Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus Peter Damm, MD,. Claus Kohl, MD, PhD,. Aksel Bertelsen, PhD: and Lars M~lsted-Pedersen, MD, PhD" Copenhagen, Denmark OBJECTIVES: The purpose of this study was to determine the incidence of diabetes in women with previous dietary-treated gestational diabetes mellitus and to identify predictive factors for development of diabetes. STUDY DESIGN: Two to 11 years post partum, glucose tolerance was investigated in 241 women with previous dietary-treated gestational diabetes mellitus and 57 women without previous gestational diabetes mellitus (control group). RESULTS: Diabetes developed in 42 (17.4%) women with previous gestational diabetes mellitus (3.7% insulin-dependent diabetes mellitus and 13.7% non-insulin-dependent diabetes mellitus). Diabetes did not develop in any of the controls. Predictive factors for diabetes development were fasting glucose level at diagnosis (high glucose, high risk), preterm delivery, and an oral glucose tolerance test result that showed diabetes 2 months post partum. In a subgroup of previous patients with gestational diabetes mellitus in whom plasma insulin was measured during an oral glucose tolerance test in late pregnancy a low insulin response at diagnosis was found to be an independent predictive factor for diabetes development. CONCLUSIONS: Women with previous dietary-treated gestational diabetes mellitus have a considerably increased risk of later having diabetes. Follow-up investigations are therefore important, especially in those women with previous gestational diabetes mellitus in whom the identified predictive factors are present. (AMJ OBSTET GVNECOL 1992;167:607-16.)
Key words: Follow-up of women with previous gestational diabetes; predictive factors for development of diabetes; insulin-dependent diabetes mellitus; non-insulin-dependent diabetes mellitus Gestational diabetes mellitus complicates 1% to 3% of all pregnancies. I. 2 Gestational diabetes mellitus is defined as a carbohydrate intolerance of varying severity with onset or first recognition during pregnancy irrespective of glycemic status after delivery.' Gestational diabetes mellitus is thus a heterogeneous disorder that in some cases can be managed satisfactorily by dietary treatment; in other cases insulin treatment is required. Gestational diabetes mellitus implies a significant risk to the mother for later development of overt diabetes! It is generally assumed that gestational diabetes mellitus primarily predisposes a patient to From the Diabetes Center, Department of Obstetrics and Gynaecology Y, Rigshospitalet," and the Statistical Research Unit, University of Copenhagen.' Supported by The Novo Foundation; Danish Diabetes Association; Danish Hospital Foundation for Medical Research, Region Copenhagen, the Faroe Islands, and Greenland; The University of Copenhagen; F.L. Smidth & Co. AI S's gavefond; the GangstedFoundation; Handelsgartner O.V.B. Olesen og aegtefaelle, fru E. Buhl Olesen's Mindelegat; the P. Carl Pedenen Foundation; the Nordisk Insulin Foundation; and the Danish Medical Research Council. Received for publication December 6, 1991; revised March 2, 1992; accepted March 13, 1992. RepTint requests: Peter Damm, MD, Diabetes Center Y 4031, Department of ObstetTics and Gynaecology, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen (7), Denmark.
611137877
non-insulin-dependent diabetes mellitus and not to insulin-dependent diabetes mellitus, but this issue has never been thoroughly investigated. In the majority of follow-up studies of women with previous gestational diabetes mellitus inhomogeneous populations have been examined, diverging definitions and diagnostic tests for gestational diabetes mellitus have been used, and different end-point criteria for subsequent development of diabetes have been applied. 5 . g Differences in methods and definitions are the most likely reasons for the miscellaneous outcome of the studies. Because it is important to predict the risk of future development of overt diabetes shortly after delivery in a woman with gestational diabetes mellitus, the objectives of the current study were to determine the incidence of insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, and impaired glucose tolerance in women with previous gestational diabetes mellitus and to identify predictive factors for the later development of overt diabetes in these women.
