Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis

Abstract

Objective: We systematically assessed the impact of metformin treatment on maternal pregnancy outcomes.

Data Sources: PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov and Cochrane databases were systematically searched (inception-19^th November 2020).

Methods of Study Selection: Randomized controlled trials reporting pregnancy outcomes in women randomized to metformin versus any other treatment for any indication were included. Outcomes included gestational weight gain (GWG), pre-eclampsia, pregnancy-induced hypertension, preterm birth, gestational age at delivery, cesarean section, gestational diabetes, glycemic control, and gastrointestinal side-effects. Two independent reviewers conducted screening, with a third available to evaluate disagreements. Risk-of-bias and GRADE assessments were conducted using Cochrane Risk-of-Bias and GRADE-pro software.

Tabulation, integration and results: Thirty-five studies (n=8033 pregnancies) met eligibility criteria. GWG was lower in pregnancies randomized to metformin versus other treatments (1.57kg±0.60kg; I₂=86%, p<0.0001), as was likelihood of pre-eclampsia (OR 0.65, 95%CI:0.47-0.91; I₂=52%, p=0.01). The risk of gastrointestinal side-effects was greater in metformin-exposed versus other treatment groups (OR 2.43, 95%CI:1.53-3.84; I₂=76%, p=0.0002). The risk of other maternal outcomes assessed was not significantly different between metformin-exposed versus other treatment groups.

Conclusions: Metformin for any indication during pregnancy is associated with lower GWG and a reduced risk of pre-eclampsia, but increased gastrointestinal side-effects compared to other treatments. 

Introduction

Metformin, an oral insulin-sensitizing and glucose-lowering drug, is widely prescribed during pregnancy. Guidelines from several global contexts, including the UK [1,2], New Zealand [3], US [4] and Canada [5] endorse metformin for the treatment of gestational diabetes mellitus (GDM). Metformin is also used in pregnancy for other conditions, including pre-existing diabetes [6] and polycystic ovarian syndrome (PCOS) [7], and has been trialled in the context of maternal obesity [8]. However, despite the widespread prescription of metformin during pregnancy, data regarding maternal pregnancy outcomes are relatively sparse, leading some clinicians to adopt a more cautious approach [9].

In the context of GDM, metformin is a practical alternative to insulin that maintains blood glucose concentrations within the normal range in a substantial proportion of patients [10]. Advantages of metformin include oral administration, cost-effectiveness, and suitability for use in low-resource settings [11]. Previous meta-analyses have raised concerns about the impacts of metformin on fetal and post-natal growth in the context of GDM [12,13]. However maternal pregnancy outcomes are less well-studied, particularly in women treated for conditions other than GDM [14-16]. Randomized trials have reported potential maternal benefits associated with metformin treatment, including reduced gestational weight gain (GWG) [14,17]. Furthermore, mixed evidence suggests that pre-eclampsia rates may be reduced in women randomized to metformin treatment [18,19].

We evaluated the impact of metformin treatment in pregnancy on the mother, by synthesizing all available randomised trial data pertaining to common maternal outcomes (including gestational weight gain, pre-eclampsia, pregnancy-induced hypertension, pre-term birth, gestational age at delivery, ceserean-section, glycemic control, adverse events and GDM). These were investigated across the range of indications for which metformin is currently prescribed or trialled in pregnancy.

Materials And Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20]. The systematic review protocol was registered prospectively in PROSPERO CRD42020167692 (Supplementary Text S1) prior to data collection. Ethical approval was not required for this meta-analysis.

Literature searches, search strategies and eligibility criteria

Systematic literature searches using pre-specified terms (Supplementary Text S2) were performed on PubMed (June 1997 to 19^th November 2020), Ovid EMBASE (1974 to 19^th November 2020), Ovid Medline (1946 to 19^th November 2020), Cochrane library (database inception to 19^th November 2020), Clinicaltrials.gov (database inception to 19^th November 2020), and Web of Science (1900 to 19^th November 2020). No language or location restrictions were applied. Studies that randomized pregnant women to metformin (not in combination with any other drug) versus any other drug treatment, placebo, or no treatment were included. Studies were included if they randomized pregnant women for any indication (including GDM, pre-existing diabetes, PCOS, or maternal obesity). All treatment indications were screened for and diagnosed according to local criteria in each study, and we did not apply exclusions with respect to this. Studies were excluded if they included participants with multiple pregnancies or if they randomized fewer than 50 women in total. Data reported only in meeting abstracts would have been included if the abstract contained sufficient information for assessment, but none fulfilled the criteria. Where insufficient information for assessment was available, authors were contacted for further information. One study provided insufficient information for assessment, however the authors did not respond to contact and therefore this study could not be included in the analysis. This Methodology is taken from our previous meta-analysis; [12].

