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CONCISE REPORT

Maternal deaths in women with lupus nephritis: a review


of published evidence
J Ritchie1*, A Smyth2*, C Tower3, M Helbert4, M Venning5 and VD Garovic6
1
Vascular Research Group, Manchester Academic Health Science Centre, University of Manchester, Salford Royal Hospital, UK; 2Department of
Medicine, National University of Ireland, Ireland; 3Maternal and Fetal Health Research Group, School of Biomedicine, University of Manchester,
St. Mary’s Hospital, UK; 4Department of Immunology, Central Manchester Foundation Trust, UK; 5Manchester Institute of Nephrology and
Transplantation, Central Manchester Foundation Trust, UK; and 6Division of Nephrology and Hypertension, Mayo Clinic, USA

Background and objectives: Pregnancies in women with systemic lupus erythematosus (SLE)
and lupus nephritis are considered high-risk due to high rates of maternal and fetal compli-
cations. However, there has not been a formal analysis addressing the issue of maternal deaths
in these women. The aim of this study was to perform a literature review of the maternal
deaths in women with SLE and lupus nephritis to: (1) identify the main causes of death and
(2) discuss possible reasons for these causes, and strategies that may improve patient care and
outcomes. Design, setting, participants, and measurement: We performed an extensive elec-
tronic literature search from 1962 to 2009 using online databases (PubMed, Embase, Lilacs,
Cochrane Controlled Trials Register, Medline, and Science Citation Index). Studies were
included if they reported pregnancies in patients with SLE and lupus nephritis with at least
one reported maternal death. Results: We identified 13 studies that reported a total of 17
deaths in the 6 week post-partum period that were attributable to SLE and lupus nephritis. In
all cases, death occurred in the setting of active disease, and was attributed either to infection
in 41.2% (n ¼ 7), or disease activity in 29.4% (n ¼ 5). The remaining deaths were due to
pulmonary embolus in 11.8% (n ¼ 2), pregnancy-associated cardiomyopathy in 5.9%
(n ¼ 1), adrenal failure due to abrupt steroid withdrawal in 5.9% (n ¼ 1), and undefined in
5.9% (n ¼ 1). Conclusions: All maternal deaths in patients with SLE and lupus nephritis
occurred in those with active disease, with disease activity/complications and infections
(mainly opportunistic) being the two major causes. The presented evidence further supports
timing of pregnancy relative to SLE activity, and the judicious use of immunosuppressive
agents in pregnant patients. Lupus (2012) 0, 1–8.

Key words: Systemic lupus erythematosus; pregnancy; lupus nephritis; maternal death
infection; disease activity

Introduction Pregnancies in women with SLE are high-risk


due to increased rates of maternal and fetal com-
Systemic lupus erythematosus (SLE) is an immune- plications. Initial reports of pregnancy in SLE sug-
mediated connective tissue disorder with strong gested poor outcomes,3 but recent data show
gender and ethnic biases. Most affected women dramatic improvements in live birth rates.4,5
are of childbearing age and pregnancy is a frequent Pregnancy in SLE must be considered from three
event.1,2 perspectives: the effect of pregnancy on disease
activity/progression; effects of disease/treatments
on the fetus; and the health of the mother during
pregnancy and after delivery.
*J Ritchie and A Smyth contributed equally as first authors The literature related to fetal and maternal out-
Correspondence to: Vesna D Garovic, Division of Nephrology and comes in SLE pregnancies is growing. However, a
Hypertension, Mayo Clinic, 200 First Street SW, Rochester, wide variety of study designs and definitions of
Minnesota 55905 USA
Email: garovic.vesna@mayo.edu
lupus and complications are used. Reviews focus
Received 8 June 2011; Accepted 8 December 2011 on end points related to fetal outcome and
! The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203311434939

