Evaluation of oral and intravenous glucose tolerance tests for the diagnosis of “prediabetes” in the puerperium

volume 88

number 3

February 1, 1964

American Journal of

Obstetrics and Gynecology

Transactions of the Nineteenth Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada

Evaluation of oral and intravenous glucose tolerance tests for the diagnosis of "prediabetes" in the puerperium E.J.LOVE,M .D. J . A . F . S T E V EN S 0 N , M . A . , M . D . , C .M . R. A. H. KINCH, M.B., B.S., F.R.C.O.G., F.R.C.S.(C) London, Ontario, Canada

"T H E term 'prediabetes' was coined to signify that period in a diabetic's life hefore the overt disorder became manifest." 18 It has been known for many years that the woman destined to become diabetic may be delivered of infants of excessive size and may incur an increased fetalloss.l, u, 16, 19, 24, 27, 28

Abnormal oral glucose tolerance curves have been demonstrated in some of these cases. 2 • 6 • 7 • 29 • 35 • 36 Rightly or wrongly, the woman with a family history of diabetes, an obstetrical history of large infants, unexplained fetal loss, repeated hydramnios, abortion, or glycosuria who has an abnormal glucose tolerance curve during pregnancy or during the puerperium has been designated "prediabetic." The fetal loss in the unrecognized prediabetic patient can be higher than in the case of well-controlled diabetes. 16 • 30 Recognition and adequate management of this condition will, however, markedly reduce the fetal loss. 8 Attempts to detect the prediabetic state are justified to reduce the fetal wastage, to circumvent the obstetrical

From the Departments of Physiology and Obstetrics and Gynecology, Faculty of Medicine, University of Western Ontario Supported by Child and Maternal Health Grant No. 605-13-30 Department of National Health and Welfare, Canada. The Society Award paper, presented at the Nineteenth Annual Meeting of the Society of Obstetricians and. Gynaecologists of Canada, Toronto, Ontario, Canada, June 14-16, 1963.

283

284

Love, Stevenson, and Kinch \111.

l

h·hr ll.i! \ I t~HJ l ()l_,q, & (;yne(.

Materials and methods

hazards of the large infant, and, as emphasized by Joslin, 21 to decrease the interval before the diagnosis of diabetes. Any case of suspected prediabetes should be investigated during pregnancy. Unfortunately, the diagnosis of prediabetes is not always thought of or looked for until after an excessively large infant has been delivered or an unexplained intrauterine or neonatal death has occurred. The present investigation was instituted to determine whether glucose tolerance tests early in the puerperium were reliable and to determine whether oral or intravenous tests yielded more valid results.

Glucose tolerance tests were obtained in normal women and those suspected of having prediabetes during the first 4 days post partum. For the purpose of this study, a woman was designated suspected prediabetic if the history fulfilled one or more of the following criteria: (a) family history of diabetes, (b) glycosuria in pregnancy, ( c ') delivery of an infant weighing more than 9 pounds, and/ or (d) history of unexplained stillbirth. For comparison, tests were carried out in normal nonpregnant and pregnant women. All subjects fasted overnight. In the oral glucose tolerance test, the subjects were

Table I. Postpartum oral glucose tolerance tests in normal and suspected prediabetic women Time of test postpartum (Hr.)

24 48 96 96

7 11 2 20

9 to 96

8

9 to 96

10

9 25 49 9

Normal women

Suspected prediabetes Family history of diabetes and/ or glycosuria Delivery of infant weighing more than 9 pounds

to to to to

2 Hour blood sugar and interpretation (mg.%)

No. women tested


I IIO to Il9 I

>120

4

5 6

6

13

2

')

6

7

2

Table II. Postpartum intravenous glucose tolerance tests in normal vvomen* Percentage difference

Time of test postpartum (Hr.)

No. of subjects

Fastinf{

30 Min.

2 to 8

11

93.0 ± 2.33t

9 to 16

6

17 to 24

60 Min.

120 Min.

between fasting and 120 min.

