Contraception and Pregnancy in Patients with Rheumatic Disease

9. Vasculitis and Pregnancy

Lindsay Lally  and Robert F. Spiera 

(1)

Division of Rheumatology, Hospital for Special Surgery, 535 E. 70th Street, New York, NY 10021, USA

Lindsay Lally (Corresponding author)

Email: lallyl@hss.edu

Robert F. Spiera

Email: spierar@hss.edu

Introduction

The primary systemic vasculitides are a heterogeneous group of disorders that are generally classified according to the size of the blood vessels involved and the organ systems affected. Several forms of primary systemic vasculitis may affect women of childbearing age. Data on pregnancy outcomes, neonatal outcomes, and effect of pregnancy on vasculitis disease activity remain limited and are predominantly reported in small case reports and series. A recent survey of a large cohort of women with several types of systemic vasculitis reported that women who conceived following a diagnosis of vasculitis had higher rates of pregnancy loss and preterm delivery compared to those who conceived prior to vasculitis diagnosis; however, vasculitis activity reportedly increased during pregnancy in fewer than 20 % of cases [1]. Vasculitis activity, end-organ damage from previous disease activity, and effects of immunosuppressive therapy all must be taken into consideration when approaching pregnancy in a woman with a systemic vasculitis. This chapter will explore the relationship between pregnancy and several primary systemic vasculitides, affecting large, medium, and small blood vessels.

Irrespective of the form of systemic vasculitis encountered, some general principles regarding pregnancy and vasculitis can be applied. As many of the systemic vasculitides are characterized by relapsing disease course, pregnancy should ideally be attempted when the disease is in remission. Maternal and neonatal outcomes are better in all forms of vasculitis when the mother enters pregnancy in remission. Similarly, because most of the vasculitides can result in accrual of permanent damage such as hypertension and renal insufficiency, thorough assessment of both vasculitis activity and damage should be performed prior to pregnancy and monitored meticulously throughout the peri-partum period. Lastly, the therapeutic armamentarium relied upon to treat many of the systemic vasculitides includes immunosuppressive agents, such as cyclophosphamide and methotrexate, that can result in reduced fertility and/or direct fetal toxicity. The teratogenic potential of these medications should be discussed with patients prior to initiation and, when possible, discontinued several months before contemplation of pregnancy.

Vasculitis can occur in the context of many autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). In these cases, the vasculitis is considered secondary. As such, treatment is generally aimed at the underlying disease process, though the concurrence of vasculitis may prompt more aggressive therapy. Vasculitis in RA typically occurs late in the disease course in patients with rheumatoid nodules and erosive joint disease. Rheumatoid vasculitis can affect medium and small blood vessels with involvement of skin, peripheral nervous system (mononeuritis or symmetric polyneuropathy), eye and heart being most common [2].

Vasculitis occurs in approximately 10–20 % of SLE patients. Immune-complex-mediated small vessel cutaneous vasculitis, including urticarial vasculitis, accounts for over 80 % of the vasculitic presentations in SLE [3]. Though less common, SLE patients can develop medium-vessel vasculitis, typically affecting peripheral nerves or visceral organs like the gastrointestinal tract.

Cutaneous vasculitis occurs in approximately 10 % of SS patients and is associated with extraglandular manifestations of disease, cryoglobulinemia, and poor prognosis [4]. A broad range of neuropathies are associated with SS ranging from small fiber sensory polyneuropathy, to mixed sensory-motor radiculoneuropathy to mononeuritis multiplex. Vasculitic involvement of the nervous system is implicated in several of these neuropathic manifestations [5]. Specifics regarding presentation, treatment, and relationship to pregnancy of these connective tissue diseases will be discussed elsewhere in the text in the chapters addressing those specific diseases.

Large Vessel Vasculitis

Takayasu’s Arteritis

Takayasu arteritis (TAK) is a granulomatous large vessel vasculitis predominantly affecting the aorta and its branches. TAK is generally a disease of young women, with a female to male ratio of 8.5–1 and the vast majority of cases presenting between 10 and 30 years of age [6]. While most prevalent in Japan, India, and Mexico, TAK can occur worldwide in a variety of ethnic populations [7].

