Pregnancy and vasculitis: A systematic review of the literature

Autoimmunity Reviews 11 (2012) A447–A459

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Review

Pregnancy and vasculitis: A systematic review of the literature Mariele Gatto, Luca Iaccarino, Mariagrazia Canova, Margherita Zen, Linda Nalotto, Roberta Ramonda, Leonardo Punzi, Andrea Doria ⁎ Division of Rheumatology, Department of Medicine, University of Padova, Padova, Italy

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Available online 3 December 2011 Keywords: Vasculitis Pregnancy Systematic review Guidelines Treatment

a b s t r a c t Primary systemic vasculitis are uncommon diseases that may affect young women in their childbearing age. To date, patients affected with primary systemic vasculitis are often diagnosed and treated earlier than in the past, due to improvement in diagnostic skills and a larger availability of effective drugs. The progressive achievement of a longer life expectancy and a better quality of life have progressively led to an increased number of pregnancies observed during the course of such diseases. Here, we review 567 pregnancies among patients with primary systemic vasculitis, in order to define the relationship between pregnancy and these conditions and to suggest guidelines for their management. However, data on pregnancy outcomes are limited and knowledge about their gestational risk is mostly provided by single case reports or at best by retrospective studies which may result in intrinsic observational bias; unfortunately, long term prospective studies are still lacking. Analysis of the data highlighted a reciprocal influence between disease course and gestational outcome, although no definite effects can be outlined. Indeed, either improvement or worsening of the different vasculitis can occur, probably due to diverse genetic, clinical and immunological background of the patients. Since disease course may vary over time, careful management of systemic vasculitis during gestation is required. Furthermore, organ failure or damage must be carefully considered, since it can lead to adverse obstetrical and fetal outcomes. © 2011 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . Search strategy. . . . . . . . . . . . . . . . . . . . . . . Search results . . . . . . . . . . . . . . . . . . . . . . . Large vessels vasculitis . . . . . . . . . . . . . . . . . . . 4.1. Takayasu's arteritis . . . . . . . . . . . . . . . . . 4.1.1. Effects of TA on pregnancy. . . . . . . . . . 4.1.2. Effects of pregnancy on TA. . . . . . . . . . 4.1.3. Management of TA during pregnancy . . . . Medium vessels vasculitis. . . . . . . . . . . . . . . . . . 5.1. Polyarteritis nodosa . . . . . . . . . . . . . . . . . 5.1.1. Effects of disease on pregnancy and vice versa 5.1.2. Management of PAN during pregnancy . . . . Small vessels vasculitis . . . . . . . . . . . . . . . . . . . 6.1. Wegener's granulomatosis . . . . . . . . . . . . . . 6.1.1. Effects of WG on pregnancy . . . . . . . . . 6.1.2. Effects of pregnancy on WG . . . . . . . . . 6.1.3. Management of WG during pregnancy . . . . 6.2. Churg–Strauss syndrome . . . . . . . . . . . . . . . 6.2.1. Effects of CSS on pregnancy . . . . . . . . . 6.2.2. Effects of pregnancy on CSS . . . . . . . . . 6.2.3. Management of CSS in pregnancy . . . . . .

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⁎ Corresponding author at: Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: + 39 049 8212190; fax: + 39 049 8212191. E-mail address: [email protected] (A. Doria). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.11.019

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6.3.

Microscopic polyangiitis . . . . . . . . . . . . . . . . . . . . 6.3.1. Effects of MPA on pregnancy and vice versa . . . . . . . 6.4. Henoch-Schönlein's Purpura . . . . . . . . . . . . . . . . . . 6.4.1. Effects of HSP on pregnancy . . . . . . . . . . . . . . 6.4.2. Effects of pregnancy on HSP . . . . . . . . . . . . . . 6.4.3. Management of HSP in pregnancy . . . . . . . . . . . 7. Any vessels vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Behçet's disease . . . . . . . . . . . . . . . . . . . . . . . . 7.1.1. Effects of BD on pregnancy . . . . . . . . . . . . . . . 7.1.2. Effects of pregnancy on BD . . . . . . . . . . . . . . . 7.1.3. Management of BD during pregnancy . . . . . . . . . . 8. Other vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Cryoglobulinemia . . . . . . . . . . . . . . . . . . . . . . . 8.1.1. Effects of cryoglobulinemia on pregnancy and vice versa . 8.1.2. Management of cryoglobulinemia during pregnancy . . . 8.2. Cogan's syndrome (CS) . . . . . . . . . . . . . . . . . . . . . 8.2.1. Effects of CS on pregnancy and vice versa . . . . . . . . 8.2.2. Management of CS during pregnancy . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Primary systemic vasculitis are uncommon diseases characterized by a great variety of symptoms, ranging from mild to life threatening manifestations and encompassing different natural histories, from self-limiting to relapsing or chronic active disease. Over the past years, the number of pregnancies among affected women greatly increased, due to improvement in survival as well as in quality of life of these patients. Frequency of pregnancy in different vasculitis depends on epidemiological factors: pregnancy is more frequent in vasculitis that have onset at younger age and affect the female gender, such as Takayasu's arteritis and Behçet disease. During pregnancy, immune and endocrine systems undergo profound transformations concerning both hormonal assessment and cytokine microenvironment: cortisol, progesterone, estradiol and testosterone increase physiologically during gestation and seem to favor Th-2 cytokine polarization at the feto-maternal interface as well as at the systemic level [1–3]. Such immunological changes may suggest a natural improvement of primarily Th1-mediated vasculitis (mainly Takayasu arteritis and Behçet disease which are the most prevalent vasculitis during pregnancy) and a worsening of Th2-driven ones, such as Wegener granulomatosis or Churg–Strauss syndrome. The course of the different vasculitis in pregnancy appears to be affected by several factors and whether or not such changes are able to modify maternal and fetal outcomes in each specific vasculitis is still uncertain. These conditions should be managed very carefully during pregnancy, since both disease complications and pharmacological treatment may have negative effects on maternal and fetal health. Furthermore, treatments mainly based on the use of cytotoxic and immunosuppressive drugs may have a detrimental effect on the fetus. To date, variations in disease activity of the different vasculitis during pregnancy and their relationship with the modification of immunoendocrine environment have not been evaluated. Most of the studies have mainly investigated the effects of disease complications on maternal and fetal outcomes, thereby including organ failure or irreversible vascular lesions. This systematic review is focused on the relationship between pregnancy and systemic primary vasculitis. Guidelines for the management of these conditions during pregnancy are also suggested. 2. Search strategy We performed a systematic review of the literature to find out all the cases of pregnancy in women affected with different vasculitis reported from 1960 to 2011, using the PubMed, Cochrane and Embase

