Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx

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Pregnancy Hypertension: An International Journal of

Womens Cardiovascular Health
journal homepage: www.elsevier.com/locate/preghy

Proteinuria in preeclampsia: Not essential to diagnosis but related to

disease severity and fetal outcomes
Xin Dong a, Wenli Gou a, Chunfang Li a, Min Wu a, Zhen Han a, Xuelan Li a,, Qi Chen b,c,
a
Department of Obstetrics & Gynaecology, First Affiliated Hospital of Xian Jiaotong University, China
b
The Hospital of Obstetrics & Gynaecology, Fudan University, China
c
Department of Obstetrics & Gynaecology, The University of Auckland, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality globally and protein-
Received 1 February 2017 uria can be one of the cardinal features of this disease. However, studies about the association of the
Received in revised form 8 March 2017 amount of proteinuria and the severity of preeclampsia, and perinatal outcomes are limited. Data on
Accepted 13 March 2017
239 women with preeclampsia were retrospectively collected from a university teaching hospital from
Available online xxxx
September 2011 to June 2013 and analysed. Data included all clinical parameters and proteinuria in a
24 h urine collection. In cases of severe preeclampsia, significantly fewer patients had proteinuria levels
Keywords:
<0.3 g/L in comparison to any of the other groups with proteinuria >0.3 g/L, but there was no difference in
Preeclampsia
Proteinuria
cases of severe preeclampsia when proteinuria levels were >0.3 g/L. Furthermore, when proteinuria levels
Severity were >0.3 g/L, the frequency of severe preeclampsia in each group was significantly higher than the fre-
Fetal outcomes quency of mild pre-eclampsia cases. Time of onset was significantly earlier in patients with proteinuria
>3 g/L in a 24 h urine collection, but time between the onset of preeclampsia and delivery was not cor-
related with the amount of proteinuria. The birth weight was significantly lower in patients with protein-
uria >3 g/L. The incidence of fetal growth restriction or stillbirth was significantly higher in patients with
proteinuria >5 g/L. Our data demonstrate that the amount of proteinuria is not associated with the severe
of preeclampsia, once proteinuria is detected, but is related to the severity of preeclampsia. The adverse
fetal outcomes appear to be the function of prematurity rather than proteinuria itself.
2017 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in
Pregnancy.

1. Introduction pregnant women when it exceeds 300 mg in a 24 h urine collection

Preeclampsia is a pregnancy-specific multisystem disorder with
unknown etiology and is a leading cause of maternal and perinatal
morbidity and mortality globally [1]. Preeclampsia occurs clinically
apparent after 20 weeks of gestation or within the first 46 weeks
postpartum by new onset hypertension and/or proteinuria [2,3]. It
is considered severe if blood pressure is increased substantially or
clinical symptoms of end-organ damage (including fetal growth
restriction) occur. Currently the only effective treatment for this
disease is to deliver the placenta at optimal time for both maternal
and fetal well-being.
In normal pregnancy, urinary protein excretion substantially
increases and total protein excretion is considered abnormal in
Corresponding authors at: The Hospital of Obstetrics & Gynaecology, Fudan
University, 419 Fangxie Road, Shanghai, China (Q. Chen).
E-mail addresses: lixuelan1225@126.com (X. Li), q.chen@auckland.ac.nz (Q.
Chen).
[4]. Proteinuria can be one of the cardinal features of preeclampsia.
However, up to 10% of women with clinical and/or histological
manifestations of preeclampsia and 20% of women with eclampsia
have no proteinuria at the time of initial presentation with clinical
symptoms, which are also called non-proteinuric preeclampsia
[5,6]. This may be because the multiple organ dysfunctions affect-
ing the kidneys and livers can occur without signs of protein and
that the amount of proteinuria does not predict the severity of dis-
ease progression. Therefore since 2014, the International Society
for the Study of Hypertension in Pregnancy [3] and American Soci-
ety of Obstetrics and Gynaecology [7] have not recommended the
use of proteinuria as a criterion with which to diagnose preeclamp-
sia. Although proteinuria is not currently recommended as a crite-
rion to diagnose preeclampsia, in reality clinicians commonly use
proteinuria levels to inform clinical decisions regarding delivery
of preeclamptic cases [8]. This because the increased levels of pro-
teinuria worsen the progress of preeclampsia and are associated
with poor perinatal outcomes [911]. These results may suggest

http://dx.doi.org/10.1016/j.preghy.2017.03.005
2210-7789/ 2017 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.

