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Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18.
Introduction
The female immune system must be actively adapted during pregnancy in order to maintain its defensive capacity and, at the same time, protect the fetus from immunological rejection. This profound immunological change may influence, in various ways, women with an autoimmune disease who are conceiving. One such way is the further development of the disease in the postpartum period. Another way is the aggravation of a pre-existing condition. Additionally, pregnancy losses can be a serious problem in many women with autoimmune diseases. In the chapter, we will review the potential pregnancy complications in the most representative autoimmune diseases.
Antiphospholipid syndrome
The relationship between pregnancy loss and antiphospholipid syndrome (APS) was recognized many years ago. Although many pathogenic mechanisms for the association of pregnancy loss and APS have been described, the exact physiopathology is not fully understood. History of previous pregnancy loss or thrombosis, besides the presence of other autoimmune diseases such as systemic lupus erythematosus (SLE), makes it possible to differentiate several groups of patients, in which the initial treatment may differ. Although establishing pregnancy outcome prognosis in this entity is difficult, pregnancy loss in APS is considered a treatable cause for pregnancy loss. The close interaction between the multidisciplinary health care team and the patient and her family is extremely important for better outcomes (1).
The prevalence of APS during pregnancy is variable based on the population studied and this criteria used for antiphospholipid antibody (aPL) detection. The aPLs can be found in normal pregnancies but their prevalence is limited. Lupus anticoagulant (LA) was found in 0.2% and anticardiolipin antibodies (aCL) in 2% of normal pregnancies (2).
Between 7 and 25% of miscarriages that cannot be explained by other causes are secondary to the presence of aPLs (1). The prevalence of aCL varies from 4.6% to 50.7% with a mean of 15.5% and the prevalence of LA ranges from 0 to 14% with a mean of 8.3%; however, in women with late pregnancy loss (after 20 weeks) the prevalence can be as high as 30% (2). This wide range in the percentages can be explained by the diversity of the population studied and the lack of standardization of aPL detection assays.
It is important to understand that the serologic tests do not closely correlate with one another (3). A patient may have high-titer aCL or anti-beta-2-glycoprotein I antibodies (aβ2GPI) or LA with or without the other autoantibodies. Some authors argue that ‘triple positivity’ (i.e. all three antibodies are positive) carry the worst prognosis (4,5) while others argue that LA alone worsens the prognosis independent of aCL or aβ2GP1 titer (6). Most experts agree that coexisting predisposing factors such as smoking, diabetes, hypertension, obesity, or renal insufficiency worsen prognosis in individual patients.
The presence of aPLs during pregnancy leads to all sorts of placental dysfunction during all three trimesters and may lead to intrauterine growth restriction, preeclampsia, placental insufficiency, and miscarriages (7-10).
Classification criteria for pregnancy loss in APS
The current classification criteria (Sidney, 2006) (11) are a revision of the original Sapporo Criteria. APS is considered as present if at least one of the clinical criteria and one of the laboratory criteria that follow are met. The clinical criteria are defined by history or presence of vascular thrombosis (documented by appropriate imaging studies or histopathology) or pregnancy morbidity as below:
- One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or
- One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency, or
- Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.
The laboratory criteria are the presence of LA in plasma, medium or high titers of aCL of the IgG or IgM isotypes (>40 GPL or MPL, or > the 99th percentile), or aβ2GPI of the IgG or IgM isotypes (in titer > the 99th percentile). All positive tests should be confirmed at least twelve weeks apart.
Mechanisms of pregnancy loss in APS
Studies with animal mouse models have shown a direct causal relationship between of aPL and pregnancy loss. Inoculation of serum of highly aPL positive women in normal female mice induces early pregnancy termination (12) and active immunization with pathogenic monoclonal aCL induces clinical manifestation of APS in BALB/c mouse (13).
It is well established that aPLs require a cofactor(s) to bind to phospholipids, e.g., apolipoprotein H, also known as β2GPI. β 2GPI is a highly glycosylated glycoprotein with five “sushi-like” domains that interacts with the membrane phospholipids through its domain 5, which is rich in lysine. The binding of aPL to β2GPI forms a complex and increases the affinity to membrane phospholipid (14). The functional role of β2GPI is not fully described but it is known that its deficiency does not seem to be related to the disease. When the aPL-β2GPI complex binds to cellular membranes including trophoblast, it leads to damage and activation of cytokines such as interleukine 3, which is important for the embryonic implantation process (15).
The three well recognized pathogenic mechanisms of aPL in pregnancy are thrombosis, imbalance between prostacyclin and thromboxane, and alteration of trophoblast adhesion molecules (16). The hypercoagulable state induced by aPL is the cause of thrombosis, placental infarction, and spiral artery vasculopathy, which leads to intrauterine growth restriction, signs of fetal hypoxia such as abnormal flow in umbilical artery, and fetal loss.
Placental spiral artery vasculopathy diminishes the flow of maternal blood to intravillous space and interfers with gas and nutrient exchange. This utero-placental insufficiency can result in intrauterine growth restriction and pregnancy loss.
In order to differentiate the placental pathology of aPL from the characteristic of SLE, Magid et al. analyzed 40 placentas and did not find any correlation of SLE activity with miscarriage, intrauterine growth restriction, or premature birth (17) although more recent data showed that the disease activity in SLE could be a predictor of pregnancy outcome (18). The placental findings in SLE patients were compatible with hypoxia-ischemia, vasculopathy, thrombosis, and chronic villitis with placental weight reduction. When placentas of APS patients were analyzed, large areas of infarct were noticed (17).
There are different hypotheses on how aPL can induce a hypercoagulable state:
- There is cross reactivity between aPL and glycosaminoglycans (important molecules similar to heparin that can act as auto anticoagulant) that produces a hypercoagulable state by inhibiting natural anticoagulants (21).
- aPL can inhibit the anticoagulant effect of protein C and S (22).
- The reduction in annexin V (normal placental anticoagulant protein) produced by the competition between aPL and annexin V to bind with phospholipids, can lead to hypercoagulability in the placenta (23).
- aPL may activate the complement system which will eading to an inflammatory process and eventually thrombosis (24).
Besides the prothrombotic mechanisms described, there is also a direct vascular damage caused by aPL in the trophoblast (25). Studies with animal models showed that aPL can act directly on the trophoblast and thus interfer with the differentiation and maturation, produce direct damage through apoptosis, inhibit syncytium formation, diminish the production of chorionic gonadotropin, and alter implantation during early pregnancy (26,27).
Infection is also a possible trigger of pathogenic aPL production. Experimental studies have shown that immunization with Haemophilus influenza and Neisseria gonorrhea can trigger antibodies against β2GPI (28). The inoculation of these antibodies in normal pregnant mice resulted in clinical manifestation of APS including pregnancy loss, thrombocytopenia and elevated activated thromboplastin time. In humans, varicella infection was associated with APS (29).
The mechanism for pregnancy loss in APS is heterogeneous, complex, and, so far, not completely understood. Future studies focused on complement activation, new antigens, genetic predisposition, and the exact thrombotic domain for aβ2GPI will help as better understand the pathological features of APS (30,31).
In summary, it is widely accepted that aPL causes recurrent embryonic loss, intrauterine growth restriction, fetal distress, severe pre-eclampsia, and pregnancy loss, some of which are due to utero-placental insufficiency caused by multiple infarcts, thrombosis and spiral artery vasculopathy. The main targets are platelets, endothelium cells, inhibition of natural anticoagulants, complement activation and fibrinolytic pathway (24,32).
Clinical findings
Clinical manifestations of APS are numerous and of a widely variable spectrum ranging from single, deep venous thrombosis (DVT) or multi organ thrombosis, which affects only pregnancy or is associated with a big array of autoimmune phenomena. Several systemic findings can be explained by vasculopathy and small vessel occlusion due to platelet aggregation and subsequent thrombosis, which may trigger venous thrombosis, arterial thrombosis, pulmonary embolization, transient cerebral ischemia, renal infarction and other conditions. The patient may present exclusively vascular thrombosis, only obstetric morbidity or a mixture of the two forms of presentation of the disease. The presence of aPL is associated with an elevated incidence of first trimester abortion, fetal loss, placental dysfunction, and pre-eclampsia. Frequently the placenta is characterized as being abnormally small and light, and histopathology shows thrombosis and infarction.
