CoChat
Sign Up
Cited by 253Pregnancy and preeclampsia studiesGestational Diabetes Research and ManagementMetabolism, Diabetes, and Cancer

Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity

Open access
Romero, Roberto, Erez, Offer, Hüttemann, Maik, Maymon, Eli, Panaitescu, Bogdan, Conde-Agudelo, Agustin, Pacora, Percy, Yoon, Bo Hyun +1 more·2017·American Journal of Obstetrics and Gynecology
DOI 10.1016/j.ajog.2017.06.003PMC PMC6084482
Open this paper in CoChat — free account

Abstract

&NA; Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non‐diabetic, pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large‐for‐gestational‐age infants (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor‐1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin.

AI snapshot

Written from the paper’s full text.

TL;DR

Metformin is a pleiotropic drug whose roles are expanding beyond diabetes to gestational diabetes, possible preeclampsia prevention, cancer risk reduction, and longevity. This narrative review summarizes historical, meta-analytic, randomized-trial, and mechanistic evidence, emphasizing mitochondrial and mTOR/nutrient-sensing pathways.

Key findings

  • In gestational diabetes meta-analyses, metformin was superior to insulin for reducing maternal weight gain and gestational hypertension; Gui et al. found no change in large-for-gestational-age (LGA), small-for-gestational-age (SGA), hypoglycemia, or preeclampsia, while Butalia et al. reported significantly decreased neonatal hypoglycemia, LGA neonates, and neonatal intensive care unit admissions.
  • Two UK randomized trials in obese non-diabetic pregnant women conflicted: EMPOWaR (BMI >30 kg/m²; metformin 500 mg titrated to a maximum tolerable dose ≤2,500 mg) had no significant effect on birth weight, maternal weight gain, preeclampsia, or combined adverse pregnancy outcomes; the Fetal Medicine Foundation trial (BMI >35 kg/m²; 1 g/day increased by 0.5 g/week to 3 g/day) did not reduce LGA but significantly reduced preeclampsia and maternal weight gain, though not gestational diabetes. The review attributes the discrepancy to differences in BMI, dose, compliance, and recruitment: 13% (443/3329) consented in EMPOWaR versus 47% (400/844) in the Fetal Medicine Foundation trial, and compliance was 67% versus almost 80% taking at least 50% of prescribed tablets.
  • Proposed preeclampsia mechanisms include reduced production of anti-angiogenic factors sFlt-1/sVEGFR-1 and soluble endoglin, improved endothelial dysfunction, and effects on the mitochondrial electron transport chain, particularly complex I; metformin also modifies cellular nutrient sensing via AMPK and mTOR. Metformin has a molecular weight of 129 Da, crosses the placenta with a reported lag time of 1.7±0.28 minutes, and meta-analyses found no increased risk of congenital malformations.
  • In cancer and aging, a meta-analysis reported that metformin-treated diabetic patients had a 31% reduction in cancer incidence and a 34% reduction in cancer mortality after adjusting for body mass index; metformin extended longevity in worms and mice but not Drosophila. The TAME trial is planned to test metformin in 3,000 subjects aged 65–79 years with a composite endpoint of cardiovascular events, cancer, dementia, and mortality.

Methods

  • Narrative review, not a systematic review or meta-analysis; no primary data collection or new experimental study is reported.
  • Synthesizes published literature on metformin history, gestational diabetes meta-analyses, randomized trials in obese non-diabetic pregnant women (EMPOWaR and the Fetal Medicine Foundation trial), mechanistic studies of preeclampsia, and evidence on cancer and aging.
  • Main analysis is qualitative synthesis and mechanistic interpretation, drawing on meta-analyses, randomized trials, animal studies, and in vitro/ex vivo placental and vascular studies.

Limitations

  • The paper does not state a formal limitations section.
  • Evident from the text: it is a narrative review with selective citation rather than a systematic search or quantitative pooling, so it may not comprehensively capture all relevant evidence.
  • Evident from the text: many mechanistic and causal claims are inferential, based on secondary literature, animal models, and in vitro findings, and the review does not independently verify the cited results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ajog.2017.06.003

Cites

294 of 294 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 221 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In a systematic review and meta-analysis, metformin was superior to insulin in reducing maternal weight gain during pregnancy.

