Reproductive Medicine in Lupus Patients

#### **Chapter 4**

## Reproductive Environment in Patients with SLE

*María del Carmen Zamora-Medina and Juanita Romero-Díaz*

#### **Abstract**

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder that predominantly affects women in reproductive years. Immunologic and hormonal adaptations during pregnancy focused on creating an ideal environment to achieve a successful pregnancy represent a challenge in SLE women as they can influence on disease activity and outcomes during pregnancy. Several diseaserelated factors such as the presence of antiphospholipid antibodies and anti-SSA/Ro can also impact in the risk of pregnancy adverse outcomes and neonatal complications. Lupus nephritis and preeclampsia share clinical and laboratory features hindering differentiation between both entities. Contraception constitutes a relevant topic in SLE patients to prevent unplanned pregnancies during periods of disease activity or potentially teratogenic drug exposure, but its potential risk on disease flares and thrombotic events is the main concern. Finally, fertility in patients with SLE can be affected by the use of drugs related to infertility that lead to premature ovarian failure. Recently, assisted reproduction technologies have emerged as a safe option in patients with SLE.

**Keywords:** systemic lupus erythematosus, pregnancy, pregnancy adverse outcomes, neonatal lupus, contraception, antiphospholipid antibodies, anti-SSA/Ro

#### **1. Introduction**

Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease, with a remitting and relapsing course. It mainly affects young women of reproductive age, so addressing issues such as pregnancy, fertility, and reproductive aspects is an essential part of the comprehensive management of these patients.

In the last decades, diagnostic and therapeutic strategies for SLE and consequently the management of pregnancy have improved. Despite these advances, pregnancies in SLE patients are still considered a high-risk condition due to an increased risk of major obstetrical and neonatal complications.

Pregnancy represents a critical period in women's life due to profound immunological and hormonal changes that mostly occur to tolerate the fetus. The interaction of SLE and immunologic adaptations of pregnancy lead to unique challenges in this setting, as alterations in immune mechanisms can have consequences both for the fetus, including a risk of miscarriage or neonatal lupus, and for the mother, including disease flare.

A close relationship between pregnancy and disease flares has been established. The association of SLE and pregnancy, mainly with active disease and lupus nephritis, has poorer outcomes, with increased frequency of preeclampsia (PE), fetal loss, preterm birth, and intrauterine growth restriction. On the other hand, pregnancy impacts on maternal disease and can be associated with disease flares requiring immunosuppressive therapy.

This chapter will address the immunological and hormonal adaptations during normal pregnancy and the differences between healthy pregnant women and women with SLE. Later, we will focus on the relationship between lupus activity and pregnancy and the impact of SLE on pregnancy outcomes.

#### **2. Interaction between pregnancy and systemic lupus erythematosus**

#### **2.1 Immunologic and neuroendocrine environment in pregnancy**

Pregnancy represents a major immunological challenge for the maternal body due to fetal expression of paternal antigens. The maternal immune system has to balance the opposing needs of maintaining robust immune reactivity to protect both the mother and the fetus from invading pathogens while at the same time tolerating highly immunogenic paternal alloantigens to sustain fetal integrity [1].

In order to protect the fetus from an attack of the maternal immune system, pregnancy induces profound immune and neuroendocrine changes in the maternal body [2]. Modulation of the function and composition of the different cellular components and immunomodulatory molecules occur during pregnancy in the mother. Also, immune tolerance to paternal antigens is promoted by migration of fetal cells and cell-free DNA to the maternal circulation during pregnancy, which can remain with the mother for decades [3].

During pregnancy, a shift of cytokine profile toward a T-helper 2 (Th2) response instead of Th1 was considered one of the most important immunological modifications. Suppression of Th CD4+ cells (Th1 response) in uncomplicated human pregnancy and Th1 polarization in patients with reproductive failure has supported the concept of successful pregnancy as a Th2 phenomenon proposed by Wegmann [4]. However, recent extensive research on the physiology of pregnancy has shown that the hypothesis that pregnancy is warranted by Th1/Th2 shift is simplistic [5].

During the different stages of pregnancy, cytokine production at the fetomaternal interface is regulated to create optimal conditions for fetal development. Interferon (IFN)-γ and TNF-α, both cytokines secreted by Th1 cells and major contributors to Th1 immune response, are necessary during early stages of pregnancy for successful implantation and placenta development but later in pregnancy could be detrimental and result in pregnancy loss [2]. Chorionic villous tissue expresses not only Th2-type cytokines but also IL-1 β and TNF-α in the first trimester [6]. On the other hand, high expression of IL-10, a pleiotropic cytokine with both immune stimulatory and immune suppressive functions, is present in the human placenta at term [7].

In line with local cytokine modulation and as a reflection of systemic effects of pregnancy, cytokine secretion in peripheral blood mononuclear cells (PBMC) changes during pregnancy. In vitro assays from whole blood of healthy pregnant women have shown a diminished pro-inflammatory response, with a decrease of TNF-α, IL-1β, and IL-6, while IL-4 and IL-10 remain stable during pregnancy [8]. During the third trimester, a reduction of IL-12 and TNF-α production was detected in monocytes from healthy pregnant women compared to postpartum values [9]. An increase of IL-4 secreting PBMC, but not of IFN-γ-positive cells, was found in the second and third trimesters of pregnancy in healthy women after stimulation with paternal antigens [10]. The same group found significantly higher numbers of IFN-γ- and IL-4-secreting

#### *Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

PBMC in all three trimesters of pregnancy and also postpartum than the nonpregnant controls, indicating a systemic upregulation of both Th1- and Th2-like immune responses during normal pregnancy [11].

Besides cytokines, regulatory molecules that modify cytokine actions such as IL-1Ra and IL-6R have been found to be increased in serum of pregnant women, as well as levels of IL-6 and IL-1. Likewise, levels of soluble TNFR were found significantly increased in the second and third trimesters of pregnancy compared to nonpregnant values [3]. Thereby, both Th1- and Th2-type cytokines are important players of immune adaptation to pregnancy at local and systemic levels. Its production is adjusted to the different stages of pregnancy and, in addition with upregulation of cytokine-regulating molecules, can exert an ideal environment to achieve a successful pregnancy.

Pregnancy also induces substantial changes in hormone levels, which have powerful effects on blood cells as they can regulate their proliferation, distribution, and function. Estrogens enhance antibody production, Th2-type immune responses, and B-cell immunity [7]. At high concentrations, such as those found in pregnancy, estrogens and gestagens stimulate the secretion of IL-4, IL-10, TGF-, and IFN while simultaneously suppressing production of TNF-α [3, 12].

Therefore, pregnancy influences the interaction between neuroendocrine and immune systems both locally and systemically with a fine balance that creates optimal, but not uniform conditions at the feto-maternal interface and in the maternal circulation.

#### **2.2 Maternal tolerance to the fetus in normal pregnancy**

Although localized mechanisms at the maternal-fetal interface contribute to fetal evasion from an immune attack, several additional mechanisms operate during pregnancy and help the fetus to evade maternal immune response.

In this context, regulatory T (Treg) cells have been shown to play a pivotal role in maternal-fetal tolerance. These Treg cells, a subset of suppressor CD4+ CD25+ cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. In recent years, it has been observed that Treg cells are essential in promoting fetal survival, avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system, a critical step for successful pregnancy [13, 14].

In healthy pregnant women, CD4+ CD25+ Treg increases rapidly in peripheral blood peaking at midgestation coinciding with the time of maximal trophoblast invasion and decreasing after delivery to prepregnancy levels [15]. Levels of Treg cells within the decidua, which represents the maternal-fetal interface, are elevated compared with those in the peripheral blood. The increase in Treg cells emphasizes the potential role for these cells in the successful development of the placenta by ensuring fetal tolerance [16].

Expansion of Treg cells is not only due to hormonal changes occurring during pregnancy, but can be driven by several other factors like decidual peptides, fetal antigens, and seminal fluid. Indeed, Treg cells act in an antigen-specific manner as they are specifically activated by MHC paternal antigens, but once activated they are able to exert suppressive effects on other local cells in an antigen-independent manner [16, 17].

The exact mechanism by which Treg cells exert their suppressive activity during pregnancy is not completely clear but is likely to be mediated by cell contactdependent and cell contact-independent manipulations of dendritic cells (DCs) and effector Th cells, as well as direct cytolytic activity on DCs and modulation of the local metabolic environment [1, 17]. Recent data support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens [18].

A prospective observational study of 101 women who underwent in vitro fertilization (IVF) showed an increased level of circulating Treg cells in pregnant women. A higher percentage of Treg in peripheral blood was associated with increased rates of pregnancy and live birth [19]. On the other hand, deficit in Treg cell number in the decidua and maternal peripheral blood has been associated with complications such as unexplained infertility, miscarriage, and preeclampsia [1, 13]. These observations support the Need for a substantial increase in Treg cell numbers for a successful pregnancy.

Interestingly, during pregnancy a bidirectional exchange of cells at the maternalfetal interface occurs, so maternal cells can cross the placenta and engraft in fetal lymph nodes in utero, a phenomenon called maternal microchimerism. Human fetal T cells are responsive against maternal alloantigen, but a pool of fetal Treg cells actively suppresses their function. Maternal microchimerism has been shown to induce development in utero of fetal Treg cells that suppress fetal antimaternal immune response, indicating a mechanism that promotes tolerance toward maternal antigens by the fetus [14, 20].

Besides Th1 and Th2 cells, there is a third subset of CD4+ T-helper cells called Th17 cells, which, like Treg cells, are implicated in pregnancy and maternal immune tolerance to the fetus [14]. These Th17 cells are defined by their ability to produce IL-17, a pro-inflammatory cytokine that promotes development of Th17 cells and interestingly, in the presence of a tolerance milieu, drives differentiation to Treg cells [21]. Both Treg and Th17 cells require transforming growth factor beta (TGF-β) for differentiation, but the copresence of IL-6 favors differentiation of pathogenic Th17 cells as it can inhibit the generation of FoxP3+ in Treg cells induced by TGF-β [22]. Th17 cells promote inflammation and generally have opposing actions to Treg cells so a reciprocal relationship between these two subsets of Th cells has been described [21].

The presence of Th17 cells in human decidua of healthy pregnancies was investigated. The first-trimester human decidua displayed a local expansion of Treg cells, while a low occurrence of Th17 cells was observed, which suggests that the inverse relationship between Treg and Th17 cells seems to be maintained at least in early stages of pregnancy [23].

