Eliana WendlandpersName, Maria Regina TorlonipersName, Maicon FalavignapersName, Janet TrujillopersName, Maria Alice Souza de Oliveira DodepersName, Maria Amélia CampospersName, Bruce Bartholow DuncanpersName, María Inês SchmidtpersName (2012date). “Gestational diabetes and pregnancy outcomes - a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) diagnostic criteria.” BMC Pregnancy and Childbirthtitle·venue.
Object of study — TWO COMPETING DIAGNOSTIC CRITERIA FOR ONE CONDITION, COMPARED ON OUTCOMES - the WHOterm and IADPSGterm definitions of gestational diabetes, meta-analysed across eight cohorts and 44,829 untreated women
Research question — whether gestational diabetes as defined by the WHOterm criteria and as defined by the IADPSG criteriaterm·def predicts adverse pregnancy outcomes, and whether the IADPSG criteriaterm·def hold outside the study that generated them
Contribution — pooled relative risks for both criteria across five outcomes, with leave-one-out sensitivity analyses removing first the study that generated one set of criteria and then the study that supplied individual patient data
phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a condition whose concept is agreed and whose boundary has been contested for thirty years — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | |
| claim-type | critique — “It is important to note that these crude associations are very small within a diagnostic context. Two reasons may explain the small associations found. First, both GDM criteria, especially the IADPSG criteria, identify lesser degrees of hyperglycemia when compared to other ones, such as those previously recommended by the ADA [ 20 ]. Second, as all the studies analyzed in this review excluded women receiving specific treatments for GDM (see Table 1 ), the range of hyperglycemia classified as GDM represents a mild degree of hyperglycemia.” | |
| method — evidence | — “As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders.” | |
| object of study — evidence | — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | |
| research question — evidence | — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | |
| contribution — evidence | — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | |
| mechanism | THE CLEANEST SEPARATION IN THE CORPUS OF WHAT A THING IS FROM WHERE ITS LINE IS: `The definition of gestational diabetes mellitus as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.` The concept is settled and the threshold is not — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | mechanisms[0] |
| mechanism | AND ONE REASON THE CUT POINTS DIVERGED IS A UNIT-CONVERSION PROBLEM ACROSS ERAS: `different cutoffs for the diagnosis of GDM were chosen, one of the issues being the difficulty in converting blood glucose values from the original studies done in the 1960s and 1970s to their plasma equivalents analyzed using new analytic methods`. A threshold's history is a measurement-technology history — “The NDDG opted, in pregnancy, to maintain the 3 h 100 g OGTT test, largely used and evaluated in the USA. The American Diabetes Association (ADA) and many other medical associations around the world adopted over the years this 3 h 100 g OGTT test. In so doing, different cutoffs for the diagnosis of GDM were chosen, one of the issues being the difficulty in converting blood glucose values from the original studies done in the 1960s and 1970s [ 1 , 3 - 5 ] to their plasma equivalents analyzed using new analytic methods.” | mechanisms[1] |
| mechanism | AND THE CIRCULARITY IS MEASURED WITH A LEAVE-ONE-OUT RATHER THAN ARGUED: `Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study ... After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.` Two of three outcomes lose significance once the generating study is removed — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | mechanisms[2] |
| mechanism | and the expectation is stated plainly: `since the IADPSG criteria were derived from the HAPO study, lower performance of these criteria in non-HAPO settings is to be expected` — “Additionally, since the IADPSG criteria were derived from the HAPO study, lower performance of these criteria in non-HAPO settings is to be expected. For large for gestational age and for cesarean delivery, results remained inconsistent across studies after excluding HAPO, which makes questionable the estimates of pooled RRs generated for these outcomes (the pooled RRs found were lower and not statistically significant).” | mechanisms[3] |
| mechanism | AND THE SAME CRITERION IDENTIFIES 24% OR 74% OF CASES DEPENDING ON THE CENTRE: `the fasting value identified OVER 70% of all cases ... while when these criteria were applied to the HAPO study as a whole, the fasting value identified ONLY ABOUT 50% ... as this rate in HAPO varied from 24% (THAILAND) TO 74% (BARBADOS), whether these differences resulted from INCOMPLETE FASTING or from other specific study or population particularity CANNOT BE CONCLUDED` — “In fact, the application of the IADPSG criteria in two published studies [ 13 , 22 ] and in the EBDG database showed that the fasting value identified over 70% of all cases of GDM so defined, while when these criteria were applied to the HAPO study as a whole, the fasting value identified only about 50% of cases. However, as this rate in HAPO varied from 24% (Thailand) to 74% (Barbados)[ 23 ], whether these differences resulted from incomplete fasting or from other specific study or population particularity cannot be concluded from current information.” | mechanisms[4] |
| mechanism | AND A STRUCTURAL REASON WHY ONE DEFINITION IS LESS STABLE THAN THE OTHER: `the IADPSG criteria are more vulnerable to heterogeneity across different settings because they allow that diagnosis be made on the basis of only one out of three possible measures`. An OR-rule over three tests makes the class depend on which test a population happens to fail - the same shape as hoste2006's `the worst of either`, with the instability named — “One hypothesis is that the IADPSG criteria are more vulnerable to heterogeneity across different settings because they allow that diagnosis be made on the basis of only one out of three possible measures (fasting, 1 h and 2 h). Given population variability in terms of the probability of being positive by fasting and post load values, as well as in terms of the possibility of having incomplete fasting (drank coffee or tea with sugar; for example), more heterogeneity could be found for the IADPSG criteria.” | mechanisms[5] |
| extends | the HAPO study and the IADPSG recommendations derived from it, whose applicability outside HAPO this review is the first to test — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | claim_relations[0] |
| critiques | the diagnostic value of both criteria - 'these crude associations are very small within a diagnostic context', and would remain so even at a relative risk of 3 — “Nevertheless, even if GDM diagnostic criteria were to reach relative risks close to 3 for these adverse outcomes in such settings, the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities [ 21 ]. This fact suggests the importance of investigating the contribution to risk discrimination of other factors, besides glycaemia, for these outcomes.” | claim_relations[1] |
