Gestational diabetes diagnosis landmarks

A Timeline

Introduction

Definition Gestational diabetes mellitus (GDM) is hyperglycemia that is first recognized at any time during pregnancy and does not reach the glycemic thresholds for diabetes2. Variable degrees of severity may be present2; 3. All women diagnosed with GDM should be evaluated postpartum, in order to detect diabetes that persists after pregnancy3. Pioneers Descriptions of pregnancy and diabetes were available long before clinical studies with a more scientific approach began. Priscilla White’s descriptions of unfavorable outcomes of diabetes in 439 pregnancies were published in the first half of the past century4. The White classification used letters of the alphabet to ascertain prognosis for both fetus and mother. As White wrote in her manuscript: "in 1948 clinical grading of the obstetric diabetic patient was made. […] Classes A to E referred to fetal risk and F to maternal risk" 4. Her classification was set based on maternal age of onset and duration of diabetes, as well as on the severity of "vascular disease". An equivalent of the metabolic alteration we now define as gestational diabetes was also described in her classification: "Class A, with highest chance for fetal survival, includes patients in whom the diagnosis of diabetes was made upon a glucose tolerance test which deviates but slightly from the normal. Such patients require no insulin and little dietary regulation" 4. This classification is no longer used5. Three other pioneers contributed to the understanding of the metabolism of the maternal/fetal/placental unit and its consequences for the fetus. In the 1960s, the Danish researcher Jorgen Pedersen formulated the Pedersen’s hypothesis which states that macrosomia is a consequence of the maternal hyperglycemic milieu leading to fetal hyperinsulinemia and subsequent excessive growth6. During the 1960s and the 1970s, Norbert Freinkel and Boyd Metzger published several studies on maternal metabolism which led to the hypothesis of "pregnancy as a tissue culture experience". The concepts of "accelerated starvation", i.e, the use of fat in metabolic routes when food is unavailable, and of "facilitated anabolism", related to "mechanisms for conserving ingested nutrients for delivery to the conceptus when the mother eats again" were described in normal pregnancies6. Moreover, since 1979, these authors have become renowned outstanding worldwide due to their effort to unify proceedings on gestational diabetes, beginning with the first workshop-conference on gestational diabetes7. Conversely, from an obstetric point of view, a study carried out by Carrington, Schurman and Reardon in the USA during the mid-1950s had already speculated on the hyperglycemia/hyperinsulinemia hypothesis8; in that paper, the authors also presented 92 cases of "prediabetic state" in pregnancy, calling those with 2-h blood glucose post-load levels over 170 mg/dl as "gestational diabetes". This was probably the first time this expression was assigned to the special type of hyperglycemia discovered in pregnancy8; 9. And in the 1960s, O’Sullivan’s studies on the diagnosis of gestational diabetes began… Present Time Although several workshop-conferences and expert meetings have been conducted to standardize GDM diagnosis, we still have multiple positions from different entities. The Table we will show next depicts current positions of some diabetes and obstetrics associations. After 2010, with the publication of the International Association of Diabetes and Pregnancy Study Group (IADPSG)10 one-step procedure, other entities endorsed the position, including the American Diabetes Association (ADA)3, the World Health Organization (WHO)2 and the Australasian Diabetes in Pregnancy Society (ADIPS)11. Nevertheless, the National Institutes of Health (NIH)12 and the American College of Obstetrics and Gynecology (ACOG)13 as well as the United States Preventive Services Task Force (USPSTF)14 did not endorse the IADPSG procedure. The Canadian Diabetes Association (CDA)15 and the National Institute for Health and Care Excellence (NICE)16 recommended their own screening and diagnostic procedures. An extensive review of other positions describing peculiar procedures in European, American and Asian countries, including China and Japan, was published by Agarwal in 201017. As the song says1: "Where do I go? Is there an answer?", we are now, and again, facing a huge dilemma on the dream toward a universal procedure for GDM diagnosis. The current IADPSG procedure raises GDM prevalence twice or more times and is also based on mathematically calculated cut points10, despite being derived from the results of a methodologically sound clinical study named "Hyperglycemia and Adverse Pregnancy Outcomes" (HAPO)18. This study evaluated more than 23 000 women and found that there was a continuous association between the risk of adverse maternal and fetal outcomes and increased plasma glucose, starting with values as low as 75 mg/dl for fasting18. Therefore, IADPSG criteria are almost as math based as those of O’Sullivan, albeit having pregnancy outcomes as endpoints18 rather than future diabetes risk, which was the endpoint adopted by O’Sullivan19. Research on GDM maternal future consequences discloses increased risk of type 2 diabetes20, whereas offspring consequences are not so well established, although obesity and type 2 diabetes risks seem to be higher9; 21; 22. For that reason, the ancient song1 is so contemporary: "Where do I go? Follow the children […]. Is there an answer in their sweet faces?". In Brazil, as well as in the USA, we still have two positions: one suggested by endocrinology societies and other recommended by obstetrics societies. Since 2014, ADA endorsed the "one-step" procedure (IADPSG) and the "two-step" procedure (NIH)3. The adoption of IADPSG criteria in Brazil raises GDM prevalence to 18%23, instead of the 7.2% figure when using WHO criteria24. Again the song is so real, when applied to GDM diagnosis: "Where will they lead me?". Raised GDM prevalence is described with the IADPSG criteria. GDM prevalence with previous criteria pointed to rates of 1.7% to 11.6% in advanced-economy countries25; and to 0.4% to 24.3%, depending on the diagnostic criteria (WHO, NDDG, ADA and others), in low and middle-income countries26. Rates of 9.3% to 25.5% were found in the HAPO centers27; despite this, lower increases were described in Irish women (from 9.4% according to WHO criteria to 12.4% according to IADPSG criteria)28. First detected hyperglycemia in pregnancy was recently estimated to be present in 16.9% of women aged 20 to 49 years old29. Strategies to implement screening were suggested with the purpose of overcoming the predicted rise in GDM prevalence with the use of IADPSG criteria30, 31. Historical landmarks that drove us to the current GDM diagnostic recommendations were plotted in the timeline we will show next. Just click on the links and you will have more information of each important event of the timeline.

