Hypertension in Pregnancy

ISSN: 1064-1955 (Print) 1525-6065 (Online) Journal homepage: https://www.tandfonline.com/loi/ihip20

The importance of proteinuria in preeclampsia

and its predictive role in maternal and neonatal
outcomes

Atakan Tanacan, Erdem Fadiloglu & Mehmet Sinan Beksac

To cite this article: Atakan Tanacan, Erdem Fadiloglu & Mehmet Sinan Beksac (2019): The
importance of proteinuria in preeclampsia and its predictive role in maternal and neonatal
outcomes, Hypertension in Pregnancy, DOI: 10.1080/10641955.2019.1590718

To link to this article: https://doi.org/10.1080/10641955.2019.1590718

Published online: 02 Apr 2019.

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HYPERTENSION IN PREGNANCY
https://doi.org/10.1080/10641955.2019.1590718

The importance of proteinuria in preeclampsia and its predictive role in

maternal and neonatal outcomes
Atakan Tanacan , Erdem Fadiloglu, and Mehmet Sinan Beksac
Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey

ABSTRACT ARTICLE HISTORY

Objective: To evaluate impact of 24-h proteinuria level in preeclampsia on maternal/perinatal Received 9 November 2018
outcomes. Accepted 1 March 2019
Methods: Singleton pregnancies with preeclampsia delivered after 24 weeks of gestation were KEYWORDS
included. Patients were divided into mild (0.3 to <2 g) (n=72), severe (2 to <5 g) (n=30), and Pregnancy; preeclampsia;
massive (≥5 g) (n=24) proteinuria groups, and cut-off values of 24-h proteinuria for composite proteinuria
adverse maternal and neonatal outcomes were calculated.
Results: Twenty-four hour proteinuria level cut-offs for composite adverse outcomes were 3275
mg (72.2% sensitivity, 85.6% specificity) and 2395 mg (72.7% sensitivity, 78% specificity)
respectively.
Conclusion: Severe and massive proteinuria were related to poor maternal, perinatal, and neo-
natal outcomes.

Introduction
Preeclampsia, a multisystem progressive pregnancy-speci-
fic disorder, is characterized by the onset of hypertension
and proteinuria, or hypertension and significant end organ
dysfunction with or without proteinuria after 20 weeks of
gestation or in the postpartum period in a previously
normotensive woman (1). Approximately 4.6% of preg-
nancies are complicated by preeclampsia worldwide (2).
Preeclampsia is a leading cause of maternal and perinatal
morbidity and mortality (3). Although the exact mechan-
isms behind the development of preeclampsia have not
been revealed yet, both maternal and fetal/placental factors
are thought to be involved in the pathophysiology of the
disease (4–6). According to most studies, impaired devel-
opment of placental vasculature early in pregnancy causes
placental underperfusion, which leads to release of antian-
giogenic factors into systemic circulation, and results in
endothelial dysfunction (4–6). Preeclampsia may affect
hematologic, cardiovascular, respiratory, neural, renal,
and hepatobiliary systems, and it may cause end organ
dysfunction (4–6). Fortunately, preeclampsia-related com-
plications mostly resolve after the delivery of the placenta
(4,6). Thus, it is critical for obstetricians to decide on the
optimal time for delivery to decrease preeclampsia-related
mortality and morbidity. Adequate assessment of the sever-
ity of preeclampsia and identification of pregnant women
at greater risk for disease-related complications may help
obstetricians to achieve better management protocols.
Until the last decade, quantification of protei-
nuria was used to assess the severity of preeclampsia
(a cut-off value of >2 g/24 h was usually used to
recommend immediate delivery) (7,8). However, in
2013 the American College of Obstetricians and
Gynecologists (ACOG) removed proteinuria as an
essential criterion for diagnosis of preeclampsia.
Additionally, they also removed massive proteinuria
(5 g/24 h) and fetal growth restriction (FGR) as
possible features of severe disease because massive
proteinuria has a poor correlation with outcome,
and management of FGR is not different from that
of pregnancies without preeclampsia. Oliguria was
also removed as a characteristic of severe disease
(1,7). Although high levels of proteinuria were
found to be associated with poor perinatal outcomes
in some studies, the effect of proteinuria on perina-
tal outcomes has not been proven precisely yet
(7–11).
The aim of this study was to evaluate the impact of
24-h levels of urinary protein on maternal/perinatal
outcomes in women with preeclampsia and to identify
cut-off values for the prediction of composite adverse
maternal/neonatal outcomes.

