Expert Review
org
Proteinuria during pregnancy: definition,
pathophysiology, methodology, and clinical
significance
Michal Fishel Bartal, MD; Marshall D. Lindheimer, MD; Baha M. Sibai, MD
Introduction
Urinalysis for protein is one of the most
commonly performed antenatal
screening tests.1 During pregnancy,
proteinuria has traditionally been a
hallmark of preeclampsia, but it is also a
nonspecific indicator of renal disease
and may result from an elevated plasma
protein concentration, increased
glomerular permeability, decreased
tubular protein reabsorption, and renal
hemodynamic alterations. It has been
reported that the rate of isolated pro-
teinuria in pregnancy may reach 8%,
whereas preeclampsia occurs among 3%
to 8% of pregnancies.2,3 Starting in 2013,
proteinuria is considered sufficient but
not necessary for the diagnosis of pre-
eclampsia; however, there is an ongoing
debate regarding the importance of
protein excretion in risk assessment,
particularly in women with hypertensive
disorders.4,5 The purpose of this review
is to describe the current knowledge
regarding the pathophysiology, defini-
tion, methods of assessment, and clinical
significance of proteinuria in pregnancy.
From the Division of Maternal-Fetal Medicine,
Department of Obstetrics, Gynecology and
Reproductive Sciences, McGovern Medical
School, The University of Texas Health Science
Center at Houston, Houston, TX (Drs Fishel
Bartal and Sibai); and Departments of Medicine
and Obstetrics and Gynecology, Pritzker School
of Medicine, The University of Chicago, Chicago,
IL (Dr Lindheimer).
Received July 5, 2020; revised Aug. 24, 2020;
accepted Aug. 27, 2020.
The authors report no conflict of interest.
Corresponding author: Michal Fishel Bartal, MD.
Michal.f.bartal@uth.tmc.edu
0002-9378/$36.00
Published by Elsevier Inc.
https://doi.org/10.1016/j.ajog.2020.08.108
ajog.
Qualitative and quantitative measurement of urine protein excretion is one of the
most common tests performed during pregnancy. For more than 100 years,
proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines
recommend that proteinuria is sufficient but not necessary for the diagnosis. Still,
in clinical practice, most patients with gestational hypertension will be diagnosed
as having preeclampsia based on the presence of proteinuria. Although the
reference standard for measuring urinary protein excretion is a 24-hour urine
collection, spot urine protein-to-creatinine ratio is a reasonable “rule-out” test for
proteinuria. Urine dipstick screening for proteinuria does not provide any clinical
benefit and should not be used to diagnose proteinuria. The classic cutoff cited to
define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine
protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated
proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3%
to 8% of pregnancies. Although this threshold is widely accepted, its origin is not
based on evidence on adverse pregnancy outcomes but rather on expert opinion
and results of small studies. After reviewing the available data, the most
important factor that influences maternal and neonatal outcome is the severity of
blood pressures and presence of end organ damage, rather than the excess
protein excretion. Because the management of gestational hypertension and
preeclampsia without severe features is almost identical in frequency of sur-
veillance and timing of delivery, the separation into 2 disorders is unnecessary. If
the management of women with gestational hypertension with a positive
assessment of proteinuria will not change, we believe that urine assessment for
proteinuria is unnecessary in women who develop new-onset blood pressure at or
after 20 weeks’ gestation. Furthermore, we do not recommend repeated mea-
surement of proteinuria for women with preeclampsia, the amount of proteinuria
does not seem to be related to poor maternal and neonatal outcomes, and
monitoring proteinuria may lead to unindicated preterm deliveries and related
neonatal complications. Our current diagnosis of preeclampsia in women with
chronic kidney disease may be based on a change in protein excretion, a
baseline protein excretion evaluation is critical in certain conditions such as
chronic hypertension, diabetes, and autoimmune or other renal disorders. The
current definition of superimposed preeclampsia possesses a diagnostic dilemma,
and it is unclear whether a change in the baseline proteinuria reflects another
systemic disease such as preeclampsia or whether women with chronic disease
such as chronic hypertension or diabetes will experience a different “normal”
pattern of protein excretion during pregnancy. Finally, limited data are available
regarding angiogenic and other biomarkers in women with chronic kidney disease
as a potential aid in distinguishing the worsening of baseline chronic kidney
disease and chronic hypertension from superimposed preeclampsia.
Key words: 24-hour urine collection, biomarker, chronic hypertension, diagnosis,
gestational hypertension, hypertensive disorder of pregnancy, preeclampsia, pregnancy,
pregnancy outcome, podocytes, prognosis, proteinuria, renal disease, superimposed
preeclampsia, urine protein-to-creatinine ratio
MONTH 2020 American Journal of Obstetrics & Gynecology 1
Expert Review
TABLE 1
Glossary of terms
Term
Bowman’s capsule
Podocytes
Slit diaphragm
GFR
Transcapillary hydraulic pressure
difference (DP)
Mean glomerular intracapillary oncotic
pressure (pGC )
Glomerular ultrafiltration coefficient (Kf )
Filtration fraction
GFR, glomerular filtration rate.
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
Pathophysiology of Proteinuria
Glomerular and tubular handling of
protein
In nonpregnant populations, the urine is
almost free of protein and healthy adults
excrete <150 mg of protein per day in
urine every day.6 Within the nephron,
the glomerular filtration barrier is
responsible for the selective filtration of
blood from the afferent arteriole to the
Bowman’s space (Table 1). The filtration
barrier includes 3 layers: the glomerular
epithelium, the basement membrane,
2 American Journal of Obstetrics & Gynecology MONTH 2020
Explanation
1. Part of the nephron that forms a cup-like
sack surrounding the glomerulus. It
consists of inner (visceral) layer
surrounding the glomerulus and outer
(parietal) layer.
2. The Bowman’s capsule encloses a space
between those 2 layers, known as the
Bowman’s space, which represents the
beginning of the urinary space and is
contiguous with the proximal convoluted
tubule of the nephron.
Terminally differentiated epithelial cells that
have a number of radiating processes
(pedicles) that cover the glomerular basement
membrane and face the renal pelvis.
Adjacent podocyte foot processes are
connected by a specialized intercellular
junction known as the slit diaphragm.
1. The volume of fluid filtered from the renal
glomerular capillaries into the Bowman’s
capsule per unit time.
2. Can be assessed using the following
equation: GFR¼(DPpGC)Kf
Transcapillary hydraulic pressure difference or
the pressure generated across the glomerulus.
Mean of the colloid osmotic pressure within the
glomerular capillaries and within the
Bowman’s capsule.
The product of the surface area available for
filtration and the hydraulic permeability (k),
which is the permeability to ultrafiltrate across
the glomerulus.
1. The portion of plasma filtered through the
cellular layers of the glomerulus.
