REVIEW URRENT C OPINION
How should we screen for gestational diabetes? Oleg Petrovic´
Purpose of review Regarding the various aspects of screening strategies for gestational diabetes mellitus (GDM) and to express important conclusions, the recent literature in the field is reviewed. Recent findings There are no randomized controlled trials examining the effects of different screening methods on health outcomes. Only few studies investigated the new screening strategies. There is an agreement that universal GDM screening is cost-effective. Several professional societies changed their own guidelines recommending universal GDM screening. Currently, the American College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynaecologists of Canada, and the U.K. National Institute for Health and Clinical Excellence recommend routine risk-factor-based screening, whereas the Canadian Diabetes Association, Australasian Diabetes in Pregnancy Society, U.S. Preventive Services Task Force, and ATLANTIC Diabetes in Pregnancy recommend that all asymptomatic women should be screened at 24–28 weeks’ gestation. The American Diabetes Association recommends screening all women with a 75-g 2-h oral glucose tolerance test (oGTT). The International Association of Diabetes and Pregnancy Study Groups recommend no glucose challenge test, but proposed new screening criteria introducing fasting glucose levels less than 5.1 mmol/l. Summary There is more and more evidence in the recent literature that GDM screening should be universally performed at 24–28 gestational weeks and followed by definitive testing in women who are labeled as high-risk population. Logically, the best strategy would be connecting the screening with diagnosing GDM in the same procedure using a 75-g oGTT, which should be evaluated. General consensus is about measuring plasma glucose to detect pregestational diabetes in high-risk populations by early testing before 20 weeks of gestation. Keywords gestational diabetes, glucose challenge test, glucose tolerance test, hyperglycemia, screening
INTRODUCTION Although gestational diabetes mellitus (GDM) is a well defined gestational condition with almost completely explained etiopathogenetic mechanisms and clinical characteristics, and clear guidelines for its regulation and postpartum follow-up, the longstanding GDM controversy remains, producing great interest among perinatologists and other professionals worldwide [1,2]. When we are questioned about screening, it can be said that GDM undoubtedly fulfills the criteria for a group of pathological conditions that justifies screening during pregnancy. Namely, the GDM incidence with 2–10% is relatively frequent in all populations of pregnant women, with the trend increasing worldwide [3–5]. If GDM is completely manifested and unrecognized or left unregulated, there is a significant risk of severe complications for mother and particularly for the fetus [5]. Conversely, if the condition is www.co-obgyn.com
diagnosed early enough, practically all these perinatal complications can be prevented or significantly reduced [6 ,7]. In view of the lack of well designed studies of screening with a sufficient number of participants, different major professional societies and expert groups from various countries or regions of the world differ considerably from one another suggesting various solutions to this important issue [5,8 ,9 ]. &&
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Perinatal Unit, Department of Gynecology and Obstetrics, University Hospital Center Rijeka, Rijeka, Croatia Correspondence to Professor Oleg Petrovic´, MD, PhD, Perinatal Unit, Department of Gynecology and Obstetrics, University Hospital Center Rijeka, Cambierieva 17a, 51000, Rijeka, Croatia. Tel: +385 51 338 555; fax: +385 51 338 555; e-mail: [email protected] Curr Opin Obstet Gynecol 2014, 26:54–60 DOI:10.1097/GCO.0000000000000049 Volume 26 Number 2 April 2014
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How should we screen for gestational diabetes? Petrovic´
KEY POINTS
and should be performed, but they are uncertain how to do this effectively [12 –15 ,16]. In 2008, the U.K. National Institute for Health and Clinical Excellence (NICE) also reported the conclusion that ‘screening, diagnosis, and treatment of gestational diabetes is cost-effective’ [17 ]. Very recently, the USPSTF changed its statement and recommended that all asymptomatic pregnant women should be screened for GDM after 24 weeks’ gestation [18 ]. If decided that there is a need for GDM screening, the next requirements certainly would be determining the population of pregnant women who should be screened for GDM and then finding the best screening method. A dilemma also remains about timing of screening. Although screening for and diagnosis of GDM should be strictly differentiated by definition, it is not always possible to clearly separate them from each other. The rationale behind GDM screening is choosing a risk group in every pregnant population that needs to be followed by subsequent definitive testing for GDM. Theoretically, a screening test has to be simple, cheap, defined with clear criteria, sensitive as much as possible, noninvasive, reproducible, and available for wide out-clinic use. In contrast, a diagnostic test can be more complex, but its specificity, positive and negative predictive values should be as high as possible. Regarding the pregnant populations, the only two possible principles of GDM screening are selective and universal. The selective principle means that the screening model would be limited only in the selected group of pregnant women with various risk factors for GDM that existed before pregnancy or are developed during pregnancy [19 ,20 ]. For example, the International Diabetes Federation (IDF) guideline stated that selective screening could be recommended, when its costeffectiveness is shown [5]. Recently, it was shown that risk factor screening can produce a significant consequence that a number of women with impaired carbohydrate metabolism would remain unrecognized and at the same time unprotected, regarding the specific perinatal complications [17 ,21,22 ]. There is no properly conducted RCT with a sufficient number of patients examined for the benefit of selective or universal screening for GDM compared with no screening. However, the universal approach seems more logical and pragmatic because it would ensure that all pregnant women would be screened and the possibility of severe GDM complications will be reduced. In the systematic review, it was concluded that women in the universal screening group were more likely to be diagnosed with GDM [23]. Moreover, regarding the &
There is more and more evidence that the universal strategies are beneficial and better than the selective ones.
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Currently, the ACOG, the SOGC, and the NICE recommend routine risk-factor-based screening, whereas the USPSTF, the ADA, the IADPSG, the ADIPS, the CDA, and the ATLANTIC DIP network recommend universal screening in asymptomatic pregnant women at 24–28 weeks’ gestation, followed by definitive testing only in those women who are labeled as high-risk population. The authors recommend measuring plasma glucose to detect overt diabetes in high-risk pregnant populations by early testing before 20 weeks of gestation and screening test should be repeated at 24–28 weeks’ gestation if initial results are normal. Although a number of countries still utilize the 50-g 1-h GCT, it seems logical and pragmatic that the best strategy to achieve cost-effective and fast clinical results would be connecting the screening with diagnosing GDM in the same testing procedure with an oral intake of 75 g of glucose. It is very likely that further standardized, well designed, outcome-based trials will be needed, but there are at least two additional leading challenges for future studies: scientific and ethical issues.
In this review article, randomized controlled trials (RCTs), non-RCTs, systematic reviews, cohort studies, and reference lists in the last 2 years are being searched with a purpose to review and discuss data about the current screening strategies for GDM.
