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Amniotic fluid levels of uric acid and creatinine in toxemic patients—possible relation to diuretic use
Amniotic fluid levels of uric acid and creatinine in toxemic patientspossible relation to diuretic use CHARLES
JOHN
CAROL
G.
NORMAN Bufialo,
STULL, G.
New
McALL’ISTER+ M.Sc.
COUREY,
M.D.,
C.M.
York
Amniotic fluid uric acid and creatinine were measured in 35 pregnant women as close to term as clinical circumstances warranted, 10 pre-eclamptic patients, 9 control subjects with diuretic therapy, and 16 control subjects without diuretic therapy. Levels of both uric acid and creatinine were significantly higher in women of both groups who had ingested diuretics. The potential harmful effects of these elevated levels on the fetus should be considered. Therapy should be re-evaluated in this light, and the almost routine prescribing of thiazide diuretics should be reconsidered.
PRE-ECLAMPSIA is characterized by edema, hypertension, and proteinura. Maternal and fetal serum levels of uric acid and creatinine increase,l reflecting decreased glomerular filtration rates of these products,* at least in the mother. Thiazide diuretics are usually prescribed to reduce edema and lower blood pressure, but they inhibit even more the elimination of uric acid and creatinine, raising their levels in sex-urn3
The thiazides readily cross the placental barrier,3 and it is of great interest to evaluate their effects upon fetal disposition of uric acid and creatinine, as reflected by amniotic fluid levels of these metabolic byproducts. We studied a number of pre-eclamptic and nontoxemic patients, some of whom had received diuretics, in order to evaluate the effects of thiazides upon amniotic fluid levels of uric acid and creatinine. Material
for publication
Accepted 13, 1972.
for
publication
February
methods
Amniotic fluid samples were obtained from 35 pregnant women who varied in gravidity and parity. Ten women were classified as preeclamptic” and 25 were used as controls.+ Patients with chronic hypertensive and renal disease were not included in the study, and none of those included had convulsions. The pre-eclamptic women had all been on diu-
From the State University of New York at Buffalo, School of Medicine, Deaconess Hospital, Department of Gynecology and Obstetrics, Division of Perinatology. ;;;;‘ved
and
25,
October
Reprint requests: Dr. Norman Courey, Dept. of Gyn./Ob., Deaconess Hospital of Buffalo, 1001 Humboldt Pkwy., Buiqalo, New York 14208. *Summer Fellow in the Department of Gynecology and Obstetrics, Deaconess Hospital, Buffalo, New York.
*After the twenty-fourth week of pregnancy, patients were included who exhibited evidence of any two of the following: edema and excessive weight gain, hypertension, or pmteinuria. tAmniocentesis was performed for these reasons: poor obstetric history. vaginal bleeding, polyhydramniosis, suspected postmaturity, Rh negative blood, or bladder infection.
560
Uric
acid
and
creatinine
in toxemic
patients
561
1816 -
.
f
.
14 -
URIC
CREATININE
ACID
12 ae g
.. 3? P F .
.
IO864//
I
1
5-
.
4-
: hd. .
$3 if 2-
3‘a . .
I-
1
I
01
0 D CONTROL
PREECLAMPTIC
.
I
PREECLAMPTIC
1
D CONTROL
0
Fig. 1. Uric acid and creatinine levels in amniotic fluid. Pre-eclamptic women who had taken diuretics, were compared with control pregnant women who either had taken diuretics (-D) or had not (0). Individual values and group 95 per cent confidence intervals are shown.
Table I Length
of
treatment
No.
of patients
Regimen
Diuretic
(tueeks)
Pre-eclamptic 6
Hydrodiuril” Hydrodiuril (plus Apresolinef
2 1 1 Control
tCiba $Merck,
)
Diuril$ Diuril (plus Apresoline)
500 mg. every 24 hr. 500 mg. every 24 hr. 2 mg. three times daily
Hydrodiuril Diazide
25 mg. by mouth 50 mg. by mouth
6-11 8-10 12 9
(nontoxemic) 6 3
“Merck,
25-50 mg. every 24 hr. 50 mg. three times daily Z-10 mg. three times daily
Sharp Pharm. Sharp
& Dohme, Co.,
Summit,
Div.
Merck
New
& Co.,
Inc.,
West
Point,
every every
6-14 6-14
24 hr. 24 hr.
.__
Pennsylvania.
Jersey.
& Dohme.
Table II. Mean Group
values
and
95 per cent No.
confidence
of women
intervals
Uric
acid
(mg.
