Lupus (2019) 28, 1407–1416

journals.sagepub.com/home/lup

PAPER

Pregnancy outcomes in women with rheumatic diseases:

a real-world observational study in Japan
E Sugawara1 , M Kato1, Y Fujieda1 , K Oku1, T Bohgaki1, S Yasuda1, T Umazume2, M Morikawa2, H Watari2
and T Atsumi1
1
Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University Faculty and Graduate School of Medicine, Sapporo, Japan;
and 2Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Objectives: We aimed to evaluate the obstetric complications and the risk factors for these
events in pregnant women with rheumatic diseases (RDs). Methods: A single-center retro-
spective study of women with RDs at Hokkaido University Hospital between 2007 and 2016
was conducted. Clinical features and maternal and fetal outcomes were retrospectively
collected. The rate of pregnancy complications was compared with the general obstetric popu-
lation (GOP) in Japan. Results: Overall, 132 pregnancies in 95 women with RDs were rec-
orded. Underlying RDs were systemic erythematosus (SLE) (n ¼ 57), antiphospholipid
syndrome (APS) (n ¼ 35), rheumatoid arthritis (n ¼ 9), and other RDs (n ¼ 31).
Antiphospholipid antibodies (aPL) were detected in 44 pregnancies (32%). Glucocorticoid
was used in 82 pregnancies (62%), and tacrolimus in 20 pregnancies (15%). There were
24 disease flares (18%), but no RD-related death was documented. We recorded 112 live
births, 6 abortions, 8 miscarriages, and 6 stillbirths. Pregnancies with RDs appeared to
have frequent, emergency cesarean sections and preterm deliveries compared with GOP
(30% vs 15% and 21% vs 14%, respectively). The median [interquartile range] birthweight
in SLE and APS was lower than GOP (2591 [2231–2958] g and 2600 [2276–2920] g vs 2950
[2650–3250] g, respectively). In pregnancies with SLE, low complement levels presented the
risk of maternal complications (odds ratio [95% CI]; 3.9 [1.0–14.9], p ¼ 0.046) and anti-
DNA antibody positivity was significantly correlated with the risk of fetal complications
(3.5 [1.1–11.2], p ¼ 0.036). In pregnancies with APS, maternal age over 35 years and duration
of disease longer than 9 years (7.4 [1.3–40.8], p ¼ 0.021, and 11.16 [1.1–118.8], p ¼ 0.046,
respectively) were significantly correlated with the risk of fetal complications. Conclusion:
Pregnancies with RDs were at increased risk of having both maternal complications
and adverse neonatal outcomes, indicating these pregnancies should be closely
monitored. Lupus (2019) 28, 1407–1416.

Key words: Rheumatic diseases; pregnancy; systemic lupus erythematosus; antiphospholipid