    “Gui et al.(75) published a systematic review and meta-analysis in which metformin was shown to be superior to insulin in reducing maternal weight gain during pregnancy as well as in the frequency of gestational hypertension (Figure 5a,); however, metformin did not change the frequency of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) fetuses or of hypoglycemia and preeclampsia(”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

      Not checked in the free run.

  • Premiseown data

    In the same randomized clinical trial, metformin administration in early pregnancy decreased the frequency of preeclampsia (secondary endpoint).

    “We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (primary endpoint), but did decrease the frequency of preeclampsia (a secondary endpoint).”
    Quote in the paperSubstantial claim
  • Premisereasoning

    Metformin readily crosses the placenta.

    “Metformin has a molecular weight of 129 Dalton, and therefore, readily crosses the placenta.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Metformin reduces glucose absorption by the gastro-intestinal tract.

    “reduction of glucose absorbtion by the gastro-intestinal tract(44, 45)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Natali, 2006, Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review, Diabetologia source

      Not checked in the free run.

    • cites [45] Foretz, 2014, Metformin: from mechanisms of action to therapies, Cell Metab source

      Not checked in the free run.

  • Interpretationnone given

    The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin).

    “The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin), and improving endothelial dysfunction, probably through an effect on the mitochondria.”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    Compared to insulin, metformin significantly decreased the frequency of neonatal hypoglycemia, LGA neonates, and admissions to a neonatal intensive care unit.

    “Butalia et al.(77) reported that, compared to insulin, metformin significantly decreased the frequency of neonatal hypoglycemia, LGA neonates, and admissions to a neonatal intensive care unit (Figure 5b,)(56, 72–74, 77–83).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Butalia, 2017, Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis, Diabetic Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is considerable evidence suggesting that metformin is safe during pregnancy.

    “There is considerable evidence suggesting that this agent is safe during pregnancy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the same meta-analysis, metformin did not change the frequency of hypoglycemia or preeclampsia.

    “however, metformin did not change the frequency of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) fetuses or of hypoglycemia and preeclampsia(75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Metformin has a molecular weight of 129 Dalton.

    “Metformin has a molecular weight of 129 Dalton, and therefore, readily crosses the placenta.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by mTOR.

    “Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by mTOR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Metformin's role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and potentially preeclampsia.

    “Originally introduced in clinical practice as an anti-diabetic agent, its role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and more recently, experimental studies, as well as observations in randomized clinical trials, suggest that metformin could have a place in the treatment or prevention of preeclampsia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Gui et al. suggested that metformin reduced the rate of gestational hypertension because of its effects on endothelial function and its decrease in the production of reactive oxygen species.

    “Gui et al.(75) suggested that metformin reduced the rate of gestational hypertension because of its effects on endothelial function and its decrease in the production of reactive oxygen species, the two mechanisms implicated in the pathophysiology of preeclampsia(84–94).”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [75] Gui, 2013, Metformin vs insulin in the management of gestational diabetes: a meta-analysis, PloS One source

      Not checked in the free run.

    • cites [84] Rodgers, 1988, Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [85] Roberts, 1989, Preeclampsia: an endothelial cell disorder, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [86] Myatt, 2009, Vascular biology of preeclampsia, J Thromb Haemost source

      Not checked in the free run.

    • cites [87] Myatt, 2000, Oxidative stress causes vascular dysfunction in the placenta, J Matern Fetal Med

      Not checked in the free run.

    • cites [88] Hubel, 1996, Decreased transferrin and increased transferrin saturation in sera of women with preeclampsia: implications for oxidative stress, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [90] Burton, 2004, Placental oxidative stress: from miscarriage to preeclampsia, J Soc Gynecol Investig source

      Not checked in the free run.

    • cites [91] Burton, 2009, Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia, Placenta source

      Not checked in the free run.

    • cites [92] Myatt, 2010, Review: reactive oxygen and nitrogen species and functional adaptation of the placenta, Placenta source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    In the EMPOWaR trial, compliance was defined as ingestion of at least one tablet for at least 29% of the days between randomization and delivery.

    “By contrast, in the EMPOWaR trial, compliance was defined as ingestion of at least one tablet for at least 29% of the days between randomization and delivery, and only 67% of women fulfilled this criterion(95).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Chiswick, 2015, Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Soluble endoglin is a cell surface co-receptor for transforming growth factor (TGF)-β1, which blocks TGF-β1-mediated activation of endothelial nitric oxide synthase (eNOS) and promotes vasorelaxation.

