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


Pregnancy and Glomerular Disease: A Systematic

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

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
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: Kings College,
London, United

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

Pregnancy is a physiologic stress, wherein failure to performed a systematic review in attempt to better Dr. Michelle A.
adapt can result in adverse pregnancy outcomes. understand these outcomes among young women Hladunewich,
Systemic and renal vasodilation results in a drop in BP Sunnybrook Health
with primary GN, we review the studies of pregnancy Sciences Centre, 3rd
along with a decrease in renal vascular resistance outcomes in lupus nephritis, and nally, we discuss a Floor, Canadian
leading to increased renal plasma ow, and conse- potential construct for management. National Institute for
quently, nearly a 50% increase in glomerular ltration. the Blind Kidney
Inadequate adaptation occurs in women with under- Centre, 1929 Bayview
Avenue, Toronto, ON,
lying hypertension and CKD, and is a poor prognostic Systematic Review of Primary Glomerular Canada M4G 3E8.
indicator. In general, more resistant hypertension and Diseases Email: michelle.
advanced CKD are associated with greater risks of A comprehensive review of pregnancy outcomes hladunewich@
renal disease progression, prematurity, and growth has been conducted in lupus nephritis (2), but there
restriction. Data from Italy estimate the risks for are limited data assessing pregnancy risk associated
deterioration of kidney function are 7.6%, 12.6%, with other forms of primary GN. Accordingly, we
16.2%, and 20% at stages 14, respectively (1). Fur- conducted a systematic review of the literature on
thermore, fetal outcomes deteriorate along this same pregnancy outcomes in women with biopsy-proven
continuum with preterm delivery before 37 weeks primary glomerular-based diseases. The outcome of
gestation increasing from 24% in stage 1 CKD to 89% interest was the frequency of live births according to
in stages 4 and 5 CKD and neonatal birth weight primary GN etiology and the inuence of baseline
dropping by approximately 1300 g between the two characteristics on pregnancy outcomes. Full study
groups (mean birth weight 29666659 and 16396870 g methods are in Supplemental Material. In summary,
in stage 1 and stages 4 and 5 CKD, respectively) (1). It results from 18 studies, including 887 women and
is important to note that only 16% of the patients in this 1414 pregnancies, were abstracted from studies pub-
study had glomerular disease, and of those with lished after 1980 (Supplemental Figure 1, Supplemental
advanced CKD (stages 35), only 11 of 45 had in Table 1). Study heterogeneity was signicant, preclud-
excess of 1 g urine protein. ing any pooling of data, and baseline characteristics
As such, pregnancy in young women with CKD were often not reported or inadequately described,
is anxiety provoking for both the patient and the precluding determination of the potential inuence of
clinician providing care, and because the heteroge- hypertension, renal insufciency, or proteinuria on
neous group of glomerular diseases often affects pregnancy outcomes (Supplemental Table 2). Over
young women, this is an area of heightened concern. time, the pathologic descriptions of some glomerular
In this invited review, we discuss pregnancy outcomes diseases have also evolved, and the denitions of 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, (e.g., spontaneous abortion, 8%; preterm delivery, 24%;
have changed. As such, the review is narrative, and urgent small for gestational age, 4%; perinatal death, 16% [3]),
contemporary data are required. Table 1 below summarizes with hypertension, impaired renal function, and nephrotic-
pregnancy outcomes. range proteinuria identied to be associated with the
The most commonly reported GN was IgA nephropathy, greatest risk (3,4). Only two studies included women with
with 12 studies including 10136 patients (one study minimal change disease (5,16) or membranous nephropa-
included two IgA cohorts) (313). The proportion of thy (5,17), and similarly, nephrotic-range proteinuria and
women with hypertension at baseline was reported in hypertension in the early stages of pregnancy were asso-
eight studies and ranged from 9% to 40%. The proportion ciated with worse pregnancy outcomes. In 33 pregnancies in
of women with increased creatinine at study entry was 24 women with membranous nephropathy (17), only 20%
rarely reported, and denitions of renal insufciency (two of 10) of women with .5 g/24 h proteinuria had a live
varied. Across all 12 studies, live birth rate ranged from infant born after 32 weeks gestation compared with 91%
70% to 100%. Live birth rates seemed to be lower before (21 of 23) with #5 g/24 h (P,0.001), suggesting man-
2000 (6,7), but were variable, likely reecting small study agement of nephrotic syndrome with pregnancy-safe im-
sizes and reporting biases in addition to improvements in munosuppression is likely critical and highlighting the
neonatal care over the decades. Only ve studies reported urgent need for contemporary, collaborative studies to
the mean birth weight, which ranged from 2911 to 3200 g, provide informed prepregnancy counseling.
