Diabetes and pregnancy: perspectives from Asia.

DIABETICMedicine DOI: 10.1111/dme.12396

Review Article Diabetes and pregnancy: perspectives from Asia G. E. Tutino1, W. H. Tam2, X. Yang3, J. C. N. Chan1,4,5, T. T. H. Lao2 and R. C. W. Ma1,4,5 1 Department of Medicine and Therapeutics, 2Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, 3Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China, 4The Li Ka Shing Institute of Health Sciences and 5Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong

Accepted 10 December 2013

Abstract There has been a marked increase in the prevalence of diabetes in Asia over recent years. Diabetes complicating pregnancy, in particular gestational diabetes, has also increased markedly in the region. Multi-ethnic studies have highlighted the increased risk of gestational diabetes mellitus among the different Asian populations. Prevalence of gestational diabetes in Asian countries varies substantially according to the screening strategy and diagnostic criteria applied, and ranges from 1% to 20%, with evidence of an increasing trend over recent years. The International Association for Diabetes in Pregnancy Study group criteria have been adopted by some Asian countries, although they present significant challenges in implementation, especially in low-resource settings. Studies on offspring of mothers with gestational diabetes have reported adverse cardiometabolic profiles and increased risk of diabetes and obesity. Gestational diabetes is likely to be a significant factor contributing to the epidemic of diabetes and other non-communicable diseases in the Asian region. In recognition of this, several large-scale prevention and intervention programmes are currently being implemented in different Asian countries in order to improve glucose control during pregnancy, as well as overall maternal health. Lessons emerging from gestational diabetes studies in Asia may help inform and provide insights on the overall burden and treatment strategies to target gestational diabetes, with the ultimate aim to reduce its adverse short- and long-term consequences. Diabet. Med. 31, 302–318 (2014)

Introduction Asia-Pacific represents the region of the world with the largest number of individuals with diabetes [1]. Type 2 diabetes in Asians is characterized by young age of onset, predisposition to b-cell failure and visceral adiposity [2]. It is estimated that there are 76 million women ranging in age from 20 to 39 years who have diabetes/ pre-diabetes and are therefore at risk of having a pregnancy complicated by diabetes [1]. Given the considerable burden of young women with diabetes in Asia, the implications of this large and increasing population of women with evidence of glucose intolerance, who may have pregnancies complicated by hyperglycaemia is very alarming. In addition, there is an even larger pool of women at risk of gestational diabetes, many of whom may escape diagnosis during pregnancy because of inadequate screening and lack of awareness. As described later in the review, there is marked variation in the Correspondence to: Ronald C. W. Ma. E-mail: [email protected] This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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reported prevalence of gestational diabetes in different countries, mainly attributable to the different diagnostic criteria applied. This has hindered awareness of the increasing prevalence of gestational diabetes that is being observed in some Asian countries. Given the increasing appreciation of the harmful short- and long-term effects of gestational diabetes, there is urgent action needed to coordinate more widespread screening, early diagnosis, and alignment of diagnostic criteria, structured management and improved follow-up targeting women with gestational diabetes as well as their offspring.

Definitions and diagnosis of gestational diabetes in Asia Gestational diabetes is defined as carbohydrate intolerance of any degree with onset or first recognition during pregnancy [3]. By contrast, hyperglycaemia during pregnancy may also be attributable to pre-existing diabetes mellitus complicating pregnancy. While this review will focus primarily on gestational diabetes, it should be noted that overlap amongst pre-gestational diabetes mellitus and gestational diabetes can and does affect the observed gestational diabetes prevalence

ª 2014 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK

Review article

in many Asian countries and both situations contribute to adverse maternal and fetal outcomes. In a recent nationwide study in China, 3% of women aged between 30 and 39 years had diabetes, with an additional 9.2% of women in that age group being affected by impaired glucose tolerance [4]. Nevertheless, the great majority of pregnancies complicated by hyperglycaemia are attributable to gestational diabetes. For example, in the latest edition of the Diabetes Atlas, it is estimated that approximately 21.4 million live births in 2013 are complicated by hyperglycaemia, of which 16% result from pre-existing diabetes complicating pregnancy, with gestational diabetes accounting for the rest [1]. The first diagnostic criteria for gestational diabetes were established on the basis of a 3-h 100-g oral glucose tolerance test, in which the threshold was arbitrarily defined at 2 standard deviations (SD) above the mean plasma glucose concentration at each hour [5]. Since then, numerous modifications have been proposed and there is much debate and geographical variation in terms of the use of the different criteria. Nonetheless, neither the criteria modified from the original O’Sullivan and Mahan criteria [6], nor the World Health Organization (WHO) 1999 criteria [7], were based specifically on perinatal outcomes. More recently, results from the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study demonstrated that a graded association existed between less severe degrees of maternal hyperglycaemia and adverse pregnancy outcomes [8]. As a result, a new diagnostic criterion was proposed by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel on the basis of these findings [9] and which has recently been adopted by the WHO since 2013 [10]. The current use of the different criteria across Asian countries is summarized in Table 1. Whilst some Asian countries have adopted the IADPSG criteria, there are significant practical difficulties in their application, especially in low-resource settings. Consequently, several Asian countries have incorporated local modifications in order to facilitate implementation of universal gestational diabetes screening. Notably, screening using fasting glucose alone may be inadequate, with a diagnostic fasting blood glucose observed in only 24% of those with gestational diabetes in Bangkok and 26% in Hong Kong [11]. In low-resource settings in China, it has been proposed that a two- step approach using fasting plasma glucose at 24 weeks with a cutoff of > 5.1 mmol/l to diagnose gestational diabetes. Subjects with a fasting plasma glucose of 4.4–5.1 mmol/l are recommended to undergo a 75-g oral glucose tolerance test at 24–28 weeks [12]. This has the potential to reduce the need for an oral glucose tolerance test in approximately 50% of cases [13]. In India, it was reported that using a 2-h glucose of ≥ 7.8 mmol/l will identify the majority of women with gestational diabetes diagnosed by the IADPSG criteria, and this more cost-effec-


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tive strategy has therefore been adopted in the national guidelines, along with foregoing the need for subjects to be fasted prior to evaluation [14]. It is worth noting that an HbA1c > 48 mmol/mol (6.5%) has not been widely adopted in Asian countries as a diagnostic criterion for diabetes, and therefore it is generally not recommended to use HbA1c to diagnose pre-existing diabetes during pregnancy.

