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Change in fetal urine production rate in growth-restricted fetuses after maternal meal ingestion
Change in Fetal Urine Production Rate in Growth-Restricted Fetuses After Maternal Meal Ingestion ICHIRO YASUHI, MD, MASANAO TOORU YAMABE, MD, PhD
HIRAI, MD, TADAYUKI
Objective: To determine if fetal urine production is affected by maternal meal ingestion in growth-restricted fetuses. Metkods: We studied 25 normal-growth fetuses in uncomplicated pregnancies and 15 growth-restricted fetuses, all after 30 weeks’ gestation. Serial fetal bladder volume measurements were obtained at 2-3 minute intervals with ultrasonography 2 hours before and 2 hours after maternal breakfast. The hourly fetal urine production rate in each maternal state was calculated from the bladder volume measurements. The amniotic fluid index (AFI) and the pulsatility index of both umbilical and fetal middle cerebral arteries were also measured. Results: Two of the 15 growth-restricted fetuses were excluded from analysis, one because it was anomalous and the other because it was not small for gestational age at birth. In the normal-growth fetuses, the hourly fetal urine production rate increased significantly after maternal breakfast (mean f standard deviation 30.2 f 11.7 versus 41.1 f 14.6 ml/hour, P < .OOl). In contrast, in the growth-restricted fetuses, the rate did not change after maternal breakfast (24.6 f 6.2 versus 24.9 f 5.7 ml/hour). Although the urine production rate before breakfast did not differ between groups, 2 hours after maternal breakfast it was significantly lower in the growth-restricted fetuses than in the control group (normal-growth) (P < .OOl).The AFI also was significantly lower in the growth-restricted fetuses than in the control group (15.0 f 3.5 versus 18.6 f 5.0 cm, P c .04). There were no significant differences in the pulsed Doppler studies. Conclusion: In contrast to normal-growth fetuses, maternal meal ingestion for growth-restricted fetuses does not increase fetal urine production. Decreased fetal urine production in the maternal fed state may lead to decreased amniotic fluid volume in growth-restricted fetuses without obvious hypoxia. (Obstet Gynecol1996;88:833-7)
From the Department of Obstetrics versity School of Medicine, Nagasaki,
VOL.
88, NO.
5, NOVEMBER
1996
and Gynecology, Japan.
Nagasaki
Uni-
ISHIMARU,
MD, PhD, AND
Oligohydramnios is often seen in growth-restricted fetuses and is strongly associated with increased perinatal mortality and morbidity.ld3 The major source of amniotic fluid (AF) during late pregnancy is fetal urine. Using ultrasonography, many authors have observed decreasedfetal urine production in small for gestational age (SGA) fetuses by serial measurements of fetal bladder volume. 4-7 Fetal oliguria in response to hypoxia is considered a main causeof oligohydramnios in SGA fetuses.“7’8However, some authors have reported that decreasedfetal urine production is not significantly correlated with a poor perinatal outcome.4 Previously, we reported that, in appropriate for gestational age (AGA) fetuses, maternal meal ingestion affected fetal urine production and resuIted in greater urine production when compared with the maternal fasting state.’ We postulated that maternal volume expansion after breakfast improved uteroplacental microcirculation, which resulted in incre&ed fluid transfer to the fetus, causing greater fetal urine production compared with that during the maternal fasting state. Because the malnutrition type of fetal growth restriction (FGR) results from chronically impaired placental transfer of nutrients from mother to fetus, maternal volume expansion by meal ingestion may not increase fetal urine production in growth-restricted fetuses. To examine this hypothesis, we investigated whether the postprandial increase of the hourly fetal urine production rate observed in AGA fetuses occurs in a similar manner in SGA fetuses.
Materials and Methods Fifteen pregnancies with suspected FGR by antenatal ultrasound screening at Nagasaki University Hospital after 30 weeks’ gestation were included in this study (SGA group). This sample size was calculated from the
0029-7844/96/$15.00 PI1 SOO29-7844(96)00274-S
833
data in our previous study,’ with (Y = .05, /3 = .20, and an effect size of 30% increase in the hourly fetal urine production rate. Twenty-five pregnancies with normalgrowth fetuses also were studied after 30 weeks’ gestation as a control group (AGA group). All pregnancies were singleton, and gestational ages were confirmed by ultrasonography before 20 weeks’ gestation. We followed all pregnancies to delivery. Infants weighing less than -1.5 or more than +1.5 standard deviations (SD) of the mean Japanese standard curve at birthlo were defined as SGA or large for gestational age, respectively. Pregnancies in which the birth weight was not SGA were excluded from the SGA group, and those in which the birth weight was not AGA were excluded from the control group. Fetuses with congenital malformations also were excluded from the study. All women with a 50-g glucose challenge test were screened at approximately 28 weeks’ gestation. Women with plasma glucose level at least 130 mg/dL on the l-hour challenge were given a 75-g glucose tolerance test. Women with glucose intolerance during pregnancy were excluded from the study, because increased fetal urine production rate during maternal fasting state has been demonstrated in diabetic pregnancy.’ We confirmed that none of the women in either the study or control group had taken any anti-inflammatory medication, such as aspirin, indomethacin, etc, during pregnancy, because use of these drugs has been associated with decreased fetal urine production.” The study protocol was the same as in our previous report.’ After overnight fasting, the study commenced at 6:00 AM and continued for 2 hours (the fasting state). Then each subject had a 600-kcal standard breakfast, including approximately 450 g of water component without any diuretic beverage. The second phase of the study took place 2 hours after breakfast (the postprandial state). No medication was given during the study. In each phase, the women were placed in the semirecumbent position, and serial fetal bladder volume measurements were obtained using ultrasonography (3.5MHz transducer, RT-8000; G.E. Yokogawa Medical Systems, Tokyo, Japan). At least one complete filling cycle was observed in each maternal state. The fetal bladder volume was calculated from the largest longitudinal, transverse, and anteroposterior bladder dimensions,l’ which were imaged serially at 2-3 minute intervals. The hourly fetal urine production rate was calculated by linear regression analysis,13 and the greatest hourly fetal urine production rate in all complete cycles observed in each state was selected for analysis. Using the same definition as in our previous study,’ the filling time of the cycle and the maximum bladder volume also were analyzed. The biparietal diameter (BPD) and the abdominal
834
Yasuhi et al
Urine Production in SGA Fetuses
Table 1. Fetal and Maternal Characteristics AGA (n = 25) Gestational age Fetal biparietal Fetal abdominal Amniotic fluid Plasma glucose Pulsatility index Pulsatility index artery
at the study (wk) diameter (cm) circumference (cm) index (cm) level (mg/ dL) of umbilical artery of middle cerebral
35.9 8.8 30.4 18.6 88.0 0.88 1.67
C C + + 2 t2
2.6 0.5 3.0 5.0 6.0 0.12 0.30
SGA (n = 13) 36.2 8.7 27.4 15.0 85.3 0.92 1.59
i i IT 2 2 % -t
1.5 0.5 1.9 3.5 5.9 0.13 0.36
P’ NS NS .oos <.04 NS NS NS
AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant. Data are expressed as mean + standard deviation. * Mann-Whitney test.
