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Metformin vs insulin in the management of gestational diabetes: A systematic review and meta-analysis
Accepted Manuscript Title: Metformin vs insulin in the management of gestational diabetes: A systematic review and meta-analysis Author: D.F. Su X.Y. Wang PII: DOI: Reference:
S0168-8227(14)00017-5 http://dx.doi.org/doi:10.1016/j.diabres.2013.12.056 DIAB 5975
To appear in:
Diabetes Research and Clinical Practice
Received date: Revised date: Accepted date:
28-3-2013 24-7-2013 28-12-2013
Please cite this article as: D.F. Su, X.Y. Wang, Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis, Diabetes Research and Clinical Practice (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.056 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis
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Abstract Objective:To evaluate the effectiveness of metformin compared with insulin in achieving glycemic control and investigate the maternal and neonatal outcomes in gestational diabetes mellitus. Methods: We searched four electronic databases from inception through December 2012.Terms for Gestational diabetes /gestational diabetes mellitus / diabetes pregnancyAND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/ Antidiabetic Medications were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality. Meanwhile, manual search of other resources and the search on Google Scholar were also carried out to identify more related articles .Rev Man 5.0 was used to analyze the data . Results: Six randomized clinical trials involving 1420 subjects were included. The current limited data suggested that using metformin in gestational diabetes subjects did not significantly increase adverse maternal outcomes and neonatal outcomes, also with less weight gain and neonatal hypoglycemia, but a higher incidence of premature birth. Conclusions: Metformin will not increase the incidence of adverse maternal outcomes and neonatal outcomes.
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1. Introduction GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1].GDM is associated with an increased risk of complications for both the mother and the baby during pregnancy and birth. The prevalence of GDM varies widely depending on the population studied, but the overall estimated prevalence in the United States is 2% to 10% [2]. Treatment for GDM could reduce adverse pregnancy outcomes [3]. Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in women with GDM who could not be controlled by medical nutrition therapy and physical activity. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight make this therapeutic option difficult for many pregnant women [4].
an
Using oral diabetes medication in women with GDM has accumulated more clinical evidence even though they have not been formally approved by the U.S. Food and Drug Administration for this indication [5].
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Metformin is one such medication and studies have shown different outcomes with metformin in women with GDM. One study evaluating the efficacy and safety of metformin treatment in women with pregestational and gestational diabetes raised concerns about a higher perinatal mortality and a higher rate of preeclampsia [6]. However, a recent large randomized controlled trial which compared metformin with insulin in the treatment of gestational diabetes (MiG trial) suggested that metformin, alone or with supplemental insulin, was an effective and safe treatment option for women with gestational diabetes [7]. A recent systematic review concluded that oral agents are suitable for managing gestational diabetes because they achieved good glycemic control and maternal and perinatal outcomes comparable with insulin, but the meta-analysis included only two trials of metformin, and did not separate metformin and glyburide [8]. Since the use of metformin in pregnant women remains controversial, we conducted a systematic review and meta-analysis of randomized controlled trials of metformin with the aim of comparing the effects and safety of metformin in gestational diabetes mellitus with insulin. 2. Methods 2.1. Eligibility criteria and Exclusion criteria A study was included in the meta-analysis if it fulfilled the following inclusion criteria: 1. Population was patients with gestational diabetes. 2. Study design was a Rnadomised Controlled Trial (RCT). 3. Intervention compared metformin vs insulin Exclusion criteria: 1) did not include human data; 2) did not separate preexisting type 2 diabetes and those diagnosed with gestational diabetes.
