ARTHRITIS & RHEUMATISM Volume 36
Number 10, October 1993, pp 1392-1397
1392
LUPUS AND PREGNANCY STUDIES
MURRAY B. UROWITZ, DAFNA D. GLADMAN, VERN T. FAREWELL,
JACQUELINE STEWART, and JOANNE McDONALD
Objective. To examine factors prior to pregnancy
in patients with systemic lupus erythematosus (SLE)
that are prognostic for the occurrence of active disease
during and shortly after pregnancy.
Methods. Case-control study of pregnant SLE
patients and nonpregnant SLE controls, using logistic
regression analyses to assess the role of prepregnancy
disease activity as a prognostic factor for flare during
pregnancy or the postpartum followup period.
Results. Lupus flares occurred frequently and in
similar percentages of pregnant SLE patients and con-
trol SLE patients. Active lupus at study entry, both in
control and in pregnant patients, was not predictive of
flare. Inactive lupus at onset was not protective against
flare in controls but was protective in pregnant lupus
patients.
Conclusion. Inactive disease at the onset of preg-
nancy in SLE provides optimum protection against the
occurrence of flare during pregnancy.
There is currently controversy in the literature
as to whether pregnancy in systemic lupus erythema-
From the Lupus Clinic, University of Toronto, and the
Rheumatic Disease Unit, Wellesley Hospital, Toronto, Ontario, and
the Departments of Statistics and Actuarial Science and Health
Studies, University of Waterloo, Waterloo, Ontario, Canada.
Murray B. Urowitz, MD, FRCP(C): Professor of Medicine,
Lupus Clinic, University of Toronto; Dafna D. Gladman, MD,
FRCP(C): Professor of Medicine, Lupus Clinic, University of To-
ronto; Vern T. Farewell, PhD: Professor, Departments of Statistics
and Actuarial Science and Health Studies, University of Waterloo;
Jacqueline Stewart, MD, FRCP(C); Joanne McDonald, MD,
FRCP(C).
Address reprint requests to Murray B. Urowitz, MD, The
Wellesley Hospital, Rheumatic Disease Unit, Room 649, Turner
Wing, 160 Wellesley Street East, Toronto, Ontario M4Y 153,
Canada.
Submitted for publication December 30, 1992; accepted in
revised form March 21, 1993.
0 1993, American College of Rheumatology
tosus (SLE) patients predisposes to flare of the under-
lying disease ( 1 4 ) . In case-control studies (2,5), the
frequency of flares of lupus during pregnancy did not
seem to differ significantly from the frequency of flares
in similarly followed up patients who were not preg-
nant. Although all of the authors report that flares do
occur during pregnancy, the prognostic factors for
such flares have not yet been adequately delineated. It
has been suggested by Tozman et a1 (6) that active
disease prior to pregnancy may be a prognostic indi-
cator for flare during pregnancy in SLE.
For the patient with lupus who wishes to be-
come pregnant, the potential state of the lupus during
the pregnancy is an important question. Will the
disease be active and therefore require some anti-
inflammatory medication such as corticosteroids or
nonsteroidal antiinflammatory drugs (NSAIDs)? These
treatments would of course have to be considered in
assessments of morbidity during the followup of such
patients. A patient may have lupus that is mildly active
at the onset of pregnancy and remains mildly active
throughout the pregnancy; while this would not be
considered a true “flare,” treatment with an NSAID
or steroid medication may still be required. Thus, it is
important to examine prepregnancy factors that are
prognostic for the occurrence of active disease during
and after pregnancy. The present study addressed that
question.
PATIENTS AND METHODS
Pregnant SLE patients,. Between July 1970 and Feb-
ruary 1988, 46 patients with 79 pregnancies were identified
from among 563 patients being followed up prospectively at
the Lupus Clinic, Wellesley Hospital, University of To-
SLE FLARE IN PREGNANCY 1393

Table 1. Features of systemic lupus erythematosus (SLE) patients in whom 79 pregnancies were
studied*
Pregnancies ending
Pregnancies ending in therapeutic
All pregnancies in delivery abortions
(n = 79) (n = 61)t (n = 18)
Age (years) at onset, mean 28.3 (21-37) 28.5 (21-37) 27.7 (21-36)
(range)
Disease duration (months) at 84.1 (0-306) 94.1 (0-306) 50.1 (8-108)
onset, mean (range)
Taking steroids at onset 58.2 59 55.6
Taking cytotoxic drugs at onset 7.7 10 0
Taking chloroquine at onset 25.3 23 33
First pregnancy, no. (%) 34 (43) 23 (37.7) 1 1 (61.1)
Increased PTT within 12 29.5 31.9 21.4
months prior to onset
Thrombocytopenia within 12 3.3 2.2 6.7
months prior to onset
Positive anti-DNA within 12 30 31 26.7
months prior to onset
Hypocomplementemia within 12 38.5 36.8 42.9
months prior to onset
Active SLE at 3 months prior 57 44 13
to onset, number
SLEDAI at 12 months prior to 6.94 (0-34) 6.63 (0-34) 7.93 (0-23)
onset, mean (range)
SLEDAI at 3 months prior to 4.92 (0-22) 5.07 (0-22) 4.47 (0-10)
onset, mean (range)
Flare during pregnancy, no. (%) 37 (46.8) 32 (52.5) 5 (27.8)
* “Onset” refers to onset of pregnancy. Unless otherwise indicated, values are percentages. PTT =
partial thromboplastin time; SLEDAI = SLE Disease Activity Index.