    “Soluble endoglin is a cell surface co-receptor for transforming growth factor (TGF)-β1, which blocks TGF-β1–mediated activation of endothelial nitric oxide synthase (eNOS) and promotes vasorelaxation(124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Venkatesha, 2006, Soluble endoglin contributes to the pathogenesis of preeclampsia, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Maternal plasma concentrations of sVEGFR-1 and soluble endoglin increase before preeclampsia is diagnosed, making them potential biomarkers for the disease.

    “that causes maternal plasma concentrations of sVEGFR-1 and soluble endoglin to increase before preeclampsia is diagnosed, making them potential biomarkers for the disease(111, 120, 128, 129, 132, 133, 137, 138, 154–179).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [111] Chaiworapongsa, 2014, Pre-eclampsia part 2: prediction, prevention and management, Nat Rev Nephrol source

      Not checked in the free run.

    • cites [120] Chaiworapongsa, 2005, Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia, J Matern Fetal Neonatal Med source

      Not checked in the free run.

    • cites [128] Erez, 2008, The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age, J Matern Fetal Neonatal Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transfection of cells with miR-210 resulted in a significant reduction in oxygen consumption by mitochondria, mitochondrial respiratory deficiency, and production of ROS.

    “Importantly, transfection of cells with miR-210 resulted in a significant reduction in oxygen consumption by mitochondria, mitochondrial respiratory deficiency, and production of ROS(207).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Muralimanoharan, 2012, MIR-210 modulates mitochondrial respiration in placenta with preeclampsia, Placenta source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Torbergsen et al. suggested that these women developed preeclampsia because their dysfunctional mitochondria could not meet the increased energy demands of pregnancy, and the failure of adequate cellular energy production led to an accumulation of ADP, which is able to mediate most of the changes seen in preeclampsia.

    “Torbergsen et al. suggested that these women developed preeclampsia because their dysfunctional mitochondria could not meet the increased energy demands of pregnancy, and the failure of adequate cellular energy production led to an accumulation of ADP, which is able to mediate most of the changes seen in preeclampsia(89, 197)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [197] Masoura, 2015, The involvement of uric acid in the pathogenesis of preeclampsia, Curr Hypertens Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both early and late preeclampsia are associated with an elevated P/O ratio.

    “while both early and late preeclampsia are associated with an elevated P/O ratio(208).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Six of 10 women with a mitochondrial disease had at least one pregnancy complicated by preeclampsia or eclampsia, whereas none had been hypertensive in the non-pregnant state.

    “Six of 10 women with a mitochondrial disease had at least one pregnancy complicated by preeclampsia or eclampsia, whereas none had been hypertensive in the non-pregnant state.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Torbergsen, 1989, Pre-eclampsia: a mitochondrial disease?, Acta Obstet Gynecol Scand source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytokines, such as TNF-α and IL-10, are altered in early and late preeclampsia, and the changes correlate with the type of histopathological changes in the placenta.

    “Although the emphasis on the toxic factors produced by an ischemic placenta has been on the balance between angiogenic and anti-angiogenic factors, evidence now suggests that cytokines, such as TNF-α and IL-10, are altered in early and late preeclampsia, and the changes correlate with the type of histopathological changes in the placenta(185).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Weel, 2016, Association between placental lesions, cytokines and angiogenic factors in pregnant women with preeclampsia, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Early-onset preeclampsia is associated with mitochondrial activation, up-regulation of OPA-1, active DNA replication (resulting from a high respiration rate), and TFAM down-regulation.

    “Thus, early-onset preeclampsia is associated with mitochondrial activation, up-regulation of OPA-1, active DNA replication (resulting from a high respiration rate), and TFAM down-regulation, while both early and late preeclampsia are associated with an elevated P/O ratio(208).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These mitochondrial changes were not limited to uterine tissues, thus implying that mitochondrial dysfunction was a systemic disorder.

    “and these mitochondrial changes were not limited to uterine tissues, thus implying that mitochondrial dysfunction was a systemic disorder.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Shanklin, 1990, Ultrastructural aspects of preeclampsia: II, mitochondrial changes, Am J Obstet Gynecol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Women with early-onset preeclampsia had a two-fold increase in the mRNA expression of OPA-1 and a three-fold increase in OPA-1 protein expression (cleaved and uncleaved forms).

