Introduction

The new glucose criteria for the diagnosis of GDM were developed by the International Association of Diabetes in Pregnancy Studies Groups (IADPSG) based on the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [1, 2]. On this basis, the diagnosis of GDM is established on a POGTT if the fasting blood glucose level (FBG) ≥ 5.1 mmol/l, the 1-hr BGL ≥ 10.0 mmol/l, or 2-hrs BGL ≥ 8.5 mmol/l [2]. The pandemic of COVID-19 that has occurred across the world in 2020 has resulted in many changes in social behavior to minimise transmission of the virus. Social distancing is a corner stone of that strategy [3]. Performing an OGTT in the morning on a fasting pregnant woman creates a practical problem of potentially exposing women to a high risk environment for 2 to 3 hours at the busiest time of the day for a collection facility. Many women and health care practitioners are questioning the need to perform a POGTT. Minimising the time spent at the collection facility is consistent with strategies seeking to ensure adequate social distancing. Several peak bodies have developed alternative diagnostic strategies to minimize the need for a POGTT to diagnose GDM although potentially these may result in higher rates of pregnancy associated complications [4].

There are other practical problems. Many patients do not tolerate the POGTT, with significant rates of abdominal discomfort, nausea and vomiting invalidating the test [5, 6]. An increasing number of pregnant women have had bariatric surgery prior to becoming pregnant and an POGTT is not recommended in this situation due to its impact on gastric motility and absorption [7–9]. In consideration of these issues, we systematically evaluated the relationship of FBG to the 1 and 2-hr BGLs on a POGTT and their relationship to available published outcome data to identify a threshold FBG level associated with a reduced risk of abnormal glucose tolerance and minimal increase in pregnancy associated complications. This strategy could potentially negate the need to undertake for the POGTT for many patients, minimising their time spent in the higher risk environment of pathology laboratories.

Methods

Results

There were 26,683 OGTTs performed from 1 January 2015 to 30 June 2015 with incomplete data on 441 tests leaving 26,242 complete OGTTs available for further analysis. There were 3,946 (15.0%) patients with GDM. The diagnosis of GDM was established in 2,262 of these 3946 cases (57.3% of positive cases; 8.6% of the whole cohort) having an elevated FBG (+/- elevated post-challenge BGLs). The length of gestation was known in 16,358 of the whole cohort, 13,239 having the test performed between 24–32 weeks of gestation, matching the entry criterion of the HAPO study [1]. Finally, 11,450 patients had the OGTT between 24–28 weeks of gestation consistent with IADPSG recommendations [2]. The number of patients having a preceding 50gm glucose challenge test could be determined from data from PathQ and was less than 5% in the study period. In patients having an OGTT prior to 24 weeks, the relationship of FBG to the post-challenge BGLs was equivalent. As there was no differences in the overall rates of GDM in any of these subgroups compared with the whole cohort, data for the whole cohort were analysed.

The relationship between fasting and post-challenge BGLs for FBG from 3.0 to 6.0mmol/l was assessed as less than 0.1% of patients had a FBG<3.0 mmol/l or >6.0mmol/l. A strong positive relationship between FBG and post-load BGLs was observed (Fig 1). At the FBG threshold (5.1 mmol/l) for the diagnosis of GDM the respective corresponding mean 1-hr and 2-hr BGLs were 8.3 ± 1.7mmol/l and 6.7 ± 1.4mmol/l, less than their corresponding diagnostic thresholds (2, 10). The overall numbers of patients, the point prevalence and the cumulative rates of elevated post-challenge BGLs at FBGs from 3.0 to 6.0mmol/l are shown (Table 1). A ROC analysis was performed to assess the optimal FBG for identifying patients having elevated post-load BGLs (Fig 2). This suggested a FBG above 4.6mmol/l was the optimal predictor for elevated post-load BGLs with a sensitivity 54.3% and specificity 77.1%. There were 19,321 (73.7%) of the whole cohort having a FBG < 4.7mmol. Of these patients, only 1054 (4.1%) had any elevation of post-challenge BGLs, less than 1/3^rd of the overall rate of GDM. There were 4,638 (17.7%) of the whole cohort having FBGs from 4.7 to 5.0mmol/l who would need further evaluation of their glucose tolerance. There were a further 630 cases of GDM (2.4% of all subjects) having elevated post-load BGLs in this subgroup having intermediate FBG levels. Of these cases, 363 of the 630 (1.4% of all subjects) had an elevated 2-hr post-load BGL.

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Fig 1. Relationship between FBG and post-load BGLs.

