East Asian Arch Psychiatry 2010;20:145-50

CASE REPORT

Dr Bonnie Wei-man Siu, MRCPsych, FHKCPsych, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Ms Hesione Miu-tung Chow, MHSc, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Ms Shirjolina Shun-ping Kwok, BHSc, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Ms Oi-lin Li, BSc, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Ms Mei-ling Koo, CertNurs, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Ms Pik-wa Poon, CertNurs, Department of Psychiatry, Castle Peak Hospital, Hong Kong.

Address for correspondence: Dr Bonnie Wei-man Siu, Department of Psychiatry, Castle Peak Hospital, Hong Kong.
Tel: (852) 2456 7111; Fax: (852) 2456 9118; Email: bonniew114m@yahoo.com

Submitted: 16 February 2010; Accepted: 27 April 2010

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Introduction

Accumulating evidence suggests that pregnancy does not protect women from mental illness.^1-3 Studies have shown that 1 in 10 women experienced depression during pregnancy.^2-3 Despite the fact that depression during pregnancy is common, new-onset acute psychosis during pregnancy is extremely rare.⁴ A classic epidemiological study⁵ estimated that the risk for developing a severe mental illness in pregnancy is 7.1 per 10,000 population per year. New-onset psychosis during pregnancy in a previously healthy woman should trigger careful investigations for an underlying medical cause.⁴

The activity of the immune system changes during pregnancy and some women may have onset or exacerbation of an autoimmune disease during pregnancy. Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems, including the heart, joints, skin, kidneys, and the nervous system, and pregnancy can exacerbate SLE.^6-8 Systemic lupus erythematosus is the autoimmune disease most commonly influenced by pregnancy as it usually occurs in women of childbearing age and its outcome is affected by hormonal changes.⁹ Prospective and retrospective studies have reported a frequency of 18 to 74% for an exacerbation of SLE during pregnancy.^10-13 Psychosis is one of the neuropsychiatric syndromes in SLE and can sometimes be the primary manifestation, antedating other evidence of the disease.¹⁴ The prevalence of psychosis in SLE varies from 2 to 7% in different studies.^15-17 Psychosis as the first presentation of SLE and exacerbation of SLE during pregnancy have been discussed extensively in the literature but, to date, there has been no local report of a pregnant woman presenting with psychosis due to SLE.^6-8,14 This report describes a Chinese woman presenting with psychosis, who was later confirmed to have SLE with antiphospholipid syndrome complicating pregnancy.

Case Report

A 28-year-old Chinese primiparous woman was referred by an obstetrician to the Department of Psychiatry, Castle Peak Hospital, Hong Kong, in 2008 for assessment. She had been taking herbal medicine for facial acne before she found out that she was pregnant on 1 January 2008. She was admitted to the Obstetrics and Gynaecology (OG) ward of Tuen Mun Hospital (TMH), Hong Kong, in late February at 14 weeks of gestation for hyperemesis gravidarum. Promethazine 25 mg 3 times daily as required was prescribed.

Because of an unplanned pregnancy and increased work stress, the patient also had depressed mood, apprehension, increased irritability, and difficulty in falling asleep. Her depressed and irritable mood was not persistent and there was no diurnal mood variation or early morning wakening. She had decreased appetite because of hyperemesis gravidarum. She had no negative cognition and no suicidal ideation. She had good past health, with no personal or family history of mental illness. She was born in Hong Kong and was educated to university level. She was living with her husband who was supportive. She had been working as an assistant social welfare officer in a home for elderly people. Premorbidly, she was an anxiety-prone person, who set high standard for herself. She did not smoke cigarettes or drink alcohol, and had no history of substance abuse. She was a Christian.

Ultrasound scan performed on the OG ward of TMH on 24 February showed a single viable fetus appropriate for its gestational age. Routine antenatal blood tests done at the Maternal and Child Health Centre revealed no abnormalities. On 25 February, she had sudden onset of irrelevant speech with labile mood. She became paranoid and restless. She complained of seeing ghosts and hearing voices talking to her incessantly. She was oriented to place and person. She was afebrile with normal blood pressure and physical examination revealed no focal neurological deficit. She was examined for suspected organic causes of acute psychosis. Electroencephalogram (EEG) revealed no abnormalities; urine for drug screen showed no significant findings; blood tests for renal function, liver function, complete blood count, calcium, phosphate, and thyroid function were normal; blood test for anti-nuclear antibody was performed. Computed tomography (CT) of the brain with the use of an abdominal shield and lumbar puncture were suggested, but her husband declined these investigations. The herbal medicine that she had been taking before she knew about the pregnancy was not available for further analysis.

