www.kidney-international.
org
Nephrotic syndrome in pregnancy poses risks with
both maternal and fetal complications
Iris De Castro1, Thomas R. Easterling2, Nisha Bansal1 and J. Ashley Jefferson1
1
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA; and
2
Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington, USA
In the absence of uncontrolled hypertension or renal
insufficiency, many consider the perinatal outcomes in
pregnant women with nephrotic syndrome to be good. To
further investigate this we performed a retrospective chart
review of women with biopsy-proven nephrotic syndrome
due to primary glomerular disease during pregnancy at
a single tertiary center. Our review determined
characteristics, presentation, management, pathologic
diagnoses, and associated renal and maternal-fetal
outcomes of 19 individuals with 26 pregnancies and 26
offspring. The mean age was 27.6 years, the mean
gestational age at the presentation of nephrotic syndrome
was 18.6 weeks, the mean creatinine was 0.85 mg/dL, mean
serum albumin was 1.98 g/dL, and the mean proteinuria
was 8.33 g/24 hours. The mean cardiac output was
8.6 L/minute, which was elevated compared to normal
pregnancy. A kidney biopsy was performed during
pregnancy in 8 individuals (median gestational age at time
of biopsy was 21 weeks), changing management in six.
Of the 26 pregnancies, maternal complications included
preeclampsia in seven, acute kidney injury in six, premature
rupture of membranes in two, and cellulitis in three. The
mean age of gestation at delivery was 35.5 weeks. Fetal
complications included low birth weight (under 2,500 g) in
14, intra-uterine growth restriction in three, and neonatal
intensive care unit admission in eight. Thus, pregnant
women with nephrotic syndrome are at high risk for
developing both maternal and fetal complications, even in
the absence of significant renal impairment or uncontrolled
hypertension at the time of presentation of nephrotic
syndrome.
Kidney International (2017) -, -–-; http://dx.doi.org/10.1016/
j.kint.2016.12.019
KEYWORDS: focal segmental glomerulosclerosis; glomerular disease; hy-
pertension; nephrotic syndrome; preeclampsia; pregnancy; proteinuria
Copyright ª 2017, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: Iris C. De Castro, University of Washington School of
Medicine, 1959 NE Pacific Street, Box 356521, Seattle, Washington 98195
USA. E-mail: icastro@uw.edu
Received 30 March 2016; revised 22 November 2016; accepted 22
December 2016
Kidney International (2017) -, -–-
clinical investigation
N
ephrotic syndrome (NS) rarely presents during preg-
nancy. Nephrosis due to primary renal disease has
been reported to occur in 0.028% of pregnancies.1
Without a histologic diagnosis, the incidence of NS second-
ary to primary glomerular disease is uncertain owing to the
difficulty in differentiating from, and the potential coexis-
tence with, preeclampsia.
Elevated creatinine is an established risk factor for adverse
pregnancy outcomes.2,3 Pregnancy may also accelerate the
progression of the maternal kidney disease. Less clear is the
effect of NS on outcomes in pregnancy in the absence of
significant renal impairment. Indeed, it has been described
that women with NS alone, without significant hypertension
or renal insufficiency, have good outcomes. There are limited
data in the literature on this select group of patients.1,4–6
Knowing the clinical course of these patients can assist in
counseling women with NS and guide the management of
these high-risk pregnancies.
RESULTS
Clinical features
The baseline characteristics of the 26 pregnancies with NS
are listed in Table 1. At the time of presentation with NS, the
mean
SD maternal age was 27.6
6.5 years, similar to
that in the general population.7 The mean gestational age
at presentation was 18.6 weeks. All patients had at least
2þ edema or anasarca documented in the chart. Laboratory
values at presentation revealed that majority of the patients
had a serum creatinine level <1 mg/dl and serum albumin
level <2 g/dl. All women had normal liver function test
results at presentation.
Kidney biopsy
All 19 subjects underwent kidney biopsy (Table 2). NS was a
new diagnosis during pregnancy in 12 of the 26 women, 8 of
whom underwent renal biopsy during pregnancy and 4 after
delivery. For patients who underwent kidney biopsy during
pregnancy, the mean age of gestation at biopsy was 21 weeks.
Two of the 8 biopsies done during pregnancy had a minor
complication (hematoma in 1 and hematuria in 1) compared
with 1 of 11 (1 small arteriovenous fistula formation) for the
women who had underwent a biopsy outside of pregnancy.
Minor complications were defined as hematoma, decreased
hematocrit, or arteriovenous fistula formation not requiring
blood transfusion or intervention. No major biopsy compli-
cations occurred. In 6 of the 8 biopsies (75%) performed in
1
clinical investigation I De Castro et al.: Nephrotic syndrome in pregnancy

