Gestational diabetes mellitus (GDM) and adverse pregnancy outcome in South Asia: A systematic review

Abstract Introduction The prevalence of gestational diabetes mellitus (GDM) is increasing in developing countries including the South Asian Nations. The current study aimed to examine the association of GDM with adverse pregnancy outcomes from foetal and maternal perspectives in South Asia. Methods A systematic review was conducted including primary studies published since January 2020 from South Asian countries. Following electronic databases were searched to locate the articles: MEDLINE, EMBASE and EMCARE. Data were extracted using a customized extraction tool and methodological quality of the included studies was assessed using modified Effective Public Health Practice Project (EPHPP) quality assessment tool. Narrative synthesis was performed as statistical pooling was not possible due to the heterogeneous nature of the studies. Results Eight studies were included in the review. Overall, the review found a positive correlation between GDM and adverse foetal outcomes such as macrosomia, neonatal hyperglycaemia, intrauterine growth retardation (IUGR), stillbirths and low birthweight (LBW), but the findings were not conclusive. GDM was also positively associated with preeclampsia but the association between GDM and C‐section delivery was not conclusive. Conclusion Policymakers, public health practitioners and researchers in South Asia should take in to account the link between GDM and adverse pregnancy outcomes while designing interventions to promote maternal health in South Asia. Researchers should focus on conducting longitudinal studies in future to clearly understand the epidemiology and pathobiology of this issue.


| INTRODUC TI ON
Gestational diabetes mellitus (GDM) can be defined as glucose intolerance of varying degree started at or detected during pregnancy. GDM is known as one of the leading causes of maternal and infant mortality. 1,2 Studies have detected several risk factors of GDM including overweight, obesity, advanced maternal age and family history of diabetes. [3][4][5] Globally, the prevalence of GDM is increasing in recent years and affects 1%-14% of all pregnancies. 6 GDM was previously considered to be a major public health problem in developed countries, but it is now a growing problem in developing countries as well. Most of the countries in the South Asian region are no exception to this with an increasing trend in the prevalence of GDM reported in these countries. 7 Evidence suggests that the prevalence of GDM is 11% higher among women from Indian subcontinent than those from Europe. 8 Among Asian countries, the highest prevalence rate is reported in China and India. 9 It is postulated that increased population density followed by the emergence of agriculture, regular famines and the retarded growth with thin physique characterization has elevated the general susceptibility to diabetes in Indian sub-continent. 10 Along with the increasing probability of being diagnosed with Type 2 diabetes mellitus after pregnancy, GDM is indicated to be closely associated with different adverse pregnancy outcomes both at the foetal and maternal level including an increased risk of caesarean-section (C-section) delivery, preeclampsia, macrosomia and intrauterine growth retardation (IUGR). [11][12][13] GDM is also associated with newborns delayed brain maturity and neurobehavioral abnormalities including comparatively lower intelligence than normal babies, language impairments, poor attention and impulsivity. 14 Therefore, it is very important that GDM is managed properly to avoid different adverse pregnancy outcomes associated with it.
Evidence suggests that the prevalence of adverse pregnancy outcomes such as preeclampsia, C-section delivery, macrosomia, low birthweight, still births and IUGR is high in South Asian countries. [15][16][17][18] For example, Poudel et al. (2020) 17 reported that the pooled stillbirth rate in India, Bangladesh, Nepal and Pakistan was 25.15 per 1,000 births. Another study reported that, the prevalence of C-section delivery is around 13% in South Asian countries. 19 Although several studies have pointed the association between GDM and adverse pregnancy outcomes, it is important that these findings are synthesized systematically to provide concrete evidence for policymakers and practitioners in South Asia. This study aimed to synthesize the evidence on the association between GDM and adverse pregnancy outcomes in South Asian countries.

| Data sources
We followed PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for conducting this review. 20 A systematic search of electronic databases such as MEDLINE,

| Study selection
Selection of the articles was based on the predefined inclusion/ exclusion criteria (Table 1). The search and screening process of the articles were conducted independently by two researchers (SKM and KK). The consistency was ensured by a third researcher (RDG). The full-text screening and selection were done by all three researchers. Any discrepancy was solved by consensus among the group.

