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Treatment of biliary stasis in the latter half of pregnancy
Treatment of biliary stasis in the latter half of pregnancy C. GEORGE MUSCILLO, M.D. Bronx, New York
STEPHEN WILLIAM GIORLANDO, M.D. Brooklyn, New York
E v E R Y obstetrician notices, in the latter half of pregnancy, 1 the high incidence of the disturbing symptom-complex known as biliary stasis. Although references are made to it in standard textbooks/• 2 there is actually very little written on the subject. A thorough search of recent literature reveals hardly any activity in this field, although the syndrome is one of the most disabling encountered in routine obstetrical practice. Objective evidence of gall bladder dysfunction is difficult to obtain in this disease, since most cases are not advanced enough to produce definitive physical or laboratory signs. Roentgenograms are contraindicated in pregnancy except in the most urgent cases, but in former days, when x-rays were taken more freely, pressure defects and nonvisualization were demonstrable. 3 Symptoms therefore became the most reliable diagnostic criteria, and the following arc considered to be the most characteristic: fat intolerance, constipation, nausea (to be distinguished from hyperemesis gravidarum), abdominal distention, gaseous eructation, in·· digestion, and pain in the area of the gall bladder. Many conditions are prevalent during pregnancy which could predispose to biliary stasis with subsequent cholelithiasis and cholecystitis: 1. The encroachment of the enlarging uterus, with resultant displacement of the
gall bladder upward and to the right, 3 predisposing to decreased gall bladder evacuation and stasis. 2. Increased intra-abdominal pressure.~ with the possibility of a further decrease in gall bladder evacuation. 3. The physiological hypercholesterolemia observed in pregnancy, 1 leading to the deposition of cholesterol foci and subsequent cholelithiasis. 4. Passive hyperemia of the liver, 2 with possible cholangitis. 5. Increased rate of hemolysis, 2 leading to bilirubin calculi. 6. The increased incidence of infection, such as ureteritis, 2 with possible hematogenous spread to the biliary tract. At the present time the only treatment generally employed is the limitation of fats and foods rich in cholesterol. Since biliary stasis can lead to chronic cholecystitis, cholelithiasis, and hepatic disorders/ it is imperative, especially during pregnancy, for the gall bladder to be evacuated regularly. 5 o-Glucitol, * C 6 H 140 6, has been found to be a potent cholagogic agent, the maximum contraction occurring after 30 minutes. 6 • 7 Concomitantly, the antispasmodic action of homatropine methylbromide also relaxes the sphincter of Oddi and dilates the bile ducts. By this reciprocal, combined action, fat digestion is aided and there is enhancement of absorption of fat-soluble vitamins A, D, E,
From the Department of Obstetrics and Gynecology, Fordham Hospital.
bromide, was supplied as ProBilagol by The Purdue Fred-
*D.Glucitol, in combination with homatropine methylerick Company, New York, New York.
