Immunol Res DOI 10.1007/s12026-014-8577-1
FRONTIERS IN AUTOIMMUNITY
Risk factors of systemic lupus erythematosus flares during pregnancy Luis J. Jara • Gabriela Medina • Pilar Cruz-Dominguez • Carmen Navarro • Olga Vera-Lastra • Miguel A. Saavedra
Ó Springer Science+Business Media New York 2014
Luis J. Jara
Abstract This review examines the risk factors for the development of systemic lupus erythematosus (SLE) flares during pregnancy. In preconception, anti-DNA, hypocomplementemia, previous thrombosis, triple antiphospholipid (aPL) antibody positivity, active lupus nephritis and discontinuation of medications such as hydroxychloroquine and azathioprine are factors associated with pregnancy failure. During pregnancy, SLE flares are associated with aPL antibodies, synergic changes of pregnancy on Th1 and TH2 cytokines, other cytokines and chemokines that interact with hormones such as estrogen and prolactin that amplify the inflammatory effect. From the clinical point of view, SLE activity at pregnancy onset, thrombocytopenia, lupus nephritis, arterial hypertension, aPL syndromes, preeclampsia is associated with lupus flares and fetal complications. In puerperium, the risk factors of flares are similar to pregnancy. Hyperactivity of immune system, autoantibodies, hyperprolactinemia, active lupus nephritis, decrease in TH2 cytokines with increase in TH1 cytokines probably participate in SLE flare. The SLE flares during pregnancy make the difference between an uncomplicated pregnancy and pregnancy with maternal and fetal complications. Therefore, the knowledge of risk factors leads the best treatment strategies to reduce flares and fetal complications in SLE patients. Keywords
Systemic lupus erythematosus Pregnancy Flares Antiphospholipid syndrome
L. J. Jara (&) Direction of Education and Research, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Seris/Zaachila s/n, Colonia La Raza, 02990 Mexico City, Mexico e-mail: [email protected]; [email protected] G. Medina Clinical Research Unit, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico P. Cruz-Dominguez Division of Research, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico
C. Navarro Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico O. Vera-Lastra Internal Medicine Department, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico M. A. Saavedra Rheumatology Department, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico C. Navarro Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
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Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease that affects predominantly women during reproductive years, and its evolution is altered by hormonal events such as menses, menopause, and especially pregnancy. According to medical advances in the care of pregnant women, the number of patients with SLE and pregnancy has increased worldwide and the pregnancy outcomes have also significantly improved. However, despite of these progresses, SLE pregnancy is considered as a high-risk pregnancy, and a multidisciplinary approach, with close medical, obstetric and neonatal monitoring, is essential for optimal outcomes [1, 2]. Fortunately, the majority of pregnancies in women with SLE are successful, and although these patients have few live births with more pregnancy complications, they can have subsequent uncomplicated pregnancies after having a poor outcome. Recent studies analyzed novel markers of poor pregnancy outcomes and new approaches to the management of lupus during pregnancy [3]. However, the activity of lupus in pregnancy remains a problem to be solved, and major organ involvement can negatively affect the outcomes. In fact, fetal adverse outcomes in obstetric SLE include fetal loss (spontaneous abortion and intrauterine fetal death) intrauterine growth restriction (IUGR), premature birth, premature rupture of membranes, neonatal lupus and perinatal mortality [4, 5]. Maternal complications in SLE patients include SLE activity, preeclampsia and arterial hypertension, especially in patients with renal involvement [6]. Risk factors for an unfavorable course of pregnancy in SLE can be immunological, neuro-endocrinological and clinical [7–9]. However, the predictive factors of lupus flare in pregnancy have not been systematically and fully elucidated. Therefore, the aim of the present review was to analyze predictors of flare and poor outcome in the preconception, pregnancy and puerperium period. Immunological factors SLE is an autoimmune disease characterized by the breakdown of immune tolerance resulting in overproduction of autoantibodies, and complement factors activation. In the clinical practice, monitoring of a patient with SLE includes measuring the titers of anti-double-stranded DNA antibodies and serum complement proteins. During pregnancy, the importance of complement levels and antidsDNA in patients with SLE was recently investigated. The results showed that low complement or positive antidsDNA in the second trimester was associated with a higher rate of pregnancy loss and preterm birth, despite of clinical activity. Hypocomplementemia and positive anti-
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dsDNA alone are predictive of poor pregnancy outcomes in the second trimester. The risks are increased in women with clinically active SLE during pregnancy [10]. SLE and pregnancy-induced hypertension (PIH) share histological findings of the placenta, complement dysregulation and fetal outcomes. Placentas of SLE (50 %) and PIH (35 %) showed a higher H-score (range of 0–300) for C4d immunoreactivity than control cases with linear staining on the membrane of syncytiotrophoblast. C4d high groups were significantly associated with low-placental weights and low birth weight in both SLE and PIH. C4d might be utilized as a biomarker for subsequent risk for IUGR and control during the gestation period in lupus pregnant patients [11]. In fact, from the clinical point of view, hypocomplementemia is associated with intrauterine growth retardation in comparison with pregnancies with normal complement activity [12]. However, the predictive value of poor pregnancy outcomes of hypocomplementemia and/or anti-dsDNA before pregnancy, regardless SLE activity, has not been systematically studied. The association between antiphospholipid (aPL) antibodies and pregnancy complications is controversial because many women with aPL antibodies may have successful pregnancies. However, recent studies suggest that lupus anticoagulant (LAC) is an important risk factor for maternal–fetal complications in SLE pregnancy when it is detected since the first trimester of pregnancy. Therefore, the LAC is the strongest predictor of serious pregnancy complications in comparison with anticardiolipin antibodies and anti-beta 2 glycoprotein I. Identification of patients at high risk will be highly informative in designing trials to prevent aPL-associated maternal and fetal morbidity [7, 13]. One of the most important immunological modifications during pregnancy is the Th1/Th2 cytokines shift. Th1 includes interferon (IFN)-c, interleukin (IL)-1, IL-2, IL-12 and tumor necrosis factor (TNF)-alpha, which stimulate cellular immunity, and Th2 includes IL-4, IL-5, IL-6 and IL-10, which induce humoral immunity and antibody production. Since SLE is mainly a Th2-mediated disease, during pregnancy, we expect a predominance of Th2 response, and an exacerbation of the disease is more possible. However, lower levels of estrogens, progesterone and Th2 cytokines were found in the third trimester of pregnancy in SLE patients compared with healthy pregnant women [14]. In order to confirm these findings, a recent prospective study evaluated again the role of some cytokines involved in the Th1–Th2 shift during pregnancy in SLE patients and healthy women. IL-8 serum levels were higher in the first and third trimesters of pregnancy in SLE patients compared with controls, INF-c serum levels in the third trimester and IL-10 serum levels in the first and third trimesters. IL-2, IL-12, IFN-c and IL-6 serum levels
