- Email: [email protected]
Gestational diabetes in the first trimester: is early testing justified?
Comment
Gestational diabetes in the first trimester: is early testing justified? Most studies demonstrating the risks of gestational diabetes1 and the benefits of treatment2 are limited to women diagnosed at 24 weeks’ gestation and later. Such data have provided the rationale for universal testing for gestational diabetes from 24 weeks’ gestation and the revised diagnostic criteria proposed by the International Association of Diabetes and Pregnancy Study Groups (IADPSG)3 and endorsed by WHO4 (diagnosis based on one or more of the following: fasting plasma glucose 5·1–6·9 mmol/L, 1 h post-load glucose ≥10·0 mmol/L, 2 h post-load glucose 8·5–11·0 mmol/L following a 2 h 75 g oral glucose tolerance test).3,4 The IADPSG does not advise routine testing for gestational diabetes before 24 weeks’ gestation, but does recommend earlier, first trimester testing for women at high risk of hyperglycaemia in pregnancy, with the intention to identify women with overt diabetes (diagnosed based on fasting plasma glucose ≥7·0 mmol/L, HbA1c ≥6·5% [41 mmol/mol], or random plasma glucose ≥11·1 mmol/L with confirmation).3 However, early testing will also lead to increased detection of milder degrees of hyperglycaemia, below the threshold of overt diabetes, a diagnosis now referred to as gestational diabetes before 24 weeks’ gestation or early gestational diabetes. One study estimated the prevalence of early gestational diabetes using pre-IADPSG criteria in a multiethnic cohort at about 30%,5 and early testing nearly doubled the incidence of gestational diabetes in a Californian cohort.6 Notably, however, significant uncertainties about the diagnostic criteria for early gestational diabetes and its management remain. No consensus exists with regard to diagnostic criteria to define early gestational diabetes. The IADPSG recommends diagnosing gestational diabetes before 24 weeks’ gestation based on a fasting plasma glucose of 5·1–6·9 mmol/L.3 However, the lower threshold has been challenged partly because it is poorly predictive of gestational diabetes at 24–28 weeks’ gestation7 and because testing before the natural decline in fasting plasma glucose during pregnancy (which occurs early in the first trimester) might lead to potential overdiagnosis.8 More recently, a fasting plasma glucose between 6·1 and 6·9 mmol/L has been proposed in China for the diagnosis of early gestational diabetes,9
but this requires confirmation in other ethnicities. WHO has expanded on the IADPSG criteria for the diagnosis of early gestational diabetes to include the same postload 1 h and 2 h glucose thresholds from the oral glucose tolerance test recommended for diagnosis from 24 weeks’ gestation.4 The Hyperglycemia and Adverse Pregnancy Outcomes study1 showed that risk of adverse pregnancy outcomes increased comparably with a 1 SD increment increase in 1 h and 2 h oral glucose tolerance test concentrations (after 24 weeks’ gestation); however, evidence to support the early gestational diabetes thresholds are lacking, as are normative maternal first trimester glycaemia data. Adding to the complexity, McIntyre and colleagues10 argued against the use of either the IADPSG fasting plasma glucose threshold or specific post-load oral glucose tolerance test glucose thresholds for diagnosing early gestational diabetes, suggesting instead that an early HbA1c of at least 5·9% (41 mmol/mol) might identify women at higher risk for adverse pregnancy outcomes. This recommendation was based on data showing that this HbA1c threshold (measured at a median of 47 days’ gestation) detected all cases of (overt) diabetes in pregnancy and predicted adverse pregnancy outcomes in a New Zealand cohort.11 Nevertheless, this recommendation has yet to gain wide acceptance and application, and whether it would exclude pregnancies that would still benefit from treatment is contentious.12 The risks associated with early gestational diabetes and the evidence for benefit of early treatment were also unclear. Previous studies have reported poor pregnancy outcomes and conflicting benefits of intervention in early gestational diabetes13,14 but are confounded by the inclusion of women with pre-gestational or overt diabetes within the early gestational diabetes cohorts and the use of varying gestational diabetes diagnostic criteria. However, it is now evident that women with early gestational diabetes, lower than the threshold for overt diabetes, are at increased risk of adverse pregnancy outcomes.5 We recently showed, using preIADPSG criteria, that women diagnosed with and treated for gestational diabetes before 24 weeks’ gestation, especially in the first trimester, were at significantly greater risk for hypertensive disorders, pre-term delivery,
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
Lancet Diabetes Endocrinol 2017 Published Online February 28, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30066-9
