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ORIGINAL RESEARCH
Usefulness of Fetal Urine Production
Measurement for Prediction of Perinatal
Outcomes in Uteroplacental Insufficiency
Seung Mi Lee, MD, PhD, Jong Kwan Jun, MD, PhD, Su Ah Kim, MD, Eun Ja Lee, MT, Byoung Jae Kim, MD,
Chan-Wook Park, MD, PhD, Joong Shin Park, MD, PhD
Objectives—To evaluate whether fetal urine production measurement is useful for
predicting adverse outcomes in patients with uteroplacental insufficiency.
Received October 29, 2013, from the Department
of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea (S.M.L.,
J.K.J., S.A.K., B.J.K., C.-W.P., J.S.P.); Department
of Obstetrics and Gynecology, Seoul Metropolitan
Government Seoul National University Boramae
Medical Center, Seoul, Korea (S.M.L., B.J.K.);
and Samsung Medison Co, Seoul, Korea (E.J.L.).
Revision requested December 9, 2013. Revised
manuscript accepted for publication March 11,
2014.
We thank Sohee Oh, PhD, of the Department
of Biostatistics, Seoul Metropolitan Government
Seoul National University Boramae Medical Center,
for statistical advice. This study was presented at
the 19th World Congress on Ultrasound in
Obstetrics and Gynecology; September 13–17,
2009; Hamburg, Germany.
Address correspondence to Jong Kwan Jun,
MD, PhD, Department of Obstetrics and
Gynecology, Seoul National University Hospital,
28 Yeongeon-dong, Jongno-gu, Seoul 110-744,
Korea.
E-mail: [email protected]
Abbreviations
AFI, amniotic fluid index; GA, gestational
age; PI, pulsatility index
doi:10.7863/ultra.33.12.2165
Methods—We enrolled patients with uteroplacental insufficiency at 24 to 40 weeks’
gestation and normal pregnancies matched for gestational age and divided them into 3
groups according to perinatal outcomes: group 1 (n = 141), a control group of normal
pregnancies; group 2 (n = 29), uteroplacental insufficiency without adverse outcomes;
and group 3 (n = 18), uteroplacental insufficiency with adverse outcomes. An adverse
outcome was defined as 1 or more of the following: (1) cesarean delivery because of
fetal distress; (2) admission to the neonatal intensive care unit; (3) cord arterial pH less
than 7.15 at birth; and (4) low 5-minute Apgar score (<7). The fetal urine production
rate was obtained by serial bladder volume measurement using virtual organ computeraided analysis. For bladder volume determination, we scanned the bladder in the 3dimensional mode and defined the bladder surface contour in the reference plane,
repeating the rotation of the reference plane with an angle of 30° and determining the
surface contour on each plane. Statistical methods, including the Mann-Whitney U test,
Fisher exact test, χ2 test, and Kruskal-Wallis analysis of variance, were used.
Results—Group 3 had a lower mean fetal urine production rate than groups 1 and 2,
whereas the urine production rate was not different between groups 1 and 2 (group 1,
49.0 mL/h; group 2, 59.4 mL/h; group 3, 20.7 mL/h; P < .001 between groups 1 and
3 and between groups 2 and 3). This difference between groups 2 and 3 remained significant after adjusting for the amniotic fluid index, umbilical artery Doppler pulsatility
index, and presence of fetal growth restriction.
Conclusions—Uteroplacental insufficiency cases with adverse perinatal outcomes had
a lower fetal urine production rate than those without adverse outcomes. This difference
might be used to predict adverse perinatal outcomes in uteroplacental insufficiency.
