- Email: [email protected]
The effect of treatment with an antihistaminic drug on blood pressure and urine in pregnant women
THE
EFFECT OF TREATMENT WITH AN ANTIHISTAMINIC DRUG ON BLOOD PRESSURE AND URINE IN PREGNANT WOMEN DAVID B. HOFFMAN, (From
M.D., NEWARK, N. 3.
the Newark
City
Hospital)
0 ADEQUATE explanation has yet been advanced for the pathogenesis of N pre-eclamptic toxemia. It seems to me that there is an impressive parallel, however, between these disorders and the type of shock produced by histaminelike substances. Recent studies1 show that in shock the?e is, at first, a rise in blood pressure. This remains high until decompensation takes place. In this connection, Moon’ writes : “Any kind of injury causes the adjacent capillaries to dilate and become more permeable. This is a local physiologic effect resulting in inflammatory hyperemia. The action of osmosis and maintenance of fluid balance between the blood and the tissues are absolutely conditioned upon the presence of a normal semi-permeable membrane between those compartments.” Moon continues by explaining that conditions which affect the endothelium adversely always alter this quality of semi-permeability : “Abnormal endothelial permeability upsets the mechanism of fluid balance and of absorption bv which the blood is maintained at a composition and volume within physiologi> limits ; as a result, the blood volume decreases, and its concentration increases. Disturbance of renal function results, for the process of filtration through the glomerular endothelium is lowered progressively with hemoconcentration.” We Shock occurs in varying degrees, and develops with varying rapidity. are here concerned with that type that does not develop too rapidly. Beside the findings as above stated, there is, in a slow-developing case of shock, “A decrease in the alkaline reserve, a hemoconcentration, a decrease in the plasma ratio of albumin to globulin, decline of the sodium, and an increase of the potassium in the blood.” In shock there is also a retention of nitrogenous waste. The urine is concentrated, its specific gravity elevated, and it contains casts, albumin, and red cells. Postmortem examination of animals or human beings who die in shock reveals congestion of the pleural and peritoneal surfaces. The venules of the omentum are congested, the mucosa of the intestinal tract develops a deep cyanotic color. The lungs, liver, and kidneys become deeply congested. The tisues of the viscera exhibit distention of the capillaries and the venules. The parenlchymatous or granular degeneration of the kidney is sometimes slight and someGmes marked. It is evidenced by the usual slight pallor and swelling of the organ, except when the pallor is overshadowed by congestion, and by fine granulation and vacuolization of the cytoplasm seen microscopically. Necrosis in the liver may concentrate around the central vein or may be irregularly distributed. These areas of parenchymatous degeneration are probably due t,o anoxia which is a marked feature of latter stages of shock. 385
386
HOFFMAN
Am. J, Obst. & Gynec. August, 1949
Cerebral tissues show hyperchromatic granules, vacuolization, and fragmentation of the tissues. This is most marked in the anterior hypothalmus. Adair, Hunt, and Amel analyzed vascular collapse in toxemias of pregnancy and found a marked fall of blood pressure, prior to delivery and unaccompanied by hemorrhage. M’cIllroy3 concluded that shock associated with the puerperal state was due to toxemia. DeLee4 confirmed t,his and stated that syncope during eclampsia is attended by acute pulmonary edema and that, the condition resembles anaphylaxis. Necropsy tindings supported this. In this connection DeLee has stated, “We believe lhat the nephrit,is (in eclampsia) is only part of the general picture affecting all the capillaries and body tissues.” And Moon1 writes, “Most of the pathologic studies on eclampsia have emphasized the renal abnormalities and have failed to record the appearance seen elsewhere. When the conditions in other viscera have been described they conform closely to the pathology of shock. ” Thus, pathologic findings in eclampsia are suggestive of ii histamine or histamine-like reaction. Chesley5 found that pregnant women who have more “available water” than normal develop toxemia seven times as often as normal subjects. When escessive “available water” and lowered serum protein were found together, there was an increased disposition to eclampsia. However, he states” that oncotic pressure of tissue fluid is not increased in toxemia and capillary permeability cannot be great as indicated by the low protein content of edema fluid. Slso, rate of filtration from arm capillaries was less than normal due to increased hydrostatic pressure of the tissue spaces. McLennan7 showed that the filtration through capillaries in pregnant toxemic women is less than filtration rate in normal pregnancy, because of the presence of edema. Studies on blood volumes in pregnant women have been in agreement that there is a gain in total volume of blood and that there is hydremia, but they do not agree on amount. Recently, Maearthur showed that there was a relative hemoconcentration in toxemic women. In spite of some conflicting evidence, I felt that there are enough pathologic findings to support the thesis that the manifestations of pre-eclamptic toxemia are due to some histamine or histamine-like substance. The work of Smith and Smith9 on the presence of (‘menstrual toxin” gave added support, in that it might be the injuring agent which would release histamine by its noxious action. Thus, I felt that a trial with an antihistamine drug on a pre-eclamptic woman would be justified, although a careful search of the literature failed t,o reveal any previous use of antihistamine drugs for this purpose.
