Original Article
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A Pilot Randomized, Controlled Trial of Metformin versus Insulin in Women with Type 2 Diabetes Mellitus during Pregnancy Jerrie S. Refuerzo, MD1 Rose Gowen, MD2 Claudia Pedroza, PhD3 Sean C. Blackwell, MD1 Susan Ramin, MD4
Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas 2 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Brownsville, Brownsville, Texas 3 Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center at Houston, Houston, Texas 4 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
Address for correspondence Jerrie S. Refuerzo, MD, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, 6431 Fannin, Suite 3.270, Houston, TX 77030 (e-mail: [email protected]).
Am J Perinatol 2015;32:163–170.
Abstract
Keywords
► type 2 diabetes mellitus ► pregnancy ► metformin
Objective Few studies support oral diabetic treatment in pregnant women with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of metformin versus insulin on achieving glycemic control and improving maternal and neonatal outcomes in pregnant women with T2DM. Study Design A pilot randomized, controlled trial was conducted of metformin versus insulin for the treatment of T2DM during pregnancy. The primary outcome was glycemic control measured with hemoglobin A1c < 7% at delivery. Maternal and neonatal outcomes were compared between groups. Results In this study, 8 women received metformin and 11 received insulin. All women in both groups achieved glycemic control by delivery (HgbA1c: metformin 5.96 5.88 vs. insulin 6.34 0.92%). There were similar rates of cesarean delivery, birth weights, neonatal intensive care unit admissions, respiratory distress syndrome, and neonatal dextrose treatment between groups. There was one case of fetal macrosomia in the insulin group, one case of shoulder dystocia in the metformin group and no cases of failed metformin therapy. Conclusion In this pilot study, glycemic control was achieved in women who received metformin and insulin. Larger studies are needed to determine whether metformin can be considered a reasonable alternative to insulin in pregnant women with T2DM.
Obesity is a national health crisis.1 With this rise in obesity, the rate of type 2 diabetes mellitus (T2DM) has also increased. Metformin is an effective agent and first-line medication in nonpregnant obese adults with T2DM.2–5 Metformin im-
proves insulin sensitivity by reducing fasting plasma glucose and insulin concentrations. It functions by decreasing hepatic glucose output by inhibition of gluconeogenesis and enhanced peripheral glucose uptake.6 It has been shown to be
received January 11, 2014 accepted after revision April 16, 2014 published online June 4, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1378144. ISSN 0735-1631.
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1 Division of Maternal Fetal Medicine, Department of Obstetrics,
Maria Hutchinson, MS1
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beneficial in reducing weight, improving lipid profiles, decreasing cardiovascular risk, and reducing fibrinolytic activity.3,5,7 An important advantage is that it is not associated with hypoglycemia.3,4 The successful treatment of diabetes with metformin has led to improvements in the overall health status of women with diabetes. As a result, many of these women are actively choosing to become pregnant leading to the growing number of pregnant women with T2DM. Adverse pregnancy outcomes in diabetic pregnancies are related to fetal hyperinsulinemia which rises in response to increased levels of maternal glucose crossing the placenta.6 Fetal hyperinsulinemia is associated with increased fetal growth, fat deposition, and demand for oxygen. Pregnant women with T2DM are at significantly increased risk of spontaneous abortions, congenital birth defects, preeclampsia, and intrauterine fetal death.8,9 Poor pregnancy outcomes are also due to macrosomia increasing the rate of shoulder dystocia leading to neonatal birth injury and potential need for cesarean delivery. Offspring born to women with T2DM have a higher rate of developing obesity and insulin resistance later in life.10–12 These pregnancy complications and the process of fetal programming in utero are directly related to the level of glycemic control during pregnancy. Pregnancy management aims to reduce pregnancy complications by returning maternal glucose levels to normal.6,9,13 Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in pregnant women with T2DM. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight makes this therapeutic option cumbersome for the pregnant patient.6 Offering an insulin sensitizing agent, such as metformin, that can be administered orally and simply just a few times a day with very few adverse effects may be appealing to these women, thereby increasing compliance and overall perinatal outcome. Although there is some evidence to suggest that metformin is safe in pregnancy and that it potentially improves both maternal and neonatal outcomes, its efficacy in pregnant women with T2DM compared with insulin is largely unknown.8,14–18 Because pregnancy is a state of hyperinsulinemia and blood sugars tend to increase with gestation, clinical concerns remain regarding whether metformin will be able to control hyperglycemia related to pregnancy. In women with T2DM on hypoglycemic agents who become pregnant, there is limited data to support either the use or withdrawal of metformin.6 From a clinical perspective, practicing health care providers are challenged with the question of whether it is reasonable to resume metformin during pregnancy in those women receiving such treatment before pregnancy. Although many studies exist examining the effects of metformin versus insulin in women gestational diabetes, there are only a few studies published focusing on metformin in women with pregestational diabetes before the onset of pregnancy.19,20 On the basis that metformin is an effective insulin sensitizer in the treatment of T2DM, we hypothesized that metformin might be an alternative to insulin in women with T2DM during pregnancy. The objective of this study was to conduct
a pilot study to determine whether metformin could be continued to control hyperglycemia and improve maternal and neonatal outcomes in a focused, subgroup of pregnant women with T2DM that were either on oral hypoglycemic agents or diet controlled before pregnancy.
