Pregnancy ahd Vasculitis

PREGNANCY AND VASCULITIS
6 January 2008

This information was extacted from a reputable medical source and edited by a non-medical person to delete disease descriptions and to change the intent to be for general persons rather than for medical professionals . The content remains substantially the same, but rearranged. Table 1 is resized, but contains the same information as the original with the addition of the comment on AATD.

NO MEDICAL DECISIONS SHOULD BE MADE ON THE BASIS OF THIS WEB FILE. CONSULT APPROPRIATE LICENSED MEDICAL PROFESSIONALS REGARDING THE SUBJECTS OF PREGNANCY AND OF VASCULITIS.

This reviews vasculitis in pregnancy and is relevant to allpersons concerned with health care of women of childbearing age. It covers recent developments in the field of vasculitis and pregnancy, summarizes current therapeutic practice and looks toward future challenges in this area.
Vasculitis in pregnancy is rare and so knowledge of how to manage these women is limited but expanding. It is known that pregnancy can have a disease-modifying effect on autoimmune connective tissue diseases such as vasculitis and that connective tissue disease can have an adverse effect on pregnancy.
It is essential that pregnant women with vasculitis are managed to the highest standards of care, in order to prevent negative outcomes not only for the mother but also for the child. This file aims to provide an approach to managing these patients with the best current evidence-based practice.

TABLE 1

Treatment used in vasculitis	Risk in pregnancy
Corticosteroids	Risk of intrauterine growth retardation with prolonged therapy
Azathioprine (Imuran)	No evidence of teratogenicity
Mycophenolate Mofetil (Cellcept)	Some reports of fetal toxicity in humans. Toxicity has been demonstrated in animal studies, should probably be avoided if possible until more is known
Rituximab (Rituxan)	A third-line agent in the treatment of Wegener's granulomatosis, the risk of toxicity in pregnancy is unknown and there is a risk of B cell depletion in the fetus
Methotrexate	A third-line agent in the treatment of Wegener's granulomatosis, the risk of toxicity in pregnancy is unknown and there is a risk of B cell depletion in the fetus
Cyclophosphamide (Cytoxan)	Known teratogen. Absolutely contraindicated, although the highest rates of malformation are during the first trimester and cyclophosphamide has been used for treatment of severe Wegener's granulomatosis in late pregnancy without short-term complication
Plasma exchange	Thought to be safe (if patient doesn't have Alpha-1 Antitrpsin Deficiencey (AATD)
Intravenous immuno- globulin(IVIg)	Thought to be safe

Overview of Vasculitis

Systemic vasculitis is a term encompassing a diverse group of diseases that are all characterized by inflammatory cell infiltration and necrosis of blood vessel walls.
The primary systemic vasculitides include Wegener's granulomatosis (WG), Takayasu's arteritis (TA), polyarteritis nodosa (PAN), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) [and some ten or so other varieties.]
Vasculitis can also be secondary to an established connective tissue disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis, or to infection or malignancy. This article will discuss the primary systemic vasculitides.

Most Common Vasculitides

Below is a brief list of some of the five most prevalent primary systemic vasculitides and information on pregnancy More detailed information may be obtained from published medical articles and texts.
The list is in alphabetical order.

Churg-Strauss Syndrome - CSS is rare and, despite this being a disease that affects women of childbearing age, there have been very few cases of CSS in pregnancy published in the medical literature and it is from these that the following conclusions have been drawn.

Does Pregnancy Affect the Disease Course of CSS?

In general, pregnancy appears to have an adverse effect on disease, with approximately half of all women who conceive while in remission suffering a relapse of disease during pregnancy.
The main symptoms of disease relapse include mononeuritis multiplex, rash and worsened asthma control.
A predictor of mortality in CSS is congestive cardiac failure from an eosinophilic myocarditis and, clearly, patients with this complication will be at increased risk of worsening cardiac function during pregnancy.

Does CSS Affect Pregnancy Outcome?

If disease remains in remission, there does not appear to be a significant effect on pregnancy outcome; women with controlled CSS tend to deliver lower birthweight, but healthy, babies.
If disease is uncontrolled, or if a woman is diagnosed with CSS during pregnancy, higher rates of maternal and fetal death are observed.

Treatment Options in CSS.

Corticosteroids are the drug of choice in treating relapses or new-onset disease in pregnancy.

