Australian and New Zealand Journal of Obstetrics and Gynaecology 2015; 55: 17–20
DOI: 10.1111/ajo.12302
Opinion
New Zealand National GDM Guidelines: an alternative view of some good practice points Janet ROWAN,1 Helen ALLEN,2 Astrid BUDDEN,3 Rose ELDER,4 Matthew FARRANT,5 Ruth HUGHES,6 Valeria IVANOVA,3 Peter MOORE,7 Catherine MARNOCH8,9 and Nicole MCGRATH10 1
Department of Obstetrics, National Women’s Health, Auckland, 2Department of Obstetrics and Gynaecology, Waitemata Women’s Health, Auckland, 3Department of Obstetrics and Gynaecology, National Women’s Health, Auckland, 4Department of Obstetrics and Gynaecology, Wellington Regional Women’s Health, Wellington, 5Department of Medicine and Obstetrics, Waitemata Women’s Health, Auckland, 6Department of Obstetrics and Gynaecology, Christchurch Women’s Hospital, University of Otago, Christchurch, 7Department of Endocrinology and Obstetrics, Christchurch Women’s Hospital, Christchurch, 8Department of Obstetrics, Waitemata Women’s Health, 9 National Women’s Health, Auckland, and 10Department of Medicine and Obstetrics, Northland Women’s Health, Whangarei, New Zealand
The New Zealand Gestational Diabetes Mellitus (GDM) Guidelines, commissioned by the Ministry of Health, contains many good points, but several recommendations are creating controversy. This opinion piece discusses an alternative approach to early pregnancy screening for diabetes. We suggest that it is reasonable to refer women with an HbA1c ≥41 mmol/mol (5.9%) for further management, rather than the recommended referral threshold of ≥50 mmol/mol (6.7%). We also suggest that, for subsequent screening for GDM at 24–28 weeks’ gestation, a 75 g oral glucose tolerance test should be offered rather than a 50 g glucose challenge test. Key words: gestational diabetes mellitus, guidelines.
During 2013, the New Zealand (NZ) Ministry of Health commissioned a group of researchers to produce National GDM Guidelines. Relevant stakeholder organisations were asked to provide a representative to this group. Meetings were scheduled to discuss the relevant issues and data available. Although consensus was limited by the lack of robust data in a number of areas, final recommendations were made and sent to the Ministry towards the end of 2013. These recommendations have been approved by the Ministry. The NZ GDM Guidelines include many useful recommendations, and we endorse much of what is written. However, there are two points around the screening pathway that we do not support and want to express an alternative view: 1 The HbA1c threshold for referral when screening women for unrecognised diabetes with the first antenatal bloods. 2 The subsequent screening pathway for GDM.
Correspondence: Dr Janet Rowan, Department of Obstetrics, National Women’s Health, Level 9 Support Building, Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand. Email: [email protected] Received 17 September 2014; accepted 18 November 2014.
The authors also have concerns regarding the diagnostic thresholds for diagnosing GDM on a 75 g oral glucose tolerance test (OGTT), as they have been arbitrarily determined without reference to the extensive data available from the HAPO trial, but we are not addressing these concerns in this article. We agree that all these areas require further study, but we consider that there is enough evidence available to date to justify a different approach to the HbA1c referral threshold and the subsequent GDM screening pathway. The approach recommended in the guidelines appears to represent an underlying philosophy of minimising the number of women diagnosed with glucose elevations in pregnancy, to avoid ‘over-diagnosis’.1 Our philosophy is one of identifying women with glucose elevations in a logical and timely manner. Women have a choice whether to proceed with any screening recommendation and a further choice about treatment. This choice is removed if appropriate screening is not offered or the process falsely reassures women that they are at low risk. In general, all glucose elevations diagnosed for the first time in pregnancy are labelled as GDM. It is recognised that this encompasses a heterogeneous population, including women with previously unrecognised diabetes, previously unrecognised prediabetes (glucose intolerance, impaired fasting glucose) and those with ‘transient’ GDM. Previously
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
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J. Rowan et al.