syndrome; rheumatoid arthritis

Introduction fetal negative outcome, have been frequently

Rheumatic diseases (RDs) such as rheumatoid
arthritis (RA), systemic lupus erythematosus
(SLE), antiphospholipid antibody syndrome
(APS), systemic sclerosis (SSc), Sjögren’s syndrome
(SS) and polymyositis/dermatomyositis (PM/DM)
occur among women of childbearing age.1 Adverse
events during pregnancy in RDs including disease
flare, preterm delivery, fetal or neonatal death and
Correspondence to: Masaru Kato, N15W7, Kita-Ku, 060-8638
Sapporo, Japan.
Email: ktmasaru@med.hokudai.ac.jp
Received 6 January 2019; accepted 28 August 2019
! The Author(s), 2019. Article reuse guidelines: sagepub.com/journals-permissions
reported,2 leading some women to avoid preg-
nancy. On the other hand, recent advances in the
treatment of RDs has significantly improved preg-
nancy management in RA and SLE, PM/DM, sys-
temic vasculitis, SS, and Behçet’s disease (BD).3-8
However, risk factors in pregnancies with RDs
remain controversial and there are no standard
guidelines. To date, although numerous agents
including immunosuppressants and biologics are
available, the effects of these drugs on pregnancies
are still uncertain. We hypothesized that women
with RDs would have higher rates of pregnancy
complications, obstetric interventions, and adverse
infant outcomes even under these treatments.
10.1177/0961203319877258
 Perinatal Outcome in rheumatic diseases
E Sugawara et al.
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The aim of the present study was to evaluate the
pregnancy outcomes and identify the risk factors of
pregnancy complications in women with RDs trea-
ted with immunosuppressants and biologics. We
retrospectively assessed both maternal and fetal
complications associated with pregnancy in those
patients.
Patients and methods
Patient population
In this retrospective cohort study, patients with
RDs who were pregnant between January 2007
and December 2016 and at Hokkaido University
Hospital in Hokkaido, Japan were enrolled. The
following criteria were used to classify each RD;
American College of Rheumatology (ACR) criteria
for SLE,9 Sapporo criteria with 2006 Sydney modi-
fications for APS,10 ACR 1987 revised criteria for
RA,11 1999 revised Japanese Ministry of Health
criteria for SS,12 Yamaguchi criteria for adult
onset Still’s disease (AOSD),13 international criteria
for the classification of BD,14 Kasukawa’s criteria
for mixed connective tissue disease (MCTD),15
Bohan and Peter’s criteria for PM/DM,16,17 the
ACR criteria for Takayasu arteritis (TA)18 and
the 2013 ACR/European League Against
Rheumatism (EULAR) classification criteria for
SSc.19 This study was performed in accordance
with the Declaration of Helsinki and the principles
of Good Clinical Practice. The protocol was
approved by the Ethics Committee (017-0479)
with a waiver of informed consent.
Clinical characteristics
Clinical characteristics including maternal demo-
graphic characteristics, history of RDs, treatment,
obstetric history, smoking habits, comorbidities,
and presence of antiphospholipid antibodies (aPL)
were recorded from medical records. In the sub-
group analysis, patients were categorized into
three groups; SLE, APS, and Others. Patients
with APS complicated with SLE were included in
the APS group. In a retrospective study, data were
analyzed from women with singleton pregnancies
who were registered with the Japan Society of
Obstetrics and Gynecology (JSOG) Successive
Pregnancy Birth Registry System and who gave
birth at 22 weeks of gestation or more.
Approximately 390 secondary and tertiary hos-
pitals participated in the JSOG system, which col-
lected information on successive deliveries that
Lupus
occurred at 22 weeks of gestation or more in
these hospitals. A total of 239,866 pregnancies
delivered in a single year (2016) was used as a con-
trol group.20 Disease activity of SLE was measured
by the SLE Pregnancy Disease Activity Index
(SLEPDAI) score21 and the British Isles Lupus
Assessment Group-2004 for pregnancy
(BILAG2004-P) index.22 Active disease was defined
as follows: a score of 4 on the SLEPDAI or a
BILAG2004-P organ domain score of 1A or
2B. The numeric BILAG-2004 global score was
calculated at each time point using the values:
A ¼ 12, B ¼ 8, C ¼ 1, and D/E ¼ 0.23 Disease activ-
ity of RA was estimated using the Disease Activity
Score-28 for Rheumatoid Arthritis with CRP
(DAS28-CRP).24 RA patients were classified into
remission, low disease activity, moderate activity,
and high activity according to predefined cut-off
values for DAS28-CRP: <2.6, 2.6 to <3.2, 3.2
to 5.1, and >5.1, respectively.25
Assessment of pregnancy outcome
Data on pregnancy outcome including abortions,
live births, birthweight of infants, gestational age
and amount of hemorrhage at delivery were col-
lected. The following complications were also rec-
orded: incidence of disease flare; emergency
cesarean section; premature rupture of membrane
(PROM); preterm delivery; gestational diabetes
mellitus (GDM); hypertensive disorder of preg-
nancy (HDP); hemolysis, elevated liver enzymes,
and low platelets (HELLP) syndrome; eclampsia;
miscarriage; stillbirth; fetal growth restriction
(FGR); neonatal death; low birthweight of infants;
care in neonatal intensive care unit (NICU); neo-
natal hypoglycemia; apnea; oxygen therapy; con-
genital abnormality; and respiratory distress
syndrome.
The following definitions were used. Disease
flare: new symptoms or worsening of the clinical
conditions requiring therapy modifications with
necessity to increase or introduce corticosteroids
and/or immunosuppressive drugs. Emergency
cesarean section: non-elective cesarean section.
PROM: the spontaneous rupture of membranes
before labor. Preterm deliveries: delivery prior to
37-week gestation. GDM: glucose intolerance with
onset or first recognition during pregnancy based
on International Association of the Diabetes and
Pregnancy Study Groups criteria.26 HELLP syn-
drome: hemolysis, elevated liver enzymes, low plate-
let syndrome defined by Sibai’s criteria.27 HDP
(Japanese criteria revised in 2018 modified according
to International Society for the study of

