ACKD

Pregnancy in Women With Systemic Lupus

and Lupus Nephritis
Sharon Maynard, Grace Guerrier, and Margaret Duffy

Pregnancy is an altered immunologic state in which hormonal changes impact the immune system to enable maternal tolerance
of the fetus. These hormonal and immunologic changes may affect disease activity in systemic lupus erythematosus.
Conversely, lupus nephritis and its complications may adversely impact pregnancy. Systemic lupus erythematosus increases
the risk of pre-eclampsia and its complications, including preterm birth and intrauterine growth restriction. Comorbidities
such as impaired kidney function and hypertension confer additional risk and complexity. Medications used to treat lupus
nephritis may impact the fetus, so therapy needs to be tailored to balance maternal benefit and fetal risk. The diagnosis of lupus
nephritis during pregnancy can be difficult, as it shares overlapping features with pre-eclampsia. Kidney biopsy is generally safe
in pregnancy, and should be considered if the result will affect management. Here we review the clinical aspects of counseling,
diagnosis, and management of lupus nephritis in pregnancy.
Q 2019 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Lupus nephritis, Pregnancy, Systemic lupus erythematosus, Prenatal care

EFFECT OF SYSTEMIC LUPUS ERYTHEMATOSUS
ON PREGNANCY
Systemic lupus erythematosus (SLE) predominantly af-
fects women of childbearing age. Pregnant women with
SLE are at increased risk for preterm birth, intrauterine
growth restriction, fetal loss, and pre-eclampsia.1-6 Pre-
eclampsia is characterized by the new onset of hyperten-
sion and proteinuria after 20 weeks of gestation. Severe
pre-eclampsia can culminate in maternal liver injury,
thrombocytopenia, microangiopathic hemolytic anemia,
acute kidney injury, neurologic injury (including stroke
and seizure), and pulmonary edema. For the fetus, pre-
eclampsia can cause intrauterine growth restriction
(IUGR), and preterm delivery is often required to preserve
maternal health. A previous history of lupus nephritis in-
creases risk for pre-eclampsia,1,2 while women with
active lupus nephritis in pregnancy have the highest risk,
up to 57% in some studies.1,3
Active lupus nephritis also increases the risk of fetal loss.
In one retrospective study of 90 pregnancies in women
with SLE, the incidence of fetal loss was 35% among
women with active lupus nephritis at conception, as
compared to 25% in women with quiescent lupus nephritis
and 9% in women with SLE without kidney involvement.1
The PROMISSE study, which excluded women with signif-
icant renal disease (Cr . 1.2 mg/dL or proteinuria .1 g/d),
reported a 4% rate of fetal death and a 1% rate of neonatal
death in women with SLE or antiphospholipid (aPL) syn-
drome.4 The majority of fetal losses occur before 28 weeks’
gestation.
From the Department of Medicine, Lehigh Valley Health Network, Allen-
town, PA.
Financial Disclosure: S.M. is a coinventor on a patent for the use of angio-
genic factors for the diagnosis and treatment of pre-eclampsia. G.G. and M.D.
have no financial interests to declare.
Address correspondence to Sharon Maynard, MD, Department of Medicine,
Lehigh Valley Health Network, 1230 South Cedar Crest Blvd, Suite 301, Allen-
town, PA 18103. E-mail: Sharon_e.maynard@lvhn.org
Ó 2019 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2019.08.013
Other predictors of poor obstetric outcome include low
kidney function at conception, hypertension, and presence
of the aPL antibodies.1-4 Proliferative (World Health
Organization class 3 or 4) lupus nephritis carries a higher
risk of pre-eclampsia and IUGR than mesangial (class 2)
or membranous (class 5) lupus nephritis.1
Angiogenic biomarkers such as soluble fms-like tyrosine
kinase 1 (sFlt1), soluble endoglin, and placental growth
factor contribute to the pathogenesis of pre-eclampsia,
and have been evaluated as predictors of pre-eclampsia
in pregnant women.7 In a study using data and samples
from the PROMISSE study, sFlt1 and the sFlt1:PlGF ratio
were found to be highly predictive of adverse pregnancy
outcomes in women with SLE or aPL syndrome.8
Although clinical utility of these biomarkers in women
with SLE has not yet been established, they may eventu-
ally have a role in risk stratification.
Improvements in disease management and perinatal
monitoring have improved pregnancy outcomes among
women with SLE, particularly those who enter pregnancy
with stable disease in remission on pregnancy-safe medi-
cations. The incidence of pregnancy loss among women
with SLE in 2000-2005 was similar to that in the general
US population.5 With careful planning, monitoring, and
management, most women with SLE, particularly those
with normal baseline kidney function, have successful
pregnancies without serious maternal or fetal complica-
tions.
EFFECTS OF PREGNANCY ON SYSTEMIC LUPUS
ERYTHEMATOSUS
In normal pregnancy, immunologic changes enable
maternal tolerance of the fetus. There is an increase in
CD41/CD251 regulatory T cells (Tregs) as well as a shift
from Th1 (proinflammatory) mediated to Th2 (anti-inflam-
matory) antibody-mediated response.6,9 This Th1 to Th2
shift can increase the activity of Th2-mediated diseases,
including SLE. SLE can also lead to a functional or quanti-
tative alteration in the Treg population.10 Hormonal
changes during pregnancy can also affect lupus activity.
In a murine model of SLE, estrogen accelerates glomerulo-
nephritis, lymphoproliferation, and mortality.11

