Lupus (2012) 21, 12711283

http://lup.sagepub.com

REVIEW

Pregnancy and renal outcomes in lupus nephritis: an update and

guide to management
K Bramham, MC Soh and C Nelson-Piercy
Maternal and Fetal Research Unit, Division of Womens Health, Kings College London, UK; and
Womens Health Academic Centre Kings Health Partners, UK

Systemic lupus erythematosis (SLE) commonly affects women of child bearing-age, and
advances in treatment have resulted in an increasing number of women with renal involvement
becoming pregnant. Knowledge of the relationship of the condition with respect to fertility
and pregnancy is important for all clinicians involved in the care of women with lupus nephritis because they have complicated pregnancies. Presentation of lupus nephritis can range
from mild asymptomatic proteinuria to rapidly progressive renal failure and may occur before,
during, or after pregnancy. The timing of diagnosis may influence pregnancy outcome.
Pregnancy may also affect the course of lupus nephritis. All pregnancies in women with
lupus nephritis should be planned, preferably after more than six-months of quiescent disease.
Predictors of poor obstetric outcome include active disease at conception or early pregnancy,
baseline poor renal function with Creatinine >100 mmol/L, proteinuria >0.5 g/24 hours, presence of concurrent antiphospholipid syndrome and hypertension. In this review the most
recent studies of pregnancies in women with lupus nephritis are discussed and a practical
approach to managing women prepregnancy, during pregnancy and post-partum is
described Lupus (2012) 21, 12711283.
Key words: Pregnancy; Renal Lupus; Systemic Lupus Erythematosus

Introduction
Systemic lupus erythematosus (SLE) commonly
aects women of child-bearing age, with renal
involvement occurring in 2049% during the disease
course.1 Using the assumption of conception at a
replacement population birth rate, it is estimated
that in a population of 1 million, there will be a
birth rate of ve to 10 pregnancies/year in women
with SLE.2 Knowledge of the relationship of the
condition with respect to fertility and pregnancy is
therefore important for all clinicians involved in
management of women with SLE. Presentation of
lupus nephritis can range from mild asymptomatic
proteinuria to rapidly progressive renal failure and
may occur before, during or after pregnancy.
Pregnancy may aect the course of lupus nephritis. The timing of diagnosis of lupus nephritis may
inuence pregnancy outcome. Women with lupus
Correspondence to: Catherine Nelson-Piercy, St Thomas Hospital,
Westminster Bridge Road, London SE1 7EH, UK.
Email: Catherine.Nelson-Piercy@gstt.nhs.uk
Received 4 January 2011; accepted 26 June 2012
! The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

nephritis have complicated pregnancies. The majority are taking multiple medications, the benets and
risks of which need to be evaluated for the safety
and well-being of the mother and fetus.

Fertility
Women with SLE have normal fertility,3,4 even if
disease is active,5 but in the presence of impaired
renal function fertility may be reduced.6 Renal
transplantation rapidly restores fertility. Women
with severe renal impairment, especially those
requiring renal replacement therapy, may be
advised to delay conception until at least a year
after transplantation.7,8
Cyclophosphamide is traditionally the rst line
agent for active lupus nephritis. Its use has previously been associated with ovarian failure.9
However, it has now been demonstrated that total
dose of cyclophosphamide and age >32 are the most
important
predictors
of
anovulation.1013
Gonadotropin-releasing hormone (GnRH) antagonists are occasionally used pre-emptively for
10.1177/0961203312456893

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1272

preservation of ovarian function in women undergoing chemotherapy with cyclophosphamide.14

Pregnancy outcome
The principal considerations for pregnant women
with lupus nephritis are: 1) the eect of the pregnancy on disease status, both during the pregnancy
and on long-term renal function, and 2) the eect of
lupus nephritis on pregnancy outcome.
Disease activity during pregnancy
Numerous reports with conicting outcomes have
attempted to assess the inuence of pregnancy on
SLE activity.1520 Comparison of these studies
is hampered by dierent denitions of disease
activity, diagnosis of renal and extra-renal disease,
inclusion of women with active disease pre-pregnancy or women with disease diagnosed during
pregnancy. Data regarding ares of SLE in
women with underlying lupus nephritis are conicting, with some studies reporting an increased rate
of ares particularly when the woman conceives
while her disease is active, while other studies do
not.2123 Renal disease activity appears to be more
common post-partum,21 whereas extrarenal disease
are occurs predominantly in the second and third
trimesters.18,24