The large vessel inflammation in TAK can result in aneurysm formation, widespread stenosis, and end-organ ischemia. Constitutional symptoms such as fever, night sweats, weight loss, and myalgia are common at presentation. As the disease progresses, vascular manifestations such as claudication, discordant blood pressures in limbs and absent pulses become more prominent. Hypertension, arterial bruits, and decreased upper extremity pulses are frequent physical exam findings. Laboratory abnormalities reflect the pro-inflammatory state with nonspecific elevations in acute phase reactants like the erythrocyte sedimentation rate and C reactive protein, anemia, and thrombocytosis. There is no specific autoantibody associated with TAK. While TAK is a clinical diagnosis, angiographic demonstration of abnormal vasculature whether by conventional arteriography or noninvasive cross-sectional imaging (CT, MRI, or PET scan) supports the diagnosis.

As TAK is most prevalent in women of reproductive age, there are many published case reports and retrospective reviews of pregnancy in TAK patients. Generally, maternal and neonatal outcomes were more favorable in patients with fewer damaged vessels and less severe disease prior to becoming pregnant [8]. Aortic aneurysms and severe valvular disease are considered contraindications for pregnancy. A systematic review of pregnancy and vasculitis published in 2012 identified 214 TAK pregnancies in the literature [9]. Preeclampsia complicated 45 % of reported TAK pregnancies and preterm delivery occurred in 16 % of cases. Low-birth weight and IUGR were noted in 20 % of newborns born to mothers with TAK. Thirty cases of fetal loss and one neonatal death in a premature infant have been reported. TAK patients with abdominal aortic and renal artery involvement are at particular risk for hypertensive-related maternal and fetal complications.

Pregnancy does not commonly alter disease activity in TAK. Disease flare or relapse during pregnancy is rare, occurring in <5 % of pregnancies. Active disease during pregnancy can usually be managed with corticosteroids. There are case reports of aortic dissection, aneurysm formation, progressive renal insufficiency, congestive heart failure, cerebral hemorrhage, and stroke occurring in pregnant patients with TAK; however, these vascular complications are usually related to sequelae of previous disease coupled with the hemodynamic changes that accompany pregnancy and not to active inflammatory disease [1011].

Worsening of preexistent hypertension during pregnancy accounts for the majority of pregnancy morbidity experienced by TAK patients. Thus, aggressive blood pressure control is necessary in the management of TAK patients during pregnancy and delivery. An anti-hypertensive regimen without the potential for fetal toxicity should be employed and may include calcium channel blockers, methyldopa or hydralazine. There are case reports of women who had renal artery angioplasty prior to conception and subsequently had uncomplicated pregnancy, causing the authors to speculate that pre-pregnancy renal artery angioplasty may play a protective role against hypertension-related pregnancy complications in TAK [12].

Stenosis and occlusion in the arteries of the upper extremities may make noninvasive blood pressure measurement from the arms difficult and necessitate measurement in an uninvolved lower extremity with an adequate sized cuff. Invasive intra-arterial blood pressure measurement may be used during delivery when scrupulous hemodynamic monitoring is critical [13]. Use of regional anesthesia, either epidural or spinal, is generally recommended during delivery to avoid fluctuations in blood pressure that may occur during active labor [1415]. Hyper- and hypo-tension should both be avoided. Cesarean section was performed in 36 % of reported TAK pregnancies, mostly for obstetric complications [5]. A case series of 33 TAK pregnancies from Japan suggest that, in addition to obstetric indications, cesarean section should be considered in patients with high systolic blood pressure at time of labor, severe disease, or aortic insufficiency or aneurysm [16]. Blood pressure must continue to be closely monitored in the days following delivery as post-partum hemodynamic changes may result in further vascular damage (e.g., aortic dissection) or regional hypoperfusion (e.g., cerebral ischemia). With careful monitoring and close collaboration between medical, obstetrical, and anesthesia providers successful maternal and fetal outcomes are possible in TAK.

Giant Cell Arteritis

Giant cell arteritis (GCA) is a systemic large vessel vasculitis affecting adults over 50 years of age. Given the population of affected patients, there are no reports of pregnancy in women with GCA. One study suggested a possible protective effect of multiparity on subsequent development of GCA. The mechanism of this proposed relationship is unknown though the authors conjecture there might be a protective effect of the high estrogen state on the vasculature [17].