Table 1 | Characteristics of patients at presentation of Table 3 | Hemodynamic variables in pregnant women with
nephrotic syndrome during pregnancy nephrotic syndrome (N [ 17)
Characteristics Valuea Variable Nephrotic Normala
Maternal age (yr)a 27.6
6.5; 28.5 (21–33) Cardiac output (l/min) 8.6
2.3 6.6
1.8
Race, N ¼ 19 (%) Stroke volume (l) 109.25
29.76 81.5
26
White 10 (53) Heart rate (bpm) 68
13 83
11
Black 1 (5) Mean arterial pressure (mm Hg) 94
11 76.8
10.3
Hispanic 5 (26) Total peripheral resistance (dyn $ s $ cm5) 922
162 996
294
Native American 2 (11) a
Normal values derived from historical control pregnant women previously
Pacific Islander 1 (5) published.8
Age of gestation, wka 18.7
9.1; 20 (11–24)
Gravidity N ¼ 26 (%)
Primigravid 7 (27)
A history of hypertension or BP level at the time of presen-
Multigravid 19 (73)
Proteinuria (g)a 8.3
6.7; 5.2 (4.2–10.0) tation of NS was not associated with adverse outcomes of
Serum creatinine (mg/dl)a 0.84
0.23; 0.80 (0.60–1.19) preeclampsia, preterm delivery, or low birth weight (LBW).
Values are expressed in mean
SD and median (interquartile range).
a Maternal UltraCOM hemodynamic data were available for
17 pregnancies and used to guide antihypertensive therapy.
pregnancy, the pathologic diagnosis led to a change in For this group, the mean systolic and diastolic BPs were
management. 129 mm Hg and 76 mm Hg, respectively (Table 3). The mean
initial cardiac output (CO) for this cohort is higher compared
Management with that of women with normal pregnancies (8.6
2.3 l/min
Of the 26 pregnancies, 7 women received prednisone, with a vs. 6.6
1.8 l/min). The total peripheral resistance, on the
daily total dose of 60 to 120 mg. Of the 7 women who other hand, was similar in our cohort and in women with
received prednisone, 6 were initiated based on the findings of normal pregnancies: 922
1162 dyn$s$cm5 and 996
294
the kidney biopsy, and 1 was empirically treated with steroids. dyn$s$cm5, respectively.8
One patient with known C3 glomerulopathy received eculi- Antihypertensive medications were used in 20 pregnancies.
zumab during pregnancy. Two pregnancies were complicated Nineteen patients received furosemide (daily dose, 20–80 mg),
by premature rupture of membranes in patients taking 16 received atenolol (daily dose, 12.5–100 mg), 4 received
prednisone. None of the patients who received steroids had clonidine (daily total dose, 0.15–0.4 mg), 1 received nifedi-
hyperglycemia, worsening edema, or wound infection. pine (daily dose, 30–40 mg), and 1 received methyldopa (daily
Anticoagulation was used in 7 pregnancies. Of the 7 dose, 500 mg). One of the 19 patients who received furose-
pregnancies, 2 patients had a focal segmental glomerulo- mide had oligohydramnios. There were 2 pregnancies
sclerosis tip lesion, 1 had membranous nephropathy, 1 had complicated by oligohydramnios. The number or the type of
minimal change disease, 1 had membranoproliferative BP medication was not related to preterm delivery or LBW.
glomerulonephritis, 1 had fibrillary glomerulonephritis,
and 1 had C3 glomerulonephritis. Six used enoxaparin 40 to Renal clinical course and outcomes
80 mg/day, and 1 used 5000 U of heparin twice daily. There The renal course of the women’s serum creatinine and pro-
was no report of adverse effects such as bleeding, abruption, teinuria is shown in Table 4. Of the 26 pregnancies, 13 pa-
or subchorionic hematoma. tients were known to have primary glomerular disease before
pregnancy (Table 5). There were 6 women in whom AKI
Blood pressure and volume management developed during pregnancy, with an increase in creatinine
At the time of the occurrence of NS during pregnancy, the ranging from 0.42 to 2.1 mg/dl. None required dialysis during
mean systolic and diastolic blood pressures (BPs) were pregnancy. We have data on the serum creatinine after de-
121 mm Hg and 74 mm Hg, respectively. Eight pregnancies livery for 5 of the 6 women in whom AKI developed during
occurred in women with chronic hypertension, 6 of whom pregnancy (Table 4). Creatinine returned to the prepregnancy
were receiving BP medications before presentation. At least 1 level in 2 of the 5 women. Three women had a persistent
BP medication was used in 20 of the 26 pregnancies (77%). worsening of renal function. (i) Case 4 had collapsing glo-
merulopathy and presented with NS (14 g/24 h) at 23 weeks
Table 2 | Kidney biopsy diagnosis gestation. Her creatinine level was 0.8 mg/dl before pregnancy
and 1 mg/dl at presentation. She was not prescribed any
Pathologic diagnosis (N [ 19) No. (%)
treatment for her focal segmental glomerulosclerosis during
Focal segmental glomerulosclerosis 8 (42) pregnancy. Her creatinine level peaked at 3.1 mg/dl during
IgA nephropathy 3 (16) pregnancy, and preeclampsia developed. She had a preterm
Membranous nephropathy 3 (16)
Fibrillary glomerulonephritis 1 (5) delivery at 28 weeks gestation due to fetal distress. She did not
Membranoproliferative glomerulonephritis 1 (5) recover renal function and was started on hemodialysis within
C3 glomerulonephritis 1 (5) a year after her delivery. (ii) Case 18 had IgA nephropathy and
Minimal change disease 1 (5) presented at 10 weeks gestation with 4.98 g/24 h proteinuria.

