A rare case of recurrent pregnancy loss associated with high-titer positivity for perinuclear anti-neutrophilic cytoplasmic antibodies.

We present a case of recurrent pregnancy loss associated with unusual constellation of utoimmunity-related features such as hypertension, severe hrombocytopenia, hypothyroidism and persistent high titers of perinuclear antineutrophilic cytoplasmic antibodies. Her clinical features did not fit into a particular diagnosis of vasculitides, systemic lupus erythematosis (SLE) or other known autoimmune diseases where this autoantibody is found in high titers. We report the unusual association of this autoantibody with recurrent early fetal demise in this case.

INTRODUCTION

Association of autoimmunity and recurrent pregnancy loss (RPL) is well known. We present a rare case of RPL associated with severe immune thrombocytopenia, accelerated hypertension, hypothyroidism, positive results for antinuclear antibodies (ANA), anti-dsDNA antibodies and persistent high-titer positivity for perinuclear antineutrophilic cytoplasmic antibodies (pANCA). Association of high titers of pANCA has not been reported with recurrent pregnancy loss so far in the literature. Although her features did not fit into the diagnosis of vasculitic/non-vasculitic autoimmune illnesses, p-ANCA titers persisted high and all her three pregnancies ended up in fetal demise.

CASE REPORT

Mrs X presented to the physician with severe headache, grade one-two dyspnea on exertion and blurring of vision. Her blood pressure was 210/130 mmHg and she was found to have hypertensive retinopathy, echocardiography showed vegetations on the mitral leaflet (non-bacterial thrombotic vegetations) along with mild-moderate mitral regurgitation and left ventricular hypertrophy, her ESR was 59 mm/h. She tested positive for ANA (1:3.2), anti-dsDNA and antimitochondrial antibody. p-ANCA was detected in high titers (indirect immunofluorescence assay for antimyeloperoxidase antibody) and cytoplasmic ANCA was negative. However, her features did not fit into the diagnosis of SLE or other autoimmune vasculitic syndromes. She was not pregnant at the time of this presentation. Her hypertension was controlled with antihypertensive medications. The echocardiographic features and ophthalmic manifestations settled over 2 weeks’ time.

Her obstetric history was remarkable with two unexplained fetal demises at 11 and 19 weeks of gestation. No other details regarding the previous pregnancies were available except for the ultrasonographic evidence suggestive of absent cardiac activity in well-formed fetuses at 11 and 19 weeks of her two previous pregnancies. Evaluation for recurrent pregnancy loss was made, which did not reveal a specific cause. Antiphospholipid Antibody (APLA) Syndrome was excluded. She was hypothyroid on medications. She tested negative for anti-Thyroid antibodies.

Her subsequent pregnancy was complicated by severe thrombocytopenia (platelets 20,000) and bone marrow biopsy suggesting peripheral destruction of platelets. She tested negative for ANA, anti-dsDNA and antiplatelet antibodies, but p-ANCA was detected in high titers (>100 U/mL). Platelet count stabilized at 25,000/mL without any bleeding features and, therefore, immunosuppressive therapy was withheld. However, fetal demise was diagnosed at 13 weeks. Manual vacuum aspiration was done after stabilizing platelet counts at 56,000/ mL with platelet transfusions and corticosteroids. Placenta did not show features of vasculitis. Thrombocytopenia improved after 1 month.

DISCUSSION

Several autoantibodies are associated with RPL.[1] However, testing for autoantibodies other than APLA is not recommended currently as their association has not been consistent.[2]

This lady had RPL, unusual constellation of autoimmunity-related features and persistently elevated p-ANCA. p-ANCA is associated with several vasculitic and non-vasculitic autoimmune disorders. Systemic necrotizing vasculitides (SNVs) are known to be associated with pregnancy complications, including miscarriage, pre-term delivery, some increase in vasculitic activity and, rarely, life-threatening complications in the mother.[3] But, her clinical features did not fit into any of the SNVs or other autoimmune diseases where p-ANCA is known to be elevated.

So far, there have been two case reports of microscopic polyangiitis (MPA) in which transplacental transfer of p-ANCA has been reported.[45] In one of them, these autoantibodies resulted in life-threatening lung and kidney manifestations in the newborn, and this has been considered as direct clinical evidence that this antibody is pathogenic. However, in the second case, the newborn was unaffected despite a high titer positivity of p-ANCA, which persisted up to 120 days in the neonate. The second case emphasizes that p-ANCA alone may not be pathogenic without other cofactors indicating disease activity.

Association of persistent high titers of p-ANCA with RPL is not reported so far in the literature. However, it is unsure whether these autoantibodies are independently responsible for her pregnancy failure. Severe thrombocytopenia reflects exacerbation of her autoimmunity during pregnancy, which in turn may be responsible for the fetal demise. We propose that immunosuppression with corticosteroids may be beneficial in her next pregnancy, despite the fact that she does not fit into the diagnosis of any particular autoimmune disorder.

Unusual autoantibodies may be associated with pregnancy failure, even without clinical manifestation of the autoimmune disease with which the autoantibodies are usually associated. Testing a panel of autoantibodies may be useful in unexplained RPL,[6] as rare autoimmunity may be associated with RPL. It may be useful to study the association of rare autoantibodies like p-ANCA with RPL. Further treatment options could be explored, which may include immunosuppression or tackling the cause of pregnancy failure with the specific autoantibody.