330 Adv Chronic Kidney Dis. 2019;26(5):330-337

 Pregnancy and Systemic Lupus Erythematosus 331

Nevertheless, it has not been clearly established that preg- Additionally, in vitro and animal studies suggest that
nancy increases the risk of SLE flares. A 2010 meta-analysis GnRH analogs may have adverse effects on lupus disease
of 2751 pregnancies in women with SLE reported an overall activity. In a mouse model, GnRH antagonist administra-
rate of lupus flare in pregnancy of 25.6%,12 which is similar tion decreased total serum immunoglobulin G and anti-
to the annual lupus flare rate in the general nonpregnant DNA antibodies and improved survival, while GnRH-a
population. Most lupus disease flares were due to lupus increased total immunoglobulin G levels and anti-DNA
nephritis, seen in 16.1% of patients. This high rate of active antibodies.22 GnRH may also act indirectly through its ef-
lupus nephritis flare in pregnancy has also been observed fects on follicle stimulating hormone and luteinizing hor-
among a cohort of women with planned pregnancies and mone: in vitro studies suggest that follicle stimulating
quiescent disease at conception.13 The likelihood of renal hormone and luteinizing hormone stimulate T-cell activa-
flare during pregnancy is highest when there is evidence tion via interleukin-2.23 Although adverse effects of
of active kidney disease (proteinuria greater than 0.5 g/ GnRH-a on lupus disease activity have not been proven
d or active urinary sediment) at the time of conception.14,15 in humans, these findings make the routine use of these
For this reason, pregnancy in women with SLE should be agents for fertility preservation in women with SLE harder
planned during a period of disease quiescence (see to justify.
Preconception Counseling, below). Family planning is important in all women of reproduc-
tive age with SLE and lupus nephritis. Pregnancy risks are
FERTILITY strongly associated with disease activity at conception,
SLE itself does not usually directly impact fertility. Howev- and many medications used to treat SLE and lupus
er, both the treatment (eg, cyclophosphamide) and the con- nephritis are contraindicated in pregnancy. Women should
sequences (eg, advanced chronic kidney disease) of lupus be counseled to use effective contraception until preg-
nephritis can decrease nancy is considered safe
fertility. Premature ovarian CLINICAL SUMMARY and desirable. Barrier
failure is a well-recognized methods of contraception
complication of cyclophos-  Pregnancy in women with lupus nephritis is associated and nonhormonal (eg, cop-
phamide treatment, with re- with an increased risk of maternal and fetal per) intrauterine devices
ported infertility rates of complications, including pre-eclampsia, preterm birth, (IUDs) are safe and effective
12%-39% in various studies. growth restriction, and fetal loss. in all women with SLE,
Risk of sustained amenorrhea regardless of aPL status or
 Preconception counseling and planning pregnancy for time
after cyclophosphamide in- when disease is quiescent on pregnancy-safe medications
disease activity. Hormonal
creases with higher total cu- can improve the chances of a successful pregnancy contraception (both com-
mulative dose and maternal outcome. bined and progestin-only)
age, with highest risk in is safe in women with stable,