t Forty-two live births, 3 stillbirths, 16 spontaneous abortions.

ronto. Pregnant patients were included in this study if they
were registered at the Lupus Clinic at the time of termination
of pregnancy (birth or abortion). Births or abortions occur-
ring prior to registration at the Clinic, even after the diagno-
sis of lupus, were excluded. All patients fulfilled the American
College of Rheumatology (formerly, the American Rheuma-
tism Association) criteria for the diagnosis of SLE (7) and were
followed up at regular intervals with clinical and laboratory
assessments, during the entire term of the pregnancy and for 3
months postpartum. Patients were seen at least once during
each trimester and in the postpartum period.
Prepregnancy features assessed. Clinical features
evaluated as possible prognostic factors included duration of
SLE, score on the SLE Disease Activity Index (SLEDAI; a
validated activity index) (8,9), and presence of major organ
involvement (vasculitis, central nervous system [CNS] in-
volvement, and renal involvement). Vasculitis was defined
either clinically or by biopsy; CNS involvement was defined
as seizures, psychosis, lupus headache, or stroke; and renal
involvement as proteinuria of >500 mg/day, or hematuria of
>5 red blood celldhigh power field, elevated creatinine level
or depressed creatinine clearance, and results of renal bi-
opsy (when performed) compatible with SLE.
A number of laboratory variables were also exam-
ined, including findings on tests for hemolytic anemia, leu-
kopenia, lymphopenia, thrombocytopenia, partial thrombo-
plastin time (PTT), lupus anticoagulant, L E cell preparation,
antinuclear antibody, anti-DNA antibody by the Farr tech-
nique using lZ5I, anti-double-stranded DNA antibodies by
the Crithidiu luciliue test, total hemolytic complement and
C3 and C4, and VDRL. Medication use was documented,
with particular reference to prednisone, chloroquine, and
azathioprine. All of these clinical and laboratory variables
were assessed at 12 and 3 months prior to the last menstrual
period, during each trimester of pregnancy, and during the
postpartum period.
Assessment of flare during and after pregnancy. Out-
comes assessed in the mothers included the SLEDAI value.
Active disease was defined as a SLEDAI score of 2 2 . A flare
in disease was defined as an increase of 2 or more absolute
units on the SLEDAI. In addition, evidence of major organ
involvement was sought, as were laboratory abnormalities.
Complications of pregnancy, including hypertension, pre-
eclampsia, and eclampsia, were recorded as present when
hypertension and proteinuria occurred in the absence of any
other clinical or laboratory indicator of active disease.
Control SLE patients. To compare our sample of
pregnant SLE patients with nonpregnant female SLE pa-
tients, we initially identified from the Lupus Clinic database
a group of 59 patients including 1 control matched with each
pregnant patient for age, sex, disease duration, and SLEDAI
score. To further examine a potential difference in rates of
flare among patients with inactive disease, we identified a
further sample of 219 female lupus patients who presented
1394 UROWITZ ET AL

Table 2. Features investigated as possible factors prognostic for SLE disease flare during pregnancy,
in 61 pregnancies ending in delivery (excluding therapeutic abortions)*
Flare (n = 32) N o flare (n = 29)
Age (years) at onset, mean 29.03 21.93
Disease duration (months) at onset, mean 98.4 89.4
Pregnancy no., mean 1.8 1.8
Duration of steroid treatment (months) at onset, 59.4 (6-190) 49.8 (1-134)
mean (range)
No. taking steroids at onset 20 17
No. taking cytotoxic drugs at 12 months or 3 4 1
months prior to onset
No. taking chloroquine at 3 months prior to 7 7
onset
No. (%) with increased PTT at 3 months prior 5/20 (25) 1/19 (5.2)
to onset
No. (%) with thrombocytopenia at 3 months 0122 1/23 (4.3)
prior to onset
No. (%) with anti-DNA at 3 months prior to 5/19 (26.3) 3/20 (15)
onset
No. (%) with hypocomplementemia at 3 months 5/18 (27.8) 9/20 (45)
‘prior to onset
No. (%) scored “active” on the SLEDAI at 3 25 (78.1) 19 (65.5)
months prior to onset
Mean SLEDAI score at 3 months prior to onset 5.4 4.6
* There was no statistically significant difference between the pregnancies in which there was an SLE
flare and those in which there was not a flare, for any of these parameters. See Table 1 fix explanations
and definitions of abbreviations.

