Skip to main content
Top

15-02-2018 | MODY | Review | Article

Clinical Management of Women with Monogenic Diabetes During Pregnancy

Journal: Current Diabetes Reports

Authors: Laura T. Dickens, Rochelle N. Naylor

Publisher: Springer US

Abstract

Purpose of Review

Monogenic diabetes accounts for 1–2% of all diabetes cases, but is frequently misdiagnosed as type 1, type 2, or gestational diabetes. Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for KATP channel-related diabetes. While diabetes treatment is defined for the most common causes of monogenic diabetes, pregnancy poses a challenge to management. Here, we discuss the key issues in pregnancy affected by monogenic diabetes.

Recent Findings

General recommendations for pregnancy affected by GCK-MODY determine need for maternal insulin treatment based on fetal mutation status. However, a recent study suggests macrosomia and miscarriage rates may be increased with this strategy. Recent demonstration of transplacental transfer of sulfonylureas also raises questions as to when insulin should be initiated in sulfonylurea-responsive forms of monogenic diabetes.

Summary

Pregnancy represents a challenge in management of monogenic diabetes, where factors of maternal glycemic control, fetal mutation status, and transplacental transfer of medication must all be taken into consideration. Guidelines for pregnancy affected by monogenic diabetes will benefit from large, prospective studies to better define the need for and timing of initiation of insulin treatment.
Literature
1.
Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345(13):971–80. https://​doi.​org/​10.​1056/​NEJMra002168.CrossRefPubMed
2.
Ledermann HM. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet. 1995;345(8950):648. https://​doi.​org/​10.​1016/​S0140-6736(95)90548-0.CrossRefPubMed
3.
Kleinberger JW, Pollin TI. Undiagnosed MODY: time for action. Curr Diab Rep. 2015;15(12):110. https://​doi.​org/​10.​1007/​s11892-015-0681-7.CrossRefPubMedPubMedCentral
4.
Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010;53(12):2504–8. https://​doi.​org/​10.​1007/​s00125-010-1799-4.CrossRefPubMed
5.
• Chakera AJ, Steele AM, Gloyn AL, Shepherd MH, Shields B, Ellard S, et al. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care. 2015;38(7):1383–92. https://​doi.​org/​10.​2337/​dc14-2769. An important article summarizing recommendations for management of GCK-MODY in pregnancy based on suspected fetal genotype.CrossRefPubMed
6.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014;311(3):279–86. https://​doi.​org/​10.​1001/​jama.​2013.​283980.CrossRefPubMed
7.
Stride A, Shields B, Gill-Carey O, Chakera AJ, Colclough K, Ellard S, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54–6. https://​doi.​org/​10.​1007/​s00125-013-3075-x.CrossRefPubMed
8.
Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013;34(5):669–85. https://​doi.​org/​10.​1002/​humu.​22279.CrossRefPubMed
9.
Pontoglio M, Prié D, Cheret C, Doyen A, Leroy C, Froguel P, et al. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep. 2000;1(4):359–65. https://​doi.​org/​10.​1093/​embo-reports/​kvd071.CrossRefPubMedPubMedCentral
10.
Isomaa B, Henricsson M, Lehto M, Forsblom C, Karanko S, Sarelin L, et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia. 1998;41(4):467–73. https://​doi.​org/​10.​1007/​s001250050931.CrossRefPubMed
11.
Bacon S, Kyithar MP, Rizvi SR, Donnelly E, McCarthy A, Burke M, et al. Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. Diabet Med. 2016;33(7):976–84. https://​doi.​org/​10.​1111/​dme.​12992.CrossRefPubMed
12.
Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med. 2009;26(4):437–41. https://​doi.​org/​10.​1111/​j.​14645491.​2009.​02690.​x.CrossRefPubMed
13.
Tuomi T, Honkanen EH, Isomaa B, Sarelin L, Groop LC. Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3. Diabetes Care. 2006;29(2):189–94. https://​doi.​org/​10.​2337/​diacare.​29.​02.​06.​dc05-1314.CrossRefPubMed
14.
Østoft SH, Bagger JI, Hansen T, Pedersen O, Faber J, Holst JJ, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–805. https://​doi.​org/​10.​2337/​dc13-3007.PubMed
15.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. https://​doi.​org/​10.​1371/​journal.​pmed.​0040118.CrossRefPubMedPubMedCentral
16.
Pingul MM, Hughes N, Wu A, Stanley CA, Gruppuso PA. Hepatocyte nuclear factor 4α gene mutation associated with familial neonatal hyperinsulinism and maturity-onset diabetes of the young. J Pediatr. 2011;158(5):852–4. https://​doi.​org/​10.​1016/​j.​jpeds.​2011.​01.​003.CrossRefPubMed
17.
Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012;97(10):E2026–30. https://​doi.​org/​10.​1210/​jc.​2012-1356.CrossRefPubMedPubMedCentral
18.
Bingham C, Hattersley AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant. 2004;19(11):2703–8. https://​doi.​org/​10.​1093/​ndt/​gfh348.CrossRefPubMed
19.
Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations. Diabetes Care. 2004;27(5):1102–7. https://​doi.​org/​10.​2337/​diacare.​27.​5.​1102.CrossRefPubMed
20.
Dubois-Laforgue D, Cornu E, Saint-Martin C, Coste J, Bellanné-Chantelot C, Timsit J, et al. Diabetes, associated clinical Spectrum, long-term prognosis, and genotype/phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care. 2017;40(11):1436–43. https://​doi.​org/​10.​2337/​dc16-2462.CrossRefPubMed
21.
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350(18):1838–49. Erratum in: N Engl J Med. 2004;351(14):1470. https://​doi.​org/​10.​1056/​NEJMoa032922.CrossRefPubMed
22.
Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355(5):456–66. https://​doi.​org/​10.​1056/​NEJMoa055068.CrossRefPubMed
23.
Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355(5):467–77. https://​doi.​org/​10.​1056/​NEJMoa061759.CrossRefPubMed
24.
ACOG Committee on Practice Bulletins, ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol. 2005;105(3):675–85.CrossRef
25.
• Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic diabetes in pregnancy cohort. Diabetes Care. 2014;37(5):1230–6. https://​doi.​org/​10.​2337/​dc13-2248. A study showing that anthropometric and glycemic data can be used to differentiate patients with GCK-MODY from gestational diabetes.CrossRefPubMed
26.
Rudland VL, Hinchcliffe M, Pinner J, Cole S, Mercorella B, Molyneaux L, et al. Identifying glucokinase monogenic diabetes in a multiethnic gestational diabetes mellitus cohort: new pregnancy screening criteria and utility of HbA1c. Diabetes Care. 2016;39(1):50–2. https://​doi.​org/​10.​2337/​dc15-1001.CrossRefPubMed
27.
Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26(1):14–8. https://​doi.​org/​10.​1111/​j.​1464-5491.​2008.​02622.​x.CrossRefPubMed
28.
Spyer G, Hattersley AT, Sykes JE, Sturley RH, MacLeod KM. Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am Obstet Gynecol. 2001;185(1):240–1. https://​doi.​org/​10.​1067/​mob.​2001.​113127.CrossRef
29.
Colom C, Corcoy R. Maturity onset diabetes of the young and pregnancy. Best Pract Res Clin Endocrinol Metab. 2010;24(4):605–15. https://​doi.​org/​10.​1016/​j.​beem.​2010.​05.​008.CrossRefPubMed
30.