Medium-Vessel Vasculitis

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to medium-sized arteries. Cutaneous, nerve, gastrointestinal, and renal involvement are common in PAN. Presentation varies depending on organ system involved; many patients present with constitutional symptoms, rash, arthralgia, and myalgia. Peripheral nerve involvement usually manifests as a mononeuritis multiplex with sudden foot or wrist drop. Symptoms of mesenteric ischemia herald gastrointestinal involvement. Hypertension and renal insufficiency accompany vascular renal involvement in PAN. Patients typically have elevated acute phase reactants during active disease; there are no specific autoantibodies associated with PAN. There is a known association between active hepatitis B virus (HBV) and PAN. While effective vaccine programs in the developed world have dramatically reduced the rates of acute HBV, large cohort studies have found an association between HBV and PAN in one-third of cases, thus all patients with PAN should be tested for HBV [18]. A focal, segmental necrotizing vasculitis of medium-sized arteries is the characteristic pathologic lesion of PAN on biopsy and can confirm the clinical diagnosis. Angiographic demonstration of microaneurysms can be an acceptable surrogate of histopathologic confirmation when tissue cannot be readily obtained [19]. In 50 % of cases, PAN can be cured with corticosteroids without additional immunosuppressive therapy, in addition to anti-viral therapy in patients with HBV-associated disease [20].

There are few case reports of pregnancy in patients with PAN as there is a slight male predominance and peak incidence is in the sixth decade of life. In general, PAN patients in remission at the time of conception experienced uncomplicated pregnancies [2122]. Three of 19 reported pregnant PAN patients developed premature membrane rupture resulting in preterm delivery without any negative long-term consequences on the mother or the infant [5]. In women with established disease prior to pregnancy, vasculitis did not flare during pregnancy. Conversely, women diagnosed with new-onset PAN during pregnancy had catastrophic outcomes [2324]. High rates of maternal mortality have been reported in de novo PAN during pregnancy with uncontrolled hypertension, renal failure, and aneurysm rupture resulting in maternal death. Nagey et al. suggested therapeutic abortion for new-onset PAN during early pregnancy given the high risk of maternal mortality.

Small Vessel Vasculitis

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) comprise the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), a group of small-vessel vasculitides characterized by pauci-immune necrotizing inflammation. AAV affects multiple organ systems with glomerulonephritis and pulmonary involvement being frequent manifestations. Women and men are affected equally. As the nomenclature suggests, these vasculitides are associated with serologically detectable ANCA. ANCAs directed against proteinase-3 (PR3) or myeloperoxidase (MPO) are associated with GPA and MPA, respectively, in the vast majority of patients; only about 30–40 % of patients with EGPA have detectable ANCA.

Before the approval of rituximab in 2010 for induction therapy in severe AAV, the cornerstone of therapy was cyclophosphamide, which is well known to cause premature ovarian failure and infertility in women of childbearing age [25]. Not surprisingly, women with GPA treated with daily oral cyclophosphamide for 6 months or less had significant loss of ovarian reserve as measured by anti-Müllerian hormone level [26]. Increased overall survival rates in AAV and the use of rituximab as a therapeutic alternative to cyclophosphamide likely account for increasing reports of pregnancy in women with a history of AAV [1].

GPA (formerly known as Wegener’s Granulomatosis) commonly involves the upper and lower respiratory tracts and the kidneys. Relapsing disease occurs in half of the patients with GPA following remission induction [2728]. The small body of literature on pregnancy in GPA includes roughly equal numbers of patients with newly diagnosed GPA during pregnancy, GPA flare during pregnancy, and women whose GPA remained in remission throughout pregnancy [29]. Both maternal and neonatal outcomes are linked to disease activity during gestation with favorable outcomes generally achieved when vasculitis remains in remission. In addition to the effect of previous cyclophosphamide on fertility, concerns regarding pregnancy in GPA involve end-organ damage from vasculitis damage such as renal insufficiency, hypertension, and subglottic stenosis.

