Scandinavian Journal of Clinical & Laboratory Investigation, 2014; 74(Suppl 244): 27–33
ORIGINAL ARTICLE
Diagnosis of gestational diabetes
DONALD R. COUSTAN
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI, USA Abstract Previous approaches to diagnosing gestational diabetes mellitus (GDM) have included 50 g, 75 g and 100 g glucose challenges, lasting 1–3 hours, with 1 or 2 elevations required. Thresholds were validated by their predictive value for subsequent diabetes, or were the same thresholds used in non-pregnant individuals. None were based on their prediction of adverse pregnancy outcomes. Diagnostic paradigms vary throughout the world, making comparisons impossible and severely limiting communication among investigators. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study collected outcome data on ⬎ 23,000 pregnancies recruited prospectively in nine countries after a blinded 75 g, 2-hour oral glucose tolerance test (OGTT) at 24–28 weeks gestation. Primary outcomes (LGA, PCS, neonatal hypoglycemia, high cord C-peptide), and most secondary outcomes (e.g. preeclampsia, preterm birth, shoulder dystocia and birth injury), were significantly, directly and continuously related to each of the three plasma glucose measurements. The International Association of Diabetes in Pregnancy Study Groups (IADPSG) developed recommendations for the use of a 75 g, 2-h OGTT, ⱖ 1 elevation diagnosing GDM, with thresholds: fasting plasma glucose ⱖ 5.1 mmol/L (92 mg/dL) , 1 h ⱖ 10 mmol/L (180 mg/dL) and 2 h ⱖ 8.5 mmol/L (153 mg/dL). These have generated wide discussion and are currently being considered throughout the world. They are pregnancy outcome-based; the 75 g glucose load will bring consistency to GTTs; universal adoption will lead to consistency of diagnostic criteria worldwide; studies of treatment at similarly mild levels of glycemia have demonstrated improvement in outcomes; use of a single abnormal value will obviate the confusion arising when one elevated value is encountered. The primary argument against the recommendations is that prevalence of GDM will rise to 16–18 %, increasing health care costs. Balanced against this is the world-wide epidemic of obesity, prediabetes and diabetes. Key Words: Oral glucose tolerance test, glucose challenge test, gestational diabetes mellitus, pregnancy, glucose, macrosomia, preeclampsia
Introduction There is no international agreement regarding diagnostic paradigms and criteria for gestational diabetes mellitus (GDM). The most commonly used paradigm in the United States [1], promulgated by the American College of Obstetricians and Gynecologists (ACOG), is a two-step process of screening with a 50 g, 1 h plasma glucose challenge test (GCT) followed by the diagnostic test, a 100 g, 3 h oral glucose tolerance test (OGTT) for those gravidas whose GCT meets or exceeds a cutoff, such as 7.2 mmol/L (130 mg/dL), 7.5 mmol/L (135 mg/dL) or 7.8 mmol/L (140 mg/dL). There are 2 sets of 100-g OGTT thresholds currently in use in the US. Both are based on the original studies of O’Sullivan and Mahan [2] in which 100-g, 3-h OGTTs were administered to 752 gravidas in the second and third trimesters and whole blood glucose determinations using the Somogyi-Nelson
method of glucose concentration measurement were evaluated as predictors of subsequent diabetes in the mothers. Two or more OGTT values exceeding 2 standard deviations above the mean (Table I) identified women whose risk of diabetes in the ensuing 20 years was approximately 50 % [3]. The requirement for two elevated values was based upon the desire to avoid misclassification due to laboratory error or the occasional individual with a single high glucose peak due to rapid absorption [2]. In subsequent years most laboratories switched from venous whole blood glucose measurements to venous plasma; in 1979 the National Diabetes Data Group (NDDG) recommended conversion of the O’Sullivan thresholds by approximately 15 % (Table I), to account for the higher levels of measured glucose in plasma than in whole blood [4]. Subsequently Carpenter and Coustan (C&C) further refined the conversion (Table I) to account for
Correspondence: Donald R. Coustan, MD, Attending Maternal-Fetal Medicine Specialist, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. E-mail: [email protected] ISSN 0036-5513 print/ISSN 1502-7686 online © 2014 Informa Healthcare DOI: 10.3109/00365513.2014.936677
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
28
D. R. Coustan
the more specific enzymatic methods of glucose measurements in addition to the use of plasma samples [5]. The above two conversions of the O’Sullivan and Mahan criteria are currently in use throughout the US. In much of the rest of the world the diagnostic test for GDM consists of a 75 g, 2-h OGTT. Until recently, the World Health Organization (WHO) promulgated one set of widely used diagnostic criteria which were basically the same as those used to diagnose diabetes and impaired glucose tolerance in non-pregnant individuals [6]. Other diagnostic criteria included those of the Canadian Diabetes Association [7] and the Australasian Diabetes in Pregnancy Society [8].
Why the need for new diagnostic criteria? In 1991 the Third International Workshop-Conference on Gestational Diabetes noted that there was no international agreement on diagnostic testing for GDM, with 50, 75 and 100 g glucose loads utilized in various parts of the world, with various sets of diagnostic criteria even with a particular glucose challenge [9]. Furthermore, the O’Sullivan criteria were validated by their predictive value for subsequent diabetes in the mother, while the WHO criteria were not developed for pregnant women, but rather were the same criteria as for non-pregnant individuals. None of the existing criteria were based upon pregnancy outcomes, despite the fact that this was the primary reason for testing pregnant women for GDM. It was expected that the 75-g, 2-h OGTT eventually would be universally employed, since this was already the case for diagnosing diabetes outside of pregnancy. The report concluded that internationally agreed upon, outcome-based criteria for GDM using the 75-g 2-h OGTT were highly desirable. Without agreement on such criteria, it is impossible to compare the prevalence of GDM across countries, and to assess the benefits or harms of identification and treatment. Seven years later the Fourth International Workshop-Conference on Gestational Diabetes [10] noted that little progress had been made, and stated, ‘…there remains a compelling need to develop diagnostic criteria…based on the specific relationships between hyperglycemia and the risk of adverse outcome.’ The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was developed in response to that need.
The HAPO study The HAPO study [11] was designed to determine what level of glucose intolerance during pregnancy, short of diabetes, is associated with increased risk of adverse outcome. It was a prospective observational study in which pregnant women in 15 field centers
Table I. Various thresholds for diagnosing gestational diabetes with 100 g, 3-h OGTT. Two or more elevated values are needed for diagnosis (mmol/L [mg/dL]). Test interval Fasting 1h 2h 3h
O’Sullivan [2]a mmol/L 5.0 9.2 8.0 7.0
(90) (165) (145) (125)
National Diabetes Data Group [4]b 5.8 10.6 9.2 8.0
(105) (190) (165) (145)
Carpenter & Coustan [5]c 5.3 (95) 10.0 (180) 8.6 (155) 7.8 (140)
aVenous whole blood, Somogyi-Nelson technique, rounded to nearest 5 mg/dL. bCorrected for conversion from whole blood to plasma, based on rounded O’Sullivan values. cCorrected for conversion of whole blood to plasma and SomogyiNelson to enzymatic glucose concentration measurement, and based on original unrounded O’Sullivan values.
in nine different countries throughout the world were recruited between 2000 and 2006, underwent a blinded 75 g, 2-h OGTT at a mean of 28 weeks gestation (range 24–32 weeks), and delivered at the field center so that data regarding maternal and neonatal outcomes could be collected. Over 23,000 women completed the study. Primary outcomes included large babies (birth weight above the 90th percentile), primary cesarean section, fetal hyperinsulinemia (cord C-peptide above the 90th percentile), and clinically diagnosed neonatal hypoglycemia. Figure 1 demonstrates that each of the three OGTT values was significantly and linearly related to each of the four primary outcomes; there were no evident inflection points in any of these relationships. The relationships held even when adjusted for various confounders such as fetal/neonatal gender, maternal BMI, field center, ethnicity, and gestational age at the time of the OGTT. Similar relationships were present for pre-specified secondary outcomes such as preeclampsia, birth trauma/shoulder dystocia and premature delivery. Again, there were no obvious inflection points, and it was clear that outcome-based diagnostic criteria for gestational diabetes would of necessity be arbitrarily selected.