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3) was a case report or case series. Outcomes of interest: Maternal outcomes were glycemic control, weight gain, cesarean delivery, hypertensive disorders. Neonatal outcomes were hypoglycemia, birth weight, macrosomia / large-for-gestational-age (LGA), small-for-gestational-age (SGA), premature birth, birth trauma, birth defect, admission to neonatal intensive care unit (NICU), respiratory distress syndrome, phototherapy. 2.2. Literature search and study selection We use the search string“Gestational diabetes /gestational diabetes mellitus / diabetes pregnancyAND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/ Antidiabetic Medications” and searched four electronic databases, MEDLINE （pubmed）, EMBASE, the Cochrane library and web of science from inception through to December 2012.In addition，manual searches of other resources (including references from selected studies) and the search on Google Scholar were also carried out to identify more related articles. The two investigators independently determined every eligible article for inclusion in the meta-analysis，and disagreements were discussed until consensus was reached. If the same result was published in multiple reports, only the latest study was included in the meta-analysis. 2.3. Data management： The two investigators independently extracted data from each included article using a data extraction form prepared for the review. The following information was extracted: first author’s name, publication year, country，patient on metformin，patient on insulin，diagnostic method for T2DM， gestational age at initiation of treatment, dosage of metformin. When quantitative data were not reported, approximate values were obtained from the figures or calculated from proportions. 2.4. Assessment of methodological quality: risk of bias Two investigators independently applied the Jadad criteria to assess the quality of each randomized trial which included the appropriateness of the randomization scheme and blinding, description of withdrawals, and a report of participants lost to follow-up [9]. 2.5. Data analysis We used ReviewManager (version 5.1.40, The Nordic Cochrane Centre, Copenhagen, Denmark) to assess treatment efficacy and publication bias. We checked the existence of publication bias or systematic heterogeneity using funnel plots as visual aids. A symmetric inverted funnel indicates that publication bias is unlikely, while an asymmetric funnel indicates the possibility of either publication bias or a systematic difference between smaller and larger study effects. Heterogeneity was
quantified by the I2 statistic. When I2 statistic was ＞ 50% it was considered that there was substantial heterogeneity [10]. In this case data
Page 3 of 8
were further explored, including subgroup analyses, in an attempt to explain the heterogeneity.
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3. Results Six RCTs [7] [11-15] fulfilled the inclusion criteria and included a total of 1420 patients. The characteristics of the trials included in the analysis are shown in Table 1. Six of the RCTs described the randomisation scheme. None of the trials were blinded. Five of the trials reported and described participant withdrawals or the reasons for loss to follow-up. None of the studies reported an intention-to-treat analysis. 3.1 Maternal outcomes: 3.1.1 Glycemic control: we choose HbA1c at 36~37weeks gestation as the indicator of glycemic control as it reflects blood glucose control over the past three months. HbA1c data were reported in four studies. There was no statistically significant difference between the metformin and insulin treated groups (WMD, 0.05%; 95% CI, –0.11 to 0.21; P=0.57). Fasting Blood Glucose: Fasting blood glucose was reported in the other three studies and there was no statistically significant difference between the two groups (WMD, 0.68 mmol/l; 95% CI, –0.62 to1.98; P=0.30). 3.1.2Weight gain: Total weight gain during pregnancy was reported in four studies and was slightly lower in the metformin group compared with the insulin group with the difference being statistically significant (WMD, -1.49 kg; 95% CI, –2.66 to -0.31; P=0.01). The other three studies reported weight gain from the start of the study until delivery with women in the metformin group experiencing statistically less weight gain (WMD, -1.13 kg; 95% CI, –1.73 to -0.52; P=0.0003). 3.1.3 Cesarean delivery：Cesarean delivery was reported in six studies with no significant difference between the two groups (RR=0.98; 95% CI, 0.74–1.29). 3.1.4 Hypertensive disorders: Four studies reported preeclampsia (RR=0.73; 95% CI, 0.48–1.12), two studies reported gestational hypertension (RR=0.60; 95% CI, 0.33–1.10) and two studies reported the pregnancy induced hypertension (RR=0.40; 95% CI, 0.16–0.99). None of these differences was significantly different between the metformin group and insulin group. 3.2 Neonatal outcomes: 3.2.1Hypoglycemia：Neonatal hypoglycemia was reported in six studies with the prevalence of neonatal hypoglycemia in metformin group being statistically lower than in the insulin group (RR=0.77; 95% CI, 0.60–0.99). 3.2.2 Birth weight：Six studies reported birth weight and there was no statistically significant difference between the two treatment groups (WMD, –52.19 ;95% CI, –104.87 to 0.49; P=0.05). Studies similarly defined macrosomia as birth weight above 4000g. Prevalence of macrosomia was reported in five studies and there was no difference between the two groups (RR, 0.83; 95% CI, 0.58–1.20).