Hypertension in Pregnancy): 1) chronic hyperten-
sion, 2) preeclampsia, 3) preeclampsia superim-
posed, and 4) gestational hypertension.28
Eclampsia: generalized convulsion and/or coma
with no other neurologic condition. Miscarriage:
spontaneous fetal loss between 12 and 21 weeks’
gestation. Stillbirth: spontaneous death of fetus
after 22 weeks’ gestation. FGR: fetal abdominal cir-
cumference in the 5th percentile assessed by ultra-
sound motions. Neonatal death: death within
28 days from birth. Low birthweight and very low
birthweight: <2500 g and <1500 g, respectively.
Neonatal hypoglycemia: whole blood glucose con-
centration of less than 47 mg/dL (2.6 mmol/L).
Apnea: episodes of cessation of breathing. Oxygen
therapy: administration of oxygen during hospital-
ization including oxygen hood, continuous positive
airway pressure, or mechanical ventilation.
Congenital abnormality: structural abnormality
with surgical, medical, or cosmetic importance.
Respiratory distress syndrome: progressive dyspnea
after birth diagnosed by neonatologist.
To determine the risk factor of maternal and
fetal complications, we conducted a subgroup ana-
lysis. The following definitions were used; Maternal
adverse events: any events including disease flares,
emergency cesarean sections, PROM, preterm
deliveries, GDM, HDP, HELLP syndrome, or
eclampsia. Fetal adverse events: any events includ-
ing miscarriages, stillbirths, FGR, neonatal deaths,
low birthweight and very low birthweight of
infants, care in NICU, neonatal hypoglycemia,
apnea, oxygen therapy, congenital abnormality, or
respiratory distress syndrome.
Statistical analysis
Descriptive statistics on women characteristics for
categorical variables are expressed as percentages
and continuous variables are expressed as median
with interquartile range (IQR) [25th–75th percent-
ile]. A reference group was used to compare preg-
nancy outcomes with the general population in
Japan. Statistical analysis was performed with the
Mann–Whitney U test for quantitative variables,
Fisher’s exact test for categorical variables and
one-way analysis of variance (ANOVA) with post
hoc Bonferroni test for multiple comparisons. We
also assessed the univariate relationships between
the risk of maternal and fetal adverse events and
maternal clinical characteristics, immunological
tests, and treatments. A multinomial logistic regres-
sion model was used to determine the predictor of
maternal and fetal adverse events. Odds ratios
(ORs) were described with 95% confidence
Perinatal Outcome in rheumatic diseases
E Sugawara et al.
1409
intervals (CI) [minimum–maximum]. P-
values < 0.05 were considered significant. All statis-
tical analyses were performed using JMPÕ Pro soft-
ware (version 13.1.0; SAS Institute Inc., Cary, NC,
USA).
Results
Maternal clinical backgrounds
A total of 132 pregnancies in 95 women (all
Japanese) with RDs were included in this retro-
spective study. There were no twin pregnancies.
There were 57 pregnancies with SLE, 35 with
APS, 9 with RA, 9 with SS, 5 with AOSD, 5 with
BD, 4 with MCTD, 4 with PM/DM, 3 with TA and
1 with Crohn’s disease (CD). We recorded no SSc
women. The median age at conception was 31.5
[28–35] years old, which was similar to that of the
general population in Japan (32 [27–37] years old),
and the median duration of the disease was 87 [36–
144] months (Supplementary Table 1). Medication
use during pregnancy was restricted to Prednisone
(82 patients), tacrolimus (20 patients) and
azathioprine (1 patient) for treatment of RDs.
Next, we categorized the pregnancies into three
groups; SLE (n ¼ 57), APS (n ¼ 35), and Others
(n ¼ 40). Patients with both SLE and APS were
subsumed into the APS group. The median mater-
nal age at conception was significantly higher in
pregnancies with APS than Others (34 [31–37]
years old vs 32 [29–35] years old, p ¼ 0.017).
Disease duration was longer in SLE patients com-
pared with Others, whereas disease duration was
shorter in APS patients (109 [48–175] months, 46
[18–95] months vs 93 [64–146] months, p ¼ 0.357,
p ¼ 0.027, respectively). There were no significant
differences in the median body mass index between
the groups. Antiphospholipid antibodies were
found in eight SLE pregnancies without APS.
Thyroid disorder was found in 14 pregnancies
(24%) with SLE, a particularly high prevalence.
There were no significant differences in the
median daily dose of Prednisone during pregnancy
between groups: 10 [5–10] mg/day in SLE, 0 [0–7.5]
mg/day in APS, and 5 [0–8.4] mg/day in Others.
Tacrolimus was used in 16 SLE (28%), 1 APS
(3%) and 3 Others (7%). Biologics were used in
five pregnancies in four patients (one
SLE þ Crohn’s disease patient, two RA patients,
and one BD patient). Etanercept was used in
three RA pregnancies, adalimumab was used
in one SLE pregnancy and infliximab was used in
one BD pregnancy. Aspirin was administrated in
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18 SLE (32%) and 28 APS (80%) pregnancies.
Heparin was administrated in 6 SLE (11%) and
27 APS (77%) pregnancies, as shown in Table 1.
Pregnancy outcome, maternal, and fetal
adverse events
Among the 132 pregnancies, there were 6 abortions
(5%), 8 miscarriages (6%) and 6 stillbirths (5%),
and the remaining 112 had live births (95%), appar-
ently lower than in the general obstetric population
(GOP) of Japan (99%). The median gestational
week was 37 [36–38] weeks in 112 live births. The
median birthweight of all live births was 2697
[2353–3035] g, which was smaller than in GOP
(2950 [2650–3250] g). Disease flares of RDs
occurred in 24 pregnancies (18%). Emergency
cesarean sections were recorded in 39 pregnancies
in RDs, more frequent than in GOP (30% vs 15%).
Preterm delivery occurred in 27 pregnancies (21%).
We observed 5 GDM (4%), 12 HDP (9%) and 5
HELLP syndrome (4%). Neonatal death occurred
in two pregnancies (1%). Thirty-seven infants
(28%) were low birthweight (less than 2500 g) and
6 infants (5%) were very low birthweight (less than
1500 g) (Table 2). Thirteen neonates needed care in
NICU (10%), and congenital abnormality was rec-
orded in six neonates (5%) and respiratory distress
syndrome was recorded in three neonates (2%).
In addition to complications related to pregnancy,
a 26-year-old SLE woman experienced multiple
vertebral compression fractures during pregnancy,
which might have been associated with the 9-month
heparin treatment to avoid a relapse of deep vein
thrombosis.
Regarding the subgroup analysis, the median
birthweight of SLE and of APS were 2591
[2231–2958] g and 2600 [2276–2920] g, respectively.
In APS, preterm deliveries were found in 13 preg-
nancies (38%) and FGR in 8 pregnancies (23%),
a particularly high prevalence.
We recorded nine RA pregnancies, whose
median DAS28-CRP was 1.86 [1.28–3.29] at the
time of conception. Etanercept was administrated
in three pregnancies, corticosteroid monotherapy
was recorded in two pregnancies, and the remaining
four pregnancies required no treatment. Six
patients remained in remission until delivery
(Supplementary Table 2).
Risk determination of maternal and fetal
complications in RDs
To determine the risk factor of maternal and fetal
complications, we conducted a subgroup analysis.
We compared the clinical features of patients with
or without maternal and fetal complications in
pregnancies. In pregnancies with maternal adverse

