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Diabetes insipidus and pregnancy
Diabetes insipidus and pregnancy JAMES C. WARREN, M.D.* ROGER S. JERNSTROM, M.D. Omaha, Nebraska
D I ABE T E S insipidus is a rare disease characterized by a relative deficiency of antidiuretic hormone (ADH) with concomitant disturbances in water balance. The pathologic changes underlying the condition are destructive lesions of variable nature located in the hypophyseodiencephalic system. 1 Among a series of 65 cases reported by Thomas 2 one third were due to intracranial tumor, one third were of unknown etiology, and the remainder were ascribed to various granulomas and inflammatory lesions. The patient with diabetes insipidus because of deficient production of ADH has a marked reduction of renal facultative reabsorption of water and as a result polyuria, polydypsia, and urine of low osmolar concentration. Various case reports and reviews of the literature have described variable effects of pregnancy when superimposed upon diabetes insipidus. s, lO Unfortunately, many of these patients were studied before the advent of precise procedures for definitive diagnosis of the condition and the reports may include cases of chronic renal disease, adrenal hyperfunction, and psychogenic polydypsia. The latter was impossible to differentiate from true diabetes insipidus before the availability of the Carter-Robbins testY In general, pregnancy has been described as worsening, ameliorating, and effecting no change in diabetes insipidus.
Two recent well-documented reports have shown marked increases in vasopressin requirements during pregnancy. One dealt with diabetes insipidus following hypophysectomy.12 This patient had large urine volumes despite increasing doses of exogenous vasopressin throughout the third trimester of pregnancy but improved after delivery. It is of interest that she received a 75 mg. maintenance dosage of cortisone with much higher doses on occasion. The second report dealt with a patient 13 whose vasopressin requirements increased during pregnancy and late in each menstrual cycle and decreased while nursing. Similar improvement while nursing has been previously reported. H There are interesting ramifications of the combination of diabetes insipidus and pregnancy other than changes in antidiuretic function. Oxytocin production has not been assayed in patients with diabetes insipidus but sites of production and storage as well as release of oxytocin and ADH secondary to electrical and physiologic stimulation are markedly simiIar.15 For this reason, labor and delivery might be expected to be pathologic. We have recently had the opportunity to observe and study 2 patients with proved diabetes insipidus during pregnancy, parturition, and the puerperium: Case 1. E. K., a 34-year-old white woman, para 5-0-0-5, had suddenly developed excessive thirst and polyuria of approximately 9 liters per day in November, 1957. She was admitted to the University of Nehraska Hospital that month
From the Department of Obstetrics and Gynecology, University of Nebraska College of Medicine. *Trainee, National Cancer Institute.
1036
Volume 8J Numhc.'1' 5
where the Carter-Robbins test confirmed a diagnosis of diabetes insipidus. Skull x-rays, visual fields, spinal fluid, fasting blood sugar, pSI, PBI, and BMR determinations were all normal. There Was no known diabetes insipidus in her family. She Was started on intranasal vasopressin but Soon changed to I c.c. (5 units) vasopressin tannate in oil every other day and was maintained on this dosage throughout pregnancy without significant change in intake and output. Total weight gain in pregnancy was 33 pounds. There was spontaneous rupture of the membranes at 11 :00 P.M. on March 31, 1959. (The estimated date of confinement was March 22.) After a 16 hour latent period contractions started on April 1. She had a first stage of 2 hours and 15 minutes, a second stage of 8 minutes, and a third stage of 13 minutes. She was delivered of a 2,755 gram infant spontaneously at 5:23 P.M., and the uterus contracted well after delivery of the placenta. . She had received 4 units of vasopressin tannate In oil (5 units per cubic centimeter) on the rnoming of delivery. Increased thirst was noted on the first postpartum day and 4 units was given daily until the sixth postpartum day when by noon the thirst and polyuria had abated and she returned to her normal schedule. She noted mild breast engorgement on the fourth postpartum day but this lasted only 24 hours. There was no spontaneous discharge of milk. Breast engorgement and "afterpains" were less than in any previous pregnancy. On April 11, 10 days after delivery, there was n~ discernible breast engorgement and the only rnllk discharge had been 3 drops from the right breast on April 8. She was given 2 units of Oxytocin intravenously and rapidly ejected about 25 drops of milk from each breast. She was readmitted on May 28, 1959, when ~ ?arter-Robbins test again confirmed diabetes InsIpidus (done after 72 hours without vasopre~sin tannate in oil). Since delivery, menstrual peflods have been normal and she has remained on vasopressin tannate in oil, I c.c. every other day with daily intakes of about 2.5 liters. Case 2. N. P., a 29-year-old white para 4-0-0-4, ~ated th~ onset of excessive thirst to Nov. 20, 958, whIch she remembered as 17 days prior to ~he o~et of her last normal menstrual period. ThIS thIrst and polyuria increased for 3 weeks and then stabilized around 7 liters intake and 5 liters output daily. Diagnosis of diabetes insipidus Was established in the third month of gestation
Diabetes insipidus and pregnancy
1037