    “Women with early-onset preeclampsia had 1) a two-fold increase in the mRNA expression of OPA (optic atrophy)-1 and a three-fold increase in OPA-1 protein expression (cleaved and uncleaved forms) in patients with early-onset preeclampsia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Vishnyakova, 2016, Mitochondrial role in adaptive response to stress conditions in preeclampsia, Sci Rep source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Brownfoot et al. suggested that metformin regulates these anti-angiogenic factors at the level of the mitochondria.

    “the report also suggested that metformin regulates these anti-angiogenic factors at the level of the mitochondria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Brownfoot, 2016, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ADP is a vasoconstrictor, causes platelet aggregation, and breaks down to uric acid.

    “ADP is a vasoconstrictor, causes platelet aggregation, and breaks down to uric acid.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [89] Many, 1996, Hyperuricemia and xanthine oxidase in preeclampsia, revisited, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [197] Masoura, 2015, The involvement of uric acid in the pathogenesis of preeclampsia, Curr Hypertens Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The placentas of patients with preeclampsia, as well as those from pregnancies with preeclampsia and SGA, overexpress the microRNA (miR)-210.

    “the placentas of patients with preeclampsia(204), as well as those from pregnancies with preeclampsia and SGA(205), overexpress the microRNA (miR)-210”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [204] Zhu, 2009, Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [205] Pineles, 2007, Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia, Am J Obstet Gynecol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miR-210 was induced by hypoxia, and RNA interference knockdown resulted in autophagosomal and siderosomal iron accumulation, implicating siderosis or interstitial trophoblasts as mechanisms in preeclampsia and SGA.

    “Additionally, it was demonstrated that miR-210 was induced by hypoxia, and RNA interference knockdown resulted in autophagosomal and siderosomal iron accumulation, implicating siderosis or interstitial trophoblasts as mechanisms in preeclampsia and SGA(206)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Lee, 2011, MiR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies, Am J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This signaling system is highly expressed in the syncytiotrophoblast, and its activity is regulated by glucose and amino-acid concentrations.

    “This signaling system is highly expressed in the syncytiotrophoblast, and its activity is regulated by glucose and amino-acid concentrations(226, 227, 240).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

      Not checked in the free run.

    • cites [227] Rosario, 2013, Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells, J Physiol source

      Not checked in the free run.

    • cites [240] Lager, 2012, Regulation of nutrient transport across the placenta, J Pregnancy

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nutrient sensing occurs through several pathways, the most important of which are the AMPK pathway, GSK-3, the hexose-amino signaling pathway, the amino-acid response signal transduction pathway, and the mTORC1 pathway.

    “Nutrient sensing occurs through several pathways(225), the most important of which are: the AMPK pathway, which is a global energy sensor in cells;glycogen synthase 3 (GSK-3), which acts as a glucose sensor;the hexose-amino signaling pathway, which depends on the availability of nutrients such as glucose, glutamine, and acetyl-CoA;the amino-acid response signal transduction pathway, which is activ”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate is also an inhibitor of HIF-1α, which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia.

    “However, succinate is also an inhibitor of HIF-1α(213), which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia(214, 215)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [213] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source

      Not checked in the free run.

    • cites [214] Kanasaki, 2008, Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia, Nature source

      Not checked in the free run.

    • cites [215] Tal, 2012, The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis, Biol Reprod source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rapamycin acts by interacting with a family of TOR molecules that is highly-conserved functionally and evolutionarily from yeast to humans, and it contains two multiprotein complexes that are functionally and structurally different: mTORC1 is rapamycin-sensitive; mTORC2 is rapamycin-resistant.

    “Rapamycin acts by interacting with a family of TOR molecules that is highly-conserved functionally and evolutionarily from yeast to humans, and it contains two multiprotein complexes that are functionally and structurally different: the first, mTORC1, is rapamycin-sensitive; and the second, mTORC2, is rapamycin-resistant(237).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Aylett, 2016, Architecture of human mTOR complex 1, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Nutrient sensing is a crucial requirement for fetal development.