She was seen by the liaison psychiatrist at TMH and was diagnosed with acute psychosis. As her husband deferred further organic examinations, including lumbar puncture and CT of the brain, and she was considered medically fit for transfer to the psychiatric ward at TMH, she was subsequently transferred on 28 February for management by the Comprehensive Child Development Service psychiatric team, which is responsible for the care of antenatal and postnatal women with mental health problems in Hong Kong.¹⁸

After admission to the psychiatric unit, her mental condition continued to fluctuate, but she was oriented to place and person. Her speech was irrelevant most of the time with loosening of association. She talked about ‘God’ and ‘Holy water’. She expressed seeing ghosts and evils, and felt she was being referred to and persecuted by the nursing staff. She was restless and irritable, and attacked the nursing staff. She was sleepless and talkative, and she shouted aloud, using foul language, at night. She believed that her food was being poisoned by the nursing staff and she only ate food brought in by her husband. After discussion with her husband about the risks and benefits of antipsychotic medications for her and her fetus, oral trifluoperazine 2 mg daily, which is considered to have minimal risk of teratogenicity,^19,20 was prescribed on 28 February.

Trifluoperazine was increased to 5 mg daily and her mental condition gradually improved after 1 week. Further discussion was held with her husband on the possibility of organic causes of acute psychosis and her husband agreed to proceed with CT of the brain with an abdominal shield, but the result was normal. However, she was found to have decreasing platelet counts from 149 x 10⁹ /L at admission to the psychiatric ward on 28 February, to 65 x 10⁹ /L on 4 March (reference range, 150-450 x 10⁹ /L). Blood test for anti-nuclear antibody was positive, with a titre of 80. She was afebrile with normal vital signs. She was clinically well-hydrated and there were no signs of bleeding tendency. A medical doctor was consulted for thrombocytopenia on 4 March, and she was suspected to have differential diagnoses of idiopathic thrombocytopenic purpura and SLE complicating pregnancy. She was transferred to the medical ward for further investigations on the same day. She had no other signs and symptoms of SLE such as rash, oral ulcer, alopecia, or joint pain.

After admission to the medical ward, a haematologist was consulted and conservative treatment with close monitoring of her platelet count was suggested. A rheumatologist was also consulted and further blood tests, including anti–double-stranded DNA and antiphospholipid antibodies (anticardiolipid antibody and lupus anticoagulant) for suspected SLE were suggested. As the medical doctor advised that she did not fulfil the diagnostic criteria for SLE, conservative treatment was recommended while waiting for the results of subsequent blood tests. She was seen by an obstetrician in the medical ward on 5 March, and physical examination revealed a uterus size compatible with gestational age and Doppler scan was positive. However, she refused psychiatric medications and her mental condition deteriorated with increased irrelevant speech and deteriorating sleep. She was transferred back to the psychiatric ward on 10 March.

In the psychiatric ward, her mental condition continued to improve. She became settled and cooperative despite some residual referential delusions. Oral trifluoperazine was gradually increased to 8 mg daily. She was seen by an obstetrician on 11 March and ultrasound scan done on the same day showed a single viable fetus appropriate for gestational age. On 3 April, at 19 weeks of gestation, she underwent diagnostic structural ultrasound investigation in the OG unit, which revealed intrauterine growth retardation, placenta praevia, severe oligohydramnios, and calcifications over the abdominal wall of the fetus. The obstetrician opined that the viability of the fetus would be low if her pregnancy continued and suggested a placental biopsy to investigate for genetic disorders of the fetus. After discussion with her husband, the obstetrician and the psychiatrist, she decided to terminate the pregnancy, which was done on 7 April, after 3 doses of per vaginal misoprostol. Ultrasound scan showed complete termination of pregnancy with no placental tissue retained in the uterus. Placenta tissue was saved for karyotyping. She was assessed by a psychiatrist, and Mental State Examination found that her mood was stable and euthymic, and she had some residual referential ideas. She was discharged home on 9 April and follow-up was arranged at the Psychiatric Specialist Outpatient Clinic at TMH.