with a SLEDAI value of 0. These patients were then
observed for flare over a subsequent period of 12 months.
Statistical analysis. Each pregnancy was treated as a
separate observation for analysis. Continuous variables
were examined using Student’s t-test. Categorical responses
were analyzed using chi-square techniques or Fisher’s exact
test where applicable. Logistic regression analyses were
performed to assess the role of disease activity at onset of
pregnancy (time 0) as a prognostic factor for flare during
pregnancy, or during the followup period in controls.
RESULTS
There were 79 pregnancies in 46 patients (40
white, 3 black, 1 Chinese, 1 Japanese, and 1 Filipino).
Twenty-eight patients had 1 pregnancy each, 10 had 2
pregnancies each, 4 had 3, 2 had 4, 1 had 5 , and 1 had
6. Of the 79 pregnancies, 18 ended in therapeutic
abortions and 61 in deliveries (42 live births, 3 still-
births, 16 spontaneous abortions).
Table 1 shows the clinical and laboratory fea-
tures of the mothers during all 79 pregnancies, sub-
grouped according to those ending in delivery or in
therapeutic abortion. The mean age at onset of preg-
nancy was similar in all 3 groups. The disease duration
at the onset of pregnancy seemed to be longest for
those women who did not have therapeutic abortions
and shortest for those who did. Similar numbers of
patients in the 3 groups were taking corticosteroids,
immunosuppressive drugs, and chloroquine at the
onset of pregnancy.
Laboratory results, including abnormalities in
the PTT, platelet count, anti-DNA antibody level, or
complement level any time during the 12 months prior
to pregnancy, were not significantly different among
the 3 groups. An elevated SLEDAI score at 3 months
prior to the onset of pregnancy, signifying active
disease, was seen for 57 of the 79 total pregnancies and
for 44 of the 61 pregnancies that did not end in
therapeutic abortion. In 13 of the 18 pregnancies
ending in therapeutic abortion, the mother had active
disease prior to the pregnancy.
A true flare of lupus was recorded as having
occurred when the SLEDAI score increased by 2 or
more units. Among the total group of 79 pregnancies,
37 were considered to have included a disease flare
and 42 to have not included a flare. In the 61 pregnan-
cies ending in delivery, 32 were found to have included
a flare during pregnancy ( 15 [47%] in the first trimes-
ter, 10 [31%] in the second trimester, 4 [13%] in the
third trimester, and 3 [9%] in the postpartum period),
and 29 to not have included a flare (Table 2). Among
the pregnancies ending in therapeutic abortion, 5 in-
cluded a flare and 13 did not (Table 3).
SLE FLARE IN PREGNANCY 1395

Table 3. Features investigated as possible factors prognostic of SLE disease flare during pregnancy,
in 18 pregnancies ending in therapeutic abortion*
Flare (n = 5 ) No flare (n = 13)
Age (years) at onset, mean 27.6 28.4
Disease duration (months) at onset, mean 55.2 48.1
Pregnancy no., mean 2.0 1.5
Duration of steroid treatment (months) at onset, 28 28
mean
No. taking steroids at onset It 9
No. taking cytotoxic drugs at 12 months or 3 0 0
months prior to onset
No. taking chloroquine at 3 months prior to 1 5
onset
No. with increased FTT at 3 months prior to 013 1I7
onset
No. with thrombocytopenia at 3 months prior 015 1/10
to onset
No. with anti-DNA at 3 months prior to onset 115 019
No. with hypocomplementemia at 3 months 215 419
prior to onset
No. scored “active” on the SLEDAI at 3 315 10113
months prior to onset
Mean SLEDAI score at 3 months prior to onset 2$ 5.5
* There was no statistically significant difference between the pregnancies in which there was an SLE
flare and those in which there was not a flare, for any of these parameters, although significance was
approached in some cases (see below). See Table 1 for explanations and definitions of abbreviations.
t P = 0.08 versus pregnancies during which there was no flare.
f P = 0.06 versus pregnancies during which there was no flare.