by a Carter-Robbins test. The patient kept her intake and output at pretreatment levels and only increased the frequency of dosage when these levels were exceeded. The dosage of vasopressin tannate in oil was increased gradually from 0.5 c.c. every 7 to 8 days in February to every 2 days in June, the sixth month of gestation. She maintained this level until time of delivery. The pregnancy was uneventful except for irregular spotting during the first 5 months. Total weight gain was 30 pounds. The estimated date of confinement was Sept. 14, 1959. On October 1, she began to have irregular contractions at 5: 00 A.M. and was admitted at 8: 00 A.M. She had hypertonic dysfunctional labor without progress for 19 hours. She was given morphine and had 6 hours rest but then (6:00 A.M., October 2) regular weak contractions began, continuing every 8 to 10 minutes for 7 hours with no significant progress. At 1: 00 P.M. the membranes were ruptured artificially, contractions became hard, of 5 minute frequency, and at 2: 00 P.M. she was delivered of a term infant without difficulty. The second stage was 5 minutes, the third 13 minutes. The uterus contracted well and blood loss was minimal. No oxytocics were given. She had some breast engorgement and nursed the baby but stated she had less milk and "afterpains" than ever before. She stopped nursing the fourth week because milk output was poor and the baby failed to gain satisfactorily until supplementation was initiated. (She had nursed each of
100 80
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lJ
60
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15
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•~20
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III
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q
o
C\I
O~~0----6~0~--~0~--~6~0--~O~--~6~O Ii 1'111 . (mlnutll)
Fig. 1. Reduction of baseline · urine output in Patient 2 after intravenous administration of vasopressin in milliunits as indicated. Values for thirty-sixth week of pregnancy are shaded; others obtained 9 weeks post partum. Baseline volumes 130 m\. (prepartum) and 140 ml. (postpartum).
1038 Warren and Jernstrom
Am.
• 70
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I
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10
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--J._--- MR
O~~~------~4~.~6------~6--9~----e-o~nt~rO-'I~'~ pp do, PP wlek
Fig. 2. Baseline urinary volume suppression-average (in per cent) for three 15 minute periods following intravenous administration of 4 mU. of vasopressin (except Patient B. T. who received 8 mU .) given at times shown in pregnant women and in nonpregnant controls. Solid lines connect points of a specific patient .
th e previous infants successfully for 3 months. ) Wall'r pxchall~(' was about tlH' sam e for the first 4 postpartum days a nd thpn showed a 20 PPI' ('ent reduction that lasted ulltil the tellth postpartum day. Since that tillle she has returned to the vasopressin tannate! in oil dosage of early pre~nallcy (0 ..') c .c. every 7 days ) .
n ecause of conflicting reports as to the effect of pregnancy on diabetes insipidus, we undertook to study the relative sensitivity of pregnant and nonpregnant women to vasopressllI. Method H ealthy, near term pregnant women from the obstetric clinic of the University of Nebraska Hospital were studied after 8 hours of dehydration. After an initial dose of 400 Illi. of water by mouth, they were given 200 ml. each 15 minutes and urinary output measured until a stable ra te of diuresis was obtained. After attaining this state of "physio-
J.
May, 1961 Obst. & Gynoc.
logical diabetes insipidus," they were given carefully measured intravenous injections of commercial vasopressin (all from the same lot) and the degree and duration of antidiuresis noted. Similar experiments were done in the early and/ or late postpartum period using proportional water load calculated on the basis of weight change. In some instances the effect of nursing was studied. Finally, similar experiments were done on nonpregnant patients and on the patients with diabetes insipidus. The latter were studied after 72 hours of deprivation of vasopressin tannate in oil. The studies were analyzed as a quantaI response and considered positive if a 25 per cent decrease in urine volume occurred for two 15 minute periods following administration of the vasopressin. A typical response is shown in Fig. 1. The data obtained from the individualized studies were categorized for analysis (Table I and Fig. 2). Results
It is obvious that observed activity of vasopressin is greater after delivery than during late pregnancy and is greatest in the nonpregnant state. From our studies we cannot be sure whether the decreased activi ty in pregnancy is due to ( a) increased rate of deactivation, (b) decreased sensitivity of the renal tubules, or (c) increased glomerular filtration rate . Our few observations on nursing seem to bear out the antidiuretic effects as noted by Cross lll in rabbits and Kalliala 17 in women, but Patient N. P. gave no response. The 2 patients with diabetes insipidus appear variable in their clinical course. In Case 1, no real change was noted in vasopressin tannate in oil requirements during pregnancy but the patient did require increased amounts for the first few days after delivery and then returned to the normal status. L abor and delivery were normal and rapid but rupture of the membranes preceded onset of labor. "Afterpains" and breast engorgement were less than in any previolls pregnancy.
Volume 81 Number 5
Diabetes insipidus and pregnancy 1039
In Case 2, progressive increase was noted in vasopressin tannate in oil requirement from the time of diagnosis in the third month of pregnancy until the sixth month, after which it remained constant until delivery. After delivery she returned to the requirements of early pregnancy. Labor was nonprogressive until after rupture of the membranes when it became very rapid and Was followed by a short second and third stage.
