Hypertension Research

103
In Pregnancy K. Takahashi et al.

ORIGINAL ARTICLE Reprint request to:

Kazuya Mimura, M.D.,

Disease flare-ups and obstetric Department of Obstetrics and

Gynecology, Osaka University
Graduate School of Medicine, 2-2
outcomes in pregnant women with Yamadaoka, Suita, Osaka, 565-
0871, Japan.

systemic lupus erythematosus E-mail: kazuya.med_ob-gyne@

hotmail.co.jp

Key words:
Kei Takahashi, Kazuya Mimura, Takeshi Kanagawa, corticosteroid, flare-up,
preeclampsia, pregnancy,
Yukiko Kinugasa-Taniguchi, Masayuki Endo, Shinya Matsuzaki, systemic lupus erythematosus
Keiichi Kumasawa, Kae Hashimoto, Takuji Tomimatsu,
Received: August 25, 2013
Tadashi Kimura Revised: October 15, 2013
Accepted: October 22, 2013
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine

Aim: The purpose of this study was to review the maternal and fetal outcomes in pregnant women with systemic lupus
erythematosus (SLE), and to evaluate the prognostic risk factors that may contribute to obstetric outcomes or SLE flare-
ups.
Methods: We evaluated 100 births in 97 SLE patients who were seen at Osaka University from 1995 to 2013. Main
outcome measures included obstetric outcomes and SLE flare-ups.
Results: The mean patient age was 30.7 4.6 years, and the nulliparity rate was 62.8%. Corticosteroids were taken by
75.3% of the patients, and 48.5% were on a dosage of 7.5 mg /day. Disease flare-up and preeclampsia occurred in
17.5% and 11.3% of the patients, respectively. Seven SLE flare-ups (41.2%) occurred after delivery. Fourteen of the
patients with a flare-up were taking high dose corticosteroids ( 7.5 mg /day) and showed significantly poorer obstetric
outcomes compared to patients taking low dose corticosteroids ( < 7.5 mg /day) (P = 0.0021).
Conclusions: A multidisciplinary approach in the care of pregnant women with SLE is important for good maternal and
fetal outcomes. Furthermore, a high daily dosage of corticosteroids may be a prognostic risk factor for adverse SLE
flare-ups.

Introduction antibodies, and history of fetal loss are also associated

Systemic lupus erythematosus (SLE) is an autoimmune
connective tissue disorder that affects various organs
including the joints, skin, heart, lungs, nervous system,
and kidneys.1) The disease mainly affects women of
childbearing age. Although SLE patients usually have
normal fertility,2) they have higher maternal and fetal
mortality and morbidity rates. Clowse et al. reported that
maternal morbidity is 20-fold higher in women with SLE
than in those without.3)
Pregnancies in SLE patients are more likely to end
in spontaneous miscarriage, and are more susceptible to
fetal growth restriction, fetal death, preeclampsia, and
preterm delivery.1,3) In addition, neonates may be at a
higher risk of having congenital heart block or neonatal
lupus erythematosus, because these conditions are
related to the presence of anti-Ro/SSA and anti-La/SSB
antibodies in the mother.4) Hypocomplementemia, active
lupus, renal involvement, existence of antiphospholipid
with an increased risk of obstetric complications.3 5)
The association between SLE flare-up and pregnancy
has been a subject of debate. Some studies have shown
an increase in SLE flare-ups during pregnancy and the
postpartum period, whereas other studies have not. The
risk of a flare-up reportedly increases if SLE is active
during the 612 months period prior to conception.6)
Therefore, clinicians often advise patients to plan
pregnancy when SLE is in remission.
The present study aimed to clarify the influence of
pregnancy on SLE course by investigating maternal and
fetal outcomes in pregnancies in patients with SLE and
evaluating the prognostic risk factors that may affect
obstetrical outcomes and SLE flare-ups.
Materials and methods
We retrospectively reviewed pregnancy outcomes in 97
women with SLE (including three twin pregnancies) in