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 Overview of Pregnancy Outcomes in Lupus Nephritis
reported both sclerosis and vascular disease to be associated The onset of lupus most frequently occurs in women of
with adverse events, but no others attempted to assess the child-bearing age (18), and therefore, it is imperative that
relationship between histologic features and outcome (14). nephrologists are comfortable with reproductive counsel-
As expected, general themes that emerged included the ing in this subpopulation. Unlike the other primary
association of adverse pregnancy outcomes, including glomerular diseases, there are now robust data to inform
perinatal death, preterm delivery, and small birth weight, pregnancy outcomes and guide a management approach,
with hypertension and renal insufciency (35). In the including a systematic review (2) and two large multicenter
second largest study of 118 pregnant women (9), women prospective studies (19,20) as well as numerous smaller
with hypertension at baseline (BP$140/90 mmHg) or retrospective analyses. The take-home message from all of
impaired renal function (eGFR,70 ml/min per 1.73 m2) these studies is that women with active disease should be
were more likely to have an unsuccessful pregnancy. strongly discouraged from conceiving until their lupus is
Perinatal mortality was 33% in women with hyperten- controlled.
sion compared with 1% in normotensive women and 14% Evidence from meta-analysis data, 37 studies of 2751
in women with renal dysfunction compared with 3% in pregnancies in 1842 women, showed a higher risk of
women with normal renal function. The largest study to adverse outcomes, including fetal loss, preeclampsia,
date, published in 2010, reported outcomes for 229 preg- preterm delivery, and small for gestational age infants,
nancies and compared renal outcomes of 136 pregnant in those with active disease in early pregnancy (2).
women with 87 nonpregnant women, all with serum Furthermore, any maternal disease are and renal are
creatinine levels #1.2 mg/dl at diagnosis (10). Although were estimated to occur in 26% and 16% of pregnan-
pregnancy did not affect renal disease progression in this cies, respectively. A recent prospective multicenter cohort
study, a second much smaller group studied with impaired study of 71 pregnancies in 61 women with lupus nephri-
renal function (n510 with baseline serum creatinine levels tis reported an increased odds for preterm delivery by 15%
.1.2 mg/dl, averaging 1.6560.39 mg/dl) showed hastened for each increase of proteinuria by 1 g/d every trimester
progression, suggesting an imminent need for more data in (20). Even low C3 and C4, without systemic manifestations,
women with IgA at more advanced stages of CKD. Finally, have been reported to be associated with increased risk
the most recently published study noted an association in a prospective cohort (21). Other factors that adversely
between proteinuria and adverse pregnancy outcomes (13). affect pregnancy outcomes, including fetal or neonatal
Time-averaged proteinuria, the arithmetic average of pro- death, birth before 36 weeks due to placental insufciency,
teinuria during pregnancy and follow-up, was inversely as- hypertension or preeclampsia, small for gestational age
sociated with infant birth weight (correlation coefcient 5 neonate (below the fth percentile), and maternal renal
20.61; P,0.001) and also associated with adverse preg- ares in women with lupus nephritis, include severity of
nancy outcomes, including severe preeclampsia and intra- preexisting disease, nonwhite ethnicity, presence of anti-
uterine death (13). The strategy for managing worsening cardiolipin antibody or lupus anticoagulant, and hyperten-
proteinuria during pregnancy in women with IgA is sion (19,21,22). One cohort study suggested that women
presently unclear. with classes 3 and 4 lupus nephritis are more likely to have
Data to support prepregnancy counseling for the other pregnancies complicated by preeclampsia and lower-birth
forms of primary glomerular disease are very sparse. weight babies than those with class 2 or 5 lupus nephritis
Only four studies reported outcomes for women with (23), but histologic class was not associated with different
FSGS (3,4,6,15), all were published before 1990, and all were outcomes in the aforementioned meta-analysis (2). As such,
small (1731 pregnancies), with limited reporting of dis- women with normal renal function and quiescent disease
ease severity or hypertension. The proportion of live births can expect to have excellent pregnancy outcomes. A recent
ranged from 55% to 94% with high rates of complications 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
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
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
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
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.
