Lupus (2019) 28, 1407–1416

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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

reported,2 leading some women to avoid preg-
Rheumatic diseases (RDs) such as rheumatoid nancy. On the other hand, recent advances in the
arthritis (RA), systemic lupus erythematosus treatment of RDs has significantly improved preg-
(SLE), antiphospholipid antibody syndrome nancy management in RA and SLE, PM/DM, sys-
(APS), systemic sclerosis (SSc), Sjögren’s syndrome temic vasculitis, SS, and Behçet’s disease (BD).3-8
(SS) and polymyositis/dermatomyositis (PM/DM) However, risk factors in pregnancies with RDs
occur among women of childbearing age.1 Adverse remain controversial and there are no standard
events during pregnancy in RDs including disease guidelines. To date, although numerous agents
flare, preterm delivery, fetal or neonatal death and including immunosuppressants and biologics are
available, the effects of these drugs on pregnancies
are still uncertain. We hypothesized that women
Correspondence to: Masaru Kato, N15W7, Kita-Ku, 060-8638
Sapporo, Japan.
with RDs would have higher rates of pregnancy
Email: ktmasaru@med.hokudai.ac.jp complications, obstetric interventions, and adverse
Received 6 January 2019; accepted 28 August 2019 infant outcomes even under these treatments.
! The Author(s), 2019. Article reuse guidelines: sagepub.com/journals-permissions 10.1177/0961203319877258
 Perinatal Outcome in rheumatic diseases
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The aim of the present study was to evaluate the occurred at 22 weeks of gestation or more in
pregnancy outcomes and identify the risk factors of these hospitals. A total of 239,866 pregnancies
pregnancy complications in women with RDs trea- delivered in a single year (2016) was used as a con-
ted with immunosuppressants and biologics. We trol group.20 Disease activity of SLE was measured
retrospectively assessed both maternal and fetal by the SLE Pregnancy Disease Activity Index
complications associated with pregnancy in those (SLEPDAI) score21 and the British Isles Lupus
patients. Assessment Group-2004 for pregnancy
(BILAG2004-P) index.22 Active disease was defined
as follows: a score of 4 on the SLEPDAI or a
Patients and methods BILAG2004-P organ domain score of 1A or
2B. The numeric BILAG-2004 global score was
Patient population 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-
In this retrospective cohort study, patients with ity of RA was estimated using the Disease Activity
RDs who were pregnant between January 2007 Score-28 for Rheumatoid Arthritis with CRP
and December 2016 and at Hokkaido University (DAS28-CRP).24 RA patients were classified into
Hospital in Hokkaido, Japan were enrolled. The remission, low disease activity, moderate activity,
following criteria were used to classify each RD; and high activity according to predefined cut-off
American College of Rheumatology (ACR) criteria values for DAS28-CRP: <2.6, 2.6 to <3.2, 3.2
for SLE,9 Sapporo criteria with 2006 Sydney modi- to 5.1, and >5.1, respectively.25
fications for APS,10 ACR 1987 revised criteria for
RA,11 1999 revised Japanese Ministry of Health Assessment of pregnancy outcome
criteria for SS,12 Yamaguchi criteria for adult
onset Still’s disease (AOSD),13 international criteria Data on pregnancy outcome including abortions,
for the classification of BD,14 Kasukawa’s criteria live births, birthweight of infants, gestational age
and amount of hemorrhage at delivery were col-
for mixed connective tissue disease (MCTD),15
lected. The following complications were also rec-
Bohan and Peter’s criteria for PM/DM,16,17 the
orded: incidence of disease flare; emergency
ACR criteria for Takayasu arteritis (TA)18 and
cesarean section; premature rupture of membrane
the 2013 ACR/European League Against
(PROM); preterm delivery; gestational diabetes
Rheumatism (EULAR) classification criteria for
mellitus (GDM); hypertensive disorder of preg-
SSc.19 This study was performed in accordance
nancy (HDP); hemolysis, elevated liver enzymes,
with the Declaration of Helsinki and the principles
and low platelets (HELLP) syndrome; eclampsia;
of Good Clinical Practice. The protocol was
miscarriage; stillbirth; fetal growth restriction
approved by the Ethics Committee (017-0479)
(FGR); neonatal death; low birthweight of infants;
with a waiver of informed consent.