2. Calculated by dividing the GFR by the renal
plasma flow.
and the slit diaphragms, which are
formed by the foot processes of the
podocytes.7 Podocytes are terminally
differentiated epithelial cells, which
cover the glomerular basement mem-
brane and face the renal pelvis. They
have octopus-like extensions from the
cell body, known as primary processes,
which further branch to form secondary
and tertiary processes. The junction be-
tween the tertiary foot processes is a
specialized region, known as the slit
diaphragm, and is thought to be a
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modified adherent junction. The slit
diaphragm contains transmembrane
proteins such as nephrin and Neph1,
which are unique to the podocytes;
adherens junction proteins such as
FAT1, P-cadherins, and catenins; and
tight junction proteins such as junctional
adhesion molecule A, occludin, and
cingulin.8e10 The foot processes have an
important role in maintaining the
integrity of the membrane and will affect
the protein filtration rate.11 The filtrate
that passes through the Bowman’s space
continues into the proximal tubule and
the loop of Henle for further processing.
The intact glomerular filter is almost
impermeable to large proteins, and
proteinuria may result from excessive
permeability of the glomerular barrier
for protein or impaired reabsorption of
protein in the proximal tubule.12 With
normal renal function, the amount of
plasma protein entering the proximal
tubule through the glomerulus depends
on the glomerular plasma flow and the
concentration and the filtration rate of
each protein. Molecular weight, shape,
and electrical charge of each protein will
affect its filtration rate. The relationship
between glomerular filtration rate (GFR)
and its determinants can be assessed
using the following equation:
GFR¼(DPpGC)Kf. In this equation,
DP is the transcapillary hydraulic pres-
sure difference or the pressure generated
across the glomerulus and pGC is the
mean glomerular intracapillary oncotic
pressure. The determinants of GFR that
can be measures or approximated in
humans include Kf and pGC. Kf is the
glomerular ultrafiltration coefficient,
calculated as the product of the surface
area available for filtration and the hy-
draulic permeability (k), which is the
permeability to ultrafiltrate across the
glomerulus. To compute pGC, one first
calculates the oncotic pressure of plasma
entering the efferent arteriole from the
glomerular tuft. The oncotic pressure
can be calculated by using the following
equation: pE¼pA/(1FF). In this equa-
tion, pA is the afferent oncotic pressure
that can be measured directly from hu-
man plasma and filtration fraction (FF)
is the portion of plasma filtered through
the cellular layers of the glomerulus,
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calculated by dividing the GFR by the
renal plasma flow.13
Once proteins enter the proximal tu-
bule, there may be tubular reabsorption,
even with large proteins such as albu-
min.8,14,15 Proteinuria of glomerular
origin occurs only when the tubular
ability to reabsorb the filtered protein
becomes saturated. It seems that the
reabsorption capacity rapidly ap-
proaches to a maximum because preg-
nant women with underlying glomerular
disorders have indicated that a small
increase in albumin filtration will result
in considerable increment in measured
proteinuria.16e18
Renal adaptation in pregnancy
In a healthy pregnancy, an approximate
doubling of urine protein level can be
expected. Early maternal renal adapta-
tion to pregnancy includes a 75% in-
crease in renal plasma flow by 16 weeks’
gestation and a 50% increase in GFR by 5
to 7 weeks’ gestation compared with
nonpregnant levels. GFR remains 50%
above the nonpregnant level throughout
pregnancy.19e22 Creatinine clearance is
the most commonly utilized method for
estimating glomerular filtration,
although it is the least precise. This is
because creatinine is secreted by the tu-
bules in addition to being cleared by the
glomeruli. Creatinine clearance is
moderately increased in pregnancy (to
110e150 mL/minute).
Increased protein excretion during
pregnancy is thought to be caused by the
increase in GFR. The increase in GFR
could result from a combination of the
following: (1) hypervolemia and hemo-
dilution lowering protein concentration
and oncotic pressure and (2) the increase
in renal blood flow. This theory is chal-
lenged by the timing of proteinuria in
serial studies; the increase in proteinuria
occurs in the second half of pregnancy,
which does not correspond to the timing
of the peak increase in glomerular
filtration.23 There is also evidence from
studies using dextran sieving that the
physiological increase in total protein
excretion in normal pregnancy is related
to increased ultrafiltration coefficients
and glomerular basement membrane
permeability in late pregnancy.24e26
These 2 bodies of evidence suggest that
the increase in GFR hypothesis does not
completely explain the timing and
pathophysiology of proteinuria in
normal pregnancy. Alterations in
tubular reabsorption capacity may also
play a role in increased protein excretion
during pregnancy.27,28
Pathophysiology of proteinuria in
preeclampsia
Proteinuria was first described in a
woman with eclampsia by Rayer in 1840,
and in 1884, Schedoff and Porockjakoff
described a link between hypertension
and eclampsia.29e31 The first theory of
the pathogenesis of proteinuria in pre-
eclampsia was related to glomerular
changes and increased permeability to
proteins. As with other types of pro-
teinuria of glomerular origin, the pro-
teinuria of preeclampsia involves
high-molecular weight proteins such as
albumin. With the introduction of elec-
tron microscopy techniques, better
visualization and localization of
glomerular components became avail-
able. Preeclampsia was found to be
associated with a distinctive glomerular
appearance of endothelial vacuolization
and hypertrophy of the cytoplasmic or-
ganelles.32 The glomeruli are enlarged
and solidified (bloodless), and the
swelling of the endothelial cells and to a
lesser extent the mesangial cells will
cause narrowing or occlusion of capillary
lumens. Spargo et al33 referred to these
lesions by the now widely accepted term
glomerular capillary endotheliosis. The
pathologic finding of endotheliosis was
later found to be present not only in
women with preeclampsia but also in in
women with gestational hypertension
without proteinuria and similarly in
normal healthy pregnancies.34 There-
fore, in recent years, the pathobiology of
renal damage in preeclampsia has shifted
from the glomerular endothelial cells to
the podocytes.35,36 Current data suggest
that the number of urinary podocytes in
women with preeclampsia is higher than
in women with gestational hypertension
or normal pregnancies (Figure 1).36,37
Furthermore, the function of the podo-
cyte and the slit diaphragm depends on
the physiological concentrations of
MONTH 2020 American Journal of Obstetrics & Gynecology
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circulating factors, such as vascular
endothelial growth factor (VEGF) and
its antagonist, the soluble receptor fms-
like tyrosine kinase 1 (sFlt-1).38e40 In
the kidney, podocytes produce VEGF,
and VEGF receptors have been found in
endothelial cells and podocytes them-
selves. Thus, paracrine and autocrine
pathways could affect the integrity of the
glomerular filtration barrier with tight
regulation of VEGF signaling to main-
tain a healthy glomerulus.13,40,41 Women
with preeclampsia have increased serum
concentrations of sFlt-1 and soluble
endoglin (sEng) and reduced concen-
trations of free VEGF and free placental
growth factor (PlGF), which are proan-
giogenic proteins that are bound and
neutralized by sFlt-1. The angiogenic
imbalance in preeclampsia may play an
important key role in the development of
both podocyte and endothelial damage
in the glomerular filtration barrier.42,43
The recent link between VEGF and the
glomerular filtration barrier in women
with preeclampsia was studied in animal
models of podocyte-specific VEGF
knockout mice that showed glomerular
endothelial cell swelling and podocyte
foot process effacement.40,44 Further-
more, animal studies found that
replacement with VEGF-121 had bene-
ficial effects with partially reversing the
glomerular lesion and decreasing
proteinuria.45
Definition of Pathologic Proteinuria
During Pregnancy
During normal pregnancy, urinary pro-
tein excretion increases from normal
nonpregnant levels and in healthy
women can reach 200 to 260 mg per day
by the third trimester.23,46,47 The classic
cutoff cited to define proteinuria during
pregnancy is a value >300 mg/24 hours.
