburide movement . RESULTS There was highly significant transfer of glyburide against concentration gradient from the fetal to the maternal circulation . Fetal-to-maternal concentration ratio was 0.92 + /- 0.23 at the start of the experimental period and 0.31 + /- 0.47 3 hours later ( P = .01 ) ( n = 5 ) . Verapamil did not modify glyburide transport . CONCLUSION This is the first direct evidence of active glyburide transport from the fetus to the mother and , in general , of any medicinal drug used during pregnancy . These experiments suggest that glyburide is actively efflux by a transporter other than P-glycoprotein . Alternatively , it is possible that a minority of glyburide is carried by P-glycoprotein , but most of the fetal load is pumped to the mother by a yet-unidentified placental transport system BACKGROUND Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug , because of concern about teratogenicity and neonatal hypoglycemia . There is little information about the efficacy of these drugs in this group of women . METHODS We studied 404 women with singleton pregnancies and gestational diabetes that required treatment . The women were r and omly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol . The primary end point was achievement of the desired level of glycemic control . Secondary end points included maternal and neonatal complications . RESULTS The mean ( + /-SD ) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter ( 6.4+/-1.1 mmol per liter ) in the glyburide group and 116+/-22 mg per deciliter ( 6.5+/-1.2 mmol per liter ) in the insulin group ( P=0.33 ) . The mean concentrations during treatment were 105+/-16 mg per deciliter ( 5.9+/-0.9 mmol per liter ) in the glyburide group and 105+/-18 mg per deciliter ( 5.9+/-1.0 mmol per liter ) in the insulin group ( P=0.99 ) . Eight women in the glyburide group ( 4 percent ) required insulin therapy . There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age ( 12 percent and 13 percent , respectively ) ; who had macrosomia , defined as a birth weight of 4000 g or more ( 7 percent and 4 percent ) ; who had lung complications ( 8 percent and 6 percent ) ; who had hypoglycemia ( 9 percent and 6 percent ) ; who were admitted to a neonatal intensive care unit ( 6 percent and 7 percent ) ; or who had fetal anomalies ( 2 percent and 2 percent ) . The cord-serum insulin concentrations were similar in the two groups , and glyburide was not detected in the cord serum of any infant in the glyburide group . CONCLUSIONS In women with gestational diabetes , glyburide is a clinical ly effective alternative to insulin therapy This document presents consensus panel recommendations for the medical care of pregnant women with preexisting diabetes , including type 1 and type 2 diabetes . The intent is to help clinicians deal with the broad spectrum of problems that arise in management of diabetes before and during pregnancy , and to prepare diabetic women for treatment that may reduce complications in the years after pregnancy . A thorough discussion of the evidence supporting the recommendations is presented in the book , Management of Preexisting Diabetes and Pregnancy , authored by the consensus panel and published by the American Diabetes Association ( ADA ) in 2008 ( 1 ) . A consensus statement on obstetrical and postpartum management will appear separately . The recommendations are diagnostic and therapeutic actions that are known or believed to favorably affect maternal and perinatal outcomes in pregnancies complicated by diabetes . The grading system adapted by the ADA was used to clarify and codify the evidence that forms the basis for the recommendations ( 2 ) . Unfortunately there is a paucity of r and omized controlled trials ( RCTs ) of the different aspects of management of diabetes and pregnancy . Therefore our recommendations are often based on trials conducted in nonpregnant diabetic women or nondiabetic pregnant women , as well as on peer- review ed experience before and during pregnancy in women with preexisting diabetes ( 3–4 ) . We also review ed and adapted existing diabetes and pregnancy guidelines ( 5–10 ) and guidelines on diabetes complications and comorbidities ( 2,3,11–14 ) . # # # A. Organization of preconception and pregnancy care # # # #
BACKGROUND While most guidelines recommend the use of insulin in women whose pregnancies are affected by pre-existing diabetes , oral agents have obvious benefits for patient acceptability and adherence .
It is necessary , however , to assess the effects of these anti-diabetic agents on maternal and infant health outcomes .
Additionally , women with previous gestational diabetes mellitus are increasingly found to be predisposed to impaired glucose tolerance and , despite the potential need for intervention for these women , there has been little evidence about the use of oral anti-diabetic agents by these women pre-conceptionally or during a subsequent pregnancy .
OBJECTIVES To investigate the effect of oral anti-diabetic agents in women with pre-existing diabetes mellitus , impaired glucose tolerance or previous gestational diabetes planning a pregnancy or pregnant women with diabetes mellitus on maternal and infant health .
The use of oral antidiabetic agents for management of gestational diabetes in a current pregnancy is evaluated in a separate Cochrane review .