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3.2.3 Prevalence of large-for-gestational-age (LGA) babies was reported in four studies and small-for-gestational-age (SGA) babies was reported in three studies. There was no statistically significant difference between the two treatment groups in LGA (RR=0.87; 95% CI, 0.69–1.11) and in SGA (RR=0.92; 95% CI, 0.61–1.39). 3.2.4 Premature birth (<37 weeks gestation): Premature birth (<37 weeks gestation) was reported in four studies with the prevalence of premature birth being slightly but significantly higher in the metformin group (10%) than in the insulin group (6.4%） (RR=1.56; 95% CI, 1.06–2.30). 3.2.5 Birth trauma：Birth trauma was reported in three studies and there was no statistically significant difference between the two groups (RR=0.79; 95% CI, 0.42–1.46). 3.2.6 Birth defect：Birth defect was reported in three studies and there was no statistically significant difference between the two groups (RR=0.84; 95% CI, 0.47–1.51). 3.2.7 Other neonatal outcomes：There was no statistically significant difference between the two treatment groups in admission to NICU (RR=0.86; 95% CI, 0.70–1.05); respiratory distress syndrome (RR=1.09; 95% CI, 0.63–1.89); phototherapy (RR=0.88; 95% CI, 0.64–1.21). 4. Discussion The lack of a significant difference in maternal glycemic control assessed by HbA1c and fasting blood glucose, suggests that metformin is equally effective as insulin in the management of gestational diabetes. In addition there were no differences in other indicators of maternal outcomes such as Cesarean delivery and hypertensive disorders between two treatment groups. However, weight gain of the pregnant women was significantly less with metformin [7]. Maternal gestational weight gain above recommended levels is associated with cesarean delivery and postpartum weight retention. Also observational evidence links gestational weight gain with fetal growth and predicts LGA which itself is a marker of neonatal morbidity[16]. However we found no evidence of this in our study, perhaps related to the relatively small difference in weigh between the two groups. Neonatal hypoglycemia occurs frequently in babies in women with GDM. In our study，the incidence of neonatal hypoglycemia in the insulin group was higher than in the metformin group. Reducing neonatal hypoglycemia with metformin treatment could avoid potentially harmful central nervous system effects [17]. Other neonatal outcomes such as birth weight，macrosomia, birth trauma, birth defect, NICU, respiratory distress syndrome, phototherapy, were not significantly different between two groups. However, we found that premature birth was slightly but significantly less in the insulin group than the metformin group, consistent with the MiG trial [7], which could be due to chance or an unrecognized effect of metformin on the labor process. In summary, using metformin in pregnancy for women with GDM [A1]appears to be safe and efficacious. Limitations in current evidence
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There are some limitations in our study that deserve comment. Firstly, our eligibility criteria resulted in only six RCTs being included resulting in a small sample size which limited our ability to draw substantial conclusions. Secondly, some outcomes were included in only two studies which limited the meta-analysis which may have lacked power to detect important differences in some of the outcomes of interest. Thirdly, the methodological quality of included trials, assessed by the Jadad scale, was variable with four articles scoring 3 to 4 points and the others 1–2 points, indicating that not all of studies were of high quality. Furthermore, the definitions of outcomes varied across studies. For example, the diagnosis of neonatal hypoglycemia among the six studies was based on different measures (less than 40 mg/dL[A2]; less than 46.8 mg/dL; no reported definition; and need for intravenous glucose).
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Implications for clinical practice and research This review has several implications for clinical practice. Firstly there is some evidence to support the benefits of metformin in the management of gestational diabetes based on level of good glycemic control and maternal and perinatal outcomes compared with insulin. Secondly, there is increasing evidence for drug administration regulators to consider the approval of metformin for use in pregnancy. However larger-scale RCTs are needed to detect clinically meaningful differences in maternal and neonatal outcomes and extend the evidence of the effectiveness and potential harms of these treatments.