Epidemiology Hyperglycaemia complicating pregnancy is estimated to affect approximately 16.9% of pregnancies globally, with the highest prevalence in South-East Asia, where an estimated 25% of pregnancies are affected [1]. The prevalence of gestational diabetes is typically comparable with that of Type 2 diabetes in the background population [15]. Known risk factors for gestational diabetes include previous history of gestational diabetes, advanced maternal age, obesity, family history of diabetes mellitus and certain ethnicities, including Asians [16–20]. Other risk factors include: high parity, excessive weight gain during pregnancy, short stature, polycystic ovarian syndrome, increased iron stores, maternal history of macrosomia, prior Caesarean section, previous stillbirth or congenital malformation and hypertension [21]. Asians in general develop diabetes and gestational diabetes at comparatively lower BMI compared with Caucasians. In a large study conducted in Vietnam, the mean BMI of women with gestational diabetes diagnosed by the IADPSG was 21.1 kg/m2 [22]. The issue of advanced maternal age is particularly relevant in many East Asian countries, where the average age of gestation has been increasing over the last few decades. Another risk factor that may be particularly important in South Asia is the role of maternal vitamin B12 deficiency, which was observed in 43% of women in a study in India and was associated with maternal insulin resistance, increased risk of gestational diabetes and increased adiposity in the offspring [23].

Prevalence of gestational diabetes in Asia

For this review, we have selected primarily studies from the literature that reported prevalence figures based on application of oral glucose tolerance test with the goal of highlighting the large variances observed and factors that obscure the true prevalence in the face of well-conducted prevalence studies. There are a number of challenges to characterizing the true prevalence of gestational diabetes in a given region. Most notable are: (1) the lack of universal screening; (2) definition of gestational diabetes vs. pre-existing diabetes; (3) the diagnostic criteria used; (4) population studied (urban vs. rural); (5) ethnicity; and (6) changing incidence over time. In the absence of universal screening, it is important to bear in mind that the reported prevalence figures may

303

304 75-g

—

—

≥ 5.1

≥ 5.5

≥ 5.1

≥ 5.3

< 7.0

≥ 7.0

≥ 5.3

≥ 5.8

Fasting (mmol/l)

—

≥ 10.0

—

≥ 10.0

≥ 10.0

—

≥ 10.0

≥ 10.5

1-h (mmol/l)

≥ 7.8

≥ 8.5

≥ 9.0 (New Zealand)

≥ 8.0 (Australia)

≥ 8.5

≥ 8.6

≥ 7.8 to < 11.0

≥ 11.1

≥ 8.6

≥ 9.1

2-h (mmol/l)

—

—

—

—

—

—

≥ 7.8

≥ 8.0

3-h (mmol/l)

Any one = gestational diabetes Non-fasting

Either one = gestational diabetes

Either one = impaired glucose tolerance Two of three = gestational diabetes Any one = gestational diabetes

Two of three = gestational diabetes Any one = borderline Two of three = gestational diabetes Any one = borderline Either one = gestational diabetes

Diagnostic measures†

India

Japan

New Zealand

USA, Australia Korea, China, Thailand, Pakistan, Philippines

Singapore, Malaysia, Thailand, Vietnam, Sri Lanka

USA Taiwan

Current practice

‡

†

*In some countries, more than one criterion is in common use. Venous plasma glucose. For references, see also Supporting Information (Table S1). ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; IADPSG, International Association of Diabetes and Pregnancy Study Groups; WHO, World Health Organization.

75-g

75-g

—

IADPSG, 2010 American Diabetes Association, 2011 Australasian Diabetes in Pregnancy Society, 2013 WHO, 2013 Australasian Diabetes in Pregnancy Society, 1998 Royal Australian and New Zealand College of Obstetrics and Gynaecology, 2011 Japanese Society of Obstetrics and Gynecology, 2011 Diabetes in Pregnancy Study Group, 2009 50-g ≥ 7.8

75-g

—

ADA, 2000, 2010

75-g

75-g

—

Carpenter and Coustan, 1982 ACOG, 2001 ADA, 2000, 2010 WHO, 1998

75-g ≥ 8.0

100-g

50-g ≥ 7.8

National Diabetes Data Group, 1979

75-g

100-g

50-g ≥ 7.8

Criteria*‡

50-g ≥ 7.8

Oral glucose tolerance test glucose load (g)

Glucose challenge test (mmol/l)

Table 1 Summary of international and regional diagnostic criteria of gestational diabetes mellitus and their use in Asian countries

DIABETICMedicine Diabetes and pregnancy: perspectives from Asia G. E. Tutino et al.


n

267 051

1300

127 (2006) 134 (2008)

9471

105 473

808

3581

9005

10 990

Location/ethnicity

USA/Caucasian/ minority

Australia/Caucasian

Australia/Aboriginal

China/Chinese


China/Chinese

Hong Kong/Chinese

Korea/Korean

Korea/Korean

Taiwan/Chinese

2001–2008

1991–1994

1991–1993

1990-1994

1999-2008

1998-1999

2006-2008

2010

1991-2000

Year

No

≥ 27

24–28

24–28

24–28

24–28

26–30

26–30

Yes, 1-h 50-g glucose challenge test, cut-off 7.2 mmol/l Yes, 1-h 50-g glucose challenge test, cut-off 7.2 mmol/l (22.8% positive) Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l

Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l No

Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l

Some subjects screened, random plasma glucose then fasting plasma glucose or glucose tolerance test. High-risk subjects received oral glucose tolerance test

Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l

≥ 28

26–30

Glucose challenge test

Gestation (weeks)

Table 2 Summary of selected studies on prevalence of gestational diabetes mellitus in Asians

Retrospective, hospital diagnostic codes. Laboratory identified. Carpenter and Coustan and

Laboratory identified. National Diabetes Data Group Laboratory identified. National Diabetes Data Group

Laboratory identified. WHO



Laboratory identified. Australasian Diabetes in Pregnancy Society (1998) and IADPSG criteria. The Australasian Diabetes in Pregnancy Society criteria were based on the results of a 75-g oral glucose tolerance test, either fasting ≥ 5.5 mmol/l or 2-h plasma glucose ≥ 8.0 mmol/l Hospital Discharge Codes. Australasian Diabetes in Pregnancy Society (1998) or IADPSG applied to same population

