Lupus nephritis and the anti-phospholipid antibody syndrome in pregnancy
Authors: Ajay K. Singh
Journal: Kidney International (2000)

A 32-year-old woman was gravida 2, para 0, and had had one spontaneous abortion. When she was 12 weeks pregnant, she presented to the emergency department at the Brigham and Women's Hospital with new-onset nephrotic syndrome and systemic lupus erythematosus. Seven years earlier, she had had swelling in the small joints of her upper and lower extremities. At that time she was told that she had rheumatoid arthritis. Hydroxychloroquine sulfate (Plaquenil) relieved her symptoms. After five years of treatment, the patient discontinued taking the Plaquenil, as she was concerned about becoming pregnant. She did very well after the medication was stopped. Approximately two years before this admission, she became pregnant. Other than a positive rapid plasma reagin, all antenatal tests were in the normal range. At approximately eight weeks gestation, the patient had a spontaneous abortion. She underwent a dilatation and curettage because of hemorrhage and was diagnosed with a septate uterus. The septum was hysteroscopically resected one year prior to the current admission. The patient had been well until approximately eight weeks into her current pregnancy, when she developed facial, hand, and leg edema. The edema gradually worsened, with a 12 pound weight gain over the next four weeks. She also noted increasing shortness of breath, abdominal distension, and decreased appetite. One day prior to admission, the patient saw her primary physician, who noted that she was moderately hypertensive, with a blood pressure of 140/80 mm Hg as compared to a blood pressure of 110/70 mm Hg at six weeks of gestation. He also noted 3+ proteinuria on dipstick. A 24-hour urine collection contained 9 g of protein; the creatinine clearance was 102 mL/min. Serum creatinine had risen to 1.6 mg/dL from 1.0 mg/dL earlier in the pregnancy. ANA was positive at 1:320. Following this visit, the patient developed vaginal bleeding and presented the next day to the emergency department at the Brigham and Women's Hospital. In the emergency room, the patient had no active vaginal bleeding. The medical history was noteworthy for a diagnosis of rheumatoid arthritis, hypothyroidism with a multinodular goiter, and mitral valve prolapse. She was taking levothyroxine sodium (Synthroid), 0.05 mg daily. She reported having one sister with an unspecified autoimmune disorder. Physical examination revealed a patient comfortable at rest. Her blood pressure was 138/78 mm Hg and she was afebrile. Her weight was 182 pounds. Head and neck examination was remarkable for facial edema. No lymphadenopathy was apparent, and the joints and skin were normal. Cardiac examination was normal. Lung examination revealed decreased breath sounds one-half way up with dullness to percussion in the right hemithorax. The abdominal examination revealed distension consistent with ascites. The uterus was not palpable. The extremities showed 2+ pitting edema bilaterally. Her calves were not tender. A pelvic examination did not reveal bleeding. The O2 saturation was 98% while breathing room air. A chest radiograph revealed a right pleural effusion and right chest wall subcutaneous emphysema. An ultrasound study demonstrated an intrauterine pregnancy at 12.5 weeks, ascites, and a right pleural effusion. A urinalysis showed a specific gravity of 1.025; pH, 6.0; 3+ protein; and 3+ blood; the rest of the parameters were negative. Sediment examination showed 25 to 30 white blood cells/high-power field and too-numerous-to-count red blood cells/high-power field with 5 to 7 coarse granular/degenerating cellular casts. The blood urea nitrogen was 35 mg/dL and the serum creatinine was 1.6 mg/dL. Electrolytes were in the normal range. A complete blood count showed a hematocrit of 25.8%, white cell count of 1536/mm3 (normal, 4000–10,000/mm3), and platelet count of 128,000/mm3 (normal, 150,000–450,000/mm3). Liver function tests were normal. Her total protein was 3.3 g/dL (normal, 6.0 to 8.0 g/dL); albumin, 1.4 g/dL (normal, 3.7 to 5.4 g/dL); calcium, 6.8 mg/dL (normal, 8.8 to 10.5 mg/dL); phosphorus, 