Study selection and data extraction

Two reviewers (JLA and CEA) independently assessed each study using pre-determined inclusion/exclusion criteria (Supplementary Table 1). A third reviewer (SEO) was available to resolve cases where eligibility was unclear. An initial screen of titles and abstracts was performed, followed by a detailed full paper screen (Supplementary Fig. S1).

Data extraction from eligible studies was conducted independently using a standardized proforma by two authors (JLA and CEA). Maternal outcome measures were: gestational weight gain (GWG, throughout pregnancy; kg), pre-eclampsia, pregnancy-induced hypertension (PIH), preterm birth (divided into spontaneous and iatrogenic), gestational age at delivery (weeks), cesarean section rates (divided into elective and emergency), glycemic control (fasting blood glucose, FBG; mg/dL and random blood glucose, RBG; mg/dL), new GDM incidence, maternal hypoglycaemia, and any reported side-effects. All outcome measures were defined as per the original study criteria, and we did not apply any exclusion with respect to these.

Quality assessment (risk of bias)

Each study was independently assessed by two authors (JLA and CEA) for quality and validity using the Cochrane Collaboration tool for assessing risk of bias. Seven risk of bias domains were systematically assessed for each study and each domain was given a rating of low risk, unknown risk or high risk of bias (Supplementary Table S2). All risk of bias analysis was conducted at the study level. (Methodology is taken from our previous meta-analysis; [12]).

The principle summary measures were unadjusted odds ratios (OR) (for dichotomous data) or differences in means (for continuous data). Meta-analysis was performed using Review Manager (RevMan) Version 5.3, Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014) and the ‘metafor’ package in R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria). Funnel plots were constructed to assess publication bias. Meta-analyses with 5 or more studies included were also subjected to Egger’s test. Heterogeneity between studies was assessed using the I-squared statistic. Any outcomes demonstrating significant inter-study heterogeneity (heterogeneity p value <0.05) were analysed using a random-effects model. Sensitivity analyses were performed using ‘leave-one-out’ sensitivity testing for individual studies. All outcomes were subjected to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis (GRADEpro Guideline Development Tool, McMaster University, USA). Sub-group analyses were performed for each treatment indication. Where the indication for randomization was diabetes in pregnancy, the included studies all compared metformin to either insulin or glyburide, hence further sub-group analyses were performed by comparator group. Where the indication for randomization was PCOS or obesity, all included studies compared metformin to placebo, therefore no further sub-group analyses were performed. A further sensitivity analysis excluding studies in which analysis was not performed on an intention-to-treat basis was also conducted. Where p values are reported, an alpha level <0.05 was considered statistically significant.

Results

Study selection and study characteristics

The PRISMA flow chart (Supplementary Fig. S1) demonstrates the screening procedure involved to attain 35 studies (8033 participants) for this meta-analysis. The majority of these studies (27 studies; 5319 participants) investigated metformin treatment for diabetes in pregnancy. A total of 8 studies (2714 participants) investigated maternal obesity (4 studies; n=1485) or PCOS (3 studies; n=930) or pre-gestational insulin resistance (1 study; n=299). No studies investigated randomisation of metformin compared to diet/lifestyle intervention alone, however these were commonly implemented alongside other treatments. Eligible studies were identified comparing metformin to insulin, glyburide, and placebo. For all indications and comparisons, the studies varied with respect to quality and design (Supplementary Table S3). The included studies demonstrated considerable heterogeneity with respect to the dosage of pharmacological agents (Supplementary Table S3). Heterogeneity also existed in the diagnostic criteria used for GDM and PCOS (Supplementary Table S4). The included studies came from a variety of geographical locations: Australasia (Australia and New Zealand), Europe (the UK, Norway and Finland), North Africa/Middle East (Egypt, Iran and Israel) and the North America/Latin America (Canada, Mexico, Brazil and Chile).