Postpartum dened as maternal outcomesexact postpartum timeframe unclear.
Data collected from 85 subjects who remained in follow-up for at least 3 years.
Number of subjects with hypertension (rather than number of pregnancies).
Glomerular Disease in Pregnancy, Blom et al.
4 Clinical Journal of the American Society of Nephrology

lupus, excluding those with creatinine concentration protein with pregnancy-compatible immunosuppression,
.1.2 mg/dl and/or a urinary protein-to-creatinine ratio and control of hypertension with pregnancy-safe antihy-
.1000 mg/g, reported that 81% did not experience any pertensive agents, while actively delaying pregnancy
adverse events (19). Severe maternal ares were rare, when these conditions cannot be met. During pregnancy,
occurring in the second trimester in only 2.5% and third careful surveillance to detect the rst signs of maternal
trimester in 3.0% of women (19). However, those with or fetal compromise is critical, whereas postpartum care
previous lupus nephritis, despite preserved GFR, have must include ongoing vigilant care of the underlying
been reported to have higher rates of preterm delivery and GN along with emotional support to assist young mothers
earlier-onset preeclampsia than women with lupus with- to cope with a chronic disease while raising a child. Table 2
out renal involvement (24). Estimates of pregnancy out- includes acceptable therapeutic agents that can be used in
comes in women with more severe renal impairment and pregnancy.
controlled lupus require extrapolation from literature that
includes different etiologies of renal disease, and the risk Prepregnancy Care
of renal progression is related to severity of renal impair- Contraception. Given the risks associated with preg-
ment and the potential for reactivation or are of the nancy in women with CKD, an unplanned pregnancy
disease. should be vigorously avoided to ensure that conception
Women with anti-Ro/Anti-Sjgrens-syndromerelated does not occur before disease quiescence or while conr-
antigen A (SSA) antibody should be informed of the po- mation of disease stability after adjustment to pregnancy-
tential risk of development of fetal heart block due to safe medications. As such, questions about sexual activity
placental transfer of Ig leading to endocardial broelasto- and contraception should be part of routine nephrology care
sis. In a retrospective cohort study of 186 pregnancies, in young women, but are often overlooked. Estrogen-
5% of offspring were affected; however, this was only containing contraception is contraindicated in all women
in women with titers $50 U/ml (25). Similarly, neonatal with vascular disease, and should be used with caution
cutaneous lupus was reported to be more common in in young women with hypertension and CKD due to the
women with high-titer anti-La/Anti-Sjgrens-syndrome increased risk of thrombosis and exacerbation of hyperten-
related antigen B (SSB) ($100 U/ml), occurring in 57% sion (31). Furthermore, there is limited evidence from
of infants (25). The European League against Rheumatism studies in women with diabetic nephropathy that estrogen
guidelines recommend that all women with suspected fetal may exacerbate preexisting proteinuria (32), possibly
dysrhythmia or myocarditis, especially those with anti-Ro/ secondary to stimulation of the renin angiotensin system
SSA and/or anti-La/SSB antibody, should have fetal echo- (RAS) (33,34). As such, progesterone-only preparations are
cardiography (26). generally recommended and include the progesterone-only
In addition to pregnancy-safe immunosuppression (in pill, which is now available with a wider dosing window in
Immunosuppression below), hydroxychloroquine is now some countries, intramuscular depot injections, and the
recognized as a critical component of disease management intrauterine coil (preferably in multiparous women due to
in women with lupus nephritis. Hydroxychloroquine is rec- difculties with insertion in nulliparous women). Barrier
ommended to be commenced or continued for all women contraception is less reliable, and therefore, is not recom-
with lupus nephritis because prospective cohort studies have mended as a sole method of birth control.