235.2 ± 10.53

162.6 ± 12.14

100.1 ± 6.80

+ 9.4 ± 8.79

75.3 + 5.14

237.4 ± 16.17

113.0 ± 20.28

64.3 ± 7.01

-14.4 ± 7.54

15

77.4 ± 2.68

230.5 ± 13.30

136.2 ± 7.88

65.7±2.71

-14.4 + 3.63

25 to 48

24

74.8 ± 2.35

238.2 ± 11.37

122.0 ± 7.65

65.9 ± 3.02

-11.4± 3.76

49 to 96

27

80.5 ± 1.46

225.8 ± 9.26

112.7± 6.02

70.9 ± 2.57

-12.2 ± 2.41

Blood sugar (mg.%)

I

*Underlined values indicate P values significantly different from 2 to 6 hour group; < 0.05.

= = = p < 0.02;--- p tMean

± standard error mean.

=

P

<

0.001; - - P

<

0.01;

Glucose tolerance tests for "prediabetes" 285

Volume 88 Number 3

.

250

~

- - NON-PREGNANT - - - - PREGNANT

-POST-PARTUM

··· ··· 9·96 HRS. P.P.

2-lllra. ......... 9-9111rL

\\\\ 100

\ ..•.........•\

0

1/z

....• 2

0

''a TIME OF TEST

TIME OF TEST (HOURS)

I

I

Otoulls,

Fig. 1. The average intravenous glucose tolerance curve which were obtained for normal women tested from 2 to 8 hours and from 9 to 96 hours post partum.

Fig. 2. The average intravenous glucose tolerance curve obtained for normal nonpregnant, for normal women late in pregnancy, and for normal women tested from 9 to 96 hours post partum.

given 100 Gm. of dextrose in flavored solution. Blood sugars were determined in the fasting state and 30, bU, and l4U minutes after the ingestion of glucose. In the intravenous test, 0.5 Gm. of dextrose per kilogram body weight, as a 20 per cent solution in distilled water, was given at a constant rate over 30 minutes. The blood sugar was determined in the fasting state, at the end of infusion, and 30 a.Jld 90 minutes later. Glucose was determined by the method of Somogyi. 33 The level of the 2 hour "true" glucose was used to interpret the results of the oral glucose tolerance test. 2 • 9 The test was considered to be normal if the 2 hour blood sugar was less than 110 mg. per cent, suspicious if between 110 and 119 mg. per cent, and abnormal if over 120 mg. per cent. In the intravenous glucose tolerance test, the blood sugar, obtained 90 minutes after the

end of infusion, is normally less than the fasting blood sugar. 1 ° For this study, the difference between the fasting and 2 hour blood sugar has been expressed as a percentage of the fasting blood sugar. Results

Postpartum oral glucose tolerance tests. In normal women. Oral glucose tolerance tests \vere obtained from 9 to 96 hours post

partum in 20 women with a normal obstetrical history and with a negative family history of diabetes. Based upon the 2 hour blood sugar, the test was considered to be norn1al in 6 women, susp1c1ous in one, and abnormal in 13 women (Table I). In suspect prediabetic patients. Eight women were tested because they had a family history of diabetes and/or glycosuria in pregnancy. The oral glucose tolerance !eS! was normal in 1, suspicious in 1, and ab~

