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Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance
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Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance Francesco Corrado, MD; Rosario D’Anna, MD; Maria L. Cannata, MD; Desirée Cannizzaro, MD; Francesco Caputo, MD; Emanuela Raffone, MD; Antonino Di Benedetto, MD OBJECTIVE: To study the prevalence of abnormal glucose tolerance among women with a single abnormal glucose tolerance test value in previous pregnancy and identify factors predictive of the later development of abnormal glucose tolerance in this group. STUDY DESIGN: In all, 58 women with gestational diabetes, 66 with a
single abnormal value in a glucose tolerance test, and 56 control women underwent a 75-g oral glucose tolerance test at a mean of 6.9 years from the index pregnancy. RESULTS: Abnormal glucose tolerance was present in 34.5% of
women with previous gestational diabetes and in 28.7% of women with 1 previous abnormal value, significantly different from the controls (9.7%). Independent risk factors that distinguished the subjects who later developed an abnormal glucose tolerance were prepregnancy
BMI, parity ⬎ 1, and first-degree relatives affected by diabetes mellitus in the group with gestational diabetes, and prepregnancy BMI, maternal age, (ⱖ 30 y) and parity ⬎ 1 in the group with a single abnormal value. Prepregnancy BMI (ⱖ26.9) proved to be the most predictive factor of abnormal glucose tolerance later in life. CONCLUSION: Sicilian women with a single abnormal value at the glu-
cose tolerance test in pregnancy have an increased likelihood of developing an abnormal glucose tolerance later in life, similar to gestational diabetes. Prepregnancy BMI was confirmed as the strongest predictive factor in both groups. Key words: abnormal glucose tolerance, gestational diabetes, mild glucose intolerance, single abnormal value
Cite this article as: Corrado F, D’Anna R, Cannata ML, Cannizzaro D, Caputo F, Raffone E, Di Benedetto A. Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance. Am J Obstet Gynecol 2007;196:339.e1-339.e5.
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estational diabetes mellitus (GDM) is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy.”1 This form of carbohydrate intolerance is a complication in 1-14% of pregnancies,2 depending on the population studied. The diagnosis is generally made by performing a 100-g oral
From the Departments of Obstetrics and Gynecology (Drs Corrado, D’Anna, Cannata, Caputo, and Raffone) and Internal Medicine (Drs Cannizzaro and Di Benedetto), University of Messina, Messina, Italy. Received May 28, 2006; received in revised form Sept. 14, 2006; accepted Nov. 16, 2006. Reprint requests: F. Corrado, MD, Department of Obstetrics and Gynecology, Policlinico Universitario “G. Martino,” 98122 Messina, Italy; [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2006.11.016
glucose tolerance test (OGTT) between the 24th and 28th week of gestation with samples obtained fasting and 1, 2, and 3 hours after ingestion of the glucose load. GDM is confirmed by ⱖ2 glucose values according to the criteria derived from O’Sullivan and Mahan’s original work3 as later modified by the National Diabetes Data Group (NDDG)4 or by Carpenter and Coustan.5 The significance of one abnormal value (OAV) remains a point of discussion. Several studies6-10 have investigated, with conflicting results, whether it should be regarded as a clinical disorder because of increased perinatal morbidity, but until now it has not been determined whether, like GDM, OAV is an independent predictor of abnormal glucose tolerance (AGT) later in life. The aims of the present study are to determine, in our Sicilian population, with only a single abnormal OGTT value during pregnancy, the long-term prevalence of AGT and the associated risk factors, which may help to predict this outcome.
M ATERIALS AND M ETHODS From January 1990 through June 1999 all consecutive pregnant women under 6 obstetricians working in the Department of Obstetrics and Gynecology of the University of Messina were invited to take part in a cross-sectional study on GDM. Data on classic risk factors (maternal age, parity, prepregnancy BMI, family history of DM in first-degree relatives) were recorded in the charts. All women had a 50-g glucose challenge test (GCT) at the 24th-28th week of gestation performed in the morning after a 12-hour overnight fast. If the 1-hour glucose value was ⱖ135 mg/dL, the subject underwent, within the next 2 weeks, a 3-hour, 100-g oral glucose tolerance test (OGTT). GDM was diagnosed when ⱖ2 glucose values equaled or exceeded 95, 180, 155, and 140 mg/dL for fasting and at 1, 2, and 3 hours after ingestion of the glucose load, respectively, according to the Carpenter and Coustan criteria.5
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All women with GDM were managed according to a standard protocol. Patients with OAV were considered normal and did not receive any specific intervention. Maternal-fetal outcomes were abstracted from patients charts. In women with GDM, a reclassification of maternal glycemic status was performed 8-10 weeks after delivery or upon cessation of breastfeeding, whichever occurred later by a 75-g OGTT, and results were revaluated according to the American Diabetes Association Expert Committee criteria11 when we start the prospective part of the study: specifically diabetes was diagnosed if fasting venous plasma glucose was ⱖ 126 mg/dL or the 2-hour, 75-g glucose value ⱖ 200 mg/dL; IFG (impaired fasting glucose), fasting glucose ⱖ 110 mg/dL and ⬍ 126 mg/dL; IGT (impaired glucose tolerance), 2-hour glucose ⱖ 140 mg/dL and ⬍ 200 mg/dL and normal fasting level (⬍110 mg/dL); IFG/IGT, fasting glucose ⱖ 110 and ⬍126 mg/dL, and 2-hour glucose ⱖ 140 and ⬍ 200 mg/dL. Beginning in 2001, we tried to contact by phone, letter, or with the help of the private gynecologist each woman from the original GDM and OAV groups. When a woman had subsequent pregnancies, only the first, the one in which the glucose intolerance was diagnosed (index pregnancy), was considered for classifying that subject into the GDM or OAV group. In the same period we selected a control group of 100 cases among the screened women investigated during an index pregnancy and who had delivery within the same time period, with a glucose value at GCT ⱖ 135 mg/dL but a totally normal OGTT, and we contacted them too. These women were chosen because well-matched with OAV patients for year of delivery and prepregnancy BMI, this last probably being the most predictive variable for AGT. An informed consent was obtained from each patient and the protocol had been already approved by Institutional Review Board. All women who consented to this follow-up underwent a 75 g-OGTT and the results were evaluated according to the Expert Committee criteria11: specifically the subjects with AGT were registered as 339.e2
