Clinic Rev Allerg Immunol (2010) 38:302–306 DOI 10.1007/s12016-009-8161-y Pregnancy and Systemic Lupus Erythematosus: Review of Clinical Features and Outcome of 51 Pregnancies at a Single Institution Graziela Carvalheiras & Pedro Vita & Susana Marta & Rita Trovão & Fátima Farinha & Jorge Braga & Guilherme Rocha & Isabel Almeida & António Marinho & Teresa Mendonça & Paulo Barbosa & João Correia & Carlos Vasconcelos Published online: 15 July 2009 # Humana Press Inc. 2009 Abstract Systemic lupus erythematosus (SLE) is mainly a disease of fertile women and the coexistence of pregnancy is by no means a rare event. How SLE and its treatment affects pregnancy outcome is still a matter of debate. Assessment of the reciprocal clinical impact of SLE and pregnancy was investigated in a cohort study. We reviewed the clinical features, treatment, and outcomes of 43 pregnant SLE patients with 51 pregnancies followed from 1993 to 2007 at a tertiary university hospital. The age of patients was 28.7±5.4 years and SLE was diagnosed at age of 23.0±6.1 years. Previous manifestations of SLE included lupus nephritis (14 patients) and secondary antiphospholipid syndrome (11 patients). Thirty-five pregnant patients (69%) were in remission for more than 6 months at the onset of pregnancy. Patients were being treated with low G. Carvalheiras (*) : P. Vita Serviço de Medicina, Centro Hospitalar do Porto, Hospital Santo António, Porto, Portugal e-mail: [email protected] S. Marta : R. Trovão : J. Braga Serviço de Obstetrícia, Centro Hospitalar do Porto, Hospital Santo António, Porto, Portugal F. Farinha : I. Almeida : A. Marinho : T. Mendonça : P. Barbosa : J. Correia : C. Vasconcelos Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Hospital Santo António, ICBAS, Porto, Portugal G. Rocha Serviço de Nefrologia, Centro Hospitalar do Porto, Hospital Santo António, Porto, Portugal doses of prednisone (29), hydroxychloroquine (20), azathioprine (five), acetylsalicylic acid (51), and low molecular weight heparin (13). Sixteen pregnancy-associated flares were documented, mainly during the second trimester (42%) and also in the following year after delivery (25%). Renal involvement was found in 11 cases (68%). Spontaneous abortion occurred in 6%, 16% had premature deliveries, and 74% were delivered at term. No cases of maternal mortality occurred. No cases of fetal malformation were recorded. There was one intrauterine fetal death and one neonatal death at 24 gestational weeks. Pregnant women with SLE are high risk patients, but we had a 90% success rate in our cohort. A control disease activity strategy to target clinical remission is essential. Keywords Systemic lupus erythematosus . Pregnancy . Flare . Maternal outcome . Fetal outcome Introduction Systemic lupus erythematosus (SLE) is mainly a disease of the fertile women and the coexistence of pregnancy is by no means a rare event. Women suffering from SLE appear not to have a reduced fertility, which is generally only present due to the drugs, or their dosing, especially cyclophosphamide, which can induce ovarian failure [1, 2]. However, pregnancies occurring in patients with SLE are considered at high risk. The management of pregnancy in SLE should start before conception so as to optimize maternal health. The disease is not itself a contraindication to pregnancy, with the exception of organ-system complications such as pulmonary hypertension and renal failure [3]. Clinic Rev Allerg Immunol (2010) 38:302–306 The impact of pregnancy on SLE activity has been debated in literature, but the majority of studies endorse an increase in disease activity during pregnancy. In some patients, this will mean a dramatic worsening of symptoms that can be life threatening, and treatment itself is limited by pregnancy. Most patients, however, will have a modest increase in symptoms making pregnancy uncomfortable but not affecting their long-term survival [4, 5]. Pregnancies for patients with lupus have a greater risk of fetal loss, preterm delivery, pre-eclampsia, intrauterine growth retardation, and neonatal lupus syndrome [6, 7]. Increased lupus activity, particularly before conception and early in pregnancy, significantly increases the risks for these complications. For this reason, timing pregnancy to coincide with a period of SLE quiescence is a worthy goal [4]. We conducted a retrospective review of all pregnant women with SLE who were followed in our center from 1993 through 2007. The purpose of this study was to assess the reciprocal clinical impact of SLE and pregnancy. 