286

\Ill

normal in 6 of these women. Ten wonu:·n who had been delivered of babies weighing over 9 pounds were also tested post partum. The test was considered to be normal in l, susp1crous m 2 and abnormal in 7 of these women. Abnormal oral glucose tolerance tests were observed in 13 of the 20 normal women and in 13 of the 18 women suspected of having prediabetes tested within the first 96 hours post partum. Thus, an abnormal oral glucose tolerance curve in the immediate postpartum period does not provide a valid basis for the diagnosis of prediabetes. Intravenous glucose tolerance tests. In normal women. Intravenous glucose tolerance tests were carried out in 83 normal women during the first 96 hours post partum. The time interval between delivery and test and the number of subjects tested in each time interval were: 2 to 8 hours, 11; 9 to 16 hours, 6; 17 to 24 hours, 15; 25 to 48 hours, 24; 49 to 96 hours, 27. The mean fasting and 2 hour blood sugars of the group of women tested from 2 to 8 hours post partum were significantly higher than for any group tested after 9 hours (Table II). The average fasting, 1 and 2 hour blood sugar levels of the group investigated from 2 to 8 hours post partum were significantly higher than those obtained for the group investigated from 9 to 96 hours post partum (Fig. 1). The average curve obtained after 9 hours, however, did not differ from those obtained in 10 normal nonpregnant women or in 10 normal pregnant women (Fig. 2). For the group tested from 2 to 8 hours from delivery, the difference between the fasting and 2 hour blood sugar was + 9.4 ± 8.79 per cent (Table II). For the group tested from 9 to 96 hours post partuin, the average percentage difference was - 12.6 ± 1.80 per cent. The individual postpartum intravenous glucose tolerance curves were compared on the basis of the fasting blood sugar and the percentage difference betwen the fasting and 2 hour blood sugar (Table III). Before 9 hours, 2 of the 11 women tested had a

I, Flfd & ( ;yf!t(

J·,.J,,I~(t(\

Love, Stevenson, and Kinch

J ( ii);,{

Table III. Comparison of fasting blood sugar and percentage difference between the fasting and the 2 hour blood sugar m normal women post partum f

Tune of test postpartum (hr.) I 25-T .9 ...

,-2,. 9 I 17 Fasting blood sugar (mg.%) <90 90 to 99 100 to 109 Percentage difference between fasting and 2 hour blood sugars 0 or < plus 20

to 8

to I to 16 24

I

I to 48

49

I to t

96

to 96

3 5 61 2

12 :l

21 3

23 61 +11

5

13

20

23

4 3 1 3

0

1

1

1

2 1

1

4

61 7 3 1

fasting blood sugar in excess of 100 mg. per cent. After 9 hours all fasting blood sugars were less than 100 mg. per cent. In 3 of the 11 subjects tested before 9 hours, the 2 hour blood sugar was 20 per cent higher than the fasting level (Table III). After 9 hours, in only 1 of the 72 women was the difference more than 20 per cent. In women with abnormal or suspicious oral glucose tolerance tests. Three women with a suspicious and 8 women with an abnormal postpartum oral glucose tolerance curve were reinvestigated using the intravenous test during or following their next pregnancy. T h e abnormality in glucose tolerance was confirmed in only 2 of these 11 women. In normal women, then, after 9 hours post partum the average intravenous glucose tolerance curve obtained is not different from that obtained in normal nonpregnant and normal pregnant women. The difference between the fasting and the 2 hour blood sugar, expressed as a percentage of the fasting level, was selected for the evaluation of subsequent tests. If the percentage difference was less than + 10 per cent, the test was considered to be normal, if between + 10 to 20 per cent as suspicious, and if over + 20 per cent as abnormal. The observation that an

Volume 88 Number3

Glucose tolerance tests for "prediabetes" 287

Table IV. Postpartum intravenous glucose tolerance tests in suspected prediabetic women Difference between fasting and 2 hour blood sugar and interpretation (%) Indication for glucose tolerance test

Family history of diabetes Glycosuria Unexplained stillbirth Delivery of infant weighing more than 9 pounds Total

<+ 10

No. women tested

Normal

27 9

29

12 4

I

I 0 to 20 Suspicious

I

>+ 20 Abnormal

2 3

4

90

69

9

12

135

109

11

15

Table V. Postpartum intravenous glucose tolerance tests in women who have been delivered of an infant weighing more than 9 pounds DiffertJnce btJtween fastings and 2 hour blood sugar and interpretation

>

+ 20 Abnormal

One baby 9 to 10 pounds Two or babies 9 to 10 pounds One baby 10 pounds Two or more babies 10 pounds One or more babies 9 pounds and stillbirth