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databases. Moreover, we hand-searched for the relevant articles referenced in other publications and not available on the web database. Every report in English and in English-written abstracts concerning pregnant women affected with the following vasculitis were included in the analysis: Takayasu's arteritis, polyarteritis nodosa, Churg–Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis, Behçet's disease, Henoch-Schönlein's purpura, Cogan's syndrome and cryoglobulinemia. Randomized controlled trials, controlled studies, prospective studies, retrospective studies, case series and case reports were considered in the analysis. Case series and case reports were distinguished according to the number of pregnancies described: we considered as case reports papers which included from one to 4 pregnancies, and case series papers which included more than 4 pregnancies. Papers had to be well written and in case reports, medical history, physical examination, and therapy had to be accurately described. Reports concerning giant cell arteritis and vasculitis associated with systemic connective tissue diseases were excluded. If a case was reported in more than one paper, only the first published paper was considered. Papers were screened by year or by month if they belonged to the same year. We used the following search terms “vasculitis”, “systemic vasculitis”, “Wegener's granulomatosis”, “Churg–Strauss syndrome”, “microscopic polyangiits”, “microscopic polyarteritis”, “polyartertitis nodosa”, “Takayasu's arteritis”, “Behçet's disease”, “Henoch-Schönlein Purpura”, “Cryoglobulinemia”, Cogan's syndrome combined with “pregnancy”, “pregnancy outcome”, “pregnancy complications”, “gestational outcome”, “fetal outcome”, “obstetrical complications”. The articles were screened by two blinded Authors by title, abstract and full-text. 3. Search results As summarized in Fig. 1, the initial search, based on the search terms, led to the finding of 2319 titles. Among these, 242 titles were pertaining to the search. By reading the abstracts, 82 of them were excluded because they did not meet the inclusion criteria and 160 were selected. Furthermore, 8 case reports were excluded after discussion by the two blinded Authors because they did not find a full agreement on the description accuracy of the cases and two were excluded because they had been reported twice [110,164]. Thus, 150 articles were selected for the study including 133 case reports, 8 case series, 1 controlled study, 6 prospective and 2 retrospective studies. No randomized controlled trials were reported. Overall, 567 pregnancies were analyzed.

M. Gatto et al. / Autoimmunity Reviews 11 (2012) A447–A459

2319 potentially relevant titles identified from web databases and journals

2077 citations were deleted based on language or lack of relevance

NO

Have the inclusion criteria been met? YES

242 citations were selected for further review of the abstracts

82 abstracts were excluded since they considered vasculitis out of pregnancy, Horton arteritis or vascultis associated with connective tissue diseases

NO

Have the inclusion criteria been met?

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arteritis (TA), and 11 case reports [52–62] (the full text of 6 cases reports, published from 1965 to 1989, was not available) with a total of 19 pregnancies in patients with polyarteritis nodosa (PAN). Among small vessel vasculitis, 48 pregnancies in 38 patients affected with Wegener's granulomatosis (WG) were described in 29 case reports [64–92] and 2 case series [62,63]; 26 pregnancies in 15 patients affected with Churg–Strauss syndrome (CSS) were described in 11 case reports [98–108] and in one case series [62]. Five pregnancies in 5 patients affected with microscopic polyangiitis (MPA) were reported in 5 case reports [111–115]. Eighteen pregnancies in 16 patients affected with Henoch-Schönlein's purpura (HSP) were reported in 16 case reports [116–131]. We also reviewed 18 case reports [145–162], three case series [139,140,142], one longitudinal study [141], one retrospective study [143] and one large case control study [144], with a total of 229 pregnancies in 131 patients with Behçet's disease (BD). Finally, 4 articles reporting 6 pregnancies in 4 patients with cryoglobulinemia [163,165–167] and 3 articles reporting 3 pregnancies in 3 patients affected with Cogan's syndrome (CS) [168–170] were reviewed. 4. Large vessels vasculitis 4.1. Takayasu's arteritis

YES 160 abstracts were selected for full-text review

10 texts were excluded based on lack of agreement among the blinded authors or data reported in more than one paper

NO

Have the inclusion criteria been met?

YES 150 full-texts articles were included in the review Fig. 1. Flow diagram of article selection for literature review.

We found 36 case reports [13–48], 5 prospective studies [5–7,9,10], 2 case series [11,12] and one retrospective study [8], with a total of 214 pregnancies in 168 patients with Takayasu's

TA is a granulomatous vasculitis which affects large vessels such as aorta, its major branches, and the pulmonary arteries. TA typically occurs in women during their childbearing age, therefore it is more common to observe pregnancy in patients with TA than in those with other vasculitis [4]. We have been able to identify TA in the literature 214 pregnancies in 168 patients affected with [5–48]. In 10 cases (5%) the patient was advised to have a termination of pregnancy; in the remaining 204 cases, several maternal and fetal complications were reported. 4.1.1. Effects of TA on pregnancy Severe hypertension and/or preeclampsia occurred in 92 out of 214 pregnancies (43%) (Table 1) and were shown to be the most common complications among pregnant patients with TA [11,12,15]. Preeclampsia is shown to have a higher prevalence among TA patients if compared to general population (43% vs. 2– 8%) and is more often associated with intrauterine fetal death in TA patients than in general population (4.8% vs. 1–2%) [22,49,50]. Uncontrolled hypertension caused one patient to undergo renal angioplasty, which was performed after therapeutic abortion [12]. Notably, a patient who underwent bilateral renal angioplasty 5 years before conception and another one, receiving bilateral renal

Table 1 Takayasu's arteritis and pregnancy. Author, year [ref]

No. of pregnancies (no. of patients)

Disease flares No. (%)

Hypertension preeclampsia No. (%)

Other maternal complicationsa No. (%)

Maternal death No. (%)

LBW IUGR No. (%)

Preterm delivery No. (%)

Medical termination No. (%)

Fetal loss No. (%)

Cesarean section No. (%)

Ishikawa, 1982 [5] Wong, 1983 [6] Matsumura, 1992 [7] Aso, 1992 [8] Kerr, 1994 [9] Sharma, 2000 [10] Ioscovich, 2009 [11] Suri, 2010 [12] Case reports [13–48] Onset in pregnancy Onset before pregn. Total

33 (27) 19 (11) 22 (18) 23 (15) 5 (27) 24 (12) 6 (3) 37 (15) 45 (40) 9 36 214 (168)

0 0 0 3 (13) 0 3 (13) 0 0 1 (2) 0 1 (3) 7 (3)

14 (42) 11 (58) 4 (18) 13 (57) 0 15 (63) 0 22 (59) 13 (29) 4 (44) 9 (25) 92 (43)

2 (6) 0 1 (5) 3 (13) 0 2 (8) 0 5 (14) 5 (11) 2 (22) 3 (8) 18 (8)

0 1 (5) 0 0 0 0 0 1 (3) 0 0 0 2 (0.9)

6 (18) 9 (47) 0 3 (13) 0 5 (21) 2 (33) 6 (16) 11 (24) 3 (33) 8 (22) 42 (20)

2 (6) 1 (5) 0 5 (22) 0 4 (17) 5 (83) 6 (16) 12 (27) 4 (44) 8 (22) 35 (16)

0 0 1 (5) 4 (17) 0 2 (8) 0 2 (5) 1 (2) 0 1 (3) 10 (5)

0 3 (16) 6 (27) 1 (4) 0 5 (21) 1 (17) 10 (27) 4 (9) 3 (33) 1 (3) 30 (14)

10 (30) 4 (21) 5 (23) 15 (65) 0 1 (4) 5 (83) 7 (19) 31 (69) 7 (78) 24 (67) 78 (36)

Pregn.: pregnancy; LBW, low birth weight; IUGR: intrauterine growth restriction. a Congestive heart failure, aortic regurgitation, aneurysms, aortic dissection, stroke.