Please cite this article in press as: X. Dong et al., Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes,
Preg. Hyper: An Int. J. Womens Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.005
2 X. Dong et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx

that the amount of proteinuria is correlated with the severity of
preeclampsia and this accordingly affects the management of
preeclampsia.
Only a handful of studies have investigated the perinatal out-
comes and maternal and fetal complications in preeclampsia in
cases with high levels of proteinuria [9,10,12]. To date in particular,
investigating the association of the amount of proteinuria in
preeclampsia and the severity of preeclampsia is limited. Therefore
in this study we performed a retrospective analysis to investigate
the association of the amount of proteinuria and the severity and
clinical outcomes of preeclampsia. All the data were obtained from
a university teaching hospital serving diverse urban and rural areas
in China.
2. Materials and methods
This investigation conforms to the principles outlined in the
Declaration of Helsinki. This study was approved by the Ethics
Committee of First Hospital of Xian Jiaotong University, China.
2.1. Study population
from ACOG (2013), based on the amount of proteinuria in a 24 h
urine collection, we divided the preeclampsia into four groups as
described below. Group 1: proteinuria in a 24 h urine collection
was <0.3 g/L; group 2: proteinuria in a 24 h urine collection was
between 0.3 g/L and 3 g/L; group 3: proteinuria in a 24 h urine col-
lection was between 3 g/L and 5 g/L; group 4: proteinuria in a 24 h
urine collection was 5 g/L.
2.3. Statistical analysis
Data were presented as median and range or percentage as
appropriate. The statistical differences in maternal age, gestational
week at diagnosis, blood pressure, gestational week at delivery,
and proteinuria in a 24 h urine collection between subgroups of
preeclampsia were assessed by the MannWhitney U test using
the Prism software package. The statistical differences in birth
weight were assessed by multiple liner regression using the SAS
software version 9.4 (SAS Institute Inc., Cary, NC, USA). Statistical
differences in the number of cases of severe preeclampsia, FGR or
stillbirth between subgroups of preeclampsia were assessed by a
Chi-square test using Prism software. P-values of <0.05 were con-
sidered significant.

