British Journal of Obstetrics and Gynaecology
March 1975 Vol. 82 pp. 221-224
EFFECT OF FRUSEMIDE ON FETAL URINE PRODUCTION BY
J. W. WLADIMIROFF Department of Obstetrics and Gynaecology Academic Hospital, Rotterdam-Dijkzigt, The Netherlands Summary Hourly fetal urinary production rate (HFUPR) was measured by an ultrasonic technique in I2 antenatal patients before and after intravenous administration of 60 mg. of frusemide. In 8 patients pregnancy was normal and in 4 there was clinical evidence of fetal growth retardation. The duration of pregnancy varied from 32 to 41 weeks. The increase in HFUPR was 80 to 150 per cent in normal patients and 95 to 131 per cent in patients with fetal growth retardation. The increase in HFUPR seemed to have no impact on fetal circulatory volume, as the fetal heart rate stayed normal throughout the study period.
can be demonstrated on an ultrasonic B mode display. It can be observed to fill and empty at regular intervals (Campbell, 1972). Measurement of the HFUPR involves measuring the fetal bladder in three dimensions and calculating the volume by means of a formula (Campbell et al., 1973). The increase in bladder volume over a known period during the process of bladder filling will give the HFUPR. In our study, bladder scanning was performed at different times of the day, as Wladimiroff and Campbell (1974) found no diurnal variation in HFUPR. In the present study, the following procedure was carried out on each patient: 1. Measurement of the HFUPR before frusemide administration. 2. Intravenous administration of 60 mg. of frusemide into a maternal antecubital vein immediately after the fetal bladder had emptied. 3. Repeated measurements of fetal bladder volume during the filling phase after frusemide administration. These measurements were done at five minute intervals in order to ascertain the onset of any change in HFUPR due to frusemide. 4. Measurement of the amount of urine passed by each patient over a period of 90 minutes following frusemide administration.
et al. (1973) recently developed an CAMPBELL ultrasonic technique of measuring hourly fetal urine production rates (HFUPR) in the human fetus. We were interested to know whether frusemide when given intravenously to the pregnant patient, would also have a diuretic effect on the fetus.
METHODS A total of 12 primigravidae between 32 and 41 weeks of pregnancy was screened (Table I). Each patient was certain of her last menstrual period. In 8 patients pregnancy was uncomplicated and in 4 there was clinical evidence of fetal growth retardation. In the latter group one patient had a slightly raised blood pressure (145190 mm. Hg). None of the patients had oedema. There was no evidence of impaired maternal renal function. The blood creatinine (72 to 108 pmol./l.) and blood uric acid levels (0 * 13 to 0 -36 mmol./l.) were within normal limits and there was no proteinuria. In the 8 uncomplicated cases, the birth weights were above the 10th centile; in the 4 complicated cases they were twice between the 5th and 10th centile and twice below the 5th centile according to the tables of Thomson et al. (1968), corrections being made for fetal sex. The fetal bladder 22 1
39 39
37 39
9 10
11 12
6 7 8
5
32 32 33 34 36 37 38 40
(weeks)
Maturity
1 2 3 4
Patient No.
*Time interval A-B ?Time interval B-C
130/80 145/90
130/75 125/80
18.0 19.0
11.0 15.0
110/70 120/75 120/70 125/80 125/80 120/80 120/75 115/75
Blood pressure (rnrn. Hg)
12.5 12.0 11.0 15.0 20.0 20.0 20.0 25.0
HFUPR (ml.)
= =
60 75
50 50
55
55
50 65 55 45 60 50
111 131 95 120
21.5 33.0
100
150
92 133 82 140 80 140
increase (per cent)
38.0 44.0
24.0 28.0 20.0 36.0 36.0 48.0 50.0 50.0
Actual rate (ml.)
-
Maximal HFUPR
11 .O 14.0
16.0 19.0
12.0 11.0 11.0 16.0 20.0 18.5 21.0 23.0
Final HFUPR (rnl.)
130/85-130/80 145/90-130/85
130/70-120/70 130/80-115/75
115/75-110/65 120/80-115/80 130/80-115/70 1 15/80 125/80-115/75 120/80 120/80-110/70 120/75-110/70
Blood pressure range (rnrn. Hg)
AFTER FRUSEMIDE ADMINISTRATION
delay between moment of rusernide administration and initial rise in HFUPR. duration of diuretic action of frusernide on the fetal kidneys.