Lupus nephritis flare

Studies from 1970 through 1992 have included 276
women who had a diagnosis of lupus nephritis
pre-pregnancy; 133 (48%) had an exacerbation
of renal disease during pregnancy, with many
developing
nephrotic-range
proteinuria.2541
However, a more recent multi-centre retrospective
study reporting renal and pregnancy outcomes of
113 pregnancies in 81 women with lupus nephritis
found renal are aected only 15% of pregnancies
and in 15% of women up to a year post-partum.42
Flares were more common in women with active
disease pre-pregnancy, in partial remission, those
with proteinuria >1 g/24 hours or with a glomerular ltration rate (GFR) <60 ml/min/1.73 m2.
Similarly, in a metanalysis of 37 heterogeneous
studies published between 1984 and 2009, including 1842 women with lupus nephritis with a wide
range of baseline renal function and 2751 pregnancies, 16% and 26% of pregnancies were complicated by renal disease activation and lupus
Lupus

are, respectively.43 This reduction in renal are

may reect improvements in pre-pregnancy counselling, where more women are advised to delay
conception until disease is controlled, together
with the development of newer immunosuppressants used before pregnancy, e.g. mycophenolate
mofetil (MMF), which has improved renal
outcome.
Progression of renal disease
The most important predictors of permanent
deterioration of renal disease in women with
chronic kidney disease (CKD) were pre-pregnancy
GFR < 40 mls/min/1.73 m2 (approximate creatinine < 150 mmol/l) and level of proteinuria (>1 g/24
hours). Imbasciati et al. concluded that both factors need to be present for a signicant risk of longterm renal damage.44
Few studies have specically studied the eect of
pregnancy on long-term renal function in lupus
nephritis. In a review of 17 studies of pregnancies
aected by SLE, 10% of women with lupus nephritis developed acute kidney injury, 3% of women
with lupus nephritis had a permanent decline in
renal function without requiring dialysis, and 6%
progressed to end-stage renal failure or death,2541
but a more recent study of lupus nephritis in pregnancy, which included 11% of women with CKD
stage 3, found only 2% of women suered a progressive deterioration in GFR and only 1% needed
renal replacement therapy.42
In women who have undergone renal transplant
for lupus nephritis, multiple pregnancies pre-transplant have been associated with greater risk of graft
failure.45 However, following renal transplantation,
pregnancy outcomes in women with lupus nephritis
are reported to be similar to those who had undergone renal transplantation for other reasons.46

Effect of lupus nephritis on pregnancy outcome

Maternal outcome
Pre-eclampsia

Pre-eclampsia is more common in women with SLE

than in the general population, even in women with
matched levels of renal impairment.33,47 The rate of
pre-eclampsia in women with lupus nephritis ranges
from 9%42 to 35%.42 Higher rates are reported in
women diagnosed with lupus nephritis during pregnancy,48 unplanned pregnancies or with active disease pre-pregnancy.49,50 Pre-eclampsia occurs at
earlier gestations in women with lupus nephritis

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1273

compared with women with SLE without renal

involvement.51
Maternal death

An extensive literature review identied 13 studies

of women with lupus nephritis between 1962 and
2009 that reported 17 deaths, all of which occurred
in women with active disease. The majority of
deaths were directly attributable to sepsis (41%)
or disease activity (29%).52 However, cases of
maternal death due to lupus are in women with
quiescent disease pre-pregnancy have been
reported.50
Fetal outcome
Fetal loss

Successful pregnancy outcome in women with

lupus
nephritis
ranges
from
65%
to
92%.22,33,39,42,47,49,53,54 Inactive lupus nephritis
pre-pregnancy in women with preserved renal function is not associated with higher rates of fetal loss
than in women with SLE without lupus nephritis.50
Active disease pre-pregnancy is associated with
increased fetal loss,22,50 but one study suggests
otherwise.53 Similarly, active SLE during pregnancy
increases rates of fetal loss,19,22,29,37,49 but this nding was not replicated in some studies.17,19,30,55 A
multicentre study of 113 pregnancies has shown
that normocomplementaemia and use of low-dose
aspirin are independently associated with favourable outcome.42

after two weeks and resolves by six months,

which correlates with the disappearance of maternal antibody.
Congenital heart block occurs in 2% of babies of
women with positive antibodies. If a previous child
has been aected, the risk increases to 1520% and
up to 50% if two children have been aected.59
The usual clinical presentation is fetal bradycardia
and/or congestive cardiac failure, and fetal/neonatal mortality may be as high as 30%.59 Regular
fetal cardiac monitoring between 18 and 26 weeks is
recommended for all women with positive anti-Ro
and/or anti-La antibodies. For aected babies that
survive to be born, delivery at a neonatal unit with
a paediatric cardiologist is advised, as pacing is
usually required. Currently no form of immunosuppressive intervention including corticosteroids,
plasma exchange or intravenous immunoglobulin
has reliably been shown to reduce the risk of congenital heart block.59,60 However, the use of
hydroxychloroquine may decrease the risk of development of neonatal heart block.61
Factors influencing pregnancy outcome
Disease activity pre-pregnancy