unrecognised diabetes and prediabetes are present at conception and can potentially be detected in early pregnancy with booking bloods. ‘Transient’ GDM occurs in women who are unable to compensate for the increasing insulin resistance that develops from mid-gestation and can be detected by appropriate testing in the second half of pregnancy. Women with GDM have increased pregnancy risks as well as long-term risks of developing or continuing with diabetes after pregnancy.2 Treating women with even mild GDM is associated with improved pregnancy outcomes.3,4 It is recognised that those diagnosed before 24 weeks’ gestation are a higher risk subgroup.5–8 Although we do not have data to know whether early intervention improves outcomes in these women, it does not seem logical to diagnose them and do nothing until 24–28 weeks’ gestation. In a trial where women with GDM were randomised to metformin or insulin treatment at a mean gestation of 30 weeks’ gestation, the HbA1c at the time of randomisation correlated with the risk of pre-eclampsia and a large for gestational age (LGA) infant, suggesting intervention was too late for a number of these women.9 In another study in women with GDM requiring insulin, earlier intervention in a subsequent pregnancy reduced the risk of macrosomia.10 Identifying a woman with glucose elevations in pregnancy also identifies a child who is at later risk of obesity, diabetes and metabolic syndrome.2 These risks are higher in GDM offspring who are LGA at birth.11 It also identifies a family that may benefit from ongoing healthy lifestyle interventions after pregnancy, which could reduce progression to diabetes.12 New Zealand (NZ) is not winning the race against obesity and diabetes, with approximately 10–15% of women between 25 and 45 years of age having diabetes or prediabetes in 2009, and this is an opportunity to start at ‘the top of the cliff’ for the next generation.13 The in utero environment is thought to be an important contributor to these later risks.14 Optimising the in utero environment throughout pregnancy is a logical aim, and this is one of the reasons for trying to identify women who have unrecognised preexisting glucose elevations as soon as possible during pregnancy. Whether this will translate into improved health in the future for the child is not yet known.
The HbA1c threshold for referral when screening women for unrecognised diabetes with the first antenatal bloods The National Guidelines acknowledge that NZ has high and increasing rates of obesity and undiagnosed diabetes in young women. It proposes that all pregnant women should be offered screening for underlying diabetes with the first antenatal blood test. An HbA1c is a marker of circulating glucose levels over time so that significant elevations in glucose levels lead to an associated increase in HbA1c level. Measuring an HbA1c is easy to add to the initial routine antenatal bloods, as it does not require fasting. Outside pregnancy, in NZ, HbA1c is used to screen for abnormal glucose levels that warrant intervention: an 18
HbA1c 41–49 mmol/mol (5.9–6.6%) is consistent with prediabetes and an HbA1c ≥50 mmol/mol (6.7%) is consistent with diabetes.15 Other countries use lower thresholds.16 The emphasis in using HbA1c for diagnosis has been on specificity rather than sensitivity, as the implications of being labelled with diabetes for an individual are great.17 A confirmatory test is recommended, particularly when borderline as, although there is little daily biological variability with HbA1c, the uncertainty of measurement (UoM) is up to 3–4 mmol/mol (0.3%) when reporting in the prediabetes range. (Labtests, Auckland) Other factors that influence red cell turnover contribute to additional alterations in HbA1c. Iron deficiency is one common factor, but the data measuring its effect are not consistent. A recent review of this suggests that on a population level and in pregnancy, the absolute effect is small.18 In routine clinical practice, the HbA1c is a useful measure of glycaemia. It is used to monitor effectiveness of management and relates to risks of complications. In women with pre-existing diabetes or prediabetes, we recommend they reduce their HbA1c as low as possible towards the reference range prior to pregnancy and, in women with type 2 diabetes, a number of guidelines recommend aiming for the normal reference range to improve pregnancy outcomes.19,20 In pregnancy, HbA1c decreases by 6- to 10-weeks’ gestation and usually remains lower through pregnancy, so anyone with an HbA1c ≥41 mmol/mol (5.9%) with their first antenatal bloods is likely to have underlying prediabetes or diabetes.21,22 It is important to note that women