100
80 60
'"E " :>
C5
...,
1
40
CI
<:
'"0
20
III
;e
. Both clinical and experimental diabetes insipidus may be of variable severity or "~ompleteness," and this is not surprising in View of the numerous etiologies of the syndrome, each with its own natural history and COurse. Brown and Rynearson 18 repOrted patients with urine concentration to specific gravities of 1.011 and 1.016 with Water deprivation. Kourilsk ylO distinguished ~ category of patients with "partial diabetes Insipidus" with urine concentration above 1.010. Cates and Garrod 2 () have shown that I .or 2 mg. of nicotine (or even inhalation of a cigarette) could cause antidiuresis in s~me patients with diabetes insipidus by stImulation of ADH release. Our patients (both nonsmokers) had a long period of antidiuresis after inhaling one or two cigarcttes (Fig. 3). Most reported cases either have become worse or have shown little change during
EK
NP
0
90 0 11m. (minutes)
0
90
Fig. 3. Change in baseline output in 2 patients with diabetcs insipidus following inhalation of cigarettes as indicated . One arrow reprcsents one cigarette.
pregnancy. Other patients have had pre~ nanties with little change and then have become worse or better in a subsequent preg-nancy, which suggests a change in the basic disease process rather than an effect of pregnancy. A few patients have shown improvement the last few weeks of pregnancy only to get worse for the first few days after delivery. This course of terminal improvement has been attributed'" to the fetal nelll'Ohypophysis, and certainly this gland contains ADH after the fourth month ,2 1 but actual release of significant amounts by the fetus has not been shown. Nursing seems to hcne-
Table I. Response to indicated doses of vasopressin (milliunits) by intravenolls 1'0utesi(·
_Patiwt
M.R. D.O.
J.V.
L. C.
H. T.
A. S.
L. R.
N.P.
F.L. R.J. B. S. J. W.
Age
Sex
27 16 32 21
F. F. F. F. F. F.
24 24
27
42 32 26
29
(Pt. 2)
F.
F. M. F. M.
Last month of pregnancy
.8.S.8.8.8.8.R-
44-
4-
4B+
444-
4-6 days post partum
6-9 weeks post partum
.8.8.8.88-
44+ 4+ 4+ 8+
.8-
8+
.R-
4+ 4+
.8+
4+
Not pregnant
4+ .B +
.8-
. *~ positive response indicates a 25 per cent dt'creasc in urine \'olullie rot, at least two 15 minute pCI-jods alter IStralion of the vasopressin. All patients were normal except N. 1'. who had diahetes insipidus.
4+
4+ 4+
admil\~
1040 Warren and Jernslrom
fit polyuria and a few cases, especially those with onset during pregnancy, have disappeared completely in the postpartum periods. It is truly difficult to understand how any patient should improve in pregnancy. Robinson 22 has shown that plasma levels of ADS* in the normal woman are elevated during pregnancy and further acutely elevated during the act of nursing. As our studies show, the response of pregnant women to exogenous vasopressin is decreased. This may be due to an increased rate of deactivation or a change in renal sensitivity. A vasopressin inactivating substance with enzyme-like characteristics has been demonstrated in the plasma of pregnant women 2 3-25 as well as in placental extracts. 2 G Nevertheless, these studies involved incubation of the plasma for 1 to 24 hours with inactivation of the octapeptide which has a half life (at least in the rat 27 ) of approximately one minute, and it is difficult to evaluate the role of this "enzyme" in total body economy. Unfortunately, no ADH disappearance curves in pregnant and nonpregnant women are available for comparison. If pregnancy causes elevated adrenal and thyroid hormone levels, these should intensify diabetes insipidus. Plasma 17-hydroxycorticoids are elevated during the latter half of pregnancy but it has also been shown that these patients have elevated levels of cortisol-binding protein and it may be that biologically active levels of hydroxycorticoids are the same as in the nonpregnant state. It is difficult to assay thyroid function during pregnancy. Though protein-bound iodine (pm) levels may be increased it has been shown that estrogen will increase the PBI level in an athyrotic patient receiving constant replacement therapy,28 suggesting increased PDI may not mean increased rate of thyroxin liberation by the thyroid. Butanol extractable iodine levels are in the upper normal range 29 and neither gives a key to activity at a ceIlular level. ·ADS, total antidiuretic activity oC plasma. This i. attributed to vasopressin or a like substance. Slope of the bioassay curve is parallel to commercial vasopressin.
Am.
May, 1961 & Gynet.