There is no consensus on which cytotoxic agent to add as second-line therapy but the least teratogenic option (i.e., azathioprine) should probably be trialled first.

Corticosteroid monotherapy should be sufficient in the majority of cases for maintenance of disease in remission.
Intravenous immunoglobulin has recently been used safely and successfully to treat a pregnant woman with relapse of known CSS.

CSS.Overall Recommendations for CSS in Pregnancy.

Women should ideally be in remission prior to conception;.
An echocardiogram should be considered to assess left-ventricular function prior to pregnancy - eosinophilic myocarditis is a rare but serious complication of CSS.
Disease relapses are common and should be controlled in the majority of cases with steroid monotherapy; there is no consensus on which second-line agent to use;.
Lung function should be monitored regularly through pregnancy and the postpartum period.

Microscopic Polyangiitis

Very little is known regarding MPA in pregnancy and there have been only a handful of case reports published, with the potential for reporting bias skewing toward adverse outcomes.
This lack of publications may in part be owing to the fact that, prior to reclassification of the vasculitides in the 1990s, many patients with MPA would have been classed as having PAN and, more recently, MPA has been classed by many alongside WG in the ANCA-associated vasculitis class.
Does Pregnancy Affect the Disease Course of MPA?

Very little is known about pregnancy's effect on MPA. In the limited published case reports, onset of disease occurred during pregnancy, which would suggest an adverse effect of pregnancy on MPA, but this is, at best, anecdotal evidence.

Does MPA Affect Pregnancy Outcome?

There have been five case reports of MPA in pregnancy. One case ended in maternal death. Of interest, in two cases the baby developed neonatal pulmonary hemorrhage and renal impairment and cord blood was positive for p-ANCA, suggesting possible neonatal transmission of disease.
Both babies responded to corticosteroids and exchange blood transfusion. Obviously, with such small patient numbers it is impossible to draw reliable conclusions from these findings.

Treatment Options in MPA.

Therapeutic options are much the same as for WG. It is important to specifically monitor liver and lung function, as in nonpregnant disease, as these are the organs predominantly affected in MPA.
Therapeutic agents used with varying success in reported cases include plasma exchange, methylprednisolone and cyclophosphamide.

Polyarteritis Nodosa -PAN is a rare disease that tends to present in older patients and thus there have been only a very few published reports of pregnancy in women with PAN from which the following observations are drawn.

Does Pregnancy Affect the Disease Course of PAN?

Of the small numbers of patients reported, it appears that pregnancy does not have an adverse effect on PAN, provided that the disease is in remission at conception. However, patients diagnosed with PAN late in pregnancy appear to perform badly, with higher rates of maternal death from renal failure, gastrointestinal hemorrhage, respiratory failure and coma.
There is currently insufficient evidence to comment reliably on whether or not pregnancy affects PAN disease activity.

Does PAN Affect the Outcome of Pregnancy?

Again, it is difficult to comment on this owing to the small numbers of published cases.
Of 15 reported pregnancies, 11 resulted in the delivery of healthy infants and two in spontaneous and two in therapeutic abortions.

Treatment of PAN in Pregnancy.

Life-threatening disease calls for the addition of cytotoxic therapy to steroid monotherapy, although there is no consensus regarding which cytotoxic agent should be the first-line treatment.
Approximately 10% of patients with PAN also have hepatitis B infection, which poses extra challenges in pregnancy and, therefore, expert virology advice should be sought preconceptually.
Owing to the generally poor outcomes of women who develop PAN during pregnancy, therapeutic abortion should be considered in early pregnancy and aggressive, potentially teratogenic therapy should be considered in late pregnancy in order to protect the mother, who has a real risk of death.
For the majority of cases of maintenance therapy, it should be possible to control the disease, particularly that which is in remission at conception, with steroid monotherapy.

Overall Recommendations for PAN in Pregnancy.

Pregnant patients with PAN perform better when they conceive during disease remission and this must be stressed to the woman prior to conception.
PAN can affect all of the major organ systems.
In general, severity and outcome are worse in the presence of the following adverse prognostic indicators: heavy proteinuria, high serum creatinine, cardiomyopathy and gastrointestinal or neurological involvement; 
Careful monitoring of these indicators is mandatory throughout pregnancy.

