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Lupus pregnancy. a prospective study of placental changes

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358
LUPUS PREGNANCY
A Prospective Study of Placental Changes
JOHN G. HANLY, DAFNA D. GLADMAN, TOBY H. ROSE, CARL A. LASKIN, and
MURRAY B. UROWITZ
Eleven patients with systemic lupus erythematosus (SLE) were monitored prospectively during pregnancy. Clinical and serologic features of disease activity
were recorded, and after delivery, a careful search for
pathologic changes in the placenta was carried out.
Seven patients delivered live infants, and 4 patients had
unsuccessful pregnancies, with fetal loss occurring between 12 and 27 weeks of gestation. One of these 4
patients had active SLE at delivery, and all had circulating lupus anticoagulant and thrombocytopenia.
Other serologic abnormalities, including anticardiolipin
and anti-Ro antibodies, were not associated with fetal
loss. The overall placental size was reduced in SLE
patients compared with that in healthy controls and in
diabetic controls. A variety of pathologic changes were
From the University of Toronto Rheumatic Disease Unit,
Women’s College Hospital, the Wellesley Hospital, and Toronto
General Hospital; the Department of Pathology, Women’s College
Hospital; and Mount Sinai Hospital Research Institute, Toronto,
Ontario, Canada.
Supported by grants from the Ontario Lupus Association
and, in part, by the Medical Research Council and the Canadian
Arthritis Society.
John G. Hanly, MD, MRCPI, FRCP(C): Rheumatology
Fellow, University of Toronto Rheumatic Disease Unit; Dafna D.
Gladman, MD FRCP(C), FACP: Associate Professor of Medicine
and Rheumatologist, University of Toronto Rheumatic Disease
Unit; Toby H . Rose, MD, FRCP(C): Assistant Professor of Medicine and Pathologist, University of Toronto, and Department of
Pathology, Women’s College Hospital; Carl A. Laskin, MD,
FRCP(C): Assistant Professor of Medicine and Rheumatologist,
University of Toronto Rheumatic Disease Unit, and Mount Sinai
Hospital Research Institute; Murray B. Urowitz, MD, FRCP(C):
Professor of Medicine and Rheumatologist, University of Toronto
Rheumatic Disease Unit.
Address reprint requests to Dafna D. Gladman, MD, Women’s College Hospital, Burton Hall, Room 423, 60 Grosvenor
Street, Toronto, Ontario, M5S lB6, Canada.
Submitted for publication February 13, 1987; accepted in
revised form August 28, 1987.
Arthritis and Rheumatism, Vol. 31, No. 3 (March 1988)
noted, including placental infarction, intraplacental hematoma, deposition of immunoglobulin and complement, and thickening of the trophoblast basement membrane. The reduction in placental size appeared to
enhance the clinical significance of these pathologic
changes.
Fetal loss is increased in patients with systemic
lupus erythematosus (SLE) because of a greater incidence of prematurity, spontaneous abortion, and iritrauterine death (1-4). To explain this increased fetal
loss, various immunologic abnormalities have been
identified, including trophoblast-reactive lymphocytotoxic antibodies (9, the lupus anticoagulant (6,7),
anti-Ro antibodies (8,9), and more recently, anticardiolipin antibodies (10,ll). Studies (without control
subjects) of combined therapy with corticosteroid and
aspirin in SLE patients and in other patients who had
histories of recurrent fetal loss have resulted in modulation of some immunologic abnormalities and a
successful outcome of pregnancy in many instances
(12,13). Despite these impressive clinical-immunologic associations, however, the precise pathophysiologic mechanisms underlying fetal loss in SLE patients
remain undetermined.
There is a relative paucity of information regarding placental changes in SLE patients. Positive
findings include placental infarction (10-14), decidual
vasculopathy (13,14), and immune complex deposition
(14,15). Ultrastructural abnormalities have not been
specifically analyzed. Furthermore, the interrelationships between pathologic findings, immunologic abnormalities, and outcome of pregnancy have not been
well documented.
The present study was undertaken in an attempt
359
LUPUS PREGNANCY
to clarify these issues and to enhance our understanding of the mechanisms underlying fetal loss in women
with SLE. Our aim was to prospectively examine
placental changes in SLE patients in relation to concurrent maternal disease activity, immunologic abnormalities, and outcome of pregnancy.
PATIENTS AND METHODS
Patients. All pregnant SLE patients seen at the
University of Toronto Rheumatic Disease Service from
January 1985 to June 1986 were asked to participate in the
study. This request was made without regard to the patient’s
obstetric history. Eleven patients, all of whom fulfilled the
American Rheumatism Association revised criteria for SLE
(161, were studied. Ten had well-documented SLE prior to
study entry, and in the remaining patient, SLE was diagnosed during the then-current pregnancy. One patient with
circulating antinuclear antibody (ANA), anti-Ro antibody,
and anti-La antibody, but no other serologic or clinical
features of SLE, was also studied.