Material and methods Subjects. During the period 1978 to 1985, 355 women with gestational diabetes mellitus' were diag-
607
608
Damm et al.
nosed at the Diabetes Center at Rigshospitalet in Copenhagen. All pregnant women consulting the department were examined for gestational diabetes mellitus by a routine screening procedure based on risk factors and fasting blood glucose values. 2 The definitive diagnosis of gestational diabetes mellitus was confirmed by a 3-hour, 50 gm oral glucose tolerance test that was considered abnormal if two or more glucose values exceeded the mean + 3 SD curve pertaining to a group of 46 normal nonpregnant controls investigated by the same procedure. 1o The mean + SD for venous plasma glucose values were 6.4 mmoilL at 0 minutes, 10.1 mmoilL at 30 minutes, 10.1 mmol/Lat 60 minutes, 8.7 mmoilL at 90 minutes, 7.6 mmoilL at 120 minutes, 7.6 mmoilL at 150 minutes, and 6.6 mmoilL at 180 minutes. All women with previous gestational diabetes mellitus were initially treated with a 5000 to 8000 kJ/ day diet, and treatment with hypoglycemic agents or insulin was only initiated if the mean of six daily glucose determinations exceeded 7 mmoilL (multiply with 18 to convert to milligrams per deciliter). Labor was routinely induced at term if spontaneous delivery had not already taken place. All women with previous gestational diabetes mellitus were subjected to a 50 gm oral glucose tolerance test about 8 weeks after delivery and were invited to yearly oral glucose tolerance tests thereafter. A subgroup of the women with previous gestational diabetes mellitus had plasma insulin measured during the oral glucose tolerance tests in pregnancy and post partum. Seventy-four women who had normal 50 gm oral glucose tolerance test results in the last trimester of pregnancy in the period 1978 to 1985 served as controls. None had a family history of diabetes. Follow-up. All women with previous gestational diabetes mellitus who had been treated with diet only and the controls were asked to participate in a follow-up study 2 to 11 years after the index pregnancy. Informed consent was obtained, and the study was approved by the local ethics committee. A 75 gm oral glucose tolerance test was performed in women with previous gestational diabetes mellitus who had no known diabetes at the time of follow-up, in women with previous gestational diabetes mellitus who had dietary-treated noninsulin-dependent diabetes mellitus at follow-up, and in the controls. In women treated with insulin at followup, l3-cell function was evaluated by an intravenous glucagon test. II Procedures Seventy-five-gram oral glucose tolerance test. The women were instructed to ingest at least 150 gm/ day of carbohydrates for at least 3 days before the oral glucose tolerance test, which was performed in the morning after a lO-hour fast. Glucose (75 gm in 250 ml water) was given perorally and capillary blood samples were taken at 0,30,60,90, 120, 150, and 180 minutes thereafter. The results of the oral glucose tolerance tests were
September 1992 Am J Obstet Gyneco1
evaluated according to the criteria of the World Health Organization. 12 Glucagon test. After an overnight fast, venous blood samples for plasma C-peptide determinations were taken before and 6 minutes after an intravenous injection of 1 mg of glucagon. Analyses Index pregnancy. Glucose was analyzed with the glucose dehydrogenase method. Until September 1982 glucose values were measured in venous plasma; capillary whole blood was used thereafter. Plasma insulin was measured by radioimmunoassay.1O Follow-up. Glucose values were measured in capillary plasma with a glucose oxidase method. Plasma C-peptide was analyzed by a radioimmunoassay kit. Calculations and statistics. The incremental area under the curve for the oral glucose tolerance tests was calculated with the trapezoidal method and the fasting value as basal value. The X2 test and the Fisher exact test were used for comparison of frequencies. Comparisons between medians of groups were made by the Mann-Whitney test. All tests were two-tailed and a p < 0.05 was considered significant. Logistic regression analysis was applied to determine which variables were significantly associated with the development of diabetes. A backward elimination procedure was chosen. Only subjects who at the postpartum examination did not have overt diabetes and for whom all the studied variables had been recorded were included in this analysis. Odds ratios and 95% confidence intervals for each predictive variable (adjusted for all other variables) are given. Data were analyzed with three different models. First, a simple model was constructed in which baseline variables were analyzed together with the fasting glucose values from the oral glucose tolerance tests at diagnosis and post partum and the main outcome of the postpartum oral