1
Comment
caesarean section, neonatal intensive-care admission, jaundice, large-for-gestational-age, and macrosomia compared with those diagnosed and treated from 24 weeks’ gestation.5 Importantly, we excluded women with overt diabetes from this study. These data suggest heterogeneity within the gestational diabetes phenotype and a continuum of risk from overt diabetes to early gestational diabetes, with gestational diabetes diagnosed from 24 weeks’ gestation being the lowest risk condition.5 Moreover, recent evidence shows that an excessive foetal growth trajectory occurs as early as 20 weeks’ gestation in women subsequently diagnosed with gestational diabetes,15 and offspring adiposity is increased in early infancy despite good antenatal maternal glycaemic control (when intervention for gestational diabetes commences from 26 weeks’ gestation),16 indicating that the prevailing delayed testing and treatment approach to gestational diabetes might not adequately ameliorate the long-term adverse effects of prolonged intra-uterine exposure to maternal hyperglycaemia and dyslipidaemia. These studies suggest that early detection is justified to identify women at higher risk of adverse maternal and neonatal outcomes, even in the absence of overt diabetes. Once diagnosed, it is of course critical to determine if an effective intervention exists. Glycaemic targets and management strategies for early gestational diabetes are assumed to be the same as those recommended for gestational diabetes diagnosed from 24 weeks’ gestation; however, this has not been validated, nor have the risks of treatment at this early stage been systematically assessed. We reported persisting poorer outcomes in women diagnosed with early gestational diabetes compared with those diagnosed from 24 weeks’ gestation, despite current best practice treatment of hyperglycaemia in both groups, including the use of insulin when indicated, but not metformin.5 Our finding that baseline HbA1c was more strongly and consistently associated with adverse outcomes in women diagnosed with gestational diabetes from 24 weeks’ gestation compared with those diagnosed with early gestational diabetes supports the notion that effects independent of maternal hyperglycaemia might contribute to risk in early gestational diabetes.12 Factors such as maternal adiposity and a more insulin-resistant phenotype might have a role in contributing to this risk.5 As we move towards greater recognition of early gestational diabetes, further research is urgently required to assess 2
the efficacy of alternative early treatment strategies, including different glycaemic targets, use of metformin versus insulin, or limiting gestational weight gain, to improve outcomes in this high-risk cohort. Ultimately, early (preventive) intervention before the development of hyperglycaemia might be needed, and this will require earlier and more accurate prediction of gestational diabetes risk, potentially combining testing for early gestational diabetes with first trimester screening for aneuploidy and pre-eclampsia. Thus far, however, the evidence is equivocal whether early pregnancy lifestyle interventions can prevent the subsequent diagnosis of gestational diabetes at 24–28 weeks’ gestation in high-risk women, with some studies (eg, RADIEL) showing a reduction in gestational diabetes incidence and others (eg, LIMIT and UPBEAT) showing no effect.17 Current evidence suggests that women with early gestational diabetes represent a high-risk cohort and an important subgroup of gestational diabetes to identify. However, there are substantial gaps in the evidence to support early testing and treatment approaches, which are currently largely extrapolated from studies of gestational diabetes from 24 weeks’ gestation, resulting in a lack of international consensus and a standardised approach to early gestational diabetes. More high quality research is urgently needed to determine the optimal tests and glycaemic thresholds that provide the best prognostic accuracy to define early gestational diabetes; the efficacy of alternative and preventive treatment strategies given that glucosecentric strategies alone appear insufficient in this highrisk cohort; and the best means of detecting women at risk of early gestational diabetes to enable targeted prevention. *Arianne N Sweeting, Glynis P Ross, Jon Hyett, Jencia Wong Royal Prince Alfred Hospital, Diabetes Centre, Sydney, Australia (ANS, GPR, JW); Sydney Medical School, University of Sydney, Sydney, Australia (ANS, GPR, JW); Royal Prince Alfred Hospital, Department of High Risk Obstetrics, Sydney, Australia (JH); and Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, Australia (JH) [email protected] We declare no competing interests. 1 2
HAPO Study Cooperative Research Group. Hyperglycaemia and adverse pregnancy outcomes. New Eng J Med 2008; 358: 1991–2002. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database Syst Rev 2009; 3: CD003395.