Alternatively, a timed excretion that is
extrapolated to this 24-hour urine value
or a urine protein-to-creatinine ratio
(UPCR) of at least 0.3 is used.4 Although
this threshold is widely accepted for
defining abnormal protein excretion, its
origin does not seem to be based on
clinical outcomes but rather on expert
opinion and small studies that have
attempted to establish statistically
normative values for pregnancy.23,46e48
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FIGURE 1
Renal injury in preeclampsia
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
In the largest prospective study evalu-
ating 270 women, the mean protein
excretion was 116.9 mg/day with the
upper limit of confidence interval (CI)
being 259.4 mg/24 hours. This cutoff
was recently challenged in a small pro-
spective longitudinal study of 65 nullip-
arous healthy women who completed a
24-hour urine collection at 2 time
points: before conception and during 30
to 32 weeks’ gestation. In this study, 45%
of healthy women with uncomplicated
pregnancies exceed the diagnostic
threshold for abnormal proteinuria with
a mean protein excretion of 254 mg/24
hours (interquartile range, 166e396 mg/
24 hours).48 Another study of 142
normotensive term pregnancies found
an UPCR of >0.3 in 13.4% of pregnan-
cies.49 Furthermore, women with twin
pregnancies may have a different
“normal” threshold because they have
greater protein excretion during preg-
nancy than singleton pregnancies.50,51 A
prospective study assessing 24-hour
protein excretion in twin vs singleton
pregnancy found increased baseline
urinary protein excretion in twin
4 American Journal of Obstetrics & Gynecology MONTH 2020
pregnancies (204.392.5 mg vs
269.3124.1 mg; P¼.004). Moreover,
43% of twin pregnancies who never
developed hypertension had a 24-hour
urine protein excretion of 300 mg.51
Given the uncertainty of the diagnostic
threshold for proteinuria diagnosis in
pregnancy and the lack of correlation to
outcome, the current diagnostic
threshold criteria should be revisited and
readdressed in future studies.48
How Should We Evaluate Proteinuria
During Pregnancy?
The reference standard for measuring
urinary protein excretion is a 24-hour
urine collection.52 More convenient
methods used in practice involve urinary
dipstick or measurement of the UPCR in
a spot urine sample. In many locations,
the spot UPCR is utilized rather than 24-
hour collections.53
Urine dipsticks
The use of a dipstick to screen the urine
for protein is an integral part of the
current antenatal care plan and usually
the first screening for proteinuria. This
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method is based on a change in pH in the
presence of anionic proteins, that is, al-
bumin and transferrin. Outside of
pregnancy, urine dipsticks have good
sensitivity as a screening tool for albu-
min loss of >30 mg per day, but speci-
ficity is limited. Urine dipstick measures
urine protein concentration and hydra-
tion or diuresis will influence the sensi-
tivity and specificity of the test.
Based on the current available data, the
accuracy of dipstick urinalysis in preg-
nancy with 1þ threshold for predicting
proteinuria of 300 mg/day is poor with a
positive likelihood ratio of 3.48 (95% CI,
1.66e7.27), a negative likelihood ratio of
0.6 (95% CI, 0.45e0.8), sensitivity of 59%
(95% CI, 37%e79%), and specificity of
28% (95% CI, 18%e41%).54 Accuracy
may be improved with a higher threshold
but the available data are limited.54e56 A
recent prospective observational study
evaluating the accuracy of urine dipstick in
pregnancy included 2212 urine samples
from 1033 pregnant women who under-
went simultaneous dipstick and UPCR
tests in the same spot urine samples at least
once. For the prediction of proteinuria
(defined as UPCR of >0.27), the dipstick
was associated with false-negative test re-
sults in 8.8% of samples and false-positive
test results in 59% of samples compared
with UPCR. Furthermore, the false-
positive rate was 78% for 1þ on dipstick
test, 21% for 2þ on dipstick test, and 1.3%
for 3þ on dipstick test. It was notable that
creatinine was consistently higher in urine
specimens without an abnormal UPCR
than in those with abnormal UPCR at any
dipstick test result. In comparison be-
tween normotensive and hypertensive
women with similar dipstick test results,
the risk of having proteinuria detected by a
dipstick was consistently higher in hyper-
tensive than normotensive women. For
example, among women with a result of
1þ on dipstick test, proteinuria was pre-
sent in 47% of hypertensive women vs
8.7% of normotensive women.57
Routine urine dipstick screening for
low-risk women does not provide any
clinical benefit,58 and proteinuria, with
dipstick analysis, cannot be accurately
detected or excluded at the þ1 threshold
and is not recommended for diagnosing
preeclampsia.
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Urine protein-to-creatinine ratio
In the spot urine tests, albumin con-
centration is normalized for the urinary
creatinine concentration to approximate
a 24-hour albumin or protein loss. It is
important to emphasize that creatinine
production and excretion are dependent
on both kidney function and muscle
mass. Urinary protein loss can vary
substantially with the time of day, so
morning samples are preferable.59 As
discussed previously, a UPCR value of
0.3 would represent abnormal pro-
teinuria during pregnancy based on the
current cutoff.60 A UPCR of <0.3 may
give a false-negative result for abnormal
24-hour urine collections but, in such
cases, the total protein excretion is usu-
ally <400 mg/day.61 A systemic review
and meta-analysis evaluating the accu-
racy of spot urinary protein and albumin
to creatinine ratios for the detection of
proteinuria in women with suspected
preeclampsia included 20 studies (2978
women). Threshold values for UPCR
ranged between 0.13 and 0.5, with
sensitivity ranging from 65% to 89% and
specificity from 63% to 87%; the area
under the receiver operating curve was
0.69. On average, across all studies, the
optimum threshold (relating to sensi-
tivity and specificity values of >75%)
seems to be between 0.30 and 0.35.
However, no threshold gave a summary
estimate of >80% for both sensitivity
and specificity.62 Another meta-analysis
included 13 studies (1214 women) of
the spot UPCR in hypertensive pregnant
women (not only suspected preeclamp-
sia). A cutoff of UPCR of >0.3 had a
sensitivity of 91% (range, 73%e97%),
specificity of 90% (range, 41%e100%),
median positive likelihood ratio of 9.1
(range, 1.54 to infinity), and median
negative likelihood ratio of 0.14 (range,
0.04e0.37). The current data suggest
that the spot UPCR is a reasonable “rule-
out” test for proteinuria of 300 mg/day
among otherwise healthy women with
gestational hypertension with or without
proteinuria on dipstick.63,64
The UPCR is not a reliable measure of
pathologic proteinuria during labor,
because an elevated UPCR (>0.3) can be
found in one-third of uncomplicated
pregnancies at term with an increase in
UPCR during labor with the highest
levels seen in the postpartum period.65
24-hour urine collection
The gold standard test remains a 24-
hour urine protein measurement, but
this method is not practical especially for
women requiring a rapid diagnosis.