Shown are the post-challenge BGL values (mean; standard deviation) on an oral glucose tolerance test in 26,242 patients between January 1, 2015 and June 30, 2015 from the three major laboratories in Queensland, Australia for FBGs between 3.0 and 6.0mmol/l. Less than 0.1% of patients had FBG below or above these values.

https://doi.org/10.1371/journal.pone.0243192.g001

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Fig 2. ROC analysis of FBG and elevated post-load BGLs.

Shown is the ROC analysis (MedCalc statistical software) for the diagnosis of GDM based on elevated 1-hr and/or 2-hr BGLs on 75 gm OGTT for FBGs from 3.0 to 6.0 mmol/l. At FBG above 4.6 mmol/l, the sensitivity was 54.3% and specificity of 77.1%.

https://doi.org/10.1371/journal.pone.0243192.g002

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Table 1. Analysis of screening FBG levels on rates of elevated post-challenge BGLs.

https://doi.org/10.1371/journal.pone.0243192.t001

Thus, based on an FBG < 4.7mmo/l, 19 of every 20 patients will be correctly diagnosed with GDM, advised to have further testing or reassured that they have a reduced risk of elevated post-challenge BGLs. The need for alternative strategies to assess glucose intolerance would be avoided in more than 4 out of 5 women. This represents a large reduction in time spent at collection facilities, minimising their exposure to a higher risk environment.

Discussion

Our study reflects contemporary clinical practice across the state of Queensland, Australia. These results provide practical information to clinicians concerning the interpretation of the FBG and the risk of having elevated post-load BGLs. This should enable a discussion between a pregnant woman and her health practitioners concerning the need for a POGTT. Individual clinicians or units may choose to have alternative FBG threshold levels for recommending further evaluation of glucose tolerance in pregnancy based on these data, although the ROC analysis suggested that a FBG > 4.6 mmol/l had the best sensitivity and specificity for having elevated post-load glucose levels, admittedly without high levels of specificity. The role of the FBG as a first step for the exclusion or diagnosis has been suggested by other investigators who found a similar BGL threshold on ROC analysis [11]. A lower level has been suggested from studies performed in Chinese populations [12, 13]. Others have recommended lower FBG thresholds [14–16] to reduce the need to perform POGTTs, referencing early outcome data reported from HAPO [2].

If used, patients with indeterminate FBGs from 4.7 mmol/l to 5.0 mmol/l will require further evaluation to define their glucose tolerance, which would typically be a POGTT. In the current environment, individual health practitioners, health centres or juristictions may use alternative strategies in this group of patients including an HbA1c, continuous glucose monitoring, home blood glucose monitoring or a subsequent 2-hr post-load BGL, as evidenced by the United Kingdom and Canadian recommendations during the COVID pandemic [4]. Alternative strategies to assess glucose tolerance in pregnancy have been previously evaluated. An HbA1c has not proved that useful for the diagnosis of GDM as opposed to overt diabetes [6, 17]. This was demonstrated in the analysis of the UK recommendations for diagnosis of GDM during the COVID-19 pandemic where a diagnostic strategy based in part on an HbA1c > 5.7% (39 mmol/mol) resulted in 81% of cases fulfilling IADPSG criteria being missed [4]. Home glucose monitoring using capillary glucose monitoring or continuous interstitial fluid glucose monitoring can be undertaken in the situation, for a week or two, or perhaps for the remainder of the pregnancy [18, 19]. Glucose monitoring strategies are more labour intensive, requiring education by the clinician, midwife or diabetes educator and incur significant expense, given the cost of monitoring strips, continuous glucose sensors, meters or reading devices and subsequent consultations for their interpretation. These strategies do not adequately exclude or establish the diagnosis of GDM if “normal” because their interpretation is not based on evidence-based thresholds for diagnosis. Rather, their interpretation is based on threshold BGLs for therapeutic intervention [18, 19]. The need for post-partum screening for the development of type 2 diabetes mellitus in these patients is unknown.

The findings of our analysis have been validated in a separate population group as a result of the need to reduce the risk of pregnant women being exposed to the Corona virus. Based on our data, an initial screening FBG at 24–28 weeks of pregnancy was recommended as an alternative strategy for diagnosing GDM in Queensland [20] with women having a FBG below 4.7mmol/l not requiring further evaluation. This strategy was subsequently recommended by the Australian Diabetes Society, ADIPS, Australian Diabetes Educators Association and Diabetes Australia [21]. The potential impact of this and other strategies has subsequently been analysed in a group of 5974 subjects from 5 HAPO research sites across several countries—Australia, Canada, England, Singapore and USA [4]. Based on the IADPSG criteria, an overall rate of diabetes of 17% was observed, similar to our rate of 15.0%. Using the Australian COVID-19 diagnostic criteria, 12.7% of subjects were diagnosed with GDM with 4.3% “missed”, having FBGs less than 4.7mmol/l but having elevated post-load BGLs. This rate of missed diagnoses of GDM is very similar to our rate (4.0%).