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correlated with disease activity in SLE patients in the first trimester of pregnancy. Cytokine profile was similar in patients with and without lupus nephritis both in the first and in the third trimesters of pregnancy. Since Th2 cytokine production seems to play a key role in SLE, and an overproduction of IL-6 and IL-10 is reported, we should expect a Th2 polarization of immune response in SLE patients compared with healthy controls, especially during pregnancy. However, the most relevant features of this study were lower than expected increase in Th2 cytokine during pregnancy in SLE patients and an increase in some Th1 cytokines, such as IL-8 and INF-c, in SLE pregnant women compared with controls. In consequence, serum levels of Th2 cytokines were similar in SLE patients compared with controls and only IL-10 was higher in SLE patients than in healthy women. Therefore, in pregnant SLE patients, the polarization toward Th2 cytokines is lower than expected [15]. This study confirms the early observations of Mun˜oz-Valle et al. [16] who demonstrated high levels of IL-10 in pregnant SLE patients in comparison with healthy pregnant women, particularly during the last trimester of pregnancy. The lower Th2 polarization observed during pregnancy could explain, in part, some studies that found a similar rate of flare between pregnant and nonpregnant SLE patients [15]. During and after pregnancy, women with SLE have increased serum concentrations of chemokines CXCL8/IL8, CXCL9/MIG, CXCL10/IP-10 and IL-10 compared to normal pregnancy, especially during active disease. In SLE pregnancy, a top of already more pro-inflammatory levels might increase their risk for pregnancy complications, flares and probably on the children during pregnancy [17]. A novel gene family called T cell immunoglobulin mucin domain-containing molecules (TIM) are members differentially expressed on Th1 and Th2 cells (TIM-1, TIM-3 and TIM-4). Genomic association and polymorphisms in the TIM in different immune-mediated diseases suggest that they have an important role in regulating autoimmunity diseases [18]. In this regard, TIM-3, by virtue of its upregulation in innate immune cells in pregnant women, enhances both innate and adaptive immune responses. Nevertheless, the abnormality of TIM-3 in pregnant woman may be deleterious to normal pregnancy. Therefore, TIM-3 may be a potential indicator to predict the risk of pregnancy loss in pregnant woman, including SLE patients [19]. The changes at day 14 of pregnancy in lupus-prone LPR (MRL/lpr) mice and MRL controls regarding cytokines, regulatory T (Treg) cells and deposition of immunocomplexes were studied. Worsened kidney function was observed during pregnancy, even in the absence of others lupus activity signs. This was accompanied by active glomerulonephritis, higher interferon-gamma and interleukin-
10 levels. C3 and immunoglobulin G deposition was enhanced in kidney and placenta from lupus-prone pregnant animals. Pregnancy enhanced the levels of Treg cells in control animals but not in lupus-prone animals. Treg cells were shown to be specific for paternal antigens; thus, these cells cannot help to kill autoreactive cells. These data are potentially of importance for lupus patients of reproductive age [20]. Ficolins are soluble molecules of the innate immune system that recognize carbohydrate molecules on microbial pathogens, apoptotic and necrotic cells. In SLE, increased of ficolin-3 was associated with hemolysis, positive Coombs test and lymphopenia, but not with SLE Disease Activity Index scores or C-reactive protein. The elevation of ficolin-3 in specific manifestations may indicate a pathogenetic role of ficolin-3 in SLE. In normal and preeclamptic pregnant, there are significant inverse correlation of circulating levels of ficolin-2 with those of cell-free fetal DNA. It is possible that ficolin-2 may be involved in the direct removal of trophoblast-derived material from the maternal circulation. Ficolin-3 concentrations are decreased in preeclamptic women, possibly as a consequence of its sequestration in the placenta. Low levels of circulating ficolin-2 might impair the clearance of shed apoptotic and necrotic placental material [21, 22]. Genetic and functional alterations of ficolins have to be investigated as a risk factor in lupus pregnant flares. Neuro-endocrine factors Estrogens The SLE is characterized by the production of autoantibodies, expansion of autoreactive B cells and glomerular deposition of immunoglobulin complexes that contribute to tisular damage. The mouse models of SLE systemic such as the NZB/ZNW F1 and MRL/lpr mouse strains spontaneously develop pathogenic autoantibodies that cause glomerulonephritis and have served to dissect the molecular pathways that regulate autoreactive B cells. On the other hand, the occurrence of SLE may be in part determined by sexual hormones which act as a trigger for disease and a modulator of disease activity [23]. In murine models, it has been demonstrated that estrogens (E2) alter the maturation of splenic B cell precursors and enhance development and activation of autoreactive marginal zone B cells. Marginal zone B cells contribute to the pathogenic autoantibody responses generated in NZB/NZW F1 mice. Estrogens also diminish B cell receptor signaling and allow for the increased survival of high-affinity DNA-reactive B cells [24]. They have stimulatory effects on SLE T cells, increasing the expression of anti-apoptotic Bcl molecule that blocks tolerance induction of T cells [25]. It is well
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known that E2 have both immunostimulating and immunosuppressive properties. In SLE, pregnancy is associated with disease flares [26]. However, whether or not SLE relapses more often during pregnancy is still controversial. Th1/Th2 shift is one of the most important immunological changes during pregnancy due to the progressive increase in E2, reaching the highest level in the third trimester. Therefore, SLE tends to worsen during pregnancy. However, recent studies reported that SLE flare-ups were less frequently observed in the last trimester of pregnancy compared to the second trimester and postpartum period. Estradiol serum levels were lower than expected during the last trimester of SLE pregnancy, probably due to a placental compromise, leading to a lower increase in IL-6, with a low humoral immune response and a low disease activity observed during that period [27]. Increased disease activity is the best predictor of preterm birth in women with SLE, despite of the activity grade. Women with low disease activity have an increased risk of this complication. Therefore, biomarkers that would identify at-risk pregnancies are necessary in order to allow interventions to prevent preterm birth. In a recent study, women with SLE with mild-moderate disease activity, high levels of ferritin and uric acid levels with low levels of E2 at mid-gestation may predict preterm birth [8]. On the other hand, E2 treatment decreases TNF-a with an increase in IL-10. Due to TNF-a function on apoptosis, the failure to produce this cytokine alters the apoptosis of activated immune cells in SLE patients exposed to high levels of estrogens, such as in pregnancy. Steroid hormone and cytokine profiles differ in SLE patients in comparison with healthy women during pregnancy leading to a dysregulation of the balance between cell-mediated and humoral immune response, which may explain the variability of the SLE course during gestation [9]. SLE flareups during pregnancy and postpartum period are usually mild to moderate with cutaneous and articular manifestations predominantly [28, 29]. Severe relapses with kidney or central nervous system involvement are reported between 5 and 46 % [30]. According to prospective studies, the incidence of flare-ups is higher in the second trimester of pregnancy and lower in the last trimester, not only due to estrogens, but also due to progesterone, testosterone and DHEA serum levels which do not have a peak in the last trimester as expected in healthy women [27, 31]. Progestogens Pregnancy is a state of immunomodulation, intense at the maternal–fetal interface and more subtle in the mother. Many of these changes are thought to be induced by progesterone, in part because maternal serum progesterone and
