FormalPara Key Summary Points

This cross-sectional study (n = 87) evaluated differences in continous glucose monitoring system (CGMS) profile between women with normoglycemia and early gestational diabetes (GDM) missed using isolated fasting plasma glucose-based strategies alternative to WHO 2013 criteria.

A total of 38 women had GDM, of whom 27 (71%) would be perceived as normoglycemic using isolated fasting plasma glucose (FPG) cutoff ≥ 5.6 mmol/L (100 mg/dL).

Women with missed diagnosis had significantly worse CGMS parameters, such as 24-h mean glucose, fasting glucose, 1-h and 2-h postprandial glucose (PPG), 1-h PPG excursion, and peak PPG.

Introduction

Gestational diabetes mellitus (GDM) is defined as “hyperglycemia that is first diagnosed during pregnancy, with glucose levels below those considered diagnostic of overt diabetes outside of pregnancy” [1]. In 2010, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for the diagnosis of GDM were introduced based on the emergence of the association between hyperglycemia and pregnancy outcomes from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [2, 3]. These criteria were derived from women recruited between 24 and 32 weeks of gestation [3]. Furthermore, the IADPSG panel suggested that the diagnosis of GDM can be considered in early pregnancy (< 20 weeks) if the fasting plasma glucose (FPG) value is elevated to 5.1–6.9 mmol/L (92–125 mg/dL) [2]. However, subsequent studies suggested that a significant proportion of women exceeding this FPG threshold had normal glucose tolerance on the oral glucose tolerance test (OGTT) performed at 24–28 weeks, in the absence of any medical treatment [4, 5]. The study by Zhu et al. found that 63% of women with mild FPG elevation (5.1–5.5 mmol/L or 92–99 mg/dL) and 47% of women with a more significant FPG elevation (5.6–6.1 mmol/L or 100–110 mg/dL) in early pregnancy had normal glucose tolerance when tested at the conventional time frame of 24–28 weeks [4]. The authors concluded that for women with FPG between 5.1 and 6.1 mmol/L, a repeat OGTT should be performed between 24 and 28 weeks of gestation to confirm the diagnosis of GDM, and isolated FPG elevation should not be considered as the criterion for diagnosis of GDM in early pregnancy. Therefore, on the basis of these data, in 2016, IADPSG revised its stand and dropped the FPG criteria for diagnosing GDM in early pregnancy [6]. In 2013, the World Health Organization (WHO) adopted the IADPSG criteria for diagnosing GDM throughout the pregnancy (including in early pregnancy), despite the absence of solid evidence to extend the diagnostic thresholds to early pregnancy [7]. Thus, the utility of IADPSG criteria in early pregnancy remains a matter of debate. Many experts believe that GDM should be diagnosed in early pregnancy using an isolated FPG approach (≥ 5.6 mmol/L) [4, 8]. Even the National Institute of Health and Care Excellence (NICE) guidelines recommend FPG cutoff ≥ 5.6 mmol/L for the diagnosis of GDM (apart from 2-h post-load plasma glucose cutoff ≥ 7.8 mmol/L or 140 mg/dL) [9]. However, the clinical implications of missing women with a milder degree of FPG elevation and/or post-load plasma glucose elevation (when using these strategies alternative to WHO 2013 criteria) remain unclear.

With this background, this study aims to evaluate whether the continous glucose monitoring system (CGMS) profile of women with isolated mild FPG elevation (5.1–5.5 mmol/L or 92–99 mg/dL), isolated post-load plasma glucose elevation [1 h ≥ 10.0 mmol/L (180 mg/dL) or 2 h ≥ 8.5 mmol/L (153 mg/dL)], or both are different from those with normoglycemia defined using WHO criteria. We have used a CGMS-derived dataset from our previous studies to answer these objectives [10, 11]. Briefly, in these studies, we reported: (a) differences in CGMS profile between women with normoglycemia and early GDM per IAPDSG/WHO 2013 criteria [10], and (b) differences in CGMS profile between women with normoglycema and early GDM by IADPSG/WHO 2013 criteria but normoglycemia defined by alternative criteria [NICE, Canadian Diabetes Association (CDA) and Diabetes in Pregnancy Study Group of India (DIPSI)] [11]. The data emerging from the current study would help to delineate the significance of a milder degree of FPG elevation in early pregnancy and of post-load plasma glucose values derived from a 75 g OGTT as well as the appropriateness of using higher isolated FPG thresholds (5.6–6.9 mmol/L or 100–125 mg/dL) for the diagnosis of GDM in early pregnancy.