CONTACT Atakan Tanacan atakantanacan@yahoo.com Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University
Hospital, Ankara, Turkey
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 A. TANACAN ET AL.
Materials and methods
We conducted a retrospective cohort study among
women with preeclampsia who delivered at Hacettepe
University Hospital between 1 January 2007 and 31
December 2017. The required data were extracted from
the Hacettepe University Hospital electronic database.
Preeclampsia was defined as systolic blood pressure
(SBP) ≥140 mm Hg or diastolic blood pressure (DBP)
≥90 mm Hg, measured in the left lateral decubitis posi-
tion, on two occasions, at least 4 h apart, together with
proteinuria (≥300 mg in a 24-h urine sample) occurring
for the first time at 20 weeks of gestation or longer
(7,12). Severe preeclampsia was defined as the presence
of any of the following parameters: (1) SBP ≥160 mm
Hg and/or DBP ≥110 mm Hg, (2) new-onset cerebral or
visual disturbances (such as photopsia and/or scotomata,
severe headache, altered mental status), (3) severe, per-
sistent right upper quadrant or epigastric pain unrespon-
sive to medication and not accounted for by an
alternative diagnosis, serum transaminase concentration
≥2 times the upper limit of normal for a specific labora-
tory, or both, (4) thrombocytopenia (<100,000 platelets/
µL), (5) progressive renal insufficiency (serum creatinine
>1.1 mg/dL) or doubling of serum creatinine concentra-
tion in the absence of other renal disease, and (6) pul-
monary edema (7,12).
Patients with singleton pregnancies who fulfilled the
above preeclampsia criteria and delivered after
24 weeks of gestation in our institution were included
in the study. Patients with diagnosis of nephropathy
before pregnancy and patients who did not deliver in
the research facility were excluded from the study.
There were 18,606 deliveries at Hacettepe University
Hospital between 1 January 2007 and 31 December
2017. Seventy-four cases were excluded due to diagno-
sis of nephropathy before pregnancy. Seven-hundred
and forty-one patients had preeclampsia after
24 weeks of gestation. Twenty-four hour urinary pro-
tein levels were assessed for 170 patients among these
741 patients. There were 44 pregnancies with multiple
gestations. Remaining 126 eligible patients were divided
into three groups according to their 24-h urinary pro-
tein levels during pregnancy: (1) mild (0.3 to <2 g)
(n = 72), (2) severe (2 to <5 g) (n = 30), and massive
(≥5 g) (n = 24) proteinuria groups (7).
Clinical and demographic features of the patients
[maternal age, parity, body mass index (BMI) (kg/m2),
preexisting hypertension and diabetes mellitus rates, gesta-
tional week at diagnosis of preeclampsia, percentage of
patients with severe preeclampsia features and frequency
of preeclampsia-associated clinical symptoms (visual and
respiratory symptoms (dyspnea and desaturation), and
epigastric pain)]; laboratory findings [24-h proteinuria
levels, rates of elevated lactate dehydrogenase (LDH)
(≥600 IU/L), thrombocytopenia (<100,000 platelets/µL),
elevated aspartate aminotransferase (AST) (≥70 U/L), and
elevated creatinine (≥1.1 mg/dL)]; maternal complications
[rates of HELLP syndrome (a syndrome consisted of
hemolysis, elevated liver enzymes, and low platelet
count), eclampsia (onset of seizures), placental abruption,
admission to intensive care unit (ICU), and necessity for
hemodialysis]; prenatal complications [rates of FGR
(defined as an estimated weight on ultrasonographic exam-
ination below 10th percentile adjusted to gestational age),
oligohydramnios (defined as amniotic fluid index ≤5),
impaired umbilical artery Doppler measurements (pulsati-
lity index >95th percentile), preterm delivery (delivery that
occurs before 37 weeks of gestation), onset of labor, mode
of delivery, gestational week at birth, birth weight, general/
regional anesthesia rates, and rates for the usage of magne-
sium sulfate]; neonatal complications [rates of small for
gestational age at delivery (birth weight <10th percentile for
gestational age on a singleton growth curve), 5th min
APGAR Score <7, birth weight <2500 g, admission to
neonatal intensive care unit (NICU), respiratory distress
syndrome (RDS), intraventricular hemorrhage (IVH),
necrotizing enterocolitis (NEC), neonatal sepsis, and neo-
natal death), rates of postpartum persistent hypertension,
and worsening of preexisting chronic hypertension] were
compared between the groups. Additionally, cut-off values
of 24-h proteinuria for composite adverse maternal and
neonatal outcomes were calculated. Furthermore, preg-
nancy and neonatal outcomes (rates of FGR, oligohydram-
nios, impaired umbilical artery Doppler parameters,
preterm delivery, onset of labor, mode of delivery, anesthe-
sia method, APGAR <7, birth weight <2500 g, admission to
NICU, RDS, IVH, NEC, neonatal sepsis, neonatal death,
composite adverse neonatal outcome, postpartum new-
onset/worsening hypertension in the mother together
with mean gestational age at birth and birth weight values)
were compared between the groups after the exclusion of
patients with severe features of preeclampsia in order to
evaluate the independent effect of proteinuria severity on
pregnancy and neonatal complications (mild proteinuria
group, n = 44; severe proteinuria group, n = 9; and massive
proteinuria group, n = 3).
The composite maternal adverse outcome was defined
as the presence of any of the following parameters: (1)
HELLP syndrome, (2) eclampsia, (3) placental abruption,
(4) admission to ICU, and (5) necessity for hemodialysis.
Furthermore, the composite neonatal adverse outcome was
defined as the presence of any of the following parameters:
(1) small for gestational age, (2) 5th min APGAR Score <7,
(3) term birth weight <2500 g, (4) admission to NICU, (5)
RDS, (6) IVH, (7) NEC, (8) neonatal sepsis, and (9)
 HYPERTENSION IN PREGNANCY 3

