Possibility to predict early postpartum glucose abnormality following gestational diabetes mellitus based on the results of routine mid-gestational screening

Introduction Women with previous gestational diabetes mellitus (GDM) have increased risk of developing glucose abnormality, but current diagnostic criteria are evidence-based for adverse pregnancy outcome. The aims of our study were: (i) to ascertain a frequency of early conversion of GDM into permanent glucose abnormality, (ii) to determine predictive potential of current GDM diagnostic criteria for prediction of postpartum glucose abnormality and (iii) to find optimal cut-off values of oral glucose tolerance test (oGTT) to stratify GDM population according to postpartum risk. Materials and methods Electronic medical records of an ethnically homogenous cohort of women diagnosed and treated for GDM in a single medical centre during the period 2005–2011 who completed postpartum oGTT up to 1 year after the index delivery were retrospectively analysed (N = 305). Results Postpartum glucose abnormality was detected in 16.7% subjects. Mid-trimester oGTT values, respective area under the curve and HbA1c were significantly associated with early postpartum glucose abnormality (P < 0.05, Mann-Whitney) and exhibited significant predictive potential for postpartum glucose abnormality risk assessment. Optimal cut-off values for discrimination of at-risk sub-population were identified using ROC analysis and their comparison with WHO and IADPSG criteria exhibited superiority of IADPSG for risk-stratification of GDM population. Conclusion Risk-based stratification at the time of GDM diagnosis could improve efficiency of the post-gestational screening for diabetes. IADPSG criteria seem to optimally capture both perinatal and maternal metabolic risks and are therefore medically and economically justified.


Introduction
Gestational diabetes mellitus (GDM), a common complication of pregnancy, is defined as any degree of glucose intolerance with the onset or the first recognition during the pregnancy (most often during the second trimester of gestation) which then typically normalizes after the delivery (or puerperium) (1). Pregnancy is a relatively short period marked by dramatic changes of hormone profile and body composition with profound effects on metabolism. While the initial phase is usually characterized by increased insulin sensitivity, later marked insulin resistance develops (2), which, in a subset of women with latent defect of insulin secretion, manifests as a GDM.
Although the reported prevalence of GDM varies considerably between countries mainly due to different diagnostic criteria used, the incidence of GDM is reported to rise worldwide (3). Hypergly- Bartáková V. et al. How to predict postpartum glucose abnormality?
caemia and Adverse Pregnancy Outcomes study (HAPO) (4) prompted an important shift in the GDM paradigm since it provided grounds for the evidence-based modification of GDM diagnostic criteria showing that perinatal morbidity (high birth weight leading to complications during delivery such as shoulder dystocia, birth injury, hyperbilirubinemia, neonatal hypoglycaemia, foetal hyperinsulinemia reflected by increased cordblood serum C-peptide levels) is proportionately related to maternal glycaemia. Recently International Association of Diabetes and Pregnancy Study Groups (IADPSG) proposed new criteria for GDM reflecting HAPO results (5). Applying IADPSG diagnostic criteria on HAPO study population the GDM incidence would reach 17.8% (6).
GDM elicits a complex medical situation affecting yet two people -mother and child -in the shortterm as well as in the long-term perspectives.
Timely diagnosis of GDM (esp. when applying evidence-based criteria) should improve short-term pregnancy and perinatal outcomes and newly proposed IADPSG diagnostic criteria are dominantly pregnancy risk-based. However, the extent of risk reduction is often regarded as minor (oral glucose tolerance test (oGTT) cut-off values calculated for "only" 75% reduction of adverse pregnancy outcomes) and disproportionate to the extra health care cost related to increased GDM prevalence when using more stringent criteria. Since recommendations issued by IADPSG will have major implications for the health care systems this stimulates an intense debate among relevant authorities in many countries (7) including Czech Republic. While Czech Diabetes Society adopted the IADPSG diagnostic criteria in April 2014, Czech Gynaecology and Obstetrics Society remains reluctant to their universal adoption and no official statement has yet been issued (8). One of the possible reasons for this hesitation in obstetric community (worldwide though) might be a paucity of data available on long-term consequences of GDM.
GDM is an established lifelong risk factor for the development of diabetes in women with GDM history. The estimation of the prevalence of permanent postpartum dysglycaemia (prediabetes or di-abetes) was the subject of several studies during the past 20 years, part of them were included in a systematic review (9) or in a meta-analysis comprising about 675,000 of women with GDM diagnosis (10). In spite of limitations of this approach (such as variable follow-up, study design, actual GDM diagnostic criteria, definition of end-points and ethnicity) women with previous GDM had at least 7-fold increase of risk of developing type 2 diabetes mellitus (T2DM) in the future compared with those with normoglycaemia during pregnancy (10). Furthermore, cumulative incidence of T2DM was shown to increase steadily during the first 5 years after the delivery, reaching a plateau in 10 years postpartum (9).
We therefore hypothesize that documented early reoccurrence or even postpartum persistence of glucose abnormality gives a very good chance for an early postpartum screening to detect a largest proportion of at-risk women. Furthermore, being able to stratify GDM population according to the risk of subsequent glucose metabolism abnormality as soon as possible (ideally already during the pregnancy), the generally unsatisfactorily low compliance in postpartum diabetes screening (11,12) could improve thanks to more persuasive arguments and possibly increased motivation of at-risk subgroup. Therefore, given that women with previous GDM have significantly increased risk of postpartum glucose abnormality and screening for GDM is very well developed and widespread, however, none of the current diagnostic criteria are evidence-based for prediction of postpartum maternal risks, the aims of our study were: (i) to ascertain a frequency of early postpartum (up to 12 months post-delivery) conversion of GDM into permanent diabetes or prediabetes, (ii) to determine a predictive potential of national modification of the World Health Organisation (WHO) diagnostic criteria used at the time of subject's enrolment and currently recommended IADPSG diagnostic criteria for prediction of postpartum glucose abnormality and (iii) to find optimal cut-offs of oGTT values capturing mother's metabolic risks to stratify GDM population according to postpartum risk of glucose abnormality. Bartáková V. et