On the other hand, increased numbers of Th17 have been found in obstetric complications such as preeclampsia and recurrent pregnancy loss (RPL). A significant increase of Treg FoxP3+ to IL-17-expressing CD4+ T cell ratio in peripheral blood at the third trimester of healthy pregnancy was reported, while an absence of a reduction of IL-17 production toward a FoxP3+ expression was observed in preeclamptic pregnancies [24]. In line with these observations, a later study reported an increased prevalence of IL-17-producing circulating T CD4+ and CD8+ cells in preeclampsia, demonstrating a shift in the Th17/Treg balance in this pregnancy complication [25].

Also, the proportion of Th17 cells in peripheral blood and decidua was significantly higher in unexplained RPL patients compared to normal pregnant women. As reported in preeclamptic pregnancies, there was an inverse relationship between Th17 cells and Treg cells in peripheral blood and decidua in unexplained RSA [26]. Another study showed an accumulation of IL-17-producing cells in decidua of inevitable abortion cases compared to normal pregnancies and missed abortions [27]. Therefore, there is evidence suggesting that balance between Th17 cells and Treg cells may be critical to pregnancy outcomes.

#### **2.3 SLE pregnancy vs. normal pregnancy**

Differences in sex steroid hormones during pregnancy have been observed in patients with SLE compared to healthy women. In a prospective study, pregnant

#### *Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

lupus patients presented lower levels of estradiol and progesterone in the second and most of the third trimester of pregnancy [28]. The inability to produce high concentrations of these sex hormones during the last two trimesters of pregnancy could be due to placental insufficiency, which in turn can be implicated with the elevated rate of fetal loss in SLE patients [29].

Levels of certain cytokines involved in the humoral immune response have been shown to be modified in the peripheral circulation of pregnant SLE patients. Serum levels of IL-6, a cytokine necessary for T cell help for B cells and proliferation of plasma cells, are lower than expected in the third trimester of gestation. Higher levels of IL-10 before conception through pregnancy and postpartum in lupus patients compared to healthy controls have been observed, suggesting a constitutional overproduction of IL-10 in SLE patients resulting in a continuous B-cell stimulation. Furthermore, levels of soluble TNF receptor I (sTNFR I) and IL-10 are significantly higher during pregnancy and postpartum in pregnant patients with active SLE compared to healthy controls [28].

Cytokine profile of PBMC in SLE and rheumatoid arthritis (RA) pregnant women was investigated in a prospective study by assessing cytokine messenger RNA (mRNA) expression using quantitative PCR. TNF-α was the most abundant cytokine mRNA expressed in PBMC in all three groups studied (healthy pregnant women, RA, and SLE pregnant patients). However, in RA and SLE patients, a general Th2 response reflected by high IL-10 levels was found [30].

Several studies have investigated the phenotype and function of Treg cells in patients with SLE. Most of the studies have shown a decrease in Treg cell numbers in SLE patients and a negative correlation with disease activity [16, 31–33]. In addition to the reduced number of Treg cells, some data suggest an impaired function of Treg in SLE like a reduced migratory ability [34]. Also, a defect in T-cell suppression has been observed in SLE, although this defect seems to be due to effector cell resistance rather than a reduced Treg suppressor capacity [35].

A pilot study have shown that circulating CD4+ CD25+ FOXP3 Treg cell numbers are markedly reduced in nonpregnant women with SLE compared with healthy controls. Treg levels remained depleted in SLE patients when pregnant, while those in healthy individuals raised, peaking at 10–12 weeks of gestation. Lower quantity of Treg cells was evident regardless of disease activity and medication in SLE patients [21]. So, considering the essential role of Treg cells at early stages of pregnancy and its implication for immune tolerance, defective functioning and decreased number of Treg cells could predispose women with SLE to pregnancy complications.

There is little work investigating the presence of Th17 cells in pregnant SLE patients, although a study supports an imbalance between Treg and numbers of Th17 cells in active SLE. An inverse correlation between Treg/Th17 ratio with severity of active SLE and anti-DNA antibody levels was reported [36]. Disease flares and severe complications of SLE, such a lupus nephritis, seem to be associated with a decrease in FoxP3+ Treg cells and an increase in Th17 cells [37, 38]. In a longitudinal study that evaluated the changes of serum IL-17 and other cytokines in SLE pregnant woman during pregnancy, serum IL-17 concentrations were higher in SLE than in controls with no changes during pregnancy [36].

As discussed previously, TGF-β is essential for the differentiation of both Treg cells and Th17 cells. In a large cohort study, reduced levels of TGF-β were associated with increased SLE activity [39]. Although TGF-β influence in reproduction and complications in pregnancy is not clear, a possible role in trophoblast invasion has been proposed as low levels of TGF-β in the second trimester of pregnant woman have been associated with an increased risk of developing preeclampsia [16]. Clearly, more studies are needed to understand the role of Treg/Th17 imbalance

in SLE pregnancies and its possible implications in the risk of maternal-fetal complications.

As mentioned above, pregnancy induces important hormonal changes. Prolactin (PRL) levels increase progressively during pregnancy and lactation in order to stimulate the synthesis of milk in the mammary glands [42]. Elevated levels of PRL have been found in almost one third of SLE patients, and higher levels during the second and third trimesters have been associated with clinical activity and poor maternal and fetal outcome [40, 41]. On the other hand, the presence of anti-PRL autoantibodies in 13.1% of pregnant patients with SLE has been reported. Likewise, a lower frequency of maternal and fetal complications in SLE patients than those without these antibodies was reported [41].

Therapeutic blockade of PRL with bromocriptine (BRC), a dopamine analog that suppresses PRL secretion, has been evaluated to prevent lupus relapses during pregnancy and postpartum. A pilot study explored the use of BRC between 25 and 35 weeks of gestation in two groups of ten pregnant SLE patients each. No patient in BRC group had disease flares, and there were lower adverse maternal and fetal outcomes in the treatment group than the group that did not receive BRC during pregnancy [42]. More recently, a randomized clinical trial evaluated the use of BRC in the postpartum of 76 SLE pregnant women. BRC administration for 2 weeks after delivery reduced the disease relapse rate of the treatment group [43].

So, results from clinical studies support the contribution of PRL to complications in pregnant SLE women and a possible role of BRC in the prevention of disease relapses during pregnancy and postpartum.

#### **3. Influence of pregnancy in SLE outcomes**

The critical immunologic adaptations during pregnancy and postpartum can impact maternal autoimmune diseases in several ways. One is triggering the onset of an autoimmune disease in postpartum or influencing disease activity of an established disease. In this manner, disease response to complex pregnancy changes depends on its pathophysiology [2].

As seen before, steroid hormones and cytokine profiles differ in SLE patients compared with healthy women during pregnancy leading to a dysregulation of the balance between cell-mediated and humoral immune responses, which could explain the variability of the SLE course during gestation [44]. Since SLE is considered mainly a Th2-mediated disease, pregnancy-related changes could trigger disease onset or increase the risk of disease exacerbations during this period [45]. Also, hormones such as estrogen and prolactin could play a role in amplifying the inflammatory effect that characterizes lupus relapses. In murine models, increasing doses of estrogen, like those seen in pregnancy, promotes physiological and immunological changes associated with increased lupus activity [46].

#### **3.1 Lupus activity and its relationship with pregnancy**

Whether SLE activity increases during pregnancy or not has been previously debated in the literature. The majority of prospective studies in SLE pregnancies have shown that the risk of disease flare is higher during pregnancy, although some discrepancies exist due to heterogeneity of lupus flare definition and tools used to assess lupus activity [2]. Newer studies using validated instruments for disease activity assessment have found a two–threefold increase in SLE activity during pregnancy [47, 48]. Even though SLE flares occur at any time during pregnancy,

#### *Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

most of these flares are considered mild to moderate in severity and may include renal, hematological, and musculoskeletal systems. Likewise, previous organ involvement predicts the same type of condition during pregnancy, particularly in the case of renal, hematological, and cutaneous activity [36].

Disease activity at conception and in the previous 6 months, both clinical and serological, is a key predictor not only for obstetrical complications but also of SLE flares during pregnancy. Prospective studies of pregnant lupus patients have reported some risk factors for SLE activity during pregnancy: a high number of relapses prior to pregnancy, high SLEDAI index before pregnancy, and preconception SLE activity [46, 49]. In fact, the risk of severe lupus flare is increased about seven times in patients with active SLE at conception [50]. Moreover, SLE disease activity immediately prior to pregnancy also impacts on damage accrual after pregnancy [51].

Besides disease activity at and before conception, several predictors for flares in pregnant patients have been described. A prospective evaluation of 254 patients found that discontinuation of hydroxychloroquine (HCQ ) was associated with a higher degree of lupus activity (measured by SLEDAI) during pregnancy as well as an increased rate of flare during this period. On the contrary, women who continued taking HCQ required lower average dose of prednisone during pregnancy [52].

In addition, primigravity seems to influence the risk of lupus flares during pregnancy. A retrospective analysis of 124 pregnancies found that the first pregnancy in SLE women was associated with an increased risk of relapse at any level, particularly in the kidney [53].

On the other side, SLE activity during or prior to pregnancy is associated with several maternal and fetal complications such as fetal loss, preterm birth, intrauterine growth retardation (IUGR), and hypertensive complications. Previous renal disease is also a risk factor for obstetric complications like PE, fetal loss, IUGR, and premature birth. Therefore, early identification and prompt treatment in pregnant women with lupus activity are essential to improve pregnancy outcomes [49]. However, recognition and management of disease flares during pregnancy can be challenging due to the physiological changes that occur during this period, which can overlap with clinical and laboratory features of active SLE [46]. For this reason, clinical data and laboratory findings in pregnant patients with SLE should be interpreted with caution. Thrombocytopenia, mild anemia, and increased erythrocyte sedimentation rate (ESR) often occur during normal pregnancy. In addition, complement levels are less reliable to identify or support the suspicion of disease activity due to its physiological increase during pregnancy, although a decrease in C3 and C4 titers as well as an increase in anti-DNA antibodies may be useful to differentiate complications such as preeclampsia and SLE activity.