| sense | `gestational diabetes` (concept) - `any degree of glucose intolerance with onset or first recognition during pregnancy`, and this part `is largely accepted` — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | senses[0] |
| sense | `gestational diabetes` (WHO sense) - the 2 h 75 g OGTT with the cut points used OUTSIDE pregnancy: fasting >= 7 mmol/l or 2 h plasma glucose >= 7.8 mmol/l, encompassing impaired glucose tolerance and diabetes — “The WHO adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose tolerance outside of pregnancy [ 2 , 3 ]. In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.” | senses[1] |
| sense | `gestational diabetes` (IADPSG sense) - fasting >= 5.1, one hour >= 10.0, or two hours >= 8.5 mmol/L, derived from the HAPO study AND BASED ON PREGNANCY OUTCOMES rather than on a distribution — “More recently, the International Association of the Diabetes in Pregnancy Study Group (IADPSG), after extensive analyses of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [ 7 ], recommended new diagnostic criteria for GDM [ 8 ] based on the 2 h 75 g OGTT: a fasting glucose ≥ 5.1 mmol/L (92 mg/dl), or a one hour result of ≥ 10.0 mmol/L (180 mg/dl), or a two hour result of ≥ 8.5 mmol/L (153 mg/dl).” | senses[2] |
| sense | `macrosomia` - `as defined by the authors`, which in practice is birth weight above 4000 g in four of five studies and something else in the fifth — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | senses[3] |
| control | excluding the HAPO study, which generated the IADPSG criteria, and re-pooling — failed — “Additionally, since the IADPSG criteria were derived from the HAPO study, lower performance of these criteria in non-HAPO settings is to be expected. For large for gestational age and for cesarean delivery, results remained inconsistent across studies after excluding HAPO, which makes questionable the estimates of pooled RRs generated for these outcomes (the pooled RRs found were lower and not statistically significant).” — rules out the circularity of judging criteria on the data that produced them - and it BOUND: after exclusion the IADPSG associations for large for gestational age and cesarean delivery were no longer statistically significant — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | controls[0] |
| control | restricting to studies that applied the OGTT universally rather than after a screening test — held — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” — rules out selection bias from testing only women already suspected of GDM — “As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders.” | controls[1] |
| control | blinding medical staff to the OGTT result so that diagnosis does not trigger treatment — partial — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” — rules out almost nothing across the pooled studies: 'only one study informed that medical staff was blinded to OGTT results' — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” | controls[2] |
| control | a common definition of the outcomes across the pooled studies — absent-declared-unreported — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” — rules out nothing - the review takes them 'as defined by the authors' and 'according to individual study definitions', so a comparison of two diagnostic definitions runs on outcome definitions that also vary — “We decided to analyze, as perinatal outcomes, large for gestational age births and macrosomia (as defined by the authors), as well as perinatal mortality (fetal death and early neonatal death). Regarding maternal outcomes, we chose to analyze cesarean delivery and preeclampsia according to individual study definitions.” | controls[3] |
| weight | the HAPO study and the IADPSG recommendations derived from it, whose applicability outside HAPO this review is the first to test — 0.9 — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | claim_relations[0] |
| weight | the diagnostic value of both criteria - 'these crude associations are very small within a diagnostic context', and would remain so even at a relative risk of 3 — 0.85 — “Nevertheless, even if GDM diagnostic criteria were to reach relative risks close to 3 for these adverse outcomes in such settings, the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities [ 21 ]. This fact suggests the importance of investigating the contribution to risk discrimination of other factors, besides glycaemia, for these outcomes.” | claim_relations[1] |
| note | macrosomia —operationalised-as→ birth weight — 'fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al)'. The outcome the criteria are judged against is itself defined per study, with the exception named rather than smoothed — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | concept_edges[1] |
| weight | macrosomia —operationalised-as→ birth weight — 0.95 — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | concept_edges[1] |
| note | impaired glucose tolerance —part-of→ GDM — 'In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting >= 7 mmol/l ...)'. A definitional clarification issued nineteen years after the original recommendation, folding two previously separate states into one class — “The WHO adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose tolerance outside of pregnancy [ 2 , 3 ]. In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.” | concept_edges[2] |
| weight | impaired glucose tolerance —part-of→ GDM — 0.95 — “The WHO adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose tolerance outside of pregnancy [ 2 , 3 ]. In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.” | concept_edges[2] |
| outcome | control — failed — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” — “Additionally, since the IADPSG criteria were derived from the HAPO study, lower performance of these criteria in non-HAPO settings is to be expected. For large for gestational age and for cesarean delivery, results remained inconsistent across studies after excluding HAPO, which makes questionable the estimates of pooled RRs generated for these outcomes (the pooled RRs found were lower and not statistically significant).” | controls[0] |
| outcome | control — held — “As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders.” — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | controls[1] |
| outcome | control — partial — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” | controls[2] |
| outcome | control — absent-declared-unreported — “We decided to analyze, as perinatal outcomes, large for gestational age births and macrosomia (as defined by the authors), as well as perinatal mortality (fetal death and early neonatal death). Regarding maternal outcomes, we chose to analyze cesarean delivery and preeclampsia according to individual study definitions.” — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | controls[3] |
| limitation | THE OUTCOMES ARE DEFINED BY THE ORIGINAL AUTHORS, NOT BY THE REVIEW: perinatal outcomes are `macrosomia (as defined by the authors)` and maternal outcomes are taken `according to individual study definitions`. A meta-analysis of definitions whose own outcome definitions vary between the studies pooled — “We decided to analyze, as perinatal outcomes, large for gestational age births and macrosomia (as defined by the authors), as well as perinatal mortality (fetal death and early neonatal death). Regarding maternal outcomes, we chose to analyze cesarean delivery and preeclampsia according to individual study definitions.” | limitations[0] |