care in neonatal intensive care unit (NICU); neo-
natal hypoglycemia; apnea; oxygen therapy; con-
Clinical characteristics
genital abnormality; and respiratory distress
Clinical characteristics including maternal demo- syndrome.
graphic characteristics, history of RDs, treatment, The following definitions were used. Disease
obstetric history, smoking habits, comorbidities, flare: new symptoms or worsening of the clinical
and presence of antiphospholipid antibodies (aPL) conditions requiring therapy modifications with
were recorded from medical records. In the sub- necessity to increase or introduce corticosteroids
group analysis, patients were categorized into and/or immunosuppressive drugs. Emergency
three groups; SLE, APS, and Others. Patients cesarean section: non-elective cesarean section.
with APS complicated with SLE were included in PROM: the spontaneous rupture of membranes
the APS group. In a retrospective study, data were before labor. Preterm deliveries: delivery prior to
analyzed from women with singleton pregnancies 37-week gestation. GDM: glucose intolerance with
who were registered with the Japan Society of onset or first recognition during pregnancy based
Obstetrics and Gynecology (JSOG) Successive on International Association of the Diabetes and
Pregnancy Birth Registry System and who gave Pregnancy Study Groups criteria.26 HELLP syn-
birth at 22 weeks of gestation or more. drome: hemolysis, elevated liver enzymes, low plate-
Approximately 390 secondary and tertiary hos- let syndrome defined by Sibai’s criteria.27 HDP
pitals participated in the JSOG system, which col- (Japanese criteria revised in 2018 modified according
lected information on successive deliveries that to International Society for the study of
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Hypertension in Pregnancy): 1) chronic hyperten- intervals (CI) [minimum–maximum]. P-

sion, 2) preeclampsia, 3) preeclampsia superim- values < 0.05 were considered significant. All statis-
posed, and 4) gestational hypertension.28 tical analyses were performed using JMPÕ Pro soft-
Eclampsia: generalized convulsion and/or coma ware (version 13.1.0; SAS Institute Inc., Cary, NC,
with no other neurologic condition. Miscarriage: USA).
spontaneous fetal loss between 12 and 21 weeks’
gestation. Stillbirth: spontaneous death of fetus
after 22 weeks’ gestation. FGR: fetal abdominal cir- Results
cumference in the 5th percentile assessed by ultra-
sound motions. Neonatal death: death within Maternal clinical backgrounds
28 days from birth. Low birthweight and very low
birthweight: <2500 g and <1500 g, respectively. A total of 132 pregnancies in 95 women (all
Neonatal hypoglycemia: whole blood glucose con- Japanese) with RDs were included in this retro-
centration of less than 47 mg/dL (2.6 mmol/L). spective study. There were no twin pregnancies.
Apnea: episodes of cessation of breathing. Oxygen There were 57 pregnancies with SLE, 35 with
therapy: administration of oxygen during hospital- APS, 9 with RA, 9 with SS, 5 with AOSD, 5 with
ization including oxygen hood, continuous positive BD, 4 with MCTD, 4 with PM/DM, 3 with TA and
airway pressure, or mechanical ventilation. 1 with Crohn’s disease (CD). We recorded no SSc
Congenital abnormality: structural abnormality women. The median age at conception was 31.5
with surgical, medical, or cosmetic importance. [28–35] years old, which was similar to that of the
Respiratory distress syndrome: progressive dyspnea general population in Japan (32 [27–37] years old),
after birth diagnosed by neonatologist. and the median duration of the disease was 87 [36–
To determine the risk factor of maternal and 144] months (Supplementary Table 1). Medication
fetal complications, we conducted a subgroup ana- use during pregnancy was restricted to Prednisone
lysis. The following definitions were used; Maternal (82 patients), tacrolimus (20 patients) and
adverse events: any events including disease flares, azathioprine (1 patient) for treatment of RDs.