#### **3.2 Lupus nephritis, pregnancy, and hypertensive complications**

Lupus nephritis is among the findings that most often induces increased morbidity and mortality during pregnancy. Indeed, lupus nephritis, especially active at the time of conception, has been associated with an increased risk of relapse during pregnancy. A higher risk of SLE activity has been reported, particularly renal flares, in pregnant patients with previous nephritis compared to those patients without history of renal involvement [54]. However, a recent prospective multicenter study did not find an increased risk of renal flares during pregnancy in patients with a history of previous renal activity and clinically active lupus nephritis at conception. Instead, history of renal flares before pregnancy predicted hypertensive


*Data from [60, 61]. BP, blood pressure; RUQ, right upper quadrant; anti-dsDNA, anti-double-stranded DNA; aPL, antiphospholipids; LFTs, liver function tests*

#### **Table 1.**

*Clinical, laboratory, and renal biopsy findings in preeclampsia and lupus nephritis during pregnancy.*

complications such as preeclampsia (PE) [55]. A meta-analysis of 37 studies reported lupus nephritis flare in 16% of pregnant lupus patients and confirmed the association of lupus nephritis at conception with an increased risk of hypertension during gestation. Adverse outcomes in pregnant patients with lupus nephritis were also related to hypertension and presence of antiphospholipid antibodies [56]. Moreover, the onset of PE seems to occur at earlier weeks of gestation in lupus nephritis patients compared to SLE patients without renal involvement [57].

Preeclampsia is a syndrome unique to pregnancy that manifests with hypertension and proteinuria and resolves following delivery. Besides classical risk factors in general population, diseases that promote endothelial dysfunction including SLE increase the risk of preeclampsia. Among lupus pregnancy cohorts, the rate of preeclampsia ranges varies widely. Whereas a meta-analysis of lupus pregnancies reports a preeclampsia rate of 7.8%, other studies suggest that it can be twice as high, particularly in women with nephritis [29, 56]. Dysfunctional angiogenesis leading to an impair in placental development has been implicated in pathogenesis of preeclampsia. Several markers in maternal serum like VEGF, placental growth factor (PlGF), and soluble fms-like tyrosine kinase (sFlt-1) have been found to be predictive of preeclampsia in lupus patients. Lower than expected levels of

*Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

proangiogenic factors VEGF and PlGF and high levels of antiangiogenic factor sFlt-1 seem to reflect poor placental perfusion and impaired angiogenesis in the rapidly growing placenta [29].

Similar to what happens in lupus flares during pregnancy, distinguish clinical indicators of lupus nephritis from pregnancy physiological features, and those related preeclampsia can be a complex task. In the first trimester of pregnancy, maternal systemic circulation suffers remarkable physiological vasodilation conditioned by relaxin, a hormone produced by the corpus luteum. As a result of systemic vasodilation, glomerular filtration rate (GFR) elevates, and serum creatinine consequently diminishes making it more difficult to identify a renal compromise in a timely manner [58]. Urine protein excretion is also increased during pregnancy, so isolated elevation of proteinuria is not necessarily indicative of active nephritis [7].

Besides physiological changes induced by pregnancy, PE and LN share some clinical and laboratory features like hypertension, proteinuria, and edema, making it difficult to distinguish between the two entities. This distinction is critical since management differs significantly; while LN requires immunosuppressive treatment, in severe PE delivery may be indicated. A detailed evaluation of biomarkers of SLE activity as anti-dsDNA, the low level of complement, active urine sediment (red cells, white cells, and cellular casts), and the presence of extrarenal SLE manifestations may be helpful in the differential diagnosis. In contrast, in pregnant women with a gestational age greater than 22 weeks and absence of sign of SLE activity, the diagnosis of PE is very likely [59].

Clinical, laboratory, and renal biopsy features present in PE and LN are shown in **Table 1**.

#### **4. Impact of SLE on pregnancy outcomes**

Despite diagnostic and therapeutic advances, pregnancies in SLE patients are still considered a high-risk condition due to an elevated risk of major obstetric and neonatal complications. A population-based study from 2000 to 2003 found that maternal mortality was 20-fold higher among women with SLE. The risk for serious medical and pregnancy complications during pregnancy was also three- to sevenfold higher for SLE women than the general population [62].

In recent years, outcomes during pregnancy in patients with SLE related to preconceptional counseling, close monitoring during pregnancy, and postpartum and multidisciplinary management have improved [63]. However, according to a recent meta-analysis comparing maternal and fetal outcomes of women with and without SLE, adverse outcomes such as spontaneous abortion (RR, 1.51), PE (RR, 1.91), thromboembolic disease (RR, 11.29), and preterm birth (RR, 3.05) are still more frequent in pregnancies of women with SLE [64]. Additionally, it has been estimated that women with SLE have fewer live births than the general population [65].

In the last two decades, the rate of fetal losses has declined from 43% in the years 1960–1965 to 17% in the period 2000-2003 [66]. Most recent studies reported a pregnancy loss rate of 10–25% in women with SLE [67]. In addition to risk factors associated with pregnancy losses in the general population, such as chromosomal and anatomical abnormalities, specific factors associated with SLE have to be Considered, including thrombocytopenia, antiphospholipid antibody (aPL) positivity or antiphospholipid syndrome (APS), lupus nephritis, and high SLE disease activity [68]. Both low complement and presence of anti-DNA in the second trimester, regardless of clinical activity, have also been associated with a higher rate of fetal loss and preterm delivery [69].

#### **4.1 Antiphospholipid antibodies and pregnancy**

The presence of antiphospholipid syndrome (APS) is one of the most important causes for pregnancy loss in women with SLE, manifesting a recurrent pregnancy loss, fetal loss, or stillbirth (pregnancy loss after 20 weeks of gestation) [29]. In addition to recurrent pregnancy loss, APS predisposes pregnant women to late gestational complications associated with impaired placental function, such as PE and fetal growth restriction. Serious complications have been reported in up to 12% of pregnancies in lupus patients. Interestingly, adverse outcomes in pregnancies of SLE women with aPL antibodies can present even during disease remission or mild activity [50].

Antiphospholipid antibodies target the placenta by binding β2 glycoprotein I (β2GPI) constitutively expressed on trophoblast cell surface, perturbing the secretion of trophoblast angiogenic factors in the first trimester of gestation and favoring adverse outcomes [70].

The prevalence of aPL antibodies in patients with SLE is variable and depends on the type of antibodies and isotype. A prevalence of 12–44% of anticardiolipin antibodies (aCL), 15–34% for lupus anticoagulant (LA), and 10–19% for anti-β2 glycoprotein I (aβ2GPI) has been reported [71], although prevalence of aPL could be underestimated due to immunosuppressive treatment. A higher frequency of thrombosis and pregnancy loss in SLE-associated APS (secondary APS) than in primary APS has been reported. Moreover, in the Hopkins lupus cohort, the diagnosis of secondary APS led to a threefold increase in pregnancy loss, especially after 20 weeks of gestation and was an independent risk factor for further pregnancy losses [68].

The association of aPL with adverse pregnancy outcomes (APOs) is variable between different aPL antibodies. Particular serological profiles have been defined as "high-risk profiles" because of its stronger association with APOs. Lupus anticoagulant rather than aCL has been identified as the primary predictor of APOs [72]. In the PROMISSE study, a large-scale multicenter prospective study of pregnant women with aPL and/or underlying stable SLE, a higher rate of APOs in pregnant patients with aPL (43.8%) compared to 15.4% of patients without aPL was observed, while poor pregnancy outcome was observed mainly in LA-positive patients. The presence of LA was identified as a baseline independent predictor of APOs (OR 8.32), while no other aPL antibody independently predicted APO [73]. The EUROAPS registry also reported that the presence of LA, isolated or in combination with aCL and/or aβ2GPI, was the strongest marker related to poor obstetric outcomes [74].

Regarding treatment, there is no current evidence that the management of pregnancy should be different in SLE-associated APS than in primary APS. Actually, treatment of pregnant patients with aPL will depend on the risk profile and history of adverse obstetric events or previous thrombosis. According to this risk, they can be classified into three groups: (a) presence of aPL antibodies in the absence of obstetric or thrombotic events, (b) high-risk profile (LA or triple positivity) or adverse obstetric events, and (c) aPL antibodies and previous thrombosis.

Although increased lupus activity does seem to not increase the risk for miscarriage, stillbirth rate is threefold higher [53]. Additionally, the timing of lupus activity seems to impact the pregnancy loss rate, with activity early in pregnancy being the most dangerous [68].

#### **4.2 Antibodies anti-SSA/Ro and anti-SSB/La and neonatal lupus**

Pregnancies exposed to anti-SSA/Ro and anti-SSB/La have an increased risk of developing neonatal lupus (NL), a passively acquired autoimmune disease

#### *Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

mediated by maternal antibodies. There are two main forms of NL: NL erythematosus (NLE) and congenital heart block (CHB). Other less frequent forms include hepatic and hematologic. NLE occurs in 5% of children born to women with anti-Ro/SSA or anti-La antibodies. It usually presents within the first 2 weeks of life as erythematous geographical lesions in light-exposed areas, resembling subacute cutaneous lupus. Rash resolves within 6–8 months of life as the maternal antibodies are cleared, without leaving residual scarring [75]. CHB is a more serious form of NL, affecting 1–2% of newborns of anti-Ro-positive women and a recurrence rate in subsequent pregnancies up to 16–20%. Incomplete forms of CHB have been described, including first-degree heart block that can progress during childhood. Permanent pacemaker will be needed in most children with CHB, and up to 20% may die in the perinatal period [76].

Starting from the second trimester, maternal IgG antibodies are actively transferred via the placental FcRn receptor to the fetus. Although the precise mechanism of injury is not fully known, one hypothesis considers a direct effect of anti-SSA/Ro and/or anti-SSB/La antibodies by binding to fetal cardiac tissue and altering cardiocyte function. In the case of anti-SSA/Ro antibodies, they can bind cross-reactive epitopes on calcium-regulating molecules such as ion channels, inducing disturbances in calcium homeostasis and signal electrogenesis at the atrioventricular node. A demonstration that anti-SSA/Ro antibodies are arrhythmogenic and inhibit inward calcium fluxes across cell membranes supports this hypothesis [77].

Another hypothesis raise that intracellular anti-SSA/Ro and SSB/La antigens translocate to the surface of cardiomyocytes undergoing apoptosis during physiological remodeling and thus become accessible to extracellular antibody. This allows the formation of pathogenic antibody-apoptotic cell immune complexes that promote a pro-inflammatory and profibrotic response [78]. In vitro studies support a protective role of β2GPI by preventing opsonization of apoptotic cardiomyocytes by maternal anti-Ro60 IgG [79].