In a recent single-center retrospective study, Tuin et al. [30] report 22 pregnancies in a cohort of 14 women with AAV (13 with GPA). All women were in remission at time of conception and all but one remained in remission throughout the pregnancy. All pregnancies resulted in live births; two pregnancies were complicated by preeclampsia and two were associated with preterm delivery. Differentiating preeclampsia from renal GPA flare during pregnancy can be difficult as hypertension, proteinuria, and elevated inflammatory markers are characteristic of both entities. ANCA titers do not reliably correlate with disease activity in the gravid or non-gravid state. Active urine sediment may suggest glomerulonephritis. Other series report higher rates of premature delivery in GPA (35 %), particularly in those with active vasculitis during gestation [5]. Women with active disease at conception historically have poor outcome with pregnancy resulting in intrauterine fetal demise, therapeutic abortion, or maternal death in one case [31].

The effect of pregnancy on vasculitis activity in GPA is variable. In women entering pregnancy in remission, a flare rate during pregnancy of 20–25 % has been reported [2627]. The rate of flare in patients entering pregnancy with active disease approached 100 %. Given high rates of relapse in the overall GPA population, it is unknown whether pregnancy itself increases risk of relapse. There are a dozen reported cases of de novo GPA diagnosed during pregnancy; a new GPA diagnosis occurred most frequently during the second or third trimester of pregnancy [32]. The severity of GPA manifestations and the gestational age of the fetus dictate therapy during pregnancy. Many GPA flares are characterized by exacerbation of otolargynogolic disease, which can typically be managed with low to moderate doses of corticosteroids. Worsening of subglottic stenosis, which may present with progressive dyspnea or stridor, can occur during pregnancy. It is advisable that in women with known or suspected subglottic disease, the airway be assessed by an otolaryngologist with expertise in GPA prior to conception and pregnancy planning; if intervention is necessary, it is of course optimal to do so prior to pregnancy. The cicatricial nature of these lesions makes them minimally responsive to immunosuppressive therapy and surgical intervention is often required [33]. Endoscopic intratracheal dilation with glucocorticoid injection has been successfully performed in pregnant patients with airway compromise. During delivery, the anesthesiologist should know the extent and diameter of a patient’s subglottic disease so appropriate equipment for endotracheal intubation is available should that be required to maintain the airway.

Severe disease, defined as organ or life-threatening disease, in the first trimester resulted in medical termination in all cases. Later in pregnancy, severe disease has been treated successfully with high-dose corticosteroids and cyclophosphamide, which may be safe in the third trimester, or intravenous immunoglobulin (IVIg) [34]. Azathioprine in combination with corticosteroids is safe in pregnancy and has also been utilized for active disease. While there is limited transmission of rituximab across the placenta, a case report of woman with GPA who received rituximab during their first trimester reported no observed adverse effect on the pregnancy or fetal development [35].

Compared to GPA, MPA is generally characterized by fewer relapses and less frequent involvement of the upper respiratory tract. There are very few pregnancies reported in MPA, which may be explained by now outdated classification criteria which categorized many of these patients as having PAN. There are three reports of de novo MPA diagnosed in late pregnancy all presenting with pulmonary–renal syndrome [3638]. Conventional therapy with cyclophosphamide and high-dose corticosteroids plus plasma exchange in one case was used with variable results; two women delivered preterm, low-birth weight infants while one woman suffered spontaneous abortion and died from sepsis. While most cases of AAV are idiopathic, some drugs can induce ANCAs and a secondary vasculitis. Propylthiouracil, which is commonly used for management of hyperthyroidism in pregnant patients due to favorable safety profile, is known to induce MPO autoantibodies [3940]. Cessation of the drug has resulted in resolution of symptoms and good maternal and neonatal outcomes were reported. Thus, in pregnant women with a suspected new diagnosis of MPA during pregnancy, careful history including medication history is important.

There is a reported case of a woman with quiescent MPA and persistently positive MPO autoantibody who relapsed at 33 weeks gestation, underwent emergent cesarean section and delivered a healthy infant [41]. Within 24 h of delivery, the infant developed pulmonary-renal syndrome and demonstrated high-titer MPO antibodies from presumed placental transfer of maternal antibody. The infant was successfully treated with corticosteroids and supportive care. There is a subsequent report of a woman with a history of MPA and persistent MPO positivity who maintained remission throughout pregnancy and delivered a healthy newborn with no evidence of vasculitis despite detectable MPO in the neonate [42].