Considering first trimester losses, 86% of miscarriages in patients with APS occur after embryonic cardiac activity is seen, but only 43% of miscarriages in patients without APS occur after this finding. This data suggests that the mechanism of pregnancy loss is different in patients with APS, as was shown earlier.
There is some theoretical suggestion that aPLs may have a role in infertility. They may affect implantation, placentation, and early embryonic development as the antibody binds to β2GP1 and is responsible for breakdown of the phospholipid adhesion molecules between different elements of trophoblast (33), but studies failed to show this association. For the time being, there is no evidence to suggest that routine screening should be done on patients with infertility, and therapy is not justified (34).
Laboratory findings
The detection of aPL is achieved by either coagulation assays (LA) or ELISA (aβ2GPI and aCL). The lack of standardization and wide variation between assays done worldwide are barriers for the designing and reliability of clinical trials (35). A task force with the experts in the field was established with the goal for achieving better quality and standardization of assays (36,37).
Lupus anticoagulant
LA assay is more specific but less sensitive when compared to aCL. It correlates better with thrombosis (especially arterial) and is the best predictor for adverse pregnancy outcome (6,38,39).
Documentation of an LA requires a four-step process: 1) Demonstration of a prolonged phospholipid-dependent coagulation-screening test such as activated Partial Thromboplastin Time or dilute Russell Viper Venom Time (aPTT or dRVVT); 2) failure to correct the prolonged screening test by mixing the patient’s plasma with normal platelet poor plasma, demonstrating the presence of an inhibitor; 3) shortening or correcting the prolonged screening test by the addition of excess phospholipid, demonstrating phospholipid dependency; and 4) exclusion of other inhibitors (40).
Anticardiolipin antibodies
aCL is detected by ELISA which allows the identification of isotype and quantification of the titer. In order for the aCL to bind its antigen, the presence of a cofactor is necessary: the β2GPI. Consequently, there are two clusters of aCL: β2GPI-dependent and β2GPI independent. It was shown that the β2GPI dependent is the one associated with thrombosis and the β2GPI independent can be found in the setting of infection and normally is not associated with the clinical manifestations of APS (41). The isotype that best correlates with thrombosis is IgG. Multiple studies showed a weak correlation between IgM and thrombosis or failed to demonstrate one (42). Although IgA is not part of the classification criteria, many authors argue that it is an independent risk factor for thrombosis (43).
Anti B2-glycoprotein I antibodies
Several studies have shown that the aβ2GPI is the type of antibody that better correlates with the presence of LA and APS clinical manifestations is IgG. This diagnostic test is performed by ELISA and was previously done in patients who exhibited clinical manifestations of APS but were negative for both aCL and LA. Nowadays its wide availability allows it to be performed more frequently.
Antiprothrombin antibodies
Although not part of the classification criteria, antiprothrombin antibodies (aPT) have been largely studied. Early reports showed no association between aPT and pregnancy morbidity, defined by two or more pregnancy losses before week 13 of pregnancy and/or one fetal death (44). A retrospective study showed that IgG aPT had predictive value of a 4.5 fold increased risk for early pregnancy loss in patients with APS, risk that was higher when compared to that of aCL (45).
Additionally, several other antibodies directed against negatively charged phospholipids such as phophatidylserine, phophatidylinositol, and phosphatidic acid or neutral charged phosphatidylethanolamine were described. Their clinical use remains very limited and is mostly done when patients present with classical clinical findings of APS but all laboratory data is negative.
In APS patients, another set of antibodies were described (e.g., anti-annexin V antibody, anti-protein C antibody, anti-protein S antibody, and anti-thrombomodulin antibody, anti-β2GPI domain 1 and domain 4/5, and anti-prothrombin-phosphatidylserine), but their clinical relevance remain uncertain.
Treatment
The treatment of obstetric APS should include a multidisciplinary team of specialists such as high-risk obstetricians, hematologists, and rheumatologists with expertise in the management of the syndrome and its possible complications. In order to attain the best pregnancy outcome, it is essential that patients use the medication correctly and have very close follow up during pregnancy. Pregnancy planning is ideal although not always achieved.
Patients must be informed that there is an increased risk of serious complications (eg, hypertension/preeclampsia, prematurity, or thrombosis) that can take place during pregnancy and the puerperium even if the proper treatment is chosen. Pregnancy should be discouraged in all women with important pulmonary hypertension because of the high risk of maternal death and should be postponed in the setting of uncontrolled hypertension or recent thrombotic events, especially stroke (34).
The management of obstetric APS is based on few well conducted studies and is still controversial. Therefore, it is important to try to personalize the management based on the patient as there is no strict protocol available supported by clinical trials. In addition, the heterogeneity and the existence of clinically different subgroups of APS make protocols hard to use. However, for educational purposes, we can divide APS during pregnancy into the following groups:
- Positive aPL patients with no history of thrombosis, pregnancy loss, or concomitant autoimmune disease.
- Patients with APS and a history of 3 or more early pregnancy losses.
- Patients with APS and a history of fetal loss (after 10 weeks) or premature birth before the 34th week due to severe pre-eclampsia or placental insufficiency
- Patients with APS and previous thrombosis.
- Patients with SLE and positive aPL.
Group 2 - Patients with APS and a history of 3 or more early pregnancy losses: Treatment with aspirin and heparin in prophylactic doses seems to increase considerably the rate of live births in patients with recurrent miscarriage, as was shown by most clinical trials (47,48) and a Cochrane systematic review (49). However, monotherapy with aspirin also had a high success rate in several observational studies and may be a therapeutic option in this group of women (34). The incidence of late complications in pregnancy including preeclampsia, intrauterine growth restriction, and preterm birth, remains high (50).
Group 3 - Patients with APS and a history of fetal loss (after 10 weeks) or premature birth before the 34th week due to severe pre-eclampsia or placental insufficiency: This group has a limited number of well-designed studies and few patients included, so there is no optimal treatment yet. Most authors recommend aspirin in combination with prophylactic doses of heparin, and both unfractioned and low molecular weight heparin are effective (34).
Group 4 - Patients with APS and previous thrombosis: All women with APS and previous thrombosis should maintain antithrombotic treatment during the entire pregnancy as well in the postpartum period considering the high rate of recurrent thrombosis (51). The gold standard treatment regimen is widely agreed to be combined treatment with low-dose aspirin and full anticoagulant doses of heparin (52). Warfarin can be used during pregnancy as an alternative to heparin after organogenesis is complete, so it must be avoided from 6 to 12 weeks (53,54).
Group 5 - Patients with SLE and positive aPL: Evidence in the literature indicates that antimalarials have antithrombotic effects on lupus patients (46). Currently, hydroxychloroquine (HCQ) and low-dose aspirin are recommended in primary thromboprophylaxis for SLE patients with positive LA or isolated and persistent aCL at medium or high titers. Postpartum prophylactic low molecular weight heparin use is advised in asymptomatic women with aPLs and lupus (34). HCQ use during pregnancy in patients with lupus also reduces the number of flares and hypertensive disorders (55). HCQ is safe for use during pregnancy as well as in breastfeeding. In the others, the management of APS (obstetric or thrombosis) will be the same as previously discussed for non-SLE pregnancy.
Intravenous immunoglobulin (IVIG) has been tested in trials with patients with APS that had unsuccessful pregnancies after treatment with heparin and aspirin due to considering its reduction in aCL levels. In comparison to low molecular weight heparin and aspirin, IVIG offered no advantage (56-58). Given the high-cost of IVIG and the lack of positive clinical trials, it should be reserved for accepted indications in pregnancy, such as thrombocytopenia. Prednisone was found to increase pregnancy morbidity in several studies when used for primary APS (46).
In patients with APS, ultrasonographic examination and umbilical artery Doppler velocimetry measurement should be done every 3 to 4 weeks starting at 18 to 20 weeks’ gestation to assess fetal growth, amniotic fluid volume, and fetal well-being. Restricted fetal growth may reflect uteroplacental failure in patients with APS (34).
Postpartum
The postpartum period is actually the greatest risk period for a woman in terms of thrombosis. Patients on prophylactic heparin during pregnancy should maintain the treatment for six weeks after delivery (50,59). Those patients with APS and prior thrombosis or stroke should maintain anticoagulation for life and switch heparin for warfarin, which is minimally secreted into the breast milk and thus is safe to use during breastfeeding, as well as heparin and aspirin (34). In patients with prior fetal death or recurrent pregnancy loss, the optimal management after pregnancy is still controversial (60). Options include no treatment or daily treatment with low-dose aspirin. It is important to avoid estrogens at all costs and to control additional thrombotic risk factors and triggering events (53).