Timeline

400 B.C.

Susruta
(India)32 Description of the diabetic syndrome: "honeyed urine"

150 A.D.

Aretaeus of Cappadocia
(Ancient Greece)32 diabetes (siphon) Description of the clinical aspects of diabetes: "Diabetes is a remarkable disorder […] moist and cold wasting of the flesh and limbs into urine […] patients never cease making water […] patient does not survive long when it is completely established for the marasmus produced is rapid and death is speedy"

1674 A.D.

Thomas Willis
(Oxford, England)32 Sweet urine (tasting): diabetes mellitus

1824 A.D.

Bennewitz, H
(Berlin, Germany)33 First case of stillbirth in "GDM"

1882 A.D.

Duncan, M.
(London, England)33 22 cases of pregnancy and diabetes death of half mothers and babies

1909 A.D.

Williams, JW
(Johns Hopkins Hospital, USA)33 Studies on glycosuria in pregnancy; first "GDM screening" in pregnancy

1921 A.D.

Banting & Best
(Canada)32 Insulin discovery

1924 A.D.

Graham, G;
(St. Bartholomew's Hospital, Londres, UK)33 First report of insulin treatment in pregnancy

Official positions

Studies

1964

O'Sullivan, JB & Mahan, CM
(Boston, USA)34; 35 Cohort 1: n=752 women; mathematical criterion: mean (SD) Cohort 2: n=1 013 women, validation criterion: future diabetes
3-h 100-g OGTT (venous blood) O’Sullivan criteria (2 cut points ≥ limits): Fasting 90 mg/dl 1-h 165 mg/dl 2-h 145 mg/dl 3-h 125 mg/dl Prevalence O’Sullivan criteria: 2.53%

WORLD HEALTH ORGANIZATION36 "Gestational diabetes refers to hyperglycaemia of diabetic levels occurring during pregnancy. This condition is responsible for embryopathia diabetica in the foetus". Cut points 2-h after 50-g or 100-g glucose load: venous glucose: ≥ 130 mg/dl capillary glucose ≥ 140 mg/dl