In the total group of 79 pregnancies, age, dis- had either continuing active disease or flare, while
ease duration, pregnancy number, duration of steroid only 13 had improvement. Of the 22 pregnancies for
therapy, and use of steroid or other disease- which disease was inactive at the onset, it remained
suppressive medications did not distinguish those in inactive in 13 (59%) and became active in 9 (41%). The
which flare occurred from those in which it did not. presence of active disease during pregnancy was sig-
Hypertension prior to pregnancy was associated with nificantly correlated with active disease at pregnancy
flare in 3 of 4 patients. Pregnancy-induced hyperten- onset (P= 0.01). In the 44 patients with active disease
sion occurred in 6 patients, all of whom had a flare. during pregnancy (of the 57 whose disease was active
However, major organ involvement (renal, CNS, vas- prior to pregnancy), the disease actually became more
culitis) was not a predictor of flare. Examination of active (i.e., flared) in 28 and remained persistently
various laboratory features also failed to reveal a active in 16.
prognostic factor for lupus flare. Similar results were The same result was found when analyzing only
found when the data were examined separately in the the 61 pregnancies resulting in a delivery (Table 4). In
group of 61 pregnancies ending in delivery (Table 2)
and in the group of 18 pregnancies ending in therapeu-
tic abortion (Table 3). Table 4. Systemic lupus erythematosus disease activity at onset of
pregnancy as a prognostic factor for active lupus during pregnancy,
The patients were then grouped according to in 61 pregnancies
whether their disease was active or inactive just prior
to the onset of pregnancy. If the disease was active, Active disease Inactive disease
at onset at onset
then active disease was examined as a prognostic (n = 44) (n = 17)
factor for continued disease activity or flare during the
pregnancy. If the disease was completely inactive Active diseaselflare during 36* 7
pregnancy
prior to pregnancy, then a flare was recorded if there Inactive disease during 8 10
was an increase of >2 units in the SLEDAI score. pregnancy
Of the 57 pregnancies during which the mother * P = 0.003 versus pregnancies in which disease was inactive at
had active SLE at the onset of pregnancy, 44 (77%) onset.
1396
Table 5. Frequency of SLE flares during the followup period in
pregnant SLE patients and nonpregnant SLE controls*
Active
diseaseiflare
during % In the 61 pregnancies resulting in births, 35 m
Study group (n) followup with flare
Pregnant SLE patients (61) 43 70
Matched SLE controls (59) 47 80
Matched controls, active 40 82
disease at onset (49)
Matched controls, inactive 7 70
disease at onset (10)
Pregnant SLE patients, active 36 82
disease at onset (44)
Pregnant SLE patients, inactive 7 41t
disease at onset (17)
Controls with SLEDAI score of 0 161 74
(219)
* Followup period consisted of pregnancy and 3 months postpartum
in pregnant patients, and 12 months in nonpregnant control patients.
“Onset” refers to onset of pregnancy or, in controls, beginning of
the 12-month study period. Matched SLE control patients were
matched with pregnant SLE patients for age, disease duration, and
SLEDAI score. See Table I for definitions.
t P = 0.002 versus the percentage of pregnant patients with active
disease at onset.
the 44 of 61 pregnancies with active disease at onset, the
disease remained active or flared in 36 and improved in
8. Of the 17 in which the SLE was inactive at onset, the
disease flared in 7 and remained inactive in 10. Active
disease at pregnancy onset was again correlated with
active disease during pregnancy (P= 0.003).
When the pregnant SLE patients were com-
pared, by logistic regression, with nonpregnant SLE
controls matched for age, sex, disease duration, and
SLEDAL score, it was further demonstrated that dis-
ease activity at pregnancy onset played a major role in
determining flare (P = 0.002) (Table 5 ) . In these
matched populations, the flare rate in the controls with
initially active disease (40 of 49, 82%) did not differ
markedly from the flare rate in the controls with
inactive disease (7 of 10, 70%), but the flare rate in
pregnant patients with initially active disease (36 of 44,
82%) was substantially higher than that among preg-
nant patients with inactive disease (7 of 17, 41%).