CHB is usually preceded by lesser degrees of conduction delays which may be reversed with early treatment. Given that the majority of conduction abnormalities develop between 18 and 24 weeks of gestation, several tools for early detection of lesser degrees of heart block are available, including fetal Doppler echocardiography, fetal kinetocardiogram, and transabdominal fetal echocardiography. Close monitoring of anti-SSA/Ro-positive pregnant women with weekly fetal Doppler echocardiography between 16 and 26 weeks of gestation and biweekly thereafter is highly recommended [61]. This enables assessment of atrial and ventricular rates, cardiac anatomy and function, and the presence or absence of hydrops. Urgent referral to a fetal medicine unit or fetal cardiology service is advised if a low fetal heart rate (<110 bpm) is detected. An increased risk of hydrops and death is present if the rate is <55 bpm [76].

Although fetal echocardiogram is the most commonly used modality, it may underestimate pathological findings of NL, so recently other biomarkers for early detection of heart disease and to monitor severity and progression of cardiac LN have been suggested, such as NT-proBNP in amniotic fluid [80].

Different strategies have been evaluated for CHB associated with anti-Ro and/ or anti-La antibodies. Prenatal therapy with fluorinated steroids like dexamethasone in mothers of fetuses with incomplete heart block is currently used; however, its role has been questioned since published data are discordant regarding its efficacy. A multiracial/ethnic US-based registry of cardiac neonatal lupus demonstrated that fluorinated steroids do not prevent heart block progression or death in cases with isolated heart block and without evidence of extranodal disease [81]. In a more recent study, the use of fluorinated steroids was not associated with

complete heart block regression or an increase in survival [82]. Therefore, the decision to administer this type of steroid, usually at high doses (at least dexamethasone 4 mg daily), should be weighed against the potential risk of adverse effects on the fetus and the mother [78].

Preventive management of anti-SSA/Ro- and/or anti-La/SSB-positive pregnant women is under investigation. Hydroxychloroquine administration during pregnancy has been associated with a decrease of recurrent NL [83]. On the other hand, recent studies failed to demonstrate efficacy of monotherapy with intravenous immunoglobulin or plasma exchange in reducing the incidence of cardiac NL [84, 85].

#### **5. Contraception, fertility, and assisted reproduction in SLE**

Contraception is a complex issue and of particular interest in SLE patients to prevent unplanned pregnancies during periods of disease activity or potentially teratogenic drug exposure. The main concerns about hormonal contraceptive methods are disease flares and risk of thromboembolism [86]. The risk of complications associated with the use of hormonal contraceptives has been evaluated by two randomized clinical trials. A first study compared a combined three-phase oral contraceptive with placebo in 183 patients with SLE. No significant differences in the number of disease flares between both groups were observed [87]. A second study compared a combined oral contraceptive, a progestogen, and non-medicated intrauterine device. Disease activity remained stable during follow-up, and only four thrombosis episodes were recorded, two episodes per hormone treatment group [88]. However, both studies excluded patients with severely active SLE, history of previous thrombosis, malignant gynecological neoplasm, acute myocardial infarction, and previous hepatopathies and patients actively smoking. Regarding aPL antibodies, patients with positivity for these antibodies were excluded in the first study, but not in the second trial. According to both studies, combined hormonal contraceptives (estrogens plus progestogens or progestins alone) are safe in patients with stable SLE in the absence of aPL, without increasing the risk of disease flares of thrombotic events.

Fertility is a relevant topic in SLE patients due to predominance of female gender and reproductive age. The reproductive issue in SLE women does not result from an increase in primary fertility rate but from an increase in the number of fetal losses and use of drugs related to infertility. Cyclophosphamide (CYC) has been associated with ovarian reserve depletion by inducing apoptosis of oocytes and granulosa somatic cells, with the consequent premature ovarian failure in a dose- and age-dependent manner. Although the exact incidence of secondary ovarian failure due to CYC is not clear, it may vary between 11 and 59%, and a higher risk is observed in women older than 30 years [89]. Simultaneous administration of GnRH agonist has been suggested to minimize the gonadotoxic effect of CYC. Other disease-modifying rheumatic drugs (DMARDs) such as mycophenolate mofetil, cyclosporine, or tacrolimus have not been associated with infertility in lupus patients [90].

On the other hand, it has recently been suggested that SLE per se has a negative effect on ovarian function and reserve, regardless of the disease activity and use of gonadotoxic immunosuppressive therapies. A study that measured levels of anti-Müllerian hormone (AMH), a marker of ovarian reserve, in lupus patients and healthy controls found lower levels of AMH in the first group, with no correlation between disease activity and duration [91].

The role of aPL antibodies as a cause of infertility is controversial, as previous retrospective studies have suggested an association between aPL antibodies and infertility. However, two recent studies have not demonstrated a higher prevalence of these antibodies in women with infertility or a correlation with the type of infertility [92, 93].

A strategy to overcome the difficulties of achieving a successful pregnancy is the use of assisted reproduction technologies (ARTs), which includes ovarian stimulation, oocyte retrieval, in vitro fertilization (IVF), and transfer of the embryo to the uterus [94]. Many stimulation protocols are available, but ovarian stimulation with human chorionic gonadotropin (hCG) is the most frequently applied. These hormones determine an estrogenic peak in order to stimulate the growth of multiple follicles, which may increase the risk of multiple pregnancy, preterm birth, and ovarian hyperstimulation syndrome, but the main concern rises around the risk of disease exacerbation or maternal complications. Although the hormonal stimulation could theoretically trigger a disease flare or the onset of thrombosis in patients with aPL antibodies, recent studies have shown that they can be safe and have a low probability of SLE flare [94, 95].

A relevant issue with the use of ARTs is the incidence of thrombotic events. During ovarian stimulation, several changes in coagulation have been described including an increase in fibrinogen, von Willebrand factor, and platelets and decrease in antithrombin III and fibrinolytic activity. These changes may induce a state of relative hypercoagulability. However, the absolute risk of thrombosis during ovarian stimulation is low due to the predominant use of estradiol (E2) and short time of stimulation. The observed incidence is quite low and related to ovarian hyperstimulation syndrome. A systematic review identified as risk factors for thromboembolic complications advanced age (>35 years) and hereditary thrombophilias, while SLE and APS were not independent risk factors [96].

Regarding the efficacy of ART, the success rate varies from 16 to 31% in women with SLE, similar to the general population [48]. The role of aPL has been examined by previous retrospective studies that suggested a relationship between aPL positivity, infertility, and multiple failures of ART procedures. However, recent evidence does not support this since the presence of aPL antibodies has not been identified as a predictor of failure during the use of ART [97]. In a prospective study of 101 infertile women with at least three unsuccessful IVF attempts, no association was found between aPL positivity and success rate [98].

Despite the lack of studies evaluating the risks and benefits of different ovarian stimulation protocols, it is suggested to avoid high serum concentration of estradiol. In the case of anovulation, ovarian induction with clomiphene citrate represents the first choice. In treatment failure, pulsatile administration of GnRH over the use of gonadotropins is preferred since the latter does not confer the risk of ovarian hyperstimulation syndrome [91].

The period of the highest risk is not ovarian stimulation but pregnancy due to elevated rates of fetal and maternal complication, so the main reason for rejecting ART in women with SLE is foremost the risk of obstetric and maternal adverse outcomes. ART is safe in patients with stable SLE; however, its use is not recommended in patients with active SLE, uncontrolled hypertension, chronic kidney disease, severe valve disease, or severe thromboembolic events [48].

#### **6. Algorithm in women with SLE**

An algorithm proposal to approach women with SLE of childbearing age is presented in **Figure 1**.

#### **Figure 1.**

*Approach to pregnant woman with SLE. Data from [76, 99]. aPL, antiphospholipid; LMWH, low-molecularweight heparin; LDA, low-dose aspirin; IUGR, intrauterine growth restriction.*

#### **7. Conclusions**

Pregnancy induces immunologic and hormonal adaptations on a pregnant woman to permit maternal tolerance to the fetus. The balance between Th17 cells and Treg cells seems critical to pregnancy outcomes, although its possible implication in maternal-fetal complications in SLE woman is not completely understood.

The relationship between SLE and pregnancy is close and bidirectional; active disease is associated with the increased risk of adverse pregnancy outcomes and pregnancy changes which impact on maternal disease triggering flares during this period.

Besides disease activity, immunologic factors related to SLE such as aPL and anti-SSA/Ro antibodies can also influence obstetric and neonatal outcomes. The *Reproductive Environment in Patients with SLE DOI: http://dx.doi.org/10.5772/intechopen.85391*

presence of aPL antibodies is one of the most important risk factors for pregnancy loss and late gestational complications in women with SLE. Treatment of pregnant patients with aPL will depend on the risk profile and history of obstetric or thrombotic events. Anti-SSA/Ro antibodies are related to neonatal lupus due to active transplacental transfer of these antibodies possibly causing direct injury to the cardiac conduction system manifesting as congenital heart block. Fetal Doppler echocardiographic monitoring between 16 and 26 weeks of gestation is highly recommended in pregnant women with anti-SSA/Ro for early detection of heart conduction delays.

Combined hormonal contraceptives are safe in women with stable SLE in the absence of aPL, without an increasing risk of disease flares or thrombotic events. Fertility in women with lupus can be affected not only by exposure to drugs related to infertility but also by SLE per se.

#### **Acknowledgements**

This work was supported by the National Institute of Medical Science and Nutrition SZ Grants [INCMNSZ-AI-024 (JRD)] and the National Council of Science and Technology [CONACYT SALUD-214395 (JRD)].

#### **Conflict of interest**

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this chapter.