circumference (AC) of the fetuses were measured at the time of the study. We also measured the amniotic fluid index (AFI)14 at the end of each maternal state. At least five consecutive regular Doppler velocity waveforms were imaged from both the umbilical artery (UA) and the middle cerebral artery at the end of each state by pulsed Doppler equipment (50-Hz wall motion filter, RT-8000; G.E. Yokogawa Medical Systems). Waveform analysis in each artery consisted of calculation of the pulsatility index (PI), and the mean value of three fetal heart cycles was used. The mean values of the AFI and PI during the two different maternal states were analyzed. A maternal venous blood sample was obtained at the end of each state to measure plasma glucose concentration. The data are presented as mean + SD. We used Wilcoxon signed-rank test and Mann-Whitney test to analyze the data. We used analysis of covariance to compare the hourly fetal urine production rate between groups. We used the gestational age and fetal AC at the time of the study as covariates. Significance was established at P < .05.
Results Two cases were excluded from the SGA group at birth, because one was AGA at birth and another had congenital malformations, including anal atresia and ventricular septal defect. All fetuses in the AGA group were AGA at birth and had no congenital abnormalities. The gestational age at birth did not differ between groups (39.1 2 1.3 weeks in the SGA group versus 39.3 ? 1.7 weeks in the AGA group). The birth weight in the SGA group was significantly lower than in the AGA group (2233 + 268 versus 2905 -+ 298 g, P < .OOl). Table 1 summarizes fetal and maternal characteristics at the time of the study. The two groups were well matched in terms of gestational age at the time of the
Obstetrics b Gynecology
Table
2. Hourly Indices
Fetal Urine Production Rate and Other Before and After Maternal Breakfast
No. of observed cycle (n) Fasting Postprandial HFLJPR (mL/h) Fasting Postprandial Filling time (min) Fasting Postprandial Bladder volume (mL) Fasting Postprandial
AGA (n = 25)
SGA (n = 13)
IJ*
2.1 2 0.9 2.4 t 0.7
2.2 2 1.1 2.2 2 0.9
NS NS
30.2 t 11.7 41.1 f 14.6+
24.6 2 6.2 24.9 t 5.7
NS <.OOl
42.9 f 14.7 33.3 2 14.0’
45.2 i: 16.5 44.5 2 19.8
NS NS
22.6 k 11.2 28.6 + 16.9*
20.2 t 9.1 22.2 2 7.0
NS NS
AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant; HFUPR = hourly fetal urine production rate. Data are expressed as mean + standard deviation. * Mann-Whitney test. + P < ,001 compared with the fasting state by Wilcoxon signed-rank test. * P < .02 compared with the fasting state by Wiicoxon signed-rank test.
study, the plasma glucose level, and the fetal BPD. The fetal AC in the SGA group was significantly smaller than in the AGA group (P = .008). Although there was no case with oligohydramnios (defined as less than 5.1 cm of AFI)14 at the time of the study, the AFI in the SGA group was significantly lower than in the AGA group. There was no significant difference in the PI of fetal arteries. The results of the serial bladder volume measurements are summarized in Table 2 and Figure 1. In the AGA group, the hourly fetal urine production rate
s 2 ‘O B - 60
AGA
70 60
$ E 50
50
40
40
30
30
20
20
10
10
Fasting Postprandial
SGA NS
Fasting Postprandial
Figure 1. Change in the hourly fetal urine production rate (HFUPR) from the fasting state to the postprandial state in each group, AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant.
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1996
increased significantly after maternal breakfast (P < .OOl).The filling time of the bladder cycle was shorter in the postprandial state than in the fasting state (P < .02) and the maximum bladder volume became greater after maternal breakfast (P < .02). In contrast, in the SGA group, no increase was observed in the hourly fetal urine production rate after maternal breakfast. There was no significant change either in the filling time or the maximum bladder volume in the SGA group. When we compared the fetal urine production rate between groups, although there was no significant difference in the fasting state, the rate after breakfast was significantly greater in the AGA group than in the SGA group (P < .OOl)(Table 2). This difference was still significant (P < -04) when we reanalyzed the data by analysis of covariance by using the gestational age and the fetal AC at the time of the study as covariates. In regard to the reduced sample size of 13 in the SGA group, the observed change in the hourly fetal urine production rate has a 95% confidence interval that corresponds to a percent change of (-20.2 to 22.6%). This percent change is less than the effect size we wanted to detect, and indicates that the reduced sample size is not a factor for detecting an effect size of 30%.