545
546
Muscillo and Giorlando
~t.'ptt:ll1bet,
\m . .L Oh;,t. &
and K. The properties and actions of this combination of drugs and the impressive results achieved elsewhere in the treatment of biliary-digestive malfunctions 8 ' 10 warranted a trial of it in the biliary stasis of pregnancy. Material and methods
All patients in this study were in the latter half of pregnancy. Those who were chosen for therapy had sufficient symptoms of biliary dysfunction to warrant repeated complaints and frequent examinations. Thirty patients were placed initially on 5 ml. three times a day, before meals, of the solution containing 4.5 Gm. o-glucitol and 1 mg. homatropine methylbromide per each 5 ml. (teaspoonful). A control group of 26 patients received the same amount of a placebo identical in taste and appearance to the active drug. After 2 weeks of treatment with the o-glucitol-homatropine solution each patient was questioned closely regarding her symptoms and the results were charted as follows: worse (-), no improvement (0), moderate improvement , marked improvement ( ++) . Those patients showing no or only moderate improvement were then placed on a dosage of 10 ml. three times a day, before meals. Patients who did not respond to treatment with the placebo after 2 weeks were given one teaspoonful of the active drug three times a day for a period of two additional weeks. The criteria for response to treatment
were necessarily subjective since the alkaline phosphatase, serum bilirubin, and cholesterol levels were found to be elevated in only one case. Results
The results of the study are summarized in Table I. Of the 30 patients treated with the drug, 27 (90 per cent) exhibited marked or moderate improvement of symptoms and 3 ( 10 per cent) no improvement; none were made worse. Seven of the 10 patients who reported only moderate or no improvement were re-treated with double the original dosage ( 10 mi. three times a day) ; all of these patients reported marked improvement on the increased dosage. Of the 26 controls treated with placebo, 7 (27 per cent) reported marked improvement of symptoms, none reported moderate improvement, and 19 ( 73 per cent) reported no improvement; again none were made worse. All of the 19 patients who reported no improvement on the placebo were then re-treated with 5 rnl. three times a day of the v-glucitol-homatropine solution; of these, 17 (or 89 per cent) reported marked improvement, none reported moderate improvement, and 2 ll per cent) reported no improvement. Thu~, of the total of 49 patients treated with the drug in the initial dose of 5 ml. three times a day, 44 ( 90 per cent) exhibited a significant degree of clinical improvement. The only untoward effect noted was laxation in one patient. !
Table I. Results of treatment with drug and placebo R~u~
I
Treatment (No. of patients in parenthesis) ProBilagol ( 30)
Original series ( 30) Re·treatment with increased dose {7 )
Placebo ( 26)
Original series ( 2 6) Failures re-treated with
!ift,l/
<;:> r10'
~ ~::,:~!~e=-T im~;::;~:nt 20 ( 67%) (100%)
27%)
7 (23%)
3 (10%)
0
(l
0
0
0
19 (73%)
2
0
11%
()
0
Volume 80 Number 3
Comment
The well-known fact that the first attack of biliary colic in women commonly occurs in the postpartum period 2 indicates that the biliary stasis of pregnancy may be more than just a troublesome symptom-complex requiring only symptomatic relief; it may also be a problem in preventive medicine. It is therefore possible that a therapeutic agent which corrects this biliary stasis may also prevent future cholelithiasis. On the basis of our consistently good results with an agent of this type in our small series of cases of biliary stasis in pregnancy, we feel that it merits considerably more use. Moreover, as
Treatment of biliary stasis 547
was noted above, if the recommended initial dosage fails to provide satisfactory improvement, the dosage should be increased until desirable results are obtained or until undesirable side effects are noted. Summary
A solution of n-glucitol and homatropine methylbromide has been found to provide effective relief in a controlled series of cases of biliary stasis in the latter half of pregnancy. The results observed to date indicate that this cholagogue offers great promise in the treatment of a common and distressing complication of pregnancy.
REFERENCES
1. Beck, A. C.: Obstetrical Practice, Baltimore,
2. 3. 4.
5.
1939, Williams & Wilkins Company. DeLee, J. B.: Principles and Practice of Obstetrics, Philadelphia, 1921, W. B. Saunders Company. Levyn, L., Beck, E. C., and Aaron, A. H.: Am. J. Roentgenol. 30: 774, 1933. Levene, G., and Scheff, S.: Am. J. Digest. Dis. 2: 533, 1957. Vignes, H.: Progres med., p. 1924, Nov. 28, 1934.
6. Wissmer, B.: Praxis, Bern 46: 463, 1957. 7. Piccinelli, 0., and Timossi, G.: Minerva med. 49: 77, 1958. 8. Leavitt, J. M.: Scientific Exhibit, Meeting of the New York State Medical Society, May, 1958. 9. Tirsch, H. S., Seley, S. A., and Trachtman, B.: Scientific Exhibit, Meeting of the American Medical Association, June, 1959. 10. Rothburd, C. M.: Am. J. Gastroenterol. (To be published.)
