Abstract
Background:
Maternal type 1 diabetes (T1D) has been linked to preterm birth and other adverse pregnancy outcomes. How these risks vary with glycated hemoglobin (or hemoglobin A1c [HbA1c]) levels is unclear.
Objective:
To examine preterm birth risk according to periconceptional HbA1c levels in women with T1D.
Design:
Population-based cohort study.
Setting:
Sweden, 2003 to 2014.
Patients:
2474 singletons born to women with T1D and 1 165 216 reference infants born to women without diabetes.
Measurements:
Risk for preterm birth (<37 gestational weeks). Secondary outcomes were neonatal death, large for gestational age, macrosomia, infant birth injury, hypoglycemia, respiratory distress, 5-minute Apgar score less than 7, and stillbirth.
Results:
Preterm birth occurred in 552 (22.3%) of 2474 infants born to mothers with T1D versus 54 287 (4.7%) in 1 165 216 infants born to mothers without diabetes. The incidence of preterm birth was 13.2% in women with a periconceptional HbA1c level below 6.5% (adjusted risk ratio [aRR] vs. women without T1D, 2.83 [95% CI, 2.28 to 3.52]), 20.6% in those with a level from 6.5% to less than 7.8% (aRR, 4.22 [CI, 3.74 to 4.75]), 28.3% in those with a level from 7.8% to less than 9.1% (aRR, 5.56 [CI, 4.84 to 6.38]), and 37.5% in those with a level of 9.1% or higher (aRR, 6.91 [CI, 5.85 to 8.17]). The corresponding aRRs for medically indicated preterm birth (n = 320) were 5.26 (CI, 3.83 to 7.22), 7.42 (CI, 6.21 to 8.86), 11.75 (CI, 9.72 to 14.20), and 17.51 (CI, 14.14 to 21.69), respectively. The corresponding aRRs for spontaneous preterm birth (n = 223) were 1.81 (CI, 1.31 to 2.52), 2.86 (CI, 2.38 to 3.44), 2.88 (CI, 2.23 to 3.71), and 2.80 (CI, 1.94 to 4.03), respectively. Increasing HbA1c levels were associated with the study's secondary outcomes: large for gestational age, hypoglycemia, respiratory distress, low Apgar score, neonatal death, and stillbirth.
Limitation:
Because HbA1c levels were registered annually at routine visits, they were not available for all pregnant women with T1D.
Conclusion:
The risk for preterm birth was strongly linked to periconceptional HbA1c levels. Women with HbA1c levels consistent with recommended target levels also were at increased risk.
Primary Funding Source:
Swedish Diabetes Foundation.
References
- 1.
Correa A ,Bardenheier B ,Elixhauser A ,Geiss LS ,Gregg E . Trends in prevalence of diabetes among delivery hospitalizations, United States, 1993-2009. Matern Child Health J. 2015;19:635-42. [PMID: 24996952] doi:10.1007/s10995-014-1553-5 CrossrefMedlineGoogle Scholar - 2.
Murphy HR ,Steel SA ,Roland JM ,Morris D ,Ball V ,Campbell PJ ,et al ;East Anglia Study Group for Improving Pregnancy Outcomes in Women with Diabetes (EASIPOD) . Obstetric and perinatal outcomes in pregnancies complicated by Type 1 and Type 2 diabetes: influences of glycaemic control, obesity and social disadvantage. Diabet Med. 2011;28:1060-7. [PMID: 21843303] doi:10.1111/j.1464-5491.2011.03333.x CrossrefMedlineGoogle Scholar - 3.
Eidem I ,Vangen S ,Hanssen KF ,Vollset SE ,Henriksen T ,Joner G ,et al . Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia. 2011;54:2771-8. [PMID: 21866407] doi:10.1007/s00125-011-2281-7 CrossrefMedlineGoogle Scholar - 4.
Owens LA ,Sedar J ,Carmody L ,Dunne F . Comparing type 1 and type 2 diabetes in pregnancy- similar conditions or is a separate approach required? BMC Pregnancy Childbirth. 2015;15:69. [PMID: 25885892] doi:10.1186/s12884-015-0499-y CrossrefMedlineGoogle Scholar - 5.
Evers IM ,de Valk HW ,Visser GH . Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328:915. [PMID: 15066886] CrossrefMedlineGoogle Scholar - 6.
Inkster ME ,Fahey TP ,Donnan PT ,Leese GP ,Mires GJ ,Murphy DJ . Poor glycated haemoglobin control and adverse pregnancy outcomes in type 1 and type 2 diabetes mellitus: systematic review of observational studies. BMC Pregnancy Childbirth. 2006;6:30. [PMID: 17074087] CrossrefMedlineGoogle Scholar - 7.