Nine patients were seen by a rheumatologist and an
obstetrician at frequent intervals, usually every 4-8 weeks,
during pregnancy. Three patients were seen only once
during the study: Patient FV had a spontaneous abortion at
12 weeks gestation, shortly after her first study assessment,
patient AD-S was diagnosed as having SLE shortly before
the end of the pregnancy, and patient JP was seen for the
first time during the final week of pregnancy. The activity of
SLE in the mother was quantified at each assessment using
the lupus activity criteria count (LACC) (17), a validated
index of disease activity in SLE, which is derived from
clinical and serologic variables. The LACC ranges from 0 to
7, and a score of 2 or more signifies the presence of active
SLE. The dosage of oral corticosteroid was adjusted by the
rheumatologist, as dictated by the overall disease activity; it
was not altered solely because of isolated immunologic
variables. In particular, no attempt was made to specifically
treat the lupus anticoagulant or anticardiolipin antibodies if
present.
Serology and other laboratory investigations. At each
clinical assessment, routine urinalysis was performed, and
peripheral blood was obtained for the following investigations: hemoglobin value, total white blood cell and differential cell counts, platelet count, ANA (on HEp-2 cell substrate), L E cell preparation, DNA antibodies (by Farr assay
IlS]), C3, C4, and total hemolytic complement (CH50)
levels, and activated partial thromboplastin time (FTT). If
the initial PTT was prolonged, the presence of an antiphospholipid-type antibody was sought using the platelet neutralization procedure (PNP) (19). The combination of a prolonged PTT and a positive PNP result was taken as an
indication of the presence of a circulating lupus anticoagulant. Other serologic variables assessed on at least I occasion during the pregnancy included antibodies to RNP, Sm,
and La antigens by counterimmunoelectrophoresis, using
rabbit thymus nuclear extract as the antigen source, and
anti-Ro antibodies by double diffusion, using human spleen
extract as the antigen source. The VDRL test was carried
out in 10 patients.
Antibodies to cardiolipin were determined by enzymelinked immunosorbent assay in 6 patients. The assay is
described in detail elsewhere (20). Briefly, test sera, at a I: 100
dilution, were added to flat-bottom microtiter plates (Gibco
Canada, Burlington, Ontario, Canada) coated with cardiolipin
micelles (Sigma, St. Louis, MO). After incubation, the plates
were washed, and urease-conjugated, heavy chain-specific,
anti-human IgG or IgM (Allelix, Mississauga, Ontario, Canada) was added. After appropriate incubation and a final
wash, urease substrate 620 (Allelix) was added. The optical
density of the individual wells was read at 620 n m using an
MR600 plate reader (Dynatech, Alexandria, VA). All values
that were at least 2 standard deviations above the mean of
normal control values were considered positive.
Pathologic study. Placental tissue was obtained from
all SLE patients (whole placenta from 9 and placental
fragments from 2 after uterine curettage) and from the
patient with isolated circulating autoantibodies. Whole placentae from 7 mothers with diabetes and from 10 healthy
mothers were used as controls. Immediately following delivery, 2 small sections were cut from the periphery of the
placenta, where the membranes reflect, and the sections
were fixed in Michel’s solution (21) for immunofluorescence
examination later. These sections and the remainder of the
placenta were taken to the pathology department for full
evaluation. The placental weight was noted, and a careful
search made for any gross evidence of infarction or hematoma formation. Sections were cut and stained with hematoxylin and eosin for routine analyses. Examinations for
deposits of IgG, IgM, IgA, and C3 were performed by direct
immunofluorescence using commercially available goat antiIgG, anti-lgM, anti-IgA, and antLC3 (Kallestad, Austin,
TX). Tissue for electron microscopy was placed in universal
fixative and postfixed in 2% osmium tetroxide.
RESULTS
The mean age of the SLE patients was 28.3
years at the time of delivery (Table I ) . Three patients
were primigravidas. Four patients were in their second pregnancy; 2 of these patients had previously had
spontaneous abortions, and the other 2 had had therapeutic abortions. Among the remaining 4 SLE patients, there had been a total of l l previous pregnancies, but only 1 live birth. In this group, fetal loss had
occurred secondary to spontaneous abortion in 7 cases
and intrauterine death in 3 cases. Four patients had a
history of renal disease, and 1 patient had a history of
central nervous system involvement.
Prior to pregnancy, 7 of these patients were
taking prednisone daily (mean 1 I .3 mg, range 2.5-20
mg), which was continued throughout the pregnancy.