Moreover, the 24-hour urine collection
may have other limitations as a result of
inadequate collection, inconvenience,
spillage, and other factors.55,64 If per-
formed, it should be accompanied by
measurement of creatinine excretion to
assess completeness of collection. The
rate of inaccurate 24-hour urine collec-
tion is much higher during pregnancy
than nonpregnant state and may
approach 50%. This is not surprising,
given the pregnancy-related reasons for
measurement error, including physio-
logical dilatation of the ureters and
incomplete bladder emptying.18,64
A systemic review and meta-analysis
of 7 studies (265 patients) comparing
24-hour urine with 12-hour urine
collection suggested that a 12-hour urine
protein collection performed well
compared with a 24-hour urine collec-
tion for the diagnosis of proteinuria. A
cutoff of 150 mg for 12-hour urine
collection had a high sensitivity of 92%
(95% CI, 86%e96%) and specificity of
99% (95% CI, 75%e100%) compared
with the 24-hour urine collection.66
Furthermore, a recent prospective
observational study of 12-hour urine
collection in 99 women with suspected
preeclampsia reported a sensitivity of
85.9% (95% CI, 81%e90%) and a
specificity of 91.7% (95% CI, 88%
e95%) compared with the 24-hour
urine collection.67
Proteinuria and preeclampsia
An important question to be answered in
order to assess the importance of pro-
teinuria during pregnancy is whether
pregnant women with new-onset hy-
pertension with proteinuria have
different maternal or perinatal outcomes
compared with hypertensive women
without proteinuria. Proteinuria in
combination with hypertension has long
been considered to be predictive of
increased maternal and neonatal adverse
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outcomes compared with women with
gestational hypertension alone,68e71 and
before the Task Force on Hypertension
in 2013, proteinuria was an essential part
of the diagnosis of preeclampsia.4,72
Furthermore, the amount of protein
was previously related to the severity of
the disease. Patients were considered to
have mild preeclampsia if they had mild
gestational hypertension and protein-
uria. Patients were considered to have
severe preeclampsia if they developed
any of the following: blood pressure of
160/110 mm Hg on 2 measurements 4
hours apart or 1 diastolic blood pressure
of 110 mm Hg treated with antihy-
pertensive medication; 5 g of protein
excreted in a 24-hour urine sampling;
thrombocytopenia; hemolysis, elevated
liver enzymes, and low platelet count
(HELLP) syndrome; pulmonary edema;
or a convulsion.
The first prospective study evaluating
the impact of elevated blood pressures
and proteinuria on pregnancy out-
comes included 12,954 women. In this
study, proteinuria was defined as a urine
dipstick of 2þ. This study found an
increase in stillbirth, perinatal mortal-
ity, and neonatal morbidity in preg-
nancies complicated with hypertension
and proteinuria compared with hyper-
tension alone.73 The presence of pro-
teinuria was considered an essential
marker for poor pregnancy outcome,
and there was a tendency to consider the
absence of proteinuria as reassuring
when managing pregnancies compli-
cated by hypertension.73e75 This
assumption was readdressed with a
secondary analysis from the Calcium
for Preeclampsia Prevention trial,
which evaluated the relationship be-
tween the severity of hypertension (with
and without proteinuria) and preg-
nancy outcomes.76 This analysis found
that women with severe hypertension
were at the highest risk of adverse
maternal or perinatal outcomes. Severe
gestational hypertension was associated
with a higher rate of low birthweight
infants and lower gestational age at de-
livery than mild gestational hyperten-
sion or mild preeclampsia.77 Another
secondary analysis from the low-dose
aspirin to prevent preeclampsia in
5
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TABLE 2
Outcomes in gestational hypertension vs preeclampsia
Maternal outcomes
Elevated liver enzymes
Placental abruption
Disseminated intravascular
coagulation
Induction of labor
Cesarean delivery
Neonatal outcomes
Preterm delivery at <37 wk
gestation
Preterm delivery at <34 wk
gestation
Small for gestational age
Birthweight of <2500 g
Intensive care unit admission 12.5e18.2
Respiratory distress
syndrome
Perinatal death
Values are expressed as percentage unless indicated otherwise.
Data adapted from Hauth et al77 and Buchbinder et al.79
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
women with previous preeclampsia78
aimed to compare the rates of adverse
perinatal outcomes in those who
developed hypertensive disorders with
those that remain normotensive in a
subsequent pregnancy. The analysis
compared the outcomes of women who
developed various degrees of hyper-
tension with or without proteinuria.
Women who developed severe gesta-
tional hypertension had higher rates of
preterm deliveries (spontaneous and
indicated) and small for gestational age
neonates than patients who remained
normotensive or those who developed
mild gestational hypertension. In
contrast, there were no differences in
perinatal outcomes between the
normotensive or mild gestational hy-
pertension and the mild preeclampsia
groups. Overall, women who had severe
gestational hypertension had more
adverse perinatal outcomes than
women who had mild gestational
6 American Journal of Obstetrics & Gynecology MONTH 2020
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Is gestational hypertension different
from preeclampsia?
There is an ongoing debate about
Preeclampsia Severe whether the quantification of urinary
Gestational without severe gestational protein remains an important diagnostic
hypertension feature hypertension
step for the evaluation of hypertension in
pregnancy and whether gestational hy-
1.1 3.2 6.3 pertension and preeclampsia are really 2
0.3e1.3 0.5e3.2 3.1e4.2 different entities.81 With the updated
definitions, most women with the diag-
0.1 0.5 3.1
nosis of preeclampsia will differ from
women with gestational hypertension
23.8 41.5 50 only by the presence of proteinuria, and
29.1 30.9 28.1 only 10% of women will present with
hypertension and systemic sign of pre-
eclampsia (thrombocytopenia, impaired
17.8 25.8 54.2
liver function, renal dysfunction, and
respiratory or cerebral disturbances) in
1 1.9 3.2
the absence of proteinuria.82 Further-
more, up to 50% of women with gesta-
6.5e6.9 4.8e9.2 10.2e20.8
tional hypertension will eventually
7.7 11.1 25.8 develop proteinuria or end organ
24.2e27.3 20.8e29 dysfunction consistent with the diag-
4.8e5.5 3.2e4.8 6.5e12.5 nosis of preeclampsia.83e85 After the
publication of the new guidelines,
0.1e1.7 0.5 0.1e3.1
limited data are available on whether
preeclampsia with or without protein-
uria will have different outcomes.