Disease activity pre-pregnancy has been shown by

several authors to inuence pregnancy outcome
and are.17,22,23,29,35,42,47,50,53,55,62 Quiescent disease
pre-pregnancy was found by one group to be the
only predictor of favourable maternal outcomes in
women with lupus nephritis.22

Pre-term delivery and small for gestational age (SGA)

Level of renal function

Pre-term delivery is common in SLE pregnancies

and is further increased in those with renal involvement, with rates up to 3058%.22,42,51,56 The risk is
greater in those with active disease during pregnancy.43 Similarly, SGA is a common complication
in pregnancies aected by lupus nephritis, occurring in 24% of women with lupus nephritis in one
study.42 In keeping with this nding, on systematic
review of 2751 pregnancies the rate of intrauterine
growth restriction (IUGR) was estimated to be
12.7%.43

Pregnant women with mild renal impairment

(Cr < 125 mmol/l) due to any aetiology are reported
to have elevated rates of maternal and fetal adverse
events
compared
to
healthy
individuals.
Complication rates increase with severity of renal
impairment and may occur in up to 70% of pregnancies of women with more severe disease
(Cr > 250 mmol/l).63 In a review of pregnancy outcome according to stage of CKD, women with
lupus nephritis have worse overall pregnancy outcome than women with the same level of renal function but other causes of CKD.64 Moroni and
Ponticelli described fetal loss in half of all conceptions in women with Cr > 106 mmol/l and 60% fetal
loss in pregnancies with creatinine rising above
133 mmol/l during pregnancy.48

Neonatal lupus syndromes

Anti-Ro (SSA) and anti-La (SSB) antibodies are

found in approximately a third of women with
SLE.57 These may cross the placenta and cause specic fetal complications, such as cutaneous neonatal syndromes and congenital heart block.
Cutaneous neonatal lupus a non-scarring
photosensitive rash occurs in 5% of women
with anti-Ro antibodies.58 It typically appears

Hypertension

Hypertension diagnosed before pregnancy aects

up to 25% of pregnancies in women with
SLE and is associated with a risk of superimposed
Lupus

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1274

pre-eclampsia, pre-term delivery, fetal growth

restriction (FGR) and placental abruption.6567
Hypertension is even more common in women
with lupus nephritis and is reported to occur in
44% of pregnancies.35 Rates of fetal loss in
women with lupus nephritis have been reported to
be higher in women with hypertension compared to
those with normal blood pressure.39,53

APS nephropathy has been reported with thrombotic microangiopathy characterised by brin
thrombi in the glomeruli and/or arterioles. It can
occur even without SLE. Histologic appearances
can also occur with hypertension, diabetes mellitus,
thrombotic thrombocytopenic purpura, systemic
sclerosis and cyclosporin use, and these conditions
must rst be excluded before APS nephropathy is
diagnosed.74

Proteinuria

Proteinuria has been associated with worse pregnancy outcomes in most series.29,34,42,49 A review
of pregnancies in women with lupus nephritis
found that proteinuria >0.5 g/24 hours was associated with a 57% rate of fetal loss, compared to
9% in women with no proteinuria.48
Histological class

There have been conicting results from smaller

studies that have suggested certain histological
classes of lupus nephritis are linked with adverse
obstetric outcomes.28,47 However, a meta-analysis
has not found any direct association between histological class of lupus nephritis and adverse pregnancy outcomes.43 Of the small number of cases
of lupus nephritis diagnosed de novo during pregnancy, class III and IV appear to develop more
severe disease than classes I and II.22,49
Antiphospholipid antibodies (aPL)

aPL are present in 3050% of patients with SLE.68

Presence of aPL is linked to arterial or venous
thrombosis, recurrent early fetal demise, unexplained fetal death at >10 weeks gestation with
normal fetal morphology or pre-term birth at <34
weeks as a result of pre-eclampsia or placental
insuciency.69 Presence of these antibodies within
the appropriate clinical setting along with objective
histological evidence of vessel thrombosis without
inammation helps to conrm the diagnosis of
antiphospholipid syndrome (APS). Women with
SLE and concurrent aPL/APS had the highest
rate of fetal loss,19,22,35 and complications such as
miscarriage, FGR and pre-term delivery have also
been reported to occur three times more often when
aPL are positive.70
Expert opinion suggests that there should be a
further subcategorisation of APS patients: those
with previous recurrent miscarriages or fetal loss
(obstetric APS) and those with previous thromboembolic events (thrombotic APS), as there appear
to be distinct dierences in pregnancy outcome
between these groups, with the former group
having fewer complications on treatment.7173
Lupus