Her blood test results, which later became available, are summarised in the Table, together with her earlier blood test results. Abortus and placenta morphology revealed a female abortus compatible with 17 to 18 weeks of gestation, with placental infarct with focal ischaemic necrosis of chorionic villi, and the fetus had low set ears and a hard abdominal wall. Based on the clinical information and investigation results, a rheumatologist confirmed the diagnosis of SLE with antiphospholipid syndrome. Oral azathioprine 50 mg daily was prescribed and her platelet count increased to 125 x 10⁹ /L subsequently. She continued to attend follow-ups at the Psychiatric Specialist Outpatient Clinic and her psychotic symptoms subsided gradually and the antipsychotic medication was gradually decreased. However, she had a subsequent depressive episode related to worries about the subsequent course of SLE, the feasibility of any future pregnancy, and her resignation from her job. The antidepressant citalopram 20 mg daily was prescribed and she was referred to a clinical psychologist for treatment. Her mood improved, and she is currently well maintained with citalopram 20 mg daily and azathioprine 50 mg daily prescribed by the psychiatric outpatient clinic and the rheumatology outpatient clinic, respectively.

Discussion

It is uncommon for a Chinese woman with good past health to present with first-episode psychosis in the second trimester of pregnancy. The sudden onset of psychotic symptoms and her fluctuating mental condition with visual hallucinations was highly suggestive of an organic cause for the psychosis, despite the negative findings of EEG and CT. It was not until after the pregnancy was terminated, when her blood test results became available that a diagnosis of SLE with antiphospholipid syndrome was made. The diagnosis was based on the 11 criteria established by the American College of Rheumatology to clarify the definition of SLE.^21,22 She matched 4 of the 11 criteria of psychosis (neurologic disorder); positive anti-nuclear antibody test; thrombocytopenia and hypocomplementaemia with low C3 (haematologic disorder); and positive antiphospholipid antibody test (immunologic disorder).

Systemic lupus erythematosus is the autoimmune disease that can be most commonly compromised by pregnancy because of its fluctuant nature with alternate periods of clinical activity and remission, and hormonal changes can trigger reactivation.⁹ Prospective and retrospective studies have reported a frequency of exacerbation of SLE during pregnancy of 18 to 74%.^10-13 Onset and exacerbation of SLE during pregnancy was first reported as long ago as 1952.⁶ In 1962, Garsenstein et al⁷ reported the increased incidence of exacerbation of SLE during the first 20 weeks of pregnancy. Zurier⁸ concluded that patients with SLE frequently had exacerbations of disease activity either during pregnancy or in the early postpartum period. Apart from pregnancy, there were other possible causes for SLE onset in this patient. The index pregnancy was unplanned by the patient so was a stressful life event, and she had increased work stress during the pregnancy. Exposure to stress can be a cause of SLE. The patient had been prescribed promethazine for hyperemesis gravidarum, which belongs to the phenothiazide group of drugs that can induce SLE. She had also taken herbal medicine for acne just before she knew she was pregnant, and it is possible that the herbal medicine precipitated the onset of SLE. The possibilities of the abnormal fetus or infection causing SLE could not be excluded for this patient.

The patient’s prominent psychotic symptoms of thought disorder, sleeplessness, talkativeness, and increased irritability suggested a differential diagnosis of schizophrenia and mania with psychotic symptoms. However, the sudden onset of psychotic symptoms during pregnancy and her fluctuating mental condition with visual hallucination indicated an organic cause, and delirium was one of the differential diagnoses. Systemic lupus erythematosus was suggested to be the cause of acute psychosis instead of delirium as she still had residual psychotic symptoms in clear sensorium before the treatment for SLE was started. Involvement of the nervous system is one of the most profound manifestations of SLE, encompassing a wide variety of neurologic and psychiatric features.^23,24 Central nervous system involvement can sometimes be the primary manifestation, antedating other evidence of the disease by months or years.¹⁴ Psychosis in association with SLE has a prevalence of 2 to 7%.^15-17 Although serum anti–ribosomal P antibodies are suggested to be strongly associated with the development of psychosis in SLE,²⁵ the patient’s serum anti–ribosomal P antibodies were negative. Antipsychotics or a combination of antipsychotics, corticosteroids, and immunosuppressants are the treatment of choice for psychosis in SLE.²⁶ Antipsychotic medication was prescribed, but corticosteroids or immunosuppressants were not started until the diagnosis of SLE was confirmed. However, antipsychotics are only used for symptomatic control of psychosis in SLE, and the mainstay of management is treatment of the underlying disease process with immunosuppressants or high-dose corticosteroids, depending on the clinical features.^26-28 When the psychosis is well controlled, antipsychotics can be decreased or stopped, with immunosuppressants and / or corticosteroids as the maintenance medications.^26-28 Data on the prognosis and long-term outcome of psychosis in SLE are rare. In a recent retrospective study, Pego-Reigosa and Isenberg²⁹ found that the long-term outcome for patients with psychosis in SLE was favourable, with 60% of the study population having complete resolution of psychosis 1 year after diagnosis and treatment, and 70% achieved complete remission for up to 20 years. The prognosis and outcome of SLE has improved in recent years, and many people with SLE have mild disease, with a 10-year survival rate of over 85%. Factors that are associated with poor prognosis (approximately 50% mortality in 10 years) include high serum creatinine levels, hypertension, nephrotic syndrome, anaemia, hypoalbuminaemia, and hypocomplementaemia at the time of diagnosis.^30,31 Apart from a slightly low complement C3, the patient did not have any of the unfavourable prognostic factors at the time of diagnosis.

