Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclearBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1567 (Published 11 March 2014) Cite this as: BMJ 2014;348:g1567
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The excellent article on Gestational Diabetes over diagnosis comes to the heart of what defines a medical condition. The association of risk factors with adverse outcomes is one method of defining disease. The example of the changes in diagnostic criteria and treatment of hypertension over the last six decades is a clear illustration of the considerations needed in determining the parameters into which a condition falls. In the 1940s, hypertension was defined at a BP ≥ 200/110mmHg in association with a cerebrovascular event or renal failure (1). Despite the knowledge that lesser degrees of systolic and diastolic blood pressures were associated with poor outcomes, the definition of hypertension was not modified until the 1960s when pharmacological advances allowed treatments to be better tolerated. Hypertension can now in effect be defined as a level of blood pressure at which the benefits of treatment outweigh the risks. The actual values of blood pressure continue to change as new evidence demonstrates safety and efficacy for a particular group.
The term Gestational Diabetes Mellitus (GDM) was first introduced to describe women with poor obstetric outcomes who had high glucose levels in subsequent pregnancies. Initial diagnostic criteria were based on values that best predicted later development of maternal T2DM (2). GDM can be viewed as an early phase of T2DM, the metabolic stress of pregnancy demonstrating a predisposition to glucose intolerance. The main fetal complication, macrosomia, encompasses a spectrum from normality to hyperglycaemia and is predicted by factors other than hyperglycaemia such as ethnicity, weight and dyslipidaemia. Importantly, maternal obesity predicts macrosomia, a common complication of untreated GDM, with numerically more macrosomic babies being born to obese mothers compared to those with GDM. Additionally maternal dyslipidaemia is a predictive factor and in some specific groups is a stronger one than glucose.
The Hyperglycaemia Adverse Pregnancy Outcomes study (HAPO) clearly demonstrates the linear relationship between glycaemia and fetal birth weight; however, there exists no evidence on treating glucose levels to the diagnostic criteria now formulated by the IADPSG and WHO in response to the study results (3). The two landmark trials demonstrating an improvement in outcomes in women with impaired glucose tolerance levels both defined GDM with a 2-post 75g load level of ≤7.8mmol/L (4, 5). Furthermore the HAPO data places a greater emphasis on fasting hyperglycaemia in direct contrast to studies demonstrating the importance of postprandial hyperglycaemia in predicting adverse fetal outcomes (6, 7).
Management policy is best guided by evidence-based medicine, the clear demonstration that a condition, within well-defined parameters, is safely and effectively managed by a certain strategy. Until such data exist we should define gestational diabetes, in terms of the data on glycaemia, with a 2-hour glucose of 7.8mmol/L. Should future evidence demonstrate that defining GDM with a combination of weight and glycaemia benefits from a particular management, then this should alter guidance.
1. M M. Historical Perspectives on the Management of Hypertension. The Journal of Clinical Hypertension. 2006;8(8):15-20.
2. O'Sullivan JB. Establishing criteria for gestational diabetes. Diabetes Care. 1980; 3(3):437-9.
3. HAPO Study Cooperative Research Group. Hyperglycaemia and Adverse Pregnancy Outcomes. The New England Journal of Medicine. 2008;358(19):1991-2002.
4. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. The New England Journal of Medicine. 2005;352(24):2477-86.
5. Landon MS, CY.; Thom, E.; Carpenter, MW.; Ramin, SM.; Casey, B.; Wapner RJ.; Varner, MW.; Rouse, DJ.; Thorp, JM.; Sciscione, A.; Catalano, P.; Harper, M.; Saade, G.; Lain, KY.; Sorokin, Y.; Peaceman, AM.; Tolosa, JE.; Anderson, GB. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. The New England Journal of Medicine. 2009;361(14):1339-48.
6. De Veciana M, Major C, MA. M, Asrat T, Toohey J, Lien J, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. The New England Journal of Medicine. 1995;333(19):1237-41.
7. Jovanovic-Peterson L, Peterson C, Reed G, Metzger B, Mills J, Knopp R, et al. Maternal postprandial glucose levels and infant birth weight: The Diabetes in Early Pregnancy Study. American Journal of Obstetrics and Gynecology. 1991;164(1):103-11.