glucose tolerance test (diabetic-nondiabetic). Second, more detailed data from the oral glucose tolerance tests were evaluated as predictive factors analyzing both glucose values measured during the oral glucose tolerance tests (0, 60, 120 minutes) and the 0 to 60- and 0 to 120-minute glucose areas under the curve in the previously created logistic regression model. Third, the predictive value of plasma insulin was analyzed in a subgroup of women in whom plasma insulin had been measured during the oral glucose tolerance test at diagnosis and post partum assessing the following variables in the second logistic regression model: insulin (0, 60, 120 minutes), the insulin areas under the curve, and insulinogenic indexes (insulin response per unit glucose stimulus) during oral glucose tolerdnce tests at 0 to 60 and 0 to 120 minutes. In this analysis the insulin variables were assessed as dichotomized variables. The expected number of women with previous gestational diabetes mellitus in whom insulin-dependent
Diabetes in women with previous gestational diabetes
Volume 167 Number 3
609
Table I. Baseline data from index pregnancy for women with previous dietary-treated gestational diabetes mellitus and in controls Women with previous gestational diabetes
Variable
Median age (yr) Quartile range Median body mass index (kg/m2, prepregnancy) Quartile range No. with body mass index ~25 kg/m2 (prepregnancy) No. with parity ~2 No. with first-degree relative with diabetes No. of white women No. who had cesarean section Median gestational week of pregnancy at delivery Quartile range Median gestational week of pregnancy at diagnostic OGTT§ Quartile range
With follow-up examination (n = 241)
Without follow-up examination (n = 57)
Controls with examination at follow-up (n = 57)
30.1* 26.2-33.6 23.0
31.3 27.1-35.5 24.8
26.7 25.1-29.3 21.5
20.2-28.0 87 (36%)
21.3-30.1 28 (49%)
20.1-26.5 16 (28%)
136 (56%)t 53 (22%)
38 (67%) 15 (26%)
19 (33%) 0(0%)
218 (90%) 50 (21%)*
50 (88%) 14 (25%)
56 (98%) 5 (9%)
39.3*
39.0
40.2
38.7-40.0 34.1
38.2-39.8 34.0
39.5-41.1 34.0
30.3-36.8
30.1-36.5
31.8-36.9
*p < 0.001 vs controls. tp < 0.005 vs controls.
:t:p < 0.05 vs controls. §Controls: gestational week for oral glucose toleJ:ance test (OG1T) during pregnancy.
diabetes mellitus developed during the period from index pregnancy to follow-up examination was calculated on the basis of recent data for the incidence of insulin-dependent diabetes mellitus in the Danish-background population (same area as the referral district of our hospital), which in the period from 1980 to 1984 was 14.2 per 105 women per year for women aged 25 to 29 years (personal communication, A. Mf/llbak, Steno Diabetes Centre, Gentofte, Denmark). This incidence was used as the background population incidence because no data on the incidence of insulin-dependent diabetes mellitus in the age group of >29 years are available.
Results Subjects. Of the 355 women with gestational diabetes mellitus, 298 could be treated satisfactorily with diet alone, 29 also needed treatment with oral hypoglycemic agents, and 28 women needed insulin therapy. Treatment with oral hypoglycemic agents at the Copenhagen center ceased in 1984. Of the 298 women with previous dietary-treated gestational diabetes mellitus, 241 (81 %) participated in the follow-up examination. Of the 57 women who did not participate, 37 refused to do so, 14 had emigrated, 1 was pregnant, and 5 did not respond to repeated requests. The baseline characteristics of the women with
previous gestational diabetes mellitus who did not attend the follow-up examination were comparable with those who attended (Table I). Baseline variables did not differ significantly between the two groups of women with previous gestational diabetes mellitus diagnosed by using venous plasma or capillary whole blood, respectively, for glucose value determination. Fifty-seven (77%) of the women in the control group took part in the follow-up examination. The 17 controls who for various reasons did not participate in the follow-up study did not differ significantly with respect to the baseline variables listed in Table I. Hence, 241 women with previous gestational diabetes mellitus and 57 controls comprise the final study groups of this report. A median of 61 days (quartile range 53 to 70) after the index pregnancy, a postpartum oral glucose tolerance test was carried out in 227 of the 241 women with previous gestational diabetes mellitus. Table II shows basal characteristics at follow-up for the women with previous gestational diabetes mellitus and the control group. Glucose tolerance at follow-up. Abnormal glucose tolerance was found in 83 (34.4%) of the women with previous gestational diabetes mellitus; 9 (3.7%) women were treated with insulin, 33 (13.7%) had non-insulindependent diabetes mellitus (oral glucose tolerance test
610
Damm et al.