30 30
25 25
144-154 138-146 120-128 132-140
40 35 30 30 25 15 15 15
A-B* B-Ct
Time interval (minutes)
140-148 128-132 140-150 136-144 150-156 134142 140-145 140-150
Fetal heart rate range (beats per minute)
BEFORE FRUSEMIDE ADMINISTRATION
~-
120-132 136-148
140-154 136-146
134-146 132-140 140-150 140-148 136-148 130-146 140-150 140-150
Fetal heart rate range per (per minute)
~
~~~
10 > 10 > 10 > 10 > 10 > 10 > 10
Rirthweight centile (Thornson er al., 1968)
TABLEI Fetal urinary output, maternal arterial blood pressure and fetal heart rate bejore and ajier intravenous frusemide administration in I 2 antenatal patients between 32 and 41 weeks' gestation
3
FRUSEMIDE AND FETAL URINE
I
I
30
31
I
32
I
I
I
I
I
I
33
34
35
36
37
38
I
39
223
I
40
gestation i n weeks
FIG.1 Relation of the HFUPR estimations to the normal range (according to the data of Wladimiroff and Campbell, 1974) before frusemide administration.
5. Measurement of maternal arterial blood pressure in the supine position, once before and every 10 minutes after frusemide administration. 6. Monitoring the fetal heart rate (FHR) by means of Doppler ultrasound before and after frusemide administration. RESULTS Before frusemide administration, HFUPR values ranged from 1 1 to 20 ml. Figure 1 shows the relation of the HFUPR estimations to the normal range according to the data of Wladimiroff and Campbell (1974). In the 8 normal pregnancies HFUPR was within the normal range; in the 4 complicated pregnancies HFUPR was below the normal range. Intravenous administration of 60 mg. of frusemide to the mother caused anincreaseinfetalurineproduction
in all cases. Full details are given in Table I. Normal pregnancies (patients 1 to 8) There was a delay between the moment of frusemide administration and the initial rise in HFUPR which ranged from 40 minutes at 32 weeks to 15 minutes at 40 weeks gestation (time interval A to B, Table I). The percentage increase in HFUPR ranged from 80 to 150 per cent. No relation to gestational age could be shown. In all 8 patients HFUPR values finally returned to the original levels, as shown in Table I. No further decrease in HFUPR was observed. The total duration of diuretic action of frusemide on the fetal kidneys, (defined as the time between initial rise and final decrease of the HFUPR to original levels), ranged from 45 to 65 minutes (time interval B to C , Table I).
224
WLADIMIROFF
Complicated pregnancies (patients 9 to 12) In the 4 complicated pregnancies the interval between the moment of frusemide administration and the initial rise in HFUPR ranged from 25 to 30 minutes. The percentage increase in HFUPR ranged from 92 to 130 per cent. In all 4 patients, HFUPR finally returned to the original levels and no further decrease in HFUPR was observed. The total duration of the diuretic action of frusemide on the fetal kidneys ranged from 50 to 75 minutes. Maternal urinary output varied from 850 to 1300 ml. No significant changes in maternal arterial blood pressure and fetal heart rate after frusemide administration were observed in any of the 12 patients. DISCUSSION Frusemide is a benzothiazide derivate which in the adult inhibits sodium reabsorption in the ascending limb of Henle’s loop and in the proximal tubules (Stason et al., 1966). Frusemide crosses the placental barrier (Pecorari et al., 1969). The raised HFUPR estimations after intravenous administration of frusemide t o the mother is the first direct proof of the presence of fetal tubular reabsorption of water and electrolytes during the last eight weeks of gestation. In normal adults (Stason et al., 1966) the delay between the moment of intravenous frusemide administration and the onset of its diuretic action is about five minutes. In our fetal studies the delay was longer. It varied from 40 minutes at 32 weeks to 15 minutes at 40 weeks gestation. This could be explained by the fact that the placental passage for frusemide becomes easier as pregnancy advances. The increased delay (25 to 30 minutes) in the 4 patients with clinical evidence of fetal growth-retardation when compared with the 3 normal patients (15 minutes, no. 6 t o 8) in the last four weeks of pregnaiicy could have been caused by a hampered