Two of these patients were also taking chloroquine,
which was discontinued, and a third was taking azathioprine, which was discontinued when it was found
HANLY ET AL
Table 1.
Clinical features at the time of delivery in 1 I pregnant women with SLE and in 1 pregnant woman with circulating autoantibodies*
Obstetric history
Patient
Age
Gravida
Para
Abortus
SM
RF
A0
DMc
LT
DM
BP
FV
DP
RL
AD-S
JP
26
30
25
29
29
25
31
34
25
25
32
24
2
2
0
0
0
0
0
0
0
0
0
I
0
I
1 (S)
1
2
7
1
I
I
5
3
3
4
2
1 (T)
0
I
6)
I (T)
0
0
2 (S)
2 (S)
1 (S)
2 (S)
Intrauterine
death
No. of SLE
criteria present
0
0
0
0
0
0
0
2
0
0
6
5
4
6
6
6
5
4
4
4
4
I
0
0
Renal
involvement
CNS
involvement
-
-
-
-
-
+
-
-
+
+
f
-
+
-
-
* Patient J P had antinuclear, anti-Ro, and anti-La antibodies, but no other serologic or clinical features of systemic lupus erythematosus (SLE).
CNS = central nervous system: S = spontaneous; T = therapeutic.
that she was pregnant. Patient JP, who had circulating
autoantibodies, was in her second pregnancy; she was
previously delivered of a female infant who had congenital heart block.
Maternal SLE disease activity, as reflected by
the first LACC score during pregnancy (mean of 7
weeks gestation, range 2-13 weeks), the score at the
final assessment before delivery (mean of 6 days,
range 0-20 days), and the mean LACC score during
pregnancy, is shown in Table 2. The mean scores did
not indicate an overall activation of SLE during pregnancy in any of the 9 patients in whom serial assess-
ments were made. However, 3 patients (SM, AO, and
LT) had active disease at their first assessment. In all
cases, control of the SLE was regained after a modest
increase in the daily dosage of prednisone (7.5-10 mg).
Two additional patients (DM and DMc) had an increase in disease activity late in their pregnancies, as
reflected in the final LACC scores. SLE remained
active in patient DM until the postpartum period,
despite an increase in the prednisone dosage from 15
mg/day to 35 mg/day. Patient DMc refused to increase
the daily dosage of prednisone. Live infants were born
to all of these patients. Patient AD-S, who was first
Table 2. Disease activity and outcome of pregnancy in I I women with SLE and in I woman with
circulating autoantibodies*
LACC score
Patient
First
Final
Mean
SM
RF
3
I
I
I
1.7
I .o
A0
DMc
LT
DM
BP
FV
DP
RL
AD-S
JP
2
I
2
1.2
I .3
1.6
1
3
I
I
ND
I
0
ND
NA
I
2
1
I
I
0
3
NA
1.8
I .0
ND
0.8
0
ND
NA
Outcome of pregnancy
(weeks gestation)
Live birth (40)
Live birth, neonatal lupus
syndrome (40)
Live birth (39)
Live birth (38)
Live birth (37)
Live birth (37)
Live birth (36)
Spontaneous abortion ( I 2)
Intrauterine death (21)
Intrauterine death (27)
Neonatal death (26)
Live birth, isolated
congenital heart block (38)
* Patient JP had antinuclear, anti-Ro, and anti-Laantibodies, but no other serologic or clinical features
of systemic lupus erythematosus (SLE). LACC = lupus activity criteria count (for details see ref. 17).
The first LACC score was obtained at 2-13 weeks of gestation (mean 7 weeks); the final LACC score
was obtained at 0-20 days before delivery (mean 6 days). ND = not done: NA = not applicable.
361
LUPUS PREGNANCY
seen at the rheumatology service 48 hours prior to
delivery, also had active SLE. Despite the prompt
administration of high doses of corticosteroids, premature delivery was precipitated by fetal distress, which
culminated in neonatal death.
Live infants were born to 7 of the SLE patients.
Three patients had spontaneous premature deliveries
of healthy live babies at 36 weeks and at 37 weeks of
gestation (1 patient and 2 patients, respectively). One
baby had a neonatal lupus syndrome, which was
manifested clinically by a transient, characteristic skin
rash. Four SLE patients (FV, DP, RL, and AD-S) had
unsuccessful pregnancies: 1 spontaneous abortion, 2
intrauterine deaths, and 1 neonatal death after premature delivery because of fetal distress. Patient JP, the
patient with circulating autoantibodies, was delivered
of a live infant who had isolated congenital heart
block.
Circulating autoantibodies and hypocomplementemia identified in the patients during pregnancy are
shown in Table 3. Ten patients were positive for ANA;
the other 2 patients previously had detectable ANAs.