>

>

> >

29 9 34 12

24 6

6

3

29

7

4

1

4

3 1 5

2

Table VI. Postpartum intravenous glucose tolerance tests in women who have been delivered of an infant weighing more than 9 pounds Difference between fasting and 2 hour blood sugar and interpretation

<

No. women

>

+ 10

+ 20 Abnormal

Normal

Family history negative Glycosuria-negative Positive family history of diabetes

56 28

43

6

7

22

2 1

4

4

6

1

Table VII. Postpartum intravenous glucose tolerance tests in suspected prediabetic women-the effect of time of test post partum Time of test post partum 49 to 96 Hours

9 to 48 Hours No. women tested

Family history of diabetes Glycosuria Delivery of infant weighing more than 9

I

No. tests abnormal

No. women tested

I

No. tests abnormal

20

0 2

9

0 1

60

3 0

30

8*

5

7 1

0

288

F('IH

Love, Stevenson, and Kinch

abnormality in glucose tolerance could he confirmed by the intravenous test in only 2 of tlw 8 women with a previous abnormal postpartum oral glucose tolerance test emphasizes that postpartum oral glucose tolerance tests should be interpreted with caution. In susjJected prediabetic women. Intravenous glucose tolerance tests were carried out in 135 women suspected at delivery of having prediabetes. The indications for the test, the number of women in each group, and the results are listed in Table IV. The tests were considered to be abnormal in 15, suspicious in 11, and normal in the remaining 109. None of the 29 women tested because of a family history of diabetes, alone, had an abnormal curve. Three of the 12 women tested post partum because of glycosuria during pregnancy had abnormal curves. None of the 4 women investigated because of an unexplained stillbirth had an abnormal curve. Twelve of the 90 women who had been delivered of at least one baby weighing over 9 pounds showed an abnormal curve. Among the women investigated because of the delivery of large infants, the incidence of abnormal curves varied with the number and weight of the infants (Table V). Five of the 12 women who had delivered two or more infants weighing over 10 pounds, had abnormal curves. An equal proportion of abnormal curves were found among the women tested because of the delivery of two or more infants weighing between 9 and 10 pounds ( 3: 9) and the women tested because of a baby weighing more than 9 pounds and an unexplained stillbirth ( 2: 6) . Few abnormal curves were found in the women tested because of the birth of one baby weighing between 9 and 10 pounds ( 1 : 29) or of a baby weighing more than 10 pounds ( 1:34). In the group of women tested because of the birth of a large baby seven of the 56 women without a family history of diabetes or glycosuria had abnormal tests (Table VI). In those women who had a family history of diabetes, 4 of the 28 tested had

:\111,

!U' \

J. ( )IJ-,~

1 ](Jhl

S ( t)/ltT.

an abnormal rut'\'l'. In the women \\ho had l;lycosuria. one of tlw 6 had an abnormal curve. Significantly, more abnormal curvP> \'v'ere discovered vvhen the intravenous glllcose tolerance test was performed from 49 to 96 hours post partum than from 8 to 48 hours postpartum (Table VII). Comment

Any woman with a family history of diabetes, with glycosuria in pregnancy or with an obstetrical history of large infants or of unexplained stillbirths should be suspected of being prediabetic. If she has an abnormal glucose tolerance during pregnancy, she is considered to be either gestational diabetic or a prediabetic. Unless this abnormality in glucose tolerance disappears in the puerperium, the woman is considered to be diabetic. O'Sullivan ~ has shown that 117 (92.9 per cent) of 126 women considered to have gestational diabetes because of abnormal oral glucose tolerance tests during pregnancy had normal curves when retested 6 weeks to 6 months after delivery. Obviously, to diagnose prediabetes as a complication of pregnancy, glucose tolerance tests are better done prior to delivery. However, this condition is not always thought of or looked for until after the delivery of an excessively large infant or after an unexplained fetal loss has occurred. In such a patient, postpartum investigation is mandatory. The postpartum diagnosis of prediabetes is made difficult by two conflicting factors. The first is that the alimentary disturbance common to labor and the puerperium may interfere with absorption. For this reason, Lund and Weese 26 recommended that the postpartum investigation be delayed until after 48 hours. Presumably, it was for this reason that Hagbard12 delayed until the fourth to seventh day postpartum his study of women who had been delivered of large infants. The second factor making the interpretation of the postpartum oral glucose tolerance test difficult is that the abnormal glucose tolerance of the prediabetic woman may rapidly return to normal in the puerperium. 2