Pre-eclamptic
10
15.8
Control Diuretics (D) No diuretics (0)
9 16
11.6 + 0.5 7.5 f. 0.7
retie regimens for various times, as had 9 of the control subjects (Table I). The samples were collected as close to term as clinical circumstances warranted. In
+ 1.3
%)
1
Creatinine
(mg.
3.3
f. 0.5
2.75 2.0
-c 0.3 + 0.3
%)
.__
the pre-eclamptic group, one patient had amniocentesis 28 days before the delivery day; the other 9 women were sampled either at or within 6 days prior to delivery. Two of
562
McAllister,
Stull,
and
Fd~t-uary Am. J. Ohavt.
Courey
the control women underwent amniocentesis 21 and 13 days, respectively, prior to delivery; the other 23, either at or within 3 days of delivery. Samples were obtained by either standard transabdominal amniocentesis or sterile catch at the time of artificial rupture of the membranes. Uric acid levels were determined by using the carbonate modification of the Folin procedure4 on the Technicon AutoAnalyzer.* Creatinine levels were determined with an automated modification of the FolinWu procedure.4 The differences between groups were analyzed statistically. Results In Fig. 1 are plotted the individual values, the means, and 95 per cent confidence intervals determined by the Student t test for each group. The pre-eclamptic women had significantly higher amniotic fluid levels of uric acid and creatinine than did the control subjects who had not ingested diuretics. (Statistical significance at least at the 95 per cent level is indicated when the confidence intervals do not over lap.) The nontoxemic patients who had received diuretics exhitited statistically significantly higher levels of uric acid and creatinine than the nondiuretic group but still significantly lower uric acid levels than the pre-eclamptic patients. Table II enumerates the means and 95 per cent confidence intervals. Comment Amniotic fluid uric acid and creatinine levels were significantly elevated in the toxemic women who had received diuretic therapy, as compared with nontoxemic patients. Since thiazide diuretics seemed to elevate amniotic fluid levels of uric acid and creatinine in nontoxemic control patients, it was “Technicon
Corp.,
Tarryton
n, New
York.
19, 1973 Cynrrol.
reasonable to assume that they also raised levels in pre-eclamptic women, The mechanism may have been through the inhibition of maternal urinary clearance and increase in already high placentally transferable serum concentrations. The diuretics may also ha\e inhibited fetal tubular secretion, thereby raising even further the fetal serum uric acid levels, which have been shown to be elevated at term in pre-eclamptic patients.5 The mean creatinine levels in our control groups were higher than others have found,6 but these may represent a larger number of postmature infants with consequently longer gestation periods. However, the statistically significant higher mean value of 3.3 mg. per cent for the toxemic group could not be accounted for by increased fetal muscle mass alone. It was a probable reflection of changes in chorioamnion diffusion characteristics’ and in maternal and fetal urinary functions, the fetus perhaps serving as a physiologic clearing mechanism for maternal creatinine. Conclusion Toxemia of pregnancy should be viewed as a condition which involves the entire fetomaternal unit rather than a maternal disorder whose facets are reflected in the fetal environment. The severity of toxemia may possibly be assessed by measurement of amniotic fluid creatinine levels. However, ‘the probable contributory effects of thiazide therapy toward raised levels should be considered in any evaluation of toxemia on fetal maturity. Therapy should be re-evaluated in this light, and the almost rote prescribing of thiazide diuretics should be reconsidered. Diuretics elevated already raised maternal serum uric acid and creatinine levels and may have the same effect in the fetus. The potential harmful effects of these elevated levels on the fetus should be considered, especially if thiazide therapy is prolonged.
REFERENCES
1.
Monkus, E., Nyham, W., kow, S.: AM. J. OBSTET. 1970.
Fogel, GYNECOL.
B., and Yan108: 91,
2. 3.
Hayashi, T.: AM. J. OBSTET. 859, 1956. Goodman, L., and Gilman,
GYNECOL.
A.:
The
71: Phar-
Volume Number
4.
5.
115 4
macological Basis of Therapeutics, New York, 1970, The Macmillan Company. Oser, B. L.: Hawk’s Physiological Chemistry, ed. 14, New York, 1965, Blakiston Division, McGraw-Hill Book Cmpany, Inc. Garnet, J. 0.: Obstet. Gynecol. 21: 123, 1963.
Uric
6. 7.
acid
and
creatinine
in toxemic
patients
563
Doran, T. A., Bjerre, S., and Porter, C.: AM. J. OBSTET. GYNECOL. 106: 325, 1970. McGaughey, H., Corey, E. L., Scoggin, W. A., Conway, H., and Thornton, N.: AM. J. OBSTET. GYNECOL. 80: 108, 1960.
