Lupus (2017) 0, 1–9

journals.sagepub.com/home/lup

REVIEW

Systemic lupus erythematosus and risk of preterm birth:

a systematic review and meta-analysis of observational studies
S Wei*, K Lai*, Z Yang and K Zeng
Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China

We performed a meta-analysis to identify the association between systemic lupus erythematosus

(SLE) and preterm birth. In this study, we studied the effects of SLE, SLE disease activity, a
history of nephritis and active nephritis on preterm birth. Searches were conducted before 20
May 2016 of PubMed, Embase, Medline and Cochrane Library of literature and article refer-
ence lists. Eleven observational case–control studies and thirteen cohort studies met the inclu-
sion criteria. The pooled relative risk (RR) for the risk of preterm birth in SLE patients versus
controls was 2.05 (95% confidence interval (CI): 1.72–3.32); for active SLE patients versus
inactive was 2.98 (95% CI: 2.32–3.83); for SLE patients with a history of lupus nephritis
versus those without nephritis it was 1.62 (95% CI: 1.35–1.95); and for SLE patients with
active nephritis versus those with quiescent nephritis it was 1.78 (95% CI: 1.17–2.70). In sum-
mary, this study identified a significant association in the above results. This association was
more significant in active SLE patients versus inactive. With respect to SLE itself, active inflam-
mation (such as disease activity) may be more hazardous for the management of the pregnancy.
This suggests that it is essential to control disease activity in order to achieve a better outcome of
SLE pregnancy. Lupus (2017) 0, 1–9.

Key words: Systemic lupus erythematosus; lupus nephritis; disease activity; preterm birth

