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An Experimental Examination of Factors Causing Ureteral Dilatation of Pregnancy1
AN EXPERIMENTAL EXAMINATION OF FACTORS CAUSING URETERAL DILATATION OF PREGNANCY1 G. VANWAGENEN AND RALPH H. JENKINS
From the Department of Obstetrics and Gynecology and Department of Urology, Yale University School of Medicine, New Haven, Conn.
Dilatation of the renal pelvis and ureter occurs in the majority of normal pregnant women. As it may be a predisposing cause of infection and perhaps of some of the hypertensive phenomena of the gravid state it becomes of great importance as a problem for experimental investigation. By means of excretory urography we have found that this "physiological hydroureter of pregnancy" has its counterpart in the pregnant rhesus monkey and it is the availability of this valuable experimental material which has made it possible for us to separate certain of the factors now believed to be contributory to this phenomenon in the upper urinary tract. Our knowledge of this subject dates from Cruveilhier, who in 1843 found ureteral dilatation in women dying during the later months of pregnancy and in the puerperium. Traut and Kuder (1938) in an excellent collective review have considered the voluminous literature of this subject which has accumulated since then. The early explanation for these changes in the ureter of pregnancy was that of a mechanical cause having to do with the anatomical relationships within the pelvis. The pressure of the pregnant uterus upon the ureters at the level of the pelvic brim and the close application of the base of the bladder to the vagina and uterus were thought to cause an ureteral obstruction. Dextrorotation of the uterus and the large iliac vessels on the right were claimed to modify this obstruction and therefore explain the greater degree of dilatation and elongation usually observed in the right urinary tract. Furthermore, the left ureter was said to be protected by the sigmoid colon. For three quarters of a century this explanation was considered an adequate one. Hofbauer (1928) from histological examination of the ureters taken from women dying in pregnancy came to the conclusion that the obstruction in the urinary tract was of an intrinsic nature and he described hypertrophy and hyperplasia in the muscle and fibrous tissue of the ureter itself and 1 Read at the annual meeting of the American Urological Association, White Sulphur Springs, W. Va. May 30, 1939.
1010
URETERAL DILATATION OF PREGNANCY
1011
in the peri-ureteral sheath. These alterations this author believed explained the phenomena in question. Other observations have concerned the newer concepts of bacterial toxins and hormones as a factor in causing atony of the ureter during pregnancy not associated with the presence of the simple mechanical obstruction. Peristaltic contractions appearing in the normal living ureter were described first by Engelman (1869) and later studied by many others. Atony in the tract of the gravid woman was suggested by Kaltenschnee in 1913. Trattner (1930) perfected an apparatus which made it possible to observe and record the peristaltic activity of the human kidney pelvis and ureter. Using Trattner's instrureent, the hydrophorograph, Traut and McLane (1936) extended observations to the pregnant woman, and these observations yielded illuminating knowledge showing that the incidence of atony in relation to the various months of pregnancy correlated exactly with the appearance of dilatation of the pelvis and ureter. It would appear, therefore, that the hormone complex of pregnancy which relaxes the smooth muscle of the uterus, thus making the continuation of pregnancy possible, influences also other structures in the body. Certain gall bladder disturbances of pregnancy associated with decreased peristalsis are attributed to a chemical influence of the hormones of pregnancy and there is a similar effect on the urinary tract with suppression or obliteration of normal peristaltic activity. The upright position of the body causes the weight of the increasingly heavier uterus to rest on the pelvic structures and a physiological obstruction of the ureters occurs during the time when this atonic condition is present. Both mechanical and hormonal influences seem certainly to be responsible for this syndrome and it is the object of this investigation to separate in a measure these two main factors. The influences of weight and torsion of the uterus were relieved by the removal of the fetus, while the hormone relationships of pregnancy were preserved by leaving the placenta undisturbed in the uterus. Material and methods. Eight rhesus monkeys were successfully mated and the date of conception estimated by the method worked out by Hartman (1932). Three of these monkeys had been born in the laboratory of Obstetrics and Gynecology some years ago and so it was possible to state their reproductive histories and to give their exact ages. Another was purchased as a young animal and matured in the colony. The remaining 4 were adult monkeys weighing from 4,000 to 5,880 gm.