Blencowe H ,Cousens S ,Oestergaard MZ ,Chou D ,Moller AB ,Narwal R ,et al . National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162-72. [PMID: 22682464] doi:10.1016/S0140-6736(12)60820-4 CrossrefMedlineGoogle Scholar - 8.
American Diabetes Association . 13. Management of diabetes in pregnancy. Diabetes Care. 2017;40Suppl 1 S114-9. CrossrefMedlineGoogle Scholar - 9. National Institute for Health and Care Excellence. Diabetes in pregnancy: management from preconception to the postnatal period. Accessed at www.nice.org.uk/guidance/ng3 on 19 March 2019. Google Scholar
- 10.
Blumer I ,Hadar E ,Hadden DR ,Jovanovic L ,Mestman JH ,Murad MH ,et al . Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227-49. [PMID: 24194617] doi:10.1210/jc.2013-2465 CrossrefMedlineGoogle Scholar - 11.
Ludvigsson JF ,Otterblad-Olausson P ,Pettersson BU ,Ekbom A . The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol. 2009;24:659-67. [PMID: 19504049] doi:10.1007/s10654-009-9350-y CrossrefMedlineGoogle Scholar - 12.
Eliasson B ,Gudbjörnsdottir S . Diabetes care—improvement through measurement. Diabetes Res Clin Pract. 2014;106 Suppl 2:S291-4. [PMID: 25550056] doi:10.1016/S0168-8227(14)70732-6 CrossrefMedlineGoogle Scholar - 13.
Ludvigsson JF ,Andersson E ,Ekbom A ,Feychting M ,Kim JL ,Reuterwall C ,et al . External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450. [PMID: 21658213] doi:10.1186/1471-2458-11-450 CrossrefMedlineGoogle Scholar - 14. Centre for Epidemiology, Swedish National Board of Health and Welfare. The Swedish Medical Birth Register: A Summary of Content and Quality. Accessed at www.socialstyrelsen.se/Lists/Artikelkatalog/Attachments/10655/2003-112-3_20031123.pdf on 19 March 2019. Google Scholar
- 15.
Brooke HL ,Talbäck M ,Hörnblad J ,Johansson LA ,Ludvigsson JF ,Druid H ,et al . The Swedish cause of death register. Eur J Epidemiol. 2017;32:765-773. [PMID: 28983736] doi:10.1007/s10654-017-0316-1 CrossrefMedlineGoogle Scholar - 16.
Hoelzel W ,Weykamp C ,Jeppsson JO ,Miedema K ,Barr JR ,Goodall I ,et al ;IFCC Working Group on HbA1c Standardization . IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study. Clin Chem. 2004;50:166-74. [PMID: 14709644] CrossrefMedlineGoogle Scholar - 17.
Høgberg U ,Larsson N . Early dating by ultrasound and perinatal outcome. A cohort study. Acta Obstet Gynecol Scand. 1997;76:907-12. [PMID: 9435727] CrossrefMedlineGoogle Scholar - 18.
Marsál K ,Persson PH ,Larsen T ,Lilja H ,Selbing A ,Sultan B . Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 1996;85:843-8. [PMID: 8819552] CrossrefMedlineGoogle Scholar - 19.
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;174:984-92. [PMID: 21841157] doi:10.1093/aje/kwr183 CrossrefMedlineGoogle Scholar - 20.
McNutt LA ,Wu C ,Xue X ,Hafner JP . Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol. 2003;157:940-3. [PMID: 12746247] CrossrefMedlineGoogle Scholar - 21.
Wacholder S . Binomial regression in GLIM: estimating risk ratios and risk differences. Am J Epidemiol. 1986;123:174-84. [PMID: 3509965] CrossrefMedlineGoogle Scholar - 22.
Richardson DB ,Kinlaw AC ,MacLehose RF ,Cole SR . Standardized binomial models for risk or prevalence ratios and differences. Int J Epidemiol. 2015;44:1660-72. [PMID: 26228585] doi:10.1093/ije/dyv137 CrossrefMedlineGoogle Scholar - 23.
Liu Y ,De A . Multiple imputation by fully conditional specification for dealing with missing data in a large epidemiologic study. Int J Stat Med Res. 2015;4:287-295. [PMID: 27429686] CrossrefMedlineGoogle Scholar - 24.
VanderWeele TJ ,Ding P . Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167:268-274. [PMID: 28693043]. doi:10.7326/M16-2607 LinkGoogle Scholar - 25.