Table 1 Patients’ general characteristics and treatments

Total SLE APS Others
(n ¼ 132) (n ¼ 57) (n ¼ 35) (n ¼ 40)

General characteristics
Maternal age, median (IQR) (years old) 31.5 (28–35) 30 (27–34) 34 (31–37)* 32 (29–35)
Duration of disease, median (IQR) (months) 87 (36–144) 109 (48–175) 46 (18–95)* 93 (61–146)
Body mass index, median (IQR) (kg/m2) 20.6 (18.9–22.5) 20.2 (17.9–21.9) 21.4 (19.7–23.2) 20.8 (29.1–22.4)
Thyroid disorder, no. (%) 21 (16) 14 (24)* 5 (14)* 2 (5)
Hypertension, no. (%) 3 (2) 1 (3) 1 (3) 1 (2)
Diabetes mellitus, no. (%) 2 (2) 0 (0) 0 (0) 2 (5)
aPL positivity, no. (%) 44 (32) 8 (14)* 35 (100)* 1 (2)
Smoking, no. (%) 11 (8) 9 (16)* 1 (3) 1 (2)
Assisted reproductive technology, no. (%) 14 (11) 4 (7) 6 (17) 4 (10)
Treatment
PSL, no. (%) 82 (62) 49 (86)* 11 (31)* 22 (55)
Dosage of PSL, median (IQR) (mg) 5 (0–8.9) 10 (5–10) 0 (0–7.5) 5 (0–8.4)
Immunosuppressant, no. (%) 21 (16) 16 (28)* 2 (6) 3 (7)
Tacrolimus, no. (%) 20 (15) 16 (28)* 1 (3) 3 (7)
Azathioprine, no. (%) 1 (1) 0 (0) 1 (3) 0 (0)
Biologics, no. (%) 5 (4) 1 (1)* 0 (0)* 4 (10)
Aspirin, no. (%) 49 (37) 18 (32)* 28 (80)* 3 (7)
Heparin, no. (%) 36 (27) 6 (11)* 27 (77)* 3 (7)

SLE: systemic lupus erythematosus; APS: antiphospholipid antibody syndrome; Others: pregnancies with rheumatoid arthritis, Sjögren’s syn-
drome, adult onset Still’s disease, Behçet’s disease, mixed connective tissue disease, polymyositis/dermatomyositis, Takayasu arteritis; GOP: general
obstetric population in Japan; aPL: antiphospholipid antibodies; PSL: prednisolone; IQR: interquartile range.
*p < 0.05, compared with other RDs, using one-way ANOVA with post hoc Bonferroni test.

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Table 2 Pregnant outcome, maternal and fetal adverse events

Total SLE APS Other RDs GOP
(n ¼ 132) (n ¼ 57) (n ¼ 35) (n ¼ 40) (n ¼ 239,866)

Pregnancy outcome
Abortions, no. (%) 6 (5) 5 (9) 0 (0) 1 (2) NA
Live births, no. (%) 112 (95) 46 (95) 29 (91) 37 (97) 238,420 (99)
Gestational weeks, median (IQR) (weeks) 37 (36–38) 37 (37–38) 37 (35–38) 38 (37–39) 38 (37–40)
Birth weight, median (IQR) (kg) 2697 (2353–3035) 2591 (2231–2958) 2600 (2276–2920) 2825 (2437–3122) 2950 (2650–3250)
Amount of hemorrhage, median (IQR) (mL) 512 (340–779) 517 (370–800) 530 (328–743) 450 (280–778) 250 (250–750)
Maternal adverse events
Total, no. (%) 81 (61) 34 (59) 26 (74) 21 (53) NA
Disease flare, no. (%) 24 (18) 13 (22) 5 (14) 6 (15) NA
Emergency cesarean section, no. (%) 39 (30) 15 (26) 12 (34) 12 (30) 36,497 (15)
PROM, no. (%) 25 (19) 8 (14) 9 (26) 8 (20) 29,569 (12)
Preterm deliveries, no. (%) 27 (21) 9 (16) 13 (38) 5 (13) 33,497 (14)
GDM, no. (%) 5 (4) 2 (3) 3 (9) 0 (0) 12,353 (5)
HDP, no. (%) 12 (9) 5 (9) 3 (9) 4 (10) 13,545 (6)
HELLP syndrome, no. (%) 5 (4) 3 (5) 2 (6) 0 (0) 127 (0.05)
Eclampsia, no. (%) 1 (1) 0 (0) 1 (3) 0 (0) 278 (0.11)
Fetal adverse events
Total, no. (%) 62 (47) 27 (47) 20 (57) 15 (38) NA
Miscarriages, no. (%) 8 (6) 4 (7) 3 (9) 1 (2) NA
Stillbirths, no. (%) 6 (5) 2 (4) 3 (9) 1 (2) 1446 (0.6)
Fetal growth restriction, no. (%) 19 (14) 6 (11) 8 (23) 5 (13) 9763 (4)
Neonatal deaths, no. (%) 2 (1) 1 (2) 1 (3) 0 (0) 388 (0.1)
Low birthweight infants (<2500 g), no. (%) 37 (28) 16 (28) 11 (31) 10 (25) 46,137 (19)
Very low birthweight infants (<1500 g), no. (%) 6 (5) 4 (7) 2 (6) 0 (0) 7700 (3)
Care in NICU, no. (%) 13 (10) 6 (10) 6 (17) 1 (3) NA
Hypoglycemia, no. (%) 5 (4) 2 (4) 2 (6) 1 (3) NA
Apnea, no. (%) 12 (9) 7 (12) 5 (14) 0 (0) NA
Oxygen therapy, no. (%) 19 (14) 9 (16) 7 (20) 3 (7) NA
Congenital abnormality, no. (%) 6 (5) 3 (5) 1 (3) 2 (5) NA
Respiratory distress syndrome, no. (%) 3 (2) 2 (4) 1 (3) 0 (0) NA