This retrospective study was performed at a university teaching

3. Results
hospital serving a diverse urban and rural population of approxi-
mately 8 million people in China. Data on 239 women with
3.1. Clinical characteristics of study population
preeclampsia were collected from the Department of Obstetrics
and Gynaecology, First Hospital of Xian, Jiaotong University of
During the study period, 239 women with preeclampsia were
China from September 2011 to June 2013. The First Hospital of
included. All clinical details of women with preeclampsia are sum-
Xian Jiaotong University is a main maternal care referral hospital
marised in Table 1. Of 239 women with preeclampsia, 97 (40.5%)
in Xian city and large numbers of women with preeclampsia, in
women were diagnosed with mild preeclampsia. There were 41
particular those women with severe preeclampsia are referred to
(16%) patients with FGR and 23 (9.6%) patients with stillbirths.
this hospital,
All women with risk factors for developing preeclampsia such
3.2. The amount of proteinuria in a 24 urine collection was associated
as pre-existing hypertension, a previous pregnancy with
with the frequency of severe preeclampsia
preeclampsia, or other underlying medical disorders such as
gestational/pre-existing diabetes, or autoimmune diseases were
To compare the severity of preeclampsia with the amount of
excluded from this study. No pregnancies conceived by in vitro fer-
proteinuria in a 24 h urine collection, we analysed the correlation
tilisation were included.
of blood pressure (both systolic and diastolic blood pressure) and
All cases that were coded as preeclampsia in the hospital elec-
the amount of proteinuria in a 24 h urine collection. There was
tronic databases were individually assessed by the senior author
no correlation between the blood pressure and the amount of pro-
to ensure that the criteria for preeclampsia, as described below,
were satisfied. Data recorded included maternal age, gestational
week at diagnosis, gravidity, parity, blood pressure, proteinuria in Table 1
a 24 h urine collection, gestational weeks at delivery, birth weight, Clinical characteristics of the study population.
fetal growth restriction (FGR) and stillbirth. Proteinuria in 24 h Preeclampsia (n = 239)
urine collection was measured within 24 h after patients admitted
Early Onset Mild PE Severe PE
to the hospital, before any treatment. (n = 135) (n = 97) (n = 142)
Preeclampsia was defined as a maternal systolic blood pressure
Maternal age (years, median/ 30 (1844) 30 (1844) 29 (1944)
140 mmHg and/or diastolic blood pressure 90 mmHg measured range)
on two occasions separated by at least 6 h, and proteinuria Gestational week at diagnosis 31+1 (20+6 34+5 (21 32+4 (20+5
>300 mg in a 24 h period, or impaired liver function and lower pla- (weeks, median/range) 34) 40+4) 38+6)
telet count, after 20 weeks of gestation in accordance with the Gestational week at delivery 33+2 (22+6 37+2 (25 34+4 (22+5
(weeks, median/range) 37+4) 42+4) 40+1)
guidelines of the American College of Obstetricians and Gynaecol-
Systolic blood pressure (mmHg, 160 (130 145 (130 165 (140
ogists [13]. Maternal systolic blood pressure 160 mmHg and/or median/range) 240) 159) 240)
diastolic blood pressure 110 mmHg was defined as severe Diastolic blood pressure (mmHg, 109 (90 100 (80 110 (78
preeclampsia. Preeclampsia occurring earlier than 34 weeks of ges- median/range) 150) 128) 150)
tation was defined as early-onset. Birth weight (g, median/range) 1780 (920 2870 1870 (920
3330) (1080 4195)
4100)
2.2. Subgroups 24 h proteinuria (g/L, median/ 2.53 (2.02 0.61 (0.07 2.41 (0.04
range) 18.8) 11.9) 18.8)
AST (IU/L) 24.5 (8.7 21.5 (8.7 25.6 (10.2
There is no clear consensus on the amount of proteinuria to be 384) 253) 384)
considered heavy/severe [14]. The majority rely on values 3 g/L ALT (IU/L) 15 (8.7346) 14.5 (6 16 (3.7
or 5 g/L in a 24 h urine collection [14], and the definition of 346) 240)
heavy/severe proteinuria ranging from 2 to 5 g/L in a 24 h urine Creatinine (mM) 62 (33.3 57.2 (33.3 62.9 (33
177) 120) 177)
collection [8]. Therefore based on these studies and the guideline

Please cite this article in press as: X. Dong et al., Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes,
Preg. Hyper: An Int. J. Womens Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.005
 X. Dong et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx 3

teinuria in 24 h urine (data not shown). Although the number of Table 3

cases of severe preeclampsia was not different among group 2, 3 The association between the amount of proteinuria in a 24 h urine collection and the
severity of preeclampsia according to the time of onset.
and 4 (proteinuria in >0.3 g/L in a 24 h urine collection), the num-
ber of cases of severe preeclampsia was significantly higher in Early onset Severe PET (n = 91) Mild PET (n = 44) (Number,
patients with proteinuria >3 g/L in a 24 h urine collection (Table 2, (n = 135) (Number, %, lower, upper CL) %, lower, upper CL)