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estradiol levels increase fivefold to tenfold throughout pregnancy. Although relationships between estrogens and SLE autoimmunity have been relatively well studied, much less is known about progesterone [32]. The effects of progesterone and synthetic progestins depend on their concentrations and differential engagement of various intracellular and membrane-associated progesterone receptors expressed in immune cell subsets, immune organs and tissues. The mechanisms, through which progesterone exerts modulatory actions, are different to those of estrogens or testosterone, on inflammation, adaptive immune responses and autoimmunity [33]. An inadequate or lower production of progesterone in follicular and luteal phase was found in SLE patients in comparison with healthy women, suggesting a possible luteal dysfunction [34]. Doria et al. [35] found in SLE pregnant patients lack of estrogen serum level increase as well as a lower progesterone serum level, during the second and—even more—the third trimester of gestation, probably due to placental compromise, accounting for the decrease in disease activity observed during the third trimester in pregnant SLE patients. Therefore, progesterone has been suggested as a possible supplementary treatment in pregnancy more than as a contributing factor for lupus flare [36]. Prolactin Prolactin (PRL) is a pituitary hormone that stimulates immune responses; it has been found elevated in SLE patients of both sexes and correlated with disease activity in several studies. An early study showed HPRL during pregnancy in association with fetal wastage and flares. Lactation seems to influence postpartum behavior of SLE [31, 37]. Circulating PRL is elevated in a number of autoimmune diseases, and about 20 % of SLE patients are hyperprolactinemic [38]. However, in a prospective study, mild hyperprolactinemia (HPRL, 20–40 ng/ml) was found in 69.7 % SLE patients, and at entry and after conventional treatment, a significant correlation between PRL levels and SLEDAI score was found [39]. HPRL in SLE has been correlated with disease activity with neuropsychiatric, kidney or hematological involvement [40]. High PRL levels seem to be associated with active SLE during pregnancy and autoantibodies. In this regard, we studied the association among SLE activity, lupus anticoagulant (LA) and maternal–fetal outcomes in 15 pregnant SLE women. High PRL levels were found during the second and third trimester in SLE patients in comparison with controls with a strong association among PRL, LAC, SLE activity and poor pregnancy outcome [41]. In another trial, we explore the role of oral dopaminergic agonist, bromocriptine (BRC) during pregnancy in patients with SLE. Patients received BRC plus prednisone or prednisone alone from 25
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to 35 weeks of gestation. PRL levels were determined at 25, 30 and 35 weeks. The SLE Pregnancy Disease Activity Index and maternal–fetal outcomes were evaluated. A significant decrease in PRL levels in BRC group compared to control group was found. Patients receiving BRC did not present flares, and they have better maternal–fetal outcomes. This study revealed the participation of PRL in SLE flares and the role of BRC in the prevention of flares and of poor maternal–fetal outcomes [42]. Previous controlled study demonstrated that oral BRC for 2 weeks in postpartum patients with SLE might be beneficial in protecting the patients from HPRL, hyperestrogenemia and disease relapse and in reducing the usage of steroid and immunosuppressant [43]. Another study determined the frequency of anti-PRL autoantibodies in SLE pregnant women and compared the outcome of pregnancy in those women with and without anti-PRL autoantibodies. The frequency of anti-PRL autoantibodies in lupus pregnancy was 13.1 %. Serum total PRL levels were significantly higher in women with anti-PRL autoantibodies compared with SLE women without the antibodies. SLE pregnant women with antiPRL autoantibodies had fewer adverse outcomes of pregnancy. The presence of high PRL levels and autoantibodies suggests the role of PRL in pregnancy outcome [44]. The interaction of lupus and pregnancy is very complex being the consensus that pregnancy can worsen the lupus disease process through hormones. Pregnancy is associated in 50–60 % of cases with a clinical flare manifesting as renal or hematological symptoms. Fortunately, severe flares are uncommon (10 %) and the risk of maternal death has decreased now from 2 to 3 % due to a better understanding of pathogenic mechanisms and close surveillance of patients [45]. Clinical factors Despite advances in the care of the mother–child binomial, pregnancy in SLE patients remains high risk. Several studies indicate that disease flares are common during lupus pregnancies, with reported rates that range from 13.5 to 65 % [5, 46]. It has been estimated that women with SLE have 2–3 times higher risk of relapse during pregnancy. Most of these flares are mild to moderate and frequently involve the renal, musculoskeletal and hematological systems, whereas the risk for a moderate to severe flare is between 15 and 30 % [5]. Lupus activity during pregnancy is associated with various maternal–fetal complications such as fetal loss and preterm birth, making important the identification of predictors of poor maternal and fetal outcomes. Thrombocytopenia, hypertension and prednisone use may be predictive factors for particular adverse outcomes [47–49]. However, the predictive clinical factors of lupus flare in pregnancy have not been
completely elucidated and several factors have been implicated. Several risk factors for relapse in pregnant patients with SLE have been described such as active disease within 6 months prior to conception, multiple exacerbations before conception, discontinuation of treatment during pregnancy and the presence of comorbidities [5]. In a prospective study of 103 pregnancies in 60 women with lupus, they were reported as risk factors for SLE activity (measured by SLEDAI) during pregnancy, a high number of relapses of disease prior to pregnancy (p \ 0.05), discontinuing chloroquine at the time of pregnancy (p \ 0.05) and high SLEDAI index ([5) before pregnancy (p [ 0.05) [50]. In a prospective analysis of a cohort of 267 pregnancies in women with lupus, it was observed that those patients with preconception activity had increased lupus activity during pregnancy compared with those patients in remission before pregnancy (p = 0.0002) [49]. In another prospective evaluation of 254 pregnancies of the Hopkins Lupus Pregnancy Cohort found that patients who stopped hydroxychloroquine at pregnancy developed more frequently disease activity (measured by SLEDAI) in this period compared with those who continued taking the medication (p = 0.05) [51]. Furthermore, in a study of 193 pregnancies in 104 woman