Although some studies revealed similar
outcomes for women with preeclampsia
with and without proteinuria,85 others
found worse outcomes for women with
hypertension or mild preeclampsia preeclampsia with proteinuria.69,75,86e89
(Table 2).79 A secondary analysis of a randomized
controlled trial (RCT) of vitamin C and
New definitions and clinical E supplementation evaluated whether
significance of proteinuria assessment hypertensive women with proteinuria
for women with hypertensive disorders (defined as proteinuria of 300e499 mg/
Based on the studies described earlier day) have comparable outcomes with
and a review of maternal mortality data women with gestational hypertension or
revealing that interventions in acutely ill preexisting chronic hypertension
women with multiple organ dysfunction without additional proteinuria. Women
were sometimes delayed because of the with proteinuria had a higher risk of
absence of proteinuria, the American severe hypertension, induction of labor,
College of Obstetricians and Gynecolo- preterm delivery, and small for gesta-
gists Task Force on Hypertension in tional age neonates than women with
Pregnancy and the International Society gestational hypertension or chronic hy-
for the Study of Hypertension in Preg- pertension. Furthermore, a subgroup of
nancy removed the requirement of pro- women with proteinuria of >500 mg/
teinuria for the diagnosis of day had worse pregnancy outcomes than
preeclampsia if there are other findings those with 300 to 400 mg/day, including
suggestive of end organ involvement earlier delivery, higher risk of cesarean
(thrombocytopenia, elevated liver delivery, and magnesium sulfate use.69
transaminases, renal insufficiency, pul- In studies with reported differences in
monary edema, or new-onset neurologic outcome with or without proteinuria, it
symptoms) (Table 3).4,53,80 is possible that proteinuria influences the
ajog.org
management of those patients and af-
fects clinical decisions such as surveil-
lance and timing of delivery. If patients
with preeclampsia are followed up more
closely, have more inpatient manage-
ment, and have more blood pressure
measurements than gestational hyper-
tension, a bias could arise regarding the
assessment of outcome related to the
timing of delivery such as preterm de-
livery and neonatal complications, sim-
ply because there are more opportunities
to make these decisions. Based on cur-
rent available data, we believe that the
most important factor that influences
maternal and neonatal outcome is the
severity of blood pressure and the pres-
ence of end organ damage, rather than
the excess protein excretion. As a corol-
lary, the separation of gestational hy-
pertension and preeclampsia into 2
separate disorders is unnecessary,
because the management of gestational
hypertension and preeclampsia without
severe features is almost identical in
frequency of surveillance and timing of
delivery (Table 4). The only difference in
the recommended management between
gestational hypertension and pre-
eclampsia is weekly assessment of pro-
teinuria in women with gestational
hypertension.80 If the management of
women with gestational hypertension
with a positive assessment of proteinuria
will not change, we believe that this
assessment is unnecessary.
We recommend that any patient
with new-onset hypertension (blood
pressure of 140 mm Hg systolic or
90 mm Hg diastolic) at or after 20
weeks’ gestation will undergo maternal
and fetal evaluation. If there are signs
or symptoms for preeclampsia with
severe features (ie, blood pressure of
160 mm Hg systolic or 110 mm
Hg diastolic, thrombocytopenia,
impaired liver function, renal insuffi-
ciency, pulmonary edema, new-onset
headache, or visual disturbances), the
patient should be admitted to the
hospital and managed according to the
guidelines for preeclampsia with severe
features. If there are no signs of severe
disease, weekly follow-up is
Expert Review
TABLE 3
Diagnostic criteria for preeclampsia
Criteria ACOG (2020)a ISSHP (2018)b
Hypertension New-onset hypertension (blood New-onset hypertension (blood
pressure of 140 mm Hg systolic or pressure 140 mm Hg systolic or
90 mm Hg diastolic) at or after 20 90 mm Hg diastolic) at or after 20
wk gestation wk gestation
On 2 occasions at least 4 h apartc
Proteinuria Not mandatory Not mandatory
300 mg in 24-h urine collection (or Proteinuria should be assessed
this amount extrapolated from a initially by automated dipstick
timed collection) or urinalysis when possible
UPCR of 0.3 or If positive (1þ), then UPCR should
be performed
Dipstick reading of 2þ (used only if A UPCR of 0.3 is abnormal
other quantitative methods are not
available)
A negative dipstick test result can
usually be accepted and further UPCR
testing is not required at that time
Massive proteinuria (>5 g/24 h) is
associated with more severe
neonatal outcomesc
In the absence of proteinuria
Hematologic Thrombocytopenia of <100109/Lc Thrombocytopenia of <150109/Lc
DICc
Hemolysisc
Renal Creatinine of 1.1 mg/dL or a Creatinine of >1.0 mg/dLc
c
insufficiency doubling of the serum creatinine in
the absence of other renal disease
Impaired liver Elevated liver transaminases to twice Elevated liver transaminases (>40
function the normal concentrationc IU/L)c with or without right upper
quadrant or epigastric abdominal
pain
Neurologic New-onset headache unresponsive Examples include eclampsia, altered
symptoms to medication and not accounted for mental status, blindness, stroke,
by alternative diagnoses or visual clonus, severe headaches, and
symptoms persistent visual scotomata
Other Pulmonary edemac Uteroplacental dysfunction (such as
fetal growth restriction, abnormal
umbilical artery Doppler wave form
analysis, or stillbirth)c
ACOG, American College of Obstetricians and Gynecologists; DIC, disseminated /intravascular coagulation; ISSHP, International
Society for the Study of Hypertension in Pregnancy; UPCR, urine protein-to-creatinine ration.
a
Adapted from American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics80;
b
Adapted from Brown et al53; c Indicate differences between the ACOG and ISSHP criteria.
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
MONTH 2020 American Journal of Obstetrics & Gynecology 7
Expert Review ajog.org

of urine protein assessment except for

TABLE 4 the following scenarios:
Current American College of Obstetricians and Gynecologists
recommendations for the surveillance and timing of delivery for women 1. Evaluate baseline existence of pro-
with gestational hypertension and preeclampsia teinuria in women with preexisting
Preeclampsia without severe conditions such as chronic hyper-
Gestational hypertension features tension, diabetes, and autoimmune
Initial Maternal and fetal evaluation Maternal and fetal evaluation disorders (Table 5).
evaluation 2. If a woman presents with pre-
Complete blood count, serum Complete blood count, serum eclamptic symptoms such as head-
creatinine, LDH, AST, ALT, and creatinine, LDH, AST, ALT, and ache, blurry vision, and epigastric
testing for proteinuria testing for proteinuria pain and is found to have normal or
Outpatient Optional Optional high normal blood pressures, we
management suggest that assessment of protein-
Follow-up 1. At least 1 visit per wk in clinic 1. At least 1 visit per wk in clinic uria would help to evaluate a possible
2. Serial ultrasound to determine 2. Serial ultrasound to determine diagnosis of preeclampsia.
fetal growth every 3e4 wk fetal growth every 3e4 wk 3. Evaluation of women presenting with
3. Amniotic fluid volume assess- 3. Amniotic fluid volume assess- signs or symptoms of nephrotic
ment at least once weekly ment at least once weekly
4. Weekly antepartum testing 4. Weekly antepartum testing range proteinuria such as severe
5. Close monitoring of blood 5. Close monitoring of blood generalized edema (Figure 3).
pressure pressure
6. Weekly laboratory test for 6. Weekly laboratory test for Does the amount of proteinuria matter
preeclampsia preeclampsia in women with preeclampsia?