Discussion Nutrients and oxygen are essential constituents that are transferred through the placenta from mother to fetus. Accordingly, chronically impaired placental transfer results in FGR, chronic fetal hypoxia, or both. Often, oligohydramnios is seen in fetuses with growth restriction and is believed to be one of the features of chronic impairment of placenta1function.lm3 Becausefetal urine is a major constituent of AF during late pregnancy,3,‘5 in such cases, oligohydramnios is considered to be a consequenceof reduced fetal urine production.5*6,15,‘6 Several studies4-7have reported decreasedfetal urine production in growth-restricted fetuses. Nicolaides et al7reported a significant correlation between the degree of decreasein urine production and the degree of fetal hypoxia in 27 SGA fetuses. They concluded that both the degree of fetal smallness and the degree of fetal hypoxemia cause oliguria. A redistribution of fetal cardiac output in response to hypoxia is considered to be the causeof fetal oliguria. Indeed, Vyas et al’ found a significant correlation between an increased PI in fetal renal arteries and fetal blood oxygen deficit. On the other hand, some authors have found that in growthrestricted fetuses there was no significant association between a poor perinatal outcome and either Iower fetal urine production4 or oligohydramnios.17 We postulate that FGR due to impaired placental function is composed of two different stages. The first stage is defined
Yasuhi
et al
Urine Production in SGA Fetuses
835
Normal
AGA Fetuses
Fetuses of Diabetic Mothers
Postprandial increase in urine production
+
Maternal hyperglycemia
*
Postprandial increase * *
b
+
Polyhydramnios
~^d e
Oligohydramnios
” impaired placental (decreased fluid &
Growth-restricted without
fetuses
Growth-restricted
chronichypoxia
-4FpydiaAincrease
with “Severely” placental (decreased
impaired function
*
*
oxygen Basal urine production
as a dysfunctional nutrient transfer with normal or only minimally decreased oxygen supply, and the second stage is characterized by impaired placental transfer of both nutrients and oxygen. A mechanism of redistribution of fetal cardiac output should be considered in the second stage. In the first stage, it is possible that not only nutrient but also fluid transfer from mother to fetus is impaired.15,i8 Our findings are consistent with this hypothesis. The fetuses in the SGA group had asymmetrical growth restriction. Becausethe results of pulsed Doppler studies both in UA and middle cerebra1 arteries were norma119~20 and did not differ between groups, it is unlikely that the fetuses in the SGA group were hypoxic, ie, they were in the first stage. In our previous study9 and in the current study, we demonstrated that fetal urine production in normal AGA fetuses increasesduring the 2 hours after maternal meal ingestion. We speculate that this postprandial increase in fetal urine production is a result of increased fluid transfer to the fetus induced by maternal plasma volume expansion. In contrast to the AGA group, there was no increase in fetal urine production after maternal breakfast in the SGA group. In this group, it is likely that the net increase of fluid transfer after maternal breakfast was disturbed. Although the hourly fetal urine production rate in the fasting state did not differ between groups, the rate after breakfast was significantly lower in the SGA group than in the AGA group. The AFI was also significantly lower in the SGA group in comparison with the AGA group. This might result from decreased fetal urine production in the maternal fed state in the growth-restricted fetuses. This, in turn, raises another question. What caused the decreased fetal urine production in the growth-restricted fetuses in the maternal postprandial state, impaired placental function or fetal smallness
836
Yasuhi et al
Urine
Production
regarding abvolume prowith growth diabetes. Asmeal ingestion. for gestational
hypoxia
chronic
*
fetuses
Figure 2. Hypothesis normal amniotic fluid duction in fetuses restriction or maternal terisks show maternal AGA = appropriate age.
in SGA
Fetuses
itself? Nicolaides et al7 reported that there was a significant correlation between delta hourly fetal urine production rate (SDS from mean) and delta AC in SGA fetuses. In contrast, we demonstrated that fetal urine production in the postprandial state was still significantly lower in the SGA group than in the AGA group, even after adjusting for fetal abdominal size. This suggests that the decreased fetal urine production rate is independent of the degree of fetal smallness.Indeed, there was no significant difference between groups in the hourly fetal urine production rate during the fasting state. The discrepancy between our results and those of Nicolaides et al might reflect differences in the fetal conditions. Nicolaides et al included many fetuses with hypoxemia, oligohydramnios, or both, and we examined only fetuses with growth restriction but without hypoxia or oligohydramnios. The difference in the two study populations and the differing results support our hypothesis of the two different stages. We used Rabinowitz’s method to calculate the hourly fetal urine production rate. Recently, Hedriana and Moore’l suggested that method using regression analysis with the ovoid formula, such as Rabinowitz’s method, overestimate the true rate by 38-45%. In their study, most errors resulted from overestimation.” Because we compared the hourly fetal urine production rate between different maternal states and between the groups, not the absolute values of the rate, the tendency to overestimate should not have affected the results of the comparison. Hedriana and Moore’l also suggested that the more bladder measurements used, the more accurate is the estimate of the hourly fetal urine production rate. The mean number of bladder measurements we used for regression analysis was 17 at fasting and 13 after breakfast in the AGA group, and 18 in both maternal states in the SGA group, more measurements
Obstefrics
& Gynecology
than those examined by Hedriana and Moore. In addi-
tion, we observed two or more complete bladder cycles in each state in most subjects. These factors should contribute to the accuracy of the results. Becausethere were no subjectswith oligohydramnios at the time of the study, we could not conclude that decreased fetal urine production in the postprandial state was directly related to oligohydramnios in growth-restricted fetuses. However, the decreasedfetal urine production was probably related to the trend of decreasing AF volume. We have summarized our hypothesis about the etiology of oligohydramnios in growth-restricted fetuses in Figure 2. We suggest that fetal urine production in normal AGA fetuses consists of basal production during the maternal fasting state and postprandial increases in fetal urine production after maternal meal ingestion. Our findings also suggest that in casesin which both nutrient and fluid transfer from mother to fetus is disturbed, the postprandial increase in fetal urine production does not occur. This is associated with a trend of decreasing AF volume. However, because oxygen supply to the fetus is not seriously disturbed and, therefore, basal urine production rate is maintained, it may not cause oligohydramnios. As disturbance of the oxygen supply increasesin severity, such asin the fetusesin the study of Nicolaides et a1,7a redistribution of fetal cardiac output occurs in response to chronic fetal hypoxia. Consequently, not only a disappearance of postprandial increasebut also a significant decrease in basal urine production may occur, leading to oligohydramnios in growth-restricted fetuses. In cases with FGR, the disappearance of the increase in fetal urine production following maternal meal ingestion may indicate an early phase of developing oligohydramnios.