shown maternal and fetal benets (20,21). Those who dis- Fertility. The desire to have a child is innate; therefore,
continue hydroxychloroquine have been reported to many women will want to conceive at some time during
have higher incidence of lupus ares, leading to greater use their journey with CKD, but both their underlying disease
of antenatal steroids (27). No increased risk of congenital as well as treatment choices can affect fertility. Along with
abnormalities is conrmed from a recent meta-analysis (28), advancing renal dysfunction are increased rates of infer-
although a higher rate of spontaneous abortion in exposed tility due to hormonal aberrations and progressive sexual
pregnancies than controls was noted with disease activity dysfunction due to medication side effects, fatigue, symp-
as a potential confounder. As such, there are no reported toms of depression, and altered body image, which can be
adverse effects on the fetus or neonate. Furthermore, there signicant due to the cosmetic side effects of commonly
are limited data to suggest up to an 85% reduction in the used immunosuppressive agents in patients with glomer-
risk of fetal growth restriction (20) and recurrence of fetal ular diseases (35). Assisted conception is, therefore, likely
heart block (29). 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.
Management Recommendations It is recognized that there is a reduction in the number
Despite lack of data in the primary glomerular diseases, of pregnancies reported with advancing severity of renal
recent evidence from the Predictors of Pregnancy Out- disease, and many women with advanced CKD report
come in Systemic Lupus Erythematosus and Antiphospho- amenorrhea or erratic cycles. A small cohort study of
lipid Syndrome (PROMISSE) Study (19) and other smaller 17 women with CKD reported an increase in luteinizing
studies in systemic lupus (20) and even vasculitis (30) that hormone in women with CKD and reduced cyclic changes
show much better outcomes in women with adequately in hypothalamic-pituitary-ovarian hormones (36), whereas
controlled disease before pregnancy have indirectly in- others have conrmed an increase in both prolactin
formed care in other glomerular diseases (Figure 1). production and clearance with reducing GFR (37). Self-
Prepregnancy optimization is dened as stabilization of reporting of menopause suggests that it occurs early in
rapid progression where possible, minimization of urine women with CKD (38), but these data are confounded by the
Clin J Am Soc Nephrol 12: cccccc, December, 2017 Glomerular Disease in Pregnancy, Blom et al. 5

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 (2,44). From this, we deduce that any active GN will
misreporting of anovulatory cycles secondary to renal disease. potentially contribute to adverse pregnancy outcomes,
The choice to use cyclophosphamide must also be made and control of the glomerular disease with pregnancy-safe
with care because there is a direct association between immunosuppression is desirable, whereas all potentially
ovarian damage and the prescribed dose, duration, teratogenic medications must be discontinued. A reasonable
and route of administration of this medication, with oral approach includes treatment with pregnancy-safe immuno-
cyclophosphamide inducing a more sustained amenor- suppression (Immunosuppression below) to attain remission
rhea than intravenous administration as noted in a Chi- for at least 36 months before a pregnancy attempt (45). In
nese study of 212 women (39). Furthermore, advancing patients without immunologic treatment options, control of
age signicantly increases the risk for irreversible ovarian urine protein with agents that block the RAS is the mainstay of
damage in young women. A controlled retrospective therapy. Although clearly teratogenic in the second and third
cohort study of 39 women age ,40 years old reported trimesters of pregnancy (BP Therapy below), data for terato-
sustained amenorrhea after cyclophosphamide therapy in genicity with only early pregnancy exposure are no longer
12% of women ,25 years of age, 27% of women 2631 years supported (46). Unfortunately, the potential use of these agents
of age, and 62% of women .30 years old (40). The use of in pregnancy planning is not derived from data published in
leuprolide acetate, a synthetic gonadotropin-releasing hor- the management of GN, but comes from small, uncontrolled
mone analog, to limit ovarian damage has not been studied studies in patients with diabetic nephropathy, wherein in-
in women with GN, and its use is not routine in this patient tensive treatment with angiotensin-converting enzyme inhibi-
population. Of three recent meta-analyses conducted in tion in addition to optimization of glucose control before
women with malignancies and rheumatologic diseases, two conception have been shown to stabilize proteinuria during
found a signicant benet with regard to resumption of pregnancy (47,48), and compared with older preexisting
menses and ovulation (41,42), whereas another found no literature, prolong gestation and improve birth weights (49).
benet of gonadotropin-releasing hormone analog cotreat- Data in other primary glomerular diseases are urgently
ment (43). It is, therefore, best to attempt to avoid cyclo- required, especially IgA nephropathy, which is a common
phosphamide in women of child-bearing age and use other entity with management outside of pregnancy that is debated.