2 Kidney International (2017) -, -–-

Kidney International (2017) -, -–-

I De Castro et al.: Nephrotic syndrome in pregnancy

Table 4 | Renal outcomes
Maternal Gestation age at Creatinine at Peak creatinine Nadir creatinine after Proteinuria at Peak proteinuria Disease-specific treatment
Case Diagnosis age (yr) presentation (wk) presentation during pregnancy pregnancy presentation during pregnancy during pregnancy
1 FSGS 29 12 0.7 1 1.1 3.7 3.7 None
2a FSGS 31 12 0.9 0.9 1.3 4 4.16 None
3a,b FSGS 34 5 0.78 1.21 c
4.1 4.1 None
4a,b FSGS, collapsing 20 23 1 3.1 2.2 14.7 21.3 None
5a FSGS 18 26 0.6 0.8 0.9 32 51 Prednisone
6a FSGS 24 40 0.7 0.7 1.2 3.64 3.64 None
7 FSGS 25 23 0.6 0.6 0.9 22 22 None
8b FSGS, tip 32 24 0.7 1.03 0.88 10 14.69 Prednisone
c
9 FSGS 26 27 0.6 0.6 4 4 None
10 FSGS, tip 33 20 0.8 0.8 0.7 6.3 6.3 Prednisone
11 FSGS 16 24 0.6 0.6 0.5 5 5 None
12a FSGS 30 34 0.9 1.1 1.1 13 13 None
13 FSGS 25 13 0.4 0.6 0.6 12 12 Prednisone
14 IgAN 24 20 0.98 1.04 0.5 4.9 6 None
15a IgAN 21 10 0.9 0.9 1.0 6 6 None
16a IgAN 34 10 1.4 1.6 1.6 5.45 5.45 None
17a IgAN 36 24 1.2 1.4 1.3 4.18 4.18 None
18a,b IgAN 34 8 1.3 1.9 1.6 4.98 11.84 None
c
19 Membranous 18 24 0.5 0.5 9.5 15.5 None
nephropathy
20a Membranous 33 11 0.9 0.9 0.7 4.6 4.6 None
nephropathy
21a Membranous 37 12 0.5 0.7 0.7 3.86 5.2 None
nephropathy
22 Membranous 21 28 0.8 0.9 0.6 5.37 5.37 None
nephropathy
23b Fibrillary GN 39 16 1.1 1.74 1.5 5 6.2 Prednisone
24 MPGN 21 22 1.1 1.3 0.9 16 16 Prednisone
25a,b C3GN 29 4 1.19 2.67 1.97 7.3 10.2 Eculizumab

clinical investigation
c
26 MCD 28 11 0.8 0.8 4.9 4.9 Prednisone
C3GN, C3 glomerulonephritis; FSGS, focal segmental glomerulosclerosis (not otherwise specified variant unless otherwise stated); GN, glomerulonephritis; IgAN, IgA nephropathy; MCD, minimal change disease; MPGN, mem-
branoproliferative glomerulonephritis, immune complex type, idiopathic.
a
Pregnancy in women with preexisting glomerular disease.
b
Pregnancy was complicated by acute kidney injury.
c
No available value.
3
 4

clinical investigation
Table 5 | Renal course during pregnancy in patients with preexisting primary glomerular disease
Mean creatinine Peak creatinine Nadir creatinine Mean proteinuria Peak proteinuria Nadir proteinuria Treatment received Maternal-fetal
Case Diagnosis before pregnancy during pregnancy after pregnancy before pregnancy during pregnancy after pregnancy during pregnancy complications
2 FSGS 1.1 0.9 0.9 — 4.16 2.46 None None
3 FSGS 0.9 1.21 — 2.97 4.1 — None None
4 FSGS, collapsing 0.8 3.1 2.2 — 21.3 43 None Superimposed
preeclampsia
Preterm delivery
RDS
NICU admission
6 FSGS 0.73 0.7 1.2 — 3.64 1.54 Prednisone None
7 FSGS — 0.6 0.9 — 22 5.6 None IUGR
Preterm delivery
12 FSGS 1.06 1.1 1.1 — 13 3.4 None None
15 IgAN 1 0.9 1 2.27 6 2.3 None None
16 IgAN 1.28 1.6 1.6 2.28 5.45 4.6 None Delayed wound
healing
IUGR
Preterm delivery
RDS
NICU admission
17 IgAN 1.33 1.5 1.6 4.95 4.18 2.4 None None
18 IgAN 1.2 1.9 1.6 2.54 11.84 0.57 None None

I De Castro et al.: Nephrotic syndrome in pregnancy

20 Membranous 0.96 0.9 0.7 5.11 4.6 2.8 None None
nephropathy
21 Membranous 0.67 0.78 0.7 2.46 5.2 1.7 None None
nephropathy
25 C3GN 1.57 2.67 1.97 8 10.2 5.5 Eculizumab Preeclampsia
RDS
C3GN, C3 glomerulonephritis; FSGS, focal segmental glomerulosclerosis (NOS variant unless otherwise stated); IgAN, IgA nephropathy; IUGR, intrauterine growth restriction; NICU, neonatal care unit; RDS, respiratory distress
Kidney International (2017) -, -–-

syndrome.
I De Castro et al.: Nephrotic syndrome in pregnancy clinical investigation