IADPSG recommendations In 2008, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) convened a meeting of over 220 delegates representing professional groups in 40 different countries to consider data from the HAPO study as well as other published data. A consensus panel of approximately 50 delegates met afterwards and organized a writing group who worked diligently over the following year to draft recommendations that were then considered at a second meeting in 2009. Thresholds were selected which identified pregnancies in which the risks of various adverse outcomes were increased with an odds ratio of 1.75, compared to mean glucose concentrations.
Diagnosis of gestational diabetes Birth Weight >90th Percentile
29
Primary C-Section
30
25
30
20
25
Frequency (%)
Frequency (%)
35
15
10
20 15
5
5 0
0 1
2
3
4
5
6
1
7
2
3
4
5
7
6
Glucose Category
Glucose Category Clinical Neonatal Hypoglycemia
Cord C-Peptide >90th Percentile
5.0
35
4.5 30
4.0
25
Frequency (%)
3.5
Frequency (%)
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
10
3.0 2.5 2.0 1.5
20 15 10
1.0
5
0.5 0
0.0 1
2
3
4
5
6
1
7
2
3
4
5
6
7
Glucose Category
Glucose Category Fasting
One hour
Two hour
Figure 1. Associations between each of the three OGTT values and each of the four primary outcomes in the HAPO study. From HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:1991–2002. Copyright ©2008 Massachusetts Medical Society. Reprinted with permission.
The resulting recommendations were published in Diabetes Care in March of 2010 [12]. Salient features of the recommendations include: •
•
Early pregnancy diagnostic testing of either all pregnant women, or only those with risk factors, to detect pre-existing diabetes with a fasting plasma glucose ⱖ 7.0 mmol/L (126 mg/dL), HbA1c ⱖ 6.5 % or random plasma glucose ⱖ 11.1 mmol/L (200 mg/dL), with the latter test requiring confirmation by either of the first two. A one-step approach to testing for GDM in which the diagnostic test, a 75-g, 2-h OGTT,
is administered at 24–28 weeks gestation to all gravidas who have not been previously diagnosed with diabetes. Gestational diabetes is diagnosed if one or more of the following thresholds is met or exceeded: 䊊 䊊 䊊
Fasting: ⬎ 5.1 mmol/L (92 mg/dL) 1 h post 75 g: ⬎ 10.0 mmol/L (180 mg/dL) 2 h post 75 g: ⬎ 8.5 mmol/L (153 mg/dL)
These new criteria are the only diagnostic thresholds based upon pregnancy outcomes rather than either their prediction of subsequent maternal diabetes or the values used to diagnose diabetes in
30
D. R. Coustan
Table II. Rates (%) of adverse outcomes in HAPO subjects without and with GDM by IADPSG criteria [12] and untreated and treated mild GDMs in MFMU network randomized trial [21]. Normal 75 g, 2 h OGTT [12] LGA (birth weight ⬎ 90th percentile Fetal hyperinsulinemia (cord C-peptide ⬎ 90th percentile) Neonatal adiposity (percent body fat ⬎ 90th percentile) Preeclampsia Shoulder dystocia/birth injury
8.3 6.7 8.5 4.5 1.3
GDM (IADPSG proposed criteria)a 16.2 17.5 16.6 9.1 1.8
Untreated mild GDMs [21]b
Treated mild GDMs [21]
14.5 22.8 NAc 5.5 4.0
7.1 17.7 NAc 2.5 1.5
differences significant at p ⬍ 0.01 or better. differences significant at p ⬍ 0.02 or better. cPercent body fat not reported, but neonatal fat mass significantly lower in offspring of treated mothers. aAll
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
bAll
non-pregnant individuals. They utilize the same 75 g 2 h OGTT protocol as is universally accepted for testing outside of pregnancy. The one-step approach with a single abnormal value needed for diagnosing GDM simplifies the process, and also eliminates the confusing issue of management of patients with a single elevated 100 g, 3 h OGTT value where two elevations are necessary. It should be noted that, when compared to all subjects in the HAPO study who did not have GDM under the recommended diagnostic criteria (rather than to those whose glucose values were at the means), GDMs had a doubling or more for most of the adverse outcomes (Table II).
Why not use the IADPSG recommendations? There has been considerable resistance to the universal adoption of the IADPSG recommendations [13,14]. In 2013 the United States National Institutes of Health convened a Consensus Conference to consider all aspects of screening and diagnosis of gestational diabetes [15]. A panel of individuals from various health professions and fields, assumed to be unbiased because none had published in the area of gestational diabetes, was convened. Experts presented reviews regarding pros and cons of the new and the existing recommendations, potential ramifications, and systematic analyses of existing data by the Agency for Healthcare Research and Quality (AHRQ). A draft recommendation was published on the web, and after public comments were considered, the final document was published [15]. The panel’s recommendation was that, while a standardized, universal approach would be desirable, the two-step approach currently widely used in the United States (a 50 g, 1 h GCT followed by a 100 g, 3 h OGTT with 2 or more elevated values diagnosing gestational diabetes) should be continued because there is not yet sufficient evidence to adopt the one-step approach recommended by IADPSG. The rationale for this recommendation included the following: (1) Adoption of the one-step approach would increase the prevalence of GDM to 15–20 %.