SLE: systemic lupus erythematosus; APS: antiphospholipid antibody syndrome; Others: rheumatoid arthritis, Sjögren’s syndrome, adult onset
Still’s disease, Behçet’s disease, mixed connective tissue disease, polymyositis/dermatomyositis, Takayasu arteritis; GOP: general obstetric popu-
lation in Japan; IQR: interquartile range; NA: not available, GDM: gestational diabetes mellitus; HDP: hypertensive disorder of pregnancy;
PROM: premature rupture of membrane; HELLP syndrome: hemolysis, elevated liver enzymes, low platelet syndrome; NICU: neonatal intensive
care unit.
*p < 0.05, compared with GOP using one-way ANOVA with post hoc Bonferroni test.

events, C3 and C4 levels at the time of conception
were significantly lower (85 [69–97] mg/dL vs 95
[83–108] mg/dL, p ¼ 0.018l; 12 [7–22] mg/dL vs 18
[14–27] mg/dL, p ¼ 0.026, respectively) and the
dosage of prednisolone was significantly higher
(7 [5.75–15] mg/day vs 5 [0–7.5] mg/day,
p ¼ 0.002), compared to those without maternal
adverse events (Table 3). Regarding fetal adverse
events in SLE, the anti-DNA antibody positivity
rate was significantly higher (20/27, 74% vs 12/30,
40%, p ¼ 0.016) and the C3 level was significantly
lower (86 [69–97] mg/dL vs 91 [81–104] mg/dL,
p ¼ 0.047) in pregnancies with events, compared
to those without events (Table 3). Univariate ana-
lysis revealed that low complement levels
(C3 < 90mg/dL and C4 <15 mg/dL; OR 4.2
[1.2–15.1], p ¼ 0.021) and a prednisolone dosage
of more than 15 mg/day (OR 9.2 [1.1–77.6],
p ¼ 0.036) were correlated with maternal adverse
events. Among these predictors, a low complement
level was identified as an independent predictor for
maternal adverse events (OR 3.9 [1.0–14.9],
p ¼ 0.046) by multivariate analysis. A SLEPDAI
score higher than 4 (OR 4.5 [1.1–18.9], p ¼ 0.031)
and anti-DNA antibody positivity (OR 4.3
[1.4–13.3], p ¼ 0.016) were risk factors for fetal
adverse events. Multivariate analysis revealed
that anti-DNA antibody positivity was an inde-
pendent predictor for fetal adverse events (OR 3.5
[1.1–11.2], p ¼ 0.036) (Table 4). Furthermore, these
parameters were also identified as prognostic
factors even after we categorized the 12 APS preg-
nancies complicated by SLE into the SLE group
(data not shown).
Maternal adverse events occurred in 26 preg-
nancies with APS (26/35, 74%) without any
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Table 3 Clinical characteristics and treatment of pregnancies with SLE

