Fetal outcome in autoimmune diseases

Autoimmunity Reviews 11 (2012) A520–A530

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Review

Fetal outcome in autoimmune diseases Graziela Carvalheiras a, Raquel Faria a, Jorge Braga b, Carlos Vasconcelos a, c,⁎ a b c

Unidade de Imunologia Clínica, Departamento de Medicina Interna, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Serviço de Obstetrícia, Maternidade de Júlio Dinis, Centro Hospitalar do Porto, Porto, Portugal Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), UMIB, Universidade do Porto, Porto, Portugal

a r t i c l e

i n f o

Available online 11 December 2011 Keywords: Fetal outcome Miscarriages Preterm deliveries Autoimmune diseases Autoantibodies

a b s t r a c t The impact on fetal outcome in women with autoimmune diseases is a result of a several conditions. Fetal success depends on early immunological changes in the mother, which rely in modifications of the innate and adaptative immune system, inducing tolerance to the semi-allogenic fetus. Others crucial factors are maternal disease activity, severity of organ damage, circulating antibodies, and drug treatment. Although fetal outcome is becoming better still it has a worse prognosis in comparison with healthy women. Diseases like antiphospholipid syndrome, systemic lupus erythematosus and vasculitis have the higher risk while rheumatoid arthritis and spondiloarthopaties the least. In the majority of the diseases the risk of poor fetal outcome directly correlates with the activity of disease. While there are no pathognomonic autoantibodies for fetal outcome, antiphospholipid and anti-thyroid antibodies have been implicated in unsuccessful pregnancies and anti-Ro and, to a lesser extent, anti-La antibodies may result in neonatal lupus syndrome congenital heart block. There is increasingly the hope that fetal outcome will be good if the disease is well controlled prior to pregnancy, and with a specialized interdisciplinary support. © 2011 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . 1.1. The fetus and the mother immune system . . . . . 1.2. Definitions of fetal outcomes . . . . . . . . . . . . Specific autoimmune diseases . . . . . . . . . . . . . . 2.1. Systemic autoimmune diseases . . . . . . . . . . . 2.1.1. Systemic lupus erythematosus (SLE) . . . . 2.1.2. Antiphospholipid antibody syndrome (APS) 2.1.3. Sjögren's syndrome (SS) . . . . . . . . . 2.1.4. Systemic sclerosis (SSc) . . . . . . . . . . 2.1.5. Rheumatoid arthritis and other arthritides . 2.1.6. Vasculitis and Behçet disease . . . . . . . 2.1.7. Inflammatory myositis . . . . . . . . . . 2.2. Intestinal inflammatory diseases . . . . . . . . . . 2.3. Hepatic autoimune diseases . . . . . . . . . . . . 2.4. Autoimmune thyroid disease . . . . . . . . . . . . 2.5. Neurological autoimune diseases . . . . . . . . . . 2.5.1. Multiple sclerosis . . . . . . . . . . . . . 2.5.2. Myastenia Gravis . . . . . . . . . . . . . 2.6. Hematological autoimune diseases . . . . . . . . . 2.7. Autoimmune bullous diseases . . . . . . . . . . . 2.8. Autoinflammatory Syndromes . . . . . . . . . . .

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⁎ Corresponding author at: Internal Medicine, Unidade de Imunologia Clínica, Hospital Santo António, Centro Hospitalar do Porto, Instituto Biomédicas Abel Salazar, Largo Abel Salazar, 4099-001 Porto, Portugal. Fax: + 351 220900633. E-mail address: [email protected] (C. Vasconcelos). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.12.002

G. Carvalheiras et al. / Autoimmunity Reviews 11 (2012) A520–A530

3. Comparative information about fetal outcome in autoimmune diseases 4. Drugs commonly used in autoimmune diseases and fetal outcome . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Autoimmune diseases occur preferentially in women on reproductive age. In the past, they were advised against pregnancy due to maternal and fetal morbidity and mortality but nowadays we know that the vast majority of rheumatic diseases if well controlled prior to pregnancy, and with a specialized interdisciplinary support, can be offered the women the possibility of being mothers [1]. The impact on fetal outcome of autoimmune diseases is a result of a myriad of conditions, such as maternal disease activity, severity of organ damage, circulating antibodies, and drug treatment. These conditions should always be evaluated, both on multisystemic diseases such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and on organ-specific diseases such as, immune thrombocytopenic purpura (ITP), myasthenia gravis (MG) or autoimmune bullous diseases. Although there is no doubt that autoimmune diseases can influence fetal outcome, there should always be kept in mind that other risk factors that occur in the general population can also occur in autoimmune patients. For instance, up to 50% of human conceptions may not succeed and the majority of losses happen in the first trimester, mainly related to advanced maternal age, anatomic anomalies, chromosomal abnormalities, endocrine dysfunction and nonautoimmune immunological problems [2]. Fetal growth is also influenced by several maternal factors like body weight, nutrition, smoking, infections, malformations and chromosomal abnormalities. Intra-uterine growth restriction (IUGR) has also been related with pre-eclampsia, eclampsia, HELLP syndrome, chronic hypertension, diabetes mellitus, chronic renal insufficiency, sickle cell disease, infections, hematologic immune-mediated disorders, malignancies, heart conditions, besides thyroid and autoimmune diseases [3–5].

