25th July 2024, A/Prof Chee L Khoo
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The current gold standard for screening for gestational diabetes mellitus (GDM) for women with no risk factors for hyperglycaemia is an oral glucose tolerance test (OGTT) at 24-28 weeks’ gestation. Women with risk factors are recommended to have an OGTT in the first trimester. Unfortunately, many women are nauseous during the first trimester and performing an OGTT during that time can be very unpalatable. Further, OGTT requires women to attend a facility with appropriate laboratory infrastructure, in a fasting state and sit there for 2 hours or more. In rural and remote areas, the practicalities of organising an OGTT can be challenging. How useful is HbA1c as a replacement for OGTT?
We know that any degree of hyperglycaemia during pregnancy (overt diabetes or GDM) is associated with poor maternal and offspring outcomes (1). The diagnosis of gestational diabetes around 28 weeks and subsequent management does reduce adverse pregnancy and birth outcomes but only by 50% at best (2,3). Is the diagnosis of GDM at 24-28 weeks too late then? There is increasing evidence that suggests that the early pregnancy metabolic milieu is a determinant of fetoplacental development and pregnancy outcomes [4-10]. In some women, by the time GDM is diagnosed at 24-28 weeks, damage to the foetus may already have occurred.
Professor David Simmons demonstrated in the landmark study, TOBOGM, that treatment of early GDM (<20 weeks) significantly improved maternal and offspring outcomes (). In other words, early diagnosis of hyperglycaemia (whether GDM or over diabetes) in pregnancy is important in preventing the early damage to the offspring.
Since the performing of OGTT in early pregnancy can be both logistically difficult and practically unpalatable, HbA1c has been investigated for screening of maternal hyperglycaemia. This might also pick up previously undiagnosed overt diabetes in pregnancy. Evidence of its utility in prediction of GDM diagnosed after 20 weeks is not abundant and the results are rather conflicting. Further, the cut-off for the diagnosis of overt diabetes and GDM varies according to different population under study.
How useful is early pregnancy HbA1c in predicting GDM diagnosed at 24-28 weeks?
The evidence on whether early HbA1c is useful in predicting GDM later is also quite conflicting. Some studies have suggested that early-pregnancy HbA1c performs poorly in the prediction of late-onset GDM diagnosed after 20 weeks’ gestation [11,12]. Other studies in unselected [13,14] and high-risk populations [14-16] have yielded inconsistent results.
In the Early Diagnosis of Diabetes in Pregnancy (EDDIE) study, 1394 women had their HbA1c measured at 8-14 weeks (17). OGTT were performed at 12-16 weeks and again at 24-28 weeks. The OGTT diagnostic cut off were fasting, 1 h- and 2 h-plasma glucose: ≥5.3, ≥ 10.0mmol/l, and/or ≥ 8.6mmol/l, respectively. They used an HbA1c cut-off of ≥ 5.4% as abnormal. While the study concluded that early-pregnancy HbA1c ≥ 5.4% was positively associated with fasting and post-load plasma glucose concentrations in an OGTT at 12—16 weeks’ gestation and predicted pharmacologically-treated early- and late-onset GDM, the accuracy was poor. It had a sensitivity of 0.55 and specificity of 0.67.
In a recently published study, Saravanan et al conducted a prospective cohort study looking at women from Kenya, India and UK. They assessed the efficacy of early HbA1c either alone or as part of a composite score (age, BMI and family history). Pregnant women aged 18–50 years of age and at less than 16 weeks of gestation (<20 weeks in Kenya), confirmed by dating ultrasound were recruited. Women with type 1 or type 2 diabetes, on metformin therapy up to 6 weeks before recruitment for anovulation or infertility, severe anaemia (haemoglobin <8 g/L), abnormal haemoglobin or haemoglobinopathies, or any serious medical illness were excluded. Women were excluded from OGTTs if fasting plasma glucose (FPG) or random plasma glucose or HbA1c was in the diabetes range (FPG ≥7∙0 mmol/L; random plasma glucose ≥11∙1 mmol/L; HbA1c ≥6∙5% or FPG was in the gestational diabetes range (≥5·1 mmol/L and ≤6·9 mmol/L).