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angioplasty and successive stenting of the renal arteries and abdominal aorta 3 years before conception, had uneventful deliveries [8,16]. Therefore, the use of angioplasty in the pre-pregnancy period may have a protective role in preventing some of the complications related to the vasculitis [16]. With regard to the newborns, low weight at birth and intrauterine growth restriction (IUGR) were seen to be the most frequent complications [5–8,10–12,41] and were reported in 42 out of 214 pregnancies (20%) (Table 1). IUGR and preeclampsia were reported to occur more frequently in patients with abdominal aorta and involvement of renal arteries [12]. Other complications included preterm delivery and fetal loss, which were reported in 35 (16%) and in 30 (14%) out of 214 pregnancies, respectively (Table 1). One case of neonatal death was reported, due to severe prematurity [12]. Suri et al. [12] found that the incidence of maternal and fetal complications (preeclampsia, preterm delivery, IUGR) was higher among TA patients who had a more severe disease (evaluated according to Ishikawa's criteria) and/or with a higher number of damaged vessels. Although TA can negatively affect the course of gestation, the outcome of pregnancy seems to be favorable in the majority of cases. 4.1.2. Effects of pregnancy on TA Pregnancy does not seem to globally increase disease activity as only 7 disease flares were observed in 214 pregnancies (3%) (Table 1). The most common manifestations during disease flare were progression of renal insufficiency, retinopathy, anemia, thrombocytopenia, increased ESR and CRP [10, 12, 19, 22]. In addition, maternal complications such as aortic insufficiency (2 cases), congestive heart failure (9 cases), aneurysm formation (2 cases) and stroke (4 cases) were reported [5,7,8,10,12,14,23]. Taken together, these data suggest that pregnancy might somehow worsen the course of the disease. One patient developed a type B aortic dissection (involving the thoracic descending aorta) 3 days after cesarean section, which was successfully treated with insertion of an endograft after intensive care management [15]; indeed, TA has to be considered an independent risk factor for development of aortic dissection in pregnancy. Although it is a rare complication in pregnant women, aortic dissection is associated with a high mortality rate, so it should be rapidly detected and treated. The diagnosis should be suspected in any pregnant woman complaining of chest pain [15]. Two cases of maternal death were reported [6,12], due to myocardial infarction and complications of accelerated hypertension. In addition, severe aortic valvular disease and aortic aneurysm are risk factors for maternal morbidity and fatality, therefore patients with these complications should be discouraged from pregnancy or a therapeutic abortion should be considered if pregnancy unexpectedly occurs. 4.1.3. Management of TA during pregnancy 4.1.3.1. Treatment of vasculitis. In the case of disease relapse during pregnancy, treatment consists of prednisone 1 mg/kg/day until disease control is obtained, thereafter prednisone can be tapered to the lowest effective dose. In refractory cases the use of azathioprine is recommended. One recent study showed that Rituximab (RTX) was effective in the treatment of refractory TA probably by restoring B cells homeostasis which has been demonstrated to be altered in active TA [51]; however, no studies on the use of RTX in pregnant TA patients are available to date. 4.1.3.2. Treatment of arterial hypertension and other complications. Hypertension is a common symptom of TA during pregnancy [12] and may drive the majority of maternal and fetal complications

[11,17], therefore it should be managed very aggressively with alfa-metildopa, calcium channel blockers or idralazine; by contrast, ACE inhibitors are contraindicated because of their fetal toxicity. It is mandatory to tightly control blood pressure (BP) using both non-invasive (BP measurement at upper and lower limbs and Doppler flow if pulses are not palpable) [11,12,15] and invasive procedures (intra-arterial monitoring through arterial cannulation) [11], especially when BP values cannot be efficiently measured due to multiple vascular stenosis [12], in the presence of hemodynamic instability or if fast fluctuation of BP is expected [11,15]. In order to prevent BP increase during vaginal pushing, spinal analgesia should be administered in patients with TA by epidural injections of bupivacaine and fentanyl, that can be repeated during labor [11]. Notably, BP monitoring should be continued at least 24–48 h after delivery, because hemodynamical changes in the post-partum period may promote aortic dissection [15]. On the other hand, it is important to ensure that BP is high enough for regional perfusion, in order to avoid hypotensive complications such as cerebral ischemia in the mother [17]. In the post-partum period, antibiotics should be used to prevent bacterial endocarditis in patients with aortic insufficiency and/or luminal narrowing of the aorta and its branches [12]. 4.1.3.3. Indication to labor induction or cesarean section in TA patients. Cesarean section was performed in 78 pregnancies out of 214 (36%). In the series of patients studied by Suri et al. [12] and among the cases reported by Lakhi et al. [15] and Ioscovich et al. [11], the most common reasons of cesarean section were cephalopelvic disproportion, placenta previa, obstetric complications, meconium stained liquor and previous cesarean sections. Induction of labor was also performed [12], due to hypertension or severe IUGR or because the patient was a NYHA II stage in her third pregnancy [11]. Apart from obstetrical reasons, Matsuura and Ishikawa [5] pointed out that patients who need cesarean section should be those (i) with a mild disease but with elevated systolic blood pressure despite adequate medical treatment, at the time of labor; (ii) with one or more complications among the following: retinopathy, secondary hypertension, aortic insufficiency, aortic/arterial aneurysm and whose BP cannot be measured at the arm; (iii) with a severe disease. Notably, in patients with hemodynamic instability due to arteritis and hypertension, cesarean section seems to be safer than vaginal delivery: in fact, a higher increase of BP is expected during labor and natural delivery [5,11,18]. After cesarean section has been performed, relieving of pain with long-acting neuraxial opioids is recommended in TA patients in order to avoid a sympathetic hyperactivation [11]. Cesarean section should not be performed routinely because it is not risk-free. Beyond the operatory risks, there are those connected to spinal, spinal-epidural or general anesthesia, that may drive both hypertensive and hypotensive complications [11]; indeed, anesthesia abolishes pain perception and therefore reduces the associated sympathetic reaction which would lead to increased peripheral resistances, hypertension and afterload increase. On the other hand, drugs used to induce anesthesia may themselves increase the risk of hypertensive crisis or, vice versa, of sudden hypotensive drops in TA patients. Particularly, combined spino-epidural anesthesia during cesarean section may lead to severe hypotension and even to ischemia in several organs, including brain, kidney, bowel and uterus [29]; nonetheless, it may be successfully used in elective cesarean section when TA is complicated by heart failure or dysrhythmias [46]. One case has been reported of sudden cardiac arrest due to epidural anesthesia for which prompt cardiopulmonary resuscitation was performed, resulting in rescue of mother and child [45]. Anesthesiologic management should therefore be extremely accurate and guarantee the hemodynamic stability of TA patients - BP