1012
G. VAN WAGENEN AND RALPH H. JENKINS
when purchased. On vaginal examination at the time of their admission to the colony these latter were considered parous animals. The period of gestation in the rhesus monkey is 168 days (6 lunar months). Three pregnancies were allowed to proceed normally and in each of the other five pregnancies the fetus was removed by abdominal section at different periods before the estimated date of parturition. The removal of the fetuses from 2 animals on the seventy-first and seventy-fourth days of pregnancy was done at a time before dilatation of the ureters had occurred. Removing the fetus by abdominal hysterotomy without injuring the placenta is a procedure in the monkey that is attended with some difficulty because usually the placenta consists of primary and secondary lobes attached to the ventral and dorsal walls of the uterus and joined by large blood vessels. In early gestation the comparatively heavy musculature of the primate uterus obscures the placental sites and the uterine contractions which follow section of the musculature and the necessary manipulations, predispose to a precipitous separation of the placenta. Urograms of the upper urinary tract were secured by injecting intravenously 15 cc of diodrast. The highest concentration of this material was found in the urinary tract at 3 to 5 minutes after injection in healthy pregnant animals. In one instance roentgenograms were taken as late as 28 to 30 minutes to visualize the ureters in M.m. 37 which was suffering from an infection. In those animals which were under deep nembutal anaesthesia there appeared to be no difference in time of excretion of the dye. It was not necessary to use anaesthesia for those animals born in the laboratory. Experiments. l. The animal designated as M.m. 71 was a primigravida. At the beginning of pregnancy she was 3 years, 7 months and 21 days old and a healthy, vigorous, animal weighing 5,800 gm. About the middle of the fourth month of pregnancy pyeloureterographs showed a dilatation of + + + in the kidney pelvis and upper two thirds of the ureter on the right side. Some dilatation ( +) was present also in the left ureter. The urinary tracts were best visualized in the 8 minute film showing that a slight retardation of excretion of dye was present. The dilatation persisted without change during the remainder of the fourth and the fifth and sixth months. A viable baby (402 gm.) was born on the one hundred sixty-eighth day of gestation and the animal was left undisturbed until the seventh day postpartum when the urograph showed a complete return of the ureters to normal size (fig. 2).
URETERAL DILATATION OF PREGNANCY
1013
2. M.m.72, a secundigravida, was 3 years, 6 months and 20 days old at the time of conception (5,430 gm.). There was no dilatation at any
a b Frc. 1. Excretory urograms. a, Normal pregnant monkey in fifth month of gestation. There is no dilatation of ureters or pelves. b, A normal monkey with dilatation of ureters and pclves.
I
Dilatation M.m. 71
baby born day 168 ++++
J,
+++
o-- --o--
--~,
++
''
+ \ 0
2 3 1 Month of gestation
4
5
6
2 1 postpartum
Frc. 2
time during the pregnancy of this animal although the fourth, fifth and sixth months were carefully studied. A baby was born on the one hundred sixty-ninth day of gestation.
1014
G. VAN W AGENEN AND RALPH H. JENKINS
3. M.m.76 was studied only during the sixth month of her pregnancy. She was a primigravida having been brought into the laboratory as a very young animal. She weighed 4,500 gm. at the beginning of gestation and a male baby was born on the one hundred sixty-fourth day. Repeated urographical study showed no change in the urinary tracts during this last month of pregnancy.
a b FIG. 3. Monkey M.m. 89. a, Normal ureters early in fifth month of pregnancy. month later ureters have become enlarged. See figure 4 for further dilatation.
b, One
4. M.m.89, (fig. 3, 4) a primigravida, was 3 years, 5 months and 13 days old and weighed 5,280 gm. at the beginning of pregnancy. Urographs showed normal ureters in the early part of the 5th month (fig. 3, a). However, in the 6th month (fig. 3, b) a definite dilatation appeared and the fetus was removed 10 days before the calculated date of parturition in order to observe any effects such a procedure might have on the hydroureter. The dilatation increased (fig. 4) a full degree after 2 days and on the seventh day decreased½ degree but all during the time the placenta
URETERAL DILATATION OF PREGNANCY
10L5
was retained it remained more distended than at the time the fetus was removed. On the one hundred seventy-second day of gestation the placenta was spontaneously expelled. Thirteen days later the dilatation decreased some with complete return to normal 30 days after the expulsion of the placenta. This was the longest time encountered in a normal animal necessary for the return of the ureters to normal size (fig. 5).