Risk of bias and sensitivity analyses

The risk of bias was moderate-to-low in the majority of included studies, however six studies were considered to have a high risk of bias (Supplementary Table 2). We performed sub-group meta-analyses, excluding the studies assessed as having a high risk of bias (Supplementary Fig. S2), which showed that removal of studies with a high risk of bias did not materially alter the outcome of the meta-analyses for any of the outcomes, therefore all studies were included. Most studies reported non-significant differences in maternal baseline characteristics between groups (including maternal age, BMI and glycemic control) (Supplementary Table S3).

We assessed the likelihood of single studies significantly influencing the overall results using leave-one-out (LOO) analysis. For the primary comparison of metformin vs. any other treatment across all indications, meta-analyses were robust to the omission of single studies (Supplementary Fig. S3), with the exception of cesarean section, RBS, and maternal hypoglycaemia, decreasing our confidence in the robustness of these findings. Funnel plots for all outcomes were assessed visually (Supplementary Fig. S4); there were no obvious asymmetries in the plots for any study outcomes. Eggers testing demonstrated a low likelihood of publication bias with respect to the primary comparisons (Supplementary Table S5).

GRADE analysis (certainty of evidence)

The majority of outcomes were classified as having a moderate certainty of evidence (Supplementary Fig. S5; primary outcomes and Supplementary Fig. S6; secondary outcomes), with one outcome having a high certainty of evidence (pregnancy-induced hypertension).

Synthesis of results

Gestational weight gain

Pregnant women randomized to metformin versus any other treatment had on average 1.57kg less gestational weight gain; (95%CI: 0.97kg to 2.17kg; I₂=86%, p<0.00001) (Figure 1) based on 14 studies including 3004 pregnancies. In the sub-group where the indication for randomization was maternal obesity, there was on average 0.89kg less GWG (p=0.04) in metformin-treated women compared to those randomized to placebo (2 studies [21,22] n=813) (Table 1). In the sub-group where the indication for randomization was PCOS, there was significantly less GWG (p<0.0001) in metformin-treated women compared to those randomised to placebo (1 study [23] n=398) (Table 1). In the sub-group of women with diabetes in pregnancy (11 studies [24-34] n=1793), randomization to metformin also resulted in significantly less GWG (p<0.0001), an effect that remained significant and of similar magnitude when further analysed by treatment type (Table 2).

Table 1:  Effect of metformin intervention in women with maternal obesity/PCOS.

Effects size estimate (95% CI) or odds ratio (95% CI).  GDM=gestational diabetes mellitus; GWG=gestational weight gain; Het=heterogeneity; PCOS=polycystic ovary syndrome; PIH=pregnancy-induced hypertension.

Table 2:  Effect of metformin intervention in women with maternal obesity/PCOS.

Effects size estimate (95% CI) or odds ratio (95% CI). Het; heterogeneity, GWG; gestational weight gain, PIH; pregnancy-induced hypertension, FBS; fasting blood glucose, RBS; random blood glucose.

Pre-eclampsia

Pregnant women randomized to metformin had a significant reduction in the likelihood of pre-eclampsia compared to those randomised to any other treatment (OR 0.65, 95%CI: 0.47 to 0.91; I₂=52%, p=0.01) (Figure 2); based on 21 studies including 5979 pregnancies. There were no significant differences in the risk of pre-eclampsia in the sub-group analyses where the indication for randomization was maternal obesity (4 studies [21,22,35,36] n=1620) or PCOS (3 studies [23,37,38] n=818) (Table 1). However, in the sub-group of women with diabetes in pregnancy, randomization to metformin resulted in significantly decreased likelihood (p=0.02) of pre-eclampsia (14 studies [24-26,28,29,31,39,40-46] n=3301) (Table 2). Effect sizes were similar across all diabetes in pregnancy groups, although these failed to reach statistical significance in sub-groups (Table 2).

Pregnancy-induced hypertension

There was no difference in the likelihood of pregnancy-induced hypertension (PIH) between women randomized to metformin versus any other treatment (OR 0.97, 95%CI: 0.77 to 1.22; I₂=0%, p=0.81) (Figure 3) based on 14 studies including 4189 pregnancies. There were no significant differences in the risk of PIH in any of the sub-group analyses where the indication for randomization was maternal obesity (3 studies [21,22,35] n=1354), PCOS (1 study [23] n=478) (Table 1) or diabetes in pregnancy (10 studies [24,26,29,30,34,39,41,45,46,47] n=2806) (Table 2).