Diagnosis during pregnancy

New diagnosis of lupus nephritis during pregnancy

is associated with worse outcomes3,22,29,32,49 both
for the fetus and the mother. Pregnancies occurring
after the diagnosis of lupus nephritis had been
established have been shown to have a lower risk
of complication by hypertension and proteinuria
than in pregnancies during which lupus nephritis
is diagnosed for the rst time, but there was no
dierence in the incidence of impaired renal
function.35

Management strategy
Pre-pregnancy counselling
All women of child-bearing age with lupus nephritis
should be oered pre-pregnancy counselling,
during which assessment for severity of renal disease, disease activity, end-organ damage and associated antibodies, which may cause further
complications (aPL, anti-Ro antibodies), should
be made. Every woman should have a full history
and examination. Evidence of any organ involvement should be quantied prior to pregnancy.
Pulmonary hypertension (dened as a resting
pulmonary arterial pressure of >25 mmHg in the
non-pregnant state) is the only absolute contraindication to pregnancy and will need to be excluded if
there are any features in the history or examination
to suggest this. Mortality rate in secondary pulmonary hypertension is 56%.75 Baseline cardiac
function should be established. Suggested investigations pre-pregnancy are listed in Table 1. Women
should have inactive disease for six months before
attempting to conceive. A period of three to six
months following changes in medication should
be allowed to enable stabilisation and dose adjustment on the new drug.
Adverse obstetric outcomes need to be quantied
for the woman. Fetal loss along with risks of preterm delivery should be discussed. Women with
severe chronic renal disease and multiple risk factors for poor obstetric outcome need to be aware of

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1275

long-term sequelae of very pre-term and growthrestricted neonates.

Medication
(See Table 3 for safety proles of medications in
pregnancy.)

Table 1 Pre-pregnancy, baseline and maternal surveillance

investigations
Laboratory investigations at baseline (preferably pre-pregnancy)
Full blood count
Urea, creatinine, electrolytes, uric acid
Liver function tests, albumin, coagulation profile
ANA
Anti-dsDNA
C3 and C4
ENA esp. anti-Ro and Anti-La
Lupus anticoagulant, anticardiolipin and b2-glycoprotein I antibodies
Urinalysis for casts, protein creatinine ratio (PCR)
24-hour urine collection for quantification of proteinuria
Other essential baseline observations
Blood pressure
Body mass index, nicotine use
Evidence of end-organ damage from SLE (or hypertension)
Other investigations to be considered at baseline for women with SLE
ECG  echocardiogram
Pulmonary function tests

ANA: antinuclear antibodies; ENA: extractable nuclear antigens; SLE:

systemic lupus erythematosus; ECG: electrocardiogram.

Corticosteroids

Maintenance steroids at the lowest possible dose

are usually continued in pregnancy as they cause
minimal adverse eects to mother or fetus.76
Prednisolone is preferable as it is metabolised by
the placenta and only 10% crosses into the fetal
circulation at maternal doses <20 mg.77 Exposure
to corticosteroids in the rst trimester may increase
rates of cleft lip and palate,78,79 however, this has
not been substantiated in all studies.80,81 Beyond
the rst trimester, corticosteroid use is associated
with increased risk of gestational diabetes, elevations in blood pressure in pregnancy, asymptomatic
infections, particularly urinary tract infections, and
pre-term deliveries.82 Currently prophylactic steroid treatment is not advised, as it has not been
shown to prevent ares.83
Other immunosuppression

Cyclosporin84,85 and tacrolimus86 are non-teratatogenic. However, there is an increased risk of gestational diabetes and hypertension in women taking
tacrolimus87 and therefore screening with a glucose
tolerance test is recommended at 28 weeks or
sooner if there are other risk factors.
Despite the United States Food and Drug
Administration (FDA) pregnancy risk classication, we have continued to use azathioprine76,88,89
and hydroxychloroquine in our pregnant women

Table 2 Suggested fetal surveillance for women with SLE

Interval

Investigations

Indications

As soon as pregnancy is confirmed

(preferably < six weeks gestation)

Viability and dating scan to determine if there is an

intrauterine pregnancy.
Establish baseline investigations in early pregnancy
(as in Table 1).

>Eight weeks

Viability scan

1113 weeks

Dating/nuchal scan

1628 weeks

Fetal cardiac monitoring

16, 1820 weeks

Fetal scanning for warfarin embryopathy

2024 weeks

Detailed anatomy scan Doppler of uterine arteries.