FIG. 4. Monkey M.m. 89. Although fetus (fig. 3, a. and b) had been removed, dilatation had increased during time placenta remained in uterus (sixth and last month of pregnancy in this monkey).
5. M.m.74 was the second observed pregnancy but the animal was parous when received and weighed 5,015 gm. at the beginning of gestation. Dilatation of both ureters was present in the fourth and fifth months. The fetus was removed on the one hundred fortieth day of gestation (latter part of 5th month). Dilatation persisted for the 15 days the placenta was retained. Five days after the placenta was spontaneously expelled (155 days after conception date), the dilatation dropped 1½ degrees. Some dilatation has been present ever since and
1016
G. VAN WAGENEN AND RALPH H. JENKINS
it possibly is associated with a peritonitis which developed after rupture of the incision. 6. M.m. 37 weighed 4,500 gm. at the time of this experiment. It was the third pregnancy observed in this multiparous animal in our laboratory. The fetus was removed on the one hundred thirtieth day of gestation and a + + + dilatation developed 2 weeks later (in the latter part of the 5th month). The placenta was expelled on the one hundred sixty-fourth day of gestation. Fourteen days later the dilatation had
I
Dilatation
I I
I
!i fetus removed day 157
M,m, 89
1...,
++++
placenta expelled day 172
,,' b. o'
+++
"·\
'
++
,I,
''
1,,\
,,l
+
J 2 3 l Months of gestation
5
4
2 l postpartum
6
FIG.5
I
Dilatation M,m, 37
& fetus removed day 130,J.
++++
I
placenta expelled day 164
' ,,' '
+++ ++
J ''
'\\
+ 0
2 l 3 Months of gestation
4
5
6
2 l postpartum
FIG. 6
been reduced ½and the ureters were completely normal 4 weeks later. It is believed a puerperal infection may have delayed the return of the ureters to normal size (fig. 6). 7. M.m.65 (fig. 7). The second observed pregnancy in this multigravida weighing 6,550 gm. at time of mating. The fetus was removed on the seventy-fourth day of gestation (third month). X-rays in the fifth month of gestation and 2 months after removal of fetus showed a beginning dilatation of the urinary tracts (fig. 7, a). In the sixth month there was an increase to a dilatation of + + + in the left and + +
URETERAL DILATATION OF PREGNANCY
1017
in the right ureter (fig. 7, b). This dilatation developed, therefore, 81 days after the removal of the fetus and while the placenta was still functioning. It was interesting that the greater dilatation occurred in the left ureter in this animal. There was a definite blunting of the calices in both kidney pelves. The placenta was delivered on the one hundred sixty-fourth day then the ureters decreased in size returning to normal in three weeks (fig. 8).
a b FIG. 7. Monkey M.m. 65. a, Fifth month of pregnancy showing a dilatation beginning to develop fully 2 months after removal of fetus. b, Maximum dilatation took place in sixth month, 3 months after fetus was removed.
8. M.m.22, a multigravida, weighed 6,185 gm. at the beginning of the third pregnancy. The fetus was removed on the seventy-first day of gestation. Dilatation was present 2 weeks later in the latter part of the fifth month and persisted until the placenta was expelled on the one hundred fifty-first day having remained in the uterus eighty days longer than the fetus. The ureters returned to normal 4 days later, a much more rapid response than was usually seen (fig. 9). Discussion. In these experiments the objective has been to separate
1018
G. VAN WAGENEN AND RALPH H. JENKINS
pressure and hormonal influences acting upon the hydroureter of pregnancy. Some of the increased weight incident to pregnancy does remain in the uterus after the fetus has been taken out. The weight of the placenta of M.m.89 whose fetus was not removed until the one hundred fifty-seventh day of gestation was 145 grams. Yet the uterus inclusive of fetus and placenta weighs considerably more than this before the fourth and fifth month when the development of urinary stasis ordinarily occurs. Dilatation M.m. 65 ++++
I
I
placenta expelled day 164
& fetus
removed day 74
+++
J
,o--o,.