who develop ‘transient’ GDM have a normal HbA1c in early pregnancy, and it is usually still within the normal range at the time of GDM diagnosis in the second half of pregnancy. Thus, HbA1c is not useful to diagnose ‘transient’ GDM. The National Guidelines recommend that women with an HbA1c ≥50 mmol/mol (6.7%) should be referred to the diabetes in pregnancy service and women with HbA1c of 41–49 mmol/mol (5.9–6.6%) should be offered dietary advice and have an OGTT at 24–28 weeks’ gestation. The guidelines acknowledge this is not an evidence-based recommendation. There are already guidelines in place at a few centres that recommend referral of women with an HbA1c ≥41 mmol/ mol (5.9%). The rationale for this practice, which has been in place since 2011, is that these women already have glucose elevations, so why wait for another 2–4 months before starting interventions and why do a routine 75 g OGTT several months later? In addition, some of these women, particularly more obese women, may have a nondiagnostic OGTT.23 The OGTT could be a false negative, or it may be that the nutrient load of her diet stresses the pancreas more than a 75 g glucose load. There is no evidence to suggest that this logical approach should be changed at present and there are several sets of New Zealand data to support this practice. The first set of data comes from a study in Christchurch in over 16 000 women.24 The primary aim of this study was to determine
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
NZ GDM Guidelines alternative view
the usefulness of HbA1c measurements for detecting unrecognised diabetes in early pregnancy, as compared with a 75 g OGTT before 20-week gestation (fasting glucose ≥7.0 mmol/L or 2 h glucose ≥11.1 mmol/L). The optimal threshold was an HbA1c ≥41 mmol/mol (5.9%) (100% sensitivity and 97.4% specificity). A threshold of 50 mmol/ mol (6.7%), as proposed by the National Guidelines, would miss 60% of women with diabetes in pregnancy. An HbA1c ≥41 mmol/mol (5.9%) also had a high specificity for early GDM (98.4%), although the sensitivity was low. Overall, 2.9% of the population had an HbA1c ≥41 mmol/mol (5.9%). Excluding women treated for diabetes in pregnancy, women who had an early pregnancy HbA1c of 41–46 mmol/mol (5.9–6.4%) had significantly increased risks of congenital anomaly, pre-eclampsia, shoulder dystocia and perinatal death compared with women with an early HbA1cs 41 mmol/mol (5.9%) at diagnosis. They concluded this represented women with underlying glucose intolerance or diabetes preceding pregnancy.26 Another Indian study demonstrated that an HbA1c threshold of 41 mmol/mol (5.9%) was 97.2% specific for GDM.27 In an American study, all women with an HbA1c >42 mmol/mol (6.0%) before 14 weeks of gestation had a diagnosis of GDM by subsequent OGTT, and the authors suggested that these women could be referred without a confirmatory OGTT.28 The most appropriate HbA1c threshold for referral does require more robust data. In particular, a trial is required to assess whether early intervention can improve pregnancy outcomes for pregnant women with an HbA1c in the prediabetes range. A final point relates to inequality of healthcare delivery. In our NZ studies from Auckland and Northland, women with HbA1c levels of 41–49 mmol/mol (5.9–6.6%) are more likely to be of Pacific or Maori ethnicity and other non-European groups. This is an opportunity to intervene earlier in these higher risk women.
The subsequent screening pathway for GDM The National Guidelines recommends that women with an HbA1c of 41–49 mmol/mol (5.9–6.6%) have a 75 g
OGTT at 24–28 weeks’ gestation and all other women should be offered a nonfasting 1-h 50 g glucose challenge test (GCT) and if that is positive, proceed to a diagnostic 75 g OGTT. As suggested in the previous section, it seems illogical to request an OGTT in women who have been identified with glucose elevations already. It also seems illogical to ask all other women to do a GCT to ascertain whether they are at increased risk of GDM, without taking into account other factors. If a woman already is at increased risk because of clinical risk factors or the population prevalence of GDM is high, it is reasonable to offer a single diagnostic OGTT. Also, as glucose levels are associated with adverse pregnancy outcomes in a continuous fashion, the OGTT result provides useful information, even if it is below the diagnostic threshold. In the past, when lifestyles were different and pregnant women were younger and had lower BMIs, the prevalence of GDM was low (2–3% of pregnancies). Therefore, women were screened with a 50 g GCT. If the 1-h glucose level was ≥7.8 mmol/L, they were asked to do a 75 g