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Conflict of interest: No potential conflicts of interest relevant to this article were reported.
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References: [1] American Diabetes Association. Gestational Diabetes Mellitus. Diabetes Care. 2013;36 (Suppl 1):S11–66 [2] National Diabetes Information Clearinghouse [Internet]. Maryland: National Institutes of Health 2011. Available at: http://diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational. Accessed November 3, 2011 [3] Falavigna M, Schmidt MI, Trujillo J, Alves LF, Wendland ER, Torloni MR, Colagiuri S, Duncan BB. Effectiveness of gestational diabetes treatment: a systematic review with quality of evidence assessment. Diabetes Res Clin Pract. 2012;98:396-405. [4] Norman RJ, Wang JX, Hague W. Should we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol. 2004 16:245-50. [5] Nicholson W, Baptiste-Roberts K. Oral hypoglycaemic agents during pregnancy: The evidence for effectiveness and safety. Best Pract Res Clin Obstet Gynaecol 2011 ;25:51-63 [6] Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med.2000;17:507–11 [7] Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–15 [8] Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis.Am J Obstet Gynecol 2010;203:457 [9] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ,Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12 [10] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 510. Oxford, UK, Cochrane Collaboration, 2011. [11] Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract 2012 ; 98:422-9. [12] Tertti K, Ekblad U, Koskinen P, Vahlberg T, Rönnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab.2013 ; 15:246-51. [13] Ijäs H, Vääräsmäki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T, Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011 ; 118:880-5. [14] Moore LE, Briery CM, Clokey D, Martin RW, Williford NJ, Bofill JA, Morrison JC. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med. 2007 ; 52: 1011-5. [15] Hassan, JA ; Karim N ; Sheikh Z . Metformin prevents macrosomia and neonatal
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morbidity in gestational diabetes. PAKISTAN JOURNAL OF MEDICAL SCIENCES 2012;28 : 384-389. [16] Rasmussen KM, Yaktine AL, Eds. Weight gain during pregnancy: reexamining the recommendations. Washington, DC, The National Academies Press, 2009 [17] Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes 2010;17:20-4
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Author : D.F. Su; X.Y. Wang 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, the Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University，300070 Tianjin, China
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S0168-8227(14)00017-5 http://dx.doi.org/doi:10.1016/j.diabres.2013.12.056 DIAB 5975
To appear in:
Diabetes Research and Clinical Practice
Received date: Revised date: Accepted date:
28-3-2013 24-7-2013 28-12-2013
Please cite this article as: D.F. Su, X.Y. Wang, Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis, Diabetes Research and Clinical Practice (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.056 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis
Ac ce p
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an
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Abstract Objective:To evaluate the effectiveness of metformin compared with insulin in achieving glycemic control and investigate the maternal and neonatal outcomes in gestational diabetes mellitus. Methods: We searched four electronic databases from inception through December 2012.Terms for Gestational diabetes /gestational diabetes mellitus / diabetes pregnancyAND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/ Antidiabetic Medications were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality. Meanwhile, manual search of other resources and the search on Google Scholar were also carried out to identify more related articles .Rev Man 5.0 was used to analyze the data . Results: Six randomized clinical trials involving 1420 subjects were included. The current limited data suggested that using metformin in gestational diabetes subjects did not significantly increase adverse maternal outcomes and neonatal outcomes, also with less weight gain and neonatal hypoglycemia, but a higher incidence of premature birth. Conclusions: Metformin will not increase the incidence of adverse maternal outcomes and neonatal outcomes.
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1. Introduction GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1].GDM is associated with an increased risk of complications for both the mother and the baby during pregnancy and birth. The prevalence of GDM varies widely depending on the population studied, but the overall estimated prevalence in the United States is 2% to 10% [2]. Treatment for GDM could reduce adverse pregnancy outcomes [3]. Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in women with GDM who could not be controlled by medical nutrition therapy and physical activity. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight make this therapeutic option difficult for many pregnant women [4].
an
Using oral diabetes medication in women with GDM has accumulated more clinical evidence even though they have not been formally approved by the U.S. Food and Drug Administration for this indication [5].