Introduction are still at high risk for perinatal complications,

including preterm birth, spontaneous abortion,
Systemic lupus erythematosus (SLE) is a systemic intrauterine growth retardation (IUGR) and even
autoimmune disease that is distinguished by its stillbirth or neonatal death. Among the perinatal
multi-organ involvement, characteristic inflamma- complications, preterm birth, which indicates
tory lesions of the skin, joints, kidneys and central birth before 37 weeks of gestational age, is of
nervous system. This chronic disease primarily major interest being a leading cause of perinatal
affects women of childbearing age; therefore, preg- morbidity.1 A multicentre prospective cohort con-
nancy is always a topic of major interest. In earlier cerning adverse pregnancy outcomes in patients
times, it was reported that SLE could become more with SLE showed that adverse pregnancy outcomes
aggressive during pregnancy, putting both the occurred in 19.0%, and preterm birth was 9% if
mother and the foetus at high risk, and so preg- first-trimester pregnancy losses were precluded.2
nancy was discouraged in SLE patients. With the Systemic inflammation and poor placental develop-
passage of time the management of the disease has ment are possible causes of preterm birth. There are
greatly improved. To some extent, as long as timing multiple studies directed at elucidating the impact
and management of gestation are closely planned in of SLE on pregnancy outcomes, and a recent article
consultation with doctors, SLE patients can achieve in the literature in respect of patients with SLE and
a successful pregnancy. However, these pregnancies lupus nephritis showed that the preterm birth rate
was considerably higher at 39.4% (95% confidence
interval (CI), 32.4%–46.4%) among all live births.3
*S Wei and K Lai have contributed equally to this work. However, the limitations are: the impact of SLE on
Correspondence to: K Zeng, Department of Dermatology, Nanfang preterm birth is controversial; there is lack of com-
Hospital, Southern Medical University, Guangzhou, Guangdong,
510515, PR China.
prehensive reporting on the association between
Email: npfkzk@163.com preterm birth and SLE patients; and no compre-
Received 20 June 2016; accepted 5 December 2016 hensive studies have provided the degree of risk –
! The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203316686704
 Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
2
for example, twice or fourfold. In this study, we
perform a systematic review and meta-analysis by
combining information from relevant studies to (1)
comprehensively study the association of SLE and
preterm birth and (2) study the effects of SLE, SLE
disease activity, a history of lupus nephritis and
active nephritis on preterm birth.
Methods
Search strategy
Two independent investigators searched PubMed,
Embase, Medline and Cochrane Library for litera-
ture before 20 May 2016 using the combinations of
terms ‘‘SLE’’ OR ‘‘lupus nephritis’’ OR ‘‘lupus’’ and
‘‘pregnancy outcome’’ OR ‘‘prenatal outcome’’ OR
‘‘perinatal outcome’’ OR ‘‘preterm’’ OR ‘‘prema-
ture’’. We sifted through potentially relevant articles,
firstly by title and abstract, and then we retrieved the
full text of articles for detailed review. Furthermore,
we scanned the reference lists of the literature that
met the inclusion criteria in our study, and searched
for those articles in the Web of Knowledge and
Google Scholar to obtain additional studies.
Inclusion and exclusion criteria
Selection criteria were determined before data col-
lection. Articles were included if they were on
observational studies and reported a quantitative
association between SLE and the risk of preterm
birth among pregnant women versus a healthy con-
trol group, active SLE and the risk of preterm birth
versus inactive, SLE patients with a history of lupus
nephritis versus without nephritis, SLE patients
with active nephritis versus quiescent nephritis.
Reviews, editorials, guidelines, case reports,
abstracts and meetings were excluded. Whenever
disagreement in study selection occurred, it was
resolved by discussion between the two main inves-
tigators until a consensus was reached. When we
identified patients that had been included in mul-
tiple papers, the analysis was limited to the study
with the highest quality (the Science Citation Index
(SCI) was highest or the citations of the literature
were highest) in order to avoid duplications.
Data extraction
A form designed a priori was used to extract the
information from the included studies. Two inde-
pendent investigators performed the data extrac-
tion. For each study, the following data were
extracted: first author name, publication year,
Lupus
study design, country, and diagnostic criteria of
SLE, SLE disease activity, active nephritis, a his-
tory of lupus nephritis and controls. When a pub-
lication reported results on a different subgroup
according to SLE, such as SLE patients with
active nephritis versus quiescent nephritis, each
subgroup was considered as a separate study in
this meta-analysis.
Data analysis
In this meta-analysis, the heterogeneity among the
studies was tested by a 2-based Q test or I2 statis-
tic.4 When p < 0.05 or I2 > 50%, the heterogeneity
was considered significant, in which case the
DerSimonian Laird random-effects model was
used to calculate the pooled relative risk (RR).
Otherwise the fixed-effects model was used.
Funnel plots were created to assess publication
bias by plotting the natural logarithm of RR
against its standard error. Begg’s test was also
used to evaluate publication bias. All tests are
two-tailed, with p < 0.05 considered statistically sig-
nificant. Subgroup analysis was conducted accord-
ing to the number of pregnancies if available. All
statistical analyses were conducted using Stata ver-
sion 10.0 (Stata Corp).
Results
Characteristics of the subjects in the selected studies
Our study searched 2475 articles, of which 2363
were deemed unsuitable by title and/or abstract
alone. The remaining 112 were independently
assessed, and 24 fulfilled study entry criteria
(Figure 1). There were eleven observational case–
control studies and thirteen cohort studies. Three
studies were prospective, twenty were retrospective,
and one was both prospective and retrospective.
The 24 studies included a total of 2448 SLE
patients and 3753 pregnancies, 870 controls and
2145 pregnancies. These studies were performed
in Asia (n ¼ 10), Northern America (n ¼ 6),
Europe (n ¼ 6), one in Turkey (Asia and Europe)
and one in Africa and Asia (Table 1).5–28
The 1982 American College of Rheumatology
(ACR) criteria for the diagnosis of SLE (15/24)
were the most commonly used criteria,29 six in the
literature used a principal diagnosis of SLE (ICD-9-
CM 710.0 or ICD-10-CA M32), but others were also
used (Table 1). The definitions of disease activity
varied, a majority (6/9) used the SLE disease activity
index (SLEDAI),32 and a few (4/9) used organ