Table 6 | Maternal and fetal outcomes pregnancy. In 2 patients with focal segmental glomerulo-
Variable Case (%) Reference (%) sclerosis, each of whom each had 3 pregnancies, the creatinine
level was unchanged before and after each pregnancy. Eight of
Mode of delivery, N ¼ 26 (%)
Vaginal 11 (42) —
the 12 pregnancies had >1 urine protein quantification value
Cesarean 15 (58) 32.7a available during pregnancy. Four of the 8 patients had no
Age of gestation at birth (wk) 35.5
4 — change in proteinuria (<0.5-g change in proteinuria), and the
Adverse maternal outcome other 4 had a decrease in proteinuria during their pregnancy,
Preeclampsia 7 (27) 3.4b
AKI 6 (23) — 3 of whom were treated with prednisone.
Cellulitis 3 (12) — There were 5 pregnancies in 3 patients with IgA
Adverse fetal outcome nephropathy. Two patients with IgA nephropathy each had
Preterm delivery <37 wk 14 (54) 11.4a 2 pregnancies. In 1 of these 2 patients, AKI developed during
Low birth weight 14 (54) 8a
IUGR 3 (11) 10b her second pregnancy, and serum creatinine did not return to
NICU admission 8 (31) — the prepregnancy level. None of the patients received treat-
AKI, acute kidney injury; IUGR, intrauterine growth restriction; NICU, neonatal ment with steroids during pregnancy.
intensive care unit.
a
Three patients had membranous nephropathy, 1 of whom
Reference data from National Vital Statistics Report.7
b
Reference data from historical data previously published.33
had 2 pregnancies. Creatinine was stable throughout preg-
nancy. Urine protein quantification values were available for
all 4 pregnancies. Proteinuria worsened during pregnancy but
Her creatinine level was 1.3 mg/dl at presentation and peaked improved to a nonnephrotic range within a year after delivery
at 1.9 mg/dl during pregnancy. She had chronic hypertension (3–12 months).
and was taking atenolol, nifedipine, and clonidine during
pregnancy. Her pregnancy was complicated by superimposed Maternal and fetal outcomes
preeclampsia, intrauterine growth restriction (IUGR), and Maternal and fetal outcomes are shown in Table 6. The live
preterm delivery at 28.4 weeks. (iii) Case 25 had C3 birth rate was 100%. The mean age of gestation at delivery
glomerulonephritis and presented with NS (7.3 g/24 h) dur- was 35.5 weeks (range, 25–40 weeks). Fourteen of the 26
ing her first trimester with a serum creatinine level of births (54%) were preterm, which is higher than the rate in
1.19 mg/dl, which peaked at 2.7 mg/dl. She was treated with the general population (11%).7 Of the preterm deliveries,
eculizumab, atenolol, and furosemide during pregnancy. She 6 were for preeclampsia, 2 for fetal distress, 2 for premature
delivered at term; however, her infant had LBW and com- rupture of membranes, 1 for cord compression, and 3 were
plications of respiratory distress. unspecified. The number of deliveries via cesarean section was
There were 12 pregnancies in 8 women with focal higher in this cohort compared with that in the general
segmental glomerulosclerosis. Three of the 12 pregnancies population (58% vs. 32.7%).9 There were 7 pregnancies
were complicated by AKI; 1 woman recovered, 1 progressed complicated by preeclampsia. Of the 7 patients who had a
to ESRD, and 1 had an unknown renal outcome post-delivery. diagnosis of preeclampsia, 2 were based on new-onset hy-
These 3 patients were not treated with steroids during pertension, 1 was based on new-onset hypertension and

Table 7 | Risk factors for adverse maternal and fetal outcomes

OR (95% CI); P value
Variable Preeclampsia Low birth weight Preterm delivery
History of hypertension 3.75 (0.77–18.21); 3.75 (0.77–18.21); 3.33 (0.68–16.30);
P ¼ 0.10 P ¼ 0.10 P ¼ 0.14
Maternal age at presentation 0.98 (0.87–1.11); 0.98 (0.87–1.11) 0.98 (0.88–1.10)
P ¼ 0.70 P ¼ 0.77 P ¼ 0.75
Serum creatinine at presentation 2.45 (0.11–55.13); 2.45 (0.11–55.13); 9.20 (0.35–238.69);
P ¼ 0.57 P ¼ 0.57 P ¼ 0.18
Peak creatinine during pregnancy 3.00 (0.73–12.27); 3.00 (0.73–12.27); 4.04 (0.61–26.80);
P ¼ 0.13 P ¼ 0.13 P ¼ 0.15
Serum albumin 0.47 (0.14–1.61); 0.47 (0.14–1.61); 0.40 (0.12–1.32);
P ¼ 0.23 P ¼ 0.23 P ¼ 0.13
Proteinuria at presentation 1.26 (1.03–1.53); 1.26 (1.03–1.53); 1.28 (1.00–1.64);
P ¼ 0.02 P ¼ 0.02 P ¼ 0.051
Peak proteinuria during pregnancy 1.19 (1.02–1.40); 1.19 (1.02–1.40); 1.22 (1.00–1.48);
P ¼ 0.03 P ¼ 0.03 P ¼ 0.045
Systolic blood pressure at presentation 1.02 (0.98–1.06); 1.02 (0.98–1.06); 1.03 (0.98–1.08);
P ¼ 0.30 P ¼ 0.30 P ¼ 0.25
Diastolic blood pressure at presentation 1.03 (0.96–1.10); 1.03 (0.96–1.10); 1.09 (1.00–1.18);
P ¼ 0.41 P ¼ 0.41 P ¼ 0.054
CI, confidence interval; OR, odds ratio.

