AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY 28:205-207 © 1992 MUNKSGAARD

Pregnancy Course and Complications in Patients with Systemic Lupus Erythematosus A. RUBBERT, K. PIRNER, L. WILDT,J .R. KALDEN, AND B. MANGER Department of Medicine III (AR., KP., JR.K., B.M.), Institute for Clinical Immunology and Rheumatology and Deparmtent of Obstetrics and Gynecology (L. W), University ofErlangen-Nurnberg, Germany ABSTRACT: Among 165 patients with systemic lupus erythematosus (SLE), we observed 21 pregnancies in 19 patients since 1987. The mean duration of disease at the time of pregnancy was 4.5 ± 3 years. All but three patients required immunosuppressive treatment before and during pregnancy. The effect of pregnancy on the course of SLE was studied. Severe disease exacerbations were rare and largely confined to patients with renal involvement. Most patients showed elevated titers of dsDNA antibodies during pregnancy but clinical activity of disease was usually mild. Complement C3 decrease appeared to be the most sensitive marker for pregnancy-related complications. The detection of antibodies to phospholipids was frequent during pregnancy in contrast to a low prevalence before and after pregnancy. Their presence could be associated with intrauterine growth retardation. Preterm delivery before the 37th week of pregnancy had to be performed in the majority of patients. None of the patients experienced abortion although three patients had to be delivered in the 29th week ofpregnancy because of increasing symptoms of preeclampsia.Two of these children died and the third child suffered from intracranial hemorrhage in the early postpartum period. Our data demonstrate that successful pregnancy outcome was related to a gestational age of more than 32 weeks, making careful monitoring and appropriate therapeutic management necessary. (Am J Reprod Immunol. 1992; 28:205-207.) Key words: SLE, pregnancy, antiphospholipid, antibodies, complement C3 INTRODUCTION

Systemic lupus erythematosus (SLE) predominantly affects young women of childbearing age and, as fertility is not impaired,' the coincidence of SLE and pregnancy is frequently encountered. There have been several reports on the relationship between SLE and pregnancy, revealing on the one hand an increased proportion of abortions, stillbirth and preterm deliveries, and, on the other hand exacerbation of SLE and deterioration of renal function.v" As sensitive and specific laboratory methods have been developed during the past few years, monitoring of disease has improved and pregnancy courses with few symptoms occur more frequently. Our study strengthens the view that successful pregnancy outcome can be achieved in most patients with

Submitted for publication August 3, 1992; accepted August 7, 1992. Address reprint requests to Dr. A. Rubbert, Dept. ofMedicine III, Krankenhausstr. 12,8520 Erhngen, Germany.

SLE, although premature delivery and pregnancy related complications are common. MATERIAL AND METHODS

Between 1987 and 1992, 21 pregnancies were observed in 19 patients with SLE, fulfilling at least four ARA criteria for SLE. 4 The patients were in continuous care in our outpatient clinic before, during, and after pregnancy. Most patients were admitted monthly during pregnancy, were physically examined, and routine blood examinations for hematology and chemistry were performed. Routine immunological assays included the measurement of anti-double-stranded DNA (dsDNA) antibodies by the Farr assay (normal up to 7 Uzml), complement C3 and C4levels (radial immunodiffusion), antibodies to Ro, La, and cardiolipin, determined by an enzyme-linked immunosorbent assay and the lupus anticoagulant (by the tissue thrombin inhibition test and the kaolin clotting time). DNA-antiDNA immune complexes were determined as described by Krapf et al. 5 Fisher's exact test was applied to evaluate the data at a significance level of P = 0.05. RESULTS