Maternal adverse events Fetal adverse events

Yes No Yes No
(n ¼ 34) (n ¼ 23) p-value (n ¼ 27) (n ¼ 30) p-value

Clinical characteristics
Maternal age, median (IQR) (years old) 29.5 (27–34) 30 (27–35) 0.388 30 (27–34) 30 (27–35) 0.557
Duration of disease, median (IQR) (months) 98 (42–173) 120 (53–200) 0.320 109 (71–167) 104 (38–183) 0.973
Body mass index, median (IQR) (kg/m2) 20.1 (17.8–21.9) 20.7 (17.9–21.9) 0.389 19.2 (17.7–21.9) 20.5 (18.4–22.0) 0.257
Thyroid disorder, no. (%) 10 (29) 4 (17) 0.361 4 (15) 10 (33) 0.131
Hypertension, no. (%) 0 (0) 1 (4) 0.403 0 (0) 1 (3) 1.000
Diabetes mellitus, no. (%) 0 (0) 0 (0) NA 0 (0) 0 (0) NA
Smoking, no. (%) 4 (12) 5 (22) 0.461 3 (11) 6 (20) 0.476
Lupus nephritis, no. (%) 10 (30) 8 (35) 0.669 8 (30) 10 (33) 0.784
Active nephritis at screening, no. (%) 2 (6) 1 (4) 0.774 2 (7) 1 (3) 0.598
SLEPDAI, median (IQR) 0 (0–4) 0 (0–0) 0.092 0 (0–4) 0 (0–1.25) 0.065
BILAG2004-P, median (IQR) 2 (1–8.3) 1 (1–2) 0.082 2 (1–10) 1 (1–3) 0.065
Serum creatinine, median (IQR) (mg/dL) 0.5 (0.4–0.6) 0.6 (0.5–0.7) 0.103 0.6 (0.4–0.6) 0.5 (0.5–0.6) 0.345
Proteinuria, median (IQR) (g/gCre) 0 (0–0) 0 (0–0) 0.562 0 (0–0) 0 (0–0) 0.275
Immunological tests
Anti-SS-A antibody positivity, no. (%) 19 (59) 9 (41) 0.268 11 (44) 17 (59) 0.212
Anti-DNA antibody positivity, no. (%) 22 (65) 10 (44) 0.173 20 (74) 12 (40) 0.016*
aPL positivity, no. (%) 7 (21) 1 (4) 0.083 4 (15) 4 (13) 0.872
C3, median (IQR) (mg/dL) 85 (69–97) 95 (83–108) 0.018* 86 (69–97) 91 (81–104) 0.047*
C4, median (IQR) (mg/dL) 12 (7–22) 18 (14–27) 0.026* 14 (8–21) 19 (10–28) 0.086
Treatment
Prednisolone, no. (%) 32 (94) 17 (74) 0.031* 25 (93) 24 (80) 0.258
Dosage of PSL, median (IQR) (mg/day) 7 (5.8–15) 5 (0–7.5) 0.002* 7 (5–15) 7 (3.5–10) 0.301
Tacrolimus, no. (%) 10 (29) 6 (26) 1.000 8 (30) 8 (27) 1.000
Aspirin, no. (%) 10 (29) 8 (35) 0.774 7 (26) 11 (37) 0.279
Heparin, no. (%) 5 (15) 1 (4) 0.384 5 (19) 1 (3) 0.091

SLE: systemic lupus erythematosus; SLEPDAI: SLE Pregnancy Disease Activity Index; BILAG2004-P: British Isles Lupus Assessment Group-2004
for pregnancy; IQR: interquartile range; aPL: antiphospholipid antibodies; PSL: prednisolone; NA: not applicable.
*p < 0.05, using Fisher’s exact test, Mann–Whitney U test.

Table 4 Predictors of adverse events in pregnancies with SLE and APS

Univariate analysis Multivariate analysis

Odds ratio Odds ratio

(95% CI) p-value (95% CI) p-value

Maternal adverse events in SLE

C3 < 90 mg/dL and C4 < 15 mg/dL 4.2 (1.2–15.1) 0.021* 3.9 (1.0–14.9) 0.046*
Dosage of PSL  15 mg/day 9.2 (1.1–77.6) 0.036* 5.9 (0.6–54.6) 0.116
Fetal adverse events in SLE
SLEPDAI  4 4.5 (1.1–18.9) 0.031* 3.2 (0.7–14.3) 0.129
Anti-DNA antibody positivity 4.3 (1.4–13.3) 0.016* 3.5 (1.1–11.2) 0.036*
Fetal adverse events in APS
Maternal age  35 years old 7.4 (1.6–35.5) 0.002* 7.4 (1.3–40.8) 0.021*
Duration of disease  9 years 11.5 (1.3–66.5) 0.013* 11.2 (1.05–118.8) 0.046*

CI: confidence interval; SLE: systemic lupus erythematosus; PSL: prednisolone; SLEPDAI: SLE Pregnancy Disease Activity Index;
APS: antiphospholipid syndrome.
*p < 0.05.

differences in clinical characteristics and treat-
ments between pregnancies with and without
events. Fetal adverse events occurred in 20 preg-
nancies with APS (20/35, 57%). Higher maternal
Lupus
age (35 [31–37] years old vs 32 [28–35] years old,
p ¼ 0.033) and longer disease duration (75 [19–128]
months vs 31 [14–63] months, p ¼ 0.043) were
observed in pregnancies with fetal adverse events
 Perinatal Outcome in rheumatic diseases
E Sugawara et al.
1413

(statistically significant), compared to those with-
out fetal events (Table 5). The following risk fac-
tors were identified as associated with fetal adverse
events by both univariate and multivariate ana-
lyses: maternal age over 35 years (OR 7.4 [1.6–
35.5], p ¼ 0.002; OR 7.4 [1.3–40.8], p ¼ 0.021,
respectively) and duration of disease longer than
9 years (OR 11.4 [1.3–66.5], p ¼ 0.013; OR 11.2
[1.1–118.8], p ¼ 0.046, respectively) (Table 4). In
Others, there were 21 maternal adverse events
(21/40, 53%) and 15 fetal adverse events (15/40,
38%). There were no significant differences in clin-
ical characteristics or treatments between
pregnancies with and without maternal or fetal
adverse events (Table 6).
Discussion
In the present study we retrospectively analyzed the
maternal and fetal outcomes in pregnant women
with RDs. Results indicate they were at increased
risk of maternal and fetal adverse events. In the
subgroup analysis, low a complement level was
identified as an independent predictor of maternal
adverse events, and anti-DNA antibody positivity