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Methods To answer the clinical question of whether metformin can be resumed in pregnancy complicated with T2DM, an openlabel, pilot, randomized, controlled trial was conducted investigating the use of metformin versus insulin in the treatment of T2DM in pregnancy at the University of Texas Health Science Center at Houston (UT Health) and at the University of Texas Health Science Center at Brownsville. The Institutional Review Board (IRB) at both institutions approved the pilot study. Strict inclusion criteria were set by the IRB at the UT Health thereby narrowing our enrollment population to a small, focused subgroup of pregnant women with pregnancies less than 20 weeks’ gestational age who had a selfreported history of T2DM with treatment of either diet control or oral hypoglycemic agents before pregnancy, and who had T2DM for less than 10 years. Women were excluded if they were on insulin before pregnancy, had multiple gestations, type 1 diabetes, known fetal chromosomal or structural defects, or contraindications to the use of metformin including renal disease, liver disease, recent myocardial infarction or sepsis, or had an HgbA1c > 9%. All participants received prenatal care through the high-risk diabetic clinic. At their initial prenatal visit, an ADA diet was recommended based on maternal weight, and instructions on self-blood glucose monitoring (SBGM) four times a day (fasting and 2 hours postprandial) were provided. Glucose levels greater than 95 mg/dL fasting and 120 mg/dL postprandial were considered abnormal. Instruction for exercise was also provided. Routine prenatal assessments were also provided as directed by the health care provider at the appropriate gestational ages including: 24 hours urine collection for total protein and creatinine clearance, ophthalmology exam to rule out diabetic retinopathy, maternal serum screening, first trimester ultrasound, anatomy ultrasound, fetal echocardiogram, growth ultrasounds every 4 weeks, and antenatal fetal surveillance beginning at 32 to 34 weeks. A maternal HgbA1c level was drawn every trimester and at the time of delivery to assess glycemic control. The HgbA1c at enrollment/randomization was considered the baseline HgbA1c. Women were randomly assigned to either metformin or insulin by the central investigational drug pharmacy at UT Health in Houston, TX. A permuted block randomization with a random fashion was used to prevent imbalances between groups. This randomization was conducted independent of the medication the participant was receiving before the onset of pregnancy. The randomization was stratified by site, Houston and Brownsville. For those gravida randomized to metformin, medication was initiated as in the nonpregnant population: Metformin 500 mg daily was initiated and women returned for routine clinical prenatal visits weekly. If greater than 50% of the
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glucose values were abnormal, metformin was increased to 500 mg twice a day. The metformin regimen was increased by 500 mg as needed for a maximum dose of 2,500 mg a day. Once glycemic control was achieved, the participant followed up every 2 weeks. If the participant required greater than 2,500 mg of metformin a day without achieving glycemic control, she was considered “failed metformin therapy” and was started on insulin, but still resumed and continued metformin. Women receiving metformin before pregnancy resumed the dose at which they were on at the start of pregnancy and increased according to the above protocol. For those women randomized to insulin, regimens were based on maternal weight and gestational age. Regimens were calculated as follows: first trimester—0.7 units/kg/day, second trimester—0.8 units/kg/day, and third trimester—0.9 to 1.0 units/kg/day. The total insulin dose was divided into: AM dose into two-thirds NPH and one-third regular insulin, PM dose into half NPH and half regular insulin. Insulin doses were increased or decreased 10 to 20% according to SBGM. Women receiving insulin before pregnancy resumed or switched to an equivalent insulin regimen as above. The primary outcome was the rate of women with an HgbA1c < 7% at the time of delivery. This primary outcome was chosen as surrogate to assess overall glycemic control due to limitation of a pilot study and logistical errors in reporting SBGM with glucose logs. Secondary outcomes included change in HgbA1c, maternal, and neonatal complications including preeclampsia, failed metformin therapy, cesarean delivery rate, macrosomia with a birth weight greater than 4,000 g, shoulder dystocia, respiratory distress syndrome (RDS) as reported by the caring neonatologist, or need for neonatal dextrose therapy. Maternal demographics and pregnancy characteristics were also collected. Because this was a pilot study, we initially anticipated enrolling 50 women in each group, for a total of 100 women.
Enrollment
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To determine a power calculation, we had reviewed recent deliveries at our institutions of women with T2DM and noted a 60% rate of women achieving an HgbA1c less than 7% at the time of delivery. If there were 50 women in each group with an effect size of 50%, a p-value < 0.05, the power would be 0.87. Statistical analysis including both traditional frequentist comparisons and Bayesian analysis was conducted. The primary outcome (rate of women with an HgbA1c < 7%) was compared between groups with chi-square test. The differences in HgbA1c levels were compared with Student t-test. Differences in gestational age at each HgbA1c laboratory draw were compared with Mann–Whitney U test. Other continuous variables were compared using Student t-test and categorical variables were compared using chi-square test. Statistical analysis was conducted using STATA 21st Edition. A p-values < 0.05 was considered significant and relative risk and 95% confidence interval (CI) were reported. Due to strict inclusion and exclusion criteria, we had limitations in our enrollment, and we were unable to achieve our sample size. Thus we decided to conduct a Bayesian analysis. Bayesian analyses are typically used to determine the effects of treatment in comparison studies with small sample sizes.21–23 After completing the study, we performed a Bayesian analysis to assess the treatment effect of metformin to insulin on the HgbA1c at delivery or in the third trimester between groups and to calculate the probability of a difference in values. A neutral prior probability was used in estimating the posterior probability that the metformin had similar effects as insulin.23
Results Due to the strict inclusion criteria, a total of 38 pregnant women were approached to participate in this study from September 2009 to August 2011, as illustrated in ►Fig. 1. Thirteen pregnant women either declined (5) or were
Assessed for Eligibility N = 38
Excluded (N = 13) -Not meeng study criteria (n = 8) -Declined (N = 5)
Randomized N = 25
Allocated to Meormin (N = 11) -Received allocated meormin (N = 11)
Allocaon
Allocated to Insulin (N = 14) -Received allocated insulin (N = 13) -Did not receive allocated insulin (N = 1)
Disconnued, Physician chose to start insulin (N = 2) Lost to follow-up (N = 1)
Follow -up
Disconnued, chose to stop study (N = 1) Lost to follow-up (N = 0)
Analyzed (N = 8) -Excluded (N = 0)
Analysis
Analyzed (N = 13) -Excluded (N = 0)
Fig. 1 Enrollment of 38 pregnant women.
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Table 1 Maternal demographics
ineligible (8). A total of 25 pregnant women with T2DM were enrolled, 11 to the metformin group and 14 to the insulin group. Three women in the metformin group and one in the insulin group were withdrawn due to the subject changing her mind after enrollment and chose not to take any insulin. Thus, 8 women in the metformin group and 13 in the insulin group completed the study and were included in the study analysis. The groups were similar in maternal age, gravidity, parity, race, and gestational age at enrollment as described in ►Table 1. There were similar rates of maternal hypertension, obesity, and morbid obesity between groups. More than 80% of these women were obese with a mean body mass index (BMI) 35.9 5.2 kg/m2 in the metformin group and a mean BMI of 40.1 8.4 kg/m2 in the insulin group. The primary outcome of an HgbA1c < 7% at delivery was achieved in 100% of women in the metformin group and 87.5% in the insulin group (relative risk 0.79 [95% CI, 0.64–1.10]). All women randomized to metformin achieved an HgbA1c < 7% by the mid-trimester. The women randomized to the insulin group had an HgbA1c drawn at an earlier gestational age compared with metformin group (insulin 6 weeks [4–10 weeks] vs. metformin 9 weeks [8–13 weeks]). There was no statistical difference between the HgbA1c at delivery between groups (metformin 5.96 5.88% vs. insulin 6.34 0.92%). There was also no statistical difference between the two groups at the time of enrollment/first
Metformin N¼8
Insulin N ¼ 13
Maternal age (y)
30.9 5.5
32.3 4.3
Gravidity
4 (1–3)
4 (1–6)
Parity
1 (0–3)
1 (0–4)
3 (37.5%)
4 (30.8%)
Race African American Caucasian
4 (50%)
6 (46.2%)
Hispanic
0 (0%)
1 (7.7%)
Other
1 (12.5%)
2 (15.4%)
Maternal hypertension
4 (50%)
4 (30.8%)
Gestational age enrollment (wk)
16 (8–19)
16 (6–18)
BMI (kg/m2)
35.9 5.2
40.1 8.4
Obese (BMI > 30 kg/m2)
7 (87.5%)
11 (84.6%)
Morbidly obese (BMI > 40 kg/m2)
1 (12.5%)
5 (38.5%)
Abbreviation: BMI, body mass index. Note: N (%), mean standard deviation, median (range).
