CJASN ePress. Published on July 12, 2017 as doi: 10.2215/CJN.

00130117

Pregnancy and Glomerular Disease: A Systematic

Review of the Literature with Management Guidelines
Kimberly Blom,* Ayodele Odutayo,* Kate Bramham, and Michelle A. Hladunewich*

Abstract
During pregnancy, CKD increases both maternal and fetal risk. Adverse maternal outcomes include progression of
underlying renal dysfunction, worsening of urine protein, and hypertension, whereas adverse fetal outcomes
*Division of
include fetal loss, intrauterine growth restriction, and preterm delivery. As such, pregnancy in young women with Nephrology,
CKD is anxiety provoking for both the patient and the clinician providing care, and because the heterogeneous Department of
group of glomerular diseases often affects young women, this is an area of heightened concern. In this invited Medicine,
review, we discuss pregnancy outcomes in young women with glomerular diseases. We have performed a Sunnybrook Health
Sciences Centre,
systematic review in attempt to better understand these outcomes among young women with primary GN, we
University of Toronto,
review the studies of pregnancy outcomes in lupus nephritis, and finally, we provide a potential construct for Toronto, Ontario,
management. Although it is safe to say that the vast majority of young women with glomerular disease will have a live Canada; and

birth, the counseling that we can provide with respect to individualized risk remains imprecise in primary GN Department of Renal
because the existing literature is extremely dated, and all management principles are extrapolated primarily from Medicine, Division of
Transplantation
studies in lupus nephritis and diabetes. As such, the study of pregnancy outcomes and management strategies in these Immunology and
rare diseases requires a renewed interest and a dedicated collaborative effort. Mucosal Biology,
Clin J Am Soc Nephrol 12: cccccc, 2017. doi: https://doi.org/10.2215/CJN.00130117 Kings College,
London, United
Kingdom

Introduction in young women with glomerular diseases. We have Correspondence:

Pregnancy is a physiologic stress, wherein failure to
adapt can result in adverse pregnancy outcomes.
Systemic and renal vasodilation results in a drop in BP
along with a decrease in renal vascular resistance
leading to increased renal plasma ow, and conse-
quently, nearly a 50% increase in glomerular ltration.
Inadequate adaptation occurs in women with under-
lying hypertension and CKD, and is a poor prognostic
indicator. In general, more resistant hypertension and
advanced CKD are associated with greater risks of
renal disease progression, prematurity, and growth
restriction. Data from Italy estimate the risks for
deterioration of kidney function are 7.6%, 12.6%,
16.2%, and 20% at stages 14, respectively (1). Fur-
thermore, fetal outcomes deteriorate along this same
continuum with preterm delivery before 37 weeks
gestation increasing from 24% in stage 1 CKD to 89%
in stages 4 and 5 CKD and neonatal birth weight
dropping by approximately 1300 g between the two
groups (mean birth weight 29666659 and 16396870 g
in stage 1 and stages 4 and 5 CKD, respectively) (1). It
is important to note that only 16% of the patients in this
study had glomerular disease, and of those with
advanced CKD (stages 35), only 11 of 45 had in
excess of 1 g urine protein.
As such, pregnancy in young women with CKD
is anxiety provoking for both the patient and the
clinician providing care, and because the heteroge-
neous group of glomerular diseases often affects
young women, this is an area of heightened concern.
In this invited review, we discuss pregnancy outcomes
performed a systematic review in attempt to better Dr. Michelle A.
understand these outcomes among young women Hladunewich,
Sunnybrook Health
with primary GN, we review the studies of pregnancy Sciences Centre, 3rd
outcomes in lupus nephritis, and nally, we discuss a Floor, Canadian
potential construct for management. National Institute for
the Blind Kidney
Centre, 1929 Bayview
Avenue, Toronto, ON,
Systematic Review of Primary Glomerular Canada M4G 3E8.
Diseases Email: michelle.
A comprehensive review of pregnancy outcomes hladunewich@
has been conducted in lupus nephritis (2), but there sunnybrook.ca
are limited data assessing pregnancy risk associated
with other forms of primary GN. Accordingly, we
conducted a systematic review of the literature on
pregnancy outcomes in women with biopsy-proven
primary glomerular-based diseases. The outcome of
interest was the frequency of live births according to
primary GN etiology and the inuence of baseline
characteristics on pregnancy outcomes. Full study
methods are in Supplemental Material. In summary,
results from 18 studies, including 887 women and
1414 pregnancies, were abstracted from studies pub-
lished after 1980 (Supplemental Figure 1, Supplemental
Table 1). Study heterogeneity was signicant, preclud-
ing any pooling of data, and baseline characteristics
were often not reported or inadequately described,
precluding determination of the potential inuence of
hypertension, renal insufciency, or proteinuria on
pregnancy outcomes (Supplemental Table 2). Over
time, the pathologic descriptions of some glomerular
diseases have also evolved, and the denitions of

www.cjasn.org Vol 12 December, 2017 Copyright 2017 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology
important pregnancy complications, such as preeclampsia,
have changed. As such, the review is narrative, and urgent
contemporary data are required. Table 1 below summarizes
pregnancy outcomes.
The most commonly reported GN was IgA nephropathy,
with 12 studies including 10136 patients (one study
included two IgA cohorts) (313). The proportion of
women with hypertension at baseline was reported in
eight studies and ranged from 9% to 40%. The proportion
of women with increased creatinine at study entry was
rarely reported, and denitions of renal insufciency
varied. Across all 12 studies, live birth rate ranged from
70% to 100%. Live birth rates seemed to be lower before
2000 (6,7), but were variable, likely reecting small study
sizes and reporting biases in addition to improvements in
neonatal care over the decades. Only ve studies reported
the mean birth weight, which ranged from 2911 to 3200 g,
and few studies (n55) reported the rate of superimposed
preeclampsia, which ranged from 0% to 25%. A minority
of studies provided long-term follow-up data. One study
reported both sclerosis and vascular disease to be associated
with adverse events, but no others attempted to assess the
relationship between histologic features and outcome (14).
As expected, general themes that emerged included the
association of adverse pregnancy outcomes, including
perinatal death, preterm delivery, and small birth weight,
with hypertension and renal insufciency (35). In the
second largest study of 118 pregnant women (9), women
with hypertension at baseline (BP$140/90 mmHg) or
impaired renal function (eGFR,70 ml/min per 1.73 m2)
were more likely to have an unsuccessful pregnancy.
Perinatal mortality was 33% in women with hyperten-
sion compared with 1% in normotensive women and 14%
in women with renal dysfunction compared with 3% in
women with normal renal function. The largest study to
date, published in 2010, reported outcomes for 229 preg-
nancies and compared renal outcomes of 136 pregnant
women with 87 nonpregnant women, all with serum
creatinine levels #1.2 mg/dl at diagnosis (10). Although
pregnancy did not affect renal disease progression in this
study, a second much smaller group studied with impaired
renal function (n510 with baseline serum creatinine levels
.1.2 mg/dl, averaging 1.6560.39 mg/dl) showed hastened
progression, suggesting an imminent need for more data in
women with IgA at more advanced stages of CKD. Finally,
the most recently published study noted an association
between proteinuria and adverse pregnancy outcomes (13).
Time-averaged proteinuria, the arithmetic average of pro-
teinuria during pregnancy and follow-up, was inversely as-
sociated with infant birth weight (correlation coefcient 5
20.61; P,0.001) and also associated with adverse preg-
nancy outcomes, including severe preeclampsia and intra-
uterine death (13). The strategy for managing worsening
proteinuria during pregnancy in women with IgA is
presently unclear.
Data to support prepregnancy counseling for the other
forms of primary glomerular disease are very sparse.
Only four studies reported outcomes for women with
FSGS (3,4,6,15), all were published before 1990, and all were
small (1731 pregnancies), with limited reporting of dis-
ease severity or hypertension. The proportion of live births
ranged from 55% to 94% with high rates of complications
(e.g., spontaneous abortion, 8%; preterm delivery, 24%;
small for gestational age, 4%; perinatal death, 16% [3]),
with hypertension, impaired renal function, and nephrotic-
range proteinuria identied to be associated with the
greatest risk (3,4). Only two studies included women with
minimal change disease (5,16) or membranous nephropa-
thy (5,17), and similarly, nephrotic-range proteinuria and
hypertension in the early stages of pregnancy were asso-
ciated with worse pregnancy outcomes. In 33 pregnancies in
24 women with membranous nephropathy (17), only 20%
(two of 10) of women with .5 g/24 h proteinuria had a live
infant born after 32 weeks gestation compared with 91%
(21 of 23) with #5 g/24 h (P,0.001), suggesting man-
agement of nephrotic syndrome with pregnancy-safe im-
munosuppression is likely critical and highlighting the
urgent need for contemporary, collaborative studies to
provide informed prepregnancy counseling.
Overview of Pregnancy Outcomes in Lupus Nephritis
The onset of lupus most frequently occurs in women of
child-bearing age (18), and therefore, it is imperative that
nephrologists are comfortable with reproductive counsel-
ing in this subpopulation. Unlike the other primary
glomerular diseases, there are now robust data to inform
pregnancy outcomes and guide a management approach,
including a systematic review (2) and two large multicenter
prospective studies (19,20) as well as numerous smaller
retrospective analyses. The take-home message from all of
these studies is that women with active disease should be
strongly discouraged from conceiving until their lupus is
controlled.
Evidence from meta-analysis data, 37 studies of 2751
pregnancies in 1842 women, showed a higher risk of
adverse outcomes, including fetal loss, preeclampsia,
preterm delivery, and small for gestational age infants,
in those with active disease in early pregnancy (2).
Furthermore, any maternal disease are and renal are
were estimated to occur in 26% and 16% of pregnan-
cies, respectively. A recent prospective multicenter cohort
study of 71 pregnancies in 61 women with lupus nephri-
tis reported an increased odds for preterm delivery by 15%
for each increase of proteinuria by 1 g/d every trimester
(20). Even low C3 and C4, without systemic manifestations,
have been reported to be associated with increased risk
in a prospective cohort (21). Other factors that adversely
affect pregnancy outcomes, including fetal or neonatal
death, birth before 36 weeks due to placental insufciency,
hypertension or preeclampsia, small for gestational age
neonate (below the fth percentile), and maternal renal
ares in women with lupus nephritis, include severity of
preexisting disease, nonwhite ethnicity, presence of anti-
cardiolipin antibody or lupus anticoagulant, and hyperten-
sion (19,21,22). One cohort study suggested that women
with classes 3 and 4 lupus nephritis are more likely to have
pregnancies complicated by preeclampsia and lower-birth
weight babies than those with class 2 or 5 lupus nephritis
(23), but histologic class was not associated with different
outcomes in the aforementioned meta-analysis (2). As such,
women with normal renal function and quiescent disease
can expect to have excellent pregnancy outcomes. A recent
large prospective cohort study of 385 women with inactive
Table 1. Pregnancy outcomes by primary glomerular disease type