SCREENING FOR GESTATIONAL DIABETES MELLITUS In general, two approaches regarding GDM diagnosis are available: GDM testing without previous screening or primary screening followed by definitive GDM diagnosis. It seems logical that the strategy of GDM detection could be at least less expensive if definitive diagnosis of GDM should not be required for the whole pregnant population. However, some authors doubt about any health advantages in screening for GDM [10 ]. The U.S. Preventive Services Task Force (USPSTF), the U.K. National Health Service, and the Canadian Task Force previously reported no sufficient high-level evidence regarding cost-effectiveness to make a recommendation for or against the routine GDM screening [11]. In contrary, a number of professional organizations and experts in this field agree that screening and diagnostics of GDM are cost-effective &
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potential psychological harms associated with GDM screening, evidence suggested that the differences between women with positive and those with negative screening results do not persist into the third trimester or postpartum period [6 ]. Nevertheless, every medical procedure as well as screening can be refused by a patient. In the USA, most obstetricians prefer universal screening with an initial 50-g glucose challenge test (GCT) [17 ,18 ,24 ]. Very recently, the Canadian Diabetes Association (CDA) not only recommends the same sequential universal screening approach, but also offers an alternative with one-step 75-g oral glucose tolerance test (oGTT) [25 ]. ATLANTIC Diabetes in Pregnancy (DIP) provides a strong evidence for universal screening [17 ]. The current Australasian Diabetes in Pregnancy Society (ADIPS) guidelines prefer universal screening of all pregnant women not known to have diabetes mellitus [26 ]. Jenum et al. [27 ] presented universal screening as the strength of their study. In seven of nine projects supported by the World Diabetes Foundation (WDF), universal screening was applied [8 ]. An additional and no less important reason for universal screening is not emphasized enough. Namely, only because of being pregnant, young women have an exclusive privilege to be screened, which creates a real chance to detect early enough their predisposition for developing diabetes mellitus later in life. As there are several different ways to screen for GDM, it could be concluded that an optimal screening method does not yet exist [5,6 ,28 ]. Screening tests can also be differentiated according to the clinical or biochemical parameters. For example, in some types of ‘clinical’ tests, prepregnancy BMI value, previous GDM, unfavorable perinatal outcomes in previous pregnancies, and familiar appearance of type 2 diabetes in combination with a fasting glycemia greater than 7.0 mmol/l or any glycemia value during the day of at least 8.0 mmol/l have been used for screening purposes [29]. Thus, the American College of Obstetricians and Gynecologists (ACOG) still advises care providers to continue to screen all pregnant women for and diagnose GDM with a two-step strategy by the woman’s history, clinical risk factors, or a laboratory test at 24–28 gestational weeks [15 ,17 ,30 ]. The NICE recommends selective screening in asymptomatic patients based on the risk factor assessment and does not advocate the use of the GCT, fasting glycemia, random blood glucose, or glucosuria [17 ]. The NICE is currently in the process of reviewing their guidelines. The Society of Obstetricians and Gynaecologists of Canada (SOGC) still recommends routine screening at 24–28 weeks’ gestation with the 50-g GCT but is against screening for low-risk &&
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women with glucose testing [31]. In contrast, about half the pregnant women in the UK and the Netherlands receive the single random glucose screening, although there is not enough evidence to recommend this test as a screening test for GDM [32 ]. According to the literature, more popular biochemical screening tests with a higher specificity than clinical ones deal with well defined fasting or 1-h values of glycemia mostly after an oral intake of 50 or 75 g of glucose [3,8 ,33 ]. They usually represent modified or abortive forms of oGTT, which is not surprising, because GDM is primarily a postprandial condition. It is logical that any oral tolerance testing has an advantage of being more efficient and more accurate in screening as well as in detecting postprandial disturbance than methods that only include fasting glycemic values [18 ,34]. In the USA, the most common 50-g GCT is positive if the obtained result after 60 min is at least 7.8 mmol/l [24 ]. The pregnant women with higher risk for GDM should be retested with a higher amount (100 or 75 g) of glucose using 3-h (or 2-h) oGTT [6 ,18 ,35 ]. A cut-off value of 7.8 mmol/l has high sensitivity and higher specificity than does the 7.2 mmol/l screening value. In a systematic review, it was concluded that a 50-g GCT is acceptable for GDM screening but cannot replace a 75-g oGTT [24 ]. So far, the authors could not recommend alternative ways to deliver glucose [36]. However, some concerns are raised about the two-step testing that delays diagnosis, misses up to one-third of GDM cases, and creates chances for various errors [10 ,37 ]. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended no GCT screening, but proposed a new screening criterion introducing fasting glucose levels less than 5.1 mmol/l [38 ,39 ]. Similar conclusions based on the studies and synthesis of available clinical trial data are reported by other authors [40 ,41 ]. Very recently, the ADIPS has endorsed the mentioned IADPSG recommendations [26 ]. However, in 2013, the National Institutes of Health (NIH) published online the draft statement that the NIH panel did not find clear evidence to support adopting the one-step model, such as that proposed by IADPSG [35 ]. The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) in 2011 recommend screening of all women without a pregestational diabetes at 24–28 weeks’ gestation with a 75-g 2-h oGTT [18 ,42 ,43 ]. In two recent studies in Norway, universal screening by 75-g oral glucose test was used [27 ,44]. On the basis of our own unpublished results, it could be assumed that pregnant women with fasting glucose levels between 4.2 and 6.9 mmol/l should be treated as a &
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How should we screen for gestational diabetes? Petrovic´ &
risk patient group and tested with oGTT [19 ]. If plasma glucose values 60 min after the ingestion of 75 g glucose are less than 7.9 mmol/l, testing can be terminated because we believe it does not deal with hyperglycemic disorder or GDM. An advantage of the screening test with 75 g of glucose in relation to an initial 50-g GCT really exists. Namely, a 75-g 1-h glycemia reading above the threshold level enables diagnosis of GDM to be completed immediately, at the same visit, only with an additional blood sample to be taken 1 h later. Similar opinions can be found in the literature [45]. Apart from being faster, more practical, and cheaper, it is also less unpleasant for the pregnant woman because of a smaller number of needle punctures (only three instead of five to six). It would be wise to think of the simpler methods that would reduce the number of blood samples tested and antenatal visits [33 ,35 ]. It can also be mentioned that despite the evidence-based associations between glycated hemoglobin (HbA1c), GDM, and perinatal outcomes, measuring serum HbA1c values for GDM screening cannot be routinely recommended because of the high rates of false-positive and false-negative findings [18 ,20 ]. USPSTF also supports this conclusion [11]. The sensitivity of glucosuria for GDM screening is even worse. Recently, two complex and timeconsuming ultrasound-based screening tests for GDM at 24–28 weeks’ gestation were tested, but with no definitive recommendation [46 ,47 ]. There is also an interesting idea to screen women for the development of GDM by measuring fasting and 2-h serum insulin levels in the first trimester, but it has not been investigated in the general pregnant population [48 ]. Apart from the methods of screening, the gestational period when pregnant women should be screened has to be pointed out. Obviously, there were some uncertainties about a time interval for screening and diagnosis of GDM [5,6 ,34,38 ]. There is also a debate about whether universal testing early in pregnancy to detect overt diabetes not diagnosed before pregnancy is either of clinical value or cost-effective [49]. If screening is performed too early in pregnancy, there is a chance that the pathologic condition cannot be detected at all, even in cases when it really exists but would develop later on [44,50,51 ]. Therefore, even without accurate indicators, it seems logical that screening should not be done before 20 weeks of gestation, with the exception of women at high risk for GDM [18 ]. The IADPSG Consensus Panel did not recommend routinely performing oGTT before 24 weeks’ gestation [38 ]. In addition, it is not logical to screen after 28 weeks because the initial phase of fetal &&
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growth acceleration has already begun. At this time, it should be quite clear for whom a strict diabetic diet is required. Conclusively, the time interval for GDM screening and diagnosis that is most commonly mentioned in the literature is between 24 and 28 weeks, but it has to be emphasized that this recommendation specifically refers to healthy women without anamnestic risk factors [6 ,8 ,11,17 ,18 ,27 ,38 ,44]. If screening has been performed in the right period of time, repeating the procedures later in pregnancy is not necessary. Namely, with increasing gestational age and antiinsulin hormonal concentrations, diagnostic threshold levels probably should also be changed or cases with GDM would be more frequently diagnosed. In conclusion, it is very important that a methodologically and timely standardized approach to screening is implemented, to be comparable and useful in clinical practice. Finally, it has to be emphasized that the efficiency of screening can be measured by a percentage of a total number of screened positive cases in relation to the subsequently detected true GDM cases. The other way to assess screening is a comparison with specific maternal and infant outcomes as has been shown in clinical studies [22 ,23,52 ]. Thus, a qualitative evaluation of any screening method cannot be objectively done without the existence of accurate diagnostic criteria and standardized primary endpoints [6 ,11,19 ,22 ]. Actually, the real question is do we have the best strategies and the right criteria for GDM diagnosis at all [6 ,8 ,19 ,36,38 ,52 ]. These facts may be the key problems in assessing the efficiency of all screening models for GDM in future. &&
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CONCLUSION The best GDM screening strategy for global use in all pregnant populations does not exist yet, but there is more and more evidence that the universal strategies are beneficial and better than the selective ones. In the last 2 years, only few studies investigated the new screening strategies. Recently, several major societies refreshed their own guidelines or changed them, recommending universal GDM screening. It is very likely that further standardized outcome-based RCTs will be needed to achieve improved screening, diagnostic and clinical results. With a purpose to standardize further studies, an important task should be to define specific hyperglycemic complications as standardized primary endpoints. However, there are at least two additional leading challenges for future studies: scientific and ethical issues. First, it is possible that any scientific evidence of screening effectiveness would only be of relative significance, because an
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efficiency of screening is relative to the accuracy of GDM diagnostic criteria and specificity of study primary endpoints. Second, consequently to the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study results, it would be unethical that medical caregivers do not react during investigation to any status of glucose intolerance with nondiagnostic results. The most important opinion should be that our professional actions have to be focused on hyperglycemia instead of trying to diagnose GDM itself. Until there is more conclusive evidence, with current knowledge and experience, screening for hyperglycemia should be universally performed in every pregnant woman where it is possible and followed by definitive testing only in those women who are labeled as high-risk population. Although there is sufficient evidence that the universal two-step screening is cost-effective, it seems wise and pragmatic that the best strategy would be connecting the screening with diagnosing GDM in the same procedure with 75 g of glucose at 24–28 weeks’ gestation. However, a number of countries, including the USA, still utilize the 50-g 1-h GCT as the most popular screening method regardless of the obvious concerns. Early testing before 20 weeks to detect overt diabetes in high-risk pregnant populations should also be a fundamental change in strategies for the prevention of relevant hyperglycemic complications. Acknowledgements None. Conflicts of interest None declared.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Ryan EA. Diagnosing gestational diabetes. Diabetologia 2011; 54:480–486. 2. Sokup A, Ruszkowska-Ciastek B, Go´ralczyk K, et al. Insulin resistance as estimated by the homeostatic method at diagnosis of gestational diabetes: estimation of disease severity and therapeutic needs in a population-based study. BMC Endocr Disord 2013; 13:21–35. 3. Jiwani A, Marseille E, Lohse N, et al. Gestational diabetes mellitus: results from a survey of country prevalence and practices. J Matern Fetal Neonatal Med 2012; 25:600–610. 4. Schneider S, Bock C, Wetzel M, et al. The prevalence of gestational diabetes in advanced economies. J Perinatol Med 2012; 40:511–520. 5. Greuter MJ, van Emmerik NM, Wouters MG, van Tulder MW. Quality of guidelines on the management of diabetes in pregnancy: a systematic review. BMC Pregnancy Childbirth 2012; 12:58–64. 6. Hartling L, Dryden DM, Guthrie A, et al. Benefits and harms of treating && gestational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med 2013; 159:115–122. In a well conducted systematic review based on RCTs, non-RCTs, and cohort studies from 15 electronic databases, the authors summarized the maternal and neonatal benefits and the harms of treating GDM. There is a clear evidence of the importance of screening for and diagnosis of GDM.