Methods
According to the current practice in Czech Republic screening for GDM is offered to all pregnant women (with exception of pre-existing diabetics) in second trimester. In case of the presence of at least two risk factors (positive family history, previous delivery of new-born with weight above 4000 g, obesity, diabetes mellitus in previous pregnancy, glycosuria, previous stillborn delivery, hypertension or preeclampsia in previous pregnancy, repeated abortions, age above 30 years) it should be performed during the first trimester. Diagnosis of GDM in the cohered diagnosed and followed in 2005-2011 period was based on the consensus criteria of Czech Diabetes Society and Czech Society for Clinical Biochemistry (13) derived from WHO criteria for subjects with impaired fasting glucose (IFG) / impaired glucose tolerance (IGT) (14) using a 3-point oGTT with 75 g glucose with threshold values (any value above cut-off diagnosing GDM): FPG ≥ 5.6 mmol/L, 1-hr after 75 g load glucose ≥ 8.8 mmol/L and/or 2-hr after 75 g load ≥ 7.8mmol/L (sample 60 minutes after challenge optional but recommended). Glycaemia was measured by hexokinase-based enzymatic method using Cobas 8000 analyser and commercial reagents (Roche) in venous plasma. HbA1c (cut off 39 mmol/mol) was measured in all subjects by ionexchange high-performance liquid chromatography (HPLC) using D-10 analyser and commercial reagents (Bio-Rad) in whole blood. Additionally, area under the curve (AUC, mmol/L/hour) was calculated from a 3-point oGTT using the trapezoid rule (15). Cut-offs of newly recommended IADPSG criteria are as follows: FPG ≥ 5.1mmol/L, 1-hr post-load glucose: ≥ 10.0 mmol/L, 2-hr postload glucose: ≥ 8.5 mmol/L.

Statistical analysis
Data are expressed as medians and interquartile ranges (IQR) or proportions for between group comparisons. Differences between groups were compared using non-parametric Mann-Whitney or Pearson chi-square tests for continuous or categorical variables, respectively, using Statistica for Windows (Statsoft Inc., Tulsa, OK, USA) software. P ≤ 0.05 was considered statistically significant unless correction for multiple comparisons were applied (P corr ). Univariate and multivariate logistic models were constructed to determine an eventual statistically significant effect of any relevant variable and Receiver Operating Characteristic (ROC) analysis was applied to test the final models. Areas under the ROC curve (AUC ROC ) were compared by Delong paired test (16). Optimal cut-off of selected glycaemic indices for prediction of postpartum GDM conversion into permanent glucose abnormality within 12 month were selected by the highest Youden indices (17), i.e. single statistic capturing diagnostic test performance (J = sensitivity + specificity -1) with value ranging from 0 to 1 (a zero value for the test giving the same proportion of positive results for groups with and without the disease and a value of 1 for no false positives or negatives).

