Oral versus intravenous
glucose tolerance
tests during pregnancy Report on 200 cases evaluated
FRED
BENJAMIN,
DONALD
J.
by both tests
M.D.
CASPER,
M.D.
Jamaica, New York
the oral glucose tolerance test has been, and still is, the test most generally used for the diagnosis of both overt and latent diabetes during pregnancy. Impaired curves are found in a high percentage of both unselected1g and selected’ cases. In the nonpregnant state, follow-up has shown that minor aberrations in the oral glucose tolerance test almost invariably denote early diabetes and are often followed by the development of overt diabetes18 2, 6 However, the significance of such minor abnormalities in the test during pregnancy has been questioned. It has frequently been alleged that the gestational changes in gastrointestinal function4v lo* ‘I, ?? and the many endocrine and metabolic alterations of pregnancy may invalidate the results of the test. Accordingly, in recent years, the intravenous test has frequently been recommended as a more reliable index of glucose tolerance in pregnancy. Since the validity and significance of either test has not yet been firmly established, prospective studies are in progress in our department. Intravenous and oral tests are being performed at similar sta‘ges throughout pregnancy, and are being followed by repeat tests post partum, including cortisone augmentation when indicated. Long-term follow-up is also in progress. F 0 R
MAN
Y
YEAR
This report deals with the early part of the study which sought initially to compare the results of both oral and intravenous glucose tolerance tests done in the same patients during the same week of gestation.
s
From the Department of Obstetrics Gynecology, Long Island Jewish Hospital-Queens Hospital Center Afiliation.
Materials
and
methods
Two hundred patients attending the antepartum clinics of the Queens Hospital Center were studied. In order to procure the maximum number of patients with abnormal glucose tolerance, a high expectancy group was chosen. Patients were selected on the basis of the following criteria: (1) a family history of diabetes mellitus, (2) a history of having had one or more infants weighing 9 pounds and over, (3) a history of unexplained stillbirths or neonatal deaths, fetal abnormality, toxemia, hydramnios, or abnormal glucose tolerance in a previous pregnancy, and (4) glycosuria, pre-eclampsia, hydramnios, a big baby, or a maternal weight of 160 pounds or over in the current pregnancy. An oral and a “rapid” intravenous glucose tolerance test were carried out in each patient in the third trimester of pregnancy. The two tests were done within 7 days of each other. The tests were done under the same standardized conditions. The patients were told to take an unrestricted carbohydrate diet for at least 3 days prior to each test. The oral test was the “standard 100 Gm. test.” The blood samples analyzed were after fasting, VQ hour, 1 hour, 2 hours, and
and
566
Volume Number
94 4
Oral
3 hours. The intravenous test employed was the “rapid intravenous test.” A fasting specimen was obtained along with specimens at 10 minute intervals up to one hour following the rapid intravenous injection of 25 Gm. glucose (50 ml. of a 50 per cent solution). The same method of drawing and examining the blood samples was applied to each subject. Venous blood was tested for “true” glucose with an autoanalyzer. The oral glucose tolerance curves were regarded as normal if the fasting blood sugar level was below 110 mg. per 100 ml., the peak value below 160 mg. per 100 ml., and the 2 hour value not over 110 mg. per 100 ml. Values above these levels were considered to represent impaired tolerance.6 The criteria used for diagnosing abnormal glucose tolerance by the intravenous test were those established by Silverstone, Solomons, and Rubricius.15 In this method, the rate of disapperance of glucose from the blood is calculated and expressed as the “K value.” This is done by plotting the blood sugar values against time in minutes on semilogarithmic paper. By using the formula K = 69.315/t (t being the time in minutes in which any blood sugar value is halved), the rate of disappearance of glucose in milligram per cent per minute is obtained. The mean K value for the third trimester of preg-
vs.
intravenous
1 2 3 4
Patient I. M. c. J.
c. C. c. R.