Patients were chosen from the prenatal clinic of the Newark City Hospital. Ninety per cent of these patients are Negro and are in the low-income group. They frequently miss their clinic appointments even though they might be ill and are informed of the importance of prenatal visits. Some who are acutely ill and are urged to enter the hospital will refuse to do so and have to be treated as ambulatory cases. The visiting nurses of this clinic see patients who miss appointmen& at3 home, take their blood pressures, and try to see that orders are
Volume 58 Number 2
EFFECT
OF AN ANTIHISTAMINIC
DRUG IN PREGNANCY
387
carried out as to rest, salt and fluid restriction, etc. If a rise in blood pressure is noted, albumin is found in the urine, or an excessive gain in weight is noted, the patients are placed on a sodium-poor diet and fluids are restricted. If, in spite of this regime, blood pressures still remain high, or albuminuria still persists, they receive 50 mg. of Pyribenzamine three times a day in conjunction with the salt and fluid restriction. This regime was tried only on patients in the clinic and was not followed in the hospital. Blood pressures were considered elevated if they were above 140/80 in patients whose normals were below this as noted in former visits to the clinic.
Patients Treated The patients were divided into three groups : Group I. No rise in blood pressure but albumin persisting in the urine. Group II. Rise in blood pressure but no albumin in the urine. Group III. Both rise in blood pressure and albumin in the urine. Group I. Albuminuria Only.-All urines were noncatheterized. Albumin was determined by heat and acetic acid and was reported as one, two, three, or four plus according to the density of the cloud. Thirteen patients in this group were treated with 50 mg. of Pyribenzamine three times daily together with salt restriction. Only patients who did not respond to the usual therapy of salt restriction were so treated. TABLE I.
PATIENT NO.
GRAVKDITY
AGE
TION TAKEN
TREATMENT
i 7
17 17
iI
3 2
If 1-h
23 :i
36 34
4 2
i: 16
4 5
i i
i i i 9 111 I.. 10 ii 11 ii i 12 13 i *Fifty milligrams
MEDICA- BEFORE
io'
iii i
34
NO. OF WEEES
AMOUNT Ol? ALBUMINURIB
2t 3t 2t
ii 3
6 s’
WEEK OF GESTATION TREATMENT* STARTED
GROUP I. ALBUMINURIA
i: 39 31 30 ii 18 18 21 37 Pyribenzamine
lt lt 2t ii If 2+ 2 2 1+ 4 1t 3 1t three times daily.
RESULTS
No change Urine negative in two weeks Urine lt in one week. Remained until deliverv Urine n&tive in one week Urine neaative in one week. Albuminreappeared one week after medication discontinued Urine negative in one week Urine negative in one week Urine negative in three weeks Urine negative in one week Urine negative in one week Urine negative in one week Urine negative in one week Urine negative in one week
The urine did not become free of albumin in two patients (Patients 1 and 3) of this group. Both of them were primiparas and both were in the very young age group. In only one patient (Patient 5) did albumin again reappear in the urine after the discontinuance of Pyribenzamine. In ten patients, the urine was free of albumin after one week of this therapy. Group II. Hypertension Only.-Twelve patients were treated in this group. Ten patients had a substantial fall in blood pressure which was maintained until delivery. On two patients (Patients 1 and 3) no improvement was noted after
HOFFMAN
388
Pyribenzamine was administered. Patient. 1 had an initial drop in blood pressure from 142/88 to 130/80, but then it gradually rose t.o 144/N) and a st,illbirth resulted. Patient 3 had to be admitted to the hospital for a pre-eclampsia and delivered a living child six days after admission. She had a hyperterlsion in her last pregnancy which had resulted in a stillborn. Patients 3, 6, K, and 9 had histories of hypertension in one or more previous pregnancies. Patient 8 stopped Pyribenzamine two weeks before delivery and there was a gradual rise in her blood pressure f rotn 124/60 to 13X;SO ant1 it rcrnainrd at this level until delivery. TABLE
PATIENT NO.
GRAVIDITY
AGE
II.
Wl!xK UP GESTATION TREATMENT* STARTED
GROUP
i
18
36
4
2
ii
20
32
8
3
vi
29
32
8
20
28
8
i
5
iii
23
24
6
vi
40
34
6
vi
29
36
4
ii
22
36
3
7
‘
8
I?
9
iii
28
36
4
10
iii
21
35
Yj
11
i
17
37
3
23
36
4
50 mg.