Kidney International (2017) -, -–- 5

clinical investigation
increasing creatinine, 3 were due to superimposed pre-
eclampsia, and 1 was due to superimposed preeclampsia and
increasing creatinine. Three pregnancies were complicated by
cellulitis; in none of these pregnancies were steroids used.
There were no episodes of thrombosis. Fetal complications
included IUGR (N ¼ 3), LBW (N ¼ 14), and neonatal
intensive care unit admissions (N ¼ 8). Proteinuria signifi-
cantly correlated with adverse outcomes of preeclampsia
(P ¼ 0.002), preterm delivery (P ¼ 0.02), and LBW
(P ¼ 0.002) (Table 7).
DISCUSSION
We performed a retrospective review of patients with NS due
to primary glomerular disease during pregnancy. In our
study, the mean age of gestation at presentation was
18.6 weeks, consistent with previous observation that pro-
teinuria before 20 weeks gestation is suggestive of primary
kidney disease rather than preeclampsia.10 Only those who
underwent a kidney biopsy were included in order to define
the renal pathology and exclude preeclampsia as the primary
cause of NS. The clinical presentation, management, and
renal and maternal-fetal outcomes are described in this study.
There have been previous studies looking into pregnancy
outcomes in specific glomerulopathies.11–14 Other studies
have described the critical role of renal function as it relates to
outcomes in pregnancy.3,15–18 There has been limited litera-
ture looking at NS as it relates to pregnancy course and
outcomes.1
Kidney biopsy
The risks of kidney biopsy during pregnancy must be care-
fully balanced with the benefits of identifying the pathologic
diagnosis. In our study, a kidney biopsy was done during
pregnancy in 8 women. Minor complications occurred in
2 patients. No major complications were reported. Most
previous studies have shown that complication rates of renal
biopsy during pregnancy are low.19,20 In contrast, Piccoli
et al.,21 in a systematic review of 39 studies that included
243 biopsies performed during pregnancy, showed a higher
rate of minor and major complications compared with renal
biopsies performed after pregnancy. These rates remain low
compared with the 6.4% to 6.7% complication rates
described in nonpregnant individuals.20
In our study, 6 of the 8 patients who underwent a renal
biopsy during pregnancy had a change or initiation of treat-
ment (mainly steroids) based on histopathology. Other
studies have confirmed that appropriately deciding to
perform a kidney biopsy during pregnancy commonly results
in a change in management.19,22 Steroids were most
commonly chosen to treat the glomerular lesion. Steroids are
generally safe during pregnancy. Prednisone does not repre-
sent a major teratogenic risk in humans at therapeutic
doses.23 Concerns include worsening maternal glucose and
BP control, premature rupture of membranes, and infec-
tion.24,25 In our study, 2 pregnancies were complicated
by premature rupture of membranes, resulting in preterm
6 Kidney International (2017) -, -–-
I De Castro et al.: Nephrotic syndrome in pregnancy
delivery in patients receiving prednisone. There were no
issues with maternal glucose control and no documented
worsening of BP with steroid use.
Hemodynamics, BP, and volume management
In most nonpregnant adults with NS, primary sodium
retention by the kidneys leads to vascular overfilling, possibly
from activation of the epithelial sodium channel by serine
proteases.26 The hemodynamic effects of NS on pregnancy are
not well described.
In this study, noninvasive hemodynamic monitoring
demonstrated that pregnant women with NS had a higher CO
compared with women with a normal pregnancy. This was
primarily due to an increase in stroke volume, reflective of
volume expansion seen in NS. This high CO state without a
corresponding decrease in total peripheral resistance poten-
tially promoted the development of hypertension in these
women. A high CO state before a later vasoconstrictive phase
has been described in patients in whom preeclampsia
develops.10,27
Severe hypertension is known to be a significant risk factor
for adverse maternal and perinatal outcomes, independent of
preeclampsia, and antihypertensive treatment of non-
proteinuric hypertension in pregnancy is considered benefi-
cial.28 Given that high BP may be considered a reflection of
increased CO or total peripheral resistance or both, some
facilities tailor their antihypertensive therapies to these vari-
ables. In our subjects, when CO is elevated, atenolol was used
to decrease pulse rate, and furosemide was used to decrease
stroke volume. Vasodilators such as nifedipine were used
when the total peripheral resistance was increased.
In our study, atenolol was commonly used due to the
increased CO in these patients. Concerns have previously
been raised about the use of atenolol in pregnancy.29,30
Lydakis et al.30 reported that atenolol was associated with
LBW and a trend toward earlier delivery compared with
women treated with alternative monotherapy. Abalos et al.29
showed a trend toward an increased risk of small for gesta-
tional age associated with beta-blockers, but also noted a
significant decrease in pre-eclampsia. By contrast, others have
not reported an increase in IUGR with atenolol.31,32 Orbach
et al.32 reported that women with chronic hypertension
treated with atenolol compared with methyldopa have a lower
rate of preterm delivery and have comparable rates of IUGR.
They concluded that the observed adverse events seen among
women treated for hypertension were due to hypertension
itself rather than choice of treatment. In our study, there was
no association between the use of atenolol and IUGR, LBW,
or preterm delivery.
Renal and maternal-fetal outcomes
Our study demonstrated that pregnant women with NS were
more likely to have preeclampsia, preterm birth, and LBW
compared with the general population.33 We found that the
degree of proteinuria was significantly associated with adverse
maternal-fetal outcomes. We did not find any association
I De Castro et al.: Nephrotic syndrome in pregnancy
between adverse outcomes and a history of hypertension,
maternal age, medications, serum creatinine, or BP at pre-
sentation. The association of proteinuria with adverse