1.1. The fetus and the mother immune system The fetus corresponds to a semi-allogenic transplant and we still don't know how the placenta, having the father's genoma on each cell, survives for 9 months without being rejected by the mother's immune system. Fetal success depends on early immunological changes in the mother, which rely in modifications of the innate and adaptative immune system, inducing tolerance to the semi-allogenic fetus [6,7]. Pro-inflammatory cytokines secreted by Th1 lymphocytes as TNF-α, IFN-γ, TNF-β, IL-1β, IL-6 and IL-2, are involved in cellular mediated immunity reactions, may have a role in embryo implantation and placental development [8], while Th-2 anti-inflammatory, humoral immunity related cytokines as IL-3, IL-4, IL-5, IL-10, IL-13 and Gm-CSF are involved in placental growth and preventing fetal rejection [6–8]. The Th1/Th2 shift correlates with the progressive increase of hormones, steroids, progesterone and estrogens, during pregnancy [7,9]. Complement can be activated and cause damage in fetal tissues, as it happens in pre-eclampsia, recurrent spontaneous abortions, intra-uterine growth retardation, and anti-phospholipid syndrome. However, there is no clear proven demonstration that complement has any relationship with pregnancy outcome [10]. As in APS placentas, complement activation was detected although with no relationship with pregnancy outcome [11]. Autoantibodies may impair fertility and affect pregnancy outcome, although by mechanisms still not completely known [12]. Although no single antibody is pathognomonic for pregnancy loss, some studies

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has shown predictive value of combination of different autoantibodies like TPO, TG and ENAs [12,13], or ASCA, aPL and aPT [12,14]. 1.2. Definitions of fetal outcomes It is important to highlight that many changes noticed in neonate already started in the fetal life, making difficult a clear separation between pathology of the fetus and of the neonate. Pregnancy can result in full term or preterm live birth delivery, or in fetal loss. Traditionally, when fetal loss occurs before 20 weeks of pregnancy it is defined as spontaneous abortion, and if it occurs later it is called stillbirth or intrauterine fetal death. The terminology used to classify pregnancy loss is inconsistent and careful must be taken in the interpretation of the literature. Miscarriage is defined as spontaneous abortion before fetal viability, and it is used both to describe loss before 24 weeks, 20 weeks, or even 12 weeks (referred as early abortion). Aiming to correctly interpret the APS miscarriages and its pathophysiology, Branch and Silver proposed other nomenclature: pre-embryonic phase (before the 3rd week of gestational age), embryonic phase (between the 3rd and 9th weeks of gestational age) and fetal phase (after the 10th week of gestational age) [15]. Recurrent loss is defined as three or more consecutive spontaneous miscarriages with or without previous live births, is a heterogeneous condition [16]. Intrauterine growth restriction (IUGR) is many times incorrectly used to refer to “small babies”, is a sonography-based definition to live births whose fetal growth has not met its growth potential. Small for gestational age (SGA) is the definition for a birth weight below the 10th percentile adjusted for gestational age for a certain population. In contrast to IUGR, SGA is not an adverse outcome and is most of the times related to the inherited constitutional features [17,18]. Full term birth is a pregnancy which terminates with a live birth between 37 and 40 weeks. Premature birth is referred to as termination of pregnancy between 21 and 36 weeks. Congenital malformation is a physical defect caused by inherit or genetic condition, toxic exposure of the fetus, birth injury and in many cases for no reason. 2. Specific autoimmune diseases The most common autoimmune diseases primarily affect women in childbearing age, as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and Hashimoto thyroiditis. In all of them, the main predictor of poor pregnancy and fetal outcome is the high disease activity in the previous 6 months and at the time of conception. Quiescent disease prior to conception infers the best pregnancies outcomes, similar to those in the general population. 2.1. Systemic autoimmune diseases 2.1.1. Systemic lupus erythematosus (SLE) While it has been long recognized that pregnancies in SLE patients are high risk to both mother and fetus, pregnancy outcomes in women with SLE have significantly improved over the last four decades, with the pregnancy loss rate falling from 43% in the 1960s to 17% by 2000 [19]. Even though, the incidences of spontaneous abortion, stillbirth, intra-uterine growth retardation, and prematurity are increased at least two-fold compared with the normal population

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[20]. Overall, about 20% of pregnancies in women with SLE end in miscarriage or stillbirth, and the risk of preterm birth are reported to be between 9 and 60% (Table 1), and there are some intervenient factors such as: previously fetal loss, active renal disease at conception, maternal hypertension and the presence of aPL [41]. The high risk to IUGR can be predicted by the presence of hypertension, active lupus and APS [18,41,42]. Furthermore, a severe disease flare may be potentially life threatening, and the drugs used to treat SLE can also adversely affect these outcomes [43]. Fetal outcome in terms of IUGR, prematurity and fetal loss were more favorable in patients with a past history of lupus nephritis, if the disease is in remission at conception [1]. The combination of high clinical activity and abnormal serology (complement or anti-dsDNA) is most predictive of a poor obstetric outcome [4]. Pregnancy loss is increased when there is proteinuria, aPL, thrombocytopenia or hypertension at the first pregnancy visit [44]. Although antibodies to nuclear antigens (ANAs) have been related to high miscarriage rate, [45] its role is not clear to be a direct effect or associated with other known antibodies [12]. High levels of prolactin (PRL) have been found in 20–30% of SLE patients, and it seems to be related with disease activity and poor fetal outcome [46]. SLE patients without anti-PRL antibodies had a significantly higher frequency of maternal and fetal complications, as premature deliveries or IUGR. In contrast SGA is higher in women with anti-PRL antibodies [47]. The PROMISSE study [38] (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus) is an ongoing prospective observational study, with preliminary data showing that 80% of lupus patients had a favorable pregnancy outcome, although there were excluded SLE patients