Pyribenaamine
12
ii *Treatment
HYPERTENSION
TOTAL NIJMBER OF WEEKS TREATED
1
4
II.
three
RESULTS
Blood pressure 142/88 to 130/X0 in one week. Gradually climbed to L&/80. Rtillbirth. Blood pressare 152/80 to 125/60 in two weeks. Remained at this level. Blood pressure 140/80, climbed steadily to 160/110. Admitted for pre-eclampsia. Blood pressure 140/X2 to 100/50 in two weeks. Remained at this level. Blood pressure 146/84 to 120/70 in three weeks. Remained at this level. Blood pressure 144/90 to 314/58 in two weeks. Remained at this level. Wood pressure 148/84 to 134/78 in our week. Remained at this level. Blood pressure 150/90 to 124/66 in one week. Patient stopped medication and blood pressure rose to 138/80 in two weeks, Blood pressure 164/W to 118/70 in one week. Next week was 130/80. Continued at. this level until delivery. Blood pressure 140/80 to 116/66 in one week. Remained at this level. Blood pressure 150/90 to 130/70 in one week. Following week 134/80. Remained until tlelivery. Blood pressure 140/80 to IOR/ in one week. Remained at this level. tirms
dally.
Group ZZZ. Albuminuria arul Hypertension.-In t.his category fifteen patients were studied, Twelve patients showed a substantial drop in the blood pressure under medication. In the other three (Patient,s 12, 13, and 15) there was either no change in the blood pressure or there was a definite rise, and no In Patient 11 there was a drop in the blood effect was seen in the albumjnuria. pressure but no effect was noted on the albuminuria. Several of the patients’ histories during this study require closer attention : PATIENT 2.-Under medication, her blood pressure dropped satisfactorily. When Pyribenzamine was discontinued, her blood pressure rose sharply and she had to be admitted to This happened twice during her pregnancy. the hospital, with a diagnosis of pre-eclampsia. After her second admission she continued Pyribenzamine and no further trouble ensued.
Volume 58 Number
EFFECT
2
OF
TABLE
AN
III.
ANTIHISTAMINIC
GROUP
III.
DRUG
HYPERTENSION
IN
AND
389
PREGNANCY
ALBUMINURIA
~-
PATIENT NO. 1
GRAVIDITY
AGE 29
2
29
3
WEEK STARTED MEDICATION*
24
21
i
24
4
24
... 111
37
5
17
i
35
6
37
111 ...
36
7
34
“111 ...
32
8
32
xi
32t
9
26
vi
32
10
21
111 ‘.’
34
11
37
v
33
12
23
i
34
13
27
i
30
14
16
i
38
15
42
v
32
milligrams Pyribenzamine flrst two days medication three weeks premature,
PATIENT medication
3.-A
was
negative
and
her
weeks.
On
her
benzamine
in
similar
started
one
was
blood
pressure
her her
three 100 mg. died two
was
blood blood
2+
albumin to negative one week lt albumin to negative in one week 2+ albumin to negative in one week I+ albumin to negative in one week I+ albumin to negative in one week It albumin to negative in one week I+ albumin to negative in one week 3t albumin to It in three weeks 1-t albumin to negative in one week It albumin to negative in one week 2t albumin. No change
a two
134/80.
pressure pressure
plus
this
Living Living Living Living Living Living Living Living Living Living
3t
albumin.
No
change
t
3t
albumin.
No
change
2t
albumin.
No
change
Stillbirth Living
I+
albumin.
No
change
Living
times
daily.
Her blood pressure when In one week, her urine was She then disappeared from the clinic for eight was X0/90, urine was negative. Under Pyri-
was
in
Living
in
times daily. Pyribenzamine three days after delivery.
existed
DELIVERY
URINE
PRESSURE
150/90 to 120/80 in one week 166/70 to 120/68 in three weeks 150/90 to 122/70 in one week 140/80 to 124/80 in two weeks 144/82 to 124/80 in one week 146/80 to 110/76 in two weeks 154/90 to 132/80 in two weeks 184/90 to 126/76 in three weeks 150/100 to 130/80 in one week 140/80 to 112/80 in two weeks 140/80 to 116/80 in two weeks 132/76 to 136/100 in one week 132/82. No change X4/78 to 148/88 in one week 132/$3 to X2/74 in t,wo weeks
situation 144/90 with
return, week
BLOOD
30
ii
i
*Fifty tFor $Birth
RESULTS
patient.
albuminuria.
182/70
and
remained
at
this
level
until
de-
livery.
patient had three stillbirths. She had pre-eelamptic toxemia during She was at first treated when her blood pressure was 140/90 with a one plus albuminuria. In one week, her urine was negative and her blood pressure was lZO/SO. Medication was discontinued at this time by error and the following week her blood pressure w&a 154/90. Her urine at this time was negative. Under Pyribenzamine, her blood pressure reached 132/80 and remained at this level until one week before delivery, when Pyribenzamine was again discontinued by the patient. Just before going into labor her blood pressure was 150/110. PATIENT
her last
five
8.-This patient has had severe pre-eclampsia since her fifth pregnancy. Her ended in a stillbirth. She placed herself on a salt-poor diet two months before her at the clinic and had been taking, daily, epsom salts for three weeks. At her first visit, her blood pressure was 184/90 with a three plus albuminuria. She refused to be hospitalized and was placed on 100 mg. Pyribenzamine three times daily. In two days her blood pressure was 162/90 and her urine contained a two plus albumin. Fifty mg. of Pyri-
last
PATIENT pregnancy appearance
7.-This pregnancies.