OGTT, with approximately 15% of those diagnosing GDM. Using this ‘two-step’ approach, studies suggested that 75–80% of women with GDM would be detected.29 When the prevalence was low, missing 20–25% of women with GDM was not so important, but now the prevalence has increased, with GDM complicating at least 5–10% of pregnancies across New Zealand, the number of ‘missed’ women is significant. The two-step approach also leads to a delay in diagnosis and will miss women with isolated fasting hyperglycaemia. It is important to note that data from NZ have shown that 23% of women who have an elevated screening test for GDM do not go on to have a diagnostic OGTT, which further increases the number of ‘missed’ cases of GDM.30 For many women, going to the laboratory once and doing a diagnostic OGTT may be the preferred option. Advocates of the two-step approach argue that a single glucose measure has limitations with respect to reproducibility and by doing the GCT first, women fail two lots of testing, so the diagnosis is more secure. Conversely, this approach means that a single glucose result (GCT) is also used to rule out GDM, which is particularly of concern in a woman with significant risk factors. A 50 g GCT may be an inadequate ‘challenge’ in obese women. As obese women with GDM are at higher risk than lean women with GDM, it is particularly important to minimise the false-negative rate in that population.31 We believe that, in New Zealand, it is appropriate to recommend a 75 g OGTT at 24- to 28-weeks’ gestation gestation to screen for GDM in women who have not already been diagnosed by earlier HbA1c screening. If a woman declines, then a 50 g GCT may be offered, as long as its limitations are understood. The rates of GDM will continue to increase. We do not see the solution is to avoid the diagnosis. It is a missed opportunity to improve pregnancy and potentially long-term outcomes for that young woman and her family. Instead of putting our
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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heads in the sand, we should be discussing our models of care. Not all women with GDM need to be seen in a specialised clinic. Instead, we need to safely triage these women to appropriate levels of monitoring and intervention, both in pregnancy and afterwards. In addition to improving pregnancy outcomes, this is an opportunity for diabetes prevention with ongoing lifestyle interventions (and possibly metformin), approaches which have been shown to be cost-effective, although we may also require public health policy changes to successfully make more significant changes across our communities.32 Also, as we further refine our knowledge about treating women with GDM, we have the potential to reduce the offspring’s susceptibility to developing obesity and diabetes as they grow up.
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References 1 Cundy T, Ackermann E, Ryan EA. Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclear. BMJ 2014; 348: g1567. 2 Malcolm J. Through the looking glass: gestational diabetes as a predictor of maternal and offspring long-term health. Diabetes Metab Res Rev 2012; 28: 307–311. 3 Crowther C, Hiller J, Moss J et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477–2486. 4 Landon MB, Spong CY, Thom E et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361: 1339–1348. 5 Sermer M, Naylor C, Gare D et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without diabetes. The Toronto tri-hospital gestational diabetes project. Am J Obstet Gynecol 1995; 173(1): 146–156. 6 Aberg A, Westbom L. Association between maternal preexisitng or gestational diabetes and health problems in children. Acta Paediatr 2001; 90: 746–750. 7 Most OL, Kim JH, Arslan AA, Klauser C. Maternal and neonatal outcomes in early glucose tolerance testing in an obstetric population in New York city. J Perinat Med 2009; 37: 114–117. 8 Hawkins JS, Lo JY, Casey BM et al. Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis. Am J Obstet Gynecol 2008; 198: 287 e1–287 e6. 9 Rowan JA, Gao W, Hague WM, McIntyre HD. Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial. Diabetes Care 2010; 33(1): 9–16. 10 Maher N, McAuliffe F, Foley M. The benefit of early treatment without rescreening in women with a history of gestational diabetes. Matern Fetal Neonatal Med 2013; 26: 318–320. 11 Boney C, Verma A, Tucker R, Vohr B. Metabolic syndrome in childhood: association with birth weight, maternal obesity and gestational diabetes mellitus. Pediatrics 2005; 115: e290– e296. 12 Ferrara A, Ehrlich SF. Strategies for diabetes prevention before and after pregnancy in women with GDM. Curr Diabetes Rev 2011; 7: 75–83. 13 Coppell KJ, Mann JI, Williams SM et al. Prevalence of diagnosed and undiagnosed diabetes and prediabetes in New