with previous poor risk factors for adverse outcomes (prednisone >20 mg/d, proteinuria >1g/24 h, and/or creatinine >1.2 mg/dL). Some markers were identified as poor outcome predictors: increase in lupus activity during pregnancy [SLEPDAI (SLE Pregnancy Disease Activity Index [48]) ≥4 at baseline and increase over baseline in SLEPDAI ≥3 at 20 or 32 weeks], high titer aPL and higher median uric acid levels at baseline. The Hopkins Lupus Cohort prospective study [42] analyzed how the lupus activity index had a negative impact on the fetal outcome, showing that high activity lupus led to increased premature birth and a decrease in live births, with almost one-quarter of these pregnancies resulting in fetal loss. The impact of lupus nephritis on fetal prognosis is not fully understood and has been a subject of controversy. This can be due to the heterogeneity of the studies design, paucity of lupus nephritis specific biomarkers and the absence of documented histological renal involvement. Several studies have suggested that renal involvement [23], hypocomplementemia [26] and the presence and degree of proteinuria at the time of conception may contribute to adverse maternal and fetal outcomes [49,50]. Recently, Gladman et al. [22] prospectively evaluated the effect of lupus nephritis on fetal and pregnancy outcomes. The fetal outcome was not different between the renal and nonrenal SLE groups except for low birth weight and congenital malformations that were more frequent in the renal group. On Smyth et al. meta-analysis [51] they only included subjects with biopsy-proven renal involvement in the lupus nephritis subgroup. The meta-regression analysis showed statistically significant positive associations between premature birth rate and active nephritis, but there was not a statistically significant association between histologic subclass and rate of unsuccessful pregnancy.

Table 1 Fetal outcome of pregnancies in women with SLE. Modified from Kitridou et al. [21]. Authors date reference

1950–1959 [21] 1960–1969 [21] 1970–1979 [21] 1980–1989 [21] 1990–1999 [21] 2000–2005 [21] Gladman et al. [22] 1970–2003 Wagner et al. [23] 1976–2007 Arfaj et al. [24] 1980–2006 Carmona et al. [25] 1985–1994 Imbasciati et al. [26] 1985–2004 Kwok et al. [27] 1985–2008 Cavallasca et al. [28] 1986–2004 Liu et al. [29] 1990–2008 Ambrosio et al. [30] 1993–2007 Our cohort [31,32] 1993–2010 Barnabe et al. [33] 1998–2009 Ko et al. [34] 1998–2010

Clark et al. [35] 1999–2001 Ideguchi et al. [36] 2000–2009 Bramham et al. [37] 2000–2008 PROMISSE study [38] 2003–2011 Wei et al. [39] 2005–2010 Giancotti et al. [40] 2007–2009

Number of pregnancies

155 307 505 543 1652 1464 Non-nephritis: 112 Nephritis:81 No nephritis: 47 Nephritis: 43 396/176 60/46 113 Non-nephritis: 25 Nephritis: 30 72/61 Active disease: 47 Inactive disease: 34 136 106 95 No nephritis: 144 Nephritis: 79 Active disease: 56 Inactive disease: 126 73 55 No previous nephritis: 64 Previous nephritis: 43 333 86 20

Fetal lossa

IUGR/SGA

Premature birth

Live birth

No (%)

No (%)

No (%)

No (%)

43 (27.5) 83 (27.0) 141 (27.9) 121 (22.3) 316 (19.1) 262 (17.9) 27 (24.1) 21 (25.9) 16 (35) 4 (9) 118 (29.7) 3 (5) 10 (9) 0 (0) 6 (20.0) 11 (15.3) 8 (17) 1 (2) 8 (5.9) 14 (13) 3 (3) 21 (14.6) 8 (21.6) 12 (23.2) 10 (7.9) NA 8 (17) 1 (1.6) 0 (0) 19 (5.7) 8 (9.3) 2 (10)

NA NA NA 131 (31.0) 89 (18.2) 51 (18.1) 13 (15.3) 18 (30.0) NA NA NA 5 (9.0) 23 (24) 9 (36) 26 (86.7) 24 (39.4) 19 (48.8) 2 (6) 19(14) 4 (4.3) 24 (25.3) 20 (17.1) 4 (11.4) 6 (14.0) 18 (17) 2 (2.7) NA 14 (22) 14 (33) NA NA NA

NA NA NA 93 (21.9) 486 (36.4) 279 (23.2) NA NA 9 (19) 22 (52) 10 (26.7) 11 (19.3) 31 (31) 6 (24.0) 18 (60.0) 28 (46.0) 25 (64) 3 (9) 31(25) 14 (15.2) 33 (34.8) 34 (25.8) 14 (42.4) 27 (63.0) 22 (18.8) 28 (38.9) 13 (28.0) 7 (11) 13 (30) 30 (9) 15 (17.4) 10 (50)

112 (72.5) 224 (73.0) 364 (72.1) 422 (75.1) 1336 (80.4) 1202 (82.1) 67 (60.0) 47 (78.3) NA NA 278 (70.2) 53 (88.3) 101 (89.4) 25 (100) 24 (80.0) 62 (86.0) 39 (83.0) 33 (97.0) 129(95) 92 (87) 92(97) 123 (85.4) 29 (78.4) 37 (66.1) 115 (91.3) 72 (98.6) 46 (84) 63 (98) 43 (100) 314 (94.3) 78 (91) 18 (90)

NA: not available data; SGA: small for gestational age; IUGR: intrauterine growth restriction. a Excluded voluntary abortions.

