Risk of severe maternal morbidity or death in relation to elevated hemoglobin A1c preconception, and in early pregnancy: A population-based cohort study

Autoři: Alexander J. F. Davidson aff001;  Alison L. Park aff001;  Howard Berger aff001;  Kazuyoshi Aoyama aff001;  Ziv Harel aff001;  Jocelynn L. Cook aff006;  Joel G. Ray aff001
Působiště autorů: University of Toronto, Toronto, Ontario, Canada aff001;  ICES, Toronto, Ontario, Canada aff002;  Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada aff003;  Department of Obstetrics and Gynaecology, St. Michael’s Hospital, Toronto, Ontario, Canada aff004;  Department of Anesthesia and Pain Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada aff005;  Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa, Ontario, Canada aff006;  The Society of Obstetricians and Gynaecologists of Canada, Ottawa, Ontario, Canada aff007
Vyšlo v časopise: Risk of severe maternal morbidity or death in relation to elevated hemoglobin A1c preconception, and in early pregnancy: A population-based cohort study. PLoS Med 17(5): e1003104. doi:10.1371/journal.pmed.1003104
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003104



The relation between prepregnancy average glucose concentration and a woman’s risk of severe maternal morbidity (SMM) is unknown. The current study evaluated whether an elevated preconception hemoglobin A1c (A1c) is associated with SMM or maternal death among women with and without known prepregnancy diabetes mellitus (DM).

Methods and findings

A population-based cohort study was completed in Ontario, Canada, where there is universal healthcare. The main cohort included 31,225 women aged 16–50 years with a hospital live birth or stillbirth from 2007 to 2015, and who had an A1c measured within 90 days before conception, including 28,075 women (90%) without known prepregnancy DM. The main outcome was SMM or maternal mortality from 23 weeks’ gestation up to 42 days postpartum. Relative risks (RRs) were generated using modified Poisson regression, adjusting for the main covariates of maternal age, multifetal pregnancy, world region of origin, and tobacco/drug dependence. The mean maternal age was 31.1 years. Overall, SMM or death arose among 682 births (2.2%). The RR of SMM or death was 1.16 (95% CI 1.14–1.19; p < 0.001) per 0.5% increase in A1c and 1.16 (95% CI 1.13–1.18; p < 0.001) after adjusting for the main covariates. The adjusted relative risk (aRR) was increased among those with (1.11, 95% CI 1.07–1.14; p < 0.001) and without (1.15, 95% CI 1.02–1.29; p < 0.001) known prepregnancy diabetes, and upon further adjusting for body mass index (BMI) (1.15, 95% CI 1.11–1.20; p < 0.001), or chronic hypertension and prepregnancy serum creatinine (1.11, 95% CI 1.04–1.18; p = 0.002). The aRR of SMM or death was 1.31 (95% CI 1.06–1.62; p = 0.01) in those with a preconception A1c of 5.8%–6.4%, and 2.84 (95% CI 2.31–3.49; p < 0.001) at an A1c > 6.4%, each relative to an A1c < 5.8%. Among those without previously recognized prepregnancy diabetes and whose A1c was >6.4%, the aRR of SMM or death was 3.25 (95% CI 1.76–6.00; p < 0.001). Study limitations include that selection bias may have incorporated less healthy women tested for A1c, and BMI was unknown for many women.


Our findings indicate that women with an elevated A1c preconception may be at higher risk of SMM or death in pregnancy or postpartum, including those without known prepregnancy DM.

Klíčová slova:

Birth – diabetes mellitus – HbA1c – Hemoglobin – Hypertensive disorders in pregnancy – Morbidity – Obesity – Pregnancy


1. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 2013;8: 228–236. doi: 10.1038/nrendo.2011.183 22064493

2. Caballero B. The Global Epidemic of Obesity. Epidemiol Rev 2007;29: 1–5. doi: 10.1093/epirev/mxm012 17569676

3. Weykamp C. HbA1c: A Review of Analytical and Clinical Aspects. Ann Lab Med 2013;33: 393–400. doi: 10.3343/alm.2013.33.6.393 24205486

4. Punthakee Z, Goldenberg R, Katz P. Diabetes Canada Clinical Practice Guidelines: Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Can J Diabetes 2018;42: S10–S15. doi: 10.1016/j.jcjd.2017.10.003

5. Gabbay-Bensiv R, Reece EA, Wang F, Yang P. Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis. World J Diabetes 2015;6: 481–488. doi: 10.4239/wjd.v6.i3.481 25897357

6. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 2009;301: 636–650. doi: 10.1001/jama.2009.113 19211471

7. Sibai BM, Caritis SN, Hauth JC, MacPherson C, VanDorsten JP, Klebanoff M, et al. Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies. Am J Obstet 2000;183: 1520–4.