3070 women in India and 4104 women in Kenya were recruited. The UK cohort had 4320 women. After exclusions, 2115, 2142 and 4320 women in India, Kenya and UK respectively underwent OGTT at booking and at 24-28 weeks. Overall, early pregnancy HbA1c on its own, or in combination with commonly used risk factors such as age, BMI, and family history of diabetes, identified about 50% of women who had gestational diabetes in late pregnancy. But when they looked at what thresholds they can rule-in or rule-out GDM and avoid OGTT at all, the results of the study were more useful. They used different thresholds in the different cohort of patients:
India
Rule-out HbA1c – 4.9%
Rule-in HbA1c – 5.4%
Kenya
Rule-out HbA1c – 5.2%
Rule-in HbA1c – 6.0%
UK
Rule-out HbA1c – 5.2%
Rule-in HbA1c – 5.6%
In other words, if the woman’s early HbA1c is below the rule-out threshold, then she is unlikely to have GDM and if the woman’s early HbA1c is above the rule-in threshold, then she is very likely to have GDM. In both of those scenarios, she can avoid an OGTT. Those that are in between the thresholds will need an OGTT at 24-28 weeks. This way, we may be able to avoid a lot of OGTTs.
In summary, while HbA1c may not be able to totally replace OGTT to diagnose GDM, it may be able to avoid OGTT in some women. As different populations are likely to have different prevalence of GDM, the thresholds will need to be tailored to that population in question. We anxiously await the imminent release of the ADIPS 2024 GDM recommendations which is expected within weeks. I will keep you updated as soon as they are out.
References
- HAPO Collaborative Research Group. Hyperglycemia and adverse pregnancy 322 outcomes. New Eng J Med. 2008; 358:1991-2002
- Saravanan P, Magee LA, Banerjee A, et al. Gestational diabetes: opportunities for improving maternal and child health. Lancet Diabetes Endocrinol 2020; 8: 793–800.
- 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
- Lassance L, Haghiac M, Leahy P, Basu S, Minium J, Zhou J, et al. Identification of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstet Gynecol. 2015;212:647e1–11.
- Desoye G. The human placenta in diabetes and obesity: friend or foe? The 2017 Norbert Freinkel Award lecture. Diabetes Care. 2018;41:1362–9.
- Stephenson J, Heslehurst N, Hall J, Schoenaker DAJM, Hutchinson J, Cade JE, et al. Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health. Lancet. 2018;391:1830–41.
- O’Tierney-Ginn P, Presley L, Myers S, Catalano P. Placental growth response to maternal insulin in early pregnancy. J Clin Endocrinol Metab. 2015;100:159–65.
- Raets L, Beunen K, Benhalima K. Screening for gestational diabetes Mellitus in early pregnancy: what is the evidence? J Clin Med. 2021;10.
- Immanuel J, Simmons D. Screening and treatment for early-onset gestational diabetes Mellitus: a systematic review and Meta-analysis. Curr Diab Rep. 2017;17:115.
- 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;39:982–7.
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- Kattini R, Hummelen R, Kelly L. Early gestational diabetes Mellitus Screening with Glycated Hemoglobin: a systematic review. J Obstet Gynaecol Can. 2020;42:1379–84.
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- Saravanan P, Deepa M, Ahmed Z, et al. Early pregnancy HbA1c as the first screening test for gestational diabetes: results from three prospective cohorts. Lancet Diabetes Endocrinol. 2024 Jun 24:S2213-8587(24)00151-7. 36. Hughes RCE, Moore PM, Gullam JE, et al. An Early Pregnancy HbA1c ≥5.9% (41 423 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk 424 of Adverse Pregnancy Outcomes. Diabetes Care. 2014; 37 (11): 2953–2959. 425
- Simmons D, Immanuel J, Hague WM, Teede H, Nolan CJ, Peek MJ, et al. Treatment of gestational diabetes Mellitus Diagnosed early in pregnancy. N Engl J Med. 2023;388:2132–44