Laboratory identified. Carpenter and Coustan /American Diabetes Association (2000), WHO

Diagnostic method/criteria

7.9% (Carpenter and Coustan), 3.5% (National

1.90%

2.20%

14.2% (96.2% gestational impaired glucose tolerance)

2006, 4.7% (Australasian Diabetes in Pregnancy Society), 5.5% (IADPSG) 2008, 14.2% (Australasian Diabetes in Pregnancy Society), 13.4% (IADPSG) 2.31% (2.03% for impaired glucose tolerance and 0.28% for diabetes) 2.4–6.8%

Age adjusted, 3.7– 6.2% over study period, highest prevalence 6.6% in 1997 9.6% (Australasian Diabetes in Pregnancy Society), 13.0% (IADPSG)

Prevalence

Chou. J Womens Health 2010; 19: 935–939

Jang. Int J Gynaecol Obstet 1995; 51: 115–122 Jang. Diabetologia 1998 41:778–783

Ko. Diabet Med 2002; 19: 80

Zhang. Diabet Med 2011; 28: 652–657

Yang. Diabetes Care 2002; 25: 847–851

Davis. Aus N Z J Obstet Gynaecol 2013; 53: 363–368

Moses. Med J Aust 2011; 194: 338–340

Ferrara. Obstet Gynecol 2004; 103:526–533

Study*

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305

306

944

2000, (1000/arm)

12 056

607

India/Indian

India/Tamil

India/Indian

1600

India/Indian

Malaysia/Multiethnic Asian

593

Thailand/Thai

1000, 451 received glucose challenge test

Thailand/Thai

797

9861, 4663 received glucose challenge test

Thailand/Thai

Thailand/Thai

n

Location/ethnicity

Table 2 (Continued)

2009–2011

2005–2007

1999–2002

1992

2006

24–28

Random

4.8–8.0 months

≥ 24

22–34

No

Yes, 1-h non-fasting 50-g glucose challenge test, cut-off 7.8 mmol/l No

Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l Yes, 1-h non-fasting 50-g glucose challenge test, cut-off 7.2 mmol/l Yes, 1-h non-fasting 50-g glucose challenge test, cut-off 7.8 mmol/l

≥ 24

2010

2nd to 3rd trimester

24–28 or 30–32

2001–2002

Not reported

Yes in subjects with one or more risk factors for gestational diabetes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l Yes in subjects with one or more risk factors for gestational diabetes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l (39.9% positive) Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l

24–28 and 34–36

2001–2002


Gestation (weeks)

Year

Laboratory identified. American Diabetes Association (2004). Two-hour fasting 75-g oral glucose tolerance test. Gestational diabetes diagnosed if two or more

Laboratory identified. O’Sullivan and Mahan (1964)/National Diabetes Data Group Laboratory identified. Carpenter and Coustan or WHO Laboratory identified. WHO


Soonthornpun. Diab Res Clin Pract 2009; 85: 203

6.5%

Laboratory identified. Carpenter and Coustan. Positive glucose challenge test in 19% of subjects, all received 100-g oral glucose tolerance test without regard to glucose challenge test result Laboratory identified. Carpenter and Coustan

3.1% (Carpenter and Coustan), 4.4% (WHO) 13.9% (17.8% urban, 13.8% semi-urban, 9.9% rural) 7.1%

0.6%

11.4%

9.3%

Chanprapaph. J Med Assoc Thai 2004; 87: 1141–1146

7.1%

Retrospective chart review, laboratory identified. National Diabetes Data Group

Arora. J Med Assoc Thai 2013; 96: 266–271 Tan. Aust N Z J Obstet Gynaecol 2007; 47: 191–197 Ramachandran. Diabetes Res Clin Pract 1994; 25: 71–74 Zargar. Diabetes Res Clin Pract 2004; 66: 139–145 Seshiah. Physicians India 2008; 56: 329–333 Rajput. Indian J Med Res 2013; 137: 728–733

Sunsaneevithayakul. J Med Assoc Thai 2004; 87: 1022– 1028.

Diabetes Data Group) 3.0% (study population), 6.4% (glucose challenge test population)

National Diabetes Data Group Laboratory identified, National Diabetes Data Group

Study*

Prevalence


DIABETICMedicine Diabetes and pregnancy: perspectives from Asia G. E. Tutino et al.



2010–2011

2008–2010

1996–2000

Not reported

Not reported

Year

24–32

24–29

24–27 (glucose challenge test), 25–29 (oral glucose tolerance test)

24–28

24–28

Gestation (weeks)

Yes, 1-h non-fasting 50-g glucose challenge test, cut-off 7.8 mmol/l No

Yes, 1-h non-fasting 50-g glucose challenge test, cut-off 7.2 mmol/l

Yes, 1-h 50-g glucose challenge test, cut-off 7.8 mmol/l No


Laboratory identified. American Diabetes Association (2010) or IADPSG

Laboratory identified. Diabetes in Pregnancy Study Group Laboratory identified. Japanese Society of Obstetrics and Gynaecology (1984). Two-hour fasting 75-g oral glucose tolerance test. Gestational diabetes diagnosed if two or more plasma glucose levels ≥ 5.56 mmol/l on fasting, ≥ 10 mmol/l at 1 h, ≥ 8.3 mmol/l at 2 h Laboratory identified. IADPSG

plasma glucose levels ≥ 5.3 mmol/l on fasting, ≥ 10 mmol/l at 1 h, ≥ 8.6 mmol/l at 2 h Laboratory identified, Carpenter and Coustan


*For references, see also Supporting Information (Table S2). IADPSG, International Association of Diabetes and Pregnancy Study Groups; WHO, World Health Organization.