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maternal complications. A recent meta-analysis, diagnostic certainty on the authors’ part, to


covering 2751 pregnancies in women with SLE record these patients as having LN in remission.
and lupus nephritis (LN), identified high maternal Active nephritis was defined as proteinuria
complication rates and an overall maternal mortal- >500 mg/day, with >5 red cells per high power
ity rate of 1%.6 The causes of these deaths were not field (or other evidence of an active sediment). An
discussed, and to date there has not been a formal elevated creatinine was not necessary to define
analysis addressing the issue of maternal death in active nephritis. Most patients presenting with de
women with SLE, and in particular, LN. One novo LN during pregnancy did not have a histolog-
review of pregnancy outcomes in patients with ical diagnosis. Renal disease flares were defined by
LN raised concerns that sepsis, not disease activity, elevations in urinary protein levels above 300 mg/
may be the leading cause of maternal mortality.2 day (physiological proteinuria of pregnancy) with
The most recent Centre for Maternal and Child autoantibody status and complement levels used to
Enquiries Report (2006–2008) notes that although distinguish disease flares from preeclampsia.
maternal mortality has declined in the United Information on the number of pregnancies and
Kingdom, maternal mortality rates attributable to proportions of patients with LN diagnosed prior
sepsis have risen.7 This highlights the challenges of to/during pregnancy was extracted and tabulated.
diagnosing and treating sepsis during pregnancy, Where LN was diagnosed prior to pregnancy, the
even in an immune competent population. cases were separated into active or inactive at
In this study, we perform a review of the litera- conception.
ture for maternal deaths in women with LN to: (1)
identify the main causes of death and (2) discuss
possible reasons for these causes, and approaches Results
aimed at improving patient care and outcomes.
One hundred and thirty-six papers were identified
Methods from the initial database searches. Of the 136
papers, 63 were excluded, leaving 73 original
papers for analysis; 59 papers did not report mater-
We performed an extensive electronic literature nal mortality, leaving 14 papers with potentially
search from 1962 to 2009 using online databases relevant information.11–24 Of these, it was unclear
(PubMed, Embase, Lilacs, Cochrane Controlled in one of the articles if the death occurred in a LN
Trials Register, Medline, and Science Citation
patient – this was also excluded22 (see Figure 1).
Index). The abstracts and full text for all papers
These 13 studies reported 19 deaths in patients
identified using the keywords ‘SLE’, ‘lupus nephri-
with LN. A death occurred 18 months post-partum
tis’, and ‘pregnancy outcome’ were reviewed.
due to pancreatitis15 and was excluded from the
Studies were included if they reported pregnancies
analysis, leaving 18 reported deaths in the immedi-
in patients with LN with at least one reported
ate peri-partum period. A death due to Bacillus
death. As most papers were case series, quality
scores were not applied, but validation criteria cereus sepsis was reported in 2 articles, leaving 17
were applied as follows. unique cases.16,18 The extent of information per-
taining to immunosuppression/histological classes
Definitions varied among studies, but causes of death were
reported for all cases, but one.
The presence of SLE was defined by the American All deaths occurred in the setting of active lupus
College of Rheumatology diagnostic criteria appro- disease, and were attributed to infection in 41.2%
priate to the age of the article.8 Maternal mortality (n ¼ 7), disease flare in 29.4% (n ¼ 5), pulmonary
was defined as that occurring during pregnancy, or embolus (PE) in 11.8% (n ¼ 2), adrenal failure
during the early post-partum period, defined as the due to abrupt termination of steroids in 5.9%
6 weeks (42 days) following pregnancy termination/ (n ¼ 1), and pregnancy-associated cardiomyopathy
delivery. The presence of LN was defined by histol- in 5.9% (n ¼ 1) (see Table 1). The cause of death
ogy, where available, and graded by either the could not be ascertained in one further case
Comerford and Cohen classification9 and, more (5.9%).23 Four deaths occurred in patients with
recently, the 1995 World Health Organization clas- SLE diagnosed during pregnancy, six in patients
sification.10 Where histology was not reported, with active disease at conception, and seven in
terms such as ‘inactive renal disease’ and ‘quiescent patients with disease flares during pregnancy.
nephritis’ were accepted as representing sufficient
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136 studies from literature


search assessed by 2
investigators

73 assessed 63 excluded

59 did not report any 14 further considered Not suitable by title


maternal death Review article
Insufficient details on lupus
nephritis

13 included in final 1 excluded as unclear if


analysis case of maternal death
occurred in a patient with
lupus nephritis

Figure 1 Flow chart of study selection.

