Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Editorial

Gestational Diabetes Mellitus: Primum Non Nocere

  1. Shivani Misra, MRCP1 and
  2. Anne Dornhorst, FRCP2
  1. From the 1Department of Metabolic Medicine, Imperial Healthcare NHS Trust, London, U.K.; and the
  2. 2Department of Medicine, Imperial College Healthcare NHS Trust, London, U.K.
  1. Corresponding author: Shivani Misra, s.misra{at}imperial.ac.uk.
Diabetes Care 2012 Sep; 35(9): 1811-1813. https://doi.org/10.2337/dc12-0689
PreviousNext
  • Article
  • Info & Metrics
  • PDF
Loading

Maturity-onset diabetes of the young (MODY) encompasses a collection of distinct forms of diabetes, which are inherited in an autosomal-dominant mode from the maternal or paternal side of the family or occasionally occur as a de novo mutation. All the genes involved affect either β-cell sensing or insulin secretion (1). The clinical presentations of MODY are heterogeneous, reflecting the different gene mutations involved, and the glucose dysregulation observed ranges from a relatively innocent rise in the fasting glucose to frank diabetes with neurological involvement (2,3).

An exact MODY prevalence within the general diabetes population has proven difficult to assess because of underrecognition and lack of routinely available and affordable diagnostic tools. A further confounder is that the reported regional prevalence of specific MODY mutations varies considerably (4). Conservative estimates suggest that between 0.14–1.8% of all cases of diabetes could be attributable to MODY (4). It is to be expected that among women screened for gestational diabetes mellitus (GDM) the prevalence of MODY will be higher, reflecting both the proportionately lower prevalence of type 2 diabetes in women of this age group and the probability that those with undiagnosed MODY will screen positive (5). From the few population studies reported, mutations in the hepatocyte nuclear factor 1 α (HNF1a) gene (MODY 3) and glucokinase (GCK) gene (MODY 2) account for the majority of cases (6).

MODY 2 is characterized by its high penetrance, early onset, and lifelong fasting hyperglycemia. It is due to mutations in the pancreatic GCK gene, which acts as the β-cell glucose sensor, setting the glucose threshold at which amplification of insulin secretion occurs (7). In MODY 2, this is set at 18–45 mg/dL (1.0–2.5 mmol/L), higher than for unaffected adults (7). Glucose tolerance can remain stable over many years, provided that insulin sensitivity also remains stable (8). Although MODY 2 is associated with lifelong fasting hyperglycemia that may progressively increase with age, long-term diabetes complications are uncommon (9,10).

MODY 2 does, however, have clinical implications in pregnancy when there is discordance between the maternal and fetal genotype; statistically this occurs in 50% of all pregnancies in which the mother or father carries the MODY mutation. When the mother is affected but not the fetus, maternal hyperglycemia causes fetal hyperinsulinemia and increased birth weight (11). By contrast, when the fetus carries the paternal MODY 2 gene, the levels of maternal glycemia are insufficient to stimulate adequate fetal insulin to sustain optimal growth, and birth weight is approximately 500 g lower than for an unaffected sibling (11). When both the mother and fetus share the MODY 2 mutation, birth weight is normal, providing the mother’s hyperglycemia is not treated, as the glucose threshold to trigger insulin secretion is similar in the mother and fetus, and fetal insulin levels remain normal. If, however, a mother with MODY 2 has her hyperglycemia treated in pregnancy and the fetus also carries the GCK mutation, birth weight can be severely compromised (12). On the basis of these observations, it has been recommended to treat hyperglycemia in the mothers with MODY 2 only when there is ultrasound evidence of accelerated fetal growth (5).

Maternal hyperglycemia at levels observed in women with MODY 2 has in observational and randomized trials been associated with adverse pregnancy outcomes (13,14). These studies have provided the evidence for the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) guidelines on the diagnosis of GDM (15). In the IADPSG guidelines, a fasting glucose value of ≥92 mg/dL (5.1 mmol/L) is considered diagnostic for GDM. As this fasting value is set lower than other commonly used diagnostic criteria, if adopted, more women with GDM would be diagnosed (16). In addition, the lower fasting value by IADPSG criteria would label all pregnant women with previously undiagnosed MODY 2 as having GDM.

If, in keeping with the IADPSG diagnostic criteria, a fasting glucose level below 92 mg/dL (5.1 mmol/L) was also adopted as a management target in GDM, this would be difficult to achieve in women with MODY 2 treated with diet alone, and would inevitably necessitate insulin therapy. More importantly these more stringent fasting glucose targets would be detrimental to fetal growth in half of all pregnancies (12).