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7. Power ML, Wilson EK, Hogan SO, et al. Patterns of preconception, prenatal and postnatal care for diabetic women by obstetrician–gynecologists. J Reprod Med 2013; 58:7–14. 8. Nielsen KK, de Courten M, Kapur A. The urgent need for universally applicable && simple screening procedures and diagnostic criteria for gestational diabetes mellitus – lessons from projects funded by the World Diabetes Foundation. Glob Health Action 2012; 5:17277. This is a unique investigation about the utilization of the internationally recommended guidelines (seven different screening procedures) for screening GDM in developing countries. A number of various problems and barriers in everyday practice were found. The authors emphasized that there is a need for an international consensus on screening for GDM and its applicability to ensure usage as wide as possible. 9. Buckley BS, Harreiter J, Damm P, et al. Gestational diabetes mellitus in & Europe: prevalence, current screening practice and barriers to screening. A review. Diabet Med 2012; 29:844–854. The recent systematic searching discovered inconsistency between screening practices across Europe and lack of consensus on testing methods and the value of routine screening. 10. Simmons D, Moses RG. Gestational diabetes mellitus: to screen or not to & screen? Is this really still a question? Diabetes Care 2013; 36:2877–2878. The authors send significant messages that any of the screening methods will miss women with GDM and that screening strategies based on the risk factors or a GCT cannot be endorsed for either health or financial reasons. 11. U.S. Preventive Services Task Force. Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 148:759–765. 12. Gillespie P, O’Neill C, Avalos G, Dunne FP. New estimates of the costs of & universal screening for gestational diabetes mellitus in Ireland. Ir Med J 2012; 105:15–18. In this interesting investigation, the authors estimated the costs of universal screening for GDM that were not low, but they emphasized that it would be more important to evaluate the cost-effectiveness of GDM screening program. 13. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational & diabetes mellitus: are the criteria proposed by the International Association of Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012; 35:529–535. On the basis of original decision model comparing the cost-effectiveness of three strategies to diagnose GDM, the authors concluded that the IADPSG screening method can be cost-effective as long as specific postpartum counseling and interventions reduce diabetes mellitus incidence. 14. Marseille E, Lohse N, Jiwani A, et al. The cost-effectiveness of gestational & diabetes screening including prevention of type 2 diabetes: application of a new model in India and Israel. J Matern Fetal Neonatal Med 2013; 26:802–810. The results of this recent study based on a new developed decision-analysis tool showed that GDM screening program and preventive measures are highly costeffective compared with no screening. 15. Mission JF, Ohno MS, Cheng YW, Caughey AB. Gestational diabetes & screening with the new IADPSG guidelines: a cost-effectiveness analysis. Am J Obstet Gynecol 2012; 207:326–328. The authors compared GDM screening using the IADPSG guidelines with a more common 50-g GCT and concluded that this newly proposed universal strategy is more expensive but still cost-effective in improving perinatal and maternal outcomes. 16. Langer O, Umans JG, Miodovnik M. The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference. J Matern Fetal Neonatal Med 2013; 26:111–115. 17. Avalos GE, Owens LA, Dunne F. Applying current screening tools for && gestational diabetes mellitus to a European population: is it time for change? Diabetes Care 2013; 36:3040–3044. In a very recent investigation, the authors retrospectively compared universal with selective screening models in a cohort of 5500 pregnant women. The results of this study represent strong evidence for a universal approach to screening for GDM. 18. Donovan L, Hartling L, Muise M, et al. Screening tests for gestational diabetes: && a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2013; 159:123–129. This current and well conducted systematic review based on 51 cohort studies represents an up-to-date and comprehensive summary of the existing evidence for all potential screening strategies for GDM and provides recommendations for clinical practice and future investigations. There is strong evidence that 50-g GCT is more efficient than fasting plasma glucose in identifying women with GDM. 19. Tomic´ V, Petrovic´ O, Crncˇevic´ Orlic´ Zˇ, Mandic´ V. Gestational diabetes and & pregnancy outcome – do we have right diagnostic criteria? J Matern Fetal Neonatal Med 2013; 26:854–859. The obtained research and unpublished results allowed to create a new one-step screening and diagnosing method with a 75-g oGTT, which hopefully should be evaluated in future research. 20. Lowe LP, Metzger BE, Dyer AR, et al. Hyperglycemia and Adverse Pregnancy & Outcome (HAPO) Study. Associations of maternal A1c and glucose with pregnancy outcome. Diabetes Care 2012; 35:574–580. In a recent retrospective study based on the HAPO study participants, the authors emphasized that HbA1c values cannot be a good alternative to an oGTT in the pregnant population. 21. Hieronimus S, Le Meaux JP. Relevance of gestational diabetes mellitus screening and comparison of selective with universal strategies. J Gynecol Obstet Biol Reprod 2010; 39 (Suppl. 2):S200–S213.