Future insights
The standardization of laboratory assays continues to be one of the most important aspects for APS research development. Considering the obstetric manifestations of the syndrome, trials comparing treatments do not have full agreement among experts, and new studies should be designed for the development of appropriate protocols. HCQ, an antimalarial used in SLE, has been shown to decrease thrombosis rate in SLE patients (46) and can dissociate aPL IgG–β2GPI complexes and reduce the amount of aPL IgG that binds to phospholipid bilayers trapping annexin A5, a potent natural anticoagulant with high affinity for anionic phospholipids (61). The use of HCQ in APS is being currently investigated. New oral anticoagulants have been developed recently and evaluated for the prevention and treatment of thromboembolic diseases. Apixaban and rivaroxaban are specific inhibitors of factor Xa while dabigatran inhibits factor IIa. The studies of their efficacy and safety in APS (but not in pregnancy) is under way. New insights regarding the pathogenesis of the disease will certainly trigger the development of new drugs and modalities of treatment.
Systemic lupus erythematosus
SLE is a chronic, multisystem autoimmune disease that predominantly occurs in women of childbearing age. The risk of obstetric complications in pregnant patients with lupus is significant. SLE increases the risk of spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth. In addition, pregnancy may be associated with flares of the disease requiring immunosuppressive therapy. Therefore, SLE pregnancies are considered high risk. Maternal health and fetal development should be monitored frequently during pregnancy. If possible, delivery should occur in a controlled setting. Therefore, pregnant women with SLE should be followed by an obstetrician who is knowledgeable in high-risk pregnancies. Fortunately, because of the medical advances, most pregnancies end in a success (62).
The prevalence of SLE is 14.6–50.8 cases per 100,000 inhabitants. The incidence of lupus is much higher in women than in men. During the childbearing years, the female-to-male ratio is about 12:1. Evidence suggests that SLE is more common in African American and Hispanic groups than in Caucasians.
In the United States, there are an estimated number of 4500 pregnancies in women with SLE each year and women with SLE have complicated pregnancies: one third will result in a ceasarean section, 33% will have preterm birth, and over 20% will be complicated by preeclampsia (63).
Regarding fetal losses, studies suggest that pregnancy losses may be decreasing in recent years. In 1960 to 1965, the mean rate of fetal loss was 43 percent. In 2000 to 2003, the rate was 17 percent (64). However, in a multiethnic population with SLE in North America, the rate of fetal losses and stillbirths was reported in percent in 2008 (65); maybe the fetal loss rate is related to co-morbidity of the patients and activity before pregnancy. So, the risk of fetal loss is higher in women with hypertension, active lupus (66), or lupus nephritis (67-69) and in those with hypocomplementemia, elevated levels of anti-DNA antibodies, aPL, or thrombocytopenia (70-71). Additional research is needed to confirm this correlation in lupus pregnancy. Several factors may predict fetal death such as lupus disease activity, active lupus nephritis, and the presence of aPL (65).
Interaction of pregnancy and systemic lupus erythematosus
Pregnancy induces dramatic immune and neuroendocrine abnormalities in the maternal body in order to protect the fetus from immunologic attack by the mother (72). Instead of a general immunosuppression that would weaken the mother’s defence against infection, a modulation of composition and function of immune-competent cells and immune-modulatory molecules takes place in the maternal system during pregnancy (73). The fetus promotes tolerance to paternal antigens by migration of fetal cells and cell-free fetal DNA into maternal circulation during normal pregnancy. Fetal cells remain in the mother for decades, and create a state of microchimerism in the mother (74).
After delivery, the maternal body adjusts again to a non-pregnant state, which is not simply a return to the condition before conception, but takes place still under the influence of the immune activation at parturition (105). Furthermore, lactation affects immune functions, which may modulate activity of autoimmune diseases. The profound immunologic adaptions necessary for maternal tolerance toward the fetus in pregnancy and the immunological reset to a non-pregnant state thereafter, do influence maternal autoimmune rheumatic diseases in several ways.
Pregnancy induces substantial changes in hormone levels starting with hormones produced by the corpus luteum and the trophoblast followed by complex alterations initiated by the hypothalamicpituitary-adrenal (HPA) axis. Hormones have powerful effects on blood cells and regulate their proliferation, distribution, and function (76). The activity of immuncompetent cells is regulated by cytokines and chemokines with T helper cells as key effectors. Cytokines are important mediators acting in concert with other factors to support successful pregnancy. In 1993, Tom Wegmann proposed the concept of successful pregnancy as a Th2 phenomenon (77) which suppressed CD4+ T helper 1 type cells (Th1).
Besides Th1 and Th2 cells, there is a third subset of CD4+T helper cells, so called Th17 cells, that activate the immune system. The Th17 cells produce several cytokines, of which the most important are cytokines of the interleukin-17 (IL-17) family (68). IL-17 has a proinflammatory effect and drives inflammation also by inducing other proinflammatory cytokines (78). Presence of proinflammatory cytokines drives development of Th17 cells whereas a milieu of tolerance promotes development of Treg (79). Th17 cells are increased at inflammation sites and in the circulation in RA, SLE, and AS (80). Increased numbers of Th17 cells are also found in pregnancy pathology, e,eg., preeclampsia and recurrent pregnancy loss (81).
SLE is characterized by a loss of tolerance both in the T cell and B cell compartment, resulting in B cell hyperreactivity with pathogenic autoantibody formation. One important factor that has emerged is the response of lupus activity to sex steroid hormones (82). Estrogens enhance antibody production, T-helper type 2 immune responses, and B-cell immunity. At high concentrations as achieved in pregnancy, estrogens as well as gestagens stimulate the secretion of IL-4, IL10, TGF-β, and IFN-γ while suppressing production of TNFα at the same time (83).
A prospective study of pregnant lupus patients measured serum levels of sex steroid hormones as well as several cytokines (84). Estradiol and progesterone were significantly lower in the second and most of the third trimester of pregnancy in lupus patients compared to healthy controls. The failure to produce high concentrations of estradiol and progesterone could be due to impaired function of the placenta which, in turn, might also be involved in the increased rate of fetal loss observed in SLE. Furthermore, reduced serum levels of sex steroid hormones could also influence the secretion of cytokines as shown in the same study (84). In SLE patients, IL-6 serum levels remained low and did not increase in the third trimester of pregnancy as was observed in healthy controls. The absence of a rise in IL-6 is interesting in the context of cytokine function: IL-6 is necessary for T cell help for B cells (85). IL-10 did rise progressively during pregnancy in healthy women (84). In contrast, IL-10 levels were significantly higher already at conception in SLE patients and remained elevated throughout pregnancy and postpartum in SLE patients. IL-10 was originally thought to be a Th2 cytokine but is a pleiotropic cytokine with both immune stimulatory and immune suppressive functions that place it outside of the Th1-Th2 paradigm (85). The persistently high levels of IL-10 indicate a constitucional overproduction of IL-10 in SLE resulting in continuous B cell stimulation. No significant differences between SLE patients and controls were found in either sTNFR I or II levels or profiles before and during pregnancy. sTNFR I levels were significantly higher during pregnancy and postpartum in SLE patients with active disease compared to healthy controls (84). Studies of regulatory T cells in SLE patients have shown reduced numbers in active lupus and impaired suppressive function of Treg (86). A pilot study indicates that there is an imbalance between Treg and number of Th17 in pregnant lupus patients (87).
On the other hand, high prolactin (PRL) levels, in turn, seem to be associated with active Systemic Lupus Erythematosus (SLE) during pregnancy. PRL is capable of influencing immune responses and it is a cytokine. Hyperprolactinemia (HPRL) has been found in 20–30% of SLE patients and it seems to be associated with clinical activity during pregnancy (88).