No. of Infants
Women (No. Average Age at Prepregnancy Prepregnancy Pregnancies with BP Creatinine
Study, yr [Survived BW, g GA, wk
of Pregnancies) Pregnancy, yr Hypertension (%) Creatinine (%) Preeclampsia (%) Postpregnancy Postpregnancy
Infants (%)]

IgA nephropathy
Surian et al. (3) 21 (29) NA NA NA NA NA 0 (0) 29 [26 (90)] NA NA
Barcel et al. (4) 10 (15) NA NA NA 0(0) NA 0 (0) 15 [14 (93)] NA NA
Jungers et al. (5) 34 (69) NA 10 (14) 3 (4) NA NA 3 (4) 70 [57 (81)] 3200 NA
Kincaid-Smith 65 (102) NA NA NA NA 16 (16) NA 102 [74 (73)] NA NA
and Fairley (6)
Packham et al. (7) 70 (116) NA 18 (16) 1 (1) NA 15 (13)a NA 118 [83 (70)] NA NA
Nagai et al. (8) 17 (19) 29 5 (26) 0 (0) NA 9 (47) 1 (5) 19[19 (100)] 2937 39
Abe (9) 118 (168) NA 15 (9) NA NA 9 (11)b NA 168 [146 (87)] NA NA
Clin J Am Soc Nephrol 12: cccccc, December, 2017

Limardo et al. (10) 136 (229) 27 27 (20)c 0 (0) 17 (9) 34 (31) 13 (9.6) 229 [195 (85)] 3039 NA
Limardo et al. (10) 10 (10) 29 4 (40) 10 (100) NA NA NA 10 [8 (80)] NA NA
Shimizu et al. (11) 29 (29) 31 NA NA 0 (0) NA NA 29 [29 (100)] 2911 38
Waness et al. (12) 12 (12) 29 2 (17) 0 (0) 3 (25) NA NA 12 [12 (100)] 3100 NA
Liu et al. (13) 62 (69) 27 7 (11) NA 6 (9) 8 (12) NA 69 [59 (86)] 2972 NA
FSGS
Surian et al. (3) 19 (25) NA NA NA NA NA 0 (0) 25 [19 (76)] NA NA
Barcel et al. (4) 13 (17) NA NA NA 1 (6) 1 (6) 0 (0) 17 [16 (94)] NA NA
Kincaid-Smith 15 (28) NA NA NA NA 5 (18) NA 28 [23 (81)] NA NA
and Fairley (6)
Packham et al. (15) 21 (31) NA 5 (24) NA NA NA 4 (13) 31 [17 (55)] NA 31
MCD
Abe et al. (16) 10 (17) NA NA NA NA NA 0 (0) 17 [12 (71)] NA NA
Jungers et al. (5) 19 (31) NA 0 (0) 0 (0) NA 0 (0) 0 (0) 34 [26 (76)] 3300 NA
MN
Jungers et al. (5) 18 (37) NA 7 (19) 0 (0) NA NA 1 (3) 37 [25 (67)] 2900 NA
Packham et al. (17) 24 (33) NA 0 (0) NA NA 3 (9) 2 (8) 33 [25 (76)] NA NA
GN, disease type
not specied
Malik et al. (90) 17 (85) 36 NA NA 14 (16) NA NA 85 [81 (95)] NA NA
Abe (91) 12 (15) 28 NA NA 7 (58) NA NA 15 [11 (73)] 2115 NA
Packham et al. (92) 91 (168) NA 20 (12) 0 (0) NA 11 of 80 without 0 (0) 169 [136 (80)] NA NA
hypertension
at baseline
Abe et al. (16) 32 (50) NA NA NA NA NA 4 (8) 50 [43 (86)] NA NA
Hou et al. (93) 12 (12) NA 6 (50) 12 (100) NA 3 (25) 9 (75) 12 [11 (92)] NA 33