8. Cnattingius S1, Villamor E, Johansson S, Edstedt Bonamy AK, Persson M, Wikström AK, et al. Maternal obesity and the risk of preterm delivery. JAMA 2013;309: 2362–70. doi: 10.1001/jama.2013.6295 23757084

9. Han CS, Herrin MA, Pitruzzello MC, Mulla MJ, Werner EF, Pettker CM, et al. Glucose and Metformin Modulate Human First Trimester Trophoblast Function: A Model and Potential Therapy for Diabetes-Associated Uteroplacental Insufficiency. Am J Reprod Immunol 2015;73: 362–371. doi: 10.1111/aji.12339 25394884

10. He MY, Wang G, Han SS, Jin Y, Li H, Wu X, et al. Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta. Open Biology 2016;6: 160064. doi: 10.1098/rsob.160064 27383629

11. Gauster M, Majali-Martinez A, Maninger S, Gutschi E, Greimel PH, Ivanisevic M, et al. Maternal type 1 diabetes activates stress response in early placenta. Placenta 2017;50: 110–116. doi: 10.1016/j.placenta.2017.01.118 28161055

12. Redman CW, Sargent IL. Review: Latest Advances in Understanding Preeclampsia. Science 2005;308: 1592–1594. doi: 10.1126/science.1111726 15947178

13. Desoye G. The Human Placenta in Diabetes and Obesity: Friend or Foe? The 2017 Norbert Freinkel Award Lecture. Diabetes Care 2018;41: 1362–1369. doi: 10.2337/dci17-0045 29934479

14. O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: A systematic overview. Epidemiology 2003;14: 368–374. doi: 10.1097/00001648-200305000-00020 12859040

15. Lisonkova S, Muraca GM, Potts J, Liauw J, Chan WS, Skoll A et al. Association Between Prepregnancy Body Mass Index and Severe Maternal Morbidity. JAMA 2018;318: 1777–1786.

16. de Boer I1, Kestenbaum B, Rue TC, Steffes MW, Cleary PA, Molitch ME, et al. Insulin Therapy, Hyperglycemia, and Hypertension in Type 1 Diabetes Mellitus. Arch Intern Med 2008;168: 1867–1873. doi: 10.1001/archinternmed.2008.2 18809813

17. Bartsch E, Medcalf KE, Park AL, Ray JG. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ 2016;353: i1753. doi: 10.1136/bmj.i1753 27094586

18. Hitti J, Sienas L, Walker S, Benedetti TJ, Easterling T. Contribution of hypertension to severe maternal morbidity. Am J Obstet Gynecol 2018;219: 405e1–405e7. doi: 10.1016/j.ajog.2018.07.002 30012335

19. Cavero-Redondo I, Martínez-Vizcaíno V, Soriano-Cano A, Martínez-Hortelano JA, Sanabria-Martínez G, Álvarez-Bueno C. Glycated haemoglobin A1c as a predictor of preeclampsia in type 1 diabetic pregnant women: A systematic review and meta-analysis. Pregnancy Hypertens 2018;14: 49–74. doi: 10.1016/j.preghy.2018.04.004 30527118

20. Ray JG, Park AL, Dzakpasu S, Dayan N, Deb-Rinker P, Luo W, et al. Prevalence of Severe Maternal Morbidity and Factors Associated with Maternal Mortality in Ontario, Canada. JAMA Net Open 2018;1: e184571. doi: 10.1001/jamanetworkopen.2018.4571 30646359

21. Shields LE, Wiesner S, Klein C, Pelletreau B, Hedriana HL. Use of Maternal Early Warning Trigger tool reduces maternal morbidity. Am J Obstet Gynecol 2016;214: 527.e1–527.e6. doi: 10.1016/j.ajog.2016.01.154 26924745

22. Dzakpasu S, Deb-Rinker P, Arbour L, Darling EK, Kramer MS, Liu S, et al. Severe Maternal Morbidity in Canada: Temporal Trends and Regional Variations, 2003–2016. J Obstet Gynaecol Can 2019;41: 1589–1598.e16. doi: 10.1016/j.jogc.2019.02.014 31060985

23. Canadian Institute for Health Information. Too Early, Too Small: A Profile of Small Babies Across Canada. 2009 [cited 2020 Apr 20]. Available from: https://secure.cihi.ca/free_products/too_early_too_small_en.pdf

24. You JJ, Alter DA, Stukel TA, McDonald SD, Laupacis A, Liu Y, et al. Proliferation of prenatal ultrasonography. Can Med Assoc J 2010; 182:143–51. doi: 10.1503/cmaj.090979 20048009

25. Arias CF and Arias CF. 2017. How do red blood cells know when to die? Roy Soc Open Sci 2017;4: e160850. doi: 10.1098/rsos.160850 28484605

26. Berard LD, Siemens R, Woo V. Diabetes Canada Clinical Practice Guidelines: Monitoring Glycemic Control. Can J Diabetes 2018;42: S47–S53. doi: 10.1016/j.jcjd.2017.10.007

