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.
Gestational diabetes mellitus, GDM, triage, postpartum, diabetes
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.
November 03, 2016 Accepted
December 12, 2016
Yashdeep Gupta, Room No 308, Biotechnology building, Department of Endocrinology & Metabolism, AIIMS, New Delhi 110029, India. E: firstname.lastname@example.org
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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.
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
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Gestational diabetes mellitus, GDM, triage, postpartum, diabetes