found that those patients with active lupus nephritis (up to 6 months before conception) had a higher overall SLE activity during pregnancy, 47.5 versus 13.4 % (p = 0.0001) [52]. Lupus nephritis, especially active at the time of conception, has been associated with an increased risk of relapse during pregnancy, although other authors have found different results [6, 52–54]. In fact, it has been observed that pregnant patients with previous lupus nephritis have a higher risk of activity to any organ, especially at renal level, compared with those patients who have never had kidney disease (54.2 vs. 25 %, p = 0.004 and 45.7 vs. 6.6 %, p = 0.00001) [6]. Risk factors for renal relapse during pregnancy have been addressed in different studies [6, 52, 54]. In a multicenter study of 113 pregnancies in 86 women with lupus nephritis, the reactivation of the disease during pregnancy was more frequent in patients with activity before pregnancy or in partial remission (proteinuria [1 g/24 h or clearance creatinine \60 ml/min/1.73 m2) [55]. Recently, in a retrospective analysis of 124 pregnancies in 120 women with lupus was found that the first pregnancy is associated with an increased risk of relapse at any level (OR 2.3, 95 % CI 0.99–5.52, p = 0.05) but mainly in the kidney (OR 3.6, 95 % CI 1.19–11.3, p = 0.02) [56]. In this regard, a recent study analyzed 95 first and 145 subsequent births in SLE patients in comparison with references. The risk of cesarean section (CS) was twofold higher in SLE patients in first and subsequent births. More newborns of patients had birth
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PRE-CONCEPTION
PREGNANCY
PUERPERIUM
Lupus Nephritis SLE activity at Onset
Diseases Activity < 6 months APS, Thrombocytopenia Hypocomplementemia Change in medications
Hormones Prolactin Estrogens
Hypertension Pre-eclampsia
Hormones Estrogens Prolactin
↑Antibodies, ↑APS, ↓ complement
Lupus Nephritis Lupus Nephritis Hormones Estrogens Prolactin
Hypertension Pre-eclampsia Hyperactivity of Immune system
Infections XX sex chromosome complement
Decidua T-reg cells
Fig. 1 .
weight less (\2,500 g), preterm birth, and congenital malformations were more frequent among SLE patients, in first birth and in subsequent births. Perinatal death was more frequent in first births among patients, but no difference was observed in subsequent births. Pregnancy complications were more frequent in SLE patients than references, especially in the first birth [57]. Finally, a recent meta-analysis of 37 selected studies found high rates of SLE flare, hypertension, nephritis and preeclampsia. Fetal complications included spontaneous abortion, stillbirth, neonatal death and IUGR. One quarter of pregnancies was unsuccessful, and the premature birth rate was 39.4 %. Active lupus nephritis seemed to increase the risk for adverse pregnancy outcomes, particularly premature birth and hypertension. These findings support the current recommendations for avoidance of pregnancy until all manifestations of nephritis are quiescent. History of nephritis was associated with higher rates of preeclampsia, thus emphasizing the need for a multispecialty approach in the care of these patients with respect to close monitoring and early recognition of clinical signs of preeclampsia.
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Positive aPL antibodies were associated with higher rates of hypertension, premature birth and induced abortion. In consequence, early screening for aPL antibodies especially LAC may identify those at risk [58].
Summary and perspectives This review examines the risk factors for the development of SLE relapses during pregnancy (Fig. 1). These factors can be summarized as follows: Preconception The main immunological risk factors of pregnancy flare used in clinical practice are as follows: aPL antibodies, especially LAC, anti-dsDNA and hypocomplementemia. In this regard, previous thrombosis, SLE diagnosis and triple aPL antibody positivity are independent factors associated with pregnancy failure in women with APS [59].
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The main hormones candidates for risk factors before conception to relapses in pregnancy are estrogen and prolactin. However, these hormones have not been analyzed as risk factors before pregnancy. Of interest, pregnant women with SLE have an increased prevalence of thyroid disease and preterm delivery [60]. The main clinical factors for reactivation of lupus in pregnancy are the activity of the disease in the 6 months before pregnancy and discontinuation of medications such as hydroxychloroquine and azathioprine. Recently, it has been proposed that 4 months of remission of SLE are sufficient to ensure a successful pregnancy in SLE patients [3]. Pregnancies in women with SLE and lupus nephritis are considered high risk due to high rates of maternal and fetal complications. However, there has not been a formal analysis addressing the issue of maternal deaths in these women. A recent study analyzed the literature from 1962 to 2009 and included reports of pregnancies in patients with SLE and lupus nephritis with at least one reported maternal death. The authors identified 13 studies that reported a total of 17 deaths in the 6-week postpartum period that were attributable to SLE and lupus nephritis. All maternal deaths in patients with SLE and lupus nephritis occurred in those with active disease, with disease activity/complications and infections (mainly opportunistic) being the two major causes [61]. Therefore, the impact of opportunistic infections and its relationship with pregnancy flare should be analyzed. Pregnancy The immunological risk factors of SLE flares during pregnancy include autoantibodies, aPL antibodies, especially LAC, Th1 and TH2 cytokines, chemokines, soluble cytokine receptors, soluble glycoproteins. The Treg cells, dendritic cells and its interaction with hormones during pregnancy need to be studied. Hormones such as estrogen and prolactin remain the main hormones that interact with the immune system to amplify the inflammatory effect that characterizes relapses. From the clinical point of view, SLE activity at pregnancy onset thrombocytopenia, lupus nephritis, arterial hypertension, aPL syndrome, preeclampsia is associated factors with lupus flares and fetal complications. Preeclampsia and miscarriage are important complications of pregnancy in women with SLE or aPL antibodies. Both autoimmune diseases are characterized by complement activation. A recent study demonstrated for first time the presence of risk variants in complement regulatory proteins (in patients with SLE and/or antiphospholipid antibodies who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease. Defective regulation of membrane cofactor protein, complement
factor H and complement factor I allows for the excessive complement activation with placental damage [62, 63]. Puerperium The risk factors of flares in puerperium are similar to pregnancy. Hyperactivity of immune system, autoantibodies, HPRL, active lupus nephritis, decrease in TH2 cytokines with increase in TH1 cytokines probably participate in SLE flare; however, other studies are necessary in order to clarify the role of immunological, hormonal and clinical factors that participate in puerperium period.
Conclusion Although medical advances have allowed patients with SLE have a better prognosis when pregnant, there are still many points to be resolved. The SLE flares during pregnancy make the difference between an uncomplicated pregnancy and pregnancy with maternal and fetal complications. Therefore, the identification of news immunogenic, hormonal and environmental factors must be identified in order to develop treatment strategies for these patients and reduce flares and fetal complications.