.I,
:''
++
''
+
'
\\,
0
0
1 2 3 Months of gestation
4
5
6
2 1 postpartum
FIG.8
Dilatation
I
M.m. 22
++++ +++
& fetus removed day 71
++ + 0
J. 0
\
-1,
'' '' '' '
I
1 2 3 Month of gestation
I
placenta expelled day 155
4
5
'6
1 2 postpartum
Fw.9
Selye, Collip and Thompson (1935) removed fetuses from the uteri or pregnant rats between the ninth and thirteenth days of gestation and were the first to show that in these animals the placentae are retained in utero until the time of parturition at which time they are spontaneously expelled. W. H. Newton (1935) confirmed this work with the mouse using a technique giving much less trauma, and Kirsch (1938) elaborated it in the rat. With Newton one of the authors (G. van W.) has lately extended these observations using the monkey. Because gestation in the rodent is comparatively short, a study of the role of the placenta
URETERAL DILATATION OF PREGNANCY
1019
in the absence of the fetus is more favorably investigated in an animal in which gestation lasts months instead of days. In the monkey as long as the placenta is retained the habitus of pregnancy is supported and although it cannot be stated in the present work that the placenta functions in its full capacity, nevertheless it appears that no abrupt interruption of the hormonal relationships of pregnancy follows the removal of the fetus alone. The span of the operations in this series covered a period from the seventy-first to the one hundred fifty-seventh day of gestation. SUMMARY
Excretory urography has shown that dilatation of the upper urinary tract occurs in the pregnant rhesus monkey (positive findings in 6 of 8 animals). Of the 6 pregnancies showing pyeloureteral dilatation one was allowed to proceed without interruption and the markedly dilated urinary tract returned to normal in 7 days. In 3 instances fetuses were removed after the dilatation had reached a degree of + + + and the dilatation was sustained or increased during the time the placentae remained in situ. After expulsion of the placenta the dilatation of the ureters always decreased returning to normal size in every case uncomplicated by infection. The most convincing data concerning the primary importance of the hormone influences of pregnancy in bringing about dilatation were those concerning two pregnancies in which the fetuses were removed on the seventy-fourth and seventy-first days of gestation. In the first animal a beginning dilatation was found in the latter half of the fifth month, 59 days after the removal of the fetus. This dilatation increased from + to + + + during the sixth month. The placenta was expelled on the one hundred sixty-fourth day of gestation after which dilatation regressed. In the second animal dilatation appeared only in the sixth month of pregnancy, 81 days after removal of the fetus. The placenta was retained until the one hundred fifty-first day of gestation and both ureters returned to normal on the fourth day afterward. CONCLUSION
Dilatation of the upper urinary tract can develop after the removal of the fetus and while the placenta remains in a functional state within the uterus. It would appear, therefore, that this physiological change is
1020
G. VAN WAGENEN AND RALPH H. JENKINS
related primarily to the state of pregnancy and secondarily to the influence of increased weight of the uterus with its contents in pregnancy. To Miss Janet Buchanan and Miss Helen Carlson we wish to express our gratitude for the excellence of the urographs. To Mr. Joseph Negri and Mr. Frank Caruso we are grateful for their care and skill in handling the animals. The Winthrop Chemical Company, Inc. generously provided the diodrast used in these experiments. This study was aided by a grant from the Fluid Research Funds of the Yale University School of Medicine granted to the Department of Obstetrics and Gynecology. REFERENCES CRUVEILHIER, J.: Traite D'anatomie. Paris, 1843. HARTMAN, CARL G.: Contrib. to Embryo!., Carnegie Institution of Washington,23: 1, 1932. HOFBAUER, J.: J. Urol., 20: 413, 1928. KALTENSCHNEE, A.: Ztschr. f. gynaek. Urol., 4: 186, 1913. KIRSCH, R. E.: Am. J. Physiol., 122: 86, 1938. NEWTON, W. H.: J. Physiol., 84: 196, 1935. SELYE, H., CoLLIP, J. B. AND THOMPSON, D. L.: Endrocrinology, 19: 151, 1935. TRAUT, H.F. AND KUDER, A.: Internat. Abst. Surg., 67: 568, 1938. TRAUT, H. F. AND McLANE, C. H.: Surg. Gynec. and Obst., 62: 65, 1936. TRATTNER, H. R.: J. Urol., 11: 477, 1924. VANWAGENEN, G. AND NEWTON, w. H.: In press.