Table 2 Hemoglobin A1C (HgbA1c) levels throughout pregnancy Metformin Total N ¼ 8
Insulin Total N ¼ 13
p-Value
Enrollment/first trimester
9 (8–13) N¼5
6 (4–10) N¼7
0.015
Mid-trimester
16.5 (11–23) N¼8
15 (10–18) N ¼ 112
0.370
Third trimester
26 (17–29) N¼5
29 (25–35) N ¼ 12
0.123
Delivery
37 (35–40) N¼5
37 (35–41) N¼8
0.565
Enrollment/first trimester
6.22 0.66
6.84 1.23
0.285
Gestational age at HgbA1c laboratory draw (wk)
Hemoglobin A1c (%) Mid-trimester
5.79 0.50
6.13 0.89
0.307
Third trimester
5.70 0.12
5.72 0.48
0.912
Delivery
5.96 5.88
6.34 0.92
0.400
Third trimester/delivery
5.88 0.59
6.01 0.89
0.729
Change in HgbA1c from enrollment to third trimester/delivery
0.13 0.50
0.61 0.83
0.223
Enrollment/first trimester
4(80.0%)
5 (71.4%)
0.285
Mid-trimester
8 (100%)
11(81.8%)
0.505
Third trimester
5 (100%)
12 (100%)
1.00
Delivery
5 (100%)
7 (87.5%)
0.411
Third trimester/delivery
5 (100%)
12 (92.3%)
0.523
Women with HgbA1c < 7% (%)
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Metformin N¼8
Insulin N ¼ 13
p-Value
Gestational age delivery (wk)
37 (35–40)
37 (35–41)
0.977
Rate of preterm birth < 37 wk
1 (12.5%)
3 (23.1%)
0.549
Induction of labor
5 (62.5%)
5 (38.5%)
0.387
Preeclampsia
0 (0%)
4 (30.8%)
0.131
Cesarean delivery rate
4 (50%)
6 (46.2%)
0.864
Prior cesarean delivery
1 (25%)
3 (23.1%)
Fetal indications
0 (0%)
1 (7.7%)
Other
3 (75%)
2 (15.4%)
Shoulder dystocia
1 (12.5%)
0 (0%)
0.381
Male gender
6 (75%)
7 (53%)
0.537
Birth weight (g)
2,930.5 483.6
3,111.5 743.1
0.972
Macrosomia (> 4,000 g)
0 (0%)
1 (7.7%)
0.422
NICU admission
1 (12.5%)
3 (23.1%)
0.149
RDS
1 (12.5%)
3 (23.1%)
0.570
Need for neonatal dextrose
0 (0%)
1 (7.7%)
0.507
Neonatal length of hospital stay (d)
3 (1–8)
2 (1–12)
0.697
Abbreviations: NICU, neonatal intensive care unit; RDS, respiratory distress syndrome. Note: N (%), mean standard deviation, median (range).
trimester, mid-trimester, and third trimester. A delivery HgbA1c was obtained in only 13 women (5 in the metformin group and 8 in the insulin group). However, either a third trimester and/or a delivery HgbA1c were obtained on all women. Thus, we determined the change in HgbA1c from enrollment to delivery or third trimester was similar between groups (metformin 0.13 0.50 vs. insulin 0.61 0.83, p ¼ 0.223) as described in ►Table 2. There were no women randomized to metformin who “failed metformin therapy” and needed insulin to treat hyperglycemia. There was no statistical difference between gestational age at delivery, or rates of preterm birth less than 37 weeks of gestation, induction of labor, preeclampsia, or cesarean delivery between groups as described in ►Table 3. In addition, there were similar birth weights and rates of male gender, neonatal intensive care unit (NICU) admissions, RDS, and the need for neonatal dextrose treatment. There was only one case of fetal macrosomia in the insulin group and one case of shoulder dystocia in the metformin group. For the Bayesian analysis, the prior distributions on values of HgbA1c were previously reported for women with gestational diabetes who were randomized to either insulin or metformin.23 There was limited data on randomized controlled trials of insulin versus metformin in pregnant women with T2DM. For the metformin group, we assumed a normal prior distribution centered at 5.6% with standard deviation (SD) of 0.5, and for the insulin group, the prior normal distribution was centered at 5.7% with SD of 0.6. For the SD parameter, we assumed a uniform prior distribution from 0 to 100.23 These prior distributions assume a prior probability of
55% of metformin group having lower values of HgbA1c compared with the insulin group (about a 50–50 chance of one treatment having lower values than the other). The posterior distribution for the insulin group had a posterior mean of 5.97% (SD ¼ 0.22) and 95% posterior interval of 5.52 to 6.4%. For the metformin group, the posterior mean was 5.88% (SD ¼ 0.33) with 95% posterior interval of 5.23 to 6.53%. The posterior probability of the metformin having lower values of HgbA1c is 60% which indicates almost no difference between the two groups.