Manifestations of lupus affected the cerebral, renal, Other causes


and pulmonary organ systems.
Disparate pathologies were implicated in the
remaining cases. Steroid withdrawal was implicated
Confounding effects of sepsis and opportunistic
in one case. Theoretically, this may have worsened
infections
disease control, although no data were reported to
In cases of mortality due to infection, there were support this hypothesis. PE was reported as
insufficient data to comment on laboratory param- the cause of death in two patients, one with anti-
eters, including white cell count, at the time of phospholipid syndrome (APS), as confirmed by the
infection. The infectious agent was not always iden- presence of antiphospholipid antibodies (aPL) and
tified, but in the four cases where it was reported, a history of deep vein thrombosis. One patient
three patients died with infection due to opportu- developed pregnancy-associated cardiomyopathy
nistic intracellular organisms. Listeria, Bacillus and died 6 weeks post-partum.
cereus, Cryptococcus, Cytomegalovirus (CMV),
and Candida, were all implicated agents (multiple Cases with intra-partum onset of lupus nephritis
organisms were identified in some patients). During
A total of 6 studies reported patients presenting
pregnancy, all 11 patients for whom details of
with de novo lupus nephritis during pregnancy,
immunosuppression were reported received cortico-
with 26 pregnancies in this group.11–13,16–18 Three
steroids, with 5 of these patients described as receiv- deaths were identified, two due to infection and one
ing high dose steroids. Of these five patients, three due to disease flare.
died of active disease and two of opportunistic
infections. In the third patient, who died of oppor-
tunistic infection, details of immunosuppression
were not reported. Azathioprine and hydroxychlor- Discussion
oquine were given to one patient each, and
cyclophosphamide was administered to three Our study demonstrates that all maternal deaths in
patients immediately after pregnancy termination patients with SLE and LN occurred in those
(Table 1). Information regarding the drug dosing with active disease. In all cases where immunosup-
and duration of treatment was mostly incomplete. pression was documented, steroid therapy had
Lupus

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Table 1 Details of cases of maternal death included in analysis


Cause/time of death
Paper Disease activity (when available) Medications Histology

Chandran12 Post-partum flare: seizures, arthritis, Disease flare/progression/ Methylprednisolone; Not described.
pulmonary hemorrhage. SLE diag- 6 weeks after delivery. cyclophosphamide.
nosed in pregnancy.
Le Thi Huong16 Developed SLE during pregnancy; Sepsis. High-dose prednisone. Diffuse proliferative
post-mortem: diffuse proliferative nephritis
GN. Died of Bacillus cereus septi-
cemia. Also reported below.
Le Thi Huong18 In both patients, active LN as evi- In both patients, death For both patients: High- Not described.
denced by severe nephrotic syn- related to sepsis. dose prednisone.
drome; deaths related to
opportunistic infections. One
known SLE, one diagnosed in
pregnancy. One died from
Bacillus cereus septicemia, one
from Listeria septicemia and one
from pulmonary Cryptococcosis.
Clowse13 One patient: high-activity lupus, 1. Infection/post-partum. Not available. Not described.
developed HELLP, then CMV, 2. Pulmonary embolus/1
Candida, multi-organ failure.Two day post-partum.
patients: low-activity lupus: one 3. Pregnancy-associated
died 1 day post-partum from PE, cardiomyopathy/6
the other 6 weeks post-partum weeks after delivery.
from cardiomyopathy.
Imbasciati17 First patient developed SLE during 1. Sepsis/few days after 1. Prednisone. 1. Diffuse proliferative
pregnancy, irreversible renal fail- delivery. 2. Prednisone. nephritis
ure, DIC, sepsis (organism not 2. Sepsis/3 weeks after 2. Diffuse proliferative
reported). spontaneous abortion nephritis
Second patient got pregnant while in (20 gestational weeks).
remission (possibly of short dura-
tion), flared in the third month,
spontaneous abortion at 20
weeks. Died 3 weeks later from
DIC, sepsis (organism not
reported).
Ainslie11 SLE existing, but undiagnosed pre- Disease flare/progression. Not available. Not described.
conception. Nephritis revealed
during pregnancy. Died from
pneumonitis.
Rahman20 Clinical evidence of active LN at con- 1. Disease flare/progres- 1. High-dose prednisone. Not described.
ception in both patients. sion/3 days after 2. High-dose corticoste-
delivery. roids, azathioprine,
2. Disease flare/progres- cyclophosphamide.
sion/2 months after
delivery.
Moroni19 Progressed to ESRD during preg- Sepsis/few days after Not available. Lupus nephritis
nancy; severe extra-renal manifes- delivery.
tations post-partum; developed
DIC, died of sepsis (organism not
reported).
Hayslett15 Active SLE during pregnancy. Adrenal failure. Prednisone. Lupus nephritis
Wagner21 Known LN, quiescent at conception. Pulmonary embolism/ Prednisone, Lupus nephritis
History of DVT and aPL. Flare in during pregnancy Hydroxychloroquine,
the first trimester, died from respi- (second trimester). Low-molecular weight
ratory failure due to pulmonary heparin.
hemorrhage and embolus.
Georgiou14 Active nephritis with positive serol- Disease flare/progression/ Prednisone, Lupus nephritis
ogy at conception, intrauterine after delivery. Cyclophosphamide,
fetal death, maternal death despite Plasmapheresis.
aggressive immunosuppression.
Garsenstein23 First onset of SLE at beginning of Disease progression after Not available. Not described.
pregnancy, including severe GN. theraputic abortion.
(continued)

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Table 1 Continued
Cause/time of death
Paper Disease activity (when available) Medications Histology

Zulman24 History of proliferative GN with Sepsis – Staphylococcal Prednisone. Proliferative Lupus


crescents. SLE flare during fourth septicemia due to puru- nephritis with
month of pregnancy. lent otitis media after crescents.
spontaneous abortion.

GN: glomerulonephritis; DIC: disseminated intravascular coagulation; ESRD: end stage renal disease; PE: pulmonary embolus; aPL:
anti-phospholipid antibody.

been used. The major cause of maternal death was immunosuppressive drugs and, in pregnant
infection, with three of four deaths reported due to patients, may be further potentiated by hormonal/
infection with opportunistic organisms. The second immunological changes. During pregnancy, the
most common cause of maternal death was disease maternal immune system adapts to allow for the
activity. The presented evidence supports current growth of a semi-allogeneic fetus. Significant
recommendations that the disease should be quies- immunological changes ensue,27,28 including inhib-
cent on stable therapy for a substantial period ited cytokine production by type-1 helper cells
(often defined as  six months) prior to concep- (Th1), and enhanced cytokine production by type-
tion.25 This may decrease complication rates due 2 helper cells (Th2) (related to the cellular and
to disease activity, and may lessen the use of aggres- humoral immune systems, respectively). It has
sive immunosuppressive therapy, thus lowering been suggested that up-regulation of Th2 cytokines
rates of opportunistic infections and related in pregnancy may increase the risk for Th2-
deaths. When LN presents de novo in pregnancy, mediated diseases, such as SLE. However, the
a logical presumption is that disease activity would role of pregnancy in causing SLE flares remains
have the greatest bearing on outcome. Our review controversial. Similar to pregnancy, SLE is an
emphasizes that even in this setting, infection con- immune-compromising condition, with reports of
tributes to adverse maternal outcomes. increased vulnerability to infectious agents.29 The
Additional cases of maternal mortality were sum of the hormonal and immunological changes
retrieved during the literature search, but did not in pregnant patients with SLE may play an impor-
meet the criteria for inclusion as defined above. For tant role in elevating the risk of a disease flare, and
example, in a study of 134 patients with SLE and creating an environment predisposed to over-
their 191 pregnancies, ‘nephritis’ was listed as the whelming infection. The challenge of balancing
cause of death in 5 of 12 reported deaths. However, immunosuppression, given the altered metabolism
the information regarding the disease activity and of some agents during pregnancy, highlights the
severity, as well as the exact timing of death was importance of planned pregnancies for this patient
incomplete, thus not allowing for detailed analyses group.
of these events. Of note, in this series, only 1 patient
died during her pregnancy, while 11 died during the Immunosuppression during pregnancy
post-abortal or post-pregnancy period.26 Another
report included three cases of maternal death that Most patients received steroids, azathioprine, and
occurred at 13, 20, and 28 weeks post-partum, in hydroxychloroquine during pregnancy, which, with
association with SLE activity.23 Taken together, the respect to fetal well-being, are considered to be rel-
published evidence suggests that the risk for mater- atively safe.30 However, induction regimens for
nal mortality is particularly high in the post-partum treatment of autoimmune disease and use of ste-
period, and that SLE exacerbations occurring roids are associated with high relative risks for
weeks after delivery may contribute to maternal major infections.31 These medications may have
mortality, thus justifying close monitoring of heightened the risk of infection in these women.
these patients. These medications also induce lymphopenia,
Several lines of evidence support the complex which may be further potentiated in pregnancy
interactions between disease activity and infections. when, relative to the total white blood cell count,
These interactions may be modified by the lymphocyte count drops and begins to rise only
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after delivery.32 The importance of a mean nadir therapies.38 Conversely, infection may influence
lymphocyte count as a predictor of major infection disease activity, with studies showing that some
has been shown in non-pregnant patients with SLE infectious agents (notably CMV) can precipitate
and ANCA vasculitis managed with regimens that SLE flares.39,40 Disease activity scores, such as
do not cause severe neutropenia.33 Thus, immuno- SLEDAI-2K, have a role in predicting a heightened
suppressive therapy may have contributed to the risk of flare during pregnancy.41 Pregnancy-specific
high rate of infections in this patient cohort. In scores, such as the Lupus Activity Index in
particular, it is of note that the infectious deaths Pregnancy,42 are validated for their abilities to pre-
in patients who were reported as receiving high dict flares,43 but are used for research purposes, not
dose steroids were all due to opportunistic in clinical practice.
infections.
Not all immunosuppressive agents result in the Histological subclass
same risk of infection in SLE patients. Steroids are
A previous meta-analysis of SLE pregnancy out-
reported to significantly increase infection risk,
comes did not find a statistically significant link
while anti-malarial agents have the opposite
between histological class and adverse pregnancy
effect.25 In addition, these data identified LN trea-
outcomes due to limited data availability.6 In this
ted with immunosuppressive therapy as a signifi-
review, not all cases reported histological subclass,
cant risk factor for serious infections. In this
nor were there sufficient cases to establish a com-
cohort, most patients had either clinical or
parator group. As such, it is not possible to com-
biopsy-proven evidence of LN.
ment on the potential relationship between the
histological class of LN and maternal mortality
Opportunistic infections
outcomes. Importantly, renal biopsy is rarely per-
In this cohort, Candida, Listeria, Bacillus cereus, formed close to or during pregnancy. This avenue
Cryptococcus and CMV were implicated agents. may merit further investigation, as histological sub-
Most of these pathogens are predominantly intra- type and disease activity may be important con-
cellular organisms. While this is likely a reflection founding variables for mortality.
of the degree of immunosuppression, inhibited Th1
T-cell responses may have had a contributory Maternal complications
effect.28
Thrombo-embolic disease was the cause of death in
Atypical infections, such as CMV and
two patients included in this review. Low molecular
Cryptococcus, are challenging to diagnose and
weight heparin therapy is used for patients with
treat.34,35 Cryptococcus most commonly affects
aPL or APS.44 However not only lupus,45,46 but
the central nervous system, with steroid therapy
pregnancy as well, may contribute to a pro-throm-
being a major risk factor for its development.35
botic state (potentially due to endothelial activa-
Other invasive fungal infections, including organ-
tion), even in patients without aPL and/or renal
isms such as Candida and Aspergillus, appear to be
disease at the point of conception. In addition, pro-
more common in patients with nephritis.36 Given
teinuria may result in urinary loss of anti-thrombin
the atypical nature of these infections, it is impera-
III, further increasing thrombotic risk. Future stud-
tive that they are considered, along with atypical
ies are needed to provide guidance as to the optimal
sites for localization. Uncommon presentations of
modalities and timing of anticoagulation in preg-
rare infective agents should also be considered.
nant SLE patients.
Bacillus cereus (noted as a cause of death in this
Of note, there were no reported deaths related to
review) is normally associated with indwelling lines
preeclampsia/eclampsia. One death was associated
and neutropenia, but has been reported in a SLE
with HELLP syndrome, believed to be a severe var-
patient with neither of these risk factors.37
iant of preeclampsia associated with Hemolysis,
Elevated Liver enzymes, and Low Platelets. While
Disease activity
SLE does not increase the risk of this condition to
Our data suggest that the combination of disease the same extent as previous preeclampsia (OR 7.19)
flare and infection may be more common than gen- or primary APS (OR 9.72), it is a recognized risk
erally recognized. Elevated SLEDAI scores corre- factor.47 Preeclampsia may also be associated with
late with more frequent infections, and worse more severe histological classes of lupus nephritis.48
outcomes.36,38 Hypocomplementemia, which com- Recent work suggests mutations in the genes
monly accompanies SLE flares, is a predictor for coding for complement regulatory proteins may
infection, independent of immunosuppressive be associated with preeclampsia in SLE and/or
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49
aPL patients. Eclampsia and preeclampsia should to immunosuppression is a vital tool in managing
remain concerns, and differentiating preeclampsia these patients.
from a disease flare is difficult, as both cause Other approaches should be considered and
increasing proteinuria, rising blood pressure, and there may be a role for preventive strategies.
thrombocytopenia.50 A LN flare is more likely Insufficient data exist to comment on medical pro-
when there is active urinary sediment, low comple- phylaxis for viral/fungal infections, but this area
ment levels, increased anti-DNA antibodies, and merits further study. Pre-conception vaccination
extra-renal lupus manifestations. Elevated uric may be another consideration, as could measure-
acid levels make the diagnosis of preeclampsia ments of antibody levels against encapsulated
more likely.51 organisms. An inactivated Varicella zoster vaccine
Finally, studies suggest that an abnormal second has been evaluated in patients undergoing autolo-
trimester Doppler flow wave in the maternal uterine gous stem cell transplantation. This reduced herpes
artery help predict development of preeclampsia in zoster episodes over the subsequent 12 months,53
this population, but this would not exclude the risk and remains an interesting avenue for future ther-
of flares. 51, 52 apy, as does the development of a CMV vac-
cine.54,55 Routine infection control measures, such
as avoidance of in-dwelling catheters, should be
Conclusion entertained. This review emphasizes the importance
of pre-pregnancy counseling and the close monitor-
This review of pregnancies complicated by LN ing of affected pregnancies. The paucity of litera-
highlights the significant risk of maternal mortality ture on such serious outcomes suggests that a
in these patients. Most of the reported deaths patient registry would be the most effective way
occurred after delivery, likely reflecting a proactive to improve knowledge and outcomes.
approach in the management of patients with
severe disease who, despite pregnancy termination,
further progress and succumb to SLE- and Funding
LN-related complications.23 In addition, pregnancy
termination may allow for more aggressive immu- This research received no specific grant from
nosuppression which, in turn, may contribute to any funding agency in the public, commercial, or
not-for-profit sectors.
maternal deaths due to opportunistic infections.
Importantly, all deaths occurred in patients with
active disease, with infection and disease activity
being the two major causes of maternal death. A References
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