Figure 1 Flow diagram of the selection of the studies.
involvement and laboratory abnormalities (Table 1).
The definitions of SLE with a history of lupus neph-
ritis was mostly (10/11) defined as those patients
with clinical, laboratory and/or histological evidence
of lupus nephritis; one did not mention the diagnos-
tic criteria (Table 1). Active nephritis was defined:
2/4 used the presence of proteinuria >500 mg in 24
hours and/or having active urine sediment at the
time of conception; 1/4 used serum creatinine
(>3 mg/dl) and a glomerular filtration rate <65 ml/
min/1.73 m2; and one did not mention the diagnostic
criteria (Table 1). Quiescent nephritis was defined as
history of lupus nephritis but not meeting the stand-
ard of active nephritis. The controls were defined as
general population (3/6), or health controls without
Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
3
adverse pregnancy outcome or other diseases
(Table 1). Antiphospholipid antibodies (aPL)(þ)
was defined as an increased aPL, while aPL()
was defined as normal.
Publication bias
Funnel plots offer a visual sense of the relationship
between effect size and precision for publication
bias amongst the studies in the meta-analysis.
Figure 2 shows the funnel plots evaluating the rela-
tionship of preterm birth and patients with SLE. In
our study, the shape of each funnel plot seemed
symmetrical except for active nephritis versus qui-
escent nephritis. The results of Begg’s test suggested
no evidence for publication bias (Table 2).
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 Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
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Table 1 Characteristics of studies included in the systematic review and meta-analysis

SLE (n) Non-SLE (n) SLE
(patients/ (patients/ disease Active
Study Region pregnancies) pregnancies) SLE activity nephritis Nephritis Controls

Al and Khalil.5 Retrospective cohort Saudi Arabia 319/396 NA 1 NA NM NM NA

Barnado et al.6 Retrospective case–control USA 220/577 217/694 1 NA NA NA General population
Bramham et al.7 Retrospective cohort UK 83/107 NA 4 NA NA 1 NA
Carmona et al.8 Prospective cohort Spain 46/60 NA 1 NA NA 1 NA
Chen et al.9 Retrospective cohort China 80/83 NA 2 2 NA NA NA
Clowse et al.10 Prospective cohort USA 203/267 NA 1,2 1 NA NA NA
Georgiou et al.11 Prospective case–control Greece 47/59 57/59 1 1 NA NA Healthy controls
Gimovsky et al.12 Retrospective (before 1980) USA 39/108 NA 3 NA NA 1 NA
and prospective (after 1980) cohort
Hamed et al.13 Retrospective case–control Egypt, 67/67 67/67 4 NA NA NA Healthy conrols without
Saudi-Arabia adverse obstetrical
outcome
Julkunen et al.14 Retrospective case–control Finland 112/242 192/417 1 NA NA NA General population
experienced only
spontaneous abortions
Ko et al.15 Retrospective cohort Korea 143/183 NA 1 2 NA 1 NA
Koh et al.16 Retrospective case–control Korea 132/183 NA 1,2 NA NA 1 NA
Kwok et al.17 Retrospective cohort China 39/55 NA 1 NA NA 1 NA
Liu et al.18 Retrospective case–control China 105/111 NA 4 2 NA NA NA
Madazli et al.19 Retrospective cohort Turkey 65/65 NA 4 1 NA 1 NA
Molokhiaet al.20 Retrospective case–control Spain 122/352 203/667 1 NA NA NA General population
Rahman et al.21 Retrospective case–control UK 24/55 NA 1 NA 1 1 NA
Saavedra et al.22 Retrospective cohort Mexico 92/95 NA 1 NA NA 1 NA
Song et al.23 Retrospective cohort China 97/97 NA 1 1,2 NA NA NA
Wagner et al.24 Retrospective cohort USA 58/90 NA 4 NA 1 1 NA
Wang et al.25 Retrospective case–control China 66/66 NA 4 2 NA NA NA
Yan Yuen et al.26 Retrospective case–control Canada 108/248 134/241 1 NA NA NA Healthy controls with
non-inflammatory
musculoskeletal disorders
Yang et al.27 Retrospective case–control China 155/155 NA 2 2 NA NA NA
Zhang et al.28 Retrospective cohort Japan 26/32 NA 1 NA 1 1 NA

NA: not available; NM: not mentioned.