Table 5 Clinical characteristics and treatment of pregnancies with APS

Maternal adverse events Fetal adverse events

Yes No Yes No
(n ¼ 26) (n ¼ 9) p-value (n ¼ 20) (n ¼ 15) p-value

Clinical characteristics
Maternal age, median (IQR) (years old) 36 (33–28) 32 (28–34) 0.369 35 (31–37) 32 (28–35) 0.033*
Duration of disease, median (IQR) (months) 49 (19–124) 35 (4–86) 0.298 75 (19–128) 31 (14–63) 0.043*
Body mass index, median (IQR) (kg/m2) 21.6 (18.7–23.1) 21.4 (20.2–23.8) 0.366 21.7 (18.9–23.1) 21.2 (20.4–24.9) 0.306
Thyroid disorder, no. (%) 4 (15) 1 (11) 1.000 2 (10) 3 (20) 0.631
Hypertension, no. (%) 1 (4) 0 (0) 1.000 1 (5) 0 (0) 1.000
Diabetes mellitus, no. (%) 0 (0) 0 (0) NA 0 (0) 0 (0) NA
Smoking, no. (%) 1 (4) 0 (0) 1.000 1 (5) 0 (0) 1.000
Treatment
PSL, no. (%) 10 (39) 1 (11) 0.217 7 (35) 4 (27) 0.721
Dosage of PSL, median (IQR) (mg/day) 0 (0–7.5) 0 (0–0) 0.216 0 (0–7.1) 0 (0–7.5) 0.214
Aspirin, no. (%) 19 (73) 9 (100) 0.153 16 (80) 12 (80) 1.000
Heparin, no. (%) 20 (77) 7 (78) 1.000 16 (80) 11 (73) 0.700

APS: antiphospholipid syndrome; IQR: interquartile range; PSL: prednisolone; NA: not applicable.
*p < 0.05, using Fisher’s exact test, Mann–Whitney U test.

Table 6 Clinical characteristics and treatment of pregnancies with Others

Maternal adverse events Fetal adverse events

Yes No Yes No
(n ¼ 21) (n ¼ 19) p-value (n ¼ 15) (n ¼ 25) p-value

Clinical characteristics
Maternal age, median (IQR) (years old) 32 (28–36) 32 (29–35) 0.573 32 (29–36) 32 (29–35) 0.876
Duration of disease, median (IQR) (months) 85 (54.5–153.5) 114 (79–146) 0.960 106 (71–142) 93 (46–154) 0.978
Body mass index, median (IQR) (kg/m2) 20.8 (20.1–22.5) 20.8 (28.9–22.4) 0.591 20.1 (19.1–23.1) 21.3 (20.1–22.4) 0.986
Thyroid disorder, no. (%) 0 (0) 2 (10.5) 0.219 0 (0) 2 (8.0) 0.519
Hypertension, no. (%) 0 (0) 1 (5.3) 0.475 0 (0) 1 (4.0) 1.000
Diabetes mellitus, no. (%) 1 (4.7) 1 (5.3) 1.000 0 (0) 2 (8.0) 0.519
Smoking, no. (%) 0 (0) 1 (5.3) 0.475 1 (6.7) 0 (0) 0.375
Treatment
PSL, no. (%) 13 (61.9) 9 (47.4) 0.525 10 (66.7) 12 (48.0) 0.331
Dosage of PSL, median (IQR) (mg/day) 5 (0–8.4) 3 (0–10) 0.767 5 (0–7.5) 5 (0–9.4) 0.721
Biologics, no. (%) 3 (14.3) 1 (5.3) 0.607 4 (20.0) 1 (4.0) 0.139

IQR: interquartile range; PSL: prednisolone.

*p < 0.05, using Fisher’s exact test, Mann–Whitney U test.