neonatal death. All patients in the study were evaluated Results

12 weeks after the delivery in terms of postpartum persis-
tent hypertension and worsening in preexisting chronic
hypertension. Blood pressure measurements together
with ancillary tests for end organ dysfunction, such as
echocardiography, complete blood count, blood biochem-
istry, and urine analysis, were performed to assess the
severity of hypertension. Worsening of preexisting chronic
hypertension was defined as new-onset/progression of end
organ dysfunction, and/or need for higher doses of anti-
hypertensive medications or addition of another drug to
achieve normotensive blood pressure values.
Statistical analyses were performed with the
Statistical Package for the Social Sciences (SPSS.22,
IBM SPSS Statistics for Windows, version 22.0.
Armonk, NY: IBM Corp.). The Kolmogorov–Smirnov
test was used to evaluate the normal distribution of the
data. Normally distributed data were presented as
means and standard deviations, while nonparametric
data were presented as median (range) values. The
one-way ANOVA and Kruskal–Wallis tests were used
to compare the parametric and nonparametric vari-
ables, respectively, between the groups; categorical vari-
ables were compared using the chi-square test. We used
receiver operating characteristic (ROC) curves to assess
the performance of 24-h proteinuria value in predicting
composite adverse maternal and neonatal outcomes.
Youden index was applied to ROC curve to choose
the best cut-off values (13). The significance level was
set as a p-value <0.05.
Written informed consent was obtained from all the
patients, and the study was approved by the institutional
ethics committee of Hacettepe University (GO 18/358).
A total of 126 women were found to be eligible accord-
ing to the study criteria, 72 (mean ± SD,
829.83 ± 56.56 mg/24 h; range 300–1956 mg), 30
(mean ± SD, 3201.06 ± 114.56 mg/24 h; range 2010–
4485 mg), and 24 (mean ± SD, 7793.16 ± 508.35 mg/
24 h; range 5200–14,796 mg) were in the mild, severe,
and massive proteinuria groups, respectively.
Demographic, clinical, and laboratory features of
participants at preeclampsia diagnosis are shown in
Table 1. There were no statistically significant differ-
ences between groups for maternal age, parity, BMI,
and preexisting hypertension and diabetes mellitus
rates. However, mean gestational week at diagnosis;
patients with severe features and rates for visual,
respiratory, and epigastric pain symptoms; rates of
LDH ≥600 IU/L; thrombocytopenia (<100,000 plate-
lets/µL); AST ≥70 U/L; and creatinine (≥1.1 mg/dL)
were all different among the groups (Table 1).
Patients with higher levels of 24-h proteinuria were
diagnosed with preeclampsia at an earlier gestational
week, and they had higher rates of severe preeclamp-
sia. Additionally, patients in massive proteinuria
group had more severe clinical symptoms of pree-
clampsia and more laboratory abnormalities com-
pared to those in mild proteinuria group. Pregnancy
complications and outcomes are shown in Table 2.
HELLP syndrome and placental abruption were sig-
nificantly more frequent in severe (p = 0.004) and
massive (p = 0.014) proteinuria groups. Although
three out of four cases with eclampsia were in the
massive proteinuria group, the small number of
events precluded significance. Additionally, rates of