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Zealand: findings from the 2008/09 Adult Nutrition Survey. N Z Med J 2013; 126: 23–42. Poston L. Intergenerational transmission of insulin resistance and type 2 diabetes. Prog Biophys Mol Biol 2011; 106(1): 315–322. Braatvedt G, Cundy T, Crooke M et al. Understanding the new HbA1c units for the diagnosis of type 2 diabetes. N Z Med J 2012; 125: 70–80. Standards of medical care in diabetes–2014. Diabetes Care 2014; 37(Suppl 1): S14–S80. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009; 32: 1327–1334. Ahmad J, Rafat D. HbA1c and iron deficiency: a review. Diabetes Metab Syndr 2013; 7: 118–122. Management of diabetes from preconception to the postnatal period: summary of NICE guidance. BMJ 2008; 336: 714– 717. McElduff A, Cheung NW, McIntyre HD et al. The Australasian Diabetes in Pregnancy Society consensus guidelines for the management of type 1 and type 2 diabetes in relation to pregnancy. Med J Aust 2005; 183: 373–377. Nielsen LR, Ekbom P, Damm P et al. HbA1c levels are significantly lower in early and late pregnancy. Diabetes Care 2004; 27: 1200–1201. O’Connor C, O’Shea PM, Owens LA et al. Trimester-specific reference intervals for haemoglobin A1c (HbA1c) in pregnancy. Clin Chem Lab Med 2012; 50: 905–909. Rowan JA, Budden A, Sadler LC. Women with a nondiagnostic 75 g glucose tolerance test but elevated HbA1c in pregnancy: an additional group of women with gestational diabetes. Aust N Z J Obstet Gynaecol 2014; 54: 177–180. Hughes RC, Moore MP, Gullam JE et al. An early pregnancy HbA1c >/=5.9% (41 mmol/mol) is optimal for detecting diabetes and identifies women at increased risk of adverse pregnancy outcomes. Diabetes Care 2014; 37: 2953– 2959. McGrath NM, Baker C, Simkins A. Increased detection of gestational diabetes mellitus by using HbA1c screening in the first antenatal blood tests. Diabet Med 2014; 31: 1277. Balaji V, Madhuri BS, Ashalatha S et al. A1C in gestational diabetes mellitus in Asian Indian women. Diabetes Care 2007; 30: 1865–1867. Rajput R, Yogesh Y, Rajput M, Nanda S. Utility of HbA1c for diagnosis of gestational diabetes mellitus. Diabetes Res Clin Pract 2012; 98(1): 104–107. Anaka O, Houlihan C, Beim R, Ranzini AC. Does firsttrimester hemoglobin A1C predict gestational diabetes and fetal outcome? Obstet Gynecol 2014; 123(Suppl 1): 38S–39S. 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. Yapa M, Simmons D. Screening for gestational diabetes mellitus in a multiethnic population in New Zealand. Diabetes Res Clin Pract 2000; 48: 217–223. Catalano P, Thomas A, Huston-Presley L, Amini S. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol 2003; 189: 1698–1704. Cefalu WT. A “spoonful of sugar” and the realities of diabetes prevention!. Diabetes Care 2014; 37: 906–908.
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
DOI: 10.1111/ajo.12302
Opinion
New Zealand National GDM Guidelines: an alternative view of some good practice points Janet ROWAN,1 Helen ALLEN,2 Astrid BUDDEN,3 Rose ELDER,4 Matthew FARRANT,5 Ruth HUGHES,6 Valeria IVANOVA,3 Peter MOORE,7 Catherine MARNOCH8,9 and Nicole MCGRATH10 1
Department of Obstetrics, National Women’s Health, Auckland, 2Department of Obstetrics and Gynaecology, Waitemata Women’s Health, Auckland, 3Department of Obstetrics and Gynaecology, National Women’s Health, Auckland, 4Department of Obstetrics and Gynaecology, Wellington Regional Women’s Health, Wellington, 5Department of Medicine and Obstetrics, Waitemata Women’s Health, Auckland, 6Department of Obstetrics and Gynaecology, Christchurch Women’s Hospital, University of Otago, Christchurch, 7Department of Endocrinology and Obstetrics, Christchurch Women’s Hospital, Christchurch, 8Department of Obstetrics, Waitemata Women’s Health, 9 National Women’s Health, Auckland, and 10Department of Medicine and Obstetrics, Northland Women’s Health, Whangarei, New Zealand
The New Zealand Gestational Diabetes Mellitus (GDM) Guidelines, commissioned by the Ministry of Health, contains many good points, but several recommendations are creating controversy. This opinion piece discusses an alternative approach to early pregnancy screening for diabetes. We suggest that it is reasonable to refer women with an HbA1c ≥41 mmol/mol (5.9%) for further management, rather than the recommended referral threshold of ≥50 mmol/mol (6.7%). We also suggest that, for subsequent screening for GDM at 24–28 weeks’ gestation, a 75 g oral glucose tolerance test should be offered rather than a 50 g glucose challenge test. Key words: gestational diabetes mellitus, guidelines.