From the Department of Obstetrics and Gynecology and Department of Urology, Yale University School of Medicine, New Haven, Conn.
Dilatation of the renal pelvis and ureter occurs in the majority of normal pregnant women. As it may be a predisposing cause of infection and perhaps of some of the hypertensive phenomena of the gravid state it becomes of great importance as a problem for experimental investigation. By means of excretory urography we have found that this "physiological hydroureter of pregnancy" has its counterpart in the pregnant rhesus monkey and it is the availability of this valuable experimental material which has made it possible for us to separate certain of the factors now believed to be contributory to this phenomenon in the upper urinary tract. Our knowledge of this subject dates from Cruveilhier, who in 1843 found ureteral dilatation in women dying during the later months of pregnancy and in the puerperium. Traut and Kuder (1938) in an excellent collective review have considered the voluminous literature of this subject which has accumulated since then. The early explanation for these changes in the ureter of pregnancy was that of a mechanical cause having to do with the anatomical relationships within the pelvis. The pressure of the pregnant uterus upon the ureters at the level of the pelvic brim and the close application of the base of the bladder to the vagina and uterus were thought to cause an ureteral obstruction. Dextrorotation of the uterus and the large iliac vessels on the right were claimed to modify this obstruction and therefore explain the greater degree of dilatation and elongation usually observed in the right urinary tract. Furthermore, the left ureter was said to be protected by the sigmoid colon. For three quarters of a century this explanation was considered an adequate one. Hofbauer (1928) from histological examination of the ureters taken from women dying in pregnancy came to the conclusion that the obstruction in the urinary tract was of an intrinsic nature and he described hypertrophy and hyperplasia in the muscle and fibrous tissue of the ureter itself and 1 Read at the annual meeting of the American Urological Association, White Sulphur Springs, W. Va. May 30, 1939.
1010
URETERAL DILATATION OF PREGNANCY
1011
in the peri-ureteral sheath. These alterations this author believed explained the phenomena in question. Other observations have concerned the newer concepts of bacterial toxins and hormones as a factor in causing atony of the ureter during pregnancy not associated with the presence of the simple mechanical obstruction. Peristaltic contractions appearing in the normal living ureter were described first by Engelman (1869) and later studied by many others. Atony in the tract of the gravid woman was suggested by Kaltenschnee in 1913. Trattner (1930) perfected an apparatus which made it possible to observe and record the peristaltic activity of the human kidney pelvis and ureter. Using Trattner's instrureent, the hydrophorograph, Traut and McLane (1936) extended observations to the pregnant woman, and these observations yielded illuminating knowledge showing that the incidence of atony in relation to the various months of pregnancy correlated exactly with the appearance of dilatation of the pelvis and ureter. It would appear, therefore, that the hormone complex of pregnancy which relaxes the smooth muscle of the uterus, thus making the continuation of pregnancy possible, influences also other structures in the body. Certain gall bladder disturbances of pregnancy associated with decreased peristalsis are attributed to a chemical influence of the hormones of pregnancy and there is a similar effect on the urinary tract with suppression or obliteration of normal peristaltic activity. The upright position of the body causes the weight of the increasingly heavier uterus to rest on the pelvic structures and a physiological obstruction of the ureters occurs during the time when this atonic condition is present. Both mechanical and hormonal influences seem certainly to be responsible for this syndrome and it is the object of this investigation to separate in a measure these two main factors. The influences of weight and torsion of the uterus were relieved by the removal of the fetus, while the hormone relationships of pregnancy were preserved by leaving the placenta undisturbed in the uterus. Material and methods. Eight rhesus monkeys were successfully mated and the date of conception estimated by the method worked out by Hartman (1932). Three of these monkeys had been born in the laboratory of Obstetrics and Gynecology some years ago and so it was possible to state their reproductive histories and to give their exact ages. Another was purchased as a young animal and matured in the colony. The remaining 4 were adult monkeys weighing from 4,000 to 5,880 gm.