#### **Author details**

María del Carmen Zamora-Medina and Juanita Romero-Díaz\* Department of Immunology and Rheumatology, National Institute of Medical Science and Nutrition Salvador Zubiran, Mexico City, Mexico

\*Address all correspondence to: juanita.romerodiaz@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[88] Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. The New England Journal of Medicine. 2005;**353**:2539-2549

[89] Janssen NM, Genta MS. The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy, and lactation. Archives of Internal Medicine. 2000;**160**:610-619

[90] Lawrenz B, Henes J, Henes M, et al. Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: Evaluation by using anti-Mullerian hormone. Lupus. 2011;**20**:1193-1197. DOI: 10.1177/0961203311409272

[91] Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Human Reproduction Update. 2008;**14**:359-366. DOI: 10.1177/0961203311409272

[92] Levine AB, Lockshin MD. Assisted reproductive technology in SLE and APS. Lupus. 2014;**23**:1239-1241. DOI: 10.1177/0961203314527370

[93] Steinvil A, Raz R, Berliner S, et al. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Thrombosis and Haemostasis. 2012;**108**:1192-1197. DOI: 10.1160/ TH12-06-0381

[94] Bellver J, Pellicer A. Ovarian stimulation for ovulation induction and in vitro fertilization in patients with systemic lupus erythematosus and antiphospholipid syndrome. Fertility and Sterility. 2009;**92**:1803-1810. DOI: 10.1016/j.fertnstert.2009.06.033

[95] Chilcott IT, Margara R, Cohen H, et al. Pregnancy outcome is not affected by antiphospholipid antibody status in women referred for in vitro fertilization. Fertility and Sterility. 2000;**73**:526-530

[96] Chan WS, Dixon ME. The "ART" of thromboembolism: A review of assisted reproductive technology and thromboembolic complications. Thrombosis Research. 2008;**121**:713-726

[97] Buckingham K, Chamley L. A critical assessment of the role of antiphospholipid antibodies in infertility. Journal of Reproductive Immunology. 2009;**80**:132-145. DOI: 10.1016/j.jri.2008.11.005

[98] Sanmarco M, Bardin N, Camoin L, et al. Antigenic profile, prevalence, and clinical significance of antiphospholipid antibodies in women referred for in vitro fertilization. Annals of the New York Academy of Sciences. 2007;**1108**:457-465

[99] Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Annals of the Rheumatic Diseases. 2017;**76**(3):476-485. DOI: 10.1136/ annrheumdis-2016-209770

#### **Chapter 5**

## Lupus Pregnancy: Risk Factors and Management

*Jose Ordi-Ros, Cristina Sole Marce and Josefina Cortes-Hernandez*

#### **Abstract**

Systemic lupus erythematosus (SLE) mainly affects women in the fertile age of life. A patient with SLE is as fertile as the general population except for treatment with drugs with ovarian toxicity, severe flare of the disease, or autoimmune oophoritis for anti-ovarian antibodies. Pregnancy in a woman with SLE implies greater maternal and fetal mortality and morbidity. Fetal loss, premature birth, intrauterine growth restriction associated with antiphospholipid antibodies (aPL), and neonatal lupus associated with anti-Ro are important fetal problems. Similarly, preeclampsia and lupus nephritis may lead to diagnostic confusion. Treatment options during pregnancy are limited to a few safe medications, which further restricts options. The loss of refractory pregnancy associated with antiphospholipid antibodies and the complete heart block associated with anti-Ro antibodies remain unresolved problems. The planning of pregnancy with sustainable treatments during pregnancy, no flare of SLE in the previous 6 months, and absence of nephritis are important for a good maternal and fetal prognosis. A gestation planning, multidisciplinary approach, and close monitoring are essential to obtain optimal results.

**Keywords:** lupus, pregnancy, fertility, antibody, treatment

#### **1. Introduction**

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of fertile age. Pregnancy causes concern for the majority of patients with SLE. The risk of the disease flare during pregnancy, the possibility of fetal loss, and the safety of drugs during pregnancy are of concern. A better understanding of the pathogenesis of SLE and good use of immunosuppressive drugs allows us to better control the disease, and we should not deprive patients with SLE of the opportunity to have children. Prepregnancy information and collaboration between specialists, such as obstetricians and perinatologists, are essential to optimize maternal and fetal outcomes in SLE pregnancies. In this chapter, important issues related to fertility, optimal time of conception, risk of disease flare during pregnancy, course of pregnancy, fetal outcome, safety of various medications used to control SLE during pregnancy and lactation, and a contraceptive education are discussed [1].

#### **2. Systemic lupus erythematosus fertility**

Fertility in patients with SLE is not greatly affected by the diagnosis of the disease. The decrease in fertility in SLE can be a consequence of the drugs used in the treatment of these patients, the flare of the disease, the organic damage caused by the disease, or advanced age. The use of cyclophosphamide (CYC) induces the majority of nonage-related infertility in patients with SLE, although the increasing use of mycophenolate mofetil (MMF) for the treatment of renal and extrarenal manifestations reduces the incidence due to its null ovarian toxicity. The risk of infertility due to CYC is associated with both the cumulative dose and an older age (>37 years old) of the woman at the time of treatment. The probability of maintaining fertility after treatment is greater for patients under 30 years of age, six or less monthly intravenous pulses, a cumulative dose of less than 7 g, and lack of amenorrhea before or during drug administration. It is less likely that other treatments in SLE have a significant impact on fertility, although nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested as possible contributors to infertility and it is suggested that high doses of corticosteroids have some effect on the cycle menstrual through its effect on the hypothalamic pituitary axis (HPA).

Patients with SLE may have menstrual disturbances or even amenorrhea secondary to very active disease. In addition, serum levels of anti-mulleriana hormone (AMH) are lower in patients with SLE not treated with CYC than in controls matched by age. It is important to emphasize that renal failure induced by lupus glomerulonephritis can cause hypofertility or infertility due to an alteration of the HPA, which can be reversed with kidney transplantation.

The profile of autoantibodies does not seem to affect fertility in women with SLE. However, the study of aPL in women with lupus is essential for predicting gestational risk, although recent controlled studies do not support an association between aPL and infertility or in vitro deficient fertilization (IVF). Evaluation or treatment of aPL in infertile women is not recommended.

Older age is an important factor of infertility in SLE, as it is in the general population. Female fertility decreases with age due to the progressive loss of the ovarian reserve; many patients with SLE are older when they try to conceive and may encounter difficulties related to age. The onset of SLE is more frequent in the first years of reproduction, and it is advised to avoid pregnancy when the disease is active. Premature ovarian failure (persistent amenorrhea with elevated levels of follicle-stimulating hormone before age 40) may be of autoimmune etiology in the general population but is rarely associated with systemic autoimmune diseases such as SLE [1, 2]. The study of anti-ovarian antibodies has contributed little to this pathology. However, treatment with corticosteroids and/or immunosuppressants has reversed the process in some cases.

#### **2.1 SLE fertility preservation**

Preserving fertility in women with SLE involves limiting cytotoxic drugs when possible and protecting the ovaries during treatment; however, prompt and effective therapy for a severe disease often takes precedence. The cryopreservation of oocytes or embryos is an effective option but requires ovarian stimulation, which may be impractical given the usual need to institute therapy quickly to avoid damage, as well as the risk of hyperstimulation in a patient with active SLE. The age of the patient to whom CYC is administered is not modifiable, but an effort must be made to minimize the total dose of CYC. The use of MMF may be the best option. Treatment with agonists of the gonadotrophic hormone receptor (GnRH) during

*Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

CYC therapy to minimize ovarian toxicity has become a common practice. Ovarian toxicity amenorrhea due to CYC has been the classic clinical sign. Now, the measurement of the AMH provides us with a better evaluation of the ovarian reserve. In a study of patients with SLE who received leuprolide with a GnRH agonist between 10 and 14 days before the CYC pulse therapy, a 68% increase in the ovarian reserve was estimated compared to patients with SLE who had not received this treatment. The GnRH agonist should not be administered immediately before the CYC. When administered during the follicular phase of the cycle, it can stimulate the ovaries and worsen ovarian damage. Patients without therapy with GnRH agonists before their first infusion can start treatment after the first cycle and receive treatment at monthly intervals thereafter [2].

#### **3. Contraception control**

SLE patients may be strongly advised to avoid pregnancy, particularly when they have severe disease-related damage or active disease or are taking teratogenic medications. Consequently, contraceptive options should be discussed with all female patients of reproductive age. Counseling patients to defer pregnancy relies on the assumption that they will utilize safe and effective contraception. In practice, SLE patients currently underutilize effective contraception, even those taking teratogenic medications [2]. Contraceptives vary in safety and efficacy. Long-acting reversible contraceptives such as intrauterine devices (IUDs) or subdermal implants have the greatest efficacy. IUDs generally contain either progesterone (levonorgesterol) or copper. Although IUDs have a low risk of infection, patients treated with immunosuppressive medications have not been specifically studied. However, HIV-infected women who have been studied do not have a greater risk of infection. Combined hormonal contraceptives include the pill, transdermal patch, and vaginal ring. Serious side effects include a three- to fivefold increased risk of venous thromboembolism and a twofold increased stroke risk. Medications commonly used for patients with SLE, such as warfarin and MMF, may interact with these agents and alter their efficacy. Concern regarding estrogen-induced flare previously has limited the use of oral contraceptives in patients with SLE. Two recent prospective studies in women with stable SLE showed no increased risk of flare with combined oral contraceptives. But oral contraceptives containing the progestin drospirenone can increase serum potassium and be dangerous in patients with nephritis or who also take angiotensin-converting enzyme (ACE) inhibitors. The vaginal ring and the patch may further increase thrombosis risk compared to oral combined contraceptives, and their safety in SLE has not been studied. No forms of estrogen-containing contraceptives are advised for use in aPL-positive patients due to the increased risk for thrombosis [3]. Progesterone-only contraceptives include oral and intramuscular forms, IUDs, and a subdermal etonogestrel implant. Depot medroxyprogesterone acetate (DMPA) injections may decrease bone density when used chronically, a concern in corticosteroid-treated patients. Progesterone-only contraceptives represent a safe and effective option for aPL-positive patients; with the possible exception of DMPA, the risk for thromboembolism is very low, and they may decrease menstrual blood loss. Emergency contraception can be considered for all SLE patients, including aPL-positive patients. Long-acting reversible contraceptives are preferable for most SLE patients, but every decision regarding contraception must balance the risk and efficacy of the method with the risk of unplanned pregnancy.