women over age 31 at the  Monitoring should include regular assessment of blood quiescent disease and nega-
pressure, renal function, proteinuria, and serologic
time of treatment.16 Infertility tive aPL status.24 Combined
markers of systemic lupus erythematosus disease activity.
is more likely after oral, as hormonal contraception
compared to intravenous,  Pregnancy-safe medications for the treatment of lupus should be discouraged in
cyclophosphamide.17 This nephritis include azathioprine, glucocorticoids, women with aPL anti-
may reflect higher total cu- calcineurin inhibitors, and hydroxychloroquine. bodies, due to a potential
mulative dose with oral ther- increased risk of throm-
apy. bosis.18 Progestin-only hor-
There are limited data regarding fertility preservation in monal contraception may be used with caution in such
women with lupus who require cyclophosphamide treat- women.
ment. The European League Against Rheumatism recom- Assisted reproductive technologies, such as ovarian
mends that gonadotropin-releasing hormone agonists stimulation and in vitro fertilization, are safe and effective
(GnRH-a) should be considered in all menstruating in women with SLE and lupus nephritis, so long as disease
women with lupus treated with alkylating agents.18 This is quiescent.18 Women with positive aPL antibodies and/or
recommendation is mostly based on experience in aPL syndrome should receive prophylactic antithrombotic
oncology patients receiving higher doses of alkylating therapy before and during ovarian stimulation, as they
agents than those used to treat lupus nephritis.19 A 2011 would during pregnancy.
retrospective study reported fertility outcomes in 44
women who received pulse cyclophosphamide for the
treatment of SLE and autoimmune disease.20 The inci- PRECONCEPTION COUNSELING
dence of primary ovarian failure was 3% in women who Preconception risk stratification, education, optimization
received GnRH-a prior to cyclophosphamide, as of disease activity, and transition to pregnancy-safe medi-
compared to 45% in those who did not. However, the cu- cations should be completed prior to attempting concep-
mulative cyclophosphamide dose in this study was high tion. Women with a history of lupus nephritis benefit
(9.8 g). With current treatment strategies for LN using from close monitoring before, during, and after pregnancy
lower dose cyclophosphamide (eg, the European Lupus by a multidisciplinary team, including a maternal-fetal
Nephritis Trial), the need for GnRH-a is less compelling.21 medicine specialist, rheumatologist, and nephrologist.25

Adv Chronic Kidney Dis. 2019;26(5):330-337


Table 1. Immunosuppressive Medications in Pregnancy
Medication
Acceptable in pregnancy
Azathioprine
Calcineurin inhibitors
(tacrolimus and cyclosporine)
Hydroxychloroquine
Glucocorticoids
332
Adverse Effects Pregnancy Recommendation* Lactation Recommendation
Case reports include small for gestational Low risk at low doses (,2 mg/kg/d) Compatible at low doses (,2 mg/kg/d)
age infants, hematologic toxicities, and
immunosuppression
HypertensionGestational diabetes Low risk. Monitor therapeutic drug levels Compatible
Withdrawal during pregnancy may cause Low risk Compatible
flare
Gestational diabetes Low risk. Use minimum effective dose Compatible
Premature rupture of membranes during pregnancy