4.6 mg/dL (normal, 2.4 to 5.0 mg/dL); magnesium, 2.7 mg/dL (normal, 1.8 to 6.4 mg/dL); and uric acid, 6.5 mg/dL. Serum cholesterol was 259 mg/dL (normal, 140 to 240 mg/dL); the triglyceride level was 379 mg/dL (normal, 35 to 135 mg/dL). Serologic tests showed a C3 of 84 mg/dL (normal, 88 to 201 mg/dL); C4, 21 mg/dL (normal, 12 to 36 mg/dL); CH50, 128 U/mL (normal, 150 to 250 U/mL); and a Clq of 27 mg/dL (normal, 8 to 12 mg/dL). The anti-double stranded (DS) DNA antibody was 78 IU (normal, 0 to 25 IU); anti-sm antibody, 4 EU/mL (normal, 0 to 20 EU/mL); anti-Ro 4 EU/mL (normal, 0 to 20 Eμ/mL); ANA, 1:640; and a negative ANCA. Her anti-cardiolipin antibody titer was <22 GPL units (normal, <15). The lupus anticoagulant screen was negative. A provisional diagnosis of lupus nephritis with nephrotic syndrome was made. The patient was treated with prednisone, 60 mg/day, and furosemide, 40 mg/day. A renal biopsy was deferred because of the pregnancy. Over the next five days, the patient had further vaginal bleeding, and her hematocrit fell to a nadir of 20%. The serum creatinine peaked at 1.8 mg/dL, and a 24-hour urine collection revealed 12 g of protein. After much discussion, the patient elected to terminate the pregnancy on the seventh day following admission. Subsequently, the ascites and peripheral edema progressively improved. Prednisone was continued at the same dosage and she was discharged from the hospital. A percutaneous renal biopsy was performed approximately 10 days following termination of the pregnancy. The biopsy consisted of two cores of renal tissue containing a total of 21 glomeruli. Five glomeruli showed periglomerular cellular or fibrocellular crescents. All glomeruli were remarkable for diffuse endocapillary cell proliferation. Few open loops were present. Numerous "wire-loop" lesions were present and frequent capillary loops revealed thickened walls with double contours. Occasional polymorphonuclear leukocytes were identified within the glomerular capillary tufts, and rare areas showed evidence of cellular damage with karyorrhectic debris. Most glomeruli showed a segmental increase in mesangial matrix and cells. The interstitium showed a few foci of mononuclear cell infiltration. There was focal mild interstitial fibrosis as well as focal mild tubular atrophy; however, most tubules were arranged in a normal back-to-back configuration with full epithelium. Mild thickening of arteries and arterioles was apparent. The activity index was 16, with a maximal score of 24. The chronicity index was 3, with a maximal score of 12. The sections were examined for reaction with antibodies against IgG, IgA, IgM, C3, albumin, fibrinogen, and kappa and lambda light chains. Twelve glomeruli were present on the examined sections. Diffuse granular reactivity was identified within glomerular tufts with antisera to IgG (3+/4+), IgA (2–3+/4+), IgM (1+/4+), and kappa/lambda light chains (trace to 1+/4+). Granular C3 (2+/4+) was identified within glomeruli in a diffuse segmental manner. The reactivity was found along glomerular capillary loops and most likely in mesangial areas. Small, segmental, confluent areas of fibrin/fibrinogen reactivity (3+/4+) were identified within some glomeruli. Linear albumin (trace) was identified along all basement membranes. Two glomeruli were examined by electron microscopy. Numerous subendothelial electron-dense deposits were identified. Rare subepithelial and more frequent mesangial deposits also were found. No specific structures were identified within the deposits. Visceral epithelial cells showed obliteration of foot processes. Diffuse mesangial cell proliferation also was evident. Based on the renal biopsy, a diagnosis of WHO class-IV diffuse proliferative lupus nephritis was made. The patient was counseled about the potential effects of cyclophosphamide on future fertility, and she elected to undergo further treatment. One month following the onset of her nephritic illness, she was given pulse intravenous cyclophosphamide therapy (1 g intravenously each month) while continuing to take prednisone, 60 mg/day. Her therapeutic regimen comprised six monthly pulses of intravenous cyclophosphamide followed by four