7. Once weekly assessment of 7. Additional quantification of
proteinuria is recommendeda proteinuria no longer The natural course of urine protein
necessarya excretion during the conservative man-
Delivery Expectant management up to 37 Expectant management up to 37
agement of preeclampsia with severe
0/7 wk gestation 0/7 wk gestation features was previously studied, and
ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase.
there are conflicting results whether the
a
Indicate differences between recommended management of gestational hypertension and preeclampsia without severe
amount of proteinuria will affect
features. maternal or neonatal outcomes. Some
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020. studies have reported that the level of
proteinuria is not associated with
adverse maternal or perinatal
recommended with close monitoring (severe headaches, blurred vision, or outcomes,74,79,82,92e96 whereas others
of blood pressure, weekly laboratory epigastric pain). The number needed to have reported that heavy proteinuria
(ie, complete blood count, serum be treated to prevent 1 case of eclampsia increases both maternal and perinatal
creatinine, aspartate aminotransferase, was 36 in women with symptoms morbidities including severe hyperten-
alanine aminotransferase), serial ultra- compared with 1 in 129 in women sion, preterm delivery, cesarean delivery,
sound to determine fetal growth every without symptoms.91 Based on the small for gestational age infants,
3 to 4 weeks, and weekly antepartum current recommendations, patient with maternal symptoms, and perinatal
testing. If there is no progression to symptoms or severe range blood pres- mortality rate.69,70,75,89,97e100
preeclampsia with severe features, in- sure will receive magnesium sulfate In a retrospective cohort study, 90% of
duction of labor at 37 weeks’ gestation whether she has proteinuria or not. women with preeclampsia managed
is recommended (Figure 2). Given the low risk of eclampsia in pa- conservatively had an increase in protein
Of note, patients with preeclampsia tients without symptoms, we do not excretion during pregnancy. Further-
with severe features should receive think further clinical trials are needed to more, 30% of women progressed to a
magnesium sulfate for seizure prophy- address the need for magnesium sulfate nephrotic range proteinuria (>5 g/day).
laxis. Although the design of most in women with severe range blood In this study, outcomes noted similar
available trials for seizure prophylaxis pressures with or without proteinuria rates in major maternal or fetal out-
with magnesium sulfate had an inclu- and proteinuria since that should not comes (ie, gestational age at delivery,
sion criteria including proteinuria, the affect the clinical decision making HELLP syndrome, eclampsia, placental
largest RCT evaluating magnesium sul- regarding seizure prophylaxis. abruption, and stillbirth) between preg-
fate for seizure prophylaxis in women Based on the current management nancies associated with marked increase
with preeclampsia90 provided data recommendations and the data available in proteinuria (2 g) and those with
about the rate of eclampsia according to regarding the progression of the disease, modest or no increase (<2 g).96 A study
the presence or absence of symptoms there is no strong evidence for the utility evaluating whether severe (5 g/day) or

8 American Journal of Obstetrics & Gynecology MONTH 2020

ajog.org
FIGURE 2
Evaluation and management of a woman with gestational hypertension or preeclampsia
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
massive (10 g/day) proteinuria affects
maternal and perinatal outcomes also
found similar rates of maternal compli-
cations (ie, eclampsia, placental abrup-
tion, HELLP syndrome) among all
groups.92 However, women with massive
proteinuria delivered at an earlier gesta-
tion with an associated higher rate of
neonatal morbidities. A multicenter
prospective international study of
women with preeclampsia explored
whether there is correlation between
maternal adverse outcomes and the de-
gree of proteinuria (assessed either by
dipstick testing, spot UPCR, or 24-hour
urine collection). This study also failed
to find any correlation between the
incidence of adverse maternal or
neonatal outcomes and degree of pro-
teinuria.82 In contrast, a retrospective
cohort study of 321 women with pre-
eclampsia assessed whether a discrimi-
nant value of proteinuria (spot UPCR) at
the time of diagnosis predicts adverse
maternal and neonatal outcomes.
Increased maternal and neonatal risk
occurred in women at the age of >35
years and with a protein excretion of 5
g/day. However, it is important to
emphasize that in this cohort adverse
maternal outcomes were defined as se-
vere hypertension, elevated liver en-
zymes, elevated creatinine,
thrombocytopenia, and neurologic
symptoms.70
Moreover, a recent secondary analysis
from a multicenter prospective study of
women with the diagnosis of pre-
eclampsia evaluated whether proteinuria
is associated with worse maternal or
neonatal outcomes. Preeclamptic preg-
nancies were classified into the following
3 groups according to the degree of
proteinuria measured by a 12- or 24-
hour urine protein collection: (1) non-
proteinuria preeclampsia (proteinuria of
<165 mg in 12 hours or <300 mg in 24
hours); (2) mild proteinuria pre-
eclampsia (proteinuria between 165 mg
and 2.7 g in 12 hours or from 300 mg to
4.9 g in 24 hours); and (3) massive
proteinuria preeclampsia (proteinuria of
MONTH 2020 American Journal of Obstetrics & Gynecology
Expert Review
>2.7 g in 12 hours or >5.0 g in 24
hours). Composite adverse maternal
outcome was defined as the presence of
any of the following: acute renal failure,
liver hematoma or rupture, acute
myocardial infarction, cortical blind-
ness, retinal detachment, cerebrovascu-
lar accident, pulmonary edema or adult
respiratory distress syndrome (RDS),
placental abruption, eclampsia, need for
a third intravenous agent to control
blood pressure, disseminated intravas-
cular coagulation, or maternal death.
Composite adverse neonatal outcome
was defined as any of the following: RDS,
any grade of intraventricular hemor-
rhage, necrotizing enterocolitis, bron-
chopulmonary dysplasia, periventricular
leukomalacia, retinopathy of prematu-
rity, seizure, or neonatal intensive care
unit admission for >48 hours for full-
term infant. This analysis included 406
women, of whom 66% had mild pro-
teinuria preeclampsia, 25.1% had non-
proteinuria preeclampsia, and 8.8% had
massive proteinuria preeclampsia.
9
Expert Review
TABLE 5
List of conditions recommended for an evaluation of proteinuria either by 24-hour urine collection or by UPCR
before pregnancy or in the first prenatal assessment
Medical condition
Any woman with abnormal creatinine value on prenatal laboratory tests
Chronic hypertension
Diabetes mellitus (type 1 or type 2)
Systemic lupus erythematosus
Acute or chronic glomerulonephritis (ie, thin basement membrane nephropathy, IgA nephropathy, membranous glomerulonephritis,
membranoproliferative glomerulonephritis, Pauci-immune glomerulonephritis, focal and segmental glomerulosclerosis, crescentic
glomerulonephritis)
Chronic heart failure
Polyarteritis nodosa
Systemic sclerosis
Autosomal dominant polycystic kidney disease
Solitary kidney or after renal transplant
IgA, immunoglobulin A; UPCR, urine protein-to-creatinine ratio.
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet Gynecol 2020.