Maynard et al
Cleft lip and palate†
Avoid in pregnancy
Cyclophosphamide Teratogenicity Contraindicated; discontinue at least Contraindicated
Pregnancy loss 12 months prior to pregnancy
Myelosuppression
Leflunomide Teratogenicity Contraindicated; discontinue at least No data
2 years prior to pregnancy
Methotrexate Teratogenicity Contraindicated; discontinue at least Contraindicated
Pregnancy loss 1 month before pregnancy
Mycophenolate mofetil Teratogenicity Contraindicated; discontinue at least No data
Adv Chronic Kidney Dis. 2019;26(5):330-337

Miscarriage 6 weeks prior to pregnancy

Rituximab Neonatal B cell depletion Limited data. Avoid during pregnancy Avoid breastfeeding during and at least
unless potential benefits outweigh 6 months after stopping rituximab
risks; discontinue at least 12 months
before conception

*The Food and Drug Administration no longer endorses the use of pregnancy risk categories. Pregnancy Lactation Labeling Rule requires the product label to specifically sum-
marize risk, clinical considerations, and data for each medication.
†In some reports, with first trimester exposure26,27; association has not been confirmed in population-based studies.28
 Pregnancy and Systemic Lupus Erythematosus
In women with active renal disease, pregnancy should be
postponed until renal disease is in remission on a
pregnancy-safe medication regimen (Table 1). The Joint
European League Against Rheumatism and European
Renal Association-European Dialysis and Transplant As-
sociation recommend that pregnancy may be safely
planned in stable patients with inactive lupus and no
more than minimal proteinuria for at least 6 months.29
Pregnancy should be delayed at least 12 months after
exposure to biologic agents, such as rituximab.
Women with advanced chronic kidney disease or active
lupus nephritis in whom remission cannot be attained
should be offered alternatives to pregnancy. Options
include delaying pregnancy until after kidney transplanta-
tion (with or without the use of assisted reproductive tech-
nologies), surrogacy, and adoption. Such decisions must
be individualized, based on the patient’s age, preferences,
and medical, social, and financial resources.
PREPREGNANCY AND PRENATAL CARE
One of the most important steps in preparing a patient for
pregnancy is transition to a pregnancy-safe medication
regimen (Table 1). Mycophenolate mofetil and cyclophos-
phamide are contraindicated in pregnancy due to terato-
genicity and fetotoxicity. Mycophenolate mofetil and
mycophenolic acid should be stopped at least 3 months
prior to conception.18 In women requiring ongoing main-
tenance immunosuppression, these agents may be re-
placed with azathioprine. Azathioprine is considered
safe in pregnancy at doses used in lupus nephritis (no
more than 2 mg/kg/d).24 Steroids and hydroxychloroquine
are useful in pregnant women with SLE, particularly for
the management of extrarenal symptoms.30 Hydroxy-
chloroquine withdrawal during pregnancy can increase
the risk of lupus flare, hence this medication should not
be stopped during pregnancy.31 Although steroids can be
safely continued, prophylactic steroid therapy does not
reduce the risk of a lupus flare during pregnancy.32 Induc-
tion therapy for lupus nephritis is discussed in “Treat-
ment,” below.
Low-dose aspirin (162 mg daily, started before 16 weeks’
gestation) is recommended to reduce pre-eclampsia risk in
women with SLE, as in all women at increased risk for pre-
eclampsia.33 Women with the aPL syndrome and SLE are
at particularly high risk for thrombosis.34 Anticoagulation
with low molecular weight heparin should be considered
in these women, especially those with a history of throm-
bosis.18
The PROMISSE trial showed that presence of aPL anti-
bodies confers an increased risk of adverse pregnancy out-
comes (odds ratio 8.32, p , 0.001).4 Given their strong
association with pregnancy loss, measurement of aPL ti-
ters is recommended prior to pregnancy and at the time
of pregnancy diagnosis.
Prenatal care should include blood pressure (BP) moni-
toring and treatment of hypertension, if present. Kidney
disease activity must be regularly monitored by urinalysis
(especially the presence of hematuria or an active urine