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How should we screen for gestational diabetes? Petrovic´ 22. Cosson E, Benbara A, Pharisien I, et al. Diagnostic and prognostic performances over 9 years of a selective screening strategy for gestational diabetes mellitus in a cohort of 18 775 subjects. Diabetes Care 2013; 36:598–603. In this extensive and relevant investigation based on a cohort of approximately 19 000 pregnant participants, the authors undoubtedly showed that selective approach to screening leads to missing at least one-third of women with GDM. They reasonably concluded that universal screening appears to be superior to the selective one. 23. Tieu J, Middleton P, McPhee AJ, Crowther CA. Screening and subsequent management for gestational diabetes for improving maternal and infant health. Cochrane Database Syst Rev 2010; 7:CD007222. doi: 10.1002/14651858. CD007222.ub2. 24. Van Leeuwen M, Louwerse MD, Opmeer BC, et al. Glucose challenge test for && detecting gestational diabetes mellitus: a systematic review. BJOG 2012; 119:393–401. In this recent systematic review that included 26 relevant studies, the authors showed that the 50-g GCT is acceptable for GDM screening but cannot replace the oGTT. They suggested that combining the GCT with other screening methods should be investigated. 25. Thompson D, Berger H, Feig D, et al. Diabetes and pregnancy. Can J Diabetes && 2013; 37 (Suppl. 1):S168–S183. This is the most recent document of the CDA Clinical Practice Guidelines Expert Committee regarding screening for GDM. The CDA currently recommends two approaches to healthcare providers. The preferred approach remains a routine 50-g GCT followed by a 75-g oGTT in pregnant women at risk. The new and alternate method is a one-step approach of a 75-g 2-h oGTT as proposed by the IADPSG. 26. Nankervis A, McIntyre HD, Moses RG, et al. Testing for gestational diabetes && mellitus in Australia. Diabetes Care 2013; 36:e64. doi: 10.2337/dc12-2345. This overview presents very recent information about the current recommendations on screening program for GDM in the Australian continent. Actually, the ADIPS introduced the new guidelines that endorse the strategy used by the IADPSG and the ADA that might be a sign toward international GDM screening consensus. 27. Jenum AK, Mørkrid K, Sletner L, et al. Impact of ethnicity on gestational & diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study Groups criteria: a population-based cohort study. Eur J Endocrinol 2012; 166:317–324. The authors investigated two different universal screening strategies proposed by WHO and IADPSG, and concluded that the new criteria resulted in identifying many pregnant women with a mild increase in fasting plasma glucose. 28. Falavigna M, Prestes I, Schmidt MI, et al. Impact of gestational diabetes & mellitus screening strategies on perinatal outcomes: a simulation study. Diabetes Res Clin Pract 2013; 99:358–365. On the basis of the results of a recent simulation study, the authors provided a conclusion that universal GDM screening has a mild influence on perinatal outcome with a slightly larger impact of screening based on IADPSG than WHO guidelines. 29. Ostlund I, Hanson U. Repeated random blood glucose measurements as universal screening test for gestational diabetes mellitus. Acta Obstet Gynecol Scand 2004; 83:46–51. 30. ACOG Practice Bulletin No. 137. Gestational diabetes mellitus. Obstet && Gynecol 2013; 122:406–416. This recent document provides the latest ACOG recommendations for the continuous use of a common two-step screening for GDM. There is a further important suggestion that before the testing approach is changed, implications of such changes should be examined. 31. Berger H, Sermer M, Farine D. Should the SOGC guidelines on screening for gestational diabetes mellitus be changed once again? J Obstet Gynaecol Can 2006; 28:536–539. 32. Van Leeuwen M, Opmeer BC, Yilmaz Y, et al. Accuracy of the random glucose & test as screening test for gestational diabetes mellitus: a systematic review. Eur J Obstet Gynecol Reprod Biol 2011; 154:130–135. This relevant meta-analysis, based on six studies, allowed the authors to conclude undoubtedly that there is no good evidence to recommend a random glucose test as a screening test for GDM. No recent study that deals with this issue is available. 33. Cheung KW, Wong SF. Gestational diabetes mellitus update and review of && literature. Reprod Sys Sexual Disord 2012; S2:002. In this up-to-date review, the authors summarized the current guidelines for GDM screening recommended by the most relevant professional organizations. They labeled selective screening by risk factors unattractive and potentially dangerous. The authors obviously prefer the universal screening because of its beneficial effects and the one-step approach that could eliminate many problems connected with the two-step model. 34. Corrado F, D’Anna R, Cannata ML, et al. Correspondence between firsttrimester fasting glycaemia, and oral glucose tolerance test in gestational diabetes diagnosis. Diabetes Metab 2012; 38:458–461. 35. VanDorsten JP, Dodson WC, Espeland MA, et al. NIH Consensus Develop&& ment Conference: diagnosing gestational diabetes mellitus. NIH Consens State Sci Statements 2013; 29:1–31. This is the most recent final statement of a U.S. NIH expert panel. Currently, in the USA, a two-step approach with a 50-g GCT followed by a 100-g 3-h oGTT is the most common screening strategy. However, it was stated that the one-step approach could offer certain benefits and operational advantages for patients and their obstetricians. &&
36. Farrar D, Duley L, Lawlor DA. Different strategies for diagnosing gestational diabetes to improve maternal and infant health. Cochrane Database Syst Rev 2011; 10:CD007122. doi: 10.1002/14651858.CD007122. pub2. 37. Sievenpiper JL, McDonald SD, Grey V, Don-Wauchope AC. Missed follow-up & opportunities using a two-step screening approach for gestational diabetes. Diabetes Res Clin Pract 2012; 96:e43–e46. In a recent study, the authors evaluated the effectiveness of the two-step screening practice and expressed grave concerns about the fact that only one-third of women with abnormal initial findings attended the official 75-g oGTT. 38. Sacks D, Hadden D, Maresh M, et al. Frequency of gestational diabetes & mellitus at collaborating centers based on IADPSG Consensus Panel – recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care 2012; 35:526–528. The authors indicate that the differences in studied pregnant populations and frequency of the GDM diagnosis may significantly impact the choice of screening strategies for GDM (fasting plasma glucose, 2-h oGTT, or 1-h oGTT). 39. Metzger B, Coustan DR, Dyer AR, et al. The diagnosis of gestational diabetes & mellitus: new paradigms or status quo? J Matern Fetal Neonatal Med 2012; 25:2564–2569. After detailed and careful reviewing of IADPSG recommendations, the authors reported their support for the IADPSG proposals for GDM screening and diagnosing. 40. Zhu WW, Fan L, Yang HX, et al. Fasting plasma glucose at 24–28 weeks to & screen for gestational diabetes mellitus: new evidence from China. Diabetes Care 2013; 36:2038–2040. Very recently, based on a cohort study of nearly 25 000 pregnant women, the authors concluded that fasting plasma glucose could be used for screening to avoid a number of the official oGTTs in resource-poor regions and countries. 41. McIntyre HD. Diagnosing gestational diabetes mellitus: rationed or rationally & related to risk? Diabetes Care 2013; 36:2879–2880. On the basis of the synthesis of available clinical and epidemiological trial data, the author characterized the IADPSG-recommended and ADA-recommended strategies as a reasonable approach to detecting pregnant women with significant hyperglycemia. 42. American Diabetes Association. Standards of medical care in diabetes – && 2013. Diabetes Care 2013; 36 (Suppl. 1):S11–S66. This is the most recent revision of ADA’s Professional Practice Committee based on a systematical searching for new evidence regarding the effectiveness of screening for GDM. Currently, the ADA changed recommendations and recommend screening at 24–28 weeks of gestation using a 75-g 2-h oGTT, and at the first visit in those pregnant women with high-risk factors. 43. Benhalima K, Van Crombrugge P, Hanssens M, et al. Gestational diabetes: && overview of the new consensus screening strategy and diagnostic criteria. Acta Clin Belg 2012; 67:255–261. The authors presented an interesting overview of the new consensus screening strategy. They concluded that the new strategy might lead to logistical problems to organize universal screening program for GDM. They also doubted about the effectiveness of the two-step screening method identifying real problems in organizing an oGTT a few days after abnormal GCT that makes GDM diagnosing suboptimal. 44. Mørkrid K, Jenum AK, Sletner L, et al. Failure to increase insulin secretory capacity during pregnancy-induced insulin resistance is associated with ethnicity and gestational diabetes. Eur J Endocrinol 2012; 167:579– 588. 45. Moses RG, Cheung NW. Point: universal screening for gestational diabetes mellitus. Diabetes Care 2009; 32:1349–1351. 46. Perovic M, Garalejic E, Gojnic M, et al. Sensitivity and specificity of ultra& sonography as a screening tool for gestational diabetes mellitus. J Matern Fetal Neonatal Med 2012; 25:1348–1353. In a recent and interesting study, the authors tried to establish a new ultrasoundbased scoring system suitable for GDM screening, but the method appears to be complex, time-consuming, and, most probably, not suitable for clinical practice. 47. Gojnic M, Stefanovic T, Perovic M, et al. Prediction of fetal macrosomia with & ultrasound parameters and maternal glycemic controls in gestational diabetes mellitus. Clin Exp Obstet Gynecol 2012; 39:512–515. In a prospective clinical trial, the authors investigated several ultrasound parameters as a potentially new screening method for GDM, but this very complex procedure has been applied too late in pregnancy to be useful as a screening method. 48. Grewal E, Kansara S, Kachhawa G, et al. Prediction of gestational diabetes & mellitus at 24 to 28 weeks of gestation by using first-trimester insulin sensitivity indices in Asian Indian subjects. Metabolism 2012; 61:715– 720. The authors presented a new and very interesting idea to screen women for GDM by measuring fasting and 2-h serum insulin levels in the first trimester of pregnancy. 49. Long H, Cundy T. Establishing consensus in the diagnosis of gestational diabetes following HAPO: where do we stand? Curr Diab Rep 2013; 13:43– 50. 50. Jang EH, Kwon HS. b-Cell dysfunction and insulin resistance in gestational glucose intolerance. Korean J Intern Med 2013; 28:294–296.
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Maternal–fetal medicine 51. O’Dwyer V, Farah N, Hogan J, et al. Timing of screening for gestational diabetes mellitus in women with moderate and severe obesity. Acta Obstet Gynecol Scand 2012; 91:447–451. In a prospective observational study, the authors concluded that an early screening for GDM before 20 weeks’ gestation could be useful, especially in selected pregnant population.
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52. Nwose EU, Richards RS, Bwititi PT, Butkowski EG. New guidelines for diagnosis of gestational diabetes: pathology-based impact assessment. N Am J Med Sci 2013; 5:191–194. This very recent study is evidence that we should be aware of the real consequences of introducing the new recommended guidelines for screening and diagnosis of GDM in clinical practice without previous epidemiologic analysis.