agents where possible and appropriate (e.g., mycophenolate
mofetil for lupus nephritis and rituximab for vasculitis). Antenatal Care
Disease Optimization. As mentioned, a sustained clin- Immunosuppression. Women with GN often receive
ical remission before conception has been noted to signif- conicting information from health care professionals re-
icantly improve maternal and fetal outcomes in women garding medication safety during pregnancy. Reassurance re-
with both lupus nephritis (19,20) and vasculitis (30), and garding balance of risk versus benet is frequently needed,
active nephritis is associated with higher rates of pre- while cautioning women that the recommendation from
eclampsia, increased premature delivery, small for gesta- pharmaceutical companies and information that they glean
tional age births, and accelerated loss of renal function 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
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
Calcineurin inhibitors
Rituximab (can be considered early in pregnancy, but no long-term safety
data on exposed infants)
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

RAS, renin angiotensin system.

Safety data for immunosuppressive agents come from large requires activation by inosinate pyrophosphorylase to me-
registry and population studies of women with transplants, tabolite 6-mercaptopurine, which is absent in the fetal liver.
but can be used to inform treatment for women with GN. Studies of transplant recipients also support safety of calci-
Prednisone is considered to be relatively safe in preg- neurin inhibitors, with no evidence of increased risk of
nancy, and benets of continuation usually considerably teratogenicity with cyclosporin or tacrolimus (5557). Fre-
outweigh any risk. Early case-control studies suggested an quently, calcineurin inhibitor concentrations fall during preg-
increased incidence of cleft lip and palate with rst trimester nancy, assumed due to increased hepatic metabolism, and may
exposure (50), but subsequent well conducted population require an increase in dose up to 20%25% compared with
studies did not conrm an association (51). Prednisone is prepregnancy doses (58). A small study of ten women suggested
metabolized by placental 11-b-hydroxysteroid dehydroge- that free tacrolimus concentrations may be greater in pregnancy
nase type 2 to inactive cortisone; therefore, the fetal dose is relative to postpartum (59); hence, low therapeutic ranges
minimal. However, dexamethasone, administered for fetal should be targeted because high concentrations may cause
lung maturation, is not inactivated, and the fetus is exposed nephrotoxicity and hypertension. Some experts do not monitor
to approximately 30% of the maternal dose. High doses of concentrations during pregnancy given the uncertainty of the
prednisone have been associated with premature rupture relevance of recommended targets in pregnancy, and instead,
of membranes (52); however, the simultaneous inuence of titrate doses as dictated by changes in the clinical condition.
preexisting disease activity contributing to preterm deliv- Cyclophosphamide and mycophenolate mofetil are
ery is unknown. Other reported complications are simi- teratogenic and should be avoided during pregnancy.
lar to those in nonpregnant patients, including high rates Cyclophosphamide is associated with calvaria, ear and
of gestational diabetes, weight gain, hypertension, osteo- craniofacial structure, limb and visceral organ abnormal-
porosis, cataracts, infection, and mood changes. Stress ities, and developmental delay with rst trimester expo-
doses of glucocorticoids (typically hydrocortisone) are rec- sure and growth restriction, suppression of hematopoiesis,
ommended during labor for women taking the equivalent and neurologic impairment with exposure in later trimes-
of prednisone 20 mg or more for .3 weeks (53). ters (60). Up to 15% of infants exposed to mycophenlate
Azathioprine is frequently the drug of choice to maintain mofetil in the rst trimester develop major congenital
disease quiescence during pregnancy. A Danish population defects, including cleft lip and palate, microtia with atresia
study compared the outcomes of 11 infants exposed in utero of the external auditory canals, micrognathia, and hyper-
to azathioprine with those of 19,418 pregnancies without telorism, and high rates of miscarriage are reported (61).
exposure and reported an increase in malformations, pre- Experience with rituximab before and during pregnancy is
maturity, and perinatal mortality (54). However, several expanding due to studies from hematologic malignancies.