Studies are arranged in order of date of publication and then alphabetically by rst author. BW, birth weight; GA, gestational age; NA, not available; MCD, minimal change disease; MN,
membranous nephropathy.
a
Postpartum dened as maternal outcomesexact postpartum timeframe unclear.
b
Data collected from 85 subjects who remained in follow-up for at least 3 years.
c
Number of subjects with hypertension (rather than number of pregnancies).
Glomerular Disease in Pregnancy, Blom et al.
3
4 Clinical Journal of the American Society of Nephrology
lupus, excluding those with creatinine concentration
.1.2 mg/dl and/or a urinary protein-to-creatinine ratio
.1000 mg/g, reported that 81% did not experience any
adverse events (19). Severe maternal ares were rare,
occurring in the second trimester in only 2.5% and third
trimester in 3.0% of women (19). However, those with
previous lupus nephritis, despite preserved GFR, have
been reported to have higher rates of preterm delivery and
earlier-onset preeclampsia than women with lupus with-
out renal involvement (24). Estimates of pregnancy out-
comes in women with more severe renal impairment and
controlled lupus require extrapolation from literature that
includes different etiologies of renal disease, and the risk
of renal progression is related to severity of renal impair-
ment and the potential for reactivation or are of the
disease.
Women with anti-Ro/Anti-Sjgrens-syndromerelated
antigen A (SSA) antibody should be informed of the po-
tential risk of development of fetal heart block due to
placental transfer of Ig leading to endocardial broelasto-
sis. In a retrospective cohort study of 186 pregnancies,
5% of offspring were affected; however, this was only
in women with titers $50 U/ml (25). Similarly, neonatal
cutaneous lupus was reported to be more common in
women with high-titer anti-La/Anti-Sjgrens-syndrome
related antigen B (SSB) ($100 U/ml), occurring in 57%
of infants (25). The European League against Rheumatism
guidelines recommend that all women with suspected fetal
dysrhythmia or myocarditis, especially those with anti-Ro/
SSA and/or anti-La/SSB antibody, should have fetal echo-
cardiography (26).
In addition to pregnancy-safe immunosuppression (in
Immunosuppression below), hydroxychloroquine is now
recognized as a critical component of disease management
in women with lupus nephritis. Hydroxychloroquine is rec-
ommended to be commenced or continued for all women
with lupus nephritis because prospective cohort studies have
shown maternal and fetal benets (20,21). Those who dis-
continue hydroxychloroquine have been reported to
have higher incidence of lupus ares, leading to greater use
of antenatal steroids (27). No increased risk of congenital
abnormalities is conrmed from a recent meta-analysis (28),
although a higher rate of spontaneous abortion in exposed
pregnancies than controls was noted with disease activity
as a potential confounder. As such, there are no reported
adverse effects on the fetus or neonate. Furthermore, there
are limited data to suggest up to an 85% reduction in the
risk of fetal growth restriction (20) and recurrence of fetal
heart block (29).
Management Recommendations
Despite lack of data in the primary glomerular diseases,
recent evidence from the Predictors of Pregnancy Out-
come in Systemic Lupus Erythematosus and Antiphospho-
lipid Syndrome (PROMISSE) Study (19) and other smaller
studies in systemic lupus (20) and even vasculitis (30) that
show much better outcomes in women with adequately
controlled disease before pregnancy have indirectly in-
formed care in other glomerular diseases (Figure 1).
Prepregnancy optimization is dened as stabilization of
rapid progression where possible, minimization of urine
protein with pregnancy-compatible immunosuppression,
and control of hypertension with pregnancy-safe antihy-
pertensive agents, while actively delaying pregnancy
when these conditions cannot be met. During pregnancy,
careful surveillance to detect the rst signs of maternal
or fetal compromise is critical, whereas postpartum care
must include ongoing vigilant care of the underlying
GN along with emotional support to assist young mothers
to cope with a chronic disease while raising a child. Table 2
includes acceptable therapeutic agents that can be used in
pregnancy.
Prepregnancy Care
Contraception. Given the risks associated with preg-
nancy in women with CKD, an unplanned pregnancy
should be vigorously avoided to ensure that conception
does not occur before disease quiescence or while conr-
mation of disease stability after adjustment to pregnancy-
safe medications. As such, questions about sexual activity
and contraception should be part of routine nephrology care
in young women, but are often overlooked. Estrogen-
containing contraception is contraindicated in all women
with vascular disease, and should be used with caution
in young women with hypertension and CKD due to the
increased risk of thrombosis and exacerbation of hyperten-
sion (31). Furthermore, there is limited evidence from
studies in women with diabetic nephropathy that estrogen
may exacerbate preexisting proteinuria (32), possibly
secondary to stimulation of the renin angiotensin system
(RAS) (33,34). As such, progesterone-only preparations are
generally recommended and include the progesterone-only
pill, which is now available with a wider dosing window in
some countries, intramuscular depot injections, and the
intrauterine coil (preferably in multiparous women due to
difculties with insertion in nulliparous women). Barrier
contraception is less reliable, and therefore, is not recom-
mended as a sole method of birth control.
Fertility. The desire to have a child is innate; therefore,
many women will want to conceive at some time during
their journey with CKD, but both their underlying disease
as well as treatment choices can affect fertility. Along with
advancing renal dysfunction are increased rates of infer-
tility due to hormonal aberrations and progressive sexual
dysfunction due to medication side effects, fatigue, symp-
toms of depression, and altered body image, which can be
signicant due to the cosmetic side effects of commonly
used immunosuppressive agents in patients with glomer-
ular diseases (35). Assisted conception is, therefore, likely
to be used more widely in women with various forms of
GN due to increased availability; however, to date, there
are no data to guide this practice.
It is recognized that there is a reduction in the number
of pregnancies reported with advancing severity of renal
disease, and many women with advanced CKD report
amenorrhea or erratic cycles. A small cohort study of
17 women with CKD reported an increase in luteinizing
hormone in women with CKD and reduced cyclic changes
in hypothalamic-pituitary-ovarian hormones (36), whereas
others have conrmed an increase in both prolactin
production and clearance with reducing GFR (37). Self-
reporting of menopause suggests that it occurs early in
women with CKD (38), but these data are confounded by the
Clin J Am Soc Nephrol 12: cccccc, December, 2017
Figure 1. | Management of glomerular disease before, during, and after pregnancy. BMI, body mass index; BPP, biophysical profile; VTE,
venous thromboembolism.
lack of biochemical evidence of menopause and may reect
misreporting of anovulatory cycles secondary to renal disease.
The choice to use cyclophosphamide must also be made
with care because there is a direct association between
ovarian damage and the prescribed dose, duration,
and route of administration of this medication, with oral
cyclophosphamide inducing a more sustained amenor-
rhea than intravenous administration as noted in a Chi-
nese study of 212 women (39). Furthermore, advancing
age signicantly increases the risk for irreversible ovarian
damage in young women. A controlled retrospective
cohort study of 39 women age ,40 years old reported
sustained amenorrhea after cyclophosphamide therapy in
12% of women ,25 years of age, 27% of women 2631 years
of age, and 62% of women .30 years old (40). The use of
leuprolide acetate, a synthetic gonadotropin-releasing hor-
mone analog, to limit ovarian damage has not been studied
in women with GN, and its use is not routine in this patient
population. Of three recent meta-analyses conducted in
women with malignancies and rheumatologic diseases, two
found a signicant benet with regard to resumption of
menses and ovulation (41,42), whereas another found no
benet of gonadotropin-releasing hormone analog cotreat-
ment (43). It is, therefore, best to attempt to avoid cyclo-
phosphamide in women of child-bearing age and use other
agents where possible and appropriate (e.g., mycophenolate
mofetil for lupus nephritis and rituximab for vasculitis).
Disease Optimization. As mentioned, a sustained clin-
ical remission before conception has been noted to signif-
icantly improve maternal and fetal outcomes in women
with both lupus nephritis (19,20) and vasculitis (30), and
active nephritis is associated with higher rates of pre-
eclampsia, increased premature delivery, small for gesta-
tional age births, and accelerated loss of renal function
Glomerular Disease in Pregnancy, Blom et al. 5
(2,44). From this, we deduce that any active GN will
potentially contribute to adverse pregnancy outcomes,
and control of the glomerular disease with pregnancy-safe
immunosuppression is desirable, whereas all potentially
teratogenic medications must be discontinued. A reasonable
approach includes treatment with pregnancy-safe immuno-
suppression (Immunosuppression below) to attain remission
for at least 36 months before a pregnancy attempt (45). In
patients without immunologic treatment options, control of
urine protein with agents that block the RAS is the mainstay of
therapy. Although clearly teratogenic in the second and third
trimesters of pregnancy (BP Therapy below), data for terato-
genicity with only early pregnancy exposure are no longer
supported (46). Unfortunately, the potential use of these agents
in pregnancy planning is not derived from data published in
the management of GN, but comes from small, uncontrolled
studies in patients with diabetic nephropathy, wherein in-
tensive treatment with angiotensin-converting enzyme inhibi-
tion in addition to optimization of glucose control before
conception have been shown to stabilize proteinuria during
pregnancy (47,48), and compared with older preexisting
literature, prolong gestation and improve birth weights (49).
Data in other primary glomerular diseases are urgently
required, especially IgA nephropathy, which is a common
entity with management outside of pregnancy that is debated.
Antenatal Care
Immunosuppression. Women with GN often receive
conicting information from health care professionals re-
garding medication safety during pregnancy. Reassurance re-
garding balance of risk versus benet is frequently needed,
while cautioning women that the recommendation from
pharmaceutical companies and information that they glean
from online sources may conict with current expert opinion.
6 Clinical Journal of the American Society of Nephrology

Table 2. Acceptable therapeutic agents in pregnancy and breastfeeding

Purpose Therapeutic Options

Management of Methyldopa
hypertension Labetalol
Long-acting nifedipine
Hydralazine
Amlodipine (used in Europe, but presently limited published safety data)
Thiazide diuretics (typically avoided, but can be considered in difcult to
control hypertension)
RAS blockade strictly contraindicated in pregnancy, but enalapril, captopril,
and quinalapril do not pass into breast milk and can be used postpartum
to manage hypertension and proteinuria
Immunosuppression Prednisone
iv Methylprednisolone
Azathioprine
Calcineurin inhibitors
Rituximab (can be considered early in pregnancy, but no long-term safety
data on exposed infants)
Plasmapheresis
Preeclampsia prevention Low-dose aspirin (7581 mg daily)
Calcium and vitamin D supplementation (in women who may be decient)
Nephrotic syndrome Low molecular weight heparin
Furosemide

RAS, renin angiotensin system.