www.AJOG.org DM, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both IFG/IGT. The variables considered as possible risk factors were: prepregnancy BMI, maternal age, parity, first-degree family history of DM, and fasting glucose value of OGTT at the index pregnancy. Glucose was measured by the glucose oxidase method in venous plasma samples. Data were logged onto a computer database and analyzed using the SPSS statistical analysis program, version 11.5 for Windows (SPSS, Chicago, IL). Results were given as mean ⫾ SD or cases and percentage. For continuous measures, one-way ANOVA or t-test were used to compare values in women with normal glucose tolerance, GDM and OAV and 2 analyses or Fisher’s exact test were performed to test for difference in categorical variables. The independent effects of the risk factors studied in women with and without AGT were analyzed by logistic regression analysis, and odds ratios with 95% CIs were calculated. All the continuous variables (maternal age at delivery, prepregnancy BMI, and OGTT fasting value) were dichotomized according to the median value before being entered into the logistic regression analysis. All statistical comparisons were twotailed. The P ⬍ .05 level was considered significant.
R ESULTS During the study period (1990 through June 1999), 87 patients were diagnosed as having GDM and 102 cases had only a single abnormal value on the OGTT-100 g. Of the 87 women with previous GDM, 82 agreed to participate in the short follow-up examination (8-10 weeks after delivery). Of the 5 women who did not participate, 3 refused, 1 did not respond, and the last 1 was pregnant again. Two patients were classified as DM at this initial follow-up test: 1 was considered to have type 1 and the other type 2 diabetes according to clinical features and antibodies to glutamic acid decarboxylase (GADA) dosage. One woman had been diagnosed as IFG, and two as IGT.
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At the long-term follow-up (5-11 years), 54 of 78 former GDM subjects (67%) agreed to complete the protocol and attended the OGTT-75 g test proposed. Two former GDM subjects had been diagnosed as DM type 2 after postdelivery follow-up and, although they were considered in the follow-up, they did not repeat the tolerance test. Of the 102 cases of OAV, 2 were pregnant again and were excluded and 66 (66%) returned for the OGTT. Of the normal control subjects, only 56 (56%) agreed to take part in the study and underwent the OGTT-75 g. There were no differences with regard to the length of follow-up among the women with prior GDM or prior OAV and the control women: 7.3 ⫾ 2.1, 6.8 ⫾ 1.8, and 6.7 ⫾ 1.9 years, respectively (nonsignificant P value). The baseline characteristics of the study groups at the index pregnancy are given in Table 1. The baseline characteristics of the women with previous OAV who did not attend the follow-up examination (n ⫽ 34) were comparable to those (n ⫽ 66) who attended it. They did not differ significantly for prepregnancy BMI (26.2 ⫾ 2.8 vs 26.0 ⫾ 4.2; P ⫽ .8), maternal age at diagnosis (33.0 ⫾ 5.4 vs 33.4 ⫾ 4.7; P ⫽ .7), mean glucose values at fasting OGTT (78.8 ⫾ 9.6 vs 80.6 ⫾ 11.5; P ⫽ .3), or parity ⬎ 1 (17/34 vs 29/66; P ⫽ .6); however, there was a trend toward a lower likelihood of first-degree relatives with diabetes (7/34 vs 27/66; P ⫽ .07). There were no significant differences in baseline characteristics between the GDM subjects who did and did not follow up. At follow-up (mean, 6.9 years), 6 of the GDM subjects had developed DM, 4 were IFG, 8 were IGT, and 2 were IFG/ IGT, for a total rate of AGT of 34.5% (20/58). For the same period in the OAV group, there were 3 cases of diabetes, 5 with IFG, 5 with IGT, and 6 with IFG/ IGT, for a total AGT rate of 28.7% (19/ 66). The corresponding rate of AGT in the control group was 9.7% (5/56), with 1 case of DM, 1 of IFG/IGT, and 3 of IGT. The prevalence of AGT at the longterm follow-up was higher in the women with previous GDM than in the control subjects (34.5% vs 9.7%; P ⫽ .002). The
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TABLE 1
Maternal demographic characteristics at the index pregnancy in the 3 groups (GDM, OAV, and controls) GDM
OAV
Control
Sample size
n ⫽ 58
n ⫽ 66
n ⫽ 56
Maternal age, years, mean ⫾ SD
34.6 ⫾ 3.8
33.4 ⫾ 4.7
32.7 ⫾ 5.2
Prepregnancy BMI, kg/m , mean ⫾ SD
28.5 ⫾ 4.3*
26.0 ⫾ 4.2
26.3 ⫾ 3.9
Fasting OGTT, mg/dL, mean ⫾ SD
81.4 ⫾ 10.9*
80.6 ⫾ 11.5
75.2 ⫾ 8.9
parity ⬎ 1, no. (%)
25 (43.1)
29 (43.9)
20 (35.7)
Family history of DM, no. (%)
23 (39.6)*
27 (40.8)
11 (19.6)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ 2 † ................................................................................................................................................................................................................................................................................................................................................................................ ‡ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ‡ ................................................................................................................................................................................................................................................................................................................................................................................
BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, 1 abnormal value for OGTT; OGTT, oral glucose tolerance test; SD, standard deviation. * P ⬍ .05, GDM vs control. †
P ⬍ .05, GDM vs OAV.
‡
P ⬍ .05, OAV vs control.
prevalence of AGT in OAV group of patients reveals a significant difference versus normal controls (28.7% vs 9.7%; P ⫽ .01). No difference of AGT prevalence was found between GDM and OAV patients (34.5% vs 28.7%; P ⫽ .6). A univariate analysis distinguishing in each pathological group (OAV and GDM) the patients affected by AGT and the normal ones identified the predictive value of the risk factors at the index pregnancy (Table 2). The same variables were analyzed again with multivariate regression (Table 3). Variables independently associated with AGT later in life in the GDM group were prepregnancy BMI, maternal age at delivery, and parity ⬎ 1. In the OAV, group prepregnancy BMI, family history of DM and parity ⬎ 1 were confirmed as independent risk factors. In both groups, prepregnancy BMI gave
the highest odds ratio (14.8 for GDM and 19.5 for OAV).
C OMMENT There is general agreement that GDM implies a significant risk to the mother for later development of AGT and specifically of overt DM (type 2 diabetes, typically). We considered IFG and IGT along with DM as unique categories of AGT because these comprise a continuum of carbohydrate derangement, according to suggestions made by the American Diabetes Association.11 Moreover, other studies have shown that IFG and IGT may progress, in nontreated patients, to type 2 diabetes.12 AGT may be already present in GDM patients, at a few weeks after delivery13-15 or later in life,16-18 in differing propor-
tions among different populations or with different methods and definitions applied. Although controversy still exists as to the criteria for the diagnosis of GDM in terms of evaluation of the OGTT-100 g, we believe that it is most conservative to use the Carpenter-Coustan criteria5 to identify the OAV subjects. If we had used the NDDG criteria to diagnose OAV we could not exclude the possibility that a higher percentage might be diabetic earlier. Furthermore, a lower screening test value (135 mg/dL, rather than 140 mg/dL) would be expected to lead to a larger number of mild glucose intolerances diagnosed.19 Achieving the right balance between sensitivity and specificity of a screening test is difficult. When we started our population screening, in 1989 and 1990, inclusive
TABLE 2
Risk factors for subsequent glucose intolerance in OAV and GDM subjects, stratified by presence or absence of AGT at a mean of 7.15 years after the index pregnancy OAV affected by AGT Yes
No
Sample size
n ⫽ 19
n ⫽ 47
Prepregnancy BMI, kg/m , mean ⫾ SD
28.2 ⫾ 2.6
25.2 ⫾ 4.4
Maternal age, years, mean ⫾ SD
33.4 ⫾ 5.5
OGTT,* mg/dL, mean ⫾ SD
85.6 ⫾ 8.9
parity ⬎ 1, no. (%)
Family history of DM, no. (%)
GDM affected by AGT P
Yes
No
n ⫽ 20
n ⫽ 38
P
.009
30.2 ⫾ 4.1
27.6 ⫾ 4.2
.02
33.4 ⫾ 4.8
.9
36.7 ⫾ 2.6
33.5 ⫾ 3.9
.002
78.6 ⫾ 11.9
.002
87.2 ⫾ 9.3
78.4 ⫾ 10.5
.003
13 (68.4)
16 (34.0)
.01
13 (65.0)
12 (31.5)
.02
12 (63.1)
15 (31.9)
.02
13 (65.0)
10 (26.3)
.006
................................................................................................................................................................................................................................................................................................................................................................................ 2 ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
AGT, abnormal glucose tolerance; BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, 1 abnormal value for OGTT; OGTT, oral glucose tolerance test; SD, standard deviation. * Fasting value.
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TABLE 3
Multivariate regression analysis of the predictive variables considered in OAV and GDM patients OAV
GDM
Significance
OR
Prepregnancy BMI
.001
19.5
Maternal age at delivery
.06
0.1
Family history of DM
.02
5.6
95% CI
Significance
OR
95% CI
.03
14.8
1.2-177.1
0.03-1.09
.01
12.6
1.7-92.3
1.24-25.10
.11
3.9
0.7-22.0
3.2-117.8
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
OGTT fasting value
.21
2.4
0.58-10.34
.11
4.7
0.6-33.7
parity ⬎ 1
.03
5.0
1.14-22.62
.02
8.9
1.3-57.5
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, single abnormal value for OGTT; OGTT, oral glucose tolerance test; OR, odds ratio.