sediment), quantification of proteinuria, and measure-
ment of kidney function and serum complement levels.
Adv Chronic Kidney Dis. 2019;26(5):330-337
333
Proteinuria may be monitored by serial measurement of
the urine protein:creatinine ratio measured in a random
urine sample, which correlates well with 24-hour urine
protein excretion in studies of hypertensive pregnant
women.35 Since trends in these parameters over time can
be useful in detecting and diagnosing both SLE flare and
pre-eclampsia, monitoring these laboratories every 4-
8 weeks is recommended.18 Fetal monitoring is important
in the latter part of pregnancy, and should include regular
assessment of fetal growth and well-being. Fetal echocar-
diogram is recommended for women with anti-Ro/anti-
€gren’s-syndrome-related antigen A (SSA) or anti-La/
Sjo
€gren’s-syndrome-related antigen B (SSB) anti-
anti-Sjo
bodies, or when abnormal cardiac activity is suspected,
because of the associated risk of congenital heart block.18
DIAGNOSIS
The diagnosis of active lupus nephritis in pregnancy can
be challenging. Differentiating between lupus nephritis
flare and pre-eclampsia can be difficult as clinical presen-
tations can be heterogeneous, and several features (eg, he-
molytic anemia) can occur in both. The HELLP syndrome
(hemolysis, elevated liver enzymes, and low platelets) is a
severe form of pre-eclampsia in which thrombocytopenia
and acute kidney injury are common. When a woman
with SLE develops worsening proteinuria, hypertension,
or worsening kidney function during pregnancy, several
clinical clues can help distinguish lupus nephritis from
pre-eclampsia/HELLP syndrome. The presence of hypo-
complementemia, elevated double-stranded deoxyribonu-
cleic acid (dsDNA) titer, active sediment, and extrarenal
lupus symptoms (ie, neutropenia, rash, photosensitivity,
arthritis, or oral ulcers) all suggest a diagnosis of lupus
nephritis. A clinical picture dominated by hypertension
and heavy proteinuria without hematuria is more sugges-
tive of pre-eclampsia. Distinguishing features of lupus
nephritis flare vs pre-eclampsia are summarized in Table 2.
Pre-eclampsia is usually diagnosed clinically, without
kidney biopsy. However, kidney biopsy should be consid-
ered when lupus nephritis, or other primary glomerular
disease, is suspected. Kidney biopsy is controversial in
pregnancy due to potential risks to the mother and fetus,
which include bleeding, infection, compromised placental
blood flow, and even fetal loss. The benefits of performing
a kidney biopsy in the setting of suspected lupus nephritis
include definitive diagnosis, which may allow addition of
immunosuppression and potential prolongation of preg-
nancy. Depending on the gestational age at the time of
nephritis onset, prolongation of pregnancy may be desir-
able to reduce the neonatal morbidity that accompanies se-
vere prematurity.
A 2013 systematic review reported outcomes of 197
women after kidney biopsy in pregnancy.37 Four women
(2%) had major bleeding complications (large perirenal
hematoma requiring blood transfusion). All major compli-
cations occurred in women biopsied between 23 and
26 weeks’ gestation. There was one case of placental
abruption resulting in preterm delivery; in another case
fetal death as a result of kidney biopsy could not be
excluded. A 2015 case series reported outcomes after
334 Maynard et al

Table 2. Clinical Features of Active Lupus Nephritis and Pre-Eclampsia

Condition
Clinical Manifestations Lupus Nephritis Pre-Eclampsia/HELLP Syndrome
Worsening kidney function Often Sometimes (more common in HELLP
syndrome36)
Hypertension (SBP . 140 or Sometimes Yes
DBP . 90 mmHg)
Proteinuria Yes Yes
Hematuria (active sediment) Yes No
Low complement levels Yes No
High anti-dsDNA antibody titer Yes No
Thrombocytopenia Sometimes (immune thrombocytopenia, Sometimes
aPL syndrome, and immune-mediated
TTP)
Hemolytic anemia Sometimes Sometimes
Neutropenia Sometimes No
Transaminitis No Sometimes
Extrarenal manifestations: rash, Yes No
photosensitivity, arthritis, or oral
ulcers
Fever Sometimes No
Timing Any time during pregnancy Onset after 20 weeks gestation until
6 weeks postpartum