Competing interests: No competing interests
We often face the dilemma of treatment with any changes in the criteria of diagnosis based on quantitative variables such as blood pressure levels, hemoglobin levels, and in the present case, the blood sugar level for gestational diabetes. There is a change in the criterion based on the new evidence piling up with each passing day. But how far do these changes often yield to better, meaning statistically proven to be significantly better, outcome than the previous criterion? The answer will not be immediately available. But it takes several years to get the results and prove or disprove the hypothesis. Time can only tell the outcome of such a drastic medical change in the criterion.
However, it is for sure that such reduction in the blood sugar level for diagnosis will lead to a higher false positive rate, putting a larger number of women who, otherwise, would have be labelled normal by earlier criterion to medications (avoidable), increasing the economic burden to the family, and above all increasing the anxiety level of the women. We still need to analyse the implications from the public health perspective. An increase in the prevalence of GDM by two to three times would translate into a two to three times increase in health expenditurs of the people and also the Government which implements diabetes control programme. Are we satisfied with a slight reduction in bad perinatal outcomes in lieu of the above large scale expenditures and affecting the general health of the people? We need to balance the benefits and the other effects, as listed above before accepting such a change. We need to wait and watch for the results of such a change, specially in developing countries, which are already burdened with resource constraints.
Competing interests: No competing interests
We thank Dr Hodson for his comment on our paper about overdiagnosis of gestational diabetes (GDM) and agree that women should be given choice about the need for intervention. However, terms fraught with emotion such as stillbirth and “risk of her baby dying” are inappropriate in this setting and unhelpful to the debate.
Firstly let us correct some factual errors. The ACHOIS study showed an increased risk of the baby being admitted to the special nursery in the treated group and not decreased1 as Dr Hodson states. Population studies and the other major intervention trial show no increased risk of stillbirth with GDM2-6. The ACHOIS study with 5 vs 0 stillbirth/neonatal deaths in the untreated vs treated groups is clearly at odds with other studies, and at least two of the 5 deaths could not plausibly be related to GDM (lethal congenital anomaly, intrauterine growth restriction)1. Dr Hodson details the improved outcomes seen with treatment in the MFMU study but these were all secondary outcomes:- treatment did not change the primary composite outcome6. Finally, and most importantly, both randomized controlled trials1;6 used a two-step process for the diagnosis of GDM, something that the newly proposed international criteria suggest dropping – a procedural change that fuels a huge increase in GDM prevalence.
The proposed criteria will double or triple GDM prevalence by capturing women with lower levels of glycaemia than those in the randomized controlled trials. Dr Hodson advocates a recipe for overdiagnosis: “treating larger groups of women for relatively smaller benefit”. We disagree. As there is no evidence that women diagnosed by the newly proposed criteria will benefit, but ample evidence that interventions and costs will increase, we consider it inappropriate to adopt them. A more rational and less emotional approach to the definition and management of GDM seems desirable.
(1) Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352(24):2477-2486.
(2) Shand AW, Bell JC, McElduff A, Morris J, Roberts CL. Outcomes of pregnancies in women with pre-gestational diabetes mellitus and gestational diabetes mellitus; a population-based study in New South Wales, Australia, 1998-2002. Diabet Med 2008; 25(6):708-715.
(3) Karmon A, Levy A, Holcberg G, Wiznitzer A, Mazor M, Sheiner E. Decreased perinatal mortality among women with diet-controlled gestational diabetes mellitus. International Journal of Gynaecology & Obstetrics 2009; 104(3):199-202.
(4) Fadl HE, Ostlund IK, Magnuson AF, Hanson US. Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabet Med 2010; 27(4):436-441.
(5) Ohana O, Holcberg G, Sergienko R, Sheiner E. Risk factors for intrauterine fetal death (1988-2009). J Matern Fetal Neonatal Med 2011; 24(9):1079-1083.
(6) Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361(14):1339-1348.