The article by Chakera et al. (17) in this issue of Diabetes Care provides proof of concept that prior knowledge of the fetal genotype can help predict fetal susceptibility to maternal hyperglycemia and can therefore favorably influence treatment in women with MODY 2. The article describes two pregnancies in women with MODY 2 in whom glycemic management was tailored on the basis of fetal genotyping, performed following chorionic villus sampling undertaken for other indications. In both pregnancies, the fetuses had inherited the maternal GCK mutation and were therefore protected from the levels of maternal hyperglycemia they were exposed to. Both women would have warranted active glycemic management by current guidelines (18). Despite significant maternal hyperglycemia and no treatment, both infants were born at term with normal birth weights.

There are increasing numbers of maternal genes being identified that influence fasting blood glucose and fetal growth (19). Our knowledge in this field will expand with further subanalyses of maternal and fetal genes from the large Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort for which detailed biochemical, anthropometric, and genetic data have been collected (19). In the absence of this knowledge and the ability to detect fetal genotype noninvasively during pregnancy, it must be acknowledged that universally applied treatment guidelines will not be appropriate for a minority of women with GDM. However as 15–20% of today’s antenatal population has GDM using the IADPSG criteria, this minority will still represent a sizable number of pregnancies (16).

Identifying and managing pregnancies appropriately when either the mother or the father carries the MODY2 gene requires a higher level of clinical suspicion among family physicians, diabetologists, and obstetricians and greater access to the necessary diagnostic tools. Until there are advances in the noninvasive genotyping of fetal DNA, for example using cell free fetal DNA, genotyping the fetus will require opportunistic use of CVS if undertaken for alternative indications.

The optimal treatment during pregnancy of women with other monogenic forms of diabetes has not been well evaluated. Permanent neonatal diabetes is believed to affect approximately 1 in 200,000 births; however, the condition is often misdiagnosed as type 1 diabetes. A variety of genes have been implicated including activating mutations in the gene encoding the Kir6.2 subunit of the β-cell ATP-sensitive K channel (KCNJ11) (20). Good glycemic control with a lower risk of hypoglycemia can be achieved in patients with the Kir6.2 mutations using treatment with sulfonylureas rather than insulin (21). However, the safety of sulfonylurea use in pregnancy has not been clearly established, and though some evidence exists on the use of glyburide, the safety of other agents such as gliclazide is unknown (22).

Gathering together sufficient numbers of women with permanent neonatal diabetes in pregnancy to establish the optimal therapy will depend on observational data from those few specialized centers that look after these women. Because of the general paucity of data, the two case reports by Gaal et al. (23) of women with KCNJ11 mutations treated exclusively during pregnancy with the sulfonylurea glicazide, is a small but helpful contribution, which when added to other anecdotal reports (24) will begin to establish a knowledge base from which guidelines can be formed. However, until safety data on the use of gliclazide in pregnancy is established, its use cannot be routinely advocated in these circumstances.

The reports from Chakera et al. and Gaal et al. both highlight that treating all women with hyperglycemia in pregnancy using generic evidenced-based algorithmic guidelines may not necessarily be in the best interests of all mothers and their babies.

Acknowledgments

No potential conflicts of interest relevant to this article were reported.