Eosinophilic Granulomatosis with Polyangiitis

EGPA (formerly known as Churg–Strauss Syndrome) is a multi-system necrotizing vasculitis with granulomatosus inflammation and peripheral and tissue eosinophilia. Allergic rhinitis, asthma, skin lesions, and peripheral neuropathy are common manifestations of EGPA. Cardiac, gastrointestinal, and central nervous system involvement portend poor prognosis [43]. Asthma is the fundamental feature of EGPA and development of asthma and atopy often precede frank vasculitic manifestations by several years.

There are approximately 25 reports in the literature of pregnancy in women with EGPA [4446]. The vast majority of EGPA pregnancies resulted in uncomplicated pregnancy with good maternal and neonatal outcome. The majority of cases reported are in women with EGPA prior to pregnancy and inactive disease at the time of conception; however, in about 7 % of cases, EGPA was diagnosed during pregnancy. Premature delivery occurred in about 25 % of pregnancies, including two twin gestations [4748]. Low-birth weight was reported in fewer than 10 % of neonates. Few cases of fetal loss have been reported [42].

EGPA flare during pregnancy seems to occur in less than one quarter of women in remission at the time of conception. Worsening of asthma is a common manifestation of EGPA during pregnancy and can usually be managed with corticosteroids. Discontinuation of inhaled steroids for asthma during pregnancy has been suggested as a trigger for diagnosis of de novo EGPA [49]. More severe disease manifestations such as mononeuritis multiplex and cardiac involvement have been reported during pregnancy. Women with severe disease have been treated with cyclophosphamide, IVIg, and azathioprine [4850]. As with EGPA not related to pregnancy, cardiac involvement is the greatest cause of mortality in these patients. There are two reports of maternal death in the peri-partum period both related to cardiac involvement as well as one report of a woman undergoing successful heart transplant after development of severe post-partum cardiomyopathy with histopathologic confirmation of EGPA [5152].

Cryoglobulinemic Vasculitis

Cryoglobulins are monoclonal or polyclonal immunoglobulins that precipitate at temperatures lower than 37 °C and dissolve with rewarming. Cryoglobulinemia refers to the vasculitic syndrome resulting from deposition of cryoglobulin-containing immune-complexes in skin, joints, kidney, or other organs throughout the body. Cryoglobulinemia is classified according to the composition of the immunoglobulins with type I referring to monoclonal IgG cryoglobulins and type II and III (mixed cryoglobulinemia) referring to presence of polyclonal IgG and IgM. Mixed cryoglobulinemia is associated with hepatitis C virus (HCV) in 80–90 % of cases [53]. Other causes of mixed cryoglobulinemia are autoimmune diseases such as SS or SLE or viral infection other than HCV.

A triad of palpable purpura, arthralgia and weakness is present in the majority of patients with cryoglobulinemic vasculitis at diagnosis. Renal involvement, a glomerulonephritis, occurs in approximately 20 % of patients. Cryoglobulins can be measured and quantified from the serum of patients; however, these samples must be kept warm to avoid precipitation of cryoglobulins prior to analysis in the lab. These patients often have positive Rheumatoid Factor (RF), as the IgM component of the cryoglobulin is an RF. Hypocomplementemia with low C4 is also common, as complement components are consumed as part of the immune-complexes. Testing for HCV should be done in all patients with suspected mixed cryoglobulinemia.

There are reports of six pregnancies in four women with cryoglobulinemia in the literature. One report of a woman with chronic HCV and cryoglobulinemia in remission at time of pregnancy reported a flare during pregnancy with arthralgia, hypertension, and proteinuria necessitating delivery via cesarean section at 31 weeks; the method by which cryoglobulinemia was differentiated from pregnancy complications like preeclampsia is not discussed [54]. Two other case reports describe women diagnosed with mixed cryoglobulinemia during pregnancy [5556]. While both women presented with palpable purpura and one had evidence of renal involvement, neither had detectable HCV or evidence of systemic autoimmune disease. Both women delivered full-term healthy neonates with no other reported pregnancy-related complications. Plasma exchange and corticosteroids were used to manage disease during pregnancy. Sibilia et al. [57] describe a woman with type I cryoglobulinemia in remission at the time of conception who remained in remission throughout pregnancy and delivered twins vaginally at 39 weeks. One twin subsequently developed a macular rash upon removal from the incubator with serologic demonstration of positive cryoglobulins which resolved with rewarming, suggesting maternal transplacental transfer of cryoglobulins [58].