Competing interests: No competing interests
The recent analysis of gestational diabetes (GDM) (BMJ 2014:348:g1567) summarises the on-going debate about whether to screen for and indeed treat gestational diabetes. The authors conclude that mild glycaemia ‘does not carry anything like the same degree of risk’ (as pre-existing type 1 or 2 diabetes) and imply that treating GDM is without clear evidence of clinically important benefit.
Two randomized controlled trials (mentioned, but not given much credit in the article) have established the clinical benefit of treating gestational diabetes. Crowther et al. showed that treating GDM reduced a composite perinatal outcome (death, bone fracture, shoulder dystocia, and nerve palsy) from 4% to 1% (p=0.01). The number needed to treat was 34. Additionally fewer babies were admitted to the neonatal unit (71% vs 61%). Landon et al. showed significant reduction in mean birth weight (3302g vs. 3408 g), neonatal fat mass (427g vs. 464 g), frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and caesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P=0.01).
To the individual woman, a four-fold reduction in the risk of her baby dying, having permanent nerve damage or bone fracture is certainly worthy of consideration. Especially as the effective intervention can be as simple as monitoring home blood glucose levels and maintaining a healthy diet. Reducing neonatal admission is also beneficial both in terms of developing early bonding between mother and baby and managing cot availability and cost. The long-term impact of stillbirth, nerve palsy or bone injury is substantial both to individuals, families and society.
Perinatal mortality is at an all time low, targeting perinatal and maternal morbidity now becomes increasingly important. Further advancement may necessitate treating larger groups of women for relatively smaller benefit. This is common to almost all obstetric conditions in the developed world. However, it is the women, who potentially live with the consequences of non-intervention, who should be given the choice and not the medical profession who take a global, rather than individual view, of worthiness.
Competing interests: No competing interests
Gestational Diabetes, medicalisation and Maturity Onset Diabetes of the Young. (MODY)
Cundy et al are right to be concerned that the new guidelines on gestational diabetes diagnosis will increase medicalisation of pregnancy.(1).
In 2013 the same authors reported secular trends toward increasing maternal age and obesity suggesting that intervention rates are unlikely to decrease in the near future.(2)
As far back as 2000 Tim Cundy et al reported that in the Canadian population, perinatal mortality in babies of women with type 2 diabetes was higher than in those with type 1 diabetes. (3)
In 2006 Mary Macintosh et al reported the continued poor outcome of diabetic pregnancy in the United Kingdom, noting high rates of perinatal mortality and congenital malformation in the babies of women with type 1 and type 2 diabetes. (4)
The problem with pregnancy is the baby receives all their nourishment from their mother, which means the mother will be nutritionally depleted if her diet is inadequate for the needs of pregnancy. It is not surprising that our poor dietary transgressions are continued into pregnancy with unwelcome consequences such as insulin resistance accompanied by the diagnosis of GD
Omega-3 and Omega-6 essential fatty acids (EFAs) are vital in pregnancy. The International Society for the Study of Fatty Acids and Lipids (l999) conclude: "Currently, the best advice we can give to pregnant women is to increase their intake of oily sea fish 'like mackerel, non-farm-fed Salmon and Tuna before, during and after pregnancy, and to breast feed. (5)
Pregnant women supplementing with fish oil were shown to have positive outcomes in foetal development (6). Fish consumption in pregnancy has been limited due to possible high levels of mercury in some fish; therefore it is possible that EFA levels are further compromised. (6)
Studies have indicated that the essential fatty acid levels in pregnant women decline during gestation, and may affect the status of the newborn. A low intake of (EFAs) omega-3 and omega-6 have been linked with health issues in children
The activity of delta-6 and delta-5-desaturase, enzymes required for the synthesis of Arachidonic acid (a source of omega 6) and Docosahexaenoic acid (DHA) (a source of omega 3) are impaired in human and experimental diabetes.
Diabetes (either type) compromises maternal Red blood cell (RBC) (DHA) and cord plasma and red blood cell arachidonic acid (RBC AA) and docosahexaenoic acid.(DHA) The association of these two fatty acids with insulin sensitivity may mean that the current finding explains the higher incidence of insulin resistance and diabetes in the offspring of diabetic women.(7)
EFA levels fluctuate with dietary intake. It is unknown at which levels EFA deficiency causes insulin resistance. Omega-3 and omega-6 fats are polyunsaturated fatty acids (PUFAs) and are both essential for homeostasis however, when consumed in the wrong ratios; PUFAs tend to stimulate inflammatory processes in the body, especially if the fats and oils are processed.