The care of these additional women will increase health care costs. (2) While the additional women who would be diagnosed with GDM under the one-step process are at increased risk for various adverse outcomes, it is not clear that they would benefit from identification and treatment. (3) Identification of these additional women as having GDM may increase patient anxiety, and may also increase ‘obstetrical harms’ such as induction of labor, intensive maternal/fetal monitoring, and cesarean section. (4) Because of the variability in the 2-h OGTT, the one-step approach is likely to generate more ‘false positive’ results than a two-step test. (5) Having to fast for the diagnostic test, and waiting 2 hours instead of the 1-hour interval for the screening test, poses an additional burden for patients. While each of these is a valid concern, it is worth considering the counter-arguments. Increased prevalence of GDM will lead to increased health care costs This should be viewed in the context of the current epidemic of obesity and diabetes throughout the world. For example, in 2007–2010, 11.9 % of adult Americans have diagnosed or undiagnosed diabetes [16]. An additional 36 % of all adult Americans, and 26 % of those between the ages of 18 and 44 years, have prediabetes [17]. GDM as defined by the IADPSG recommendations is somewhat akin to prediabetes. Thus an 18 % prevalence of GDM would be considerably lower than the current prevalence of diabetes and prediabetes in our population. Despite the fact that increasing the thresholds for diagnosing diabetes and prediabetes in nonpregnant individuals would lower the prevalence and decrease short-term health care costs, no one advocates that solution. Rather, our various health care systems work to develop improved methods to provide efficient and effective care to those afflicted with diabetes, and to prevent the eventual development of diabetes in those with prediabetes. As the
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Diagnosis of gestational diabetes prevalence of gestational diabetes increases markedly, as is already the case using the current twostep approach [18], it will be important to develop novel approaches to counseling and care. It is likely that patients with milder gestational diabetes may not require daily self-glucose monitoring, and could test every other day or even less frequently [19]. Group prenatal visits and counseling may be a reasonable way to lower costs and improve quality of care. It is an open question whether the risk of stillbirth with milder GDM is high enough to require antenatal testing with the same intensity as for more severe GDM and for pre-existing diabetes. It is worth noting that diet treatment was successful in attaining good glucose control in 80–92 % of mild GDMs in randomized trials [20,21] suggesting that expanding the prevalence of GDM will not lead to large numbers of patients requiring insulin or oral agents. A recent study compared the cost-effectiveness of universal diagnostic testing with the IADPSG one-step approach and screening with the current ACOG two-step approach [22]. The investigators took into account available data regarding benefits of treatment in preventing preeclampsia and other adverse outcomes for mild gestational diabetes. The compilation of the costs of treatment of GDM did not assume less intensive monitoring or intervention for the milder GDMs, a potential cost-saving opportunity discussed above. The IADPSG one-step approach was more expensive than the two-step approach but was more cost effective in improving maternal and neonatal outcomes. Although the IADPSG recommendations were based on the likelihood of adverse pregnancy outcomes, women who meet these GDM criteria are presumably also at increased risk for the development of type 2 diabetes. Diagnosing GDM constitutes a ‘teachable moment,’ an opportunity to counsel patients about the likelihood of subsequent diabetes, ways of reducing that risk, and the importance of testing after pregnancy and at intervals thereafter to detect diabetes in its early stages. Another recent study [23] compared the cost-effectiveness of the one-step versus two-step approaches and reported that the IADPSG one-step approach was cost-effective if post-delivery care reduces the incidence of subsequent diabetes in the mother. This finding underscores the importance of caregivers using the occasion of the diagnosis of GDM to counsel patients about the risk of diabetes in the future, and arranging follow-up testing and care for former GDMs. In an analysis of the subgroup of 350 subjects in the Diabetes Prevention Program who had previous GDM and prediabetes at enrollment, the annual incidence of type 2 diabetes of 15 % was cut in half by either metformin treatment or intensive lifestyle intervention [24]. The number needed to treat to prevent one case of diabetes over
31
3 years was six for metformin and five for intensive lifestyle intervention. Uncertainties regarding benefits of identifying and treating so many additional GDMs There are no randomized trials of identification and treatment of GDM using the new IADPSG diagnostic thresholds. However, there are two published randomized trials using other criteria for mild gestational diabetes, in which many of the subjects would have overlapped with the new criteria. The Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Network (MFMU) trial [21] enrolled 958 gravidas whose blinded OGTT (administered after a 50 g 1 h GCT was 7.5–11.1 mmol/L [135–200 mg/dL]) demonstrated two elevated values (Carpenter & Coustan criteria) but whose fasting plasma glucose was ⬍ 5.3 mmol/L (95 mg/dL). Although the glucose challenge was 100 g rather than 75 g, the fasting, 1 and 2 h mean values of the subjects were within one standard deviation of the IADPSG cutoffs for fasting, 1 h and 2 h time periods. Participants were randomized to identification and treatment of GDM versus usual care, with caregivers blinded to the OGTT results in the latter group. Identification and treatment of GDM reduced the likelihood of large for gestational age (⬎ 90th percentile) and macrosomic (⬎ 4 kg) babies by more than half. Cesarean section, shoulder dystocia and preeclampsia were also significantly lower. Rates of these various adverse outcomes in the untreated group were similar to the rates in HAPO study participants who would have GDM under the new criteria (Table II), and who also were neither identified nor treated as GDMs in this observational study. Identification and treatment of GDM in the MFMU trial reduced these rates considerably. The other randomized trial of identification and treatment of GDM [20] recruited patients whose elevated 75 g, 2-h OGTT results were based on thresholds lower than those of the IADPSG recommendations. Gravidas whose 2 h, 75-g OGTT values were 7.8–11.1 mmol/L (140–199 mg/dL) made up the study cohort, as long as their fasting plasma glucose was ⬍ 7.8 mmol/L (⬍ 140 mg/dL). The mean fasting plasma glucose in subjects was 4.8 mmol/L (86 mg/dL). Recall that the IADPSG recommended 2-h cutoff for GDM was 8.5 mmol/L (153 mg/dL). Using a similar study design to the MFMU Network study described above, the investigators found very similar reductions in adverse outcomes with identification and treatment of GDM. While neither of the above two RCTs used the identical GDM criteria as IADPSG, and both used a two-step approach to identifying potential subjects, the results demonstrate a benefit to identifying and treating GDM which was mild, with thresholds overlapping those of the IADPSG.
32
D. R. Coustan
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Fasting and waiting 2 hours for the test is an additional burden With the 2-step process, for patients whose 50 g, 1-h GCT is below the threshold for further testing, there is no question that having the test without regard to the last meal, and waiting 1 hour for the blood draw, is preferable to fasting and waiting 2 hours for test completion when the one-step process is followed. However, patients whose screening test exceeds the threshold must come on a subsequent occasion, fasting, for the diagnostic OGTT and wait 3 hours for completion. Depending upon the threshold chosen for the screening portion of the two-step process, and the racial/ethnic characteristics of the population, between 9 and 30 % require the additional OGTT [25]. For those patients the burden of two separate visits, one of which is in the fasting state, and a total of 4 hours’ time with five blood draws, compares quite unfavorably with a single visit (fasting), 2 hours’ time, and three blood draws. The 2-h OGTT is unstable and the 1-step test is likely to increase false positives There is no doubt that glucose tolerance tests are unstable, with less than optimal precision. However, the one-step test is a diagnostic test, and not a screening test, so false positives are not a consideration. If the consensus panel used the term ‘false positive’ to mean individuals who are diagnosed with GDM who do not have adverse outcomes, then it is implied that the diagnosis of GDM is a screening test with the ‘disease’ being the adverse perinatal outcomes. In that case, both the one-step and the two-step process will have many ‘false positives’ not to mention ‘false negatives’ pregnancies in which adverse outcomes occur in the absence of GDM. However, identifying and treating GDM has never been considered as a way to prevent all big babies, or all cases of preeclampsia. Rather, GDM offers the opportunity to prevent adverse outcomes in a particularly high-risk group of patients. Finally, it must be pointed out that instability of the 75 g, 2-h OGTT is not limited to pregnant women. This test is the world-wide standard for diagnosing diabetes in nonpregnant individuals, despite its instability.