| Data extraction and quality assessment
Data from each of the selected studies were extracted using a data extraction template. Information such as title, authors, publication year, country, study design, study population and key findings were quality assessment tool. 21 Selected studies were evaluated against four methodological domains: study design and appropriateness of the outcome measure, sample representativeness, data analysis and interpretation. In each individual study, for every domain, a score was assigned: 1 (weak), 2 (moderate) or 3 (strong). The score was then combined to get the total methodological quality score assigned to an individual article. A score of 4-6, 7-9 and 10-12 were graded as weak, moderate and strong respectively. 21

| Data synthesis
Data synthesis involved systematic collating, combining and summarizing the findings of the selected literatures to answer the research question of the review. 22 Data analysis can be accomplished either using statistical pooling or where it is inappropriate by best evidence synthesis approach. Considering the heterogeneous nature of the included studies, the findings of the included studies were analysed as best evidence synthesis instead of statistical pooling.

| Literature selection
A total of 157 articles were identified through initial searching of the electronic databases, of which 10 articles were excluded as duplicate records (Table 1)

| Characteristics of included studies
Characteristics of included studies are shown in Table 2. Among the eight studies included, 8,9,[23][24][25][26][27][28] six studies 8,24-28 utilized prospective observational study design while the remaining two studies 9,23 used a retrospective study design. All the studies selected were primary studies carried out in South Asian countries. Five studies were conducted in India, 8,9,[26][27][28] one in Pakistan, 23 one in Bangladesh 24 and one in Sri Lanka. 25 All the studies were conducted in hospital settings except one study which was carried out in rural areas of Assam, India. 26 In five studies, GDM was diagnosed in accordance with the WHO criteria and was measured performing an oral glucose tolerance test (OGTT), 9,23,[25][26][27] while in other studies (n = 3), patient recall were used. 8,24,28

| Methodological qualities of included studies
Methodological quality of the included studies was ranked against the predefined criteria and six 8,9,23,25,27,28 of the eight studies were classified as of moderate quality while two studies 24,26 were of weak methodological quality. revealed that GDM has a role in adverse pregnancy outcomes both among the foetus such as neonatal hyperglycaemia, macrosomia, stillbirths, intrauterine growth retardation (IUGR) and low birthweight (LBW) and mothers such as preeclampsia and C-section. The findings are shown in Table 3.

| GDM and neonatal hyperglycaemia
Islam et al. 24 presented the role of GDM on neonatal hyperglycaemia. The authors reported that 40% of the GDM mothers have an infant with hyperglycaemia in neonatal period. However, the study did not report the values in any control group making it difficult to draw any concrete conclusions.

| GDM and macrosomia
All the studies 8,9,[23][24][25][26][27][28] investigated the role of GDM on macrosomia. Six studies 8,9,[25][26][27][28] showed that higher percentage of pregnant women with GDM have a foetal outcome of macrosomia compared to women with no GDM. Akhter et al. 23 and Islam et al. 24 reported that macrosomia was highly prevalent among GDM mother, although the findings were inconclusive due to lack of a control group. Wahi et al. 28 reported that there was no significant association between GDM and LBW. Shefali et al. 27 found that prevalence of LBW was higher among the control group compared to the GDM group.

| GDM and intrauterine growth retardation (IUGR)
Role of GDM on IUGR was measured by two studies 9,23 but the findings were not conclusive. Akhter et al. 23 found that 7.1% of the GDM women have IUGR but did not report anything regarding the control group; thus, making it difficult to draw any conclusion. Saxena et al. 9 also did not find any conclusive evidence on the association between GDM and IUGR.

| GDM and stillbirths
Only Wahi et al. 28 investigated the association between GDM and adverse pregnancy outcomes in the form of stillbirths. The study reported that prevalence of GDM was significantly higher among the GDM group (p = .02) compared to the control group.

| GDM and preeclampsia
Six of the eight studies investigated the association between GDM and preeclampsia or pregnancy-induced hypertension. Irrespective of the study setting, all the studies reported a positive association between GDM and preeclampsia. Although Akhter et al. 23 and Misra and Das 8 did not report the result in comparison to a control group, they reported that prevalence of preeclampsia was very high (20.8%) among the pregnant women with GDM. On the other hand, Jayawardane et al., 25 Mahanta et al., 26 Saxena et al. 9 and Wahi et al. 28 reported the association between GDM and preeclampsia in comparison to a control group and reported that GDM group had significantly higher occurrence of preeclampsia compared to that of the control group.

| GDM and C-section delivery
Three studies 9,23,25 investigated the role of GDM on C-section delivery. While Saxena et al. 9 reported a positive association between GDM and C-section delivery, the other two studies 23,25 did not find any significant association.

