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Gestational Diabetes in Malaysia: A Systematic Review of Prevalence, Risk Factors and Outcomes

Gestational diabetes mellitus (GDM) is glucose intolerance first diagnosed during pregnancy. In Malaysia, the prevalence, risk factors, and maternal/foetal outcomes vary somewhat among the local studies. In this systematic review of Malaysian studies, we synthesise relevant data from 13 journal articles (including 10,285 women with gestational diabetes). A meta-analysis of twelve datasets showed a prevalence of 21.5% (95% CI 17.3 to 25.9%, random effect model). Clinical factors in the mother found to increase her risk of GDM were consistent with international data. A meta-analysis of complications showed statistically significant increase for macrosomia (OR 3.08, 95% CI 1.77 to 5.36) but not for pre-eclampsia (OR 1.44, 95% CI 0.52 to 4.00) and caesarean delivery (OR 1.31, 95% CI 0.98 to 1.75). The high prevalence of gestational diabetes mellitus and documented adverse consequences support the need for universal screening of this condition in all pregnant women in Malaysia.


INTRODUCTION
Gestational diabetes mellitus (GDM) is glucose intolerance first diagnosed during pregnancy. GDM poses a huge health burden in both the short and long term. Both mother and baby of GDM are at greater risk of complications during pregnancy and delivery. Poorly managed GDM results in higher perinatal morbidity and mortality (Contreras et al. 2008). After delivery, both mother and newborn are also at a greater risk of developing type 2 diabetes mellitus, obesity, and subsequent cardiovascular diseases (Kramer et al. 2019;Nouhjah et al. 2017). Hyperglycaemia in pregnancy is associated with macrosomia and polyhydramnios. During delivery, these infants of poorly controlled GDM will be more susceptible to birth related complications of prolonged labour, shoulder dystocia, birth asphyxia, and increased rates of admission to neonatal intensive care unit (NICU). Caesarean delivery rates are higher in GDM for various reasons apart from estimated birth weight exceeding 4 kg (Boriboonhirunsarn & Waiyanikorn 2016).
The prevalence of GDM varies worldwide depending on the diagnostic criteria and reporting rates. A metaanalysis of 50 population-based prevalence studies showed that Asia has the highest prevalence (South Asia 11.4%, East Asia 10.8%), while lower rates were seen in Australia with 3.6%, North America with 4.5% and North Europe with 6% (Behboudi-Gandevani et al. 2019). Locally, there is some variation in the prevalence, risk factors and maternal/foetal outcomes of this condition. Synthesised data in these domains derived from metaanalysis can help policy makers and clinicians with regard to the implementation of screening programme and clinical care of such patients.

MATERIALS AND METHODS
We searched PubMed (using the MESH terms 'Diabetes', 'Gestational' and 'Malaysia') and Scopus (using text word 'gestational diabetes' and 'Malaysia') on 31 st December 2019. These searches were supplemented by a Google Scholar search using the same text words. The citations were processed using Endnote 7 citation manager. Keywords of all citations were coded for study designs, study settings (primary care, tertiary care), country of study (Malaysia, non-Malaysia), and any prevalence, risk factors or maternal or foetal/neonatal outcome data.
The inclusion criteria of eligible studies were: Original research conducted in Malaysia; Studies that provide data on prevalence, risk factors, maternal or foetal/neonatal outcome data of GDM; for prevalence data, GDM must be diagnosed using an oral glucose tolerance test (oGTT); for risk factor assessment, the recruitment of antenatal women should be universal rather than selective; and for maternal and foetal/neonatal outcome data, both prospective and retrospective studies are acceptable.
Full text of eligible studies was retrieved. Relevant data in the included studies were extracted by a pair of investigators and checked by a senior researcher. The number of study participants (total sample and number diagnosed with GDM) and other relevant data (study setting, patient selection, oGTT method) were extracted. Meta-analysis was performed using MedCalc Statistical Software using fixed effect model if study heterogeneity (I 2 ) is less than 50%, otherwise random effect model was used (MedCalc 2019). Sensitivity analysis was performed for prevalence data taking into account the study setting, patient selection and oGTT procedure.
This systematic review was prepared following PRISMA guideline (Moher et al. 2009). The quality assessment of the published studies was assessed using a checklist published by Munn et al. (2015).