emergency cesarean sections, PROM, preterm Next, we categorized the pregnancies into three
deliveries, GDM, HDP, HELLP syndrome, or groups; SLE (n ¼ 57), APS (n ¼ 35), and Others
eclampsia. Fetal adverse events: any events includ- (n ¼ 40). Patients with both SLE and APS were
ing miscarriages, stillbirths, FGR, neonatal deaths, subsumed into the APS group. The median mater-
low birthweight and very low birthweight of nal age at conception was significantly higher in
infants, care in NICU, neonatal hypoglycemia, pregnancies with APS than Others (34 [31–37]
apnea, oxygen therapy, congenital abnormality, or years old vs 32 [29–35] years old, p ¼ 0.017).
respiratory distress syndrome. Disease duration was longer in SLE patients com-
pared with Others, whereas disease duration was
Statistical analysis shorter in APS patients (109 [48–175] months, 46
[18–95] months vs 93 [64–146] months, p ¼ 0.357,
Descriptive statistics on women characteristics for p ¼ 0.027, respectively). There were no significant
categorical variables are expressed as percentages differences in the median body mass index between
and continuous variables are expressed as median the groups. Antiphospholipid antibodies were
with interquartile range (IQR) [25th–75th percent- found in eight SLE pregnancies without APS.
ile]. A reference group was used to compare preg- Thyroid disorder was found in 14 pregnancies
nancy outcomes with the general population in (24%) with SLE, a particularly high prevalence.
Japan. Statistical analysis was performed with the There were no significant differences in the
Mann–Whitney U test for quantitative variables, median daily dose of Prednisone during pregnancy
Fisher’s exact test for categorical variables and between groups: 10 [5–10] mg/day in SLE, 0 [0–7.5]
one-way analysis of variance (ANOVA) with post mg/day in APS, and 5 [0–8.4] mg/day in Others.
hoc Bonferroni test for multiple comparisons. We Tacrolimus was used in 16 SLE (28%), 1 APS
also assessed the univariate relationships between (3%) and 3 Others (7%). Biologics were used in
the risk of maternal and fetal adverse events and five pregnancies in four patients (one
maternal clinical characteristics, immunological SLE þ Crohn’s disease patient, two RA patients,
tests, and treatments. A multinomial logistic regres- and one BD patient). Etanercept was used in
sion model was used to determine the predictor of three RA pregnancies, adalimumab was used
maternal and fetal adverse events. Odds ratios in one SLE pregnancy and infliximab was used in
(ORs) were described with 95% confidence one BD pregnancy. Aspirin was administrated in
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18 SLE (32%) and 28 APS (80%) pregnancies. In addition to complications related to pregnancy,
Heparin was administrated in 6 SLE (11%) and a 26-year-old SLE woman experienced multiple
27 APS (77%) pregnancies, as shown in Table 1. vertebral compression fractures during pregnancy,
which might have been associated with the 9-month
Pregnancy outcome, maternal, and fetal heparin treatment to avoid a relapse of deep vein
adverse events thrombosis.
Among the 132 pregnancies, there were 6 abortions Regarding the subgroup analysis, the median
(5%), 8 miscarriages (6%) and 6 stillbirths (5%), birthweight of SLE and of APS were 2591
and the remaining 112 had live births (95%), appar- [2231–2958] g and 2600 [2276–2920] g, respectively.
ently lower than in the general obstetric population In APS, preterm deliveries were found in 13 preg-
(GOP) of Japan (99%). The median gestational nancies (38%) and FGR in 8 pregnancies (23%),
week was 37 [36–38] weeks in 112 live births. The a particularly high prevalence.
We recorded nine RA pregnancies, whose
median birthweight of all live births was 2697
[2353–3035] g, which was smaller than in GOP median DAS28-CRP was 1.86 [1.28–3.29] at the
time of conception. Etanercept was administrated
(2950 [2650–3250] g). Disease flares of RDs
in three pregnancies, corticosteroid monotherapy
occurred in 24 pregnancies (18%). Emergency
cesarean sections were recorded in 39 pregnancies was recorded in two pregnancies, and the remaining
in RDs, more frequent than in GOP (30% vs 15%). four pregnancies required no treatment. Six
patients remained in remission until delivery
Preterm delivery occurred in 27 pregnancies (21%).
(Supplementary Table 2).
We observed 5 GDM (4%), 12 HDP (9%) and 5
HELLP syndrome (4%). Neonatal death occurred
Risk determination of maternal and fetal
in two pregnancies (1%). Thirty-seven infants
complications in RDs
(28%) were low birthweight (less than 2500 g) and
6 infants (5%) were very low birthweight (less than To determine the risk factor of maternal and fetal
1500 g) (Table 2). Thirteen neonates needed care in complications, we conducted a subgroup analysis.