To change from warfarin to LMWH (if woman with

APS is on warfarin)
Commence aspirin.
For comparison when a flare or superimposed preeclampsia develops.
To determine if there is a viable fetus/evidence of a
fetal pole or heartbeat.
To confirm estimated date of delivery and determine
if there are any possible fetal congenital
anomalies.
To pick up congenital heart block only for
women with anti-Ro and La positive.
Only for women who were on warfarin in the first
trimester (> six weeks).
To pick up any congenital anomalies. Absence of
notching of the Dopplers of the uterine arteries
has excellent negative predictive value for development of subsequent pre-eclampsia.

*Subsequent scans are indicated only

for women with hypertension,
lupus nephritis or APS.

* If abnormal Dopplers or growth at 20 weeks, four

weekly follow-up scans for growth and Dopplers
of the umbilical artery are suggested.
In women with very poor obstetric history, fortnightly growth scans (Dopplers of the umbilical
artery) after 24 weeks.

SLE: systemic lupus erythematosus; LMWH: low-molecular-weight heparin; APS: antiphospholipid syndrome.
Lupus

Lupus

US FDA y

C
B (but risk category goes
to D from  30 weeks
gestation)

C prior to <30 weeks

gestation. D  30
weeks gestation

NA
D

Drug

Paracetamol
NSAIDS

COX II inhibitors

Prednisolone/IV
methylprednisolone

Hydroxychloroquine
Azathioprine

Cyclosporin

Tacrolimus

MMF

Cyclophosphamide

Intravenous
Immunoglobulin

Unknown

B3C

NA

D**
D

5
5

animal data

After 30 weeks
gestation.

Limited as most
would be metabolised by the
placenta.

5
5

A
C

Unknown.
Teratogenicity
observed in animal
studies.
Possible increase in
oral clefts.

Human teratogenicity

ADEC *

Transplacental
passage

Table 3 Safety of commonly used medications for SLE/lupus nephritis in pregnancy.108

Chromosomal
abnormalities and
cytopaenia with an
increased rate of
spontaneous miscarriages reported.
None reported

5
Constriction of ductus
arteriosus and renal
blood flow restriction in late
pregnancy
Likely to cause closure of the ductus
arteriosis as with
NSAIDs
Rare except at
large doses. (cataract, adrenal insufficiency and
infection)
5
Sporadic congenital
abnormalities, transient immune alterations in neonates
Transient immune
alterations in the
neonate.
Hyperkalaemia and
renal impairment
Congenital malformations of the external
and middle ear have
been reported.

Fetal/neonatal effects

For those breastfeeding, not

encouraged
if > 60 mg prednisolone daily.

Probably safe

5 Stop drug three

months prior to
conception.
However, in active
disease, benefits of
commencing treatment after the first
trimester should be
balanced against
effects against the
fetus.
(Only after the first
trimester, only if
there is life-threatening maternal
disease.)

(continued)

Probably safe

Unknown. Small
amounts enter
breast milk.

Intermittent use is
probably safe until
third trimester.

Authors recommendations about its use in

breast-feeding

(Until 28 weeks
gestation)

Authors recommendations about its use in

pregnancy

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1276

Rituximab

ADEC *
From 16 weeks
gestation.

Transplacental
passage
Not reported

Human teratogenicity
Limit to severe
disease.

Inadequate data.
However, as these
are proteins and
will be broken
down by the
infants gastrointestinal tract, theoretically it should be
safe in breastfeeding.

Authors recommendations about its use in

breast-feeding

ADEC interpretation
Drugs which have been taken by a large number of pregnant women and
women of childbearing age without any proven increase in the frequency
of malformations or other direct or indirect harmful effects on the fetus
having been observed.
B1: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed.
Studies in animals have not shown evidence of an increased occurrence of
fetal damage.
B2: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed. Studies in animals are inadequate or
may be lacking, but available data show no evidence of an increased
occurrence of fetal damage.
B3: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of
which is considered uncertain in humans.
Drugs which, owing to their pharmacological effects, have caused or may be
suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Accompanying texts should be consulted for further details.
Drugs which have caused, are suspected to have caused, or may be expected
to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Accompanying texts should be consulted for further details.
Drugs which have such a high risk of causing permanent damage to the fetus
that they should not be used in pregnancy or when there is a possibility of
pregnancy.

Yes. Neonatal B-cell

depletion reported
occurring for up to
six months from
exposure.

Fetal/neonatal effects

Authors recommendations about its use in

pregnancy

SLE: systemic lupus erythematosus; 5: no effect; : yes/authors feel it is safe to be used in pregnancy or breastfeeding; yUS FDA: United States Food and Drug Administration; *ADEC:
Australian Drug Evaluation Committee; NSAIDS: non-steroid anti-inflammatory drugs; MMF: mycophenolate mofetil. **The reason for the D category in hydroxychloroquine in ADEC is
because it was classified as chloroquine, which is used at much higher doses for the treatment of malaria.