Safety data for immunosuppressive agents come from large
registry and population studies of women with transplants,
but can be used to inform treatment for women with GN.
Prednisone is considered to be relatively safe in preg-
nancy, and benets of continuation usually considerably
outweigh any risk. Early case-control studies suggested an
increased incidence of cleft lip and palate with rst trimester
exposure (50), but subsequent well conducted population
studies did not conrm an association (51). Prednisone is
metabolized by placental 11-b-hydroxysteroid dehydroge-
nase type 2 to inactive cortisone; therefore, the fetal dose is
minimal. However, dexamethasone, administered for fetal
lung maturation, is not inactivated, and the fetus is exposed
to approximately 30% of the maternal dose. High doses of
prednisone have been associated with premature rupture
of membranes (52); however, the simultaneous inuence of
preexisting disease activity contributing to preterm deliv-
ery is unknown. Other reported complications are simi-
lar to those in nonpregnant patients, including high rates
of gestational diabetes, weight gain, hypertension, osteo-
porosis, cataracts, infection, and mood changes. Stress
doses of glucocorticoids (typically hydrocortisone) are rec-
ommended during labor for women taking the equivalent
of prednisone 20 mg or more for .3 weeks (53).
Azathioprine is frequently the drug of choice to maintain
disease quiescence during pregnancy. A Danish population
study compared the outcomes of 11 infants exposed in utero
to azathioprine with those of 19,418 pregnancies without
exposure and reported an increase in malformations, pre-
maturity, and perinatal mortality (54). However, several
hundreds of pregnancy outcomes in transplant recipients
prescribed azathioprine during pregnancy have been re-
ported with rates of congenital malformations comparable
with those in the general population (55). Azathioprine
requires activation by inosinate pyrophosphorylase to me-
tabolite 6-mercaptopurine, which is absent in the fetal liver.
Studies of transplant recipients also support safety of calci-
neurin inhibitors, with no evidence of increased risk of
teratogenicity with cyclosporin or tacrolimus (5557). Fre-
quently, calcineurin inhibitor concentrations fall during preg-
nancy, assumed due to increased hepatic metabolism, and may
require an increase in dose up to 20%25% compared with
prepregnancy doses (58). A small study of ten women suggested
that free tacrolimus concentrations may be greater in pregnancy
relative to postpartum (59); hence, low therapeutic ranges
should be targeted because high concentrations may cause
nephrotoxicity and hypertension. Some experts do not monitor
concentrations during pregnancy given the uncertainty of the
relevance of recommended targets in pregnancy, and instead,
titrate doses as dictated by changes in the clinical condition.
Cyclophosphamide and mycophenolate mofetil are
teratogenic and should be avoided during pregnancy.
Cyclophosphamide is associated with calvaria, ear and
craniofacial structure, limb and visceral organ abnormal-
ities, and developmental delay with rst trimester expo-
sure and growth restriction, suppression of hematopoiesis,
and neurologic impairment with exposure in later trimes-
ters (60). Up to 15% of infants exposed to mycophenlate
mofetil in the rst trimester develop major congenital
defects, including cleft lip and palate, microtia with atresia
of the external auditory canals, micrognathia, and hyper-
telorism, and high rates of miscarriage are reported (61).
Experience with rituximab before and during pregnancy is
expanding due to studies from hematologic malignancies.
Transplacental transfer occurs, and B cell depletion was
reported in 11 of 90 exposed infants, with increasing
incidence and severity from second trimester adminis-
tration to term (62); hence, if required in pregnancy, early
Clin J Am Soc Nephrol 12: cccccc, December, 2017
treatment is preferable. In our practice, we currently consider
rituximab only as a last resort in early pregnancy pending
further data. Neonatal monitoring is recommended before
routine vaccination, with delay if necessary. There are no long-
term follow-up studies of infants with in utero exposure to
rituximab, and therefore, its potential deleterious effects on the
developing immune system remain unknown.
BP Therapy. To date, there have been no studies con-
ducted to establish BP treatment goals in young women with
any form of CKD, but it is well accepted that poorly
controlled hypertension during pregnancy signicantly wor-
sens both maternal and fetal outcomes, and experts agree
that maintaining BP,140/90 mmHg is prudent in this
patient population (63); the safety of which has been recently
conrmed in an unblinded, multicenter, randomized, con-
trolled study in pregnant women with either chronic or ges-
tational nonproteinuric hypertension (64). The Control of
Hypertension in Pregnancy Study (CHIPS) randomized 987
women to either less tight (target diastolic BP 5100 mmHg)
or tight (target diastolic BP 585 mmHg) BP control. The
achieved BP difference was 85.3 compared with 89.9 mmHg
in the tight versus less tight group, respectively. No signi-
cant difference between the groups was noted in the primary
outcome, a composite of pregnancy loss or high-level neo-
natal care for .48 hours, which was 31.4% in the less tight
versus 30.7% in the tight control group. Of note, there was
also no difference in low birth babies or perinatal mortality.
The most signicant trial nding was that women receiving
less tight (versus tight) control more commonly developed
severe hypertension (.160/110 mmHg) at 40.6% versus
27.5% (P,0.001), which would be a particularly concerning
deterioration in a woman with underlying kidney disease.
There are a number of drug options for the management
of hypertension in pregnancy, including methyldopa, labe-
talol, hydralazine, and long-acting nifedipine. Although
labetalol is frequently considered the rst-line agent, a
secondary analysis of the CHIPS cohort noted that women
treated with methyldopa (versus labetalol) had fewer ad-
verse perinatal and maternal outcomes, including fewer
babies who were small for gestational age, fewer deliver-
ies ,34 and ,37 weeks, less severe hypertension, and pre-
eclampsia (65). The use of methyldopa seemed to be
especially benecial for women with preexisting hyper-
tension. Another study showed higher rates of respiratory
distress syndrome, sepsis, and seizures in infants of mothers
with chronic hypertension dispensed only labetalol com-
pared with those dispensed only methyldopa (adjusted odds
ratio, 1.51; 95% condence interval [95% CI], 1.02 to 2.22) (66),
suggesting that this is an area that requires further research in
women with CKD. Although diuretics are often avoided due
to the theoretical concern of intravascular contraction, they
can be used in select women. Similarly, other b-blockers (e.g.,
metoprolol) and calcium channel blockers (e.g., amlodipine
and diltiazem) have been used, but again, only in women in
whom the aforementioned safer alternatives are not tolerated
pending further studies. Inhibitors of the RAS are strictly
contraindicated beyond the rst trimester due to their
potential to cause cardiac and renal defects, including atrial
septal defects, ventricular septal defects, pulmonary stenosis,
patent ductus arteriosus, renal dysgenesis, and the associated
complications of oligohydramnios (limb contractures, pul-
monary hypoplasia, and hypocalvaria) (67).
Glomerular Disease in Pregnancy, Blom et al. 7
Management of Worsening Proteinuria. Worsening
proteinuria in pregnancy poses a signicant diagnostic
and therapeutic challenge to the practicing clinician. Al-
though lupus nephritis and vasculitis may are during
pregnancy, the effect of pregnancy on the other primary
glomerular diseases is unclear. Certainly, GN can present or
are during pregnancy, and at least early on in pregnancy,
the diagnostic approach is similar to the nonpregnant state,
including a careful urinalysis and the relevant serologic assess-
ment. With the exception of serology and complement levels,
there are presently no other established biomarkers for use in
pregnancy. Although M-type phospholipase A2 receptor in
membranous nephropathy (68) and soluble urokinase plas-
minogen activator receptor in FSGS (69) have been described