303 Internal medicine and obstetrics management protocol General management guidelines for standard of care in pregnant SLE patients are used in our institution and were applied, as possible, to all patients in this study. Pregnancy should be planned after at least 6 months remission of SLE. A preconceptional consultation is mandatory. Frequent consultation of obstetrics and internal medicine for precocious detection of SLE flares, pre-eclampsia, gestational diabetes, intrauterine growth retardation (IUGR), congenital heart block, and risk assessment for spontaneous preterm delivery. Serial ultrasound with Doppler and fetal echocardiography were preformed weekly from 16 to 26 weeks of gestation and biweekly from 26 to 32 weeks of gestation. Serial monitoring of hematological and immunological parameters are frequent. Low dose acetylsalicylic acid was introduced as soon as pregnancy was documented if not already prescribed. Anticoagulation with low molecular weight heparin used in all patients with antiphospholipid syndrome (APS). There is a low threshold for admitting patients and programmed delivery to take place at 37 to 38 weeks of gestation as well as an early reevaluation in puerperium. Materials and methods Assessment of SLE flare Patients We retrospectively reviewed the medical records of 51 consecutive pregnancies in 43 SLE patients from January 1993 to December 2007, regarding the clinical features, treatment, and outcomes, in a tertiary university hospital (Hospital Geral de Santo António, Porto, Portugal). These patients belong to the Hospital Santo Antonio lupus cohort, which includes more than 400 patients, and is one of the largest in Portugal. All patients met at least four of the 1997 Revised American College of Rheumatology criteria for SLE [25]. Each pregnancy was counted as a separate observation. Baseline maternal information included age, past obstetric history, duration of SLE, previous and current manifestations of SLE, previous diagnosis of antiphospholipid syndrome, and medications. Active disease at conception was defined as the use of >10 mg of prednisone daily, the use of any immunosuppressive agent, or an SLE Disease Activity Index (SLEDAI) score ≥2 [26]. Baseline laboratory data included: hematological parameters (hemoglobin, red and white cell and platelet counts, and erythrocyte sedimentation rate), serum levels of creatinine, urinalysis including microscopy, and 24-h urine collection for measurement of total proteinuria. Immunological evaluation included: antinuclear antibodies, double-stranded DNA antibodies, anti-Ro/SS-A and anti-La/SS-B antibodies, anti-cardiolipin (aCL) and anti-β2 glycoprotein antibodies, lupus anticoagulant test, and C3 and C4 complement components. Patients were also assessed for disease flare, defined with the use of criteria from the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) trial. Mild/ moderate flare included new or worsened cutaneous disease, nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, fever attributable to SLE, the addition of nonsteroidal anti-inflammatory drug or hydroxychloroquine, an increase in prednisone up to a dose of 0.5 mg/kg/day, or an increased SLEDAI score ≥3. Severe flare was defined as new or worse central nervous system disease, vasculitis, nephritis, myositis, hemolytic anemia, platelet count <60,000/μL, the addition of cyclophosphamide, azathioprine, or methotrexate, hospitalization for SLE-related manifestations, or an increase prednisone to >0.5 mg/kg/day. Obstetric assessment Gestational age of pregnancy loss or delivery was recorded. Fetal outcomes for live births included birth weight, prematurity (<37 weeks of gestation), extreme prematurity (<28 weeks of gestation), 1- and 5-min Apgar scores, admission to the neonatal intensive care unit, neonatal lupus rash, and congenital heart block. Statistical analysis Statistical analysis was performed using Statistical Package for Social Sciences, version 16 of the SPSS, Inc. Compar- 304 Clinic Rev Allerg Immunol (2010) 38:302–306 ison of qualitative variables when applied was carried out using