September 1992 Am J Obstet Gynecol
Table II. Basal characteristics at follow-up for women with previous dietary-treated gestational diabetes mellitus and in controls
Variable
Median age (yr) Quartile range Median body mass index (kg/m 2)
Quartile range No. with body mass index kg/m2
~25
No. using oral contraceptives No. with parity ~2 Median length of follow-up (yr) Quartile range
Women with previous gestational diabetes mellitus (n = 241)
Controls (n = 57)
36.0 31.9-40.1 25.2
34.0 32.2-36.0 22.9
3 weeks before term, 0; delivery :s3 weeks before term, 1. :j:Variable III: Log 120-minute glucose in millimoles per liter. §Variable IV: Log 0 to 120-minute glucose area under the curve in millimoles per liter per minute.
women with gestational diabetes mellitus I to 19 years before; using life-table analysis, they estimated an incidence of diabetes of 40% 17 years after pregnancy. With a follow-up time of 22 to 28 years, O'Sullivan' reported that >35% of women with previous gestational diabetes mellitus later had diabetes according to World Health Organization criteria; using life table analysis, he found the incidence of diabetes to be > 50%. In a Hispanic population in Los Angeles, Mestman et al." reported a frequency of diabetes in women with previous gestational diabetes mellitus of 65% 12 to 18 years after index pregnancy. In contrast to the findings of several other studies, there was no significant correlation in our study between the incidence of diabetes and the duration of follow-up. This difference might partly be the result of the relative short median follow-up time (6 years, range 2 to II); it could also be because the current definition of gestational diabetes mellitus includes women who continue to have abnormal glucose tolerances post partum. Also, the finding that some women with previous gestational diabetes mellitus had insulin-dependent diabetes mellitus shortly after pregnancy might contribute to the discrepancy. That we did not observe differences in the baseline variables between those women with previous gestational diabetes mellitus who did and those who did not attend the follow-up examination suggests that the women with previous gestational diabetes mellitus who did not participate in the followup examination were not self-selected for any particular risk of diabetes or impaired glucose tolerance. Unlike the majority of previous studies, our study focused
on women with previous dietary-treated gestational diabetes because it has previously been shown in our population,'3 that a very high percentage of women with previous gestational diabetes mellitus who need insulin treatment during pregnancy have overt diabetes shortly after pregnancy. The plasma glucose cut-off limit for initiation of treatment with oral hypoglycemic agents or insulin in our study was higher than that reported in some of the previous studies. Some of the differences between the findings of our study and those studies previously published might be explained by differences in the profile of confounding variables with respect to the development of non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus in the different ethnic populations studied. In Denmark the incidence of insulindependent diabetes mellitus is relatively high, whereas the incidence of non-insulin-dependent diabetes mellitus is relatively low compared with the population of Hispanic women in Los Angeles. It must also be considered that our population in general had a lower relative body weight than that reported in the majority of the previous studies. Another main objective of our study was to identify predictive factors for the later development of diabetes in women with previous gestational diabetes mellitus. Because different diagnostic tests and criteria for the diagnosis of gestational diabetes mellitus are being used, we decided first to analyze the data in a way that was not dependent of the glucose load of the oral glucose tolerance test. Because of the limited number of women in whom insulin-dependent diabetes mellitus
614
Damm et al.
September 1992 Am J Obstet Gyneco1
Table VI. Third model: Independent predictive factors of future development of overt diabetes in women with previous dietary-treated gestational diabetes according to multiple logistic regression analysis (n = 89)
p
Variable
Coefficient ± SE
Odds ratio
95% Confidence interval
Value
I. Fasting glucose at di-
9.8451 ± 3.4518
6.94
1.83-26.24
0.0043
2.3945 ± 1.1430
3.15
1.08-9.23
0.0362
-1.6189 ± 0.7626
5.26
1.13-22.50
0.0338
agnostic OGTT* II. 0-120-minute glucose area under the curve at postpartum oral glucose tolerance testt III. 0-60-minute insulin area under the curve at diagnostic oral glucose tolerance testt Intercept
-30.8871 ± 10.3518
Odds ratio and confidence intervals for parameters analyzed as continuous variables are calculated comparing 75th percentile with 25th percentile as examples of high and low values. *Variable I: Log fasting glucose in millimoles per liter. tVariable II: Log 0 to 120-minute glucose area under the curve in millimoles per liter per minute. tVariable III: 0 to 60-minute insulin area under the curve at the diagnostic oral glucose tolerance test >75th percentile, 1; 0 to 60-minute insulin area under the curve at the diagnostic oral glucose tolerance test :s75th percentile, O.