pulses of cyclophosphamide, one every three months. Her cyclophosphamide treatment has since been discontinued (cumulative dose, 10 g over 18 months). Her prednisone dose has been tapered gradually. Over the past five years, she has experienced no further renal or extrarenal manifestations of lupus. Her renal function has remained stable. One year following her acute illness, the serum creatinine was 0.8 mg/dL. An iothalamate test of glomerular filtration rate showed 100 mL/min/1.73 m2, and a 24-hour urine collection contained 423 mg protein. Four years following her acute illness, the serum creatinine remained at 0.8 mg/dL, with a creatinine clearance of 141 mL/min and a 24-hour urine protein excretion of 233 mg. At last follow-up, approximately five years following her acute illness, her serum creatinine was 0.9 mg/dL with a creatinine clearance of 120 mL/min and undetectable amounts of protein in a 24-hour urine collection. DR. AJAY K. SINGH (Clinical Director, Renal Division, Brigham and Women's Hospital; and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, USA): Systemic lupus erythematosus (SLE) and the anti-phospholipid antibody syndrome (APS) are autoimmune syndromes that occur most commonly in women during their reproductive years. Forty years ago, approximately one of every 1660 pregnancies involved a mother with SLE. The frequency of pregnancy in lupus patients is now severalfold higher for a variety of reasons, including the emergence of immunosuppressive agents to better manage lupus, the marked improvement in obstetric care, and the realization among patients and physicians that pregnancy is not contraindicated in SLE. Today's case presentation highlights a number of questions that will be the focus of my discussion. First, what is the effect of pregnancy on the immune system and how is it of relevance to patients with SLE? Second, how does pregnancy affect SLE activity? In particular, what is the lupus flare rate during pregnancy, and does pregnancy exacerbate SLE activity? Further, does the clinical severity of lupus at onset of pregnancy predict the probability of further worsening of disease during that pregnancy? Third, what is the effect of SLE on pregnancy? In particular, how does SLE affect maternal and fetal outcome? Finally, what is the role of the anti-phospholipid antibody syndrome on pregnancy and fetal outcome, and how should APS be managed? Among the many physiologic adaptations that occur during pregnancy, the adaptation of the immune system in the mother to a semi-allogeneic fetus is, perhaps, the least well understood. This immunologic balancing act allows the mother to avoid mounting a vigorous immune response to the presence of paternal major histocompatibility (MHC) antigens, and yet allows her to maintain normal immune competence for defense against micro-organisms. Although there are no significant differences in the absolute numbers of T- and B-lymphocytes and NK cell numbers, strong evidence demonstrates a switch from a Th1 to a Th2 response in pregnancy1Saito S. Sakai M. Sasaki Y. Tanebe K. Tsuda H. Michimata T. Quantitative analysis of peripheral blood Th0, Th1, Th2 and the TH1: Th2 cell ratio during normal human pregnancy and preeclampsia.Clin Exp Immunol. 1999; 117: 550-555Crossref PubMed Scopus (345) Google Scholar, as well as several potentially important functional adaptations. Comparisons of the mixed-lymphocyte reactions (MLR) of normal pregnant women and their non-pregnant, HLA-identical sisters indicate that, despite the presence of fetal (paternal) HLA antigens, maternal MLR are neither stimulated nor suppressed2Moore M. Sargent I.L. Ting A. Redman C.W. Maternal cell-mediated immunity in pregnancy: Lymphocyte responses of mothers and their non-pregnant HLA identical sisters to paternal HLA.Clin Exp Immunol. 1983; 54: 91-94PubMed Google Scholar,3Vanderbeeken Y. Vlieghe M.P. Duchateau J. Delespesse G. Suppressor T-lymphocytes in pregnancy.Am J Reprod Immunol. 