    “Nutrient sensing is a crucial requirement for fetal development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Brownfoot et al. found that metformin can improve endothelial dysfunction, reduce the expression of vascular adhesion molecule 1 mRNA induced by TNFα, and improve whole-blood vessel angiogenesis impaired by sFlt-1 or sVEGFR-1.

    “Brownfoot et al.(20) found that metformin can improve endothelial dysfunction, reduce the expression of vascular adhesion molecule 1 mRNA induced by TNFα, and improve whole-blood vessel angiogenesis impaired by sFlt-1 or sVEGFR-1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Brownfoot, 2016, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rapamycin can prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.

    “Rapamycin can also prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [230] Zoncu, 2011, mTOR: from growth signal integration to cancer, diabetes and ageing, Nat Rev Mol Cell Biol source

      Not checked in the free run.

    • cites [231] Hirota, 2011, Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [232] Shimobayashi, 2014, Making new contacts: the mTOR network in metabolism and signalling crosstalk, Nat Rev Mol Cell Biol source

      Not checked in the free run.

    • cites [233] Kim, 2015, MTOR: a pharmacologic target for autophagy regulation, J Clin Invest source

      Not checked in the free run.

    • cites [234] Deng, 2016, P53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing, J Clin Invest source

      Not checked in the free run.

    • cites [235] Kennedy, 2016, The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging, Cell Metab source

      Not checked in the free run.

    • cites [236] Xie, 2016, MTOR inhibitors in cancer therapy, F1000Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Both mTOR complexes control cell growth and metabolism in response to the availability of nutrients, energy, and growth factors.

    “Both complexes control cell growth and metabolism in response to the availability of nutrients, energy, and growth factors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Aylett, 2016, Architecture of human mTOR complex 1, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTOR has key properties in the placenta that include its activation by insulin, IGF-1, and leptin, and its inhibition by cortisol.

    “mTOR has key properties in the placenta(225, 226) that include its activation by insulin, IGF-1, and leptin, and its inhibition by cortisol.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [225] Jansson, 2013, Role of placental nutrient sensing in developmental programming, Clin Obstet Gynecol source

      Not checked in the free run.

    • cites [226] Roos, 2009, Placental mTOR links maternal nutrient availability to fetal growth, Biochem Soc Trans source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The key structure in the placenta responsible for nutrient sensing is the syncytiotrophoblast.

    “The key structure in the placenta responsible for nutritient sensing is the syncytiotrophoblast, which covers the villous tree and is in direct contact with the maternal blood in the intervillous space.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The changes in the mitochondrial function in preeclampsia suggest there are perturbations in the cellular energy balance of patients with this syndrome that affect cell growth and division (especially in the placenta and the fetus); all are modified by metformin.

    “The changes in the mitochondrial function in preeclampsia suggest there are perturbations in the cellular energy balance of patients with this syndrome that affect cell growth and division (especially in the placenta and the fetus); all are modified by metformin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metformin is currently classified as category B in the United States and as category C in Australia.

    “and is currently classified as category B in the United States and as category C in Australia (247, 248).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [247] Gray, 2017, The emerging role of metformin in gestational diabetes mellitus, Diabetes Obes Metab source

      Not checked in the free run.

    • cites [248] Nestler, 2008, Metformin for the treatment of the polycystic ovary syndrome, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nucleocytoplasmic shuttling regulates mTORC activity, and this effect can be reversed by RNA silencing.

    “Nucleocytoplasmic shuttling regulates mTORC activity, an effect that can be reversed by RNA silencing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [278] Wu, 2016, An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Those who were exposed to metformin during fetal life had a larger upper arm circumference and bigger subscapular skin folds and biceps, suggesting a better fat distribution than children exposed to insulin.

    “Those who were exposed to metformin during fetal life had a larger upper arm circumference and bigger subscapular skin folds and biceps, suggesting a better fat distribution than children exposed to insulin(251).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Rowan, 2011, Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin has a molecular weight of 129 dalton, and it crosses the placenta in direct diffusion without affecting the facilitated transfer of glucose.

    “Metformin has a molecular weight of 129 dalton, and it crosses the placenta in direct diffusion without affecting the facilitated transfer of glucose(242).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Nanovskaya, 2006, Transfer of metformin across the dually perfused human placental lobule, Am J Obstet Gynecol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a meta-analysis, metformin-treated diabetic patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index.