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monitoring appears again to be paramount. Drugs (bupivacaine and fentanyl, lidocaine and fentanyl) should be administered gradually (fractionated doses in 20–30 min) to maintain BP values in a narrow range [11]. Regional anesthesia should be used in spite of general anesthesia, as during regional anesthesia cerebral perfusion is easily detectable because the patient is awake [11]. If general anesthesia has to be administered, the patient should be monitored very tightly, since endotracheal intubation might induce hypertensive crisis due to sympathetic activation and therefore increase the risk of hypertensive complications such as heart failure, cerebral hemorrhage and aneurysm rupture [11,17]. Ioscovich et al. [11] suggested avoiding exaggerated BP variations by using a slowly titrated neuraxial technique. 5. Medium vessels vasculitis

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be mentioned that all the fatal cases were reported before 1983 which is the reason why they are not included in Table 2. Concerning fetal complications, the lowest weight at birth (1000 g) was reported in a baby whose mother had PAN onset during pregnancy [62] and who also underwent urgent cesarean section because of hemoperitonitis and hemodynamic failure. One miscarriage and three preterm deliveries were reported among the cases in which data are fully available [58,62]. 5.1.2. Management of PAN during pregnancy Patients with disease onset during pregnancy are at high risk of death, therefore, therapeutic abortion should be considered in early phase of pregnancy, whereas high-dose corticosteroid and cyclophosphamide have been suggested in late pregnancy [4]. 6. Small vessels vasculitis

5.1. Polyarteritis nodosa

6.1. Wegener's granulomatosis

PAN is a disorder characterized by necrotizing inflammation of medium size or small arteries. In patients with PAN prevalent features are general symptoms, musculoskeletal, skin and gastrointestinal manifestations, and peripheral neuropathy, especially mononeuritis multiplex [4]. Nineteen case reports on pregnancy in PAN patients are available in the literature (Table 2) [52–62]. 5.1.1. Effects of disease on pregnancy and vice versa In three out of 19 pregnancies, the patients developed premature membrane rupture (PROM) which led to preterm delivery [62]. Patients who conceive during disease remission seem to have a favorable outcome with no maternal death, rare disease relapse and, in the majority of cases, delivery of healthy—although premature and low birth weight babies. Conversely, maternal outcome was poor when PAN was diagnosed during pregnancy [4]. Impressively, 7 out of 8 patients who had PAN onset during pregnancy died during gestation or within 42 days from delivery [56,58]; the eighth had PROM at 14th week and was treated with cervix cerclage, but cesarean section had to be achieved at 27th week of gestation because of pancreatic artery aneurysm rupture and hemoperitonitis [62]. However, it has to

WG is an uncommon, small-vessel, necrotizing vasculitis which usually affects upper respiratory tract, lungs, and kidney. The disease peaks after the age of 40, thus, pregnancies in women with WG are uncommonly observed [4]. To date 48 pregnancies in 38 patients are available in literature [62–92]. Disease started during gestation in 15 out of 48 pregnancies and before conception in the other 33; among the latter group, WG was inactive at conception in 30 cases and active in the remaining three. In five cases (10%), a therapeutic abortion was performed (Table 3). 6.1.1. Effects of WG on pregnancy Premature delivery appears to be a common complication of pregnancy in patients with WG, being reported in 17 out of 48 pregnancies (35%) (Table 3), particularly in those with active disease during gestation or with WG onset during pregnancy [4,67,68,71,74,75,77,78, 80,82,84,87,89,91,92]. Other maternal complications included preeclampsia, PROM, prepartum hemorrhage and retroplacental hematoma [62,69]. Spontaneous abortion occurred in 4 out of 48 pregnancies (8%); however, it is worthy to note that all of the three patients with a known WG who conceived when the disease was active had a poor

Table 2 Polyarteritis nodosa and pregnancy. Cases available in literature 1989-2011a. No. of pregnancies (no. of patients)

Disease manifestations before pregnancy

Disease status at conception

Disease manifestations during pregnancy/ puerperium

Obstetrical complications

Outcome

Weeks at delivery

Fetal weight

Delivery

Maternal

Fetal

Owen, 1989 [58]

1 (1)

NA

Remission

31

Low

Healthy

1 (1)

NA

NA

NA

NA

Good

Healthy

Fernandes, 1996 [60]

1 (1)

Remission

39

3170 g

Good

Healthy

Owada, 2005 [61]

1 (1)

Stable

No flare

NA

NA

NA

Good

Healthy

Pagnoux, 2010 [62]

4 (4)

Hypertension, multiple neuropathy, aneurysms in renal arteries, hematuria, arrhythmias, myocardial infarction Slight joint tenderness, microhematuria, proteinuria Recurrent subcutaneous nodules on lower limbs –

Cesarean Section Cesarean Section Cesarean Section

Good

Aya, 1996 [59]

Hypertension, worsening of renal function Severe hypertension, preeclampsia No flare

Stable

PROM

41

3600 g

Vaginal

Good

Healthy

Onset during pregnancy

27

1000 g

Cesarean Section

Good

Healthy

Arthralgias, skin purpura, mononeuritis multiplex Recurrent purpura, necrotic subcutaneous nodules

Stable

PROM Rupture of pancreatic artery PROM

32

2400 g

Vaginal

Good

Healthy

Mild activity

No flare

–

–

–

Good

Miscarriage at 6 weeks

Author, year [ref.]

PROM: premature membrane rupture; NA: not available. a Other 11 pregnancies were reported from 1965 to 1989 but were not considered in the table because the full-text were not available.