Incidence of postpartum glucose abnormality
Incidence of any disorder of glucose metabolism (i.e. diabetes or prediabetes) up to 1 year postpartum was 16

Relationship between mid-trimester parameters and postpartum glucose intolerance
Characteristics of subjects at the time of GDM diagnosis with respect to their postpartum GDM normalization or persistence are shown in Table 1. Glycaemia in all three time-points of mid-trimester oGTT, AUC oGTT and mid-trimester HbA1c were significantly higher in the group of GDM women with the postpartum disorder compared to those with normal glucose tolerance (NGT) postpartum. Finally, using ROC analysis combined with Youden statistics we attempted to find optimal cut-off values of parameters evaluated at mid-trimester best reflecting postpartum risk in our study population (see Table 2) and to determine to which extent they differ from the newly proposed IADPSG criteria.

Discussion
In this report, using a cohort of 305 metabolically well characterized GDM subjects we ascertained incidence of post-GDM glucose abnormality 16.7% the first year postpartum, during which time 10.5% of women with GDM history manifested prediabetes, 5.2% T2DM and 1% T1DM. Furthermore, we demonstrated that routine glycaemic parameters (FPG, 1-h and 2-h post 75 g load glucose) examined in all pregnant women as a part of their standard antenatal care can reliably predict early postpartum glucose intolerance and thus improve health outcomes and perspectives in this group of young women at high risk for diabetes (10) and cardiovascular diseases (18). Finally, optimal cut-off values for maternal risk of postpartum diabetes ascertained in our sample are in general very close to the IADPSG criteria that are evidence-based for the perinatal outcomes.
As mentioned earlier, early postpartum screening has a great chance to detect glucose abnormality in large proportion of women who can then be efficiently intervened. For this reason we studied population of GDM cases who have been re-tested within the first 12 months postpartum sinceaccording to our view -positive attitude towards lifestyle changes lasting for some time after pregnancy might still span the early postpartum period and repeated oGTT is thus attended by a realistic maximum of cases. In spite of the currently practiced recommendations -to repeat testing for diabetes or prediabetes roughly 3-6 months after delivery and then every 3 years (19), considerable proportion of women with GDM history fail to turn up (11,12). This is quite unfortunate considering diabetes development is largely preventable by lifestyle and pharmacologic interventions (20).
This unsatisfactorily low compliance in postpartum screening can either be changed by various strategies to increase motivation of GDM patients to seek the postpartum test or by timely antepartum stratification of GDM cases according to their post-gestational metabolic risk. The latter strategy -selective postpartum follow-up of high risk subgroup is according to our view more effective and prompted us to undertake the current study.
Although it is physiologically highly plausible that the degree of impairment of glucose homeostasis in pregnancy is continually reflected in the postpartum glucose (in)tolerance, studies relating antepartum glycaemic indices to postpartum status with the attempt to quantitatively estimate the risk and to predict postpartum diabetes are still limited. Previous studies have shown post-load glucose levels (1-hr, 2-hr or 3-hr of antepartum oGTT) (21)   al. showed that FPG and HbA1c were significant predictors of postpartum diabetes (25). Finally, antepartum disposition index was shown to be predictive for postpartum glucose intolerance (26). However, majority of these studies employed either (i) medical practice distinct from the one currently provided in our country (and most of the Europe) such as two-step screening algorithm, higher glucose load in diagnostic oGTT (100 g), more frequent sampling (including 30 min and/or 3-hr), later testing spanning the third trimester, (ii) longer postpartum follow-up or (iii) measurements done solely for the research purposes not covered by a standard medical care such as insulin measurement to assess insulin sensitivity (HOMA insulin resistance index, insulin sensitivity index) and beta cell function (HOMA beta cell index, insulinogenic and oral disposition index).
In the current study we found significantly higher mid-gestation FPG, 1-hr and 2-hr post-75g load glucose, AUC oGTT and HbA1c in GDM women with persistent postpartum glucose metabolism abnormality compared to those with NGT postpartum. Relative risk of post-partum persistence of glucose intolerance gradually increased with the number of above threshold values whereas all three glycaemic indices above threshold (i.e. FPG, 1-hr and 2-hr post 75 g load glucose) conferred independent predictive potential for postpartum glucose intolerance. Inclusion of HbA1c among the standard screening/diagnostic parameters for GDM might be profitable due to limited reproducibility of oGTT (27), however further studies are required to assess the cost-benefit relationship.