Key Words—fetal growth restriction; fetal urine production rate; obstetric ultrasound;
preeclampsia; uteroplacental insufficiency; virtual organ computer-aided analysis
P
reeclampsia and fetal growth restriction are characterized
by uteroplacental insufficiency,1 which leads to fetal hypoxia
and a subsequent reflex redistribution of the fetal cardiac
output, resulting in increased blood flow to the brain and heart and
decreased fetal renal blood flow.2–7
However, uteroplacental insufficiency is not always associated
with an adverse perinatal outcome. Because of the diverse disease
spectrum of preeclampsia, clinicians encounter preeclamptic women
with severe maternal conditions that necessitate immediate delivery,
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Lee et al—Fetal Urine Production in Uteroplacental Insufficiency
in contrast to fetuses with relatively mild conditions and
without fetal growth restriction. There is a debate over the
management of fetal growth restriction, predominantly
because of the failure to differentiate between pathologic
fetal growth restriction and constitutional small size.
Therefore, there have been many studies on the
parameters for predicting adverse perinatal outcomes in
uteroplacental insufficiency, including Doppler sonography
of the umbilical artery, middle cerebral artery, ductus
venosus, and maternal uterine artery and the amniotic fluid
volume.8–15 The prediction of adverse outcomes in uteroplacental insufficiency remains a challenge in obstetric
medicine because of the diverse spectrum of preeclampsia
and fetal growth restriction.
Considering the pathophysiologic mechanisms of
blood redistribution in fetal hypoxia, the fetal urine production rate could be postulated as a new parameter for
prediction of adverse outcomes. There have been few
studies on the relationship between the fetal urine production rate and adverse perinatal outcomes in uteroplacental
insufficiency,16,17 and the results are inconsistent. It has
been suggested recently that serial measurements of the
fetal bladder volume by 3-dimensional sonography could
be used to obtain the fetal urine production rate.18–26
The objective of this study was to evaluate whether
fetal urine production rate measurement is useful for
predicting adverse outcomes in patients with uteroplacental insufficiency.
Materials and Methods
Study Population
We enrolled singleton pregnant women with uteroplacental
insufficiency at 24 to 40 weeks’ gestation at Seoul National
University Hospital. Women with normal pregnancies
matched for gestational age (GA; within 1 week; ratio, 1:3)
were enrolled as controls. Uteroplacental insufficiency was
defined as hypertensive disease in pregnancy or fetal growth
restriction; hypertensive disease in pregnancy included
gestational hypertension, preeclampsia/eclampsia, chronic
hypertension, and superimposed preeclampsia according
to the schema of the Working Group of the National High
Blood Pressure Education Program.27 Fetal growth
restriction was defined as estimated fetal weight below the
10th percentile for GA28 without identifiable maternal disease, and cases with aneuploidy or major anomalies were
excluded.
A patient was considered to have a normal pregnancy
if she met the following criteria: no medical or obstetric
complications, such as fetal growth restriction, hyperten-
2166
sive disease, diabetes, maternal vascular disease, or fetal
anomalies that might affect the fetal urine production. The
Institutional Review Board of Seoul National University
Hospital approved this study, and patients gave their written consent for the collection of data for research purposes.
A total of 47 cases with uteroplacental insufficiency
were enrolled and matched for GA (within 1 week), with
141 controls. The study population was divided into 3 groups
according to perinatal outcomes: group 1 (n = 141), control
group of normal pregnancies; group 2 (n = 29), uteroplacental insufficiency without adverse outcomes; and group 3
(n = 18), uteroplacental insufficiency with adverse outcomes.
Groups 2 and 3 included gestational hypertension (n = 8),
mild preeclampsia (n = 8), severe preeclampsia (n = 14),
chronic hypertension (n = 5), superimposed preeclampsia (n = 3), and isolated fetal growth restriction (n = 9).
An adverse perinatal outcome was defined by 1 or more of
the following criteria, adapted from previous studies with
modifications29,30: (1) cesarean delivery because of fetal
distress; (2) admission to the neonatal intensive care unit;
(3) cord arterial pH less than 7.15 at birth; and (4) low 5minute Apgar score (<7).