Ludvigsson JF ,Håberg SE ,Knudsen GP ,Lafolie P ,Zoega H ,Sarkkola C ,et al . Ethical aspects of registry-based research in the Nordic countries. Clin Epidemiol. 2015;7:491-508. [PMID: 26648756] doi:10.2147/CLEP.S90589 CrossrefMedlineGoogle Scholar - 26.
Nielsen GL ,Møller M ,Sørensen HT . HbA1c in early diabetic pregnancy and pregnancy outcomes: a Danish population-based cohort study of 573 pregnancies in women with type 1 diabetes. Diabetes Care. 2006;29:2612-6. [PMID: 17130193] CrossrefMedlineGoogle Scholar - 27.
Maresh MJ ,Holmes VA ,Patterson CC ,Young IS ,Pearson DW ,Walker JD ,et al ;Diabetes and Pre-eclampsia Intervention Trial Study Group . Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes. Diabetes Care. 2015;38:34-42. [PMID: 25368104] doi:10.2337/dc14-1755 CrossrefMedlineGoogle Scholar - 28.
Jensen DM ,Korsholm L ,Ovesen P ,Beck-Nielsen H ,Moelsted-Pedersen L ,Westergaard JG ,et al . Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care. 2009;32:1046-8. [PMID: 19265024] doi:10.2337/dc08-2061 CrossrefMedlineGoogle Scholar - 29.
Suhonen L ,Hiilesmaa V ,Teramo K . Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia. 2000;43:79-82. [PMID: 10663219] CrossrefMedlineGoogle Scholar - 30.
Ekbom P ,Damm P ,Feldt-Rasmussen B ,Feldt-Rasmussen U ,Jensen DM ,Mathiesen ER . Elevated third-trimester haemoglobin A 1c predicts preterm delivery in type 1 diabetes. J Diabetes Complications. 2008;22:297-302. [PMID: 18413167] doi:10.1016/j.jdiacomp.2007.03.008 CrossrefMedlineGoogle Scholar - 31. Multicenter survey of diabetic pregnancy in France. Gestation and diabetes in France study group. Diabetes Care. 1991;14:994-1000. [PMID: 1797514] CrossrefMedlineGoogle Scholar
- 32.
Lepercq J ,Coste J ,Theau A ,Dubois-Laforgue D ,Timsit J . Factors associated with preterm delivery in women with type 1 diabetes: a cohort study. Diabetes Care. 2004;27:2824-8. [PMID: 15562192] CrossrefMedlineGoogle Scholar - 33.
Starikov RS ,Inman K ,Chien EK ,Anderson BL ,Rouse DJ ,Lopes V ,et al . Can hemoglobin A1c in early pregnancy predict adverse pregnancy outcomes in diabetic patients? J Diabetes Complications. 2014;28:203-7. [PMID: 24268941] doi:10.1016/j.jdiacomp.2013.10.004 CrossrefMedlineGoogle Scholar - 34.
Tennant PW ,Glinianaia SV ,Bilous RW ,Rankin J ,Bell R . Pre-existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-based study. Diabetologia. 2014;57:285-94. [PMID: 24292565] doi:10.1007/s00125-013-3108-5 CrossrefMedlineGoogle Scholar - 35.
Chwalisz K ,Garfield RE . Nitric oxide as the final metabolic mediator of cervical ripening. Hum Reprod. 1998;13:245-8. [PMID: 9557812] CrossrefMedlineGoogle Scholar - 36.
Thomson AJ ,Lunan CB ,Cameron AD ,Cameron IT ,Greer IA ,Norman JE . Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial. Br J Obstet Gynaecol. 1997;104:1054-7. [PMID: 9307534] CrossrefMedlineGoogle Scholar - 37.
Starikov R ,Dudley D ,Reddy UM . Stillbirth in the pregnancy complicated by diabetes. Curr Diab Rep. 2015;15:11. [PMID: 25667005] doi:10.1007/s11892-015-0580-y CrossrefMedlineGoogle Scholar - 38.
Glinianaia SV ,Tennant PW ,Bilous RW ,Rankin J ,Bell R . HbA(1c) and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study. Diabetologia. 2012;55:3193-203. [PMID: 23015260] doi:10.1007/s00125-012-2721-z CrossrefMedlineGoogle Scholar - 39.
Emilsson L ,Lindahl B ,Köster M ,Lambe M ,Ludvigsson JF . Review of 103 Swedish healthcare quality registries. J Intern Med. 2015;277:94-136. [PMID: 25174800] doi:10.1111/joim.12303 CrossrefMedlineGoogle Scholar - 40.
Middleton P ,Crowther CA ,Simmonds L . Different intensities of glycaemic control for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev. 2016:CD008540. [PMID: 27142841] doi:10.1002/14651858.CD008540.pub4 CrossrefMedlineGoogle Scholar - 41.