developed, it was not possible in a multivariate analysis to evaluate predictive factors for insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus separately; for that reason, the dependent variable in the analysis was development of diabetes. Fasting glucose at the diagnostic oral glucose tolerance test, preterm delivery, and an oral glucose tolerance test result showing diabetes 2 months after delivery were independent predictors for development of diabetes. Other studies have also shown that an increased fasting glucose value at diagnosis is a predictor of future overt diabetes.'·9 Metzger et al. l4 found that the incidence of diabetes in women with previous gestational diabetes mellitus 1 year post partum increased from 23% at a fasting venous plasma glucose value
Key words: Follow-up of women with previous gestational diabetes; predictive factors for development of diabetes; insulin-dependent diabetes mellitus; non-insulin-dependent diabetes mellitus Gestational diabetes mellitus complicates 1% to 3% of all pregnancies. I. 2 Gestational diabetes mellitus is defined as a carbohydrate intolerance of varying severity with onset or first recognition during pregnancy irrespective of glycemic status after delivery.' Gestational diabetes mellitus is thus a heterogeneous disorder that in some cases can be managed satisfactorily by dietary treatment; in other cases insulin treatment is required. Gestational diabetes mellitus implies a significant risk to the mother for later development of overt diabetes! It is generally assumed that gestational diabetes mellitus primarily predisposes a patient to From the Diabetes Center, Department of Obstetrics and Gynaecology Y, Rigshospitalet," and the Statistical Research Unit, University of Copenhagen.' Supported by The Novo Foundation; Danish Diabetes Association; Danish Hospital Foundation for Medical Research, Region Copenhagen, the Faroe Islands, and Greenland; The University of Copenhagen; F.L. Smidth & Co. AI S's gavefond; the GangstedFoundation; Handelsgartner O.V.B. Olesen og aegtefaelle, fru E. Buhl Olesen's Mindelegat; the P. Carl Pedenen Foundation; the Nordisk Insulin Foundation; and the Danish Medical Research Council. Received for publication December 6, 1991; revised March 2, 1992; accepted March 13, 1992. RepTint requests: Peter Damm, MD, Diabetes Center Y 4031, Department of ObstetTics and Gynaecology, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen (7), Denmark.
611137877
non-insulin-dependent diabetes mellitus and not to insulin-dependent diabetes mellitus, but this issue has never been thoroughly investigated. In the majority of follow-up studies of women with previous gestational diabetes mellitus inhomogeneous populations have been examined, diverging definitions and diagnostic tests for gestational diabetes mellitus have been used, and different end-point criteria for subsequent development of diabetes have been applied. 5 . g Differences in methods and definitions are the most likely reasons for the miscellaneous outcome of the studies. Because it is important to predict the risk of future development of overt diabetes shortly after delivery in a woman with gestational diabetes mellitus, the objectives of the current study were to determine the incidence of insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, and impaired glucose tolerance in women with previous gestational diabetes mellitus and to identify predictive factors for the later development of overt diabetes in these women.
Material and methods Subjects. During the period 1978 to 1985, 355 women with gestational diabetes mellitus' were diag-
607
608
Damm et al.