Measurement of Fetal Urine Production and Doppler
Velocimetry
On sonography, fetal biometric parameters, the amniotic
fluid index (AFI), the fetal urine production rate, and
Doppler velocimetric parameters of the fetal umbilical
artery and middle cerebral artery and maternal uterine arteries were measured in the absence of labor or rupture of
membranes. For acquisition of the fetal urine production
rate, we measured the fetal bladder volume serially at intervals of 5 to 10 minutes, using the rotational virtual organ
computer-aided analysis method with a 3-dimensional
ultrasound scanner (Accuvix XQ; Samsung Medison Co,
Seoul, Korea), according to previously described methods.18 The bladder was scanned in the 3-dimesional
mode and stored for subsequent calculation. For the volume measurement, we selected the reference plane on
virtual organ computer-aided analysis and defined the
bladder surface contour. The next step was to rotate
the reference plane around the vertical axis with an angle
of 30° and repeatedly determine the surface contour on
each plane (a total of 6 planes). The bladder volume was
calculated after all of the contours were traced [urine
production rate (milliliters per hour) = (second bladder
volume – first bladder volume) × (60/x), where x was the
interval in minutes between bladder volume measurements]. After calculating the urine production rate from
the serial volume change in the bladder volume, the urine
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Lee et al—Fetal Urine Production in Uteroplacental Insufficiency
production rate divided by estimated fetal weight and
multiples of the standard deviation of the urine production rate [(measured urine production rate – mean urine
production rate at each GA)/standard deviation of the
urine production rate at each GA] were adopted for
adjustment of the fetal weight or GA. The mean and
standard deviation of the urine production rate at each
GA were adopted from previously reported reference
data in normal pregnancies.18
For the Doppler measurements, we measured the pulsatility index (PI) of the umbilical artery, middle cerebral
artery, and maternal uterine artery 3 times, and an average
value was used. The cerebroplacental ratio was determined
by the following formula: cerebroplacental Doppler ratio =
middle cerebral artery PI/umbilical artery PI. The Z score
of the cerebroplacental Doppler ratio was defined as follows using the mean and standard deviation for each GA
from the data of Baschat and Gembruch31: Z score of the
cerebroplacental Doppler ratio = (measured cerebroplacental Doppler ratio – mean cerebroplacental Doppler
ratio at each GA)/standard deviation of the cerebroplacental Doppler ratio at each GA.
Statistical Analyses
Statistical analyses were performed with SPSS software
(IBM Corporation, Armonk, NY). Differences were evaluated by the Mann-Whitney U test, χ2 test, or Fisher exact
test as appropriate. Kruskal-Wallis analysis of variance was
used for comparison of continuous variables among the
groups. Logistic regression analysis was conducted for multivariate analysis. P < .05 was considered significant.
Results
Table 1 shows the maternal characteristics and perinatal
outcomes. The cases with uteroplacental insufficiency
(groups 2 and 3) had a higher proportion of nulliparity and
a lower GA at delivery and lower birth weights than those
in group 1.
In Table 2, the AFI, fetal urine production rate, and
Doppler velocimetric measurement results for each group
are summarized. The cases with uteroplacental insufficiency (groups 2 and 3) had lower AFI than those with
normal pregnancies (group 1). The frequency of oligohydramnios and the mean fetal urine production rate, standard
deviation of the urine production rate, urine production rate
divided by estimated fetal weight, and Doppler indices
were not different between groups 1 and 2, whereas group
3 had a lower mean fetal urine production rate, standard
deviation of the urine production rate, urine production
rate divided by estimated fetal weight, middle cerebral
artery PI, cerebroplacental Doppler ratio, and Z score of
the cerebroplacental Doppler ratio and a higher umbilical
artery PI and uterine artery PI than group 2. The frequency
of oligohydramnios was higher in group 3 than in groups 1
and 2. This relationship between the standard deviation of
the urine production rate and adverse perinatal outcomes
in the cases with uteroplacental insufficiency remained
significant even after adjusting for the AFI, umbilical
artery Doppler PI, and presence of fetal growth restriction
(Table 3).