JOHN
CAROL
G.
NORMAN Bufialo,
STULL, G.
New
McALL’ISTER+ M.Sc.
COUREY,
M.D.,
C.M.
York
Amniotic fluid uric acid and creatinine were measured in 35 pregnant women as close to term as clinical circumstances warranted, 10 pre-eclamptic patients, 9 control subjects with diuretic therapy, and 16 control subjects without diuretic therapy. Levels of both uric acid and creatinine were significantly higher in women of both groups who had ingested diuretics. The potential harmful effects of these elevated levels on the fetus should be considered. Therapy should be re-evaluated in this light, and the almost routine prescribing of thiazide diuretics should be reconsidered.
PRE-ECLAMPSIA is characterized by edema, hypertension, and proteinura. Maternal and fetal serum levels of uric acid and creatinine increase,l reflecting decreased glomerular filtration rates of these products,* at least in the mother. Thiazide diuretics are usually prescribed to reduce edema and lower blood pressure, but they inhibit even more the elimination of uric acid and creatinine, raising their levels in sex-urn3
The thiazides readily cross the placental barrier,3 and it is of great interest to evaluate their effects upon fetal disposition of uric acid and creatinine, as reflected by amniotic fluid levels of these metabolic byproducts. We studied a number of pre-eclamptic and nontoxemic patients, some of whom had received diuretics, in order to evaluate the effects of thiazides upon amniotic fluid levels of uric acid and creatinine. Material
for publication
Accepted 13, 1972.
for
publication
February
methods
Amniotic fluid samples were obtained from 35 pregnant women who varied in gravidity and parity. Ten women were classified as preeclamptic” and 25 were used as controls.+ Patients with chronic hypertensive and renal disease were not included in the study, and none of those included had convulsions. The pre-eclamptic women had all been on diu-
From the State University of New York at Buffalo, School of Medicine, Deaconess Hospital, Department of Gynecology and Obstetrics, Division of Perinatology. ;;;;‘ved
and
25,
October
Reprint requests: Dr. Norman Courey, Dept. of Gyn./Ob., Deaconess Hospital of Buffalo, 1001 Humboldt Pkwy., Buiqalo, New York 14208. *Summer Fellow in the Department of Gynecology and Obstetrics, Deaconess Hospital, Buffalo, New York.
*After the twenty-fourth week of pregnancy, patients were included who exhibited evidence of any two of the following: edema and excessive weight gain, hypertension, or pmteinuria. tAmniocentesis was performed for these reasons: poor obstetric history. vaginal bleeding, polyhydramniosis, suspected postmaturity, Rh negative blood, or bladder infection.
560
Uric
acid
and
creatinine
in toxemic
patients
561
1816 -
.
f
.
14 -
URIC
CREATININE
ACID
12 ae g
.. 3? P F .
.
IO864//
I
1
5-
.
4-
: hd. .
$3 if 2-
3‘a . .
I-
1
I
01
0 D CONTROL
PREECLAMPTIC
.
I
PREECLAMPTIC
1
D CONTROL
0
Fig. 1. Uric acid and creatinine levels in amniotic fluid. Pre-eclamptic women who had taken diuretics, were compared with control pregnant women who either had taken diuretics (-D) or had not (0). Individual values and group 95 per cent confidence intervals are shown.
Table I Length
of
treatment
No.
of patients
Regimen
Diuretic
(tueeks)
Pre-eclamptic 6
Hydrodiuril” Hydrodiuril (plus Apresolinef
2 1 1 Control
tCiba $Merck,
)
Diuril$ Diuril (plus Apresoline)
500 mg. every 24 hr. 500 mg. every 24 hr. 2 mg. three times daily
Hydrodiuril Diazide
25 mg. by mouth 50 mg. by mouth
6-11 8-10 12 9
(nontoxemic) 6 3
“Merck,
25-50 mg. every 24 hr. 50 mg. three times daily Z-10 mg. three times daily
Sharp Pharm. Sharp
& Dohme, Co.,
Summit,
Div.
Merck
New
& Co.,
Inc.,
West
Point,
every every
6-14 6-14
24 hr. 24 hr.
.__
Pennsylvania.
Jersey.
& Dohme.
Table II. Mean Group
values
and
95 per cent No.
confidence
of women
intervals
Uric
acid
(mg.