Preterm birth (all-cause, spontaneous and iatrogenic)

There was no difference in the overall likelihood of preterm birth between women randomized to metformin versus other interventions (OR 0.91, 95%CI: 0.67 to 1.22; I₂=58%, p=0.52) (Figure 4 a) based on 27 studies including 6959 pregnancies. When sub-group analysis was performed separating spontaneous and iatrogenic preterm birth, there was no significant effect of randomization to metformin versus other treatments on likelihood of either type of preterm birth (Figures 4 b & 4 c).

In women with maternal obesity (4 studies [21,22,35,36] n=1620) (Table 1) or diabetes in pregnancy (19 studies [26,29-31,33,34,39-45,47-52] n=4443) (Table 2), the likelihood of preterm birth was not different between women randomized to metformin versus other treatments. However, in the sub-group where the indication for randomization was PCOS (3 studies [23,37,38] n=827), randomization to metformin was associated with reduced likelihood of preterm birth (p=0.01) (Table 1).

Gestational age at delivery

Randomization to metformin vs. any other treatment did not significantly influence gestational age at delivery (-0.08 weeks, 95%CI: -0.21 weeks to 0.04 weeks; I₂=48%, p=0.19) (Figure 5), based on 18 studies including 3818 pregnancies. There was no significant difference in gestational age at delivery where the indication for randomization was maternal obesity (2 studies [21,22] n=948) (Table 1) or diabetes in pregnancy (16 studies [24,25,26,27,28,29,31,32,33,41,43,44,45,46,53,54] n=2870) (Table 2). No studies reported gestational age at delivery in the sub-group of women with PCOS (Table 1).

Cesarean section (all cause, emergency and elective)

There was a trend to suggest lower likelihood of delivery by cesarean section in women randomized to metformin versus other treatments (OR 0.86, 95%CI: 0.73 to 1.01; I₂=46%, p=0.06) (Figure 6 a) based on 29 studies including 6122 pregnancies. When sub-group analysis was performed separating emergency and elective cesarean section, there was no significant effect of randomization to metformin versus other treatments on likelihood of either type of cesarean section (Figures 6 b & 6 c).

In the sub-group where the indication for randomization was maternal obesity (3 studies [21,22,35] n=1352), randomization to metformin (vs. placebo) was associated with reduced likelihood (p=0.03) of cesarean section (Table 1). Where the indication for randomisation was PCOS (2 studies [23,38] n=1352) (Table 1) or diabetes in pregnancy (22 studies [24-33,39,40,42,44-50,53,54] n=3516) (Table 2) randomization to metformin versus other treatments did not alter likelihood of cesarean section.

Side effects

Randomisation to metformin versus placebo was associated with increased likelihood of nausea, vomiting and diarrhoea, but not abdominal pain or non-gastrointestinal side-effects (Supplementary Table 6). Nausea, vomiting, and diarrhoea were all significantly increased when the indication for metformin randomization was maternal obesity (Table 1). However, when the indication for randomization was PCOS, fewer studies were available for analysis and only the likelihood of diarrhoea was significantly increased with metformin versus placebo (Table 1). Trials involving women with diabetes in pregnancy either did not report gastrointestinal side effects in the insulin arm, or reported zero values. Between 2-46% of women randomised to metformin for treatment of diabetes in pregnancy reported gastrointestinal side-effects (weighted average incidence 12.5%; Appendix 15) and 0-6% of women stopped medication due to these side effects (weighted average incidence 14.3%), (Supplementary Table S7).

GDM in participants randomised for indications other than diabetes

Randomization to metformin vs. any other treatment did not alter the likelihood of subsequent GDM diagnosis (OR 1.07, 95%CI: 0.87 to 1.33; I₂=0%, (p=0.52) (Supplementary Fig. S7), based on 7 studies including 2063 pregnancies. Whether the indication for randomization was maternal obesity (3 studies [21,22,35] n=1206) or PCOS (3 studies [23,37,38] n=746) (Table 1), randomisation to metformin did not alter likelihood of GDM.

Glycemic control in diabetes in pregnancy

There was no significant difference in FBS (19 studies, n=3673) or RBS (18 studies, n=3610) measurements in women with diabetes in pregnancy randomised to metformin versus other treatments (Table 2). Maternal hypoglycemia was significantly (p=0.005) less likely in women randomized to metformin vs. other treatments (Supplementary Fig. S8), based on 6 studies including 1149 pregnancies [30,34,45,46,49,53], however this effect is driven entirely by studies where insulin was the comparator group (Table 2).