A receiver operating characteristic curve was constructed to determine a cutoff value for the standard deviation of the urine production rate for prediction of adverse
outcomes in uteroplacental insufficiency (Figure 1). Using a
threshold of –0.67 for the standard deviation of the urine
Table 1. Maternal Characteristics and Perinatal Outcomes
Characteristic
Maternal age, y
Nulliparity
GA at measurement, wk
EFW at measurement, g
GA at delivery, wk
Birth weight, g
Group 1
(n = 141)
32 ± 4
80 (57)
35.2 ± 3.5
2485 ± 693
39.9 ± 1.2
3361 ± 352
Pa
NS
<.05
<.05
NS
<.001
<.001
Group 2
(n = 29)
32 ± 3
24 (83)
36.6 ± 3.3
2577 ± 728
38.1 ± 1.4
2842 ± 533
Pb
Group 3
(n = 18)
Pc
NS
NS
<.001
<.001
<.001
<.001
33 ± 5
16 (89)
33.3 ± 3.3
1620 ± 705
34.1 ± 3.4
1649 ± 708
NS
<.01
<.05
<.001
<.001
<.001
Pd
NS
<.005
<.005
<.001
<.001
<.001
Data are presented as mean ± SD, compared by the Mann-Whitney U test or Kruskal-Wallis analysis of variance, as appropriate, and number
(percent), compared by the Fisher exact test or χ2 test, as appropriate. EFW indicates estimated fetal weight; and NS, not significant.
aComparison between groups 1 and 2.
bComparison between groups 2 and 3.
cComparison between groups 1 and 3.
dComparison among groups 1, 2, and 3.
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Lee et al—Fetal Urine Production in Uteroplacental Insufficiency
production rate, values of 0.67 or less had sensitivity of
72.2%, specificity of 82.8%, a positive predictive value
of 72.2%, and a negative predictive value of 82.8% for prediction of adverse outcomes.
In cases with uteroplacental insufficiency (groups 2
and 3), the urine production rate, standard deviation of the
urine production rate, and urine production rate divided
by estimated fetal weight had a positive correlation with
the cerebroplacental Doppler ratio (P < .05 for each),
and the urine production rate and standard deviation of the
urine production rate had also a significantly positive correlation with the Z score of the cerebroplacental Doppler
ratio (P < .05 for each). Figure 2 shows the relationship
between the standard deviation of the urine production rate
and Z score of the cerebroplacental Doppler ratio.
tal ratio had a positive correlation in the cases with uteroplacental insufficiency.
A decreased amniotic fluid volume has been reported
to be associated with adverse pregnancy outcomes, including an increased risk of cesarean delivery for fetal distress, low
Apgar scores, and perinatal mortality and morbidity.32–35
This relationship between oligohydramnios and adverse
outcomes is hypothesized to result from decreased fetal
urine production in impaired placental function.2 For this
reason, an adequate amniotic fluid volume has been an
important marker for fetal well-being, especially in highrisk pregnancies.36 However, a good correlation between
the actual amniotic fluid volume and the AFI/single deepest pocket is not well verified, although they are the most
commonly used predictive modalities.37 We hypothesized
that direct measurement of fetal urine production could
be of benefit in the evaluation of fetal well-being and prediction of adverse perinatal outcomes.