J. Obst.
A situation with both increased blood levels and increased inactivation rate could be maintained only by an increased rate of ADH secretion, while failure of normal pregnant women to manifest a reduction in water intake and output with elevated blood levels of ADS suggests a decrease in renal tubule sensitivity or an increase in water delivery to the distal tubule secondary to the elevated glomerular filtration rate of pregnancy. Whatever may be the stimulus for the increased ADH secretion rate, it seems reasonable that the pregnant patient with diabetes insipidus, even though she may have an incomplete lesion and respond partially, would not increase secretion to the degree that a normal patient would and would become relatively worse during prcg-' nancy. This has been the case in most welldocumented reports and in our Case 2. If this result be less than dramatic it could, however, he masked by excessive amounts of vasopressin tannate in oil. We feel this may be so in Case 1. On the other hand, if nursing further stimulates ADH release in the patient with "partial" diabetes insipidus during a period of increasing sensitivity to vasopressin, she may require less or even no exogenous hormone. Experimentally, bilateral interruption of the supraoptic-hypophysial tract has been followed by diabetes insipidus, clear-cut dystocia, and death during labor in cats and guinea pigs, attributed to lack of oxytocin. so Among reports of diabetes insipidus in women one patient has been observed to have two prolonged labors with light contractions and finally spontaneous delivery of a dead fetus. 31 This woman had one successful delivery following Pituitrin stimulation. No other reported cases indicate clearcut II terine failure in labor. Our second patient had 26 hours of labor without progress only to be delivered in one hour after rupture of the membranes. Her previous two labors were 3 to 4 hours in duration. The role of endogenous oxytocin in labor remains in dispute but we are inclined to believe, for many reasons, that it plays a part in normal parturition,
Volume 81 Number 5
Diabetes insipidus and pregnancy
1041
Summary
It seems reasonable that a patient with diabetes insipidus, particularly if incomplete, could still release oxytocin, since sites of storage (and synthesis?) of the two octapeptides, though confined to the general area of the hypothalamus and neurohypophysis, do show relative spatial differences. 21 At any rate, fairly normal labor and delivery without postpartum atony is the rule in this disorder. It appears that oxytocin release, while it may be decreased to some degree, ~ill be satisfactory for delivery, particularly If rupture of the membranes is effected.
·
1. The clinical course of 2 patients with diabetes insipidus in pregnancy has been presented. One required increased administration of vasopressin for stable water exchange, one was maintained on the prepregnancy dosage. In both delivery was effected and oxytocics were not required for or after delivery of the placenta. 2. The antidiuretic activity of exogenous vasopressin was shown to be decreased in pregnancy with increase after delivery. 3. Possible influences of pregnancy on diabetes insipidus are discussed.
REFERENCES
1. Anderson, W. A. D . : Pathology, ed. 2, St. Louis, 1953, The C. V. Mosby Company, p. 987. 2. Thomas, W. C., Jr.: J. Clin. Endocrino!. 17: 565, 1957. 3. BIotner, H., and Kunkel, P.: New England J. Med. 227: 287, 1942. 4. Carfagno, S. C., Durant, T. M., and Shuman, C. R.: A. M. A. Arch. Int. Med. 92: 542, 1953. 5. Hendricks, C. H .: Obst. & Gynec. Surv. 9: 323, 1954. 6. Train, T. S. R.: J. Obst. & Gynaec. Brit. Emp. 64: 731, 1957. 7. Alexander, S. A., and Downs, J. T.: Obst. & Gynec. 10: 682, 1957. 8. McLaren, H. C., and McLeod, M.: J. Obst. & Gynaec. Brit. Emp. 49: 51, 1942. 9. McKenzie, C. H., and Swain, F. M.: Minnesota Med. 38: 809, 1955. 10. Tannenbaum, A. J., Bertling, M. H., and Burwell, S. C., Jr.: AM. J. OnST. & GYNEC. 63: 472, 1952. 11. Carter, A. C., and Robbins, J.: J. Clin. Endocrino!. 7: 753, 1947. 12 . . Elgin, J. M., Jr., and Jessiman, A. G.: J. Clin. Endoerino!. 19: 369, 1959. 13. Scheer, R. L., Raisz, L. G., and Lloyd, C. W.: J. Clin. Endocrino\. 19: 805, 1959. 14. Alexander, S. A., and Downes, J. T., III: Obst. & Gynec. 10: 682, 1957. 15. Abrahams, V. C., and Pickford, Mary: J. Physio\. 126: 329, 1954. 16. Cross, B. A.: J. Physio\. 114: 447, 1951. 17. Kalliala, H., and Karvonen, M. J.: Ann. med. exper. et bio\. Fenniae 29: 233, 1951.