1012
G. VAN WAGENEN AND RALPH H. JENKINS
when purchased. On vaginal examination at the time of their admission to the colony these latter were considered parous animals. The period of gestation in the rhesus monkey is 168 days (6 lunar months). Three pregnancies were allowed to proceed normally and in each of the other five pregnancies the fetus was removed by abdominal section at different periods before the estimated date of parturition. The removal of the fetuses from 2 animals on the seventy-first and seventy-fourth days of pregnancy was done at a time before dilatation of the ureters had occurred. Removing the fetus by abdominal hysterotomy without injuring the placenta is a procedure in the monkey that is attended with some difficulty because usually the placenta consists of primary and secondary lobes attached to the ventral and dorsal walls of the uterus and joined by large blood vessels. In early gestation the comparatively heavy musculature of the primate uterus obscures the placental sites and the uterine contractions which follow section of the musculature and the necessary manipulations, predispose to a precipitous separation of the placenta. Urograms of the upper urinary tract were secured by injecting intravenously 15 cc of diodrast. The highest concentration of this material was found in the urinary tract at 3 to 5 minutes after injection in healthy pregnant animals. In one instance roentgenograms were taken as late as 28 to 30 minutes to visualize the ureters in M.m. 37 which was suffering from an infection. In those animals which were under deep nembutal anaesthesia there appeared to be no difference in time of excretion of the dye. It was not necessary to use anaesthesia for those animals born in the laboratory. Experiments. l. The animal designated as M.m. 71 was a primigravida. At the beginning of pregnancy she was 3 years, 7 months and 21 days old and a healthy, vigorous, animal weighing 5,800 gm. About the middle of the fourth month of pregnancy pyeloureterographs showed a dilatation of + + + in the kidney pelvis and upper two thirds of the ureter on the right side. Some dilatation ( +) was present also in the left ureter. The urinary tracts were best visualized in the 8 minute film showing that a slight retardation of excretion of dye was present. The dilatation persisted without change during the remainder of the fourth and the fifth and sixth months. A viable baby (402 gm.) was born on the one hundred sixty-eighth day of gestation and the animal was left undisturbed until the seventh day postpartum when the urograph showed a complete return of the ureters to normal size (fig. 2).
URETERAL DILATATION OF PREGNANCY
1013
2. M.m.72, a secundigravida, was 3 years, 6 months and 20 days old at the time of conception (5,430 gm.). There was no dilatation at any
a b Frc. 1. Excretory urograms. a, Normal pregnant monkey in fifth month of gestation. There is no dilatation of ureters or pelves. b, A normal monkey with dilatation of ureters and pclves.
I
Dilatation M.m. 71
baby born day 168 ++++
J,
+++
o-- --o--
--~,
++
''
+ \ 0
2 3 1 Month of gestation
4
5
6
2 1 postpartum
Frc. 2
time during the pregnancy of this animal although the fourth, fifth and sixth months were carefully studied. A baby was born on the one hundred sixty-ninth day of gestation.
1014
G. VAN W AGENEN AND RALPH H. JENKINS
3. M.m.76 was studied only during the sixth month of her pregnancy. She was a primigravida having been brought into the laboratory as a very young animal. She weighed 4,500 gm. at the beginning of gestation and a male baby was born on the one hundred sixty-fourth day. Repeated urographical study showed no change in the urinary tracts during this last month of pregnancy.
a b FIG. 3. Monkey M.m. 89. a, Normal ureters early in fifth month of pregnancy. month later ureters have become enlarged. See figure 4 for further dilatation.
b, One
4. M.m.89, (fig. 3, 4) a primigravida, was 3 years, 5 months and 13 days old and weighed 5,280 gm. at the beginning of pregnancy. Urographs showed normal ureters in the early part of the 5th month (fig. 3, a). However, in the 6th month (fig. 3, b) a definite dilatation appeared and the fetus was removed 10 days before the calculated date of parturition in order to observe any effects such a procedure might have on the hydroureter. The dilatation increased (fig. 4) a full degree after 2 days and on the seventh day decreased½ degree but all during the time the placenta
URETERAL DILATATION OF PREGNANCY
10L5
was retained it remained more distended than at the time the fetus was removed. On the one hundred seventy-second day of gestation the placenta was spontaneously expelled. Thirteen days later the dilatation decreased some with complete return to normal 30 days after the expulsion of the placenta. This was the longest time encountered in a normal animal necessary for the return of the ureters to normal size (fig. 5).