### **4. Fertility and assisted reproductive techniques**

Fertility is generally unimpaired in patients with systemic lupus erythematosus (SLE), unless they have been treated with cyclophosphamide (CYC). Although CYC is less commonly used for nephritis than in the past because of the availability of MMF, prevention of CYC-induced infertility remains an important concern. Concurrent gonadotropin-releasing hormone (GnRH) analogue therapy, usually leuprolide, appears to decrease risk of premature ovarian failure by CYC. Embryo and oocyte cryopreservation is options to preserve fertility in patients who are stable enough to safely undergo ovarian hyperstimulation. Patients with lupus may undergo assisted reproduction techniques, including in vitro fertilization (IVF). Ovarian hyperstimulation syndrome (OHSS) is a rare complication of IVF resulting in a capillary leak syndrome; severe OHSS increases risk for thrombosis and renal compromise. Even in a well-controlled cycle, elevated estrogen levels may increase risk of flare and thrombosis in SLE patients. However, thrombosis in aPL-positive patients undergoing IVF is rare, but most reported patients have been treated prophylactically with anticoagulants. Prophylactic anticoagulation may be considered in patients with high-risk aPL profiles and is mandatory for those with confirmed APS. However, aPL antibodies as a cause of failed IVF or infertility is not accepted, and anticoagulation is not indicated to improve IVF cycle outcome [2, 3].

#### **5. Preconception orientation**


Good information to the patients and pregnancy planning is essential for a woman with SLE who wants a child. Pregnancy planning is a key point for women

#### **Table 1.**

*Preconception visit checklist and contraindications to pregnancy in women with SLE.*

*Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

with SLE. Postponing conception until the disease is inactive for at least the previous 6 months significantly improves the results. Women with irreversible lesions in vital organs are more likely to suffer maternal-fetal morbidity and mortality during and after pregnancy. The pregnancy should be delayed, such as a severe disease flare in the previous 6 months, a recent stroke, and active lupus nephritis. In some situations, pregnancy may be contraindicated (**Table 1**). A profile of autoantibodies, such as aPL (anticardiolipin, anti-β2 glycoprotein I, and lupus anticoagulant), serum levels of complement, anti-SSA, and anti-SSB antibodies [4], is essential as risk factors for complications during pregnancy. Keeping the SLE inactive and the function of organs with safe medications during pregnancy should be a goal. There is an increased risk of complications among women with severe impairment of organ function, with or without serious pre-existing damage. The care of pregnant women with SLE must focus on three mainstays: a coordinated medical-obstetrical care, a well-defined management protocol, and a well-structured prenatal follow-up.

#### **6. Laboratory evaluation during prenatal care**

In pregnancy, it is necessary to perform routine pregnancy testing plus other tests that include a complete blood count, kidney and liver function, and proteins in a 24-hour urine collection (**Table 2**). Complementary studies should include additional tests such as complement study (C3 and C4), aCL, LA, aβ2GPI, anti-DNA, anti-SSA, and anti-SSB antibodies [4]. Evaluate the activity of the disease during the prenatal phase. The hormonal changes during pregnancy cause an alteration of the domain of Th1 to Th2 lymphocytes, and, consequently, it is expected that autoimmune disorders involving the Th2 response, such as SLE, are activated. In general, it is accepted that pregnancy can lead to higher rates of outbreaks of the disease, ranging from 25 to 65%. Skin rashes and musculoskeletal symptoms are less common, while renal and hematological flares are more frequent. The risk of flare seems to be related to the onset of disease activity 6–12 months before conception. There is an increased risk of flares during pregnancy when there is lupus nephritis at conception and even in women with pre-existing nephritis in remission. One study showed an exacerbation rate of 30% of SLE activity during pregnancy or postpartum in women with pre-existing lupus nephritis. It is sometimes difficult to distinguish signs and symptoms related to pregnancy from those due to SLE. Some ambiguous manifestations such as fatigue, headaches, arthralgias, edema, hair loss, palmar and malar erythema, anemia, and thrombocytopenia can be confused with clinical manifestations of SLE. An evaluation by physicians experienced in pregnant women with SLE is important. Blood tests with basal blood counts and urinalysis with measurement of proteinuria are useful to control the state of the disease and identify the flare. The production of C3 and C4 increases in the liver during pregnancy, and, therefore, their levels may be within the range of normality in cases of active SLE. Relative variations of complement are more important than absolute levels, and a 25% drop in serum complement levels may suggest a flare of lupus. The determination of the products of complement degradation would be the best way to identify a greater activation. Currently, we have indices to measure the activity of SLE during pregnancy, such as the pregnancy activity index of systemic lupus erythematosus (SLEPDAI) and the index of lupus activity in pregnancy (LAI-P). In practice, the clinical judgment of an experienced clinician is still considered the gold standard, and these indices are essential for publications on SLE and pregnancy. The SLEPDAI scale is an instrument similar to the SLE disease activity index (SLEDAI) to evaluate the activity of lupus, assigning different scores for the


*3 If positive for first time, repeat in 12 weeks.*

#### **Table 2.**

*Systemic lupus erythematosus pregnancy evaluation and monitoring.*

various clinical and laboratory manifestations of lupus activity, however, taking into account the changes, physiological factors of pregnancy, and main pathologies of the pregnancy-puerperal cycle that can simulate an active SLE. The risk of hypertensive disorders during pregnancy increases in the context of active lupus nephritis. The frequency of preeclampsia varies from 7.5 to 22.5% for all women with SLE. Renal involvement of lupus is often associated with hypertension, and the diagnosis of preeclampsia is difficult because it may coincide with chronic hypertension exacerbated during pregnancy. Likewise, in the case of women with SLE with residual glomerular lesions, an increase in proteinuria can be observed, due to the increase in the glomerular filtration rate during pregnancy, and this fact is not related to preeclampsia. The diagnosis of preeclampsia may be more difficult due to the increase in blood pressure and previous proteinuria. The differential diagnosis of preeclampsia in patients with lupus may be facilitated by changes in the C3, C4, and CH50 measurements, since a reduction in these levels is expected during lupus activity. Other laboratory tests are useful to perform a differential diagnosis, such as an abnormal urinary sediment, erythrocytic dysmorphia or cell casts, and increased titers of anti-DNA antibodies (common in lupus nephritis). SLE of onset during pregnancy should be considered as an active lupus and may be associated with a worse outcome of pregnancy. Differentiating preeclampsia into an early SLE during pregnancy is a challenge and often delays the diagnosis of SLE. Among patients with stable SLE at the time of conception, it is expected that the activity of the disease does not worsen, and even if so, the flare is usually mild and involves some type of treatment modification.

#### **7. Evaluation of fetal growth and vitality**

Fetal complications are frequent in patients with SLE. Miscarriages and intrauterine fetal death can occur in 20% of pregnancies in patients with SLE. Patients

#### *Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

with a history of nephritis have a higher risk of such adverse outcomes. The rate of restriction of fetal growth (FGR) is close to 30%, even in mild disease, with an increased risk if there is renal involvement. Several studies concluded that the result of the mortality rate for women with SLE tends to be higher, a condition strongly associated with the presence of flares of the disease during pregnancy. Serial obstetric ultrasound is the most important method to guide the monitoring of fetal growth. The measurement of the length of the cranial crown in the first trimester is presented as the most accurate measurement. At 16–22 weeks of gestation, an anatomical survey should be followed that considers the diagnosis of fetal anomalies, which also allows the first growth monitoring. In each 4-week period, new scans must be performed, measuring the volume of amniotic fluid. If preeclampsia is diagnosed, the interval should be reduced. The monitoring of fetal vitality is an important part of the prenatal care of patients with SLE. This should include the nonstress test (NST), the biophysical profile (BPP), and the Doppler velocimetry of the fetal umbilical artery, beginning at 26–28 weeks and continuing weekly until birth. In patients with SLE, alterations of the umbilical artery Doppler velocimetry should be handled in a similar way to those without the condition. The normal evaluation of these tests has a high negative predictive value for fetal death. A relationship exists between abnormal uterine artery Doppler and posterior fetal loss, preeclampsia, FGR, and preterm birth. For women with anti-SSA/anti-SSB antibodies, fetal echocardiography should be performed between 18 and 26 weeks to exclude congenital heart blockage of the fetus. An urgent referral to a tertiary care center should be requested in case of abnormal fetal heart rate, mainly a low heart rate.

#### **8. Recommended SLE treatment during pregnancy**

An active SLE is harmful to the mother and the fetus, and an appropriate reflection is necessary between the risks and benefits of the indicated treatment. In practice, it is common for women with SLE to interrupt their medication before conception, for fear of fetotoxicity, which happens through medical advice and proper planning [5]. Stopping the medication can lead to an active SLE and unfavorable pregnancy outcomes. Immunosuppressive treatment in pregnant women with quiescent lupus should not be changed unless it induces fetal malformations. The glucocorticoids and antimalarials are the drugs most used in the treatment of lupus and should be maintained at the same doses during pregnancy. Prednisone at a dose of 5–10 mg/day is considered safe and sustainable during pregnancy. The mild flare of the disease can be treated with low doses of prednisone (less than 20 mg/day), and higher doses of corticosteroids, such as intravenous pulses, will be indicated to treat moderate to severe lupus activity. The antimalarial is not teratogenic and is recommended to prevent the activity of the disease and reduce the risk of cardiac neonatal lupus in patients with anti-Ro antibodies. The use of immunosuppressants is possible during pregnancy, and azathioprine is the safest. Changing other immunosuppressants to azathioprine in a patient with SLE who wants pregnancy is recommended. Some recent report describes leukopenia, thrombocytopenia, and slow development of children exposed to azathioprine during pregnancy. Cyclosporine and tacrolimus, classified as category C by the Federal Drug Association (FDA), are safe during pregnancy initially demonstrated in pregnant women with kidney transplantation. CYC should not be prescribed during the first trimester for causing fetal chromosome, if it can be used during the second or third trimester for severe flares not controlled with pulses of methylprednisolone or other immunosuppressants. The use of CYC during the second and third trimesters does not seem to increase the risk of congenital anomalies, although spontaneous abortions and premature labor may be more frequent. Treatment with mycophenolate mofetil may be another option during the second and third trimesters, although more experience is lacking. Leflunomide is associated with teratogenic and fetotoxic effects in animals, and its metabolite is detectable in plasma up to 2 years after the interruption. In pregnant women, it is formally contraindicated, and pregnancy should be excluded before starting a treatment with leflunomide. Methotrexate, classified as drug X by the FDA, is teratogenic and produces abortion at high doses; therefore, it is contraindicated in pregnancy. If used in the first trimester, it is associated with FGR and some important malformations, such as absence or hypoplasia of the frontal bones, craniosynostosis, large fontanelle, and ocular hypertelorism. Thalidomide or thalidomide-like is used for the treatment of cutaneous lupus, producing malformations in the fetus, such as phocomelia by thalidomide. Rituximab has a very low transplacental transfer during the first trimester of pregnancy, and some studies of safe pregnancies and deliveries have already been reported in cases of exposure; in the second or third trimester, it can cross the placenta and induce severe neonatal lymphopenia. Therefore, in these cases, live vaccines should be avoided in these children during the first 6 months of life. High blood pressure is a common condition among patients with lupus nephritis; an adequate treatment of blood pressure during pregnancy can reduce the progression of the disease and avoid several adverse pregnancy outcomes. The labetalol, nifedipine, hydralazine, and methyldopa are safe medications to treat hypertension in pregnant women. Angiotensin-converting enzyme (ACE) inhibitors should be avoided due to their association with multiple congenital anomalies. A low dose of aspirin is recommended, since it reduces the risk of preeclampsia and perinatal death; In addition, it is associated with an increase in birth weight in those cases with risk factors, including kidney disease. Complete anticoagulation with low molecular weight heparin (LMWH) is recommended if there has been a previous thrombotic event. Calcium supplements are required, mainly for those women who use corticosteroids and heparin. Also, vitamin D supplements can be given, but it does not reduce unfavorable obstetric risks.