18. Brown, W. E., Jr., and Rynearson, E. H.: Proc. Staff Meet. Mayo Clin. 19: 67, 1944. 19. Kourilsky, R.: Ann. med. 48: 288, 1947. 20. Cates, J. E., and Garrod, Oliver: Clin. Sc. 10: 145, 1951. 21 . Colston Research Society, H. Heller, editor: The Neurohypophysis, New York, 1957, Academic Press, Inc. 22. Robinson, K. W., Hawker, R. W., and Robertson, P. A.: J. Clin. Endocrino!. 17: 320, 1957. 23 . Dieckmann, W. J., Egenolf, G. F., Morley, B., and Pottinger, R . E.: AM. J. OUST. & GYNEC. 60: 1043, 1950. 24. McCartney, C. P., Va\lach, F . .J., and Pottinger, R. E.: AM. J. OOST. & GYNEC. 63: 847, 1952. 25. Hawker, R. W.: J. Endoerino\. 14: 400, 1957. 26. Hawker, R. W.: Quart. J. Exper. Physio!. 41: 301, 1956. 27 . State University of New York, Upstate Medical Center Dedication Year Conference 011 the Endocrinology of Reproduction, Syracuse, 1958. C. W. Lloyd, editor: Recent Progress in the Endocrinology of Reproduction, New York. 1959, Academic Press, Inc. 28. Engbring, N. H., and Engstron, W. W.: J. Clin. Endocrino\. 19: 783, 1959. 29. Benson, R. C., Pickering, D. E., Kontaxis, N. E., and Fisher, D. A.: Obst. & Gynec. 14: 11, 1959. 30. Fisher, C., Magoun, H. W., and Ranson, S. W.: AM. J. OOST. & GYNEC. 36: 1, 1938. 31. Maranon y Posadillo, G.: Brit. M . J. 2: 769, 1947.
D I ABE T E S insipidus is a rare disease characterized by a relative deficiency of antidiuretic hormone (ADH) with concomitant disturbances in water balance. The pathologic changes underlying the condition are destructive lesions of variable nature located in the hypophyseodiencephalic system. 1 Among a series of 65 cases reported by Thomas 2 one third were due to intracranial tumor, one third were of unknown etiology, and the remainder were ascribed to various granulomas and inflammatory lesions. The patient with diabetes insipidus because of deficient production of ADH has a marked reduction of renal facultative reabsorption of water and as a result polyuria, polydypsia, and urine of low osmolar concentration. Various case reports and reviews of the literature have described variable effects of pregnancy when superimposed upon diabetes insipidus. s, lO Unfortunately, many of these patients were studied before the advent of precise procedures for definitive diagnosis of the condition and the reports may include cases of chronic renal disease, adrenal hyperfunction, and psychogenic polydypsia. The latter was impossible to differentiate from true diabetes insipidus before the availability of the Carter-Robbins testY In general, pregnancy has been described as worsening, ameliorating, and effecting no change in diabetes insipidus.
Two recent well-documented reports have shown marked increases in vasopressin requirements during pregnancy. One dealt with diabetes insipidus following hypophysectomy.12 This patient had large urine volumes despite increasing doses of exogenous vasopressin throughout the third trimester of pregnancy but improved after delivery. It is of interest that she received a 75 mg. maintenance dosage of cortisone with much higher doses on occasion. The second report dealt with a patient 13 whose vasopressin requirements increased during pregnancy and late in each menstrual cycle and decreased while nursing. Similar improvement while nursing has been previously reported. H There are interesting ramifications of the combination of diabetes insipidus and pregnancy other than changes in antidiuretic function. Oxytocin production has not been assayed in patients with diabetes insipidus but sites of production and storage as well as release of oxytocin and ADH secondary to electrical and physiologic stimulation are markedly simiIar.15 For this reason, labor and delivery might be expected to be pathologic. We have recently had the opportunity to observe and study 2 patients with proved diabetes insipidus during pregnancy, parturition, and the puerperium: Case 1. E. K., a 34-year-old white woman, para 5-0-0-5, had suddenly developed excessive thirst and polyuria of approximately 9 liters per day in November, 1957. She was admitted to the University of Nehraska Hospital that month
From the Department of Obstetrics and Gynecology, University of Nebraska College of Medicine. *Trainee, National Cancer Institute.
1036
Volume 8J Numhc.'1' 5
where the Carter-Robbins test confirmed a diagnosis of diabetes insipidus. Skull x-rays, visual fields, spinal fluid, fasting blood sugar, pSI, PBI, and BMR determinations were all normal. There Was no known diabetes insipidus in her family. She Was started on intranasal vasopressin but Soon changed to I c.c. (5 units) vasopressin tannate in oil every other day and was maintained on this dosage throughout pregnancy without significant change in intake and output. Total weight gain in pregnancy was 33 pounds. There was spontaneous rupture of the membranes at 11 :00 P.M. on March 31, 1959. (The estimated date of confinement was March 22.) After a 16 hour latent period contractions started on April 1. She had a first stage of 2 hours and 15 minutes, a second stage of 8 minutes, and a third stage of 13 minutes. She was delivered of a 2,755 gram infant spontaneously at 5:23 P.M., and the uterus contracted well after delivery of the placenta. . She had received 4 units of vasopressin tannate In oil (5 units per cubic centimeter) on the rnoming of delivery. Increased thirst was noted on the first postpartum day and 4 units was given daily until the sixth postpartum day when by noon the thirst and polyuria had abated and she returned to her normal schedule. She noted mild breast engorgement on the fourth postpartum day but this lasted only 24 hours. There was no spontaneous discharge of milk. Breast engorgement and "afterpains" were less than in any previous pregnancy. On April 11, 10 days after delivery, there was n~ discernible breast engorgement and the only rnllk discharge had been 3 drops from the right breast on April 8. She was given 2 units of Oxytocin intravenously and rapidly ejected about 25 drops of milk from each breast. She was readmitted on May 28, 1959, when ~ ?arter-Robbins test again confirmed diabetes InsIpidus (done after 72 hours without vasopre~sin tannate in oil). Since delivery, menstrual peflods have been normal and she has remained on vasopressin tannate in oil, I c.c. every other day with daily intakes of about 2.5 liters. Case 2. N. P., a 29-year-old white para 4-0-0-4, ~ated th~ onset of excessive thirst to Nov. 20, 958, whIch she remembered as 17 days prior to ~he o~et of her last normal menstrual period. ThIS thIrst and polyuria increased for 3 weeks and then stabilized around 7 liters intake and 5 liters output daily. Diagnosis of diabetes insipidus Was established in the third month of gestation