Current status The IADPSG recommendations were published in 2010. In 2011 the American Diabetes Association (ADA) adopted these recommendations with a few minor changes [26], although in 2014 ADA altered its recommendations [27], such that either the onestep or the two-step protocol was acceptable, based on the NIH Consensus Panel’s 2013 recommendations. ACOG continues to support the two-step approach [1]. In 2013 the World Health Organization
adopted the recommendation for the one-step IADPSG approach [28]. At the time of this writing professional organizations throughout the world are considering whether to adopt some variation of the IADPSG one-step approach, or to continue with the various other approaches currently in use. As more research is carried out with the IADPSG approach, the situation is likely to be clarified, although this will probably take considerable time. It is to be hoped that eventually there will be a single, uniform approach to identifying GDM in use throughout the world. Questions and answers Q (Young): Which recommendations are being used in the USA? A (Coustan): In the USA we are waiting for the ACOG recommendations for gestational diabetes. Q (O’Shea): Regarding screening for gestational diabetes, you have spoken of the disparity between the USA and Europe, but we have disparity in approach in Ireland. There are several issues: (1) One problem is economic because, to have fasting, 1-hour and 2-hour specimens collected, the patients have to stay for a long period in the clinic which can be difficult for them. Could we do just the 1-hour specimen, since the 2-hour value picks up only an additional 2 % of cases? (2) Could we do fasting glucose and HBA1c picking up at least 20 % of cases then screen the others fully? (3) Should there be universal screening or targeting of those at high risk? A (Coustan): A single, fasting measurement is ideal for convenience but also a 1 hour, or fasting and 1-hour or 2-hour post glucose load, all contribute independently to adverse outcomes and for this reason, all three are recommended. However, in different centers there are different attitudes. Regarding HbA1c, it is very useful in early pregnancy in pre-existing diabetes. It’s not very sensitive for gestational diabetes. Economic problems are a big issue in every country but the solution is not to ignore the problem and strive for cheaper solutions. Q (Kallner): When we make these recommendations we work with population means and medians but when we move to the real world we have to judge results from an individual patient: When you say 5.1 mmol/L as cut off for fasting glucose, that translates into an individual result with an uncertainty. If you look at the German recommendation they allow an uncertainty of 11 % (95 % level) for glucose measurements. This means ⫾ 1 mmol/L, i.e. an uncertainty interval of 4.1–6.1 (k ⫽ 2) mmol/L. In a recent study we found an uncertainty of ⫾ 3 % or 4.9–5.3 mmol/L (k ⫽ 2). The cut-off is not as distinct as you
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Diagnosis of gestational diabetes assume and decisions need to take the uncertainty into account. A (Coustan): In the laboratory this is a problem not only for glucose. What is the alternative to cutoff? It depends on a good quality control in the laboratory. There is concern in the real world on the real value of the quality control. Whether the CV is 1 % or 5 %, there has to be a cut off somewhere. Q (Kallner): As an alternative we may incorporate the uncertainty depending on what you want, to increase sensitivity or specificity. A (Coustan): That is true for screening but not for diagnosis. Q (Kallner): It could be applied also to diagnosis. Do we know if the cut-off has been set to optimize rule-in or rule-out? Comment (Young): The test is defining the disease so it is difficult to speak about the sensitivity and specificity of the test. Comment (Lazzarotto): A screening test needs very high sensitivity, and consequently the specificity could be lower. Comment (Coustan): I do not agree because I would like 100 % for both sensitivity and specificity. Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
References [1] American College of Obstetricians and Gynecologists Practice Bulletin #137. Gestational diabetes mellitus. Obstet Gynecol 2013;122:406–16. [2] O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964;13:278–85. [3] O’Sullivan JB. Subsequent morbidity among gestational diabetic women. In Sutherland HW, Stowers JM (eds), Carbohydrate metabolism in pregnancy and the newborn. New York: Churchill Livingstone, 1984. pp. 174–80. [4] National Diabetes Data group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039–57. [5] Carpenter MW, Coustan DR. Criteria for screening tests of gestational diabetes. Am J Obstet Gynecol 1982;144: 768–73. [6] World Health Organization website: About Diabetes. Accessed 5 February 2014 from: http://www.who.int/diabetes/ action_online/basics/en/index1.html [7] Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008: clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32: S1–201. [8] Templeton M, Pieris-Caldwell I. Gestational diabetes mellitus in Australia, 2005–2006. Australian Institute of Health and Welfare. 2008. Accessed 5 February 2014 from: http:// www.aihw.gov.au/publication-detail/?id ⫽ 6442468189 [9] Metzger BE and the Organizing Committee. Summary and recommendations of the Third International WorkshopConference on Gestational Diabetes Mellitus. Diabetes 1991; 40(Suppl. 2):197–201.
33
[10] Metzger BE, Coustan DR and The Organizing Committee. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(Suppl. 2):B161–7. [11] The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002. [12] Metzger BE, Gabbe SG, Persson B, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3):676–82. [13] Cundy T. Proposed new diagnostic criteria for gestational diabetes – a pause for thought? Diabet Med 2012;29: 176–80. [14] Ryan EA. Diagnostic criteria for gestational diabetes: who decides? Can Med Ass J 2012;184:1341–2. [15] National Institutes of Health Consensus Development Conference Panel. National Institutes of Health consensus development conference statement: diagnosing gestational diabetes mellitus, March 4–6, 2013. Obstet Gynecol 2013; 122:358–69. [16] Table 45. Accessed 17 April 2014 from: http://www.cdc.gov/ nchs/data/hus/hus12.pdf#0545 [17] Bullard KM, Saydah SH, Imperatore G, et al. Secular changes in US prediabetes prevalence defined by Hb A1c and fasting plasma glucose. Diabetes Care 2013;36: 2286–93. [18] Bardenheier BH, Elixhauser A, Imperatore G, et al. Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care 2013;36:1209–14. [19] Mendez-Figueroa H, Daley J, Lopes VV, et al. Comparing daily versus less frequent blood glucose monitoring in patients with mild gestational diabetes. J Maternal Fetal Neonatal Med 2013;26:1268–72. [20] Crowther CA, Hiller JE, Moss JR, et al. for the Australian Carbohydrate Intolerance Study of Pregnant Women (ACHOIS) Study Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. [21] Landon MB, Spong CY, Thom E, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:1339–48. [22] Mission JF, Ohno MS, Cheng YW, Caughey AB. Gestational diabetes screening with the new IADPSG guidelines: a costeffectiveness analysis. Am J Obstet Gynecol 2012;207: 326.e1–9. [23] Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the International Association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012; 35:529–35. [24] Ratner RE, Christophi CA, Metzger BE, et al. Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of GDM: effects of metformin and lifestyle interventions. J Clin Endo Metab 2008; 93:4774–9. [25] Esakoff TF, Cheng YW, Caughey AB. Screening for gestational diabetes: different cut-offs for different ethnicities? Am J Obstet Gynecol 2005;193:1040–4. [26] American Diabetes Association. Standards of Care 2011. Diabetes Care 2011;34(Suppl. 1):s15. [27] American Diabetes Association. Standards of Care 2014. Diabetes Care 2014;37(Suppl. 1): s18–20. [28] World Health Organization. Accessed 5 February 2014 from: http://www.who.int/diabetes/publications/Hyperglycaemia_ In_Pregnancy/en/
ORIGINAL ARTICLE
Diagnosis of gestational diabetes
DONALD R. COUSTAN