2772

624

Japan/Japanese

Vietnam/Vietnamese

2651

500

India/Indian

Japan/Japanese

687

n

India/Indian

Location/ethnicity

Table 2 (Continued)

Yachi. Diabet Med 2013; 30: 70–73 Hirst. PLoS Med 2012; 9: e100122

6.1% (American Diabetes Association), 20.3% (IADPSG)

Tripathi. J Obstet Gynaecol Res 2012; 38: 351–357 Kalra. Indian J Endocrinol Metab 2013; 17: 677–680 Miyakoshi. Diabetes Res Clin Pract 2003; 60: 63–67

Study*

4.5%

1.8%

6.6%

1.4%

Prevalence

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somewhat underestimate the true prevalence. The highest prevalence of gestational diabetes reported was from a recent study in an urban population of 4151 consecutive antenatal women irrespective of gestational weeks in Chennai, India. In this study, conducted between 2005 and 2007, prevalence of gestational diabetes diagnosed according to the WHO criteria was reported to be 17.8%. One major limitation with this study was that there were likely cases of pre-gestational diabetes included [24]. A review of Table 2 highlights the wide range of reported prevalence of gestational diabetes within the Asia Pacific region, and even among different studies conducted in the same country. While the definition of gestational diabetes permits a degree of uniformity as applied to various populations, it is undermined by the fact that it inevitably includes cases of undiagnosed pre-gestational diabetes. The IADPSG recommends early screening of overt diabetes at the first antenatal screening using traditional diagnostic thresholds for Type 2 diabetes, acknowledging that whether universal early antenatal screening is necessary will depend on the background frequency of diabetes in the population [9]. Given the increasing prevalence of diabetes among women of childbearing age in Asians, universal early antenatal screening is therefore particularly important. For women without evidence of overt diabetes in early pregnancy, universal screening using a 75-g oral glucose tolerance test at 24–28 weeks is advocated by the IADPSG. Local guidelines among Asian countries are increasingly moving to adopt universal screening (Table 1). For example, universal screening has been implemented in Korea for more than 10 years [25]. Broader use of universal screening should aid in our understanding of the true number of pregnancies affected by gestational diabetes. A number of gestational diabetes screening strategies have been proposed, including the application of risk factors and the use of a glucose challenge test. Whether or not screening with risk factors or a glucose challenge test to select patients meeting certain criteria for a subsequent oral glucose tolerance test, the rate of screening will have consequences for the observed prevalence of gestational diabetes. The application of clinical risk factors, for example, has been associated with a true positive rate of less than 50% [26]. This point was demonstrated by Tan et al., where 22% of a multi-ethnic Asian population in Malaysia with confirmed gestational diabetes detected by a two-step universal screening approach (using a glucose challenge test threshold set at ≥ 7.6 mmol/l) had no clinical risk factors and would have been missed by a screening strategy based on clinical risk factors. Furthermore, the sensitivity and specificity of a 1-h 50-g glucose challenge test varies substantially, with glucose cut-offs between 7.2 and 11.1 mmol/l [27]. Similar effects on prevalence can be deduced based on findings by Miyakoshi et al. in a Japanese population [28]. In general, the application of screening strategies results in lower reported prevalence of gestational diabetes.

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Diabetes and pregnancy: perspectives from Asia G. E. Tutino et al.

The revised criteria for the diagnosis of gestational diabetes based on findings from the HAPO study have been embraced by the IADSPG and the American Diabetes Association, among others. The new criteria are anticipated to markedly increase the number of pregnancies affected by a diagnosis of gestational diabetes and hence its prevalence [16]. For example, in a Vietnamese population, application of the IADSPG criteria resulted in a more than tripling of gestational diabetes prevalence as compared with the two-step American Diabetes Association criteria (20.3% vs. 6.1%, respectively) [22].

Comparison of urban vs. rural studies

There is rapid urbanization in many developing countries in Asia. An association between urban vs. rural living and the prevalence of gestational diabetes has been reported in a number of studies from India. For instance, the overall prevalence of gestational diabetes in women from the Kashmiri region was 3.8%. Among subjects from urban areas, the prevalence of gestational diabetes was double that observed in rural areas (5.5% vs. 2.4%, respectively). Women from urban areas were also significantly more obese compared with women from rural areas [29]. Another study across three areas from India’s Chennai region found that urban living was associated with a significantly higher prevalence of gestational diabetes compared with semi-urban and rural living, with reported rates of 17.8%, 13.8% and 9.9%, respectively [30]. An increased prevalence of gestational diabetes in urban areas coincides with that of known and newly diagnosed diabetes in India, with urban living also being associated with higher BMI and waist circumference [31].

Insights from multi-ethnic studies

It is widely accepted that Asians and subjects of Polynesian heritage are at increased risk of gestational diabetes [16]. Differences in screening programmes and diagnostic criteria have made it impractical to compare prevalence rates across studies. Nevertheless, there are a number of retrospective studies utilizing hospital discharge or birth certificate records in multi-ethnic populations that may inform our understanding of ethnic differences in the prevalence of gestational diabetes. Some of these studies have highlighted the increased risk of gestational diabetes among Asian populations [32]. In a retrospective analysis of deliveries to women of Japanese, Chinese and Filipino ethnicity conducted in California between 1998 and 2001, Rao et al. reported that gestational diabetes was more common among Chinese (6.5%) and Filipina women (6.1%) compared with Japanese women (3.4%, P = 0.013) [33]. The HAPO study group have also noted marked geographical variation in the frequency of gestational diabetes as defined using the IADPSG criteria among the recruiting field centres, ranging from 12.4% in


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(a)

(b)

FIGURE 1 Secular trends in the prevalence of gestational diabetes in Asia. Data based on studies and surveys utilizing universal screening and the same diagnostic cut-off. (a) Data from Tianjin City, China [36]. (b) Data based on the Korean National Health Insurance Corporation [25].

Brisbane, 14.4% in Hong Kong, 23.3% in Bangkok to 25.1% in Singapore [34].