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Metformin is one such medication and studies have shown different outcomes with metformin in women with GDM. One study evaluating the efficacy and safety of metformin treatment in women with pregestational and gestational diabetes raised concerns about a higher perinatal mortality and a higher rate of preeclampsia [6]. However, a recent large randomized controlled trial which compared metformin with insulin in the treatment of gestational diabetes (MiG trial) suggested that metformin, alone or with supplemental insulin, was an effective and safe treatment option for women with gestational diabetes [7]. A recent systematic review concluded that oral agents are suitable for managing gestational diabetes because they achieved good glycemic control and maternal and perinatal outcomes comparable with insulin, but the meta-analysis included only two trials of metformin, and did not separate metformin and glyburide [8]. Since the use of metformin in pregnant women remains controversial, we conducted a systematic review and meta-analysis of randomized controlled trials of metformin with the aim of comparing the effects and safety of metformin in gestational diabetes mellitus with insulin. 2. Methods 2.1. Eligibility criteria and Exclusion criteria A study was included in the meta-analysis if it fulfilled the following inclusion criteria: 1. Population was patients with gestational diabetes. 2. Study design was a Rnadomised Controlled Trial (RCT). 3. Intervention compared metformin vs insulin Exclusion criteria: 1) did not include human data; 2) did not separate preexisting type 2 diabetes and those diagnosed with gestational diabetes.
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3) was a case report or case series. Outcomes of interest: Maternal outcomes were glycemic control, weight gain, cesarean delivery, hypertensive disorders. Neonatal outcomes were hypoglycemia, birth weight, macrosomia / large-for-gestational-age (LGA), small-for-gestational-age (SGA), premature birth, birth trauma, birth defect, admission to neonatal intensive care unit (NICU), respiratory distress syndrome, phototherapy. 2.2. Literature search and study selection We use the search string“Gestational diabetes /gestational diabetes mellitus / diabetes pregnancyAND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/ Antidiabetic Medications” and searched four electronic databases, MEDLINE （pubmed）, EMBASE, the Cochrane library and web of science from inception through to December 2012.In addition，manual searches of other resources (including references from selected studies) and the search on Google Scholar were also carried out to identify more related articles. The two investigators independently determined every eligible article for inclusion in the meta-analysis，and disagreements were discussed until consensus was reached. If the same result was published in multiple reports, only the latest study was included in the meta-analysis. 2.3. Data management： The two investigators independently extracted data from each included article using a data extraction form prepared for the review. The following information was extracted: first author’s name, publication year, country，patient on metformin，patient on insulin，diagnostic method for T2DM， gestational age at initiation of treatment, dosage of metformin. When quantitative data were not reported, approximate values were obtained from the figures or calculated from proportions. 2.4. Assessment of methodological quality: risk of bias Two investigators independently applied the Jadad criteria to assess the quality of each randomized trial which included the appropriateness of the randomization scheme and blinding, description of withdrawals, and a report of participants lost to follow-up [9]. 2.5. Data analysis We used ReviewManager (version 5.1.40, The Nordic Cochrane Centre, Copenhagen, Denmark) to assess treatment efficacy and publication bias. We checked the existence of publication bias or systematic heterogeneity using funnel plots as visual aids. A symmetric inverted funnel indicates that publication bias is unlikely, while an asymmetric funnel indicates the possibility of either publication bias or a systematic difference between smaller and larger study effects. Heterogeneity was
quantified by the I2 statistic. When I2 statistic was ＞ 50% it was considered that there was substantial heterogeneity [10]. In this case data
Page 3 of 8
were further explored, including subgroup analyses, in an attempt to explain the heterogeneity.