maternal-fetal outcomes has been previously reported.
Packham et al.13 evaluated 33 pregnancies in women with
membranous nephropathy and found that proteinuria was
the only predictor of a poor maternal and fetal outcome. Park
et al.14 described 62 pregnancies with lupus nephritis and
found that proteinuria >0.5 g/d was associated with adverse
outcomes. Liu et al.12 showed a similar association between
proteinuria and adverse pregnancy outcomes in their cohort
with IgA nephropathy. In our study, all subjects had very
heavy proteinuria (mean, 8.96 g) and marked edema, much
greater than described in these previous studies.
In women with underlying renal disease, both the effect of
pregnancy on maternal renal disease and the effect of renal
disease on the pregnancy are considered. The maternal-fetal
outcomes are mostly dependent on the severity of the renal
dysfunction and BP control. In a retrospective cohort of
360 women with chronic glomerulonephritis and serum
<1.2 mg/dl, Jungers et al.26 found that the incidence of end-
stage renal disease was similar between those who conceived
and those who did not conceive. By contrast, pregnancy
in women with a creatinine level >1.5 mg/dl or eGFR
<60 ml/min per 1.73 m2 may be associated with a progressive
decrease in GFR.17,18
The incidence of maternal and obstetric complications
such as preterm delivery, growth restriction, and LBW is
higher in women with moderate to severe renal insuffi-
ciency. Piccoli et al.16 found that adverse outcomes were
more common in patients with chronic kidney disease
compared with those without: preterm delivery (44% vs.
5%), cesarean section (44% vs. 25%), and neonatal intensive
care unit admission (26% vs. 1%). Another study noted that
across the functional stages of chronic kidney disease, there
is a trend toward a higher risk of onset of hypertension and
the development of proteinuria.15 A review by Nevis et al.3
reported that the overall maternal adverse events were
5-fold higher in women with CKD compared with women
without. By contrast, the presence of NS due to renal dis-
ease, in the absence of significant renal insufficiency or
hypertension, has been described to have minimal effects on
the natural course of renal disease or maternal-fetal out-
comes.1,27 In this study, we included only subjects with a
serum creatinine level <1.5 mg/dl at presentation to mini-
mize the impact of renal function. The mean serum creat-
inine level in our subjects was 0.85 mg/dl. This is slightly
higher than that in the general population of pregnant
women, but at a range at which the maternal-fetal outcomes
are not greatly worsened. Similarly, 8 subjects had a known
history of hypertension, 6 of whom were taking antihyper-
tensive medications at presentation. BP was well controlled
in these subjects.
NS in pregnancy presents a diagnostic and management
dilemma. Women presenting with proteinuria before
20 weeks gestation should be suspected to have primary
Kidney International (2017) -, -–-
clinical investigation
glomerulonephropathy. Kidney biopsy is generally safe in this
group and is valuable in guiding management, but subjects
should be carefully selected. Although previous studies have
shown that the risk of biopsy complications during pregnancy
is generally low, there is the added potential harm to the fetus
should an adverse event occur, especially after 24 weeks when
the fetus is already viable. Steroid therapy is generally safe, but
should be guided by a pathologic diagnosis. Volume man-
agement in these patients should be closely monitored.
Patients should be counseled that although the live birth rate
is good, there is a high risk of the development of pre-
eclampsia, preterm delivery, and LBW. As such, patients
should be followed by a multidisciplinary team of obstetri-
cians and nephrologists who are adept at managing women
with renal disease.
Limitations of the study
As the presentation of NS during pregnancy is uncommon,
the underlying pathologic diagnoses are heterogeneous. All of
the patients were referred for tertiary maternal care, and it is
possible that our patients represent those at the highest risk of
adverse maternal-fetal outcomes.
Conclusions
Contrary to previous studies that reported good maternal-
fetal outcomes in pregnant women with NS and relatively
preserved renal function, we have shown a high incidence of
both maternal and fetal complications in this population that
correlate with the degree of proteinuria. Such patients need to
be managed carefully by an experienced multidisciplinary
team to optimize maternal-fetal outcomes.
MATERIALS AND METHODS
Study design and population
We performed a retrospective study of patients with biopsy-proven
primary glomerulopathy and NS during pregnancy. Electronic
medical records were queried using ICD-9 billing codes. Ninety-two
pregnancies with NS listed as a diagnosis during pregnancy were
identified and reviewed by a single reviewer. The majority were
referred to University of Washington Medical Center as a tertiary
referral center for high-risk obstetric care. Of the 92 pregnancies, 53
were excluded due to the absence of any laboratory data or
nephrotic-range proteinuria during pregnancy.
For the purposes of this study, NS was defined as nephrotic-range
proteinuria (>3.5 g/24 h and/or >3.5 g/g on spot urine protein-to-
creatinine ratio) with hypoalbuminemia (<3 g/dl) and edema.
Subjects were only included if they had undergone kidney biopsy
during or outside of pregnancy to define renal pathology. Subjects
were excluded if they had incomplete data on the renal or maternal-
fetal course or if they had a secondary glomerular disease from a
systemic, viral, or autoimmune condition. We included only subjects
with a serum creatinine level <1.5 mg/dl at presentation to minimize
the impact of renal dysfunction. Previous studies have shown that
pregnancy in women with a creatinine level >1.5 mg/dl or an esti-
mated glomerular filtration rate <60 ml/min per 1.73 m2 may be
associated with a progressive decrease in the glomerular filtration
rate.17,18 Eight patients were excluded due to incomplete data on
maternal course and fetal outcomes or an absence of pathologic
7
clinical investigation I De Castro et al.: Nephrotic syndrome in pregnancy