Yet women with T2DM or GD are often placed on low fat diets. Including highly processed low fat spreads and margarines. Olive oil is a good choice of fat to lower the use of processed PUFAs in the diet, however it does not provide EFAs essential in pregnancy.
Obesity is thought to be the highest risk for developing GD. Many of those diagnosed with GD may have been on endless rounds of slimming diets, yo-yo dieting, have eating disorders such as bulimia, anorexia nervosa or habitual comfort eating. There may also be confusion over what actually constitutes a healthy diet. In the quest for pregnancy women may also be advised by a medical practitioner to lose weight. It should be borne in mind that pregnancy and subsequent breast feeding is an arduous process. The highest priority should be to prepare emotionally, physically and nutritionally for pregnancy. There should also be attention to essential fatty acid status. The unending quest to find more cases of diabetes is another case of overdiagnosis without any regard for evidence or care of the people affected.
Gestational diabetes has been described as;
“Carbohydrate intolerance of varying degrees of severity with onset or first recognition during pregnancy,” (8)
Yet many people with diabetes and GD are placed on high carbohydrate diets with the potential to increase their blood glucose levels. The high blood glucose levels further compromise the EFA levels.
Once gestational diabetes has been diagnosed in the UK, The National Institute for clinical Excellence (NICE) suggest hypoglycaemic therapy should be considered for women with gestational diabetes if diet and exercise fail to maintain blood glucose targets during a period of 1–2 weeks (9)
This offers a very limited window of opportunity to restore insulin sensitivity. Woman may be rapidly placed on therapies such as insulin injections with the inherent dangers of hypoglycaemia to both the mother and baby.
A type 2 diabetes patient is typically resistant to insulin, so to get the same level of blood glucose control as in a type 1 diabetes patient, the dose of insulin may need to be several times greater (10) In practice this can lead to pregnancy difficulties such as malformation, but there are also raised chances of miscarriage, preeclampsia, pre-term labour and stillbirth, and diabetic eye damage to the mother can worsen rapidly (11). This statement has direct implications for those mothers diagnosed as having gestational diabetes keeping glycaemic levels ideal for a healthy pregnancy.(10)(11)
The main desired outcome of treating mild gestational diabetes is to reduce macrosomia. (12)(13)
However, one significant cause of macrosomia is linked to Maturity Onset Diabetes of the Young (MODY) this form of diabetes appears to be overlooked in pregnancy management.
Maturity onset diabetes of the young (MODY) was a term first used in the 1970s by the eminent diabetologist Professor Robert Tattersall. (14)(15) It describes inheritable diabetes distinct from type 1 (insulin-dependent) and type 2 (noninsulin-dependent) diabetes.
MODY represents approximately 5% of diabetes diagnosed before the age of
45 (encompassing the reproductive years) (16). However, it is estimated that approximately 80% of cases are misdiagnosed as either Type 1 (T1DM) or Type 2 (T2DM) diabetes (16) (17)
HNF4A-MODY: Mutations in HNF4A are far less common,
representing only 10% of all MODY cases. (18)
Fetal heterozygosity results in significant macrosomia (average increase of 790 grams) due to increased in utero insulin secretion and subsequent neonatal transient or prolonged hypoglycemia (19).
Certainly there is a requirement for more evidence concerning gestational diabetes before overdiagnosing women and causing worry and distress at such a vulnerable time.
(1) Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclear. Tim Cundy, Evan Ackermann, Edmond A Ryan, BMJ 2014;348:g1567
(2) Obstetric interventions for women with type 1 or type 2 diabetes. Cundy T, Morgan J, O'Beirne C, Gamble G, Budden A, Ivanova V, Wallace M. Int J Gynaecol Obstet. 2013 Oct;123(1):50-3. doi: 10.1016/j.ijgo.2013.04.022. Epub 2013 Jul 12.