Lupus flares during pregnancy
An important aspect of pregnancy in lupus patients is the risk of the occurrence of disease flares. It is not simple to quantify the incidence of such complications because many clinical studies were done using individual definitions of flare. In recent times, many efforts were made to create a “pregnancy-version” of existing activity indexes such as ECLAM, SLEDAI, SLAM, and LAI in order to make studies more comparable (89). The literature reports discordant results from prospective, controlled observational studies: some showed that women are at increased risk of lupus flares when pregnant while other studies reached the opposite conclusion, finding a flare rate unchanged as compared to non-pregnant SLE patients (89). Timing of relapse is also variable among studies (89). A disease flare can occur at any time, but there may be a trend towards flares in the third trimester. Since the timing of flares is unpredictable, regular follow-up is indicated throughout pregnancy and post-partum. A point on which everyone seems to agree, is that the risk of flare depends on the level of maternal disease activity in the 6–12 months before conception. It is increased in women with repeated flares before conception (89) who discontinue useful medications (in particular HCQ) (90) and, in particular, in women with active glomerulonephritis at the time of conception (91). Poor control of disease activity before pregnancy may also have detrimental effects on pregnancy outcome. It has been observed that disease activity for the 6 months before the conception was associated with an increase in the rate of pregnancy loss (92). Patients with the combination of high clinical activity of SLE and either low complement or positive anti-dsDNA had the highest rate of pregnancy loss and preterm birth (93). Hence, the importante of a careful evaluation of the maternal condition before and during pregnancy. As a matter of fact, patients who started a pregnancy in a stable remission period and who continued medications experienced few flares, mostly mild and generally well managed with a temporary increase in prednisone dose (90).
Another important task for clinicians is to distinguishing lupus activity from physiological changes of pregnancy and from other pregnancy complications that may mimic, in particular, a renal flare. Life-threatening conditions such as pre-eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets) may develop early in pregnancy (around the 20th week) and should be promptly recognized in order to prevent rapid progression.
Maternal outcome
Organ involvement and pregnancy
Patients with a high degree of irreversible organ damage are more likely to suffer complications or worsening of the previous damage during and after pregnancy (90).
Lupus Nephritis (LN) is a major manifestation of SLE and, therefore, it is a common situation today to have a pregnancy in SLE women with a biopsy-proven diagnosis of renal disease. SLE patients with active lupus nephritis are at higher risk for pregnancy complications than SLE patients without renal disease, and should be advised against pregnancy until a renal remission of at least 6 months duration, better 12–18 according to most recent recommendations (94), has been achieved. Women with quiescent disease (proteinuria <500 mg/day and inactive urinary sediment) and unaffected renal function are at reasonably low risk during pregnancy but should be tightly monitored. In normal pregnancy, the glomerular filtration rate increases by 30–50% and creatinine clearance rises to over 100 ml/min, causing a decrease in serum creatinine. Tubular reabsorption of protein is decreased during pregnancy, that’s why an increase in the normal amount of proteinuria to 150–180 mg/24 h is possible. On the other hand, a new onset of proteinuria >300 mg/24 h can be considered as pathological in pregnant patients without proteinuria at baseline. Variable results have been reported on the pregnancy outcome in SLE women with a pre-existing LN. The rate of successful pregnancies varied between 65% and 92% whereas the incidence of flares ranged from 8 to 30% (91-97). A recent systematic review and meta-analysis of pregnancy outcome (98) demonstrated a significant association between active LN and both the onset of maternal hypertension during pregnancy and the rate of premature birth. History of nephritis was also associated with pre-eclampsia. Another important question to be addressed is whether pregnancy would deteriorate renal function permanently. Different findings were reported, but it seems that permanent damage is more likely to occur in those patients that already have a severe impairment of renal function at conception (91-92,99-100).
Apart from LN, different organ involvement may be negatively influenced by pregnancy. Patients with restrictive pulmonary disease may worsen during pregnancy due to thoracic compression by the growing uterus. Likewise, women with cardiac disease may be at risk of heart failure due to volume overload caused by the normal increase in circulating volume (101). Pregnancy should be considered absolutely contraindicated in women with symptomatic pulmonary hypertension, which carries a higher than 30% maternal mortality during late pregnancy and the puerperium (102).
Morbidity and mortality
A recent study done in the United States on pregnancy related admissions (information derived from discharge codes) showed that women with SLE may be at increased risk of serious medical complications and mortality in comparison to non-SLE pregnant women (103). At the time of conception, SLE patients had more co-morbid conditions than healthy coetaneous. SLE patients, in particular suffered from pre-gestational diabetes, arterial hypertension, pulmonary hypertension, renal failure, and thrombophilia much more frequently than healthy women (103). Moreover, SLE patients tend to become pregnant at an older age in comparison to the general population. Even when adjusted for the increased age, the risk of maternal complications in women with SLE remains higher than in healthy pregnant. In particular, it was estimated a 2–4-fold increase in the rate of caesarean section, pre-eclampsia and eclampsia, especially in women taking high-dose prednisone, with preexisting hypertension and/or renal insufficiency (103). In a different cohort (PROMISSE study), 15% of SLE patients developed pre-eclampsia, rising to 22% if there were also positive aPL (104). The risk for sepsis and pneumonia was found to be greatly increased due to both disease-related immune dysregulation and immunosuppressive therapy (103). Also hematological complications requiring transfusion, e.g., post-partum haemorrhage, antepartum bleeding, anemia at delivery, and thrombocytopenia, were more common in lupus patients (104). The risk of both venous thromboembolism and stroke was 6,5- fold higher compared to healthy pregnant and also the maternal mortality rate was increased, with an excess risk estimated at 20 times higher than in general population (103). These data, collected using the discharge diagnosis, may be not comparable with those derived by tertiary referral centers in which a careful multidisciplinary management of pregnant women with SLE allows a better prognosis for both maternal and fetal outcome. However, these data underline the potential risk for an increased maternal morbidity and mortality and suggest the need for a high level of vigilance during SLE pregnancy.
Pregnancy and neonatal outcome
Pregnancy outcome
Despite major improvement in the last decades, the risk of obstetric and neonatal complications in SLE pregnancy is greater than in general population. It has been estimated that women with SLE have fewer live births compared to the general population, in particular, those with high disease activity (105). Maternal lupus activity and the presence of concomitant APS were found to be associated with major obstetrical complications (92,105) being estimated that about 20% of pregnancies in women with SLE end with a fetal wastage (106). The rate of preterm birth (delivery before 37 weeks gestation) is increased in SLE patients. The incidence, according to recent studies, seems to vary between 23 and 28% (107). Preterm birth is usually spontaneous, mainly due to the Premature Rupture of Membranes (PPROM), but there is also an important percentage of cases in which delivery is induced to protect the health of the mother and/or of the baby (onset of fetal distress or pre-eclampsia) (108). Risk factors for preterm delivery include disease activity prior to and during pregnancy (including serological activity, i.e., high titre anti-DNA antibodies, low serum complement levels) (93), higher prednisone dose, hypertension (92), and thyroid disease (109). Particular attention must be placed at babies born before 28 weeks gestation because they are at highest risk of neonatal death and for both long-term medical complications and cognitive impairment (110). Regarding the birth of babies with low weight (<2500 g) or small for gestational age (SGA: birth weight less than the 10th percentile for gestational age), these conditions are more common in SLE pregnancies, ranging from 6 to 35% (107). This finding is not surprising because placental insufficiency, which is frequent in lupus pregnancies (111), leads to an intrauterine growth restriction (IUGR) and to the birth of growth-restricted infants.
Current standard of care in SLE pregnancy includes Doppler studies of uterine arteries and the umbilical artery, which are helpful to assess placental function and to prevent the occurrence of complications such as pre-eclampsia and fetal distress (90). Uterine Doppler studies are useful as a screening test starting from the 20th week and being the 24th week is the best moment for the evaluation. At this time, the test has a high negative predictive value, which means that a normal result will be rarely associated with obstetric complications. The positive predictive value is low, which means that an increased resistance of uterine arteries could suggest an adverse outcome, but the risk is poorly quantifiable. Differently, umbilical Doppler ultrasound gives a more accurate definition of the placental function, showing various degree of impairment such as increased resistance, absent diastolic flow, or even reverse diastolic flow, which is a clear sign of placental insufficiency and fetal distress (112). Many of the previously cited fetal complications may be related to the presence of aPL (this topic will be discussed in a separate paragraph).
On the other hand, women with SLE are at high risk of adverse pregnancy outcomes. However, those who have a perinatal death in their first pregnancy can expect a live birth in a subsequent pregnancy (113).
Neonatal lupus erythematosus
Neonatal lupus erythematosus (NLE) refers to a clinical spectrum of cutaneous, cardiac, and systemic abnormalities observed in newborn infants whose mothers have autoantibodies against Ro/SSA and La/SSB. The condition is rare and usually benign and self-limited but sometimes may be associated with serious sequelae. This is a passive transfer of anti-Ro/SSA and/or anti-La/SSB antibodies that occurs in some babies of mothers with autoimmune disease (114).