Contraindicated in pregnancy. Studies in animals or human beings have demonstrated fetal

abnormalities or there is evidence of fetal risk based on human experience, or both, and the
risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant.

Risk cannot be ruled out. Either studies in animals have revealed adverse effects on the fetus
(teratogenic or embryocidal effects or other) and there are no controlled studies in women, or
studies in women and animals are not available. Drugs should be given only if the potential
benefits justify the potential risk to the fetus.
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be
acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious
disease for which safer drugs cannot be used or are ineffective).

No evidence of human risk in controlled studies. Either animal-reproduction studies have not
demonstrated a fetal risk but there are no controlled studies in pregnant women, or animalreproduction studies have shown an adverse effect (other than a decrease in fertility) that was not
confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in
later trimesters.

Risk categories in pregnancy by US FDA and ADEC

Category
FDA interpretation
A
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester
with no evidence of risk in later trimesters. The possibility of fetal harm appears remote.

US FDA y

Drug

Table 3 Continued

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1277

Lupus

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1278

based on several studies documenting its safety in

pregnancy.76,90 These drugs should not be discontinued; a are of SLE91 is more detrimental to both
mother and fetus. Much of the data regarding fetotoxic eects of hydroxychloroquine stem from the
studies in which high-dose chloroquine was used to
treat malaria in pregnancy with resultant fetal
neurological decits such as interference with hearing, balance and vision. Interestingly, the FDA suggests that hydroxychloroquine be used as an
alternative for chloroquine-sensitive malaria in
pregnant women. Hydroxychloroquine has an
extremely long half-life; cessation after conception
does not prevent exposure of the fetus to the drug.
Azathioprine76,88,89 and hydroxychloroquine are
safe to use throughout pregnancy76,90 and should
not be discontinued, especially as this may result in
a are of SLE.91
MMF

MMF is now a rst-line agent for the treatment of

lupus nephritis. In 2004 the rst case of teratogenicity in human pregnancy was described.92 Since
then 26 cases of early exposure in 18 renal transplant patients have been reported, and a clinical
syndrome has been identied including hypoplastic
nails, shortened fth ngers, diaphragmatic hernia,
microtia (ear deformity) micrognathia, cleft lip and
palate and congenital heart defects.93 Women are
now advised to switch from MMF at least three
months pre-pregnancy to an immunosuppressive
agent that has a safer prole in pregnancy, e.g.
azathioprine, cyclosporin or tacrolimus. There are
some situations where alternatives have been tried
without success or with serious side eects and
MMF is the only treatment able to achieve disease
stability. The woman needs to be counselled carefully about the relative risks to the fetus if she
remains on MMF during her pregnancy.
Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB)

Before 2006 ACEI were not advised in the second

or third trimester because of an association with
fetal complications, including growth restriction,
oligohydramnios, hypocalvaria, renal dysplasia,
anuria, renal failure and often fetal death.94 A
report in 2005 suggested that ACEI and ARB use
in the rst trimester is also associated with a
2.7-fold increase in congenital malformations.95
Abnormalities include cardiovascular, central nervous system and renal defects.
Women with minimal proteinuria taking ACEI/
ARB for blood pressure control may be switched to
an alternative antihypertensive known to be safe in
Lupus

pregnancy, e.g. nifedipine, amlodipine, labetalol,

methyl dopa or doxazosin. Women with proteinuria
controlled by ACEI/ARB with mild renal impairment can be advised to stop taking their medication
when they start trying to conceive, with close monitoring of blood pressure. Others may have heavy
proteinuria, which may advance their deterioration
in renal function whilst they are attempting to conceive, particularly older women and those with more
severe renal impairment; therefore, having a prolonged period without ACEI/ARB may be ill
advised. It is then recommended that ACEI/ARB
be discontinued as soon as the pregnancy is conrmed, as the period of teratogenicity is considered
to be from six weeks onwards. Women with an
irregular menstrual cycle, in whom pregnancy conrmation may be delayed, need to be assessed and
advised on an individual basis.
Non-dihydropyridine calcium channel blockers
(e.g. diltiazem) in small studies have demonstrated
signicant anti-proteinuric eects on women with
underlying renal disease and could be considered as
an alternative to an ACEI/ARB in pregnancy.96,97
Antenatal care
During pregnancy, women should be regularly
reviewed by a multidisciplinary antenatal team,
including obstetricians with expertise in maternal
medicine, midwives, rheumatologists, nephrologists
and/or obstetric physicians, to provide meticulous
lupus-specic monitoring. Routine investigations at
the start and during pregnancy are listed in Table 1.
Recommended fetal surveillance is described in
Table 2. All women with lupus nephritis should
be advised to take low-dose aspirin unless there
are contraindications, as it has been shown to
reduce the risk of pre-eclampsia by 17% in highrisk pregnancies98 and is also associated with
improved fetal and neonatal survival in women
with lupus nephritis.42
Disease flare