Hypertension Research in Pregnancy 2013 Japan Society for the Study of Hypertension in Pregnancy Hypertens Res Pregnancy 2013; 1: 103107 103
Flare-ups and Obstetric outcomes in SLE pregnancies

our hospital between January 1995 and June 2013. All Table 1. Demographic characteristics of patients
patients met at least four of the 1997 Revised American (n = 97)
College of Rheumatology criteria for SLE. Characteristics
Baseline maternal characteristics included age,
nulliparity rate, past obstetric history, SLE duration, Maternal age (y) 30.7 4.6
previous renal disease, medications, and the presence of Nulliparity 61 (62.8%)
antiphospholipid syndrome. Demographic data, disease History of spontaneous abortion 14 (14.4%)
History of IUFD ( > 12 wks) 2 (2%)
activity, obstetric complications during pregnancy and
Duration of disease (y) 8.3 0.6
puerperium, and medication given during pregnancy were
Previous renal disease 30 (30.9%)
recorded. Laboratory data included complete blood count, History of positive dsDNA 51 (52.6%)
liver function tests, serum creatinine levels, urinalysis, History of positive SSA/SSB 46 (47.4%)/5 (5.2%)
and levels of lupus anticoagulant, antinuclear antibodies, Diagnosis of APS 7 (7.2%)
anti-SSA/SSB antibodies, anticardiolipin antibodies, and Positive lupus anticoagulant 14 (14.4%)
serum complement levels. Levels of lupus anticoagulant Positive anticardiolipin 11 (11.3%)
were measured with dilute Russells viper venom time, Medical therapy
antinuclear antibodies with radioimmuno-assay, and the Corticosteroids 7.5 mg /day 47 (48.5%)
other antibodies with enzyme linked immunosorbent Corticosteroids < 7.5 mg /day 26 (26.8%)
assay. Immunosuppressive drugs 5 (5.2%)
Patients were assessed for SLE flare-up using the criteria None 24 (24.7%)
from the Safety of Estrogens in Lupus Erythematosus IUFD, intrauterine fetal death; APS, antiphospholipid
National Assessment (SELENA) trial, which included antibody syndrome.
new or worsened cutaneous disease, nasopharyngeal
ulcers, pleuritis, pericarditis, arthritis, fever attributable
to SLE, a change in SLE Disease Activity Index of > 3 Results
points, the addition of a nonsteroidal anti-inflammatory
drug or hydroxychloroquine, or an increase in prednisone Patient characteristics
dosage of < 0.5 mg/kg/day. A severe flare-up was Clinical characteristics of the patients are summarized
defined as new or worsened central nervous system in Table 1. The mean maternal age was 30.7 4.6 years,
disease; vasculitis; nephritis; myositis; hemolytic anemia; and the nulliparity rate was 62.8%. Renal involvement
platelet count < 60,000/l; the necessity of addition (lupus nephritis) was present in 30 patients (30.9%).
of cyclophosphamide, azathioprine, or methotrexate; Lupus anticoagulant and anticardiolipin antibodies
hospitalization for SLE-related manifestations; or an were positive in 14.4% and 11.3% of the patients,
increase in prednisone dosage of > 0.5 mg/kg/day. respectively. Of these, seven (7.2%) fulfilled the criteria
Fetal growth restriction, premature birth, preeclampsia, for antiphospholipid syndrome.
hemolysis, elevated liver enzymes, low platelets (HELLP The details of the pregnant women who received
syndrome), and fetal loss were evaluated. Fetal growth medical therapy are presented in Table 1. The drugs used
restriction was defined as birth weight < 5th percentile included corticosteroids, azathioprine, cyclosporine, and
of the normal growth curve. Preeclampsia was defined methotrexate. Corticosteroids were used in 73 (75.3%)
as hypertension (systolic blood pressure > 140 mmHg patients, and 47 (48.5%) patients were on a dosage of
or diastolic blood pressure > 90 mmHg on two separate 7.5 mg/day. The seven patients who met the criteria
occasions) and proteinuria ( > 300 mg/24 h) arising de for antiphospholipid syndrome were treated with
novo after the 20th week of pregnancy.7) Fetal loss was anticoagulants along with corticosteroids. Six (6.2%)
defined as fetal death after 22 weeks of gestation and patients were undergoing steroid pulse therapy during
premature birth (preterm) as live birth before 37 weeks their pregnancy or after delivery and were considered to
of gestation. Diagnosis of antiphospholipid syndrome have had active disease.
was established according to the updated Sapporo
classification.8) All newborns were examined for neonatal SLE pregnancy-associated flare-ups
lupus erythematosus and atrioventricular block by a Obstetrical and perinatal outcomes of the patients are
pediatrician. presented in Tables 2 and 3, respectively. Seventeen SLE
Variables measured in interval scales were described flare-ups were documented, of which seven (41.2%) were
as mean standard deviation, and statistical comparisons severe. Flare-ups occurred mainly during the postpartum
between groups were performed using the Chi-squared period (41.2%) and the third trimester (29.4%), as shown
test with GraphPad Prism (GraphPad Software, San Diego, in Table 3. Flare-ups were significantly more frequent in
CA). Significant differences were defined as P < 0.05. the 14 patients on high dose corticosteroids ( 7.5 mg/