Possibility to reliably predict postpartum diabetes using routine and financially covered parameters assessed in mid-gestation is a desirable scenario; however, former non-evidence-based WHO diagnostic criteria did not seem to reflect both relevant medical outcomes -i.e. short-term neonatal and obstetrical risks nor long-term maternal metabolic risk -to the same extent as shown by several studies (28,29). Although the initial diagnostic criteria of GDM proposed by Carpenter and Coustan (30) were based primarily on the risk of subsequent maternal diabetes, further modifications incl. IADPSG criteria favoured predominantly the peri-natal risks. It becomes increasingly apparent that a dual set of diagnostic criteria might be necessary if we should capture all adverse outcomes of GDM including postpartum maternal glucose abnormality. Due to this reason we applied ROC analysis to find optimal discriminating cut-offs (yielding the highest AUC ROC ) for mid-gestation FPG, 1-hr and 2-hr post 75 g load glucose and HbA1c. The actual suggested cut-offs are more stringent for FPG (≥ 5.1 mmol/L) than those currently practiced according to WHO criteria (≥ 5.6 mmol/L) and are in fact identical with consensus criteria derived from the HAPO study recommended by IADPSG (≥ 5.1 mmol/L). Furthermore, our analysis justifies the relevance of 1-h post 75 g load glucose measurement since the suggested 2-h cut-off value equals to the current WHO GDM diagnostic value. Postpartum glucose abnormality risk-based 1-h post 75 g load cut-off (≥ 10.7 mmol/L) is less inclusive than the current GDM criteria by IADPSG (≥ 10 mmol/L). We can therefore speculate that substantially elevated 1-h post 75 g load glucose (possibly in combination with HbA1c > 36 mmol/ mol) is the most sensitive and discriminative parameter distinguishing subset of DM cases with increased risk of postpartum glucose abnormality.
We are of course aware of several limitations such as that our study cohort does not represent the entire GDM population and model constructed from a retrospective data of single cohort study with possible selection bias needs to be replicated and validated. Furthermore, direct comparison of former and new (IADPSG) WHO criteria in terms of sensitivity and specificity is unfortunately not possible in the same study sample since it was recruited by former national modification of WHO criteria and is therefore distorted by different cut-offs (esp. higher upper limit for FPG). Nevertheless, as a proof of principle this study provides incentive to explore the predictive potential of routine diagnostic criteria in larger scale studies.
The major message of the current study is principally conveyed by the finding that prevalence of early postpartum glucose abnormality is not negligible and reaches 16.7% during the first year postdelivery. Furthermore, by annotation of current GDM diagnostic criteria it appears possible to yield extra information not only on obstetrical and neonatal but also maternal metabolic risks. Apparently, currently practiced simple dichotomization of the mid-trimester oGTT into physiological and pathological reduces information gained from a standard routine well accessible test. Modification of the criteria with the complex view (e.g. dual set of cut-offs) of both obstetrical/neonatal and future metabolic risk could help to identify high risk population to be followed immediately postpartum at no additional cost on top of routine antenatal care. The documented efficiency of early diagnosis and lifestyle or pharmacological intervention on prevention or postponing diabetes development is a powerful argument for further development of risk-based model. Subsequent long-term health care economic benefits represent significant added value of the proposed approach.
In conclusion, parameters of glucose metabolism measured during 24-28 th week of pregnancy fulfilling criteria of GDM diagnosis exhibited highly statistically significant differences between women with and without persistent postpartum glucose metabolism abnormality and conferred significant predictive potential for early postpartum glucose abnormality. Considering generally lowcompliance of GDM women in postpartum screening, risk-based stratification of GDM population could improve efficiency of the screening for diabetes after the delivery and decrease the burden of its metabolic and cardiovascular consequences in this high-risk population. IADPSG criteria recommended by Czech Diabetes Society (and in many other countries in Europe) seem to optimally capture both perinatal and maternal metabolic risks and are therefore medically and economically justified.