Table 1. Clinical and demographical features of the patients together with the laboratory findings.
Massive
Mild proteinuria Severe proteinuria proteinuria
Variables group (n = 72) group (n = 30) group (n = 24) P-value
Maternal age (years, mean ± SD)a 30.82 ± 0.75 30.87 ± 0.98 31.46 ± 1.17 0.89
Parity (n, %)b 0.24
Primipara 39 (54.2%) 21 (70%) 12 (50%)
Multipara 33 (45.8%) 9 (30%) 12 (50%)
BMI (kg/m2, mean ± SD)a 29.32 ± 0.65 27.73 ± 0.78 29.58 ± 0.93 0.30
Preexisting hypertension (n, %)b 18 (25%) 10 (33.3%) 11 (45.8%) 0.15
Preexisting diabetes mellitus (n, %)b 11 (15.3%) 2 (6.7%) 2 (8.3%) 0.39
Gestational week at diagnosis (mean ± SD)a 33.26 ± 0.46 30.62 ± 0.69 28.82 ± 0.79 <0.001
Patients with severe preeclampsia features (n, %)b 28 (38.9%) 21 (70%) 21 (87.5%) <0.001
Visual symptomsb 5 (6.9%) 6 (20%) 16 (66.7%) <0.001
Respiratory symptomsb 3 (4.2%) 1 (3.3%) 9 (37.5%) <0.001
Epigastric painb 11 (15.3%) 5 (16.7%) 13 (54.2%) <0.001
Proteinuria level (mg/24 h)a 829.83 ± 56.56 3201.06 ± 114.56 7793.16 ± 508.35 <0.001
LDH ≥600 IU/Lb 12 (16.7%) 14 (46.7%) 17 (70.8%) <0.001
Thrombocytopenia (<100,000 platelets/µL)b 11 (15.3%) 10 (33.3%) 12 (50%) 0.002
AST ≥70 U/Lb 8 (11.1%) 8 (26.7%) 15 (62.5%) <0.001
Creatinine (≥1.1 mg/dL)b 4 (5.6%) 3 (10%) 13 (54.2%) <0.001
BMI: body mass index; LDH: lactate dehydrogenase; AST: aspartate aminotransferase.
a
One-way ANOVA test was used for the statistical analysis.
b
Chi-square test was used for the statistical analysis.
4 A. TANACAN ET AL.

Table 2. Pregnancy complications and outcomes.

Mild proteinuria group Severe proteinuria group Massive proteinuria group
Variables (n = 72) (n = 30) (n = 24) P-value
HELLP syndrome (n, %)a 8 (11.1%) 8 (26.7%) 10 (41.7%) 0.004
Eclampsia (n, %)a 1 (1.4%) 2 (6.7%) 3 (12.5%) 0.074
Placental abruption (n, %)a 1 (1.4%) 0 (0%) 3 (12.5%) 0.014
Usage of magnesium sulfate (n, %)a 32 (45.1%) 17 (56.7%) 22 (91.7%) <0.001
Admission to ICU (n, %)a 3 (4.2%) 4 (13.3%) 17 (70.8%) <0.001
Necessity for hemodialysis (n, %)a 1 (1.4%) 1 (3.3%) 5 (20.8%) <0.001
Composite maternal adverse outcome (n, %)a 5 (6.9%) 12 (40%) 19 (79.2%) <0.001
FGR (n, %)a 22 (30.6%) 16 (53.3%) 20 (83.3%) <0.001
Oligohydramnios (n, %)a 19 (26.4%) 16 (53.3%) 19 (79.2%) <0.001
Impaired umbilical artery Doppler 12 (16.7%) 14 (46.7%) 19 (79.2%) <0.001
parameters (n, %)a
Preterm delivery (n, %)a 42 (58.3%) 26 (86.6%) 24 (100%) <0.001
Onset of labor (n, %)a 0.150
Spontaneous 12 (16.7%) 1 (3.4%) 2 (8.3%)
induced 60 (83.3%) 28 (96.6%) 22 (91.7%)
Mode of delivery (n, %)a 0.252
Vaginal 6 (8.3%) 1 (3.3%) 0 (0%)
Cesarean 66 (91.7%) 29 (96.7%) 24 (100%)
Gestational age at birth (mean ± SD)b 34.87 ± 0.40 31.64 ± 0.73 31.55 ± 0.57 <0.001
Birth weight (mean ± SD)b 2453.66 ± 118.06 1570.33 ± 156.17 1409.58 ± 107.60 <0.001
Anesthesia (n, %)a <0.001
General 21 (29.2%) 19 (63.3%) 19 (79.2%)
Regional 51 (70.8%) 11 (36.7%) 5 (20.8%)
Postpartum new-onset/worsening hypertension 17 (23.6%) 14 (48.3%) 21 (87.5%) <0.001
(n, %)a
HELLP: a syndrome consisted of hemolysis, elevated liver enzymes, and low platelet count; ICU: intensive care unit; FGR: fetal growth restriction.
a
Chi-square test was used for the statistical analysis.
b
One-way ANOVA test was used for the statistical analysis.

magnesium sulfate administration, hemodialysis,
admission to ICU, and the composite adverse mater-
nal outcome were higher in severe and massive pro-
teinuria groups (p < 0.001). Furthermore, rates for
FGR, oligohydramnios, impaired umbilical artery
Doppler measurements, and preterm delivery were
all higher in severe and massive proteinuria groups
(p < 0.001). The massive proteinuria group had the
highest rate of maternal and prenatal complications.
No differences were observed between the groups for
labor onset and mode of delivery. Rates of induced
labor and cesarean section were very high for all
groups. However, there were significant differences
between the groups for mean gestational age at
birth and mean birth weight, severe and massive
proteinuria groups had lower values in both. Rates
of general anesthesia were higher in severe and mas-
sive proteinuria groups, as so, rates of postpartum
new-onset/worsening hypertension reaching 87.5% in
the massive proteinuria group.
Neonatal outcomes and complications are shown in
Table 3. There were differences between the groups for

Table 3. Neonatal complications and outcomes.