8.
9.
10. 11.
12.
13.
14.
15. 16.
17.
18.
19. 20. 21.
22.
References 1. Manning FA, Hill LM, Platt LD. Qualitative amniotic fluid volume determination by ultrasound: Antepartum detection of intrauterine growth retardation. Am J Obstet Gynecol 1981;139:254-8. 2. Smith CS, Weiner S. Amniotic fluid assessment. In: Chervenak FA, Isaacson GC, Campbell S, eds. Ultrasound in obstetrics and gynecology. Boston: Little, Brown and Co., 1993;555-63. 3. Flack NJ, Fisk NM. Oligohydramnios and associated fetal complications. Fetal Matern Med Rev 1993;5:147-66. 4. Wladimiroff JW, Campbell S. Fetal urine-production rates in normal and complicated pregnancy. Lancet 1974;i:151-4. 5. Van Otterlo LC, Wladimiroff JW, Wallenburg HCS. Relationship between fetal urine production and amniotic fluid volume in normal pregnancy and pregnancy complicated by diabetes. Br J Obstet Gynaecol 1977;84:205-9. 6. Kujak A, Kirkinen I’, Latin V, Ivankovic D. Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies. Am J Obstet Gynecol 1981;141:266-70. 7. Nicolaides KH, Peters MT, Vyas S, Rabinowitz R, Rosen DJD,
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Campbell S, Relation of rate of urine production to oxygen tension in small-for-gestational-age fetuses. Am J Obstet Gynecol1990;162; 387-91. Vyas S, Nicolaides KH, Peters MT, Campbell S. Renal artery flow-velocity waveforms in normal and hypoxemic fetuses. Am J Obstet Gynecol 1989;161:168-72. Yasuhi I, Ishimaru T, Hirai M, Yamabe T. Hourly fetal urine production rate in the fasting and the postprandial state of normal and diabetic pregnant women. Obstet Gynecol 1994;84:64-8. Nishida H, Sakanoue M, Kurachi K, Asada A, Kubo S, Funakawa H. Fetal growth curve of Japanese. Ada Neonat Jpn 19&4;20:90-7. Kirshon B, Moise KJ Jr, Wasserstrum N, Ou CN, Huhta JC. Influence of short-term indomethacin therapy on fetal urine output. Obstet Gynecol 1988;72:51-3. Campbell S, Wladimiroff JW, Dewhurst CJ. The antenatal measurement of fetal urine production. J Obstet Gynaecol Br Commonw 1973;80:680-6. Rabinowitz R, Peters MT, Campbell S, Nicolaides KH. Measurement of fetal urine production in normal pregnancy by real-time ultrasonography. Am J Obstet Gynecol 1989;161:1264-6. Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. J Reprod Med 1987;32:601-4. Gilbert WM, Moore TR, Brace RA. Amniotic fluid volume dynamics. Fetal Med Rev 1991;3:89-104. Rabinowitz R, Rosen DJD, Nicolaides KH, Wladimiroff JW. Fetal urine production. In: Chervenak FA, Isaacson GC, Campbell S, eds. Ultrasound in obstetrics and gynecology. Boston: Little, Brown and Co., 1993;547-54. Lin CC, She&h Z, Lopata R. The association between oligohydramnios and intrauterine growth retardation. Obstet Gynecol 1990;76: 1100-4. Cock ML, Wlodek ME, Hooper SB, McCrabb GJ, Harding R. The effects of twenty-four hours of reduced uterine blood flow on fetal fluid balance in sheep. Am J Obstet Gynecol 1994;170:1442-51. Vaille JC, Cohen I. Middle cerebral artery blood flow in normal and growth-retarded fetuses. Am J Obstet Gynecol1990;162:391-6. Arduini D, Rizzo G. Doppler ultrasonography in uteroplacental insufficiency. Fetal Matern Med Rev 1994;6:153-66. Hedriana HL, Moore TR. Accuracy limits ,of ultrasonographic estimation of human fetal urinary flow rate. Am J Obstet Gynecol 1994;171:989-92. Hedriana HL, Moore TR. Ultrasonographic evaluation of human fetal urinary flow rate: Accuracy limits of bladder volume estimation. Am J Obstet Gynecol1994;170:1250-4.
Address reprint requeststo: Ichiro Yasuhi, MD Department of Obstetrics and Gynecology Nagasaki University School of Medicine I-7-1 Sakamato Nagasaki 852 lapan
Received Received Accepted
March 4, 1996. in revised form June 7, 1996. June 20, 1996.