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
Comment
3
International Association of Diabetes in Pregnancy Study Groups. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676–682. 4 Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract 2014; 103: 341–63. 5 Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus in early pregnancy: evidence for poor pregnancy outcomes despite treatment. Diabetes Care 2016; 39: 75–81. 6 Alunni ML, Roeder HA, Moore TR, Ramos GA. First trimester gestational diabetes screening–change in incidence and pharmacotherapy need. Diabetes Res Clin Pract 2015; 109: 135–140. 7 Corrado F, D’Anna R, Cannata ML, et al. Correspondence between first-trimester fasting glycaemia and oral glucose tolerance test in gestational diabetes diagnosis. Diabetes Metab 2012; 38: 458–61. 8 Mills JL, Jovanovic L, Knopp R, et al. Physiological reduction in fasting plasma glucose concentration in the first trimester of normal pregnancy: the diabetes in early pregnancy study. Metabolism 1998; 47: 1140–44. 9 Zhu WW, Yang HX, Wei YM, et al. Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care 2013; 36: 586–90. 10 McIntyre HD, Sacks DA, Barbour LA, et al. Issues with the diagnosis and classification of hyperglycemia in early pregnancy. Diabetes Care 2016; 39: 53–54.
11 Hughes RCE, 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: 2953–59. 12 Sweeting AN, Ross GP, Hyett J, et al. Baseline HbA1c to identify high risk gestational diabetes: utility in early versus standard gestational diabetes. J Clin Endocrinol Metab 2017; 102: 150–56. 13 Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R. Gestational diabetes mellitus diagnosed during early pregnancy. Am J Obstet Gynecol 2000; 182: 346–50. 14 Super DM, Edelberg SC, Philipson EH, Hertz RH, Kalhan SC. Diagnosis of gestational diabetes in early pregnancy. Diabetes Care 1991; 14: 288–94. 15 Sovio U, Murphy HR, Smith GC. Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women. Diabetes Care 2016; 39: 982–87. 16 Logan KM, Emsley RJ, Jeffries S, et al. Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus. Diabetes Care 2016; 39: 1045–51. 17 Ma RCW, Schmidt MI, Tam WH, McIntyre HD, Catalano PM. Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and post partum. Lancet Diabetes Endocrinol 2016; 4: 1037–49.
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
3
Gestational diabetes in the first trimester: is early testing justified? Most studies demonstrating the risks of gestational diabetes1 and the benefits of treatment2 are limited to women diagnosed at 24 weeks’ gestation and later. Such data have provided the rationale for universal testing for gestational diabetes from 24 weeks’ gestation and the revised diagnostic criteria proposed by the International Association of Diabetes and Pregnancy Study Groups (IADPSG)3 and endorsed by WHO4 (diagnosis based on one or more of the following: fasting plasma glucose 5·1–6·9 mmol/L, 1 h post-load glucose ≥10·0 mmol/L, 2 h post-load glucose 8·5–11·0 mmol/L following a 2 h 75 g oral glucose tolerance test).3,4 The IADPSG does not advise routine testing for gestational diabetes before 24 weeks’ gestation, but does recommend earlier, first trimester testing for women at high risk of hyperglycaemia in pregnancy, with the intention to identify women with overt diabetes (diagnosed based on fasting plasma glucose ≥7·0 mmol/L, HbA1c ≥6·5% [41 mmol/mol], or random plasma glucose ≥11·1 mmol/L with confirmation).3 However, early testing will also lead to increased detection of milder degrees of hyperglycaemia, below the threshold of overt diabetes, a diagnosis now referred to as gestational diabetes before 24 weeks’ gestation or early gestational diabetes. One study estimated the prevalence of early gestational diabetes using pre-IADPSG criteria in a multiethnic cohort at about 30%,5 and early testing nearly doubled the incidence of gestational diabetes in a Californian cohort.6 Notably, however, significant uncertainties about the diagnostic criteria for early gestational diabetes and its management remain. No consensus exists with regard to diagnostic criteria to define early gestational diabetes. The IADPSG recommends diagnosing gestational diabetes before 24 weeks’ gestation based on a fasting plasma glucose of 5·1–6·9 mmol/L.3 However, the lower threshold has been challenged partly because it is poorly predictive of gestational diabetes at 24–28 weeks’ gestation7 and because testing before the natural decline in fasting plasma glucose during pregnancy (which occurs early in the first trimester) might lead to potential overdiagnosis.8 More recently, a fasting plasma glucose between 6·1 and 6·9 mmol/L has been proposed in China for the diagnosis of early gestational diabetes,9