Diabetes insipidus and pregnancy
1037
by a Carter-Robbins test. The patient kept her intake and output at pretreatment levels and only increased the frequency of dosage when these levels were exceeded. The dosage of vasopressin tannate in oil was increased gradually from 0.5 c.c. every 7 to 8 days in February to every 2 days in June, the sixth month of gestation. She maintained this level until time of delivery. The pregnancy was uneventful except for irregular spotting during the first 5 months. Total weight gain was 30 pounds. The estimated date of confinement was Sept. 14, 1959. On October 1, she began to have irregular contractions at 5: 00 A.M. and was admitted at 8: 00 A.M. She had hypertonic dysfunctional labor without progress for 19 hours. She was given morphine and had 6 hours rest but then (6:00 A.M., October 2) regular weak contractions began, continuing every 8 to 10 minutes for 7 hours with no significant progress. At 1: 00 P.M. the membranes were ruptured artificially, contractions became hard, of 5 minute frequency, and at 2: 00 P.M. she was delivered of a term infant without difficulty. The second stage was 5 minutes, the third 13 minutes. The uterus contracted well and blood loss was minimal. No oxytocics were given. She had some breast engorgement and nursed the baby but stated she had less milk and "afterpains" than ever before. She stopped nursing the fourth week because milk output was poor and the baby failed to gain satisfactorily until supplementation was initiated. (She had nursed each of
100 80
•E
l I
lJ
60
" • .~
15
>40
•~20
q
•
III
~
q
o
C\I
O~~0----6~0~--~0~--~6~0--~O~--~6~O Ii 1'111 . (mlnutll)
Fig. 1. Reduction of baseline · urine output in Patient 2 after intravenous administration of vasopressin in milliunits as indicated. Values for thirty-sixth week of pregnancy are shaded; others obtained 9 weeks post partum. Baseline volumes 130 m\. (prepartum) and 140 ml. (postpartum).
1038 Warren and Jernstrom
Am.
• 70
NP
eo
8T
50 JY
40
~o
I
-=e t ••
10
# 10
--J._--- MR
O~~~------~4~.~6------~6--9~----e-o~nt~rO-'I~'~ pp do, PP wlek
Fig. 2. Baseline urinary volume suppression-average (in per cent) for three 15 minute periods following intravenous administration of 4 mU. of vasopressin (except Patient B. T. who received 8 mU .) given at times shown in pregnant women and in nonpregnant controls. Solid lines connect points of a specific patient .
th e previous infants successfully for 3 months. ) Wall'r pxchall~(' was about tlH' sam e for the first 4 postpartum days a nd thpn showed a 20 PPI' ('ent reduction that lasted ulltil the tellth postpartum day. Since that tillle she has returned to the vasopressin tannate! in oil dosage of early pre~nallcy (0 ..') c .c. every 7 days ) .
n ecause of conflicting reports as to the effect of pregnancy on diabetes insipidus, we undertook to study the relative sensitivity of pregnant and nonpregnant women to vasopressllI. Method H ealthy, near term pregnant women from the obstetric clinic of the University of Nebraska Hospital were studied after 8 hours of dehydration. After an initial dose of 400 Illi. of water by mouth, they were given 200 ml. each 15 minutes and urinary output measured until a stable ra te of diuresis was obtained. After attaining this state of "physio-
J.
May, 1961 Obst. & Gynoc.
logical diabetes insipidus," they were given carefully measured intravenous injections of commercial vasopressin (all from the same lot) and the degree and duration of antidiuresis noted. Similar experiments were done in the early and/ or late postpartum period using proportional water load calculated on the basis of weight change. In some instances the effect of nursing was studied. Finally, similar experiments were done on nonpregnant patients and on the patients with diabetes insipidus. The latter were studied after 72 hours of deprivation of vasopressin tannate in oil. The studies were analyzed as a quantaI response and considered positive if a 25 per cent decrease in urine volume occurred for two 15 minute periods following administration of the vasopressin. A typical response is shown in Fig. 1. The data obtained from the individualized studies were categorized for analysis (Table I and Fig. 2). Results
It is obvious that observed activity of vasopressin is greater after delivery than during late pregnancy and is greatest in the nonpregnant state. From our studies we cannot be sure whether the decreased activi ty in pregnancy is due to ( a) increased rate of deactivation, (b) decreased sensitivity of the renal tubules, or (c) increased glomerular filtration rate . Our few observations on nursing seem to bear out the antidiuretic effects as noted by Cross lll in rabbits and Kalliala 17 in women, but Patient N. P. gave no response. The 2 patients with diabetes insipidus appear variable in their clinical course. In Case 1, no real change was noted in vasopressin tannate in oil requirements during pregnancy but the patient did require increased amounts for the first few days after delivery and then returned to the normal status. L abor and delivery were normal and rapid but rupture of the membranes preceded onset of labor. "Afterpains" and breast engorgement were less than in any previolls pregnancy.