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Risk factors of systemic lupus erythematosus flares during pregnancy Luis J. Jara • Gabriela Medina • Pilar Cruz-Dominguez • Carmen Navarro • Olga Vera-Lastra • Miguel A. Saavedra
Ó Springer Science+Business Media New York 2014
Luis J. Jara
Abstract This review examines the risk factors for the development of systemic lupus erythematosus (SLE) flares during pregnancy. In preconception, anti-DNA, hypocomplementemia, previous thrombosis, triple antiphospholipid (aPL) antibody positivity, active lupus nephritis and discontinuation of medications such as hydroxychloroquine and azathioprine are factors associated with pregnancy failure. During pregnancy, SLE flares are associated with aPL antibodies, synergic changes of pregnancy on Th1 and TH2 cytokines, other cytokines and chemokines that interact with hormones such as estrogen and prolactin that amplify the inflammatory effect. From the clinical point of view, SLE activity at pregnancy onset, thrombocytopenia, lupus nephritis, arterial hypertension, aPL syndromes, preeclampsia is associated with lupus flares and fetal complications. In puerperium, the risk factors of flares are similar to pregnancy. Hyperactivity of immune system, autoantibodies, hyperprolactinemia, active lupus nephritis, decrease in TH2 cytokines with increase in TH1 cytokines probably participate in SLE flare. The SLE flares during pregnancy make the difference between an uncomplicated pregnancy and pregnancy with maternal and fetal complications. Therefore, the knowledge of risk factors leads the best treatment strategies to reduce flares and fetal complications in SLE patients. Keywords
Systemic lupus erythematosus Pregnancy Flares Antiphospholipid syndrome
L. J. Jara (&) Direction of Education and Research, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Seris/Zaachila s/n, Colonia La Raza, 02990 Mexico City, Mexico e-mail: [email protected]; [email protected] G. Medina Clinical Research Unit, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico P. Cruz-Dominguez Division of Research, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico
C. Navarro Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico O. Vera-Lastra Internal Medicine Department, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico M. A. Saavedra Rheumatology Department, Hospital de Especialidades, Centro Me´dico La Raza, Instituto Mexicano del Seguro Social, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico C. Navarro Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
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Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease that affects predominantly women during reproductive years, and its evolution is altered by hormonal events such as menses, menopause, and especially pregnancy. According to medical advances in the care of pregnant women, the number of patients with SLE and pregnancy has increased worldwide and the pregnancy outcomes have also significantly improved. However, despite of these progresses, SLE pregnancy is considered as a high-risk pregnancy, and a multidisciplinary approach, with close medical, obstetric and neonatal monitoring, is essential for optimal outcomes [1, 2]. Fortunately, the majority of pregnancies in women with SLE are successful, and although these patients have few live births with more pregnancy complications, they can have subsequent uncomplicated pregnancies after having a poor outcome. Recent studies analyzed novel markers of poor pregnancy outcomes and new approaches to the management of lupus during pregnancy [3]. However, the activity of lupus in pregnancy remains a problem to be solved, and major organ involvement can negatively affect the outcomes. In fact, fetal adverse outcomes in obstetric SLE include fetal loss (spontaneous abortion and intrauterine fetal death) intrauterine growth restriction (IUGR), premature birth, premature rupture of membranes, neonatal lupus and perinatal mortality [4, 5]. Maternal complications in SLE patients include SLE activity, preeclampsia and arterial hypertension, especially in patients with renal involvement [6]. Risk factors for an unfavorable course of pregnancy in SLE can be immunological, neuro-endocrinological and clinical [7–9]. However, the predictive factors of lupus flare in pregnancy have not been systematically and fully elucidated. Therefore, the aim of the present review was to analyze predictors of flare and poor outcome in the preconception, pregnancy and puerperium period. Immunological factors SLE is an autoimmune disease characterized by the breakdown of immune tolerance resulting in overproduction of autoantibodies, and complement factors activation. In the clinical practice, monitoring of a patient with SLE includes measuring the titers of anti-double-stranded DNA antibodies and serum complement proteins. During pregnancy, the importance of complement levels and antidsDNA in patients with SLE was recently investigated. The results showed that low complement or positive antidsDNA in the second trimester was associated with a higher rate of pregnancy loss and preterm birth, despite of clinical activity. Hypocomplementemia and positive anti-
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dsDNA alone are predictive of poor pregnancy outcomes in the second trimester. The risks are increased in women with clinically active SLE during pregnancy [10]. SLE and pregnancy-induced hypertension (PIH) share histological findings of the placenta, complement dysregulation and fetal outcomes. Placentas of SLE (50 %) and PIH (35 %) showed a higher H-score (range of 0–300) for C4d immunoreactivity than control cases with linear staining on the membrane of syncytiotrophoblast. C4d high groups were significantly associated with low-placental weights and low birth weight in both SLE and PIH. C4d might be utilized as a biomarker for subsequent risk for IUGR and control during the gestation period in lupus pregnant patients [11]. In fact, from the clinical point of view, hypocomplementemia is associated with intrauterine growth retardation in comparison with pregnancies with normal complement activity [12]. However, the predictive value of poor pregnancy outcomes of hypocomplementemia and/or anti-dsDNA before pregnancy, regardless SLE activity, has not been systematically studied. The association between antiphospholipid (aPL) antibodies and pregnancy complications is controversial because many women with aPL antibodies may have successful pregnancies. However, recent studies suggest that lupus anticoagulant (LAC) is an important risk factor for maternal–fetal complications in SLE pregnancy when it is detected since the first trimester of pregnancy. Therefore, the LAC is the strongest predictor of serious pregnancy complications in comparison with anticardiolipin antibodies and anti-beta 2 glycoprotein I. Identification of patients at high risk will be highly informative in designing trials to prevent aPL-associated maternal and fetal morbidity [7, 13]. One of the most important immunological modifications during pregnancy is the Th1/Th2 cytokines shift. Th1 includes interferon (IFN)-c, interleukin (IL)-1, IL-2, IL-12 and tumor necrosis factor (TNF)-alpha, which stimulate cellular immunity, and Th2 includes IL-4, IL-5, IL-6 and IL-10, which induce humoral immunity and antibody production. Since SLE is mainly a Th2-mediated disease, during pregnancy, we expect a predominance of Th2 response, and an exacerbation of the disease is more possible. However, lower levels of estrogens, progesterone and Th2 cytokines were found in the third trimester of pregnancy in SLE patients compared with healthy pregnant women [14]. In order to confirm these findings, a recent prospective study evaluated again the role of some cytokines involved in the Th1–Th2 shift during pregnancy in SLE patients and healthy women. IL-8 serum levels were higher in the first and third trimesters of pregnancy in SLE patients compared with controls, INF-c serum levels in the third trimester and IL-10 serum levels in the first and third trimesters. IL-2, IL-12, IFN-c and IL-6 serum levels