| limitation | and the exception is printed rather than smoothed: macrosomia is `defined by authors as birth weight > 4000 g, except Aberg et al` — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | limitations[1] |
| limitation | AND THE CRITERIA PREDICT WITHOUT DISCRIMINATING: `these crude associations are very small within a diagnostic context` and `even if GDM diagnostic criteria were to reach relative risks close to 3 ... the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities`. A definition can be significantly associated with an outcome and still not sort the people in front of you — “Nevertheless, even if GDM diagnostic criteria were to reach relative risks close to 3 for these adverse outcomes in such settings, the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities [ 21 ]. This fact suggests the importance of investigating the contribution to risk discrimination of other factors, besides glycaemia, for these outcomes.” | limitations[2] |
| limitation | and the analyses are deliberately crude, for a reason tied to what the criteria are FOR: `As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders` — “As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders.” | limitations[3] |
| limitation | AND ONLY ONE STUDY IN EIGHT BLINDED THE STAFF TO THE TEST RESULT: `Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results` — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” | limitations[4] |
finding · quantity · variable · definition · key-term — grounded in the full text| finding | — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | content_tags.findings[0] |
| finding | — “The NDDG opted, in pregnancy, to maintain the 3 h 100 g OGTT test, largely used and evaluated in the USA. The American Diabetes Association (ADA) and many other medical associations around the world adopted over the years this 3 h 100 g OGTT test. In so doing, different cutoffs for the diagnosis of GDM were chosen, one of the issues being the difficulty in converting blood glucose values from the original studies done in the 1960s and 1970s [ 1 , 3 - 5 ] to their plasma equivalents analyzed using new analytic methods.” | content_tags.findings[1] |
| finding | — “Because the HAPO study was used to generate the IADPSG criteria, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteria, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery.” | content_tags.findings[2] |
| finding | — “In fact, the application of the IADPSG criteria in two published studies [ 13 , 22 ] and in the EBDG database showed that the fasting value identified over 70% of all cases of GDM so defined, while when these criteria were applied to the HAPO study as a whole, the fasting value identified only about 50% of cases. However, as this rate in HAPO varied from 24% (Thailand) to 74% (Barbados)[ 23 ], whether these differences resulted from incomplete fasting or from other specific study or population particularity cannot be concluded from current information.” | content_tags.findings[3] |
| finding | — “One hypothesis is that the IADPSG criteria are more vulnerable to heterogeneity across different settings because they allow that diagnosis be made on the basis of only one out of three possible measures (fasting, 1 h and 2 h). Given population variability in terms of the probability of being positive by fasting and post load values, as well as in terms of the possibility of having incomplete fasting (drank coffee or tea with sugar; for example), more heterogeneity could be found for the IADPSG criteria.” | content_tags.findings[4] |
| finding | — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | content_tags.findings[5] |
| finding | — “Nevertheless, even if GDM diagnostic criteria were to reach relative risks close to 3 for these adverse outcomes in such settings, the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities [ 21 ]. This fact suggests the importance of investigating the contribution to risk discrimination of other factors, besides glycaemia, for these outcomes.” | content_tags.findings[6] |
| finding | — “We decided to analyze, as perinatal outcomes, large for gestational age births and macrosomia (as defined by the authors), as well as perinatal mortality (fetal death and early neonatal death). Regarding maternal outcomes, we chose to analyze cesarean delivery and preeclampsia according to individual study definitions.” | content_tags.findings[7] |
| finding | — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” | content_tags.findings[8] |
| quantity | 24-74 % — the share of IADPSG-defined cases identified by the fasting value alone, across HAPO centres - Thailand to Barbados, one criterion — “In fact, the application of the IADPSG criteria in two published studies [ 13 , 22 ] and in the EBDG database showed that the fasting value identified over 70% of all cases of GDM so defined, while when these criteria were applied to the HAPO study as a whole, the fasting value identified only about 50% of cases. However, as this rate in HAPO varied from 24% (Thailand) to 74% (Barbados)[ 23 ], whether these differences resulted from incomplete fasting or from other specific study or population particularity cannot be concluded from current information.” | content_tags.quantities[0] |
| quantity | 5.1 mmol/L fasting — the IADPSG fasting threshold, against the WHO's 7 mmol/l — “More recently, the International Association of the Diabetes in Pregnancy Study Group (IADPSG), after extensive analyses of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [ 7 ], recommended new diagnostic criteria for GDM [ 8 ] based on the 2 h 75 g OGTT: a fasting glucose ≥ 5.1 mmol/L (92 mg/dl), or a one hour result of ≥ 10.0 mmol/L (180 mg/dl), or a two hour result of ≥ 8.5 mmol/L (153 mg/dl).” | content_tags.quantities[1] |
| quantity | 4000 g — the birth weight above which four of five studies called a birth macrosomic — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | content_tags.quantities[2] |
| quantity | 1 of 8 studies — the number that blinded medical staff to the OGTT result — “Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.” | content_tags.quantities[3] |
| variable | birth weight — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | content_tags.variables[0] |
| definition | gestational diabetes mellitus — “The definition of gestational diabetes mellitus (GDM) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.” | content_tags.definitions[0] |
| definition | IADPSG criteria — “More recently, the International Association of the Diabetes in Pregnancy Study Group (IADPSG), after extensive analyses of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [ 7 ], recommended new diagnostic criteria for GDM [ 8 ] based on the 2 h 75 g OGTT: a fasting glucose ≥ 5.1 mmol/L (92 mg/dl), or a one hour result of ≥ 10.0 mmol/L (180 mg/dl), or a two hour result of ≥ 8.5 mmol/L (153 mg/dl).” | content_tags.definitions[1] |
| definition | macrosomia — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | content_tags.definitions[2] |
| concept | WHO — not defined in this paper's own words; the older criteria - the non-pregnant cut points applied in pregnancy — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | concepts[0] |