Copyright 0 1996 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.
Yasuhi et al
Urine
Production
in SGA
Fetuses
and
837
HIRAI, MD, TADAYUKI
Objective: To determine if fetal urine production is affected by maternal meal ingestion in growth-restricted fetuses. Metkods: We studied 25 normal-growth fetuses in uncomplicated pregnancies and 15 growth-restricted fetuses, all after 30 weeks’ gestation. Serial fetal bladder volume measurements were obtained at 2-3 minute intervals with ultrasonography 2 hours before and 2 hours after maternal breakfast. The hourly fetal urine production rate in each maternal state was calculated from the bladder volume measurements. The amniotic fluid index (AFI) and the pulsatility index of both umbilical and fetal middle cerebral arteries were also measured. Results: Two of the 15 growth-restricted fetuses were excluded from analysis, one because it was anomalous and the other because it was not small for gestational age at birth. In the normal-growth fetuses, the hourly fetal urine production rate increased significantly after maternal breakfast (mean f standard deviation 30.2 f 11.7 versus 41.1 f 14.6 ml/hour, P < .OOl). In contrast, in the growth-restricted fetuses, the rate did not change after maternal breakfast (24.6 f 6.2 versus 24.9 f 5.7 ml/hour). Although the urine production rate before breakfast did not differ between groups, 2 hours after maternal breakfast it was significantly lower in the growth-restricted fetuses than in the control group (normal-growth) (P < .OOl).The AFI also was significantly lower in the growth-restricted fetuses than in the control group (15.0 f 3.5 versus 18.6 f 5.0 cm, P c .04). There were no significant differences in the pulsed Doppler studies. Conclusion: In contrast to normal-growth fetuses, maternal meal ingestion for growth-restricted fetuses does not increase fetal urine production. Decreased fetal urine production in the maternal fed state may lead to decreased amniotic fluid volume in growth-restricted fetuses without obvious hypoxia. (Obstet Gynecol1996;88:833-7)
From the Department of Obstetrics versity School of Medicine, Nagasaki,
VOL.
88, NO.
5, NOVEMBER
1996
and Gynecology, Japan.
Nagasaki
Uni-
ISHIMARU,
MD, PhD, AND
Oligohydramnios is often seen in growth-restricted fetuses and is strongly associated with increased perinatal mortality and morbidity.ld3 The major source of amniotic fluid (AF) during late pregnancy is fetal urine. Using ultrasonography, many authors have observed decreasedfetal urine production in small for gestational age (SGA) fetuses by serial measurements of fetal bladder volume. 4-7 Fetal oliguria in response to hypoxia is considered a main causeof oligohydramnios in SGA fetuses.“7’8However, some authors have reported that decreasedfetal urine production is not significantly correlated with a poor perinatal outcome.4 Previously, we reported that, in appropriate for gestational age (AGA) fetuses, maternal meal ingestion affected fetal urine production and resuIted in greater urine production when compared with the maternal fasting state.’ We postulated that maternal volume expansion after breakfast improved uteroplacental microcirculation, which resulted in incre&ed fluid transfer to the fetus, causing greater fetal urine production compared with that during the maternal fasting state. Because the malnutrition type of fetal growth restriction (FGR) results from chronically impaired placental transfer of nutrients from mother to fetus, maternal volume expansion by meal ingestion may not increase fetal urine production in growth-restricted fetuses. To examine this hypothesis, we investigated whether the postprandial increase of the hourly fetal urine production rate observed in AGA fetuses occurs in a similar manner in SGA fetuses.
Materials and Methods Fifteen pregnancies with suspected FGR by antenatal ultrasound screening at Nagasaki University Hospital after 30 weeks’ gestation were included in this study (SGA group). This sample size was calculated from the
0029-7844/96/$15.00 PI1 SOO29-7844(96)00274-S
833
data in our previous study,’ with (Y = .05, /3 = .20, and an effect size of 30% increase in the hourly fetal urine production rate. Twenty-five pregnancies with normalgrowth fetuses also were studied after 30 weeks’ gestation as a control group (AGA group). All pregnancies were singleton, and gestational ages were confirmed by ultrasonography before 20 weeks’ gestation. We followed all pregnancies to delivery. Infants weighing less than -1.5 or more than +1.5 standard deviations (SD) of the mean Japanese standard curve at birthlo were defined as SGA or large for gestational age, respectively. Pregnancies in which the birth weight was not SGA were excluded from the SGA group, and those in which the birth weight was not AGA were excluded from the control group. Fetuses with congenital malformations also were excluded from the study. All women with a 50-g glucose challenge test were screened at approximately 28 weeks’ gestation. Women with plasma glucose level at least 130 mg/dL on the l-hour challenge were given a 75-g glucose tolerance test. Women with glucose intolerance during pregnancy were excluded from the study, because increased fetal urine production rate during maternal fasting state has been demonstrated in diabetic pregnancy.’ We confirmed that none of the women in either the study or control group had taken any anti-inflammatory medication, such as aspirin, indomethacin, etc, during pregnancy, because use of these drugs has been associated with decreased fetal urine production.” The study protocol was the same as in our previous report.’ After overnight fasting, the study commenced at 6:00 AM and continued for 2 hours (the fasting state). Then each subject had a 600-kcal standard breakfast, including approximately 450 g of water component without any diuretic beverage. The second phase of the study took place 2 hours after breakfast (the postprandial state). No medication was given during the study. In each phase, the women were placed in the semirecumbent position, and serial fetal bladder volume measurements were obtained using ultrasonography (3.5MHz transducer, RT-8000; G.E. Yokogawa Medical Systems, Tokyo, Japan). At least one complete filling cycle was observed in each maternal state. The fetal bladder volume was calculated from the largest longitudinal, transverse, and anteroposterior bladder dimensions,l’ which were imaged serially at 2-3 minute intervals. The hourly fetal urine production rate was calculated by linear regression analysis,13 and the greatest hourly fetal urine production rate in all complete cycles observed in each state was selected for analysis. Using the same definition as in our previous study,’ the filling time of the cycle and the maximum bladder volume also were analyzed. The biparietal diameter (BPD) and the abdominal
834
Yasuhi et al
Urine Production in SGA Fetuses
Table 1. Fetal and Maternal Characteristics AGA (n = 25) Gestational age Fetal biparietal Fetal abdominal Amniotic fluid Plasma glucose Pulsatility index Pulsatility index artery
at the study (wk) diameter (cm) circumference (cm) index (cm) level (mg/ dL) of umbilical artery of middle cerebral
35.9 8.8 30.4 18.6 88.0 0.88 1.67
C C + + 2 t2
2.6 0.5 3.0 5.0 6.0 0.12 0.30
SGA (n = 13) 36.2 8.7 27.4 15.0 85.3 0.92 1.59
i i IT 2 2 % -t
1.5 0.5 1.9 3.5 5.9 0.13 0.36
P’ NS NS .oos <.04 NS NS NS
AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant. Data are expressed as mean + standard deviation. * Mann-Whitney test.