(3) Cundy T, Gamble G, Townend K, Henley PG, Macpherson P, Roberts AB. Perinatal mortality in type 2 diabetes mellitus Diabet Med 2000; 17:33-9.
(4) Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study.BMJ. 2006 Jul 22;333(7560):177. Epub 2006 Jun 16.
(5) Sattar, Berry & Grier,(1999). the International Society for the Study of Fatty Acids and Lipids( l999) Doctors from the Dept. of Biochemistry, Glasgow Royal Infirmary, and Dept. of Medicine, W. Glasgow Hospital, and Dept. of Obstetrics & Gynaecology, Glasgow Royal Infirmary,
(6) Krauss-Etschmann S, Shadid R, Campoy C, et al.(2007) Effects of fish-oil and folate supplementation of pregnant women on maternal and foetal Source: American Journal of Clinical Nutrition Source: American Journal of Clinical Nutrition.
(7) Min Yoegy, Clara Lowy, Kebreab Ghebremeskel, Beverley Thomas, Brigid Offley-Shore and Michael Crawford Journal of Clinical Nutrition, Vol. 82, No. 6,1162-1168,December2005. © 2005 American Society for Clinical Nutrition
(8) Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(suppl 2):161-7S.
(9) 18.104.22.168 Diabetes in pregnancy: Management of diabetes and its complications from pre-conception to the postnatal period
http://publications.nice.org.uk/diabetes-in-pregnancy-cg63/guidance#gest... Accessed 31 Mar 2014
(10) A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes David M. Nathan, John B. Buse, Mayer B. Davidson, Robert J. Heine, Rury R. Holman, Robert Sherwin, Bernard Zinman, Diabetes Care August 2006vol. 29 no. 8 1963-1972
(11)Diabetes in pregnancy Management of diabetes and its complications from
pre-conception to the postnatal period Issue date: March 2008 (reissued July 2008) http://www.nice.org.uk/nicemedia/live/11946/41321/41321.PDF accessed 31 Mar 2014
(12) Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med2005;352:2477-86.
(13) Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med2009;361:1339-48.
(14) Mild familial diabetes with dominant inheritance. Tattersall RB Q J Med. 1974 Apr; 43(170):339-57.
(15) A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people.Tattersall RB, Fajans SS Diabetes. 1975 Jan; 24(1):44-53.
(16) Thanabalasingham G, Pal A, Selwood MP, Dudley C, Fisher K, Bingley
PJ, Ellard S, Farmer AJ, McCarthy MI, Owen KR Systematic assessment
of etiology in adults with a clinical diagnosis of young-onset type
2 diabetes is a successful strategy for identifying maturity-onset
diabetes of the young. Diabetes Care. 2012 35:1206-1212.
(17). Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we
missing? Diabetologia. 2010 53:2504-2508.
(18). Stoffel M, Duncan SA The maturity-onset diabetes of the young
(MODY1) transcription factor HNF4alpha regulates expression of genes
required for glucose transport and metabolism. Proc Natl Acad Sci U S
(19). Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard
S, Ferrer J, Hattersley AT Macrosomia and hyperinsulinaemic
hypoglycaemia in patients with heterozygous mutations in the HNF4A
gene. PLoS Med. 2007;4:e118
Competing interests: No competing interests
This paper warns about the dangers of overdiagnosis related to a proposed shift in the diagnostic threshold for gestational diabetes, but I think that overdiagnosis is already happening. Over the last twenty years I have seen a marked increase in the numbers of women attending my surgery having been given a diagnosis of gestational diabetes. They are often anxious and bewildered, but submit to the regular blood glucose monitoring. I can't remember the last patient who needed any hypoglycaemic medication, nor whose blood glucose went above 10 mM.
I suspect that alterations in glucose metabolism are included in those physiological changes of pregnancy that we do not really understand. In the past we used to treat all pregnant women whose haemoglobin level strayed below the normal non-pregnant limits because we did not appreciate that the dilutional anaemia of pregnancy is physiological. Surely, rather than risk labelling yet more women with an unhelpful diagnosis, we should be going in the other direction and recognise that there is a cohort of often overweight pregnant women with impaired glucose tolerance who simply need some basic dietary advice and support.
Competing interests: No competing interests