Secular trends

Much of the global data concerning gestational diabetes prevalence has suggested an increasing trend over time [35]. Studies on secular trends in gestational diabetes within Asia are rather limited, although studies conducted in India suggest increasing prevalence over recent years (Table 2). In a study in Tianjin, China, where universal screening for gestational diabetes has been an integral part of antenatal care since 1998, a steady increase in prevalence of gestational diabetes has been reported. All women entering antenatal care were subjected to a 1-h 50-g glucose challenge test, followed by 75-g oral glucose tolerance test if the glucose challenge test revealed glucose > 7.8 mmol/l, and gestational diabetes was diagnosed according to the 1998 WHO diagnostic criteria. Among 105 473 subjects who underwent screening over a 10-year period, the unadjusted prevalence for the population was 4.5% (95% CI 4.4–4.6). The age-adjusted prevalence of gestational diabetes increased by 2.8 times from 1999 to 2008 (from 2.4% to 6.8%, P < 0.0001 for trend) (Fig. 1) [36]. Nationwide data from Korea has similarly shown a marked increase in gestational diabetes prevalence over recent years (Fig. 1) [25]. ª 2014 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK

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Pathophysiology of gestational diabetes While the underlying pathophysiology of gestational diabetes in Asians is similar to that seen in other populations, several factors may play a particularly important role among Asians. Normal pregnancy induces insulin resistance through the production of various placental hormones that serve as insulin antagonists. In gestational diabetes, there is in addition a reduced insulin response because of b-cell dysfunction, and this is relative to the degree of insulin resistance, which could also be aggravated by other factors [37]. Features of b-cell dysfunction include impaired first-phase insulin secretion, prolonged and increased second-phase insulin release, reduced insulinogenic indices, increased hepatic glucose output, changes in insulin kinetics and defective insulin secretion. Defective insulin secretion tends to persist after delivery and is prominent in lean women with gestational diabetes [38]. At the same time, there is exaggerated resistance to the ability of insulin to stimulate glucose utilization and to suppress both glucose production and fatty acid levels. Post-partum testing often shows a greater than normal degree of insulin resistance in both obese and lean women, suggesting underlying chronic insulin resistance. Visceral adiposity and impaired insulin response to glucose have been identified as the major pathophysiological abnormalities present in Korean women with gestational diabetes, [39] and are consistent with the overall phenotype of diabetes in Asians [2,40]. Several studies have highlighted the increased risk of diabetes and glucose abnormalities in Asians at comparatively lower BMI compared with Western populations, which is partly related to increased visceral adiposity in Asians [2]. These characteristics are highlighted in a population-based multi-ethnic cohort of women in Oslo, Norway, which noted that East Asians had lower pre-pregnant BMI compared with women from Western Europe, South Asia, the Middle East and elsewhere. In addition, East and South Asians were noted to be more insulin resistant in early pregnancy compared with the other groups, with the differences even larger after adjustments for BMI. Furthermore, the increase in b-cell function during pregnancy was significantly less in East and South Asians, with the increase not matching the increase in insulin resistance during pregnancy [41]. A contributing factor to insulin resistance is a heightened level of oxidative stress on top of that induced by pregnancy. This results from overproduction of free radicals and/or a defect in the antioxidant defences, which is related to increased lipid peroxidation, protein oxidation and transitional metals such as iron, the supplementation of which increases lipid peroxidation [42]. Indeed, increased third-trimester iron status in women with gestational diabetes was first reported in Hong Kong Chinese women, and serum ferritin level was shown to be a significant determinant of the oral glucose tolerance test 2-h value [43,44]. This association

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was subsequently confirmed by other studies [45,46] and is attributable to increased intake of dietary haeme iron, but not total dietary, non-haeme, or supplemental iron intake as reported previously [47]. Increased iron status is the most likely cause for associations between a-thalassemia trait [48] and high first-trimester haemoglobin (> 13 g/dl) [49] with increased risk of gestational diabetes in the Hong Kong Chinese, and the protective effect of iron-deficiency anaemia against gestational diabetes [50]. However, serum ferritin is also an inflammatory marker and maternal chronic hepatitis B virus infection is one of the explanations for the association between high ferritin and gestational diabetes in Chinese women [51]. In fact, maternal hepatitis B virus infection has since been shown to be an independent risk factor for gestational diabetes in both high-risk [52] and the general [53] obstetric population. Given the high prevalence of hepatitis B virus, especially among East Asian populations, better understanding of the role of the hepatitis B virus in gestational diabetes in Asians is needed. In addition to dietary haeme iron, several other dietary factors, including increased intake of red meat, refined grains, sugar-sweetened beverages, have also been found to be associated with increased risk of gestational diabetes [54]. The high intake of high glycaemic-index white rice in many East Asian populations may be an important dietary risk factor [55]. In South Asian populations, reduced dietary B12 resulting in vitamin B12 deficiency has been found to be associated with insulin resistance and gestational diabetes, especially among women with high folate levels [23]. Apart from increased leptin and decreased adiponectin [37,56], circulating inflammatory markers such as tumour necrosis factor alpha (TNFa), interleukin 6 (IL-6) and C-reactive protein (CRP), were also found to be increased in gestational diabetes [37,57]. The pathophysiological abnormalities such as insulin resistance, endothelial dysfunction, central obesity, dysplipidaemia, oxidative stress and chronic inflammation are common to both pre-eclampsia and gestational diabetes, which explains the significantly increased rate of pre-eclampsia in women with gestational diabetes [57]. It is likely that improved socio-economic conditions and the nutrition transition in many Asian populations, together with endemic infection with hepatitis B virus, have contributed to the high prevalence of gestational diabetes amongst these ethnic groups through increased obesity and iron status, oxidative stress and chronic inflammation. A subset of women with gestational diabetes have evidence of islet cell autoimmunity, with prevalence of islet cell antibodies ranging from 1.6% to 38%, together with a variable incidence of other autoantibodies, including insulin autoantibodies and glutamic acid decarboxylase (GAD) antibodies, who may develop autoimmune diabetes in later life [58]. In a study from Japan, the prevalence of anti-GAD antibodies was 35.4% in all patients with Type 1 diabetes, 50.3% in patients with Type 1 diabetes of less than 1-year

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duration, 4.3% in patients with Type 2 diabetes and 10.5% in patients diagnosed with gestational diabetes, compared with 2.2% in normal subjects [59]. A more recent study noted prevalence of anti-GAD antibodies of 1.7% in Korean women with gestational diabetes [60]. Interestingly, fulminant Type 1 diabetes, a particularly severe form of Type 1 diabetes reported predominantly in East Asian populations, and characterized by the absence of autoantibodies, has been noted to present during or after pregnancy [61].