1 Fasting 75 56 65 68
1 5
how
I
NO. 1 2 3 4
Patient I. M. c. J.
c. C. c. R.
Fasting 77 62 68 68
2 hour
137 131 124
/ v&es 198 173 162 141
567
The results can be classified into 2 main groups, i.e., a group in which the oral and intravenous tests were in agreement, and a group in which they were not. In the former group, there were 2 categories, namely, one in which both tests were normal and another in which both showed impaired carbohydrate tolerance. The group in which the results were at variance with each other also consisted of two sets of patients, i.e., patients in whom the oral test indicated impaired glucose tolerance with a normal intravenous test and vice versa. In fifty-six (28 per cent) of the 200 patients studied, both oral and intravenous tests indicated normal glucose tolerance. In sixty-one (30.5 per cent) of the 200 patients, abnormal tolerance was found in both oral and intravenous tests. Seventy-nine (39 5 per cent) of the cases showed impaired tolerance by the oral test with normal intravenous results. Only 4 cases (2 per cent) had abnormal tolerance when tested by the intra-
I
145 157 117 132
oral with test
2 hour
I
( mifk?s 186 141 146 117
1 mi?ks 159 126 124 102
abnormal
3 how
97 109 105 81
I inEifk:PYelt
56 69 82
glucose tolerance tests in patients showing intravenous tolerance (blood sugar in mg. $%)
abnormal
tests
Results
Table II. Intravenous with
tolerance
nancy is 1.86 mg. per cent per minute, and the lower limit of normal is 1.13 mg. per cent per minute.15 In the present study, K values of 1.13 mg. per cent per minute or lower were, therefore, regarded as denoting abnormal tolerance.
Table I. Oral glucose tolerance tests in patients showing normal intravenous tolerance and K values of corresponding intravenous (blood sugar in mg. %) No.
glucose
normal
1 mi%r 129 114 114 94
1.02 1.04 1.00 0.98
oral
1 mi%zs 125 106 103 38
1 mftes 112 95 84
1
K 1.02 1.04 1.00 0.98
568
Benjamin
and
Februai y 15, 1966 Am. J. Obst. & Gynec.
Casper
Table III. Over-all comparison of results of oral and intravenous glucose tolerance tests ’ No.
of
case.5 Agreement
Disagreement
Both Both
tests tests
normal abnormal
Total Oral abnormal, intravenous normal Oral normal, intravenous abnormal Total
56 61 ~___ 117 79
Per cent 28 30.5 58.5 39.5
4
2
83
41.5
venous method, in spite of normal findings when oral glucose tolerance tests were done. The details of these latter results are shown in Tables I and II, and a summary of the over-all comparison of the results of the two tests is presented in Table III. Comment The incidence of abnormal oral glucose tolerance tests in a large series of unselected pregnancies has been found to be in the region of 6 per cent.lg When pregnant women are selected, as was done in the present series, on the basis of a family history of diabetes or obstetric factors suggesting abnormal glucose tolerance, the incidence is high, in some reports being as much as 81 per centg; the corresponding figure in the series in this report is 70 per cent. On the other hand, when intravenous glucose tolerance tests are employed, the incidence of abnormality is low. During normal pregnancy no change has been found in intravenous glucose tolerance,4s *, lo, I13 I5 in fact, glucose tolerance has been shown to be improved by this method.15 Even when cases with a high expectancy rate are selected, the intravenous tolerance test has yielded a smaller incidence of abnormal tolerance-22.6 per cent in the series of Solomons, Silverstone, and PosnerlG and 32.5 per cent in our own series. There have been few reports on the comparison of the 2 types of tests done on the same patients at the same stage of preanancy. In such reports only a small number of patients were investigated, 8 by Kaplan,” and 27 by Welsh.ls Only one other study reported by Ocampo, Coseriu, and Quilligan’”