diagnosis or who had a creatinine level >1.5 mg/dl at presentation.
Five were excluded due to the presence of systemic illness causing
secondary proteinuric glomerular disease. There were 19 patients
included in this series with 26 pregnancies (Figure 1).
Clinical features
Information about the clinical and laboratory data was obtained
from the mother’s records. We describe the clinical features at the
time of presentation of NS during pregnancy. The cohort was
grouped based on the etiology of their primary glomerular disease.
The course of their glomerular disease and management are
described.
CO and total peripheral resistance measurements are included
when available. CO and total peripheral resistance values were ob-
tained using UltraCOM CO Monitor (Lawrence Medical Associates,
Eastchester, NY). This noninvasive method of measurement has been
validated in pregnant individuals.34
Maternal and fetal course and outcomes
We searched the chart for maternal complications including pre-
eclampsia, acute kidney injury, poor wound healing, pulmonary
embolism, and infection. The diagnosis of preeclampsia was
abstracted from the chart and defined as new-onset hypertension
with systolic BP of $140 mm Hg or diastolic BP $90 mm Hg on 2
occasions occurring after 20 weeks of gestation on a previously
normotensive patient. For patients with chronic or preexisting hy-
pertension before their pregnancy or before 20 weeks gestation,
preeclampsia was defined as worsening hypertension (increase in
systolic BP by 30 mm Hg and diastolic BP by 15 mm Hg), central
nervous system symptoms, hepatic abnormalities, thrombocyto-
penia, worsening renal function, or pulmonary edema. Acute kidney
injury was defined as increase in serum creatinine of 0.3 mg/dl or
decrease in glomerular filtration rate >50%. We included the
following fetal outcomes: gestational age at delivery, route of delivery,
IUGR, birth weight, respiratory distress syndrome, and neonatal
intensive care unit admission. Preterm delivery was defined as
<37 weeks, and LBW was defined as <2500 g. We analyzed
the association of possible risk factors in the development of
preeclampsia, preterm delivery, and LBW.
The study received approval from Human Subjects Committee at
the University of Washington.
Statistical analysis
The baseline characteristics, biopsy findings, hemodynamic param-
eters, and maternal-fetal outcomes of the study population are
described and expressed as mean
SD when applicable. For vari-
ables that were skewed, we reported the median (interquartile
range). We used Pearson’s correlation to test correlations between
preeclampsia, LBW, and preterm birth and several risk factors
including history of chronic hypertension, maternal age, serum
creatinine, serum albumin, proteinuria, and medications. All
analyses were implemented using Stata, version 13 (StataCorp
LP, College Station, TX). The results were considered statistically
significant if P < 0.05.

99 pregnancies with nephroƟc

syndrome per ICD billing code

53 pregnancies excluded due to absence

of laboratory data or nephroƟc range
proteinuria

39 pregnancies with nephroƟc

syndrome

13 pregnancies excluded
6 no pathologic diagnosis
5 systemic illness resulƟng in secondary
proteinuric disease
2 creaƟnine >1.5 mg/dl
26 pregnancies with nephroƟc
syndrome due to primary glomerular
disease

Figure 1 | Patient selection. ICD, International Classification of Diseases.

