Rituximab – A novel therapy for severe ITP in pregnancy: A case report

Short abstract

Background

Rituximab is a novel second-line agent for the treatment of immune thrombocytopenic purpura. Minimal data exist on the use of rituximab in pregnancy. This case illustrates the successful treatment of severe immune thrombocytopenic purpura diagnosed in pregnancy, refractory to all other medical management.

Case

A 32-year-old nulliparous woman was diagnosed with severe immune thrombocytopenic purpura at the time of booking for antenatal care (platelet level of 13 × 10⁹/L). Standard treatment failed to adequately increase her platelet count. Therapy with rituximab was instituted, and her platelet count rose to normal levels, without side effects, and remained at a normal level throughout the pregnancy. There were no maternal or neonatal ill-effects of rituximab therapy.

Conclusion

Rituximab is potentially a safe treatment option for the management of immune thrombocytopenic purpura in pregnancy with good maternal and neonatal outcome when conventional treatments have been unsuccessful. Research is limited to case reports, and therefore limited information currently exists to guide clinicians.

A 32-year-old primiparous woman presented to our hospital for routine booking of antenatal care at 11 weeks of gestation. She reported no significant medical, surgical, gynaecological or family history. An ultrasound scan was performed which confirmed a singleton intrauterine pregnancy and established the estimated date of delivery. Routine booking investigations were performed as per protocol. An initial full blood count revealed a platelet count of 13 × 10⁹/L. Otherwise, the initial booking blood tests were normal, with negative serology (HIV, hepatitis B, syphilis), rubella immune and blood group O rhesus D positive with no antibodies.

Following this, she was referred to the haematology team for further investigations and management. Following routine investigations (antinuclear antibody, lupus anticoagulant, anti-B2-glycoprotein antibodies and anti-cardiolipin antibodies were all negative) a presumptive diagnosis of immune thrombocytopenic purpura (ITP) was given and treatment instituted. Initial treatment included intravenous immunoglobulin (IVIG) and subsequently azathioprine. This resulted in a short-lived response in platelet number (see Figure 1).

Figure 1.

Platelet numbers over time.

With the failure of a sustained response to all agents used to date, a multidisciplinary discussion was held. Given the concerns regarding the risk of high dose steroids and complications with prolonged therapy, steroid use was avoided. Bone marrow aspirate was not performed in view of the initial response to IVIG. A review of the use of rituximab in pregnancy in the literature was conducted. This option was discussed with the patient in detail, including any potential risks. The patient consented to the medication, and at 19 weeks of gestation, four doses of rituximab at a dose of 375 mg/m² of the body surface area were administered weekly for 4 weeks. This elicited an excellent response and platelet numbers rose to a normal range (Figure 1).

From a fetal viewpoint, the pregnancy continued as normal, with normal anatomy ultrasound and growth assessment. Although the maternal platelet count normalised after treatment, the usual precautions regarding fetal intervention were maintained due to the theoretical risk of fetal thrombocytopenia.

This lady presented in spontaneous labour at 37 weeks of gestation. She made excellent progress. The platelet count on the day of delivery was 153 × 10⁹/L, allowing the use of epidural anaesthesia for intrapartum analgesia. There was a spontaneous vaginal delivery of a live-born female infant weighing 3.14 kg, who was in excellent condition.

Umbilical cord blood were taken at delivery, and neonatal blood was assayed on day 4 of life. All neonatal platelet counts and lymphocyte counts were normal. The mother had a routine postnatal course and was discharged home with the early transfer home team. Her platelets remained normal post-natally. All paediatric checks were normal and reassuring. Monitoring of neonatal B lymphocytes on an ongoing basis did not take place.

Postnatal haematology follow up occurred at 6 weeks. She remained well with a platelet titre of 135 × 10⁹/L without any requirement for medication. She was discharged to routine haematology team care and follow-up.

Discussion

ITP is an autoimmune condition wherein auto-antibodies to platelet surface antigens cause the peripheral destruction of platelets by the reticuloendothelial system, especially the spleen.¹ It is relatively rarely encountered in pregnancy, with an incidence of 1–2 per 10,000 pregnancies.¹ It is a diagnosis of exclusion with no diagnostic test and all other causes of thrombocytopenia in pregnancy must be considered.

Rituximab is a chimeric monoclonal antibody directed against the B cell surface antigen CD20.² It has been widely used in the treatment of B cell lymphoid malignancies and in autoimmune conditions such as rheumatoid arthritis and vasculitis.^3,4 It is not licensed for the treatment of ITP but is used for this indication in an ‘off-label’ capacity with good reported results in non-randomised and descriptive studies.^5–7 There are no human studies on the effect of rituximab in pregnancy. The FDA in the United States places it in category C⁸ (use only if clearly needed and benefit outweighs risk) while in the United Kingdom the recommendation is similar.⁹

There are isolated case reports of both normal and abnormal morphological outcome and normal developmental neonatal outcome following unplanned conceptions in women being treated with the drug.^{10–12,14,15} In one case, a woman with rheumatoid arthritis received rituximab at weeks 2 and 4 of gestation in addition to methotrexate; both medications were stopped, and the pregnancy continued with the delivery of a live-born infant at term. Another woman received ritixumab (for treatment of TTP) 9 weeks before confirmed pregnancy; the pregnancy continued healthily, and a live-born infant was delivered at 39 weeks. Follow-up for both of these infants was normal at 2.5 years.¹⁰ A case series of six women receiving rituximab before conception described four normal pregnancies and term deliveries. One woman delivered a live born infant at 31 weeks; another woman delivered a live-born infant at 32 weeks with a congenital anomaly of oesophageal atresia.¹² A further case series of 8 cases (one with ITP) described four pre-term deliveries and four-term deliveries, all infants were morphologically normal.¹² It has also been used in the setting of non-Hodgkin lymphoma in early pregnancy without fetal or neonatal ill-effects.¹⁵

There is very little in the literature on the use of rituximab for the treatment of ITP in pregnancy.^12–14 One paper described administration of rituximab for 4 weeks to a woman with ITP. Despite successfully completing a pregnancy previously with corticosteroids, and having had a splenectomy, standard treatment in a subsequent pregnancy (IVIG and corticosteroids) failed to raise the platelet count. A treatment course of rituximab was commenced. A live-born infant was born at 38 weeks of gestation; the infant was initially admitted to neonatal intensive care but recovered well and was well to follow-up at 1 year.¹² The second case was similar to ours – a 34-year-old woman presenting with ITP at 23 weeks of gestation where standard treatment was unsuccessful (corticosteroids, IVIG, splenectomy). Due to ongoing bleeding, rituximab was administered at 26 weeks of gestation with a sustained rise in platelet count (>100 × 10⁹/L). There were no neonatal complications of rituximab therapy.¹³ It is also important to note that neonates exposed to rituximab in utero have a risk of B lymphocyte depletion, especially if it is administered within 6 months of delivery.¹⁴

Conclusion

As illustrated in the above case, rituximab is potentially a viable treatment option for the management of ITP in pregnancy when standard treatments have been unsuccessful, with good maternal and neonatal outcome. However, the limited research basis means that further studies are required before more detailed recommendations can be made.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The patient has given written consent for inclusion in this case report.

Guarantor

FD.

Contributorship

Principal composition and literature review for this case report was performed by FD. All other authors were involved in the review and correction process prior to submission.