circumference (AC) of the fetuses were measured at the time of the study. We also measured the amniotic fluid index (AFI)14 at the end of each maternal state. At least five consecutive regular Doppler velocity waveforms were imaged from both the umbilical artery (UA) and the middle cerebral artery at the end of each state by pulsed Doppler equipment (50-Hz wall motion filter, RT-8000; G.E. Yokogawa Medical Systems). Waveform analysis in each artery consisted of calculation of the pulsatility index (PI), and the mean value of three fetal heart cycles was used. The mean values of the AFI and PI during the two different maternal states were analyzed. A maternal venous blood sample was obtained at the end of each state to measure plasma glucose concentration. The data are presented as mean + SD. We used Wilcoxon signed-rank test and Mann-Whitney test to analyze the data. We used analysis of covariance to compare the hourly fetal urine production rate between groups. We used the gestational age and fetal AC at the time of the study as covariates. Significance was established at P < .05.
Results Two cases were excluded from the SGA group at birth, because one was AGA at birth and another had congenital malformations, including anal atresia and ventricular septal defect. All fetuses in the AGA group were AGA at birth and had no congenital abnormalities. The gestational age at birth did not differ between groups (39.1 2 1.3 weeks in the SGA group versus 39.3 ? 1.7 weeks in the AGA group). The birth weight in the SGA group was significantly lower than in the AGA group (2233 + 268 versus 2905 -+ 298 g, P < .OOl). Table 1 summarizes fetal and maternal characteristics at the time of the study. The two groups were well matched in terms of gestational age at the time of the
Obstetrics b Gynecology
Table
2. Hourly Indices
Fetal Urine Production Rate and Other Before and After Maternal Breakfast
No. of observed cycle (n) Fasting Postprandial HFLJPR (mL/h) Fasting Postprandial Filling time (min) Fasting Postprandial Bladder volume (mL) Fasting Postprandial
AGA (n = 25)
SGA (n = 13)
IJ*
2.1 2 0.9 2.4 t 0.7
2.2 2 1.1 2.2 2 0.9
NS NS
30.2 t 11.7 41.1 f 14.6+
24.6 2 6.2 24.9 t 5.7
NS <.OOl
42.9 f 14.7 33.3 2 14.0’
45.2 i: 16.5 44.5 2 19.8
NS NS
22.6 k 11.2 28.6 + 16.9*
20.2 t 9.1 22.2 2 7.0
NS NS
AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant; HFUPR = hourly fetal urine production rate. Data are expressed as mean + standard deviation. * Mann-Whitney test. + P < ,001 compared with the fasting state by Wilcoxon signed-rank test. * P < .02 compared with the fasting state by Wiicoxon signed-rank test.
study, the plasma glucose level, and the fetal BPD. The fetal AC in the SGA group was significantly smaller than in the AGA group (P = .008). Although there was no case with oligohydramnios (defined as less than 5.1 cm of AFI)14 at the time of the study, the AFI in the SGA group was significantly lower than in the AGA group. There was no significant difference in the PI of fetal arteries. The results of the serial bladder volume measurements are summarized in Table 2 and Figure 1. In the AGA group, the hourly fetal urine production rate
s 2 ‘O B - 60
AGA
70 60
$ E 50
50
40
40
30
30
20
20
10
10
Fasting Postprandial
SGA NS
Fasting Postprandial
Figure 1. Change in the hourly fetal urine production rate (HFUPR) from the fasting state to the postprandial state in each group, AGA = appropriate for gestational age; SGA = small for gestational age; NS = not significant.
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increased significantly after maternal breakfast (P < .OOl).The filling time of the bladder cycle was shorter in the postprandial state than in the fasting state (P < .02) and the maximum bladder volume became greater after maternal breakfast (P < .02). In contrast, in the SGA group, no increase was observed in the hourly fetal urine production rate after maternal breakfast. There was no significant change either in the filling time or the maximum bladder volume in the SGA group. When we compared the fetal urine production rate between groups, although there was no significant difference in the fasting state, the rate after breakfast was significantly greater in the AGA group than in the SGA group (P < .OOl)(Table 2). This difference was still significant (P < -04) when we reanalyzed the data by analysis of covariance by using the gestational age and the fetal AC at the time of the study as covariates. In regard to the reduced sample size of 13 in the SGA group, the observed change in the hourly fetal urine production rate has a 95% confidence interval that corresponds to a percent change of (-20.2 to 22.6%). This percent change is less than the effect size we wanted to detect, and indicates that the reduced sample size is not a factor for detecting an effect size of 30%.