Mild proteinuria group Severe proteinuria group Massive proteinuria group
Variables (n = 72) (n = 30) (n = 24) P-value
Gestational age at birth (n, %)a <0.001
<34 weeks 24 (33.3%) 19 (63.3%) 17 (70.8%)
34–37 weeks 18 (25%) 7 (23.3%) 7 (29.2%)
>37 weeks 30 (41.7%) 4 (13.4%) 0 (0%)
SGA (n, %)a 22 (30.6%) 16 (53.3%) 20 (83.3%) <0.001
APGAR <7 (n, %)a 15 (20.8%) 17 (56.7%) 19 (79.2%) <0.001
Birth weight <2500 g (n, %)a 37 (51.4%) 24 (80%) 24 (100%) <0.001
Admission to NICU (n, %)a 40 (55.6%) 26 (86.7%) 23 (95.8%) <0.001
Neonatal complicationsa <0.001
RDS (n, %) 4 (5.6%) 8 (26.7%) 8 (33.3%)
IVH (n, %) 1 (1.4%) 1 (3.3%) 3 (12.5%)
NEC (n, %) 1 (1.4%) 1 (3.3%) 4 (16.7%)
Neonatal sepsis (n, %) 2 (2.8%) 0 (0%) 1 (4.2%)
Neonatal death (n, %) 3 (4.2%) 4 (13.3%) 3 (12.5%)
Composite adverse neonatal 11 (15.3%) 14 (46.7%) 19 (79.2%) <0.001
outcome (n, %)a
SGA: small for gestational age; NICU: neonatal intensive care unit; RDS: respiratory distress syndrome; IVH: intraventricular hemorrhage;
NEC: necrotizing enterocolitis.
a
Chi-square test was used for the statistical analysis.
 HYPERTENSION IN PREGNANCY 5

Table 4. Pregnancy and neonatal complications and outcomes after the exclusion of patients with severe features of preeclampsia
from each group.
Mild proteinuria group Severe proteinuria group Massive proteinuria group
Variables (n = 44) (n = 9) (n = 3) P-value
FGR (n, %)a 12 (27.3%) 5 (55.5%) 1 (33.3%) 0.254
Oligohydramnios (n, %)a 11 (25%) 5 (55.5%) 1 (33.3%) 0.19
Impaired umbilical artery Doppler parameters 5 (11.4%) 5 (55.5%) 1 (33.3%) 0.008
(n, %)a
Preterm delivery (n, %)a 20 (45.4%) 7 (77.7%) 3 (100%) 0.028
Onset of labor (n, %)a 0.097
Spontaneous 8 (18.2%) 1 (11.1%) 2 (66.6%)
induced 36 (81.8%) 8 (88.8%) 1 (33.3%)
Mode of delivery (n, %) 0.827
Vaginal 5 (11.4%) 1 (11.1%) 0 (0%)
Cesarean 39 (88.6%) 8 (88.8%) 3 (100%)
Anesthesia (n, %)a 0.015
General 10 (22.7%) 6 (66.6%) 0 (0%)
Regional 34 (77.3%) 3 (33.3%) 3 (100%)
Gestational age at birth (n, %)a 0.02
<34 weeks 9 (20.5%) 6 (66.6%) 2 (66.6%)
34–37 weeks 11 (25%) 2 (22.2%) 1 (33.3%)
>37 weeks 24 (54.5%) 1 (11.2%) 0 (0%)
SGA (n, %)a 12 (27.3%) 5 (55.5%) 1 (33.3%) 0.254
APGAR <7 (n, %)a 6 (13.6%) 4 (44.4%) 1 (33.3%) 0.08
Birth weight <2500 g (n, %)a 17 (38.6%) 7 (77.7%) 3 (100%) 0.018
Gestational age at birth (mean ± SD)b 35.64 ± 3.37 31.51 ± 4.26 33.00 ± 2.64 0.006
Birth weight (mean ± SD)b 2658.63 ± 960.97 1546.66 ± 891.03 1850.0 ± 511.17 0.005
Admission to NICU (n, %)a 20 (45.4%) 7 (77.7%) 2 (66.6%) 0.182
Neonatal complicationsa <0.001
RDS (n, %) 0 (0%) 1 (11.1%) 0 (0%)
IVH (n, %) 1 (2.2%) 0 (0%) 0 (0%)
NEC (n, %) 0 (0%) 0 (0%) 1 (33.3%)
Neonatal sepsis (n, %) 2 (4.4%) 0 (0%) 0 (0%)
Neonatal death (n, %) 1 (2.2%) 2 (22.2%) 1 (33.3%)
Composite adverse neonatal outcome (n, %)a 4 (9%) 3 (33.3%) 2 (66.6%) 0.01
Postpartum new-onset/worsening hypertension 3 (6.8%) 3 (33.3%) 2 (66.6%) 0.03
(n, %)a
FGR: fetal growth restriction; SGA: small for gestational age; NICU: neonatal intensive care unit; RDS: respiratory distress syndrome; IVH: intraventricular hemorrhage;
NEC: necrotizing enterocolitis.
a
Chi-square test was used for the statistical analysis.
b
One-way ANOVA test was used for the statistical analysis.