groups 3, p = 0.03 and group 4, p = 0.0006), compared to those <0.3 g/L (group 8 (61%) (31%, 86%) 5 (39%) (13%, 68%)
patients with proteinuria <0.3 g/L in a 24 h urine collection. In 1, n = 13)
0.33 g/L 34 (56%) (43%, 69%) 26 (46%) (30%, 56%)
addition the number of cases of severe preeclampsia was signifi- (group 2,
cantly higher in each group when individually compared with n = 60)
the number of cases of mild preeclampsia in each group (group 35 g/L (group 24 (80%) (61%, 92%) 6 (20%) (7%, 38%)a
2, 3 and 4, when proteinuria levels were >0.3 g/L) (Table 2, 3, n = 30)
5 g/L (group 25 (78%) (60%, 90%) 7 (22%) (9%, 39%)a
p < 0.05).
4, n = 32)
Time of onset and time of delivery were significantly earlier in
Late onset Severe PET (n = 51) Mild PET (n = 53) (Number,
patients with proteinuria >3 g/L in a 24 h urine collection, com-
(n = 104) (Number, %, lower, upper CL) %, lower, upper CL)
pared to those patients with proteinuria <3 g/L in a 24 h urine col-
<0.3 g/L (group 7 (32%) (13%, 54%) 15(68%) (45%, 86%)
lection (Table 2, groups 3 and 4, p < 0.001). However, there was no
1, n = 22)
significant difference in the average time between the onset of 0.33 g/L 31 (51%) (37%, 64%) 30 (49%) (36%, 62%)
preeclampsia and delivery between any of the 4 proteinuria groups (group 2,
(18 days, 14 days, 14 days and 11 days in each group, respectively) n = 61)
(p = 0.11, ANOVA). 35 g/L (group 9 (56%) (30%, 80%) 7 (44%) (19%, 70%)
3, n = 16)
We also analysed the changes in proteinuria with the severity of
5 g/L (group 4 (80%) (29%, 99%) 1 (20%) (50%, 71%)
preeclampsia according to the time of onset. In early onset 4, n = 5)
preeclampsia, when the proteinuria was >3 g/L in a 24 h urine col-
PET: preeclampsia.
lection, the frequency of severe preeclampsia was significantly
a: p < 0.01 compared to mild preeclampsia in same group.
higher than the frequency of mild preeclampsia. However, in late
onset preeclampsia, the frequency of severe preeclampsia was
not different from that of mild preeclampsia regardless the amount Table 4
of proteinuria in a 24 h urine collection (Table 3). The association between the amount of proteinuria in a 24 h urine collection and
neonatal outcomes.

Proteinuria FGR Stillbirth Apgar at 1 min <7

3.3. The amount of proteinuria in a 24 urine collection was correlated (n = 239) (number, %) (number, %) (number, %)
with perinatal outcomes
<0.3 g/L (group 1, 4 (11%) 1 (3%) 1 (3%)
n = 35)
To compare whether the amount of proteinuria in a 24 h urine 0.33 g/L (group 2, 18 (15%) 4 (3.4%) 9 (7.5%)
collection is associated with perinatal outcomes, we analysed the n = 121)
c
correlation of the amount of proteinuria in a 24 h urine collection 35 g/L (group 3, 8 (17.3%) 9 (19.5%) 8 (25%)d
n = 46)
and birth weight, and the number of cases of FGR, and the number
5 g/L (group 4, 11 (29.7%)a 7 (18.9%)b 5 (17.8%)
of cases where the fetal Apgar score at 1minute was <7, and the n = 37)
number of cases of stillbirth (Table 4). After adjusting the gesta-
FGR: Fetal growth restriction.
tional age, birth weight was significantly lower in patients with
a: P = 0.038 compared to the number of FGR in preeclampsia with proteinuria
proteinuria 5 g/L or 3-5 g/L in a 24hour urine collection groups <0.3 g/L or between 0.3 and 3 g/L.
in comparison to the <0.3 g/L or 0.33 g/L 24 h collection groups b: P = 0.036 compared to the number of stillbirth in preeclampsia with proteinuria
(Table 5, p = 0.002). There was no difference in birth weight <0.3 g/L.
between patients with 5 g/L and patients with 3-5 g/L proteinuria c: P = 0.043 compared to the number of stillbirth in preeclampsia with proteinuria
<0.3 g/L or between 0.3 and 3 g/L.
in a 24 h urine collection (p = 0.653).
d: P = 0.008 compared to the number of Apgar at 1 min <7 with other three groups.
The number of cases of FGR was significantly higher in patients
with 5 g/L proteinuria in a 24 h urine collection compared with
the other three groups (Table 4, p = 0.038). The number of cases other groups (Table 4, p = 0.041). The number of cases where the
of stillbirths were significantly higher in patients with 5 g/L or fetal Apgar score at 1minute was <7 was not different between
35 g/L proteinuria in a 24 h urine collection compared with two

Table 2
The association between the amount of proteinuria in a 24 h urine collection and the severity of preeclampsia.

