Gestational Diabetes Mellitus—Triage for Preventive Intervention

US Endocrinology, 2016;12(2): DOI: https://doi.org/10.17925/USE.2016.12.02.99

Abstract:

Gestational diabetes mellitus (GDM) is a heterogeneous condition, as exemplified by our inability to agree upon screening and diagnostic criteria. Not all women with GDM carry the same long-term risk of diabetes. We therefore propose a triage system to identify women with GDM who are at higher risk of converting to diabetes mellitus, in a shorter time frame after pregnancy. Such women can be offered personalized risk assessment information.
Keywords: Gestational diabetes mellitus, GDM, triage, postpartum, diabetes
Disclosure: Achini Wijesinghe, Sonali Gunatilake, Dina Shrestha, Yashdeep Gupta, Noel Somasundaram, Uditha Bulugahapitiya, and Sanjay Kalra have nothing to disclose in relation to this article. No funding was received for the publication of this article.
Compliance with Ethics:This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Received: November 03, 2016 Accepted December 12, 2016
Correspondence: Yashdeep Gupta, Room No 308, Biotechnology building, Department of Endocrinology & Metabolism, AIIMS, New Delhi 110029, India. E: yash_deep_gupta@yahoo.co.in
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

ACCEPTED MANUSCRIPT -- This manuscript has been accepted for publication. The manuscript may undergo some minor revisions before it is published in its final form.

Women with gestational diabetes mellitus (GDM) carry a multidimensional and trans-generational impact.1 It poses a huge medical and public health burden on society today, which can be mitigated if appropriate proactive and preventive strategies are put in place. These include early screening and identification of women with GDM, provision of appropriate non-pharmacological and pharmacological therapy, and regular follow up after delivery to detect and treat diabetes in a timely manner. GDM is similar to pre-diabetes in many ways.2,3 Though it differs because of its association with pregnancy, the pathophysiologic features are the same as those operating in impaired glucose tolerance. Studies have reported that women with GDM are several times more likely to develop subsequent type 2 diabetes mellitus (T2DM) compared to women without GDM, with approximately 50% developing diabetes within 10 years.4 Asian Indians stand at higher risk for earlier conversion to diabetes, compared to Caucasians. Studies from India have found high conversion rates to T2DM even within five years of delivery.5–8

This reality has made GDM screening, diagnosis, management, and postpartum follow-up an international public health priority.

Triage system
GDM is a heterogeneous condition, as exemplified by our inability to agree upon screening and diagnostic criteria.3 Not all women with GDM carry the same long term risk of diabetes. We therefore propose a triage system to identify women with GDM who are at higher risk of converting to diabetes mellitus, in a shorter time frame after pregnancy. Such women can be offered personalized risk assessment information.9 Women at higher risk should be encouraged to breastfeed their infants,10 called for relatively frequent follow-up, supported with intensive lifestyle modification advice, and prescribed preventive pharmacotherapy. The health care system can use its limited resources to focus on these high risk women, and achieve greater public health benefits with a targeted approach.