STEPHEN WILLIAM GIORLANDO, M.D. Brooklyn, New York
E v E R Y obstetrician notices, in the latter half of pregnancy, 1 the high incidence of the disturbing symptom-complex known as biliary stasis. Although references are made to it in standard textbooks/• 2 there is actually very little written on the subject. A thorough search of recent literature reveals hardly any activity in this field, although the syndrome is one of the most disabling encountered in routine obstetrical practice. Objective evidence of gall bladder dysfunction is difficult to obtain in this disease, since most cases are not advanced enough to produce definitive physical or laboratory signs. Roentgenograms are contraindicated in pregnancy except in the most urgent cases, but in former days, when x-rays were taken more freely, pressure defects and nonvisualization were demonstrable. 3 Symptoms therefore became the most reliable diagnostic criteria, and the following arc considered to be the most characteristic: fat intolerance, constipation, nausea (to be distinguished from hyperemesis gravidarum), abdominal distention, gaseous eructation, in·· digestion, and pain in the area of the gall bladder. Many conditions are prevalent during pregnancy which could predispose to biliary stasis with subsequent cholelithiasis and cholecystitis: 1. The encroachment of the enlarging uterus, with resultant displacement of the
gall bladder upward and to the right, 3 predisposing to decreased gall bladder evacuation and stasis. 2. Increased intra-abdominal pressure.~ with the possibility of a further decrease in gall bladder evacuation. 3. The physiological hypercholesterolemia observed in pregnancy, 1 leading to the deposition of cholesterol foci and subsequent cholelithiasis. 4. Passive hyperemia of the liver, 2 with possible cholangitis. 5. Increased rate of hemolysis, 2 leading to bilirubin calculi. 6. The increased incidence of infection, such as ureteritis, 2 with possible hematogenous spread to the biliary tract. At the present time the only treatment generally employed is the limitation of fats and foods rich in cholesterol. Since biliary stasis can lead to chronic cholecystitis, cholelithiasis, and hepatic disorders/ it is imperative, especially during pregnancy, for the gall bladder to be evacuated regularly. 5 o-Glucitol, * C 6 H 140 6, has been found to be a potent cholagogic agent, the maximum contraction occurring after 30 minutes. 6 • 7 Concomitantly, the antispasmodic action of homatropine methylbromide also relaxes the sphincter of Oddi and dilates the bile ducts. By this reciprocal, combined action, fat digestion is aided and there is enhancement of absorption of fat-soluble vitamins A, D, E,
From the Department of Obstetrics and Gynecology, Fordham Hospital.
bromide, was supplied as ProBilagol by The Purdue Fred-
*D.Glucitol, in combination with homatropine methylerick Company, New York, New York.