1984; 5: 20-24Crossref PubMed Scopus (9) Google Scholar. Studies also report either normal or reduced NK cell cytolytic activity as well as suppression of lymphocyte proliferation. These alterations appear to be modulated by a 34 kD protein produced by lymphocytes named the progesterone-induced blocking factor (PIBF), which both influences lymphocyte and NK function and modulates the Th1 to Th2 switch4Szekeres-Bartho J. Faust Z. Varga P. Szereday L. Kelemen K. The immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production.Am J Reprod Immunol. 1996; 35: 348-351Crossref PubMed Scopus (144) Google Scholar,5Szekeres-Bartho J.F.Z. Varga P. The expression of a progesterone-induced immunomodulatory protein in pregnancy lymphocytes.Am J Reprod Immunol. 1995; 34: 342-348Crossref PubMed Scopus (98) Google Scholar. Because production of immunoglobulin and circulating levels of IgG, IgM, and IgA also are normal, B-cell function is likely intact. The mother does produce antibodies against some fetal (paternal) HLA antigens beginning at around eight weeks of gestation6Reed E. Beer A.E. Hutcherson H. King D.W. Suciu-Foca N. The alloantibody response of pregnant women and its suppression by soluble HLA antigens and anti-idiotypes antibodies.J Reprod Immunol. 1991; 20: 115-128Abstract Full Text PDF PubMed Scopus (43) Google Scholar; however, these autoantibodies are non-cytotoxic and regulated by an idiotypic network7Suciu-Foca N. Rohowsky-Kochan C. Reed E. Haars R. Bonagura V. King D.W. Reemstma K. Idiotypic network regulations of immune responses to HLA.Fed Proc. 1985; 44: 2483-2487Google Scholar that facilitates control of the immune response. Thus, pregnancy manifests selective functional changes in maternal immune responses that include a switch from Th1 to Th2 and a dampening of the response to fetal (paternal) HLA antigens. The maternal immune response during pregnancy has been investigated with respect to both rheumatoid arthritis and SLE. Rheumatoid arthritis tends to remit rather than flare in pregnancy8Nelson J. Hughes K.A. Smith A.G. Nisperos B.B. Branchaud A.M. Hansen J.A. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis.N Engl J Med. 1993; 329: 466-471Crossref PubMed Scopus (270) Google Scholar,9Formby B. Immunologic response in pregnancy: Its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.Endocrinol Metab Clin North Am. 1995; 24: 187-205PubMed Google Scholar. This salutary effect of pregnancy on the disease activity appears to be modulated by a maternal-fetal disparity in HLA-DR and DQ antigens8Nelson J. Hughes K.A. Smith A.G. Nisperos B.B. Branchaud A.M. Hansen J.A. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis.N Engl J Med. 1993; 329: 466-471Crossref PubMed Scopus (270) Google Scholar as well as a switch from Th1 to Th2 T-cell responses. Unlike investigations into rheumatoid arthritis, studies in murine lupus models suggest that a switch to Th2 responses favors further activation of the immune response in SLE. Thus, the predominance of Th2 responses in pregnancy might explain why lupus tends to flare during pregnancy. Immunologic adaptations during pregnancy are influenced by major endocrine changes, which might be relevant to pregnancy-associated lupus activity. Progesterone, estrogen, and androgen levels increase markedly during pregnancy. These changes are at first orchestrated by the corpus luteum, which makes progesterone during the initial six to eight weeks of gestation. Subsequently, progesterone is synthesized and secreted by the placenta. In addition to progesterone, the feto-placental unit is a major source of production of estrogen via a pathway involving the fetal adrenal gland and the compounds dehydroepiandrosterone and dehydroepiandrosterone sulfate. Maternal concentrations of progesterone and estrogen increase to four to eight times the level observed in the non-pregnant state. The effects of these compounds on the immune system are complex. As I alluded to earlier, progesterone suppresses lymphocyte proliferation by modulating the Th1/Th2 cytokine balance [reviewed in9Formby B. Immunologic response in pregnancy: Its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.Endocrinol Metab Clin North Am. 1995; 24: 187-205PubMed Google Scholar through the release by lymphocytes of PIBF8Nelson J. Hughes K.A. Smith A.G. Nisperos B.B. Branchaud A.M. Hansen J.A. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis.N Engl J Med. 1993; 329: 466-471Crossref PubMed Scopus (270) Google Scholar. Progesterone-induced blocking factor then mediates the immunomodulatory effects of progesterone through the induction of Th2-type cytokines by activated lymphocytes. In addition, progesterone-induced lymphocytes produce soluble factors that favor the synthesis of prostaglandin E, which in turn might suppress IL-2 production from both NK cells and T-lymphocytes. Estrogens, on the other hand, stimulate an increase in maternal hepatic protein synthesis, which raises the concentration of a variety of serum proteins. Although estrogen is stimulatory for T-cell responses and autoantibody production, the fact that neither T-cell function nor immunoglobulin production increases dramatically during pregnancy suggests counterbalancing influences10Weinberg E. Pregnancy associated depression of cell mediated immunity.Rev Infect Dis. 1984; 6: 814-831Crossref PubMed Scopus (298) Google Scholar. These counterbalancing immune suppressive factors include progesterone, α-fetoprotein, a pregnancy-specific β1-glycoprotein, pregnancy-associated α2-macroglobulin, and human chorionic gonadotropin10Weinberg E. Pregnancy associated depression of cell mediated immunity.Rev Infect Dis. 1984; 6: 814-831Crossref PubMed Scopus (298) Google Scholar. Whether progesterone-induced Th2 activity modulates lupus during pregnancy is still open to debate. Studies of pregnant lupus patients matched with non-pregnant controls suggest that pregnancy does not exacerbate clinical lupus activity11Lockshin M. Reinitz E. Druzin M.L. Murrman M. Estes D. Lupus pregnancy.Am J Med. 1984; 77: 893-898Abstract Full Text PDF PubMed Scopus (226) Google Scholar,12Meehan R. Dorsey J.K. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy.J Rheumatol. 1987; 14: 252-258PubMed Google Scholar, but this remains a controversial issue. On the other hand, there appears to be agreement that lupus that is active at the onset of pregnancy is activated further during pregnancy, as evidenced by either clinical activation of disease, worsening of serologies, or both. One explanation for this difference could be that lymphocytes, after being activated during a pre-pregnancy exacerbation of disease, become more responsive to Th2 cytokines during pregnancy. According to this hypothesis, pregnancy does not induce flaring of lupus, but already active lupus can worsen during pregnancy because of the Th2 bias in immune responses. The mechanisms underlying maternal tolerance to the semi-allogeneic fetus at the feto-placental interface also are beginning to be understood. Rejection of the trophoblast is prevented through the regulated expression of major HLA antigens by placental trophoblast cells13Hunt J. Orr H.T. HLA and maternal-fetal recognition.FASEB J. 1992; 6: 2344-2348PubMed Google Scholar. Transcription and translation of the highly polymorphic class-I HLA-A, -B, and -C genes, whose products play a critical role in graft rejection, are blocked in trophoblast cells. In place of HLA-A, -B, and -C, trophoblast cells express HLA-G, a nonclassic, nonpolymorphic major histocompatibility complex class-I molecule, which is expressed in a restricted fashion on trophoblasts. Expression of HLA-G also appears to inhibit NK cell activity, as well as T-cell function. The role of HLA-G has been discussed elsewhere in detail14Carosella E. Immunotolerant functions of HLA-G.Cell Mol Life Sci. 1999; 55: 327-333Crossref PubMed Scopus (32) Google Scholar. While trophoblast cells do not express class-II HLA-D antigens, they do express Fas ligand, thereby conferring immune privilege. Furthermore, trophoblasts express the complement regulatory proteins CD46, CD55, and CD5915Weetman A. The immunology of pregnancy.Thyroid. 1999; 9: 643-646Crossref PubMed Scopus (161) Google Scholar. A number of cytokine responses also appear to be important in implantation16Hill J. Cytokines considered critical in pregnancy.Am J Reprod Immunol. 