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How should we screen for gestational diabetes? Oleg Petrovic´
Purpose of review Regarding the various aspects of screening strategies for gestational diabetes mellitus (GDM) and to express important conclusions, the recent literature in the field is reviewed. Recent findings There are no randomized controlled trials examining the effects of different screening methods on health outcomes. Only few studies investigated the new screening strategies. There is an agreement that universal GDM screening is cost-effective. Several professional societies changed their own guidelines recommending universal GDM screening. Currently, the American College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynaecologists of Canada, and the U.K. National Institute for Health and Clinical Excellence recommend routine risk-factor-based screening, whereas the Canadian Diabetes Association, Australasian Diabetes in Pregnancy Society, U.S. Preventive Services Task Force, and ATLANTIC Diabetes in Pregnancy recommend that all asymptomatic women should be screened at 24–28 weeks’ gestation. The American Diabetes Association recommends screening all women with a 75-g 2-h oral glucose tolerance test (oGTT). The International Association of Diabetes and Pregnancy Study Groups recommend no glucose challenge test, but proposed new screening criteria introducing fasting glucose levels less than 5.1 mmol/l. Summary There is more and more evidence in the recent literature that GDM screening should be universally performed at 24–28 gestational weeks and followed by definitive testing in women who are labeled as high-risk population. Logically, the best strategy would be connecting the screening with diagnosing GDM in the same procedure using a 75-g oGTT, which should be evaluated. General consensus is about measuring plasma glucose to detect pregestational diabetes in high-risk populations by early testing before 20 weeks of gestation. Keywords gestational diabetes, glucose challenge test, glucose tolerance test, hyperglycemia, screening
INTRODUCTION Although gestational diabetes mellitus (GDM) is a well defined gestational condition with almost completely explained etiopathogenetic mechanisms and clinical characteristics, and clear guidelines for its regulation and postpartum follow-up, the longstanding GDM controversy remains, producing great interest among perinatologists and other professionals worldwide [1,2]. When we are questioned about screening, it can be said that GDM undoubtedly fulfills the criteria for a group of pathological conditions that justifies screening during pregnancy. Namely, the GDM incidence with 2–10% is relatively frequent in all populations of pregnant women, with the trend increasing worldwide [3–5]. If GDM is completely manifested and unrecognized or left unregulated, there is a significant risk of severe complications for mother and particularly for the fetus [5]. Conversely, if the condition is www.co-obgyn.com
diagnosed early enough, practically all these perinatal complications can be prevented or significantly reduced [6 ,7]. In view of the lack of well designed studies of screening with a sufficient number of participants, different major professional societies and expert groups from various countries or regions of the world differ considerably from one another suggesting various solutions to this important issue [5,8 ,9 ]. &&
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Perinatal Unit, Department of Gynecology and Obstetrics, University Hospital Center Rijeka, Rijeka, Croatia Correspondence to Professor Oleg Petrovic´, MD, PhD, Perinatal Unit, Department of Gynecology and Obstetrics, University Hospital Center Rijeka, Cambierieva 17a, 51000, Rijeka, Croatia. Tel: +385 51 338 555; fax: +385 51 338 555; e-mail: [email protected] Curr Opin Obstet Gynecol 2014, 26:54–60 DOI:10.1097/GCO.0000000000000049 Volume 26 Number 2 April 2014
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How should we screen for gestational diabetes? Petrovic´
KEY POINTS
and should be performed, but they are uncertain how to do this effectively [12 –15 ,16]. In 2008, the U.K. National Institute for Health and Clinical Excellence (NICE) also reported the conclusion that ‘screening, diagnosis, and treatment of gestational diabetes is cost-effective’ [17 ]. Very recently, the USPSTF changed its statement and recommended that all asymptomatic pregnant women should be screened for GDM after 24 weeks’ gestation [18 ]. If decided that there is a need for GDM screening, the next requirements certainly would be determining the population of pregnant women who should be screened for GDM and then finding the best screening method. A dilemma also remains about timing of screening. Although screening for and diagnosis of GDM should be strictly differentiated by definition, it is not always possible to clearly separate them from each other. The rationale behind GDM screening is choosing a risk group in every pregnant population that needs to be followed by subsequent definitive testing for GDM. Theoretically, a screening test has to be simple, cheap, defined with clear criteria, sensitive as much as possible, noninvasive, reproducible, and available for wide out-clinic use. In contrast, a diagnostic test can be more complex, but its specificity, positive and negative predictive values should be as high as possible. Regarding the pregnant populations, the only two possible principles of GDM screening are selective and universal. The selective principle means that the screening model would be limited only in the selected group of pregnant women with various risk factors for GDM that existed before pregnancy or are developed during pregnancy [19 ,20 ]. For example, the International Diabetes Federation (IDF) guideline stated that selective screening could be recommended, when its costeffectiveness is shown [5]. Recently, it was shown that risk factor screening can produce a significant consequence that a number of women with impaired carbohydrate metabolism would remain unrecognized and at the same time unprotected, regarding the specific perinatal complications [17 ,21,22 ]. There is no properly conducted RCT with a sufficient number of patients examined for the benefit of selective or universal screening for GDM compared with no screening. However, the universal approach seems more logical and pragmatic because it would ensure that all pregnant women would be screened and the possibility of severe GDM complications will be reduced. In the systematic review, it was concluded that women in the universal screening group were more likely to be diagnosed with GDM [23]. Moreover, regarding the &
There is more and more evidence that the universal strategies are beneficial and better than the selective ones.
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Currently, the ACOG, the SOGC, and the NICE recommend routine risk-factor-based screening, whereas the USPSTF, the ADA, the IADPSG, the ADIPS, the CDA, and the ATLANTIC DIP network recommend universal screening in asymptomatic pregnant women at 24–28 weeks’ gestation, followed by definitive testing only in those women who are labeled as high-risk population. The authors recommend measuring plasma glucose to detect overt diabetes in high-risk pregnant populations by early testing before 20 weeks of gestation and screening test should be repeated at 24–28 weeks’ gestation if initial results are normal. Although a number of countries still utilize the 50-g 1-h GCT, it seems logical and pragmatic that the best strategy to achieve cost-effective and fast clinical results would be connecting the screening with diagnosing GDM in the same testing procedure with an oral intake of 75 g of glucose. It is very likely that further standardized, well designed, outcome-based trials will be needed, but there are at least two additional leading challenges for future studies: scientific and ethical issues.
In this review article, randomized controlled trials (RCTs), non-RCTs, systematic reviews, cohort studies, and reference lists in the last 2 years are being searched with a purpose to review and discuss data about the current screening strategies for GDM.