nosed at the Diabetes Center at Rigshospitalet in Copenhagen. All pregnant women consulting the department were examined for gestational diabetes mellitus by a routine screening procedure based on risk factors and fasting blood glucose values. 2 The definitive diagnosis of gestational diabetes mellitus was confirmed by a 3-hour, 50 gm oral glucose tolerance test that was considered abnormal if two or more glucose values exceeded the mean + 3 SD curve pertaining to a group of 46 normal nonpregnant controls investigated by the same procedure. 1o The mean + SD for venous plasma glucose values were 6.4 mmoilL at 0 minutes, 10.1 mmoilL at 30 minutes, 10.1 mmol/Lat 60 minutes, 8.7 mmoilL at 90 minutes, 7.6 mmoilL at 120 minutes, 7.6 mmoilL at 150 minutes, and 6.6 mmoilL at 180 minutes. All women with previous gestational diabetes mellitus were initially treated with a 5000 to 8000 kJ/ day diet, and treatment with hypoglycemic agents or insulin was only initiated if the mean of six daily glucose determinations exceeded 7 mmoilL (multiply with 18 to convert to milligrams per deciliter). Labor was routinely induced at term if spontaneous delivery had not already taken place. All women with previous gestational diabetes mellitus were subjected to a 50 gm oral glucose tolerance test about 8 weeks after delivery and were invited to yearly oral glucose tolerance tests thereafter. A subgroup of the women with previous gestational diabetes mellitus had plasma insulin measured during the oral glucose tolerance tests in pregnancy and post partum. Seventy-four women who had normal 50 gm oral glucose tolerance test results in the last trimester of pregnancy in the period 1978 to 1985 served as controls. None had a family history of diabetes. Follow-up. All women with previous gestational diabetes mellitus who had been treated with diet only and the controls were asked to participate in a follow-up study 2 to 11 years after the index pregnancy. Informed consent was obtained, and the study was approved by the local ethics committee. A 75 gm oral glucose tolerance test was performed in women with previous gestational diabetes mellitus who had no known diabetes at the time of follow-up, in women with previous gestational diabetes mellitus who had dietary-treated noninsulin-dependent diabetes mellitus at follow-up, and in the controls. In women treated with insulin at followup, l3-cell function was evaluated by an intravenous glucagon test. II Procedures Seventy-five-gram oral glucose tolerance test. The women were instructed to ingest at least 150 gm/ day of carbohydrates for at least 3 days before the oral glucose tolerance test, which was performed in the morning after a lO-hour fast. Glucose (75 gm in 250 ml water) was given perorally and capillary blood samples were taken at 0,30,60,90, 120, 150, and 180 minutes thereafter. The results of the oral glucose tolerance tests were
September 1992 Am J Obstet Gyneco1
evaluated according to the criteria of the World Health Organization. 12 Glucagon test. After an overnight fast, venous blood samples for plasma C-peptide determinations were taken before and 6 minutes after an intravenous injection of 1 mg of glucagon. Analyses Index pregnancy. Glucose was analyzed with the glucose dehydrogenase method. Until September 1982 glucose values were measured in venous plasma; capillary whole blood was used thereafter. Plasma insulin was measured by radioimmunoassay.1O Follow-up. Glucose values were measured in capillary plasma with a glucose oxidase method. Plasma C-peptide was analyzed by a radioimmunoassay kit. Calculations and statistics. The incremental area under the curve for the oral glucose tolerance tests was calculated with the trapezoidal method and the fasting value as basal value. The X2 test and the Fisher exact test were used for comparison of frequencies. Comparisons between medians of groups were made by the Mann-Whitney test. All tests were two-tailed and a p < 0.05 was considered significant. Logistic regression analysis was applied to determine which variables were significantly associated with the development of diabetes. A backward elimination procedure was chosen. Only subjects who at the postpartum examination did not have overt diabetes and for whom all the studied variables had been recorded were included in this analysis. Odds ratios and 95% confidence intervals for each predictive variable (adjusted for all other variables) are given. Data were analyzed with three different models. First, a simple model was constructed in which baseline variables were analyzed together with the fasting glucose values from the oral glucose tolerance tests at diagnosis and post partum and the main outcome of the postpartum oral glucose tolerance test (diabetic-nondiabetic). Second, more detailed data from the oral glucose tolerance tests were evaluated as predictive factors analyzing both glucose values measured during the oral glucose tolerance tests (0, 60, 120 minutes) and the 0 to 60- and 0 to 120-minute glucose areas under the curve in the previously created logistic regression model. Third, the predictive value of plasma insulin was analyzed in a subgroup of women in whom plasma insulin had been measured during the oral glucose tolerance test at diagnosis and post partum assessing the following variables in the second logistic regression model: insulin (0, 60, 120 minutes), the insulin areas under the curve, and insulinogenic indexes (insulin response per unit glucose stimulus) during oral glucose tolerdnce tests at 0 to 60 and 0 to 120 minutes. In this analysis the insulin variables were assessed as dichotomized variables. The expected number of women with previous gestational diabetes mellitus in whom insulin-dependent
Diabetes in women with previous gestational diabetes
Volume 167 Number 3
609
Table I. Baseline data from index pregnancy for women with previous dietary-treated gestational diabetes mellitus and in controls Women with previous gestational diabetes
Variable
Median age (yr) Quartile range Median body mass index (kg/m2, prepregnancy) Quartile range No. with body mass index ~25 kg/m2 (prepregnancy) No. with parity ~2 No. with first-degree relative with diabetes No. of white women No. who had cesarean section Median gestational week of pregnancy at delivery Quartile range Median gestational week of pregnancy at diagnostic OGTT§ Quartile range
With follow-up examination (n = 241)
Without follow-up examination (n = 57)
Controls with examination at follow-up (n = 57)
30.1* 26.2-33.6 23.0
31.3 27.1-35.5 24.8
26.7 25.1-29.3 21.5
20.2-28.0 87 (36%)
21.3-30.1 28 (49%)
20.1-26.5 16 (28%)
136 (56%)t 53 (22%)
38 (67%) 15 (26%)
19 (33%) 0(0%)
218 (90%) 50 (21%)*
50 (88%) 14 (25%)
56 (98%) 5 (9%)
39.3*
39.0
40.2
38.7-40.0 34.1
38.2-39.8 34.0
39.5-41.1 34.0
30.3-36.8
30.1-36.5
31.8-36.9
*p < 0.001 vs controls. tp < 0.005 vs controls.