Conclusion In this pilot study, all pregnant women in both groups achieved euglycemia by the third trimester and delivery. Women who received metformin achieved an HgbA1c < 7% by the second trimester compared with the third trimester in those women who received insulin. Metformin treatment resulted in similar maternal and fetal outcomes compared with insulin. Although insulin has traditionally been the treatment of choice for hyperglycemia in pregnant women with T2DM, this small trial supports continuing metformin as the primary treatment option in pregnant women with T2DM who were treated with an oral diabetic agent before pregnancy. The greatest limitation of this study was the inability to achieve our targeted sample size. This study was conducted over 2 years and only enrolled a total of 38 women primarily due to poor recruitments of participants. A significant factor that impacted recruitment was the strict exclusion criterion, American Journal of Perinatology
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Table 3 Pregnancy and neonatal outcomes
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in particular, the exclusion of women with T2DM who were on insulin before pregnancy. Prior studies have reported that 83.5% of women with T2DM and Type 1 DM have used insulin alone before pregnancy.17 Thus, this single exclusion criterion reduced the number of women who were eligible for this study. Another exclusion criteria was the HgbA1c > 9%. This criterion influenced the enrollment of fairly controlled diabetic women, and thus could represent the underlying cause for the lack of difference in change in HgbA1c seen between groups. It could also be the reason why none of the pregnant women in the metformin group failed metformin therapy. Another factor affecting recruitment was the reluctance of managing physicians to allow their patients to participate in the study due to their own personal clinical practice patterns and beliefs on how pregnant women with T2DM should be managed. Despite this much needed randomized controlled trial to answer the questions regarding important clinical management of a high-risk obstetrical population, a small sample size (N ¼ 38) was attained with a 23.7% attrition rate. Recent trends demonstrate that the use of oral diabetic medications preconception has increased from 0.7% in 2001 to 1.7% in 2007, primarily due to the use of metformin.17 During this time period, the use of metformin during pregnancy rose from 0.01 to 0.19% overall. The majority of women (79%) used metformin for the diagnosis of infertility related to polycystic ovarian syndrome (PCOS). Only 13.6% used metformin for T2DM. Of the women on metformin before pregnancy, 8.8% of women continued metformin during pregnancy, whereas 16.8% switched to insulin, 3% switched to a different oral diabetic agent, and 68.0% did not use any treatment at all. Of the women who continued metformin during pregnancy, approximately two-thirds switched to insulin or other oral agents by the second trimester. We chose to use metformin instead of glyburide (sulfonylurea) due to its high efficacy in obese women, beneficial effects on the cardiovascular status, and limited adverse effects. Although glyburide is widely used for the treatment of gestational diabetes, it carries the maternal risk of hypoglycemia, hyperinsulinemia, and weight gain.4,5,16,24 In addition, metformin is a pregnancy category B drug, whereas glyburide is a category C drug.4,14 Metformin has been used by women throughout pregnancy. The first studies were performed by Coetzee and Jackson during the 1970s.18 Women with insulin independent diabetes were prospectively followed throughout gestation, 22 women received metformin compared with 42 women who received insulin. The perinatal mortality rate was 50/1,000 for those on metformin versus 51/1,000 on insulin. Neonatal birth weight greater than 4,000 g occurred in only 10% of women on metformin. There were no cases of maternal hypoglycemia or lactic acidosis. In addition, metformin use in the first trimester was not associated with congenital anomalies.25 In a follow-up study, Coetzee and Jackson were able to achieve glycemic control in women on metformin within 24 hours compared with 2 to 3 weeks for insulin.26 The most recent randomized controlled trial of metformin versus insulin during pregnancy was in 751 women with gestational diabetes conducted in Australia.27 There was no
difference in maternal or neonatal outcomes and fasting glucose levels and HgbA1c results were similar between both groups. Side effects in 7.4% of women led to cessation of metformin treatment and 46.3% required insulin due to failed metformin therapy. Women in the metformin group gained less weight and had more weight loss compared with insulin. Importantly, women who received metformin reported that they were more likely to choose metformin even after delivery and that the ease of medication administration improved their treatment plan. This suggests that mode of medication administration could impact compliance with treatment and improve overall pregnancy outcomes. Others metformin studies have been conducted primarily in women with PCOS treated for infertility. A randomized, double-blinded controlled pilot study was performed on 18 women with PCOS who conceived on metformin compared with 22 women with PCOS who received a placebo.28 Women who received the metformin had a lower rate of pregnancy complications (0% metformin vs. 32% placebo) including preterm birth, sepsis, deep venous thrombosis, or adult RDS. There were no differences in neonatal outcomes such as birth weight. Another study involving women with PCOS who conceived on metformin showed a lower rate of developing gestational diabetes later in pregnancy (3% metformin vs. 31% no metformin).29 Despite the numerous studies examining the effects of metformin versus insulin in women gestational diabetes and PCOS, there is only two studies published focusing on metformin in women with pregestational diabetes before the onset of pregnancy. Ibrahim et al conducted a randomized controlled trial of 90 women with either gestational diabetes or insulin resistant pregestational diabetes. Although we initiated enrollment and randomization before 20 weeks, their subjects began treatment after 20 weeks.19 One group received metformin with a fixed dose of insulin, and the other group received metformin and increasing doses of insulin. They concluded that adding metformin to insulin therapy in insulin-resistant diabetes was effective in proper glycemic control and resulted in reduced hospital stay, maternal and neonatal hypoglycemia, NICU admissions, and neonatal RDS. Similar to our study, Hickman et al conducted a randomized controlled trial of metformin versus insulin of women with both gestational diabetes (N ¼ 18) and type 2 diabetes (N ¼ 15).20 They reported a 43% failure rate of metformin alone resulting in the addition of insulin to achieve glycemic control. Women who received metformin experienced fewer episodes of hypoglycemia. An ongoing randomized controlled trial involving pregnant with T2DM metformin in addition to insulin versus insulin alone is currently being conducted in Canada (NCT 01353391). In summary, we found that in this small pilot, randomized controlled trial, metformin was able to achieve glycemic control in pregnant women with T2DM. There were no differences in maternal and neonatal outcomes compared with insulin. It is unclear whether the results of this study are due to its small sample size, enrollment of fairly controlled diabetic women or due to metformin’s relative ease of self-administration, thereby improving medication compliance and pregnancy outcomes.
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Acknowledgments This work was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Award UL1 000371 from the National Center for Advancing Translational Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Research or the National Institutes of Health. This work was also supported by the Larry C. Gilstrap, MD, Center for Perinatal and Women’s Health Research, University of Texas Health Science Center at Houston, Houston, TX.
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cemia is maintained in diabetic pregnant women with vascular compromise. Am J Obstet Gynecol 1984;149(6):617–623 Glueck CJ, Goldenberg N, Streicher P, Wang P. Metformin and gestational diabetes. Curr Diab Rep 2003;3(4):303–312 Glueck CJ, Goldenberg N, Streicher P, Wang P. The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. Expert Opin Pharmacother 2002;3(11):1557–1568 Simmons D, Walters BN, Rowan JA, McIntyre HD. Metformin therapy and diabetes in pregnancy. Med J Aust 2004;180(9): 462–464 Lawrence JM, Andrade SE, Avalos LA, et al; Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) Study Group. Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007. Obstet Gynecol 2013; 121(1):106–114 Coetzee EJ, Jackson WP. Pregnancy in established non-insulindependent diabetics. A five-and-a-half year study at Groote Schuur Hospital. S Afr Med J 1980;58(20):795–802 Ibrahim MI, Hamdy A, Shafik A, Taha S, Anwar M, Faris M. The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Arch Gynecol Obstet 2014; 289(5):959–965 Hickman MA, McBride R, Boggess KA, Strauss R. Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial. Am J Perinatol 2013;30(6):483–490 Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a conundrum. BMJ 1995;311(7020): 1621–1625 Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A. Bayesian statistical inference enhances the interpretation of contemporary randomized controlled trials. J Clin Epidemiol 2009; 62(1):13–21, e5 Goodman SN. Introduction to Bayesian methods I: measuring the strength of evidence. Clin Trials 2005;2(4):282–290, discussion 301–304, 364–378 Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343(16):1134–1138 Coetzee EJ, Jackson WP. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 1984;65(16):635–637 Coetzee EJ, Jackson WP. The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract19851986:1(5):281–287 Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358(19):2003–2015 Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod 2004;19(8): 1734–1740 Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17(11):2858–2864
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Because the pregnant women in this study had good glycemic control based on enrollment HgbA1c, this small subset of women may represent those who may benefit the most from continuing metformin rather than switching to insulin. Metformin is prescribed commonly before pregnancy, and over the last decade, more women are continuing its use during pregnancy. Thus, future studies are needed to determine whether metformin can continue to be used as an alternative to insulin in pregnant women with T2DM.