SLE diagnostic criteria: 1 – United States College of Rheumatology (ACR) 1982 criteria;29 2 – updated ACR criteria;30 3 – American
Rheumatology Association;31 4 – a principal diagnosis of systemic lupus erythematosus (ICD-9-CM 710.0; OR ICD-10-CA M32);
SLE disease activity: 1 – organ involvement and laboratory abnormalities, such as the presence of arthritis, typical skin lesions such as malar rash,
vasculitis, serositis, psychosis or any other neurological manifestation that may be attributed to SLE, leucopenia (4000 mm3), Coombs-positive
autoimmune haemolytic anaemia, or thrombocytopenia (<100,000 mm3) not associated with antiphospholipid antibodies; 2 – systemic lupus
erythematosus disease activity index-SLEDAI.32
Active nephritis: 1 – the presence of proteinuria >500 mg in 24 hours and/or having an active urine sediment, with or without an elevation in serum
creatinine, at the time of conception; 2 – serum creatinine (>3 mg/dl) and a glomerular filtration rate of <65 ml/min/1.73 m2.
A history of lupus nephritis: 1 – clinical, laboratory and/or histologic evidence of lupus nephritis before conception;

Quantitative synthesis and heterogeneity analysis active SLE pregnancies (n ¼ 382) was 2.98
The pooled RR of preterm birth in SLE patients versus
(95% CI: 2.32–3.83), compared to inactive
controls (n ¼ 684), with no statistically significant het-
For this study, six studies were included.6,11,13,14,20,26 erogeneity across studies (I2 ¼ 41.30%, p ¼ 0.09),
The pooled RR in SLE pregnancies (n ¼ 1545) was the fixed-effects model is reported (Figures 2(b)
2.05 (95% CI: 1.72–3.32), compared to controls and 3(b)). Subgroup analysis was conducted
(n ¼ 2145), with statistical heterogeneity across stu- according to the number of pregnancies.
dies (I2 ¼ 66.50%, p ¼ 0.01), the random-effects The pooled RR in active SLE pregnancies
model is reported (Figures 2(a) and 3(a)). was 4.65 (95% CI: 2.71–7.98), compared to
inactive in subgroup of singleton, 2.43 (95% CI:
The pooled RR of preterm birth in active SLE patients 1.85–3.20) in multiple pregnancies. In our subgroup
versus inactive analysis, we found that singleton conferred a
For this study, nine studies were high RR to active SLE patients versus inactive
included.9–11,15,18,19,23,25,27 The pooled RR in (Figure 4).
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 Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
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Figure 2 Funnel plot of the association between SLE and preterm birth: (a) SLE patients versus controls; (b) active SLE patients
versus inactive; (c) SLE patients with a history of lupus nephritis versus without nephritis; (d) SLE patients with active nephritis
versus quiescent nephritis.

Table 2 The data of the studies

Study RR and 95% CI I2 (%) p Begg’s

SLE patients versus controls 2.05 (1.27,3.32) 66.5 0.01 0.71

Active SLE versus inactive 2.98 (2.32,3.83) 41.3 0.09 1.00
SLE with a history of lupus nephritis versus without nephritis 1.62 (1.35,1.95) 42.1 0.07 0.44
Active nephritis versus quiescent nephritis 1.78 (1.17,2.70) 8.80 0.35 0.09

RR: risk ratio; CI: confidence interval; SLE: systemic lupus erythematosus.

The pooled RR of preterm birth in SLE patients with a
history of lupus nephritis versus without nephritis
For this study, eleven studies were
included.5,7,8,12,15–17,19,22,24,28 The pooled RR in
SLE pregnancies with a history of lupus nephritis
(n ¼ 530) was 1.62 (95% CI: 1.35–1.95), compared
to SLE pregnancies without nephritis (n ¼ 1020),
with no statistically significant heterogeneity
across studies (I2 ¼ 42.10%, p ¼ 0.07), the fixed-
effects model is reported (Figures 2(c) and 3(c)).
The pooled RR of preterm birth in SLE patients with
active nephritis versus quiescent nephritis
For this study, four studies were included.5,21,24,28
The pooled RR in SLE pregnancies with
active nephritis (n ¼ 97) was 1.78 (95% CI:
1.17–2.70), compared to SLE pregnancies
with quiescent nephritis (n ¼ 188), with no
statistically significant heterogeneity (I2 ¼ 8.80%,
p ¼ 0.35), the fixed-effects model is reported
(Figures 2(d) and 3(d)).