Diagnosis of lupus activity may be dicult, as many

features of pregnancy mimic SLE disease activity
(see Table 4). In our experience one of the most reliable ways of diagnosing disease are is by asking the
woman whether symptoms are typical of her SLE.
Pre-eclampsia and lupus nephritis flare

Distinguishing between pre-eclampsia and active

lupus nephritis can be a clinical challenge for
nephrologists and obstetricians, as both conditions
are associated with hypertension, proteinuria,
thrombocytopenia and renal impairment, although

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1279

Table 4

To help distinguish between pre-eclampsia and a flare of lupus (esp. lupus nephritis)
Pre-eclampsia

Flare of lupus

Casts in MSU
RBC in MSU
Hypertension
Involvement of skin and joints

>0.3 g/day or PCR > 30

Absent
Absent
Present
No

Seizures

Present in eclampsia

Urate
Albumin
LFT
C3 and C4

Elevated
Low
May be deranged
Unchanged from baseline in
early pregnancy
Unchanged

(in lupus nephritis)

Present (if lupus nephritis)
Present (if lupus nephritis)
May be present
Malar rash, photosensitive rash
or evidence of arthritis
Present if there is neurological
involvement
Not elevated unless CKD
Very low if nephrotic syndrome
Rarely deranged in a flare of SLE
Low

Proteinuria

Anti-dsDNA

Elevated

PCR: protein creatinine ratio; MSU: Mid stream urine; RBC: red blood cells; CKD: chronic kidney disease; LFT: liver
function tests; SLE: systemic lupus erythematosus.

novel anti-angiogenic factors, which are dierentially expressed in pre-eclampsia, may be helpful
in the future.99 Diagnosis is even more challenging
in women with pre-existing hypertension or proteinuria. Hypertension should be treated with
drugs such as methydopa, nifedipine, hydralazine,
labetolol and doxazocin that are safe in pregnancy.
A woman with conrmed pre-eclampsia should be
monitored for FGR.
Table 4 shows the features that pre-eclampsia
and lupus nephritis have in common and useful
markers to help distinguish and diagnose the two
conditions. One study suggested that anti-dsDNA
antibodies are more useful for distinguishing preeclampsia and active lupus nephritis than low C3
and C4. Complement levels are usually elevated in
pregnancy, and have been shown to fall in the
absence of are in more than 50% of pregnancies
complicated by lupus nephritis,49 but others report
them to be useful in diagnosing are in
pregnancy.100
If the diagnosis of acute lupus nephritis is suspected at less than 2428 weeks gestation, a biopsy
may be appropriate since the result is likely to aect
management decisions. Despite reports suggesting
renal biopsy is safe in pregnancy,101 many are reluctant to perform the procedure. Increased vascular
perfusion to the kidneys in pregnancy theoretically
increases the risk of bleeding or haematoma formation post-biopsy, hence an experienced operator is
necessary.
If the diagnosis of lupus nephritis is conrmed,
steroids are the treatment of choice. For more severe
disease, pulsed intravenous methylprednisolone
may be indicated. Adjustment of or the introduction
of steroid-sparing agents, usually azathioprine, may

be necessary. Beyond 28 weeks gestation, when the

fetus is viable, delivery may be the most appropriate
course if mother or fetus is at risk in order to allow
diagnosis and administration of cytotoxic drugs. In
cases of severe are in pregnancy where both mother
and baby are at risk, pulsed intravenous cyclophosphamide could be considered after the rst trimester
if there is a severe maternal disease.102 Risk of
neonatal B-cell depletion is of concern with
rituximab.103 Termination may occasionally be discussed in order to facilitate more aggressive treatment of disease, especially in early pregnancy.
Thromboprophylaxis

All pregnant women become increasingly prothrombotic throughout pregnancy because of alterations in haemostatic proles.104,105 Those with
aPL are at particularly high risk. Women with
SLE have higher rates of thromboembolism than
background levels and have a further elevated risk
in pregnancy, particularly if there is a history of
thromboembolism.106
Women with lupus nephritis potentially have the
additional complication of proteinuria, which is
associated with further procoagulant changes.107
Thromboprophylaxis is currently recommended in
all pregnant women with proteinuria >3 g/24 hours
or protein creatinine ratio (PCR) >300 mg/mmol
and serum albumin <30 g/l.108,109 It is prescribed
according to the level of renal impairment. Both
low-molecular-weight heparin (LMWH) and
unfractionated heparin are safe in pregnancy.
Women with renal impairment