hundreds of pregnancy outcomes in transplant recipients Transplacental transfer occurs, and B cell depletion was
prescribed azathioprine during pregnancy have been re- reported in 11 of 90 exposed infants, with increasing
ported with rates of congenital malformations comparable incidence and severity from second trimester adminis-
with those in the general population (55). Azathioprine tration to term (62); hence, if required in pregnancy, early
Clin J Am Soc Nephrol 12: cccccc, December, 2017 Glomerular Disease in Pregnancy, Blom et al. 7

treatment is preferable. In our practice, we currently consider Management of Worsening Proteinuria. Worsening
rituximab only as a last resort in early pregnancy pending proteinuria in pregnancy poses a signicant diagnostic
further data. Neonatal monitoring is recommended before and therapeutic challenge to the practicing clinician. Al-
routine vaccination, with delay if necessary. There are no long- though lupus nephritis and vasculitis may are during
term follow-up studies of infants with in utero exposure to pregnancy, the effect of pregnancy on the other primary
rituximab, and therefore, its potential deleterious effects on the glomerular diseases is unclear. Certainly, GN can present or
developing immune system remain unknown. are during pregnancy, and at least early on in pregnancy,
BP Therapy. To date, there have been no studies con- the diagnostic approach is similar to the nonpregnant state,
ducted to establish BP treatment goals in young women with including a careful urinalysis and the relevant serologic assess-
any form of CKD, but it is well accepted that poorly ment. With the exception of serology and complement levels,
controlled hypertension during pregnancy signicantly wor- there are presently no other established biomarkers for use in
sens both maternal and fetal outcomes, and experts agree pregnancy. Although M-type phospholipase A2 receptor in
that maintaining BP,140/90 mmHg is prudent in this membranous nephropathy (68) and soluble urokinase plas-
patient population (63); the safety of which has been recently minogen activator receptor in FSGS (69) have been described
conrmed in an unblinded, multicenter, randomized, con- in case reports, their use in pregnancy requires further study.
trolled study in pregnant women with either chronic or ges- Of note, pregnancy is essentially a state of acute-phase
tational nonproteinuric hypertension (64). The Control of response, and therefore, complement levels should be normal
Hypertension in Pregnancy Study (CHIPS) randomized 987 or high. Falling complement, even within the normal range,
women to either less tight (target diastolic BP 5100 mmHg) suggests that lupus is becoming more active.
or tight (target diastolic BP 585 mmHg) BP control. The Kidney biopsy is not contraindicated in pregnancy, but
achieved BP difference was 85.3 compared with 89.9 mmHg should be considered only when the information garnered
in the tight versus less tight group, respectively. No signi- is likely to affect the treatment approach. In lupus and
cant difference between the groups was noted in the primary vasculitis, serology can often assist with diagnosis, ren-
outcome, a composite of pregnancy loss or high-level neo- dering biopsy less necessary. However, the presentation of
natal care for .48 hours, which was 31.4% in the less tight de novo signicant proteinuria or nephrotic syndrome early
versus 30.7% in the tight control group. Of note, there was in pregnancy (during the rst or second trimester) typically
also no difference in low birth babies or perinatal mortality. does necessitate a renal biopsy to establish a diagnosis and
The most signicant trial nding was that women receiving guide immunosuppressive therapy, and it is considered safe as
less tight (versus tight) control more commonly developed long as BP is adequately controlled. A recent meta-analysis of 39
severe hypertension (.160/110 mmHg) at 40.6% versus studies that compared the associated complications of 243
27.5% (P,0.001), which would be a particularly concerning antepartum with 1236 postpartum kidney biopsies showed a
deterioration in a woman with underlying kidney disease. signicantly higher complication rate with antepartum com-
There are a number of drug options for the management pared with postpartum biopsies (7% versus 1%; P50.001), but
of hypertension in pregnancy, including methyldopa, labe- fortunately, most complications were minor, such as loin pain
talol, hydralazine, and long-acting nifedipine. Although and macroscopic hematuria early in gestation, with all signif-
labetalol is frequently considered the rst-line agent, a icant complications occurring between 23 and 26 weeks (70). Of
secondary analysis of the CHIPS cohort noted that women note, the aim of 23 of the studies was to study the morphology
treated with methyldopa (versus labetalol) had fewer ad- of preeclampsia, the potential presence of which should be
verse perinatal and maternal outcomes, including fewer considered a contraindication to biopsy given the associ-
babies who were small for gestational age, fewer deliver- ated hypertension and the potential to develop coagulopa-
ies ,34 and ,37 weeks, less severe hypertension, and pre- thies (hemolysis, elevated liver enzymes and low platelets).