Demarini S ,Mimouni F ,Tsang RC ,Khoury J ,Hertzberg V . Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol. 1994;83:918-22. [PMID: 8190431] CrossrefMedlineGoogle Scholar - 42.
Farrag OA . Prospective study of 3 metabolic regimens in pregnant diabetics. Aust N Z J Obstet Gynaecol. 1987;27:6-9. [PMID: 3304264] CrossrefMedlineGoogle Scholar - 43.
Sacks DA ,Feig DS ,Liu IL ,Wolde-Tsadik G . Managing type I diabetes in pregnancy: how near normal is necessary? J Perinatol. 2006;26:458-62. [PMID: 16761010] CrossrefMedlineGoogle Scholar - 44.
Murphy HR ,Bell R ,Cartwright C ,Curnow P ,Maresh M ,Morgan M ,et al . Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study. Diabetologia. 2017;60:1668-1677. [PMID: 28597075] doi:10.1007/s00125-017-4314-3 CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
Jonas F. Ludvigsson,
Karolinska Institutet, Stockholm, Sweden, Örebro University Hospital, Örebro, Sweden, University of Nottingham, Nottingham, United Kingdom, and Columbia University College of Physicians and Surgeons, New York, New York (J.F.L.)
Karolinska Institutet, Stockholm, Sweden (M.N., J.S., O.S.)
Karolinska Institutet, Stockholm, Sweden; Centre of Registers Västra Götaland and University of Gothenburg, Gothenburg, Sweden (S.G., S.F.)
Centre of Registers Västra Götaland, Gothenburg, Sweden (A.S.)
Karolinska Institutet, Stockholm, Sweden, and Statens Serum Institut, Copenhagen, Denmark (B.P.)
Grant Support: By grants from the Swedish Diabetes Foundation. Dr. Pasternak was supported by an investigator grant from the Strategic Research Area Epidemiology Program at Karolinska Institutet and the Swedish Research Council (2016-01974). Dr. Stephansson was supported by grants from the Swedish Research Council (2013-2429) and the Stockholm County Council (ALF project 20130156) and received financial support from the strategic Research Program in Epidemiology at Karolinska Institutet.
Disclosures: Dr. Neovius reports grants from Pfizer and AstraZeneca and personal fees from Itrim, outside the submitted work. Dr. Pasternak reports grants from the Swedish Diabetes Foundation, Strategic Research Area Epidemiology Program at Karolinska Institutet, and Swedish Research Council during the conduct of the study, and grants from the Novo Nordisk Foundation outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1974.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol: Available from Dr. Ludvigsson (e-mail, jonasludvigsson@yahoo.
Corresponding Author: Jonas F. Ludvigsson, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden; e-mail, jonasludvigsson@yahoo.
Current Author Addresses: Dr. Ludvigsson: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Drs. Neovius, Söderling, Stephansson, and Pasternak: Clinical Epidemiology Division T2, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden.
Drs. Gudbjörnsdottir, Svensson, and Franzén: The Swedish National Diabetes Register, Västra Götalandsregionen, Medicinaregatan 18G, Gothenburg 413 45, Sweden.
Author Contributions: Conception and design: J.F. Ludvigsson, M. Neovius, J. Söderling, S. Gudbjörnsdottir, A.M. Svensson, S. Franzén, O. Stephansson, B. Pasternak.
Analysis and interpretation of the data: J.F. Ludvigsson, M. Neovius, J. Söderling, B. Pasternak.
Drafting of the article: J.F. Ludvigsson.
Critical revision for important intellectual content. J.F. Ludvigsson, M. Neovius, J. Söderling, S. Gudbjörnsdottir, A.M. Svensson, S. Franzén, O. Stephansson, B. Pasternak.
Final approval of the article: J.F. Ludvigsson, M. Neovius, J. Söderling, S. Gudbjörnsdottir, A.M. Svensson, S. Franzén, O. Stephansson, B. Pasternak.
Provision of study materials or patients: M. Neovius, A.M. Svensson.
Statistical expertise: J.F. Ludvigsson, J. Söderling, S. Franzén.
Obtaining of funding: M. Neovius, B. Pasternak.
Administrative, technical, or logistic support: J.F. Ludvigsson, M. Neovius.
Collection and assembly of data: J.F. Ludvigsson, M. Neovius, A.M. Svensson, O. Stephansson, B. Pasternak.
This article was published at Annals.org on 23 April 2019.
Submit a Comment
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.
*All comments submitted after October 1, 2021 and selected for publication will be published online only.