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Diabetes insipidus and pregnancy 1039
In Case 2, progressive increase was noted in vasopressin tannate in oil requirement from the time of diagnosis in the third month of pregnancy until the sixth month, after which it remained constant until delivery. After delivery she returned to the requirements of early pregnancy. Labor was nonprogressive until after rupture of the membranes when it became very rapid and Was followed by a short second and third stage.
100
80 60
'"E " :>
C5
...,
1
40
CI
<:
'"0
20
III
;e
. Both clinical and experimental diabetes insipidus may be of variable severity or "~ompleteness," and this is not surprising in View of the numerous etiologies of the syndrome, each with its own natural history and COurse. Brown and Rynearson 18 repOrted patients with urine concentration to specific gravities of 1.011 and 1.016 with Water deprivation. Kourilsk ylO distinguished ~ category of patients with "partial diabetes Insipidus" with urine concentration above 1.010. Cates and Garrod 2 () have shown that I .or 2 mg. of nicotine (or even inhalation of a cigarette) could cause antidiuresis in s~me patients with diabetes insipidus by stImulation of ADH release. Our patients (both nonsmokers) had a long period of antidiuresis after inhaling one or two cigarcttes (Fig. 3). Most reported cases either have become worse or have shown little change during
EK
NP
0
90 0 11m. (minutes)
0
90
Fig. 3. Change in baseline output in 2 patients with diabetcs insipidus following inhalation of cigarettes as indicated . One arrow reprcsents one cigarette.
pregnancy. Other patients have had pre~ nanties with little change and then have become worse or better in a subsequent preg-nancy, which suggests a change in the basic disease process rather than an effect of pregnancy. A few patients have shown improvement the last few weeks of pregnancy only to get worse for the first few days after delivery. This course of terminal improvement has been attributed'" to the fetal nelll'Ohypophysis, and certainly this gland contains ADH after the fourth month ,2 1 but actual release of significant amounts by the fetus has not been shown. Nursing seems to hcne-
Table I. Response to indicated doses of vasopressin (milliunits) by intravenolls 1'0utesi(·
_Patiwt
M.R. D.O.
J.V.
L. C.
H. T.
A. S.
L. R.
N.P.
F.L. R.J. B. S. J. W.
Age
Sex
27 16 32 21
F. F. F. F. F. F.
24 24
27
42 32 26
29
(Pt. 2)
F.
F. M. F. M.
Last month of pregnancy
.8.S.8.8.8.8.R-
44-
4-
4B+
444-
4-6 days post partum
6-9 weeks post partum
.8.8.8.88-
44+ 4+ 4+ 8+
.8-
8+
.R-
4+ 4+
.8+
4+
Not pregnant
4+ .B +
.8-
. *~ positive response indicates a 25 per cent dt'creasc in urine \'olullie rot, at least two 15 minute pCI-jods alter IStralion of the vasopressin. All patients were normal except N. 1'. who had diahetes insipidus.
4+
4+ 4+
admil\~
1040 Warren and Jernslrom
fit polyuria and a few cases, especially those with onset during pregnancy, have disappeared completely in the postpartum periods. It is truly difficult to understand how any patient should improve in pregnancy. Robinson 22 has shown that plasma levels of ADS* in the normal woman are elevated during pregnancy and further acutely elevated during the act of nursing. As our studies show, the response of pregnant women to exogenous vasopressin is decreased. This may be due to an increased rate of deactivation or a change in renal sensitivity. A vasopressin inactivating substance with enzyme-like characteristics has been demonstrated in the plasma of pregnant women 2 3-25 as well as in placental extracts. 2 G Nevertheless, these studies involved incubation of the plasma for 1 to 24 hours with inactivation of the octapeptide which has a half life (at least in the rat 27 ) of approximately one minute, and it is difficult to evaluate the role of this "enzyme" in total body economy. Unfortunately, no ADH disappearance curves in pregnant and nonpregnant women are available for comparison. If pregnancy causes elevated adrenal and thyroid hormone levels, these should intensify diabetes insipidus. Plasma 17-hydroxycorticoids are elevated during the latter half of pregnancy but it has also been shown that these patients have elevated levels of cortisol-binding protein and it may be that biologically active levels of hydroxycorticoids are the same as in the nonpregnant state. It is difficult to assay thyroid function during pregnancy. Though protein-bound iodine (pm) levels may be increased it has been shown that estrogen will increase the PBI level in an athyrotic patient receiving constant replacement therapy,28 suggesting increased PDI may not mean increased rate of thyroxin liberation by the thyroid. Butanol extractable iodine levels are in the upper normal range 29 and neither gives a key to activity at a ceIlular level. ·ADS, total antidiuretic activity oC plasma. This i. attributed to vasopressin or a like substance. Slope of the bioassay curve is parallel to commercial vasopressin.