placental passage due to placental insufficiency. The duration of frusemide activity in the normal and growth-retarded fetuses did not apparently differ. The percentage increase in fetal urinary output following the intravenous administration of 60 mg. frusemide varied considerably. Stason et al. (1966) who made similar observations on normal adults, stated that the variation in urinary output was a direct result of individuality in the response of tubules to frusemide. Whether the same applies to fetal tubules is uncertain as the amount of frusemide ultimately reaching the fetal kidneys was unknown. However, as the percentage increases in HFUPR in the normal patients and those with a growth-retarded fetus was similar, it is possible that fetal tubular function is essentially the same in these two groups. This would support the theory that the reduced HFUPR in growth-retarded fetuses is due to fetal renal hypoplasia (Wladimiroff and Campbell, 1974), rather than increased fetal tubular action as found in sheep (Greshani er al., 1972). Finally, the increase in HFUPR after frusemide apparently had no gross impact on fetal circulatory volume, as the fetal heart rate stayed normal throughout the study period. REFERENCES Campbell, S. (1972): British Journal of Hospital Medicine, 8, 541. Campbell, S., Wladimiroff, J. W., and Dewhurst, C. J. (1973): Journal of Obstetrics and Gynaecology of the British Commonwealth, 80, 680. Gresham, D. L., Rankin, J. H. G . , Makowski, E. L., Meschia, G., and Battaglia, S. C. (1972): Journal of Clinical Investigation, 51, 149. Pecorari, D., Ragni, N., and Autera, C. (1969): Ateneo parmense, 40, 2. Stason, W. B., Cannon, P. J., Heinemann, H. O., and Laragh, J. H. (1966): Circulation, 34, 910. Thomson, A, M., Billewicz, W. Z., and Hytten, F. E. (1 968) : Journal of Obstetrics and Gynaecology of the British Commonwealth, 75, 903. Wladimiroff, J. W., and Campbell, S. (1974): Lancet, 1, 151.
March 1975 Vol. 82 pp. 221-224
EFFECT OF FRUSEMIDE ON FETAL URINE PRODUCTION BY
J. W. WLADIMIROFF Department of Obstetrics and Gynaecology Academic Hospital, Rotterdam-Dijkzigt, The Netherlands Summary Hourly fetal urinary production rate (HFUPR) was measured by an ultrasonic technique in I2 antenatal patients before and after intravenous administration of 60 mg. of frusemide. In 8 patients pregnancy was normal and in 4 there was clinical evidence of fetal growth retardation. The duration of pregnancy varied from 32 to 41 weeks. The increase in HFUPR was 80 to 150 per cent in normal patients and 95 to 131 per cent in patients with fetal growth retardation. The increase in HFUPR seemed to have no impact on fetal circulatory volume, as the fetal heart rate stayed normal throughout the study period.
can be demonstrated on an ultrasonic B mode display. It can be observed to fill and empty at regular intervals (Campbell, 1972). Measurement of the HFUPR involves measuring the fetal bladder in three dimensions and calculating the volume by means of a formula (Campbell et al., 1973). The increase in bladder volume over a known period during the process of bladder filling will give the HFUPR. In our study, bladder scanning was performed at different times of the day, as Wladimiroff and Campbell (1974) found no diurnal variation in HFUPR. In the present study, the following procedure was carried out on each patient: 1. Measurement of the HFUPR before frusemide administration. 2. Intravenous administration of 60 mg. of frusemide into a maternal antecubital vein immediately after the fetal bladder had emptied. 3. Repeated measurements of fetal bladder volume during the filling phase after frusemide administration. These measurements were done at five minute intervals in order to ascertain the onset of any change in HFUPR due to frusemide. 4. Measurement of the amount of urine passed by each patient over a period of 90 minutes following frusemide administration.
et al. (1973) recently developed an CAMPBELL ultrasonic technique of measuring hourly fetal urine production rates (HFUPR) in the human fetus. We were interested to know whether frusemide when given intravenously to the pregnant patient, would also have a diuretic effect on the fetus.