parameters had been accepted as effective also for recognizing women with milder metabolic anomalies that had been correlated with an unfavorable outcome of pregnancy.6,7 It may be worthwhile to extend screening programs and search for milder degrees of metabolic derangement, lowering the cutoff level. This choice obviously leads to a higher rate of false positive results and increases the economic cost of the diagnostic procedure, but we welcome the opportunity to identify a more extended group with a potential increase of perinatal morbidity. Probably, however, we will have the possibility of sharing a protocol with a “one-step” approach, with a wide agreement within the scientific community. In this case series, the prevalence of AGT at the long-term follow-up in the women with previous GDM was higher than in the control subjects. We note that all the patients of the control group had a positive GCT (with all 4 values at the OGTT below the thresholds to define GDM). Nevertheless, with truly normal control patients (ie, both normal GCT and normal OGTT), we would expect the statistical differences between GDM or OAV and control patients to be maintained or reinforced. Furthermore, the prevalence of AGT in the control group is similar to the prevalence of DM and AGT in an Italian female population of the same age20 or in another whitepopulation Mediterranean country,21 both representative of our normal population. The significance of OAV at the OGTT100 g in pregnancy has not previously been investigated as a predictive factor 339.e4
for AGT later in life. Although several studies6-10 have considered the impact of this nontreated metabolic condition on obstetric outcome, with conflicting results, we have not been able to identify any other studies on the long-term follow-up of OAV white patients and the associated risk factors with regard to abnormal glucose tolerance. This study demonstrates the prevalence of AGT in this group of patients and reveals a significant difference relative to normal controls. Because the OAV patients who did not participate in our study (n ⫽ 34) were similar for the risk factors considered, it is likely that for the women participating the demonstrated incidence of AGT is similar to what would be expected if the whole population of OAV patients were examined. No difference of AGT prevalence was found between GDM and OAV patients, supporting the idea that OAV can be considered as a part of a continuum with GDM in the carbohydrate derangement brought about by the insulin resistance in pregnancy. These findings are in accordance with recent WHO recommendations, reclassifying cases once defined as impaired glucose tolerance (IGT) as part of GDM. Our second objective was to identify predictive factors for the later development of AGT in the OAV group and compare them to the risk factors found in the GDM group. At the univariate analyses, all the risk factors considered in the GDM group appeared to be predictive of AGT later in life (Table 2). Maternal age, prepregnancy BMI, parity ⬎ 1,
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first-degree relatives affected by DM, and fasting glucose at the diagnostic OGTT were all statistically significant in comparison to nonaffected women, and prepregnancy BMI, maternal age at delivery, and parity ⬎ 1 were then confirmed as independent predictors in the multivariate regression analysis. In the OAV group, 4 of the 5 risk factors considered were predictive in univariate analysis. Only maternal age was not significantly predictive. It seems likely that this lack of independent predictive value for maternal age may have been related to the small sample size and the relatively narrow range of maternal ages included. In the multivariate regression, fasting glucose value at OGTT was not a statistically significant independent risk factor, again possibly because of sample size issues and a fairly narrow range of fasting glucose values. The family history of DM remained a good predictive factor. In both groups, BMI and parity ⬎ 1 were revealed as independent strong predictors of subsequent AGT. Parity as a risk factor can probably be explained on the basis of each insulin resistance state related to pregnancy representing a stress factor for the pancreatic beta cells, which may contribute to a progressive decline of their function.22 Obviously, in cases of preexisting obesity or excessive weight gain in pregnancy the resistance is more pronounced, and insulin compensatory secretion may be inadequate (GDM or OAV) and persist or return after delivery (AGT). However, because parity is not modifiable our attention is focused on BMI.
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www.AJOG.org It is not surprising that overweight is a significant risk in the patients affected by GDM. This relationship was confirmed in the OAV patients (crude odds ratios of 14.8 for GDM and 19.5 for OAV). Obesity increases insulin resistance and favors progression in glucose intolerance until it becomes DM. Indeed, decreased tissue sensitivity to insulin has been demonstrated23 in patients with a single abnormal OGTT value and was indistinguishable from GDM patients according to the homeostasis model assessment (HOMA). Identification of BMI as a risk factor could have great clinical importance, because BMI can be modified (ie, weight loss can be achieved) with an active lifestyle and a caloriecontrolled diet, perhaps reducing this progression.24,25 In conclusion, the present study reveals (to our knowledge, for the first time) an increased likelihood of developing an AGT in OAV white patients similar to that for GDM patients, confirms BMI as the strongest predictor, and tends to support the idea that those patients with prior GDM or OAV must, following the ADA guidelines, be educated regarding lifestyle modifications that lessen insulin resistance. f REFERENCES 1. Metzger BE, Coustan DR; The Organizing Committee. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(Suppl 2):B161-7. 2. Engelgau MM, Herman WH, Smith PS, German RR, Aubert RE. The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 1995;18:1029-33. 3. O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964;13:278-85.
4. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039-57. 5. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 1982;144:768-73. 6. Langer O, Brustman L, Anyaegbunam A, Mazze R. The significance of one abnormal glucose tolerance test value on adverse outcome in pregnancy. Am J Obstet Gynecol 1987;157:758-63. 7. Lindsay MK, Graves W, Klein L. The relationship of one abnormal glucose tolerance test value and pregnancy complications. Obstet Gynecol 1989;73:103-6. 8. Forest JC, Masse J, Garrido-Russo M. Glucose tolerance test during pregnancy: the significance of one abnormal value. Clin Biochem 1994;27:299-304. 9. Sermer M, Naylor CD, Gare DJ, et al; Toronto Tri-Hospital Gestational Diabetes Project. Impact of increasing carbohydrate intolerance on maternal-fetal outcome in 3637 women without gestational diabetes. Am J Obstet Gynecol 1995;173:146-56. 10. Vambergue A, Nuttens MC, Goeusse P, Biausque S, Lepeut M, Fontaine P. Pregnancy induced hypertension in women with gestational carbohydrate intolerance: the diagest study. Eur J Obstet Gynecol Reprod Biol 2002;102:31-5. 11. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97. 12. Lauenborg J, Hansen T, Jensen DM, et al. Increasing incidence of diabetes after gestational diabetes. Diabetes Care 2004;27: 1194-9. 13. Dalfrà MG, Lapolla A, Masin M, et al. Antepartum and early postpartum predictors of type 2 diabetes development in women with gestational diabetes mellitus. Diabetes Metab 2001;27:675-80. 14. Buchanan TA, Xiang A, Kjos SL, et al. Gestational diabetes: antepartum characteristics that predict postpartum glucose intolerance and type 2 diabetes in Latino women. Diabetes 1998;47:1302-10. 15. Kjos SL, Buchanan TA, Greenspoon JS, Montoro M, Bernstein GS, Mestman JH. Ges-
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tational diabetes mellitus: the prevalence of glucose intolerance and diabetes mellitus in the first two months post partum. Am J Obstet Gynecol 1990;163:93-8. 16. Damm P, Kuhl C, Bertelsen A, MolstedPedersen L. Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus. Am J Obstet Gynecol 1992;167:607-16. 17. Coustan DR, Carpenter MW, O’Sullivan P, Carr S. Gestational diabetes: predictors of subsequent disordered glucose metabolism. Am J Obstet Gynecol 1993;168:1139-45. 18. Albareda M, Caballero A, Badell G, et al. Diabetes and abnormal glucose tolerance in women with previous gestational diabetes. Diabetes Care 2003;26:1199-205. 19. Bonomo M, Gandini ML, Mastropasqua A, et al. Which cutoff level should be used in screening for glucose intolerance in pregnancy? Am J Obstet Gynecol 1998;179: 179-85. 20. Pilotto L, Gaggioli A, Lo Noce C, et al. Il diabete in Italia: un problema di sanità pubblica [Diabetes in Italy: a public health problem; in Italian]. Ital Heart J Suppl 2004;5:480-6. 21. Castell C, Tresserras R, Serra J, Goday A, Lloveras G, Salleras L. Prevalence of diabetes in Catalonia (Spain): an oral glucose tolerance test-based population study. Diabetes Res Clin Pract 1999;43:33-40. 22. Peters RK, Kjos SL, Xiang A, Buchanan TA. Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet 1995;347:227-30. 23. Ergin T, Lembet A, Duran H, et al. Does insulin secretion in patients with one abnormal glucose tolerance test value mimic gestational diabetes mellitus? Am J Obstet Gynecol 2002;186:204-9. 24. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50. 25. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
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Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance Francesco Corrado, MD; Rosario D’Anna, MD; Maria L. Cannata, MD; Desirée Cannizzaro, MD; Francesco Caputo, MD; Emanuela Raffone, MD; Antonino Di Benedetto, MD OBJECTIVE: To study the prevalence of abnormal glucose tolerance among women with a single abnormal glucose tolerance test value in previous pregnancy and identify factors predictive of the later development of abnormal glucose tolerance in this group. STUDY DESIGN: In all, 58 women with gestational diabetes, 66 with a
single abnormal value in a glucose tolerance test, and 56 control women underwent a 75-g oral glucose tolerance test at a mean of 6.9 years from the index pregnancy. RESULTS: Abnormal glucose tolerance was present in 34.5% of
women with previous gestational diabetes and in 28.7% of women with 1 previous abnormal value, significantly different from the controls (9.7%). Independent risk factors that distinguished the subjects who later developed an abnormal glucose tolerance were prepregnancy
BMI, parity ⬎ 1, and first-degree relatives affected by diabetes mellitus in the group with gestational diabetes, and prepregnancy BMI, maternal age, (ⱖ 30 y) and parity ⬎ 1 in the group with a single abnormal value. Prepregnancy BMI (ⱖ26.9) proved to be the most predictive factor of abnormal glucose tolerance later in life. CONCLUSION: Sicilian women with a single abnormal value at the glu-
cose tolerance test in pregnancy have an increased likelihood of developing an abnormal glucose tolerance later in life, similar to gestational diabetes. Prepregnancy BMI was confirmed as the strongest predictive factor in both groups. Key words: abnormal glucose tolerance, gestational diabetes, mild glucose intolerance, single abnormal value
Cite this article as: Corrado F, D’Anna R, Cannata ML, Cannizzaro D, Caputo F, Raffone E, Di Benedetto A. Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance. Am J Obstet Gynecol 2007;196:339.e1-339.e5.
G
estational diabetes mellitus (GDM) is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy.”1 This form of carbohydrate intolerance is a complication in 1-14% of pregnancies,2 depending on the population studied. The diagnosis is generally made by performing a 100-g oral
From the Departments of Obstetrics and Gynecology (Drs Corrado, D’Anna, Cannata, Caputo, and Raffone) and Internal Medicine (Drs Cannizzaro and Di Benedetto), University of Messina, Messina, Italy. Received May 28, 2006; received in revised form Sept. 14, 2006; accepted Nov. 16, 2006. Reprint requests: F. Corrado, MD, Department of Obstetrics and Gynecology, Policlinico Universitario “G. Martino,” 98122 Messina, Italy; [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2006.11.016
glucose tolerance test (OGTT) between the 24th and 28th week of gestation with samples obtained fasting and 1, 2, and 3 hours after ingestion of the glucose load. GDM is confirmed by ⱖ2 glucose values according to the criteria derived from O’Sullivan and Mahan’s original work3 as later modified by the National Diabetes Data Group (NDDG)4 or by Carpenter and Coustan.5 The significance of one abnormal value (OAV) remains a point of discussion. Several studies6-10 have investigated, with conflicting results, whether it should be regarded as a clinical disorder because of increased perinatal morbidity, but until now it has not been determined whether, like GDM, OAV is an independent predictor of abnormal glucose tolerance (AGT) later in life. The aims of the present study are to determine, in our Sicilian population, with only a single abnormal OGTT value during pregnancy, the long-term prevalence of AGT and the associated risk factors, which may help to predict this outcome.