Proteinuria (n = 239) Mild PET Severe PET Time of onset (weeks, Delivery time (weeks, Time of onset to delivery (days,
(number, %) (number, %) mean/SD) mean/SD) mean/SD)
<0.3 g/L (group 1, 20 (57%) 15 (43%) 34+5 4.2 37+1 4.2 18 22
n = 35)
a +1 +1
0.33 g/L (group 2, 46 (38%) 75 (62%) 34 3.7 36 2.7 14 16
n = 121)
35 g/L (group 3, 14 (30%) 32 (70%)a,b 30+6 5.4c 33+2 4.2d 14 21
n = 46)
5 g/L (group 4, n = 37) 6 (16%) 31 (84%)a,b 30+6 4.0c 32+4 3.6d 11 10

PET: preeclampsia.
a: P < 0.05 compared to mild PET in same group.
b: P < 0.03 compared to the number of severe PET with proteinuria <0.3 g/L.
c: P < 0.001 compared to time of onset in preeclampsia with proteinuria <0.3 g/L or 0.33 g/L.
d: P < 0.001 compared to time of onset in preeclampsia with proteinuria <0.3 g/L or 0.33 g/L.

Please cite this article in press as: X. Dong et al., Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes,
Preg. Hyper: An Int. J. Womens Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.005
4 X. Dong et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx
Table 5
The association between the amount of proteinuria in a 24 h urine collection and
birth weight after adjusting gestational age.
Proteinuria (n = 216)* Birth weight (g, mean) 95% Confidence
Limits (g)
<0.3 g/L (group 1, n = 34) 2560 2401 2791
0.33 g/L (group 2, n = 117) 2398 2313 2482
35 g/L (group 3, n = 35) 2152 1987 2316
5 g/L (group 4, n = 30) 2201 2022 2380
*
There were 23 still births in study population.
group 1 and 2 and 4. Whilst the number of cases where the fetal
Apgar score at 1minute was <7 was significant higher in patients
with 3-5 g/L proteinuria in a 24 h urine collection (Table 4,
p = 0.008).
4. Discussion
Screening for proteinuria is currently not essential in diagnosis
of preeclampsia in antepartum care of pregnant women because
the symptoms of preeclampsia are multiple and nonspecific. How-
ever, perinatal outcomes including fetal growth restriction (FGR),
neonatal complications, stillbirth and preterm delivery may be
associated with amount of proteinuria [9,10]. There is current a
debate in the merit of assessing proteinuria in terms of diagnosis
of preeclampsia, in particular in severe preeclampsia. The NICE
guideline has already not recommended repeating and following
up the amount of proteinuria once the proteinuria has been
detected [15]. The American Society of Obstetrics and Gynaecology
also does not recommend requiring proteinuria for the diagnosis of
preeclampsia if other severe preeclampsia features are present
such as liver dysfunction and lower platelet count in 2013 [7].
However, a review study suggested that defining the amount of
proteinuria in the diagnosis of preeclampsia should be focused
on in order to distinguish mild from severe preeclampsia [8].
Although up to 10% of cases of preeclampsia have no protein-
uria at the time of clinical presentation [5,6], the combination of
blood pressure and proteinuria was considered a hallmark of
increased adverse perinatal outcomes and increased risk to mater-
nal wellbeing [1618]. This is because severe proteinuria is
thought to develop late in the progression of preeclampsia [18].
A recent survey study suggested that proteinuria of >3 g/L in a
24 h urine collection is considered as one of the criterion for severe
preeclampsia [14]. However in our current study, we found that
62% of cases of preeclampsia with 0.33 g/L proteinuria over 24 h
were severe, which is significantly higher than the percentage of
mild preeclampsia with same levels of proteinuria (38%). In addi-
tion, we further found that more than 70% of cases of severe
preeclampsia were seen in patients with proteinuria >3 g/L in a
24 h urine collection, indicating the majority of cases of severe