METHODS A total of 12 primigravidae between 32 and 41 weeks of pregnancy was screened (Table I). Each patient was certain of her last menstrual period. In 8 patients pregnancy was uncomplicated and in 4 there was clinical evidence of fetal growth retardation. In the latter group one patient had a slightly raised blood pressure (145190 mm. Hg). None of the patients had oedema. There was no evidence of impaired maternal renal function. The blood creatinine (72 to 108 pmol./l.) and blood uric acid levels (0 * 13 to 0 -36 mmol./l.) were within normal limits and there was no proteinuria. In the 8 uncomplicated cases, the birth weights were above the 10th centile; in the 4 complicated cases they were twice between the 5th and 10th centile and twice below the 5th centile according to the tables of Thomson et al. (1968), corrections being made for fetal sex. The fetal bladder 22 1
39 39
37 39
9 10
11 12
6 7 8
5
32 32 33 34 36 37 38 40
(weeks)
Maturity
1 2 3 4
Patient No.
*Time interval A-B ?Time interval B-C
130/80 145/90
130/75 125/80
18.0 19.0
11.0 15.0
110/70 120/75 120/70 125/80 125/80 120/80 120/75 115/75
Blood pressure (rnrn. Hg)
12.5 12.0 11.0 15.0 20.0 20.0 20.0 25.0
HFUPR (ml.)
= =
60 75
50 50
55
55
50 65 55 45 60 50
111 131 95 120
21.5 33.0
100
150
92 133 82 140 80 140
increase (per cent)
38.0 44.0
24.0 28.0 20.0 36.0 36.0 48.0 50.0 50.0
Actual rate (ml.)
-
Maximal HFUPR
11 .O 14.0
16.0 19.0
12.0 11.0 11.0 16.0 20.0 18.5 21.0 23.0
Final HFUPR (rnl.)
130/85-130/80 145/90-130/85
130/70-120/70 130/80-115/75
115/75-110/65 120/80-115/80 130/80-115/70 1 15/80 125/80-115/75 120/80 120/80-110/70 120/75-110/70
Blood pressure range (rnrn. Hg)
AFTER FRUSEMIDE ADMINISTRATION
delay between moment of rusernide administration and initial rise in HFUPR. duration of diuretic action of frusernide on the fetal kidneys.
30 30
25 25
144-154 138-146 120-128 132-140
40 35 30 30 25 15 15 15
A-B* B-Ct
Time interval (minutes)
140-148 128-132 140-150 136-144 150-156 134142 140-145 140-150
Fetal heart rate range (beats per minute)
BEFORE FRUSEMIDE ADMINISTRATION
~-
120-132 136-148
140-154 136-146
134-146 132-140 140-150 140-148 136-148 130-146 140-150 140-150
Fetal heart rate range per (per minute)
~
~~~
10 > 10 > 10 > 10 > 10 > 10 > 10
Rirthweight centile (Thornson er al., 1968)
TABLEI Fetal urinary output, maternal arterial blood pressure and fetal heart rate bejore and ajier intravenous frusemide administration in I 2 antenatal patients between 32 and 41 weeks' gestation
3
FRUSEMIDE AND FETAL URINE
I
I
30
31
I
32
I
I
I
I
I
I
33
34
35
36
37
38
I
39
223
I
40
gestation i n weeks
FIG.1 Relation of the HFUPR estimations to the normal range (according to the data of Wladimiroff and Campbell, 1974) before frusemide administration.
5. Measurement of maternal arterial blood pressure in the supine position, once before and every 10 minutes after frusemide administration. 6. Monitoring the fetal heart rate (FHR) by means of Doppler ultrasound before and after frusemide administration. RESULTS Before frusemide administration, HFUPR values ranged from 1 1 to 20 ml. Figure 1 shows the relation of the HFUPR estimations to the normal range according to the data of Wladimiroff and Campbell (1974). In the 8 normal pregnancies HFUPR was within the normal range; in the 4 complicated pregnancies HFUPR was below the normal range. Intravenous administration of 60 mg. of frusemide to the mother caused anincreaseinfetalurineproduction
in all cases. Full details are given in Table I. Normal pregnancies (patients 1 to 8) There was a delay between the moment of frusemide administration and the initial rise in HFUPR which ranged from 40 minutes at 32 weeks to 15 minutes at 40 weeks gestation (time interval A to B, Table I). The percentage increase in HFUPR ranged from 80 to 150 per cent. No relation to gestational age could be shown. In all 8 patients HFUPR values finally returned to the original levels, as shown in Table I. No further decrease in HFUPR was observed. The total duration of diuretic action of frusemide on the fetal kidneys, (defined as the time between initial rise and final decrease of the HFUPR to original levels), ranged from 45 to 65 minutes (time interval B to C , Table I).