binary and multinomial logistic regression. Statistical significance was defined as p<0.05. Results Patient characteristics The mean age of our patients was 28.7 ± 5.4 years, minimum 17 and maximum 42. SLE was diagnosed at age of 23.0±6.1 years. Previous manifestations of SLE included: (1) cutaneous and articular in 67% (29 patients), lupus nephritis in 33% (14 patients), and secondary antiphospholipid syndrome in 26% (11 patients). Although patients were advised according to the management protocol to become pregnant only after at least 6 months of SLE remission, 14 pregnancies (28%) occurred during active disease or before completion of 6 months of SLE remission. Autoantibodies were positive as follows: antinuclear antibodies in 48 cases (94%), anti-dsDNA in 22 (43%), anti-cardiolipin (aCL) in 21 (41%), anti-SS-A in 12 (24%), anti-beta2-glicoprotein in ten (20%), anti-SS-B in two (4%), and anti-RNP in one (2%). Low complement was found in 22 cases (43%). Patients were being treated with low doses of prednisone less that 10 mg/day (29), hydroxychloroquine (20), azathioprine (five), low dose acetylsalicylic acid (51), and low molecular weight heparin twice a day (13). SLE pregnancy-associated flares Sixteen pregnancy-associated flares (31%) were documented and the systems involved are shown in Table 1. There were no significant associations with flare severity: four (25%) were mild, five (31%) were moderate, and seven (44%) were severe. Flares occurred mainly during the second trimester (42%) and also in the following year after delivery (25%), as shown in Table 2. Renal involvement was the most frequently found, being reported in 11 cases (68%). Previous renal involvement was present in six of these cases and seems to increase the risk of Table 1 Systems involved in SLE flare Manifestations Pregnancies Percent of flares Renal Severe thrombocytopenia Catastrophic APS Neurologic (convulsions) Cutaneous 11 2 1 1 1 69% 13% 6% 6% 6% Table 2 Distribution of the 16 flares during and after pregnancy Period No. of flares Percent 1st trimester 2nd trimester 3rd trimester Puerperium Until 1 year after childbirth 1 7 3 1 4 8% 42% 17% 8% 25% renal flare (3.8 times), although not significant (p=0.069) due to the reduced sample size. We found as possible flare-associated predictors the treatment with azathioprine (hazard ratio of 9.1, p=0.010) and prednisolone (hazard ratio of 7.3, p=0.018). Pregnancy outcome No cases of maternal mortality were recorded. Spontaneous abortion occurred in 6%, 16% had premature deliveries, and 74% were delivered at term (Table 3). There was one intrauterine fetal death and one neonatal death due to prematurity; both at 24 gestational weeks, but no cases of fetal malformation were recorded. No significant associations between SLE manifestations and pregnancy outcome or between autoantibodies and pregnancy outcome were found. Neonatal lupus syndrome Two cases of neonatal lupus syndrome occurred. One case of first degree heart block in a newborn whose mother was anti-SS-B positive and one case of photosensitive rash interpreted as cutaneous manifestation of lupus. Discussion The hormonal and physiologic changes that occur in pregnancy can induce lupus activity. Likewise, the increased inflammatory response during a lupus flare can cause significant pregnancy complications. Many of the signs and symptoms that occur during pregnancy can be easily mistaken for signs of active SLE. Symptoms such as severe fatigue, melasma, post-partum hair loss, increased shortness of breath, arthralgias, and headaches frequently accompany normal pregnancy, and could be difficult to distinguish from SLE flare [4, 5]. Recent prospective studies showed a favorable outcome in SLE pregnant women [8–10]. They include a different selection of patients with SLE than those included in retrospective studies, mainly those with less severe disease. In most of our patients, the disease was clinically inactive at conception and this fact may explain the Clinic Rev Allerg Immunol (2010) 38:302–306 Table 3 Pregnancy outcomes 305 Outcome No. of pregnancies Percent Spontaneous abortion (1st trimester) Medical interruption Intrauterine fetal death Premature deliveries Medical indication Spontaneous Delivered at term 3 1 1 6% 2% 2% 6 2 38 12% 4% 74% discrepancy with studies including a