Genetics of gestational diabetes It is well known that subjects with a family history of diabetes also have an increased risk of gestational diabetes. Mutations in autosomes that give rise to the various types of monogenic maturity-onset diabetes of the young (MODY) can also be associated with gestational diabetes, but these probably represent cases of pre-existing diabetes unmasked by screening during pregnancy [62]. The prevalence of these monogenic forms of diabetes among Asian women with gestational diabetes is not known. Several common genetic variants identified to be associated with Type 2 diabetes through genome-wide association studies, namely variants near CDKAL1, CDKN2A-CDKN2B, HHEX, IGF2BP2, TCF7L2 and KCNQ1, have been found to be associated with gestational diabetes in Koreans [63,64]. The first published genome-wide association study was conducted in the Korean population and included 468 women with gestational diabetes and 1242 control subjects without diabetes in the discovery phase. In a meta-analysis with a total of 3424 subjects, two loci associated with Type 2 diabetes were found to be associated with gestational diabetes at genome-wide significance, with modest effects: rs7754840 in CDKAL1 (odds ratio 1.52, P = 6.65 9 10–16), and rs10830962, a variant near MTNR1B (odds ratio 1.45, P = 2.49 9 10-13) [65]. Interestingly, these variants associated with gestational diabetes, similar to variants for Type 2 diabetes, appear to impact mainly on b-cell function [63]. There are an increasing number of studies that aim to identify epigenetic changes associated with gestational diabetes or maternal hyperglycaemia [66]. Given the importance of gestational diabetes and its potential contribution to the epidemic of non-communicable diseases, better understanding of the molecular changes associated with maternal diabetes and its transgenerational effects may be an important avenue to identify markers that can predict those at risk, or provide new strategies for intervention [67].

Maternal and neonatal complications Pregnancy in women with Type 1 diabetes is less frequently encountered in the Asian populations compared with Caucasian populations, although pregnancies complicated by Type 2 diabetes are increasing. Maternal complications are often related to macro- and microvascular complications,


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including hypertensive and renal disorders, and pre-existing retinopathy can deteriorate rapidly during pregnancy. There is increased risk of infections, especially urinary tract infections, which in turn could aggravate maternal diabetes and create additional complications such as ketoacidosis. Furthermore, obstetric complications in early pregnancy, such as hyperemesis gravidarum, could easily aggravate any concurrent metabolic disturbance and lead to ketoacidosis or hypoglycaemia. However, the maternal impact of gestational diabetes is far greater, given it is much more common. The HAPO study has demonstrated clearly that untreated but sub-threshold glucose intolerance was associated with adverse maternal and neonatal outcomes, including Caesarean delivery, pre-eclampsia and preterm birth, neonatal hypoglycaemia, fetal hyperinsulinaemia, birth injury (predominantly shoulder dystocia), neonatal hyperbilirubinaemia and neonatal intensive care unit admission [8]. Among Hong Kong Chinese women, those with gestational diabetes diagnosed in the third trimester not only had different characteristics, including higher age and BMI at booking and third-trimester haemoglobin levels, but also a significantly higher incidence of pre-eclampsia and shorter length of gestation, despite apparent satisfactory glycaemic control with dietary management [68]. Indeed, the incidence of preterm birth before 37 weeks and before 32 weeks’ gestation in Chinese women was significantly correlated with increasing glucose intolerance, and the oral glucose tolerance test 2-h glucose value was an independent determinant of gestational length, even when treatment was given to all women diagnosed with gestational diabetes [69]. In a prospective cohort study in Vietnam, among 2772 women who underwent a 75-g oral glucose tolerance test at approximately 28 weeks, women with ‘borderline’ gestational diabetes (diagnosed by the IADPSG criteria) and gestational diabetes (diagnosed by the American Diabetes Association criteria) were more likely to deliver preterm [odds ratio 1.52 (1.03–2.24) and odds ratio 1.49 (1.16–1.91), respectively]. Risk of neonatal hypoglycaemia was increased by approximately 4-fold for women diagnosed using either criteria. This study highlighted the potential burden of gestational diabetes identified using the IADPSG criteria, as well as its healthcare impact [22]. Of note, despite that significantly more women will be diagnosed to have gestational diabetes using the IADPSG criteria in this Asian population, it did not appear to confer better discrimination in terms of the risk of adverse outcome. It is likely that even aggressive treatment may not be sufficient to reverse the adverse effect of maternal glucose intolerance once gestational diabetes is diagnosed, and close maternal and fetal surveillance is mandatory regardless of the apparent degree of glycaemic control. Gestational diabetes is well known to be a harbinger of future Type 2 diabetes. The cumulative incidence of Type 2 diabetes in women with previous gestational diabetes increased from 2.6% at 6 weeks to 70% at 28 years after


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delivery [70]. In Hong Kong Chinese women with a history of gestational diabetes, testing at 6 weeks post-partum revealed that 23% and 13%, respectively, had impaired glucose tolerance and diabetes mellitus [71]. After the index pregnancy, these women revealed a 1.6% conversion rate to Type 2 diabetes per year, with significantly higher rates of Type 2 diabetes (24.4% vs. 5.3%), impaired glucose regulation (26.6% vs. 14.9%) and hypertension (35.6% vs. 16.0%) than women with normal glucose tolerance at 15 years [72]. What the best strategy is to detect post-partum diabetes is still a matter of debate, although rates of post-partum testing remain suboptimal in many Asian countries. Another often neglected issue is the emotional impact of a diagnosis of gestational diabetes, especially given the potential increase in prevalence using the IADPSG criteria. Indeed, a growing body of evidence has revealed increased maternal anxiety associated with a diagnosis of gestational diabetes. Mothers with gestational diabetes in Vietnam who participated in short focus groups reported feelings of increased apprehension, largely stemming from a general lack of information around the disorder [73]. Similarly, a study of South Asian women conducted in Australia at diagnosis and post-partum reported that subjects expressed concern about effects on long-term health, fear, shock and distress with the diagnosis [74]. While our understanding of the emotional impact resulting from a diagnosis of gestational diabetes will benefit from further research, including among Asian populations, women in these studies clearly expressed a lack of culturally sensitive advice concerning actions they could take, such as lifestyle modifications.