390
HOFFMAN
Am. J. Obsr.
& Gym
Aunust, 1949
benzamine were then ordered three times daily. Her blood prcssurc gradually ~Iroppc~I 10 126/76 in about three weeks and her urine contained a one plus albumin. The next three weeks she did not appear in clinic and no medication mas given. Her blood pressure gradual]! climbed to 170/90 and her urine contained a three plus albumin. She was hospitalized at. this time and she delivered a living child a week later. PATIENT Y.-This patient had a history of pre-eelampsia in her second and third pregnancies. Under Pyribenzamine therapy, her blood pressure dropped from 144/80 to 126/52 in one week. This medication was discontinued and in three weeks time her blood pressure rose to 150/100. Under Pyribenzamine her blood pressure again gradually dropped to 130/80 and remained at this level until delivery. PATIENT Il.-This patient’s blood pressure dropped under Pyribenzamine from 14OJ80 to 116/80 in two weeks. No change occurred in t,he albuminuria (two plus when medication was started). Her blood pressure gradually climbed and reached 132/66 in three ,weeks. It remained at this last level until delivery.
PATIENT 12.-On a salt-free diet, this patient’s blood pressure dropped from 140/W to 112/70. However, her urine still contained a three plus albumin. Pyribenzamine, 50 mg. three times daily, was prescribed. Four days after Pyribenzamine was ordered, her blood pressure was 170/110. She was admitted to t,he hospital for a pre-eclampt,ic toxemia for a period of one week. When she returned to the clinic a day aft,er discharge from the hospital her blood pressure was 132/76 and she had a three plus albuminuria. Again 50 mg. three times daily were ordered and her blood pressure rose to 136/100. Her urine still contained a three plus albuminuria. She delivered soon after this visit to the clinic, three weeks prematurely, and her baby died two days after birth. PATIENT 13.-This patient’s blood pressure rose suddenly from 120/80 to 170/90 with a three plus albuminuria. One hundred mg. Pyribenzamine three times daily were ordered. No change occurred in the hypertension or the albuminuria in two days rend the patient was admitted to the hospital for pre-eclamptic toxemia. She returned to the clinic two weeks later at which time her blood pressure was 132/B and her urine containedthree plus albumin. She was placed on 50 mg. Pyribenzamine three times daily. No change occurred in the hypertension or the amount of albumin in the urine. She delivered a stillborn infant eight weeks later. PATIENT 15.-This patient was started on 50 mg. Pyribenzamine when her blood pressure was 132/72 and her urine contained a one plus albumin. Her blood pressure gradually climbed to 152/74 and no change occurred in the amount of albumin in the urine.
Summary 1. Forty patients were treated with Pyribenzamine. 2. Thirteen patients had albuminuria: a. Eleven became albumin free. b. Two showed no improvement. 3. Twelve patients were treated for hypertension : a. Ten showed a definite drop in blood pressure. b. Two were not benefited. 4. Fifteen patients with hypertension and albuminuria were treated : a. Twelve showed a definite drop in blood pressure. In eleven of these, the urine became albumin free and they improved.
EFFECT
Volume 58 Number 2
OF AN ANTIHISTAMINIC
DRUG IN PREGNANCY
391
b. Three were not benefited either in hypertension or albuminuria. One of these had a stillborn infant and one had a premature infant that died two days after birth. Conclusion From this study, I believe that there is some value in the use of an antihistaminic drug in pregnant women with a rise in blood pressure, albuminuria, or a combination of both. Further confirmatory evidence would be desirable. I would
like
to
express
my
appreciation
to Drs.
and Louis E. Goldberg for their criticism and help. Pyribenzamine was supplied by Ciba Pharmaceutical
John
N.
Pannullo,
William
Antopol,
Products, Inc.
References 1. 2. 3. 4. 5. 6.
7. 8. 9.
Moon, Virgil II.: Shock, Philadelphia, 1942, Lea & Febiger, page 126. Adair, F. L., Hunt, A. B., and Are& R. E.: J. A. M. A. 107: 1026, 1936. McIllroy, P. T.: Cited by Moon, ref. 1, page 167. DeLee, Joseph B.: Principles and Practice of Obstetrics, ed. 6. Philadelphia, 1933, W. B. Saunders Company, page 392. Chesley, Leon C., and Chesley, Elizabeth R.: AM. J. OBST. & GYNEC. 45: 748, 1943. Chesley, Leon C.: AM. J. OBST. & GYWW. 48: 565, 1944. McLennan, Charles E.: AM. J. OBST. & GYNEC. 46: 63, 1943. Macarthur, J. L.: AM. J. OBST. & GYNEC. 55: 382, 1948. Smith, 0. Watkins, and Smith, George Van 8.: AM. J. OBST. & GYNEC. 54: 201 and 212, 1947. 31 LIWOLN
PARK
EFFECT OF TREATMENT WITH AN ANTIHISTAMINIC DRUG ON BLOOD PRESSURE AND URINE IN PREGNANT WOMEN DAVID B. HOFFMAN, (From
M.D., NEWARK, N. 3.