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI, USA Abstract Previous approaches to diagnosing gestational diabetes mellitus (GDM) have included 50 g, 75 g and 100 g glucose challenges, lasting 1–3 hours, with 1 or 2 elevations required. Thresholds were validated by their predictive value for subsequent diabetes, or were the same thresholds used in non-pregnant individuals. None were based on their prediction of adverse pregnancy outcomes. Diagnostic paradigms vary throughout the world, making comparisons impossible and severely limiting communication among investigators. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study collected outcome data on ⬎ 23,000 pregnancies recruited prospectively in nine countries after a blinded 75 g, 2-hour oral glucose tolerance test (OGTT) at 24–28 weeks gestation. Primary outcomes (LGA, PCS, neonatal hypoglycemia, high cord C-peptide), and most secondary outcomes (e.g. preeclampsia, preterm birth, shoulder dystocia and birth injury), were significantly, directly and continuously related to each of the three plasma glucose measurements. The International Association of Diabetes in Pregnancy Study Groups (IADPSG) developed recommendations for the use of a 75 g, 2-h OGTT, ⱖ 1 elevation diagnosing GDM, with thresholds: fasting plasma glucose ⱖ 5.1 mmol/L (92 mg/dL) , 1 h ⱖ 10 mmol/L (180 mg/dL) and 2 h ⱖ 8.5 mmol/L (153 mg/dL). These have generated wide discussion and are currently being considered throughout the world. They are pregnancy outcome-based; the 75 g glucose load will bring consistency to GTTs; universal adoption will lead to consistency of diagnostic criteria worldwide; studies of treatment at similarly mild levels of glycemia have demonstrated improvement in outcomes; use of a single abnormal value will obviate the confusion arising when one elevated value is encountered. The primary argument against the recommendations is that prevalence of GDM will rise to 16–18 %, increasing health care costs. Balanced against this is the world-wide epidemic of obesity, prediabetes and diabetes. Key Words: Oral glucose tolerance test, glucose challenge test, gestational diabetes mellitus, pregnancy, glucose, macrosomia, preeclampsia
Introduction There is no international agreement regarding diagnostic paradigms and criteria for gestational diabetes mellitus (GDM). The most commonly used paradigm in the United States [1], promulgated by the American College of Obstetricians and Gynecologists (ACOG), is a two-step process of screening with a 50 g, 1 h plasma glucose challenge test (GCT) followed by the diagnostic test, a 100 g, 3 h oral glucose tolerance test (OGTT) for those gravidas whose GCT meets or exceeds a cutoff, such as 7.2 mmol/L (130 mg/dL), 7.5 mmol/L (135 mg/dL) or 7.8 mmol/L (140 mg/dL). There are 2 sets of 100-g OGTT thresholds currently in use in the US. Both are based on the original studies of O’Sullivan and Mahan [2] in which 100-g, 3-h OGTTs were administered to 752 gravidas in the second and third trimesters and whole blood glucose determinations using the Somogyi-Nelson
method of glucose concentration measurement were evaluated as predictors of subsequent diabetes in the mothers. Two or more OGTT values exceeding 2 standard deviations above the mean (Table I) identified women whose risk of diabetes in the ensuing 20 years was approximately 50 % [3]. The requirement for two elevated values was based upon the desire to avoid misclassification due to laboratory error or the occasional individual with a single high glucose peak due to rapid absorption [2]. In subsequent years most laboratories switched from venous whole blood glucose measurements to venous plasma; in 1979 the National Diabetes Data Group (NDDG) recommended conversion of the O’Sullivan thresholds by approximately 15 % (Table I), to account for the higher levels of measured glucose in plasma than in whole blood [4]. Subsequently Carpenter and Coustan (C&C) further refined the conversion (Table I) to account for
Correspondence: Donald R. Coustan, MD, Attending Maternal-Fetal Medicine Specialist, Women & Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. E-mail: [email protected] ISSN 0036-5513 print/ISSN 1502-7686 online © 2014 Informa Healthcare DOI: 10.3109/00365513.2014.936677
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
28
D. R. Coustan
the more specific enzymatic methods of glucose measurements in addition to the use of plasma samples [5]. The above two conversions of the O’Sullivan and Mahan criteria are currently in use throughout the US. In much of the rest of the world the diagnostic test for GDM consists of a 75 g, 2-h OGTT. Until recently, the World Health Organization (WHO) promulgated one set of widely used diagnostic criteria which were basically the same as those used to diagnose diabetes and impaired glucose tolerance in non-pregnant individuals [6]. Other diagnostic criteria included those of the Canadian Diabetes Association [7] and the Australasian Diabetes in Pregnancy Society [8].
Why the need for new diagnostic criteria? In 1991 the Third International Workshop-Conference on Gestational Diabetes noted that there was no international agreement on diagnostic testing for GDM, with 50, 75 and 100 g glucose loads utilized in various parts of the world, with various sets of diagnostic criteria even with a particular glucose challenge [9]. Furthermore, the O’Sullivan criteria were validated by their predictive value for subsequent diabetes in the mother, while the WHO criteria were not developed for pregnant women, but rather were the same criteria as for non-pregnant individuals. None of the existing criteria were based upon pregnancy outcomes, despite the fact that this was the primary reason for testing pregnant women for GDM. It was expected that the 75-g, 2-h OGTT eventually would be universally employed, since this was already the case for diagnosing diabetes outside of pregnancy. The report concluded that internationally agreed upon, outcome-based criteria for GDM using the 75-g 2-h OGTT were highly desirable. Without agreement on such criteria, it is impossible to compare the prevalence of GDM across countries, and to assess the benefits or harms of identification and treatment. Seven years later the Fourth International Workshop-Conference on Gestational Diabetes [10] noted that little progress had been made, and stated, ‘…there remains a compelling need to develop diagnostic criteria…based on the specific relationships between hyperglycemia and the risk of adverse outcome.’ The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was developed in response to that need.
The HAPO study The HAPO study [11] was designed to determine what level of glucose intolerance during pregnancy, short of diabetes, is associated with increased risk of adverse outcome. It was a prospective observational study in which pregnant women in 15 field centers
Table I. Various thresholds for diagnosing gestational diabetes with 100 g, 3-h OGTT. Two or more elevated values are needed for diagnosis (mmol/L [mg/dL]). Test interval Fasting 1h 2h 3h
O’Sullivan [2]a mmol/L 5.0 9.2 8.0 7.0
(90) (165) (145) (125)
National Diabetes Data Group [4]b 5.8 10.6 9.2 8.0
(105) (190) (165) (145)
Carpenter & Coustan [5]c 5.3 (95) 10.0 (180) 8.6 (155) 7.8 (140)
aVenous whole blood, Somogyi-Nelson technique, rounded to nearest 5 mg/dL. bCorrected for conversion from whole blood to plasma, based on rounded O’Sullivan values. cCorrected for conversion of whole blood to plasma and SomogyiNelson to enzymatic glucose concentration measurement, and based on original unrounded O’Sullivan values.
in nine different countries throughout the world were recruited between 2000 and 2006, underwent a blinded 75 g, 2-h OGTT at a mean of 28 weeks gestation (range 24–32 weeks), and delivered at the field center so that data regarding maternal and neonatal outcomes could be collected. Over 23,000 women completed the study. Primary outcomes included large babies (birth weight above the 90th percentile), primary cesarean section, fetal hyperinsulinemia (cord C-peptide above the 90th percentile), and clinically diagnosed neonatal hypoglycemia. Figure 1 demonstrates that each of the three OGTT values was significantly and linearly related to each of the four primary outcomes; there were no evident inflection points in any of these relationships. The relationships held even when adjusted for various confounders such as fetal/neonatal gender, maternal BMI, field center, ethnicity, and gestational age at the time of the OGTT. Similar relationships were present for pre-specified secondary outcomes such as preeclampsia, birth trauma/shoulder dystocia and premature delivery. Again, there were no obvious inflection points, and it was clear that outcome-based diagnostic criteria for gestational diabetes would of necessity be arbitrarily selected.