The major potential problem of considering a FBG < 4.7 mmol/l as being “normal” is that 4.0% of these cases in our study and 4.3% in the subgroup of HAPO have elevated post-load BGLs and are not identified with GDM. The concern is whether these pregnancies are associated with higher rates of pregnancy-associated complications. We cannot assess this as we have no outcome data. However, data from HAPO provides reassurance that this is not the case. Firstly, in our analysis 70% of subjects had FBG < 4.5 mmol/l reported to be associated with a low risk of some adverse outcomes in the original HAPO study report, irrespective of their post-challenge glucose levels [2]. Secondly, an analysis of 6128 subjects from 5 HAPO centres assessed several pregnancy-related outcomes in patients whose FBG was above or below the 75^th centile (FBG < 4.6 mmol/l). This did not show any difference in adverse outcomes these women compared with women not diagnosed with GDM [22].

Finally, the recent analysis of the impact of the different the COVID-19 GDM diagnostic strategies reported the rates of adverse pregnancy outcomes [4]. The rates of adverse pregnancy outcomes in this missed group were compared to women not diagnosed with GDM by either the IADPSG or the Australian COVID-19 strategy. There was no increased rate of any adverse pregnancy in the “missed group” (Table 2). There was no difference in the rate of neonatal hypoglycaemia observed in the “missed GDM group”. Although there was a non-significant increase in the number of cases of LGA, neonatal adiposity and neonatal hyperinsulinaemia, there was a lower number of subjects requiring a Caesarian section. Interestingly, a lower number of cases of pregnancy-associated hypertension was also observed. Thus, there was no evidence that a screening strategy based on a ROC-validated FBG less than 4.7mmol/l resulted in missing cases of GDM having an excess of important adverse pregnancy outcomes.

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Table 2. Rates of adverse pregnancy outcomes in subgroup of women in HAPO (adapted from data of McIntyre et al; Ref 4).

https://doi.org/10.1371/journal.pone.0243192.t002

Our study has several strengths. The birth rate in Queensland during this period was estimated to be 30,829 based on the number of babies enrolled in the Queensland Newborn Screening Program. Therefore, our study captured the POGTT data of nearly 85% of all live births. The OGTT data is derived from tests performed by both private and public pathology providers likely to include all socio-economic, ethnic and geographical groups. At the last census in 2011, 20% of all Queenslanders were born overseas coming from 220 counties speaking over 220 languages [23]. Over 80% of OGTTs were tested between 24–32 weeks consistent with HAPO [1] and their results were no different to the whole cohort. A minimal number of patients had prior glucose challenge tests eliminating any significant bias by preferentially selecting subjects with elevated post-challenge BGLs. The similarity of our rates of glucose tolerance in pregnancy to the HAPO subgroup analysis validates our observations.

In conclusion, this analysis suggests that a 2-step diagnostic pathway based on an initial FBG can be used to identify women having either “normal” glucose tolerance associated with a low risk in pregnancy-associated adverse outcomes, or women with GDM. It reduces the need to perform POGTTs in the current environment by approximately 80%. These women with indeterminant FBGs will need to consider having a POGTT or undertake alternative strategies to assess glucose tolerance. Importantly, adopting this 2-step approach still enables the effective identification of cases of GDM at increased risk of adverse pregnancy outcomes [4], including those at highest risk having elevated fasting and post-load BGLs [24]. It negates the need to do an POGTT if an FBG has been performed for other reasons as our study provides data to make an adequate risk assessment in this circumstance. It is a simple, in-expensive, reliable and readily understood measurement of glucose, better tolerated than the POGTT that can have a role in the assessment of glucose intolerance in pregnancy in the current COVID-19 environment, in health care environments with limited resources and potentially in other clinical circumstances eg patients post bariatric surgery. These date when considered together with the outcome data from a subgroup of HAPO suggests that this two step-diagnostic approach could be considered as a more efficient and cost-effective strategy for the diagnosis of GDM. It would significantly reduce the need for a POGGT and avoid labelling 25% of women with a diagnosis of GDM whose pregnancies are not associated with increased rates of adverse outcomes, avoiding providing un-necessary additional resources for education, blood glucose monitoring or therapeutic intervention.

Supporting information