104 Hypertens Res Pregnancy 2013; 1: 103107

 K. Takahashi et al.

Table 2. Maternal outcomes

Corticosteroids Corticosteroids
Outcome Total
( 7.5 mg /day) ( < 7.5 mg /day)
Onset during pregnancy 4 (4.1%)
Flare-up during pregnancy 17 (17.5%) 14/47 (29.2%) 3/50 (6%)
Mild to moderate 10 (10.3%) 8 2
Severe 7 (7.2%) 6 1
Preeclampsia 11 (11.3%) 6/47 (12.8%) 5/50 (10%)
HELLP syndrome 1 (1.0%)
HELLP, hemolysis, elevated liver enzyme levels and a low platelet count.

Table 3. Distribution of 17 flare-ups during and Table 4. Fetal outcomes (n = 100)

after pregnancy Outcome No. patients (%)
Flare-up occurrence No. patients (%) Stillbirth 4 (4%)
1st trimester 2 (11.8%) Premature birth 5 (5%)
2nd trimester 3 (17.6%) <37 weeks of generation 21 (21%)
3rd trimester 5 (29.4%) 3237 weeks 15 (15%)
Puerperium 7 (41.2%) 2832 weeks 5 (5%)
<28 weeks 1 (1%)
Birth weight (g) 2,498 554
day) compared to those on < 7.5 mg/day (29.2% vs. 6%, Fetal growth restriction 21
P = 0.0021). Previous renal disease was present in eight Caesarean section 24 (24.7%)
of the 17 flare-up cases and appeared to increase the risk Atrioventricular block 0
of disease flare-up, albeit not significantly (P = 0.25). No Neonatal lupus 3 (3%)
significant association was confirmed between elevated
autoantibodies and any of the adverse maternal outcomes.
Discussion
Obstetrical complications and perinatal outcomes
Eleven patients were diagnosed with preeclampsia; five Pregnancy outcomes for SLE patients have improved in
(45.5%) were severe and one (9.0%) was complicated by recent years due to better care during the preconception
HELLP syndrome (Table 2). Six patients were on high and prenatal periods. However, maternal and fetal
dose corticosteroids ( 7.5 mg/day), whereas five were complications still occur, and the impact of maternal SLE
on low doses. There was no significant difference in the on pregnancy outcomes remains unclear. Despite some
occurrence of preeclampsia by corticosteroid dose. evidence suggesting that regulatory T cells affect disease
Mean gestational age at delivery was 37.4 3.5 weeks, flare-ups in SLE patients, the underlying mechanism has
and mean birth weight was 2,498 554 g. Deliveries yet to be characterized. Furthermore, the differentiation
before 37 and 32 gestational weeks occurred in 21% between disease flare-up and preeclampsia is sometimes
and 6% of patients, respectively. Fetal growth restriction difficult. We reviewed obstetric outcomes in patients
was diagnosed in 21 patients (21%), and preeclampsia with SLE and compared our results with those of prior
developed in five (23.8%) of these patients. Stillbirths studies to evaluate potential predictors of poor pregnancy
occurred in three patients (3%) at 15, 19, and 30 weeks outcomes.
of gestation (Table 4). Our study suggested that corticosteroid dosage could
We could detect no remarkable association between be a predictor of disease flare-up, with a threshold of
assumed prognostic risk factors (anticardiolipin antibodies, 7.5 mg/day. According to a previous study, the risk
antiphospholipid syndrome, renal involvement, and of flare-up depends on the level of maternal disease
SLE flare-up during pregnancy; Table 1) and obstetric activity in the 612 months period before conception.6)
outcomes (fetal loss, fetal growth restriction, and/ Kobayashi et al. reported that 75% of pregnant patients
or preeclampsia and preterm birth). Patients with with flare-ups had been in active disease phase at the
preeclampsia had a higher rate of fetal growth restriction onset of pregnancy, whereas 13% had been in remission.9)
(45.5%) than patients with flare-ups (17.6%), although no In addition, the frequency of premature deliveries in
significant difference was found (P = 0.2). patients who had received more than 15 mg/day of
prednisolone was significantly higher compared with