1992; 28: 123-126Crossref PubMed Scopus (57) Google Scholar. Interferon-γ, which usually increases HLA expression, appears to have no effect on trophoblast cells in situ. On the other hand, increased expression of cytokines, including IL-1, TNF-α, IFN-γ, GM-CSF, and CSF-1, influence blastocyst attachment, trophoblast outgrowth, implantation, proliferation of trophoblast cell lines, and placental function. Uterine decidual and placental cells also bias the Th response towards Th2. Finally, the placental barrier restricts the traffic of cytotoxic cells to the fetus, and cytotoxic antibodies are removed by the placenta before they reach the fetal circulation. The balancing of immunologic and endocrine factors ensures the success of pregnancy. In essence, there are two battlegrounds: systemic, where tolerance of the maternal immune system to fetal (paternal) antigens in the circulation occurs, and local, at the feto-placental interface. Some evidence indicates that the level of disparity between maternal and fetal antigens (of the major HLA antigens) in pregnancy influences immune responsiveness, at least in patients with rheumatoid arthritis. Whether this finding is applicable to SLE remains to be seen. Studies from murine models suggest that the time of greatest likelihood for activation of lupus is the "child-bearing" period (rather than pregnancy itself) because the immune stimulatory effect of estrogen is unopposed at this age. In the NZB/W murine model of SLE, reduction in the estrogen stimulus or an increase in the androgenic influence is associated with amelioration in disease activity17Melez K. Reeves J.P. Steinberg A.D. Regulation of the expression of autoimmunity in NZBxNZW F1 mice by sex hormones.J Immunopharmacol. 1978; 1: 27-42Crossref Scopus (31) Google Scholar. In addition, sporadic evidence links exogenous estrogen therapy with the precipitation of a lupus flare. This issue is reviewed elsewhere in greater detail18Buyon J. Hormone replacement therapy in postmenopausal women with systemic lupus erythematosus.J Am Med Womens Assoc. 1998; 53: 13-17PubMed Google Scholar. However, as I said earlier, to the extent that autoimmune activity proximate to the onset of pregnancy (<6 months) is associated with a greater flare rate during pregnancy, it is likely that the level of autoimmune activity at the onset of pregnancy influences subsequent disease activity during gestation. The potential impact of pregnancy on lupus activity has been debated for decades. Bridge and Foley concluded in a 1954 article that "there is no constant effect of pregnancy on this disease"19Bridge R.G. Foley F.E. Placental transmission of lupus erythematosus factor.Am J Med Sci. 1954; 227: 1-8Crossref PubMed Google Scholar. A large number of studies have since examined this issue, but no consensus has emerged. The lupus flare rate, examined in numerous studies11Lockshin M. Reinitz E. Druzin M.L. Murrman M. Estes D. Lupus pregnancy.Am J Med. 1984; 77: 893-898Abstract Full Text PDF PubMed Scopus (226) Google Scholar, 12Meehan R. Dorsey J.K. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy.J Rheumatol. 1987; 14: 252-258PubMed Google Scholar, 20Zurier R. Argyros T.G. Urman J.D. Warren J. Rothfield N.F. Systemic lupus erythematosus: Management during pregnancy.Obstet Gynecol. 1978; 51: 178-180PubMed Google Scholar, 21Zulman J. Talal N. Hoffman G.S. Epstein W.V. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus.J Rheumatol. 1980; 7: 37-49PubMed Google Scholar, 22Devoe L. Taylor R. Systemic lupus erythematosus in pregnancy.Am J Obstet Gynecol. 1979; 135: 473-479PubMed Scopus (44) Google Scholar, 23Jungers P. Dougados M. Pelissier C. Kuttenn F. Tron F. Lesavre P. Bach J.-F. Lupus nephropathy and pregnancy.Arch Intern Med. 1982; 142: 771-776Crossref PubMed Scopus (119) Google Scholar, 24Petri M. Howard D. Repke J. Frequency of lupus flare in pregnancy: The Hopkins Lupus Pregnancy Center experience.Arthritis Rheum. 1991; 34: 1538-1545Crossref PubMed Scopus (350) Google Scholar, ranges from approximately 20% to 60% Figure 1. Retrospective studies invariably have noted an increased flare rate in pregnant women with lupus. However, these studies have significant limitations, including variable definitions of a lupus flare. For example, in one study reporting a flare rate of 22%, lupus flare was not defined at all20Zurier R. Argyros T.G. Urman J.D. Warren J. Rothfield N.F. Systemic lupus erythematosus: Management during pregnancy.Obstet Gynecol. 