    “In a meta-analysis(255), metformin-treated diabetic patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index(255).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] Gandini, 2014, Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders, Cancer Prev Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There were no differences in fat measurements, total fat mass, and percentage of body fat between children exposed in utero to metformin and those exposed to insulin.

    “Moreover, there were no differences in fat measurements, total fat mass, and percentage of body fat(251).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [251] Rowan, 2011, Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Metformin has beneficial effects in gestational hypertension and preeclampsia in obese women.

    “Metformin, long known to be an herbal medicine, has evolved from its use as a popular treatment for diabetes into a drug with a significantly wider array of beneficial effects ranging from cancer treatment to extending longevity, as well as, in our field, gestational hypertension and preeclampsia in obese women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    By preventing access to the nucleus, RagC becomes incapable of stimulating mTORC1 and therefore stimulates cellular growth.

    “By preventing access to the nucleus, RagC becomes incapable of stimulating mTORC1 and, therefore, stimulates cellular growth (Figure 12)(278).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [278] Wu, 2016, An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer, Cell source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    Findings on metformin's lifespan extension in worms and mice are applicable to humans.

    “Metformin, long known to be an herbal medicine, has evolved from its use as a popular treatment for diabetes into a drug with a significantly wider array of beneficial effects ranging from cancer treatment to extending longevity, as well as, in our field, gestational hypertension and preeclampsia in obese women.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • There are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota.

    “We now know there are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 (GLP-1) levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota (25–29).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Gui meta-analysis is cited as supporting a reduction in preeclampsia

    Minor

    The paper says the trial's reduction in preeclampsia was consistent with Gui et al., but earlier states that Gui et al. found no change in preeclampsia frequency.

  • Blocking mTORC1 is said to stimulate growth

    Minor

    The passage says preventing RagC from stimulating mTORC1 therefore stimulates cellular growth, despite describing the same mechanism as growth-inhibiting.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Simonnet, 1927, [Sur les propietes hypoglycemiantes du sulfate de galegine.], Bull Soc Chim Biol Paris, 8
  2. Paulesco, 1921, [Recherches sur le role du pancreas dans l’assimilation nutritive.], Arch Int Physiol, 17, 85
  3. Jackson, 1979, Side-effects of metformin, S Afr Med J, 56, 1113
  4. Myatt, 2000, Oxidative stress causes vascular dysfunction in the placenta, J Matern Fetal Med, 9, 79
  5. Charles, 2004, Metformin crosses the placenta: a modulator for fetal insulin resistance?, Br Med J, 327, 880

Cited by

Sorted by citations

Related

Authors
Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B. H., & Grossman, L. I.
Affiliations
  • United States Department of Health and Human Services (US)
  • Ben-Gurion University of the Negev (IL)
  • Wayne State University (US)
  • Seoul National University (KR)
Corresponding author
  • Romero, Roberto
  • Erez, Offer
ORCID
Venue
American Journal of Obstetrics and Gynecology
Publisher
Elsevier BV
Published
2017-09
Volume
217
Issue
3
Pages
282-302
ISSN
0002-9378 (ISSN-L)
DOI
10.1016/j.ajog.2017.06.003
PMC
PMC6084482
OpenAlex
W2625297718
Semantic Scholar
4dc479bc8b2017b127f102653c2604ced2829137
Cited by
253
References
294
Citations by year
2026: 10 · 2025: 16 · 2024: 24 · 2023: 25 · 2022: 34 · 2021: 38 · 2020: 29 · 2019: 30 · 2018: 39 · 2017: 8
FWCI
4.93
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Obstetrics and Gynecology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201300006C, ZIAHD002400)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, gestational diabetes mellitus, preeclampsia prevention, prediabetes, polycystic ovary syndrome, macrosomia, large for gestational age, anti-angiogenic factors, soluble fms-like tyrosine kinase-1, soluble endoglin, endothelial dysfunction, mitochondrial function, rapamycin, energy homeostasis, placental transfer, drug safety in pregnancy, chemoprevention, longevity, aging
MeSH terms
Female, Humans, Hypoglycemic Agents, Longevity, Maternal-Fetal Exchange, Metformin, Neoplasms, Pre-Eclampsia, Pregnancy, Randomized Controlled Trials as Topic, Diabetes, Gestational, Maternal Nutritional Physiological Phenomena, Fetal Development, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review