gestational age at birth, birth weight, rates of SGA,
APGAR <7, admission to NICU, neonatal complica-
tions (RDS, IVH, NEC, neonatal sepsis, and neonatal
death), and composite adverse neonatal outcomes (all
p < 0.001). Neonatal complications were more frequent
in severe and massive proteinuria groups and the latter
exhibited the highest rate.
Pregnancy and neonatal complications and out-
comes after the exclusion of patients with severe
features of preeclampsia from each group are shown
in Table 4. No differences were observed between the
groups for the rates of FGR, oligohydramnios, onset
of labor, mode of delivery, SGA, APGAR <7, and
admission to NICU. On the other hand, the rates of
impaired umbilical artery Doppler parameters, pre-
term delivery, anesthesia method, gestational age at
birth, birth weight <2500 g, neonatal complications,
composite adverse neonatal outcome, and postpar-
tum new-onset/worsening hypertension were all dif-
ferent among the groups. Additionally, mean
gestational age at birth and birth weight were found
to be different between the groups (Table 4). Rates of
pregnancy and neonatal complications were still
more frequent in severe and massive proteinuria
groups compared to mild proteinuria group after
the exclusion of patients with severe features of
preeclampsia.
ROC analysis of 24-h proteinuria in predicting
composite adverse maternal and neonatal outcomes
is shown in Figure 1 and Figure 2 (composite
adverse maternal outcome) and 2 (composite
adverse neonatal outcome). Area under the curve
(AUC) was calculated as 0.783 (95% CI: 0.674–
0.892) and 0.760 (95% CI: 0.666–0.855) for compo-
site adverse maternal and neonatal outcomes,
respectively. The values in ROC curves with the
best balance of sensitivity/specificity were 3275
(72.2% sensitivity, 85.6% specificity) and 2395 mg/
24 h (72.7% sensitivity, 78% specificity) for compo-
site adverse maternal and neonatal outcomes,
respectively, according to the results obtained from
the Youden index.
6 A. TANACAN ET AL.
Figure 1. ROC curve of 24-h proteinuria value in predicting
composite adverse maternal outcome (AUC: 0.783, 95% CI:
0.674–0.892). Cut-off value for 24-h proteinuria measurement
is 3275 mg with 72.2% sensitivity and 85.6% specificity,
p < 0.001.
Figure 2. ROC curve of 24-h proteinuria value in predicting
composite adverse neonatal outcome (AUC: 0.760, 95% CI:
0.666–0.855). Cut-off value for 24-h proteinuria measurement
is 2395 mg with 72.7% sensitivity and 78% specificity,
p < 0.001.
Discussion
Preeclampsia, one of the most challenging issues in obste-
trics, causes severe maternal/perinatal mortality and
morbidity (3). Despite advances in medicine, the exact
cause of preeclampsia and the curative treatment, other
than delivery of the placenta, have not been established
yet. Thus, management protocols for preeclampsia are
conservative and supportive at present (14,15), including
prevention of preeclampsia-related maternal/perinatal
mortality and morbidity by management of hypertension,
seizure prophylaxis, optimization of delivery time, pre-
vention of prematurity-related complications, transfer of
the mother to a tertiary health-care center, and admission
of patients with severe complications to ICU (14,15).
Although conservative management may be applied in
some selected preterm pregnancies, immediate delivery
may be needed in most of the severe cases (16). Therefore,
appropriate assessment of severity of preeclampsia and
identification of pregnancies at a greater risk for disease-
related complications are critical for physicians.
Although, quantification of proteinuria was once used
to assess the severity of preeclampsia, ACOG eliminated
proteinuria as an essential criterion for diagnosis of
preeclampsia in 2013 (1,7). On the other hand, various
studies in literature have demonstrated the worsening
maternal/perinatal outcomes with increasing levels of
proteinuria (7,8,10,11). Preeclampsia causes specific
renal histological changes, termed “glomerular endothe-
liosis” (17), which results in swelling of endothelial cell,
loss of fenestrations, and occlusion of capillary lumens
which in turn lead to proteinuria (17). Thus, severity of
preeclampsia was considered to be in direct proportion
to the severity of proteinuria. Nevertheless, Lindheimer
and Kanter suggested a more physiologic approach to
assessment of proteinuria in pregnancy and concluded
that the level of proteinuria should not guide the man-
agement of preeclampsia (18). Von Dadelszen et al.
developed and validated the “fullPIERS model” with
the aim of identifying the risk of fatal or life-threatening
complications in women with preeclampsia within 48 h
of hospital admission in a prospective multicenter study
and they did find association of 24 h proteinuria levels
with the combined adverse outcomes (19). Payne et al.
examined the ability of three different proteinuria assess-
ment methods (urinary dipstick, spot urine protein-crea-
tinine ratio, and 24-h urine collection) to predict adverse
pregnancy outcomes in their multicenter cohort study,
however, finding that no single method could predict
adverse perinatal outcome (20). Furthermore, Van der
Tuuk et al. used the data from a Dutch multicenter
randomized controlled trial in their cohort study and
analyzed whether a composite adverse neonatal outcome
could be predicted from clinical data, including patient
and delivery characteristics, as well as laboratory find-
ings. The level of proteinuria with the dipstick test was
not found to be significant in their study (21). On the