Methods

Settings and Study Design

We performed this cross-sectional study at the All India Institute of Medical Sciences, New Delhi, India (a public tertiary care hospital catering predominantly to a low- and middle-income population) from July 2017 to June 2019. We received approval from the institutional ethics committee of the All India Institute of Medical Sciences, New Delhi, India (Reference No. IECPG-96/22.03.2017 dated 24 March 2017) and written informed consent from all participating women. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. All investigations and study-related procedures were exempted for the study participants. These included blood investigations performed as a part of OGTT, the insertion of the CGMS sensor into the abdomen, and a blood glucose meter for CGMS calibration.

Inclusion and Exclusion Criteria

We included women with singleton pregnancy between 8+0 and 19+6 weeks period of gestation. We excluded women with diabetes in pregnancy (overt diabetes in pregnancy or pre-existing diabetes) and women with GDM on diet and lifestyle modifications for more than 1 week. We also excluded women with a history of significant organ impairment, chronic infections, connective tissue disorders, chronic inflammatory conditions, and intake of steroids or drugs known to cause hyperglycemia. We further excluded women who had normoglycemia at the initial visit but were detected to have GDM subsequently.

Diagnostic Criteria for GDM

GDM was defined per WHO 2013 criteria [FPG ≥ 5.1 mmol/L (92 mg/dL), and/or 1 h post-load plasma glucose ≥ 10.0 mmol/L (180 mg/dL), and/or 2 h post-load plasma glucose ≥ 8.5 mmol/L (153 mg/dL)] [7]. To diagnose GDM in early pregnancy (< 20 weeks), WHO has adopted the IADPSG criteria, initially proposed for use after 20 weeks of gestation.

Procedure on Day of Testing

We invited women in a fasting state (minimum fast of 8 h). At the study visit, we filled out a detailed questionnaire that captured demographic details, education, employment status, obstetric history, and family history of diabetes mellitus. We administered 75 g anhydrous glucose load (83.3 g glucose monohydrate) and measured venous plasma glucose at 0, 60, and 120 min. After the completion of OGTT, we inserted the CGMS sensor into the abdomen (on the same visit between 1200 and 1500 hours). We used the Enlite sensor with an iPro2 recorder (Medtronic MiniMed Northridge, CA 91325, USA), a retrospective CGMS device, for this study. To monitor and calibrate the CGMS device, we provided all study participants with a blood glucose meter (Contour Plus, Bayer HealthCare LLC). After 4 days of installation, we removed the sensor and used Medtronic Care Link Software to upload the data.

A total of 864 values were collected over 72 h, starting from 2330 hours on the day of CGMS insertion (as suggested by Hernandez et al.), for reporting of meal-related parameters along with 24-h mean glucose [12]. We have provided the details on OGTT, anthropometric measurements [weight, height, body mass index (BMI), and blood pressure], estimation of biochemical parameters (plasma glucose and HbA1c), the procedure of CGMS insertion, instructions to the study participants, and definition of CGMS-based parameters in Supplementary Material (Appendix S1 and Table S1).

Statistical Analysis

We used Stata 15.0 (Stata Corp, College Station, TX, USA) for statistical analyses. We compared variables with normal distribution using the Student’s t test (for independent samples). Beta coefficients (± SE) of the glycemic parameters were assessed using linear regression analysis after adjusting for important confounding variables like age, period of gestation, prepregnancy body mass index (BMI), and parity. Data are presented as n (%) or mean ± SD. We considered a p value of less than 0.05 as statistically significant.