predominance of patients with more severe and chronic manifestations of SLE and showing flare rates as high as 60% [11, 12]. To minimize the risk of flare during pregnancy, the disease should be inactive for at least 6 months prior to conception [3]. The mother needs to be followed up regularly after delivery because of the high risk of post-partum flare [5]. Renal flares are more common in those who had active disease at conception than those in remission [3, 13]. The pre-existence of lupus nephritis is an important risk factor. Pregnancy outcome is especially affected by renal disease, and even inactive renal lupus is associated with increased risk of fetal loss, pre-eclampsia, and intrauterine growth restriction [1, 14, 15]. Differentiating lupus flares from pregnancy-related physiological changes or active lupus nephritis from pre-eclampsia often poses a challenge to the physician, although it should be noted that the two may coexist. Features that suggest a renal flare include a rise in anti-dsDNA antibodies, low or dropping complement levels, clinical evidence of a lupus flare in other organs, and active urinary sediment. Pre-eclampsia is suggested by rising uric acid and liver enzyme levels in the presence of inactive urinary sediment. Despite these indicators, it is not always possible to differentiate between a lupus nephritis flare and pre-eclampsia. The treatment of these two conditions is different: pre-eclampsia will remit with delivery of the fetus, but active SLE will require immunosupression [3–5]. It is now well established that the presence of antiphospholipid antibodies (aPL), namely the lupus anticoagulant (LA) and anti-cardiolipin antibodies (aCL), are important risk factors for abortion in both SLE and nonSLE patients [16, 17]. However, if appropriately managed, the antiphospholipid syndrome is “one of the few tractable causes of pregnancy losses” [18]. Clinical evidence clearly favors the use of antiaggregant/anticoagulant agents, mainly aspirin and heparin, to prevent aPL-associated miscarriages [19]. There are very few data about the long-term outcome of children born to patients with aPL. An increased occurrence of learning disabilities was already reported in children born from SLE patients, and aPL might be considered at least part of the pathogenic factors responsible for them [18]. Concerning medical therapy, only cyclophosphamide, mycophenolate mofetil, methotrexate, and leflunomide are totally contraindicated drugs both in pregnancy and lactation because of their teratogenicity and embryotoxicity. Minimal data on cyclosporine and TNF alpha inhibitors during pregnancy limit their use during pregnancy, whereas azathioprine may be continued in pregnant patients on the basis of recent data. Hydroxychloroquine should not be stopped in early pregnancy, because this could precipitate a flare, and its long half-life means the fetus would continue to be safely exposed to the drug for several weeks, even after discontinuation. Only one of 20 patients in our study on hydroxychloroquine stopped taking the drug. That patient had an intrauterine fetal death at 24 gestational weeks. The dose of prednisolone should ideally be kept at 10 mg daily or less because of increased risk of maternal hypertension, pre-eclampsia, gestational diabetes, and infection [4–6, 18, 20, 21]. There is no evidence that flares, which generally respond to prednisone therapies, could be prevented by a steroid prophylaxis. Some authors recommend the use of prednisone throughout pregnancy for all pregnant lupus patients [22, 23], but others disagree [3, 14, 21]. Neonatal lupus syndrome is associated with maternal anti-Ro/SS-A and anti-La/SS-B antibodies. It may occur in the offspring of women with these conditions, regardless of their clinical diagnosis and even if the mother is asymptomatic. Congenital heart block occurs between 18 and 30 weeks, and fetal echocardiography should be performed over this period to enable early detection. This irreversible complication occurs in 2% of fetuses of women with the anti-Ro antibody, with a recurrence rate of 16% in subsequent pregnancies [24]. Also, cholestatic hepatitis, cytopenias, and photosensitive rash are grouped under the heading of “neonatal lupus syndrome”. Those aspects are usually transient, and are also linked to anti-Ro