eclampsia (65). The use of methyldopa seemed to be Furthermore, biopsy becomes more technically difcult as
especially benecial for women with preexisting hyper- the gravid uterus grows, often precluding prone positioning.
tension. Another study showed higher rates of respiratory As such, the risks often outweigh the benets of
distress syndrome, sepsis, and seizures in infants of mothers establishing a diagnosis after approximately 30 weeks of
with chronic hypertension dispensed only labetalol com- gestation, but each patient requires careful individual-
pared with those dispensed only methyldopa (adjusted odds ized consideration. In patients in whom renal biopsy has
ratio, 1.51; 95% condence interval [95% CI], 1.02 to 2.22) (66), been delayed to the postpartum period, it is ideal to wait
suggesting that this is an area that requires further research in approximately 46 weeks for complete resolution of poten-
women with CKD. Although diuretics are often avoided due tial coexisting endotheliosis (71), but again, the clinical
to the theoretical concern of intravascular contraction, they condition will dictate the most appropriate timing.
can be used in select women. Similarly, other b-blockers (e.g., After a diagnosis is established, immunosuppressive
metoprolol) and calcium channel blockers (e.g., amlodipine treatment should begin promptly, because the symptoms
and diltiazem) have been used, but again, only in women in of nephrotic syndrome can be severe in pregnant women.
whom the aforementioned safer alternatives are not tolerated In addition to the already reviewed immunosuppressive
pending further studies. Inhibitors of the RAS are strictly options (Immunosuppression above), pulse methylpred-
contraindicated beyond the rst trimester due to their nisolone and plasmapheresis are options that can be
potential to cause cardiac and renal defects, including atrial applied for a more rapid effect where appropriate. How-
septal defects, ventricular septal defects, pulmonary stenosis, ever, supportive therapy is often required while awaiting
patent ductus arteriosus, renal dysgenesis, and the associated a response to denitive treatment or when denitive
complications of oligohydramnios (limb contractures, pul- diagnosis or treatment is delayed. Peripheral edema is
monary hypoplasia, and hypocalvaria) (67). 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 dysfunction by binding to proangiogenic factors, including
albumin levels also decrease in normal pregnancy (72), and vascular endothelial factor and placental growth factor
therefore, hypoalbuminemia can also be severe. Conserva- (PlGF), neutralizing their effects (80,81). Both sFlt and
tive treatments include compression stockings and avoid- endoglin have been shown to increase before onset of
ance of prolonged standing. Loop diuretics are appropriate preeclampsia and correlate with disease severity, whereas
for severe edema, and supportive albumin infusions have circulating levels of vascular endothelial factor and PlGF
been reported in case reports of women with severe have been noted to signicantly decrease. As such, circu-
nephrosis (73,74). Severe hypoalbuinemia (albumin ,25 g/L) lating levels of sFlt1 and PlGF are promising potential
is also associated with an increased risk of venous throm- biomarkers that can predict risk as well as assist diagnos-
boembolic events (75), and pregnancy itself is a prothrom- tically in women with GN, in whom the diagnosis is
botic state. Unfortunately, there are no available data to especially complex. In women with CKD and chronic
guide the use of anticoagulation in this patient population, hypertension, low maternal PlGF concentrations had high
and practice varies signicantly. Expert opinion suggests diagnostic accuracy for superimposed preeclampsia re-
that women with severe proteinuria and serum albumin quiring delivery within 14 days (82). Unfortunately, these
,20 g/L should receive thromboprophylaxis throughout biomarkers are not as yet widely available, and pres-
pregnancy, but anticoagulation should also be considered ently, the diagnosis must be made clinically (Table 3). In
in those with less severe nephrotic syndrome with addi- women with GN and worsening BP or proteinuria, a care-
tional risk factors for, for example, obesity, immobility, ful assessment of the placenta along with fetal growth can
membranous nephropathy, or vasculitis. Subcutaneous low substantially aid in the diagnosis of preeclampsia because
molecular weight heparin is the anticoagulant of choice. poor or decreasing fetal growth in conjunction with
Although thromboprophylaxis is typically held before abnormal placental examinations have been showed to
anticipated delivery, it should be resumed as soon as be diagnostically useful in patients with CKD (83). The
possible and continued for at least 6 weeks, because the need to assess the mother in conjunction with placental and
postpartum period carries a particularly high risk of fetal parameters speaks to the importance of collaborative
thrombosis (76). care between nephrology and obstetrics.