M ATERIALS AND M ETHODS From January 1990 through June 1999 all consecutive pregnant women under 6 obstetricians working in the Department of Obstetrics and Gynecology of the University of Messina were invited to take part in a cross-sectional study on GDM. Data on classic risk factors (maternal age, parity, prepregnancy BMI, family history of DM in first-degree relatives) were recorded in the charts. All women had a 50-g glucose challenge test (GCT) at the 24th-28th week of gestation performed in the morning after a 12-hour overnight fast. If the 1-hour glucose value was ⱖ135 mg/dL, the subject underwent, within the next 2 weeks, a 3-hour, 100-g oral glucose tolerance test (OGTT). GDM was diagnosed when ⱖ2 glucose values equaled or exceeded 95, 180, 155, and 140 mg/dL for fasting and at 1, 2, and 3 hours after ingestion of the glucose load, respectively, according to the Carpenter and Coustan criteria.5
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All women with GDM were managed according to a standard protocol. Patients with OAV were considered normal and did not receive any specific intervention. Maternal-fetal outcomes were abstracted from patients charts. In women with GDM, a reclassification of maternal glycemic status was performed 8-10 weeks after delivery or upon cessation of breastfeeding, whichever occurred later by a 75-g OGTT, and results were revaluated according to the American Diabetes Association Expert Committee criteria11 when we start the prospective part of the study: specifically diabetes was diagnosed if fasting venous plasma glucose was ⱖ 126 mg/dL or the 2-hour, 75-g glucose value ⱖ 200 mg/dL; IFG (impaired fasting glucose), fasting glucose ⱖ 110 mg/dL and ⬍ 126 mg/dL; IGT (impaired glucose tolerance), 2-hour glucose ⱖ 140 mg/dL and ⬍ 200 mg/dL and normal fasting level (⬍110 mg/dL); IFG/IGT, fasting glucose ⱖ 110 and ⬍126 mg/dL, and 2-hour glucose ⱖ 140 and ⬍ 200 mg/dL. Beginning in 2001, we tried to contact by phone, letter, or with the help of the private gynecologist each woman from the original GDM and OAV groups. When a woman had subsequent pregnancies, only the first, the one in which the glucose intolerance was diagnosed (index pregnancy), was considered for classifying that subject into the GDM or OAV group. In the same period we selected a control group of 100 cases among the screened women investigated during an index pregnancy and who had delivery within the same time period, with a glucose value at GCT ⱖ 135 mg/dL but a totally normal OGTT, and we contacted them too. These women were chosen because well-matched with OAV patients for year of delivery and prepregnancy BMI, this last probably being the most predictive variable for AGT. An informed consent was obtained from each patient and the protocol had been already approved by Institutional Review Board. All women who consented to this follow-up underwent a 75 g-OGTT and the results were evaluated according to the Expert Committee criteria11: specifically the subjects with AGT were registered as 339.e2
www.AJOG.org DM, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both IFG/IGT. The variables considered as possible risk factors were: prepregnancy BMI, maternal age, parity, first-degree family history of DM, and fasting glucose value of OGTT at the index pregnancy. Glucose was measured by the glucose oxidase method in venous plasma samples. Data were logged onto a computer database and analyzed using the SPSS statistical analysis program, version 11.5 for Windows (SPSS, Chicago, IL). Results were given as mean ⫾ SD or cases and percentage. For continuous measures, one-way ANOVA or t-test were used to compare values in women with normal glucose tolerance, GDM and OAV and 2 analyses or Fisher’s exact test were performed to test for difference in categorical variables. The independent effects of the risk factors studied in women with and without AGT were analyzed by logistic regression analysis, and odds ratios with 95% CIs were calculated. All the continuous variables (maternal age at delivery, prepregnancy BMI, and OGTT fasting value) were dichotomized according to the median value before being entered into the logistic regression analysis. All statistical comparisons were twotailed. The P ⬍ .05 level was considered significant.
R ESULTS During the study period (1990 through June 1999), 87 patients were diagnosed as having GDM and 102 cases had only a single abnormal value on the OGTT-100 g. Of the 87 women with previous GDM, 82 agreed to participate in the short follow-up examination (8-10 weeks after delivery). Of the 5 women who did not participate, 3 refused, 1 did not respond, and the last 1 was pregnant again. Two patients were classified as DM at this initial follow-up test: 1 was considered to have type 1 and the other type 2 diabetes according to clinical features and antibodies to glutamic acid decarboxylase (GADA) dosage. One woman had been diagnosed as IFG, and two as IGT.