1965

NATIONAL DIABETES DATA GROUP41 O'Sullivan’s criteria, plasma conversion NDDG criteria (2 cut points ≥ limits): Fasting 105 mg/dl 1-h 190 mg/dl 2-h 165 mg/dl 3-h 145 mg/dl

1979

WORLD HEALTH ORGANIZATION
(WHO)37 Adoption of the same criteria used for diabetes diagnosis in non-pregnant adults WHO criteria: Diabetes Fasting ≥ 140 mg/dl and/or 2-h ≥ 200 mg/dl IGT Fasting < 140 mg/dl + 2-h ≥ 140 mg/dl and < 200 mg/dl

FIRST WORKSHOP-CONFERENCE ON GESTATIONAL DIABETES7

1980

Pettitt et al
(USA)46 n = 604 PIMA women (811 pregnancies) 2-h 75-g OGTT Diabetes: 2-h ≥ 200 mg/dl Macrosomia and mortality: raise with increasing glucose levels Increased risk of future diabetes (n = 233) 28% IGT x 8% normal

CARPENTER & COUSTAN
(USA)47 Mathematical conversion of whole blood glucose to plasma values + rounding to the nearest 5 mg/dl Carpenter & Coustan criteria (2 cut points ≥ limits): Fasting 95 mg/dl 1-h 180 mg/dl 2-h 155 mg/dl 3-h 140 mg/dl

1982

1988

Li & al
(Hong Kong)48 n=618 Chinese women 2-h 75-g OGTT Prevalence WHO criteria: IGT 3.9% DM 0.8%

1991

Lind & al
(Diabetic Pregnancy Study Group - EASD)49 n = 1 009 European women 75-g OGTT (fasting, 2-h and intermediate points; venous plasma glucose or capillary whole–blood glucose) Fasting ≥ 7 mmol/l 1-h ≥ 11 mmol/l 2-h ≥ 9 mmol/l Prevalence DPSG-EASD criteria: 2-h ≥ 8 mmol/l: 7.8% 2-h ≥ 9 mmol/l: 3.2%

1995

Martin & al
(Melbourne, Australia)50 n=1 371 Australian women Prevalence: 2-h ≥ 9 mmol/l = 1.5% 2-h ≥ 8 mmol/l = 4.2% 2-h ≥ 7.8 mmol/l = 5.2%

Sacks & al
(USA)51 n = 3 505 American women Universal 2-h 75-g OGTT Continuous association of weight percentiles with glucose values Mathematical criterion (mean + 2 SD, rounded to the nearest 5 mg/dl): Sacks criteria (2 cut points ≥ limits): Fasting 100 mg/dl 1-h 195 mg/dl 2-h 160 mg/dl Prevalence Sacks criteria: 3.2%

IV WORKSHOP-CONFERENCE ON GESTATIONAL DIABETES + AMERICAN DIABETES ASSOCIATION
(USA)44 Carpenter & Coustan criteria for the 3-h 100-g OGTT

1998

Sermer & al
(Toronto-Tri-Hospital Gestational Diabetes Project, Canada)52 n = 4 247 women screened (50-g OGTT) n = 3 836 100-g OGTT Untreated borderline GDM group (less than NDDG) had more macrosomia and cesarean delivery Prevalence NDDG criteria: 3.8%

WORLD HEALTH ORGANIZATION40 Adoption of the same criteria used for diabetes diagnosis in non-pregnant adults Gestational diabetes = GDM or impaired glucose tolerance WHO criteria: Diabetes Fasting ≥ 126 mg/dl and/or 2-h ≥ 200 mg/dl IGT Fasting < 126 mg/dl + 2-h ≥ 140 mg/dl and < 200 mg/dl

1999

AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS
(ACOG, USA)53 Carpenter & Coustan criteria for the 3-h 100-g OGTT

2001

Schmidt & al
(Brazil)24 n = 4 977 Brazilian women Universal 2-h 75-g OGTT ADA: increased risk of macrosomia (NS), preeclampsia and perinatal death WHO: increased risk of macrosomia, preeclampsia and perinatal death (NS) Prevalence ADA criteria: 2.4% Prevalence WHO criteria: DM = 0.4%; IGT = 7.2%