Anti-RNP and anti-Sm antibodies were present in 1
patient, anti-Ro antibodies were present in 5 patients,
anti-La antibodies were detected in 1 patient, and
anti-DNA antibodies were found in 9 patients. Hypocomplementemia was detected in 5 patients. One patient had a low absolute C3 level, 4 patients showed low
levels of C4, and 1 patient had a low level of CH5O.
The presence of antiphospholipid antibodies
and of thrombocytopenia during pregnancy are shown
in Table 4. The PTT was prolonged in 4 patients, all of
whom had a positive PNP result, which confirmed the
presence of an antiphospholipid antibody. In 2 patients
with a prolonged PTT in whom serial assessments were
available (patients DP and RL), the PTT remained
prolonged throughout pregnancy. Anticardiolipin antibodies were detected in all 6 patients examined (IgG in
5 patients and IgM in 4 patients). Serial anticardiolipin
levels in 5 patients (SM, DMc, LT, DM, and BP)
fluctuated within and above the normal range. The
VDRL test result was negative in all 10 patients tested.
Of interest, thrombocytopenia (<150 x lO’/liter) was
present in the same 4 patients who had a prolonged PTT
and a positive PNP result. The lowest platelet count
varied from 97 x 10’lliter to 127 x lO’/liter. The
decrease in the platelet count during pregnancy ranged
from 73 x lO’/liter to 105 x lO’/liter, and it occurred
within 3 weeks of fetal loss.
The 4 patients who had unsuccessful pregnancies all had thrombocytopenia and circulating lupus
anticoagulant, as indicated by a prolonged PTT and a
positive PNP result. In only 1 of these patients (AD-S)
were anticardiolipin levels known, and it is interesting
that this patient’s anticardiolipin levels were higher
than those in any of the patients with successful
pregnancies in whom the data were available. The
presence of other autoantibodies or of hypocomplementemia was not consistently associated with fetal
loss. Furthermore, there was no apparent obstetric
cause of fetal loss, such as intrauterine infection or
strangulation by the umbilical cord. Of the 7 SLE
Table 3. Autoantibodies, hypocomplementemia, and outcome of pregnancy in 11 women with SLE and in 1 woman with circulating
autoantibodies*
~
~~~
~
H ypocomplementemia
Patient
SM
RF
A0
DMc
LT
DM
BP
FV
DP
RL
AD-S
JP
ANA
+
+
+
+
+
+
+
+
+
i
RNP
Sm
Ro
La
DNA
+
+
+
+
+
+
+
+
+
-
c3
c4
CH.50
Outcome of pregnancy
Live birth
Live birth, neonatal
lupus syndrome
Live birth
Live birth
Live birth
Live birth
Live birth
Spontaneous abortion
Intrauterine death
Intrauterine death
Neonatal death
Live birth, isolated
congenital heart block
* Patient JP had antinuclear antibody (ANA), anti-Ro, and anti-La antibodies, but no other serologic or clinical features of systemic lupus
erythematosus (SLE).
HANLY ET AL
362
Table 4. Antiphospholipid antibodies, thrombocytopenia, and outcome of pregnancy in 11 women with SLE and in 1 woman with
circulating autoantibodies*
PTT
Patient
PN P
IgM
kG
VDRL
Thromboc ytopenia
Outcome of pregnancy
Live birth
Live birth, neonatal
lupus syndrome
Live birth
Live birth
Live birth
Live birth
Live birth
Spontaneous abortion
Intrauterine death
intrauterine death
Neonatal death
Live birth, isolated
congenital heart block
SM
RF
N
N
ND
ND
ND
+
ND
-
ND
A0
DMc
LT
DM
BP
FV
DP
RL
AD-S
JP
N
N
N
N
N
E
E
E
E
N
ND
ND
ND
ND
ND
ND
ND
-
-
(43/33)
(55/32)
(47/33)
(4707)
+
+
+
+
+
+
+
+
+
+
ND
ND
ND
ND
ND
ND
ND
ND
ND
+
+
-
-
-
ND
-
+
+
+
+
-
* Patient J P had antinuclear, anti-Ro, and anti-La antibodies, but no other serologic or clinical features of systemic lupus erythematosus (SLE).
PTT = activated partial thromboplastin time (N = normal; E = elevated; numbers in parentheses are the results, in seconds, compared with
the control values); PNP = platelet neutralization procedure (see Patients and Methods and ref. 19 for details). A platelet count <150 x 109/liter
showed thrombocytopenia. ND = not done.
patients who gave birth to live infants, 5 had elevated
levels of anticardiolipin antibodies, and 4 had anti-Ro
antibodies. Patient JP, whose infant had isolated congenital heart block, and patient RF, whose infant had a
transient neonatal lupus syndrome, also had circulating
anti-Ro antibodies.