These autoantibodies may cause damage to the developing tissue and increase the risk of bearing infants with NLE. Approximately 98% of affected infants have maternal transfer of autoantibodies against Ro/SSA, La/SSB, and, less commonly, U1-RNP. However, only 1–2% of mothers with these autoantibodies have neonates with NLE regardless of whether the mothers are symptomatic or not (114).
The diagnosis is usually established based on the clinical features and the demonstration of neonatal Lupus-associated antibodies in the serum of the mother or the affected infant. The most common clinical manifestations of NLE are, in decreasing order of frequency: dermatological, cardiac, and hepatic abnormalities. Some infants may also have hematological, neurological, or splenic abnormalities. The most serious complication in the neonate is complete heart block, which occurs in approximately 2 percent of such pregnancies. Isolated skin rash occurs in a similar percentage (114-116).
Laboratory studies
At the first visit after or when pregnancy is confirmed, the following assessments are recommended:
- Physical examination, including blood pressure evaluation
- Renal function tests, including determination of the glomerular filtration rate, urinalysis, and tests of the urine protein–to–urine creatinine ratio
- Complete blood count (CBC)
- Test for anti-Ro/SSA and anti-La/SSB antibodies
- LA and aCL studies
- Anti–double-stranded DNA (anti-dsDNA) test
- Complement (CH50 or C3 and C4) tests
During the first two trimesters, a monthly platelet count or CBC is recommended. The following evaluations are recommended at the end of each trimester of pregnancy:
- Determination of the glomerular filtration rate and measurement of the urine protein–to–urine creatinine ratio
- aCL measurement
- Complement (CH50 or C3 and C4) test
- Anti-dsDNA antibody study
Flares of SLE are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies. In comparison, complement levels are usually (but not always) increased in patients with preeclampsia (63,67,117).
Treatment
None of the medications used in the treatment of SLE is absolutely safe during pregnancy. Hence, whether to use medications should be decided after careful assessment of the risks and benefits in consultation with the patient. During the first trimester, most of the drugs should be avoided. Although, breastfeeding is feasible for most women with SLE, some medications may enter breast milk. Therefore, immunosuppressive agents are contraindicated, and long-acting non-steroidal anti-inflammatory drugs (NSAIDs) are inadvisable. Short-acting NSAIDs, antimalarials, azathioprine, low-dose prednisone, warfarin, and heparin seem to be safe.
Renal involvement
Patients with a significant flare of LN should be treated with high-dose prednisone and antihypertensive medication (e.g., hydralazine, methyldopa, and calcium channel blockers but not angiotensin converting enzyme inhibitors or some beta blockers).
There is little if any experience with pulse methylprednisolone in pregnancy, and its effects on the fetus are unknown. Cyclophosphamide is not safe during pregnancy, but azathioprine can be used cautiously. In addition, the fetus should be delivered as soon as possible (118-129).
Patients with renal disease should be monitored jointly by a nephrologist and by an obstetrician familiar with the effects of renal disease on pregnancy. General principles of management include the following:
- Increased frequency of prenatal visits; these should occur every two weeks until the third trimester and then weekly.
- Early detection and treatment of asymptomatic bacteriuria.
- Serial monitoring (at least monthly) of maternal renal function.
- Close monitoring for the development of preeclampsia.
- Fetal surveillance with ultrasound and fetal heart rate monitoring to assess fetal growth and well-being.
- Aggressive treatment of maternal hypertension. Preterm intervention may be necessary in the presence of deteriorating renal function, severe preeclampsia, fetal growth restriction, or nonreassuring fetal testing (e.g., fetal distress). In most women, elective delivery is indicated if labor has not occurred by the estimated date of confinement.
Neonatal lupus erythematosus
Maternal use of HCQ may be associated with reduced rates of cardiac manifestations in the newborn, including congenital heart block and isolated cardiomyopathy, and maternal HCQ use is also associated with a decreased risk of recurrence of cardiac neonatal lupus in subsequent pregnancies (131). However, antimalarial agents have potential toxicity and such a slow onset of action that their use in the treatment of this transient condition is probably not indicated. Systemic corticosteroids and immunosuppressive agents are generally not indicated in the treatment of NLE. However, infants with severe hepatic and hematological involvement may require treatment with systemic corticosteroids, intravenous immunoglobulin, and/or immunosuppressive agents (114).
Contraception, fertility and assisted reproduction
Contraception for SLE/APS patients goes beyond the simple need of avoiding unwanted pregnancies. Several conditions may require an effective contraception: early stage of the disease, very active disease, severe organ involvement or damage, and use of embryotoxic/fetotoxic drugs. Therefore, contraceptive counseling is essential in the rheumatological practice, but in “real life” most women do not receive any information about this issue (132). A common misconception among women with SLE is that they “cannot use birth control,” since the “classical” estrogen-containing pill is generally contraindicated. The message should be that women with SLE can be considered good candidates for many contraceptive methods, including hormonal contraceptives, and the most suitable one should be chosen individually (133).
The three main types of contraceptives are: barrier methods, intrauterine device (IUD), and hormonal method. Barrier methods are an effective, cheap method of preventing pregnancy and sexually transmitted disease. However the unintended pregnancy rate remains high–around 17% for condom and diaphragm. The IUD is available in a non medicated or medicated form (with progesterone). With typical use, the rate of unplanned pregnancy is low (around 2%). Complications could be irregular bleeding alter placement, the risk of expulsion of the device (5% falling out over the 5 year life of the device) and the risk of infection after insertion that can lead to pelvic inflammatory disease (PID). Current IUD devices are actually safer also in high risk groups (134), but the infectious risk should be anyway monitored overtime. It could be preferable to use IUD in patients with a single sexual partner and a mild treatment (no immunosuppressive drugs, prednisone lower than 10 mg per day). The use of estrogen-containing oral contraceptives (OC) has been greatly discouraged because of initial reports of SLE flare due to the hormonal treatment and subsequently supported by growing experimental evidence of the role of estrogens in the pathogenesis of SLE (135). However, two recent randomized clinical trials (136,137) supported the safety of low dose combined OC in a well-defined population of stable SLE patients with inactive or stable active disease in regard to the risk of SLE flare. On the other hand, the presence of aPL remains a major contraindication to combined OC due to the increased risk of thrombosis. Progestin-only preparations (daily oral pill, depot medroxyprogesterone, subcutaneous implants) do not appear to increase immune activity and are not associated with increased rate of flares nor does the dose of progestin increase the risk for thrombosis. A recent large study in SLE patients showed good gynecological tolerability (low rate of discontinuation for breakthrough bleeding or hypoestrogenia) (138). A major concern about the use of progesterone can be the effect on bone health. However, the reduction of bone mineral density has been shown to be reversible after discontinuation of treatment (139).
Women affected by SLE have an overall fertility rate similar to that of the normal obstetric population with a mean family size of 2 live births (140). However, there are a few conditions in which fertility may be impaired (141). Patients with chronic renal failure may have reduced fertility (142). Most of the immunosuppressive drugs do not influence fertility, with the exception of CYC (143). The risk of infertility is related to the cumulative dose of the drug and to the age of the patient, being “older” women with a lower ovarian reserve at higher risk for premature ovarian failure. Protection of ovarian function can be provided by treatment with gonadotropin-releasing hormone analogues (144). Women should be informed that NSAIDs may inhibit ovulation, therefore they should stop them at day 8 of the menstrual cycle when they want to conceive (145). Whatever is the cause of infertility, related or not to the disease, patients with SLE/APS may ask for medical assisted reproductive techniques (ARTs). The most used technique is IVF-ET (in Vitro fertilization and embryo transfer), which requires ovarian stimulation for oocyte pick-up. Ovarian stimulation is actually what may create concern in SLE/APS women for several reasons. These are base on theory basis and on small series reports (146): 1) high dose estrogens may induce a disease flare; 2) the enhanced hormonal milieu may increase the risk of thrombosis, especially in those women with aPL; 3) these complications may become lifethreatening in the case of ovarian hyperstimulation syndrome; 4) there could be a trend toward a worse prognosis for both pregnancy rate and live-birth rate after ARTs. Antithrombotic prophylaxis should be carried out on women with aPL with special attention for those who had a prior thrombosis (147).