NICU (10%), and congenital abnormality was rec- We compared the clinical features of patients with
orded in six neonates (5%) and respiratory distress or without maternal and fetal complications in
syndrome was recorded in three neonates (2%). 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 p ¼ 0.036) were correlated with maternal adverse
were significantly lower (85 [69–97] mg/dL vs 95 events. Among these predictors, a low complement
[83–108] mg/dL, p ¼ 0.018l; 12 [7–22] mg/dL vs 18 level was identified as an independent predictor for
[14–27] mg/dL, p ¼ 0.026, respectively) and the maternal adverse events (OR 3.9 [1.0–14.9],
dosage of prednisolone was significantly higher p ¼ 0.046) by multivariate analysis. A SLEPDAI
(7 [5.75–15] mg/day vs 5 [0–7.5] mg/day, score higher than 4 (OR 4.5 [1.1–18.9], p ¼ 0.031)
p ¼ 0.002), compared to those without maternal and anti-DNA antibody positivity (OR 4.3
adverse events (Table 3). Regarding fetal adverse [1.4–13.3], p ¼ 0.016) were risk factors for fetal
events in SLE, the anti-DNA antibody positivity adverse events. Multivariate analysis revealed
rate was significantly higher (20/27, 74% vs 12/30, that anti-DNA antibody positivity was an inde-
40%, p ¼ 0.016) and the C3 level was significantly pendent predictor for fetal adverse events (OR 3.5
lower (86 [69–97] mg/dL vs 91 [81–104] mg/dL, [1.1–11.2], p ¼ 0.036) (Table 4). Furthermore, these
p ¼ 0.047) in pregnancies with events, compared parameters were also identified as prognostic
to those without events (Table 3). Univariate ana- factors even after we categorized the 12 APS preg-
lysis revealed that low complement levels nancies complicated by SLE into the SLE group
(C3 < 90mg/dL and C4 <15 mg/dL; OR 4.2 (data not shown).
[1.2–15.1], p ¼ 0.021) and a prednisolone dosage Maternal adverse events occurred in 26 preg-
of more than 15 mg/day (OR 9.2 [1.1–77.6], 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- age (35 [31–37] years old vs 32 [28–35] years old,
ments between pregnancies with and without p ¼ 0.033) and longer disease duration (75 [19–128]
events. Fetal adverse events occurred in 20 preg- months vs 31 [14–63] months, p ¼ 0.043) were
nancies with APS (20/35, 57%). Higher maternal observed in pregnancies with fetal adverse events
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(statistically significant), compared to those with- pregnancies with and without maternal or fetal
out fetal events (Table 5). The following risk fac- adverse events (Table 6).
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– Discussion
35.5], p ¼ 0.002; OR 7.4 [1.3–40.8], p ¼ 0.021,
respectively) and duration of disease longer than In the present study we retrospectively analyzed the
9 years (OR 11.4 [1.3–66.5], p ¼ 0.013; OR 11.2 maternal and fetal outcomes in pregnant women
[1.1–118.8], p ¼ 0.046, respectively) (Table 4). In with RDs. Results indicate they were at increased
Others, there were 21 maternal adverse events risk of maternal and fetal adverse events. In the
(21/40, 53%) and 15 fetal adverse events (15/40, subgroup analysis, low a complement level was
38%). There were no significant differences in clin- identified as an independent predictor of maternal
ical characteristics or treatments between 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.