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correlated with disease activity in SLE patients in the first trimester of pregnancy. Cytokine profile was similar in patients with and without lupus nephritis both in the first and in the third trimesters of pregnancy. Since Th2 cytokine production seems to play a key role in SLE, and an overproduction of IL-6 and IL-10 is reported, we should expect a Th2 polarization of immune response in SLE patients compared with healthy controls, especially during pregnancy. However, the most relevant features of this study were lower than expected increase in Th2 cytokine during pregnancy in SLE patients and an increase in some Th1 cytokines, such as IL-8 and INF-c, in SLE pregnant women compared with controls. In consequence, serum levels of Th2 cytokines were similar in SLE patients compared with controls and only IL-10 was higher in SLE patients than in healthy women. Therefore, in pregnant SLE patients, the polarization toward Th2 cytokines is lower than expected [15]. This study confirms the early observations of Mun˜oz-Valle et al. [16] who demonstrated high levels of IL-10 in pregnant SLE patients in comparison with healthy pregnant women, particularly during the last trimester of pregnancy. The lower Th2 polarization observed during pregnancy could explain, in part, some studies that found a similar rate of flare between pregnant and nonpregnant SLE patients [15]. During and after pregnancy, women with SLE have increased serum concentrations of chemokines CXCL8/IL8, CXCL9/MIG, CXCL10/IP-10 and IL-10 compared to normal pregnancy, especially during active disease. In SLE pregnancy, a top of already more pro-inflammatory levels might increase their risk for pregnancy complications, flares and probably on the children during pregnancy [17]. A novel gene family called T cell immunoglobulin mucin domain-containing molecules (TIM) are members differentially expressed on Th1 and Th2 cells (TIM-1, TIM-3 and TIM-4). Genomic association and polymorphisms in the TIM in different immune-mediated diseases suggest that they have an important role in regulating autoimmunity diseases [18]. In this regard, TIM-3, by virtue of its upregulation in innate immune cells in pregnant women, enhances both innate and adaptive immune responses. Nevertheless, the abnormality of TIM-3 in pregnant woman may be deleterious to normal pregnancy. Therefore, TIM-3 may be a potential indicator to predict the risk of pregnancy loss in pregnant woman, including SLE patients [19]. The changes at day 14 of pregnancy in lupus-prone LPR (MRL/lpr) mice and MRL controls regarding cytokines, regulatory T (Treg) cells and deposition of immunocomplexes were studied. Worsened kidney function was observed during pregnancy, even in the absence of others lupus activity signs. This was accompanied by active glomerulonephritis, higher interferon-gamma and interleukin-
10 levels. C3 and immunoglobulin G deposition was enhanced in kidney and placenta from lupus-prone pregnant animals. Pregnancy enhanced the levels of Treg cells in control animals but not in lupus-prone animals. Treg cells were shown to be specific for paternal antigens; thus, these cells cannot help to kill autoreactive cells. These data are potentially of importance for lupus patients of reproductive age [20]. Ficolins are soluble molecules of the innate immune system that recognize carbohydrate molecules on microbial pathogens, apoptotic and necrotic cells. In SLE, increased of ficolin-3 was associated with hemolysis, positive Coombs test and lymphopenia, but not with SLE Disease Activity Index scores or C-reactive protein. The elevation of ficolin-3 in specific manifestations may indicate a pathogenetic role of ficolin-3 in SLE. In normal and preeclamptic pregnant, there are significant inverse correlation of circulating levels of ficolin-2 with those of cell-free fetal DNA. It is possible that ficolin-2 may be involved in the direct removal of trophoblast-derived material from the maternal circulation. Ficolin-3 concentrations are decreased in preeclamptic women, possibly as a consequence of its sequestration in the placenta. Low levels of circulating ficolin-2 might impair the clearance of shed apoptotic and necrotic placental material [21, 22]. Genetic and functional alterations of ficolins have to be investigated as a risk factor in lupus pregnant flares. Neuro-endocrine factors Estrogens The SLE is characterized by the production of autoantibodies, expansion of autoreactive B cells and glomerular deposition of immunoglobulin complexes that contribute to tisular damage. The mouse models of SLE systemic such as the NZB/ZNW F1 and MRL/lpr mouse strains spontaneously develop pathogenic autoantibodies that cause glomerulonephritis and have served to dissect the molecular pathways that regulate autoreactive B cells. On the other hand, the occurrence of SLE may be in part determined by sexual hormones which act as a trigger for disease and a modulator of disease activity [23]. In murine models, it has been demonstrated that estrogens (E2) alter the maturation of splenic B cell precursors and enhance development and activation of autoreactive marginal zone B cells. Marginal zone B cells contribute to the pathogenic autoantibody responses generated in NZB/NZW F1 mice. Estrogens also diminish B cell receptor signaling and allow for the increased survival of high-affinity DNA-reactive B cells [24]. They have stimulatory effects on SLE T cells, increasing the expression of anti-apoptotic Bcl molecule that blocks tolerance induction of T cells [25]. It is well
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known that E2 have both immunostimulating and immunosuppressive properties. In SLE, pregnancy is associated with disease flares [26]. However, whether or not SLE relapses more often during pregnancy is still controversial. Th1/Th2 shift is one of the most important immunological changes during pregnancy due to the progressive increase in E2, reaching the highest level in the third trimester. Therefore, SLE tends to worsen during pregnancy. However, recent studies reported that SLE flare-ups were less frequently observed in the last trimester of pregnancy compared to the second trimester and postpartum period. Estradiol serum levels were lower than expected during the last trimester of SLE pregnancy, probably due to a placental compromise, leading to a lower increase in IL-6, with a low humoral immune response and a low disease activity observed during that period [27]. Increased disease activity is the best predictor of preterm birth in women with SLE, despite of the activity grade. Women with low disease activity have an increased risk of this complication. Therefore, biomarkers that would identify at-risk pregnancies are necessary in order to allow interventions to prevent preterm birth. In a recent study, women with SLE with mild-moderate disease activity, high levels of ferritin and uric acid levels with low levels of E2 at mid-gestation may predict preterm birth [8]. On the other hand, E2 treatment decreases TNF-a with an increase in IL-10. Due to TNF-a function on apoptosis, the failure to produce this cytokine alters the apoptosis of activated immune cells in SLE patients exposed to high levels of estrogens, such as in pregnancy. Steroid hormone and cytokine profiles differ in SLE patients in comparison with healthy women during pregnancy leading to a dysregulation of the balance between cell-mediated and humoral immune response, which may explain the variability of the SLE course during gestation [9]. SLE flareups during pregnancy and postpartum period are usually mild to moderate with cutaneous and articular manifestations predominantly [28, 29]. Severe relapses with kidney or central nervous system involvement are reported between 5 and 46 % [30]. According to prospective studies, the incidence of flare-ups is higher in the second trimester of pregnancy and lower in the last trimester, not only due to estrogens, but also due to progesterone, testosterone and DHEA serum levels which do not have a peak in the last trimester as expected in healthy women [27, 31]. Progestogens Pregnancy is a state of immunomodulation, intense at the maternal–fetal interface and more subtle in the mother. Many of these changes are thought to be induced by progesterone, in part because maternal serum progesterone and