Among the 219 female patients with an initial
SLEDAI score of 0 who were followed up for 12
months, 161 flares were observed (74%). Logistic
regression of data on these women and on the pregnant
patients, adjusted for disease duration and age, indi-
cated no significant difference between flare rates in
the pregnant women with initially active disease and
UROWITZ ET AL
the controls with inactive disease, but a significantly
lower rate of flare in the pregnant patients with initially
inactive disease compared with controls (P = 0.002)
(Table 5).
others were taking corticosteroids at pregnancy onset;
in 11 of these patients, the SLE became or remained
inactive, and in 24 it remained active or flared during
pregnancy. Of the 18 patients whose disease remained
inactive during pregnancy, 7 took steroids throughout
the pregnancy, but the dosage was 510 mg/day in all
but 2. Of the 43 patients whose disease was persis-
tently active or flared during pregnancy, 15 took
corticosteroids during pregnancy, at dosages > 10 mg/
day in 12 (Table 6). Thus, more of the patients with
active disease took higher-dose prednisone during
pregnancy (P < 0.05).
Persistent disease activity during pregnancy
was not associated with fetal loss, with 6 of 19 losses
occurring in the inactive disease group and 13 of 19 in
the active disease/flare group. Since very few patients
had a change in disease activity status between 12
months and 3 months prior to pregnancy, it was not
possible to compare these 2 variables as predictors of
subsequent disease activity.
DISCUSSION
The issue of SLE disease activity during preg-
nancy has focused on flare of the disease. The concept
of flare implies more disease than existed at baseline.
However, persistently active SLE at a constant level
pre-, during, and post-pregnancy, though not neces-
sarily seen as a “flare,” would still require medical
management, especially the use of antiinflammatory
Table 6. Corticosteroid therapy during 61 pregnancies in systemic
lupus erythematosus patients
Persistently
active
Inactive disease disease/
during Rare during
pregnancy pregnancy
(n = 18) (n = 43)
No. taking steroids at onset of 11 24
pregnancy
No. taking steroids throughout 7 IS
pregnancy
No. taking steroids at >10 mg/ 2 12”
day during pregnancy
* P < 0.05 versus patients with inactive disease during pregnancy.
SLE FLARE IN PREGNANCY
and immunosuppressive treatments. We have exam-
ined this issue by investigating disease activity prior to
pregnancy as a prognostic factor for the state of SLE
during and shortly after pregnancy, with consequent
implications for the choice of therapy in these patients.
As well, we have compared disease activity or flare in
pregnant lupus patients with findings in age-, sex-,
disease duration-, and disease activity-matched non-
pregnant SLE patients being followed up prospec-
tively in our lupus clinic and in a large number of lupus
patients with inactive disease who were followed up
for 12 months.
A search for factors prognostic of SLE flare in all
of the pregnant patients in this study did not reveal any
clinical or laboratory features predictive of flare. Hyper-
tension at the onset of pregnancy and pregnancy-induced
hypertension were associated with flare, but the num-
bers of affected patients were small.
In our case-control studies, flares in lupus
occurred frequently and in similar percentages of
pregnant SLE patients and control SLE patients.
Active lupus at onset, both in controls and in pregnant
patients, was not predictive of flare. Inactive lupus at
onset was not protective against flare in controls, but
was protective in pregnant SLE patients (P = 0.002).
How pregnancy and inactive lupus together protect
against flare is not clear.
In 57 of the total of 79 pregnancies and 44 of the
61 ending in delivery, the lupu s was active at the onset
of pregnancy. This active disease necessitated treat-
ment with corticosteroids during pregnancy in 22
patients, and an increased percentage of these patients
required >10 mg of prednisone per day.
Although fetal outcome is not reported in detail
herein, no increase in fetal loss was demonstrated in
the patients with active disease during pregnancy.
Our results are consistent with those of Lock-
shin and colleagues (2,5) and Mintz et al (3), who
found no increase in flares during pregnancy, although
their studies did not use a validated measure of disease
activity. Petri et a1 (4) used both the Lupus Activity
Index (10) and the SLEDAI in addition to physician
global assessment, and found a higher rate of flare
1397
during pregnancy compared with the rate in the same
patients postpartum or in the Johns Hopkins Univer-
sity lupus cohort overall. However, the controls were
not matched to the patient group for disease activity.
Moreover, one might speculate that the flare rate in
patients postpartum would be lower because they
might have had increased medications for flares during
pregnancy.
Women with SLE who are considering preg-
nancy may be counseled about persistently active SLE
or flare in SLE, based on the status of their disease
activity at onset. Whenever possible, the physician
and the patient should strive to achieve inactive dis-
ease at onset of pregnancy, to provide for optimum
conditions for protection against disease flare during
pregnancy.
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