Figure 1 shows a comparison of the weights of
placentae from 9 SLE patients, 10 healthy controls,
and 7 control subjects with diabetes. Weights are
expressed in units of standard deviations (Z values)
(22) from the predicted mean for normal subjects,
according to the method of Gruenwald and Minh (23).
The placentae from the SLE patient group were
smaller than were those from both control groups.
Five SLE placentae were more than 1 standard deviation below the expected mean, and l was more than
2 standard deviations below the expected mean. A
similar trend was seen in the ratios of placental weight
to birth weight, as compared with the expected values
for gestation (23). For 7 SLE patients, the ratio was
lower than was expected, which shows that the birth
weight was not reduced, despite the reduction in
placental size. In contrast, the ratio of placental weight
to birth weight was greater than the predicted ratio for
all healthy and diabetic controls. The finding that 7 of
the normal placentae were more than 1 standard
deviation above the predicted mean was not expected,
and the reason for this is not clear. The methods we
used to weigh the placentae were similar to those
described by Gruenwald and Minh (23). In the present
study, all placentae were examined according to the
same protocol in the same pathology department. If
anything, the use of Gruenwald's data would minimize
any reduction in placental weights in the SLE patients
we studied.
:
6 -
4 '
w
3
2 '
s
N
8
:
-I
0 '
-2
-4
HEALTHY DIABETIC
CONTROLS CONTROLS
Figure 1. Weights of placentae from patients with systemic lupus
erythematosus (SLE), patient JP, who had circulating autoantibodies but no other serologic or clinical features of SLE (0),healthy
control subjects, and control subjects with diabetes. Units are
standard deviations (Z values) (22) from the predicted mean for
normal subjects, according to the method of Gruenwald and Minh
(23).
LUPUS PREGNANCY
363
Additional pathologic findings in the placentae
are summarized in Table 5. Two SLE patients (RF and
AD-S) had extensive placental infarction that occupied
an estimated 30-40% of the entire placental mass.
Two additional patients (BP and RL) had intraplacental hematomas, one of which occupied an estimated 30% of the involved placenta. These findings
were not present in placentae from either of the
control groups. Decidual vessels were identified in 4
SLE placentae (from patients SM, DM, RL, and
AD-S) and in the placenta from the woman with
circulating autoantibodies (patient JP). All decidual
vessels were considered to be normal and had no
evidence of infiltration by acute or chronic inflammatory cells.
Linear or granular deposition of IgG or C3,
localized to the trophoblast basement membrane, was
identified by immunofluorescence in 1 SLE placenta,
in the placenta from patient JP, and in 8 of the control
placentae (6 healthy controls and 2 diabetic controls).
Electron microscopy revealed thickening of the trophoblast basement membrane (Figure 2) in 3 SLE
placentae and in the placenta from patient JP. This
finding was not detected in any of the normal placentae
studied, but it was present in 2 placentae from diabetic
mothers. Splitting of the trophoblast basement mem-
brane was also detected in placental tissue from 1
diabetic patient.
Correlations between placental weights and
clinical and serologic variables were difficult to ascertain because of the small number of patients involved.
However, the following abnormalities were more frequently present during pregnancy in the 6 SLE patients with the lowest placental weights, compared
with the 3 patients with placentae of normal or above
normal weight: active SLE (LACC score 2 2 ) (83%
versus 33%), lupus anticoagulant and thrombocytopenia (33% versus O%), and hypocomplementemia (67%
versus 33%). Interestingly, the presence of anticardiolipin antibodies was not associated with a reduction in
placental weight (67% versus 66%). Fetal loss was not
always associated with a reduction in placental size; 4
SLE patients with small placentae (SM, AO, LT, and
DM) had healthy babies. The remaining 2 patients (RL
and AD-S), who had unsuccessful pregnancies, had
the lowest placental weights of any study subject; an
intraplacental hematoma and placental infarction, respectively, were found in the placentae.
There was no consistent association of other
pathologic abnormalities with disease activity, the
presence of autoantibodies, or the presence of hypocomplementemia. Of the 4 patients with circulating
Table 5. Pathologic findings in placentae from I I women with SLE, 1 woman with circulating autoantibodies, and 10 healthy and 7
diabetic control subiects*
Subject
SLE patients
SM
RF
A0
DMc
LT
DM
BP
FV
DP
RL
AD-S
Patient JP
Control subjects
Healthy
Diabetic
Placental
weight
(Z value)
Gross and
microscopic
appearance
- 1.39
Normal
Infarction
Normal
Normal
Normal
Normal
Hematoma
NA
NA
Hematorna
Infarction
Normal
IgG, C3
Normal
ND
Normal
Normal
Normal
Normal
Normal
Normal
ND
Normal
c3
Normal
Normal
Normal
Normal
ND
Trophoblast
Trophoblast
Normal
Trophoblast
NA
NA
Trophoblast
Normal
IgG (n = I),
C3 (n = 5 )
C3 (n = 2)
Normal
0.23
- 1.74
2.00
- 1.34
- 1.08
0.73
NA
NA
- 1.86
-2.12
0.35
Normal
Immunofluorescence
findings
Electron microscopy findings
BM thickening
BM thickening
BM thickening
BM thickening
Trophoblast BM thickening (n = 21,
splitting of trophoblast BM (n = I )
* Patient JP had antinuclear, anti-Ro, and anti-La antibodies, but no other serologic or clinical features of systemic lupus erythematosus (SLE).