| concept | IADPSG — not defined in this paper's own words; the newer criteria, derived from HAPO and based on pregnancy outcomes — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | concepts[1] |
| concept | macrosomia — not defined in this paper's own words; the perinatal outcome, defined by each original study's authors — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | concepts[2] |
| concept | birth weight — not defined in this paper's own words; the quantity macrosomia is operationalised by - above 4000 g, with one exception — “As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDM diagnosed through WHO criteria and fetal macrosomia (defined by authors as birth weight > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%).” | concepts[3] |
| concept | impaired glucose tolerance — not defined in this paper's own words; one of the two states the WHO definition of GDM was clarified to cover — “The WHO adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose tolerance outside of pregnancy [ 2 , 3 ]. In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.” | concepts[4] |
| concept | GDM — not defined in this paper's own words; gestational diabetes mellitus - the class encompassing impaired glucose tolerance and diabetes under the WHO clarification — “The WHO adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose tolerance outside of pregnancy [ 2 , 3 ]. In 1999, WHO clarified that GDM encompassed impaired glucose tolerance and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.” | concepts[5] |
| 1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23 | — “For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHO and the IADPSG criteria (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteria.” | content_tags.statistics[0] |
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BMC Pregnancy Childbirth BMC Pregnancy Childbirth 61 bmcpcnc BMC Pregnancy and Childbirth 1471-2393 BMC PMC3352245 PMC3352245.1 3352245 3352245 22462760 10.1186/1471-2393-12-23 1471-2393-12-23 1 Research Article Gestational diabetes and pregnancy outcomes - a systematic review of the World Health Organization (WHOterm) and the International Association of Diabetes in Pregnancy Study Groups (IADPSGterm) diagnostic criteria WendlandpersName Eliana M 1 elianawend@gmail.com TorlonipersName Maria Regina 2 ginecologia@terra.com.br FalavignapersName Maicon 3 mfalavigna@yahoo.com.br TrujillopersName Janet 3 njtrujill@gmail.com DodepersName Maria Alice 4 malicedode@terra.com.br CampospersName Maria Amélia 5 ameliaac@terra.com.br DuncanpersName Bruce B 3 bbduncan@ufrgs.br SchmidtpersName Maria Inês 3 maria.schmidtpersName@ufrgs.br 1 Federal University of Health Sciences, Porto Alegre, Brazil 2 São Paulo Federal University, São Paulo, Brazil 3 Federal University of Rio Grande do Sul, Porto Alegre, Brazil 4 Federal University of Pelotas, Pelotas, Brazil 5 Conceição Hospital, Porto Alegre, Brazil 2012 31 3 2012 12 204956 23 23 14 11 2011 31 3 2012 31 03 2012 16 05 2012 13 04 2026 Copyright ©2012 WendlandpersName et al; licensee BioMed Central Ltd. 2012 WendlandpersName et al; licensee BioMed Central Ltd. https://creativecommons.org/licenses/by/2.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background Two criteria based on a 2 h 75 g OGTT are being used for the diagnosis of gestational diabetes (GDMterm), those recommended over the years by the World Health Organization (WHOterm), and those recently recommended by the International Association for Diabetes in Pregnancy Study Group (IADPSGterm), the latter generated in the HAPO study and based on pregnancy outcomes. Our aim is to systematically review the evidence for the associations between GDMterm (according to these criteria) and adverse outcomes.
Methods We searched relevant studies in MEDLINE, EMBASE, LILACS, the Cochrane Library, CINHAL, WHO-Afro library, IMSEAR, EMCAT, IMEMR and WPRIM. We included cohort studies permitting the evaluation of GDMterm diagnosed by WHOterm and or IADPSG criteriaterm·def against adverse maternal and perinatal outcomes in untreated women. Only studies with universal application of a 75 g OGTT were included. Relative risks (RRs) and their 95% confidence intervals (CI) were obtained for each study. We combined study results using a random-effects model. Inconsistency across studies was defined by an inconsistency index (I 2 ) > 50%.
Results Data were extracted from eight studies, totaling 44,829 women. Greater risk of adverse outcomes was observed for both diagnostic criteria. When using the WHOterm criteria, consistent associations were seen for macrosomiaterm (RR = 1.81; 95%CI 1.47-2.22; p < 0.001); large for gestational age (RR = 1.53; 95%CI 1.39-1.69; p < 0.001); perinatal mortality (RR = 1.55; 95% CI 0.88-2.73; p = 0.13); preeclampsia (RR = 1.69; 95%CI 1.31-2.18; p < 0.001); and cesarean delivery (RR = 1.37;95%CI 1.24-1.51; p < 0.001). Less data were available for the IADPSG criteriaterm·def, and associations were inconsistent across studies (I 2 ≥ 73%). Magnitudes of RRs and their 95%CIs were 1.73 (1.28-2.35; p = 0.001) for large for gestational age; 1.71 (1.38-2.13; p < 0.001) for preeclampsia; and 1.23 (1.01-1.51; p = 0.04) for cesarean delivery. Excluding either the HAPO or the EBDG studies minimally altered these associations, but the RRs seen for the IADPSG criteriaterm·def were reduced after excluding HAPO.
Conclusions The WHOterm and the IADPSG criteriaterm·def for GDMterm identified women at a small increased risk for adverse pregnancy outcomes. Associations were of similar magnitude for both criteria. However, high inconsistency was seen for those with the IADPSG criteriaterm·def. Full evaluation of the latter in settings other than HAPO requires additional studies.
pmc-status-qastatus 0 pmc-status-live yes pmc-status-embargo no pmc-status-released yes pmc-prop-open-access yes pmc-prop-olf no pmc-prop-manuscript no pmc-prop-legally-suppressed no pmc-prop-has-pdf yes pmc-prop-has-supplement yes pmc-prop-pdf-only no pmc-prop-suppress-copyright no pmc-prop-is-real-version no pmc-prop-is-scanned-article no pmc-prop-preprint no pmc-prop-in-epmc yes pmc-license-ref CC BY Background The definition of gestational diabetes mellitusterm·def (GDMterm) as any degree of glucose intolerance with onset or first recognition during pregnancy is largely accepted. However, the precise level of glucose intolerance characterizing gestational diabetes has been controversial over the last three decades.
In 1979-1980, U.S. National Diabetes Data Group (NDDG) [ 1 ] and the World Health Organization (WHOterm) [ 2 ] established that the 2 h 75 g oral glucose tolerance test (OGTT) should be the main diagnostic test for glucose intolerance outside of pregnancy.
Regarding glucose intolerance during pregnancy, two different approaches were taken. The NDDG opted, in pregnancy, to maintain the 3 h 100 g OGTT test, largely used and evaluated in the USA. The American Diabetes Association (ADA) and many other medical associations around the world adopted over the years this 3 h 100 g OGTT test. In so doing, different cutoffs for the diagnosis of GDMterm were chosen, one of the issues being the difficulty in converting blood glucose values from the original studies done in the 1960s and 1970s [ 1 , 3 - 5 ] to their plasma equivalents analyzed using new analytic methods.