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At the long-term follow-up (5-11 years), 54 of 78 former GDM subjects (67%) agreed to complete the protocol and attended the OGTT-75 g test proposed. Two former GDM subjects had been diagnosed as DM type 2 after postdelivery follow-up and, although they were considered in the follow-up, they did not repeat the tolerance test. Of the 102 cases of OAV, 2 were pregnant again and were excluded and 66 (66%) returned for the OGTT. Of the normal control subjects, only 56 (56%) agreed to take part in the study and underwent the OGTT-75 g. There were no differences with regard to the length of follow-up among the women with prior GDM or prior OAV and the control women: 7.3 ⫾ 2.1, 6.8 ⫾ 1.8, and 6.7 ⫾ 1.9 years, respectively (nonsignificant P value). The baseline characteristics of the study groups at the index pregnancy are given in Table 1. The baseline characteristics of the women with previous OAV who did not attend the follow-up examination (n ⫽ 34) were comparable to those (n ⫽ 66) who attended it. They did not differ significantly for prepregnancy BMI (26.2 ⫾ 2.8 vs 26.0 ⫾ 4.2; P ⫽ .8), maternal age at diagnosis (33.0 ⫾ 5.4 vs 33.4 ⫾ 4.7; P ⫽ .7), mean glucose values at fasting OGTT (78.8 ⫾ 9.6 vs 80.6 ⫾ 11.5; P ⫽ .3), or parity ⬎ 1 (17/34 vs 29/66; P ⫽ .6); however, there was a trend toward a lower likelihood of first-degree relatives with diabetes (7/34 vs 27/66; P ⫽ .07). There were no significant differences in baseline characteristics between the GDM subjects who did and did not follow up. At follow-up (mean, 6.9 years), 6 of the GDM subjects had developed DM, 4 were IFG, 8 were IGT, and 2 were IFG/ IGT, for a total rate of AGT of 34.5% (20/58). For the same period in the OAV group, there were 3 cases of diabetes, 5 with IFG, 5 with IGT, and 6 with IFG/ IGT, for a total AGT rate of 28.7% (19/ 66). The corresponding rate of AGT in the control group was 9.7% (5/56), with 1 case of DM, 1 of IFG/IGT, and 3 of IGT. The prevalence of AGT at the longterm follow-up was higher in the women with previous GDM than in the control subjects (34.5% vs 9.7%; P ⫽ .002). The
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TABLE 1
Maternal demographic characteristics at the index pregnancy in the 3 groups (GDM, OAV, and controls) GDM
OAV
Control
Sample size
n ⫽ 58
n ⫽ 66
n ⫽ 56
Maternal age, years, mean ⫾ SD
34.6 ⫾ 3.8
33.4 ⫾ 4.7
32.7 ⫾ 5.2
Prepregnancy BMI, kg/m , mean ⫾ SD
28.5 ⫾ 4.3*
26.0 ⫾ 4.2
26.3 ⫾ 3.9
Fasting OGTT, mg/dL, mean ⫾ SD
81.4 ⫾ 10.9*
80.6 ⫾ 11.5
75.2 ⫾ 8.9
parity ⬎ 1, no. (%)
25 (43.1)
29 (43.9)
20 (35.7)
Family history of DM, no. (%)
23 (39.6)*
27 (40.8)
11 (19.6)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ 2 † ................................................................................................................................................................................................................................................................................................................................................................................ ‡ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ‡ ................................................................................................................................................................................................................................................................................................................................................................................
BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, 1 abnormal value for OGTT; OGTT, oral glucose tolerance test; SD, standard deviation. * P ⬍ .05, GDM vs control. †
P ⬍ .05, GDM vs OAV.
‡
P ⬍ .05, OAV vs control.
prevalence of AGT in OAV group of patients reveals a significant difference versus normal controls (28.7% vs 9.7%; P ⫽ .01). No difference of AGT prevalence was found between GDM and OAV patients (34.5% vs 28.7%; P ⫽ .6). A univariate analysis distinguishing in each pathological group (OAV and GDM) the patients affected by AGT and the normal ones identified the predictive value of the risk factors at the index pregnancy (Table 2). The same variables were analyzed again with multivariate regression (Table 3). Variables independently associated with AGT later in life in the GDM group were prepregnancy BMI, maternal age at delivery, and parity ⬎ 1. In the OAV, group prepregnancy BMI, family history of DM and parity ⬎ 1 were confirmed as independent risk factors. In both groups, prepregnancy BMI gave
the highest odds ratio (14.8 for GDM and 19.5 for OAV).
C OMMENT There is general agreement that GDM implies a significant risk to the mother for later development of AGT and specifically of overt DM (type 2 diabetes, typically). We considered IFG and IGT along with DM as unique categories of AGT because these comprise a continuum of carbohydrate derangement, according to suggestions made by the American Diabetes Association.11 Moreover, other studies have shown that IFG and IGT may progress, in nontreated patients, to type 2 diabetes.12 AGT may be already present in GDM patients, at a few weeks after delivery13-15 or later in life,16-18 in differing propor-
tions among different populations or with different methods and definitions applied. Although controversy still exists as to the criteria for the diagnosis of GDM in terms of evaluation of the OGTT-100 g, we believe that it is most conservative to use the Carpenter-Coustan criteria5 to identify the OAV subjects. If we had used the NDDG criteria to diagnose OAV we could not exclude the possibility that a higher percentage might be diabetic earlier. Furthermore, a lower screening test value (135 mg/dL, rather than 140 mg/dL) would be expected to lead to a larger number of mild glucose intolerances diagnosed.19 Achieving the right balance between sensitivity and specificity of a screening test is difficult. When we started our population screening, in 1989 and 1990, inclusive
TABLE 2
Risk factors for subsequent glucose intolerance in OAV and GDM subjects, stratified by presence or absence of AGT at a mean of 7.15 years after the index pregnancy OAV affected by AGT Yes
No
Sample size
n ⫽ 19
n ⫽ 47
Prepregnancy BMI, kg/m , mean ⫾ SD
28.2 ⫾ 2.6
25.2 ⫾ 4.4
Maternal age, years, mean ⫾ SD
33.4 ⫾ 5.5
OGTT,* mg/dL, mean ⫾ SD
85.6 ⫾ 8.9
parity ⬎ 1, no. (%)
Family history of DM, no. (%)
GDM affected by AGT P
Yes
No
n ⫽ 20
n ⫽ 38
P
.009
30.2 ⫾ 4.1
27.6 ⫾ 4.2
.02
33.4 ⫾ 4.8
.9
36.7 ⫾ 2.6
33.5 ⫾ 3.9
.002
78.6 ⫾ 11.9
.002
87.2 ⫾ 9.3
78.4 ⫾ 10.5
.003
13 (68.4)
16 (34.0)
.01
13 (65.0)
12 (31.5)
.02
12 (63.1)
15 (31.9)
.02
13 (65.0)
10 (26.3)
.006
................................................................................................................................................................................................................................................................................................................................................................................ 2 ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
AGT, abnormal glucose tolerance; BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, 1 abnormal value for OGTT; OGTT, oral glucose tolerance test; SD, standard deviation. * Fasting value.