Discussion

Our results demonstrate that exposure to metformin versus other treatments during pregnancy reduced GWG, an effect consistently observed across all sub-group and sensitivity analyses. The likelihood of developing pre-eclampsia was also significantly reduced in women randomized to metformin compared to other treatments, although this effect was driven by trials involving women with diabetes in pregnancy. Randomization to metformin was associated with a borderline significant reduction (p=0.06) in the likelihood of cesarean section in women randomized to metformin compared to other treatments, an effect which was driven by women with obesity compared to placebo. Significantly reduced likelihood of preterm birth was only observed in women with PCOS, randomized to metformin compared with placebo. Women randomised to metformin versus insulin for treatment of diabetes in pregnancy had a significantly lower likelihood of experiencing hypoglycemia. However the likelihood of gastrointestinal symptoms (nausea, vomiting and diarrhoea) was significantly increased in women randomised to metformin versus other treatments. Other maternal outcomes including pregnancy-induced hypertension, gestational age at delivery, incidence of GDM and glycemic control were not significantly different in metformin-treated compared to other treatment groups.

A major strength of this study is the breadth of outcomes affecting women during pregnancy that have been included. Our focus on maternal outcomes complements our previous work performed on fetal and childhood outcomes [12,13]. We also performed extensive sub-group and sensitivity evaluation of our conclusions.

The drawing of definitive conclusions from our meta-analysis is limited by both the quantity and quality of the studies available. In particular, there was a paucity of trials randomizing women with PCOS (3 studies, n=930 women) or maternal obesity (4 studies, n=1485 women), limiting our confidence in conclusions relating specifically to treatment for these indications and therefore we urge a conservative view with regard to interpretation of this sub-group analyses. No randomized trials were found that compared metformin specifically with dietary/lifestyle intervention, although several studies included these interventions for both trial arms. Our search results highlight the need for more high-quality studies investigating metformin use during pregnancy. A further reason for caution in interpretation is the high heterogeneity in dose and starting gestation of metformin treatment between the various included studies.

Overall, metformin use during pregnancy is associated with a greater risk of experiencing gastrointestinal side-effects than placebo or other treatments. Gastrointestinal symptoms are reported in 20-30% of patients treated with metformin outside of pregnancy [56]. A variety of mechanisms are proposed including bile-salt malabsorption, gut serotonin secretion, and alterations to glucose and incretin metabolism [56]. These symptoms may be more common in women [58] and more difficult to tolerate during pregnancy due to concomitant pregnancy-related nausea, vomiting, and food aversions [57,58].

Clear evidence of benefit from randomisation to metformin across all sub-groups is limited to a reduction in GWG, which may be related to direct actions of metformin which can inhibit food intake, via increased concentration of growth/differentiation-factor-15 (GDF15) [59]. Excessive GWG is associated with perinatal complications including increased risk of fetal growth anomalies, risk of GDM, cesarean birth and pre-eclampsia [34,60]. Moreover, increased GWG is associated with long-term (later in life) health risks to the mother including post-partum weight retention, obesity [61,62] and increased risk of developing type 2 diabetes [63] and cardiovascular disease [64]. Limiting GWG may also improve outcomes for future pregnancies [65]. The average weight gain observed in pregnancies affected by GDM is approximately 9kg [60] therefore a reduction of 1.55kg (17%, as observed here) constitutes a potentially clinically significant reduction in total GWG.

The likelihood of pre-eclampsia was reduced in women with diabetes in pregnancy randomized to metformin versus other treatments. Several studies have reported a higher incidence of pre-eclampsia in women with GDM compared to those with normal glucose tolerance [66]; it is thus possible that the impact of metformin in reducing the likelihood of pre-eclampsia may only be detectable in populations with higher baseline risk. Mechanistically, metformin may prevent pre-eclampsia via reduction of anti-angiogenic factors, improvements of endothelial function via actions on the mitochondria and/or via actions through the mammalian target of rapamycin (mTOR) pathway by modification of cellular homeostasis and energy deposition [67]. Previous meta-analyses have explored the impact of metformin on pre-eclampsia risk, with mixed results [18,19,68]. At least one previous meta-analysis that included both GDM and non-GDM pregnancies and analysed both randomized and observational data [68] found no significant effect of metformin on pre-eclampsia risk, which is in keeping with our observation that pre-eclampsia risk is not reduced in euglycemic pregnancies.