Abbreviations: aPL, antiphospholipid antibody; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; SBP, systolic blood
pressure; TTP, thrombotic thrombocytopenic purpura.

kidney biopsy in pregnancy in 11 women with SLE.38 The
majority of patients (9/11) had no history of lupus nephritis
prior to biopsy. Biopsy resulted in a change in clinical man-
agement in 10/11 women, either by the addition of immu-
nosuppression or termination of pregnancy. There were no
major biopsy complications (bleeding requiring transfu-
sion, hemodynamic instability, inadvertent injury to the
surrounding organs/fetus, or death to the mother or fetus.)
Taken together, these studies support the use of kidney bi-
opsy in pregnancy when information gained is likely to
inform management.
The gestational age at the time of clinical decision-
making is an important consideration in whether to
perform a kidney biopsy. In the first trimester, kidney
biopsy is low risk, and the threshold for biopsy is the
same as in a nonpregnant patient. In late pregnancy, it
is often prudent to postpone the biopsy until after
delivery, with consideration of early delivery in the
case of severe maternal disease. Women presenting in
mid-gestation (between 20 and 32 weeks) are the most
challenging, as it may be too early to “wait things
out,” and preterm delivery carries a high neonatal
morbidity. Tailored treatment for lupus nephritis (see
below), with or without kidney biopsy, may be recom-
mended. In such cases, informed decision-making by
the patient, in consultation with the maternal-fetal med-
icine specialist, nephrologist, and neonatologist, is
particularly important.
TREATMENT
Pharmacologic management of active lupus nephritis can
be problematic in pregnancy. According to the Kidney Dis-
ease: Improving Global Outcomes clinical practice guide-
lines, patients with class III or IV lupus nephritis should
receive initial therapy with glucocorticoids combined
with either cyclophosphamide or mycophenolate mofe-
til.39 In pregnancy, the risks and benefits of treatment
(Table 1) need to be balanced against the potential
maternal and fetal risks of relapsed, undertreated, or un-
treated lupus nephritis.
Corticosteroids (eg, prednisone, methylprednisolone)
are inactivated by the placenta and are safe in pregnancy.
But corticosteroids, either as monotherapy or in conjunc-
tion with other pregnancy-safe immunosuppression such
as azathioprine and hydroxychloroquine (see below),
may not be effective as induction therapy for severe lupus
nephritis. Mycophenolate mofetil and cyclophosphamide
are teratogenic and fetotoxic. Mycophenolate mofetil
causes microtia (underdevelopment of the ear), ocular de-
fects, and cleft lip.40 Cyclophosphamide’s teratogenicity,
documented in animal models, includes limb defects, cleft
palate, micrognathia, hydrocephaly, and fetal loss.41
Cyclophosphamide and mycophenolate mofetil should
be particularly avoided in the first trimester when the
risk for teratogenicity is the highest. If these drugs are be-
ing considered, maternal counseling regarding the risks
and benefits of both treatment and conservative manage-
ment, including the option of pregnancy termination,
should be provided.
Although tacrolimus and cyclosporine are safe in preg-
nancy, efficacy data for their use in lupus nephritis are
limited. Two small, randomized trials in nonpregnant Chi-
nese patients suggest that tacrolimus plus corticosteroids
is noninferior to cyclophosphamide plus corticosteroids
in achieving complete remission of lupus nephritis at
6 months.42,43 It is important to closely monitor blood