The WHOterm adopted the 2 h 75 g OGTT in pregnancy, recommending the same diagnostic cut points established for the diagnosis of impaired glucose toleranceterm outside of pregnancy [ 2 , 3 ]. In 1999, WHOterm clarified that GDMterm encompassed impaired glucose toleranceterm and diabetes (fasting ≥ 7 mmol/l or ≥ 126 mg/dl; 2 h plasma glucose ≥ 7.8 mmol/l or 140 mg/dl) [ 6 ] and, over the years has maintained their recommendations.
More recently, the International Association of the Diabetes in Pregnancy Study Group (IADPSGterm), after extensive analyses of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [ 7 ], recommended new diagnostic criteria for GDMterm [ 8 ] based on the 2 h 75 g OGTT: a fasting glucose ≥ 5.1 mmol/L (92 mg/dl), or a one hour result of ≥ 10.0 mmol/L (180 mg/dl), or a two hour result of ≥ 8.5 mmol/L (153 mg/dl).
A considerable number of prospective studies have now investigated the use of a 2 h 75 g OGTT in pregnancy in relation with various pregnancy outcomes, thus allowing evaluation of these two main diagnostic criteria. Thus, the purpose of this study is to summarize, through a systematic review, the association of GDMterm, as diagnosed by the WHOterm and the IADPSG criteriaterm·def, with adverse pregnancy outcomes, in untreated women. In so doing, the applicability of the IADPSG criteriaterm·def to non-HAPO settings is also evaluated.
Methods Criteria for considering studies for this review Types of study Cohort studies (prospective or retrospective) were considered for inclusion in this systematic review if they provided sufficient information to estimate the associations of the WHOterm and/or the IADPSG criteriaterm·def with related perinatal and maternal outcomes.
To avoid selection bias, we included only studies that applied the OGTT universally to all participants. We therefore excluded studies applying the OGTT only in women with certain clinical risk factors (such as family history, obesity, previous GDMterm) or in those positive in pre-OGTT glucose screening (with, for example, a 50 g challenge test and/or a fasting glucose). We also excluded studies that did not distinguish pre-gestational diabetes mellitus from GDMterm, those not allowing the distinction between treated and untreated groups, and those not reporting outcomes for women classified as having a normal OGTT.
Types of participants We accepted studies which included women of any race, parity, age, body weight or other socio-demographic characteristics.
Types of diagnostic tests Only studies based on a 2 hour 75 g OGTT performed during the 2 nd or the 3 rd trimesters were included, and only if they provided results for a diagnosis based on at least the 2 h post-load glucose. Studies based on capillary glucose measurements were included.
Types of outcome measures We decided to analyze, as perinatal outcomes, large for gestational age births and macrosomiaterm (as defined by the authors), as well as perinatal mortality (fetal death and early neonatal death). Regarding maternal outcomes, we chose to analyze cesarean delivery and preeclampsia according to individual study definitions.
Search methods for the identification of studies The search strategy used the following general terms, adapted to each database: "gestational diabetes" or "glucoseintolerance" and the appropriate terms for each of the maternal and perinatal adverse outcomes specified above. Specific terms used for the electronic search are detailed in the Additional file 1 : Description of the electronic search strategy used to perform the literature search.
We searched ten electronic databases (MEDLINE, EMBASE, LILACS, the Cochrane Library (CENTRAL), CINHAL, WHO-Afro library, IMSEAR, EMCAT, IMEMR and WPRIM) for articles published from inception up to March 15, 2011. No language or country restrictions were applied. We also searched for additional studies from classical review articles. The reference lists of all articles selected for full text reading were reviewed for additional potentially eligible studies.
Data collection and analysis Selection of studies All citations identified were entered into an electronic database and duplicates were deleted. Initially, two investigators independently screened the titles and abstracts of potentially relevant studies for eligibility. When the information was not sufficient to determine if the article was eligible for inclusion, the article's full text was obtained for further evaluation. Discrepancies were discussed until consensus was reached.
Data extraction and management Two independent investigators reviewed the eligible studies and extracted data using a standardized form prepared for this review. Disagreements were discussed and resolved in a consensus meeting. When raw quantitative data were not reported, approximate values were obtained from the figures or calculated from percentages.
Assessment of methodological quality The methodological quality of the included studies was assessed by examining factors which might affect the strength of the association between glucose levels and outcomes. In particular, the following factors were assessed in each study: i) adequate selection of participants: consecutive recruitment from prenatal clinics; ii) adequate standardization of the glucose tolerance test (pre-analytic factors such as anhydrous glucose, plasma immediately separated or kept with glycolytic inhibitors and kept refrigerated until centrifugation; and analytic factors such as enzymatic method of measurement and laboratory quality control); iii) adequate report of losses to follow up and; iv) medical staff blinded to OGTT results.
Data synthesis Data for the WHOterm and the IADPSG criteriaterm·def were aggregated and presented as relative risk (RR) with 95% confidence interval (CI). Meta-analysisterm·mth data were combined using random-effect models, with restricted maximum-likelihood (REML) estimation. The statistical analysis was performed using the R version 2.11.1 software, package metafor version 1.6-0 [ 9 ]. As our aim was to investigate diagnostic criteria based on their capacity to predict GDM-related outcomes for classification purposes rather than for etiological investigation, all statistical analyses were crude, without adjustment for potential confounders.
Assessment of heterogeneity Overall results were calculated based on the random effects model. We assessed heterogeneity using the Cochrane's χ2 statistics with a significance level of 0.10. Inconsistency indexes (I 2 ) were also calculated, and a value greater than 50% was considered an indicator of high inconsistency between studies [ 10 ].
Sensitivity analysis and assessment of publication bias We did sensitivity analyses in order to examine the influence of the HAPO study and Brazilian Study of Gestational Diabetes (EBDG) on the magnitude and consistency of associations with outcomes. In addition to REML, we also aggregated data with other variance estimators (Maximum Likelihood, Empirical Bayes, Sidik-Jonkman and DerSimonean and Laird) and with a fixed effect model in order to assess the robustness of the model.
Publication bias was tested using a funnel plot and Egger's test based on weighted regression [ 11 ].