Results

Baseline Characteristics

We enrolled 87 women (GDM, n = 38) at 14.0 ± 3.2 weeks of gestation. The mean age and BMI were 28.6 ± 4.5 years and 26.4 ± 4.7 kg/m2, respectively. A total of 31 (35.6%) participants were in the first trimester. Table 1 summarizes the baseline characteristics of study participants.

Table 1 Baseline characteristics of study participants
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Glycemic Parameters in Women with Isolated Post-Load Plasma Glucose Elevation

Of 38 women diagnosed with GDM by WHO 2013 criteria, 10 (26.3%) had isolated post-load plasma glucose elevation (1-h ≥ 10.0 mmol/L or 2-h ≥ 8.5 mmol/L) and thus would be missed using the isolated FPG criterion for diagnosing GDM. In an unadjusted analysis, the mean 1-h postprandial glucose (PPG), peak PPG, 1-h PPG excursion, and 24-h mean glucose were significantly higher in these women than those with normoglycemia (Table 2). In the adjusted analysis (Table 2), the beta coefficient (± SE) was significantly higher in such women for the mean 1-h PPG (β = 0.64 ± 0.28, p = 0.026) and 1-h PPG excursion (β = 0.72 ± 0.29, p = 0.018), compared to those with normoglycemia.

Table 2 Comparison of continuous glucose monitoring-based glycemic data between women with normoglycemia and women with isolated post-load plasma glucose elevation (1-h ≥ 10.0 mmol/L or 2-h ≥ 8.5 mmol/L)
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Glycemic Parameters in Women with Isolated Mild FPG Elevation

Of 38 women diagnosed as GDM by IADPSG criteria, 10 (26.3%) had isolated FPG elevation of 5.1–5.5 mmol/L (92–99 mg/dL). These women will be missed if a higher FPG threshold of 5.6–6.9 mmol/L (100–125 mg/dL) is used to diagnose GDM. Such women had significantly higher fasting, pre-meal, 1-h and 2-h PPG, peak PPG, 1-h PPG excursion, and 24-h mean glucose than those with normoglycemia (Table 3). In an adjusted analysis (Table 3), beta coefficient was significantly higher in such women for mean fasting glucose (β = 0.47 ± 0.19, p = 0.016), 1-h PPG (β = 0.68 ± 0.22, p = 0.003), peak PPG (β = 0.66 ± 0.24, p = 0.008), and 24-h mean glucose (β = 0.37 ± 0.14, p = 0.012), compared to those with normoglycemia.

Table 3 Comparison of continuous glucose monitoring-based glycemic data between women with normoglycemia and those with isolated mild fasting plasma glucose elevation (5.1–5.5 mmol/L)
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Glycemic Parameters in Women with Mild FPG Elevation and/or Post-Load Glucose Elevation

Of 38 women diagnosed with GDM by WHO 2013 criteria, 27 (71.1%) had isolated post-load elevation, mild fasting glucose elevation, or both. These women will be missed if an isolated FPG threshold of 5.6–6.9 mmol/L is used to diagnose GDM. These women had significantly higher fasting, 1-h and 2-h PPG, PPG excursion, peak PPG, and 24-h mean glucose than women with normoglycemia (Table 4). In an adjusted analysis (Table 4), beta coefficient was significantly higher in such women for mean 1-h PPG (β = 0.86 ± 0.19, p < 0.001), mean 2-h PPG (β = 0.35 ± 0.15, p = 0.023), 1-h PPG excursion (β = 0.75 ± 0.20, p < 0.001), peak PPG (β = 0.76 ± 0.20, p < 0.001), and 24-h mean glucose (β = 0.26 ± 0.11, p = 0.015), compared to those with normoglycemia.