FIG. 4. Monkey M.m. 89. Although fetus (fig. 3, a. and b) had been removed, dilatation had increased during time placenta remained in uterus (sixth and last month of pregnancy in this monkey).
5. M.m.74 was the second observed pregnancy but the animal was parous when received and weighed 5,015 gm. at the beginning of gestation. Dilatation of both ureters was present in the fourth and fifth months. The fetus was removed on the one hundred fortieth day of gestation (latter part of 5th month). Dilatation persisted for the 15 days the placenta was retained. Five days after the placenta was spontaneously expelled (155 days after conception date), the dilatation dropped 1½ degrees. Some dilatation has been present ever since and
1016
G. VAN WAGENEN AND RALPH H. JENKINS
it possibly is associated with a peritonitis which developed after rupture of the incision. 6. M.m. 37 weighed 4,500 gm. at the time of this experiment. It was the third pregnancy observed in this multiparous animal in our laboratory. The fetus was removed on the one hundred thirtieth day of gestation and a + + + dilatation developed 2 weeks later (in the latter part of the 5th month). The placenta was expelled on the one hundred sixty-fourth day of gestation. Fourteen days later the dilatation had
I
Dilatation
I I
I
!i fetus removed day 157
M,m, 89
1...,
++++
placenta expelled day 172
,,' b. o'
+++
"·\
'
++
,I,
''
1,,\
,,l
+
J 2 3 l Months of gestation
5
4
2 l postpartum
6
FIG.5
I
Dilatation M,m, 37
& fetus removed day 130,J.
++++
I
placenta expelled day 164
' ,,' '
+++ ++
J ''
'\\
+ 0
2 l 3 Months of gestation
4
5
6
2 l postpartum
FIG. 6
been reduced ½and the ureters were completely normal 4 weeks later. It is believed a puerperal infection may have delayed the return of the ureters to normal size (fig. 6). 7. M.m.65 (fig. 7). The second observed pregnancy in this multigravida weighing 6,550 gm. at time of mating. The fetus was removed on the seventy-fourth day of gestation (third month). X-rays in the fifth month of gestation and 2 months after removal of fetus showed a beginning dilatation of the urinary tracts (fig. 7, a). In the sixth month there was an increase to a dilatation of + + + in the left and + +
URETERAL DILATATION OF PREGNANCY
1017
in the right ureter (fig. 7, b). This dilatation developed, therefore, 81 days after the removal of the fetus and while the placenta was still functioning. It was interesting that the greater dilatation occurred in the left ureter in this animal. There was a definite blunting of the calices in both kidney pelves. The placenta was delivered on the one hundred sixty-fourth day then the ureters decreased in size returning to normal in three weeks (fig. 8).
a b FIG. 7. Monkey M.m. 65. a, Fifth month of pregnancy showing a dilatation beginning to develop fully 2 months after removal of fetus. b, Maximum dilatation took place in sixth month, 3 months after fetus was removed.
8. M.m.22, a multigravida, weighed 6,185 gm. at the beginning of the third pregnancy. The fetus was removed on the seventy-first day of gestation. Dilatation was present 2 weeks later in the latter part of the fifth month and persisted until the placenta was expelled on the one hundred fifty-first day having remained in the uterus eighty days longer than the fetus. The ureters returned to normal 4 days later, a much more rapid response than was usually seen (fig. 9). Discussion. In these experiments the objective has been to separate
1018
G. VAN WAGENEN AND RALPH H. JENKINS
pressure and hormonal influences acting upon the hydroureter of pregnancy. Some of the increased weight incident to pregnancy does remain in the uterus after the fetus has been taken out. The weight of the placenta of M.m.89 whose fetus was not removed until the one hundred fifty-seventh day of gestation was 145 grams. Yet the uterus inclusive of fetus and placenta weighs considerably more than this before the fourth and fifth month when the development of urinary stasis ordinarily occurs. Dilatation M.m. 65 ++++
I
I
placenta expelled day 164
& fetus
removed day 74
+++
J
,o--o,.