Long-term complications in offspring and transgenerational effects The long-term complications of exposure to maternal hyperglycaemia have been known for some time [75] and several studies from the region have provided important insights around the long-term complications of gestational diabetes on the offspring. In Korea, Cho et al. conducted one of the first prospective follow-up studies of children from mothers with gestational diabetes. From 909 mothers with gestational diabetes or impaired glucose tolerance who attended for follow-up, 298 offspring were recruited for evaluation at mean age 4.1 1.1 years (range 2.4–8.8). A case–control comparison of 202 offspring of mothers with gestational diabetes and 96 offspring of mothers with impaired glucose tolerance revealed that offspring of mothers with gestational diabetes aged < 5 years had significantly higher BMI than offspring of mothers with impaired glucose tolerance. A greater proportion of offspring of mothers with gestational diabetes had a BMI ≥ 95th percentile (8.5% vs. 4.3%). The gradient of association between age and fasting insulin was higher for offspring with gestational diabetes than impaired glucose tolerance, suggesting that exposure to

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maternal hyperglycaemia may lead to long-term changes in the cardiometabolic profile and risk of obesity in the offspring [76]. Another prospective follow-up study from Hong Kong evaluated offspring of mothers with gestational diabetes or offspring of mothers with normal glucose tolerance and noted significantly higher blood pressure, and a more adverse lipid profile, with lower HDL cholesterol, at age 8 years. Elevated cord blood insulin was associated with an 8-fold increased risk of glucose intolerance in the offspring [77]. When the children were re-evaluated at age 15 years, in utero hyperinsulinaemia was found to be a strong predictor of increased weight and the metabolic syndrome, as well as increased arterial stiffness, highlighting the persistent impact of the intrauterine environment on long-term cardiometabolic risk in the offspring [78,79]. These observations highlighting the increased cardiometabolic risk in those exposed to intra-uterine hyperglycaemia are consistent with those reported in earlier studies in the West [80,81]. However, given the high prevalence of young-onset diabetes and gestational diabetes in Asian countries, it has been postulated that the contribution of maternal hyperglycaemia and gestational diabetes to the overall burden of diabetes are likely to be higher in Asia, especially among developing countries undergoing rapidly changing lifestyles (Fig. 2) [67,82,83]. In these areas undergoing rapid economic development, the dual contribution of maternal under-nutrition on one hand, and gestational diabetes on the other, leads to two interrelated transgenerational cycles of nutrient-mediated teratogenesis and fuel-mediated teratogenesis, respectively, and is believed to


drive the epidemic of diabetes and other non-communicable diseases in Asia (Fig. 3) [84,85]. Some of these transgenerational effects may be mediated by epigenetic changes and can be further exacerbated by the presence of maternal obesity [83]. Interestingly, studies from Taiwan and other parts of Asia have reported a U-shaped association between birthweight and future risk of diabetes, highlighting the potential contribution of (often undetected) maternal hyperglycaemia during pregnancy among those with increased birthweight [86]. Gestational diabetes has been estimated to account for 18–30% of Type 2 diabetes in subsequent generations in a simulation study in a population with young-onset diabetes [87]. Given the burden of hyperglycaemia during pregnancy in Asia, this can have significant implications on public health resources and policies within the region.

Treatment and intervention The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and the US National Institute of Child Health and Human Development Maternal—Fetal Medicine Unit (NICHD MFM) network trials have demonstrated that intensive intervention can lead to a reduced rate of Caesarean section, macrosomia, shoulder dystocia and pre-eclampsia [88,89]. Whilst the two trials have provided the evidence base for the benefit of glucose control during pregnancy, it is not entirely clear what are optimal glucose levels. For example, current guidelines in China recommend targets of fasting blood glucose ≤ 5.3 mmol/l, 1-h postprandial glucose

FIGURE 2 Transgenerational diabetes following exposure to maternal hyperglycaemia and gestational diabetes. According to the conceptual framework of developmental origins of health and disease, the risk of non-communicable diseases increases during an individual’s lifespan, and interventions early in life, when developmental plasticity is comparatively higher, is more effective than treatment later in life. Gestational diabetes not only identifies women on a high-risk trajectory, who is at increased risk of gestational diabetes in future pregnancies, as well as diabetes later in life. In addition, partly through intra-uterine hyperglycaemia, the mother also transmits increased risk of non-communicable diseases to the offspring. Post-natal metabolic evaluation and intervention may reduce the future risk of diabetes in the woman. Interventions in the pre-conceptual period, or early during pregnancy, may potentially benefit both the mother and the offspring. Reproduced from Hanson et al. (2012) [83] which is an Open Access article with the Creative Commons Attribution License.

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FIGURE 3 The two cycles highlighting the contribution of intra-uterine environment and exposures in early development on the long-term risk of diabetes and other non-communicable diseases in developing countries. Maternal under-nutrition increases the risk of insulin resistance and diabetes in the offspring (nutrient-mediated teratogenesis), while maternal over-nutrition and hyperglycaemia also contribute to offspring risk of diabetes and obesity (fuel-mediated teratogenesis). Both have long-term transgenerational effects that can contribute to the epidemic of diabetes. Reproduced from Ma et al. 2013 [85] with permission from Elsevier.

of ≤ 7.8 mmol/l and 2-h postprandial glucose of ≤ 6.7 mmol/l for women with gestational diabetes [90]. A randomized controlled trial in China has attempted to translate the established intervention protocol from the ACHOIS trial into the three-tiered antenatal care system in urban Tianjin, China. The initial findings from the trial suggested that the shared care approach was associated with an 80% reduction in the rate of macrosomia (defined as birthweight ≥ 4000 g) compared with usual care [91]. Lifestyle modification plays an essential role in glycaemic control. In addition to dietary intervention, physical activity of at least 30 min of light to moderate intensity 5–7 times per week is usually recommended. However, neither the ACHOIS nor the NICHD and MFM network trials had a physical activity component in their intervention protocol. Furthermore, there are limited published trials evaluating the effects of exercise in women with gestational diabetes. Additional evidence to guide recommendations on optimal physical activity to control hyperglycaemia among Asian women with gestational diabetes is needed.

example, in China, the use of oral anti-hyperglycaemic agents is still not approved for use in pregnancy [93]. Given the difficulty in achieving optimal blood glucose control, there is also increasing reliance on multiple daily injections or continuous subcutaneous insulin infusion in some countries. There are relatively limited data on experience in the use of insulin analogues for the management of diabetes complicating pregnancy or gestational diabetes in Asian populations, although the ultra-short-acting analogues may help towards optimizing postprandial glucose. In a randomized, open-label, parallel study comparing premixed insulin aspart 30 [biphasic insulin aspart (BIAsp 30)] and premixed human insulin in the management of gestational diabetes, 323 affected women at a single centre in India were randomized to receive 6 units of either insulin at a 1:1 ratio. The two groups achieved comparable glucose control, with rates of macrosomia not different between the two groups and the group on aspart insulin requiring less insulin overall [94].