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estradiol levels increase fivefold to tenfold throughout pregnancy. Although relationships between estrogens and SLE autoimmunity have been relatively well studied, much less is known about progesterone [32]. The effects of progesterone and synthetic progestins depend on their concentrations and differential engagement of various intracellular and membrane-associated progesterone receptors expressed in immune cell subsets, immune organs and tissues. The mechanisms, through which progesterone exerts modulatory actions, are different to those of estrogens or testosterone, on inflammation, adaptive immune responses and autoimmunity [33]. An inadequate or lower production of progesterone in follicular and luteal phase was found in SLE patients in comparison with healthy women, suggesting a possible luteal dysfunction [34]. Doria et al. [35] found in SLE pregnant patients lack of estrogen serum level increase as well as a lower progesterone serum level, during the second and—even more—the third trimester of gestation, probably due to placental compromise, accounting for the decrease in disease activity observed during the third trimester in pregnant SLE patients. Therefore, progesterone has been suggested as a possible supplementary treatment in pregnancy more than as a contributing factor for lupus flare [36]. Prolactin Prolactin (PRL) is a pituitary hormone that stimulates immune responses; it has been found elevated in SLE patients of both sexes and correlated with disease activity in several studies. An early study showed HPRL during pregnancy in association with fetal wastage and flares. Lactation seems to influence postpartum behavior of SLE [31, 37]. Circulating PRL is elevated in a number of autoimmune diseases, and about 20 % of SLE patients are hyperprolactinemic [38]. However, in a prospective study, mild hyperprolactinemia (HPRL, 20–40 ng/ml) was found in 69.7 % SLE patients, and at entry and after conventional treatment, a significant correlation between PRL levels and SLEDAI score was found [39]. HPRL in SLE has been correlated with disease activity with neuropsychiatric, kidney or hematological involvement [40]. High PRL levels seem to be associated with active SLE during pregnancy and autoantibodies. In this regard, we studied the association among SLE activity, lupus anticoagulant (LA) and maternal–fetal outcomes in 15 pregnant SLE women. High PRL levels were found during the second and third trimester in SLE patients in comparison with controls with a strong association among PRL, LAC, SLE activity and poor pregnancy outcome [41]. In another trial, we explore the role of oral dopaminergic agonist, bromocriptine (BRC) during pregnancy in patients with SLE. Patients received BRC plus prednisone or prednisone alone from 25
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to 35 weeks of gestation. PRL levels were determined at 25, 30 and 35 weeks. The SLE Pregnancy Disease Activity Index and maternal–fetal outcomes were evaluated. A significant decrease in PRL levels in BRC group compared to control group was found. Patients receiving BRC did not present flares, and they have better maternal–fetal outcomes. This study revealed the participation of PRL in SLE flares and the role of BRC in the prevention of flares and of poor maternal–fetal outcomes [42]. Previous controlled study demonstrated that oral BRC for 2 weeks in postpartum patients with SLE might be beneficial in protecting the patients from HPRL, hyperestrogenemia and disease relapse and in reducing the usage of steroid and immunosuppressant [43]. Another study determined the frequency of anti-PRL autoantibodies in SLE pregnant women and compared the outcome of pregnancy in those women with and without anti-PRL autoantibodies. The frequency of anti-PRL autoantibodies in lupus pregnancy was 13.1 %. Serum total PRL levels were significantly higher in women with anti-PRL autoantibodies compared with SLE women without the antibodies. SLE pregnant women with antiPRL autoantibodies had fewer adverse outcomes of pregnancy. The presence of high PRL levels and autoantibodies suggests the role of PRL in pregnancy outcome [44]. The interaction of lupus and pregnancy is very complex being the consensus that pregnancy can worsen the lupus disease process through hormones. Pregnancy is associated in 50–60 % of cases with a clinical flare manifesting as renal or hematological symptoms. Fortunately, severe flares are uncommon (10 %) and the risk of maternal death has decreased now from 2 to 3 % due to a better understanding of pathogenic mechanisms and close surveillance of patients [45]. Clinical factors Despite advances in the care of the mother–child binomial, pregnancy in SLE patients remains high risk. Several studies indicate that disease flares are common during lupus pregnancies, with reported rates that range from 13.5 to 65 % [5, 46]. It has been estimated that women with SLE have 2–3 times higher risk of relapse during pregnancy. Most of these flares are mild to moderate and frequently involve the renal, musculoskeletal and hematological systems, whereas the risk for a moderate to severe flare is between 15 and 30 % [5]. Lupus activity during pregnancy is associated with various maternal–fetal complications such as fetal loss and preterm birth, making important the identification of predictors of poor maternal and fetal outcomes. Thrombocytopenia, hypertension and prednisone use may be predictive factors for particular adverse outcomes [47–49]. However, the predictive clinical factors of lupus flare in pregnancy have not been
completely elucidated and several factors have been implicated. Several risk factors for relapse in pregnant patients with SLE have been described such as active disease within 6 months prior to conception, multiple exacerbations before conception, discontinuation of treatment during pregnancy and the presence of comorbidities [5]. In a prospective study of 103 pregnancies in 60 women with lupus, they were reported as risk factors for SLE activity (measured by SLEDAI) during pregnancy, a high number of relapses of disease prior to pregnancy (p \ 0.05), discontinuing chloroquine at the time of pregnancy (p \ 0.05) and high SLEDAI index ([5) before pregnancy (p [ 0.05) [50]. In a prospective analysis of a cohort of 267 pregnancies in women with lupus, it was observed that those patients with preconception activity had increased lupus activity during pregnancy compared with those patients in remission before pregnancy (p = 0.0002) [49]. In another prospective evaluation of 254 pregnancies of the Hopkins Lupus Pregnancy Cohort found that patients who stopped hydroxychloroquine at pregnancy developed more frequently disease activity (measured by SLEDAI) in this period compared with those who continued taking the medication (p = 0.05) [51]. Furthermore, in a study of 193 pregnancies in 104 woman found that those patients