:t:p < 0.05 vs controls. §Controls: gestational week for oral glucose toleJ:ance test (OG1T) during pregnancy.
diabetes mellitus developed during the period from index pregnancy to follow-up examination was calculated on the basis of recent data for the incidence of insulin-dependent diabetes mellitus in the Danish-background population (same area as the referral district of our hospital), which in the period from 1980 to 1984 was 14.2 per 105 women per year for women aged 25 to 29 years (personal communication, A. Mf/llbak, Steno Diabetes Centre, Gentofte, Denmark). This incidence was used as the background population incidence because no data on the incidence of insulin-dependent diabetes mellitus in the age group of >29 years are available.
Results Subjects. Of the 355 women with gestational diabetes mellitus, 298 could be treated satisfactorily with diet alone, 29 also needed treatment with oral hypoglycemic agents, and 28 women needed insulin therapy. Treatment with oral hypoglycemic agents at the Copenhagen center ceased in 1984. Of the 298 women with previous dietary-treated gestational diabetes mellitus, 241 (81 %) participated in the follow-up examination. Of the 57 women who did not participate, 37 refused to do so, 14 had emigrated, 1 was pregnant, and 5 did not respond to repeated requests. The baseline characteristics of the women with
previous gestational diabetes mellitus who did not attend the follow-up examination were comparable with those who attended (Table I). Baseline variables did not differ significantly between the two groups of women with previous gestational diabetes mellitus diagnosed by using venous plasma or capillary whole blood, respectively, for glucose value determination. Fifty-seven (77%) of the women in the control group took part in the follow-up examination. The 17 controls who for various reasons did not participate in the follow-up study did not differ significantly with respect to the baseline variables listed in Table I. Hence, 241 women with previous gestational diabetes mellitus and 57 controls comprise the final study groups of this report. A median of 61 days (quartile range 53 to 70) after the index pregnancy, a postpartum oral glucose tolerance test was carried out in 227 of the 241 women with previous gestational diabetes mellitus. Table II shows basal characteristics at follow-up for the women with previous gestational diabetes mellitus and the control group. Glucose tolerance at follow-up. Abnormal glucose tolerance was found in 83 (34.4%) of the women with previous gestational diabetes mellitus; 9 (3.7%) women were treated with insulin, 33 (13.7%) had non-insulindependent diabetes mellitus (oral glucose tolerance test
610
Damm et al.
September 1992 Am J Obstet Gynecol
Table II. Basal characteristics at follow-up for women with previous dietary-treated gestational diabetes mellitus and in controls
Variable
Median age (yr) Quartile range Median body mass index (kg/m 2)
Quartile range No. with body mass index kg/m2
~25
No. using oral contraceptives No. with parity ~2 Median length of follow-up (yr) Quartile range
Women with previous gestational diabetes mellitus (n = 241)
Controls (n = 57)
36.0 31.9-40.1 25.2
34.0 32.2-36.0 22.9
3 weeks before term, 0; delivery :s3 weeks before term, 1. :j:Variable III: Log 120-minute glucose in millimoles per liter. §Variable IV: Log 0 to 120-minute glucose area under the curve in millimoles per liter per minute.