in case reports, their use in pregnancy requires further study.
Of note, pregnancy is essentially a state of acute-phase
response, and therefore, complement levels should be normal
or high. Falling complement, even within the normal range,
suggests that lupus is becoming more active.
Kidney biopsy is not contraindicated in pregnancy, but
should be considered only when the information garnered
is likely to affect the treatment approach. In lupus and
vasculitis, serology can often assist with diagnosis, ren-
dering biopsy less necessary. However, the presentation of
de novo signicant proteinuria or nephrotic syndrome early
in pregnancy (during the rst or second trimester) typically
does necessitate a renal biopsy to establish a diagnosis and
guide immunosuppressive therapy, and it is considered safe as
long as BP is adequately controlled. A recent meta-analysis of 39
studies that compared the associated complications of 243
antepartum with 1236 postpartum kidney biopsies showed a
signicantly higher complication rate with antepartum com-
pared with postpartum biopsies (7% versus 1%; P50.001), but
fortunately, most complications were minor, such as loin pain
and macroscopic hematuria early in gestation, with all signif-
icant complications occurring between 23 and 26 weeks (70). Of
note, the aim of 23 of the studies was to study the morphology
of preeclampsia, the potential presence of which should be
considered a contraindication to biopsy given the associ-
ated hypertension and the potential to develop coagulopa-
thies (hemolysis, elevated liver enzymes and low platelets).
Furthermore, biopsy becomes more technically difcult as
the gravid uterus grows, often precluding prone positioning.
As such, the risks often outweigh the benets of
establishing a diagnosis after approximately 30 weeks of
gestation, but each patient requires careful individual-
ized consideration. In patients in whom renal biopsy has
been delayed to the postpartum period, it is ideal to wait
approximately 46 weeks for complete resolution of poten-
tial coexisting endotheliosis (71), but again, the clinical
condition will dictate the most appropriate timing.
After a diagnosis is established, immunosuppressive
treatment should begin promptly, because the symptoms
of nephrotic syndrome can be severe in pregnant women.
In addition to the already reviewed immunosuppressive
options (Immunosuppression above), pulse methylpred-
nisolone and plasmapheresis are options that can be
applied for a more rapid effect where appropriate. How-
ever, supportive therapy is often required while awaiting
a response to denitive treatment or when denitive
diagnosis or treatment is delayed. Peripheral edema is
common in healthy pregnancies and can be severe in
8 Clinical Journal of the American Society of Nephrology
pregnant women with the nephrotic syndrome. Serum
albumin levels also decrease in normal pregnancy (72), and
therefore, hypoalbuminemia can also be severe. Conserva-
tive treatments include compression stockings and avoid-
ance of prolonged standing. Loop diuretics are appropriate
for severe edema, and supportive albumin infusions have
been reported in case reports of women with severe
nephrosis (73,74). Severe hypoalbuinemia (albumin ,25 g/L)
is also associated with an increased risk of venous throm-
boembolic events (75), and pregnancy itself is a prothrom-
botic state. Unfortunately, there are no available data to
guide the use of anticoagulation in this patient population,
and practice varies signicantly. Expert opinion suggests
that women with severe proteinuria and serum albumin
,20 g/L should receive thromboprophylaxis throughout
pregnancy, but anticoagulation should also be considered
in those with less severe nephrotic syndrome with addi-
tional risk factors for, for example, obesity, immobility,
membranous nephropathy, or vasculitis. Subcutaneous low
molecular weight heparin is the anticoagulant of choice.
Although thromboprophylaxis is typically held before
anticipated delivery, it should be resumed as soon as
possible and continued for at least 6 weeks, because the
postpartum period carries a particularly high risk of
thrombosis (76).
Preeclampsia Prevention, Diagnosis, and Manage-
ment. Women with CKD are at a substantially increased
risk for the development of placental disease, and hence,
preeclampsia. A recent systematic review and meta-
analysis reported a tenfold increased risk of preeclampsia
among women with CKD compared with the general
population, with effect modiers including prepregnancy
proteinuria and the type of underlying disease (77). Rates
of preeclampsia were higher in women with nondiabetic
nephropathy, suggesting that glomerular disease might
be particularly hazardous (77). As such, all women with
GN are candidates for preventative strategies. Low-dose
aspirin is now considered part of standard care. In a
meta-analysis of 34 randomized, controlled trials, low-
dose aspirin started at or before 16 weeks of gestation was
associated with a signicant reduction in preeclampsia
(relative risk [RR], 0.47; 95% CI, 0.34 to 0.65) and in-
trauterine growth restriction (RR, 0.44; 95% CI, 0.30 to 0.65) (78).
Early administration of low-dose aspirin also resulted in a
signicant reduction of severe preeclampsia and preterm de-
livery. Similarly, calcium supplementation has been shown
to reduce the incidence of preeclampsia. In a Cochrane
review of 12 randomized, controlled trials of over 15,000
women, wherein at least 1 g calcium supplementation was
compared with placebo, there was a signicant reduction in
the risk of preeclampsia (RR, 0.48; 95% CI, 0.33 to 0.69)
that was even more pronounced in high-risk woman and
those with a low calcium intake (79). As such, calcium
intake should be assessed and supplemented as needed.
An understanding of the pathophysiology facilitates the
diagnosis of preeclampsia. The cascade that results in pre-
eclampsia begins with insufcient placentation character-
ized by inadequate trophoblast invasion and impaired
spiral artery remodeling, which ultimately results in
placental ischemia and the release of antiangiogenic fac-
tors, soluble fms-like tyrosine kinase-1 (sFlt1) and endog-
lin, that induce widespread maternal vascular endothelial
dysfunction by binding to proangiogenic factors, including
vascular endothelial factor and placental growth factor
(PlGF), neutralizing their effects (80,81). Both sFlt and
endoglin have been shown to increase before onset of
preeclampsia and correlate with disease severity, whereas
circulating levels of vascular endothelial factor and PlGF
have been noted to signicantly decrease. As such, circu-
lating levels of sFlt1 and PlGF are promising potential
biomarkers that can predict risk as well as assist diagnos-
tically in women with GN, in whom the diagnosis is
especially complex. In women with CKD and chronic
hypertension, low maternal PlGF concentrations had high
diagnostic accuracy for superimposed preeclampsia re-
quiring delivery within 14 days (82). Unfortunately, these
biomarkers are not as yet widely available, and pres-
ently, the diagnosis must be made clinically (Table 3). In
women with GN and worsening BP or proteinuria, a care-
ful assessment of the placenta along with fetal growth can
substantially aid in the diagnosis of preeclampsia because
poor or decreasing fetal growth in conjunction with
abnormal placental examinations have been showed to
be diagnostically useful in patients with CKD (83). The
need to assess the mother in conjunction with placental and
fetal parameters speaks to the importance of collaborative
care between nephrology and obstetrics.
To date, the cornerstone of safe management is expedit-
ed delivery, but in a small, open label study, removal of sFlt1
by dextran apheresis seemed safe and prolonged pregnancy
Table 3. Diagnosing preeclampsia: Placental and fetal clues
First trimester screen1113 wk gestation
Pregnancy-associated plasma protein A
Activate inulin-like growth factors that facilitate
placental growth
Maternal serum screen1520 wk gestation
a-Fetoprotein
Source is fetal liver; therefore, presence suggests
breach in the placental villi
Human chorionic gonadotropin
Excessive secretion by an abnormal
syncytiotrophoblast (beware as cleared by kidneys;
therefore, less use in more advanced CKD)
Dimeric inhibin assay
Excessive secretion by an abnormal trophoblast
Abnormal placental appearance