Composite adverse maternal outcomes
were not increased in women with pre-
eclampsia with massive proteinuria
compared with those with mild or non-
proteinuria preeclampsia. However,
massive proteinuria preeclampsia was
associated with preterm delivery at <34
0/7 weeks’ gestation in >80% of cases,
which was almost twice as high as the
mild proteinuria preeclampsia group
and almost 4 times higher than in the
nonproteinuria group. In addition,
enrollment occurred much earlier in
women with massive proteinuria indi-
cating that the diagnosis was made at a
more preterm gestational age. The
higher neonatal morbidity rate observed
in infants born to massive proteinuria
women was most likely related to the
earlier gestational age at delivery, with
RDS being the most common neonatal
complication affecting almost half of
these infants.97 This analysis emphasized
a very important confounding factor to
consider in studies assessing severity of
proteinuria and outcomes. Because
proteinuria of 5 g/day was previously
one of the diagnostic criteria for severe
preeclampsia, the test result may have
influenced decisions regarding the
timing of delivery management. For
example, earlier delivery precipitated by
10 American Journal of Obstetrics & Gynecology MONTH 2020
heavy proteinuria may reduce maternal
complications (leading to an underesti-
mation of the predictive value of the test)
or increase perinatal morbidity owing to
prematurity (leading to an over-
estimation of its content). The amount
of proteinuria could have an association
with the outcome, rather than a predic-
tive outcome.101
In conclusion, we do not think that
the progression of proteinuria in women
with preeclampsia should change the
management or outcomes, and we do
not recommend repeated measuring of
protein extraction for women with the
diagnosis of preeclampsia.
Isolated gestational proteinuria
Isolated gestational proteinuria is
defined as new-onset proteinuria after
20 weeks’ gestation with normal blood
pressure and no other symptoms or signs
of preeclampsia. Based on the current
diagnostic criteria, women with pro-
teinuria alone are not diagnosed as
having preeclampsia until they also
exhibit hypertension. Thus, isolated
gestational proteinuria is a retrospective
diagnosis. The exact incidence of iso-
lated proteinuria is unknown, but a
prospective study evaluating 11,651 low-
risk women (excluding women with
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preexisting hypertension, diabetes or
preeclampsia) who had at least 1 pro-
teinuria measurement during pregnancy
found single episodes of isolated gesta-
tional proteinuria of 1þ on dipstick
evaluation in 7.7% of the women. Of
note, only 2% of women experienced
proteinuria on more than 1 occasion.
Furthermore, established risk factors for
preeclampsia such as maternal age,
higher prepregnancy body mass index,
nulliparity, and twin pregnancy were
associated with increased risk of devel-
oping proteinuria.2 Another observa-
tional study of 938 women with
singleton pregnancies, who had at least 1
UPCR evaluation during pregnancy,
noted isolated gestational proteinuria in
1.9% of women.102 The outcome of
women with isolated proteinuria alone
seems favorable,103e105 but up to 30% of
women with isolated gestational pro-
teinuria may progress to preeclampsia.84,
102,106e108
A retrospective study aimed to
evaluate whether maternal outcome will
differ between women with preeclamp-
sia who first presented with hyperten-
sion without proteinuria compared with
women who first presented with pro-
teinuria alone without hypertension.
Women presented with hypertension
and proteinuria at the same time were
ajog.org
FIGURE 3
Massive edema during
pregnancy
A, Generalized edema and ascites in a woman
with lupus nephritis at 23 weeks. B, Vulvar
edema in a woman with diabetic nephropathy at
24 weeks.
Fishel Bartal. Proteinuria during pregnancy. Am J Obstet
Gynecol 2020.
excluded. Of 190 women with pre-
eclampsia, 49 (25%) presented with
proteinuria first with subsequent devel-
opment of hypertension. Women with
proteinuria onset preeclampsia were
diagnosed earlier with preeclampsia,
with an increased risk of fetal growth
restriction, HELLP syndrome, and
neonatal complications.109
As discussed previously, women with
preeclampsia have increased serum con-
centrations of sFlt-1 and sEng and
reduced concentrations of VEGF and
PlGF.110,111 A study of 108 women with
isolated gestational hypertension have
also noted altered levels of angiogenic
factors compared with health controls.
Serum concentrations of PlGF were
noted to be lower in women with gesta-
tional proteinuria than those of control
subjects as early as 10 to 12 weeks’
gestation. However, levels of sFlt-1 and
sEng are elevated only at term, when peak
concentrations were attained. At term,
levels of sFlt-1, sEng, and PlGF before the
onset of gestational proteinuria were not
altered as much as in women who later
developed preeclampsia. Nevertheless,
the authors concluded that gestational
proteinuria might be a mild variant of
preeclampsia.103 Because women with
gestational proteinuria are at a high risk of
progression to subsequent preeclampsia,
we recommend close monitoring of
blood pressures and other symptoms of
preeclampsia in those women if a protein
excretion test was done and proteinuria
was diagnosed. Otherwise, because we do
not recommend regular assessment of
protein excretion during pregnancy, it is
important to establish regular follow-up
of blood pressures during pregnancy,
especially in women with risk factors for
preeclampsia such as advanced maternal
age, nulliparity, obesity, and twin
pregnancy.
Proteinuria in women with preexisting
conditions
The best indicator of kidney function is
the GFR. The current international
guidelines define chronic kidney disease
(CKD) as decreased kidney function of
<60 mL/minute per 1.73 m2 or markers
of kidney damage or both of at least 3-
month duration, regardless of the un-
derlying cause.112,113 Proteinuria is one
of the measures of kidney damage. The
list of the conditions of which an evalu-
ation of proteinuria either by 24-hour
urine collection or by UPCR is recom-
mended before pregnancy or in the first
prenatal assessment is presented in
Table 5. Because our current diagnosis of
preeclampsia in women with CKD may
be based on a change in protein excre-
tion, a baseline evaluation is critical.
The presence of proteinuria before 20
weeks’ gestation is consistent with the
presence of known or undetected renal
disease. In many of these women, renal
dysfunction may be minimal, and the
presence of underlying renal diseases may
not be suspected until proteinuria is
detected during pregnancy. With
advanced gestation, an exacerbation of
maternal hypertension or an increase in
urinary protein excretion could be related
to the development of preeclampsia or
may be caused by the exacerbation of the
underlying renal disease.
Preeclampsia occurs in up to 40% of
pregnancies of women with CKD. When
pregnant women with CKD have
MONTH 2020 American Journal of Obstetrics & Gynecology
Expert Review
increasing proteinuria or blood pressure
during pregnancy, the main challenge is to
decide whether they have renal worsening
owing to preeclampsia or whether it is a
worsening of their basic renal dysfunc-
tion.114 Regular diagnostic criteria for
preeclampsia are not useful in women
with CKD because most patients will have
baseline blood pressures, proteinuria, and
creatinine above the diagnostic threshold
of preeclampsia. Furthermore, for
example, previous studies examining
changes in 24-hour urine protein in
pregnant women with diabetic nephrop-
athy revealed a 2.1- to 5.3-fold increase
during the third trimester compared with
preconception or first-trimester values;
preeclampsia is being diagnosed in 42% to
73% of these pregnancies, with a higher
risk of preeclampsia in patients with dia-
betes mellitus with early pregnancy
proteinuria.115e119
Chronic hypertension
The cutoff for a normal baseline protein
excretion or creatinine for women with
chronic hypertension is also not well
defined. In a subgroup analysis of
women with chronic hypertension that
were enrolled in a multicenter, ran-
domized trial comparing low-dose
aspirin with placebo for the prevention
of preeclampsia, women with baseline
proteinuria had an increased risk of
preterm deliveries, small for gestational
age infants, neonatal intensive care unit
admission, and adverse neonatal out-
comes compared with women without
proteinuria early in pregnancy. Those
adverse neonatal outcomes occurred
despite the facts that the rates of super-
imposed preeclampsia were similar in
the 2 groups and none of the women
with proteinuria at baseline had
placental abruption.120 Similar findings
were noted in a retrospective study
evaluating 447 women with chronic hy-
pertension who received antihyperten-
sive therapy in the first half of pregnancy
and completed urine protein quantifi-
cation before 20 weeks’ gestation.