AMERICAN DIABETES ASSOCIATION
(USA)54 Carpenter & Coustan criteria for the 2-h 75-g OGTT

2002

2008

HAPO Study18 n = 23 316 multiethnic women (9 countries) Universal 2-h 75-g OGTT "strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels" Prevalence IADPSG criteria: 17.8%

IADPSG10 Consensus recommendation for glucose thresholds IADPSG criteria (1 cut point ≥ limits): Fasting 92 mg/dl 1-h 180 mg/dl 2-h 153 mg/dl IADPSG criteria: "average glucose values at which odds for birth weight < 90th percentile, cord C-peptide < 90th percentile, and percent body fat < 90th percentile reached 1.75 times the estimated odds of these outcomes at mean glucose values, based on fully adjusted logistic regression models"

2010

State of the Art

Hyperglycemia in pregnancy is initially evaluated by a fasting plasma glucose measured at the first prenatal visit: a value < 92 mg/dl is normal; ≥ 92 mg/dl and < 126 mg/dl: gestational diabetes; ≥ 126 mg/dl: diabetes 10. Eventually, an oral glucose tolerance test could be performed before the recommended 24 to 28 gestational weeks window. Glucose load and cut points adopted by several entities are in the Table. To convert mmol/l to mg/dl, multiply by 18.

Table. Gestational diabetes: current criteria for the oral glucose tolerance test (OGTT).

Position Load
(g)		 Cut points
mg/dl
(mmol/l)		 Cut points for diagnosis
Fasting 1 h 2 h 3 h
IADPSG10/ADA3 75 92
(5.1)		 180
(10.0)		 153
(8.5)		 - ≥ 1
WHO2 75 92
(5.1)		 180
(10.0)		 153
(8.5)		 - ≥ 1
ADIPS11 75 -
(5.1)		 -
(10.0)		 -
(8.5)		 - ≥ 1
NIH12/ACOG13*; ADA3** 100 95
(5.3)		 180
(10.0)		 155
(8.6)		 140
(7.8)		 ≥ 2
CDA15*** 75 -
(5.3)		 -
(10.6)		 -
(9.0)		 - ≥ 1
NICE16 75 -
(5.6)		 - -
(7.8)		 - ≥ 1
USPSTF14 One-or two-step screening after 24 weeks

IADPSG: International Association of Diabetes and Pregnancy Study Group; ADA: American Diabetes Association; WHO: World Health Organization; ADIPS: Australasian Diabetes in Pregnancy Society; NIH: National Institutes of Health; ACOG: American College of Obstetrics and Gynecology; CDA: Canadian Diabetes Association; NICE: National Institute for Health and Care Excellence; USPSTF: United States Preventive Services Task Force. * 1-h 50-g oral glucose challenge test: 135 or 140 mg/dl, followed by a 3-h 100-g OGTT; two values meeting or exceeding Carpenter & Coustan criteria: fasting: 95 mg/dl; 1-h: 180 mg/dl; 2-h: 155 mg/dl; 3-h 140 mg/dl or NDDG: National Diabetes Data Group criteria: fasting 105 mg/dl; 1-h 190 mg/dl; 2-h 165 mg/dl; 3-h 145 mg/dl. ** Since 2014, ADA endorsed a "one-step" approach (IADPSG) or a "two-step" approach (NIH). *** First approach: oral glucose challenge test 1-h 50-g (140 mg/dl) followed by a 2-h 75-g OGTT: fasting 95 mg/dl, 1-h: 191 mg/dl; 2-h: 160 mg/dl; Second approach: one-step 2-h 75-g OGTT and IADPSG criteria.

Conclusion

"Where do I go? Is there an answer?" 1 Although an improvement towards the adoption of worldwide procedures for the diagnosis of gestational diabetes has occurred over time, we are still far from the dream expressed in John Lennon´s song Imagine 55: "You may say I'm a dreamer But I'm not the only one I hope someday you'll join us And the world will be as one"

References

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