The patient was diagnosed to have SLE with antiphospholipid syndrome, which is also known as ‘sticky blood’, an autoimmune disorder in which the body makes antibodies to its own phospholipids or plasma proteins. Clinically important antiphospholipid antibodies are associated with thrombosis and vascular disease, and antiphospholipid syndrome is associated with recurrent spontaneous abortion and intrauterine growth retardation in the second and third trimesters of pregnancy. The diagnosis of antiphospholipid syndrome was made for this patient because of the positive antiphospholipid antibody test and the obstetric complications.^32,33

The patient was concerned about the feasibility of any future pregnancy after the diagnosis of SLE with antiphospholipid syndrome. Systemic lupus erythematosus can become exacerbated during pregnancy, and is associated with significant maternal and fetal morbidity, including spontaneous miscarriage, pre-eclampsia, intrauterine growth retardation, fetal death, and preterm delivery.³⁴ Neonatal lupus is a rare disease that can occur in neonates born to women with SLE, and is associated with serious heart problems in the babies and anti-Ro and anti-La autoantibodies in the women’s blood.³⁴ Antiphospholipid syndrome is associated with placental insufficiency with preterm labour, intrauterine growth retardation, pre- eclampsia, and fetal death.^35-38 Although women with SLE who became pregnant are at high risk, many of them continue to have full-term babies. Pregnancy counselling and planning are important and, ideally, women should have no signs or symptoms of disease and should not have medications for at least 6 months before becoming pregnant.³⁹ Pregnant women with SLE who are known to have antibodies for anti-Ro or anti-La should have regular echocardiograms from the 16th to 30th weeks of pregnancy to monitor the fetal heart. During pregnancy, medications that can be considered for SLE are corticosteroids such as prednisone, and immunosuppressants like azathioprine and cyclosporine A, while methotrexate, cyclophosphamide, and mycophenolate are contraindicated.^37,40 Low-molecular- weight heparin and low-dose aspirin can be used to reduce the incidence of recurrent miscarriage, intrauterine growth retardation, and fetal death for pregnant patients with antiphospholipid syndrome.⁴¹ Intravenous immunoglobulin can be considered for pregnant women with SLE, especially those with a history of recurrent spontaneous abortions.⁴²

This is the first local report of a patient presenting with psychosis in SLE having an antiphospholipid syndrome with onset in the second trimester of pregnancy. This report highlights the importance of consideration of an organic cause for psychosis, including SLE, especially when it occurs for the first time in a previously healthy pregnant woman. This patient was prescribed oral trifluoperazine, a first-generation antipsychotic that is considered to carry minimal risk of teratogenicity.^19,20

There is controversy about whether corticosteroids or immunosuppressants, which could have adverse effects on the fetus, should be given earlier when the diagnosis of SLE had not yet been confirmed, despite a high possibility of SLE based on the presentation of psychosis, decreased platelet count, and positive anti-nuclear antibody test. This patient decided to terminate the pregnancy as the viability of the fetus was low. At subsequent follow-ups, she has been advised on the consequences of any future pregnancy and to discuss any planned pregnancy with the psychiatrist and rheumatologist to maintain an optimum mental and physical condition.

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