Our finding that metformin reduces the rate of cesarean section in obese women may relate to our previous finding of lower birth weight associated with randomization to metformin, [12] as there is increased likelihood of vaginal delivery with smaller fetuses. Maternal obesity is associated with increased birth weight [69] hence the impact of metformin in reducing fetal size and thus decreasing the risk of cesarean section may be amplified in this sub-group.

In weighing the risks and benefits of metformin treatment in pregnancy to the materno-fetal dyad, our meta-analysis highlights largely neutral or positive maternal outcomes, with the notable exception of increased likelihood of gastrointestinal side effects. From the fetal point of view however, it has previously been demonstrated that randomisation to metformin treatment for GDM is associated with increased risk of low birth-weight followed by accelerated growth in childhood [12,13], independent of maternal glycemic control [13]. It is particularly important to carefully consider the impacts of metformin treatment on both mother and baby as there are other suitable alternative treatments for GDM and no necessity for drug treatment for PCOS or maternal obesity in pregnancy. Moreover, there are other methods of controlling GWG, for example diet and lifestyle modification. Individual pregnant women may weigh the importance of limiting gestational weight gain or of avoiding gastrointestinal symptoms differently, and these findings may thus influence decision-making around metformin treatment in pregnancy.

Data availability

The data for this meta-analysis are freely available. The PROSPERO protocol can be found at https://www.crd.york.ac.uk/prospero CRD ID: CRD42020167692.

Declarations

Author contributions

JLT-A collected the data, contributed data or analysis tools, performed the analysis and wrote the paper. SEO conceived and designed the analysis and wrote the paper. CEA conceived and designed the analysis, contributed data or analysis tools, performed the analysis and wrote the paper.

Additional information

Competing interests: The author(s) declare no competing interests.