Hypertens Res Pregnancy 2013; 1: 103107 105

Flare-ups and Obstetric outcomes in SLE pregnancies
pregnancies maintained on 015 mg/day prednisolone.
However, no report has investigated the relationship
between corticosteroid dosage and disease flare-up rate.
With respect to the effects of pregnancy on SLE, there
have been conflicting reports regarding SLE flare-ups
during pregnancy. This likely stems from the differences
in the definition of flare-up and the number of patients
included in the studies, as well as the methodological
differences in study designs. SLE flare-ups during
pregnancy have been reported to occur at rates in the
range of 7.768%.1012) Flare-up rates appear to decrease
if pregnancies are postponed until a period of disease
remission.6) The SLE flare-up rate was 17.5% in our
study, which is in agreement with the literature published
recently.10,11) Pregnancy-associated flare-ups are observed
mainly during the second trimester (42%) and in the
year after delivery (25%).10) In our study, SLE flare-ups
occurred mainly during the third trimester (29.4%) and
puerperium (41.2%). Although the rates differ slightly
between these studies, knowing typical flare-up rates
during pregnancy and puerperium may help clinicians
differentiate between a disease flare-up and preeclampsia.
Overall, pregnancies in SLE patients are at greater
risk of spontaneous miscarriage, preeclampsia, fetal
growth restriction, fetal death, and preterm delivery.3,13,14)
Preeclampsia rate was 11.3% in our study, which
falls within the range of 538% reported by previous
reports.3,15,16) There was no significant association
between the occurrence of preeclampsia and dosage of
corticosteroid or previous renal disease. Fetal growth
restriction was present in 45.5% of the patients with
preeclampsia and appeared to increase the risk of
preeclampsia, with no statistical significance (P = 0.2).
Pregnancies complicated by SLE have spontaneous
abortion rates in the range of 635%, which are higher
than in the general population.16) Because our study
group consisted of SLE patients who were under regular
antenatal follow-up, patients who had an abortion in
the present pregnancy were not included in the study.
However, 16.4% of our multiparous women had a history
of abortion or intrauterine fetal death, consistent with
previous studies. Previous studies reported that 17% of
pregnant women with SLE had positive test results for
antiphospholipid antibodies;17,18) this rate is higher than
the 7.2% found in our study.
Live birth rate in our study was 96%, which is in
agreement with recently reported live birth rates of > 85%
in SLE patients.1,19) The fetal growth restriction rate in
our patient population was similar (21%) to previously
reported rates (1030%).20) The incidence of fetal loss
was 4% in our study, whereas reported frequencies
of fetal loss vary between 0% and 22%;16,21) these
differences may be attributed to factors such as variation
in patient selection and use of modern obstetric care and
106 Hypertens Res Pregnancy 2013; 1: 103107
treatment. We found that 21% of deliveries occurred
before 37 weeks in our SLE patients, which is higher
than in non-SLE pregnancies. This finding agrees with a
previous report, which showed that preterm delivery rate
increases nearly six-fold in SLE pregnancies.15) As for the
neonatal outcomes, we detected no atrioventricular block
and noted neonatal lupus in three. These findings were
consistent with previous reviews.
Some studies suggest that elevated dsDNA antibody,
presence of renal involvement, hypocomplementemia, and
antiphospholipid syndrome are prognostic risk factors for
adverse obstetrical outcomes in SLE pregnancies;15,16,22)
however, significant influences of these prognostic risk
factors on adverse obstetric outcomes have not been fully
demonstrated.12) We also detected no association between
these factors and SLE flare-ups, or with any adverse
outcomes.
Currently, no method exists for distinguishing between
a disease flare-up and preeclampsia during pregnancy.
Yet, correct diagnosis is critical for optimal management.
Initiation or intensification of immunosuppressive
therapy is required when SLE flare-ups occur, whereas
delivery of the child and the placenta is the only cure
available for severe preeclampsia. In our retrospective
review, the reported daily corticosteroid dosage helped
us distinguish between these two conditions. The soluble
fms-like tyrosine kinase 1/placental growth factor ratio
defined by Verdonk et al. may also help identify a disease
flare-up.23)
Pregnancy in SLE patients is considered high risk, and
management should start before conception. Pregnancy
should be planned when patient health is optimal, i.e.,
when the disease is in clinical remission for at least
6 months, and while on a decreased steroid dosage.
Most SLE patients have successful pregnancies and
deliver healthy babies with appropriate rheumatological,
obstetric, and neonatal monitoring. However, some cases
have severe complications, emphasizing the importance
of clinicians role in monitoring and diagnosing disease
flare-up or preeclampsia, and selecting appropriate
management depending on the condition.
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific
Research (25462555, 23592402) from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan and from the Japan Society for the Promotion of
Science.
Conflict of interest
We declare no conflicts of interest.