but this requires confirmation in other ethnicities. WHO has expanded on the IADPSG criteria for the diagnosis of early gestational diabetes to include the same postload 1 h and 2 h glucose thresholds from the oral glucose tolerance test recommended for diagnosis from 24 weeks’ gestation.4 The Hyperglycemia and Adverse Pregnancy Outcomes study1 showed that risk of adverse pregnancy outcomes increased comparably with a 1 SD increment increase in 1 h and 2 h oral glucose tolerance test concentrations (after 24 weeks’ gestation); however, evidence to support the early gestational diabetes thresholds are lacking, as are normative maternal first trimester glycaemia data. Adding to the complexity, McIntyre and colleagues10 argued against the use of either the IADPSG fasting plasma glucose threshold or specific post-load oral glucose tolerance test glucose thresholds for diagnosing early gestational diabetes, suggesting instead that an early HbA1c of at least 5·9% (41 mmol/mol) might identify women at higher risk for adverse pregnancy outcomes. This recommendation was based on data showing that this HbA1c threshold (measured at a median of 47 days’ gestation) detected all cases of (overt) diabetes in pregnancy and predicted adverse pregnancy outcomes in a New Zealand cohort.11 Nevertheless, this recommendation has yet to gain wide acceptance and application, and whether it would exclude pregnancies that would still benefit from treatment is contentious.12 The risks associated with early gestational diabetes and the evidence for benefit of early treatment were also unclear. Previous studies have reported poor pregnancy outcomes and conflicting benefits of intervention in early gestational diabetes13,14 but are confounded by the inclusion of women with pre-gestational or overt diabetes within the early gestational diabetes cohorts and the use of varying gestational diabetes diagnostic criteria. However, it is now evident that women with early gestational diabetes, lower than the threshold for overt diabetes, are at increased risk of adverse pregnancy outcomes.5 We recently showed, using preIADPSG criteria, that women diagnosed with and treated for gestational diabetes before 24 weeks’ gestation, especially in the first trimester, were at significantly greater risk for hypertensive disorders, pre-term delivery,
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
Lancet Diabetes Endocrinol 2017 Published Online February 28, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30066-9
1
Comment
caesarean section, neonatal intensive-care admission, jaundice, large-for-gestational-age, and macrosomia compared with those diagnosed and treated from 24 weeks’ gestation.5 Importantly, we excluded women with overt diabetes from this study. These data suggest heterogeneity within the gestational diabetes phenotype and a continuum of risk from overt diabetes to early gestational diabetes, with gestational diabetes diagnosed from 24 weeks’ gestation being the lowest risk condition.5 Moreover, recent evidence shows that an excessive foetal growth trajectory occurs as early as 20 weeks’ gestation in women subsequently diagnosed with gestational diabetes,15 and offspring adiposity is increased in early infancy despite good antenatal maternal glycaemic control (when intervention for gestational diabetes commences from 26 weeks’ gestation),16 indicating that the prevailing delayed testing and treatment approach to gestational diabetes might not adequately ameliorate the long-term adverse effects of prolonged intra-uterine exposure to maternal hyperglycaemia and dyslipidaemia. These studies suggest that early detection is justified to identify women at higher risk of adverse maternal and neonatal outcomes, even in the absence of overt diabetes. Once diagnosed, it is of course critical to determine if an effective intervention exists. Glycaemic targets and management strategies for early gestational diabetes are assumed to be the same as those recommended for gestational diabetes diagnosed from 24 weeks’ gestation; however, this has not been validated, nor have the risks of treatment at this early stage been systematically assessed. We reported persisting poorer outcomes in women diagnosed with early gestational diabetes compared with those diagnosed from 24 weeks’ gestation, despite current best practice treatment of hyperglycaemia in both groups, including the use of insulin when indicated, but not metformin.5 Our finding that baseline HbA1c was more strongly and consistently associated with adverse outcomes in women diagnosed with gestational diabetes from 24 weeks’ gestation compared with those diagnosed with early gestational diabetes supports the notion that effects independent of maternal hyperglycaemia might contribute to risk in early gestational diabetes.12 Factors such as maternal adiposity and a more insulin-resistant phenotype might have a role in contributing to this risk.5 As we move towards greater recognition of early gestational diabetes, further research is urgently required to assess 2