The full database for the EBDG study was available which allowed analysis for both criteria for all outcomes. The EBDG study was approved by local institutional review boards and informed consent was obtained from all participants. Data from the other studies were obtained from published articles cited in the list of references.
Results Results of the literature search Figure 1 (flow chart) describes the process of study identification and inclusion, and the reasons for exclusions. Our search identified 5985 references, without duplicates. Nine citations were retrieved from the reference lists of the full-text articles. After revising all titles and abstracts, 202 potentially relevant citations were identified and full papers were obtained for all. A total of 9 publications pertaining to 8 studies met the selection criteria and were included in this systematic review. For a description of excluded studies, see Additional file 2 : List of excluded articles. The full database for the EBDG study was available which allowed analysis for both criteria for all outcomes.
Figure 1 Flow chart for the process of study identification and inclusion .
Included studies Data on the adverse outcomes associated with diagnostic criteria were extracted from 8 studies (9 publications) [ 7 , 12 - 19 ], all of which were published in full in peer reviewed journals (Table 1 ). Of the 8 included studies, three were retrospective and information was gathered through data linkage or chart review [ 15 , 17 , 18 ]. One study was performed in the United States [ 13 ], one in Asia [ 18 ], two in the Middle East [ 17 ], one in Europe [ 12 ], two in Latin America [ 14 , 16 ] and one was a multi country study [ 7 , 19 ]. All but one study [ 12 ] used venous plasma glucose based on the oral glucose tolerance test to diagnose GDMterm. Taken together, the 8 studies provided information on a total of 44829 women. The database of the Brazilian Study of Gestational Diabetes (EBDG) [ 16 ] was used to generate data when results from other studies were not available from the published literature.
Table 1 Main characteristics of the studies included Study N Incidence of GDMterm (%) 1 Ethnicity Maternal age 2 Gestational age at OGGT (weeks) 2 Pre-gravid BMI 2 Study criteria for GDMterm treatment 3 mmol/L Aberg 2001 [ 12 ] Sweden 4773 5.2 Not reported Not reported 25-30 Not reported 2 hs PG > 9.0 Black 2010 [ 13 ] USA 8711 19.4 White: 7.2; Black: 10.;1 Hispanic: 74.4; Asian: 7.4; Other: 0.9 29.1 ± 5.9 26.7 ± 2.9 27.5 ± 6.1 At least 2 abnormal values: FPG ≥ 5.5; 1 hPG ≥ 10.8; 2 hPG ≥ 8.9 EBDG 2001 [ 16 ] Brazil 4998 7.5 White: 44.9 Mixed: 41.1 Black: 13.6 Other: 0.4 27.8 ± 5.5 24-28 23.4 ± 4.0 2 hPG ≥ 10.0 Forsbach 1997 [ 14 ] Mexico 667 16.0 Hispanic 18 - 44 34.2 (24-40) Not reported 2 hPG > 10.0 HAPO 2008, 2010 [ 7 , 19 ] multi-countries 23316 11.4 White: 48.3 Black: 11.6 Hispanic: 8.5 Asian: 29.0 Other: 2.6 29.2 ± 5.8 27.8 ± 1.8 27.7 ± 5.1 FPG > 5.8; or 2 hPG > 10.0; or RPG ≥ 8.9 Khan 1994 [ 15 ] Pakistan 1278 4.9 Not reported 26.7 ± 4.6 16 - 20 Not reported . At least 2 abnormal values: FPG > 5.8; 1 hPG > 10.3; 2 hPG > 7.8/3 hPG > 6.8 Shirazian 2008 [ 17 ] Iran 670 12.1 Not reported NR 24-28 Not reported At least 2 abnormal values: FPG ≥ 5.5; 1 hPG ≥ 10.0; 2 hPG ≥ 8.3 Sugaya 2000 [ 18 ] Japan 416 32.5 Asian 30.3 ± 4.3 25.4 ± 8.2 22.4 ± 3.8 At least 2 abnormal values: FPG ≥ 5.5; 1 hPG ≥ 10.0; 2 hPG ≥ 8.3 GDMterm: Gestational diabetes; OGTT: Oral glucose tolerance test; PG: Plasma glucose; FPG: Fasting PG; RPG: random PG 1 GDMterm incidence according to WHOterm except for Black et al., whoterm used the IASDPG criteria 2 Range or mean ± SD 3 The meta-analyses only included untreated women, as defined in each study We only analyzed results for untreated women. Because of the ethical need to offer treatment to women identified as having GDMterm by the diagnostic criteria in use at the moment of the testing, some studies excluded such women and others presented results permitting the separation of those whoterm received treatment. As seen in Table 1 in some cases, this resulted in study samples with a very narrow glucose range.
Quality assessment of the studies included is summarized in Table 2 . Most of the studies (6/8) had adequate selection of participants, half of them presented adequate test standardization and reported losses to follow-up and only one study informed that medical staff was blinded to OGTT results.
Table 2 Assessment of methodological quality of included studies Study Adequate selection of participants Adequate test standardization Adequate report of losses to follow-up Medical staff blinded to OGTT results Aberg, 2001 [ 1 ] Uncertain No Uncertain No Black, 2010 [ 13 ] Yes Uncertain Yes No EBDG, 2001 [ 16 ] Yes Yes Yes No Forsbach, 1997 [ 14 ] Yes Yes Uncertain No HAPO, 2008, 2010 [ 7 , 19 ] Yes Yes Yes Yes Khan, 1994 [ 15 ] Yes Uncertain Uncertain Uncertain Shirazian, 2008 [ 17 ] Yes Yes No Uncertain Sugaya, 2000 [ 18 ] Uncertain Uncertain Yes No Perinatal outcomes As seen in Figure 2 , a total of five studies allowed evaluation of the association between GDMterm diagnosed through WHOterm criteria and fetal macrosomiaterm (defined by authors as birth weightterm > 4000 g, except Aberg et al [ 12 ]). The corresponding pooled relative risk (RR) was 1.81 (95%CI 1.47-2.22; p < 0.001), with very homogenous results across studies (I 2 = 0%). We did not identify any published study allowing evaluation of macrosomiaterm according to the IADSPG diagnostic criteria. Therefore, we performed this analysis using the EBDG database and the RR was 1.38 (95%CI 1.14-1.68; p = 0.001).