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A Pilot Randomized, Controlled Trial of Metformin versus Insulin in Women with Type 2 Diabetes Mellitus during Pregnancy Jerrie S. Refuerzo, MD1 Rose Gowen, MD2 Claudia Pedroza, PhD3 Sean C. Blackwell, MD1 Susan Ramin, MD4
Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas 2 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Brownsville, Brownsville, Texas 3 Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center at Houston, Houston, Texas 4 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
Address for correspondence Jerrie S. Refuerzo, MD, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, 6431 Fannin, Suite 3.270, Houston, TX 77030 (e-mail: [email protected]).
Am J Perinatol 2015;32:163–170.
Abstract
Keywords
► type 2 diabetes mellitus ► pregnancy ► metformin
Objective Few studies support oral diabetic treatment in pregnant women with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of metformin versus insulin on achieving glycemic control and improving maternal and neonatal outcomes in pregnant women with T2DM. Study Design A pilot randomized, controlled trial was conducted of metformin versus insulin for the treatment of T2DM during pregnancy. The primary outcome was glycemic control measured with hemoglobin A1c < 7% at delivery. Maternal and neonatal outcomes were compared between groups. Results In this study, 8 women received metformin and 11 received insulin. All women in both groups achieved glycemic control by delivery (HgbA1c: metformin 5.96 5.88 vs. insulin 6.34 0.92%). There were similar rates of cesarean delivery, birth weights, neonatal intensive care unit admissions, respiratory distress syndrome, and neonatal dextrose treatment between groups. There was one case of fetal macrosomia in the insulin group, one case of shoulder dystocia in the metformin group and no cases of failed metformin therapy. Conclusion In this pilot study, glycemic control was achieved in women who received metformin and insulin. Larger studies are needed to determine whether metformin can be considered a reasonable alternative to insulin in pregnant women with T2DM.
Obesity is a national health crisis.1 With this rise in obesity, the rate of type 2 diabetes mellitus (T2DM) has also increased. Metformin is an effective agent and first-line medication in nonpregnant obese adults with T2DM.2–5 Metformin im-
proves insulin sensitivity by reducing fasting plasma glucose and insulin concentrations. It functions by decreasing hepatic glucose output by inhibition of gluconeogenesis and enhanced peripheral glucose uptake.6 It has been shown to be
received January 11, 2014 accepted after revision April 16, 2014 published online June 4, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1378144. ISSN 0735-1631.
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1 Division of Maternal Fetal Medicine, Department of Obstetrics,
Maria Hutchinson, MS1
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beneficial in reducing weight, improving lipid profiles, decreasing cardiovascular risk, and reducing fibrinolytic activity.3,5,7 An important advantage is that it is not associated with hypoglycemia.3,4 The successful treatment of diabetes with metformin has led to improvements in the overall health status of women with diabetes. As a result, many of these women are actively choosing to become pregnant leading to the growing number of pregnant women with T2DM. Adverse pregnancy outcomes in diabetic pregnancies are related to fetal hyperinsulinemia which rises in response to increased levels of maternal glucose crossing the placenta.6 Fetal hyperinsulinemia is associated with increased fetal growth, fat deposition, and demand for oxygen. Pregnant women with T2DM are at significantly increased risk of spontaneous abortions, congenital birth defects, preeclampsia, and intrauterine fetal death.8,9 Poor pregnancy outcomes are also due to macrosomia increasing the rate of shoulder dystocia leading to neonatal birth injury and potential need for cesarean delivery. Offspring born to women with T2DM have a higher rate of developing obesity and insulin resistance later in life.10–12 These pregnancy complications and the process of fetal programming in utero are directly related to the level of glycemic control during pregnancy. Pregnancy management aims to reduce pregnancy complications by returning maternal glucose levels to normal.6,9,13 Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in pregnant women with T2DM. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight makes this therapeutic option cumbersome for the pregnant patient.6 Offering an insulin sensitizing agent, such as metformin, that can be administered orally and simply just a few times a day with very few adverse effects may be appealing to these women, thereby increasing compliance and overall perinatal outcome. Although there is some evidence to suggest that metformin is safe in pregnancy and that it potentially improves both maternal and neonatal outcomes, its efficacy in pregnant women with T2DM compared with insulin is largely unknown.8,14–18 Because pregnancy is a state of hyperinsulinemia and blood sugars tend to increase with gestation, clinical concerns remain regarding whether metformin will be able to control hyperglycemia related to pregnancy. In women with T2DM on hypoglycemic agents who become pregnant, there is limited data to support either the use or withdrawal of metformin.6 From a clinical perspective, practicing health care providers are challenged with the question of whether it is reasonable to resume metformin during pregnancy in those women receiving such treatment before pregnancy. Although many studies exist examining the effects of metformin versus insulin in women gestational diabetes, there are only a few studies published focusing on metformin in women with pregestational diabetes before the onset of pregnancy.19,20 On the basis that metformin is an effective insulin sensitizer in the treatment of T2DM, we hypothesized that metformin might be an alternative to insulin in women with T2DM during pregnancy. The objective of this study was to conduct
a pilot study to determine whether metformin could be continued to control hyperglycemia and improve maternal and neonatal outcomes in a focused, subgroup of pregnant women with T2DM that were either on oral hypoglycemic agents or diet controlled before pregnancy.