the efficacy of alternative early treatment strategies, including different glycaemic targets, use of metformin versus insulin, or limiting gestational weight gain, to improve outcomes in this high-risk cohort. Ultimately, early (preventive) intervention before the development of hyperglycaemia might be needed, and this will require earlier and more accurate prediction of gestational diabetes risk, potentially combining testing for early gestational diabetes with first trimester screening for aneuploidy and pre-eclampsia. Thus far, however, the evidence is equivocal whether early pregnancy lifestyle interventions can prevent the subsequent diagnosis of gestational diabetes at 24–28 weeks’ gestation in high-risk women, with some studies (eg, RADIEL) showing a reduction in gestational diabetes incidence and others (eg, LIMIT and UPBEAT) showing no effect.17 Current evidence suggests that women with early gestational diabetes represent a high-risk cohort and an important subgroup of gestational diabetes to identify. However, there are substantial gaps in the evidence to support early testing and treatment approaches, which are currently largely extrapolated from studies of gestational diabetes from 24 weeks’ gestation, resulting in a lack of international consensus and a standardised approach to early gestational diabetes. More high quality research is urgently needed to determine the optimal tests and glycaemic thresholds that provide the best prognostic accuracy to define early gestational diabetes; the efficacy of alternative and preventive treatment strategies given that glucosecentric strategies alone appear insufficient in this highrisk cohort; and the best means of detecting women at risk of early gestational diabetes to enable targeted prevention. *Arianne N Sweeting, Glynis P Ross, Jon Hyett, Jencia Wong Royal Prince Alfred Hospital, Diabetes Centre, Sydney, Australia (ANS, GPR, JW); Sydney Medical School, University of Sydney, Sydney, Australia (ANS, GPR, JW); Royal Prince Alfred Hospital, Department of High Risk Obstetrics, Sydney, Australia (JH); and Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, Australia (JH) [email protected] We declare no competing interests. 1 2
HAPO Study Cooperative Research Group. Hyperglycaemia and adverse pregnancy outcomes. New Eng J Med 2008; 358: 1991–2002. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database Syst Rev 2009; 3: CD003395.
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
Comment
3
International Association of Diabetes in Pregnancy Study Groups. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676–682. 4 Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract 2014; 103: 341–63. 5 Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus in early pregnancy: evidence for poor pregnancy outcomes despite treatment. Diabetes Care 2016; 39: 75–81. 6 Alunni ML, Roeder HA, Moore TR, Ramos GA. First trimester gestational diabetes screening–change in incidence and pharmacotherapy need. Diabetes Res Clin Pract 2015; 109: 135–140. 7 Corrado F, D’Anna R, Cannata ML, et al. Correspondence between first-trimester fasting glycaemia and oral glucose tolerance test in gestational diabetes diagnosis. Diabetes Metab 2012; 38: 458–61. 8 Mills JL, Jovanovic L, Knopp R, et al. Physiological reduction in fasting plasma glucose concentration in the first trimester of normal pregnancy: the diabetes in early pregnancy study. Metabolism 1998; 47: 1140–44. 9 Zhu WW, Yang HX, Wei YM, et al. Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care 2013; 36: 586–90. 10 McIntyre HD, Sacks DA, Barbour LA, et al. Issues with the diagnosis and classification of hyperglycemia in early pregnancy. Diabetes Care 2016; 39: 53–54.
11 Hughes RCE, 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: 2953–59. 12 Sweeting AN, Ross GP, Hyett J, et al. Baseline HbA1c to identify high risk gestational diabetes: utility in early versus standard gestational diabetes. J Clin Endocrinol Metab 2017; 102: 150–56. 13 Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R. Gestational diabetes mellitus diagnosed during early pregnancy. Am J Obstet Gynecol 2000; 182: 346–50. 14 Super DM, Edelberg SC, Philipson EH, Hertz RH, Kalhan SC. Diagnosis of gestational diabetes in early pregnancy. Diabetes Care 1991; 14: 288–94. 15 Sovio U, Murphy HR, Smith GC. Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women. Diabetes Care 2016; 39: 982–87. 16 Logan KM, Emsley RJ, Jeffries S, et al. Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus. Diabetes Care 2016; 39: 1045–51. 17 Ma RCW, Schmidt MI, Tam WH, McIntyre HD, Catalano PM. Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and post partum. Lancet Diabetes Endocrinol 2016; 4: 1037–49.
www.thelancet.com/diabetes-endocrinology Published online February 28, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30066-9
3