SCREENING FOR GESTATIONAL DIABETES MELLITUS In general, two approaches regarding GDM diagnosis are available: GDM testing without previous screening or primary screening followed by definitive GDM diagnosis. It seems logical that the strategy of GDM detection could be at least less expensive if definitive diagnosis of GDM should not be required for the whole pregnant population. However, some authors doubt about any health advantages in screening for GDM [10 ]. The U.S. Preventive Services Task Force (USPSTF), the U.K. National Health Service, and the Canadian Task Force previously reported no sufficient high-level evidence regarding cost-effectiveness to make a recommendation for or against the routine GDM screening [11]. In contrary, a number of professional organizations and experts in this field agree that screening and diagnostics of GDM are cost-effective &
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potential psychological harms associated with GDM screening, evidence suggested that the differences between women with positive and those with negative screening results do not persist into the third trimester or postpartum period [6 ]. Nevertheless, every medical procedure as well as screening can be refused by a patient. In the USA, most obstetricians prefer universal screening with an initial 50-g glucose challenge test (GCT) [17 ,18 ,24 ]. Very recently, the Canadian Diabetes Association (CDA) not only recommends the same sequential universal screening approach, but also offers an alternative with one-step 75-g oral glucose tolerance test (oGTT) [25 ]. ATLANTIC Diabetes in Pregnancy (DIP) provides a strong evidence for universal screening [17 ]. The current Australasian Diabetes in Pregnancy Society (ADIPS) guidelines prefer universal screening of all pregnant women not known to have diabetes mellitus [26 ]. Jenum et al. [27 ] presented universal screening as the strength of their study. In seven of nine projects supported by the World Diabetes Foundation (WDF), universal screening was applied [8 ]. An additional and no less important reason for universal screening is not emphasized enough. Namely, only because of being pregnant, young women have an exclusive privilege to be screened, which creates a real chance to detect early enough their predisposition for developing diabetes mellitus later in life. As there are several different ways to screen for GDM, it could be concluded that an optimal screening method does not yet exist [5,6 ,28 ]. Screening tests can also be differentiated according to the clinical or biochemical parameters. For example, in some types of ‘clinical’ tests, prepregnancy BMI value, previous GDM, unfavorable perinatal outcomes in previous pregnancies, and familiar appearance of type 2 diabetes in combination with a fasting glycemia greater than 7.0 mmol/l or any glycemia value during the day of at least 8.0 mmol/l have been used for screening purposes [29]. Thus, the American College of Obstetricians and Gynecologists (ACOG) still advises care providers to continue to screen all pregnant women for and diagnose GDM with a two-step strategy by the woman’s history, clinical risk factors, or a laboratory test at 24–28 gestational weeks [15 ,17 ,30 ]. The NICE recommends selective screening in asymptomatic patients based on the risk factor assessment and does not advocate the use of the GCT, fasting glycemia, random blood glucose, or glucosuria [17 ]. The NICE is currently in the process of reviewing their guidelines. The Society of Obstetricians and Gynaecologists of Canada (SOGC) still recommends routine screening at 24–28 weeks’ gestation with the 50-g GCT but is against screening for low-risk &&
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women with glucose testing [31]. In contrast, about half the pregnant women in the UK and the Netherlands receive the single random glucose screening, although there is not enough evidence to recommend this test as a screening test for GDM [32 ]. According to the literature, more popular biochemical screening tests with a higher specificity than clinical ones deal with well defined fasting or 1-h values of glycemia mostly after an oral intake of 50 or 75 g of glucose [3,8 ,33 ]. They usually represent modified or abortive forms of oGTT, which is not surprising, because GDM is primarily a postprandial condition. It is logical that any oral tolerance testing has an advantage of being more efficient and more accurate in screening as well as in detecting postprandial disturbance than methods that only include fasting glycemic values [18 ,34]. In the USA, the most common 50-g GCT is positive if the obtained result after 60 min is at least 7.8 mmol/l [24 ]. The pregnant women with higher risk for GDM should be retested with a higher amount (100 or 75 g) of glucose using 3-h (or 2-h) oGTT [6 ,18 ,35 ]. A cut-off value of 7.8 mmol/l has high sensitivity and higher specificity than does the 7.2 mmol/l screening value. In a systematic review, it was concluded that a 50-g GCT is acceptable for GDM screening but cannot replace a 75-g oGTT [24 ]. So far, the authors could not recommend alternative ways to deliver glucose [36]. However, some concerns are raised about the two-step testing that delays diagnosis, misses up to one-third of GDM cases, and creates chances for various errors [10 ,37 ]. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended no GCT screening, but proposed a new screening criterion introducing fasting glucose levels less than 5.1 mmol/l [38 ,39 ]. Similar conclusions based on the studies and synthesis of available clinical trial data are reported by other authors [40 ,41 ]. Very recently, the ADIPS has endorsed the mentioned IADPSG recommendations [26 ]. However, in 2013, the National Institutes of Health (NIH) published online the draft statement that the NIH panel did not find clear evidence to support adopting the one-step model, such as that proposed by IADPSG [35 ]. The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) in 2011 recommend screening of all women without a pregestational diabetes at 24–28 weeks’ gestation with a 75-g 2-h oGTT [18 ,42 ,43 ]. In two recent studies in Norway, universal screening by 75-g oral glucose test was used [27 ,44]. On the basis of our own unpublished results, it could be assumed that pregnant women with fasting glucose levels between 4.2 and 6.9 mmol/l should be treated as a &
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How should we screen for gestational diabetes? Petrovic´ &
risk patient group and tested with oGTT [19 ]. If plasma glucose values 60 min after the ingestion of 75 g glucose are less than 7.9 mmol/l, testing can be terminated because we believe it does not deal with hyperglycemic disorder or GDM. An advantage of the screening test with 75 g of glucose in relation to an initial 50-g GCT really exists. Namely, a 75-g 1-h glycemia reading above the threshold level enables diagnosis of GDM to be completed immediately, at the same visit, only with an additional blood sample to be taken 1 h later. Similar opinions can be found in the literature [45]. Apart from being faster, more practical, and cheaper, it is also less unpleasant for the pregnant woman because of a smaller number of needle punctures (only three instead of five to six). It would be wise to think of the simpler methods that would reduce the number of blood samples tested and antenatal visits [33 ,35 ]. It can also be mentioned that despite the evidence-based associations between glycated hemoglobin (HbA1c), GDM, and perinatal outcomes, measuring serum HbA1c values for GDM screening cannot be routinely recommended because of the high rates of false-positive and false-negative findings [18 ,20 ]. USPSTF also supports this conclusion [11]. The sensitivity of glucosuria for GDM screening is even worse. Recently, two complex and timeconsuming ultrasound-based screening tests for GDM at 24–28 weeks’ gestation were tested, but with no definitive recommendation [46 ,47 ]. There is also an interesting idea to screen women for the development of GDM by measuring fasting and 2-h serum insulin levels in the first trimester, but it has not been investigated in the general pregnant population [48 ]. Apart from the methods of screening, the gestational period when pregnant women should be screened has to be pointed out. Obviously, there were some uncertainties about a time interval for screening and diagnosis of GDM [5,6 ,34,38 ]. There is also a debate about whether universal testing early in pregnancy to detect overt diabetes not diagnosed before pregnancy is either of clinical value or cost-effective [49]. If screening is performed too early in pregnancy, there is a chance that the pathologic condition cannot be detected at all, even in cases when it really exists but would develop later on [44,50,51 ]. Therefore, even without accurate indicators, it seems logical that screening should not be done before 20 weeks of gestation, with the exception of women at high risk for GDM [18 ]. The IADPSG Consensus Panel did not recommend routinely performing oGTT before 24 weeks’ gestation [38 ]. In addition, it is not logical to screen after 28 weeks because the initial phase of fetal &&
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growth acceleration has already begun. At this time, it should be quite clear for whom a strict diabetic diet is required. Conclusively, the time interval for GDM screening and diagnosis that is most commonly mentioned in the literature is between 24 and 28 weeks, but it has to be emphasized that this recommendation specifically refers to healthy women without anamnestic risk factors [6 ,8 ,11,17 ,18 ,27 ,38 ,44]. If screening has been performed in the right period of time, repeating the procedures later in pregnancy is not necessary. Namely, with increasing gestational age and antiinsulin hormonal concentrations, diagnostic threshold levels probably should also be changed or cases with GDM would be more frequently diagnosed. In conclusion, it is very important that a methodologically and timely standardized approach to screening is implemented, to be comparable and useful in clinical practice. Finally, it has to be emphasized that the efficiency of screening can be measured by a percentage of a total number of screened positive cases in relation to the subsequently detected true GDM cases. The other way to assess screening is a comparison with specific maternal and infant outcomes as has been shown in clinical studies [22 ,23,52 ]. Thus, a qualitative evaluation of any screening method cannot be objectively done without the existence of accurate diagnostic criteria and standardized primary endpoints [6 ,11,19 ,22 ]. Actually, the real question is do we have the best strategies and the right criteria for GDM diagnosis at all [6 ,8 ,19 ,36,38 ,52 ]. These facts may be the key problems in assessing the efficiency of all screening models for GDM in future. &&
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CONCLUSION The best GDM screening strategy for global use in all pregnant populations does not exist yet, but there is more and more evidence that the universal strategies are beneficial and better than the selective ones. In the last 2 years, only few studies investigated the new screening strategies. Recently, several major societies refreshed their own guidelines or changed them, recommending universal GDM screening. It is very likely that further standardized outcome-based RCTs will be needed to achieve improved screening, diagnostic and clinical results. With a purpose to standardize further studies, an important task should be to define specific hyperglycemic complications as standardized primary endpoints. However, there are at least two additional leading challenges for future studies: scientific and ethical issues. First, it is possible that any scientific evidence of screening effectiveness would only be of relative significance, because an
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efficiency of screening is relative to the accuracy of GDM diagnostic criteria and specificity of study primary endpoints. Second, consequently to the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study results, it would be unethical that medical caregivers do not react during investigation to any status of glucose intolerance with nondiagnostic results. The most important opinion should be that our professional actions have to be focused on hyperglycemia instead of trying to diagnose GDM itself. Until there is more conclusive evidence, with current knowledge and experience, screening for hyperglycemia should be universally performed in every pregnant woman where it is possible and followed by definitive testing only in those women who are labeled as high-risk population. Although there is sufficient evidence that the universal two-step screening is cost-effective, it seems wise and pragmatic that the best strategy would be connecting the screening with diagnosing GDM in the same procedure with 75 g of glucose at 24–28 weeks’ gestation. However, a number of countries, including the USA, still utilize the 50-g 1-h GCT as the most popular screening method regardless of the obvious concerns. Early testing before 20 weeks to detect overt diabetes in high-risk pregnant populations should also be a fundamental change in strategies for the prevention of relevant hyperglycemic complications. Acknowledgements None. Conflicts of interest None declared.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Ryan EA. Diagnosing gestational diabetes. Diabetologia 2011; 54:480–486. 2. Sokup A, Ruszkowska-Ciastek B, Go´ralczyk K, et al. Insulin resistance as estimated by the homeostatic method at diagnosis of gestational diabetes: estimation of disease severity and therapeutic needs in a population-based study. BMC Endocr Disord 2013; 13:21–35. 3. Jiwani A, Marseille E, Lohse N, et al. Gestational diabetes mellitus: results from a survey of country prevalence and practices. J Matern Fetal Neonatal Med 2012; 25:600–610. 4. Schneider S, Bock C, Wetzel M, et al. The prevalence of gestational diabetes in advanced economies. J Perinatol Med 2012; 40:511–520. 5. Greuter MJ, van Emmerik NM, Wouters MG, van Tulder MW. Quality of guidelines on the management of diabetes in pregnancy: a systematic review. BMC Pregnancy Childbirth 2012; 12:58–64. 6. Hartling L, Dryden DM, Guthrie A, et al. Benefits and harms of treating && gestational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med 2013; 159:115–122. In a well conducted systematic review based on RCTs, non-RCTs, and cohort studies from 15 electronic databases, the authors summarized the maternal and neonatal benefits and the harms of treating GDM. There is a clear evidence of the importance of screening for and diagnosis of GDM.