Women with baseline proteinuria had
increased risks of preeclampsia, preterm
birth, and growth restriction. In preg-
nant women with treated chronic hy-
pertension, baseline proteinuria was
11
Expert Review
associated with increased rates of pre-
eclampsia, preterm birth, and growth
restriction compared with women who
did not have proteinuria.121 A retro-
spective study of 755 women with
chronic hypertension and a baseline
assessment of renal function (UPCR and
serum creatinine) before 20 weeks’
gestation found that baseline serum
creatinine of 0.75 mg/dL and UPCR of
0.12 were associated with increased
risks of severe preeclampsia before 34
weeks’ gestation and preeclampsia at any
gestational age. These thresholds are
much lower than typically considered
abnormal. Furthermore, 33.3% of
women with chronic hypertension and
baseline renal function tests above the
objectively determined cutoffs developed
severe preeclampsia at <34 weeks’ gesta-
tion, and 66.7% developed any type of
preeclampsia during the pregnancy.122
Preeclampsia is considered super-
imposed when it complicates preexisting
chronic hypertension. Up to 25% of
women with chronic hypertension will
be diagnosed as having superimposed
preeclampsia.123 Superimposed pre-
eclampsia is not always easy to diagnose
and is often a diagnosis of exclusion.
Based on the current available guide-
lines, a sudden increase in baseline hy-
pertension or a sudden increase of
proteinuria (above the threshold for
normal or a clear change from baseline)
would prompt an assessment for a
possible diagnosis of superimposed
preeclampsia.124 The definition of
superimposed preeclampsia possess a
diagnostic dilemma, and it is unclear
whether changes in the baseline pro-
teinuria reflect another systemic disease
such as preeclampsia or whether women
with chronic hypertension will experi-
ence a different “normal” pattern of
protein excretion during pregnancy. The
consequences of diagnosing a patient
with superimposed preeclampsia may
not be significant if it occurs close to
term, but if the blood pressure rises to a
severe range earlier in pregnancy it may
lead to more maternal-fetal testing,
hospitalization, and interventions lead-
ing to preterm delivery instead of
just adjusting the blood pressure
medications.125
12 American Journal of Obstetrics & Gynecology MONTH 2020
Limited data are available regarding
the angiogenic profile in women with
chronic hypertension or CKD as a po-
tential marker in distinguishing the
worsening of baseline disease and
superimposed preeclampsia.105,126,127
Most of the predictive studies on the
use of angiogenic factors for prediction
of preeclampsia in high-risk population
have also included women with chronic
hypertension, but the interpretation of
those studies only for women with
chronic hypertension is limited.128e132 A
secondary analysis on the low-dose
aspirin to prevent preeclampsia in
women with previous preeclampsia78
evaluated the differences in circulating
concentrations of sFlt1, sEng, and the
proangiogenic PlGF in high-risk preg-
nancy. This cohort included 313 women
with chronic hypertension and 194
women with preexisting diabetes. Sig-
nificant differences in angiogenic factors
during the third trimester were found in
women who develop preeclampsia
compared with appropriate controls in
all high-risk groups. However, the sFlt1
concentrations were not elevated before
the onset of preeclampsia in the chronic
hypertension or diabetes group
compared with the control group.133
Another prospective study evaluating
78 women with chronic hypertension
found that women with uncontrolled
blood pressure had higher levels of sFlt1
and a higher sFlt1-to-PlGF ratio before
delivery,134 whereas an observational
study including 60 women with chronic
hypertension found only higher sFlt1-
to-PlGF ratio in women who developed
superimposed preeclampsia with similar
levels of sFlt1 or PlGF compared with
women who did not develop pre-
eclampsia.135 A longitudinal prospective
cohort of women with CKD (n¼121)
and chronic hypertension (n¼44)
quantified PlGF in the diagnosis of
superimposed preeclampsia requiring
delivery within 14 days of diagnosis.
Lower maternal PlGF concentrations
had a high diagnostic accuracy for
superimposed preeclampsia requiring
delivery within 14 days (receiver oper-
ator characteristic, 0.85). The sensitivity,
specificity, and positive and negative
predictive values of PlGF concentrations
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below the fifth percentile (100 pg/mL)
for predicting delivery within 2 weeks for
women with chronic hypertension or
CKD were 75%, 77.5%, 26%, and 96%,
respectively, although these data
included only 40 women with super-
imposed preeclampsia. The diagnostic
utility of low PlGF concentrations was
also confirmed in women with CKD or
chronic hypertension (n¼123) for
superimposed preeclampsia requiring
delivery within 14 days with a receiver
operator characteristic of 0.82 in a vali-
dation cohort.114,126
More research is needed on normal
and abnormal protein secretion for
women with chronic hypertension or
other preexisting renal disorders during
pregnancy to define a pathologic cutoff
in this population and to better define
the existence of preeclampsia in this
population.
Summary and Future Directions
Preeclampsia is a common disorder and
evaluating protein excretion has become
one of the most common screening tests
performed during pregnancy. This re-
view and clinical opinion focused on
proteinuria in pregnancy and its corre-
lation to clinical outcomes. There are no
convincing data that support 300 mg/day
as a cutoff for abnormal protein excre-
tion. The lack of appropriate validation
of normal protein excretion during
pregnancy in low-risk and high-risk
population challenges the clinicians’
ability to trust the current cutoff as a
guideline for management. Further-
more, during the past 10 years, there
have been a significant change in the
demographics of obstetrical population
in the United States and most of the
western countries.136 Pregnant women
who are older, obese, undergoing in vitro
fertilization, or carrying multifetal
gestation may have protein excretion
that exceeds the established thresholds in
the absence of clinically apparent dis-
ease. Although proteinuria is essential
for diagnosis and follow-up in women
with chronic hypertension, diabetes
mellitus, and other chronic renal disor-
ders, it has limited value in patients who
develop hypertension during pregnancy.
Based on current data and our
ajog.org
experience, we suggest that the current
management of women with gestational
hypertension or preeclampsia should be
based on more reliable signs and symp-
toms such as blood pressure control or
end organ damage. There are needs to
(1) determine the necessity for protein
assessment during pregnancy for
women without chronic renal disorders
or predisposing conditions; (2) assess
normal and abnormal protein excretion
in pregnancy for women with risk fac-
tors for preeclampsia such as advanced
maternal age, obesity, and fertility
treatment; (3) readdress the subclassifi-
cation of hypertensive disorder in preg-
nancy and assess whether there is a value
to define preeclampsia differently from
gestational hypertension; (4) better un-
derstand normal protein excretion dur-
ing pregnancy in women with chronic
hypertension and explore whether
worsening of proteinuria affects out-
comes and justifies the diagnosis of
superimposed preeclampsia; and (5)
design and evaluate studies addressing
other biomarkers that could be used for
the diagnosis of preeclampsia in women
with chronic renal disorders. - the renal proximal tubule. J Am Soc Nephrol
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