Rheumatoid arthritis
It has been established that women, especially those at reproductive age, are more susceptible to rheumatoid arthritis (RA) than men. On the other hand, it was thought that the beginning of RA would be delayed by pregnancy and the disease risk would be reduced during gestation. Ever since, various studies have show disease remission in about 75% of patients with RA who got pregnant during the active state of the disease while it may relapse in the postpartum period in 90% of the patients (148-150). In addition to steroid hormone action, immunological changes and the increased galactosylation of IgG seem to play important roles in RA improvement during gestation (151). In 1999, Barret published the largest prospective study with 140 women and showed that most of them presented an increased level of pain and articular edema from 1 to 6 months after delivery. Endogenous hormone influence on RA is reinforced by the fact that the use of oral contraceptive pills plays a protective role in RA incidence. Another explanation for the improvement of the disease activity during pregnancy would be the enhanced immunological tolerance observed during this period. It is believed that immunological changes related to pregnancy are due to maternal exposure to fetal antigens that have a paternal origin (152). Nelson and colleagues noticed a higher number of class II HLA incompatibilities between the mother and the child in women who presented reduced disease activity during pregnancy (153). In addition, the higher Th2 response which occurs during pregnancy also seems to influence the disease activity level, improving RA and worsening SLE (154).
There is no scientific evidence relating parity to the risk of presenting the disease or its severity (155). In patients with RA, there have been reports of higher incidence of premature membrane rupture, longer hospital stay after delivery, and more cesarean births than general population (149), but the results are conflicting considering the incidence of pre-eclampsia in this group of patients (149, 155).
Although most of the patients have the disease in remission during pregnancy, a small number of patients with RA may have disease activity in this period. RA flare in pregnant woman may be treated with low doses of prednisone, HCQ, sulfasalazine and even anti-TNFs, if necessary (156).
Anti-TNF agents such as infliximab, adalimumab, and etarnacept have received a B classification from the FDA (156) meaning they do not appear to cause fetal anomalies in animals and there are no adequate and well-controlled studies in pregnant women. A recent survey with members of the American College of Rheumatology (ACR) has shown that most of them agree that treatment should not be started during pregnancy, but most specialists would not interrupt treatment with biological agents, which had been started before pregnancy.
Current data on the use of anti-TNF agents on pregnant human females is encouraging. A cohort of 30 women with RA exposed to adalimumab during pregnancy has yielded 90% live births, prematurity of birth in 11% of cases and two congenital anomalies (microcephaly and non descending testicles), which was similar to the control group without drug exposure (157). The results from a pregnancy-reporting database with an even larger number of patients that used infliximab have not shown an increased risk of pregnancy loss or congenital anomalies (157). Because of the in utero transfer of these drugs, a few authors recommend their discontinuation at the beginning of the third trimester to avoid immunosuppression in the newborn (157). The CTL4 receptor blocker, abatacept, as well as rituximab and tocilizumab must not be initiated during gestation and should be discontinued due to their limited experience with pregnant women (151).
Treatment with methotrexate (MTX), prescribed alone or in combination with biological therapies, must be discontinued for at least 3 months before conception or switched to azathioprine in patients planning conception due to elevated risk of fetal malformations. If the patient becomes pregnant while using MTX, high doses of folic acid (>10mg/d) must be administered although the severe cases of teratogenicity may result in spontaneous abortion. Restarting immunosuppressive therapy with MTX shortly after delivery decreases the risk of postpartum RA flare, but MTX is also excreted in breast milk and should not be used while breastfeeding (158).
Considering patients using leflunomide, its active metabolite undergoes extensive enterohepatic circulation and may persist in the body for up to 2 years. It should be discontinued for this period prior to conception or cholestyramine wash-out should be prescribed (155). If the patient becomes pregnant while using this medication, cholestyramine should be administered until there is no further detection of leflunomide level in the serum. The OTIS databank shows 9.3% of congenital anomalies are related to the use of leflunomide, which does not differ from the RA control population (13%) but is larger than that of a healthy population (3.5%) (157).
Undifferentiated connective tissue disease
Undifferentiated connective tissue disease (UCTD) which, in general, affects women before their 40s, is characterized by clinical manifestations of one or more systemic autoimmune diseases but does not fulfill classification criteria for any disease specifically. The UCTD can persist as an undifferentiated picture or may migrate to a defined diagnostic such as SLE, systemic sclerosis, Sjögrens syndrome, RA or other diseases. The differentiation into a defined entity, when it happens, generally takes place in the first two or three years (159). The concerning complications of UCTD that can happen during pregnancy are the development of nephritis related to SLE or myositis probably related to polymyositis. Just as in patients with SLE, conception in a stable phase of the disease and after three years of development yields a better gestational result. Pre-natal follow-up in with a multidisciplinary team is essential with special attention to signs of disease activity along with obstetric and fetal complications (159). HCQ is recommended during pregnancy and can be used when breastfeeding without any problem (160).
Sjögren’s syndrome
This is an inflammatory autoimmune syndrome that, apart from general and musculoskeletal symptoms, is clinically characterized by the drying of oral and ocular mucosa as proven by objective tests. The presence of anti-Ro/SSA antibodies (70 to 80%) is part of the diagnostic criteria (161) and may even precede clinical manifestations. It is thought that these antibodies when in Sjogren’s syndrome may induce neonatal lupus syndrome with a higher frequency rates than in mothers with SLE, and the surveillance approach must be the same as in SLE patients (162). Apart from rheumatic diseases, Sjögren’s syndrome may be associated with thyroiditis and autoimmune liver diseases, with an increased risk for the development lymphoproliferative diseases such as lymphomas.
Systemic sclerosis
Skin involvement remains stable during pregnancy in systemic sclerosis, but it may worsen after birth (163). Raynaud’s phenomenon usually gets better because of physiological changes that lead to increase cardiac output. Gastroesophageal reflux disease, which already frequently occurs in disease free pregnant women, generally gets even worse in systemic sclerotic patients and recurrent episodes of vomit may cause Mallory-Weiss syndrome in the already damaged by the disease-related fibrotic esophagus (149). It is extremely important to make the diagnosis right away and act fast to avoid life-threatening bleeding.
The most serious complication in systemic sclerosis pregnant women is renal crisis due to sudden arterial hypertension. Rise in creatinine with no proteinuria in the initial phase of acute kidney injury makes the diagnosis of systemic sclerosis renal crisis likely. Renal crisis is much more common in patients with less than five years of disease with diffuse skin involvement, positive anti-topoisomerase1 and previous exposure to high doses of steroids (149).
Another serious complication is pulmonary hypertension. This complication of systemic sclerosis is associated with 30 to 50% maternal mortality rates and requires stronger vigilance 48 to 72 hours after delivery (149) when physiological changes may lead to cardiovascular instability. Screening should be done before conception and its diagnosis during pregnancy may be an indication of therapeutic abortion once it may endanger the mother’s life (149).
Because they have a higher chance of hypertensive disease, women with systemic sclerosis have higher rates of preeclampsia and their hospital stay tends to be longer after delivery than healthy women. Hepatic enzyme elevation and proteinuria with edema are more common in preeclampsia and HELLP syndrome than scleroderma renal crisis (149).
Polymyositis and dermatomyositis
Polymyositis (PM) is a systemic autoimmune disease characterized by inflammation of the striated musculature. When inflammation of the muscle is associated with characteristic cutaneous manifestations, it is called dermatomyositis (DM). Myositis may have the onset in childhood or in post-menopause period; therefore pregnancies in patients affected with PM or DM are rare and the available data on pregnancy are from case reports or small series. A retrospective study showed higher risk of flares during pregnancy of the cases diagnosed in the childhood, even the ones in remission for years, than the ones diagnosed in adult life (159). The best obstetric result is obtained when the disease is controlled by conception time (164).
If there is disease activity with elevation of muscular enzymes within the first trimester of gestation, the obstetric outcome is worse than if this elevation occurs in the second or the third trimester. The treatment is normally prednisone 1mg/Kg/day until CPK normalization. The association with azathioprine or cyclosporine, in general, is necessary and it has a sparing effect of steroid. In refractory cases, IVIG or plasmapharesis are possible modalities as they are safe during pregnancy (159).