Volume 88 Number 3

Lund and Weese 26 observed that three of the 4 women with abnormal glucose tolerance curves in late pregnancy, when retested in the puerperium, had completely normal curves by the third postpartum day. In Barnes' study/ two patients, in whom a definite abnormality in glucose tolerance was observed during pregnancy, had a normal glucose tolerance within 3 days of delivery. Although no evidence is presented, Carrington7 believes that a return to normal tolerance may occur as early as 24 hours post partum and in many women does so within 72 hours. 8 As a result of the present study, we have now abandoned the use of the oral glucose tolerance test in the puerperium. Contrary to Carrington's statement that, "In suspected cases, postpartum glucose tolerance tests are valid only when positive but must be considered inconclusive when negative," we would suggest that an abnormal oral glucose tolerance test in the puerperium is never conclusive. Indeed, there is considerable evidence to suggest that throughout pregnancy 5 oral glucose tolerance t e s t s should be interpreted with caution. Although the oral glucose tolerance test may be abnorma}/ 5 • 25 ' 26 • 32 the intravenous test remains normal throughout normal pregnancy. 3 • 4 • 5 • 11 • 13 • 20 • a4 It has also been found that both normal anq suspect women with a definite abnormality in oral glucose tolerance may show a normal intravenous glucose tolerance when retested during the same pregnancy. 22 ' 34 In our hands, the intravenous glucose tolerance test has been reliable as early as 9 hours after delivery. This test, therefore, provides a diagnostic measure for prediabetes as soon as possible after delivery. The intravenous test, as outlined, is simple, tolerated well by the patient, and has no untoward side effects. In this study using the postpartum intravenous tolerance test, 11.1 per cent of the suspected cases showed abnormal curves, and another 8.1 per cent showed suspicious curves. We can find no comparable study of intravenous glucose tolerance tests in the

Glucose tolerance tests for "prediabetes" 289

puerperium. Perhaps a few abnormal curves were missed by failing to test within 48 hours of delivery for, in some women, the abn~rmality may disappear in the very early puerperium. The most important single indication for the postpartum glucose tolerance test is the delivery of a large infant. We must emphasize that in our experience few of these women do, in fact, have an abnormal glucose tolerance. Paternal prediabetes or diabetes17• 23 and genetic factors 31 may play a significant role in the etiology of the large baby. The greatest incidence of abnormal curves obtained in this study was in those women with the most suggestive prediabetic history, i.e., 2 or more large infants and/or fetal loss. Yet, even in this group, the majority had normal intravenous glucose tolerance tests. We should always remember Hagbard's observation 12 that although the prediabetic woman may be delivered of larger infants than normal and incur a greater perinatal loss, it does not follow that a woman with these findings is necessarily prediabetic. Summary and conclusions

Although, the most logical time to diagnose prediabetes complicating pregnancy is before delivery an investigation of glucose tolerance can just as easily be done in the immediate postpartum period. The use of the oral glucose tolerance test within the first 4 days post partum is unreliable, almost as many abnormal curves being observed in a group of normal women as in a group of women suspected of being prediabetic. The intravenous glucose tolerance test, on the other hand, has proved to be simple, tolerated well by the patient, and gives reliable results as soon as 9 hours post partum. Appreciation is expressed to the general physicians, obstetricians, and the intern and nursing staffs of Victoria Hospital, London, for their cooperation in this study, to the staff and private patients included in this study, and to Dr. Harriet MacDonald and Mrs. Sylvia Woods for their technical assistance.