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In SLE patients, aPLs are found in 30–80% and it is one of the risk factors heralding complications and flare during pregnancy [52]. There are indications that the combination of APS and SLE results in a higher frequency of these complications than APS alone [53]. The prevalence of anti-Ro and/or anti-La antibodies in SLE patient is about 35% but only in 5% of mothers IgG antibodies cross the placenta, between weeks 16 and 32 gestation [54]. It is also important to be aware that approximately half the cases of neonatal lupus will occur in pregnancies where the woman has not been diagnosed with a connective tissue disease [41]. The transmission of anti-Ro and, to a lesser extent, anti-La antibodies may result in neonatal lupus syndrome, presenting as congenital heart block (CHB) in uterus or other clinical manifestations in newborns such as skin rash, liver abnormalities, thrombocytopenia and neurologic abnormalities [55]. CHB is the most severe complication, caused by the binding of maternal anti-Ro and/or anti-La antibodies to fetal cardiac tissue, resulting in transient myocarditis and subsequent fibrosis of the atrioventricular node. CHB occurs in 2% of the fetuses of women with the anti-Ro antibody, and has a recurrence rate of 15%–20% in subsequent pregnancies [56]. Mortality due to CHB, in utero or in the first three months of life, is estimated to be 16–30% [57,58]. In a large multicenter cohort study they have prospectively followed 100 anti-Ro/SSApositive women (53 SLE; 122 pregnancies) and 107 anti-Ro/SSAnegative women (58 SLE; 140 pregnancies), concluding that the presence of these antibodies is associated with CHB but does not negatively affect other pregnancy outcome [59]. Complete CHB is diagnosed when fetal bradycardia is identified usually between 18 and 28 weeks. All babies born to mothers with anti-Ro/La should have an electrocardiogram after birth to look for first- and second-degree heart block as they may progress to third-degree later. It is important to closely monitor these pregnancies by serial doppler echocardiography, but guidelines vary among countries and among units. Permanent pacemakers are required by 67% of survivors with complete CHB, although the cumulative probability of survival at 3 years of age was only 80% in one report [60]. First and second degree heart block and heart failure due to myocarditis may be reversed by dexamethasone or betamethasone (as they cross the placenta unlike prednisolone) but there is no evidence for reversal of third degree heart block. Affected fetuses should be referred to a pediatric cardiologist for close monitoring [58,61]. Intravenous immunoglobulin (IVIG) therapy did not effectively prevent recurrence of CHB [62,63]. 2.1.2. Antiphospholipid antibody syndrome (APS) Antiphospholipid antibody syndrome (APS) has well known association with pregnancy loss and other obstetric complications. Miscarriage, fetal losses and prematurity related to pre-eclampsia or placental insufficiency are part of the criteria for APS diagnosis [64]. Several studies have reported the relationship between the positivity for antiphospholipid antibodies (aPL) or lupus anticoagulant (LA) and pregnancy and fetal adverse outcome in different clinical settings. Hence one must be careful on its accurate analysis and conclusions since they represent heterogeneous population: patients with and without SLE, patients with different APS criteria, different antibody types and titers, different antibodies assays, and patients with and without extra-obstetric manifestation. As previously pointed, Brench and Silver [15] proposed differentiation between embryonic loss (till the 9th week of gestational age) and fetal loss, especially for APS, once there are different mechanisms involved: non immune or aloimmune causes (advanced maternal age, anatomic anomalies, chromosomal abnormalities, endocrine dysfunction) are responsible for the first, and thrombotic events and placental inflammation due to complement activation and impairment of trophoblast function are responsible for the last [65,66]. Fetal death (second and third trimester) is hence far more common in APS than expected [67], as opposite to the general population, in whom the majority of losses happen in the first trimester [2].

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Unsuccessful pregnancies can occur in up to 90%, in women with recurrent miscarriage or fetal loss and positive aPL, without treatment [68]. LA, anti-cardiolipin (aCL) or anti-beta2 glycoprotein I (anti-b2GPI) are associated with pregnancy loss with a positive predictive value (PPV) of 75% [12]. LA is a better predictor of poor outcome than is high titer IgG aPL and IgG anti-b2GPI (Table 2) [11,67,69]. Low aCL antibodies titers were not predictive of miscarriage, contrary to IgG aCL above 19U or LA presence, which had an OR 9.1 compared with women without antibodies [70]. In a recent study, high aCL titers (more than four-fold the upper limit of normal) were associated with 5.7 times more adverse fetal and neonatal poor outcome than all the other aCL titers pregnancies. Only 35% of the high titers pregnancies delivered full term healthy babies [71]. Antiprothrombin antibodies were also found more frequent in recurrent miscarriage than in normal pregnancies [72]. In the Euro-Phospholipid Project cohort, 1580 pregnancies in 590 women were analyzed. There were 35.4% of miscarriages, 16.9% of fetal losses and 10.6% of preterm deliveries [73]. In an analysis of 5 years of the some cohort, 13.7% had IUGR [74]. Very few studies compare the outcome of the different APS phenotype. Thrombotic APS had significant higher rates of preterm delivery and small for gestational age (SGA) babies than those with obstetric APS [75]. The catastrophic APS carries a severe prognosis both for the mother and the fetus. Out of the first 255 cases collected on the “CAPS Registry”, [76] fifteen cases of pregnant women were identified and 54% of these did not result in a live birth. In SLE patients, aPL's are found in 30–80% [52] and fetal loss is higher when LA antibodies or aCL are present. Between 1983 and 1993, 20 series were published analyzing the risk of miscarriage in 1399 SLE patients who had LA present or were positive for IgG or IgM aCL [67]. When LA was present the risk was 1.4 to 15.4-fold and when they were positive for IgG aCL the risk was 0.69 to 58fold compared to non-aPL SLE patients. The risk is more elevated when there are high persistent titers of IgG aCL. In one series, the risk of fetal loss rises to up to 64% when they are between 50 and 100 U/L and 75% with titers above 100 U/L [77]. In another series, the risk is up to 88% [78]. Even though, when SLE patients with aCL or LA were treated with aspirin and LMWH, the fetal outcome was similar to non-aPL SLE patients [52]. The institution of treatment with aspirin and heparin has diminished 54% of all fetal losses in women with aPL or LA [79]. When LA or aCL antibodies are present, even when no previous obstetric adverse outcome occurred, aspirin treatment should be started. In women with previous obstetric criteria for APS, aspirin and LMWH should be started as soon as these women know they are pregnant. The doubt remains when there were one or two miscarriages (early embryonic loss) in a positive aPL woman. Literature is not conclusive, but an expert survey showed that 2/3 of the physicians would prescribe aspirin and LMWH in highly selected profile (older women, assisted reproduction techniques, LA positivity or high aCL/anti-b2GPI titers) [80]. For women who are on oral anticoagulation for thrombotic APS, warfarin or

