Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis
A. Alqudah
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorM. C. McKinley
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorR. McNally
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorU. Graham
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK
Search for more papers by this authorC. J. Watson
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorT. J. Lyons
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Division of Endocrinology and Diabetes, Medical University of South Carolina, Charleston, SC, USA
Search for more papers by this authorCorresponding Author
L. McClements
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Correspondence to: Lana McClements. E-mail: [email protected].Search for more papers by this authorA. Alqudah
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorM. C. McKinley
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorR. McNally
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorU. Graham
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK
Search for more papers by this authorC. J. Watson
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Search for more papers by this authorT. J. Lyons
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Division of Endocrinology and Diabetes, Medical University of South Carolina, Charleston, SC, USA
Search for more papers by this authorCorresponding Author
L. McClements
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
Correspondence to: Lana McClements. E-mail: [email protected].Search for more papers by this authorAbstract
Aims
To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy.
Methods
A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group.
Results
Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33–2.26); P = 0.76; I2 = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56–2.61); P = 0.62; I2 = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48–0.95); P = 0.02; I2 = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin).
Conclusions
In studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.
Supporting Information
| Filename | Description |
|---|---|
| dme13523-sup-0001-FigS1.tifTIFF image, 231.8 KB | Figure S1. Meta-analyses of HbA1c (%) in metformin vs. insulin treatment group, RCTs only. A meta-analysis of HbA1c recorded between 36 and 37 weeks. Random effects models were used to combine estimates and analyses were carried out using RevMan 5.3 software; standard mean difference was calculated; the overall effect was measured using Z-test with P values < 0.05 being statistically significant. Heterogeneity was calculated using a chi-squared test and measured by I2 statistic. |
| dme13523-sup-0002-FigS2.tifTIFF image, 257.7 KB | Figure S2. A meta-analysis comparing the risk ratio of pre-eclampsia in metformin only vs. insulin only treatment group, RCTs combined. Random effects models were used to combine estimates and analyses were carried out using RevMan 5.3 software; risk ratio was calculated; the overall effect was measured using Z-test with P values less than 0.05 being statistically significant. Heterogeneity was calculated using a chi-squared test and measured by I2 statistic. |
| dme13523-sup-0003-TableS1.tifTIFF image, 119 KB | Table S1. Study quality assessment using the Critical Appraisal Skills Programme tool. |
| dme13523-sup-0004-TableS2.tifTIFF image, 50 KB | Table S2. Percentage of patients in metformin group who were supplemented with additional insulin, RCTs only. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 American College of Obstetricians and Gynecologists. Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Obstet Gynecol 2013; 122: 1122–1131.
- 2Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension 2014; 64: 644–652.
- 3Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367: 1066–1074.
- 4Manten GTR, Sikkema MJ, Voorbij HAM, Visser GHA, Bruinse HW, Franx A. Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction. Hypertens Pregnancy 2007; 26: 39–50.
- 5Libby G, Murphy DJ, McEwan NF, Greene SA, Forsyth JS, Chien PW et al. Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: an intergenerational study from the Walker cohort. Diabetologia 2007; 50: 523–530.
- 6Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991–2002.
- 7Palomba S, de Wilde MA, Falbo A, Koster MPH, La Sala GB, Fauser BCJM. Pregnancy complications in women with polycystic ovary syndrome. Hum Reprod Update 2015; 21: 575–592.
- 8Abell SK, Boyle JA, de Courten B, Soldatos G, Wallace EM, Zoungas S et al. Impact of type 2 diabetes, obesity and glycaemic control on pregnancy outcomes. Aust New Zeal J Obstet Gynaecol 2017; 57: 308–314.
- 9Yu Y, Jenkins AJ, Nankervis AJ, Hanssen KF, Scholz H, Henriksen T et al. Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women. Diabetologia 2009; 52: 160–168.
- 10McCance DR, Holmes VA, Maresh MJA, Patterson CC, Walker JD, Pearson DWM et al. Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes [DAPIT]: a randomised placebo-controlled trial. Lancet 2010; 376: 259–266.
- 11Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG et al. Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 160: 695.
- 12Cassina M, Dona M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Hum Reprod Update 2014; 20: 656–669.
- 13Rowan 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: 2003–2015.
- 14Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R et al. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med 2016; 374: 434–443.
- 15Ainuddin J, Karim N, Hasan AA, Naqvi SA. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial. Diabetes Res Clin Pract 2015; 107: 290–299.
- 16Vanky E, Stridsklev S, Heimstad R, Romundstad P, Skogøy K, Kleggetveit O et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 2010; 95: E448–455.