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3. Results Six RCTs [7] [11-15] fulfilled the inclusion criteria and included a total of 1420 patients. The characteristics of the trials included in the analysis are shown in Table 1. Six of the RCTs described the randomisation scheme. None of the trials were blinded. Five of the trials reported and described participant withdrawals or the reasons for loss to follow-up. None of the studies reported an intention-to-treat analysis. 3.1 Maternal outcomes: 3.1.1 Glycemic control: we choose HbA1c at 36~37weeks gestation as the indicator of glycemic control as it reflects blood glucose control over the past three months. HbA1c data were reported in four studies. There was no statistically significant difference between the metformin and insulin treated groups (WMD, 0.05%; 95% CI, –0.11 to 0.21; P=0.57). Fasting Blood Glucose: Fasting blood glucose was reported in the other three studies and there was no statistically significant difference between the two groups (WMD, 0.68 mmol/l; 95% CI, –0.62 to1.98; P=0.30). 3.1.2Weight gain: Total weight gain during pregnancy was reported in four studies and was slightly lower in the metformin group compared with the insulin group with the difference being statistically significant (WMD, -1.49 kg; 95% CI, –2.66 to -0.31; P=0.01). The other three studies reported weight gain from the start of the study until delivery with women in the metformin group experiencing statistically less weight gain (WMD, -1.13 kg; 95% CI, –1.73 to -0.52; P=0.0003). 3.1.3 Cesarean delivery：Cesarean delivery was reported in six studies with no significant difference between the two groups (RR=0.98; 95% CI, 0.74–1.29). 3.1.4 Hypertensive disorders: Four studies reported preeclampsia (RR=0.73; 95% CI, 0.48–1.12), two studies reported gestational hypertension (RR=0.60; 95% CI, 0.33–1.10) and two studies reported the pregnancy induced hypertension (RR=0.40; 95% CI, 0.16–0.99). None of these differences was significantly different between the metformin group and insulin group. 3.2 Neonatal outcomes: 3.2.1Hypoglycemia：Neonatal hypoglycemia was reported in six studies with the prevalence of neonatal hypoglycemia in metformin group being statistically lower than in the insulin group (RR=0.77; 95% CI, 0.60–0.99). 3.2.2 Birth weight：Six studies reported birth weight and there was no statistically significant difference between the two treatment groups (WMD, –52.19 ;95% CI, –104.87 to 0.49; P=0.05). Studies similarly defined macrosomia as birth weight above 4000g. Prevalence of macrosomia was reported in five studies and there was no difference between the two groups (RR, 0.83; 95% CI, 0.58–1.20).
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3.2.3 Prevalence of large-for-gestational-age (LGA) babies was reported in four studies and small-for-gestational-age (SGA) babies was reported in three studies. There was no statistically significant difference between the two treatment groups in LGA (RR=0.87; 95% CI, 0.69–1.11) and in SGA (RR=0.92; 95% CI, 0.61–1.39). 3.2.4 Premature birth (<37 weeks gestation): Premature birth (<37 weeks gestation) was reported in four studies with the prevalence of premature birth being slightly but significantly higher in the metformin group (10%) than in the insulin group (6.4%） (RR=1.56; 95% CI, 1.06–2.30). 3.2.5 Birth trauma：Birth trauma was reported in three studies and there was no statistically significant difference between the two groups (RR=0.79; 95% CI, 0.42–1.46). 3.2.6 Birth defect：Birth defect was reported in three studies and there was no statistically significant difference between the two groups (RR=0.84; 95% CI, 0.47–1.51). 3.2.7 Other neonatal outcomes：There was no statistically significant difference between the two treatment groups in admission to NICU (RR=0.86; 95% CI, 0.70–1.05); respiratory distress syndrome (RR=1.09; 95% CI, 0.63–1.89); phototherapy (RR=0.88; 95% CI, 0.64–1.21). 4. Discussion The lack of a significant difference in maternal glycemic control assessed by HbA1c and fasting blood glucose, suggests that metformin is equally effective as insulin in the management of gestational diabetes. In addition there were no differences in other indicators of maternal outcomes such as Cesarean delivery and hypertensive disorders between two treatment groups. However, weight gain of the pregnant women was significantly less with metformin [7]. Maternal gestational weight gain above recommended levels is associated with cesarean delivery and postpartum weight retention. Also observational evidence links gestational weight gain with fetal growth and predicts LGA which itself is a marker of neonatal morbidity[16]. However we found no evidence of this in our study, perhaps related to the relatively small difference in weigh between the two groups. Neonatal hypoglycemia occurs frequently in babies in women with GDM. In our study，the incidence of neonatal hypoglycemia in the insulin group was higher than in the metformin group. Reducing neonatal hypoglycemia with metformin treatment could avoid potentially harmful central nervous system effects [17]. Other neonatal outcomes such as birth weight，macrosomia, birth trauma, birth defect, NICU, respiratory distress syndrome, phototherapy, were not significantly different between two groups. However, we found that premature birth was slightly but significantly less in the insulin group than the metformin group, consistent with the MiG trial [7], which could be due to chance or an unrecognized effect of metformin on the labor process. In summary, using metformin in pregnancy for women with GDM [A1]appears to be safe and efficacious. Limitations in current evidence