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was identified as an independent predictor of fetal deliveries. Among the APS group, 24 pregnancies
adverse events in pregnancies with SLE. On the were treated with a combination of heparin and
other hand, higher maternal age and longer disease aspirin, however, 17 pregnancies experienced
duration were revealed to be risk factors for fetal maternal adverse events, and 14 pregnancies
adverse events in pregnancies with APS. experienced fetal adverse events. Treatment with
Tacrolimus was not identified as a risk factor for low molecular weight heparin in addition to
maternal or fetal adverse events. We have also aspirin has been recommended for women with
reported a case of multiple vertebral compression APS in review articles,38 however, pregnancy com-
fractures during pregnancy that might be asso- plications were still reported to be frequent in
ciated with heparin treatment. spite of this combination therapy.39 Further clin-
According to previous studies, approximately ical studies including randomized controlled stu-
50% of patients with RA experienced improvement dies are needed to determine the optimal
of RA during pregnancy.29 To date, although its management of pregnancies with APS. Of note,
etiology is still unknown, some pregnancy-related tacrolimus was administrated in 20 pregnancies
factors, including maternal–fetal disparity at the in our cohort. Tacrolimus is a calcineurin inhibitor
human leukocyte antigen locus, fetal microchimer- that causes immunosuppression by preventing T-
ism, and type I interferon gene expression30 have cell activation and interleukin-2 transcription.
been reported to be associated with pregnancy- Tacrolimus is considered to be safe during preg-
induced improvement of RA. However, discontinu- nancy, however, successful pregnancies involving
ation of anti-rheumatic drugs during pregnancy tacrolimus have been mainly reported in women
could be a risk factor for disease flare.31 after organ transplantation.40,41 The data concern-
Moreover, high RA disease activity has been ing the safety and efficacy of tacrolimus in preg-
reported to be associated with pregnancy complica- nancy with lupus nephritis are limited to case
tions including preterm delivery and various nega- reports and case series.42,43 A recent retrospective
tive pregnancy outcomes.4,32,33 To obtain better study demonstrated the safety and efficacy of
pregnancy outcomes, the disease activity of RA tacrolimus in pregnancy SLE.44 In our cohort,
therefore needs to be well controlled before and tacrolimus was not identified as a risk factor for
during pregnancy. maternal or fetal adverse events. Moreover, par-
In our cohort, biologics were used in five preg- ameters related to higher disease activity and a
nancies (one SLE þ Crohn’s disease, four RA (two higher glucocorticoid dose were identified as a
patients) and one BD) at conception and continued prognostic factor for maternal and fetal adverse
until delivery. Except for severe fetal abnormality events for SLE, suggesting the importance of con-
and stillbirth in the BD pregnancy, the remaining trol and maintenance of the disease. Tacrolimus
women had healthy children, although PROM was may be a safe and effective treatment for SLE
recorded in one RA pregnancy and FGR was rec- during pregnancy.
orded in another. Our cohort did not have miscar- For successful pregnancies with SLE, evaluation
riages or fetal infection. Tumor necrosis factor of disease activity is necessary. However, it is some-
(TNF) inhibitors are classified as pregnancy cat- times difficult to distinguish physiological changes
egory B drugs (no documented human toxicity) including skin rash, joint pain, anemia, thrombocy-
by the U.S. Food and Drug Administration.34,35 topeni, and proteinuria from SLE exacerbations.45
TNF inhibitors are suggested to be selected under In order to exclude these confounding features,
consideration of the difference in placental transfer SLEPDAI, the Lupus Activity Index in Pregnancy
related to molecule structure and half-life. (LAI-P), and the Modified Systemic Lupus Activity
According to recent EULAR recommendations, Measure (m-SLAM) were proposed in 1999.21
all TNF inhibitors can be safely used during the More recently, the Modified-European Consensus
first two trimesters of gestation. Etanercept and Lupus Activity Measurement (m-ECLAM)46 and
certolizumab pegol are particularly recommended BILAG2004-P22 were introduced. In the current
because of their low transplacental passage.36 study, we measured disease activity of SLE with
Certolizumab pegol lacks an antibody Fc region, SLEPDAI and BILAG2004-P. It may be beneficial
which is known to play a crucial role in placental for monitoring SLE pregnancies to use more than
transfer.37 one pregnancy-specific activity index.
Our cohort also demonstrated that pregnancies Our study has several limitations. First, this is a
with APS had a higher rate of pregnancy compli- single-center retrospective study; we could not
cations including lower birthweight, and a higher therefore exclude selection or information bias on
rate of emergency cesarean section, and preterm the results. Second, since we examined a small
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 Perinatal Outcome in rheumatic diseases
E Sugawara et al.
1415

number of patients in some groups and the sample Supplemental material

sizes of the explanatory variables were small, the
statistical power of the tests may also be small. In Supplemental material for this article is available
the subgroup analysis, we included RA, SS, AOSD, online.
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- References
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