antibodies [5, 18, 21]. Two cases of neonatal lupus were registered: one with congenital heart block and the other with photosensitive rash. 306 Conclusion With improvements in diagnosis and treatment, the prognosis of patients with SLE has generally improved in recent years. Similarly, the outlook for women who become pregnant in the setting of this disorder is far more optimistic than it was in the past. However, the risk of significant morbidity to both the mother and the fetus still exists. Management of SLE in pregnancy is a multidisciplinary effort including an internist, an obstetrician with experience in management of patients with SLE, and, if indicated by the patient’s renal status, a nephrologist. It is essential that the maternal disease is well controlled prior to, during, and after pregnancy to ensure the best possible outcome for the mother and child. References 1. Mecacci F, Pieralli A, Bianchi B, Paidas MJ (2007) The impact of autoimmune disorders and adverse pregnancy outcome. Semin Perinatol 31:223–226 2. Chakravarty EF, Colón I, Langen ES, Nix DA et al (1982) Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 142:159–164 3. Khamashta MA (2006) Systemic lupus erythematosus and pregnancy. Best Pract Res Clin Rheumatol 20(4):685–694 4. Clowse MEB (2007) Lupus activity in pregnancy. Rheum Dis Clin N Am 33:237–252 5. Gordon C (2004) Pregnancy and autoimmune diseases. Best Pract Res Clin Rheumatol 18(3):359–379 6. D’Cruz DP, Khamashta MA, Hughes GRV (2007) Systemic lupus erythematosus. Lancet 369:587–596 7. Ruiz-Irastorza G, Khamashta MA (2004) Evalution of systemic lupus erythematosus activity during pregnancy. Lupus 13:679–682 8. Tincani A, Faden D, Tarantini M et al (1992) Systemic lupus erythematosus and pregnancy: a prospective study. Clin Exp Rheumatol 10:439–446 9. Lima F, Buchanam NM, Khamashta MA, Kerslake S, Hughes GRV (1995) Obstetric outcome in systemic lupus erythematosus. Semin Arthritis Rheum 25:184–192 10. Laskin CA, Clark C, Sptitzer KA. Decrease in pregnancy loss rates in systemic lupus erythematosus over a 40-year period. Fertil Steril—Abstracts 2005;84(1):S445–S446. Clinic Rev Allerg Immunol (2010) 38:302–306 11. Nossent HC, Swaak TJG (1990) Systemic lupus erythematosus VI. Analysis of the interrelationship with pregnancy. J Rheumatol 17:771–776 12. Petri M, Howard D, Repke J (1991) Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 34:1538–1545 13. Moroni G, Quaglini S, Banfi G et al (2002) Pregnancy in lupus nephritis. Am J Kidney Dis 40:713–720 14. Cervera R, Font J, Carmona F, Balasch J (2002) Pregnancy outcome in systemic lupus erythematosus: good news for the new millennium. Autoimmunity Reviews 1:354–359 15. Tandon A, Ibanez D, Gladman DD, Urowitz MB (2004) The effect of pregnancy on lupus nephritis. Arthritis Rheum 50:3941– 3946 16. Cervera R, Font J, López-Soto A, Casals F et al (1990) Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus. Prospective analysis of a series of 100 patients. Ann Rheum Dis 49:109–113 17. Cervera R, Piette JC, Font J et al (2002) Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 46:1019–1027 18. Ticani A, Rebaioli CB, Frassi M et al (2005) Pregnancy and autoimmunity: maternal treatment and maternal disease influence on pregnancy outcome. Autoimmunity Reviews 4:423–428 19. Silveira LH, Hubble CL, Jara LJ et al (1992) Prevention of anticardiolipin antibody-related pregnancy losses with prednisone and aspirin. Am J Med 93:403–411 20. Khanna D, McMahon M, Furst DE (2004) Safety of tumor necrosis factor-alpha antagonists. Drug Saf 27:307–324 21. Meyer O (2004) Making pregnancy safer for patients with lupus. Jt Bone Spine 71:178–182 22. Petri M, Howard D, Repke J et al (1992) The Hopkins Lupus Pregnancy Center: 1987–1991 update. Am J Reprod Immunol 28:188–191 23. Lockshin M, Reinitz E, Druzin ML et al (1984) Lupus pregnancy: a case–control prospective study demonstrating absence of lupus exacerbations during or after pregnancy. Am J Med 77: 893–889 24. Brucato A, Frassi M, Franceschini F et al (2001) Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectophoresis: a prospective study of 100 women. Arthritis Rheum 44:1832– 1835 25. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725 26. Bombardier C, Gladman DD, Urowitz MB et al (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35:630–40