.I,
:''
++
''
+
'
\\,
0
0
1 2 3 Months of gestation
4
5
6
2 1 postpartum
FIG.8
Dilatation
I
M.m. 22
++++ +++
& fetus removed day 71
++ + 0
J. 0
\
-1,
'' '' '' '
I
1 2 3 Month of gestation
I
placenta expelled day 155
4
5
'6
1 2 postpartum
Fw.9
Selye, Collip and Thompson (1935) removed fetuses from the uteri or pregnant rats between the ninth and thirteenth days of gestation and were the first to show that in these animals the placentae are retained in utero until the time of parturition at which time they are spontaneously expelled. W. H. Newton (1935) confirmed this work with the mouse using a technique giving much less trauma, and Kirsch (1938) elaborated it in the rat. With Newton one of the authors (G. van W.) has lately extended these observations using the monkey. Because gestation in the rodent is comparatively short, a study of the role of the placenta
URETERAL DILATATION OF PREGNANCY
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in the absence of the fetus is more favorably investigated in an animal in which gestation lasts months instead of days. In the monkey as long as the placenta is retained the habitus of pregnancy is supported and although it cannot be stated in the present work that the placenta functions in its full capacity, nevertheless it appears that no abrupt interruption of the hormonal relationships of pregnancy follows the removal of the fetus alone. The span of the operations in this series covered a period from the seventy-first to the one hundred fifty-seventh day of gestation. SUMMARY
Excretory urography has shown that dilatation of the upper urinary tract occurs in the pregnant rhesus monkey (positive findings in 6 of 8 animals). Of the 6 pregnancies showing pyeloureteral dilatation one was allowed to proceed without interruption and the markedly dilated urinary tract returned to normal in 7 days. In 3 instances fetuses were removed after the dilatation had reached a degree of + + + and the dilatation was sustained or increased during the time the placentae remained in situ. After expulsion of the placenta the dilatation of the ureters always decreased returning to normal size in every case uncomplicated by infection. The most convincing data concerning the primary importance of the hormone influences of pregnancy in bringing about dilatation were those concerning two pregnancies in which the fetuses were removed on the seventy-fourth and seventy-first days of gestation. In the first animal a beginning dilatation was found in the latter half of the fifth month, 59 days after the removal of the fetus. This dilatation increased from + to + + + during the sixth month. The placenta was expelled on the one hundred sixty-fourth day of gestation after which dilatation regressed. In the second animal dilatation appeared only in the sixth month of pregnancy, 81 days after removal of the fetus. The placenta was retained until the one hundred fifty-first day of gestation and both ureters returned to normal on the fourth day afterward. CONCLUSION
Dilatation of the upper urinary tract can develop after the removal of the fetus and while the placenta remains in a functional state within the uterus. It would appear, therefore, that this physiological change is
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G. VAN WAGENEN AND RALPH H. JENKINS
related primarily to the state of pregnancy and secondarily to the influence of increased weight of the uterus with its contents in pregnancy. To Miss Janet Buchanan and Miss Helen Carlson we wish to express our gratitude for the excellence of the urographs. To Mr. Joseph Negri and Mr. Frank Caruso we are grateful for their care and skill in handling the animals. The Winthrop Chemical Company, Inc. generously provided the diodrast used in these experiments. This study was aided by a grant from the Fluid Research Funds of the Yale University School of Medicine granted to the Department of Obstetrics and Gynecology. REFERENCES CRUVEILHIER, J.: Traite D'anatomie. Paris, 1843. HARTMAN, CARL G.: Contrib. to Embryo!., Carnegie Institution of Washington,23: 1, 1932. HOFBAUER, J.: J. Urol., 20: 413, 1928. KALTENSCHNEE, A.: Ztschr. f. gynaek. Urol., 4: 186, 1913. KIRSCH, R. E.: Am. J. Physiol., 122: 86, 1938. NEWTON, W. H.: J. Physiol., 84: 196, 1935. SELYE, H., CoLLIP, J. B. AND THOMPSON, D. L.: Endrocrinology, 19: 151, 1935. TRAUT, H.F. AND KUDER, A.: Internat. Abst. Surg., 67: 568, 1938. TRAUT, H. F. AND McLANE, C. H.: Surg. Gynec. and Obst., 62: 65, 1936. TRATTNER, H. R.: J. Urol., 11: 477, 1924. VANWAGENEN, G. AND NEWTON, w. H.: In press.