Lupus
 Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
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Figure 3 Forest plots of the association between SLE and preterm birth: (a) SLE patients versus controls; (b) active SLE patients
versus inactive; (c) SLE patients with a history of lupus nephritis versus without nephritis; (d) SLE patients with active nephritis
versus quiescent nephritis.

Figure 4 Forest plot of subgroup analysis for active SLE versus inactive.

Lupus

Discussion
This meta-analysis provided an overview of published
evidence on the association between SLE and preterm
birth. Overall, there were 2.98-fold and a 2.05-fold
increases in the risk of preterm birth in active SLE
versus inactive SLE and in SLE patients versus con-
trols, respectively; a 1.00 to 2.00-fold increase in SLE
patients with active nephritis versus quiescent neph-
ritis, a history of lupus nephritis versus without neph-
ritis. According to the above, disease activity may be a
significant risk for preterm birth, compared to the
other studies included. Disease activity at the time
of conception is a strong predictor of continued activ-
ity during pregnancy. Therefore, in order to achieve a
better outcome for SLE pregnancy, it is essential to
control disease activity before conception. Though a
study showed SLE hospitalization had an increased
risk of preterm birth compared to without hospital-
ization, this may be the bias of a single research or a
confounding factor, for example age, disease activity
or parity.33
Preterm birth, even a few weeks prior to term, is
associated with delayed development and lung
immaturity of the newborn, as well as poorer long-
term outcomes for children.34 The main reasons that
SLE patients tend to experience more preterm births
may be the following. (1) Activation of the maternal
or foetal hypothalamus pituitary axis leads to a rise
in placental corticotropin-releasing hormone, and
prompts labour through cortisol and prostaglandin
production.35 (2) Inflammation from local and sys-
temic infections can induce labour through cytokine,
prostaglandin, elevated anti dsDNA and hypocom-
plementemia.36 (3) Levels of oestrogen have been
used for decades as a marker of placental health
and correlate with gestational age at delivery;37,38
women with SLE have been shown to have a
lower oestradiol level during pregnancy, on average,
compared with a healthy population,39 and one
study showed low oestradiol as a potential marker
for preterm delivery in women with mild to moder-
ate disease activity.40 (4) Finally, oral prednisone
may be associated with preterm birth, independently
of the inflammation that it is treating.41,42 In conclu-
sion, clinical or subclinical inflammation, presence
of autoantibody, hormonal dysfunction, immune
alterations of lupus and the drugs used for control-
ling disease activity contribute to preterm birth.
When there is disease activity at conception, the clin-
ical inflammation, autoantibody, immune alter-
ations of lupus and drugs used are much higher in
quantity, which leads to more preterm
births.10,15,18,23,25,27,43,44
Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
7
Patients with elevated levels of aPL often experi-
ence adverse pregnancy outcomes comprising
recurrent spontaneous abortions, intrauterine
growth retardation and pre-eclampsia, suggesting
that these antibodies may influence embryonic
implantation and induce thrombosis of the utero-
placental vasculature.45 There were many studies
that researched the pregnancy complications of
aPL in pregnancies without SLE. The studies
were relatively few in SLE patients, especially for
preterm birth. We also tried to study the pooled
RR of preterm birth in aPL(þ) pregnancies with
SLE versus aPL(). In this study, four studies
were included5,13,15,19 and one was excluded
because of abnormal aPL including both low and
high titres.6 The pooled RR in aPL(þ) SLE preg-
nancies (n ¼ 201) was 1.38 (95% CI: 0.76–2.52),
compared to aPL() (n ¼ 336), with statistically
significant heterogeneity across studies
(I2 ¼ 74.50%, p ¼ 0.01), the random effects model
is reported (Figure 5). There was no statistically
significant difference in aPL(þ) SLE pregnancies
versus aPL(). The reason might be that the limit
of studies and pregnancies.
In our study, we found a 2.98-fold increase in the
risk of preterm birth in active SLE versus inactive
SLE, which was especially significant. The reason