Preeclampsia Prevention, Diagnosis, and Manage- To date, the cornerstone of safe management is expedit-
ment. Women with CKD are at a substantially increased ed delivery, but in a small, open label study, removal of sFlt1
risk for the development of placental disease, and hence, by dextran apheresis seemed safe and prolonged pregnancy
preeclampsia. A recent systematic review and meta-
analysis reported a tenfold increased risk of preeclampsia
among women with CKD compared with the general
Table 3. Diagnosing preeclampsia: Placental and fetal clues
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 First trimester screen1113 wk gestation
be particularly hazardous (77). As such, all women with Pregnancy-associated plasma protein A
GN are candidates for preventative strategies. Low-dose Activate inulin-like growth factors that facilitate
placental growth
aspirin is now considered part of standard care. In a
Maternal serum screen1520 wk gestation
meta-analysis of 34 randomized, controlled trials, low- a-Fetoprotein
dose aspirin started at or before 16 weeks of gestation was Source is fetal liver; therefore, presence suggests
associated with a signicant reduction in preeclampsia breach in the placental villi
(relative risk [RR], 0.47; 95% CI, 0.34 to 0.65) and in- Human chorionic gonadotropin
trauterine growth restriction (RR, 0.44; 95% CI, 0.30 to 0.65) (78). Excessive secretion by an abnormal
Early administration of low-dose aspirin also resulted in a syncytiotrophoblast (beware as cleared by kidneys;
signicant reduction of severe preeclampsia and preterm de- therefore, less use in more advanced CKD)
livery. Similarly, calcium supplementation has been shown Dimeric inhibin assay
to reduce the incidence of preeclampsia. In a Cochrane Excessive secretion by an abnormal trophoblast
Abnormal placental appearance
review of 12 randomized, controlled trials of over 15,000
Length ,10 cm, thickness .4 cm, heterogeneous
women, wherein at least 1 g calcium supplementation was appearance, echogenic cystic areas
compared with placebo, there was a signicant reduction in Abnormal uterine artery Doppler examination
the risk of preeclampsia (RR, 0.48; 95% CI, 0.33 to 0.69) Presence of bilateral notching or pulsatility index
that was even more pronounced in high-risk woman and .1.45
those with a low calcium intake (79). As such, calcium Abnormal umbilical artery Doppler
intake should be assessed and supplemented as needed. Absent or reverse end diastolic ow
An understanding of the pathophysiology facilitates the Poor fetal growth
diagnosis of preeclampsia. The cascade that results in pre- Decreasing growth percentile
eclampsia begins with insufcient placentation character- Intrauterine growth restriction or growth below the
tenth percentile for gestational age
ized by inadequate trophoblast invasion and impaired
Abdominal circumference below the 2.5th percentile.
spiral artery remodeling, which ultimately results in
placental ischemia and the release of antiangiogenic fac-
Modied from data presented at http://www.mountsinai.on.
tors, soluble fms-like tyrosine kinase-1 (sFlt1) and endog- ca/care/placenta-clinic, with permission.
lin, that induce widespread maternal vascular endothelial
Clin J Am Soc Nephrol 12: cccccc, December, 2017 Glomerular Disease in Pregnancy, Blom et al. 9

in women with early-onset preeclampsia (84). Controlled Fortunately, such studies are underway within existing GN
studies are needed to further investigate dextran apheresis collaborative groups, including Cure Glomerulonephrop-
as a therapeutic option. Magnesium sulfate will be pre- athy, which will hopefully provide important data to help
scribed to prevent escalation to eclampsia and must be guide young women making this life-altering decision.
used with caution in women with renal dysfunction. Close
collaboration between high-risk obstetrics and nephrology is Disclosures
essential to establish the diagnosis and safely manage these None.
vulnerable women and babies because the false diagnosis
of preeclampsia will result in unnecessary urgent delivery
and iatrogenic prematurity, whereas the failure to detect
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