the Newark
City
Hospital)
0 ADEQUATE explanation has yet been advanced for the pathogenesis of N pre-eclamptic toxemia. It seems to me that there is an impressive parallel, however, between these disorders and the type of shock produced by histaminelike substances. Recent studies1 show that in shock the?e is, at first, a rise in blood pressure. This remains high until decompensation takes place. In this connection, Moon’ writes : “Any kind of injury causes the adjacent capillaries to dilate and become more permeable. This is a local physiologic effect resulting in inflammatory hyperemia. The action of osmosis and maintenance of fluid balance between the blood and the tissues are absolutely conditioned upon the presence of a normal semi-permeable membrane between those compartments.” Moon continues by explaining that conditions which affect the endothelium adversely always alter this quality of semi-permeability : “Abnormal endothelial permeability upsets the mechanism of fluid balance and of absorption bv which the blood is maintained at a composition and volume within physiologi> limits ; as a result, the blood volume decreases, and its concentration increases. Disturbance of renal function results, for the process of filtration through the glomerular endothelium is lowered progressively with hemoconcentration.” We Shock occurs in varying degrees, and develops with varying rapidity. are here concerned with that type that does not develop too rapidly. Beside the findings as above stated, there is, in a slow-developing case of shock, “A decrease in the alkaline reserve, a hemoconcentration, a decrease in the plasma ratio of albumin to globulin, decline of the sodium, and an increase of the potassium in the blood.” In shock there is also a retention of nitrogenous waste. The urine is concentrated, its specific gravity elevated, and it contains casts, albumin, and red cells. Postmortem examination of animals or human beings who die in shock reveals congestion of the pleural and peritoneal surfaces. The venules of the omentum are congested, the mucosa of the intestinal tract develops a deep cyanotic color. The lungs, liver, and kidneys become deeply congested. The tisues of the viscera exhibit distention of the capillaries and the venules. The parenlchymatous or granular degeneration of the kidney is sometimes slight and someGmes marked. It is evidenced by the usual slight pallor and swelling of the organ, except when the pallor is overshadowed by congestion, and by fine granulation and vacuolization of the cytoplasm seen microscopically. Necrosis in the liver may concentrate around the central vein or may be irregularly distributed. These areas of parenchymatous degeneration are probably due t,o anoxia which is a marked feature of latter stages of shock. 385
386
HOFFMAN
Am. J, Obst. & Gynec. August, 1949
Cerebral tissues show hyperchromatic granules, vacuolization, and fragmentation of the tissues. This is most marked in the anterior hypothalmus. Adair, Hunt, and Amel analyzed vascular collapse in toxemias of pregnancy and found a marked fall of blood pressure, prior to delivery and unaccompanied by hemorrhage. M’cIllroy3 concluded that shock associated with the puerperal state was due to toxemia. DeLee4 confirmed t,his and stated that syncope during eclampsia is attended by acute pulmonary edema and that, the condition resembles anaphylaxis. Necropsy tindings supported this. In this connection DeLee has stated, “We believe lhat the nephrit,is (in eclampsia) is only part of the general picture affecting all the capillaries and body tissues.” And Moon1 writes, “Most of the pathologic studies on eclampsia have emphasized the renal abnormalities and have failed to record the appearance seen elsewhere. When the conditions in other viscera have been described they conform closely to the pathology of shock. ” Thus, pathologic findings in eclampsia are suggestive of ii histamine or histamine-like reaction. Chesley5 found that pregnant women who have more “available water” than normal develop toxemia seven times as often as normal subjects. When escessive “available water” and lowered serum protein were found together, there was an increased disposition to eclampsia. However, he states” that oncotic pressure of tissue fluid is not increased in toxemia and capillary permeability cannot be great as indicated by the low protein content of edema fluid. Slso, rate of filtration from arm capillaries was less than normal due to increased hydrostatic pressure of the tissue spaces. McLennan7 showed that the filtration through capillaries in pregnant toxemic women is less than filtration rate in normal pregnancy, because of the presence of edema. Studies on blood volumes in pregnant women have been in agreement that there is a gain in total volume of blood and that there is hydremia, but they do not agree on amount. Recently, Maearthur showed that there was a relative hemoconcentration in toxemic women. In spite of some conflicting evidence, I felt that there are enough pathologic findings to support the thesis that the manifestations of pre-eclamptic toxemia are due to some histamine or histamine-like substance. The work of Smith and Smith9 on the presence of (‘menstrual toxin” gave added support, in that it might be the injuring agent which would release histamine by its noxious action. Thus, I felt that a trial with an antihistamine drug on a pre-eclamptic woman would be justified, although a careful search of the literature failed t,o reveal any previous use of antihistamine drugs for this purpose.