References

1. NICE Guidelines. Diabetes in pregnancy management from preconception to the postnatal period. 2015. Available at: nice.org.uk/guidance/ng3. Retrieved Feb 25, 2020.
2. Scottish Intercollegiate Guidelines Network (2014) Management of diabetes a national clinical guideline. Available at: sign.ac.uk/pdf/sign116.pdf. Cited Feb 25, 2020.
3. Diabetes in Pregnancy: Quick reference guide for health professionals on the screening, diagnosis and treatment of gestational diabetes in New Zealand. Wellington: Ministry of Health; 2014.
4. Society for Maternal-Fetal Medicine W, D.C (2018) SMFM Statement: Pharmacological treatment of gestational diabetes. Am J Obstet Gynecol.218, B2-B4 (2018).
5. Feig, D.S. et al. Clinical practice guidelines. Diabetes in Pregnancy. Diabetes Canada clinical practice guidelines expert committee. Canadian J Diab.42, S255-S282 (2018).
6. Sanchez-Rangel, E. & Inzucchi, S.E. Metformin: clinical use in type 2 diabetes. Diabetologia60, 1583-1593 (2017).
7. Lashen, H. Role of metformin in polycystic ovary syndrome. Ther Adv Endocrinol Metab 2010;1:117-128.
8. Dodd, J.M., Grivell., R.M, Deussen., A.R & Hague, W.M. Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes. Cochrane Syst Re 7:1-45 (2018).
9. Barbour, L.A. et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol219, e1–e7 (2018).
10. Ito, H. et al. Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus. Metab. (Lond).12, 83 (2010).
11. Polasek, T.M., Doogue, M.P. & Thynne, T.R.J. Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy. Adv. Drug. Saf. 9:287-295 (2018).
12. Tarry-Adkins, J.L., Aiken, C.E, & Ozanne, S.E. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLoS Med.16, e1002848 (2019).
13. Tarry-Adkins, J.L., Aiken, C.E, & Ozanne, S.E. Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis. PLoS Med.17, e1003126 (2020).
14. Butalia, S. et al. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Med.34, 27-36 (2017).
15. Zhu, B. et al. Metformin versus insulin in gestational diabetes mellitus: a meta-analysis of randomized clinical trials. Ir J Med Sci185, 371-381 (2016).
16. Feng, Y. & Yang, H. Metformin - a potentially effective drug for gestational diabetes mellitus: a systematic review and meta-analysis. J Matern-Fetal Neonatal Med 2017; 30:1874-81.
17. D'Ambrosio V, Brunelli R, Vena F, Di Mascio D, Marchetti C, Boccherini C et al (2019) Metformin reduces maternal weight gain in obese pregnant women: A systematic review and meta-analysis of two randomized controlled trials. Diabetes Metab. Res. Rev.35, e3164 (2019).
18. Aqudah, A. et al. Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis. Med. 35, 160-172 (2018).
19. Kalafat, E., Sukur, Y.E., Abdi, A., Thilaganathan, B. & Khalil, A. Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: systematic review and meta-analysis of randomized trials. Ultrasound Obstet Gynecol. 52, 706-714 (2018).
20. Moher, D., Liberati, A., Tetzlaff, J. & Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int. Med. 151, 264-269 (2019).
21. Chiswick C. et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diab. Endocrinol.3, 778-786 (2015).
22. Dodd, J.M. et al. Effect of metforminin addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol.7, 15-24 (2019).
23. Løvvik, T.S. et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol.7, 256-266 (2019).
24. Ainuddin, J., Karim, N., Hasan, A.A. & Naqvi, S.A. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial. Diabetes Res. Clin. Prac. 107, 290-299 (2015).
25. Ainuddin, J., Karim, N., Zaheer, S., Ali, S.S. & Hasan, A.A. Metformin Treatment in Type 2 Diabetes in Pregnancy: An active controlled, parallel-group, randomized, open label study in patients with type 2 diabetes in pregnancy. Diabetes Res. 325851 (2015).
26. Eid, S.R. et al. Is metformin a viable alternative to insulin in the treatment of gestational diabetes mellitus (GDM)? Comparison of maternal and neonatal outcomes. Egyptian Pediatric Association Gazette. 66, 15-21 (2018).
27. Hassan, J.A., Karem, N. & Sheikh, Z. Metformin prevents macrosomia and neonatal morbidity in gestational diabetes. J. Med. Sci. 28, 384-389 (2012).
28. Ijas, H. et al. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG. 118, 880-885 (2011).
29. Niromanesh, S. et al. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res. Clin. Pract.98, 422-429 (2012).
30. Somani, P.S., Sahana, P.K., Chaudhuri, P. & Sengupta, N. Treatment of gestational diabetes mellitus: Insulin or metformin? Evol. Med. Dent. Sci. 5, 4423-4429 (2016).
31. Nachum Z. et al. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes40, 332-337 (2017).
32. Silva, J.C. et al. Metformin compared with glyburide for the management of gestational diabetes. Int J. Gynaecol. Obstet.11, 37-40 (2010).
33. Silva, J.C., Fachin, D.R., Coral, M.L. & Bertini, A.M. Perinatal impact of the use of metformin and glyburide for the treatment of gestational diabetes mellitus. Perinat.Med.40, 225-228 (2012).
34. Feig DS. et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes8, 834-844 (2020).
35. Syngelaki, A. et al. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. Engl. J. Med. 374, 434-443 (2016).
36. Nascimento, I.B., Sales, W.B. & Dienstmann, G. The impact of the use of metformine for obese pregnant women in prevention of pre-eclampsia. Scientia Medica Porto Alegre30, e-35338 (2020).