Discussion Nutrients and oxygen are essential constituents that are transferred through the placenta from mother to fetus. Accordingly, chronically impaired placental transfer results in FGR, chronic fetal hypoxia, or both. Often, oligohydramnios is seen in fetuses with growth restriction and is believed to be one of the features of chronic impairment of placenta1function.lm3 Becausefetal urine is a major constituent of AF during late pregnancy,3,‘5 in such cases, oligohydramnios is considered to be a consequenceof reduced fetal urine production.5*6,15,‘6 Several studies4-7have reported decreasedfetal urine production in growth-restricted fetuses. Nicolaides et al7reported a significant correlation between the degree of decreasein urine production and the degree of fetal hypoxia in 27 SGA fetuses. They concluded that both the degree of fetal smallness and the degree of fetal hypoxemia cause oliguria. A redistribution of fetal cardiac output in response to hypoxia is considered to be the causeof fetal oliguria. Indeed, Vyas et al’ found a significant correlation between an increased PI in fetal renal arteries and fetal blood oxygen deficit. On the other hand, some authors have found that in growthrestricted fetuses there was no significant association between a poor perinatal outcome and either Iower fetal urine production4 or oligohydramnios.17 We postulate that FGR due to impaired placental function is composed of two different stages. The first stage is defined
Yasuhi
et al
Urine Production in SGA Fetuses
835
Normal
AGA Fetuses
Fetuses of Diabetic Mothers
Postprandial increase in urine production
+
Maternal hyperglycemia
*
Postprandial increase * *
b
+
Polyhydramnios
~^d e
Oligohydramnios
” impaired placental (decreased fluid &
Growth-restricted without
fetuses
Growth-restricted
chronichypoxia
-4FpydiaAincrease
with “Severely” placental (decreased
impaired function
*
*
oxygen Basal urine production
as a dysfunctional nutrient transfer with normal or only minimally decreased oxygen supply, and the second stage is characterized by impaired placental transfer of both nutrients and oxygen. A mechanism of redistribution of fetal cardiac output should be considered in the second stage. In the first stage, it is possible that not only nutrient but also fluid transfer from mother to fetus is impaired.15,i8 Our findings are consistent with this hypothesis. The fetuses in the SGA group had asymmetrical growth restriction. Becausethe results of pulsed Doppler studies both in UA and middle cerebra1 arteries were norma119~20 and did not differ between groups, it is unlikely that the fetuses in the SGA group were hypoxic, ie, they were in the first stage. In our previous study9 and in the current study, we demonstrated that fetal urine production in normal AGA fetuses increasesduring the 2 hours after maternal meal ingestion. We speculate that this postprandial increase in fetal urine production is a result of increased fluid transfer to the fetus induced by maternal plasma volume expansion. In contrast to the AGA group, there was no increase in fetal urine production after maternal breakfast in the SGA group. In this group, it is likely that the net increase of fluid transfer after maternal breakfast was disturbed. Although the hourly fetal urine production rate in the fasting state did not differ between groups, the rate after breakfast was significantly lower in the SGA group than in the AGA group. The AFI was also significantly lower in the SGA group in comparison with the AGA group. This might result from decreased fetal urine production in the maternal fed state in the growth-restricted fetuses. This, in turn, raises another question. What caused the decreased fetal urine production in the growth-restricted fetuses in the maternal postprandial state, impaired placental function or fetal smallness
836
Yasuhi et al
Urine
Production
regarding abvolume prowith growth diabetes. Asmeal ingestion. for gestational
hypoxia
chronic
*
fetuses
Figure 2. Hypothesis normal amniotic fluid duction in fetuses restriction or maternal terisks show maternal AGA = appropriate age.
in SGA
Fetuses
itself? Nicolaides et al7 reported that there was a significant correlation between delta hourly fetal urine production rate (SDS from mean) and delta AC in SGA fetuses. In contrast, we demonstrated that fetal urine production in the postprandial state was still significantly lower in the SGA group than in the AGA group, even after adjusting for fetal abdominal size. This suggests that the decreased fetal urine production rate is independent of the degree of fetal smallness.Indeed, there was no significant difference between groups in the hourly fetal urine production rate during the fasting state. The discrepancy between our results and those of Nicolaides et al might reflect differences in the fetal conditions. Nicolaides et al included many fetuses with hypoxemia, oligohydramnios, or both, and we examined only fetuses with growth restriction but without hypoxia or oligohydramnios. The difference in the two study populations and the differing results support our hypothesis of the two different stages. We used Rabinowitz’s method to calculate the hourly fetal urine production rate. Recently, Hedriana and Moore’l suggested that method using regression analysis with the ovoid formula, such as Rabinowitz’s method, overestimate the true rate by 38-45%. In their study, most errors resulted from overestimation.” Because we compared the hourly fetal urine production rate between different maternal states and between the groups, not the absolute values of the rate, the tendency to overestimate should not have affected the results of the comparison. Hedriana and Moore’l also suggested that the more bladder measurements used, the more accurate is the estimate of the hourly fetal urine production rate. The mean number of bladder measurements we used for regression analysis was 17 at fasting and 13 after breakfast in the AGA group, and 18 in both maternal states in the SGA group, more measurements
Obstefrics
& Gynecology
than those examined by Hedriana and Moore. In addi-
tion, we observed two or more complete bladder cycles in each state in most subjects. These factors should contribute to the accuracy of the results. Becausethere were no subjectswith oligohydramnios at the time of the study, we could not conclude that decreased fetal urine production in the postprandial state was directly related to oligohydramnios in growth-restricted fetuses. However, the decreasedfetal urine production was probably related to the trend of decreasing AF volume. We have summarized our hypothesis about the etiology of oligohydramnios in growth-restricted fetuses in Figure 2. We suggest that fetal urine production in normal AGA fetuses consists of basal production during the maternal fasting state and postprandial increases in fetal urine production after maternal meal ingestion. Our findings also suggest that in casesin which both nutrient and fluid transfer from mother to fetus is disturbed, the postprandial increase in fetal urine production does not occur. This is associated with a trend of decreasing AF volume. However, because oxygen supply to the fetus is not seriously disturbed and, therefore, basal urine production rate is maintained, it may not cause oligohydramnios. As disturbance of the oxygen supply increasesin severity, such asin the fetusesin the study of Nicolaides et a1,7a redistribution of fetal cardiac output occurs in response to chronic fetal hypoxia. Consequently, not only a disappearance of postprandial increasebut also a significant decrease in basal urine production may occur, leading to oligohydramnios in growth-restricted fetuses. In cases with FGR, the disappearance of the increase in fetal urine production following maternal meal ingestion may indicate an early phase of developing oligohydramnios.