Chakera AJ, Carleton VL, Ellard S, Wong J, Yue DK, Pinner J, et al. Antenatal diagnosis of fetal genotype determines if maternal hyperglycemia due to a glucokinase mutation requires treatment. Diabetes Care. 2012;35(9):1832–4. https://​doi.​org/​10.​2337/​dc12-0151.CrossRefPubMedPubMedCentral
31.
•• Bacon S, Schmid J, McCarthy A, Edwards J, Fleming A, Kinsley B, et al. The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am J Obstet Gynecol. 2015;213(2):236.e1–7. https://​doi.​org/​10.​1016/​j.​ajog.​2015.​04.​037. A retrospective study of GCK-MODY in pregnancy that observed a trend towards lower rates of macrosomia in GCK-unaffected offspring with insulin treatment of the mother and higher miscarriage rates in GCK-MODY pregnancies.CrossRef
32.
Kjos SL, Schaefer-Graf U, Sardesi S, Peters RK, Buley A, Xiang AH, et al. A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Diabetes Care. 2001;24(11):1904–10. https://​doi.​org/​10.​2337/​diacare.​24.​11.​1904.CrossRefPubMed
33.
Singh R, Pearson ER, Clark PM, Hattersley AT. The long-term impact on offspring of exposure to hyperglycaemia in utero due to maternal glucokinase gene mutations. Diabetologia. 2007;50(3):620–4. https://​doi.​org/​10.​1007/​s00125-006-0541-8.CrossRefPubMed
34.
• Schwartz RA, Rosenn B, Aleksa K, Koren G. Glyburide transport across the human placenta. Obstet Gynecol. 2015;125(3):583–8. https://​doi.​org/​10.​1097/​AOG.​0000000000000672​. A study showing transplacental glyburide transfer does occur and is highly variable between patients.CrossRefPubMed
35.
Hebert MF, Ma X, Naraharisetti SB, Krudys KM, Umans JG, Hankins GD, et al. Obstetric-fetal pharmacology research unit network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85(6):607–14. https://​doi.​org/​10.​1038/​clpt.​2009.​5.CrossRefPubMedPubMedCentral
36.
Poolsup N, Suksomboon N, Amin M. Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: a meta-analysis. PLoS One. 2014;9(10):e109985. https://​doi.​org/​10.​1371/​journal.​pone.​0109985.CrossRefPubMedPubMedCentral
37.
•• Shepherd M, Brook AJ, Chakera AJ, Hattersley AT. Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer. Diabet Med. 2017;34(10):1332–9. https://​doi.​org/​10.​1111/​dme.​13388. An important article providing recommendations for management of sulfonylurea-treated monogenic diabetes in pregnancy.CrossRefPubMed
38.
Feig DS, Briggs GG, Kraemer JM, Ambrose PJ, Moskovitz DN, Nageotte M, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care. 2005;28(8):1851–5. https://​doi.​org/​10.​2337/​diacare.​28.​8.​1851.CrossRefPubMed
39.
Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S, et al. Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med. 2006;23(12):1301–6. https://​doi.​org/​10.​1111/​j.​1464-5491.​2006.​01999.​x.CrossRefPubMed
40.
Slingerland AS, Hattersley AT. Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab. 2006;91(7):2782–8. https://​doi.​org/​10.​1210/​jc.​2006-0201.CrossRefPubMed
41.
Gaal Z, Klupa T, Kantor I, Mlynarski W, Albert L, Tolloczko J, et al. Sulfonylurea use during entire pregnancy in diabetes because of KCNJ11 mutation: a report of two cases. Diabetes Care. 2012;35(6):e40. https://​doi.​org/​10.​2337/​dc12-0163.CrossRefPubMedPubMedCentral
42.
Myngheer N, Allegaert K, Hattersley A, McDonald T, Kramer H, Ashcroft FM, et al. Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes. Diabetes Care. 2014;37(12):3333–5. https://​doi.​org/​10.​2337/​dc14-1247.CrossRefPubMed
43.
De Franco E, Caswell R, Houghton JA, Iotova V, Hattersley AT, Ellard S. Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes. Diabet Med. 2017;34(4):582–5. https://​doi.​org/​10.​1111/​dme.​13180.CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »