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Lupus (2012) 0, 1–8

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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 deaths in women with lupus nephritis
2
maternal complications. A recent meta-analysis,
covering 2751 pregnancies in women with SLE
and lupus nephritis (LN), identified high maternal
complication rates and an overall maternal mortal-
ity rate of 1%.6 The causes of these deaths were not
discussed, and to date there has not been a formal
analysis addressing the issue of maternal death in
women with SLE, and in particular, LN. One
review of pregnancy outcomes in patients with
LN raised concerns that sepsis, not disease activity,
may be the leading cause of maternal mortality.2
The most recent Centre for Maternal and Child
Enquiries Report (2006–2008) notes that although
maternal mortality has declined in the United
Kingdom, maternal mortality rates attributable to
sepsis have risen.7 This highlights the challenges of
diagnosing and treating sepsis during pregnancy,
even in an immune competent population.
In this study, we perform a review of the litera-
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
aimed at improving patient care and outcomes.
Methods
We performed an extensive electronic literature
search from 1962 to 2009 using online databases
(PubMed, Embase, Lilacs, Cochrane Controlled
Trials Register, Medline, and Science Citation
Index). The abstracts and full text for all papers
identified using the keywords ‘SLE’, ‘lupus nephri-
tis’, and ‘pregnancy outcome’ were reviewed.
Studies were included if they reported pregnancies
in patients with LN with at least one reported
death. As most papers were case series, quality
scores were not applied, but validation criteria
were applied as follows.
Definitions
The presence of SLE was defined by the American
College of Rheumatology diagnostic criteria appro-
priate to the age of the article.8 Maternal mortality
was defined as that occurring during pregnancy, or
during the early post-partum period, defined as the
6 weeks (42 days) following pregnancy termination/
delivery. The presence of LN was defined by histol-
ogy, where available, and graded by either the
Comerford and Cohen classification9 and, more
recently, the 1995 World Health Organization clas-
sification.10 Where histology was not reported,
terms such as ‘inactive renal disease’ and ‘quiescent
nephritis’ were accepted as representing sufficient
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diagnostic certainty on the authors’ part, to
record these patients as having LN in remission.
Active nephritis was defined as proteinuria
>500 mg/day, with >5 red cells per high power
field (or other evidence of an active sediment). An
elevated creatinine was not necessary to define
active nephritis. Most patients presenting with de
novo LN during pregnancy did not have a histolog-
ical diagnosis. Renal disease flares were defined by
elevations in urinary protein levels above 300 mg/
day (physiological proteinuria of pregnancy) with
autoantibody status and complement levels used to
distinguish disease flares from preeclampsia.
Information on the number of pregnancies and
proportions of patients with LN diagnosed prior
to/during pregnancy was extracted and tabulated.
Where LN was diagnosed prior to pregnancy, the
cases were separated into active or inactive at
conception.
Results
One hundred and thirty-six papers were identified
from the initial database searches. Of the 136
papers, 63 were excluded, leaving 73 original
papers for analysis; 59 papers did not report mater-
nal mortality, leaving 14 papers with potentially
relevant information.11–24 Of these, it was unclear
in one of the articles if the death occurred in a LN
patient – this was also excluded22 (see Figure 1).
These 13 studies reported 19 deaths in patients
with LN. A death occurred 18 months post-partum
due to pancreatitis15 and was excluded from the
analysis, leaving 18 reported deaths in the immedi-
ate peri-partum period. A death due to Bacillus
cereus sepsis was reported in 2 articles, leaving 17
unique cases.16,18 The extent of information per-
taining to immunosuppression/histological classes
varied among studies, but causes of death were
reported for all cases, but one.
All deaths occurred in the setting of active lupus
disease, and were attributed to infection in 41.2%
(n ¼ 7), disease flare in 29.4% (n ¼ 5), pulmonary
embolus (PE) in 11.8% (n ¼ 2), adrenal failure
due to abrupt termination of steroids in 5.9%
(n ¼ 1), and pregnancy-associated cardiomyopathy
in 5.9% (n ¼ 1) (see Table 1). The cause of death
could not be ascertained in one further case
(5.9%).23 Four deaths occurred in patients with
SLE diagnosed during pregnancy, six in patients
with active disease at conception, and seven in
patients with disease flares during pregnancy.
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73 assessed
59 did not report any
maternal death
13 included in final
analysis
Figure 1 Flow chart of study selection.
Manifestations of lupus affected the cerebral, renal,
and pulmonary organ systems.
Confounding effects of sepsis and opportunistic
infections
In cases of mortality due to infection, there were
insufficient data to comment on laboratory param-
eters, including white cell count, at the time of
infection. The infectious agent was not always iden-
tified, but in the four cases where it was reported,
three patients died with infection due to opportu-
nistic intracellular organisms. Listeria, Bacillus
cereus, Cryptococcus, Cytomegalovirus (CMV),
and Candida, were all implicated agents (multiple
organisms were identified in some patients). During
pregnancy, all 11 patients for whom details of
immunosuppression were reported received cortico-
steroids, with 5 of these patients described as receiv-
ing high dose steroids. Of these five patients, three
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-
oquine were given to one patient each, and
cyclophosphamide was administered to three
patients immediately after pregnancy termination
(Table 1). Information regarding the drug dosing
and duration of treatment was mostly incomplete.
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136 studies from literature
search assessed by 2
investigators
63 excluded
14 further considered Not suitable by title
Review article
Insufficient details on lupus
nephritis
1 excluded as unclear if
case of maternal death
occurred in a patient with
lupus nephritis
Other causes
Disparate pathologies were implicated in the
remaining cases. Steroid withdrawal was implicated
in one case. Theoretically, this may have worsened
disease control, although no data were reported to
support this hypothesis. PE was reported as
the cause of death in two patients, one with anti-
phospholipid syndrome (APS), as confirmed by the
presence of antiphospholipid antibodies (aPL) and
a history of deep vein thrombosis. One patient
developed pregnancy-associated cardiomyopathy
and died 6 weeks post-partum.
Cases with intra-partum onset of lupus nephritis
A total of 6 studies reported patients presenting
with de novo lupus nephritis during pregnancy,
with 26 pregnancies in this group.11–13,16–18 Three
deaths were identified, two due to infection and one
due to disease flare.
Discussion
Our study demonstrates that all maternal deaths in
patients with SLE and LN occurred in those
with active disease. In all cases where immunosup-
pression was documented, steroid therapy had
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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
Paper Disease activity
Zulman24 History of proliferative GN with
crescents. SLE flare during fourth
month of pregnancy.
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
infection, with three of four deaths reported due to
infection with opportunistic organisms. The second
most common cause of maternal death was disease
activity. The presented evidence supports current
recommendations that the disease should be quies-
cent on stable therapy for a substantial period
(often defined as  six months) prior to concep-
tion.25 This may decrease complication rates due
to disease activity, and may lessen the use of aggres-
sive immunosuppressive therapy, thus lowering
rates of opportunistic infections and related
deaths. When LN presents de novo in pregnancy,
a logical presumption is that disease activity would
have the greatest bearing on outcome. Our review
emphasizes that even in this setting, infection con-
tributes to adverse maternal outcomes.
Additional cases of maternal mortality were
retrieved during the literature search, but did not
meet the criteria for inclusion as defined above. For
example, in a study of 134 patients with SLE and
their 191 pregnancies, ‘nephritis’ was listed as the
cause of death in 5 of 12 reported deaths. However,
the information regarding the disease activity and
severity, as well as the exact timing of death was
incomplete, thus not allowing for detailed analyses
of these events. Of note, in this series, only 1 patient
died during her pregnancy, while 11 died during the
post-abortal or post-pregnancy period.26 Another
report included three cases of maternal death that
occurred at 13, 20, and 28 weeks post-partum, in
association with SLE activity.23 Taken together, the
published evidence suggests that the risk for mater-
nal mortality is particularly high in the post-partum
period, and that SLE exacerbations occurring
weeks after delivery may contribute to maternal
mortality, thus justifying close monitoring of
these patients.
Several lines of evidence support the complex
interactions between disease activity and infections.
These interactions may be modified by
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Cause/time of death
(when available) Medications Histology
Sepsis – Staphylococcal Prednisone. Proliferative Lupus
septicemia due to puru- nephritis with
lent otitis media after crescents.
spontaneous abortion.
immunosuppressive drugs and, in pregnant
patients, may be further potentiated by hormonal/
immunological changes. During pregnancy, the
maternal immune system adapts to allow for the
growth of a semi-allogeneic fetus. Significant
immunological changes ensue,27,28 including inhib-
ited cytokine production by type-1 helper cells
(Th1), and enhanced cytokine production by type-
2 helper cells (Th2) (related to the cellular and
humoral immune systems, respectively). It has
been suggested that up-regulation of Th2 cytokines
in pregnancy may increase the risk for Th2-
mediated diseases, such as SLE. However, the
role of pregnancy in causing SLE flares remains
controversial. Similar to pregnancy, SLE is an
immune-compromising condition, with reports of
increased vulnerability to infectious agents.29 The
sum of the hormonal and immunological changes
in pregnant patients with SLE may play an impor-
tant role in elevating the risk of a disease flare, and
creating an environment predisposed to over-
whelming infection. The challenge of balancing
immunosuppression, given the altered metabolism
of some agents during pregnancy, highlights the
importance of planned pregnancies for this patient
group.
Immunosuppression during pregnancy
Most patients received steroids, azathioprine, and
hydroxychloroquine during pregnancy, which, with
respect to fetal well-being, are considered to be rel-
atively safe.30 However, induction regimens for
treatment of autoimmune disease and use of ste-
roids are associated with high relative risks for
major infections.31 These medications may have
heightened the risk of infection in these women.
These medications also induce lymphopenia,
which may be further potentiated in pregnancy
when, relative to the total white blood cell count,
the lymphocyte count drops and begins to rise only
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after delivery.32 The importance of a mean nadir
lymphocyte count as a predictor of major infection
has been shown in non-pregnant patients with SLE
and ANCA vasculitis managed with regimens that
do not cause severe neutropenia.33 Thus, immuno-
suppressive therapy may have contributed to the
high rate of infections in this patient cohort. In
particular, it is of note that the infectious deaths
in patients who were reported as receiving high
dose steroids were all due to opportunistic
infections.
Not all immunosuppressive agents result in the
same risk of infection in SLE patients. Steroids are
reported to significantly increase infection risk,
while anti-malarial agents have the opposite
effect.25 In addition, these data identified LN trea-
ted with immunosuppressive therapy as a signifi-
cant risk factor for serious infections. In this
cohort, most patients had either clinical or
biopsy-proven evidence of LN.
Opportunistic infections
In this cohort, Candida, Listeria, Bacillus cereus,
Cryptococcus and CMV were implicated agents.
Most of these pathogens are predominantly intra-
cellular organisms. While this is likely a reflection
of the degree of immunosuppression, inhibited Th1
T-cell responses may have had a contributory
effect.28
Atypical infections, such as CMV and
Cryptococcus, are challenging to diagnose and
treat.34,35 Cryptococcus most commonly affects
the central nervous system, with steroid therapy
being a major risk factor for its development.35
Other invasive fungal infections, including organ-
isms such as Candida and Aspergillus, appear to be
more common in patients with nephritis.36 Given
the atypical nature of these infections, it is impera-
tive that they are considered, along with atypical
sites for localization. Uncommon presentations of
rare infective agents should also be considered.
Bacillus cereus (noted as a cause of death in this
review) is normally associated with indwelling lines
and neutropenia, but has been reported in a SLE
patient with neither of these risk factors.37
Disease activity
Our data suggest that the combination of disease
flare and infection may be more common than gen-
erally recognized. Elevated SLEDAI scores corre-
late with more frequent infections, and worse
outcomes.36,38 Hypocomplementemia, which com-
monly accompanies SLE flares, is a predictor for
infection, independent of immunosuppressive
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therapies.38 Conversely, infection may influence
disease activity, with studies showing that some
infectious agents (notably CMV) can precipitate
SLE flares.39,40 Disease activity scores, such as
SLEDAI-2K, have a role in predicting a heightened
risk of flare during pregnancy.41 Pregnancy-specific
scores, such as the Lupus Activity Index in
Pregnancy,42 are validated for their abilities to pre-
dict flares,43 but are used for research purposes, not
in clinical practice.
Histological subclass
A previous meta-analysis of SLE pregnancy out-
comes did not find a statistically significant link
between histological class and adverse pregnancy
outcomes due to limited data availability.6 In this
review, not all cases reported histological subclass,
nor were there sufficient cases to establish a com-
parator group. As such, it is not possible to com-
ment on the potential relationship between the
histological class of LN and maternal mortality
outcomes. Importantly, renal biopsy is rarely per-
formed close to or during pregnancy. This avenue
may merit further investigation, as histological sub-
type and disease activity may be important con-
founding variables for mortality.
Maternal complications
Thrombo-embolic disease was the cause of death in
two patients included in this review. Low molecular
weight heparin therapy is used for patients with
aPL or APS.44 However not only lupus,45,46 but
pregnancy as well, may contribute to a pro-throm-
botic state (potentially due to endothelial activa-
tion), even in patients without aPL and/or renal
disease at the point of conception. In addition, pro-
teinuria may result in urinary loss of anti-thrombin
III, further increasing thrombotic risk. Future stud-
ies are needed to provide guidance as to the optimal
modalities and timing of anticoagulation in preg-
nant SLE patients.
Of note, there were no reported deaths related to
preeclampsia/eclampsia. One death was associated
with HELLP syndrome, believed to be a severe var-
iant of preeclampsia associated with Hemolysis,
Elevated Liver enzymes, and Low Platelets. While
SLE does not increase the risk of this condition to
the same extent as previous preeclampsia (OR 7.19)
or primary APS (OR 9.72), it is a recognized risk
factor.47 Preeclampsia may also be associated with
more severe histological classes of lupus nephritis.48
Recent work suggests mutations in the genes
coding for complement regulatory proteins may
be associated with preeclampsia in SLE and/or
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aPL patients. Eclampsia and preeclampsia should
remain concerns, and differentiating preeclampsia
from a disease flare is difficult, as both cause
increasing proteinuria, rising blood pressure, and
thrombocytopenia.50 A LN flare is more likely
when there is active urinary sediment, low comple-
ment levels, increased anti-DNA antibodies, and
extra-renal lupus manifestations. Elevated uric
acid levels make the diagnosis of preeclampsia
more likely.51
Finally, studies suggest that an abnormal second
trimester Doppler flow wave in the maternal uterine
artery help predict development of preeclampsia in
this population, but this would not exclude the risk
of flares. 51, 52
Conclusion
This review of pregnancies complicated by LN
highlights the significant risk of maternal mortality
in these patients. Most of the reported deaths
occurred after delivery, likely reflecting a proactive
approach in the management of patients with
severe disease who, despite pregnancy termination,
further progress and succumb to SLE- and
LN-related complications.23 In addition, pregnancy
termination may allow for more aggressive immu-
nosuppression which, in turn, may contribute to
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
major limitation of this study is the lack of a con-
trol group of pregnancies not resulting in death in
patients with SLE or LN, which would allow for
comparative analyses of risk factors for maternal
death. Despite this limitation, our findings provide
support for the current recommendations calling
for avoidance of pregnancy until all manifestations
of SLE are quiescent, with the patient on stable
immunosuppression. This may decrease rates of
complications, including maternal death, due to
disease activity. Additionally, use of aggressive
immunosuppression might be reduced, also lower-
ing rates of opportunistic infections and maternal
death. As a corollary, physicians must be vigilant
when using immunosuppression in pregnancy and
may consider focusing on lymphocyte count and
T-cell subsets to guide therapy. The potential for
a disease flare to lead to a severe infective episode
must also be considered. Overall, a balanced (i.e.
risk of infection versus treatment benefit) approach
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to immunosuppression is a vital tool in managing
these patients.
Other approaches should be considered and
there may be a role for preventive strategies.
Insufficient data exist to comment on medical pro-
phylaxis for viral/fungal infections, but this area
merits further study. Pre-conception vaccination
may be another consideration, as could measure-
ments of antibody levels against encapsulated
organisms. An inactivated Varicella zoster vaccine
has been evaluated in patients undergoing autolo-
gous stem cell transplantation. This reduced herpes
zoster episodes over the subsequent 12 months,53
and remains an interesting avenue for future ther-
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
entertained. This review emphasizes the importance
of pre-pregnancy counseling and the close monitor-
ing of affected pregnancies. The paucity of litera-
ture on such serious outcomes suggests that a
patient registry would be the most effective way
to improve knowledge and outcomes.
Funding
This research received no specific grant from
any funding agency in the public, commercial, or
not-for-profit sectors.
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