preeclampsia have proteinuria >0.3 g/L in a 24 h urine collection
(Table 2). Even in the group of women with preeclampsia with pro-
teinuria <0.3 g/L in a 24 h urine collection, 43% of cases were
severe. Our data also show that the frequency of severe preeclamp-
sia was not different when proteinuria >0.3 g/L. Taken together,
our data may suggest that the amount of proteinuria (>0.3 g/L) is
not correlated with severe preeclampsia, once proteinuria is
detected. Our finding is supported by previous reports that sug-
gested that the amount of proteinuria should not be a criterion
of severe preeclampsia [14,15]. However, our data also show that
the frequency of severe preeclampsia with higher amount of pro-
teinuria (>0.3 g/L) was significantly higher than the cases of mild
preeclampsia with same amount of proteinuria. This suggests that
the amount of proteinuria is related to the progression of the
Please cite this article in press as: X. Dong et al., Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes,
Preg. Hyper: An Int. J. Womens Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.005
severity of preeclampsia, potentially as a result of the increased
extent of kidney damages seen in severe preeclampsia.
It has previously been suggested that maternal morbidity in
either severe or mild preeclampsia with different amount of pro-
teinuria was not different [9]. Therefore in this study we analysed
the changes in proteinuria with the severity of preeclampsia
according to the time of disease onset. In early onset preeclampsia,
we found the frequency of severe preeclampsia was significantly
higher than the frequency of mild preeclampsia when the protein-
uria in a 24 h urine collection was >3 g/L. However in late onset
preeclampsia, the frequency between severe and mild preeclamp-
sia was not different regardless the amount of proteinuria in a 24 h
urine collection. This data suggests that amount of proteinuria may
appear to be an indicator for early-onset preeclampsia and pro-
gression to severe preeclampsia.
The correlation between the amount of proteinuria and time of
onset in preeclampsia has not yet been investigated. Some studies
have suggested that the amount of proteinuria is associated with
maternal complications [12,19], whilst others concluded that
preeclampsia with a massive proteinuria did not increase maternal
complications [9]. In our current study, we found that time of onset
of preeclampsia with proteinuria >3 g/L in a 24 h urine collection
(group 3 and 4) was significantly earlier than that in preeclampsia
with proteinuria <3 g/L in 24 h (group 1 and 2). This data may sug-
gest that the amount of proteinuria is positively correlated with
time of onset of preeclampsia. Urinary protein excretion increases
substantially due to a combination of increased glomerular filtra-
tion rate (GFR) and increased permeability of the glomerular base-
ment membrane during pregnancy [20]. The renal histologic lesion
in preeclampsia is glomerular endotheliosis which results in a
lower GFR and effective renal plasma flow (ERPF) [2124]. It is
unclear whether renal dysfunction is the primary or secondary
cause in the pathogenesis of preeclampsia. Our data may suggest
that renal dysfunction could occur earlier due to the severity of
glomerular endotheliosis seen in preeclampsia [25]. But we inter-
estingly found that there was no difference in time between the
onset of preeclampsia and delivery among all the groups. This
potentially suggests that the amount of proteinuria in preeclamp-
sia is not correlated with the time of delivery, although in clinical
practice, heavy proteinuria is usually considered as an indicator to
deliver preeclamptic patients [8].
With increasing amount of proteinuria, there is increased risk of