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7. Power ML, Wilson EK, Hogan SO, et al. Patterns of preconception, prenatal and postnatal care for diabetic women by obstetrician–gynecologists. J Reprod Med 2013; 58:7–14. 8. Nielsen KK, de Courten M, Kapur A. The urgent need for universally applicable && simple screening procedures and diagnostic criteria for gestational diabetes mellitus – lessons from projects funded by the World Diabetes Foundation. Glob Health Action 2012; 5:17277. This is a unique investigation about the utilization of the internationally recommended guidelines (seven different screening procedures) for screening GDM in developing countries. A number of various problems and barriers in everyday practice were found. The authors emphasized that there is a need for an international consensus on screening for GDM and its applicability to ensure usage as wide as possible. 9. Buckley BS, Harreiter J, Damm P, et al. Gestational diabetes mellitus in & Europe: prevalence, current screening practice and barriers to screening. A review. Diabet Med 2012; 29:844–854. The recent systematic searching discovered inconsistency between screening practices across Europe and lack of consensus on testing methods and the value of routine screening. 10. Simmons D, Moses RG. Gestational diabetes mellitus: to screen or not to & screen? Is this really still a question? Diabetes Care 2013; 36:2877–2878. The authors send significant messages that any of the screening methods will miss women with GDM and that screening strategies based on the risk factors or a GCT cannot be endorsed for either health or financial reasons. 11. U.S. Preventive Services Task Force. Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 148:759–765. 12. Gillespie P, O’Neill C, Avalos G, Dunne FP. New estimates of the costs of & universal screening for gestational diabetes mellitus in Ireland. Ir Med J 2012; 105:15–18. In this interesting investigation, the authors estimated the costs of universal screening for GDM that were not low, but they emphasized that it would be more important to evaluate the cost-effectiveness of GDM screening program. 13. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational & diabetes mellitus: are the criteria proposed by the International Association of Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012; 35:529–535. On the basis of original decision model comparing the cost-effectiveness of three strategies to diagnose GDM, the authors concluded that the IADPSG screening method can be cost-effective as long as specific postpartum counseling and interventions reduce diabetes mellitus incidence. 14. Marseille E, Lohse N, Jiwani A, et al. The cost-effectiveness of gestational & diabetes screening including prevention of type 2 diabetes: application of a new model in India and Israel. J Matern Fetal Neonatal Med 2013; 26:802–810. The results of this recent study based on a new developed decision-analysis tool showed that GDM screening program and preventive measures are highly costeffective compared with no screening. 15. Mission JF, Ohno MS, Cheng YW, Caughey AB. Gestational diabetes & screening with the new IADPSG guidelines: a cost-effectiveness analysis. Am J Obstet Gynecol 2012; 207:326–328. The authors compared GDM screening using the IADPSG guidelines with a more common 50-g GCT and concluded that this newly proposed universal strategy is more expensive but still cost-effective in improving perinatal and maternal outcomes. 16. Langer O, Umans JG, Miodovnik M. The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference. J Matern Fetal Neonatal Med 2013; 26:111–115. 17. Avalos GE, Owens LA, Dunne F. Applying current screening tools for && gestational diabetes mellitus to a European population: is it time for change? Diabetes Care 2013; 36:3040–3044. In a very recent investigation, the authors retrospectively compared universal with selective screening models in a cohort of 5500 pregnant women. The results of this study represent strong evidence for a universal approach to screening for GDM. 18. Donovan L, Hartling L, Muise M, et al. Screening tests for gestational diabetes: && a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2013; 159:123–129. This current and well conducted systematic review based on 51 cohort studies represents an up-to-date and comprehensive summary of the existing evidence for all potential screening strategies for GDM and provides recommendations for clinical practice and future investigations. There is strong evidence that 50-g GCT is more efficient than fasting plasma glucose in identifying women with GDM. 19. Tomic´ V, Petrovic´ O, Crncˇevic´ Orlic´ Zˇ, Mandic´ V. Gestational diabetes and & pregnancy outcome – do we have right diagnostic criteria? J Matern Fetal Neonatal Med 2013; 26:854–859. The obtained research and unpublished results allowed to create a new one-step screening and diagnosing method with a 75-g oGTT, which hopefully should be evaluated in future research. 20. Lowe LP, Metzger BE, Dyer AR, et al. Hyperglycemia and Adverse Pregnancy & Outcome (HAPO) Study. Associations of maternal A1c and glucose with pregnancy outcome. Diabetes Care 2012; 35:574–580. In a recent retrospective study based on the HAPO study participants, the authors emphasized that HbA1c values cannot be a good alternative to an oGTT in the pregnant population. 21. Hieronimus S, Le Meaux JP. Relevance of gestational diabetes mellitus screening and comparison of selective with universal strategies. J Gynecol Obstet Biol Reprod 2010; 39 (Suppl. 2):S200–S213.