Page 5 of 8
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There are some limitations in our study that deserve comment. Firstly, our eligibility criteria resulted in only six RCTs being included resulting in a small sample size which limited our ability to draw substantial conclusions. Secondly, some outcomes were included in only two studies which limited the meta-analysis which may have lacked power to detect important differences in some of the outcomes of interest. Thirdly, the methodological quality of included trials, assessed by the Jadad scale, was variable with four articles scoring 3 to 4 points and the others 1–2 points, indicating that not all of studies were of high quality. Furthermore, the definitions of outcomes varied across studies. For example, the diagnosis of neonatal hypoglycemia among the six studies was based on different measures (less than 40 mg/dL[A2]; less than 46.8 mg/dL; no reported definition; and need for intravenous glucose).
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Implications for clinical practice and research This review has several implications for clinical practice. Firstly there is some evidence to support the benefits of metformin in the management of gestational diabetes based on level of good glycemic control and maternal and perinatal outcomes compared with insulin. Secondly, there is increasing evidence for drug administration regulators to consider the approval of metformin for use in pregnancy. However larger-scale RCTs are needed to detect clinically meaningful differences in maternal and neonatal outcomes and extend the evidence of the effectiveness and potential harms of these treatments.
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Conflict of interest: No potential conflicts of interest relevant to this article were reported.
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References: [1] American Diabetes Association. Gestational Diabetes Mellitus. Diabetes Care. 2013;36 (Suppl 1):S11–66 [2] National Diabetes Information Clearinghouse [Internet]. Maryland: National Institutes of Health 2011. Available at: http://diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational. Accessed November 3, 2011 [3] Falavigna M, Schmidt MI, Trujillo J, Alves LF, Wendland ER, Torloni MR, Colagiuri S, Duncan BB. Effectiveness of gestational diabetes treatment: a systematic review with quality of evidence assessment. Diabetes Res Clin Pract. 2012;98:396-405. [4] Norman RJ, Wang JX, Hague W. Should we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol. 2004 16:245-50. [5] Nicholson W, Baptiste-Roberts K. Oral hypoglycaemic agents during pregnancy: The evidence for effectiveness and safety. Best Pract Res Clin Obstet Gynaecol 2011 ;25:51-63 [6] Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med.2000;17:507–11 [7] Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–15 [8] Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis.Am J Obstet Gynecol 2010;203:457 [9] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ,Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12 [10] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 510. Oxford, UK, Cochrane Collaboration, 2011. [11] Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract 2012 ; 98:422-9. [12] Tertti K, Ekblad U, Koskinen P, Vahlberg T, Rönnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab.2013 ; 15:246-51. [13] Ijäs H, Vääräsmäki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T, Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011 ; 118:880-5. [14] Moore LE, Briery CM, Clokey D, Martin RW, Williford NJ, Bofill JA, Morrison JC. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med. 2007 ; 52: 1011-5. [15] Hassan, JA ; Karim N ; Sheikh Z . Metformin prevents macrosomia and neonatal
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morbidity in gestational diabetes. PAKISTAN JOURNAL OF MEDICAL SCIENCES 2012;28 : 384-389. [16] Rasmussen KM, Yaktine AL, Eds. Weight gain during pregnancy: reexamining the recommendations. Washington, DC, The National Academies Press, 2009 [17] Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes 2010;17:20-4
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Author : D.F. Su; X.Y. Wang 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, the Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University，300070 Tianjin, China
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