Mixed connective tissue disease
Mixed Connective Tissue Disease (MCTD) is characterized by the overlap of clinical characteristics of various systemic autoimmune diseases associated anti-RNP antibodies, which induce a specific speckled pattern of anti nuclear antibody (ANA). The prognosis tends to be better than in SLE and systemic sclerosis and reports of flares with pregnancy are very rare (159).
Systemic necrotizing vasculitides
There are few prospective studies of pregnant women with vasculitis. When pregnancy is planned for a period of remission in women with granulomatosis with angiitis (previously called Wegener’s granulomatosis), microscopic poliangiitis (fulfilling the group nominated as ANCA associated vasculitis), and Churg-Strauss syndrome, usually there is no further intercurrence (149). Takayasu’s arteritis may have hypertensive complications during pregnancy despite stable disease (165). The risk of flaring is higher when pregnancy occurs with active or recently diagnosed disease.
Takayasu’s arteritis
This is described as a granulomatous vaculitis that affects preferably large caliber vessels like the aorta, its branches and pulmonary arteries. Takayasu’s affects typically women in fertile age; therefore it is more commonly associated pregnancy than other systemic necrotizing vasculitides. The aortic valve disease and aortic aneurysm resulting from Takayasu’s arteritis may be fatal risk factors in case of pregnancy, therefore, in these cases, pregnancy must be discouraged. These patients have a higher frequency of maternal hypertension and preeclampsia than normal controls, in addition to a higher chance of developing cardiac insufficiency, renal insufficiency, and brain hemorrhage. In spite of those possible complications, in general, pregnancy outcome is favorable in these patients once adequately managed by specialists. Fortunately, the disease clinical activity does not seem to flare with pregnancy (165).
Maternal and gestational outcome seems to be influenced by arterial hypertension. Arterial blood pressure monitoring in women with Takayasu’s arteritis may be harder in the presence of different central and peripheral blood pressures. In some cases, it is recommended invasive monitoring of blood pressure and elective cesarean delivery should be considered in patients with severe retinopathy, impaired umbilical artery flow, associated preeclampsia or inability of maternal and fetal monitoring (165). If disease treatment is necessary, it is normally prednisone 1mg/kg/day combined with azathioprine with subsequent reduction after improvement. Arterial hypertension must be aggressively treated with methyldopa, calcium channel blockers or hydralazine, while ACE inhibitors must be avoided (165).
Intra-uterine growth restriction was present in most studies evaluating pregnant woman with Takayasu’s arteritis and affected up to 50% of pregnancies(166). It was associated with more severe disease or involvement of abdominal aorta and renal artery suggesting that fetal growth restriction was the result of impaired placental blood flow (165). One author described an elevated incidence of preterm birth and pre-eclampsia in this group of patients (167) but this finding was not confirmed by other authors.
Granulomatosis with angiitis
It is a necrotizing vasculitis of small vessels with preference for superior respiratory tract and kidneys and higher incidence in women between 40 and 50 years old. It is normally associated with the presence of anti-neutrophil antibody (ANCA). Reports of pregnancy in patients with granulomatosis with poliangiitis are rare. Thirty eight gestations in patients with were reported: 21 were in remission during pregnancy, 13 were diagnosed during the pregnancy and 4 had active disease when became pregnant. Disease flare seems to occur with a higher frequency in the first trimester or during puerperium and is more severe when the patient becomes pregnant while the disease is still activite (149). As in SLE, differential diagnosis between renal vasculitis and eclampsia is important and the ANCA titer may be helpful (159). A few authores have reported an increased incidence of prematurity and pre-eclampsia (168).
Microscopic polyangiitis
It is an autoimmune systemic necrotizing vasculitis with preference for small vessels. Just as granulomatosis with polyangiits, it includes with the presence of ANCA but with a different antigen: myeloperoxidase (anti-MPO). There are reports of anti-MPO antibodies trespassing the placenta and inducing mild microscopic polyangiitis-like disease (169). Patients with microscopic polyangiitis can present with pulmonary–renal hemorrhage syndromes, clinically similar to what can be seen in antiglomerular basement membrane disease (168). As mentioned with previous entities, the best pregnancy outcomes are when the patient is currently in remission and has a planed pregnancy and adequate follow up.
Churg-Strauss syndrome
In Churg-Strauss syndrome, the systemic involvement of small blood vessels with pulmonary involvement accompanied by hypereosinophilia is remarkable. The involvement of cardiac and respiratory systems is more common in recurrence (149). Asthma is more common, but cardiac involvement may bring irreversible damage (149). Once more, adequate planning is essential. The disease reactivation seem to occur in half the patients that get pregnant while in remission with worsening of asthma, mononeuritis multiplex, and cutaneous lesions. Even though there are reports of prematurity, in most cases, birth occurs at term. The worst obstetric outcomes were from patients that had the onset of the disease during pregnancy. Disease flare is usually treated with prednisone (159).
Behçet’s disease
Behçet’s disease is systemic inflammatory process characterized by genital and oral ulcerations, in addition to ocular, gastroenterological, thrombotic, and neurologic manifestations. There is some reduction of disease activity in most pregnancies, although exacerbation may occur in one-sixth to one-fourth of patients (149,159). Most common recurrences were worsening of ulcerations in mucosa, arthritis and ocular inflammation (159). Anticoagulation during pregnancy and postpartum should be considered in patients with previous thrombosis (157). Some case reports and retrospective series indicate that the obstetric results are encouraging, but monitoring and fast treatment, when warranted, is crucial (159).
Disease modifying anti-rheumatic drugs and its use during pregnancy and breastfeeding
In the 90s, the FDA recognized flaws in its proposed system of safety information about medication throughout pregnancy and breast-feeding, and started to look for ways to improve it. Several public auditions were organized to obtain information from specialists and scientists. There was an overall agreement that the letter category is extremely simplistic and provides an inaccurate vision of the risks. At the same time, it does not facilitate data update with new information achievement, when those become available. The new proposal is to remove letter category and report the information in three sections:
- The first is called “fetal risk summary” and must describe what is known about medication effects on the fetus and, when there is any risk, if this one is grounded in studies taken in animals or in humans. In this proposal it must be informed a conclusion based in available data depending on the quantity and quality.
- Another section called “clinical considerations” must indicate the effects of the use of drugs taken by the mother before knowing about the pregnancy. This section will also have discussion about the risk of disease in the mother or the fetus, information about dosage, and what to do in case of complications.
- The third section called “data” must describe in better detail the available data on humans and animals utilized in the development of the fetal risk summary. This section will also bring information about any database of exposed individuals, which collects and maintains data on already approved drugs’ effects that are prescribed to pregnant women.
These new sections of recommendations about medication use in breast-feeding will inform about the quantity excreted in the breast milk and the potential effects on lactation. Some recently approved drugs will already use the new classification form, while the already established ones will gradually migrate to the new classification.
Aspirin and acetaminophen
Aspirin is used during pregnancy and puerperium in low doses only (80 to 100 mg/day), especially in patients with recurrent fetal loss related to APS, and is not associated with increased risk of antenatal complications or neonatal morbidity (11). Higher doses are associated with premature closure of ductus arteriosus and impaired renal function, especially with third trimester exposure (158). Acetaminophen may be used during the entire gestation and breast-feeding in the lowest dosage possible (149).
Non-steroidal antiinflamatories and COX inhibitors
The lowest dose possible should be used for a short time and it is recommended to be completely discontinued after the 32th week, because of the risks of fetal and maternal hemorrhage in addition to fetal renal disfunction, oligodramnia and premature closure of arterial duct(158). Some of them were considered safe by the America Pediatrics Society to be used during breast-feeding (for example ibuprofen, indomethacin, naproxen) (158). Prescription of acetaminophen should be considered before these medications for pain control. The COX-2 inhibitors, like celecoxib, have small data during pregnancy, may influence renal formation and its use should be avoided during pregnancy (151).
Antimalarials
Antimalarials have been broadly used in rheumatology for many decades. Even though chloroquine and HCQ trespass the placenta, no fetal defects were observed in pregnant women exposed to these substances. Chloroquine is broadly used in malaria treatment during pregnancy. From Johns Hopkins University SLE cohort, Clowse did not demonstrate any associated risk to this medication in pregnancy (169). There are no malformations, ocular involvements or growth retardations described despite extended fetal exposure to HCQ in numerous studies. Chloroquine has smaller data when compared to HCQ, but no long-term sequel was also demonstrated (158). In addition, a randomized double-blinded placebo controlled Brazilian study, did not show any complication related to HCQ (170).