Adv Chronic Kidney Dis. 2019;26(5):330-337

 Pregnancy and Systemic Lupus Erythematosus
levels of calcineurin inhibitors in pregnancy, as higher
dosages are often required in pregnancy to achieve
therapeutic levels.44
Clinical trials have evaluated the efficacy of rituximab
and abatacept as add-on therapy for induction of lupus
nephritis, in addition to mycophenolate mofetil or cyclo-
phosphamide.45,46 These studies did not demonstrate
any additional benefit of rituximab or abatacept,
respectively, in comparison to placebo in achieving
remission of lupus nephritis. Additionally, although
there is no clear evidence of teratogenicity or other
adverse fetal or neonatal effects, the safety of these drugs
in pregnancy has not been demonstrated. Rituximab
crosses the placenta and has the potential to cause
neonatal B-cell depletion. Therefore, rituximab should be
avoided during pregnancy, unless the benefits outweigh
the potential risks.
Azathioprine is effective as maintenance therapy in
women with a history of lupus nephritis. Azathioprine is
considered safe for use in pregnancy at dosages used in
SLE (2 mg/kg/d or less).47 In women requiring mainte-
nance therapy for lupus nephritis who desire pregnancy,
azathioprine should usually be started prior to conception
and continued throughout pregnancy. Methotrexate and
leflunomide should be discontinued prior to attempting
conception (see Table 1).
Hydroxychloroquine is safe in pregnancy. Women who
stop hydroxychloroquine during pregnancy have more
lupus disease activity and a higher rate of lupus flares;
thus, it should be continued for the duration in pregnancy
in women who are taking it at the time of concep-
tion.31,48,49 For mothers who are anti-Ro positive, hydrox-
ychloroquine markedly reduces the risk of congenital
heart block.50 However, it is not effective as an induction
agent.
Some patients with a history of lupus nephritis and
quiescent, stable disease may be managed safely during
pregnancy with hydroxychloroquine alone. For patients
in whom maintenance therapy is indicated, azathioprine
may be used. If there is evidence of increasing disease ac-
tivity, treatment may be intensified with glucocorticoids
and/or calcineurin inhibitors. Higher doses of corticoste-
roids followed by rapid dose reduction, in addition to
low risk immunosuppressants such as calcineurin inhibi-
tors and/or azathioprine, may be required in women
with a significant renal flare. For severe or refractory lupus
nephritis flare with end-organ or life-threatening disease,
the use of cyclophosphamide or mycophenolate mofetil
may be appropriate. The decision to use these treatments
requires extensive counseling and shared decision-
making, including the option of pregnancy termination
when appropriate.
SUPPORTIVE MANAGEMENT
Hypertension is common in women with lupus nephritis
in pregnancy, especially when there is advanced chronic
kidney disease, acute nephritis flare, or superimposed
pre-eclampsia. Specific BP targets have not been defined
for pregnant women with SLE or lupus nephritis. In
nonpregnant individuals with or without CKD, the Amer-
Adv Chronic Kidney Dis. 2019;26(5):330-337
335
ican Heart Association (AHA)/American College of Cardi-
ology (ACC) recommends a treatment goal of less than
130/80 mm Hg.51 This is probably a reasonable goal in
pregnancy women with SLE and lupus nephritis. The
2015 CHIPS (Control of Hypertension in Pregnancy Study)
trial showed that hypertensive pregnant women random-
ized to a “tight” BP target (diastolic BP 85 mmHg) had no
adverse fetal effects or adverse pregnancy outcomes as
compared to women randomized to a “less tight” BP
target (diastolic BP 100 mmHg). There was a trend toward
a higher incidence of small for gestational age newborns in
the “tight control” group, but the difference was not statis-
tically significant.52 This trial was not powered to detect
maternal benefit of tighter BP control; nevertheless,
women in the tight BP group had a lower rate of severe
hypertension, transaminitis, and thrombocytopenia. This
trial suggests that a diastolic BP target of 85 mmHg is
safe in pregnancy. Notably, women with proteinuria and
chronic kidney disease were excluded from this trial.
First-line agents for the treatment of hypertension in preg-