Variable Vessel Vasculitis

Behçet’s Disease

Behçet’s disease (BD) is a systemic vasculitis that can involve small, medium, or large vessels in the arterial or venous system. Recurrent oral and genital ulcers are a hallmark of BD. Other manifestations can include skin lesions, arthritis, uveitis, gastrointestinal ulceration, and thrombosis. BD is most prevalent in persons of Mediterranean or east Asian decent. Usually diagnosed in young adults aged 20–40, Behçet’s has equal prevalence in men and women in endemic areas, but women are affected more commonly in reports from the USA and northern Europe [59]. BD is a clinical diagnosis that requires presence of recurrent oral ulcers in combination with other systemic manifestations including skin lesions, pathergy, genital ulcers, or eye disease. There is an association of BD with human leukocyte antigen (HLA) B51; however, there are no serologic tests specific for the diagnosis.

As BD often presents in women of childbearing age, there are multiple series reporting pregnancies in women with BD. Generally few maternal and fetal complications are reported with rates of preeclampsia, premature delivery, growth restriction, and fetal loss paralleling that of the general population [60]. One case–control study matching 135 pregnancies from 31 BD patients with age- and parity-matched healthy controls found complications, including hypertension, gestational diabetes, and premature delivery, in 26 % of BD pregnancies compared to 2 % of control pregnancies [61]. They also reported significantly higher rates of miscarriage (20 vs 6 %) and cesarean section (15 vs 5 %) in BD compared to controls. Similar results have not been echoed in other sizable cohorts of BD pregnancies.

Several studies suggest a protective effect of pregnancy on BD with improved or stable disease in 70 % of patients, even amongst those with active disease entering pregnancy [6061]. In the approximately 20 % of patients who flared during pregnancy, genital ulcers, rash, arthritis, and uveitis were the commonest manifestations. There is a case report of colonic perforation from active BD of the gastrointestinal tract during pregnancy [62]. Active disease during pregnancy can usually be managed with corticosteroids. Colchicine, which can be helpful for the mucocutaneous manifestations of BD, was recently shown to be safe and non-teratogenic during pregnancy in a cohort of women that included those with BD [63]. Azathioprine, which is often the immunosuppressive agent of choice for ocular BD, can also be safely utilized during pregnancy. Infliximab, a tumor necrosis factor (anti-TNF) alpha inhibitor, has been used for refractory uveitis during pregnancy with no reported adverse maternal or neonatal events [64]. Though there are limited observational data, use of anti-TNF therapy appears to be safe for both mother and fetus during pregnancy [65].

BD and pregnancy both increase propensity for thrombosis; as such, there are several reports of thrombotic events during pregnancy and the post-partum period [66]. In the setting of thromboembolism, anticoagulation with heparin is usually administered in combination with immunosuppressive therapy. Some experts advocate for prophylactic anticoagulation in the peri-partum period for those patients with history of previous thrombosis given the risk for massive and potentially fatal thromboembolism during this critical period. Others have suggested IVC filter placement, as this may also mitigate risk of fatal thromboemboli [6667].

Rare cases of neonatal BD, born to mothers with active BD during pregnancy, have been described [6869]. All of the neonates had transient oral ulcers and pustular skin lesions noted shortly after birth which resolved with supportive care. There are also several reported cases of gastrointestinal BD in neonates, including one from a mother who had no history of BD [7071]. Corticosteroids have been used to successfully treat infants with severe colonic ulcerations attributable to BD. Examination of placental pathology from two women with BD showed necrotizing villitis and decidual vasculitis with a neutrophil predominant infiltration, which is similar to histology of BD in other organ systems [72]. The authors speculate that placental involvement may account for both intrauterine transmission of BD and high rates of fetal loss described in some cohorts.

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