Table 2 Meta-analysis of the risk of recurrent miscarriage related to antiphospholipid antibody in women with no autoimmune disease. Modified from Opatrny L et al. and Meyer et al. [66,68]. Autoantibodies

Gestational age at fetal loss

No. patients

Median Odds-ratio (OR)

LA IgG anticardiolipine

b 24 weeks b 24 weeks b 13 weeks (early miscarriage) b 24 weeks b 13 weeks (early miscarriage)

1123 701 2353

13.35 3.56 3.57

1199 1010

5.61 2.12

IgM anticardiolipine IgG anti-beta2-GPI

LA — lupus anticoagulant; GPI — glycoprotein I.

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acenocumarol should be switched to LMWH or UFH (unfractioned heparin) as soon as possible [81]. Intravenous immunoglobulin (IVIG) has been used to prevent fetal losses in APS women who still fail to deliver a live birth despite aspirin and LMWH. Although the results are controversial, they tend to show efficacy [82,83] and prevention of late complications as pre-eclampsia [84]. Intrauterine growth restriction (IUGR) occurs in 30% of APS pregnancies [1,67,85,86] and prematurity in about one third of all APS pregnancies [67,87,88]. They are related to pre-eclampsia and placental insufficiency, which are highly frequent in APS: preeclampsia occurs in 18–48% of APS pregnancies and placental insufficiency in about 50% [87,88]. In the general population, IUGR is related to IgG aCL in 12–24% [89,90] and its predictive value is 30% for developing IUGR [91]. These antibodies are also related to prematurity in about 12% [85,92]. There is no relation of pre-eclampsia and its complications with LA presence [91] but aCL IgG e IgM, anti-b2GPI and antiphosphatidilserine were related to relapse of pre-eclampsia [72,85,91–95]. HELLP (Hemolytic anemia Elevated Liver enzymes and Low Platelet count) syndrome occurs in 10–12% of pre-eclampsia pregnancies and it is 100 fold times more frequent in APS patients [67], and it is often difficult to differentiate them. Some studies reported less than 50% of live births when HELLP complicated an APS pregnancy [96]. The role of aspirin and LMWH on preventing late pregnancy complications is controversial. While aspirin has proven to prevent preeclampsia in the general population, the combination of them seems to be of no benefit on preventing preterm deliveries [96]. 2.1.3. Sjögren's syndrome (SS) Sjögren's syndrome is one of most common autoimmune diseases but it often only starts post menopause (after the fourth decade) and thus pregnancies are not frequent. The hallmark of fetal outcome in Sjögren's syndrome is the effect of anti-Ro (SS-A) and anti-La (SSB) antibodies and its relation with CHB and neonatal lupus (see above). Small series have reported increased rate of spontaneous abortion and fetal loss (relative risk 2.0) not related to anti-SS-A, anti-SS-B or antiphospholipid antibodies [97,98]. These were not confirmed in a more recent report on which there was an increased incidence of small for gestational age (SGA) babies, and this was the first to be population based [99]. There is no increased rate of prematurity [97–99]. 2.1.4. Systemic sclerosis (SSc) Systemic sclerosis peaks its incidence in the fifth decade and hence pregnancy is rare. The younger patients were discouraged to get pregnant in the past but, nowadays, with careful monitoring the risk for mothers and fetus are limited [100–102]. Series reports from tertiary centers, showed an increased rate of miscarriage compared with the expect for the general Caucasian women (15% versus 10%) [100–102], but in a large north-American population-based study, with 508 pregnancies in scleroderma, the rate of live births was similar to the general population [103]. In one prospective study, fetal loss was rare and related to long standing diffuse scleroderma [104]. In another retrospective study [101] there was decreased incidence of live birth in pregnancies after the onset of the disease compared to those before the onset of disease. Small for gestational age infants occurred in up to 50% [100–105]. On the large north-American study the risk of IUGR [103] on scleroderma was 3.7-fold increased compared to the general population. On the same study, the pre-eclampsia relative risk was also 3.7-fold increased and these are most probably related. Preterm delivery rate has been 29% [102] and 39% [101] in tertiary center report series. 2.1.5. Rheumatoid arthritis and other arthritides Rheumatoid arthritis and other arthritides occur mainly in childbearing age and they have global good outcome. In most cohorts