8.
9.
10. 11.
12.
13.
14.
15. 16.
17.
18.
19. 20. 21.
22.
References 1. Manning FA, Hill LM, Platt LD. Qualitative amniotic fluid volume determination by ultrasound: Antepartum detection of intrauterine growth retardation. Am J Obstet Gynecol 1981;139:254-8. 2. Smith CS, Weiner S. Amniotic fluid assessment. In: Chervenak FA, Isaacson GC, Campbell S, eds. Ultrasound in obstetrics and gynecology. Boston: Little, Brown and Co., 1993;555-63. 3. Flack NJ, Fisk NM. Oligohydramnios and associated fetal complications. Fetal Matern Med Rev 1993;5:147-66. 4. Wladimiroff JW, Campbell S. Fetal urine-production rates in normal and complicated pregnancy. Lancet 1974;i:151-4. 5. Van Otterlo LC, Wladimiroff JW, Wallenburg HCS. Relationship between fetal urine production and amniotic fluid volume in normal pregnancy and pregnancy complicated by diabetes. Br J Obstet Gynaecol 1977;84:205-9. 6. Kujak A, Kirkinen I’, Latin V, Ivankovic D. Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies. Am J Obstet Gynecol 1981;141:266-70. 7. Nicolaides KH, Peters MT, Vyas S, Rabinowitz R, Rosen DJD,
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Campbell S, Relation of rate of urine production to oxygen tension in small-for-gestational-age fetuses. Am J Obstet Gynecol1990;162; 387-91. Vyas S, Nicolaides KH, Peters MT, Campbell S. Renal artery flow-velocity waveforms in normal and hypoxemic fetuses. Am J Obstet Gynecol 1989;161:168-72. Yasuhi I, Ishimaru T, Hirai M, Yamabe T. Hourly fetal urine production rate in the fasting and the postprandial state of normal and diabetic pregnant women. Obstet Gynecol 1994;84:64-8. Nishida H, Sakanoue M, Kurachi K, Asada A, Kubo S, Funakawa H. Fetal growth curve of Japanese. Ada Neonat Jpn 19&4;20:90-7. Kirshon B, Moise KJ Jr, Wasserstrum N, Ou CN, Huhta JC. Influence of short-term indomethacin therapy on fetal urine output. Obstet Gynecol 1988;72:51-3. Campbell S, Wladimiroff JW, Dewhurst CJ. The antenatal measurement of fetal urine production. J Obstet Gynaecol Br Commonw 1973;80:680-6. Rabinowitz R, Peters MT, Campbell S, Nicolaides KH. Measurement of fetal urine production in normal pregnancy by real-time ultrasonography. Am J Obstet Gynecol 1989;161:1264-6. Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. J Reprod Med 1987;32:601-4. Gilbert WM, Moore TR, Brace RA. Amniotic fluid volume dynamics. Fetal Med Rev 1991;3:89-104. Rabinowitz R, Rosen DJD, Nicolaides KH, Wladimiroff JW. Fetal urine production. In: Chervenak FA, Isaacson GC, Campbell S, eds. Ultrasound in obstetrics and gynecology. Boston: Little, Brown and Co., 1993;547-54. Lin CC, She&h Z, Lopata R. The association between oligohydramnios and intrauterine growth retardation. Obstet Gynecol 1990;76: 1100-4. Cock ML, Wlodek ME, Hooper SB, McCrabb GJ, Harding R. The effects of twenty-four hours of reduced uterine blood flow on fetal fluid balance in sheep. Am J Obstet Gynecol 1994;170:1442-51. Vaille JC, Cohen I. Middle cerebral artery blood flow in normal and growth-retarded fetuses. Am J Obstet Gynecol1990;162:391-6. Arduini D, Rizzo G. Doppler ultrasonography in uteroplacental insufficiency. Fetal Matern Med Rev 1994;6:153-66. Hedriana HL, Moore TR. Accuracy limits ,of ultrasonographic estimation of human fetal urinary flow rate. Am J Obstet Gynecol 1994;171:989-92. Hedriana HL, Moore TR. Ultrasonographic evaluation of human fetal urinary flow rate: Accuracy limits of bladder volume estimation. Am J Obstet Gynecol1994;170:1250-4.
Address reprint requeststo: Ichiro Yasuhi, MD Department of Obstetrics and Gynecology Nagasaki University School of Medicine I-7-1 Sakamato Nagasaki 852 lapan
Received Received Accepted
March 4, 1996. in revised form June 7, 1996. June 20, 1996.
Copyright 0 1996 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.
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Urine
Production
in SGA
Fetuses
and
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