Erythropoetin requirements increase during pregnancy, and women with moderate/severe renal
Lupus

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1280

impairment may require the introduction or

increased doses of erythropoiesis-stimulating
agents. Vitamin D supplementation is recommended and review by a dietician for caloric, calcium and phosphate intake may be necessary.
It is recommended for women requiring renal
replacement therapy either before or during
pregnancy that haemodialysis frequency should be
increased to ve to seven times per week, aiming for
more than 20 hours, in order to improve clearance
and reduce dramatic volume shifts. Target predialysis urea of <20 mmol/L is usually suggested.
This regimen appears to have been successful in
several cases.110112
Post-partum
Post-partum monitoring is essential, as many ares
of disease and thromboembolic complications
occur within six months following delivery.18 All
drugs which are recommended during pregnancy
are also considered to be safe during breast-feeding,
although data supporting cyclosporin and tacrolimus use are still limited. Enalapril may be safely
used in women who are breast-feeding as it is not
excreted in breast milk.113

Conclusion
With eective treatment of lupus nephritis and
women regaining their fertility post-transplantation, more women are now contemplating pregnancy. Despite the best treatment, women with
lupus nephritis tend to have complicated pregnancies. Risks are reduced with inactive disease prepregnancy. Flares of lupus nephritis do not
appear to be increased by pregnancy, but may be
dicult to distinguish from pre-eclampsia.
Pre-pregnancy counselling is advised to help
women make an informed decision about risks and
potential complications associated with pregnancy.
Immunosuppression needs to be reviewed along
with all other medications. Careful assessment for
complicating factors including end-organ damage,
anti-Ro and anti-La antibodies, aPL and the presence of hypertension and proteinuria is important.
Antenatal care should be delivered by a multidisciplinary team with expertise in the care of women with
SLE and renal disease. Surveillance for disease are
and pregnancy complications is essential.
Ultimately, it is maternal well-being that determines favourable obstetric outcome. Pregnancy
should no longer be considered a contraindication
to eective investigation and management of a
Lupus

woman with lupus nephritis as clinicians managing

pregnancies are becoming increasingly familiar
with the wide range of therapeutic agents available.
Take-home messages
1. Clinicians dealing with pregnant women will
soon need to familiarise themselves with the
management of lupus nephritis as more eective treatment strategies are enabling women of
childbearing age to contemplate pregnancy.
2. All pregnancies in women with lupus nephritis
should be planned, preferably after more than
six months of quiescent disease. Care should be
centred on expertise in dealing with SLE/lupus
nephritis with a multi-disciplinary approach.
3. Predictors of poor obstetric outcome include
active disease pre-pregnancy or early pregnancy; baseline poor renal function with
Cr >100 mmol/L; proteinuria >0.5 g/24 hours;
presence of concurrent APS; or hypertension.
4. Establishing baseline blood tests pre-pregnancy
or in early pregnancy will aid in identication
of a are or developing pre-eclampsia.
5. Flares of lupus nephritis are often dicult to
distinguish from developing pre-eclampsia
though falling complement levels and rising
anti-dsDNA levels coupled with active urinary
sediment with casts would point toward a are.
6. Most immunosuppressives used in lupus nephritis with the exception of MMF and cyclophosphamide are non-teratogenic and safe to
be continued in pregnancy, as avoidance of a
are is paramount.
7. Women should be screened for developing diabetes and hypertension/pre-eclampsia, along
with any symptoms and signs of a are.
8. Women on renal replacement therapy will
require increasing frequency of haemodialysis
with a pre-dialysis target urea of < 20 mmol/L.
9. Fertility is rapidly restored post-renal transplant, and contraception should be discussed
pending a planned pregnancy.
10. Most medications used are compatible with
breast-feeding.
Flares
post-partum
are
common with immune reconstitution.

Funding
This research received no specic grant from any
funding agency in the public, commercial, or notfor-prot sectors.
The authors disclose receipt of the following
nancial support for the research and/or

Pregnancy and renal outcomes in lupus nephritis

K Bramham et al.

1281

authorship of this article: the Department of Health

via The National Institute for Health Research
(NIHR) Comprehensive and Biomedical Research
Centre Award to Guys and St Thomas NHS
Foundation trust in partnership with Kings
College London for K. Bramhams salary.

18
19
20

Conflict of interest statement

21

None declared.

22
23

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