Placental weight is expressed in units of standard deviations (Z values) (22) from the predicted mean for normal subjects (23). ND = not done:
BM = basement membrane; NA = not available (only fragments of placental tissue were obtained for examination after uterine curettage).
HANLY ET AL
364
A
B
Figure 2. Electron microscopic appearance of placental tissue samples. A, Normal trophoblast basement membrane. B, Thickened
trophoblast basement membrane in section from a patient with systemic lupus erythematosus. (Magnification x 3,800.)
lupus anticoagulant, 2 (RL and AD-S) had definite
evidence of major vascular events (extensive placental
infarction and large intraplacental hematoma). In the
other 2 patients with circulating anticoagulant (FV and
DP), placental infarction or hematoma formation could
not be determined from the fragments of placental
tissue that were available for examination; both patients
had uterine curettage because of incomplete spontaneous abortion and because of intrauterine death, respectively. Two additional patients (RF and BP) had substantial macroscopic placental changes, but in contrast
to the patients just described, circulating lupus anticoagulant was not present, placental size was normal, and
both patients were delivered of live infants.
DISCUSSION
Although the outcome of pregnancy in patients
with SLE has improved considerably in recent years,
the frequency of fetal loss remains higher in SLE
patients than in the general population (24). To date,
studies have individually identified clinical, immunologic, and pathologic abnormalities (1-15) that explain
this increased fetal loss, but the precise pathophysiologic mechanisms remain unclear. The present study is
a comprehensive evaluation of pregnancy in a group of
SLE patients, with special emphasis on pathologic
changes in the placenta. The finding of reduced placental size in SLE patients suggests that these patients’ pregnancies are vulnerable to any pathologic
changes which may occur. In particular, placental
infarction, possibly mediated through immunologic
mechanisms, is poorly tolerated.
The association of active SLE with prematurity
and fetal death, which has been reported by others
(1,3,24), was evident in this study. Disease activity
was quantified by the LACC score, which is a validated index of disease activity in SLE (17). Three
patients had active SLE at their first assessment, and
3 other patients had active disease at their final assess-
LUPUS PREGNANCY
ment before delivery. However, 5 of these patients
had serial assessments performed during pregnancy,
and they had normal mean LACC scores, which
indicated quiescent SLE overall. All 5 patients had
live infants; 2 of the infants were premature. In the
remaining patient, who had only one assessment during the study and had one of the highest LACC scores
recorded, the pregnancy was unsuccessful.
Autoantibodies that have been associated with
fetal loss in SLE patients include the lupus anticoagulant (6,7,12,13), anticardiolipin antibodies (10,l l), and
anti-Ro antibodies (8,9). The lupus anticoagulant is an
immunoglobulin (IgM or IgG) directed against 1 or a
group of phospholipids (25). It is usually identified by
the failure of a prolonged phospholipid-dependent
coagulation time to return to normal when the patient’s plasma is mixed at a 1:l ratio with normal
plasma (26). The methods of the present study were
adopted because of evidence of their greater specificity compared with the more conventional methods
(19). In our study, the presence of a circulating lupus
anticoagulant during pregnancy was consistently associated with fetal loss. All 4 patients with unsuccessful
pregnancies had circulating lupus anticoagulant.
Thrombocytopenia, which is associated with the lupus
anticoagulant (4) and fetal loss in SLE (lo), was also
present in these 4 patients. Furthermore, fetal loss had
occurred in 10 of 11 previous pregnancies in these 4
patients. Antibodies to cardiolipin have recently been
associated with fetal loss in SLE patients (10,ll).
The association between anticardiolipin antibodies (measured by immunologic solid-phase assays)
and the lupus anticoagulant (measured by functional
coagulation assays) is uncertain. Harris et a1 (27)
reported a strong correlation; Lockshin et al(l0) were
unable to confirm the findings. Furthermore, limited
experience with changes in the levels of both antibodies after therapy with corticosteroids has revealed
discordant responses (7,12,13,27-30). It is possible
that although both are of the same family of antiphospholipid antibodies, they are not necessarily the same
(25,31). In the present study, anticardiolipin antibodies
were not associated with fetal loss, which occurred in
only 1 of 6 patients in whom the antibodies were
identified. Anti-Ro antibodies were present in both of
the mothers of infants with neonatal lupus syndrome
and isolated congenital heart block, but these antibodies were not associated with fetal loss, as has been
reported by others (9).