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How should we screen for gestational diabetes? Petrovic´ 22. Cosson E, Benbara A, Pharisien I, et al. Diagnostic and prognostic performances over 9 years of a selective screening strategy for gestational diabetes mellitus in a cohort of 18 775 subjects. Diabetes Care 2013; 36:598–603. In this extensive and relevant investigation based on a cohort of approximately 19 000 pregnant participants, the authors undoubtedly showed that selective approach to screening leads to missing at least one-third of women with GDM. They reasonably concluded that universal screening appears to be superior to the selective one. 23. Tieu J, Middleton P, McPhee AJ, Crowther CA. Screening and subsequent management for gestational diabetes for improving maternal and infant health. Cochrane Database Syst Rev 2010; 7:CD007222. doi: 10.1002/14651858. CD007222.ub2. 24. Van Leeuwen M, Louwerse MD, Opmeer BC, et al. Glucose challenge test for && detecting gestational diabetes mellitus: a systematic review. BJOG 2012; 119:393–401. In this recent systematic review that included 26 relevant studies, the authors showed that the 50-g GCT is acceptable for GDM screening but cannot replace the oGTT. They suggested that combining the GCT with other screening methods should be investigated. 25. Thompson D, Berger H, Feig D, et al. Diabetes and pregnancy. Can J Diabetes && 2013; 37 (Suppl. 1):S168–S183. This is the most recent document of the CDA Clinical Practice Guidelines Expert Committee regarding screening for GDM. The CDA currently recommends two approaches to healthcare providers. The preferred approach remains a routine 50-g GCT followed by a 75-g oGTT in pregnant women at risk. The new and alternate method is a one-step approach of a 75-g 2-h oGTT as proposed by the IADPSG. 26. Nankervis A, McIntyre HD, Moses RG, et al. Testing for gestational diabetes && mellitus in Australia. Diabetes Care 2013; 36:e64. doi: 10.2337/dc12-2345. This overview presents very recent information about the current recommendations on screening program for GDM in the Australian continent. Actually, the ADIPS introduced the new guidelines that endorse the strategy used by the IADPSG and the ADA that might be a sign toward international GDM screening consensus. 27. Jenum AK, Mørkrid K, Sletner L, et al. Impact of ethnicity on gestational & diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study Groups criteria: a population-based cohort study. Eur J Endocrinol 2012; 166:317–324. The authors investigated two different universal screening strategies proposed by WHO and IADPSG, and concluded that the new criteria resulted in identifying many pregnant women with a mild increase in fasting plasma glucose. 28. Falavigna M, Prestes I, Schmidt MI, et al. Impact of gestational diabetes & mellitus screening strategies on perinatal outcomes: a simulation study. Diabetes Res Clin Pract 2013; 99:358–365. On the basis of the results of a recent simulation study, the authors provided a conclusion that universal GDM screening has a mild influence on perinatal outcome with a slightly larger impact of screening based on IADPSG than WHO guidelines. 29. Ostlund I, Hanson U. Repeated random blood glucose measurements as universal screening test for gestational diabetes mellitus. Acta Obstet Gynecol Scand 2004; 83:46–51. 30. ACOG Practice Bulletin No. 137. Gestational diabetes mellitus. Obstet && Gynecol 2013; 122:406–416. This recent document provides the latest ACOG recommendations for the continuous use of a common two-step screening for GDM. There is a further important suggestion that before the testing approach is changed, implications of such changes should be examined. 31. Berger H, Sermer M, Farine D. Should the SOGC guidelines on screening for gestational diabetes mellitus be changed once again? J Obstet Gynaecol Can 2006; 28:536–539. 32. Van Leeuwen M, Opmeer BC, Yilmaz Y, et al. Accuracy of the random glucose & test as screening test for gestational diabetes mellitus: a systematic review. Eur J Obstet Gynecol Reprod Biol 2011; 154:130–135. This relevant meta-analysis, based on six studies, allowed the authors to conclude undoubtedly that there is no good evidence to recommend a random glucose test as a screening test for GDM. No recent study that deals with this issue is available. 33. Cheung KW, Wong SF. Gestational diabetes mellitus update and review of && literature. Reprod Sys Sexual Disord 2012; S2:002. In this up-to-date review, the authors summarized the current guidelines for GDM screening recommended by the most relevant professional organizations. They labeled selective screening by risk factors unattractive and potentially dangerous. The authors obviously prefer the universal screening because of its beneficial effects and the one-step approach that could eliminate many problems connected with the two-step model. 34. Corrado F, D’Anna R, Cannata ML, et al. Correspondence between firsttrimester fasting glycaemia, and oral glucose tolerance test in gestational diabetes diagnosis. Diabetes Metab 2012; 38:458–461. 35. VanDorsten JP, Dodson WC, Espeland MA, et al. NIH Consensus Develop&& ment Conference: diagnosing gestational diabetes mellitus. NIH Consens State Sci Statements 2013; 29:1–31. This is the most recent final statement of a U.S. NIH expert panel. Currently, in the USA, a two-step approach with a 50-g GCT followed by a 100-g 3-h oGTT is the most common screening strategy. However, it was stated that the one-step approach could offer certain benefits and operational advantages for patients and their obstetricians. &&
36. Farrar D, Duley L, Lawlor DA. Different strategies for diagnosing gestational diabetes to improve maternal and infant health. Cochrane Database Syst Rev 2011; 10:CD007122. doi: 10.1002/14651858.CD007122. pub2. 37. Sievenpiper JL, McDonald SD, Grey V, Don-Wauchope AC. Missed follow-up & opportunities using a two-step screening approach for gestational diabetes. Diabetes Res Clin Pract 2012; 96:e43–e46. In a recent study, the authors evaluated the effectiveness of the two-step screening practice and expressed grave concerns about the fact that only one-third of women with abnormal initial findings attended the official 75-g oGTT. 38. Sacks D, Hadden D, Maresh M, et al. Frequency of gestational diabetes & mellitus at collaborating centers based on IADPSG Consensus Panel – recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care 2012; 35:526–528. The authors indicate that the differences in studied pregnant populations and frequency of the GDM diagnosis may significantly impact the choice of screening strategies for GDM (fasting plasma glucose, 2-h oGTT, or 1-h oGTT). 39. Metzger B, Coustan DR, Dyer AR, et al. The diagnosis of gestational diabetes & mellitus: new paradigms or status quo? J Matern Fetal Neonatal Med 2012; 25:2564–2569. After detailed and careful reviewing of IADPSG recommendations, the authors reported their support for the IADPSG proposals for GDM screening and diagnosing. 40. Zhu WW, Fan L, Yang HX, et al. Fasting plasma glucose at 24–28 weeks to & screen for gestational diabetes mellitus: new evidence from China. Diabetes Care 2013; 36:2038–2040. Very recently, based on a cohort study of nearly 25 000 pregnant women, the authors concluded that fasting plasma glucose could be used for screening to avoid a number of the official oGTTs in resource-poor regions and countries. 41. McIntyre HD. Diagnosing gestational diabetes mellitus: rationed or rationally & related to risk? Diabetes Care 2013; 36:2879–2880. On the basis of the synthesis of available clinical and epidemiological trial data, the author characterized the IADPSG-recommended and ADA-recommended strategies as a reasonable approach to detecting pregnant women with significant hyperglycemia. 42. American Diabetes Association. Standards of medical care in diabetes – && 2013. Diabetes Care 2013; 36 (Suppl. 1):S11–S66. This is the most recent revision of ADA’s Professional Practice Committee based on a systematical searching for new evidence regarding the effectiveness of screening for GDM. Currently, the ADA changed recommendations and recommend screening at 24–28 weeks of gestation using a 75-g 2-h oGTT, and at the first visit in those pregnant women with high-risk factors. 43. Benhalima K, Van Crombrugge P, Hanssens M, et al. Gestational diabetes: && overview of the new consensus screening strategy and diagnostic criteria. Acta Clin Belg 2012; 67:255–261. The authors presented an interesting overview of the new consensus screening strategy. They concluded that the new strategy might lead to logistical problems to organize universal screening program for GDM. They also doubted about the effectiveness of the two-step screening method identifying real problems in organizing an oGTT a few days after abnormal GCT that makes GDM diagnosing suboptimal. 44. Mørkrid K, Jenum AK, Sletner L, et al. Failure to increase insulin secretory capacity during pregnancy-induced insulin resistance is associated with ethnicity and gestational diabetes. Eur J Endocrinol 2012; 167:579– 588. 45. Moses RG, Cheung NW. Point: universal screening for gestational diabetes mellitus. Diabetes Care 2009; 32:1349–1351. 46. Perovic M, Garalejic E, Gojnic M, et al. Sensitivity and specificity of ultra& sonography as a screening tool for gestational diabetes mellitus. J Matern Fetal Neonatal Med 2012; 25:1348–1353. In a recent and interesting study, the authors tried to establish a new ultrasoundbased scoring system suitable for GDM screening, but the method appears to be complex, time-consuming, and, most probably, not suitable for clinical practice. 47. Gojnic M, Stefanovic T, Perovic M, et al. Prediction of fetal macrosomia with & ultrasound parameters and maternal glycemic controls in gestational diabetes mellitus. Clin Exp Obstet Gynecol 2012; 39:512–515. In a prospective clinical trial, the authors investigated several ultrasound parameters as a potentially new screening method for GDM, but this very complex procedure has been applied too late in pregnancy to be useful as a screening method. 48. Grewal E, Kansara S, Kachhawa G, et al. Prediction of gestational diabetes & mellitus at 24 to 28 weeks of gestation by using first-trimester insulin sensitivity indices in Asian Indian subjects. Metabolism 2012; 61:715– 720. The authors presented a new and very interesting idea to screen women for GDM by measuring fasting and 2-h serum insulin levels in the first trimester of pregnancy. 49. Long H, Cundy T. Establishing consensus in the diagnosis of gestational diabetes following HAPO: where do we stand? Curr Diab Rep 2013; 13:43– 50. 50. Jang EH, Kwon HS. b-Cell dysfunction and insulin resistance in gestational glucose intolerance. Korean J Intern Med 2013; 28:294–296.
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Maternal–fetal medicine 51. O’Dwyer V, Farah N, Hogan J, et al. Timing of screening for gestational diabetes mellitus in women with moderate and severe obesity. Acta Obstet Gynecol Scand 2012; 91:447–451. In a prospective observational study, the authors concluded that an early screening for GDM before 20 weeks’ gestation could be useful, especially in selected pregnant population.
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52. Nwose EU, Richards RS, Bwititi PT, Butkowski EG. New guidelines for diagnosis of gestational diabetes: pathology-based impact assessment. N Am J Med Sci 2013; 5:191–194. This very recent study is evidence that we should be aware of the real consequences of introducing the new recommended guidelines for screening and diagnosis of GDM in clinical practice without previous epidemiologic analysis.
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