employed the rapid intravenous test. In this latter series, 22 patients were studied, and these .fell into a completely different category from the one reported here. All the cases in their study had been screened as negative for family history of diabetes, oversized babies, unexplained stillbirths or neonatal deaths, and a history of hydramnios. The present study indicates that when a large group of patients with a high expectancy rate were tested at the same time in pregnancy by both oral and intravenous glucose tolerance tests, both tests showed normal results in 28 per cent and impaired glucose tolerance in 30.5 per cent. In 39.5 per cent the oral test alone was abnormal, and in only 2 per cent was the intravenous test alone abnormal. In over 40 per cent of the patients studied by both methods, the results were not in agreement. The implications of such findings need clarification. Our results indicate that if the intravenous test is abnormal, the oral is practically always abnormal as well, but in over half (79 out of 140, or 56 per cent) .of the cases where the oral test showed impaired tolerance, the intravenous test suggested normal tolerance. In spite of several recent suggestions that the intravenous test should replace the oral, we know of no follow-up study in which both tests have been done, and been repeated after delivery, and then followed-up on a long-term basis. There is no firm evidence that the oral test is not a true index of glucose tolerance in pregnancy, or that it may produce false positive results. On the other hand, although the intravenous test, when positive, may be a dependable index of impaired tolerance, there is no proof that it does not miss cases of impaired tolerance completely and yield a number of false negative results. It may be significant that the incidence of abnormal oral glucose tolerance tests in a large unselected pregnant population of 17,000 pregnant women as reported by Wilkerson’g was 6.2 per cent. This is a strikingly similar incidence to the number of women in the general population who will, overt
in
their
the oral
later
years,
develop
mild
or
would suggest that test in pregnancy may indeed al-
diabetes.17,
“‘I ‘I‘his
Volume Number
94 4
ways uncover latent or potential diabetes and be a sensitive and reliable index of its future development. The intravenous test may be more reliable than the oral during pregnancy in not yielding false positive results; but the possibility exists that this test may not be dependable for the detection of minor or even appreciable impairment in islet function. The greater and more SUStained release of insulin following intravenous administration of glucose may so overwhelm the mechanism of placental insulin degradation that the normal fall in blood sugar may occur despite functionally inadequate islets’* (plasma insulin levels are higher following intravenously administered glucose than following intravenous tolbutamide) .I49 23 The low renal threshold, so frequent in pregnancy and the unphysiologic blood sugar levels produced by intravenous glucose may result in an unusually marked loss of glucose in the urine, sufficient to produce an artifactual low blood sugar.l* The true status of these tests and their relative and absolute reliability can be determined by long-term prospective studies. We are currently conducting such a long-term investigation. This present report merely compares the results of oral and intravenous tests in the same 200 patients and is one of the early steps in this study. The need for clarification of these issues is highlighted by the current confusion as to the management of pregnancy in patients exhibiting temporary gestational aberrations in the oral glu-
Oral
vs. intravenous
glucose
tolerance
tests
569
cose tolerance test. Many obstetricians attribute a serious significance to such aberrations, maintaining that these patients are prone to similar complications (such as an increased perinatal loss) which occur in the established diabetic patient.3y 5~ 7l 21 Aggressive therapy on the basis of these tests (including delivery of the patient before term) has been instituted. Other? regard such findings as being of no significance. There seems at present to be no unequivocal basis for either stand when based on glucose tolerance tests. Summary
1. Oral and intravenous glucose tolerance tests were performed during the same week in the third trimester of pregnancy in each of 200 selected patients. 2. In 58.5 per cent of the 200 subjects studied the results of the two tests were in agreement, both being normal in 28 per cent and abnormal in 30.5 per cent. In 41.5 per cent, there was a discrepancy between the two tests. In 39.5 per cent the oral alone was abnormal and in only 2 per cent was the intravenous test the only indication of impaired glucose tolerance. 3. Fifty-six per cent of the patients revealing abnormal glucose tolerance by the oral test were shown to have normal tolerance when tested intravenously. 4. The possible significance and implications of these findings are discussed.
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