Lupus
 Perinatal Outcome in rheumatic diseases
E Sugawara et al.
1414
was identified as an independent predictor of fetal
adverse events in pregnancies with SLE. On the
other hand, higher maternal age and longer disease
duration were revealed to be risk factors for fetal
adverse events in pregnancies with APS.
Tacrolimus was not identified as a risk factor for
maternal or fetal adverse events. We have also
reported a case of multiple vertebral compression
fractures during pregnancy that might be asso-
ciated with heparin treatment.
According to previous studies, approximately
50% of patients with RA experienced improvement
of RA during pregnancy.29 To date, although its
etiology is still unknown, some pregnancy-related
factors, including maternal–fetal disparity at the
human leukocyte antigen locus, fetal microchimer-
ism, and type I interferon gene expression30 have
been reported to be associated with pregnancy-
induced improvement of RA. However, discontinu-
ation of anti-rheumatic drugs during pregnancy
could be a risk factor for disease flare.31
Moreover, high RA disease activity has been
reported to be associated with pregnancy complica-
tions including preterm delivery and various nega-
tive pregnancy outcomes.4,32,33 To obtain better
pregnancy outcomes, the disease activity of RA
therefore needs to be well controlled before and
during pregnancy.
In our cohort, biologics were used in five preg-
nancies (one SLE þ Crohn’s disease, four RA (two
patients) and one BD) at conception and continued
until delivery. Except for severe fetal abnormality
and stillbirth in the BD pregnancy, the remaining
women had healthy children, although PROM was
recorded in one RA pregnancy and FGR was rec-
orded in another. Our cohort did not have miscar-
riages or fetal infection. Tumor necrosis factor
(TNF) inhibitors are classified as pregnancy cat-
egory B drugs (no documented human toxicity)
by the U.S. Food and Drug Administration.34,35
TNF inhibitors are suggested to be selected under
consideration of the difference in placental transfer
related to molecule structure and half-life.
According to recent EULAR recommendations,
all TNF inhibitors can be safely used during the
first two trimesters of gestation. Etanercept and
certolizumab pegol are particularly recommended
because of their low transplacental passage.36
Certolizumab pegol lacks an antibody Fc region,
which is known to play a crucial role in placental
transfer.37
Our cohort also demonstrated that pregnancies
with APS had a higher rate of pregnancy compli-
cations including lower birthweight, and a higher
rate of emergency cesarean section, and preterm
Lupus
deliveries. Among the APS group, 24 pregnancies
were treated with a combination of heparin and
aspirin, however, 17 pregnancies experienced
maternal adverse events, and 14 pregnancies
experienced fetal adverse events. Treatment with
low molecular weight heparin in addition to
aspirin has been recommended for women with
APS in review articles,38 however, pregnancy com-
plications were still reported to be frequent in
spite of this combination therapy.39 Further clin-
ical studies including randomized controlled stu-
dies are needed to determine the optimal
management of pregnancies with APS. Of note,
tacrolimus was administrated in 20 pregnancies
in our cohort. Tacrolimus is a calcineurin inhibitor
that causes immunosuppression by preventing T-
cell activation and interleukin-2 transcription.
Tacrolimus is considered to be safe during preg-
nancy, however, successful pregnancies involving
tacrolimus have been mainly reported in women
after organ transplantation.40,41 The data concern-
ing the safety and efficacy of tacrolimus in preg-
nancy with lupus nephritis are limited to case
reports and case series.42,43 A recent retrospective
study demonstrated the safety and efficacy of
tacrolimus in pregnancy SLE.44 In our cohort,
tacrolimus was not identified as a risk factor for
maternal or fetal adverse events. Moreover, par-
ameters related to higher disease activity and a
higher glucocorticoid dose were identified as a
prognostic factor for maternal and fetal adverse
events for SLE, suggesting the importance of con-
trol and maintenance of the disease. Tacrolimus
may be a safe and effective treatment for SLE
during pregnancy.
For successful pregnancies with SLE, evaluation
of disease activity is necessary. However, it is some-
times difficult to distinguish physiological changes
including skin rash, joint pain, anemia, thrombocy-
topeni, and proteinuria from SLE exacerbations.45
In order to exclude these confounding features,
SLEPDAI, the Lupus Activity Index in Pregnancy
(LAI-P), and the Modified Systemic Lupus Activity
Measure (m-SLAM) were proposed in 1999.21
More recently, the Modified-European Consensus
Lupus Activity Measurement (m-ECLAM)46 and
BILAG2004-P22 were introduced. In the current
study, we measured disease activity of SLE with
SLEPDAI and BILAG2004-P. It may be beneficial
for monitoring SLE pregnancies to use more than
one pregnancy-specific activity index.
Our study has several limitations. First, this is a
single-center retrospective study; we could not
therefore exclude selection or information bias on
the results. Second, since we examined a small

number of patients in some groups and the sample
sizes of the explanatory variables were small, the
statistical power of the tests may also be small. In
the subgroup analysis, we included RA, SS, AOSD,
BD, MCTD, PM/DM, and TA in the same group
due to the small number of patients. To precisely
analyze the risk of each disease in the group, fur-
ther studies are needed. Third, this study was con-
ducted at a single tertiary center, we may collect
relatively high-risk pregnancies. This study is a hos-
pital-based single center study that may not be a
representative of entire RD pregnancies. Fourth,
hydroxychloroquine (HCQ) was not used to treat
SLE in our cohort as HCQ was not approved in
Japan until 2015. Considering its beneficial effects
in pregnancy,47 continuation of HCQ treatment
during pregnancy has been recommended.48 We
need further investigation on SLE pregnancies fol-
lowing this approval of HCQ to assess its effect on
pregnancy outcomes.
In summary, women with RDs are at an
increased risk of having both maternal and
fetal complications. Women with RDs should
be counseled before pregnancy about the risk of
pregnancy loss, and maternal and neonatal mor-
bidity and mortality. Their disease activity
should be well controlled. A close monitoring of
pregnancies with RDs by a team of experts is neces-
sary to minimize maternal and fetal complications.
Further prospective and multicenter studies
are needed to confirm the predictive factors for
maternal and fetal complications in pregnancies
with RDs.
Declaration of conflicting interests
The authors declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
ORCID iD
E Sugawara https://orcid.org/0000-0003-2464-
1833
Y Fujieda https://orcid.org/0000-0003-4705-
341X
Perinatal Outcome in rheumatic diseases
E Sugawara et al.
1415
Supplemental material
Supplemental material for this article is available
online.
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