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Methods To answer the clinical question of whether metformin can be resumed in pregnancy complicated with T2DM, an openlabel, pilot, randomized, controlled trial was conducted investigating the use of metformin versus insulin in the treatment of T2DM in pregnancy at the University of Texas Health Science Center at Houston (UT Health) and at the University of Texas Health Science Center at Brownsville. The Institutional Review Board (IRB) at both institutions approved the pilot study. Strict inclusion criteria were set by the IRB at the UT Health thereby narrowing our enrollment population to a small, focused subgroup of pregnant women with pregnancies less than 20 weeks’ gestational age who had a selfreported history of T2DM with treatment of either diet control or oral hypoglycemic agents before pregnancy, and who had T2DM for less than 10 years. Women were excluded if they were on insulin before pregnancy, had multiple gestations, type 1 diabetes, known fetal chromosomal or structural defects, or contraindications to the use of metformin including renal disease, liver disease, recent myocardial infarction or sepsis, or had an HgbA1c > 9%. All participants received prenatal care through the high-risk diabetic clinic. At their initial prenatal visit, an ADA diet was recommended based on maternal weight, and instructions on self-blood glucose monitoring (SBGM) four times a day (fasting and 2 hours postprandial) were provided. Glucose levels greater than 95 mg/dL fasting and 120 mg/dL postprandial were considered abnormal. Instruction for exercise was also provided. Routine prenatal assessments were also provided as directed by the health care provider at the appropriate gestational ages including: 24 hours urine collection for total protein and creatinine clearance, ophthalmology exam to rule out diabetic retinopathy, maternal serum screening, first trimester ultrasound, anatomy ultrasound, fetal echocardiogram, growth ultrasounds every 4 weeks, and antenatal fetal surveillance beginning at 32 to 34 weeks. A maternal HgbA1c level was drawn every trimester and at the time of delivery to assess glycemic control. The HgbA1c at enrollment/randomization was considered the baseline HgbA1c. Women were randomly assigned to either metformin or insulin by the central investigational drug pharmacy at UT Health in Houston, TX. A permuted block randomization with a random fashion was used to prevent imbalances between groups. This randomization was conducted independent of the medication the participant was receiving before the onset of pregnancy. The randomization was stratified by site, Houston and Brownsville. For those gravida randomized to metformin, medication was initiated as in the nonpregnant population: Metformin 500 mg daily was initiated and women returned for routine clinical prenatal visits weekly. If greater than 50% of the
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glucose values were abnormal, metformin was increased to 500 mg twice a day. The metformin regimen was increased by 500 mg as needed for a maximum dose of 2,500 mg a day. Once glycemic control was achieved, the participant followed up every 2 weeks. If the participant required greater than 2,500 mg of metformin a day without achieving glycemic control, she was considered “failed metformin therapy” and was started on insulin, but still resumed and continued metformin. Women receiving metformin before pregnancy resumed the dose at which they were on at the start of pregnancy and increased according to the above protocol. For those women randomized to insulin, regimens were based on maternal weight and gestational age. Regimens were calculated as follows: first trimester—0.7 units/kg/day, second trimester—0.8 units/kg/day, and third trimester—0.9 to 1.0 units/kg/day. The total insulin dose was divided into: AM dose into two-thirds NPH and one-third regular insulin, PM dose into half NPH and half regular insulin. Insulin doses were increased or decreased 10 to 20% according to SBGM. Women receiving insulin before pregnancy resumed or switched to an equivalent insulin regimen as above. The primary outcome was the rate of women with an HgbA1c < 7% at the time of delivery. This primary outcome was chosen as surrogate to assess overall glycemic control due to limitation of a pilot study and logistical errors in reporting SBGM with glucose logs. Secondary outcomes included change in HgbA1c, maternal, and neonatal complications including preeclampsia, failed metformin therapy, cesarean delivery rate, macrosomia with a birth weight greater than 4,000 g, shoulder dystocia, respiratory distress syndrome (RDS) as reported by the caring neonatologist, or need for neonatal dextrose therapy. Maternal demographics and pregnancy characteristics were also collected. Because this was a pilot study, we initially anticipated enrolling 50 women in each group, for a total of 100 women.
Enrollment
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To determine a power calculation, we had reviewed recent deliveries at our institutions of women with T2DM and noted a 60% rate of women achieving an HgbA1c less than 7% at the time of delivery. If there were 50 women in each group with an effect size of 50%, a p-value < 0.05, the power would be 0.87. Statistical analysis including both traditional frequentist comparisons and Bayesian analysis was conducted. The primary outcome (rate of women with an HgbA1c < 7%) was compared between groups with chi-square test. The differences in HgbA1c levels were compared with Student t-test. Differences in gestational age at each HgbA1c laboratory draw were compared with Mann–Whitney U test. Other continuous variables were compared using Student t-test and categorical variables were compared using chi-square test. Statistical analysis was conducted using STATA 21st Edition. A p-values < 0.05 was considered significant and relative risk and 95% confidence interval (CI) were reported. Due to strict inclusion and exclusion criteria, we had limitations in our enrollment, and we were unable to achieve our sample size. Thus we decided to conduct a Bayesian analysis. Bayesian analyses are typically used to determine the effects of treatment in comparison studies with small sample sizes.21–23 After completing the study, we performed a Bayesian analysis to assess the treatment effect of metformin to insulin on the HgbA1c at delivery or in the third trimester between groups and to calculate the probability of a difference in values. A neutral prior probability was used in estimating the posterior probability that the metformin had similar effects as insulin.23
Results Due to the strict inclusion criteria, a total of 38 pregnant women were approached to participate in this study from September 2009 to August 2011, as illustrated in ►Fig. 1. Thirteen pregnant women either declined (5) or were
Assessed for Eligibility N = 38
Excluded (N = 13) -Not meeng study criteria (n = 8) -Declined (N = 5)
Randomized N = 25
Allocated to Meormin (N = 11) -Received allocated meormin (N = 11)
Allocaon
Allocated to Insulin (N = 14) -Received allocated insulin (N = 13) -Did not receive allocated insulin (N = 1)
Disconnued, Physician chose to start insulin (N = 2) Lost to follow-up (N = 1)
Follow -up
Disconnued, chose to stop study (N = 1) Lost to follow-up (N = 0)
Analyzed (N = 8) -Excluded (N = 0)
Analysis
Analyzed (N = 13) -Excluded (N = 0)
Fig. 1 Enrollment of 38 pregnant women.