women with gestational diabetes mellitus I to 19 years before; using life-table analysis, they estimated an incidence of diabetes of 40% 17 years after pregnancy. With a follow-up time of 22 to 28 years, O'Sullivan' reported that >35% of women with previous gestational diabetes mellitus later had diabetes according to World Health Organization criteria; using life table analysis, he found the incidence of diabetes to be > 50%. In a Hispanic population in Los Angeles, Mestman et al." reported a frequency of diabetes in women with previous gestational diabetes mellitus of 65% 12 to 18 years after index pregnancy. In contrast to the findings of several other studies, there was no significant correlation in our study between the incidence of diabetes and the duration of follow-up. This difference might partly be the result of the relative short median follow-up time (6 years, range 2 to II); it could also be because the current definition of gestational diabetes mellitus includes women who continue to have abnormal glucose tolerances post partum. Also, the finding that some women with previous gestational diabetes mellitus had insulin-dependent diabetes mellitus shortly after pregnancy might contribute to the discrepancy. That we did not observe differences in the baseline variables between those women with previous gestational diabetes mellitus who did and those who did not attend the follow-up examination suggests that the women with previous gestational diabetes mellitus who did not participate in the followup examination were not self-selected for any particular risk of diabetes or impaired glucose tolerance. Unlike the majority of previous studies, our study focused
on women with previous dietary-treated gestational diabetes because it has previously been shown in our population,'3 that a very high percentage of women with previous gestational diabetes mellitus who need insulin treatment during pregnancy have overt diabetes shortly after pregnancy. The plasma glucose cut-off limit for initiation of treatment with oral hypoglycemic agents or insulin in our study was higher than that reported in some of the previous studies. Some of the differences between the findings of our study and those studies previously published might be explained by differences in the profile of confounding variables with respect to the development of non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus in the different ethnic populations studied. In Denmark the incidence of insulindependent diabetes mellitus is relatively high, whereas the incidence of non-insulin-dependent diabetes mellitus is relatively low compared with the population of Hispanic women in Los Angeles. It must also be considered that our population in general had a lower relative body weight than that reported in the majority of the previous studies. Another main objective of our study was to identify predictive factors for the later development of diabetes in women with previous gestational diabetes mellitus. Because different diagnostic tests and criteria for the diagnosis of gestational diabetes mellitus are being used, we decided first to analyze the data in a way that was not dependent of the glucose load of the oral glucose tolerance test. Because of the limited number of women in whom insulin-dependent diabetes mellitus
614
Damm et al.
September 1992 Am J Obstet Gyneco1
Table VI. Third model: Independent predictive factors of future development of overt diabetes in women with previous dietary-treated gestational diabetes according to multiple logistic regression analysis (n = 89)
p
Variable
Coefficient ± SE
Odds ratio
95% Confidence interval
Value
I. Fasting glucose at di-
9.8451 ± 3.4518
6.94
1.83-26.24
0.0043
2.3945 ± 1.1430
3.15
1.08-9.23
0.0362
-1.6189 ± 0.7626
5.26
1.13-22.50
0.0338
agnostic OGTT* II. 0-120-minute glucose area under the curve at postpartum oral glucose tolerance testt III. 0-60-minute insulin area under the curve at diagnostic oral glucose tolerance testt Intercept
-30.8871 ± 10.3518
Odds ratio and confidence intervals for parameters analyzed as continuous variables are calculated comparing 75th percentile with 25th percentile as examples of high and low values. *Variable I: Log fasting glucose in millimoles per liter. tVariable II: Log 0 to 120-minute glucose area under the curve in millimoles per liter per minute. tVariable III: 0 to 60-minute insulin area under the curve at the diagnostic oral glucose tolerance test >75th percentile, 1; 0 to 60-minute insulin area under the curve at the diagnostic oral glucose tolerance test :s75th percentile, O.
developed, it was not possible in a multivariate analysis to evaluate predictive factors for insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus separately; for that reason, the dependent variable in the analysis was development of diabetes. Fasting glucose at the diagnostic oral glucose tolerance test, preterm delivery, and an oral glucose tolerance test result showing diabetes 2 months after delivery were independent predictors for development of diabetes. Other studies have also shown that an increased fasting glucose value at diagnosis is a predictor of future overt diabetes.'·9 Metzger et al. l4 found that the incidence of diabetes in women with previous gestational diabetes mellitus 1 year post partum increased from 23% at a fasting venous plasma glucose value