QUALITY ASSESSMENT
All the included studies received a moderate to high quality rating in our critical appraisal.

PREVALENCE OF GESTATIONAL DIABETES
Eleven publications provided data on prevalence of GDM (Table 1) (Basri et al. 2018;Gill et al. 2012;Hasbullah et al. 2020;Idris et al. 2009;Ismail et al. 2013Ismail et al. , 2011Kalok et al. 2018;Logakodie et al. 2018;Shamsuddin et al. 2001;Tan et al. 2012Tan et al. , 2007. One publication contained two separate datasets of GDM prevalence (Basri et al. 2018). These studies were conducted in various settings (primary care and tertiary care), and recruited pregnant women with and without risk factors of GDM. Although all of them used oGTT to confirm the presence of GDM, the methods employed in administrating oGTT and diagnostic threshold were highly variable. 1-step procedure (75 g oGTT) was used in seven studies (eight datasets) and 2-step procedure (a 50 g glucose challenge test followed by a 75 g oGTT in selected cases) was done in three studies.
The prevalence rate of GDM in the primary studies ranged from 11.4 to 37.9%, a 3.3-fold difference. A meta-analysis of twelve datasets involving 9587 antenatal women showed very high study heterogeneity (I 2 =95.97) with a prevalence of 21.5% (95% CI 17.3 to 25.9%, random effect model) ( Figure 2). Sensitivity analysis showed no difference in the prevalence by setting. However, prevalence of GDM appeared to be lower if there was less selection bias while 2-step procedure tends to under-detect GDM compared to 1-step procedure ( Table 2).

