Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications

Chiswick, Carolyn; Reynolds, Rebecca M.; Denison, Fiona C.; Drake, Amanda J.; Forbes, Shareen; Newby, David E.; Walker, Brian R.; Quenby, Siobhán; Wray, Susan; Weeks, Andrew; Lashen, Hany; Rodríguez, Aryelly; Murray, Gordon; Whyte, Sonia; Andrew, Ruth; Homer, Natalie; Semple, Scott; Gray, Calum; Aldhous, Marian C.; Noble, Karen; Cunningham‐Burley, Sarah; Keely, Alice; Norman, Jane E.

doi:10.3310/eme03070

Cited by 8 publications

(8 citation statements)

References 154 publications

(8 reference statements)

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“…Therefore, as there is an increase in glucose clearance, metformin treatment also resulted in an increase in EGP under fasting conditions (baseline 10.9 [IQR 10.1-12.4] vs post metformin 13.8 [11.7-15.0] μmol min −1 kg −1 , p < 0.001) ( This data from dual-tracer MMTs has provided some interesting insight into the mechanism of action of metformin. Metformin treatment was associated with increased fasting glucose clearance, which has been previously reported in clamp data [3,[8][9][10]. The increase in clearance could represent increased glucose uptake by the intestine, which has recently been postulated as a 'glucose sink' [11,12].…”

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confidence: 53%

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

et al. 2019

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confidence: 53%

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

et al. 2019

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“…When these children ( n = 144) were followed up at 5–10 years of age [63], children whose mothers were treated with metformin maintained the increased BMI observed at 4 years of age (difference in means 0.41 kg/m 2 , 95% CI 0.03 to 0.78). Moreover, data from a randomised trial of 449 overweight or obese normoglycaemic women randomised to metformin or placebo from 16 weeks of gestation (EMPOWaR), showed that neonates exposed to metformin compared to placebo in utero were thinner at birth (lower neonatal ponderal index), suggesting very early differences in body composition [64,65]. Our confidence in our finding of a higher tendency towards lower lean mass and greater adiposity in metformin-exposed compared to insulin-exposed children is increased by these studies.…”

Section: Discussionmentioning

confidence: 99%

Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis

2019

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Background Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown. Methods and findings PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies ( n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies ( n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference −107.7 g, 95% CI −182.3 to −32.7, I 2 = 83%, p = 0.005) and lower ponderal indices (mean difference −0.13 kg/m 3 , 95% CI −0.26 to 0.00, I 2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies ( n = 411 infants) reported measures of infant growth (18–24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I 2 = 4%, p = 0.03). Three studies ( n = 520 children) reported mid-childhood growth parameters (5–9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m 2 , 95% CI 0.23 to 1.33, I 2 = 7%, p = 0.005) followin...

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“…However, accumulating evidence is of variable quality and inconclusive, indicating either negligible or beneficial effect on various neonatal parameters, but also increased risk of childhood adiposity found in a long-term follow-up of a single national cohort of children born to women with polycystic ovary syndrome. [56][57][58][59][60][61] Our review also refers to areas for future research. The obvious knowledge gap is caused by a quickly increasing, but still incoherent amount of evidence regarding pregnancy and early life in humans.…”

Section: Knowledge Gaps and Area For Future Researchmentioning

confidence: 99%

Role of gestational weight gain, gestational diabetes, breastfeeding, and hypertension in mother-to-child obesity transmission

Skrypnik

Bogdański

Zawiejska

et al. 2019

Polish Archives of Internal Medicine

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Given the reported 30% prevalence of early-life obesity in the Western world, the nongenetic, maternally derived risk factors for excess body mass in offspring have been widely investigated recently. This review article aimed to analyze the results of 67 articles published from 2014 onwards that investigated causative non-genetic-based associations between maternal and infantile excess body mass. Excessive gestational weight gain was found to increase the incidence of excess body mass in offspring, reaching nearly 20% at 2 years of age. Furthermore, gestational diabetes mellitus (GDM) increases the risk of offspring that is large for gestational age. The offspring of mothers with GDM and mothers with dyslipidemia in the first trimester of pregnancy had higher rates of excess body mass. In addition, breastfeeding for a period of less than 6 months was one of the 4 factors that were most strongly associated with childhood obesity. Pregnancy-induced hypertension raises the risk of childhood obesity by 50%. In conclusion, excessive gestational weight gain, GDM, maternal dyslipidemia, breastfeeding for a period of less than 6 months, and hypertensive disorders of pregnancy are associated with maternal and childhood obesity and are perinatal risk factors of excess body mass in offspring. Their occurrence should be monitored and prevention of these factors should become the principal aim of obesity prevention programs for children. Occurrence of these factors may justify intense screening to diagnose early stages of metabolic disorders in offspring, even in adulthood. Further large-scale studies are warranted to draw a firm conclusion.

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Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications

Cited by 8 publications

References 154 publications

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis

Role of gestational weight gain, gestational diabetes, breastfeeding, and hypertension in mother-to-child obesity transmission

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