#### **9. Lupus flare management during pregnancy**

Many physiological changes in pregnancy can overlap with the characteristics of active disease, which makes differentiation difficult (**Table 3**). Some common laboratory tests also become less reliable: mild anemia and thrombocytopenia are common, the erythrocyte sedimentation rate (ESR) increases, and up to 300 mg/day proteinuria can occur during normal pregnancy. Complement levels increase by 10–50% during normal pregnancy and may appear to remain in the "normal" range, despite the activity of the disease. Anti-DNA antibodies may be useful in the evaluation of disease activity. The scales of activity of the specific disease of pregnancy, the activity index of pregnancy SLE (SLEPDAI), the LAI-P, and the BILAG2004-Pregnancy index have been developed with modifications in the descriptors. A combination of laboratory parameters along with clinical judgment may be the best tool to evaluate the activity of the disease. Based on the numerous risks associated with pregnancy, it is recommended that women with SLE have a preconception assessment and multidisciplinary management with maternal-fetal drugs and rheumatology during pregnancy. Active SLE at the time of conception is a predictor of adverse outcomes. It is suggested that the disease remain inactive for 6 months before attempting pregnancy. Laboratory tests should include, at a minimum, antiphospholipid antibodies (LA, IgG and IgM aCL, IgG, and


#### **Table 3.**

*Overlapping features of pregnancy and systemic lupus erythematosus (SLE).*

IgM anti-aβ2GPI I antibodies), anti-Ro/SSA and anti-La/SSB antibodies, and an evaluation of renal function (creatinine, protein/creatinine ratio in urine). Women who have anti-Ro/SSA and anti-La/SSB antibodies should have intensive fetal monitoring for cardiac arrest with fetal echocardiography by weekly pulsed Doppler (to measure the mechanical PR interval) beginning at 16–18 weeks and continuing up to 26–28 weeks of pregnancy. Ideally, all women with SLE should receive HCQ and low doses of aspirin during pregnancy, unless contraindicated. Women who continue HCQ during pregnancy have fewer outbreaks of disease and better outcomes as well as mothers with positive anti-Ro/SSA and anti-LA/ SSB antibodies. Low-dose aspirin initiated at 12–16 weeks of gestation reduces the risk of preeclampsia and fetal growth restriction [6]. The interruption of medications used to control the activity of the disease increases the risk of flares and complications associated with pregnancy. Serial ultrasound exams should be performed to assess fetal growth and fetal monitoring before delivery should begin in the third trimester. Renal involvement is common in patients with SLE and may be suspected in the presence of proteinuria or elevated serum creatinine. Hypertension and nephrotic syndrome consist of intense proteinuria, hypoalbuminemia, and peripheral edema, and patients have characteristically low levels of complement (C3) and high levels of anti-DNA. The involvement of the renal vasculature in cases of lupus nephritis is a sign of poor prognosis. In thrombotic microangiopathy, damage to the endothelial cells of small arterioles and capillaries results in thrombosis and mortality. Neuropsychiatric symptoms observed should be considered and excluded, including electrolyte abnormalities, infection, renal failure, and the effects of drugs. In the absence of a standard gold diagnostic test, this can represent a significant clinical challenge, especially in pregnancy and the postpartum period, where specific conditions of pregnancy, such as preeclampsia and eclampsia, can produce the same symptoms. The APS is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies. A small subset of patients with APS (<1%) develops multiple organ failure secondary to a disseminated thrombotic disease, a condition called catastrophic APS (CAPS) that has a mortality rate of up to 50%.

The treatment of flares during pregnancy is guided by the severity and involvement of the organ, similar to the state of nonpregnancy. However, the choice of agents is limited to safe medications, as discussed above. The steroids should be used in the lowest possible doses, but short cycles of high doses can be used for flare control. NSAIDs can produce malformations, and in general their indication in the SLE is in disuse. The antimalarial should be continued throughout pregnancy. Azathioprine and anti-calcineurin can occur throughout pregnancy. Azathioprine is a safe immunosuppressant with much experience in pregnancy, although delays in the development of the offspring have recently been reported. IVIg and plasmapheresis are still alternative options, but the increased risk of thrombosis with IVIg and fluid overload should be considered, although it is rarely necessary if we exclude intravenous Ig treatment of severe thrombocytopenia in pregnancy. Physiological changes in pregnancy such as an increase in glomerular filtration rate and renal plasma flow can worsen pre-existing kidney disease. However, in theory, a rapid decrease in the levels of the pregnancy hormone, particularly estrogen, may be advantageous. It is known that the immunosuppressive drugs used to treat SLE, such as CYC, cross the placenta and have teratogenic effects. In addition, this particular medication has been associated with premature and irreversible ovarian failure.

#### **10. Lupus pregnancy, nephritis, and eclampsia**

Lupus nephritis is an important risk factor for both maternal and fetal complications. A meta-analysis of 37 studies from 1980 to 2009 included 2751 pregnancies with SLE: the SLE flare rate was 25.6%, and the rates of preterm birth and IUGR were 39.4 and 12.7%, respectively. Positive associations were identified between preterm birth and active nephritis, hypertension and active nephritis, and preeclampsia and history of nephritis [7]. Up to 25% of women with SLE will develop preeclampsia compared to 5% in the general population. Doctors who treat lupus and pregnancy should ask themselves questions like does the presence of increased proteinuria and hypertension represent a flare or does the presence of increased proteinuria and hypertension represent the onset of preeclampsia? At the beginning of pregnancy, the presence of new or worsening proteinuria and hypertension will almost always represent a flare of lupus nephritis. However, beyond 20 weeks of gestation, differentiating a flare of preeclampsia poses a diagnostic as well as a therapeutic challenge (**Table 4**). Flare of lupus nephritis in pregnancy may be the first presentation of lupus and is relatively rare in those without previous nephritis or inactive nephritis at the beginning of pregnancy. However, if a woman has proteinuria, hypertension, renal function decreased at the beginning of pregnancy, and a history of lupus nephritis, she is likely to have a flare of lupus nephritis. The clinical history plus appropriate biochemical investigations is key to the diagnosis of clinical complications in SLE and pregnancy. The complement should be normal or high in pregnancy because it behaves as an acute phase reactant since this is pregnancy. The decrease in complement, even within the normal range, should alert us to a possible flare of SLE and more when associated with an increase in anti-dsDNA. If proteinuria is significant and unexpected, it can mean a change in immunosuppression and even renal biopsy if the woman is in the first trimester or in part during the second trimester, although it is only necessary if the clinic and laboratory are discordant. Always keep in mind if the woman is at risk of bleeding after the biopsy and for how long anticoagulation can be delayed in a pregnant woman with intense proteinuria and possibly phospholipid antibodies who, therefore, have a high risk of thrombovenous embolism, since the procoagulant


*Abbreviations: HELLP, hemolysis, elevated liver enzymes, and low platelets; SLE, systemic lupus erythematosus; sFlt-1, soluble fms-like tyrosine kinase; PlGF, placental growth factor.*

#### **Table 4.**

*Differentiation of preeclampsia from lupus nephritis flare in pregnancy.*

factors are added, pregnancy, nephropathy, SLE activity, and/or aPL. If the risk of having thromboembolism outweighs the benefit of a firm diagnosis, a biopsy should not be done. However, if there is a biochemistry compatible with a flare of lupus, patient's history contains nephritis flares and it is seems that it is going to be repeated; a kidney biopsy could be justified. The distinction of nephritis from lupus of pregnancy preeclampsia (from 26/40 weeks of gestation) can be difficult. In both, there will be an increase in proteinuria, hypertension, generalized symptoms, thrombocytopenia, and kidney damage. In women with isolated preeclampsia, there should be no hematuria, urinary cylinders, a decreasing complement, or increasing anti-dsDNA. However, a flare of lupus nephritis increases the risk of preeclampsia, so, again, distinguishing the two can be a challenge for the clinician. The two treatments are different; preeclampsia requires delivery sooner rather than later, and lupus nephritis requires immunosuppressive treatment. It is not yet a usual practice, but it is likely to be exceptionally useful, measuring angiogenic and antiangiogenic factors, to determine if there is preeclampsia present. Women with APS and SLE who developed preeclampsia had a median of sFlt-1 (tyrosine kinase similar to soluble fms), low placental growth levels (PIGF), and a significantly higher sFlt-1/PlGF ratio, and significantly higher PIGF levels lower compared with women with APS and SLE and without preeclampsia after 12 weeks of gestation. These differences increased with gestational age. The sFlt-1/PlGF ratio became a significant predictor of preeclampsia at 12 weeks, showing the highest levels at 20, 24, and 28 weeks of gestation [8, 9]. Later, the fall of the placental growth factor predicted the appearance of preeclampsia even in women with pre-existing chronic kidney disease. A recent publication highlights the evidence (or more commonly the lack of evidence) for the best use of antirheumatic drugs before and during pregnancy. Women who take azathioprine, hydroxychloroquine, cyclosporine, and tacrolimus can safely breastfeed their babies, so women who take these medications should not be discouraged from breastfeeding.

There are still no safety data on the MMF, so breastfeeding is discouraged if MMF is required. The woman with SLE and pregnancy should be treated as highrisk. At the controls ask for symptoms of the disease to detect SLE flare, and always check the blood pressure to detect preeclampsia. A blood and urine test should be done every quarter to detect biological changes in the complement and anti-DNA that suggest a flare. The fetus must be carefully monitored to detect growth and blood flow. Good multidisciplinary coordination among obstetrician, nephrologists, rheumatologists, and nursing experts is essential for better results.