Am.
May, 1961 & Gynet.
J. Obst.
A situation with both increased blood levels and increased inactivation rate could be maintained only by an increased rate of ADH secretion, while failure of normal pregnant women to manifest a reduction in water intake and output with elevated blood levels of ADS suggests a decrease in renal tubule sensitivity or an increase in water delivery to the distal tubule secondary to the elevated glomerular filtration rate of pregnancy. Whatever may be the stimulus for the increased ADH secretion rate, it seems reasonable that the pregnant patient with diabetes insipidus, even though she may have an incomplete lesion and respond partially, would not increase secretion to the degree that a normal patient would and would become relatively worse during prcg-' nancy. This has been the case in most welldocumented reports and in our Case 2. If this result be less than dramatic it could, however, he masked by excessive amounts of vasopressin tannate in oil. We feel this may be so in Case 1. On the other hand, if nursing further stimulates ADH release in the patient with "partial" diabetes insipidus during a period of increasing sensitivity to vasopressin, she may require less or even no exogenous hormone. Experimentally, bilateral interruption of the supraoptic-hypophysial tract has been followed by diabetes insipidus, clear-cut dystocia, and death during labor in cats and guinea pigs, attributed to lack of oxytocin. so Among reports of diabetes insipidus in women one patient has been observed to have two prolonged labors with light contractions and finally spontaneous delivery of a dead fetus. 31 This woman had one successful delivery following Pituitrin stimulation. No other reported cases indicate clearcut II terine failure in labor. Our second patient had 26 hours of labor without progress only to be delivered in one hour after rupture of the membranes. Her previous two labors were 3 to 4 hours in duration. The role of endogenous oxytocin in labor remains in dispute but we are inclined to believe, for many reasons, that it plays a part in normal parturition,
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Diabetes insipidus and pregnancy
1041
Summary
It seems reasonable that a patient with diabetes insipidus, particularly if incomplete, could still release oxytocin, since sites of storage (and synthesis?) of the two octapeptides, though confined to the general area of the hypothalamus and neurohypophysis, do show relative spatial differences. 21 At any rate, fairly normal labor and delivery without postpartum atony is the rule in this disorder. It appears that oxytocin release, while it may be decreased to some degree, ~ill be satisfactory for delivery, particularly If rupture of the membranes is effected.
·
1. The clinical course of 2 patients with diabetes insipidus in pregnancy has been presented. One required increased administration of vasopressin for stable water exchange, one was maintained on the prepregnancy dosage. In both delivery was effected and oxytocics were not required for or after delivery of the placenta. 2. The antidiuretic activity of exogenous vasopressin was shown to be decreased in pregnancy with increase after delivery. 3. Possible influences of pregnancy on diabetes insipidus are discussed.
REFERENCES
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18. Brown, W. E., Jr., and Rynearson, E. H.: Proc. Staff Meet. Mayo Clin. 19: 67, 1944. 19. Kourilsky, R.: Ann. med. 48: 288, 1947. 20. Cates, J. E., and Garrod, Oliver: Clin. Sc. 10: 145, 1951. 21 . Colston Research Society, H. Heller, editor: The Neurohypophysis, New York, 1957, Academic Press, Inc. 22. Robinson, K. W., Hawker, R. W., and Robertson, P. A.: J. Clin. Endocrino!. 17: 320, 1957. 23 . Dieckmann, W. J., Egenolf, G. F., Morley, B., and Pottinger, R . E.: AM. J. OUST. & GYNEC. 60: 1043, 1950. 24. McCartney, C. P., Va\lach, F . .J., and Pottinger, R. E.: AM. J. OOST. & GYNEC. 63: 847, 1952. 25. Hawker, R. W.: J. Endoerino\. 14: 400, 1957. 26. Hawker, R. W.: Quart. J. Exper. Physio!. 41: 301, 1956. 27 . State University of New York, Upstate Medical Center Dedication Year Conference 011 the Endocrinology of Reproduction, Syracuse, 1958. C. W. Lloyd, editor: Recent Progress in the Endocrinology of Reproduction, New York. 1959, Academic Press, Inc. 28. Engbring, N. H., and Engstron, W. W.: J. Clin. Endocrino\. 19: 783, 1959. 29. Benson, R. C., Pickering, D. E., Kontaxis, N. E., and Fisher, D. A.: Obst. & Gynec. 14: 11, 1959. 30. Fisher, C., Magoun, H. W., and Ranson, S. W.: AM. J. OOST. & GYNEC. 36: 1, 1938. 31. Maranon y Posadillo, G.: Brit. M . J. 2: 769, 1947.