The fetal urine production rate, as measured by 2dimensional sonography, has been consistently reported
to be decreased in cases with fetal growth restriction in
human studies,16,17,38–42 but the relationship between a
decreased fetal urine production rate and adverse perinatal outcomes in cases with fetal growth restriction has not
been reported consistently. Wladimiroff and Campbell16
Discussion
The principal findings of this study are as follows: (1) in
the patients with uteroplacental insufficiency, the cases
with adverse perinatal outcomes had a lower fetal urine
production rate than those without adverse outcomes, and
this difference remained significant after adjustment for
the presence of fetal growth restriction and AFI; and
(2) the fetal urine production rate and the cerebroplacenTable 2. Fetal Urine Production Rate, AFI, and Doppler Measurements
Characteristic
AFI, cm
Group 1
(n = 141)
14.0 ± 4.3
(n = 93)
Oligohydramnios (AFI <5 cm)
1/93 (1)
UPR, mL/h
49.0 ± 32.6
UPR_SD*
–0.04 ± 1.00
UPR_Wt, mL/h/kg
19.0 ± 10.8
UA_PI
0.77 ± 0.17
(n = 26)
MCA_PI
1.38 ± 0.36
(n = 26)
UtA_PI
0.60 ± 0.17
(n = 27)
CPR
1.86 ± 0.54
(n = 26)
Z-CPR
–0.18 ± 1.18
(n = 26)
Pa
<.005
NS
NS
NS
NS
NS
NS
NS
NS
NS
Group 2
(n = 29)
11.3 ± 3.9
(n = 28)
0/28 (0)
59.4 ± 33.5
0.13 ± 0.88
22.8 ± 11.2
0.75 ± 0.18
(n = 25)
1.30 ± 0.36
(n = 23)
0.71 ± 0.25
(n = 24)
1.84 ± 0.61
(n = 23)
–0.21 ± 1.47
(n = 23)
Pb
NS
<.05
<.001
<.001
<.005
<.05
<.05
<.05
<.005
<.005
Group 3
(n = 18)
9.3 ± 4.9
(n = 18)
4/18 (22)
20.7 ± 11.7
–0.93 ± 0.56
13.1 ± 6.0
0.94 ± 0.21
(n = 14)
1.05 ± 0.26
(n = 13)
1.02 ± 0.47
(n = 15)
1.15 ± 0.46
(n = 13)
–1.82 ± 1.14
(n = 13)
Pc
Pd
<.001
<.001
<.005
<.001
<.001
<.05
<.05
<.005
<.001
<.001
<.05
<.05
<.01
<.05
<.005
<.005
<.001
<.005
<.005
<.005
Data are presented as mean ± SD, compared by the Mann-Whitney U test or Kruskal-Wallis analysis of variance, as appropriate, and number
(percent), compared by the Fisher exact test or χ2 test, as appropriate. CRP indicates cerebroplacental Doppler ratio; MCA, middle cerebral artery;
NS, not significant; SD, standard deviation; UA, umbilical artery; UPR, urine production rate; UtA, uterine artery; and Wt, estimated fetal weight.
aComparison between groups 1 and 2.
bComparison between groups 2 and 3.
cComparison between groups 1 and 3.
dComparison among groups 1, 2, and 3.
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Lee et al—Fetal Urine Production in Uteroplacental Insufficiency
reported a decreased fetal urine production rate in cases
with growth-restricted neonates; however, they did not find
a correlation between a reduced fetal urine production rate
and perinatal asphyxia, defined as an umbilical cord pH less
than 7.25, late deceleration patterns on continuous fetal
heart rate monitoring, or a 1-minute Apgar score of 4 or
less at birth. In contrast, Nicolaides et al17 found a significant correlation between the degree of decreased urine
production and the degree of fetal hypoxemia. In our study,
the fetal urine production rate was lower in cases with
uteroplacental insufficiency and adverse perinatal outcomes than those with uteroplacental insufficiency without adverse outcomes. This relationship remained
significant even after adjustment for the AFI, umbilical
artery Doppler PI, and presence of fetal growth restriction,
CI indicates confidence interval; NS, not significant; OR, odds ratio;
SD, standard deviation; and UPR, urine production rate.
which are known strong predictors of adverse pregnancy
outcomes. For comparison, we evaluated the standard
deviation of the urine production rate to adjust for GA,
because the fetal urine production rate has been reported
to increase as a function of GA.18 The standard deviation
of the urine production rate was lower in cases with uteroplacental insufficiency and adverse perinatal outcomes
than in the cases with uteroplacental insufficiency without
adverse outcomes, and this relationship remained significant after adjustment.