| DISCUSS ION
This systematic review was aimed at finding the role of GDM on adverse pregnancy outcomes at both foetal and maternal level. Most of the studies included in the review followed a prospective observational design and were carried out in hospital settings in India.
Overall, the study findings revealed that GDM was associated with foetal macrosomia. While some studies identified the association of GDM on other adverse foetal outcomes such as neonatal hyperglycaemia, LBW, stillbirths and IUGR, the evidence was not conclusive. Although the association between GDM and preeclampsia or pregnancy-induced hypertension among pregnant mothers was identified, it is difficult to conclude the associations between GDM and C-section delivery.
Consistent with the findings of the present review, other studies have affirmed that untreated GDM is often linked to foetal macrosomia (children with birthweight greater than 4,000 grams). 29,30 The major reason behind the increased risk of macrosomia among pregnant mother with GDM is the enhanced insulin resistance of the mother 31 due to a higher amount of glucose passing through the placenta into foetal circulation. Consequently, this extra amount of glucose is stored as body fat in the foetus and causes macrosomia. 32 Similar to the findings from our review, other studies have reported positive correlation among GDM, stillbirths and LBW. 33,34 The leading causes of stillbirths related to GDM are reported to be abnormalities of placenta, congenital malformations and IUGR. 35 Foetal anaerobic metabolism with hypoxia and acidosis resulting from hyperglycaemia is a common metabolic cause of diabetes-related stillbirth. 36 Women with GDM can give birth to neonates with different metabolic disorders. Neonatal hypoglycaemia is one of them which results from hyperinsulinism leading to neurodevelopmental outcomes. 37 Therefore, if GDM can be controlled, the prevalence rate of neonatal hypoglycaemia can also be controlled as they are interrelated.
Other studies have confirmed the correlation between GDM and adverse outcomes of the pregnant mothers such as preeclampsia and C-section delivery. [38][39][40] Preeclampsia is a common pregnancy-related complication induced by GDM, characterized by high blood pressure resulted from increased insulin resistance. 41 Hypertensive disorders can be increased two-to threefold in pregnancies due to high blood glucose level. 42 However, several other maternal factors are also associated with preeclampsia including maternal cardiovascular disease, renal disease, overweight and obesity. 43 A strong positive association was found between GDM and C-section delivery in a study from China among pregnant women in Chengdu, Sichuan province. 44 However, in our systematic review, although one study reported positive association, two studies did not find any positive association between C-section delivery and GDM. More studies are required to have a conclusive evidence on this.
As the review highlights the importance of GDM in increasing the prevalence of adverse pregnancy outcomes, it is important that policymakers and practitioners emphasize more on the preventive measures of GDM not only for the sake of GDM alone but also to prevent adverse pregnancy outcomes simultaneously.
There are not many direct causes of adverse pregnancy outcomes that are documented; therefore, controlling GDM can indirectly act as a preventive measure for adverse pregnancy outcomes as well. It is important that national and regional policies regarding the prevention and management of GDM also incorporate policies that embed GDM management for adverse pregnancy outcomes.
Regional collaborations between different stakeholders need to be strengthened with shared understanding, planning and implementation to address the problem. For example, using the platform of the South Asian Association for Regional Cooperation (SAARC) in active engagement among policymakers and practitioners from these countries can be of value in this regard. The findings of the present review are also important from the clinicians' perspectives of this region. As the review reports positive correlation between GDM and adverse pregnancy outcomes, it is important that clinicians also consider the possibilities of any adverse pregnancy outcomes while recommending the treatment regimens for GDM patients.
To the authors' knowledge, as no other recent systematic reviews have been conducted summarizing the role of GDM on adverse pregnancy outcomes focusing in South Asia. 45 This review is particularly important as it provides synthesized evidence from South Asian countries for policymakers and clinical as well as public health practitioners to enact effective initiatives to address the issue.
However, one should be cautious while interpreting the findings of the research as the quality of the included studies was relatively moderate 8,9,23,25,27,28 to poor. 24,26 Moreover, most of the included studies followed a prospective observational design and reported differences in the prevalence of adverse outcomes between GDM and non-GDM group, but they did not report a causative association between GDM and adverse pregnancy outcomes. There was significant heterogeneity among selected studies in terms of participants' age, BMI, dietary patterns, study design and the methods of diagnostic criteria and this could have affected the reliability and validity of the findings. It is to be noted that there were limited studies on the association between GDM and pregnancy outcomes in some of the South Asian countries including Afghanistan, Maldives and Bhutan.

| CON CLUS ION
Overall, the findings from the current systematic review suggests a positive association between GDM and adverse pregnancy outcomes in South Asian countries. The review provides valuable information for policymakers and practitioners to undertake effective initiatives to address the issue and to improve the GDM-related care for reproductive aged women. The findings also indicate the need to undertake longitudinal studies to better understand the causative link between GDM and adverse pregnancy outcomes in South Asian countries.

CO N FLI C T O F I NTE R E S T
The authors report that there is no conflict of interest to disclose.