may be the active inflammation impacting the
maternal endocrine system, for example cortisol
and prostaglandin, and humoral immunity on the
preterm birth. Also the disease activity needs
more prednisone to control disease progression,
which may be associated with preterm birth.
Steroids are almost always used in all the studies
included, and a few showed in the subgroup, but we
could not analyse the individual effect. SLE
patients with active nephritis have an increased
risk of 78% compared to those with quiescent
nephritis. Active lupus nephritis seemed to increase
the risk for premature birth, similar to previous
studies.3,28 Our findings provide further support
for the current recommendations calling for avoid-
ance of pregnancy until all manifestations of neph-
ritis are quiescent. Additionally, a history of
nephritis, defined as existing before conception,
including active and quiescent nephritis, was also
associated with higher rates of preterm birth.
Several limitations of this meta-analysis should
be noted. Firstly, cohort studies and case–control
studies may be susceptible to detection bias, recall
bias and selection bias. However, it may be impos-
sible to design a randomized controlled trial, and
there is no such literature included in this study.
Second, as the studies included in this meta-analysis
were all observational studies, the positive
Lupus
 Systemic lupus erythematosus and risk of preterm birth
S Wei et al.
8
Figure 5 Forest plot of the association between SLE and preterm birth in aPL(þ) pregnancies with SLE versus aPL().
association in our studies may have influences from
unmeasured factors in some way. Third, none of the
studies included provided the degree of drug load
and risk of preterm birth. Therefore, we were
unable to conduct a dose–response analysis to
assess the relationship more precisely. This applies
also to the renal biopsy histological subtype and
the degree of proteinuria. Fourth, there was some
evidence of an increased risk of preterm birth
in SLE pregnancies conceived after a diagnosis
of maternal SLE, compared to those
conceived before pregnancy.12,20 However, we did
not consider this confounding factor due to the lim-
ited literature.
Despite these limitations, this meta-analysis also
demonstrated some advantages. First, no publica-
tion bias was detected, indicating that all of the
pooled results should be unbiased. Second, this
meta-analysis included a total of 2448 SLE patients
and 3753 pregnancies, 870 controls and 2145 preg-
nancies, from fourteen countries, between 1984 and
2016, which decreases the selection bias. Third, we
comprehensively studied the influence of SLE, dis-
ease activity and a history of lupus nephritis on
preterm birth. Fourth, by performing a meta-ana-
lysis, we had more power to detect existing associ-
ations than the individual studies alone, especially
given the degree of risk.
In summary, we found that pregnant women with
SLE remained at high risk of preterm birth. This
study revealed 2.98-fold and 2.05-fold increases in
the risk of preterm birth in active SLE versus inactive
SLE and in SLE patients versus controls, respect-
ively; a 1.00 to 2.00-fold increase in SLE patients
with active nephritis versus quiescent nephritis and
a history of lupus nephritis versus without nephritis.
The risk was more significant especially in active SLE
Lupus
versus inactive. With respect to SLE itself, the active
inflammation (such as disease activity) may be more
dangerous for pregnant women with SLE. This sug-
gests that it is essential to control disease activity in
order to decrease preterm birth in SLE pregnant
women. However, further research is needed into
the association between inflammation and preterm
birth in SLE pregnant women.
Author Contributions
KZ conceived and designed the study. ZHY, SSW
and KL collected the data, SSW, ZHY and KL did
the analysis. SSW and KL drafted the manuscript,
KZ and KL revised the manuscript, and all authors
provided critical review and approval of the final
version.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
Funding
The author(s) disclosed receipt of the following
financial support for the research, authorship,
and/or publication of this article: This work was
supported by the National Natural Science
Foundation of China (Grant Number 81301371),
the Guangdong Natural Science Foundation
(Grant Number 2014A030313350).

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