IADPSG recommendations In 2008, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) convened a meeting of over 220 delegates representing professional groups in 40 different countries to consider data from the HAPO study as well as other published data. A consensus panel of approximately 50 delegates met afterwards and organized a writing group who worked diligently over the following year to draft recommendations that were then considered at a second meeting in 2009. Thresholds were selected which identified pregnancies in which the risks of various adverse outcomes were increased with an odds ratio of 1.75, compared to mean glucose concentrations.
Diagnosis of gestational diabetes Birth Weight >90th Percentile
29
Primary C-Section
30
25
30
20
25
Frequency (%)
Frequency (%)
35
15
10
20 15
5
5 0
0 1
2
3
4
5
6
1
7
2
3
4
5
7
6
Glucose Category
Glucose Category Clinical Neonatal Hypoglycemia
Cord C-Peptide >90th Percentile
5.0
35
4.5 30
4.0
25
Frequency (%)
3.5
Frequency (%)
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
10
3.0 2.5 2.0 1.5
20 15 10
1.0
5
0.5 0
0.0 1
2
3
4
5
6
1
7
2
3
4
5
6
7
Glucose Category
Glucose Category Fasting
One hour
Two hour
Figure 1. Associations between each of the three OGTT values and each of the four primary outcomes in the HAPO study. From HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:1991–2002. Copyright ©2008 Massachusetts Medical Society. Reprinted with permission.
The resulting recommendations were published in Diabetes Care in March of 2010 [12]. Salient features of the recommendations include: •
•
Early pregnancy diagnostic testing of either all pregnant women, or only those with risk factors, to detect pre-existing diabetes with a fasting plasma glucose ⱖ 7.0 mmol/L (126 mg/dL), HbA1c ⱖ 6.5 % or random plasma glucose ⱖ 11.1 mmol/L (200 mg/dL), with the latter test requiring confirmation by either of the first two. A one-step approach to testing for GDM in which the diagnostic test, a 75-g, 2-h OGTT,
is administered at 24–28 weeks gestation to all gravidas who have not been previously diagnosed with diabetes. Gestational diabetes is diagnosed if one or more of the following thresholds is met or exceeded: 䊊 䊊 䊊
Fasting: ⬎ 5.1 mmol/L (92 mg/dL) 1 h post 75 g: ⬎ 10.0 mmol/L (180 mg/dL) 2 h post 75 g: ⬎ 8.5 mmol/L (153 mg/dL)
These new criteria are the only diagnostic thresholds based upon pregnancy outcomes rather than either their prediction of subsequent maternal diabetes or the values used to diagnose diabetes in
30
D. R. Coustan
Table II. Rates (%) of adverse outcomes in HAPO subjects without and with GDM by IADPSG criteria [12] and untreated and treated mild GDMs in MFMU network randomized trial [21]. Normal 75 g, 2 h OGTT [12] LGA (birth weight ⬎ 90th percentile Fetal hyperinsulinemia (cord C-peptide ⬎ 90th percentile) Neonatal adiposity (percent body fat ⬎ 90th percentile) Preeclampsia Shoulder dystocia/birth injury
8.3 6.7 8.5 4.5 1.3
GDM (IADPSG proposed criteria)a 16.2 17.5 16.6 9.1 1.8
Untreated mild GDMs [21]b
Treated mild GDMs [21]
14.5 22.8 NAc 5.5 4.0
7.1 17.7 NAc 2.5 1.5
differences significant at p ⬍ 0.01 or better. differences significant at p ⬍ 0.02 or better. cPercent body fat not reported, but neonatal fat mass significantly lower in offspring of treated mothers. aAll
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
bAll
non-pregnant individuals. They utilize the same 75 g 2 h OGTT protocol as is universally accepted for testing outside of pregnancy. The one-step approach with a single abnormal value needed for diagnosing GDM simplifies the process, and also eliminates the confusing issue of management of patients with a single elevated 100 g, 3 h OGTT value where two elevations are necessary. It should be noted that, when compared to all subjects in the HAPO study who did not have GDM under the recommended diagnostic criteria (rather than to those whose glucose values were at the means), GDMs had a doubling or more for most of the adverse outcomes (Table II).
Why not use the IADPSG recommendations? There has been considerable resistance to the universal adoption of the IADPSG recommendations [13,14]. In 2013 the United States National Institutes of Health convened a Consensus Conference to consider all aspects of screening and diagnosis of gestational diabetes [15]. A panel of individuals from various health professions and fields, assumed to be unbiased because none had published in the area of gestational diabetes, was convened. Experts presented reviews regarding pros and cons of the new and the existing recommendations, potential ramifications, and systematic analyses of existing data by the Agency for Healthcare Research and Quality (AHRQ). A draft recommendation was published on the web, and after public comments were considered, the final document was published [15]. The panel’s recommendation was that, while a standardized, universal approach would be desirable, the two-step approach currently widely used in the United States (a 50 g, 1 h GCT followed by a 100 g, 3 h OGTT with 2 or more elevated values diagnosing gestational diabetes) should be continued because there is not yet sufficient evidence to adopt the one-step approach recommended by IADPSG. The rationale for this recommendation included the following: (1) Adoption of the one-step approach would increase the prevalence of GDM to 15–20 %.