adverse fetal outcomes [26]. However, the amount of excess pro-
teinuria underpinning this association has not been defined [26].
One study concluded that there was an association between fetal
outcomes and massive proteinuria (>5 g/L in a 24 h urine collec-
tion) [9]. In our current study, we found the number of cases of
FGR was not associated with the amount of proteinuria unless pro-
teinuria levels in preeclampsia were >5 g/L in a 24 h urine collec-
tion. We also found that birth weight was lower and the number
of still birth was higher in preeclampsia with proteinuria >3 g/L.
These results suggest that fetal outcomes may be associated with
the amount of proteinuria in preeclampsia. However, in this study
we also found that the time of delivery was earlier in preeclampsia
with proteinuria >3 g/L. Therefore the adverse fetal outcomes such
as lower birth weight or higher number of cases of stillbirth may be
because of preterm delivery or the function of prematurity rather
than of heavy amount of proteinuria itself [9].
In conclusion, our data demonstrate that the amount of protein-
uria is not correlated with the severe preeclampsia, once protein-
uria is detected, but is associated with severity of preeclampsia,
in particular in early onset preeclampsia. In addition, we found that
the amount of proteinuria is positively correlated with time of
onset in preeclampsia, but time between the onset of preeclampsia
and delivery is not associated with the amount of proteinuria.
Adverse fetal outcome appears to be a result of the prematurity
 X. Dong et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health xxx (2017) xxxxxx
rather than proteinuria itself. Although the evaluation of protein-
uria is not important in establishing the diagnosis of preeclampsia,
our data may suggest that proteinuria is related to the severity of
preeclampsia.
Declaration of interest
None of authors have a conflict of interest.
Acknowledgements
This study was supported by Shanxi Province Science and Tech-
nology Development project, China (Grant number 2015SF124 and
2016KW-006). Authors would like to thank Dr. Arier Lee, a statisti-
cian from The University of Auckland, New Zealand for statistical
analysis support.
References
[1] B. Sibai, G. Dekker, M. Kupferminc, Pre-eclampsia, The Lancet 365 (9461)
(2005) 785799.
[2] A.C. Staff, S.J. Benton, P. von Dadelszen, J.M. Roberts, R.N. Taylor, et al.,
Redefining preeclampsia using placenta-derived biomarkers, Hypertension 61
(5) (2013) 932942.
[3] A.L. Tranquilli, G. Dekker, L. Magee, J. Roberts, B.M. Sibai, W. Steyn, et al., The
classification, diagnosis and management of the hypertensive disorders of
pregnancy: a revised statement from the ISSHP, Pregnancy Hypertens. 4 (2)
(2014) 97104.
[4] K. Higby, C.R. Suiter, J.Y. Phelps, T. Siler-Khodr, O. Langer, Normal values of
urinary albumin and total protein excretion during pregnancy, Am. J. Obstet.
Gynecol. 171 (4) (1994) 984989.
[5] B.M. Sibai, Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive
cases, Am. J. Obstet. Gynecol. 163 (3) (1990) 10491054. discussion 54-5.
[6] C.E. Thornton, A. Makris, R.F. Ogle, J.M. Tooher, A. Hennessy, Role of proteinuria
in defining pre-eclampsia: clinical outcomes for women and babies, Clin. Exp.
Pharmacol. Physiol. 37 (4) (2010) 466470.
[7] Hypertension in Pregnancy. American College of Obstetricians and
Gynecologists Womens Health Care Physician, 2013, November.
[8] M.D. Lindheimer, D. Kanter, Interpreting abnormal proteinuria in pregnancy:
the need for a more pathophysiological approach, Obstet. Gynecol. 115 (2 Pt 1)
(2010) 365375.
[9] M.G. Newman, A.G. Robichaux, C.M. Stedman, R.K. Jaekle, M.T. Fontenot, T.
Dotson, et al., Perinatal outcomes in preeclampsia that is complicated by