Table 4 Comparison of continuous glucose monitoring-based glycemic data between women with normoglycemia and those with mild fasting plasma glucose elevation (5.1–5.5 mmol/L) and/or post-load glucose elevation (1-h ≥ 10.0 mmol/L or 2-h ≥ 8.5 mmol/L)
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Discussion

In the present study, we found that a substantial proportion of women identified as GDM in early pregnancy by the WHO 2013 criteria would be missed if alternative approaches for diagnosis are used. For example, nearly one-fourth of women with GDM would be missed if mild isolated FPG elevation (5.1–5.5 mmol/L) is discounted and a similar number would be missed if post-load plasma glucose values are not accounted for. Furthermore, nearly three-fourths of women with GDM had isolated mild FPG elevation, isolated post-load glucose elevation, or a combination of both and would be missed if FPG cutoff ≥ 5.6 mmol/L alone is considered for the diagnosis. Notably, these women differ from normoglycemic women in several CGMS parameters of clinical significance. These results are significant, given the well-known relationship between glycemia and adverse pregnancy outcomes [3]. The differences in various CGMS parameters between women with normoglycemia and those with a missed diagnosis of GDM on isolated FPG-based strategies alternative to WHO criteria are presented in Fig. 1.

Fig. 1
figure 1

Bar diagram showing continuous glucose monitoring-based glycemic data among women with a missed diagnosis of gestational diabetes using isolated fasting plasma glucose-based strategies alternative to WHO criteria (all comparisons with normoglycemic group, n = 49). Group 1, women with isolated post-load plasma glucose elevation (1-h ≥ 10.0 mmol/L or 2-h ≥ 8.5 mmol/L, n = 10). Group 2, women with isolated mild fasting plasma glucose elevation (5.1–5.5 mmol/L, n = 10). Group 3, women with mild fasting plasma glucose elevation (5.1–5.5 mmol/L) and/or post-load plasma glucose elevation (1-h ≥ 10.0 mmol/L or 2-h ≥ 8.5 mmol/L, n = 27). F fasting glucose, PreP preprandial glucose, 1-h PP 1-h postprandial glucose, 2-h PP 2-h postprandial glucose, PV peak postprandial glucose value, 1-h PPE 1-h postprandial glucose excursion, 24-h mean 24-h mean glucose

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When we used an isolated FPG approach (5.1–6.9 mmol/L) that was initially proposed by IADPSG, the diagnosis of GDM was missed in 10 (26.3%) participants. Even after adjusting various parameters that influence glucose values, the beta coefficient was significantly higher for the mean 1-h PPG (β = 0.64) and 1-h PPG excursion (β = 0.72) in such women compared to normoglycemic women. These findings highlight the importance of a 75 g OGTT with measurement of 1-h and 2-h plasma glucose for diagnosing GDM in early pregnancy, similar to conventional GDM.

In 2016, the IADPSG revised its stand and suggested that the evidence to support the use of FPG for the diagnosis of GDM in early pregnancy was not strong [6]. This was based on the emergence of data from independent studies in Italy and China [4, 5], where authors demonstrated that early FPG levels ≥ 5.1 mmol/L were poorly predictive of later GDM at 24–28 weeks of gestation. For example, Zhu et al. from China found that the incidences of GDM were 37.0%, 52.7%, and 66.2%, respectively, for women with FPG at the first prenatal visit between 5.1 and 5.5, 5.6 and 6.09, and 6.1–6.9 mmol/L, respectively [4]. The authors suggested that individuals with FPG of 5.6 mmol/L or above should be started on medical nutrition therapy and OGTT repeated at 24–28 weeks, while those with FPG of 6.1 mmol/L or above should be treated as standard GDM. Considering that an FPG level of 5.6 mmol/L formed the basis for recommending treatment with nutrition therapy in the study by Zhu et al. [4], and the same level is proposed as the cutoff for diagnosis of early GDM by Cosson et al. [8], and for diagnosis of GDM by NICE criteria [9], we evaluated the significance of a milder degree of FPG elevation (5.1–5.5 mmol/L). A total of 10 (26.3%) participants had isolated mild FPG elevation, and the beta coefficient for fasting plasma glucose (β = 0.47), mean 1-h PPG (β = 0.68), peak PPG (β = 0.66), and 24-h mean glucose (β = 0.37) was significantly higher in such women compared to those with normoglycemia. The use of an isolated “high” FPG approach (≥ 5.6 mmol/L) missed the diagnosis of GDM in 27 (71.0%) participants. We found that the beta coefficient for mean 1-h PPG (β = 0.86), mean 2-h PPG (β = 0.35), 1-h PPG excursion (β = 0.75), peak PPG (β = 0.76), and 24 h mean glucose (β = 0.26) was significantly higher in such women compared to those with normoglycemia.