The care of these additional women will increase health care costs. (2) While the additional women who would be diagnosed with GDM under the one-step process are at increased risk for various adverse outcomes, it is not clear that they would benefit from identification and treatment. (3) Identification of these additional women as having GDM may increase patient anxiety, and may also increase ‘obstetrical harms’ such as induction of labor, intensive maternal/fetal monitoring, and cesarean section. (4) Because of the variability in the 2-h OGTT, the one-step approach is likely to generate more ‘false positive’ results than a two-step test. (5) Having to fast for the diagnostic test, and waiting 2 hours instead of the 1-hour interval for the screening test, poses an additional burden for patients. While each of these is a valid concern, it is worth considering the counter-arguments. Increased prevalence of GDM will lead to increased health care costs This should be viewed in the context of the current epidemic of obesity and diabetes throughout the world. For example, in 2007–2010, 11.9 % of adult Americans have diagnosed or undiagnosed diabetes [16]. An additional 36 % of all adult Americans, and 26 % of those between the ages of 18 and 44 years, have prediabetes [17]. GDM as defined by the IADPSG recommendations is somewhat akin to prediabetes. Thus an 18 % prevalence of GDM would be considerably lower than the current prevalence of diabetes and prediabetes in our population. Despite the fact that increasing the thresholds for diagnosing diabetes and prediabetes in nonpregnant individuals would lower the prevalence and decrease short-term health care costs, no one advocates that solution. Rather, our various health care systems work to develop improved methods to provide efficient and effective care to those afflicted with diabetes, and to prevent the eventual development of diabetes in those with prediabetes. As the
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Diagnosis of gestational diabetes prevalence of gestational diabetes increases markedly, as is already the case using the current twostep approach [18], it will be important to develop novel approaches to counseling and care. It is likely that patients with milder gestational diabetes may not require daily self-glucose monitoring, and could test every other day or even less frequently [19]. Group prenatal visits and counseling may be a reasonable way to lower costs and improve quality of care. It is an open question whether the risk of stillbirth with milder GDM is high enough to require antenatal testing with the same intensity as for more severe GDM and for pre-existing diabetes. It is worth noting that diet treatment was successful in attaining good glucose control in 80–92 % of mild GDMs in randomized trials [20,21] suggesting that expanding the prevalence of GDM will not lead to large numbers of patients requiring insulin or oral agents. A recent study compared the cost-effectiveness of universal diagnostic testing with the IADPSG one-step approach and screening with the current ACOG two-step approach [22]. The investigators took into account available data regarding benefits of treatment in preventing preeclampsia and other adverse outcomes for mild gestational diabetes. The compilation of the costs of treatment of GDM did not assume less intensive monitoring or intervention for the milder GDMs, a potential cost-saving opportunity discussed above. The IADPSG one-step approach was more expensive than the two-step approach but was more cost effective in improving maternal and neonatal outcomes. Although the IADPSG recommendations were based on the likelihood of adverse pregnancy outcomes, women who meet these GDM criteria are presumably also at increased risk for the development of type 2 diabetes. Diagnosing GDM constitutes a ‘teachable moment,’ an opportunity to counsel patients about the likelihood of subsequent diabetes, ways of reducing that risk, and the importance of testing after pregnancy and at intervals thereafter to detect diabetes in its early stages. Another recent study [23] compared the cost-effectiveness of the one-step versus two-step approaches and reported that the IADPSG one-step approach was cost-effective if post-delivery care reduces the incidence of subsequent diabetes in the mother. This finding underscores the importance of caregivers using the occasion of the diagnosis of GDM to counsel patients about the risk of diabetes in the future, and arranging follow-up testing and care for former GDMs. In an analysis of the subgroup of 350 subjects in the Diabetes Prevention Program who had previous GDM and prediabetes at enrollment, the annual incidence of type 2 diabetes of 15 % was cut in half by either metformin treatment or intensive lifestyle intervention [24]. The number needed to treat to prevent one case of diabetes over
31
3 years was six for metformin and five for intensive lifestyle intervention. Uncertainties regarding benefits of identifying and treating so many additional GDMs There are no randomized trials of identification and treatment of GDM using the new IADPSG diagnostic thresholds. However, there are two published randomized trials using other criteria for mild gestational diabetes, in which many of the subjects would have overlapped with the new criteria. The Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Network (MFMU) trial [21] enrolled 958 gravidas whose blinded OGTT (administered after a 50 g 1 h GCT was 7.5–11.1 mmol/L [135–200 mg/dL]) demonstrated two elevated values (Carpenter & Coustan criteria) but whose fasting plasma glucose was ⬍ 5.3 mmol/L (95 mg/dL). Although the glucose challenge was 100 g rather than 75 g, the fasting, 1 and 2 h mean values of the subjects were within one standard deviation of the IADPSG cutoffs for fasting, 1 h and 2 h time periods. Participants were randomized to identification and treatment of GDM versus usual care, with caregivers blinded to the OGTT results in the latter group. Identification and treatment of GDM reduced the likelihood of large for gestational age (⬎ 90th percentile) and macrosomic (⬎ 4 kg) babies by more than half. Cesarean section, shoulder dystocia and preeclampsia were also significantly lower. Rates of these various adverse outcomes in the untreated group were similar to the rates in HAPO study participants who would have GDM under the new criteria (Table II), and who also were neither identified nor treated as GDMs in this observational study. Identification and treatment of GDM in the MFMU trial reduced these rates considerably. The other randomized trial of identification and treatment of GDM [20] recruited patients whose elevated 75 g, 2-h OGTT results were based on thresholds lower than those of the IADPSG recommendations. Gravidas whose 2 h, 75-g OGTT values were 7.8–11.1 mmol/L (140–199 mg/dL) made up the study cohort, as long as their fasting plasma glucose was ⬍ 7.8 mmol/L (⬍ 140 mg/dL). The mean fasting plasma glucose in subjects was 4.8 mmol/L (86 mg/dL). Recall that the IADPSG recommended 2-h cutoff for GDM was 8.5 mmol/L (153 mg/dL). Using a similar study design to the MFMU Network study described above, the investigators found very similar reductions in adverse outcomes with identification and treatment of GDM. While neither of the above two RCTs used the identical GDM criteria as IADPSG, and both used a two-step approach to identifying potential subjects, the results demonstrate a benefit to identifying and treating GDM which was mild, with thresholds overlapping those of the IADPSG.
32
D. R. Coustan
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Fasting and waiting 2 hours for the test is an additional burden With the 2-step process, for patients whose 50 g, 1-h GCT is below the threshold for further testing, there is no question that having the test without regard to the last meal, and waiting 1 hour for the blood draw, is preferable to fasting and waiting 2 hours for test completion when the one-step process is followed. However, patients whose screening test exceeds the threshold must come on a subsequent occasion, fasting, for the diagnostic OGTT and wait 3 hours for completion. Depending upon the threshold chosen for the screening portion of the two-step process, and the racial/ethnic characteristics of the population, between 9 and 30 % require the additional OGTT [25]. For those patients the burden of two separate visits, one of which is in the fasting state, and a total of 4 hours’ time with five blood draws, compares quite unfavorably with a single visit (fasting), 2 hours’ time, and three blood draws. The 2-h OGTT is unstable and the 1-step test is likely to increase false positives There is no doubt that glucose tolerance tests are unstable, with less than optimal precision. However, the one-step test is a diagnostic test, and not a screening test, so false positives are not a consideration. If the consensus panel used the term ‘false positive’ to mean individuals who are diagnosed with GDM who do not have adverse outcomes, then it is implied that the diagnosis of GDM is a screening test with the ‘disease’ being the adverse perinatal outcomes. In that case, both the one-step and the two-step process will have many ‘false positives’ not to mention ‘false negatives’ pregnancies in which adverse outcomes occur in the absence of GDM. However, identifying and treating GDM has never been considered as a way to prevent all big babies, or all cases of preeclampsia. Rather, GDM offers the opportunity to prevent adverse outcomes in a particularly high-risk group of patients. Finally, it must be pointed out that instability of the 75 g, 2-h OGTT is not limited to pregnant women. This test is the world-wide standard for diagnosing diabetes in nonpregnant individuals, despite its instability.