other hand, Dong et al. demonstrated in their retro-
spective study that severe proteinuria was associated
with onset of preeclampsia and delivery at an earlier
gestational age, and a higher incidence of FGR (22).
Additionally, Kim et al. in their retrospective study also
concluded that massive proteinuria might be associated
with early-onset preeclampsia and early delivery (23).
Moreover, Guida et al. in their retrospective study
demonstrated that quantifying the severity of proteinuria
could identify a subgroup of women with preeclampsia
at increased risk of adverse outcomes (7). Furthermore,
Bouzari et al. designated cut-off values for 24-h urine
proteinuria to predict pregnancy complications in a ret-
rospective cohort study (12). Cut-off values of 1250,
1750, 1650, and 1350 mg were reported to be associated
with higher rates of RDS, placental abruption, FGR, and
admission to NICU, respectively, in the mentioned study
(12). These cut-off values were lower than the cut-off
values which were found in our study.
Patients with higher levels of 24-h proteinuria had
been diagnosed with preeclampsia at earlier gestational
week, and had higher rates of severe preeclampsia features
in our study. Moreover, patients in the massive protei-
nuria group had more severe clinical symptoms of pre-
eclampsia, and higher values for laboratory tests than
those in the mild proteinuria group. These findings were
similar with other studies in literature (7,12,22,23).
HELLP syndrome, placental abruption, eclampsia, rates
for usage of magnesium sulfate, admission to ICU, neces-
sity for hemodialysis, and composite adverse maternal
outcome were higher in severe and massive proteinuria
groups. Similarly, rates for FGR, oligohydramnios,
impaired umbilical artery Doppler measurements, and
preterm delivery were higher in severe and massive pro-
teinuria groups. Furthermore, the rates of maternal and
prenatal complications were highest in the massive pro-
teinuria group. These findings were also compatible with
literature (7,12,22,23). On the other hand, rates of
induced labor and cesarean section were very high for
all groups most probably due to the clinical management
protocols of our institution. Cesarean section and induc-
tion of labor are generally preferred for the delivery of
high-risk pregnancies in our clinic. Severe and massive
proteinuria groups had lower values for gestational week
at birth, birth weight, and the rates of general anesthesia
were more frequent in both groups in our study. Besides,
the rates of postpartum new-onset/worsening hyperten-
sion were more frequent in severe and massive protei-
nuria groups consistent with literature (7,12,22,23).
Furthermore, rates of pregnancy and neonatal complica-
tions were still more frequent in severe and massive
proteinuria groups after the exclusion of patients with
severe features. According to the results of our study,
HYPERTENSION IN PREGNANCY 7
neonatal complications were more frequent in severe
and massive proteinuria groups and consistent with the
previous studies (7,12,22,23). Remarkably, retrospective
studies in the literature found a significant relationship
between the severity of proteinuria and the composite
adverse maternal/neonatal outcomes, whereas this rela-
tionship was not found in prospective studies.
The limitations of the study were the relatively small
sample size, retrospective design, and single-center
experience. However, a relatively large number of para-
meters and the presence of long-term patient outcomes
were the main strengths of our study.
In conclusion, our study demonstrated that severe and
massive proteinurias were related to poor maternal, peri-
natal, and neonatal outcomes. Physicians should be extre-
mely cautious, especially in patients with preeclampsia who
have higher levels (3275 mg/24 h for composite adverse
maternal outcome and 2395 mg/24 h for composite adverse
neonatal outcome) of 24-h urinary protein. Further, multi-
center, observational cohort studies with larger number of
patients are necessary for more precise results.
Acknowledgments
Special thanks to all the health-care staff of our institution for