Pharmacological treatment

Public health implications and ongoing prevention programmes

The majority of women with gestational diabetes who require pharmacological treatment are treated with insulin in Asian countries [92]. While use of glyburide and metformin has been noted to be effective in randomized clinical trials, there is still comparatively limited use of oral agents in the treatment of gestational diabetes in the region. For

Gestational diabetes identifies women at high risk for subsequent progression to Type 2 diabetes and postpartum evaluation and education are important for early identification and prevention of Type 2 diabetes. There has been growing recognition of the impact of the intra-uterine environment and early development on the future risk of


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non-communicable diseases. In addition, increasing appreciation of the harmful long-term effects of maternal hyperglycaemia and gestational diabetes on metabolic outcomes in the offspring has focused attention on improving preconceptual as well as optimizing maternal health during pregnancy as an opportunity to improve outcomes both for the mother and offspring [83]. In order to effectively address the burden of gestational diabetes and non-communicable diseases, these programmes need to address several aspects: improving awareness of diabetes complicating pregnancy; promoting advocacy of diabetes and women, including gestational diabetes; incorporating diabetes screening and management into reproductive and sexual health education and services; and using information technology to improve compliance to treatment and follow-up [95]. Recent application of a model to examine cost, healthcare impact and cost-effectiveness of gestational diabetes screening and intervention in India and Israel has noted that gestational diabetes interventions are highly cost-effective by WHO standards, despite the diverse healthcare settings examined [96]. Several such large-scale programmes have been initiated in Asia over recent years. These include initiatives led by government as well as non-governmental organizations. For example, through support from the World Diabetes Foundation, a large-scale programme is being conducted in China across more than 20 cities to implement structured management of gestational diabetes, which to date has successfully taught 215 gestational diabetes trainers and more than 15 000 healthcare professionals [97]. In India, the Federation of Obstetric and Gynaecological Societies of India, the Diabetes in Pregnancy Study Group India and the World Diabetes Federation has launched a large-scale initiative for training of trainers. This programme, launched in May 2013, aims to prepare 100 specialty trainers to train 1000 obstetricians and gynaecologists in 25 centres across India in order to empower them to improve early detection, case management, counselling, referral and prevention of gestational diabetes, and to facilitate the development of specialized clinics focusing on diabetes in pregnancy [98]. The Ministry of Health in Malaysia, in partnership with academia and industry, has launched a public–private partnership named Yo Mama to target maternal health as a strategy to reduce adverse outcomes [99]. Some of the barriers encountered in improving maternal health related to gestational diabetes through these programmes have been highlighted. These include: the lack of trained healthcare providers, including female doctors; high staff turnover; lack of standard protocols, consumables and equipment; the financing of health services and treatment; inadequate or absent referral systems, feedback mechanisms and follow-up systems; travel distance to health facilities; local cultural perceptions about diet, female body size and weight changes during pregnancy; societal negligence of women’s health; and the need to empower women regarding their own health [100]. Ongoing and future programmes will

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need to tackle these obstacles, as well as forge stronger ties between healthcare services and providers in the area of obstetrics care, endocrinology, maternal and child health and primary care, among others. Despite their challenges, these important programmes provide proof of concept on how to translate these intervention programmes to a larger scale in order to optimize maternal health during pregnancy, improve detection of hyperglycaemia and glucose control during pregnancy and impact on the long-term risk of non-communicable diseases in Asia and beyond.

Conclusion In summary, the prevalence of gestational diabetes reported in Asia varies extensively, partly reflecting a lack of uniformity in screening methodologies and diagnostic criteria. Nevertheless, marked increased risks among women of Asian heritage are a consistent finding among regional and international studies. Moreover, irrespective of the diagnostic criteria used, the trend appears to suggest an increasing prevalence with time. Recent studies in Asian populations have identified several genetic variants linked to Type 2 diabetes with the development of gestational diabetes, suggesting a common pathophysiology, likely through affecting b-cell function. Implications from the HAPO study have shifted the diagnostic focus from future maternal diabetes risk to prevention of adverse perinatal outcomes. As such, the number of women affected by diabetes in pregnancy is anticipated to increase sharply. There is a general lack of awareness for the deleterious effects of gestational diabetes despite substantial evidence to the contrary. There is an urgent need to harmonize diagnostic criteria, taking into account regional and ethnic considerations. The WHO took a step towards this end by recently updating their diagnostic criteria for gestational diabetes, adopting the IADPSG recommendations. However, innovation in implementation and additional research around cost–benefit are essential next steps to ensure their practical application in Asian populations. Increased use of prevention and intervention programmes, along with enhanced awareness efforts, are essential to address the growing burden of gestational diabetes and its consequent harmful effects on short- and long-term maternal and offspring health outcomes. Women with gestational diabetes clearly require culturally sensitive solutions to aid them in coping with the additional burden of gestational diabetes on top of those already incurred by expectant mothers. Evidence suggests that strategies exist to identify women with gestational diabetes and that active management can ameliorate many of its damaging effects.

Funding sources

RCWM received grant support from the European Foundation for the Study of Diabetes (EFSD)/Chinese Diabetes Society (CDS)/Lilly Collaborative Research Programme, and


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the General Research Fund of the Research Grants Council of Hong Kong (CU471713). WHT received grant support from the General Research Fund of the Research Grants Council of Hong Kong (CU473408).

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Competing interests

RCWM has received speaker honoraria or consultancy fees over the last 3 years from Boehringer-Ingelheim, Eli Lilly, Bayer, Danone, Nestle, Pfizer and Takeda, and research support for conducting clinical studies and trials from Astra Zeneca and Merck Sharp and Dohme. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research.

Acknowledgements

We wish to thank Dr Lay-Kok Tan and Dr Abel Soh from Singapore, Professor Hak Jang and Professor Nam H. Cho from Korea, Dr Hema Divakar, Dr Susheela Rani, Dr Uday Thanawala, Dr Veeraswamy Seshaih and Professor Chittaranjan Yajnik from India, Dr Takashi Sugiyama from Japan and Professor Chaicharn Deerochanawong from Thailand for their helpful discussion and providing comments on regional practices. We apologize that, because of limited space, we are only able to cite a fraction of the studies conducted in Asia.

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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. References for Table 1. Table S2. References for Table 2.


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