nancy include methyldopa, nifedipine, and labetalol. Hy-
dralazine can also be used in pregnancy with severe
hypertension. There are little data on the use of nondihydro-
pyridine calcium channel blockers, alpha-antagonists, and
aldosterone antagonists in pregnancy. Thiazide diuretics do
not appear to cause fetal harm, and while they should not
be initiated during pregnancy, they may be continued, espe-
cially in patients requiring multiple agents for BP control.53
Agents that block the renin-angiotensin-aldosterone
system are contraindicated beyond the first trimester
because of high rates of fetal anomalies. Both
angiotensin-converting enzyme inhibitors (ACEi) and
angiotensin receptor antagonists cause neonatal complica-
tions with second and third trimester exposure, including
kidney failure, cardiac defects, limb abnormalities, oligo-
hydramnios, and IUGR.54 Direct renin inhibitors should
also be avoided in pregnancy. There is no definitive evi-
dence of teratogenicity of ACEi with first trimester expo-
sure,55 but most experts advise discontinuation of these
agents prior to conception or at the time of pregnancy
diagnosis.
After delivery, women with proteinuria should usually
start or resume an ACEi; captopril, quinapril, and enalapril
are poorly excreted in breast milk and are safe to use in
breastfeeding women.56 Beta-blockers with high protein
binding, such as labetalol and propranolol, are not concen-
trated in breast milk and are safe to continue. Beta-blockers
with low protein binding, such as atenolol or metoprolol,
should be avoided in breastfeeding women.56 Mineralo-
corticoid receptor antagonists such as spironolactone or
eplerenone have not been proven safe to use in pregnancy,
although there is one case report of adequate virilization in
2 male fetuses born to a mother exposed to high doses of
aldosterone.57
Edema is common in pregnancy, especially near term.
However, in pregnant women with SLE, edema can some-
times signify proteinuria, whether from lupus nephritis
flare or superimposed pre-eclampsia. Since diuretics
have a theoretical risk of maternal volume depletion and
reduced uteroplacental perfusion, their use should be
336 Maynard et al
avoided unless pulmonary edema is present or peripheral
edema is severe.
Progressive loss of kidney function during pregnancy
may require dialysis initiation. Reported fetal outcomes
in pregnant women on hemodialysis vary widely, and
appear to be improving over time. A 1994 review article
reported that women who conceived after starting dialysis
had only a 52% successful pregnancy rate.58 In the Toronto
experience, women who received intensive dialysis (43 6
6 h/wk) had a live birth rate of 86.4% and a median gesta-
tional age at delivery of 36 weeks, as compared to a live
birth rate of 61.4% and median gestational age at delivery
of 27 weeks in a historical controls receiving less intensive
dialysis (17 6 5 h/wk).59 Other studies have also supported
the use of intensive dialysis to pregnancy outcomes. For
example, Luders and colleagues36 reported a live birth
rate of 89.2% in a cohort of 93 pregnancies in women dia-
lyzed daily, but less intensely (15.4 6 4 h/wk). Women who
initiate dialysis after conception have higher live birth
rates than women who are already on dialysis at the
time of conception.60 Peritoneal dialysis is associated
with a higher rate of small for gestational age infants as
compared with hemodialysis.61 Hence, hemodialysis is
usually considered the modality of choice in pregnancy.
Women who maintain blood urea nitrogen levels ,35-
50 mg/dL have better neonatal and pregnancy outcomes
as compared to women with higher levels of blood urea ni-
trogen.36,62
Pregnancy in women with SLE and lupus nephritis re-
quires careful planning, counseling, and monitoring.
Risks include pre-eclampsia, intrauterine growth restric-
tion, nephritis flare during pregnancy, and fetal loss.
The diagnosis and management of lupus nephritis flare
is complex and requires a multidisciplinary approach.
Careful pregnancy planning, patient education, and pre-
natal monitoring can lead to successful pregnancy out-
comes in most women with SLE and a history of lupus
nephritis.
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