Patient Characteristics Nineteen SLE patients with 21 pregnancies were enrolled. At the time of pregnancy, patients had a mean age of 29.3 ± 3.7 years, range 23 to 37 years. The mean duration ofSLE at the time of pregnancy was 4.3 ± 3.3 years, range 0 to 11 years. In one patient, SLE diagnosis was established during pregnancy. Among the clinical manifestations of SLE, arthralgias (in 18 of 19 patients or 94.7%) and skin involvement (in 17 or 19 patients or 89.5%) were most frequently encountered. Leukopenia and thrombopenia were present in 13 (68.4%) and seven (36.8%) patients, respectively. In four patients (21%), proteinuria ranging from 1.3 to 3.7 glday was present at the onset of pregnancy. Four patients (21%) had a history of pleural effusions and two patients had pericarditis within the last two years before pregnancy. A deep vein thrombosis was diagnosed in four patients (21%) before and in one patient during pregnancy. Obstetrical Data Ten patients (52.6%) had already been pregnant before the diagnosis ofSLE was established (Table I). The majority ofthese pregnancies led to abortion (58%) or preterm delivery (15.8%). After the diagnosis of SLE was established, the incidence of abortion decreased to 9.5%, but an increase in the proportion of preterm deliveries was noted (62%). The patients included in the study had a mean pregnancy duration of 35.7 ± 3.6 weeks (ranging from 29 to

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RUBBERT ET AL.

TABLE I. Occurrence and Outcome of Pregnancy in Patients Before and After the Diagnosis of SLE was Established Before SLE Pregnant patients (no.) No. of pregnancies Pregnancies/patient Spontaneous abortions Stillbirths Preterm delivery Postpartum death ofnewbom

10 19 1.9 11

o 3 o

After ALE 19 21 1.1 2

o 13 2

40 weeks) after the diagnosis ofSLE was established. Spontaneous delivery occurred in seven of 21 patients (30%) and eight of 21 patients (38%) were submitted to cesarean section. Impaired placental development was present in seven of 21 patients (30%) and symptoms of preeclampsia in five of21 patients (23.8%). Duringp~eg­ nancy the majority of patients (19 of21 or 90.4%) received corticosteroids, ranging from 6 to 96 mg prednyliden daily. However, a daily dose of more than 24 mg was necessary only in five patients. Low dose aspirin (daily dose 100 mg) was administered to 11 of 21 patients (52.4%) and subcutaneous heparin to two patients. Twopatients were on azathioprine until they became aware of their pregnancy; three other patients received chloroquine during the first weeks of their pregnancy. One patient suffered from herpes zoster during the 23rd week of gestation and did well after intravenous immunoglobulin therapy.

Course ofSLE During Pregnancy Elevated dsDNA antibodies (more than 20 Uzml) were detected in 16 of 21 patients (76.2%) before pregnancy, in 17 of 21 patients (81%) during pregnancy, but in only nine of21 patients (43%) after pregnancy. Decreased levels of C3 complement (normal range 85 to 193 mg/dl) were observed in seven of21 patients (30%) before pregnancy, in nine of21 patients (42.9%) during pregnancy, but in only six of 21 patients (28.6%) after pregnancy. Antibodies to Ro and La antigen were detected in six and four patients, respectively; however, cardiac conduction abnormalities or neonatal lupus were not observed in any case. Antibodies to phospholipids (anticardiolipin or the lupus anticoagulant) were present in five of 17 patients (29.4%) before, in 11 of 19 patients (58%) during, and in three of 19 patients (15.8%) after pregnancy. Seven patients showed impaired placental function; four of these patients had positive tests for the lupus anticoagulant, and three patients showed anticardiolipin antibodies. As judged by clinical and immunological parameters, SLE disease activity was considered low in 11 of 21 pregnancies, intermediate in four of21 pregnancies and high in six of 21 pregnancies. An increase in disease activity was clinically apparent during 11 of21 pregnancies with patients predominantly complaining of musculoskeletal symptoms. All patients with renal involvement showed an increased daily proteinuria (up to 10 g/day). Postpartum, SLE exacerbation occurred in two patients, both with preexisting nephropathy and deterioration of renal function, with an overt hemolytic anemia in one. Mild SLE disease activity was noticed in six patients after delivery. Course ofComplement C3 During Pregnancy Patients with an uncomplicated pregnancy course showed an increase of complement C3 during pregnancy