with active lupus nephritis (up to 6 months before conception) had a higher overall SLE activity during pregnancy, 47.5 versus 13.4 % (p = 0.0001) [52]. Lupus nephritis, especially active at the time of conception, has been associated with an increased risk of relapse during pregnancy, although other authors have found different results [6, 52–54]. In fact, it has been observed that pregnant patients with previous lupus nephritis have a higher risk of activity to any organ, especially at renal level, compared with those patients who have never had kidney disease (54.2 vs. 25 %, p = 0.004 and 45.7 vs. 6.6 %, p = 0.00001) [6]. Risk factors for renal relapse during pregnancy have been addressed in different studies [6, 52, 54]. In a multicenter study of 113 pregnancies in 86 women with lupus nephritis, the reactivation of the disease during pregnancy was more frequent in patients with activity before pregnancy or in partial remission (proteinuria [1 g/24 h or clearance creatinine \60 ml/min/1.73 m2) [55]. Recently, in a retrospective analysis of 124 pregnancies in 120 women with lupus was found that the first pregnancy is associated with an increased risk of relapse at any level (OR 2.3, 95 % CI 0.99–5.52, p = 0.05) but mainly in the kidney (OR 3.6, 95 % CI 1.19–11.3, p = 0.02) [56]. In this regard, a recent study analyzed 95 first and 145 subsequent births in SLE patients in comparison with references. The risk of cesarean section (CS) was twofold higher in SLE patients in first and subsequent births. More newborns of patients had birth
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PRE-CONCEPTION
PREGNANCY
PUERPERIUM
Lupus Nephritis SLE activity at Onset
Diseases Activity < 6 months APS, Thrombocytopenia Hypocomplementemia Change in medications
Hormones Prolactin Estrogens
Hypertension Pre-eclampsia
Hormones Estrogens Prolactin
↑Antibodies, ↑APS, ↓ complement
Lupus Nephritis Lupus Nephritis Hormones Estrogens Prolactin
Hypertension Pre-eclampsia Hyperactivity of Immune system
Infections XX sex chromosome complement
Decidua T-reg cells
Fig. 1 .
weight less (\2,500 g), preterm birth, and congenital malformations were more frequent among SLE patients, in first birth and in subsequent births. Perinatal death was more frequent in first births among patients, but no difference was observed in subsequent births. Pregnancy complications were more frequent in SLE patients than references, especially in the first birth [57]. Finally, a recent meta-analysis of 37 selected studies found high rates of SLE flare, hypertension, nephritis and preeclampsia. Fetal complications included spontaneous abortion, stillbirth, neonatal death and IUGR. One quarter of pregnancies was unsuccessful, and the premature birth rate was 39.4 %. Active lupus nephritis seemed to increase the risk for adverse pregnancy outcomes, particularly premature birth and hypertension. These findings support the current recommendations for avoidance of pregnancy until all manifestations of nephritis are quiescent. History of nephritis was associated with higher rates of preeclampsia, thus emphasizing the need for a multispecialty approach in the care of these patients with respect to close monitoring and early recognition of clinical signs of preeclampsia.
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Positive aPL antibodies were associated with higher rates of hypertension, premature birth and induced abortion. In consequence, early screening for aPL antibodies especially LAC may identify those at risk [58].
Summary and perspectives This review examines the risk factors for the development of SLE relapses during pregnancy (Fig. 1). These factors can be summarized as follows: Preconception The main immunological risk factors of pregnancy flare used in clinical practice are as follows: aPL antibodies, especially LAC, anti-dsDNA and hypocomplementemia. In this regard, previous thrombosis, SLE diagnosis and triple aPL antibody positivity are independent factors associated with pregnancy failure in women with APS [59].
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The main hormones candidates for risk factors before conception to relapses in pregnancy are estrogen and prolactin. However, these hormones have not been analyzed as risk factors before pregnancy. Of interest, pregnant women with SLE have an increased prevalence of thyroid disease and preterm delivery [60]. The main clinical factors for reactivation of lupus in pregnancy are the activity of the disease in the 6 months before pregnancy and discontinuation of medications such as hydroxychloroquine and azathioprine. Recently, it has been proposed that 4 months of remission of SLE are sufficient to ensure a successful pregnancy in SLE patients [3]. Pregnancies in women with SLE and lupus nephritis are considered high risk due to high rates of maternal and fetal complications. However, there has not been a formal analysis addressing the issue of maternal deaths in these women. A recent study analyzed the literature from 1962 to 2009 and included reports of pregnancies in patients with SLE and lupus nephritis with at least one reported maternal death. The authors identified 13 studies that reported a total of 17 deaths in the 6-week postpartum period that were attributable to SLE and lupus nephritis. All maternal deaths in patients with SLE and lupus nephritis occurred in those with active disease, with disease activity/complications and infections (mainly opportunistic) being the two major causes [61]. Therefore, the impact of opportunistic infections and its relationship with pregnancy flare should be analyzed. Pregnancy The immunological risk factors of SLE flares during pregnancy include autoantibodies, aPL antibodies, especially LAC, Th1 and TH2 cytokines, chemokines, soluble cytokine receptors, soluble glycoproteins. The Treg cells, dendritic cells and its interaction with hormones during pregnancy need to be studied. Hormones such as estrogen and prolactin remain the main hormones that interact with the immune system to amplify the inflammatory effect that characterizes relapses. From the clinical point of view, SLE activity at pregnancy onset thrombocytopenia, lupus nephritis, arterial hypertension, aPL syndrome, preeclampsia is associated factors with lupus flares and fetal complications. Preeclampsia and miscarriage are important complications of pregnancy in women with SLE or aPL antibodies. Both autoimmune diseases are characterized by complement activation. A recent study demonstrated for first time the presence of risk variants in complement regulatory proteins (in patients with SLE and/or antiphospholipid antibodies who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease. Defective regulation of membrane cofactor protein, complement
factor H and complement factor I allows for the excessive complement activation with placental damage [62, 63]. Puerperium The risk factors of flares in puerperium are similar to pregnancy. Hyperactivity of immune system, autoantibodies, HPRL, active lupus nephritis, decrease in TH2 cytokines with increase in TH1 cytokines probably participate in SLE flare; however, other studies are necessary in order to clarify the role of immunological, hormonal and clinical factors that participate in puerperium period.
Conclusion Although medical advances have allowed patients with SLE have a better prognosis when pregnant, there are still many points to be resolved. The SLE flares during pregnancy make the difference between an uncomplicated pregnancy and pregnancy with maternal and fetal complications. Therefore, the identification of news immunogenic, hormonal and environmental factors must be identified in order to develop treatment strategies for these patients and reduce flares and fetal complications.
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