Clinical and Research Implications

The diagnosis of GDM during early pregnancy is controversial. Various professional organizations propose different strategies for diagnosing early GDM, which suggests insufficient evidence to inform consensus [8, 13]. There are data which suggest that both FPG and OGTT performed during early pregnancy show poor concordance (in terms of GDM diagnosis) with OGTT obtained after 24 weeks of gestation [4, 5, 14]. This is especially true for milder degree of FPG elevation in early pregnancy. However, recent evidence also suggests that women diagnosed with isolated FPG elevation (5.1–6.9 mmol/L) in early pregnancy have adverse pregnancy outcomes, despite a normal OGTT after 24 weeks of gestation [15,16,17]. Similarly, isolated HbA1c elevation during early pregnancy has been associated with adverse outcomes [18, 19]. In our study, we evaluated and compared various meal-related parameters and 24-h mean glucose values between women with normoglycemia and those with a missed diagnosis of GDM using strategies alternative to WHO 2013 criteria and found clinically meaningful differences in various glycemia-related parameters. Future studies, preferably CGMS based and using a larger sample size, will be required to validate our study findings and to determine whether these differences noted during early pregnancy have a bearing on pregnancy outcomes.

Strengths and Limitations

To the best of our knowledge, ours is the first CGMS-based study that evaluates the impact of using strategies alternative to WHO criteria for the diagnosis of GDM in early pregnancy. These strategies include an isolated “standard” FPG approach (5.1–6.9 mmol/L), as initially suggested by IADPSG and an isolated “high” FPG approach (5.6–6.9 mmol/L), which has been proposed more recently by several experts. The former approach missed patients with isolated post-load glucose derangements, while the latter additionally missed patients with a milder degree of FPG elevation. Since women missed with these alternative strategies fared significantly worse in terms of CGMS parameters of clinical significance, the decision to consider them “normal” may not be appropriate. We have acquired and reported data per the standard methodology proposed by Hernandez et al. [12]. The study has certain limitations, most notably that we did not evaluate pregnancy outcomes. Although ours is a relatively sizeable CGMS-based study, the numbers are still small to evaluate pregnancy outcomes and present meaningful differences. Future extensive multicentric studies that are adequately powered to detect pregnancy outcomes will better inform the clinical significance of these differences in CGMS data. We acquired data for 3 days rather than the suggested duration of 10–14 days [20]. Acquisition of data for 14 days would have required the serial insertion of multiple sensors (in a single subject), which was logistically challenging, as many women had normoglycemia. We did not perform a functional data analysis, as done by other authors [18]; however, considering that the clinical decisions are often taken in terms of CGMS parameters proposed by Hernandez et al., we evaluated them as per their standard format.

Conclusion

An isolated FPG threshold, especially the higher cutoff ≥ 5.6 mmol, can potentially miss a large proportion of women (nearly three-fourths) with GDM as per WHO criteria. Eventually, such women fare significantly different from normoglycemic women in terms of various CGMS parameters of clinical interest, with a potential bearing on pregnancy outcomes. Further studies are needed to substantiate the evidence base for diagnosing GDM in early pregnancy.