290

Love, Stevenson, and Kinch

REFERENCES

2.

3. 4.

5. 6.

7. 8. 9. 10.

11. 12. 13.

14. 15. 16. 17. 18.

Alkn, E.: AM. J. On sT. & Gnaw. 38: 982. 1939. Barnes, P. H'.: Canad. M-. A. ]. 85: 681, 1961. Burt, R. L.: Obst. & Gynec. 4: 58, 195+. Burt, R. L.: Clin. Obst. & Gynec. 3: 310, 1960. Burt, R. L.: Diabetes 11: 227, 1962. Carrington, E. R., Shuman, C. R., and Reardon, H. S.: Obst. & Gynec. 9: 664, 1957. Carrington, E. R., Reardon, H. S., and Shuman, C. R.: J. A. M. A. 166: 245, 1958. Carrington, E. R.: Clin. Obst. & Gynec. 3: 911, 1960. Conn, J. W.: Diabetes 7: 347, 1958. Duncan, G. G. Diseases of Metabolism, ed. 3, Philadelphia, 1952, W. B. Saunders Company. Elias, H., Gudemann, J., and Roubitschek, R.: Wien. Arch. inn. Med. 11: 567, 1925, referred to by Burt. 4 Hagbard, L.: Acta obst. et gynec. scandinav. Suppl. 4, 37: 497, 1958. Herold, K.: Arch. Gynak. 79: 323, 1926, referred to by Burt.4 Hertzstein, L., and Dolger, H.: AM. J. 0BsT. & GYNEC. 51: 420, 1946. Hurwitz, D., and Jensen, D.: New England J. Med. 234: 327, 1946. Jackson, W. P. U.: Brit. M.]. 2: 690, 1952. Jackson, W. P. U.: ]. Clin. Endocrinol. 14: 177, 1954. Jackson, W. P. U.: Diabetes 11: 334, 1962.

F.·lm,:u) 1, 19M .\m. J. Oh
19 . .fohn, H. L.: Am. J Digest Dis. 17: 219, 1950. :!I). Johnson. D. G., and Bonsnes, R. W.: J. Clin. Invest. 27: 745, 1948. 21. Joslin, E. P., Root, H. F.. White, P., and Marble, A.: Treatment of Diabetes Mellitus, Philadelphia, 1952, Lea & Febiger. 22. Kaplan, N. M.: Arch. Intern. Med. 107: 212, 1961. 23. Kellock, T. D.: Lancet 1: 1252, 1961. 24. Kriss, ]. P., and Futcher, P. H.: ]. Clin. Endocrinol. 8: 380, 1948. 25. Labbe, M., and Chevki, M.: Compt. rend. Sor. de bioi. 94: 302, 1926, referred to by Burt.• 26. Lund, C. ]., and Weese, W. H.: AM. ]. OnsT. & GYNEC. 65: 815, 1953. 27. Miller, H. C., Hurwitz, D., and Kuder, K.: J. A. M. A. 124: 271, 1944. 28. Miller, H. C.: New England J. Mcd. 233: 376, 1945. 29. O'Sullivan, ]. B.: New England ]. Med. 264: 1082, 1961. 30. Pedowitz, P., and Shlevin, E. L.: BulL New York Acad. Med. 28: 440, 19.'>2. 31. Penrose, L. S.: In Hagbard, L.: Acta. obst. et gynec. scandinav. 37: 497, 1958. 32. Rowe, A. W.: J. A. M. A. 89: 1403, 1927. 33. Somoygi, M.: J. Bioi. Chern. 160: 69, 1945. 34. Welsh, G. W.: Diabetes 9: 466, 1960. 35. Wilkerson, H. L. C., and Remein. Q. R.: Diabetes 6: 324. 1957. 36. Wilkerson, H. L. C.: Am. ]. Pub. Health 49: 1032, 1959.