Determinants of risk
A recent meta-analysis assessed 39 relevant studies on GDM, including 95,750 women.11 Body Mass Index (BMI) (realtive risk [RR] 1.95 [95% confidence interval (CI) 1.60, 2.31]), family history of diabetes (RR 1.70 [95% CI 1.47, 1.97]), non-white ethnicity (RR 1.49 [95% CI 1.14, 1.94]) and advanced maternal age (RR 1.20 [95% CI 1.09, 1.34]) were associated with future risk of T2DM. There was an increase in risk with early diagnosis of GDM (RR 2.13 [95% CI 1.52, 3.56]), raised fasting glucose (RR 3.57 [95% CI 2.98, 4.04]), increased glycated hemoglobin (HbA1c) (RR 2.56 [95% CI 2.00, 3.17]) and use of insulin (RR 3.66 [95% CI 2.78, 4.82]). Multiparity (RR 1.23 [95% CI 1.01, 1.50]), hypertensive disorders in pregnancy (RR 1.38 [95% CI 1.32, 1.45]) and preterm delivery (RR 1.81 [95% CI 1.35, 2.43]) were associated with future diabetes.11 Prepregnancy obesity, excessive weight gain from prepregnancy to postpartum, and weight gain after pregnancy are associated with increased risk of T2DM after GDM.12,13 Lie et al. evaluated the effects of prepregnancy BMI and weight change from prepregnancy to postpartum on postpartum T2DM risk among Chinese women with GDM. The multivariable-adjusted hazard ratios based on different levels of prepregnancy BMI (<23, 23–24.9, 25–29.9, and ≥30 kg/m2) were 1.00, 1.77, 2.35, and 6.54 (p<0.001) for incident T2DM. Compared with women with stable weight (±3 kg), those with weight gain ≥7 kg had an 86% increased risk of diabetes.12 Moon et al. evaluated the effect of weight gain on the development of T2DM after GDM in Asian women who have a relatively low BMI. A total of 418 women with previous GDM or gestational impaired glucose tolerance were recruited and underwent an oral glucose tolerance test at six weeks postpartum and annually thereafter. They observed an increased risk of incident diabetes as the tertile of BMI change increased (8.6%, 12.6%, and 16.9%, p=0.039).13 Breastfeeding has long-term protective effect of lactation on the development of T2DM in women with gestational diabetes mellitus.14

Kwak et al. used a genetic risk score based on 48 genetic variants associated with diabetes and found improved prediction of T2DM in women with a history of GDM apart over clinical risk factors.15 Metabolomics signature can also predict the transition from GDM to T2DM.16 In a separate study, genetic variants in CDKN2A/2B and haematopoietically expressed homeobox gene (HHEX) were associated with early conversion of GDM to diabetes, while variants in CDKAL1 were associated with late conversion.9

The HHEX encodes a transcription factor that is involved in ventral pancreas development. The CDKN2A and CDKN2B genes encode p16INK4a and p15INK4b, respectively, both of which regulate β-cell replication. The data imply that the decreased β-cell function in early converters might be due to genetic predisposition conferred by these variants in HHEX, at least in part. The variant that was significantly associated with late conversion to T2DM was located in CDKAL1. The CDKAL1 gene encodes cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1. This variant is also well known for its association with T2DM and decreased insulin secretion. Additionally, a recent large-scale genome wide association (GWA) study showed that a variant in this gene is significantly associated with BMI in East Asians. It might be possible that the risk of T2DM in late converters conferred by this variant is modulated through an interaction with obesity.9

