Long-term effects of prenatal exposure to metformin on the health of children based on follow-up studies of randomized controlled trials: a systematic review and meta-analysis

Abstract

Purpose

Oral antidiabetic medication of metformin is increasingly used in pregnant women with gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS) and obesity. The drug passes through the placenta and can potentially influence the fetus. The aim of the study is to investigate the possible long-term effects of prenatal exposure to metformin on growth and development of the offspring.

Methods

A systematic review and meta-analysis was conducted to examine the longer term outcomes by the follow-up studies of the already published RCTs focusing on the body composition, metabolic parameters and neurophysiological development of the children prenatally exposed to metformin. The primary sources of the reviewed studies through August 2018, with restriction on the language of English, were Pubmed and Embase.

Results

11 follow-up studies were included, with a maximal age of children being 13 years, comprising 823 children of mothers with GDM or PCOS who were randomized to either metformin or insulin/placebo during pregnancy. From the pooled meta-analysis we found that children prenatal exposure to metformin were associated with a significantly heavier weight (MD = 0.48 kg, 95% CI 0.24 kg, 0.73 kg; P = 0.0001, I2 = 0). As for other parameters of body composition, metabolic parameters and neurophysiological development, the results were similar between metformin and placebo/insulin use.

Conclusion

Increased offspring weight was more observed in children prenatal exposure to metformin. Heathcare providers and patients should be aware that metformin is increasingly prescribed in pregnancy based on the relatively limited evidences but nonetheless encouraging long-term offspring data are available.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Mitanchez D, Burguet A, Simeoni U (2014) Infants born to mothers with gestational diabetes mellitus: mild neonatal effects, a long-term threat to global health. J Pediatr. 164:445–450

    Article  PubMed  Google Scholar 

  2. 2.

    Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE et al (2015) Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 3:778–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R et al (2016) Metformin versus placebo in obese pregnant women without diabetes mellitus. N Engl J Med. 374:434–443

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Vanky E, Zahlsen K, Spigset O, Carlsen SM (2005) Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 83:1575–1578

    Article  PubMed  Google Scholar 

  5. 5.

    Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S (2012) Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract. 98:422–429

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Mesdaghinia E, Samimi M, Homaei Z, Saberi F, Moosavi SG, Yaribakht M (2013) Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial. Int J Prev Med. 4:327–333

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RP (2013) Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol. 209(34):e1–7

    Google Scholar 

  8. 8.

    Moore L, Briery C, Clokey D, Martin R, Williford N, Bofill J et al (2007) Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med. 52:1011–1015

    CAS  PubMed  Google Scholar 

  9. 9.

    Scarpello JH, Howlett HC (2008) Metformin therapy and clinical uses. Diab Vasc Dis Res. 5:157–167

    Article  PubMed  Google Scholar 

  10. 10.

    Ali AT, Ferris WF, Naran NH, Crowther NJ (2011) Insulin resistance in the control of body fat distribution: a new hypothesis. Horm Metab Res. 43:77–80

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Li G, Zhao S, Cui S, Li L, Xu Y, Li Y (2015) Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs. Arch Gynecol Obstet. 292:111–120

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Zhao LP, Sheng XY, Zhou S, Yang T, Ma LY, Zhou Y et al (2015) Metformin versus insulin for gestational diabetes mellitus: a meta-analysis. Br J Clin Pharmacol. 80:1224–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L (2017) Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet Med. 34:27–36

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 151:264–269

    Article  PubMed  Google Scholar 

  15. 15.

    Tartarin P, Moison D, Guibert E, Dupont J, Habert R, Rouiller-Fabre V et al (2012) Metformin exposure affects human and mouse fetal testicular cells. Hum Reprod. 27:3304–3314

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. March 2011. Cochrane Collaboration, 2011. Available at: https://www.cochrane-handbook.org. Accessed March 29, 2016.

  17. 17.

    Review Manager (RevMan) [Computer program]. Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011

  18. 18.

    Hanem LGE, Stridsklev S, Júlíusson PB, Salvesen Ø, Roelants M, Carlsen SM et al (2018) Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: follow-up of two RCTs. J Clin Endocrinol Metab. 103:1612–1621

    Article  PubMed  Google Scholar 

  19. 19.

    Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S et al (2018) Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care. 6:e000456

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Van Dam JM, Garrett AJ, Schneider LA, Hodyl NA, Goldsworthy MR, Coat S et al (2018) Reduced cortical excitability, neuroplasticity, and salivary cortisol in 11–13-year-old children born to women with gestational diabetes mellitus. EBioMedicine. 31:143–149

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Tertti K, Toppari J, Virtanen HE, Sadov S, Rönnemaa T (2016) Metformin treatment does not affect testicular size in offspring born to mothers with gestational diabetes. Rev Diabet Stud. 13:59–65

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wouldes TA, Battin M, Coat S, Rush EC, Hague WM, Rowan JA (2016) Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch Dis Child Fetal Neonatal Ed. 101:F488–493

    Article  PubMed  Google Scholar 

  23. 23.

    Battin MR, Obolonkin V, Rush E, Hague W, Coat S, Rowan J (2015) Blood pressure measurement at two years in offspring of women randomized to a trial of metformin for GDM: follow up data from the MiG trial. BMC Pediatr. 15:54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ijäs H, Vääräsmäki M, Saarela T, Keravuo R, Raudaskoski T (2015) A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG 122:994–1000

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Tertti K, Eskola E, Rönnemaa T, Haataja L (2015) Neurodevelopment of two-year-old children exposed to metformin and insulin in gestational diabetes mellitus. J Dev Behav Pediatr. 36:752–757

    Article  PubMed  Google Scholar 

  26. 26.

    Carlsen SM, Martinussen MP, Vanky E (2012) Metformin’s effect on first-year weight gain: a follow-up study. Pediatrics 130:e1222–e1226

    Article  PubMed  Google Scholar 

  27. 27.

    Rø TB, Ludvigsen HV, Carlsen SM, Vanky E (2012) Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest. 72:570–575

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM (2011) Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34:2279–2284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tertti K, Ekblad U, Koskinen P, Vahlberg T, Rönnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab. 2013;15:246-251.

  30. 30.

    Vanky E, Stridsklev S, Heimstad R, Romundstad P, Skogøy K, Kleggetveit O et al (2010) Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 95:E448–455

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM (2004) Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod. 19:1734–1740

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Rowan 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.

  33. 33.

    Ijäs H, Vääräsmäki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T et al (2011) Metformin should be considered in the treatment of gestational diabetes: a prospective randomized study. BJOG 118:880–885

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Salomäki-Myftari H, Vähätalo LH, Ailanen L, Pietilä S, Laiho A, Hänninen A et al (2016) Neuropeptide Y overexpressing female and male mice show divergent metabolic but not gut microbial responses to prenatal metformin exposure. PLoS One 11:e0163805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Authors

Contributions

QX: designed the study, collected data, and analyzed/interpreted data wrote the draft critically for important intellectual content approved the final version to be published. QX: collected data, and analyzed/interpreted data critically for important intellectual content approved the final version to be published.

Corresponding author

Correspondence to Qing Xu.

Ethics declarations

Conflict of interest

There are none to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xu, Q., Xie, Q. Long-term effects of prenatal exposure to metformin on the health of children based on follow-up studies of randomized controlled trials: a systematic review and meta-analysis. Arch Gynecol Obstet 299, 1295–1303 (2019). https://doi.org/10.1007/s00404-019-05124-w

Download citation

Keywords

  • Metformin
  • Gestational diabetes mellitus
  • Polycystic ovary syndrome
  • Offspring