Patients were chosen from the prenatal clinic of the Newark City Hospital. Ninety per cent of these patients are Negro and are in the low-income group. They frequently miss their clinic appointments even though they might be ill and are informed of the importance of prenatal visits. Some who are acutely ill and are urged to enter the hospital will refuse to do so and have to be treated as ambulatory cases. The visiting nurses of this clinic see patients who miss appointmen& at3 home, take their blood pressures, and try to see that orders are
Volume 58 Number 2
EFFECT
OF AN ANTIHISTAMINIC
DRUG IN PREGNANCY
387
carried out as to rest, salt and fluid restriction, etc. If a rise in blood pressure is noted, albumin is found in the urine, or an excessive gain in weight is noted, the patients are placed on a sodium-poor diet and fluids are restricted. If, in spite of this regime, blood pressures still remain high, or albuminuria still persists, they receive 50 mg. of Pyribenzamine three times a day in conjunction with the salt and fluid restriction. This regime was tried only on patients in the clinic and was not followed in the hospital. Blood pressures were considered elevated if they were above 140/80 in patients whose normals were below this as noted in former visits to the clinic.
Patients Treated The patients were divided into three groups : Group I. No rise in blood pressure but albumin persisting in the urine. Group II. Rise in blood pressure but no albumin in the urine. Group III. Both rise in blood pressure and albumin in the urine. Group I. Albuminuria Only.-All urines were noncatheterized. Albumin was determined by heat and acetic acid and was reported as one, two, three, or four plus according to the density of the cloud. Thirteen patients in this group were treated with 50 mg. of Pyribenzamine three times daily together with salt restriction. Only patients who did not respond to the usual therapy of salt restriction were so treated. TABLE I.
PATIENT NO.
GRAVKDITY
AGE
TION TAKEN
TREATMENT
i 7
17 17
iI
3 2
If 1-h
23 :i
36 34
4 2
i: 16
4 5
i i
i i i 9 111 I.. 10 ii 11 ii i 12 13 i *Fifty milligrams
MEDICA- BEFORE
io'
iii i
34
NO. OF WEEES
AMOUNT Ol? ALBUMINURIB
2t 3t 2t
ii 3
6 s’
WEEK OF GESTATION TREATMENT* STARTED
GROUP I. ALBUMINURIA
i: 39 31 30 ii 18 18 21 37 Pyribenzamine
lt lt 2t ii If 2+ 2 2 1+ 4 1t 3 1t three times daily.
RESULTS
No change Urine negative in two weeks Urine lt in one week. Remained until deliverv Urine n&tive in one week Urine neaative in one week. Albuminreappeared one week after medication discontinued Urine negative in one week Urine negative in one week Urine negative in three weeks Urine negative in one week Urine negative in one week Urine negative in one week Urine negative in one week Urine negative in one week
The urine did not become free of albumin in two patients (Patients 1 and 3) of this group. Both of them were primiparas and both were in the very young age group. In only one patient (Patient 5) did albumin again reappear in the urine after the discontinuance of Pyribenzamine. In ten patients, the urine was free of albumin after one week of this therapy. Group II. Hypertension Only.-Twelve patients were treated in this group. Ten patients had a substantial fall in blood pressure which was maintained until delivery. On two patients (Patients 1 and 3) no improvement was noted after
HOFFMAN
388
Pyribenzamine was administered. Patient. 1 had an initial drop in blood pressure from 142/88 to 130/80, but then it gradually rose t.o 144/N) and a st,illbirth resulted. Patient 3 had to be admitted to the hospital for a pre-eclampsia and delivered a living child six days after admission. She had a hyperterlsion in her last pregnancy which had resulted in a stillborn. Patients 3, 6, K, and 9 had histories of hypertension in one or more previous pregnancies. Patient 8 stopped Pyribenzamine two weeks before delivery and there was a gradual rise in her blood pressure f rotn 124/60 to 13X;SO ant1 it rcrnainrd at this level until delivery. TABLE
PATIENT NO.
GRAVIDITY
AGE
II.
Wl!xK UP GESTATION TREATMENT* STARTED
GROUP
i
18
36
4
2
ii
20
32
8
3
vi
29
32
8
20
28
8
i
5
iii
23
24
6
vi
40
34
6
vi
29
36
4
ii
22
36
3
7
‘
8
I?
9
iii
28
36
4
10
iii
21
35
Yj
11
i
17
37
3
23
36
4
50 mg.