and population based studies, there is no increased risk of miscarriage or fetal loss [33,106–109]. There is an increased risk of SGA babies in several studies [33,108–111], related to high disease activity at the time of conception and in one to the use of prednisolone, but not sulfasalazine, during pregnancy [108]. Rheumatoid arthritis and other arthritides have 1.85 to 3-fold increased risk of preterm delivery [33,109,112]. Perinatal high mortality has also been described [109]. The elective cesarean rate has been reported high in all arthritides in several studies and countries [109,112,113], but women with ankylosing spondylitis have the higher rate [109,114], probably due to the pelvic stiffness and pain. 2.1.6. Vasculitis and Behçet disease Except for Takayasu's disease there are very few reports on pregnancy in patients with vasculitis, namely because of the old age at which they occur. Globally, the fetal outcome is good, but there are some adverse prognostic risk factors such as active disease and organ involvement, including damage from vasculitis: chronic kidney disease, arterial hypertension, cardiomyopathy, tracheal stenosis and persistente asthma [115]. Miscarriages and preterm births were common in a tertiary center cohort [116], in which 30% had fetal death, and 37% had a preterm delivery, despite of 14 out of 19 were in vasculitis remission. In Takayasu's arteritis, IUGR and preterm delivery occurred in 30% of pregnancies in two series [17,115,117] and more frequently in patients with more severe disease [17,118]. Pregnant cases of polyarteritis nodosa are rare and some cases of fetal death were described [17,115]. Rare cases were described of pregnancy in patients with microscopic polyangiitis but there is one case of lung-renal syndrome in the neonate because of ANCA, anti-MPO, transplacentar transfer [115]. Data from 30 women with Wegener disease [115], revealed a good fetal outcome in 95%, with prematurity in 28% of the neonates, excluding those women with spontaneous or therapeutic abortion when the disease was active. Reports of pregnancy in Churg–Strauss syndrome pointed to a favorable fetal outcome with more than 80% with live term deliveries [115], but with low birth weight [118]. In Henoch–Schonlein Purpura the pregnancy prognosis also seems good, but there are reports of miscarriage and fetal death in utero [115]. Behçet disease may affect pregnancy outcome [17] with no significant increased risk in fetal outcome [115]. In a case–control study, 20% of 135 Behçet's pregnancies miscarried [119]. 2.1.7. Inflammatory myositis The inflammatory myositis are very rare and it occurs mainly after the childbearing age, therefore few reports are available on the fetal outcome in this group of autoimmune diseases. The fetal and pregnancy outcomes are overall related with the disease activity [120,121]. The fetal prognosis is better in the juvenile form of dermatomyositis, with more than 70% of full term live births, [121,122] compared with the adult form in whom only 50% present full term delivery [120–123]. Active myositis during pregnancy caries a risk of fetal loss in up to 43% compared to 13% when the disease is controlled. IUGR and preterm delivery can happen in 33% when the disease is active [121]. If disease starts during pregnancy, the fetal outcome is poor with 50% of fetal loss and high rates of prematurity [122,124]. 2.2. Intestinal inflammatory diseases Inflammatory bowel diseases (IBD) are diagnosed early in life. About 50% of patients are diagnosed before 35 years of age, with one quarter being pregnant after IBD diagnosis [125]. A metaanalysis with 3907 pregnant women with IBD concludes that they are at increased risk of giving birth prematurely, having low-birthweight infants, and having cesarean sections comparing with women who do not have IBD. Premature delivery was almost twice

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as likely compared to the general population. However these results must be carefully interpreted, because it was unclear which factors increased the risk, including disease activity [126]. In patients who remain in remission or have only mildly active disease, the spontaneous abortion rate is similar to the general population (~ 10%) [127,128]. Anti-sacchromyces cerevisiae (ASCAs) are a marker for future development Crohn's disease (CD) [129]. As showed by Shoenfeld et al., they have been associated with recurrent miscarriage (OR 3.9 and PPV 19.4%) [12,14]. The risk for poor fetal outcome appears to be higher in women with Crohn's disease (CD) than in those with ulcerative colitis (UC) [130]. Crohn's disease has been reported to be associated with intrauterine growth restriction and pre-term labor, and fetal loss has been significantly associated with the activity of Crohn's disease at the time of conception [131]. With increased disease activity fetal loss goes up to 60% in severe Crohn's disease, 18–40% in active but non-fulminant ulcerative colitis and goes up to 60% in fulminant ulcerative colitis requiring surgery [128,132,133]. Smoking is related to CD activity and in the general population it is responsible for low birth weight, contrary of UC [134]. Congenital abnormalities have been related to UC, however this may be confounding by disease activity or drug treatment. It seems that there is no relationship with increased risk of congenital abnormalities in IBD [127,135–137]. Several studies had been report the effect of thiopurines in fetal outcome. In the CESAME cohort [138], involving 215 pregnancies, 75.7% Crohn's disease and 21.8% ulcerative colitis, it was proved that thiopurine use in pregnancy is not associated with increased risks, including congenital abnormalities. Flexible sigmoidoscopy seems to be safe for the fetus, although it should be used only when necessary [139]. Because of advances in the medical management, surgical intervention for fulminant colitis during pregnancy, has been rarely described, however they can be safely used for fetal and maternal outcome [140]. 2.3. Hepatic autoimune diseases In the past, pregnancy related to Autoimmune Hepatitis (AIH) was associated with a high rate of fetal complications, including preterm delivery and fetal death, with ratios up to 50% [141]. Nowadays there are doubts about those conclusions, since they included women diagnosed as having “chronic active hepatitis”, many of them probably without the revised International Group criteria for AIH [142,143]. In a review at the Institute of Liver Studies at King's College Hospital London, they only include pregnant women with criteria for AIH, in a total of 35 pregnancies. Fetal loss rate was 14.3% and preterm delivery was also low, 6% [143]. Similar results were confirmed by Candida et al. on 101 pregnancies, showing 19% of fetal death rate, most of them occurring before 20th week of gestation [144]. Few reports have been published about fetal outcome in Primary Biliary Cirrhosis (PBC), showing an increased risk for preterm delivery and stillbirth [145]. Ursodeoxycholic acid and dexamethasone have been used for treatment of active PBC during pregnancy, without poor outcome [145–147]. 2.4. Autoimmune thyroid disease The fetal thyroid gland starts secreting thyroid hormones around week 12, and fetal TSH receptors become responsive to TSH and to TSH-receptors antibodies around the 20th week. In contrast with T4 and TSH, maternal TSH-receptor antibodies (TRAb) readily cross the placenta and can cause overstimulation of the fetal thyroid gland during the second half of pregnancy [148]. Approximately 10–15% of the population has anti-thyroid antibodies (ATAs), and they have been suggested to be independent markers of poor fetal outcome. The incidence of ATA in euthyroid women with recurrent fetal loss and miscarried appears to be increasing compared with controls of