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Table 1 Maternal demographics
ineligible (8). A total of 25 pregnant women with T2DM were enrolled, 11 to the metformin group and 14 to the insulin group. Three women in the metformin group and one in the insulin group were withdrawn due to the subject changing her mind after enrollment and chose not to take any insulin. Thus, 8 women in the metformin group and 13 in the insulin group completed the study and were included in the study analysis. The groups were similar in maternal age, gravidity, parity, race, and gestational age at enrollment as described in ►Table 1. There were similar rates of maternal hypertension, obesity, and morbid obesity between groups. More than 80% of these women were obese with a mean body mass index (BMI) 35.9 5.2 kg/m2 in the metformin group and a mean BMI of 40.1 8.4 kg/m2 in the insulin group. The primary outcome of an HgbA1c < 7% at delivery was achieved in 100% of women in the metformin group and 87.5% in the insulin group (relative risk 0.79 [95% CI, 0.64–1.10]). All women randomized to metformin achieved an HgbA1c < 7% by the mid-trimester. The women randomized to the insulin group had an HgbA1c drawn at an earlier gestational age compared with metformin group (insulin 6 weeks [4–10 weeks] vs. metformin 9 weeks [8–13 weeks]). There was no statistical difference between the HgbA1c at delivery between groups (metformin 5.96 5.88% vs. insulin 6.34 0.92%). There was also no statistical difference between the two groups at the time of enrollment/first
Metformin N¼8
Insulin N ¼ 13
Maternal age (y)
30.9 5.5
32.3 4.3
Gravidity
4 (1–3)
4 (1–6)
Parity
1 (0–3)
1 (0–4)
3 (37.5%)
4 (30.8%)
Race African American Caucasian
4 (50%)
6 (46.2%)
Hispanic
0 (0%)
1 (7.7%)
Other
1 (12.5%)
2 (15.4%)
Maternal hypertension
4 (50%)
4 (30.8%)
Gestational age enrollment (wk)
16 (8–19)
16 (6–18)
BMI (kg/m2)
35.9 5.2
40.1 8.4
Obese (BMI > 30 kg/m2)
7 (87.5%)
11 (84.6%)
Morbidly obese (BMI > 40 kg/m2)
1 (12.5%)
5 (38.5%)
Abbreviation: BMI, body mass index. Note: N (%), mean standard deviation, median (range).
Table 2 Hemoglobin A1C (HgbA1c) levels throughout pregnancy Metformin Total N ¼ 8
Insulin Total N ¼ 13
p-Value
Enrollment/first trimester
9 (8–13) N¼5
6 (4–10) N¼7
0.015
Mid-trimester
16.5 (11–23) N¼8
15 (10–18) N ¼ 112
0.370
Third trimester
26 (17–29) N¼5
29 (25–35) N ¼ 12
0.123
Delivery
37 (35–40) N¼5
37 (35–41) N¼8
0.565
Enrollment/first trimester
6.22 0.66
6.84 1.23
0.285
Gestational age at HgbA1c laboratory draw (wk)
Hemoglobin A1c (%) Mid-trimester
5.79 0.50
6.13 0.89
0.307
Third trimester
5.70 0.12
5.72 0.48
0.912
Delivery
5.96 5.88
6.34 0.92
0.400
Third trimester/delivery
5.88 0.59
6.01 0.89
0.729
Change in HgbA1c from enrollment to third trimester/delivery
0.13 0.50
0.61 0.83
0.223
Enrollment/first trimester
4(80.0%)
5 (71.4%)
0.285
Mid-trimester
8 (100%)
11(81.8%)
0.505
Third trimester
5 (100%)
12 (100%)
1.00
Delivery
5 (100%)
7 (87.5%)
0.411
Third trimester/delivery
5 (100%)
12 (92.3%)
0.523
Women with HgbA1c < 7% (%)
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Metformin N¼8
Insulin N ¼ 13
p-Value
Gestational age delivery (wk)
37 (35–40)
37 (35–41)
0.977
Rate of preterm birth < 37 wk
1 (12.5%)
3 (23.1%)
0.549
Induction of labor
5 (62.5%)
5 (38.5%)
0.387
Preeclampsia
0 (0%)
4 (30.8%)
0.131
Cesarean delivery rate
4 (50%)
6 (46.2%)
0.864
Prior cesarean delivery
1 (25%)
3 (23.1%)
Fetal indications
0 (0%)
1 (7.7%)
Other
3 (75%)
2 (15.4%)
Shoulder dystocia
1 (12.5%)
0 (0%)
0.381
Male gender
6 (75%)
7 (53%)
0.537
Birth weight (g)
2,930.5 483.6
3,111.5 743.1
0.972
Macrosomia (> 4,000 g)
0 (0%)
1 (7.7%)
0.422
NICU admission
1 (12.5%)
3 (23.1%)
0.149
RDS
1 (12.5%)
3 (23.1%)
0.570
Need for neonatal dextrose
0 (0%)
1 (7.7%)
0.507
Neonatal length of hospital stay (d)
3 (1–8)
2 (1–12)
0.697
Abbreviations: NICU, neonatal intensive care unit; RDS, respiratory distress syndrome. Note: N (%), mean standard deviation, median (range).
trimester, mid-trimester, and third trimester. A delivery HgbA1c was obtained in only 13 women (5 in the metformin group and 8 in the insulin group). However, either a third trimester and/or a delivery HgbA1c were obtained on all women. Thus, we determined the change in HgbA1c from enrollment to delivery or third trimester was similar between groups (metformin 0.13 0.50 vs. insulin 0.61 0.83, p ¼ 0.223) as described in ►Table 2. There were no women randomized to metformin who “failed metformin therapy” and needed insulin to treat hyperglycemia. There was no statistical difference between gestational age at delivery, or rates of preterm birth less than 37 weeks of gestation, induction of labor, preeclampsia, or cesarean delivery between groups as described in ►Table 3. In addition, there were similar birth weights and rates of male gender, neonatal intensive care unit (NICU) admissions, RDS, and the need for neonatal dextrose treatment. There was only one case of fetal macrosomia in the insulin group and one case of shoulder dystocia in the metformin group. For the Bayesian analysis, the prior distributions on values of HgbA1c were previously reported for women with gestational diabetes who were randomized to either insulin or metformin.23 There was limited data on randomized controlled trials of insulin versus metformin in pregnant women with T2DM. For the metformin group, we assumed a normal prior distribution centered at 5.6% with standard deviation (SD) of 0.5, and for the insulin group, the prior normal distribution was centered at 5.7% with SD of 0.6. For the SD parameter, we assumed a uniform prior distribution from 0 to 100.23 These prior distributions assume a prior probability of
55% of metformin group having lower values of HgbA1c compared with the insulin group (about a 50–50 chance of one treatment having lower values than the other). The posterior distribution for the insulin group had a posterior mean of 5.97% (SD ¼ 0.22) and 95% posterior interval of 5.52 to 6.4%. For the metformin group, the posterior mean was 5.88% (SD ¼ 0.33) with 95% posterior interval of 5.23 to 6.53%. The posterior probability of the metformin having lower values of HgbA1c is 60% which indicates almost no difference between the two groups.