Figure 2 Relative incidence (RR) of macrosomiaterm among those with and without gestational diabetes as defined by WHOterm and IADPSGterm diagnostic criteria .
When we assessed large for gestational age births, defined as birthweight ≥ 90 th percentile for gestational age (Figure 3 ), the association seen for the WHOterm criteria (four studies) was slightly lower (RR = 1.53, 95% CI 1.39-1.69; p < 0.001), and very homogeneous across studies (I 2 = 0%). Regarding the IADPSG criteriaterm·def, the large inconsistency across the three studies evaluated (I 2 = 93%) limited the validity of the pooled RR (1.73; 95%CI 1.28-2.35; p = 0.001).
Figure 3 Relative incidence (RR) of large for gestational age infants among those with and without gestational diabetes as defined by WHOterm and IADPSGterm diagnostic criteria .
With regard to perinatal mortality (Figure 4 ), only two studies provided sufficient data for the evaluation of the WHOterm criteria. Their summary produced a homogenous (I 2 = 0%) association of clinically relevant size but lacking statistical significance (RR = 1.55, 95%CI 0.88-2.73; p = 0.128). No studies were available to evaluate the IADSPG diagnostic criteria with regard to perinatal mortality. Analysis with the EBDG database yielded similar, non-statistically significant, results (RR = 1.40, 95%CI 0.91-2.14; p = 0.122).
Figure 4 Association between perinatal mortality and gestational diabetes as defined by WHOterm and IADPSGterm diagnostic criteria .
Maternal outcomes Four studies [ 13 , 16 , 18 , 19 ] provided data on preeclampsia, one of which included cases of transient hypertension or unspecified hypertension in the same group as preeclampsia [ 13 ]. As presented in Figure 5 , there was a positive and statistically significant association between the WHOterm diagnostic criteria and preeclampsia (pooled RR = 1.69, 95%CI 1.31-2.18; p < 0.001) with reasonable consistency across the three studies evaluated (I 2 = 38%). When analyzed by the IADPSG criteriaterm·def, the pooled RR for the same outcome was of similar magnitude (RR = 1.71, 95%CI 1.38-2.13; p < 0.001), but aggregated very inconsistent results for the three available studies (I 2 = 73%).
Figure 5 Association between preeclampsia and gestational diabetes as defined by WHOterm and IADPSGterm diagnostic criteria .
Figure 6 presents data pertaining to studies with sufficient information to evaluate diagnostic criteria as predictors for cesarean delivery. Both diagnostic criteria detected women with an increased risk, the association being slightly higher when GDMterm was diagnosed according with the WHOterm criteria (RR = 1.37, 95%CI 1.24-1.51; p < 0.001) than with the IADSPG criteria (RR = 1.23, 95%CI 1.01-1.51; p = 0.044). The associations were consistent across the four studies analyzed according to the WHOterm criteria (I 2 = 29%), but were inconsistent across the three studies that used the IADSPG criteria (I 2 = 93%).
Figure 6 Association between cesarean delivery and gestational diabetes as defined by WHOterm and IADPSGterm diagnostic criteria .
Sensitivity analyses and assessment of publication bias Because the HAPO study was used to generate the IADPSG criteriaterm·def, we performed post hoc subgroup analysis excluding the HAPO study (Figure 7 ) for all outcomes for which it contributed data. For the analyses of the IADPSG criteriaterm·def, the pooled RRs after exclusion were always somewhat smaller than the RR for the HAPO study alone. After exclusion, the pooled RRs remained statistically significant for preeclampsia (p = 0.006), but not for large for gestational age and cesarean delivery. For the analyses of the WHOterm criteria, the pooled RRs excluding HAPO were generally greater than the RR for the HAPO study alone, although not statistically significantly so; and remained statistically significant after the exclusion.
Figure 7 Sensitivity analysis excluding the HAPO study .
As the EBDG study was used in all analysis, sometimes using individual patient data from the original database, we also performed post hoc sensitivity analyses excluding this study (Figure 8 ). For the analyses of the IADPSG criteriaterm·def, this exclusion led to somewhat increased pooled RRs, statistically different from the RRs for the EBDG study for large for gestational age and cesarean delivery; after the exclusion of the EBDG study, the pooled RRs remained statistically significant. For the analyses of the WHOterm criteria, pooled RRs were generally smaller after exclusion of the EBDG study, but remained statistically significant.
Figure 8 Sensitivity analysis excluding the EBDG study .
It was not possible to assess the influence of the HAPO study on macrosomiaterm, as no HAPO data were available for this outcome. With respect to the influence of the EBDG study, its exclusion led to an increase in the pooled RR for the WHOterm criteria (from RR 1.81 to RR 2.17).
Meta-analyses performed with different variance estimators had little impact on the RR and on the I 2 . Stronger associations were found with fixed-effect models for outcomes assessed with the IADPSG criteriaterm·def (Additional file 3 : Meta-analyses performed with different variance estimators to generate pooled relative risks for the IADSPG and WHOterm criteria for gestational diabetes in the prediction of pregnancy outcomes).
Funnel plots and the Egger's regression asymmetry test (data not shown) did not reveal evidence for publication bias, although small number of studies compromised this analysis.
Discussion This is the first systematic review to assess the magnitude of the associations between different GDMterm diagnostic criteria and several clinically relevant outcomes. We focused analyses on the two main diagnostic criteria currently under debate for a 75 g OGTT - i.e., those recommended by the WHOterm and those recently proposed by the IADSPG on the basis of pregnancy outcomes. In addition to providing estimates for the magnitude of the increased risk predicted by these two criteria, we also evaluated the application of the IADPSG criteriaterm·def to settings other than that of the HAPO study.
Our summary estimates of relative risk demonstrate that GDMterm diagnostic criteria based on both the WHOterm and the IADPSG criteriaterm·def predict perinatal and maternal adverse outcomes. The strength of the crude associations found ranged from 1.23 (95% CI 1.01-1.51) for cesarean delivery, to 1.81 (95% CI 1.47-2.22) for macrosomiaterm. For the three outcomes for which meta-analyses were possible for both criteria (large for gestational age, preeclampsia and cesarean delivery), the magnitude of the effects were similar for the WHOterm and the IADPSG criteriaterm·def (1.53 vs. 1.73; 1.69 vs. 1.71; 1.37 vs. 1.23, respectively), although the inconsistency across studies limited aggregate estimation for the IADPSG criteriaterm·def. Sensitivity analyses excluding either the HAPO or the EBDG study did not materially change the magnitude of these associations (changes varying between 1 and 13%).