Pyribenaamine
12
ii *Treatment
HYPERTENSION
TOTAL NIJMBER OF WEEKS TREATED
1
4
II.
three
RESULTS
Blood pressure 142/88 to 130/X0 in one week. Gradually climbed to L&/80. Rtillbirth. Blood pressare 152/80 to 125/60 in two weeks. Remained at this level. Blood pressure 140/80, climbed steadily to 160/110. Admitted for pre-eclampsia. Blood pressure 140/X2 to 100/50 in two weeks. Remained at this level. Blood pressure 146/84 to 120/70 in three weeks. Remained at this level. Blood pressure 144/90 to 314/58 in two weeks. Remained at this level. Wood pressure 148/84 to 134/78 in our week. Remained at this level. Blood pressure 150/90 to 124/66 in one week. Patient stopped medication and blood pressure rose to 138/80 in two weeks, Blood pressure 164/W to 118/70 in one week. Next week was 130/80. Continued at. this level until delivery. Blood pressure 140/80 to 116/66 in one week. Remained at this level. Blood pressure 150/90 to 130/70 in one week. Following week 134/80. Remained until tlelivery. Blood pressure 140/80 to IOR/ in one week. Remained at this level. tirms
dally.
Group ZZZ. Albuminuria arul Hypertension.-In t.his category fifteen patients were studied, Twelve patients showed a substantial drop in the blood pressure under medication. In the other three (Patient,s 12, 13, and 15) there was either no change in the blood pressure or there was a definite rise, and no In Patient 11 there was a drop in the blood effect was seen in the albumjnuria. pressure but no effect was noted on the albuminuria. Several of the patients’ histories during this study require closer attention : PATIENT 2.-Under medication, her blood pressure dropped satisfactorily. When Pyribenzamine was discontinued, her blood pressure rose sharply and she had to be admitted to This happened twice during her pregnancy. the hospital, with a diagnosis of pre-eclampsia. After her second admission she continued Pyribenzamine and no further trouble ensued.
Volume 58 Number
EFFECT
2
OF
TABLE
AN
III.
ANTIHISTAMINIC
GROUP
III.
DRUG
HYPERTENSION
IN
AND
389
PREGNANCY
ALBUMINURIA
~-
PATIENT NO. 1
GRAVIDITY
AGE 29
2
29
3
WEEK STARTED MEDICATION*
24
21
i
24
4
24
... 111
37
5
17
i
35
6
37
111 ...
36
7
34
“111 ...
32
8
32
xi
32t
9
26
vi
32
10
21
111 ‘.’
34
11
37
v
33
12
23
i
34
13
27
i
30
14
16
i
38
15
42
v
32
milligrams Pyribenzamine flrst two days medication three weeks premature,
PATIENT medication
3.-A
was
negative
and
her
weeks.
On
her
benzamine
in
similar
started
one
was
blood
pressure
her her
three 100 mg. died two
was
blood blood
2+
albumin to negative one week lt albumin to negative in one week 2+ albumin to negative in one week I+ albumin to negative in one week I+ albumin to negative in one week It albumin to negative in one week I+ albumin to negative in one week 3t albumin to It in three weeks 1-t albumin to negative in one week It albumin to negative in one week 2t albumin. No change
a two
134/80.
pressure pressure
plus
this
Living Living Living Living Living Living Living Living Living Living
3t
albumin.
No
change
t
3t
albumin.
No
change
2t
albumin.
No
change
Stillbirth Living
I+
albumin.
No
change
Living
times
daily.
Her blood pressure when In one week, her urine was She then disappeared from the clinic for eight was X0/90, urine was negative. Under Pyri-
was
in
Living
in
times daily. Pyribenzamine three days after delivery.
existed
DELIVERY
URINE
PRESSURE
150/90 to 120/80 in one week 166/70 to 120/68 in three weeks 150/90 to 122/70 in one week 140/80 to 124/80 in two weeks 144/82 to 124/80 in one week 146/80 to 110/76 in two weeks 154/90 to 132/80 in two weeks 184/90 to 126/76 in three weeks 150/100 to 130/80 in one week 140/80 to 112/80 in two weeks 140/80 to 116/80 in two weeks 132/76 to 136/100 in one week 132/82. No change X4/78 to 148/88 in one week 132/$3 to X2/74 in t,wo weeks
situation 144/90 with
return, week
BLOOD
30
ii
i
*Fifty tFor $Birth
RESULTS
patient.
albuminuria.
182/70
and
remained
at
this
level
until
de-
livery.
patient had three stillbirths. She had pre-eelamptic toxemia during She was at first treated when her blood pressure was 140/90 with a one plus albuminuria. In one week, her urine was negative and her blood pressure was lZO/SO. Medication was discontinued at this time by error and the following week her blood pressure w&a 154/90. Her urine at this time was negative. Under Pyribenzamine, her blood pressure reached 132/80 and remained at this level until one week before delivery, when Pyribenzamine was again discontinued by the patient. Just before going into labor her blood pressure was 150/110. PATIENT
her last
five
8.-This patient has had severe pre-eclampsia since her fifth pregnancy. Her ended in a stillbirth. She placed herself on a salt-poor diet two months before her at the clinic and had been taking, daily, epsom salts for three weeks. At her first visit, her blood pressure was 184/90 with a three plus albuminuria. She refused to be hospitalized and was placed on 100 mg. Pyribenzamine three times daily. In two days her blood pressure was 162/90 and her urine contained a two plus albumin. Fifty mg. of Pyri-
last
PATIENT pregnancy appearance
7.-This pregnancies.