Conclusion In this pilot study, all pregnant women in both groups achieved euglycemia by the third trimester and delivery. Women who received metformin achieved an HgbA1c < 7% by the second trimester compared with the third trimester in those women who received insulin. Metformin treatment resulted in similar maternal and fetal outcomes compared with insulin. Although insulin has traditionally been the treatment of choice for hyperglycemia in pregnant women with T2DM, this small trial supports continuing metformin as the primary treatment option in pregnant women with T2DM who were treated with an oral diabetic agent before pregnancy. The greatest limitation of this study was the inability to achieve our targeted sample size. This study was conducted over 2 years and only enrolled a total of 38 women primarily due to poor recruitments of participants. A significant factor that impacted recruitment was the strict exclusion criterion, American Journal of Perinatology
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Table 3 Pregnancy and neonatal outcomes
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in particular, the exclusion of women with T2DM who were on insulin before pregnancy. Prior studies have reported that 83.5% of women with T2DM and Type 1 DM have used insulin alone before pregnancy.17 Thus, this single exclusion criterion reduced the number of women who were eligible for this study. Another exclusion criteria was the HgbA1c > 9%. This criterion influenced the enrollment of fairly controlled diabetic women, and thus could represent the underlying cause for the lack of difference in change in HgbA1c seen between groups. It could also be the reason why none of the pregnant women in the metformin group failed metformin therapy. Another factor affecting recruitment was the reluctance of managing physicians to allow their patients to participate in the study due to their own personal clinical practice patterns and beliefs on how pregnant women with T2DM should be managed. Despite this much needed randomized controlled trial to answer the questions regarding important clinical management of a high-risk obstetrical population, a small sample size (N ¼ 38) was attained with a 23.7% attrition rate. Recent trends demonstrate that the use of oral diabetic medications preconception has increased from 0.7% in 2001 to 1.7% in 2007, primarily due to the use of metformin.17 During this time period, the use of metformin during pregnancy rose from 0.01 to 0.19% overall. The majority of women (79%) used metformin for the diagnosis of infertility related to polycystic ovarian syndrome (PCOS). Only 13.6% used metformin for T2DM. Of the women on metformin before pregnancy, 8.8% of women continued metformin during pregnancy, whereas 16.8% switched to insulin, 3% switched to a different oral diabetic agent, and 68.0% did not use any treatment at all. Of the women who continued metformin during pregnancy, approximately two-thirds switched to insulin or other oral agents by the second trimester. We chose to use metformin instead of glyburide (sulfonylurea) due to its high efficacy in obese women, beneficial effects on the cardiovascular status, and limited adverse effects. Although glyburide is widely used for the treatment of gestational diabetes, it carries the maternal risk of hypoglycemia, hyperinsulinemia, and weight gain.4,5,16,24 In addition, metformin is a pregnancy category B drug, whereas glyburide is a category C drug.4,14 Metformin has been used by women throughout pregnancy. The first studies were performed by Coetzee and Jackson during the 1970s.18 Women with insulin independent diabetes were prospectively followed throughout gestation, 22 women received metformin compared with 42 women who received insulin. The perinatal mortality rate was 50/1,000 for those on metformin versus 51/1,000 on insulin. Neonatal birth weight greater than 4,000 g occurred in only 10% of women on metformin. There were no cases of maternal hypoglycemia or lactic acidosis. In addition, metformin use in the first trimester was not associated with congenital anomalies.25 In a follow-up study, Coetzee and Jackson were able to achieve glycemic control in women on metformin within 24 hours compared with 2 to 3 weeks for insulin.26 The most recent randomized controlled trial of metformin versus insulin during pregnancy was in 751 women with gestational diabetes conducted in Australia.27 There was no
difference in maternal or neonatal outcomes and fasting glucose levels and HgbA1c results were similar between both groups. Side effects in 7.4% of women led to cessation of metformin treatment and 46.3% required insulin due to failed metformin therapy. Women in the metformin group gained less weight and had more weight loss compared with insulin. Importantly, women who received metformin reported that they were more likely to choose metformin even after delivery and that the ease of medication administration improved their treatment plan. This suggests that mode of medication administration could impact compliance with treatment and improve overall pregnancy outcomes. Others metformin studies have been conducted primarily in women with PCOS treated for infertility. A randomized, double-blinded controlled pilot study was performed on 18 women with PCOS who conceived on metformin compared with 22 women with PCOS who received a placebo.28 Women who received the metformin had a lower rate of pregnancy complications (0% metformin vs. 32% placebo) including preterm birth, sepsis, deep venous thrombosis, or adult RDS. There were no differences in neonatal outcomes such as birth weight. Another study involving women with PCOS who conceived on metformin showed a lower rate of developing gestational diabetes later in pregnancy (3% metformin vs. 31% no metformin).29 Despite the numerous studies examining the effects of metformin versus insulin in women gestational diabetes and PCOS, there is only two studies published focusing on metformin in women with pregestational diabetes before the onset of pregnancy. Ibrahim et al conducted a randomized controlled trial of 90 women with either gestational diabetes or insulin resistant pregestational diabetes. Although we initiated enrollment and randomization before 20 weeks, their subjects began treatment after 20 weeks.19 One group received metformin with a fixed dose of insulin, and the other group received metformin and increasing doses of insulin. They concluded that adding metformin to insulin therapy in insulin-resistant diabetes was effective in proper glycemic control and resulted in reduced hospital stay, maternal and neonatal hypoglycemia, NICU admissions, and neonatal RDS. Similar to our study, Hickman et al conducted a randomized controlled trial of metformin versus insulin of women with both gestational diabetes (N ¼ 18) and type 2 diabetes (N ¼ 15).20 They reported a 43% failure rate of metformin alone resulting in the addition of insulin to achieve glycemic control. Women who received metformin experienced fewer episodes of hypoglycemia. An ongoing randomized controlled trial involving pregnant with T2DM metformin in addition to insulin versus insulin alone is currently being conducted in Canada (NCT 01353391). In summary, we found that in this small pilot, randomized controlled trial, metformin was able to achieve glycemic control in pregnant women with T2DM. There were no differences in maternal and neonatal outcomes compared with insulin. It is unclear whether the results of this study are due to its small sample size, enrollment of fairly controlled diabetic women or due to metformin’s relative ease of self-administration, thereby improving medication compliance and pregnancy outcomes.
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Acknowledgments This work was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Award UL1 000371 from the National Center for Advancing Translational Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Research or the National Institutes of Health. This work was also supported by the Larry C. Gilstrap, MD, Center for Perinatal and Women’s Health Research, University of Texas Health Science Center at Houston, Houston, TX.
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Because the pregnant women in this study had good glycemic control based on enrollment HgbA1c, this small subset of women may represent those who may benefit the most from continuing metformin rather than switching to insulin. Metformin is prescribed commonly before pregnancy, and over the last decade, more women are continuing its use during pregnancy. Thus, future studies are needed to determine whether metformin can continue to be used as an alternative to insulin in pregnant women with T2DM.
Refuerzo et al.