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reproductive age without previous abortions [149,150]. The association of ATAs with recurrent miscarriage founded by Marai et al. [13], was not corroborate by Shoenfeld et al., however they conclude that anti-thyroglobulin antibodies (ATG) were associated with late pregnancy loss compared with controls (OR 8.44, PPV 40%) [14]. In the literature, it has also been described the relationship between ATAs and mother's older age [151,152]. Recently, an Asian–Indian cohort has proved that miscarriage rate was 3 times more common in women with thyroid peroxidase antibodies (TPO-Abs), and older women with TPO-Abs were also more prone to pregnancy loss [153]. Toulis et al. also provided evidence that the presence of TPO-Abs is associated with an increased risk for spontaneous miscarriage in women achieving a pregnancy through an IVF [154]. In a Tunisian prospective study cohort involving 147 women with thyroid disorders, they found a higher prevalence for positive anti-thyroid peroxidase antibodies (TPO-Ab) (6.5%), than hypothyroidism (3.2%) and hyperthyroidism (1.3%). That subgroup was also associated with a higher prevalence of non-thyroid autoimmune disease and a trend toward increase of past gestational hypertension, late abortion and fetal death [155]. Hyperthyroidism occurs in 1 to 2 of every 1000 pregnant women, and the most common cause is Graves' disease (80% to 85%). Other causes include functioning adenoma, thyroiditis, and excessive thyroid hormone intake [156]. Uncontrolled hyperthyroidism can lead to serious fetal outcome, including preterm delivery, placental abruption, increasing risk of miscarriage and stillbirth, with a fetal death rate estimated up to 20% [148,157]. Fetal hyperthyroidism occurs in less than 0.01% of pregnancies, and can be suspect through fetal tachycardia, fetal goiter, accelerated bone maturation, IUGR, low birth weight and malformations [148,157]. This may be the reflection of the mother's thyroid hormones or the mother's stimulating TRAbs [148]. Antithyroid drugs, such as methimazole and propylthiouracil, which also cross the placenta, are used to treat both maternal and fetal hyperthyroidism, as the lowest effective dose, in order to minimize the risk of fetal hypothyroidism [158,159]. The prevalence of hypothyroidism has been described as 1–2.5% in the literature [156,160]. In Hashimoto's thyroiditis, both hypothyroidism and thyroid autoantibodies have been implicated in pregnancy complications. Besides increased risk of low birth weight, stillbirths, neonatal respiratory distress and congenital anomalies (hydrocephalus and hypospadias), maternal hypothyroidism during pregnancy has also been demonstrated to affect neuropsychological development of the child, which could be irreversible. As previously noted, the fetal thyroid does not begin to concentrate iodine until 10–12 weeks of gestation, thus during this period the mother must provide for all the fetus's thyroxin requirements, essential to the normal fetal brain development [156]. It is thus necessary to screen and treat mother's hypothyroidism with L-thyroxine prior to conception or early in the first trimester, just to optimize fetal outcome [161,162]. 2.5. Neurological autoimune diseases 2.5.1. Multiple sclerosis Studies on fetal outcome in Multiple sclerosis have conflicting results. One prospective and some retrospective studies showed no increase risk [163–165], in opposition to a retrospective study from the Norwegian National registry [166]. The PRIMS (pregnancy in multiple sclerosis) study involving 256 pregnancies had only 5% spontaneous abortions and 2% stillbirths [167]. But a recent meta-analysis [168] reporting 13144 MS patients showed miscarriage rates between 20 and 30%, prematurity rate of 10%, and low birthweight was 5.80% (range 4.80–6.90%). Small for their gestational age (SGA) seems to be increased independent of treatment or disease stage [169,170], although when confounding factors were controlled there was no significant difference [165].

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2.5.2. Myastenia Gravis In women with Myastenia Gravis (MG) the development of fetal abnormalities due to transplacental passage of IgG antiacetylcholine receptor (AChR) antibodies is an important concern and circulating antibodies were related to inhibition of fetal movement possible resulting on the most severe malformation: arthrogryposis multiplex congenita, a rare disease characterized by multiple joint contractures in utero and pulmonary hypoplasia [171,172]. Despite that, others studies showed no statistical difference on rate of serious birth defects, [173] neonatal mortality, birth weight, or prematurity [174,175]. 2.6. Hematological autoimune diseases In immune thrombocytopenic purpura (ITP) pregnant women, the maternal autoantibodies may cross the placental barrier, and lead to the destruction of fetal platelets and induce moderate to severe thrombocytopenia in the fetus, which could be fatal. This is a not predictable situation except if it happened in a previous pregnancy. So the fetal platelet count should be determined immediately before or during labor [176–179]. 2.7. Autoimmune bullous diseases All autoimmune bullous disease can occur in pregnancy but are relatively rare. Severe pemphigus during pregnancy may be associated with fetal prematurity and death [180]. In a retrospective study of 779 pemphygus, 52 pregnancies were registered with an abortion rate of 9.6%, which was slightly more frequent when the disease had started during pregnancy [181]. Fetus of mothers with Pemphigus vulgaris are at risk of developing the disease, probably due to transplacental transmission of maternal antibodies. It has high fetal mortality rate [182]. Pemphigoid gestationis is a rare bullous disease related to pregnancy, but the second most common diagnosed overall. It results from a mismatch between maternal and fetus HLA with paternal antigens, inducing production of antiplacental antibodies that crossreact with the same proteins in skin. There are publications reporting increased fetal mortality and morbidity (small for gestational age and low birth weight) and related to premature delivery, but it was not confirmed by others [183,184].