545
546
Muscillo and Giorlando
~t.'ptt:ll1bet,
\m . .L Oh;,t. &
and K. The properties and actions of this combination of drugs and the impressive results achieved elsewhere in the treatment of biliary-digestive malfunctions 8 ' 10 warranted a trial of it in the biliary stasis of pregnancy. Material and methods
All patients in this study were in the latter half of pregnancy. Those who were chosen for therapy had sufficient symptoms of biliary dysfunction to warrant repeated complaints and frequent examinations. Thirty patients were placed initially on 5 ml. three times a day, before meals, of the solution containing 4.5 Gm. o-glucitol and 1 mg. homatropine methylbromide per each 5 ml. (teaspoonful). A control group of 26 patients received the same amount of a placebo identical in taste and appearance to the active drug. After 2 weeks of treatment with the o-glucitol-homatropine solution each patient was questioned closely regarding her symptoms and the results were charted as follows: worse (-), no improvement (0), moderate improvement , marked improvement ( ++) . Those patients showing no or only moderate improvement were then placed on a dosage of 10 ml. three times a day, before meals. Patients who did not respond to treatment with the placebo after 2 weeks were given one teaspoonful of the active drug three times a day for a period of two additional weeks. The criteria for response to treatment
were necessarily subjective since the alkaline phosphatase, serum bilirubin, and cholesterol levels were found to be elevated in only one case. Results
The results of the study are summarized in Table I. Of the 30 patients treated with the drug, 27 (90 per cent) exhibited marked or moderate improvement of symptoms and 3 ( 10 per cent) no improvement; none were made worse. Seven of the 10 patients who reported only moderate or no improvement were re-treated with double the original dosage ( 10 mi. three times a day) ; all of these patients reported marked improvement on the increased dosage. Of the 26 controls treated with placebo, 7 (27 per cent) reported marked improvement of symptoms, none reported moderate improvement, and 19 ( 73 per cent) reported no improvement; again none were made worse. All of the 19 patients who reported no improvement on the placebo were then re-treated with 5 rnl. three times a day of the v-glucitol-homatropine solution; of these, 17 (or 89 per cent) reported marked improvement, none reported moderate improvement, and 2 ll per cent) reported no improvement. Thu~, of the total of 49 patients treated with the drug in the initial dose of 5 ml. three times a day, 44 ( 90 per cent) exhibited a significant degree of clinical improvement. The only untoward effect noted was laxation in one patient. !
Table I. Results of treatment with drug and placebo R~u~
I
Treatment (No. of patients in parenthesis) ProBilagol ( 30)
Original series ( 30) Re·treatment with increased dose {7 )
Placebo ( 26)
Original series ( 2 6) Failures re-treated with
!ift,l/
<;:> r10'
~ ~::,:~!~e=-T im~;::;~:nt 20 ( 67%) (100%)
27%)
7 (23%)
3 (10%)
0
(l
0
0
0
19 (73%)
2
0
11%
()
0
Volume 80 Number 3
Comment
The well-known fact that the first attack of biliary colic in women commonly occurs in the postpartum period 2 indicates that the biliary stasis of pregnancy may be more than just a troublesome symptom-complex requiring only symptomatic relief; it may also be a problem in preventive medicine. It is therefore possible that a therapeutic agent which corrects this biliary stasis may also prevent future cholelithiasis. On the basis of our consistently good results with an agent of this type in our small series of cases of biliary stasis in pregnancy, we feel that it merits considerably more use. Moreover, as
Treatment of biliary stasis 547
was noted above, if the recommended initial dosage fails to provide satisfactory improvement, the dosage should be increased until desirable results are obtained or until undesirable side effects are noted. Summary
A solution of n-glucitol and homatropine methylbromide has been found to provide effective relief in a controlled series of cases of biliary stasis in the latter half of pregnancy. The results observed to date indicate that this cholagogue offers great promise in the treatment of a common and distressing complication of pregnancy.
REFERENCES
1. Beck, A. C.: Obstetrical Practice, Baltimore,
2. 3. 4.
5.
1939, Williams & Wilkins Company. DeLee, J. B.: Principles and Practice of Obstetrics, Philadelphia, 1921, W. B. Saunders Company. Levyn, L., Beck, E. C., and Aaron, A. H.: Am. J. Roentgenol. 30: 774, 1933. Levene, G., and Scheff, S.: Am. J. Digest. Dis. 2: 533, 1957. Vignes, H.: Progres med., p. 1924, Nov. 28, 1934.
6. Wissmer, B.: Praxis, Bern 46: 463, 1957. 7. Piccinelli, 0., and Timossi, G.: Minerva med. 49: 77, 1958. 8. Leavitt, J. M.: Scientific Exhibit, Meeting of the New York State Medical Society, May, 1958. 9. Tirsch, H. S., Seley, S. A., and Trachtman, B.: Scientific Exhibit, Meeting of the American Medical Association, June, 1959. 10. Rothburd, C. M.: Am. J. Gastroenterol. (To be published.)