(Fig. 1) when compared to prepregnancy levels. Patient 1 (Fig. 1) had suffered from three abortions before the diagnosis of SLE was established. Elevated titers of free dsDNA antibodies were never present, but DNA-antiDNAimmune complexes were detected. She showed a decline of C3 levels during the second trimester that was clinically accompanied by an increase in arthralgias. Both complaints and complement levels responded well to an increased dose of corticosteroids. Nearly all patients with a decrease of C3 levels (normal range 85-193 mg/dl) presented with either pregnancyor SLE-related clinical problems (Table 11). However, one patient, who had suffered from an SLE flare three months before pregnancy, showed a decline ofC3 from 140 mg/dl in the 16th week of gestation to 83 mg/dl in the 24th week of gestation. In the 29th week of gestation, the patient presented with increased proteinuria, hypertension, and edema and caesarean section had to be performed. The child died a few days later due to infectious complications.

Outcome for Children Although the mean birth weight was decreased to 2533 ± 967 g, the majority of newborns (15 of21 or 71.4%) did well after delivery. Two abortions were performed during the first 10 weeks of pregnancy (Table 11). One child suffered from staphylococcal and fungal skin infection but responded to appropriate treatment. Two children had to be delivered in the 29th week of pregnancy due to impaired placental involvement and symptoms of preeclampsia. Both children died because of intracerebral bleeding and infectious complications. Another child delivered in the 29th week of gestation developed normally despite postpartum intracerebral hemorrhage. Outcome for Patients With Renal Involvement Renal involvement with a daily proteinuria ranging from 1.3 to 3.7 g was present in four patients before preg-

(3 mg/dl

140

0----0

100

Poltt 101O_-----o/

80

Po~t2~=-A--"""

vor4

8121620

2428

32 3640

~

Fig. 1. During uncomplicated SLE pregnancies, an increase in complement C3 levels (normal range 85 to 193 mg/dl) can be observed as shown. C3 levels and dsDNA antibody levels of three patients during pregnancy are depicted.

PREGNANCY AND SLE

TABLE II. Outcome of Patients With Decreased Complement C3 Levels During Pregnancy Min. C3 (mg/dl)

Max. anti-ds DNA (u/ml)

2 3

78 78 33

20 65 723

4

55

102

5

83

7

6

82 51

27 105

7 8

37 60

27 32

Patient 1

Clinical course Placental insufficiency Placental insufficiency Proteinuria, hypertension during pregnancy Increase of proteinuria, preeclampsia Increase of proteinuria, cesarean section week 29 No problems No problems, but CNS Involvement later Abortion week 12 Increase in proteinuria, abortion week 11

nancy. All showed an increase of proteinuria during pregnancy (ranging from 6 to 10 g/day) which persisted in three of four patients after pregnancy despite a more aggressive immunosuppressive treatment. Before pregnancy, one patient received low-dosesteroids, two patients received azathioprine, and the fourth patient received chloroquine. After pregnancy, cyclophosphamide therapy was initiated in two patients, and the two other patients received chloroquine (followedby cyclophosphamide after five months because of deteriorating renal function) and cyclosporin A, respectively. Pregnancy was complicated by preeclampsia in two patients, by abortion in one patient, and by preterm delivery in one patient in the 29th week of gestation with subsequent death of the child. DISCUSSION

Although fertility is unimpaired in patients with SLE, pregnancy is often complicated by abortions, preterm deliveries, and stillbirths. Half of our patients had been pregnant before the diagnosis of SLE was established, with abortions in 58%. However, pregnancies after diagnosis of SLE predominantly led to preterm deliveries, suggesting that immunosuppressive treatment, which was given to the majority of patients, may be beneficial to the course of pregnancy. Duration of pregnancy and neonatal birth weight was lower for women with SLE than for women not affiicted with the disease.' Impaired placental development and symptoms of preeclampsia were frequently encountered and may have contributed to the low percentage of spontaneous deliveries. Several pathogenetic mechanisms, including the transplacental transfer of antinuclear antibodies," the deposition of immune complexes at the trophoblast membrane," or the fresence of cross-reactive lymphocytotoxic antibodies have been proposed to account for adverse outcome of SLE pregnancies. In our patients, antibodies to Ro or La were detected in half of them; however, cardiac conduction abnormalities or a neonatal lupus was not observed in any case. Antibodies to phospholipids (lupus anticoagulant or cardiolipin) may promote thrombosis, the initiation of decidual vasculopathy and placental infarction and therefore interfere with placental development.f Interestingly, a substantial proportion of patients showed antibodies to phospholipids exclusively