37. Jamal, A., Milani, F. & Al-Yasin, A. Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS. J. Reprod. Med.10, 265-270 (2012).
38. Vanky, E. et al. Metforminversus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. Clin. Endocrinol. Metab.95, E448-E455 (2010).
39. Borg, H. & Ezat, S. Metformin Opposed to Insulin in the Management of Gestational Diabetes Res. Obstet. Gynecol. 4, 17-26 (2016).
40. Khan, R.M.A., Mukhtar, A. & Khawar, A. Comparison of metformin with insulin in the management of gestational diabetes. Medical Forum Monthly. 28, 105-109 (2017).
41. Rowan, J.A, Hague, W.M., Gao, W., Battin, M.R. & Moore, M.P. Metformin versus insulin for the treatment of gestational diabetes. Engl. J. Med.358, 2003-2015 (2008).
42. Saleh, H.S., Abdelsalam, W.A., Mowafy, H.E & Abd ElHameid, A.A. Could Metformin Manage Gestational Diabetes Mellitus instead of Insulin? J. Reprod. Med. 3480629 (2016).
43. Spaulonci, C.P., Bernardes, L.S., Trindade, T.C., Zugaib, M. & Francisco, R.P. Randomized trial of metformin vs insulin in the management of gestational diabetes. AJOG209, e1-7 (2013).
44. Tertti, K., Ekblad, U., Koskinen, P., Vahlberg, T. & Ronnemaa, T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes, Obesity Metab.15, 246-251 (2013).
45. Wasim, T., Shaukat, S., Javaid, L., Mukhtar, S. & Amer, W. Comparison of metformin and insulin for management of gestational diabetes mellitus: A randomized control trial. J. Med. Sci. 13, 823-827 (2019).
46. Moore, L.E., Clokey, D., Rappaport, V.J. & Curet, L.B. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Gynecol. 115, 55-59 (2010).
47. George, A. et al. Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide--a randomised controlled trial. N. Z. J. Obstet. Gynaecol.55, 47-52 (2015).
48. Arshad, R., Khanam. S., Shaikh, F. & Karim, N. Feto-maternal outcomes and Glycemic control in Metformin versus insulin treated Gestational Diabetics. J. Med. Sci.33, 1182-1187 (2017).
49. Ashoush, S., El-Said, M., Fathi, H. & Abdelnaby, M. Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus. Obstet. Gynaecol. Res. 42, 640-647 (2016).
50. Galal, M., El Bassioune, W.M. & Sherif, L. Metformin versus insulin in treatment of gestational diabetes mellitus: A Randomized Controlled Trial. J. Obst. Gynecol. 12, 23-27 (2019).
51. Ghomian, N et al. The efficacy of metformin compared with insulin in regulating blood glucose levels during gestational diabetes mellitus: A randomized clinical trial. Cell Physiol. 234, 4695-4701 (2019).
52. Mesdaghinia, E. et al. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial. J.Prev. Med. 4, 327-333 (2013).
53. Ibrahim, M.I. et al. The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Gynecol. Obstet.289, 959-965 (2014).
54. Moore, L.E. et al. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. Reprod. Med. 52, 1011-1015 (2007).
55. Valdés E. et al. Metforminas a prophylactic treatment of gestational diabetes in pregnant patients with pregestational insulin resistance: A randomized study. Obstet. Gynaecol. Res. 44, 81-86 (2018).
56. Bouchoucha, M., Uzzan, B. & Cohen, R. Metformin and digestive disorders. Diabetes Metab. 37, 90-96 (2011).
57. Dujic T. et al. Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes64, 1786-1793 (2015).
58. Bustos, M., Venkataramanan, R. & Caritis, S. Appetite sensations and nausea and vomiting in pregnancy: an overview of the explanations. Food Nutr 51, 394-417 (2012).
59. Coll, A.P et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature578, 444-448 (2019).
60. Aiken, C.E.M., Hone. L., Murphy, H.R. & Meek, C.L. Improving outcomes in gestational diabetes: does gestational weight gain matter? Med.36, 167-176 (2019).
61. Rooney, B.L. & Schauberger, C.W. Excess pregnancy weight gain and long-term obesity: One decade later. Gynecol. 100, 245-252 (2002).
62. Amorim, A.R., Rössner, S., Neovius, M., Lourenço, P.M. & Linné, Y. Does excess pregnancy weight gain constitute a major risk for increasing long-term bmi? Obesity (Silver Spring)15, 1278-1286 (2007).
63. Hedderson, M.M., Gunderson, E.P. & Ferrara, A. Gestational weight gain and risk of gestational diabetes mellitus. Gynecol.115, 597-604 (2010).
64. Fraser, A. et al. Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: The avon longitudinal study of parents and children (alspac). Am J Clin Nutr 93, 1285-1292 (2011).
65. Teulings, N.E.W.D., Masconi, K.L., Ozanne, S.E., Aiken, C.E. & Wood, A.M. Effect of interpregnancy weight change on perinatal outcomes: systematic review and meta-analysis. BMC Pregnancy Childbirth 19, 386 (2019).
66. Schneider, S., Freerksen, N., Rohrig, S., Hoeft B. & Maul, H. Gestational diabetes and preeclampsia-similar risk factor profiles? Early Hum. Dev. 88, 179-184 (2012).
67. Romero, R et al. Metformin, the aspirin of the 21^st century: its role in gestational diabetes, prevention of preeclampsia and cancer, and the promotion of longevity. AJOG217, 282-302 (2017).
68. Nascimento, I.B.D et al. Evaluation of Preeclampsia Results after Use of Metformin in Gestation: Systematic Review and Meta-analysis. Bras. Ginecol. Obstet. 40, 713-721 (2018).
69. Tenenbaum-Gavish K, Tenenbaum K, Hod M. Impact of maternal obesity on fetal health. Fetal Diagn Ther. 34, 1-7 (2013).