390
HOFFMAN
Am. J. Obsr.
& Gym
Aunust, 1949
benzamine were then ordered three times daily. Her blood prcssurc gradually ~Iroppc~I 10 126/76 in about three weeks and her urine contained a one plus albumin. The next three weeks she did not appear in clinic and no medication mas given. Her blood pressure gradual]! climbed to 170/90 and her urine contained a three plus albumin. She was hospitalized at. this time and she delivered a living child a week later. PATIENT Y.-This patient had a history of pre-eelampsia in her second and third pregnancies. Under Pyribenzamine therapy, her blood pressure dropped from 144/80 to 126/52 in one week. This medication was discontinued and in three weeks time her blood pressure rose to 150/100. Under Pyribenzamine her blood pressure again gradually dropped to 130/80 and remained at this level until delivery. PATIENT Il.-This patient’s blood pressure dropped under Pyribenzamine from 14OJ80 to 116/80 in two weeks. No change occurred in t,he albuminuria (two plus when medication was started). Her blood pressure gradually climbed and reached 132/66 in three ,weeks. It remained at this last level until delivery.
PATIENT 12.-On a salt-free diet, this patient’s blood pressure dropped from 140/W to 112/70. However, her urine still contained a three plus albumin. Pyribenzamine, 50 mg. three times daily, was prescribed. Four days after Pyribenzamine was ordered, her blood pressure was 170/110. She was admitted to t,he hospital for a pre-eclampt,ic toxemia for a period of one week. When she returned to the clinic a day aft,er discharge from the hospital her blood pressure was 132/76 and she had a three plus albuminuria. Again 50 mg. three times daily were ordered and her blood pressure rose to 136/100. Her urine still contained a three plus albuminuria. She delivered soon after this visit to the clinic, three weeks prematurely, and her baby died two days after birth. PATIENT 13.-This patient’s blood pressure rose suddenly from 120/80 to 170/90 with a three plus albuminuria. One hundred mg. Pyribenzamine three times daily were ordered. No change occurred in the hypertension or the albuminuria in two days rend the patient was admitted to the hospital for pre-eclamptic toxemia. She returned to the clinic two weeks later at which time her blood pressure was 132/B and her urine containedthree plus albumin. She was placed on 50 mg. Pyribenzamine three times daily. No change occurred in the hypertension or the amount of albumin in the urine. She delivered a stillborn infant eight weeks later. PATIENT 15.-This patient was started on 50 mg. Pyribenzamine when her blood pressure was 132/72 and her urine contained a one plus albumin. Her blood pressure gradually climbed to 152/74 and no change occurred in the amount of albumin in the urine.
Summary 1. Forty patients were treated with Pyribenzamine. 2. Thirteen patients had albuminuria: a. Eleven became albumin free. b. Two showed no improvement. 3. Twelve patients were treated for hypertension : a. Ten showed a definite drop in blood pressure. b. Two were not benefited. 4. Fifteen patients with hypertension and albuminuria were treated : a. Twelve showed a definite drop in blood pressure. In eleven of these, the urine became albumin free and they improved.
EFFECT
Volume 58 Number 2
OF AN ANTIHISTAMINIC
DRUG IN PREGNANCY
391
b. Three were not benefited either in hypertension or albuminuria. One of these had a stillborn infant and one had a premature infant that died two days after birth. Conclusion From this study, I believe that there is some value in the use of an antihistaminic drug in pregnant women with a rise in blood pressure, albuminuria, or a combination of both. Further confirmatory evidence would be desirable. I would
like
to
express
my
appreciation
to Drs.
and Louis E. Goldberg for their criticism and help. Pyribenzamine was supplied by Ciba Pharmaceutical
John
N.
Pannullo,
William
Antopol,
Products, Inc.
References 1. 2. 3. 4. 5. 6.
7. 8. 9.
Moon, Virgil II.: Shock, Philadelphia, 1942, Lea & Febiger, page 126. Adair, F. L., Hunt, A. B., and Are& R. E.: J. A. M. A. 107: 1026, 1936. McIllroy, P. T.: Cited by Moon, ref. 1, page 167. DeLee, Joseph B.: Principles and Practice of Obstetrics, ed. 6. Philadelphia, 1933, W. B. Saunders Company, page 392. Chesley, Leon C., and Chesley, Elizabeth R.: AM. J. OBST. & GYNEC. 45: 748, 1943. Chesley, Leon C.: AM. J. OBST. & GYWW. 48: 565, 1944. McLennan, Charles E.: AM. J. OBST. & GYNEC. 46: 63, 1943. Macarthur, J. L.: AM. J. OBST. & GYNEC. 55: 382, 1948. Smith, 0. Watkins, and Smith, George Van 8.: AM. J. OBST. & GYNEC. 54: 201 and 212, 1947. 31 LIWOLN
PARK