During 2013, the New Zealand (NZ) Ministry of Health commissioned a group of researchers to produce National GDM Guidelines. Relevant stakeholder organisations were asked to provide a representative to this group. Meetings were scheduled to discuss the relevant issues and data available. Although consensus was limited by the lack of robust data in a number of areas, final recommendations were made and sent to the Ministry towards the end of 2013. These recommendations have been approved by the Ministry. The NZ GDM Guidelines include many useful recommendations, and we endorse much of what is written. However, there are two points around the screening pathway that we do not support and want to express an alternative view: 1 The HbA1c threshold for referral when screening women for unrecognised diabetes with the first antenatal bloods. 2 The subsequent screening pathway for GDM.
Correspondence: Dr Janet Rowan, Department of Obstetrics, National Women’s Health, Level 9 Support Building, Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand. Email: [email protected] Received 17 September 2014; accepted 18 November 2014.
The authors also have concerns regarding the diagnostic thresholds for diagnosing GDM on a 75 g oral glucose tolerance test (OGTT), as they have been arbitrarily determined without reference to the extensive data available from the HAPO trial, but we are not addressing these concerns in this article. We agree that all these areas require further study, but we consider that there is enough evidence available to date to justify a different approach to the HbA1c referral threshold and the subsequent GDM screening pathway. The approach recommended in the guidelines appears to represent an underlying philosophy of minimising the number of women diagnosed with glucose elevations in pregnancy, to avoid ‘over-diagnosis’.1 Our philosophy is one of identifying women with glucose elevations in a logical and timely manner. Women have a choice whether to proceed with any screening recommendation and a further choice about treatment. This choice is removed if appropriate screening is not offered or the process falsely reassures women that they are at low risk. In general, all glucose elevations diagnosed for the first time in pregnancy are labelled as GDM. It is recognised that this encompasses a heterogeneous population, including women with previously unrecognised diabetes, previously unrecognised prediabetes (glucose intolerance, impaired fasting glucose) and those with ‘transient’ GDM. Previously
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
17
J. Rowan et al.
unrecognised diabetes and prediabetes are present at conception and can potentially be detected in early pregnancy with booking bloods. ‘Transient’ GDM occurs in women who are unable to compensate for the increasing insulin resistance that develops from mid-gestation and can be detected by appropriate testing in the second half of pregnancy. Women with GDM have increased pregnancy risks as well as long-term risks of developing or continuing with diabetes after pregnancy.2 Treating women with even mild GDM is associated with improved pregnancy outcomes.3,4 It is recognised that those diagnosed before 24 weeks’ gestation are a higher risk subgroup.5–8 Although we do not have data to know whether early intervention improves outcomes in these women, it does not seem logical to diagnose them and do nothing until 24–28 weeks’ gestation. In a trial where women with GDM were randomised to metformin or insulin treatment at a mean gestation of 30 weeks’ gestation, the HbA1c at the time of randomisation correlated with the risk of pre-eclampsia and a large for gestational age (LGA) infant, suggesting intervention was too late for a number of these women.9 In another study in women with GDM requiring insulin, earlier intervention in a subsequent pregnancy reduced the risk of macrosomia.10 Identifying a woman with glucose elevations in pregnancy also identifies a child who is at later risk of obesity, diabetes and metabolic syndrome.2 These risks are higher in GDM offspring who are LGA at birth.11 It also identifies a family that may benefit from ongoing healthy lifestyle interventions after pregnancy, which could reduce progression to diabetes.12 New Zealand (NZ) is not winning the race against obesity and diabetes, with approximately 10–15% of women between 25 and 45 years of age having diabetes or prediabetes in 2009, and this is an opportunity to start at ‘the top of the cliff’ for the next generation.13 The in utero environment is thought to be an important contributor to these later risks.14 Optimising the in utero environment throughout pregnancy is a logical aim, and this is one of the reasons for trying to identify women who have unrecognised preexisting glucose elevations as soon as possible during pregnancy. Whether this will translate into improved health in the future for the child is not yet known.