27. Health Quality Ontario. Point-of-care hemoglobin A1c testing: an evidence-based analysis. Ont Health Technol Assess Ser 2014;14: 1–30 [cited 2020 Apr 20]. Available from: https://www.hqontario.ca/Portals/0/Documents/evidence/reports/eba-poc-hba1c-140731-en.pdf

28. Little RR, Rohlfing C, Sacks DB. The National Glycohemoglobin Standardization Program: Over 20 Years of Improving Hemoglobin A1c Measurement. Clin Chem 2019;65: 839–848. doi: 10.1373/clinchem.2018.296962 30518660

29. Steer P. The epidemiology of preterm labour. Brit J Obstet Gynecol 2005;112: 1–3.

30. Dzakpasu S, Deb-Rinker P, Arbour L, Darling EK, Kramer MS, Liu S, et al. Severe maternal morbidity surveillance: Monitoring pregnant women at high risk for prolonged hospitalisation and death. Paediatr Perinat Epidemiol 2019 Aug 12. doi: 10.1111/ppe.12574 31407359

31. Yelland LN, Salter AB, Ryan P. Performance of the modified Poisson regression approach for estimating relative risks from clustered prospective data. Am J Epidemiol. 2011;174: 984–992. doi: 10.1093/aje/kwr183 21841157

32. Harel Z, McArthur E, Hladunewich M, Dirk JS, Wald R, Garg AX, et al. Serum Creatinine Levels Before, During, and After Pregnancy. JAMA 2019;321: 205–207. doi: 10.1001/jama.2018.17948 30644975

33. Hughes RCE, Rowan J, Florkowski CM. Is There a Role for HbA1c in Pregnancy? Curr Diab Rep 2016;16: 4–14. doi: 10.1007/s11892-015-0697-z

34. Gallagher EJ, Le Roith D, Bloomgarden Z. Review of hemoglobin A(1c) in the management of diabetes. J Diabetes 2009;1: 9–17. doi: 10.1111/j.1753-0407.2009.00009.x 20923515

35. Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med 2014;29: 388–94. doi: 10.1007/s11606-013-2595-x 24002631

36. Berger H, Melamed N, Murray-Davis B, Hasan H, Mawjee K, Barrett J et al. Prevalence of Pre-Pregnancy Diabetes, Obesity, and Hypertension in Canada. J Obstet Gynaecol Can 2019; Mar 23. pii: S1701-2163(19)30068-4. doi: 10.1016/j.jogc.2019.01.020 30914233

37. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007–2008 to 2015–2016. JAMA 2018;319: 1723–1725. doi: 10.1001/jama.2018.3060 29570750

38. Vijayakumar P, Nelson RG, Hanson RL, Knowler WC, Sinha M. HbA1c and the Prediction of Type 2 Diabetes in Children and Adults. Diabetes Care 2017;40: 16–21. doi: 10.2337/dc16-1358 27810987

39. Zhang X1, Gregg EW, Williamson DF, Barker LE, Thomas W, Bullard KM, et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care 2010;33: 1665–73. doi: 10.2337/dc09-1939 20587727

40. Lawton BA, Jane MacDonald E, Stanley J, Daniells K, Geller SE. Preventability review of severe maternal morbidity. Acta Obstet Gynecol Scand 2019;98: 515–522. doi: 10.1111/aogs.13526 30586147

41. Seidler AL, Askie L, Ray JG. Optimal aspirin dosing for preeclampsia prevention. Am J Obstet Gynecol 2018;219: 117–118. doi: 10.1016/j.ajog.2018.03.018 29588190

42. Bartsch E, Park AL, Kingdom JC, Ray JG. Risk threshold for starting low dose aspirin in pregnancy to prevent preeclampsia: an opportunity at a low cost. PLoS ONE 2015;10: e0116296. doi: 10.1371/journal.pone.0116296 25789633

43. Roberge S, Giguère Y, Villa P, Nicolaides K, Vainio M, Forest JC, et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol 2012;29: 551–6. doi: 10.1055/s-0032-1310527 22495898

44. Feig DS, Berger H, Donovan L, Godbout A, Kader T, Keely E, et al. Diabetes Canada Clinical Practice Guidelines: Diabetes in Pregnancy. Can J Diabetes 2018;42: S255–S282 doi: 10.1016/j.jcjd.2017.10.038

45. Selvin E, Zhu H, Brancati F. Elevated A1C in Adults Without a History of Diabetes in the U.S. Diabetes Care 2009;32: 828–833. doi: 10.2337/dc08-1699 19196895

46. Ray JG, O'Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94: 435–44. doi: 10.1093/qjmed/94.8.435 11493721

47. Stephenson J, Heslehurst N, Hall J, Schoenaker DAJM, Hutchinson J, Cade JE, et al. Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health. Lancet 2018;391: 1830–1841. doi: 10.1016/S0140-6736(18)30311-8 29673873

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