Length ,10 cm, thickness .4 cm, heterogeneous
appearance, echogenic cystic areas
Abnormal uterine artery Doppler examination
Presence of bilateral notching or pulsatility index
.1.45
Abnormal umbilical artery Doppler
Absent or reverse end diastolic ow
Poor fetal growth
Decreasing growth percentile
Intrauterine growth restriction or growth below the
tenth percentile for gestational age
Abdominal circumference below the 2.5th percentile.
Modied from data presented at http://www.mountsinai.on.
ca/care/placenta-clinic, with permission.
Clin J Am Soc Nephrol 12: cccccc, December, 2017
in women with early-onset preeclampsia (84). Controlled
studies are needed to further investigate dextran apheresis
as a therapeutic option. Magnesium sulfate will be pre-
scribed to prevent escalation to eclampsia and must be
used with caution in women with renal dysfunction. Close
collaboration between high-risk obstetrics and nephrology is
essential to establish the diagnosis and safely manage these
vulnerable women and babies because the false diagnosis
of preeclampsia will result in unnecessary urgent delivery
and iatrogenic prematurity, whereas the failure to detect
superimposed preeclampsia may have severe maternal and
fetal consequences. Mode of delivery should be dictated by
standard obstetric practice and should not be inuenced by
the presence or severity of GN.
Postpartum Care
Both immunosuppressive medications and antihyperten-
sive treatments deemed safe during pregnancy are also
typically of acceptable risk during breastfeeding, and
breastfeeding should be encouraged in women with all
forms of CKD due to the established fetal and maternal
benets, despite manufacturer recommendations, which
invariably suggest that lactation be avoided. Minimal
prednisone and azathioprine are excreted in breast milk
(85). Levels of both the calcineurin inhibitors have been
assayed in breast milk and assessed in neonates, with most
frequently undetectable levels for cyclosporin (86) and
at most, 0.23% of the maternal weightadjusted dose for
tacrolimus (87). However, the change in maternal physiology
mandates early reassessment of trough levels and readjustment
of dose to avoid nephrotoxicity in both the mother and
potentially, the baby. At times, signicant disease activity
necessitates the use of either mycophenolate mofetil or cyclo-
phosphamide, precluding breastfeeding. The large monoclonal
antibodies do not pass into breast milk, and rituximab may
prove a viable alternative for some forms of active nephritis
in the postpartum. With respect to antihypertensive agents,
methyldopa, labetalol, and long-acting nifedipine are most
used. Diuretics again may theoretically hamper milk supply
due to dehydration and are typically avoided. A number of
inhibitors of the RAS have been assessed in breast milk and
have been deemed absent, including enalapril, captopril (88),
and quinalapril (89). As such, targeting of proteinuria with
RAS inhibition can be initiated early in the postpartum
period. Because these pregnancies are high risk, the emo-
tional toll that they can have on a young woman cannot be
understated. Careful screening for postpartum depression
and lack of coping is mandatory, and ongoing multidisci-
plinary support is critical for maternal wellbeing.
Summary
Although it is safe to say that the vast majority of young
women with glomerular disease will have a live birth, the
counseling that we can provide with respect to individu-
alized risk remains imprecise. In the primary glomerular
diseases, the existing literature is extremely dated, and all
management principles are extrapolated primarily from
studies in lupus nephritis. As such, the study of pregnancy
outcomes and management strategies in these rare dis-
eases requires a renewed interest and a dedicated collab-
orative effort to answer the many unanswered questions.
Glomerular Disease in Pregnancy, Blom et al. 9
Fortunately, such studies are underway within existing GN
collaborative groups, including Cure Glomerulonephrop-
athy, which will hopefully provide important data to help
guide young women making this life-altering decision.
Disclosures
None.
References
1. Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S, Lepori N,
Tuveri M, Massidda M, Marchi C, Mura S, Coscia A, Biolcati M,
Gaglioti P, Nichelatti M, Pibiri L, Chessa G, Pani A, Todros T: Risk
of adverse pregnancy outcomes in women with CKD. J Am Soc
Nephrol 26: 20112022, 2015
2. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic
VD: A systematic review and meta-analysis of pregnancy out-
comes in patients with systemic lupus erythematosus and lupus
nephritis. Clin J Am Soc Nephrol 5: 20602068, 2010
3. Surian M, Imbasciati E, Cosci P, Banfi G, Barbiano di Belgiojoso G,
Brancaccio D, Minetti L, Ponticelli C: Glomerular disease and
pregnancy. A study of 123 pregnancies in patients with primary
and secondary glomerular diseases. Nephron 36: 101105, 1984
4. Barcelo P, Lopez-Lillo J, Cabero L, Del Ro G: Successful pregnancy
in primary glomerular disease. Kidney Int 30: 914919, 1986
5. Jungers P, Forget D, Henry-Amar M, Albouze G, Fournier P,
Vischer U, Droz D, Noel LH, Grunfeld JP: Chronic kidney disease
and pregnancy. Adv Nephrol Necker Hosp 15: 103141, 1986
6. Kincaid-Smith P, Fairley KF: Renal disease in pregnancy. Three
controversial areas: Mesangial IgA nephropathy, focal glomerular
sclerosis (focal and segmental hyalinosis and sclerosis), and reflux
nephropathy. Am J Kidney Dis 9: 328333, 1987
7. Packham DK, North RA, Fairley KF, Whitworth JA, Kincaid-Smith P:
IgA glomerulonephritis and pregnancy. Clin Nephrol 30: 1521, 1988
8. Nagai Y, Waschizawa Y, Suzuki T, Fushimi T, Hirata K, Kawamura
S, Schiina K, Tanaka M, Maeda M: Influence of gestation on renal
function in gravida with IgA nephropathy. Nihon Jinzo Gakkai Shi
31: 635641, 1989
9. Abe S: Pregnancy in IgA nephropathy. Kidney Int 40: 10981102, 1991
10. Limardo M, Imbasciati E, Ravani P, Surian M, Torres D, Gregorini G,
Magistroni R, Casellato D, Gammaro L, Pozzi C; Rene e Gravidanza
Collaborative Group of the Italian Society of Nephrology: Preg-
nancy and progression of IgA nephropathy: Results of an Italian
multicenter study. Am J Kidney Dis 56: 506512, 2010
11. Shimizu A, Takei T, Moriyama T, Itabashi M, Uchida K, Nitta K:
Effect of kidney disease stage on pregnancy and delivery out-
comes among patients with immunoglobulin A nephropathy.
Am J Nephrol 32: 456461, 2010
12. Waness A, Al Sayyari A, Salih SB, Al Shohaib S: Increased risk of
hypertension,proteinuriaandpreeclampsiainpregnantSaudifemales
with IgA nephropathy. Hypertens Pregnancy 29: 385389, 2010
13. Liu Y, Ma X, Lv J, Shi S, Liu L, Chen Y, Zhang H: Risk factors
for pregnancy outcomes in patients with IgA nephropathy: A
matched cohort study. Am J Kidney Dis 64: 730736, 2014
14. Packham D, Whitworth JA, Fairley KF, Kincaid-Smith P: Histo-
logical features of IgA glomerulonephritis as predictors of preg-
nancy outcome. Clin Nephrol 30: 2226, 1988
15. Packham DK, North RA, Fairley KF, Ihle BU, Whitworth JA, Kincaid-
Smith P: Pregnancy in women with primary focal and segmental
hyalinosis and sclerosis. Clin Nephrol 29: 185192, 1988
16. Abe S, Amagasaki Y, Konishi K, Kato E, Sakaguchi H, Iyori S: The
influence of antecedent renal disease on pregnancy. Am J Obstet
Gynecol 153: 508514, 1985
17. Packham DK, North RA, Fairley KF, Whitworth JA, Kincaid-Smith
P: Membranous glomerulonephritis and pregnancy. Clin Nephrol
28: 5664, 1987
18. Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS:
Understanding the epidemiology and progression of systemic
lupus erythematosus. Semin Arthritis Rheum 39: 257268, 2010
19. Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD,
Sammaritano L, Branch DW, Porter TF, Sawitzke A, Merrill JT,
Stephenson MD, Cohn E, Garabet L, Salmon JE: Predictors of
pregnancy outcomes in patients with lupus: A cohort study. Ann
Intern Med 163: 153163, 2015
10 Clinical Journal of the American Society of Nephrology
20. Moroni G, Doria A, Giglio E, Tani C, Zen M, Strigini F, Zaina B, Tincani
A, de Liso F, Matinato C, Grossi C, Gatto M, Castellana P, Limardo M,
Meroni PL, Messa P, Ravani P, Mosca M: Fetal outcome and rec-
ommendations of pregnancies in lupus nephritis in the 21st century. A
prospective multicenter study. J Autoimmun 74: 612, 2016
21. Moroni G, Doria A, Giglio E, Imbasciati E, Tani C, Zen M, Strigini F,