Takayasu's Arteritis

TA predominantly affects women of childbearing age and so the issue of pregnancy is an important one. To date, there have been three major case series of pregnant patients with TA with 76 pregnancies in total, and the guidelines below are drawn mainly from these series.

Does Pregnancy Affect the Disease Course of TA?

TA disease activity, as measured by serum C-Reactive Protein (CRP) and erythrocyte sedimentation rate (ESR), suggests that inflammation may actually be reduced during pregnancy.
In any case, there does not appear to be an increase in disease activity.
MRI is used as a noninvasive, nonradioactive means of assessing disease activity and response to treatment, by providing high-resolution images of the vessels commonly involved in TA.

Aortic wall uptake, by contrast, is suggestive of active arteritis. PET scanning is increasingly being used to assess disease activity in patients with large-vessel vasculitides such as TA, and may be more accurate than measurement of serological inflammatory markers.

However, PET scanning should be avoided during pregnancy owing to the radiation dose involved and MRI is best avoided in the first trimester of pregnancy. These tools are best used preconceptually to ensure that disease remission has been achieved prior to pregnancy.

Does TA Affect Pregnancy Outcome?

In general, it appears that TA is compatible with favorable maternal and fetal outcomes. Out of 76 pregnancies, 65 resulted in live births (86%) and there was one maternal death from myocardial infarction 14 days postpartum.
Maternal complications included hypertension (41%) and preeclampsia (35%), which were managed medically in the majority of cases.

Less common but more serious maternal complications included congestive heart failure, progressive renal failure, intracerebral hemorrhage during the second stage of labor and death.

TA appears to be associated with an increased incidence of intrauterine growth retardation (26% of patients).
Both maternal and fetal complications were more common in patients who had diffuse disease with abdominal aortic involvement and uncontrolled hypertension and in those who presented to antenatal services late in pregnancyFertility is not adversely affected by TA as long as tetragenic agents are not used.

Treatment of TA in Pregnancy.

Corticosteroids are the first-line treatment, as in nonpregnant diseaseIn nonpregnant cohorts, approximately half of all patients treated for TA respond to corticosteroids and approximately a third of nonresponders achieve remission with subsequent cytotoxics.
If first-line steroid therapy fails, then an appropriate cytotoxic agent thought to be least harmful in pregnancy should be used (e.g., azathioprine)It appears that most pregnant patients with TA can be maintained on corticosteroids alone during pregnancy.
Blood pressure (BP) control is paramount; monitoring should be performed via femoral cuffs as upper limb pulses may be absent due to diseaseAntihypertensive agents that have been used with success include α-methyldopa, nifedipine, β-blockers and hydralazine.
Prophylactic antibiotics should be considered at the time of delivery to prevent bacterial endocarditis and septicemia if there is aortic valve disease.
There are no further recommendations on which cytotoxic drugs should be used as third-line therapy in nonpregnant disease; those with the least teratogenic potential should be considered by a multidisciplinary expert team.

Overall Recommendations for TA in Pregnancy

TA should be in remission prior to conception as women with active disease in pregnancy have worse maternal and fetal outcomes.
Disease activity should be assessed and monitored and MRI scanning when feasible should be considered preconceptually.
The patient should be aware that pregnancy outcome is less favorable in extensive disease with abdominal aorta involvement.
Monitoring of BP and for signs of heart and renal failure is required throughout pregnancy. BP monitoring during labor is especially important owing to the increased risk of intracerebral hemorrhage at this time.
Central arterial monitoring may be required.

Wegener's Granulomatosis.

It can be a very severe disease, which in itself may discourage patients from trying to conceive, and a major first-line agent for treatment of WG is cyclophosphamide, which can cause ovarian failure and which is usually prescribed in conjunction with contraceptive medication owing to its potential for teratogenicity.

This means that the evidence base for treating pregnant women with WG is limited to low numbers of women, 29 in total, in a series of published case reports, the findings of which are reported below.
There are currently no agreed guidelines or standards for management of these patients.

Does Pregnancy Affect the Disease Course of WG?

Pregnancy appears to have an adverse effect on WG; a quarter of the patients in disease remission relapsed during pregnancy and approximately a third of patients developed or were newly diagnosed with WG during pregnancy.

Of those patients who conceived during an active phase of disease, all experienced a flare or worsening of symptoms. Postpartum, severe disease relapse has been reported in a woman who had been in remission for 7 years.