224
WLADIMIROFF
Complicated pregnancies (patients 9 to 12) In the 4 complicated pregnancies the interval between the moment of frusemide administration and the initial rise in HFUPR ranged from 25 to 30 minutes. The percentage increase in HFUPR ranged from 92 to 130 per cent. In all 4 patients, HFUPR finally returned to the original levels and no further decrease in HFUPR was observed. The total duration of the diuretic action of frusemide on the fetal kidneys ranged from 50 to 75 minutes. Maternal urinary output varied from 850 to 1300 ml. No significant changes in maternal arterial blood pressure and fetal heart rate after frusemide administration were observed in any of the 12 patients. DISCUSSION Frusemide is a benzothiazide derivate which in the adult inhibits sodium reabsorption in the ascending limb of Henle’s loop and in the proximal tubules (Stason et al., 1966). Frusemide crosses the placental barrier (Pecorari et al., 1969). The raised HFUPR estimations after intravenous administration of frusemide t o the mother is the first direct proof of the presence of fetal tubular reabsorption of water and electrolytes during the last eight weeks of gestation. In normal adults (Stason et al., 1966) the delay between the moment of intravenous frusemide administration and the onset of its diuretic action is about five minutes. In our fetal studies the delay was longer. It varied from 40 minutes at 32 weeks to 15 minutes at 40 weeks gestation. This could be explained by the fact that the placental passage for frusemide becomes easier as pregnancy advances. The increased delay (25 to 30 minutes) in the 4 patients with clinical evidence of fetal growth-retardation when compared with the 3 normal patients (15 minutes, no. 6 t o 8) in the last four weeks of pregnaiicy could have been caused by a hampered
placental passage due to placental insufficiency. The duration of frusemide activity in the normal and growth-retarded fetuses did not apparently differ. The percentage increase in fetal urinary output following the intravenous administration of 60 mg. frusemide varied considerably. Stason et al. (1966) who made similar observations on normal adults, stated that the variation in urinary output was a direct result of individuality in the response of tubules to frusemide. Whether the same applies to fetal tubules is uncertain as the amount of frusemide ultimately reaching the fetal kidneys was unknown. However, as the percentage increases in HFUPR in the normal patients and those with a growth-retarded fetus was similar, it is possible that fetal tubular function is essentially the same in these two groups. This would support the theory that the reduced HFUPR in growth-retarded fetuses is due to fetal renal hypoplasia (Wladimiroff and Campbell, 1974), rather than increased fetal tubular action as found in sheep (Greshani er al., 1972). Finally, the increase in HFUPR after frusemide apparently had no gross impact on fetal circulatory volume, as the fetal heart rate stayed normal throughout the study period. REFERENCES Campbell, S. (1972): British Journal of Hospital Medicine, 8, 541. Campbell, S., Wladimiroff, J. W., and Dewhurst, C. J. (1973): Journal of Obstetrics and Gynaecology of the British Commonwealth, 80, 680. Gresham, D. L., Rankin, J. H. G . , Makowski, E. L., Meschia, G., and Battaglia, S. C. (1972): Journal of Clinical Investigation, 51, 149. Pecorari, D., Ragni, N., and Autera, C. (1969): Ateneo parmense, 40, 2. Stason, W. B., Cannon, P. J., Heinemann, H. O., and Laragh, J. H. (1966): Circulation, 34, 910. Thomson, A, M., Billewicz, W. Z., and Hytten, F. E. (1 968) : Journal of Obstetrics and Gynaecology of the British Commonwealth, 75, 903. Wladimiroff, J. W., and Campbell, S. (1974): Lancet, 1, 151.