The finding of a small placenta in mothers with
SLE is of particular interest. The explanation for this
365
is not entirely clear, although it may be related to
either disease activity or serologic abnormalities. The
fact that fetal size, as reflected by birth weight, was
not reduced suggests that, despite a small placenta,
fetal nutrition was not significantly impaired. However, a reduction in placental size may impair the
capacity to tolerate additional insults, whether specific
or nonspecific in nature. In support of this, it is
noteworthy that in 2 patients (RF and BP) who had
substantial macroscopic placental abnormalities but
were delivered of live infants, the size of the placenta
was above the expected mean for gestation, whereas
in 2 other patients (RL and AD-S) who had similar
macroscopic changes but unsuccessful pregnancies,
the size of the placenta was more than 1 standard
deviation below the expected mean.
The literature does not clearly show whether
any single form of placental injury predominates in
SLE patients. Decidual vasculopathy was noted by
Abramowsky et al (14), but in our study, this was not
present in any of the 4 SLE patients in whom decidual
vessels were identified, despite the presence of active
disease in 2 of them at their final assessment before
delivery. Placental infarction secondary to intraluminal thrombosis has also been suggested, particularly in
those patients with antiphospholipid antibodies (1014,32). In the present study, placental infarction was
found in 2 patients, 1 of whom had circulating lupus
anticoagulant. Deposition of immunoglobulin and
complement components in the trophoblast basement
membrane has also been described in SLE patients
(14,15). It is possible that such immunoglobulin deposits may have specific reactivity with trophoblast antigens, as has been suggested by Bresnihan et a1 (5).
However, in our study, trophoblast deposition of
immunoreactive agents, as detected by direct immunofluorescence, was an infrequent and nonspecific
finding. Electron microscopic examination of SLE
placental tissue revealed thickening of the trophoblast
basement membrane. This was also noted in placental
tissue from women with diabetes, and it has previously
been reported in women with diseases other than SLE
(33). Although nonspecific, it may represent the result
of, or the response to, some form of injury to the
trophoblast, which might be mediated by a n immunologic, vascular, or as-yet-unidentified mechanism.
It is therefore likely that there are several
mechanisms that can lead to placental injury in women
with SLE. The clinical significance of the resulting
placental damage may be enhanced by a reduced
placental size. Careful monitoring of the size of the
366
HANLY ET AL
placenta throughout pregnancy, with serial ultrasound
examinations in conjunction with hormonal measurements of placental function (101, may allow more
accurate identification of those SLE patients w h o are
at greatest risk of fetal loss.
REFERENCES
1. Fraga A, Mintz G, Orozco J, Orozco JH: Sterility and
fertility rates, fetal wastage and maternal morbidity in
systemic lupus erythematosus. J Rheumatol 1:293-298,
1974
2. Tozman ECS, Urowitz MB, Gladman DD: Systemic
lupus erythematosus and pregnancy. J Rheumatol 7:
624-632, 1980
3. Fine LG, Barnett EV, Danovitch GM, Nissenson AR,
Conolly ME, Lieb SM, Barrett CT: Systemic lupus
erythematosus in pregnancy. Ann Intern Med 94:667677, 1981
4. Lockshin MD: Lupus pregnancy. Clin Rheum Dis 11:
61 1-632, 1985
5. Bresnihan B, Grigor RR, Oliver N, Lewkonia RM,
Hughes GRV, Lovins RE, Faulk WP: Immunological
mechanism for spontaneous abortion in systemic lupus
erythematosus. Lancet 11: 1205-1207, 1977
6. Nilsson IM, Astedt B, Hedner U, Berezin D: Intrauterine death and circulating anticoagulant, “antithromboplastin.” Acta Med Scand 197:153-159, 1975
7. Lubbe WF, Butler WS, Palmer SJ, Liggins GC: Lupus
anticoagulant in pregnancy. Br J Obstet Gynaecol 91:
357-363, 1984
8. Hull RG, Harris EN, Morgan SH, Hughes GRV: AntiRo antibodies and abortion in women with SLE (letter).
Lancet 11:1 138, 1983
9. Watson RM, Braunstein BL, Watson AJ, Hochberg
MC, Provost TT: Fetal wastage in women with antiRo(SSA) antibody. J Rheumatol 13:90-94, 1986
10. Lockshin MD, Druzin ML, Goei S, Qamar T , Magid
MS, Jovanovic L, Ferenc M: Antibody to cardiolipin as
a predictor of fetal distress or death in pregnant patients
with systemic lupus erythematosus. N Engl J Med 313:
152-156, 1985
1 1 . Derue G, Englert HJ, Harris EN, Hughes GRV: Fetal
loss in systemic lupus: association with anticardiolipin
antibodies. J Obstet Gyniecol 5:207-209, 1985
12. Lubbe WF, Butler WS, Palmer SJ, Liggins GC: Fetal
survival after prednisone suppression of maternal lupusanticoagulant. Lancet 1:1361-1363, 1983
13. Branch DW, Scott JR, Kochenour NK, Hershgold E:
Obstetric complications associated with the lupus anticoagulant. N Engl J Med 313:1322-1326, 1985
14. Abramowsky CR, Vegas ME, Swinehart G, Gyues MT:
Decidual vasculopathy of the placenta in lupus erythematosus. N Engl J Med 303:668-672, 1980
15. Grennan DM, McCormick JN, Wojtach D, Carty M, Behan
W: Immunological studies of the placenta in systemic lupus
erythematosus. AM Rheum Dis 37:129-134, 1978
16. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ,
Rothfield N F , Schaller JG, Talal N, Winchester RJ: The
1982 revised criteria for the classification of systemic
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
lupus erythematosus. Arthritis Rheum 25: 1271-1277,
1982
Urowitz MB, Gladman DD, Tozman ECS, Goldsmith
CH: The lupus activity criteria count (LACC). J Rheumatol 11:783-787, 1984
Pincus T, Schur PH, Rose JA. Decker JL. Talal N:
Measurement of serum DNA binding activity in lupus
erythematosus. N Engl J Med 281:701-705, 1969
Triplett DA, Brandt JT, Kaczor D , Schaeffer J: Laboratory diagnosis of lupus inhibitors: a comparison of the
tissue thromboplastin inhibition procedure with a new
platelet neutralization procedure. Am J Clin Pathol
79:678-682, 1983
Richardson J, Soloninka CA, Laskin CA: Enzymelinked immunosorbent assay for anti-phospholipid antibodies. Submitted for publication
Michel B, Milner Y, David K: Preservation of tissuefixed immunoglobulins in skin biopsies of patients with
lupus erythematosus and bullous diseases: a preliminary
report. J Invest Dermatol 59:449-452, 1973
Wonnacott TH, Wonnacott RJ:Introductory Statistics. Third
edition. New York, John Wiley & Sons, 1977, pp 73-107
Gruenwald P, Minh HN: Evaluation of body and organ
weights in perinatal pathology. 11. Weights of body and
placenta of surviving and of autopsied infants. Am J
Obstet Gynecol 82:312-319, 1961
Mintz G, Niz J, Gutierrez G, Garcia-Alonso A, Karchmer S: Prospective study of pregnancy in systemic lupus
erythematosus: results of a multidisciplinary approach. J
Rheumatol 13:732-739, 1986
Thiargarajan P, Shapiro SS, de Marco L: Monoclonal
immunoglobulin MA coagulation inhibitor with phospholipid specificity: mechanism of a lupus anticoagulant. J
Clin Invest 66:397-405, 1980
Green D, Hongie C, Kazmier FJ, Lechner K, Mannucci
PM, Rizza CR, Sultan Y: Report of the working party on
acquired inhibitors of coagulation: studies of the “lupus”
anticoagulant. Thromb Haemost 49: 144-146, 1983
Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Louizou S, Hughes GRV: Anticardiolipin antibodies: detection by radioimmunoassay and
association with thrombosis in systemic lupus erythematosus. Lancet II:1211-1214, 1983
Lockshin MD, Druzin ML: Antiphospholipid antibodies
and pregnancy (letter). N Engl J Med 313:1351, 1985
Goei S, Qamar T, Lockshin M: Clinical patterns and
response to therapy of antibody to cardiolipin (abstract).
Arthritis Rheum (suppl) 29( 1):S13, 1986
Derksen RHWM, Biesma D, Bouma BN, Gmelig Meyling FHJ, Kater L: Discordant effects of prednisone on
anticardiolipin antibodies and the lupus anticoagulant
(letter). Arthritis Rheum 29:1295-1296, 1986
Asherson RA, Harris N , Gharavi A, Hughes GRV:
Myocardial infarction in systemic lupus erythematosus
and “lupus-like’’ disease (letter). Arthritis Rheum 29:
1292-1293, 1986
Hughes GRV: Thrombosis, abortion, cerebral disease, and
the lupus anticoagulant. Br Med J 287:1088-1089, 1983
Fox H: Pathology of the Placenta. Major Problems in
Pathology. Vol. VII. Toronto, WB Saunders, 1978, pp
167-170
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