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Table 3 Granulomatous vasculitis and pregnancy. Case reports and case series on Wegener's Granulomatosis [62–92] and Churg–Strauss syndrome [62,98–108] available in literature. No. of pregn. (no. of patients)

Disease relapsea,b No. (%)

Hypertension Preeclampsia No. (%)

Maternal death No. (%)

LBW/IUGR No. (%)

Preterm delivery No. (%)

Fetal loss No (%)

Medical termination No. (%)

Cesarean section No. (%)

Wegener's granulomatosis (WG) WG onset during pregnancy WG onset before pregnancy - Active at pregnancy onset - Inactive at pregnancy onset Total

15 (15) 33 (23) 3 30 48 (38)

– 15 (45) 3 (100) 12 (40) 15 (45)c

2 (13) 6 (18) 0 6 (20) 8 (17)

1 (7) 1 (3) 1 (33) 0 2 (4)

3 (20) 9 (27) – 9 (30) 12 (25)

7 (44) 10 (30) – 10 (33) 17 (35)

1 (7) 3 (9) 1 (33) 2 (6) 4 (8)

2 (13) 3 (9) 2 (66) 1 (3) 5 (10)

4 (27) 13 (39) – 13 (43) 17 (35)

Churg–Strauss syndrome (CSS) CSS onset during pregnancy CSS onset before pregnancy - Active at pregnancy onset - Inactive at pregnancy onset Total

7 (7) 19 (8) 2 17 26 (15)

– 5 (26) 1 (50) 4 (24) 5 (26)c

– – – – –

0 2 (11) 1 (50) 1 (6) 2 (8)

0 2 (11) 0 2 (12) 2 (8)

3 (43) 3 (16) 0 3 (18) 6 (23)

0 5 (26) 1 (50) 4 (24) 5 (19)

1 (14) 1 (5) 0 1 (6) 2 (8) d

2 (29) 2 (11) 0 2 (12) 4 (15)

Pregn.: pregnancies; LBW: low birth weight; IUGR: intrauterine growth restriction. a WG: Generalized lesions of the mucosa and paranasal sinuses, kidney function deterioration, upper (ear, nose, throat) and/or lower (bronchi, lungs) respiratory tract symptoms, arthritis, ulcerated skin lesions, bowel ischemia, limb ischemia, epistaxis. b CSS: Asthma exacerbation, acute respiratory failure, peripheral nervous system exacerbations, maculopapular rash. c Percentage calculated on pregnancies with disease onset before conception. d Both were performed for reasons unrelated to the vasculitis.

pregnancy outcome with one intrauterine death (33%) [84] and two therapeutic abortions (66%) [77,80], one followed by maternal death [77]. Cesarean section was performed in 17 out of 48 pregnancies (35%) (Table 3) providing successful delivery. 6.1.2. Effects of pregnancy on WG Patients with active disease at conception or those with disease onset during pregnancy are at high risk of poor outcome because of maternal complications and death. Thus, during active disease patients should avoid pregnancy using adequate contraception [69]. In patients who conceived when the disease was in remission, relapse occurred in 12 cases out of 30 (40%), while all of the patients whose disease was active at conception relapsed (100%) (Table 3). However, it is not known if these figures are higher than those expected in non-pregnant WG patients. Disease manifestations during flare mainly consisted of respiratory symptoms exacerbations, subglottic stenosis, skin lesions, arthritis/arthralgias and renal function deterioration which led to end-stage renal disease in one case [62,69,76,77,80,81,83–85]. The relapse or worsening of renal disease in late pregnancy can be difficult to differentiate from preeclampsia. Very few parameters are useful in this regard, among them active urine sediment, which is indicative of glomerulonephritis, and hypertension, which is more commonly observed in preeclampsia, seem to be the most reliable. Moreover, as in systemic lupus erythematosus patients, the possibility that both features coexist at the same time cannot be ruled out. 6.1.3. Management of WG during pregnancy The treatment of disease relapse during pregnancy largely depends on the type and extension of the disease manifestations. For features limited to the upper airways local treatment, antibiotics and, if necessary, low-dose oral prednisone are recommended. Systemic manifestations require more aggressive treatment with high-dose oral prednisone (1 mg/kg/day), or i.v. pulse methylprednisolone (0.5–1 g daily for three consecutive days). In case of insufficient response to corticosteroids, azathioprine should be started. The doses of corticosteroids and azathioprine required to achieve remission were higher in patients who had a newly diagnosed WG, compared to patients with a known disease [67,68]. In presence of life-threatening manifestations occurring during the second or third trimester of pregnancy, cyclophosphamide can be considered only as a last chance treatment [4–7,63–66], since very few data on its safety are available [62,67].

Based on two successful randomized controlled trials [93,94], FDA recently approved the use of RTX in combination with glucocorticoids for the treatment of ANCA associated vasculitis. Although long term studies on RTX safety in pregnancy are still lacking, several reports demonstrate that it may be safely administered, even if RTX is able to cross the placenta (especially from 16th week) and may induce transitory Bcell depletion in the newborn [95]. However, B cells recovery occurs within 6 months from birth and no adverse effects (i.e. increased rate of infections) were reported among the children [96,97]. Thus, RTX may be considered as an alternative treatment in case of refractory WG and/or if cyclophosphamide is not likely to be used. Recently, intravenous immunoglobulins (IVIG) have been used to successfully treat two cases of new onset WG during pregnancy [67,68]. Both patients gave birth to healthy babies and in one case the treatment led to rapid healing of cutaneous ulcerations and pulmonary nodules, showing that IVIG may be safely and effectively used in spite of immunosuppressive therapy during pregnancy in patients with WG [68]. 6.2. Churg–Strauss syndrome CSS is a disorder characterized by pulmonary and systemic smallvessel vasculitis, extravascular granulomas and hypereosinophilia, occurring in patients with asthma and allergic rhinitis [4]. Twenty-six pregnancies have been reported in the literature (Table 3) [62,98–108]; 17 of them ended with the delivery of 19 healthy babies (two twin pregnancies) [62,108]. 6.2.1. Effects of CSS on pregnancy Among the newborns of CSS mothers, prematurity was observed in 6 out of 26 cases (23%) (Table 3), even though the majority of these patients delivered normal, sometimes low birth weight infants; however, one case of severe IUGR was reported [98]. Two elective terminations of pregnancies were performed for reasons unrelated to the vasculitis [101,103]; among the remaining 24 pregnancies, five fetal losses were reported [62,99,103]. Cesarean section was performed in 2 out of 7 cases (29%) in whom the disease started during pregnancy [104,106] and in 2 out of 17 (12%) with an inactive disease at conception [62] (Table 3). 6.2.2. Effects of pregnancy on CSS CSS relapse was reported in 4 out of 17 women (24%) who conceived while disease was in remission (Table 3), including one case

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in which disease relapse was lethal [99]. During relapse, the prevalent manifestations were worsening of asthma, mononeuritis multiplex and skin rash. Corradi et al. [101] reported the case of a woman with severe heart involvement that required heart transplantation after an uneventful delivery occurred. The explanted heart showed prominent necrotizing eosinophilic vasculitis of the distal coronary branches. One case of acute maternal heart failure was observed in the case series of Pagnoux et al. [62]. Two cases of maternal deaths have been reported [99,102] and were caused by respiratory complications and cardiac involvement. Patients with disease onset during pregnancy had a very poor prognosis and the severity of the disease affected the patients' outcome, especially if the heart was involved [99,101]. 6.2.3. Management of CSS in pregnancy Prednisone is used in CSS relapses during pregnancy, and the dosage should be modified according to the severity of manifestations. Recently, IVIG were added to steroids to successfully treat CSS flare during pregnancy with improvement of CSS manifestations, including peripheral neurologic disorders [105,106,109]. As seen for WG, IVIG may represent a safe and efficient alternative to cytotoxic drugs in pregnancy. In CSS patients, bronchospasm during pregnancy and postpartum should be carefully handled [4]. 6.3. Microscopic polyangiitis MPA is a systemic, pauci-immune, necrotizing, small-vessel vasculitis. MPA was initially recognized as a subset of PAN from which it may be difficult to distinguish. It is also possible that in many series reported in literature MPA patients had been grouped with PAN. However, unlike PAN, most patients with MPA developed severe renal disease and pulmonary hemorrhage [4]. Six case reports on pregnancy in patients with MPA are available in the literature; however one case was reported twice [110,111], thus 5 pregnancies were overall reported (Table 4) [111–115].