Zaina B, Tincani A, Gatto M, de Liso F, Grossi C, Meroni PL,
Cabiddu G, Messa P, Ravani P, Mosca M: Maternal outcome in
pregnant women with lupus nephritis. A prospective multicenter
study. J Autoimmun 74: 194200, 2016
22. Chakravarty EF, Colon I, Langen ES, Nix DA, El-Sayed YY, Genovese
MC, Druzin ML: Factors that predict prematurity and preeclampsia
in pregnancies that are complicated by systemic lupus erythe-
matosus. Am J Obstet Gynecol 192: 18971904, 2005
23. Carmona F, Font J, Moga I, Lazaro I, Cervera R, Pac V, Balasch J:
Class III-IV proliferative lupus nephritis and pregnancy: A study of
42 cases. Am J Reprod Immunol 53: 182188, 2005
24. Bramham K, Hunt BJ, Bewley S, Germain S, Calatayud I,
Khamashta MA, Nelson-Piercy C: Pregnancy outcomes in sys-
temic lupus erythematosus with and without previous nephritis.
J Rheumatol 38: 19061913, 2011
25. Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E: The
importance of the level of maternal anti-Ro/SSA antibodies as a
prognostic marker of the development of cardiac neonatal lupus
erythematosus a prospective study of 186 antibody-exposed fe-
tuses and infants. J Am Coll Cardiol 55: 27782784, 2010
26. Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R,
Costedoat-Chalumeau N, Doria A, Fischer-Betz R, Forger F,
Moraes-Fontes MF, Khamashta M, King J, Lojacono A, Marchiori F,
Meroni PL, Mosca M, Motta M, Ostensen M, Pamfil C, Raio L,
Schneider M, Svenungsson E, Tektonidou M, Yavuz S, Boumpas D,
Tincani A: EULAR recommendations for womens health and the
management of family planning, assisted reproduction, pregnancy
and menopause in patients with systemic lupus erythematosus and/or
antiphospholipid syndrome. Ann Rheum Dis 76: 476485, 2017
27. Clowse ME, Magder L, Witter F, Petri M: Hydroxychloroquine in
lupus pregnancy. Arthritis Rheum 54: 36403647, 2006
28. Kaplan YC, Ozsarfati J, Nickel C, Koren G: Reproductive outcomes
following hydroxychloroquine use for autoimmune diseases: A system-
atic review and meta-analysis. Br J Clin Pharmacol 81: 835848, 2016
29. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA,
Kim MY, Saxena A, Friedman D, Llanos C, Piette JC, Buyon JP:
Maternal use of hydroxychloroquine is associated with a reduced
risk of recurrent anti-SSA/Ro-antibody-associated cardiac mani-
festations of neonatal lupus. Circulation 126: 7682, 2012
30. Fredi M, Lazzaroni MG, Tani C, Ramoni V, Gerosa M, Inverardi F,
Sfriso P, Caramaschi P, Andreoli L, Sinico RA, Motta M, Lojacono
A, Trespidi L, Strigini F, Brucato A, Caporali R, Doria A, Guillevin
L, Meroni PL, Montecucco C, Mosca M, Tincani A: Systemic
vasculitis and pregnancy: A multicenter study on maternal and
neonatal outcome of 65 prospectively followed pregnancies.
Autoimmun Rev 14: 686691, 2015
31. Lidegaard , Lkkegaard E, Jensen A, Skovlund CW, Keiding N:
Thrombotic stroke and myocardial infarction with hormonal
contraception. N Engl J Med 366: 22572266, 2012
32. Ahmed SB, Hovind P, Parving HH, Rossing P, Price DA, Laffel LM,
Lansang MC, Stevanovic R, Fisher ND, Hollenberg NK: Oral con-
traceptives, angiotensin-dependent renal vasoconstriction, and risk
of diabetic nephropathy. Diabetes Care 28: 19881994, 2005
33. Ahmed SB, Kang AK, Burns KD, Kennedy CR, Lai V, Cattran DC,
Scholey JW, Miller JA: Effects of oral contraceptive use on the renal
and systemic vascular response to angiotensin II infusion. J Am
Soc Nephrol 15: 780786, 2004
34. Kang AK, Duncan JA, Cattran DC, Floras JS, Lai V, Scholey JW,
Miller JA: Effect of oral contraceptives on the renin angiotensin
system and renal function. Am J Physiol Regul Integr Comp
Physiol 280: R807R813, 2001
35. Bailie GR, Elder SJ, Mason NA, Asano Y, Cruz JM, Fukuhara S,
Lopes AA, Mapes DL, Mendelssohn DC, Bommer J, Young EW:
Sexual dysfunction in dialysis patients treated with antihyper-
tensive or antidepressive medications: Results from the DOPPS.
Nephrol Dial Transplant 22: 11631170, 2007
36. Lim VS, Henriquez C, Sievertsen G, Frohman LA: Ovarian
function in chronic renal failure: Evidence suggesting hypotha-
lamic anovulation. Ann Intern Med 93: 2127, 1980
37. Hou SH, Grossman S, Molitch ME: Hyperprolactinemia in pa-
tients with renal insufficiency and chronic renal failure requiring
hemodialysis or chronic ambulatory peritoneal dialysis. Am J
Kidney Dis 6: 245249, 1985
38. Holley JL, Schmidt RJ, Bender FH, Dumler F, Schiff M: Gyneco-
logic and reproductive issues in women on dialysis. Am J Kidney
Dis 29: 685690, 1997
39. Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS, Wong RW, Au
TC: Long-term outcome of diffuse proliferative lupus glomeru-
lonephritis treated with cyclophosphamide. Am J Med 119: 355.
e25355.e33, 2006
40. Boumpas DT, Austin HA 3rd, Vaughan EM, Yarboro CH, Klippel
JH, Balow JE: Risk for sustained amenorrhea in patients with
systemic lupus erythematosus receiving intermittent pulse cy-
clophosphamide therapy. Ann Intern Med 119: 366369, 1993
41. Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-
Nashar SA, Al-Inany HG, Falcone T: Gonadotropin-releasing
hormone analog cotreatment for preservation of ovarian function
during gonadotoxic chemotherapy: A systematic review and
meta-analysis. Fertil Steril 95: 906914, 2011
42. Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F, Demeestere
I, Levaggi A, Giraudi S, Lambertini M, DAlonzo A, Canavese G,
Pronzato P, Bruzzi P: Gonadotropin-releasing hormone analogues
for the prevention of chemotherapy-induced premature ovarian
failure in cancer women: Systematic review and meta-analysis of
randomized trials. Cancer Treat Rev 40: 675683, 2014
43. Elgindy E, Sibai H, AbdelghaniA, Mostafa M:Protectingovariesduring
chemotherapy through gonad suppression: A systematic review and
meta-analysis. Obstet Gynecol 126: 187195, 2015
44. Koh JH, Ko HS, Lee J, Jung SM, Kwok SK, Ju JH, Park SH: Preg-
nancy and patients with preexisting lupus nephritis: 15 Years of
experience at a single center in Korea. Lupus 24: 764772, 2015
45. Cabiddu G, Castellino S, Gernone G, Santoro D, Moroni G,
Giannattasio M, Gregorini G, Giacchino F, Attini R, Loi V, Limardo
M, Gammaro L, Todros T, Piccoli GB: A best practice position
statement on pregnancy in chronic kidney disease: The Italian Study
Group on Kidney and Pregnancy. J Nephrol 29: 277303, 2016
46. Diav-Citrin O, Shechtman S, Halberstadt Y, Finkel-Pekarsky V,
Wajnberg R, Arnon J, Di Gianantonio E, Clementi M, Ornoy A:
Pregnancy outcome after in utero exposure to angiotensin con-
verting enzyme inhibitors or angiotensin receptor blockers.
Reprod Toxicol 31: 540545, 2011
47. Hod M, van Dijk DJ, Karp M, Weintraub N, Rabinerson D, Bar J, Peled
Y, Erman A, Boner G, Ovadia J: Diabetic nephropathyand pregnancy:
The effect of ACE inhibitors prior to pregnancy on fetomaternal
outcome. Nephrol Dial Transplant 10: 23282333, 1995
48. Bar J, Chen R, Schoenfeld A, Orvieto R, Yahav J, Ben-Rafael Z,
Hod M: Pregnancy outcome in patients with insulin dependent
diabetes mellitus and diabetic nephropathy treated with ACE inhib-
itors before pregnancy. J Pediatr Endocrinol Metab 12: 659665, 1999
49. Nielsen LR, Damm P, Mathiesen ER: Improved pregnancy out-
come in type 1 diabetic women with microalbuminuria or di-
abetic nephropathy: Effect of intensified antihypertensive
therapy? Diabetes Care 32: 3844, 2009
50. Fraser FC, Sajoo A: Teratogenic potential of corticosteroids in
humans. Teratology 51: 4546, 1995
51. Hviid A, Molgaard-Nielsen D: Corticosteroid use during preg-
nancy and risk of orofacial clefts. CMAJ 183: 796804, 2011
52. Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly
EN, Matthews SG, Saigal S, Asztalos E, Ross S, Delisle MF,
Amankwah K, Guselle P, Gafni A, Lee SK, Armson BA; MACS
Collaborative Group: Multiple courses of antenatal corticoste-
roids for preterm birth (MACS): A randomised controlled trial.
Lancet 372: 21432151, 2008
53. Lockwood CJ, Radunovic N, Nastic D, Petkovic S, Aigner S,
Berkowitz GS: Corticotropin-releasing hormone and related
pituitary-adrenal axis hormones in fetal and maternal blood during
the second half of pregnancy. J Perinat Med 24: 243251, 1996
54. Nrgard B, Pedersen L, Fonager K, Rasmussen SN, Srensen HT:
Azathioprine, mercaptopurine and birth outcome: A population-
based cohort study. Aliment Pharmacol Ther 17: 827834, 2003
55. Coscia LA, Constantinescu S, Moritz MJ, Frank AM, Ramirez CB,
Maley WR, Doria C, McGrory CH, Armenti VT: Report from the
National Transplantation Pregnancy Registry (NTPR): Outcomes of