References:
1. Mahtab H, Pathan MF, Ahmed T, et al., The Dhaka Declaration 2015, Indian J Endocrinol Metab, 2015;19:441.
2. Langer O, Umans JG, Miodovnik M, The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference, J Matern Fetal Neonatal Med, 2013;26:111–5.
3. Gupta Y, Kalra B, Baruah MP, Singla R, Kalra S, Updated guidelines on screening for gestational diabetes, Int J Womens Health, 2014;7:539–50.
4. Bellamy L, Casas JP, Hingorani AD, Williams D, Type 2 diabetes mellitus after gestational diabetes: a systematic review and metaanalysis, Lancet, 2009;373:1773–9.
5. Gupta Y, Kapoor D, Desai A, et al., Conversion of gestational diabetes mellitus to future Type 2 diabetes mellitus and the predictive value of HbA1c in an Indian cohort, Diabet Med, 2016;[Epub ahead of print] 6. Krishnaveni GV, Hill JC, Veena SR, et al., Gestational diabetes and the incidence of diabetes in the 5 years following the index pregnancy in South Indian women, Diabetes Res Clin Pract, 2007;78:398–404.
7. Kale SD, Yajnik CS, Kulkarni SR, et al., High risk of diabetes and metabolic syndrome in Indian women with gestational diabetes mellitus, Diabet Med, 2004;21:1257–8.
8. Mahalakshmi MM, Bhavadharini B, Kumar M, et al., Clinical profile, outcomes, and progression to type 2 diabetes among Indian women with gestational diabetes mellitus seen at a diabetes center in south India, Indian J Endocrinol Metab, 2014;18:400–6.
9. Kwak SH, Choi SH, Jung HS, et al., Clinical and genetic risk factors for type 2 diabetes at early or late post partum after gestational diabetes mellitus, J Clin Endocrinol Metab, 2013;98:E744–52.
10. Kalra B, Gupta Y, Kalra S. Breast feeding: preventive therapy for type 2 diabetes, J Pak Med Assoc, 2015;65:1134–6.
11. Rayanagoudar G, Hashi AA, Zamora J, Khan KS, Hitman GA, Thangaratinam S, Quantification of the type 2 diabetes risk in women with gestational diabetes: a systematic review and metaanalysis of 95,750 women, Diabetologia, 2016;25:1–9.
12. Liu H, Zhang C, Zhang S, et al., Prepregnancy body mass index and weight change on postpartum diabetes risk among gestationaldiabetes women, Obesity (Silver Spring), 2014;22:1560–7.
13. Moon JH, Kwak SH, Jung HS, et al., Weight Gain and Progression to Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus, J Clin Endocrinol Metab, 2015;100:3548–55.
14. Ziegler AG, Wallner M, Kaiser I, et al., Long-term protective effect of lactation on the development of type 2 diabetes in women with recent gestational diabetes mellitus, Diabetes, 2012;61:3167–71.
15. Kwak SH, Choi SH, Kim K, et al., Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score, Diabetologia, 2013;56:2556–63.
16. Allalou A, Nalla A, Prentice KJ, et al., A Predictive Metabolic Signature for the Transition From Gestational Diabetes Mellitus to Type 2 Diabetes, Diabetes, 2016;65:2529–39.
17. Retnakaran R, Glucose tolerance status in pregnancy: a window to the future risk of diabetes and cardiovascular disease in young women, Curr Diabetes Rev, 2009;5:239–44.
18. Bentley-Lewis R, Huynh J, Xiong G, et al., Metabolomic profiling in the prediction of gestational diabetes mellitus, Diabetologia, 2015;58:1329–32.
19. Garber AJ, Abrahamson MJ, Barzilay JI, et al., AACE/ACE comprehensive diabetes management algorithm 2015, Endocrine Practice, 2015;21:438–47.
20. Bhavadharini B, Anjana RM, Mahalakshmi MM, et al., Glucose tolerance status of Asian Indian women with gestational diabetes at 6 weeks to 1 year postpartum (WINGS-7), Diabetes Res Clin Pract, 2016;117:22–7.
21. Leuridan L, Wens J, Devlieger R, Verhaeghe J, Mathieu C, Benhalima K. Glucose intolerance in early postpartum in women with gestational diabetes: Who is at increased risk? Prim Care Diabetes, 2015;9:244–52.
22. Buchanan TA, Xiang AH, Peters RK, et al., Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women, Diabetes, 2002;51:2796–803.
23. Ratner R, Christophi C, Metzger B, et al., Prevention of diabetes in women with a history of gestational diabetes; effects of metformin and lifestyle interventions. J Clin Endocrinol Metab, 2008;93:4774–4779.
24. Kim C. Maternal outcomes and follow-up after gestational diabetes mellitus, Diabet Med, 2014;31:292–301 25. Qiao Q, Hu G, Tuomilehto J, et al., Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts, Diabetes Care, 2003;26:1770–80.
26. Gupta Y, Gupta A. Post-partum screening after gestational diabetes. Lancet Diabet Endocrinol, 2013;1:90–1
Keywords: Gestational diabetes mellitus, GDM, triage, postpartum, diabetes