Current status The IADPSG recommendations were published in 2010. In 2011 the American Diabetes Association (ADA) adopted these recommendations with a few minor changes [26], although in 2014 ADA altered its recommendations [27], such that either the onestep or the two-step protocol was acceptable, based on the NIH Consensus Panel’s 2013 recommendations. ACOG continues to support the two-step approach [1]. In 2013 the World Health Organization
adopted the recommendation for the one-step IADPSG approach [28]. At the time of this writing professional organizations throughout the world are considering whether to adopt some variation of the IADPSG one-step approach, or to continue with the various other approaches currently in use. As more research is carried out with the IADPSG approach, the situation is likely to be clarified, although this will probably take considerable time. It is to be hoped that eventually there will be a single, uniform approach to identifying GDM in use throughout the world. Questions and answers Q (Young): Which recommendations are being used in the USA? A (Coustan): In the USA we are waiting for the ACOG recommendations for gestational diabetes. Q (O’Shea): Regarding screening for gestational diabetes, you have spoken of the disparity between the USA and Europe, but we have disparity in approach in Ireland. There are several issues: (1) One problem is economic because, to have fasting, 1-hour and 2-hour specimens collected, the patients have to stay for a long period in the clinic which can be difficult for them. Could we do just the 1-hour specimen, since the 2-hour value picks up only an additional 2 % of cases? (2) Could we do fasting glucose and HBA1c picking up at least 20 % of cases then screen the others fully? (3) Should there be universal screening or targeting of those at high risk? A (Coustan): A single, fasting measurement is ideal for convenience but also a 1 hour, or fasting and 1-hour or 2-hour post glucose load, all contribute independently to adverse outcomes and for this reason, all three are recommended. However, in different centers there are different attitudes. Regarding HbA1c, it is very useful in early pregnancy in pre-existing diabetes. It’s not very sensitive for gestational diabetes. Economic problems are a big issue in every country but the solution is not to ignore the problem and strive for cheaper solutions. Q (Kallner): When we make these recommendations we work with population means and medians but when we move to the real world we have to judge results from an individual patient: When you say 5.1 mmol/L as cut off for fasting glucose, that translates into an individual result with an uncertainty. If you look at the German recommendation they allow an uncertainty of 11 % (95 % level) for glucose measurements. This means ⫾ 1 mmol/L, i.e. an uncertainty interval of 4.1–6.1 (k ⫽ 2) mmol/L. In a recent study we found an uncertainty of ⫾ 3 % or 4.9–5.3 mmol/L (k ⫽ 2). The cut-off is not as distinct as you
Scand J Clin Lab Invest Downloaded from informahealthcare.com by York University Libraries on 08/13/14 For personal use only.
Diagnosis of gestational diabetes assume and decisions need to take the uncertainty into account. A (Coustan): In the laboratory this is a problem not only for glucose. What is the alternative to cutoff? It depends on a good quality control in the laboratory. There is concern in the real world on the real value of the quality control. Whether the CV is 1 % or 5 %, there has to be a cut off somewhere. Q (Kallner): As an alternative we may incorporate the uncertainty depending on what you want, to increase sensitivity or specificity. A (Coustan): That is true for screening but not for diagnosis. Q (Kallner): It could be applied also to diagnosis. Do we know if the cut-off has been set to optimize rule-in or rule-out? Comment (Young): The test is defining the disease so it is difficult to speak about the sensitivity and specificity of the test. Comment (Lazzarotto): A screening test needs very high sensitivity, and consequently the specificity could be lower. Comment (Coustan): I do not agree because I would like 100 % for both sensitivity and specificity. Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
References [1] American College of Obstetricians and Gynecologists Practice Bulletin #137. Gestational diabetes mellitus. Obstet Gynecol 2013;122:406–16. [2] O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964;13:278–85. [3] O’Sullivan JB. Subsequent morbidity among gestational diabetic women. In Sutherland HW, Stowers JM (eds), Carbohydrate metabolism in pregnancy and the newborn. New York: Churchill Livingstone, 1984. pp. 174–80. [4] National Diabetes Data group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039–57. [5] Carpenter MW, Coustan DR. Criteria for screening tests of gestational diabetes. Am J Obstet Gynecol 1982;144: 768–73. [6] World Health Organization website: About Diabetes. Accessed 5 February 2014 from: http://www.who.int/diabetes/ action_online/basics/en/index1.html [7] Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008: clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32: S1–201. [8] Templeton M, Pieris-Caldwell I. Gestational diabetes mellitus in Australia, 2005–2006. Australian Institute of Health and Welfare. 2008. Accessed 5 February 2014 from: http:// www.aihw.gov.au/publication-detail/?id ⫽ 6442468189 [9] Metzger BE and the Organizing Committee. Summary and recommendations of the Third International WorkshopConference on Gestational Diabetes Mellitus. Diabetes 1991; 40(Suppl. 2):197–201.
33
[10] Metzger BE, Coustan DR and The Organizing Committee. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(Suppl. 2):B161–7. [11] The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002. [12] Metzger BE, Gabbe SG, Persson B, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3):676–82. [13] Cundy T. Proposed new diagnostic criteria for gestational diabetes – a pause for thought? Diabet Med 2012;29: 176–80. [14] Ryan EA. Diagnostic criteria for gestational diabetes: who decides? Can Med Ass J 2012;184:1341–2. [15] National Institutes of Health Consensus Development Conference Panel. National Institutes of Health consensus development conference statement: diagnosing gestational diabetes mellitus, March 4–6, 2013. Obstet Gynecol 2013; 122:358–69. [16] Table 45. Accessed 17 April 2014 from: http://www.cdc.gov/ nchs/data/hus/hus12.pdf#0545 [17] Bullard KM, Saydah SH, Imperatore G, et al. Secular changes in US prediabetes prevalence defined by Hb A1c and fasting plasma glucose. Diabetes Care 2013;36: 2286–93. [18] Bardenheier BH, Elixhauser A, Imperatore G, et al. Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care 2013;36:1209–14. [19] Mendez-Figueroa H, Daley J, Lopes VV, et al. Comparing daily versus less frequent blood glucose monitoring in patients with mild gestational diabetes. J Maternal Fetal Neonatal Med 2013;26:1268–72. [20] Crowther CA, Hiller JE, Moss JR, et al. for the Australian Carbohydrate Intolerance Study of Pregnant Women (ACHOIS) Study Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. [21] Landon MB, Spong CY, Thom E, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:1339–48. [22] Mission JF, Ohno MS, Cheng YW, Caughey AB. Gestational diabetes screening with the new IADPSG guidelines: a costeffectiveness analysis. Am J Obstet Gynecol 2012;207: 326.e1–9. [23] Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the International Association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012; 35:529–35. [24] Ratner RE, Christophi CA, Metzger BE, et al. Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of GDM: effects of metformin and lifestyle interventions. J Clin Endo Metab 2008; 93:4774–9. [25] Esakoff TF, Cheng YW, Caughey AB. Screening for gestational diabetes: different cut-offs for different ethnicities? Am J Obstet Gynecol 2005;193:1040–4. [26] American Diabetes Association. Standards of Care 2011. Diabetes Care 2011;34(Suppl. 1):s15. [27] American Diabetes Association. Standards of Care 2014. Diabetes Care 2014;37(Suppl. 1): s18–20. [28] World Health Organization. Accessed 5 February 2014 from: http://www.who.int/diabetes/publications/Hyperglycaemia_ In_Pregnancy/en/