The HbA1c threshold for referral when screening women for unrecognised diabetes with the first antenatal bloods The National Guidelines acknowledge that NZ has high and increasing rates of obesity and undiagnosed diabetes in young women. It proposes that all pregnant women should be offered screening for underlying diabetes with the first antenatal blood test. An HbA1c is a marker of circulating glucose levels over time so that significant elevations in glucose levels lead to an associated increase in HbA1c level. Measuring an HbA1c is easy to add to the initial routine antenatal bloods, as it does not require fasting. Outside pregnancy, in NZ, HbA1c is used to screen for abnormal glucose levels that warrant intervention: an 18
HbA1c 41–49 mmol/mol (5.9–6.6%) is consistent with prediabetes and an HbA1c ≥50 mmol/mol (6.7%) is consistent with diabetes.15 Other countries use lower thresholds.16 The emphasis in using HbA1c for diagnosis has been on specificity rather than sensitivity, as the implications of being labelled with diabetes for an individual are great.17 A confirmatory test is recommended, particularly when borderline as, although there is little daily biological variability with HbA1c, the uncertainty of measurement (UoM) is up to 3–4 mmol/mol (0.3%) when reporting in the prediabetes range. (Labtests, Auckland) Other factors that influence red cell turnover contribute to additional alterations in HbA1c. Iron deficiency is one common factor, but the data measuring its effect are not consistent. A recent review of this suggests that on a population level and in pregnancy, the absolute effect is small.18 In routine clinical practice, the HbA1c is a useful measure of glycaemia. It is used to monitor effectiveness of management and relates to risks of complications. In women with pre-existing diabetes or prediabetes, we recommend they reduce their HbA1c as low as possible towards the reference range prior to pregnancy and, in women with type 2 diabetes, a number of guidelines recommend aiming for the normal reference range to improve pregnancy outcomes.19,20 In pregnancy, HbA1c decreases by 6- to 10-weeks’ gestation and usually remains lower through pregnancy, so anyone with an HbA1c ≥41 mmol/mol (5.9%) with their first antenatal bloods is likely to have underlying prediabetes or diabetes.21,22 It is important to note that women who develop ‘transient’ GDM have a normal HbA1c in early pregnancy, and it is usually still within the normal range at the time of GDM diagnosis in the second half of pregnancy. Thus, HbA1c is not useful to diagnose ‘transient’ GDM. The National Guidelines recommend that women with an HbA1c ≥50 mmol/mol (6.7%) should be referred to the diabetes in pregnancy service and women with HbA1c of 41–49 mmol/mol (5.9–6.6%) should be offered dietary advice and have an OGTT at 24–28 weeks’ gestation. The guidelines acknowledge this is not an evidence-based recommendation. There are already guidelines in place at a few centres that recommend referral of women with an HbA1c ≥41 mmol/ mol (5.9%). The rationale for this practice, which has been in place since 2011, is that these women already have glucose elevations, so why wait for another 2–4 months before starting interventions and why do a routine 75 g OGTT several months later? In addition, some of these women, particularly more obese women, may have a nondiagnostic OGTT.23 The OGTT could be a false negative, or it may be that the nutrient load of her diet stresses the pancreas more than a 75 g glucose load. There is no evidence to suggest that this logical approach should be changed at present and there are several sets of New Zealand data to support this practice. The first set of data comes from a study in Christchurch in over 16 000 women.24 The primary aim of this study was to determine
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
NZ GDM Guidelines alternative view
the usefulness of HbA1c measurements for detecting unrecognised diabetes in early pregnancy, as compared with a 75 g OGTT before 20-week gestation (fasting glucose ≥7.0 mmol/L or 2 h glucose ≥11.1 mmol/L). The optimal threshold was an HbA1c ≥41 mmol/mol (5.9%) (100% sensitivity and 97.4% specificity). A threshold of 50 mmol/ mol (6.7%), as proposed by the National Guidelines, would miss 60% of women with diabetes in pregnancy. An HbA1c ≥41 mmol/mol (5.9%) also had a high specificity for early GDM (98.4%), although the sensitivity was low. Overall, 2.9% of the population had an HbA1c ≥41 mmol/mol (5.9%). Excluding women treated for diabetes in pregnancy, women who had an early pregnancy HbA1c of 41–46 mmol/mol (5.9–6.4%) had significantly increased risks of congenital anomaly, pre-eclampsia, shoulder dystocia and perinatal death compared with women with an early HbA1cs 41 mmol/mol (5.9%) at diagnosis. They concluded this represented women with underlying glucose intolerance or diabetes preceding pregnancy.26 Another Indian study demonstrated that an HbA1c threshold of 41 mmol/mol (5.9%) was 97.2% specific for GDM.27 In an American study, all women with an HbA1c >42 mmol/mol (6.0%) before 14 weeks of gestation had a diagnosis of GDM by subsequent OGTT, and the authors suggested that these women could be referred without a confirmatory OGTT.28 The most appropriate HbA1c threshold for referral does require more robust data. In particular, a trial is required to assess whether early intervention can improve pregnancy outcomes for pregnant women with an HbA1c in the prediabetes range. A final point relates to inequality of healthcare delivery. In our NZ studies from Auckland and Northland, women with HbA1c levels of 41–49 mmol/mol (5.9–6.6%) are more likely to be of Pacific or Maori ethnicity and other non-European groups. This is an opportunity to intervene earlier in these higher risk women.