pregnancy after transplantation. Clin Transpl 2010: 6585, 2010
Clin J Am Soc Nephrol 12: cccccc, December, 2017
56. Bar Oz B, Hackman R, Einarson T, Koren G: Pregnancy outcome
after cyclosporine therapy during pregnancy: A meta-analysis.
Transplantation 71: 10511055, 2001
57. Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D: Review
of the course and outcome of 100 pregnancies in 84 women treated
with tacrolimus. Transplantation 70: 17181721, 2000
58. Kim H, Jeong JC, Yang J, Yang WS, Ahn C, Han DJ, Park JS, Park SK:
The optimal therapy of calcineurin inhibitors for pregnancy in
kidney transplantation. Clin Transplant 29: 142148, 2015
59. Zheng S, Easterling TR, Umans JG, Miodovnik M, Calamia JC,
Thummel KE, Shen DD, Davis CL, Hebert MF: Pharmacokinetics of
tacrolimus during pregnancy. Ther Drug Monit 34: 660670, 2012
60. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB,
Koren G: Fetal outcome after in utero exposure to cancer che-
motherapy. Arch Intern Med 152: 573576, 1992
61. stensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp
H, Doria A, Rai R, Meroni P, Cetin I, Derksen R, Branch W, Motta
M, Gordon C, Ruiz-Irastorza G, Spinillo A, Friedman D, Cimaz R,
Czeizel A, Piette JC, Cervera R, Levy RA, Clementi M, De Carolis
S, Petri M, Shoenfeld Y, Faden D, Valesini G, Tincani A: Anti-
inflammatory and immunosuppressive drugs and reproduction.
Arthritis Res Ther 8: 209, 2006
62. Chakravarty EF, Murray ER, Kelman A, Farmer P: Pregnancy outcomes
after maternal exposure to rituximab. Blood 117: 14991506, 2011
63. Hladunewich MA, Bramham K, Jim B, Maynard S: Managing
glomerular disease in pregnancy. Nephrol Dial Transpant 32
[Suppl 1]: i48i56, 2017
64. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE,
Menzies J, Sanchez J, Singer J, Gafni A, Gruslin A, Helewa M,
Hutton E, Lee SK, Lee T, Logan AG, Ganzevoort W, Welch R,
Thornton JG, Moutquin JM: Less-tight versus tight control of hy-
pertension in pregnancy. N Engl J Med 372: 407417, 2015
65. Magee LA; CHIPS Study Group, von Dadelszen P, Singer J, Lee T,
Rey E, Ross S, Asztalos E, Murphy KE, Menzies J, Sanchez J, Gafni
A, Gruslin A, Helewa M, Hutton E, Koren G, Lee SK, Logan AG,
Ganzevoort JW, Welch R, Thornton JG, Moutquin JM: Do
labetalol and methyldopa have different effects on pregnancy
outcome? Analysis of data from the Control of Hypertension In
Pregnancy Study (CHIPS) trial. BJOG 123: 11431151, 2016
66. Xie RH, Guo Y, Krewski D, Mattison D, Walker MC, Nerenberg K,
Wen SW: Association between labetalol use for hypertension in
pregnancy and adverse infant outcomes. Eur J Obstet Gynecol
Reprod Biol 175: 124128, 2014
67. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer
S, Gideon PS, Hall K, Ray WA: Major congenital malformations
after first-trimester exposure to ACE inhibitors. N Engl J Med 354:
24432451, 2006
68. Al-Rabadi L, Ayalon R, Bonegio RG, Ballard JE, Fujii AM,
Henderson JM, Salant DJ, Beck LH Jr.: Pregnancy in a patient
with primary membranous nephropathy and circulating anti-
PLA2R antibodies: A case report. Am J Kidney Dis 67: 775778,
2016
69. Kemper MJ, Wei C, Reiser J: Transmission of glomerular perme-
ability factor soluble urokinase plasminogen activator receptor
(suPAR) from a mother to child. Am J Kidney Dis 61: 352, 2013
70. Piccoli GB, Daidola G, Attini R, Parisi S, Fassio F, Naretto C,
Deagostini MC, Castelluccia N, Ferraresi M, Roccatello D, Todros
T: Kidney biopsy in pregnancy: Evidence for counselling? A
systematic narrative review. BJOG 120: 412427, 2013
71. Hladunewich MA, Myers BD, Derby GC, Blouch KL, Druzin ML,
Deen WM, Naimark DM, Lafayette RA: Course of preeclamptic
glomerular injury after delivery. Am J Physiol Renal Physiol 294:
F614F620, 2008
72. Abbassi-Ghanavati M, Greer LG, Cunningham FG: Pregnancy
and laboratory studies: A reference table for clinicians. Obstet
Gynecol 114: 13261331, 2009
73. Sebestyen A, Varbiro S, Sara L, Deak G, Kerkovits L, Szabo I, Kiss I,
Paulin F: Successful management of pregnancy with nephrotic
syndrome due to preexisting membranous glomerulonephritis: A
case report. Fetal Diagn Ther 24: 186189, 2008
74. Ope-Adenuga S, Moretti M, Lakhi N: Management of membra-
nous glomerulonephritis in pregnancy: A multidisciplinary
challenge. Case Rep Obstet Gynecol 2015: 839376, 2015
75. Barbour SJ, Greenwald A, Djurdjev O, Levin A, Hladunewich MA,
Nachman PH, Hogan SL, Cattran DC, Reich HN: Disease-specific
Glomerular Disease in Pregnancy, Blom et al. 11
risk of venous thromboembolic events is increased in idiopathic
glomerulonephritis. Kidney Int 81: 190195, 2012
76. Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind
MS: Risk of a thrombotic event after the 6-week postpartum pe-
riod. N Engl J Med 370: 13071315, 2014
77. Zhang JJ, Ma XX, Hao L, Liu LJ, Lv JC, Zhang H: A systematic review
and meta-analysis of outcomes of pregnancy in CKD and CKD
outcomes in pregnancy. Clin J Am Soc Nephrol 10: 19641978, 2015
78. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S,
Forest JC, Giguere Y: Prevention of preeclampsia and intrauterine
growth restriction with aspirin started in early pregnancy: A meta-
analysis. Obstet Gynecol 116: 402414, 2010
79. Hofmeyr GJ, Atallah AN, Duley L: Calcium supplementation
during pregnancy for preventing hypertensive disorders and re-
lated problems. Cochrane Database Syst Rev 3: CD001059, 2006
80. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann
TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP,
Karumanchi SA: Excess placental soluble fms-like tyrosine kinase
1 (sFlt1) may contribute to endothelial dysfunction, hypertension,
and proteinuria in preeclampsia. J Clin Invest 111: 649658, 2003
81. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM,
Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D,
DAmore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP,
Letarte M, Karumanchi SA: Soluble endoglin contributes to the
pathogenesis of preeclampsia. Nat Med 12: 642649, 2006
82. Bramham K, Seed PT, Lightstone L, Nelson-Piercy C, Gill C,
Webster P, Poston L, Chappell LC: Diagnostic and predictive bio-
markers for pre-eclampsia in patients with established hypertension
and chronic kidney disease. Kidney Int 89: 874885, 2016
83. Piccoli GB, Gaglioti P, Attini R, Parisi S, Bossotti C, Olearo E,
Oberto M, Ferraresi M, Rolfo A, Versino E, Biolcati M, Todros T:
Pre-eclampsia or chronic kidney disease? The flow hypothesis.
Nephrol Dial Transplant 28: 11991206, 2013
84. ThadhaniR,Kisner T,HagmannH,BossungV,NoackS,Schaarschmidt
W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC,
Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA,
Benzing T: Pilot study of extracorporeal removal of soluble fms-like
tyrosine kinase 1 in preeclampsia. Circulation 124: 940950, 2011
85. Constantinescu S, Pai A, Coscia LA, Davison JM, Moritz MJ,
Armenti VT: Breast-feeding after transplantation. Best Pract Res
Clin Obstet Gynaecol 28: 11631173, 2014
86. Nyberg G, Haljamae U, Frisenette-Fich C, Wennergren M,
Kjellmer I: Breast-feeding during treatment with cyclosporine.
Transplantation 65: 253255, 1998
87. Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C:
Breastfeeding and tacrolimus: Serial monitoring in breast-fed and
bottle-fed infants. Clin J Am Soc Nephrol 8: 563567, 2013
88. Beardmore KS, Morris JM, Gallery ED: Excretion of antihyper-
tensive medication into human breast milk: A systematic review.
Hypertens Pregnancy 21: 8595, 2002
89. Begg EJ, Robson RA, Gardiner SJ, Hudson LJ, Reece PA, Olson SC,
Posvar EL, Sedman AJ: Quinapril and its metabolite quinaprilat in
human milk. Br J Clin Pharmacol 51: 478481, 2001
90. Malik GH, Al-Mohaya S, Shaikh JF, Al-Wakeel J, Al-Hozaim W,
Kechrid M, Al-Duhami H, Shetia MS, El Gamal H, Hammed D:
Repeated pregnancies in patients with non-immunoglobulin a
mesangioproliferative glomerulonephritis. Am J Nephrol 21:
378382, 2001
91. Abe S: Pregnancy in glomerulonephritic patients with decreased
renal function. Hypertens Pregnancy 15: 305312, 1996
92. Packham DK, North RA, Fairley KF, Whitworth JA, Lloren PR, Lee E,
Kincaid-Smith P: Pregnancy in women with diffuse mesangial
proliferative glomerulonephritis. Clin Nephrol 29: 193198, 1988
93. Hou SH, Grossman SD, Madias NE: Pregnancy in women with renal
disease and moderate renal insufficiency. Am J Med 78: 185194, 1985
K. B. and A.O. contributed equally to this work.
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