  • © 2012 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

  1. ↵
    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(Suppl. 1):S62–S69
    OpenUrlFREE Full Text
  2. ↵
    1. Tattersall RB
    . Mild familial diabetes with dominant inheritance. Q J Med 1974;43:339–357
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Rubio-Cabezas O,
    2. Minton JA,
    3. Kantor I,
    4. Williams D,
    5. Ellard S,
    6. Hattersley AT
    . Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 2010;59:2326–2331
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Shields BM,
    2. Hicks S,
    3. Shepherd MH,
    4. Colclough K,
    5. Hattersley AT,
    6. Ellard S
    . Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010;53:2504–2508
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Colom C,
    2. Corcoy R
    . Maturity onset diabetes of the young and pregnancy. Best Pract Res Clin Endocrinol Metab 2010;24:605–615
    OpenUrlCrossRefPubMed
  6. ↵
    1. Estalella I,
    2. Rica I,
    3. Perez de Nanclares G,
    4. et al
    ; Spanish MODY Group. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf) 2007;67:538–546
    OpenUrlPubMed
  7. ↵
    1. Byrne MM,
    2. Sturis J,
    3. Clément K,
    4. et al
    . Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994;93:1120–1130
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Martin D,
    2. Bellanné-Chantelot C,
    3. Deschamps I,
    4. Froguel P,
    5. Robert JJ,
    6. Velho G
    . Long-term follow-up of oral glucose tolerance test-derived glucose tolerance and insulin secretion and insulin sensitivity indexes in subjects with glucokinase mutations (MODY2). Diabetes Care 2008;31:1321–1323
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Barrio R,
    2. Bellanné-Chantelot C,
    3. Moreno JC,
    4. et al
    . Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab 2002;87:2532–2539
    OpenUrlCrossRefPubMed
  10. ↵
    1. Velho G,
    2. Blanché H,
    3. Vaxillaire M,
    4. et al
    . Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 1997;40:217–224
    OpenUrlCrossRefPubMed
  11. ↵
    1. Hattersley AT,
    2. Beards F,
    3. Ballantyne E,
    4. Appleton M,
    5. Harvey R,
    6. Ellard S
    . Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 1998;19:268–270
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Spyer G,
    2. Hattersley AT,
    3. Sykes JE,
    4. Sturley RH,
    5. MacLeod KM
    . Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am J Obstet Gynecol 2001;185:240–241
    OpenUrlCrossRefPubMed
  13. ↵
    1. Crowther CA,
    2. Hiller JE,
    3. Moss JR,
    4. McPhee AJ,
    5. Jeffries WS,
    6. Robinson JS
    ; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–2486
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Landon MB,
    2. Spong CY,
    3. Thom E,
    4. et al
    ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:1339–1348
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    1. Metzger BE,
    2. Gabbe SG,
    3. Persson B,
    4. et al
    ; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682
    OpenUrlFREE Full Text
  16. ↵
    1. Sacks DA,
    2. Hadden DR,
    3. Maresh M,
    4. et al
    ; HAPO Study Cooperative Research Group. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care 2012;35:526–528
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Chakera AJ,
    2. Carleton VL,
    3. Ellard S,
    4. et al
    . Antenatal diagnosis of fetal genotype determines if maternal hyperglycemia due to a glucokinase mutation requires treatment. Diabetes Care 2012;35:1832–1834
  18. ↵
    1. Metzger BE,
    2. Buchanan TA,
    3. Coustan DR,
    4. et al
    . Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl. 2):S251–S260
  19. ↵
    1. Freathy RM,
    2. Hayes MG,
    3. Urbanek M,
    4. et al
    ; HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups. Diabetes 2010;59:2682–2689
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Rubio-Cabezas O,
    2. Klupa T,
    3. Malecki MT
    ; CEED3 Consortium. Permanent neonatal diabetes mellitus—the importance of diabetes differential diagnosis in neonates and infants. Eur J Clin Invest 2011;41:323–333
    OpenUrlCrossRefPubMed
  21. ↵
    1. Klupa T,
    2. Skupien J,
    3. Mirkiewicz-Sieradzka B,
    4. et al
    . Efficacy and safety of sulfonylurea use in permanent neonatal diabetes due to KCNJ11 gene mutations: 34-month median follow-up. Diabetes Technol Ther 2010;12:387–391
    OpenUrlCrossRefPubMed
  22. ↵
    1. Langer O,
    2. Conway DL,
    3. Berkus MD,
    4. Xenakis EM,
    5. Gonzales O
    . A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134–1138
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Gaal Z,
    2. Klupa T,
    3. Kantor I,
    4. et al
    . Sulfonylurea use during entire pregnancy in diabetes because of KCNJ11 mutation: a report of two cases. Diabetes Care 2012;35:e40
  24. ↵
    1. Klupa T,
    2. Kozek E,
    3. Nowak N,
    4. et al
    . The first case report of sulfonylurea use in a woman with permanent neonatal diabetes mellitus due to KCNJ11 mutation during a high-risk pregnancy. J Clin Endocrinol Metab 2010;95:3599–3604
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top
Diabetes Care: 35 (9)

In this Issue

September 2012, 35(9)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Gestational Diabetes Mellitus: Primum Non Nocere
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Gestational Diabetes Mellitus: Primum Non Nocere
Shivani Misra, Anne Dornhorst
Diabetes Care Sep 2012, 35 (9) 1811-1813; DOI: 10.2337/dc12-0689

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Gestational Diabetes Mellitus: Primum Non Nocere
Shivani Misra, Anne Dornhorst
Diabetes Care Sep 2012, 35 (9) 1811-1813; DOI: 10.2337/dc12-0689
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Acknowledgments
    • References
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • A1C Targets Should Be Personalized to Maximize Benefits While Limiting Risks
  • American Diabetes Association’s Standards of Care: A Paradigm Shift in the Dissemination of Information
  • Lessons From Peglispro: IMAGINE How to Improve Drug Development and Affordability
Show more Editorial

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.