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was given, but unfortunately the patient died owing to pulmonary infections. Milne et al. [114] reported another case in whom MPA occurred at 24th week of gestation and was successfully treated with plasmaexchange, cyclophosphamide 1 g i.v. and pulse methylprednisolone 1 g daily for three continuative days, then switched to oral prednisone 60 mg/day. To reduce the risk of infections, prophylactic treatment with cotrimoxazole and oral anti-fungal agents was introduced. In the case reported by Silva et al. [112], MPA was diagnosed 4.5 years before the patient became pregnant and she was in remission at pregnancy onset. Maintenance therapy was continued with low dose prednisone and azathioprine and the pregnancy was uneventful. In fact, it is possible that, as for PAN or other vasculitis, patients with MPA diagnosed prior to pregnancy have a more favorable outcome with no need of aggressive treatment, which may increase the risk of maternal and fetal mortality. The pregnancies reported by Bansal et al. [111] and Morton et al. [115] ended with a live birth, but both of the authors described the intriguing occurrence of an MPA-like syndrome in the newborn, which could potentially be due to the transfer of maternal ANCA through the placenta; however, in one of these two cases [115] ANCA were not detected in the serum of the baby. In this case, the purpuric rash spontaneously faded over 3 days. In contrast, in the case reported by Bansal et al. [111], a therapy with high doses i.v. of hydrocortisone and exchange transfusions with packed red blood cells had to be performed, since the newborn developed pulmonary hemorrhage and renal involvement. It has been suggested that treatment of the mother with immunosuppressive therapy (corticosteroids and azathioprine) may prevent the onset of a MPA-like syndrome in the child, despite the placental transfer of autoantibodies [112]. Other complications affecting the fetus included two cases of low birth weight and prematurity [111,114]. Cesarean section was performed in one of the two cases [111]. Neither fetal losses nor medical terminations of pregnancy were reported.

6.4. Henoch-Schönlein's Purpura 6.3.1. Effects of MPA on pregnancy and vice versa From the analysis of the data, MPA was seen to relapse in two out of three cases with disease onset before pregnancy [111,115] with worsening in respiratory function and serological activity. Fever, joint swelling and pain and exacerbation of skin rashes were also reported [115]. Cetinkaya et al. [113] described a patient who developed MPA at 16th week of gestation. Treatment with high dose methylprednisolone (1 g/day for 3 days) and one pulse cyclophosphamide (0.5 g)

HSP is an IgA-mediated necrotizing vasculitis of the small vessels which predominantly affects children and is therefore infrequently observed during pregnancy. Common features of the disease include palpable purpura (usually beginning at the upper surface of the lower limbs and possibly extending to the abdomen and troncus), arthralgia/arthritis and gastrointestinal involvement leading to pain and less commonly diarrhea and/or gastrointestinal bleeding. Renal involvement is more likely to

Table 4 Microscopic polyangiitis and pregnancy. Author, year, [ref.]

Time of No. of pregnancies disease onset (no. of patients)

Disease manifestations before pregnancy

Remission

Onset during pregnancy Onset during pregnancy

Severe manifestations Renopulmonary syndrome

Before Arthritis, vasculitic pregnancy rash

Remission

Bansal, 2004 [111]

1 (1)

Remission

Silva, 2009 [112]

1 (1)

Before Pulmonary pregnancy hemorrhage, glomerulonephritis Before Generalized malaise, pregnancy arthralgias peripheral neuropathy, skin rashes During – pregnancy During – pregnancy

1 (1)

Maternal Fetal

At term Fever, joint swelling, skin rash 33 Respiratory impairment and anti-MPO increasing No flare 38

1 (1)

Milne, 2005 [114]

Outcome

Weeks at Weight at Mode of delivery delivery delivery

Disease manifestations during pregnancy/ puerperium

Morton, 1998 [115]

Cetinkaya, 2002 [113] 1 (1)

Obstetrical complications

Disease status at conception

2975 g

Vaginal delivery

Good

1950 g

Cesarean Good section

3630 g

Vaginal delivery

Good

Transitory vasculitic rash in a healthy baby Recovered after reno-pulmonary syndrome Healthy

–

–

–

Death

-

35

1440 g

Vaginal delivery

Good

Healthy

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affect adults rather than children. The outcome is usually good with no sequelae. Eighteen cases of HSP during pregnancy have been reported in the literature [116–131]. 6.4.1. Effects of HSP on pregnancy All of the described pregnancies had a favorable outcome with the delivery of healthy babies, except for one case where spontaneous abortion occurred [116]. The most common maternal complication appeared to be worsening of hypertension and its possible complications such as preeclampsia or eclampsia [117,123,124] which was reported in 3 out of 18 cases (approximately 17%). Pregnancy outcome was reported to be poorer among patients with new onset HSP by the majority of the Authors [116,117,123,131], except one [118]. Spontaneous abortion, IUGR and preterm delivery were also reported (one case each) [116,124,128] and cesarean section was performed in 5 out of 18 cases (28%) [119,120,124,126,127]. In some studies, placentas were analyzed and no signs of vasculitis or infarction were reported [118–121]. Interestingly, HSP seems unlikely to be transferred from mother to baby, since IgA are unable to cross the placenta [119–121]. 6.4.2. Effects of pregnancy on HSP The most common manifestations observed in HSP pregnant women were palpable purpura, arthralgia and abdominal pain, which have been reported in 14 out of 18 pregnancies (77%) [116–119,122,125,126,129–131], but more severe manifestations such as necrotizing cutaneous ulcerations [119] or acute renal failure [123] have also been reported. Notably, all of the four patients with HSP onset before gestation experienced remarkable disease manifestations, such as necrotizing cutaneous lesions, arthralgia and abdominal pain [118,120,126,130]. Two long-term follow up studies demonstrated that renal complications such as secondary hypertension and/or proteinuria occur more frequently in HSP women who had had the disease onset in childhood [132,133]. Cummins et al. [118] suggested that pregnancy may be a trigger event for recurrent HSP in susceptible individuals, including those whose disease arose during childhood. Among the 18 cases reported in the literature, 14 patients had HSP onset de novo during pregnancy: none of them developed severe complications, except for one patient requiring hemodialysis due to acute renal failure [123]. Some authors reported significant renal disease occurrence in new onset HSP during pregnancy [122,134], but this observation was not confirmed by others [118–120]. Special attention should be paid to renal function, since renal involvement is more frequent and severe in adults than in children [135] and may be difficult to distinguish from preeclampsia during pregnancy [120,121].