massive proteinuria, Am. J. Obstet. Gynecol. 188 (1) (2003) 264268.
[10] S. Thangaratinam, A. Coomarasamy, F. OMahony, S. Sharp, J. Zamora, K.S.
Khan, et al., Estimation of proteinuria as a predictor of complications of pre-
eclampsia: a systematic review, BMC Med. 7 (2009) 10.
Please cite this article in press as: X. Dong et al., Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes,
Preg. Hyper: An Int. J. Womens Card. Health (2017), http://dx.doi.org/10.1016/j.preghy.2017.03.005
5
[11] J.L. Morgan, D.B. Nelson, S.W. Roberts, C.E. Wells, D.D. McIntire, F.G.
Cunningham, Association of baseline proteinuria and adverse outcomes in
pregnant women with treated chronic hypertension, Obstet. Gynecol. 128 (2)
(2016) 270276.
[12] K. Erkenekli, C. Iskender, E. Oztas, A.S. Ozgu-Erdinc, A. Yucel, D. Uygur, Clinical,
but not laboratory features are predictive of risk of subsequent development of
preeclampsia in patients with isolated proteinuria after midgestation,
Hypertens. Pregnancy 34 (4) (2015) 495505.
[13] Hypertension in pregnancy, Report of the American College of Obstetricians
and Gynecologists Task Force on Hypertension in Pregnancy, Obstet. Gynecol.
122 (5) (2013) 11221131.
[14] A.L. Tranquilli, M.A. Brown, G.G. Zeeman, G. Dekker, B.M. Sibai, The definition
of severe and early-onset preeclampsia. Statements from the International
Society for the Study of Hypertension in Pregnancy (ISSHP), Pregnancy
Hypertens. 3 (1) (2013) 4447.
[15] Hypertension in pregnancy: diagnosis and management of hypertensive
disorders during pregnancy. NICE National Institute for Health and Clinical
Excellence clinical guideline 2010.
[16] F.G. Cunningham, K.J. Leveno, L.C. Gilstrap, J.C. Hauth, K.D. Wenstrom,
Williams Obstetrics, McGraw-Hill, New York, 2001. p. 567618.
[17] C.C. Lin, M.D. Lindheimer, P. River, A.H. Moawad, Fetal outcome in
hypertensive disorders of pregnancy, Am. J. Obstet. Gynecol. 142 (3) (1982)
255260.
[18] S. Ferrazzani, A. Caruso, S. De Carolis, I.V. Martino, S. Mancuso, Proteinuria and
outcome of 444 pregnancies complicated by hypertension, Am. J. Obstet.
Gynecol. 162 (2) (1990) 366371.
[19] K. Bramham, C.E. Poli-de-Figueiredo, P.T. Seed, A.L. Briley, L. Poston, A.H.
Shennan, et al., Association of proteinuria threshold in pre-eclampsia with
maternal and perinatal outcomes: a nested case control cohort of high risk
women, PLoS ONE 8 (10) (2013) e76083.
[20] M. Roberts, M.D. Lindheimer, J.M. Davison, Altered glomerular permselectivity
to neutral dextrans and heteroporous membrane modeling in human
pregnancy, Am. J. Physiol. 270 (2 Pt 2) (1996) F338F343.
[21] N.S. Assali, S.A. Kaplan, S.J. Fomon, R.A. Douglass, Renal function studies in
toxemia of pregnancy; excretion of solutes and renal hemodynamics during
osmotic diuresis in hydropenia, J. Clin. Invest. 32 (1) (1953) 4451.
[22] C.P. McCartney, B. Spargo, A.B. Lorincz, Y. Lefebvre, R.E. Newton, Renal
structure and function in pregnant patients with acute hypertension; osmolar
concentration, Am. J. Obstet. Gynecol. 90 (1964) 579592.
[23] H.E. Sarles, S.S. Hil, A.L. LeBlanc, G.H. Smith, C.O. Canales, A.R. Remmers,
Sodium excretion patterns during and following intravenous sodium chloride
loads in normal and hypertensive pregnancies, Am. J. Obstet. Gynecol. 102 (1)
(1968) 17.
[24] P. Moran, P.H. Baylis, M.D. Lindheimer, J.M. Davison, Glomerular ultrafiltration
in normal and preeclamptic pregnancy, J. Am. Soc. Nephrol. 14 (3) (2003) 648
652.
[25] V.E. Pollak, J.B. Nettles, The kidney in toxemia of pregnancy: a clinical and
pathologic study based on renal biopsies, Medicine 39 (1960) 469526.
[26] P. Chan, M. Brown, J.M. Simpson, G. Davis, Proteinuria in pre-eclampsia: how
much matters?, BJOG 112 (3) (2005) 280285