#### **11. Pregnancy and antiphospholipid antibodies**

Pregnancy in women with SLE and aPL-positive courses with obstetric is 80% of cases. The current standard treatment for patients with obstetric includes LDA (75–100 mg/day) and low molecular weight heparin (subcutaneous enoxaparin, dalteparin, nadroparin, or subcutaneous tinzaparin) or unfractionated heparin. These recommendations are based on the results of randomized controlled trials comparing LDA alone or in combination with heparin with APS [7]. Kutteh et al. reported a significant improvement in the rate of live births with LDA and heparin versus LDA alone (80 versus 44%, P < 0.05). Rai et al. showed a significantly higher rate of live births with LDA and unfractionated heparin (5000 units) versus LDA alone (71 versus 42%, OR, 3.37, 95% CI, 1.40–8.10). However, no differences were found in the results with the combined treatment versus the LDA in two other randomized trials, both with LMWH, with live birth rates close to 80% in both groups. The heterogeneity in the findings seems to be attributed to the relatively poor results in women who received LDA alone in the two previous studies. In addition, data from observational studies have reported pregnancy success rates of 79–100% with LDA alone in this subgroup of women, although many of these cases had low levels of aPL antibodies. The current recommendation for the treatment of obstetric APS is to initiate LDA plus LMWH at therapeutic doses.

All women should be evaluated for risk factors for venous thromboembolism and should receive postpartum thromboprophylaxis. The Royal College of Gynecology in the United Kingdom, for example, recommends, for aPL-positive women without clinical manifestations of APS, 7 days after thromboprophylaxis of labor, and for women with APS, this extends to 6 weeks. All women with APS can deliver natural light, unless there are obstetric reasons to suggest otherwise. In addition, all women should be encouraged to stop smoking and reduce/discontinue alcohol consumption in accordance with the national pregnancy guidelines. Patients with a recent thrombotic event in the last 3 months, particularly high blood pressure and/or uncontrolled, should be encouraged to postpone new pregnancies. Patients with pulmonary hypertension in general are advised not to get pregnant. Women with previous thrombosis should receive long-term anticoagulation once the risk of postpartum hemorrhage has stabilized. Both AVK (antivitamin K) and heparins are compatible with breastfeeding. With respect to fetal monitoring during pregnancy, the bilateral uterine notch between 23 and 25 weeks of gestation has been shown to be an independent risk factor for the development of early-onset preeclampsia and gestational hypertension. Therefore, the bilateral notch of the uterine artery should be considered in the risk assessment for the development of these pregnancy complications. The evaluation of thrombotic risk should also be considered in patients with a history of obstetric primary health center. Among others, Lefevre et al. demonstrated that patients with obstetric APS have a higher thrombotic risk compared to healthy women (3.3 versus 0–0.5/100 patient years), even if treated with LDA. Similarly, in a 10-year observational study of 1592 women

#### *Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

with pure obstetric SAP and no history of thrombosis, Gris et al. demonstrated that the LA was a risk factor for superficial and superficial venous thrombosis and unprovoked distal and similar results have been demonstrated in other studies.

The current treatment to prevent obstetric morbidity in primary health center (PHC) has improved the outcome of pregnancy at a rate of live births of more than 70%. Given that 30% of women continue to have complications during pregnancy, international groups are currently evaluating different options to improve pregnancy outcomes in women with APS. The additional use of low doses of steroids has been evaluated in refractory APS. It has been suggested that intravenous immunoglobulin improves pregnancy complications in obstetric PHC. Treatment with pravastatin suggests a beneficial role in those women with preeclampsia related to established aPL. In their case series, 11 patients are treated with pravastatin 20 mg/day in addition to the standard treatment, while the controls continued alone with LDA and LMWH. In all patients exposed to pravastatin, signs of preeclampsia, such as blood pressure and proteinuria, improved and signs of placental perfusion remained stable without further deterioration compared to the control group. HCQ has also been evaluated. The HCQ immunomodulator can have beneficial effects not only in the treatment of thrombotic APS but also in the prevention of pregnancy complications [10]. The European randomized controlled multicenter trial "HYPATIA" will evaluate the role of HCQ versus placebo in pregnant women with aPL and, hopefully, provide stronger evidence on the use of HCQ in this context. Complement activation, and therefore a potential role for eculizumab, has also been introduced as a potential target for therapy with APS. The participation of complement activation was investigated for the first time in murine models of pregnancy morbidities related to aPL, and increasing evidence is emerging from both in vitro and in vivo studies. The complement can be activated by binding of the C3 fragment to the Fc receptor of aPL antibodies or by the formation of autoantibodies against C1q, which are frequently detected in patients with APS. The activation of the complement pathway and, consequently, the production of inflammatory molecules such as C5a by aPL, can directly activate platelets and monocytes, inducing the coagulation cascade, which leads to the clinical manifestations of APS. Although in the current literature several case reports describe the successful use of eculizumab in severe cases of APS, such as catastrophic antiphospholipid syndrome (CAPS) and cases of APS and thrombotic microangiopathy, the potential role of eculizumab should be further investigated.

#### **12. Neonatal lupus**

Pregnancies in women with anti-Ro and anti-La have an increased risk of developing neonatal lupus (NLS) with or without lupus. Maternal antibodies cross the placental barrier giving a passively acquired fetal autoimmunity. Cutaneous lesions of subacute lupus and hematologic and/or hepatic alterations of the NLS tend to resolve with the elimination of maternal antibodies from 6 to 8 months of age, but the lesion of the developing fetal cardiac conduction pathway can be irreversible. Cardiac injuries include conduction defects, structural abnormalities, cardiomyopathy, and congestive heart failure, but the most serious complication is the development of irreversible complete heart block (CHB), which is associated with a high fetal mortality of 20%. NLS can affect 2% of pregnancies exposed to anti-Ro, but recurrence rates in new pregnancies are 16–20% after a first NLS event. The majority (up to 70%) of the survivors require the insertion of a permanent pacemaker and periodic changes of the same as the child will grow. The CHB may be preceded by lower degrees of driving delays, although it may be sudden onset. Most of the events

occur between 18 and 24 weeks of gestation, but there are later cases, and even postpartum CHB has been described. Early detection and initiation of treatment could stop progression to CHB, but reversal of established CHB has not been reported. Multiple monitoring tools have been proposed for the early detection of cardiac conduction disorder, but fetal Doppler echocardiography remains the most widely used method. The most vulnerable period is between 18 and 24 weeks of pregnancy, so it is recommended in this period of pregnancy to monitor weekly all exposed fetuses, and then every 2 weeks. The detection of an early conduction defect with a prolonged RP interval should indicate the start of a prophylactic treatment to avoid CHB, although we do not have any effective guidelines. The maternal administration of fluorinated corticosteroids and beta-agonists has shown benefits in some specific cases. The treatment of established CHB remains an unresolved problem with minimal benefit with any available approach. The high risk of recurrence in subsequent pregnancies justifies prophylactic therapy for pregnancies at risk. The beneficial effects of IVIg were reported in open studies, but two randomized controlled trials were negative. Both trials have been criticized for their methodology, but the use of IVIg in this context can still be considered as an option. HCQ again deserves special mention. Several studies have shown that HCQ reduces the risk of cardiac NLS in fetuses at risk and possible recurrences. In view of the multiple beneficial effects of HCQ, it is indicated in all pregnant women with lupus and anti-Ro [11].

#### **13. Delivery**

Women with SLE have an increased risk of preterm birth. This can occur spontaneously or due to maternal and/or fetal complications, such as a flare of severe lupus, preeclampsia, and FGR. Between 24 and 34 weeks of gestation, the acceleration of fetal lung maturation is essential, with steroids (preferably betamethasone), regardless of any steroid administered previously. Magnesium sulfate when gestational age is <32 weeks, due to its neuroprotective benefits for the fetus, should be administered in cases of severe preeclampsia. The objective in a pregnant patient with SLE should be a spontaneous delivery at term via the vagina. However, available data have revealed that women with SLE undergo a higher cesarean section (>33%, odds ratio (OR) 1.7, confidence interval (CI) 95% 1.6–1.9). Despite this, it is recommended that cesarean sections be reserved only for obstetric indications, due to their additional risk factor for venous thromboembolism (VTE), blood loss and infection, and repercussions for future pregnancies. Intravenous hydrocortisone may be necessary to overcome the physiological stress of labor if long-term oral steroids, which are very common in SLE, have been taken. The standard prophylactic LMWH should be discontinued at the start of spontaneous delivery and the night before induced labor or elective cesarean section. Regional anesthesia (epidural or spinal) can be performed 12 hours after the last dose of LMWH.

#### **14. Postpartum care**

In the puerperium, we must control the activity of the SLE for the detection of flare or coexisting preeclampsia. The treatment for postpartum active SLE is similar to that of nonpregnant women. However, the use of some drugs may have effects on the nursing infant. Therefore, the risks and benefits of continuing to breastfeed should be clarified to the nursing mother. All women who received antenatal LMWH should continue using it for 6 weeks after delivery, in a prophylactic dose, since the puerperium is also a period of increased risk of VTE. In patients with

*Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

SLE, postpartum advice to offer safe contraception is particularly important. Good options are long-acting reversible contraception methods. The use of progestogens is only safe and can become an appropriate option. Contraceptives containing estrogen will not use women with aPL or APS, SLE with moderate to severe flare, lupus nephritis, and some other conditions, such as hypertension, smoking, obesity, or previous VTE, since they increase the risk of VTE. In cases of well-defined SLE with stable and/or mild disease, the use of combined oral contraceptives may be indicated. Contraceptive barrier methods have a high failure rate (15–32%) and, therefore, should not be used as a single method.

### **Abbreviations**


*Lupus - New Advances and Challenges*

### **Author details**

Jose Ordi-Ros1 \*, Cristina Sole Marce2 and Josefina Cortes-Hernandez1

1 Internal Medicine, Vall d'Hebron Hospital, Barcelona, Spain

2 Lupus Research Unit, Vall d'Hebron Research Institute, Barcelona, Spain

\*Address all correspondence to: jordi@vhebron.net

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Lupus Pregnancy: Risk Factors and Management DOI: http://dx.doi.org/10.5772/intechopen.83652*

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Section 3