A systematic review that included random and observational clinical studies aimed to examine antimalarials safety in the ocular function of exposed women’s children. The authors used the GRADE established criteria to analyze the papers. Twelve studies with a total of 588 born children from mothers treated with chloroquine or HCQ during gestation fulfilled inclusion’s criteria. Five studies with a total of 251 exposed fetuses did not report any ocular abnormality (160). Therefore, the current evidence suggests that there is no fetal ocular toxicity with antimalarials. They are secreted in breast-milk, but there was no report of adverse effects in breast-fed children whose mothers used HCQ (158).
Corticosteroids
The morbidities related to steroid use are those that might occur with non-pregnant women, including bone avascular necrosis, osteopenia, immunosuppression, hyperglycemia, hypertension, cataract, etc. It may also precipitate pregnancy complications, e.g., gestational diabetes, arterial hypertension and premature rupture of membranes, so the lowest effective dose must be used (ideally not more than 15 mg/day) (149). Short acting agents (prednisone or prednisolone) for disease treatment should be used, which are metabolized by placenta’s 11-β-hydroxysteroid and reduce fetal exposure to approximately 10% of maternal dosage (149). Calcium supplementation is recommended (up to 1200mg of calcium carbonate) and vitamin D (up to 400U/day). Patients using chronic steroids must receive stress dose hydrocortisone supplementation (intravenous hydrocortisone 100 mg every 8 h) when emergency surgery is necessary, c-section or prolonged labor (171). Long-term studies have not shown an increased risk of teratogenicity, although a few reports associated first trimester exposure with an increased relative risk of oral clefts with low absolute risk (158). Corticosteroids do not enter breast milk in large quantities and there is no contraindication to breast-feeding in women who are on corticosteroid therapy (171). Women that are breast-feeding and using higher doses should wait 4 hours after taking the pill to breast-feed, reducing the drug concentration in the breast-milk (158).
Azathioprine
This immunosuppressant and steroid sparing agent is not associated with teratogenicity in humans as the fetal liver is not capable of metabolizing azathioprine into its active form (158) although teratogenicity has been reported in animal studies (151). Azathioprine is generally the immunosuppressive of choice in most centers specialized in high risk pregnancy because of the safety profile and its steroid sparing property. It should be prescribed (up to 200mg/day) when the disease activity is hard to control and/or the patient is already taking 20mg or more of prednisone for more than one month. The treatment with azathioprine is compatible to breast-feeding with no risks for the child (158).
Sulfasalazine
There is no reason to believe that the safety studied with this drug in inflammatory bowel disease patients is different from RA or other rheumatic diseases. The drug should be continued (up to 2g/day) in patients planning to get pregnant and, in fact, is the first line for patients with inflammatory bowel disease. Studies with a large number of patients did not show any teratogenicity (171). Folate supplementation is necessary preconception and during pregnancy because sulfasalazine is a potent inhibitor of the reduced folate carrier. Although there is some theoretical concern that sulfasalazine may displace bilirubin and cause neonatal jaundice, there have been no reports of kernicterus in infants exposed to sulfasalazine (158)
Cyclophosphamide
This immunosuppressive agent is contraindicated during pregnancy and patients at childbearing age should be counseled regarding its risks. In most academic centers it is routine to screen with chorionic gonadotropin before every pulse therapy with the agent and if pregnancy is wanted it should be discontinued for at least three months (171). In life threatening situations it has been used in second or third trimesters in the past but nowadays safer agents such as rituximab and mycophenolate mofetil are available.
Methotrexate
MTX is an antimetabolite that interferes in purine synthesis. It induces abortion and teratogenesis and, therefore, must not be used in pregnant women. Once again, childbearing women taking the drug should be counseled regarding its risks and in case the patient decides to get pregnant, MTX should be discontinued three months prior and folic acid supplementation should be started (158). If the patient becomes pregnant while on the drug, the recommendation is to use double doses of folic acid (10mg/day) during the whole pregnancy period. MTX is contraindicated during breastfeeding because it is excreted in breast milk and can accumulate in the infant’s tissues (151).
Leflunomide
This medication is classified as category X by FDA because animal reproduction studies indicate that leflunomide is both embryotoxic and teratogenic, mainly leading to craniofacial, skeletal, and cardiovascular malformations (151). The experience reported by OTIS included 64 pregnancies exposed to leflunomide, compared to 108 non-exposed patients and failed to show any difference with regards to microcephaly or other embryopathies. It is important to notice that 95% of the study group underwent leflunomide washout with cholestyramine (158). Leflunomide may induce fetal effects similar to methotrexate, but with the possibility of being quickly reversed as soon as pregnancy is diagnosed, with administration of cholestyramine (8g PO, 3 times a day for 11 days, without risks for the pregnancy) until there is no level of serum leflunomide detectable. It is secreted in breast milk and administration is contraindicated during breastfeeding (151).
Mycophenolate mofetil
This agent has been mainly used for the treatment of systemic lupus nephritis as its safety profile is better than cyclophosphamide. It is also used after transplant surgery to avoid graft rejection. Human studies have shown teratogenicity and a specific syndrome characterized by craniofacial malformations of ear, oral cavity and ocular abnormalities. Limb, cardiovascular, renal and nervous system malformations were reported as well. It is currently category D from FDA and is contraindicated in breastfeeding (172)
Biologicals
These are monoclonal antibodies or fusion receptor blocking proteins that can dramatically interfere with the immune response. Targets are cytokines such as TNF, IL-1, IL-6 and signaling molecules such as CTLA-4, BLyS or CD20. These agents are relatively new and were introduced into the market in the last two decades after many years of study. This is a very active research field and many new drugs are under development and currently being studied. Available data is from series of cases and registry records. The risk of using certain biological agents in pregnancy is not from proven teratogenicity but is due to unknown long-term safety for the fetus. There are no available data with regards to lactation and the use of biologicals, therefore, their use should be avoided during breastfeeding (158).
Anti-TNF
Etanercept, infliximab, adalimumab, golimumab and certolizumab are considered risk B by the FDA. Although the experience and knowledge with the use of such medications in pregnant women are increasing, there is no definite safety answer for its use. No adverse effects on fetal development have been described in animal studies and sporadic adverse events in humans were reported, but they had insufficient power to determine toxicity or safety (149). In RA patients there seems to be no risk in the preconception period and in the first trimester, as the drug does not cross the placenta in this phase (151). Considering the lack of data, most authors recommend discontinuation of therapy as soon as pregnancy is diagnosed (149,156).
Rituximab, abatacept, tocilizumab
Rituximab is a monoclonal antibody against CD20, expressed in B lymphocytes. It does cross the placenta and due to the lack of data about side effects with its before conception and during the first trimester, it is recommended that it be discontinued one year before pregnancy. Exposure to rituximab during the second and third trimester seems to cause depletion of fetal B cells (158). The use of rituximab during the pregnancy can be considered in RA with difficult control, SLE nephritis, ANCA associated vasculitis, and serious forms of APS, such as thrombocytopenia, hemolytic anemia and renal microangiopathy.
Tocilizumab is an antibody directed against IL-6 receptor. There is no adequate data about pregnant patients and use of tocilizumab. Animal studies show increased rate of abortion and fetal mortality but the dose used was 100 times higher than used in humans. It should be discontinued three to six months before pregnancy (158).
Abatacept is a fusion protein anti CTLA4 that works by blocking important activation signaling for the T lymphocyte. It does cross the palcenta but studies in animals did not show any sign of teratogenicity. Data in humans is limited and it is recommended to discontinue the drug 10 weeks prior to pregnancy.
None of the three described medications should be used during breastfeeding due to lack of safety data. They are rated category C by the FDA.
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- Introduction
- Antiphospholipid syndrome
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Undifferentiated connective tissue disease
- Sjögren’s syndrome
- Systemic sclerosis
- Polymyositis and dermatomyositis
- Mixed connective tissue disease
- Systemic necrotizing vasculitides
- Takayasu’s arteritis
- Granulomatosis with angiitis
- Microscopic polyangiitis
- Churg-Strauss syndrome
- Behçet’s disease
- Disease modifying anti-rheumatic drugs and its use during pregnancy and breastfeeding
- References
- Systemic autoimmune diseases and pregnancy - AutoimmunitySystemic autoimmune diseases and pregnancy - Autoimmunity
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