Thus, HSP course seems to be unpredictable during pregnancy, since either improvement, no effects or marked exacerbations have been reported [118–120,124,130]. 6.4.3. Management of HSP in pregnancy Although HSP is often self limiting, corticosteroids are frequently used to treat HSP during pregnancy [136]. However, the use of corticosteroids remains controversial, since they do not affect the prognosis of the disease, but appear to have a beneficial effect on severe skin lesions, arthritis and gastrointestinal symptoms [118,137]. One study suggested that corticosteroids may have a protective effect against nephritis [138]. 7. Any vessels vasculitis 7.1. Behçet's disease BD is a chronic, relapsing, multisystemic, inflammatory process characterized by recurrent oral and genital ulcers, ocular, gastrointestinal, neurological manifestations, and thrombosis. It predominantly affects young women during childbearing age, therefore it is not rare to observe pregnancy in patients with BD [4]. Data regarding the reciprocal influence of BD and pregnancy derive from the analysis of 229 pregnancies in 131 patients diagnosed with BD, obtained from several case reports, five small series and one large retrospective study (Table 5) [139–162]. 7.1.1. Effects of BD on pregnancy Pregnancy complications included hypertension/preeclampsia (3 cases out of 229 pregnancies) and fetal complications: 3 premature deliveries (1%), 2 IUGR (0.8%), and 21 fetal losses (9%). Cesarean section was performed in 12 out of 229 cases (5%) (Table 5). In contrast with the low prevalence of maternal and fetal complications, a large case control-study [144], in which 77 pregnancies in BD patients and 288 pregnancies in healthy controls were enrolled, showed that in BD patients the pregnancy complication rate was 26%, significantly higher than that observed in the control group (2%). Moreover, the frequency of spontaneous abortion was also significantly higher in BD patients as compared with controls (20.8% vs. 5.2%). Other pregnancy complications in BD patients mainly consisted of hypertension and gestational diabetes mellitus [144]. Hwang et al. [161] have recently described multiple necrotic lesions involving two placentas in mothers with BD: histopathological findings consisted of multiple foci of necrotizing villitis with predominant neutrophilic infiltrate and granuloma-like histiocytic aggregates. Several lymphocytes (CD3 and CD8 positive) were also present. The decidua showed signs of vasculitis with endothelial damage and neutrophilic infiltration of the vessel wall. These observations suggest that placenta may be involved from the early phases of pregnancy, although this does not necessarily lead to an adverse

Table 5 Behçet's disease and pregnancy. Author, year [ref.]

No. of pregnancies (no. of patients)

Disease relapsea No. (%)

Disease improvement No. (%)

Hypertension preeclampsia No. (%)

Thrombo-embolic eventsb No. (%)

Preterm delivery No. (%)

LBW/IUGR No. (%)

Fetal loss No. (%)

Cesarean section No. (%)

Hamza, 1988 [139] Bang, 1997 [140] Marsal, 1997 [141] Gul, 2000 [142] Uzun, 2003 [143] Jadaon, 2005 [144] Case reports [145–162] Total

21 20 25 16 44 77 26 229

9 (43) 12 (60) 2 (8) 9 (56) 12 (27) 12 (16) 13 (50) 68 (30)

12 8 23 7 23 54 10 137

0 0 0 0 0 3 (4) 0 3 (1)

0 0 1 (4) 0 0 1 (1) 4 (15) 6 (3)

0 0 1 (4) 0 0 1 (1) 1 (4) 3 (1)

0 0 0 0 0 0 2 (8) 2 (0.8)

0 0 1 (4) 0 3 (7) 16 (21) 1 (4) 21 (9)

0 0 0 0 0 9 (12) 3 (12) 12 (5)

(8) (20) (10) (16) (28) (31) (18) (131)

(57) (40) (92) (44) (52) (70) (38) (60)

LBW: low birth weight, IUGR: intrauterine growth restriction. a Oral/genital ulcerations, eritema nodosum, necrotic pseudofollicolitis/skin lesions, uveitis, arthritis. b Budd-Chiari syndrome, deep vein thrombosis, superior vena cava thrombosis, cerebral venous thrombosis, intracardiac thrombosis, pulmonary embolism.

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pregnancy outcome. It has been suggested that placental lesions could represent the mother-to-fetus diffusion of lesional lymphocytes, which might explain neonatal BD occurring in babies of some BD patients [161]. 7.1.2. Effects of pregnancy on BD The disease tends to improve during pregnancy in approximately 60% of cases, whereas disease relapse was reported in 30% of cases (Table 5); in the last 10%, BD remained stable throughout the pregnancy. During relapses, disease manifestations consisted mainly of oral or genital ulcers, eritema nodosum, arthritis and uveitis. Vascular involvement, including deep vein thrombosis, Budd-Chiari syndrome, pulmonary embolism, superior vena cava thrombosis, cerebral venous thrombosis and intracardiac thrombosis, has been reported in six cases [141,144,145,157,160,162]. 7.1.3. Management of BD during pregnancy During pregnancy corticosteroids are the treatment of choice, while colchicine is contraindicated because of its mutagenic potential [161]. If a thromboembolic event occurs, heparin is usually added to the immunosuppressive therapy [157]. Notably, one case was reported of post-partum deep vein thrombosis refractory to standard anticoagulation which progressed to involve inferior vena cava and right ventricle and which was successfully treated with lepirudin (a direct thrombin inhibitor) and subsequent thrombolysis [162]. Both BD and pregnancy/puerperium represent acquired predisposing conditions that increase thrombotic risk, so their coexistence in a patient raises the question whether or not that patient should undergo prophylactic anticoagulation. Although this concern does not have a definite answer yet, we suggest standard anticoagulation at least in those patients who have already had a previous venous thrombosis. Careful management of BD pregnant patients should be performed, since they are at risk of massive and potentially fatal thromboembolism [162]. In summary, although the lack of prospective studies does not allow to draw a definite conclusion, these data suggest that pregnancy might not worsen the course of maternal disease and may even ameliorate it. However, it seems that BD may adversely affect pregnancy outcome. Therefore, patients should be tightly monitored during pregnancy and post partum, since relapses could occasionally occur and early diagnosis and prompt treatment can guarantee the most favorable pregnancy outcome. 8. Other vasculitis So far, we have discussed the most common vasculitis that may affect gestational outcome. Although less frequently, other vasculitis have been reported in pregnant women. 8.1. Cryoglobulinemia The presence in the blood of immunoglobulins that precipitate at low temperatures and dissolve after rewarming is referred to as cryoglobulinemia. Cryoglobulins may consist of monoclonal Ig (type I cryoglobulinemia), monoclonal IgM associated to polyclonal IgG (type II) or both polyclonal IgG and IgM (type III) [163]. The last two types are named mixed cryoglobulinemia and may be essential or secondary to autoimmune diseases, malignancies or infections (typically HCV), whereas type I cryoglobulinemia is mostly idiopathic and/or associated to lymphoproliferative disorders [164]. The immune-complexes deposits cause vascular damage and vasculitis of small and medium-sized vessels [163,164]. We were able to find seven cases of cryoglobulinemia during pregnancy, but one case was reported twice [164,165], thus six pregnancies were overall available [163,165–167] (Table 6).

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8.1.1. Effects of cryoglobulinemia on pregnancy and vice versa Gupta et al. [163] reported the case of a new onset cryoglobulinemic vasculitis during pregnancy, characterized by palpable, pruritic macular rash on the lower limbs without any other associated symptoms; the manifestations recovered due to medical treatment and the pregnancy was uneventful. Noteworthy, Sibilia et al. [165] reported the case of neonatal cryoglobulinemia caused by transplacental transfer of IgG from the mother to the baby: the patient was affected with type I cryoglobulinemia and although her symptoms improved spontaneously during pregnancy, one of the twins she delivered showed cryoglobulinemic manifestations as he was removed from the incubator. The baby recovered when he was warmed and no recurrences were observed, after the physiological clearance of maternal IgG. The case described by Alberico et al. [166] successfully ended with a healthy baby, although preeclampsia occurred. Out of the three patients reported by Juverdenau et al.[167] two uneventfully delivered, whereas the last unfortunately miscarried concomitantly with the vasculitic flare-up. 8.1.2. Management of cryoglobulinemia during pregnancy Cold avoidance remains a basic rule for patients with cryoglobulinemia and warming of mother and cryoglobulinemic newborn helped patients to recover [165]. Prednisolone was used to treat persistent symptoms in one patient [163]. Plasmapheresis was successfully performed in one patient [163], but other Authors suggest that it should be avoided since it may not be efficient and could drive some negative effects on both the mother and the baby [165]. 8.2. Cogan's syndrome (CS) Cogan's syndrome (CS) mainly affects eyes and ears resulting in interstitial keratitis and vestibuloauditory dysfunction [168]; however, it may either involve large or small-sized vessels, causing systemic vasculitis [168,170]. Three cases of CS during pregnancy have been reported (Table 6) [168–170]. 8.2.1. Effects of CS on pregnancy and vice versa In two out of three cases, CS relapses were reported during pregnancy [168,169], whereas in the latter the disease remained in remission [170]. Disease flares were characterized by ocular symptoms and relapse of interstitial keratitis [168,169]. The newborns were healthy and no perinatal complications were reported, but in one case labor induction and cesarean section were performed because of oligohydramnios [170]. Although data are limited, exacerbations of the disease might be expected during pregnancy, thus a tight control of mother and fetus should be performed [170]. 8.2.2. Management of CS during pregnancy Hydroxychloroquine can be used as maintenance therapy [170]. However, during disease relapses corticosteroids should be administered, either systemically or as a topic treatment [168]. 9. Conclusions The modulation of immune functions induced by pregnancy period may influence the course of vasculitis, which may in turn affect fetal or maternal outcome [4]. Unfortunately, no extensive data on pregnancy in patients with systemic vasculitis are available, due to the low incidence of such diseases, the low female-to-male ratio and disease onset, which often occurs after childbearing age. Most of the information we have derives from case reports and retrospective studies, since long term prospective studies are not available.

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Table 6 Cryoglobulinemia and Cogan's syndrome during pregnancy. Disease status at pregnancy onset

Disease manifestations during pregnancy/puerperium

Obstetrical complications

Outcome

Weeks at delivery

Weight at delivery

Mode of delivery

Maternal

Fetal

Before pregnancy

NA

Remission

31

1570 g

Cesarean section

Good

NA

1 [twins] (1)

Before pregnancy

Remission

39

2440 g 2690 g

Vaginal delivery

Good

One healthy; One with cyanotic skin maculesa

Gupta, 2008 [163]

1 (1)

During pregnancy

Livedo reticularis Purpuric and necrotic lesions on lower limbs Acrocyanosis –

Mild hypertension and proteinuria, anemia, arthralgias, itch No flare

Full term

3674 g

Vaginal delivery

Good

Healthy

Juverdenau, 2008 [167]

3 (1)

During first pregnancy

1st pregnancy: –

Palpable macular rash on both legs Leg rash, peripheral edema, glomerulonephritis, proteinuria, hypertension Vasculitic rash, liver function deterioration Flare at 6th week Monoenuritis multiplex

39

NA

Cesarean section

Good response to therapy

NA

–

–

–

Good

Miscarriage

37

4380 g

Cesarean section

Good

Good

38

3820 g

Vaginal delivery

Good

Healthy

At term 38

NA 3410 g

Vaginal delivery Cesarean section

Good Good

Healthy Healthy

No. of pregnancies (no. of patients)

Time of disease onset

Cryoglobulinemia Alberico, 1998 [166]

1 (1)

Sibilia 2004 [165]

2nd pregnancy: NA

Onset during pregnancy Onset during pregnancy

3rd pregnancy: skin rashes, flu-like symptoms

Intermittent symptoms Controlled by therapy

Cogan's syndrome Deliveliotou, 2007 [168]

1 (1)

Before pregnancy

Hearing loss, tinnitus

Remission

Bakalianou, 2008 [169] Currie, 2009 [170]

1 (1) 1 (1)

Before pregnancy Before pregnancy

Not available Vestibulitis, keratitis

Remission Remission

NA: not available. a Recovered after rewarming.

Pain, redness, photophobia, eyes lacrimation Recurrent interstitial keratitis No flare

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Disease manifestations before pregnancy

Author, year, [ref.]

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Nevertheless, some general guidelines for the management of patients with vasculitis during pregnancy can be suggested: 1) adequate contraception should be performed until patients receive high dose of cytotoxic medications and disease control is achieved; 2) pregnancies should be planned when the disease is in remission since this reduces maternal complications, increasing the chances of a successful pregnancy; 3) tight monitoring during gestation and postpartum is recommended; 4) vasculitic flares, which more commonly occur if disease is active at conception, should be promptly and even aggressively treated, since disease activity may be hazardous to the fetus more than drugs; 5) pregnancies complicated by vasculitis onset have a particularly severe prognosis, therefore efficient management and close clinical surveillance are indicated; 6) mode of delivery (vaginal or cesarean) should be tailored to each patient according to her health status and to disease activity or complications; 7) beside corticosteroids and immunosuppressants, new drugs are emerging for treatment of severe and/or refractory vasculitis that might improve maternal and fetal outcome; 8) in patients with systemic vasculitis the risk of thromboembolic events is increased, therefore a treatment with aspirin or low molecular weight heparin should be considered.

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