Does WG Affect Pregnancy Outcome?

WG appears to have an adverse effect on pregnancy.

Patients who have active disease or develop new disease when they become pregnant have a worse outcome than patients in whom disease was controlled at the time of conception; they have higher rates of spontaneous and therapeutic abortions and higher rates of maternal death.

Prematurity and cesarean sections are common in WG, whether disease is controlled or not.
Patients with WG who develop glomerulonephritis are at increased risk of preeclampsia, prematurity, intrauterine growth retardation and late pregnancy loss.
Patients with WG are at increased risk of venous thrombotic events over and above the risk posed by pregnancy itself.
Subglottic stenosis, which is seen in pregnant women with WG, can cause significant problems, particularly at delivery, when a temporary tracheotomy may need to be considered.

Treatment of WG in Pregnancy.

Any relapse or new onset of disease is potentially life threatening, as it is in the nonpregnant state, and therefore needs to be treated aggressively with the most appropriate medication.
Where possible, drugs thought to be relatively safe in pregnancy (e.g., azathioprine and prednisolone) should be used.

Some patients have remained in remission on prednisolone monotherapy during pregnancy, but it is generally felt that the addition of a cytotoxic agent results in more effective treatment.

A recent randomized controlled trial suggests that, in nonpregnant patients, azathioprine is as effective as the gold-standard cyclophosphamide in the remission phase of WG, and there are pilot data suggesting that high-dose azathioprine is as effective at inducing remission in relapsed disease.
If azathioprine and prednisolone are insufficient, then drugs with a potential or known risk to the fetus (e.g., methotrexate, mycophenolate, rituximab and cyclophosphamide) will need to be considered.
There have been case reports in which cyclophosphamide was used for severe WG relapse during late pregnancy without short-term complication.
The risk of maternal death needs to be balanced against the potential risk of medication to the fetus, and decisions should be discussed in a multidisciplinary setting, taking the patient's views into account.
Most patients in remission continue immunosuppressive treatment during pregnancy. A common therapeutic regime is azathioprine, usually with low-dose prednisolone.

Overall Recommendations for WG in Pregnancy

Women with WG should receive prepregnancy counseling.
WG is a serious disease and any relapse during pregnancy will need to be treated aggressively to avoid the risk of both maternal and fetal death.

This may involve the use of drugs with teratogenic potential.

Pregnancy probably has an adverse effect on WG and may increase the risk of disease relapse.
WG probably increases the risk of prematurity and spontaneous abortion, of requiring therapeutic abortion and cesarian section and of maternal death.
It is strongly advisable for a woman to be in remission prior to conception.
If a woman is trying to conceive, she should be switched from any teratogenic therapy to an alternative such as azathioprine, possibly with prednisolone.
Antenatal monitoring must involve members of a multidisciplinary team, including a rheumatology specialist, from early in the pregnancy.
Close monitoring of renal function (urea and electrolytes, proteinuria, BP) and routine full blood count and ANCA, ESR/CRP testing is of paramount importance.
Relapses must be treated aggressively and effectively, using drugs known to be safe in pregnancy where possible.

Conclusion

Systemic vasculitis is rare and the published data on vasculitis in pregnancy are limited to case reports and case series.
With this small and imperfect database, it is impossible to compile fully comprehensive guidelines on the management of these patients. However, enough is known regarding the treatment of vasculitis in general and about potential toxicities of many widely used therapeutic agents to enable researchers to build on this imperfect database and provide best-available guidelines and information for clinicians.
Consideration can be given to the use of Luperon (Leuprolide) to prevent ovulation when the patient is taking cyclophosphamide.
It is highly unlikely that large randomized, controlled, multicenter studies of sufficient numbers of pregnant women with vasculitis will be conducted. There are many barriers to these studies, not least of which are the obvious reluctance of pharmaceutical companies to trial new drugs in pregnant women, the rarity of the vasculitides and the natural reluctance of women to participate in such trials.
The next best approach will be observational cohort studies from large centers that have developed skills in managing rare autoimmune disorders to guide clinicians in looking after these women.
The biologic agents, especially B cell-depleting monoclonals such as rituximab, will increasingly be used in treatment-resistant patients with vasculitis.

Although contraindicated in pregnancy, a knowledge base is slowly accumulating in women with other disorders, such as SLE, who have achieved remission following rituximab and who have then had successful pregnancies.