8 Kidney International (2017) -, -–-

I De Castro et al.: Nephrotic syndrome in pregnancy
DISCLOSURE
All the authors declared no competing interests.
REFERENCES
1. Studd JW, Blainey JD. Pregnancy and the nephrotic syndrome. BMJ.
1969;1:276–280.
2. Hayslett JP, Reece EA. Managing diabetic patients with nephropathy and
other vascular complications. Baillieres Clin Obstet Gynaecol. 1994;8:
405–424.
3. Nevis IF, Reitsma A, Dominic A, et al. Pregnancy outcomes in women
with chronic kidney disease: a systematic review. Clin J Am Soc Nephrol.
2011;6:2587–2598.
4. Hamilton P, Myers J, Gillham J, et al. Urinary protein selectivity in
nephrotic syndrome and pregnancy: resurrection of a biomarker when
renal biopsy is contraindicated. Clin Kidney J. 2014;7:595–598.
5. Lamkee MJ, Bratvold GE. Renal glomerulo-tubular mechanisms during
toxemia of pregnancy. West J Surg Obstet Gynecol. 1961;69:121–128.
6. Lo JO, Kerns E, Rueda J, et al. Minimal change disease in pregnancy.
J Matern Fetal Neonatal Med. 2014;27:1282–1284.
7. Hamilton BE, Martin JA, Osterman MJ, et al. Births: final data for 2014.
Natl Vital Stat Rep. 2015;64:2–3.
8. Easterling TR, Benedetti TJ, Schmucker BC, et al. Maternal hemodynamics
in normal and preeclamptic pregnancies: a longitudinal study. Obstet
Gynecol. 1990;76:1061–1069.
9. Hamilton BE, Martin JA, Osterman MJ, et al. Births: final data for 2014.
Natl Vital Stat Rep. 2015;64:7–8.
10. Kincaid-Smith P, Fairley KF. The differential diagnosis between
preeclamptic toxemia and glomerulonephritis in patients with
proteinuria during pregnancy. Perspect Nephrol Hypertens. 1976;5:
157–167.
11. Carr DB, Koontz GL, Gardella C, et al. Diabetic nephropathy in pregnancy:
suboptimal hypertensive control associated with preterm delivery. Am J
Hypertens. 2006;19:513–519.
12. Liu Y, Ma X, Lv J, et al. Risk factors for pregnancy outcomes in patients
with IgA nephropathy: a matched cohort study. Am J Kidney Dis. 2014;64:
730–736.
13. Packham DK, North RA, Fairley KF, et al. Membranous glomerulonephritis
and pregnancy. Clin Nephrol. 1987;28:56–64.
14. Park EJ, Jung H, Hwang J, et al. Pregnancy outcomes in patients with
systemic lupus erythematosus: a retrospective review of 62 pregnancies at
a single tertiary center in South Korea. Int J Rheum Dis. 2014;17:887–897.
15. Piccoli GB, Cabiddu G, Attini R, et al. Risk of adverse pregnancy outcomes
in women with CKD. J Am Soc Nephrol. 2015;26:2011–2022.
16. Piccoli GB, Attini R, Vasario E, et al. Pregnancy and chronic kidney
disease: a challenge in all CKD stages. Clin J Am Soc Nephrol. 2010;5:
844–855.
17. Imbasciati E, Pardi G, Capetta P, et al. Pregnancy in women with chronic
renal failure. Am J Nephrol. 1986;6:193–198.
Kidney International (2017) -, -–-
clinical investigation
18. Imbasciati E, Gregorini G, Cabiddu G, et al. Pregnancy in CKD stages 3 to
5: fetal and maternal outcomes. Am J Kidney Dis. 2007;49:753–762.
19. Chen TK, Gelber AC, Witter FR, et al. Renal biopsy in the management of
lupus nephritis during pregnancy. Lupus. 2015;24:147–154.
20. Whittier WL, Korbet SM. Timing of complications in percutaneous renal
biopsy. J Am Soc Nephrol. 2004;15:142–147.
21. Piccoli GB, Daidola G, Attini R, et al. Kidney biopsy in pregnancy:
evidence for counselling? A systematic narrative review. BJOG. 2013;120:
412–427.
22. Day C, Hewins P, Hildebrand S, et al. The role of renal biopsy in women
with kidney disease identified in pregnancy. Nephrol Dial Transplant.
2008;23:201–206.
23. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal
exposure to corticosteroids: prospective cohort study and meta-analysis
of epidemiological studies. Teratology. 2000;62:385–392.
24. Guller S, Kong L, Wozniak R, et al. Reduction of extracellular matrix
protein expression in human amnion epithelial cells by glucocorticoids: a
potential role in preterm rupture of the fetal membranes. J Clin
Endocrinol Metab. 1995;80:2244–2250.
25. Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and
immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8:
209.
26. Jungers P, Houillier P, Forget D, et al. Influence of pregnancy on the
course of primary chronic glomerulonephritis. Lancet. 1995;346:
1122–1124.
27. Muller-Deile J, Schiffer M. Preeclampsia from a renal point of view:
Insights into disease models, biomarkers and therapy. World J Nephrol.
2014;3:169–181.
28. Magee LA, von Dadelszen P, Singer J, et al. The CHIPS Randomized
Controlled Trial (Control of Hypertension in Pregnancy Study): is severe
hypertension just an elevated blood pressure? Hypertension. 2016;68:
1153–1159.
29. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to
moderate hypertension during pregnancy. Cochrane Database Syst Rev.
2014:CD002252.
30. Lydakis C, Lip GY, Beevers M, et al. Atenolol and fetal growth in
pregnancies complicated by hypertension. Am J Hypertens. 1999;12:
541–547.
31. Easterling TR, Brateng D, Schmucker B, et al. Prevention of preeclampsia:
a randomized trial of atenolol in hyperdynamic patients before onset of
hypertension. Obstet Gynecol. 1999;93:725–733.
32. Orbach H, Matok I, Gorodischer R, et al. Hypertension and
antihypertensive drugs in pregnancy and perinatal outcomes. Am J
Obstet Gynecol. 2013;208:e301–e306.
33. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United
States, 1980-2010: age-period-cohort analysis. BMJ. 2013;347:f6564.
34. Easterling TR, Watts DH, Schmucker BC, et al. Measurement of cardiac
output during pregnancy: validation of Doppler technique and clinical
observations in preeclampsia. Obstet Gynecol. 1987;69:845–850.
9