- 17Catalano PM, McIntyre HD, Cruickshank JK, McCance DR, Dyer AR, Metzger BE et al. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care 2012; 35: 780–786.
- 18Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol 2004; 286: H1389–1193.
- 19Skeffington KL, Higgins JS, Mahmoud AD, Evans AM, Sferruzzi-Perri AN, Fowden AL et al. Hypoxia, AMPK activation and uterine artery vasoreactivity. J Physiol 2015; 5: 1357–1369.
- 20Banek CT, Bauer AJ, Needham KM, Dreyer HC, Gilbert JS. AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat. Am J Physiol Heart Circ Physiol 2013; 304: H1159–1165.
- 21Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ et al. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol 2016; 214: 356.e1–356.e15.
- 22Goh JEL, Sadler L, Rowan J. Metformin for gestational diabetes in routine clinical practice. Diabet Med 2011; 28: 1082–1087.
- 23Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 2001; 54: 1046–1055.
- 24Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004; 19: 1323–1330.
- 25Glueck CJ, Goldenberg N, Pranikoff J, Khan Z, Padda J, Wang P. Effects of metformin intervention before and throughout pregnancy on obstetric and neonatal outcomes in patients with polycystic ovary syndrome. Curr Med Res Opin 2013; 29: 55–62.
- 26De Leo V, Musacchio MC, Piomboni P, Di Sabatino A, Morgante G. The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications. Eur J Obstet Gynecol Reprod Biol 2011; 157: 63–66.
- 27Jamal A, Milani F, Al-Yasin A. Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS. Iran J Reprod Med 2012; 10: 265–270.
- 28Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women [EMPOWaR]: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2015; 3: 778–786.
- 29Vanky 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: 1734–1740.
- 30Tertti 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: 246–251.
- 31Ainuddin JA, Karim N, Zaheer S, Ali SS, Hasan AA. 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. J Diabetes Res 2015: 1–11.
- 32Ijäs H, Vääräsmäki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T et al. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011; 118: 880–885.
- 33Niromanesh 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: 422–429.
- 34Hickman M, McBride R, Boggess K, Strauss R. Metformin Compared with Insulin in the Treatment of Pregnant Women with Overt Diabetes: A Randomized Controlled Trial. Am J Perinatol 2012; 30: 483–490.
- 35Beyuo T, Obed SA, Adjepong-Yamoah KK, Bugyei KA, Oppong SA, Marfoh K. Metformin versus insulin in the management of pre-gestational diabetes mellitus in pregnancy and gestational diabetes mellitus at the Korle Bu Teaching Hospital: A randomized clinical trial. PLoS One 2015; 10: e0125712.
- 36Hellmuth E, Damm P, Mølsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 2000; 17: 507–511.
- 37Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RPV. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol 2013; 209: e1–7.
- 38Yogev Chen, Hod Coustan, Oats McIntyre et al. Hyperglycemia and Adverse Pregnancy Outcome [HAPO] study: preeclampsia. Am J Obstet Gynecol 2010; 202: e1–7.
- 39North RA, McCowan LME, Dekker GA, Poston L, Chan EHY, Stewart AW et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort. BMJ 2011; 342: d1875.
- 40Montoro MN, Kjos SL, Chandler M, Peters RK, Xiang AH, Buchanan TA. Insulin Resistance and Preeclampsia in Gestational Diabetes Mellitus. Diabetes Care 2005; 28: 1995–2000.
- 41Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P et al. Metformin for non-diabetic patients with coronary heart disease [the CAMERA study]: a randomised controlled trial. Lancet Diabetes Endocrinol 2014; 2: 116–124.
- 42Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler S et al. Impact of Intensive Lifestyle and Metformin Therapy on Cardiovascular Disease Risk Factors in the Diabetes Prevention Program. Diabetes Care 2005; 28: 888–894.
- 43Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008; 359: 1577–1589.
- 44Barrett H. Predictors of Pre-eclampsia in Women in the Metformin in Gestational Diabetes (Mig) Study. J Diabetes Metab 2014; 5: 395–410.
- 45Lamminpää R, Vehviläinen-Julkunen K, Gissler M, Selander T, Heinonen S. Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland. J Matern Neonatal Med 2016; 29: 55–59.
10.3109/14767058.2014.986450 Google Scholar
- 46Myatt L, Redman C, Staff A, Hansson S, Wilson M, Laivuori H et al. Strategy for Standardization of Preeclampsia Research Study Design. Hypertension 2014; 63: 1293–1301.
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