RISK FACTORS OF GESTATIONAL DIABETES
We found four studies reporting risk factors for GDM in Malaysia (Gill et al. 2012;Shamsuddin et al. 2001;Tan et al. 2012Tan et al. , 2007. In this analysis, we included only studies that recruited all antenatal women rather those with or without certain risk factors. Clinical factors in the mother found to increase her risk of GDM were: older maternal age, obesity, glycosuria, abnormal GCT, family history of diabetes, previous GDM and history of stillbirth (Table  3). We found seven studies that provided maternal, foetal/ neonatal complications data (Basri et al. 2018;Ismail et al. 2013Ismail et al. , 2011Kalok et al. 2018;Kampan et al. 2013;Logakodie et al. 2018;Nordin et al. 2006). One study containing two separate datasets were analysed separately (Basri et al. 2018). Maternal complications that were associated with GDM were caesarean delivery rate, induction of labour, polyhydramnios, pre-eclampsia, and premature labour. Foetal/neonatal, complications that were associated with GDM were birth trauma, hyperbilirubinaemia, hypoglycaemia, low Apgar score, macrosomia, NICU admission, polycythaemia, respiratory distress syndrome, and stillbirth (Table 4).
A meta-analysis of complications reported in three or more datasets showed statistically significant increase for macrosomia (OR 3.08, 95% CI 1.77 to 5.36) but not for preeclampsia (OR 1.44, 95% CI 0.52 to 4.00) and caesarean section (OR 1.31, 95% CI 0.98 to 1.75) ( Table 5).  The pooled prevalence of GDM in Malaysia as shown in our meta-analysis is approximately 21.5% (95% CI 17.3% to 25.9%, random effect model, Table 1). There is some uncertainty in this pooled prevalence in view of high study heterogeneity, possibly as a result of differences in the patient recruitment, diagnostic methods and criteria of oGTT. In the selection of studies for this meta-analysis, we have excluded one retrospective cohort study derived from the Malaysian Obstetric Registry (Muniswaran et al. 2017). Although this study has a large sample size (n=22,044), the antenatal women were recruited at delivery from the obstetrics register of 14 public hospitals. The diagnostic method and criteria of GDM were also not clearly described.
Our pooled prevalence of GDM appeared to be higher than the pooled prevalence for Asian countries Nguyen et al. 2018) (10.1-11.5%). In these meta-analyses, only two Malaysian prevalence studies were included Nguyen et al. 2018). When compared to the country-specific meta-analyses of prevalence studies, our pooled prevalence is also higher than those of Iran with 3.41% (Jafari-Shobeiri et al. 2015), Turkey with 7.7% (Karaçam & CelIk 2021), China with 14.8% (Gao et al. 2019), and India with 19.19% using IADPSG method of diagnosis (Li et al. 2018).
There are concerns in adopting universal screening for GDM in resource limited countries despite ACHOIS trial had shown intervention for women suffering from mild gestational diabetes did reduce some of its complications such as fetal overgrowth, shoulder dystocia, caesarean delivery, and hypertensive disorders (Landon et al. 2009). However, there appears to be some compelling evidence for the adoption of universal screening for GDM in antenatal mothers in Malaysia. Firstly, the incidence of GDM is substantially high, affecting possibly one in five pregnant women in this country. Secondly, selective screening may miss a substantial number of eligible women, e.g. Shamsuddin et al. (2001) reported 28% of GDM women in their study did not have any risk factors used in the selective screening. Furthermore, Gill et al. (2012) also did not find improved efficiency of GDM screening using a scoring system derived from nine known GDM risk factors.
Currently two Malaysian clinical practice guidelines (HTAU 2017(HTAU , 2015 recommend screening of antenatal women using 75 g oGTT at booking based on the presence of risk factors, and, if negative, to repeat the same at 24-28 weeks gestation. Both these guidelines adopted the IADPSG guideline (Lapolla et al. 2011) but with some difference for the 2 h post-glucose load threshold (Type 2 Diabetes CPG: FPG ≥ 5.1, 2HPP ≥ 8.5 (Health Technology Assessment Unit 2015); DM in Pregnancy CPG: FPG ≥ 5.1, 2HPP ≥ 7.8 (Health Technology Assessment Unit 2017)). The Health Technology Assessment Unit of the Ministry of Health Malaysia, as developer of the national guideline, should initiate efforts to avoid such confusion.

DIABETES
Our analysis identified several complications as a result of GDM. However, in our meta-analysis, only macrosomia is a statistically significant outcome but not pre-eclampsia or caesarean section. In our literature review, we found that the above complications are by and large associated with GDM in other systematic reviews (Hosseini & Janghorbani 2018;Natamba et al. 2019;Wendland et al. 2012), however, some inconsistency is also found, e.g. Natamba's systematic review (2019) of studies in Sub-Sahara Africa also did not show an increased risk of caesarean section.

STUDY LIMITATIONS
This systematic review is based on a comprehensive retrieval of Malaysian journal articles on the topic of GDM. We are confident that we have identified most, if not all, relevant publications on this topic. However, publication bias cannot be excluded. In addition, pooled analysis is compounded by missing data in the original publications. Furthermore, beside the variable diagnostic methods and threshold for GDM, it is also possible there are inconsistent definitions for other outcomes such as macrosomia and pre-eclampsia. Thus, we wish to echo the call by Feig et al. (2015) for codification of the definitions and reporting of variables in future investigation on GDM.

CONCLUSION
This systematic review comprehensively summarises the available published literature on the prevalence, risk factors, and complications/outcomes of GDM in Malaysian women. Our study emphasised the high prevalence of GDM, summarised various risk factors associated with it and substantial complications that may result and recommend universal screening of this important health condition in pregnancy.