The positive correlation between the urine production
rate and the cerebroplacental ratio suggests a compensatory redistribution of fetal blood flow in fetal hypoxia.
A lower cerebroplacental ratio reflects increased blood flow
to the fetal brain and reduced flow to the umbilical and renal
arteries, resulting in a lower fetal urine production rate.
The degree of decreased fetal urine production suggests
the severity of fetal hypoxia, enabling the clinician to
predict an adverse perinatal outcome by the fetal urine production rate.
We included cases with hypertensive disease in pregnancy and those with fetal growth restriction. There might
be different pathophysiologic mechanisms for these two
disease entities. However, when confining the analysis to
cases with hypertensive disease in pregnancy, the fetal
urine production rate, standard deviation of the urine production rate, and urine production rate divided by esti-
Figure 1. Receiver operating characteristic curve for the standard deviation of the urine production rate (UPR_SD) for prediction of adverse
outcomes in uteroplacental insufficiency.
Figure 2. Correlation between the standard deviation of the urine production rate (UPR_SD) and Z score of the cerebroplacental Doppler ratio
(Z_CPR) in cases with uteroplacental insufficiency (r = 0.354; P < .05).
Table 3. Relationships of the Variables With Adverse Perinatal Outcome
in Cases With Uteroplacental Insufficiency, Analyzed by Overall
Logistic Regression Analysis
Variable
UPR_SD
Fetal growth restriction
AFI
Umbilical artery PI
OR
0.153
17.497
1.060
1.466
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95% CI
0.025–0.944
0.971–315.161
0.808–1.390
0.001–1924.628
P
<.05
.052
NS
NS
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Lee et al—Fetal Urine Production in Uteroplacental Insufficiency
mated fetal weight were lower in cases with adverse perinatal outcomes than in cases without adverse outcomes
(P < .05 for each). When confining the analysis to cases
with isolated fetal growth restriction (without hypertensive disease), the fetal urine production rate was lower in
cases with adverse perinatal outcomes than those without
adverse outcomes, with marginal statistical significance
(P < .05 for the fetal urine production rate; P = .050 for
the standard deviation of the urine production rate and
urine production rate divided by estimated fetal
weight). Nevertheless, it should be reminded that some
cases with mild hypertensive disease in pregnancy such as
gestational hypertension and cases with constitutionally
small fetuses might not constitute actual uteroplacental
insufficiency.
Doppler abnormalities of fetal and maternal vessels
deteriorate as fetal growth worsens, suggesting a sequential
pattern of disease progression.12 Turan et al43 recently
identified the sequence of the progression of arterial and
venous Doppler abnormalities from the onset of placental
insufficiency in fetal growth restriction. In our study, the
temporal relationship between a decreased fetal urine production rate and Doppler abnormalities was not determined.
Further prospective studies are warranted to demonstrate
this temporal relationship.
To our knowledge, this study is the first report on the
fetal urine production rate in cases with uteroplacental
insufficiency measured by virtual organ computer-aided
analysis with 3-dimensional sonography, which is better
than 2-dimensional sonography for organ measurements.44
We also demonstrated a positive correlation between the
fetal urine production rate and the cerebroplacental ratio in
cases with uteroplacental insufficiency.
In conclusion, the fetal urine production rate was significantly lower only in the cases with uteroplacental insufficiency and adverse perinatal outcomes; it was not lower
in cases with uteroplacental insufficiency without adverse
outcomes. This result suggests that a difference in the fetal
urine production rate might be used to predict adverse
perinatal outcomes in uteroplacental insufficiency.
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