their respectable effort for the patients.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
ORCID
Atakan Tanacan http://orcid.org/0000-0001-8209-8248
References
[1] Obstetricians ACo, Gynecologists. Hypertension in
pregnancy. Report of the American college of obstetri-
cians and gynecologists’ task force on hypertension in
pregnancy. Obstet Gynecol. 2013;122(5):1122.
[2] Abalos E, Cuesta C, Grosso AL, et al. Global and
regional estimates of preeclampsia and eclampsia: a
systematic review. Eur J Obstetrics Gynecol Reprod
Biol. 2013;170(1):1–7.
[3] Van Lerberghe W. The world health report 2005: make
every mother and child count. Geneva, Switzerland: World
Health Organization; 2005.
[4] Gilbert JS, Ryan MJ, LaMarca BB, et al. Pathophysiology
of hypertension during preeclampsia: linking placental
8 A. TANACAN ET AL.
ischemia with endothelial dysfunction. Am J Physiol
Heart Circ Physiol. 2008;294(2):H541–H550.
[5] Leijnse JE, de Heus R, de Jager W, et al. First trimester
placental vascularization and angiogenetic factors are
associated with adverse pregnancy outcome. Pregnancy
Hypertens. 2018;13:87–94.
[6] Silva D, Marreiro D, Moita Neto JM, et al. Oxidative
stress and immunological alteration in women with pre-
eclampsia. Hypertens Pregnancy. 2013;32(3):304–311.
[7] Guida JP, Parpinelli MA, Surita FG, Costa ML. The
impact of proteinuria on maternal and perinatal out-
comes among women with pre-eclampsia. Int J Gynecol
Obstet. 2018;143(1):101–107.
[8] Newman MG, Robichaux AG, Stedman CM, et al.
Perinatal outcomes in preeclampsia that is complicated
by massive proteinuria. Am J Obstet Gynecol. 2003;188
(1):264–268.
[9] Tranquilli A, Dekker G, Magee L, et al. The classifica-
tion, diagnosis and management of the hypertensive
disorders of pregnancy: a revised statement from the
ISSHP. Pregnancy Hypertens. 2014;4(2):97.
[10] Mateus J, Newman R, Sibai BM, et al. Massive urinary
protein excretion associated with greater neonatal risk
in preeclampsia. AJP Rep. 2017;7(1):e49.
[11] Parlakgümüş HA, Şimşek E, Çok T, et al. The relationship
between proteinuria in severe preeclampsia and maternal
and fetal outcomes. Gynecology Obstet Reprod Med.
2012;18:1.
[12] Bouzari Z, Javadiankutenai M, Darzi A, et al. Does
proteinura in preeclampsia have enough value to pre-
dict pregnancy outcome. Clin Exp Obstet Gynecol.
2014;41(2):163–168.
[13] Fluss R, Faraggi D, Reiser B. Estimation of the youden
index and its associated cutoff point. Biomet J J Math
Methods Biosci. 2005;47(4):458–472.
[14] Dekker GA. Management of preeclampsia. Pregnancy
Hypertens. 2014;4(3):246–247.
[15] English FA, Kenny LC, McCarthy FP. Risk factors and
effective management of preeclampsia. Integr Blood
Press Control. 2015;8:7.
[16] Magee LA, Pels A, Helewa M, et al. Diagnosis, evalua-
tion, and management of the hypertensive disorders of
pregnancy: executive summary. J Obstet Gynaecology
Canada. 2014;36(5):416–438.
[17] Stillman IE, Karumanchi SA. The glomerular injury of
preeclampsia. J Am Soc Nephrol. 2007;18(8):2281–
2284.
[18] Lindheimer MD, Kanter D. Interpreting abnormal protei-
nuria in pregnancy: the need for a more pathophysiologi-
cal approach. Obstetrics Gynecol. 2010;115(2):365–375.
[19] von Dadelszen P, Payne B, Li J, et al. Prediction of
adverse maternal outcomes in pre-eclampsia: develop-
ment and validation of the fullPIERS model. Lancet.
2011;377(9761):219–227.
[20] Payne B, Magee LA, Côté A-M, et al. PIERS protei-
nuria: relationship with adverse maternal and perinatal
outcome. J Obstet Gynaecology Canada. 2011;33
(6):588–597.
[21] van der Tuuk K, Holswilder-Olde Scholtenhuis M,
Koopmans C, et al. Prediction of neonatal outcome in
women with gestational hypertension or mild pree-
clampsia after 36 weeks of gestation. J Matern Fetal
Neonatal Med. 2015;28(7):783–789.
[22] Dong X, Gou W, Li C, et al. Proteinuria in preeclamp-
sia: not essential to diagnosis but related to disease
severity and fetal outcomes. Pregnancy Hypertens.
2017;8:60–64.
[23] Kim MJ, Kim YN, Jung EJ, et al. Is massive proteinuria
associated with maternal and fetal morbidities in pre-
eclampsia? Obstet Gynecol Sci. 2017;60(3):260–265.