Pre-eclamptic
10
15.8
Control Diuretics (D) No diuretics (0)
9 16
11.6 + 0.5 7.5 f. 0.7
retie regimens for various times, as had 9 of the control subjects (Table I). The samples were collected as close to term as clinical circumstances warranted. In
+ 1.3
%)
1
Creatinine
(mg.
3.3
f. 0.5
2.75 2.0
-c 0.3 + 0.3
%)
.__
the pre-eclamptic group, one patient had amniocentesis 28 days before the delivery day; the other 9 women were sampled either at or within 6 days prior to delivery. Two of
562
McAllister,
Stull,
and
Fd~t-uary Am. J. Ohavt.
Courey
the control women underwent amniocentesis 21 and 13 days, respectively, prior to delivery; the other 23, either at or within 3 days of delivery. Samples were obtained by either standard transabdominal amniocentesis or sterile catch at the time of artificial rupture of the membranes. Uric acid levels were determined by using the carbonate modification of the Folin procedure4 on the Technicon AutoAnalyzer.* Creatinine levels were determined with an automated modification of the FolinWu procedure.4 The differences between groups were analyzed statistically. Results In Fig. 1 are plotted the individual values, the means, and 95 per cent confidence intervals determined by the Student t test for each group. The pre-eclamptic women had significantly higher amniotic fluid levels of uric acid and creatinine than did the control subjects who had not ingested diuretics. (Statistical significance at least at the 95 per cent level is indicated when the confidence intervals do not over lap.) The nontoxemic patients who had received diuretics exhitited statistically significantly higher levels of uric acid and creatinine than the nondiuretic group but still significantly lower uric acid levels than the pre-eclamptic patients. Table II enumerates the means and 95 per cent confidence intervals. Comment Amniotic fluid uric acid and creatinine levels were significantly elevated in the toxemic women who had received diuretic therapy, as compared with nontoxemic patients. Since thiazide diuretics seemed to elevate amniotic fluid levels of uric acid and creatinine in nontoxemic control patients, it was “Technicon
Corp.,
Tarryton
n, New
York.
19, 1973 Cynrrol.
reasonable to assume that they also raised levels in pre-eclamptic women, The mechanism may have been through the inhibition of maternal urinary clearance and increase in already high placentally transferable serum concentrations. The diuretics may also ha\e inhibited fetal tubular secretion, thereby raising even further the fetal serum uric acid levels, which have been shown to be elevated at term in pre-eclamptic patients.5 The mean creatinine levels in our control groups were higher than others have found,6 but these may represent a larger number of postmature infants with consequently longer gestation periods. However, the statistically significant higher mean value of 3.3 mg. per cent for the toxemic group could not be accounted for by increased fetal muscle mass alone. It was a probable reflection of changes in chorioamnion diffusion characteristics’ and in maternal and fetal urinary functions, the fetus perhaps serving as a physiologic clearing mechanism for maternal creatinine. Conclusion Toxemia of pregnancy should be viewed as a condition which involves the entire fetomaternal unit rather than a maternal disorder whose facets are reflected in the fetal environment. The severity of toxemia may possibly be assessed by measurement of amniotic fluid creatinine levels. However, ‘the probable contributory effects of thiazide therapy toward raised levels should be considered in any evaluation of toxemia on fetal maturity. Therapy should be re-evaluated in this light, and the almost rote prescribing of thiazide diuretics should be reconsidered. Diuretics elevated already raised maternal serum uric acid and creatinine levels and may have the same effect in the fetus. The potential harmful effects of these elevated levels on the fetus should be considered, especially if thiazide therapy is prolonged.
REFERENCES
1.
Monkus, E., Nyham, W., kow, S.: AM. J. OBSTET. 1970.
Fogel, GYNECOL.
B., and Yan108: 91,
2. 3.
Hayashi, T.: AM. J. OBSTET. 859, 1956. Goodman, L., and Gilman,
GYNECOL.
A.:
The
71: Phar-
Volume Number
4.
5.
115 4
macological Basis of Therapeutics, New York, 1970, The Macmillan Company. Oser, B. L.: Hawk’s Physiological Chemistry, ed. 14, New York, 1965, Blakiston Division, McGraw-Hill Book Cmpany, Inc. Garnet, J. 0.: Obstet. Gynecol. 21: 123, 1963.
Uric
6. 7.
acid
and
creatinine
in toxemic
patients
563
Doran, T. A., Bjerre, S., and Porter, C.: AM. J. OBSTET. GYNECOL. 106: 325, 1970. McGaughey, H., Corey, E. L., Scoggin, W. A., Conway, H., and Thornton, N.: AM. J. OBSTET. GYNECOL. 80: 108, 1960.