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TABLE 3
Multivariate regression analysis of the predictive variables considered in OAV and GDM patients OAV
GDM
Significance
OR
Prepregnancy BMI
.001
19.5
Maternal age at delivery
.06
0.1
Family history of DM
.02
5.6
95% CI
Significance
OR
95% CI
.03
14.8
1.2-177.1
0.03-1.09
.01
12.6
1.7-92.3
1.24-25.10
.11
3.9
0.7-22.0
3.2-117.8
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
OGTT fasting value
.21
2.4
0.58-10.34
.11
4.7
0.6-33.7
parity ⬎ 1
.03
5.0
1.14-22.62
.02
8.9
1.3-57.5
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OAV, single abnormal value for OGTT; OGTT, oral glucose tolerance test; OR, odds ratio.
parameters had been accepted as effective also for recognizing women with milder metabolic anomalies that had been correlated with an unfavorable outcome of pregnancy.6,7 It may be worthwhile to extend screening programs and search for milder degrees of metabolic derangement, lowering the cutoff level. This choice obviously leads to a higher rate of false positive results and increases the economic cost of the diagnostic procedure, but we welcome the opportunity to identify a more extended group with a potential increase of perinatal morbidity. Probably, however, we will have the possibility of sharing a protocol with a “one-step” approach, with a wide agreement within the scientific community. In this case series, the prevalence of AGT at the long-term follow-up in the women with previous GDM was higher than in the control subjects. We note that all the patients of the control group had a positive GCT (with all 4 values at the OGTT below the thresholds to define GDM). Nevertheless, with truly normal control patients (ie, both normal GCT and normal OGTT), we would expect the statistical differences between GDM or OAV and control patients to be maintained or reinforced. Furthermore, the prevalence of AGT in the control group is similar to the prevalence of DM and AGT in an Italian female population of the same age20 or in another whitepopulation Mediterranean country,21 both representative of our normal population. The significance of OAV at the OGTT100 g in pregnancy has not previously been investigated as a predictive factor 339.e4
for AGT later in life. Although several studies6-10 have considered the impact of this nontreated metabolic condition on obstetric outcome, with conflicting results, we have not been able to identify any other studies on the long-term follow-up of OAV white patients and the associated risk factors with regard to abnormal glucose tolerance. This study demonstrates the prevalence of AGT in this group of patients and reveals a significant difference relative to normal controls. Because the OAV patients who did not participate in our study (n ⫽ 34) were similar for the risk factors considered, it is likely that for the women participating the demonstrated incidence of AGT is similar to what would be expected if the whole population of OAV patients were examined. No difference of AGT prevalence was found between GDM and OAV patients, supporting the idea that OAV can be considered as a part of a continuum with GDM in the carbohydrate derangement brought about by the insulin resistance in pregnancy. These findings are in accordance with recent WHO recommendations, reclassifying cases once defined as impaired glucose tolerance (IGT) as part of GDM. Our second objective was to identify predictive factors for the later development of AGT in the OAV group and compare them to the risk factors found in the GDM group. At the univariate analyses, all the risk factors considered in the GDM group appeared to be predictive of AGT later in life (Table 2). Maternal age, prepregnancy BMI, parity ⬎ 1,
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first-degree relatives affected by DM, and fasting glucose at the diagnostic OGTT were all statistically significant in comparison to nonaffected women, and prepregnancy BMI, maternal age at delivery, and parity ⬎ 1 were then confirmed as independent predictors in the multivariate regression analysis. In the OAV group, 4 of the 5 risk factors considered were predictive in univariate analysis. Only maternal age was not significantly predictive. It seems likely that this lack of independent predictive value for maternal age may have been related to the small sample size and the relatively narrow range of maternal ages included. In the multivariate regression, fasting glucose value at OGTT was not a statistically significant independent risk factor, again possibly because of sample size issues and a fairly narrow range of fasting glucose values. The family history of DM remained a good predictive factor. In both groups, BMI and parity ⬎ 1 were revealed as independent strong predictors of subsequent AGT. Parity as a risk factor can probably be explained on the basis of each insulin resistance state related to pregnancy representing a stress factor for the pancreatic beta cells, which may contribute to a progressive decline of their function.22 Obviously, in cases of preexisting obesity or excessive weight gain in pregnancy the resistance is more pronounced, and insulin compensatory secretion may be inadequate (GDM or OAV) and persist or return after delivery (AGT). However, because parity is not modifiable our attention is focused on BMI.
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www.AJOG.org It is not surprising that overweight is a significant risk in the patients affected by GDM. This relationship was confirmed in the OAV patients (crude odds ratios of 14.8 for GDM and 19.5 for OAV). Obesity increases insulin resistance and favors progression in glucose intolerance until it becomes DM. Indeed, decreased tissue sensitivity to insulin has been demonstrated23 in patients with a single abnormal OGTT value and was indistinguishable from GDM patients according to the homeostasis model assessment (HOMA). Identification of BMI as a risk factor could have great clinical importance, because BMI can be modified (ie, weight loss can be achieved) with an active lifestyle and a caloriecontrolled diet, perhaps reducing this progression.24,25 In conclusion, the present study reveals (to our knowledge, for the first time) an increased likelihood of developing an AGT in OAV white patients similar to that for GDM patients, confirms BMI as the strongest predictor, and tends to support the idea that those patients with prior GDM or OAV must, following the ADA guidelines, be educated regarding lifestyle modifications that lessen insulin resistance. f REFERENCES 1. Metzger BE, Coustan DR; The Organizing Committee. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(Suppl 2):B161-7. 2. Engelgau MM, Herman WH, Smith PS, German RR, Aubert RE. The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 1995;18:1029-33. 3. O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964;13:278-85.
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