1978; 51: 178-180PubMed Google Scholar. In contrast, in several other studies (in which the flare rate ranged from 37.5% to 54.0%), clinical criteria defined a lupus flare21Zulman J. Talal N. Hoffman G.S. Epstein W.V. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus.J Rheumatol. 1980; 7: 37-49PubMed Google Scholar, 22Devoe L. Taylor R. Systemic lupus erythematosus in pregnancy.Am J Obstet Gynecol. 1979; 135: 473-479PubMed Scopus (44) Google Scholar, 23Jungers P. Dougados M. Pelissier C. Kuttenn F. Tron F. Lesavre P. Bach J.-F. Lupus nephropathy and pregnancy.Arch Intern Med. 1982; 142: 771-776Crossref PubMed Scopus (119) Google Scholar. Retrospective studies also have been dogged by small numbers of patients (as few as eight patients in one study22Devoe L. Taylor R. Systemic lupus erythematosus in pregnancy.Am J Obstet Gynecol. 1979; 135: 473-479PubMed Scopus (44) Google Scholar), non-random selection of subjects, use of patients with more severe underlying disease, and either the lack of a control group or the use of patients as their own controls. In studies in which carefully matched non-pregnant patients were used as controls, no excess flare rate was noted with pregnancy11Lockshin M. Reinitz E. Druzin M.L. Murrman M. Estes D. Lupus pregnancy.Am J Med. 1984; 77: 893-898Abstract Full Text PDF PubMed Scopus (226) Google Scholar,12Meehan R. Dorsey J.K. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy.J Rheumatol. 1987; 14: 252-258PubMed Google Scholar, whereas in studies in which patients themselves functioned as controls, an excess flare rate was documented21Zulman J. Talal N. Hoffman G.S. Epstein W.V. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus.J Rheumatol. 1980; 7: 37-49PubMed Google Scholar,24Petri M. Howard D. Repke J. Frequency of lupus flare in pregnancy: The Hopkins Lupus Pregnancy Center experience.Arthritis Rheum. 1991; 34: 1538-1545Crossref PubMed Scopus (350) Google Scholar. The main problem with self-controls is that signs of active disease can diminish over time in patients with SLE. Furthermore, the use of historical controls rather than concurrent controls or the use of "published flare rates in other populations" has obvious limitations. Studies that report a relatively low rate of lupus flare in the control population also are not necessarily representative of the observed rate in other centers, and comparisons among studies might not be valid. In some studies, the level of disease activity at the onset of pregnancy has been poorly documented. Single-center studies are also open to biases. For example, studies from a high-risk obstetric center can comprise patients who have a history of more severe lupus—and therefore more likely to flare—compared with those from less-specialized centers where the patients might have less-severe disease. Prospective controlled studies unfortunately have also generated conflicting results. Lockshin et al reported that the lupus flare rate is approximately 20% and found no difference in the flare rate when pregnant lupus patients are compared with matched non-pregnant lupus controls11Lockshin M. Reinitz E. Druzin M.L. Murrman M. Estes D. Lupus pregnancy.Am J Med. 1984; 77: 893-898Abstract Full Text PDF PubMed Scopus (226) Google Scholar. In contrast, Petri and coworkers reported a flare rate of approximately 60% and suggested that pregnancy exacerbates lupus activity24Petri M. Howard D. Repke J. Frequency of lupus flare in pregnancy: The Hopkins Lupus Pregnancy Center experience.Arthritis Rheum. 1991; 34: 1538-1545Crossref PubMed Scopus (350) Google Scholar,25Petri M. Genovese M. Engle E. Hochberg M. Definition, incidence and clinical description of flare in systemic lupus erythematosus: A prospective cohort study.Arthritis Rheum. 1991; 34: 937-944Crossref PubMed Scopus (265) Google Scholar. Several factors might explain this large discrepancy between prospective studies from experienced centers. The most important factor, as is the case with retrospective analyses, appears to be a lack of consensus on the definition of a lupus flare, even in carefully designed, prospective studies. Worsening of disease activity along a continuum