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during pregnancy before low dose aspirin therapy was started. In conclusion, there may be several mechanisms which contribute to the development ofSLE-induced placental vasculopathy and hypoperfusion. In agreement with other studies,lo,11 the course ofSLE was unimpaired by subsequent pregnancy, low disease activity, or a remission period of several months before pregnancy occurred. Complications may be of significant clinical importance in patients with preexisting renal, eNS, or cardiac disease. In all our patients with renal involvement, an increase in daily proteinuria was observed during pregnancy, requiring postpartum intensification of immunosuppressive therapy in most of them. We conclude that SLE patients with renal disease should be carefully counselled with regard to family planning. Preeclampsia and exacerbation of SLE with deterioration of renal function may be difficult to differentiate in these patients. Buyon et al. 12 suggested monitoring the course of complement C3 because uncomplicated SLE as well as non-SLE pregnancies are characterized by an increase of C3 during pregnancy. However, in our patient population, monitoring complement C3 levels was helpful in more than patients with renal disease. A decrease ofC3 levels was frequently associated with clinical problems, either SLE- or pregnancy-related and seemed to be a more sensitive marker than the levels of dsDNA-antibodies. CONCLUSION

Outcome of pregnancy was favorable and uncomplicated in SLE patients without renal disease, so long as careful monitoring and treatment adjustment was done. Increasing knowledge of both physiology and immunology of pregnancy and of the pathogenesis of SLE will deepen our understanding of the underlying pathomechanisms and help to improve treatment modalities for pregnant SLE patients. REFERENCES 1. Fraga A, Montz G, Orozco J, Orozco JH. Sterility and fertility rates, fetal wastage and maternal morbidity in systemic lupus erythematosus. J Rheumatol. 1974; 1:293-298. 2. Baguley E, MacLachlan N, Hughes GRV. SLE and pregnancy. Clin Exp Rheumatol. 1988; 6:183-185. 3. Gimovsky ML, Montoro M, Paul RH. Pregnancy outcome in women with systemic lupus erythematosus. ObstetGyneco1.1982; 63:686-692. 4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982; 25:1271-1277. 5. Krapf FE, Farber L, Manger B, et al. Nachweis und Bedeutung von DNA-antiDNA-Immunokomplexen bei Patienten mit systemischern Lupus erythematodes. Z Rheumatol. 1988; 47:292. 6. Buyon JP, Ben-Chetrit E, Kaip S, et al. Acquired congenital heart block. J Clin Invest. 1989; 84:627 -634. 7. Grenan OM, McCormick IN, Wojtacha 0, et al. Immunological studies of the placenta in systemic lupus erythematosus. Ann Rheum Dis. 1978; 37:129-134. 8. Bresnihan B, Gregor RR, Oliver M, et al. Immunological mechanism for spontaneous abortion in systemic,lupus erythematosus. Lancet. 1977; ii:1205-1207. 9. Branch OW, ScottJR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med. 1985; 313:1322-1326. 10. Lockshin MD, Reinitz E, Druzin ML, et al. Lupus pregnancy. Casecontrol prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med. 1984; 77:893-898. 11. 'Ibzman EC, Urowitz MB, Gladman DO. Systemic lupus erythematosus and pregnancy. J Rheumatol. 1980; 7:624-632. 12. Buyon JP, Cronstein BN, Morris M, et al. Serum complement values (C3 and C4) to differentiate between systemic lupus activity and preeclampsia. Am J Med. 1986; 81:194-200.

Pregnancy course and complications in patients with systemic lupus erythematosus.

Among 165 patients with systemic lupus erythematosus (SLE), we observed 21 pregnancies in 19 patients since 1987. The mean duration of disease at the ...
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