Table 3 Comparative information about fetal outcome risk in active autoimmune diseases. Diseases

Miscarriage

Fetal loss

Premature births

IUGR/ SGA

SLE APS Sjögren syndrome Systemic sclerosis Rheumatoid arthritis and other arthritidis Vasculitis Takayasu arteritis Polyarteritis nodosa Wegener granulomatosis Churg–Strauss syndrome Henoch–Scholein Purpura Behçet disease Inflammatory myositis Multiple sclerosis Myastenia Gravis Hepatic autoimune diseases Inflammatory bowel diseases Autoimmune thyroid diseases Autoimmune bullous diseases Autoinflamatory diseases

++ +++ + + −

++ +++ + + −

+++ +++ − ++ +

++ ++ + ++ +

++ ++ + + − + ++ ++ − + + ++ NA −

++ ++ + + − + +++ − + + ++ + NA −

++ +++ ++ +++ − + ++ + − − ++ + + −

++ NA NA ++ − NA ++ − − NA + + NA −

(+++) very high risk; (++) high risk; (+) low risk; (−) no difference to the general population; NA — not available data; SLE — systemic lupus erythematosus; APS — antiphospholipid antibodies syndrome.

but others have known related malformations in animals or humans and should be avoided. For pain control, non steroid anti-inflammatory drugs should not be used. Paracetamol and opioids are safe, except for tramadol that showed embryogenic effects in animals [191]. Low dose aspirin is safely used in APS and pre-eclampsia prophylaxis but higher analgesic doses can impair fetal renal function and clotting ability or pulmonary hypertension in newborn [17]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in pregnancy due to teratogenicity but, if renal scleroderma crisis exists, it can be used as life-saving therapy [192]. Biologic therapy is quite recent and few reports are available about fetal outcome. In general, they are not recommended during pregnancy, although experts don't agree whether, for example, TNFinhibitors should or not be stopped on patients who became pregnant [188,190].

2.8. Autoinflammatory Syndromes 5. Conclusions The knowledge of Autoinflammatory Syndromes, and its anomalies in the innate immune system, is in rapidly expansion, especially about the most common Familiar Mediterranean Fever (FMF). These patients risk of early abortion is increased if inflammatory attacks occur during pregnancy and thus the use of colchicine is recommended during the conception and the pregnancy [185]. No other significant increase in fetal outcome has been reported [186]. 3. Comparative information about fetal outcome in autoimmune diseases Table 3 summarizes the main adverse fetal outcome in pregnant women with active autoimmune diseases compared to the general population. 4. Drugs commonly used in autoimmune diseases and fetal outcome Many classes of drug therapy are used for treatment of autoimmune diseases with potential fetal morbidity (Table 4) [11,17,187–190]. Preconception counseling is crucial. Some of them are known to be safe and should be continued during pregnancy,

In general autoimmune diseases still carries a higher risk for a bad fetal outcome in comparison with healthy mothers. But there are clear evidence of a great improvement in this situation during the last years, so these autoimmune women have the chance of being mothers if they are properly managed in a multidisciplinary outpatient clinic. There is no pathognomic autoantibody for pregnancy loss but antiphospholipid and antithyroid antibodies are linked to pregnancy loss, while anti-Ro/SSA antibodies are associated with fetal alterations. In some diseases, like APS, obstetrical and fetal issues are major problems, while in others, like RA and AS they are less critical problems. In SLE, obstetrical and fetal prognosis are clearly related to the activity of the disease at that moment. Pre-pregnancy planning, with an open discussion with the patient, is essential to reduce complications and pregnancy should happen during inactive stable disease for at least 6 months. Fetal outcome depends on an adequate fetal monitoring, routine obstetric ultrasound, biophysical profile, umbilical uterine artery Doppler blood-flow waveforms and fetal echocardiography. No drug is safe beyond all doubt in pregnancy but, on time discontinuation of teratogenic drugs and keeping the non-teratogenic, as for

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Table 4 Drugs commonly used in autoimmune diseases and fetal outcome. Modified from Jain et al. [17]. Class

Drug

Risk assessment

Fetal outcome

Immunossupressives

Corticosteroids

Safe at low doses

DMARD's

Hydroxycloroquine Sulfasalazine Azathioprine 6-mercaptopurine Cyclosporin A Tacrolimus Cyclophosphamide

Safe Safe (requires folic acid supplementation) Safe (b 2 mg/kg/day) Not recommended Safe (b 2.5 mg/kg/day) Safe Contraindicated

>15 mg/day: preterm delivery, increased risk of oral cleft and palate None Increased of oral cleft and cardiovascular anomlities

Methotrexate

Contraindicated

Leflunomide Mycophenolate of mofetil

Contraindicated Contraindicated

Gold Salts Anti-TNF (infliximab, etanercept, adalimumab, golizumab, certolizumab) Anakinra

Safe Apparently safe Not recommended

Biological therapy

Others

Abatacept Rituximab Tocilizumab Colchicine Thalidomide

IVIg Heparin Coumarinics (warfarin)

Apparently safe Not recommended Not recommended Not recommended Not recommended Safe Teratogenic

Safe Safe Contraindicated on 1st trimester and close to delivery

>2 mg/kg/day: depresses hematopoiesis Cleft palate, prematurity, SGA, IUGR IUGR None Growth defects, development delay, craniofacial defects, distal limb defects Congenital abnormalities in central nervous system, cranial ossification, limbs, palate and IUGR Embriotoxic and teratogenic in animals Craniofacial malformations, limb abnormalities, congenital cardiovascular, renal, or central nervous system malformation None No evidence; insufficient data

No evidence; insufficient data No evidence; insufficient data No evidence; insufficient data No pregnancies til date None Limb defects, phocomelia, fetal cardiac, gastrointestinal, bone, external ear, eye, urogenital tract abnormalities SGA None Nasal and limb hypoplasia, central nervous system abnormalities

DMARD's: disease modifying agent antirheumatic drugs, SGA: small for gestational age/IUGR: intrauterine growth restriction.

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