The subsequent screening pathway for GDM The National Guidelines recommends that women with an HbA1c of 41–49 mmol/mol (5.9–6.6%) have a 75 g
OGTT at 24–28 weeks’ gestation and all other women should be offered a nonfasting 1-h 50 g glucose challenge test (GCT) and if that is positive, proceed to a diagnostic 75 g OGTT. As suggested in the previous section, it seems illogical to request an OGTT in women who have been identified with glucose elevations already. It also seems illogical to ask all other women to do a GCT to ascertain whether they are at increased risk of GDM, without taking into account other factors. If a woman already is at increased risk because of clinical risk factors or the population prevalence of GDM is high, it is reasonable to offer a single diagnostic OGTT. Also, as glucose levels are associated with adverse pregnancy outcomes in a continuous fashion, the OGTT result provides useful information, even if it is below the diagnostic threshold. In the past, when lifestyles were different and pregnant women were younger and had lower BMIs, the prevalence of GDM was low (2–3% of pregnancies). Therefore, women were screened with a 50 g GCT. If the 1-h glucose level was ≥7.8 mmol/L, they were asked to do a 75 g OGTT, with approximately 15% of those diagnosing GDM. Using this ‘two-step’ approach, studies suggested that 75–80% of women with GDM would be detected.29 When the prevalence was low, missing 20–25% of women with GDM was not so important, but now the prevalence has increased, with GDM complicating at least 5–10% of pregnancies across New Zealand, the number of ‘missed’ women is significant. The two-step approach also leads to a delay in diagnosis and will miss women with isolated fasting hyperglycaemia. It is important to note that data from NZ have shown that 23% of women who have an elevated screening test for GDM do not go on to have a diagnostic OGTT, which further increases the number of ‘missed’ cases of GDM.30 For many women, going to the laboratory once and doing a diagnostic OGTT may be the preferred option. Advocates of the two-step approach argue that a single glucose measure has limitations with respect to reproducibility and by doing the GCT first, women fail two lots of testing, so the diagnosis is more secure. Conversely, this approach means that a single glucose result (GCT) is also used to rule out GDM, which is particularly of concern in a woman with significant risk factors. A 50 g GCT may be an inadequate ‘challenge’ in obese women. As obese women with GDM are at higher risk than lean women with GDM, it is particularly important to minimise the false-negative rate in that population.31 We believe that, in New Zealand, it is appropriate to recommend a 75 g OGTT at 24- to 28-weeks’ gestation gestation to screen for GDM in women who have not already been diagnosed by earlier HbA1c screening. If a woman declines, then a 50 g GCT may be offered, as long as its limitations are understood. The rates of GDM will continue to increase. We do not see the solution is to avoid the diagnosis. It is a missed opportunity to improve pregnancy and potentially long-term outcomes for that young woman and her family. Instead of putting our
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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heads in the sand, we should be discussing our models of care. Not all women with GDM need to be seen in a specialised clinic. Instead, we need to safely triage these women to appropriate levels of monitoring and intervention, both in pregnancy and afterwards. In addition to improving pregnancy outcomes, this is an opportunity for diabetes prevention with ongoing lifestyle interventions (and possibly metformin), approaches which have been shown to be cost-effective, although we may also require public health policy changes to successfully make more significant changes across our communities.32 Also, as we further refine our knowledge about treating women with GDM, we have the potential to reduce the offspring’s susceptibility to developing obesity and diabetes as they grow up.
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