References
1. DCruz DP, Khamashta MA, Hughes GRV. Systemic lupus
erythematosus. Lancet. 2007; 369: 587 596.
2. Lawrenz B, Henes J, Henes M, et al. Impact of systemic lupus
erythematosus on ovarian reserve in premenopausal women:
evaluation by using anti-muellerian hormone. Lupus. 2011; 20:
11931197.
3. Clowse ME, Jamison M, Myers E, James AH. A national study of
the complications of lupus in pregnancy. Am J Obstet Gynecol.
2008; 199: 127.e1 6.
4. Brucato A, Frassi M, Franceschini F, et al. Risk of congenital
complete heart block in newborns of mothers with anti-Ro/
SSA antibodies detected by counter immunoelectrophoresis. A
prospective study of 100 women. Arthritis Rheum. 2001; 44:
18321835.
5. Corts-Hernndez J, Ordi-Ros J, Paredes F, Casellas M, Castillo
F, Vilardell-Tarres M. Clinical predictors of fetal and maternal
outcome in systemic lupus erythematosus: a prospective study of
103 pregnancies. Rheumatology. 2002; 41: 643 650.
6. Doria A, Tincani A, Lockshin M. Challenges of lupus pregnancies.
Rheumatology. 2008; 47 (suppl 3): iii9 12.
7. Watanabe K, Naruse K, Tanaka K, Metoki H, Suzuki Y.
Statement of the Society: Outline of Definition and Classification
of Pregnancy induced Hypertension (PIH). Hypertens Res
Pregnancy. 2013; 1: 3 4.
8. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus
statement on an update of the classification criteria for definite
antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4:
295306.
9. Kobayashi N, Yamada H, Kishida T, et al. Hypocomplementemia
correlates with intrauterine growth retardation in systemic lupus
erythematosus. Am J reprod Immunol. 1999; 42: 153 159.
10. Carvalheiras G, Vita P, Marta S, et al. Pregnancy and systemic
lupus erythematosus: review of clinical features and outcome of
51 pregnancies at a single institution. Clinic Rev Allerg Immunol.
2010; 38: 302306.
11. Madazli R, Yuksel MA, Oncul M, Imamoglu M, Yilmaz H.
K. Takahashi et al.
Obstetric outcomes and prognostic factors of lupus pregnancies.
Arch Gynecol Obstet. 2013; in press.
12. Cavallaca JA, Laborde HA, Ruda-Vega H, Nasswetter GG.
Maternal and fetal outcomes of 72 pregnancies in argentine patients
with systemic lupus erythematosus (SLE). Clin Rheumatol. 2008;
27: 41 46.
13. Molad Y, Borkowski T, Monselise A, et al. Maternal and
fetal outcome of lupus pregnancy: a prospective study of 29
pregnancies. Lupus. 2005; 14: 145 151.
14. Stojan G, Baer AN. Flares of systemic lupus erythematosus
during pregnancy and the puerperium: prevention, diagnosis and
management. Expert Rev Clin Immunol. 2012; 8: 439 453.
15. Chakravarty EF, Colon I, Langen ES, et al. Factors that predict
prematurity and preeclampsia in pregnancies that are complicated
by systemic lupus erythematosus. Am J Obstet Gynecol. 2005; 192:
1897 1904.
16. Mok CC, Wong RWS. Pregnancy in systemic lupus erythematosus.
Postgrad Med J. 2001; 77: 157 165.
17. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA.
Outcome of lupus pregnancy: a controlled study. Rheumatology.
2000; 39: 1014 1019.
18. Mavragani CP, Dafni UG, Tzioufas AG, Moutsopoulos HM.
Pregnancy outcome and anti-Ro/ SSA in autoimmune disease. A
retrospective cohort study. Br J Rheumatol. 1998; 37: 740 745.
19. Al Arfaj AS, Khalil N. Pregnancy outcome in 396 pregnancies in
patients with SLE in Saudi Arabia. Lupus. 2010; 19: 1665 1673.
20. Witter FR, Petri M. Antenatal detection of intrauterine growth
restriction in patients with systemic lupus erythematosus. Int J
Gynaecol Obstet. 2000; 71: 67 68.
21. Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for
pregnancy loss in lupus. Obstet Gynecol. 2006; 107: 293 299.
22. Whitelaw DA, Hall D, Kotze T. Pregnancy in systemic lupus
erythematosus: a retrospective study from a developing community.
Clin Rheumatol. 2008; 27: 577 580.
23. Verdonk K, Visser W, Russcher H, Jan Danser AH, Steegers EA,
van den Meiracker AH. Differencial diagnosis of preeclampsia:
remember the solble fms-like thyrosine kinase 1 / placental growth
factor ratio. Hypertension. 2012; 60: 884 890.
Hypertens Res Pregnancy 2013; 1: 103107 107