It is important to note that these crude associations are very small within a diagnostic context. Two reasons may explain the small associations found. First, both GDMterm criteria, especially the IADPSG criteriaterm·def, identify lesser degrees of hyperglycemia when compared to other ones, such as those previously recommended by the ADA [ 20 ]. Second, as all the studies analyzed in this review excluded women receiving specific treatments for GDMterm (see Table 1 ), the range of hyperglycemia classified as GDMterm represents a mild degree of hyperglycemia. Given the continuum of risk in the association between plasma glucose and pregnancy outcomes [ 7 ], if both criteria were applied to a broader spectrum, such as the one seen in the usual clinical setting, which includes women at greater risk given their higher glucose level, the association should be stronger. Nevertheless, even if GDMterm diagnostic criteria were to reach relative risks close to 3 for these adverse outcomes in such settings, the relative risks would still be unlikely to reflect major diagnostic discrimination in terms of post test probabilities [ 21 ]. This fact suggests the importance of investigating the contribution to risk discrimination of other factors, besides glycaemia, for these outcomes.
It is also important to interpret the heterogeneity found across studies, most seen for the IADPSG criteriaterm·def. Potential reasons for heterogeneity include different population characteristics, study design and nature of the diagnostic criteria. As sensitivity analyses examining the influence of the EBDG and the HAPO studies did reveal some changes in the heterogeneity found, particularities about each of these study settings need to be considered. The HAPO study is a large multi-country study conducted from 2000 to 2006 with a strict research protocol. The EBDG study is a multicenter study conducted in Brazil in the 1990's with a less strict protocol, in a scenario of less intervention, following women with a wider range of hyperglycemia. A more strict protocol, with more control over incomplete fasting, such as that seen in the HAPO study, could produce larger associations with the IADPSG criteriaterm·def, which diagnoses an appreciable fraction of cases on the basis of the fasting value. In fact, the application of the IADPSG criteriaterm·def in two published studies [ 13 , 22 ] and in the EBDG database showed that the fasting value identified over 70% of all cases of GDMterm so defined, while when these criteria were applied to the HAPO study as a whole, the fasting value identified only about 50% of cases. However, as this rate in HAPO varied from 24% (Thailand) to 74% (Barbados)[ 23 ], whether these differences resulted from incomplete fasting or from other specific study or population particularity cannot be concluded from current information. The lack of blinding to glucose levels in most studies (except HAPO) could lead to GDMterm treatment, and thus reduce the magnitude of the associations; so we excluded such women. Although undetected intervention may still be present even after these exclusions, for example, diet, it is unlikely that this would cause more heterogeneity in the IADPSGterm than in the WHOterm analyses.
One hypothesis is that the IADPSG criteriaterm·def are more vulnerable to heterogeneity across different settings because they allow that diagnosis be made on the basis of only one out of three possible measures (fasting, 1 h and 2 h). Given population variability in terms of the probability of being positive by fasting and post load values, as well as in terms of the possibility of having incomplete fasting (drank coffee or tea with sugar; for example), more heterogeneity could be found for the IADPSG criteriaterm·def. Another possibility, worth exploring in future studies, is whether the heterogeneity stems from differences in the prevalence or characteristics of obesity in the underlying populations.
Additionally, since the IADPSG criteriaterm·def were derived from the HAPO study, lower performance of these criteria in non-HAPO settings is to be expected. For large for gestational age and for cesarean delivery, results remained inconsistent across studies after excluding HAPO, which makes questionable the estimates of pooled RRs generated for these outcomes (the pooled RRs found were lower and not statistically significant). For preeclampsia, results across studies became consistent, but with an RR (1.54; 95% CI 1.32-1.79) smaller (p = 0.006) than that found for the HAPO study (2.02; 95%CI 1.78-2.29).
Our study has some limitations. First, few studies were available to evaluate important outcomes such as perinatal mortality and long-term outcomes in offspring. Yet, positive associations were found for macrosomiaterm and pregnancy related hypertension, two clinically relevant outcomes. Second, as we excluded studies conducted with selective screening and studies not allowing analysis of untreated women, we eliminated several otherwise good studies which were included in other reviews on GDMterm screening [ 24 ]. Publication bias could not be excluded because of the small number of studies examined.
Our study also has several strong points, including its originality, extensive search strategy, inclusion of studies independent of language, strict methodological rigor, assessment of study quality, and sensitivity and subgroup analyses to investigate the applicability of the IADPSG criteriaterm·def in settings other than the HAPO study.
Conclusions In conclusion, the meta-analyses of studies examining the WHOterm and IADPSG criteriaterm·def demonstrate small increased risk for adverse pregnancy outcomes, with generally similar magnitudes of associations for each criteria. For the WHOterm criteria, positive associations were consistent across studies. For the IADPSG criteriaterm·def, additional studies will be needed to adequately estimate the magnitude of associations when applied to non-HAPO settings.
Competing interests All authors have completed the Unified Competing Interest form, declaring the absence of financial interests that may be relevant to the submitted work.
Authors' contributions MIS participated in all the aspects of the project and was the overall supervisor. Additional participation was as follows: Writing the protocol: EMW and MRT; developing the search strategy: EMW; searching and selecting trials: EMW, MRT, MAC, MAD, JT; data extraction: JT, EMW, MRT; data analysis: MF; drafting and final review: All. All authors read and approved the final manuscript.
Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2393/12/23/prepub Supplementary Material Additional file 1 Description of the electronic search strategy used to perform the literature search .
Click here for file Additional file 2 List of excluded articles .
Click here for file Additional file 3 Meta-analyses performed with different variance estimators to generate pooled relative risks for the IADSPG and WHOterm criteria for gestational diabetes in the prediction of pregnancy outcomes .
Click here for file Acknowledgements Financial support was received from the World Health Organization (Registration 2010/119177-0, APW 200308151).
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