Rituximab and pregnancy: Late-onset neutropenia in a 2-month infant whose mother received rituximab 2 weeks prior to childbirth

Abstract

Late-onset neutropenia (LON) is a rare adverse event that has not been reported from in utero exposure. We describe a case of LON in an infant, whose mother had neuromyelitis optica and received rituximab in the third trimester due to re-emergence of CD19 B cells. The newborn was born without complications but 2 months later was found to have grade IV neutropenia. No etiology was identified. Neutropenia self-resolved within 1 week. This case emphasizes an unmet need for developing guidelines and protocols to manage in utero rituximab exposure.

Introduction

Rituximab is an IgG1 chimeric monoclonal antibody used for treating many autoimmune disorders and is widely prescribed off-label for neuromyelitis optica spectrum disorder (NMOSD). ¹ It acts by depleting pre-B, naive, and memory B lymphocytes. The most common side effects of rituximab are infusion-related reactions and respiratory, urinary, and herpetic infections due to B-cell depletion; however, there are other rare but important adverse events such as hypogammaglobulinemia, CD4 lymphopenia, and late-onset neutropenia (LON). ¹

LON is defined as absolute neutrophil count (ANC) of ⩽1.5 × 10⁹/L (Grade II-IV neutropenia per Common Terminology Criteria for Adverse Events) occurring 4 weeks up to 1 year after receiving rituximab in the absence of a better explanation. ² It is an underrecognized adverse event and the true incidence is unknown, but it has been estimated to be around 5%–8%.^1,3 Most cases of LON are self-limited with variable severity ranging from asymptomatic neutropenia to severe infections requiring hospitalizations. The mechanism of LON is not completely understood as neutrophils are not known to have CD20 receptors.

Information about the safety of rituximab during pregnancy is limited to case reports and case series. Reported in utero exposure in 12 women has been associated with transient infant B-cell depletion. However, there has not been evidence of any pattern of congenital structural abnormalities or major adverse outcomes such as spontaneous abortion or stillbirth.^4,5 Pre-pregnancy exposure is likely safe, particularly when administered at least 3 months prior to conception. ⁵ There have not been any reports of delayed adverse events in newborns of mothers receiving rituximab during pregnancy. Here, we report the first case of delayed-onset neutropenia in a newborn exposed to rituximab during pregnancy.

Case report

A 29-year-old woman with aquaporin-4 antibody-positive NMOSD, stable on rituximab infusion 1000 mg every 6 months for 5 years, became pregnant 1 month after her last infusion. At 36 weeks of gestation, 279 days after her last infusion, the patient was re-infused with 1000 mg rituximab due to the re-emergence of CD19+ B cells from 0% to 1% within 2 weeks between measurements, and a concern for further increase in CD19 counts to 2% or higher by the time of delivery. CD19 counts of 2% or higher are associated with a greater likelihood of NMO relapse.^6,7

After receiving rituximab, she remained clinically stable and 2 weeks later, at term, she delivered her newborn without complications, via vaginal delivery. The newborn was born healthy, and she was discharged home. However, 2 months later, the infant developed Grade IV neutropenia in the setting of a fever and somnolence. His ANC was 0.00, with no other abnormalities found in the other cell lines. The normal ANC range on 2-month infants is estimated to fall between 1.0 and 9.0 × 10⁹/L. ⁸ With this finding, the infant was admitted to the hospital for evaluation and close monitoring. An evaluation, including blood cultures and respiratory viral panel, was unrevealing for infectious cause. The infant remained stable and within 4 days with no intervention, his ANC recovered to 1.51 × 10⁹/L. Given the negative workup and self-resolution of neutropenia, rituximab in utero exposure was felt to be the most likely etiology.

Discussion

This is the first case of an infant who developed LON after rituximab exposure in utero. Due to the increased risk of relapse of NMOSD during pregnancy and associated morbidity and mortality to both mother and the fetus, pregnant women may need to receive rituximab while pregnant.

Limited case reports have shown rituximab to be a relatively safe medication to administer during the first trimester of pregnancy. ⁴ Due to active transport of IgG antibodies across the placenta beginning around weeks 22–26, neonatal B-cell depletion is specially likely when rituximab is given in the second and third trimesters. ⁹ In newborns, transient hematological abnormalities such as B-cell depletion, thrombocytopenia, neutropenia, and anemia have been identified when given before or during pregnancy. ⁴ In a study of 54 patients who received rituximab within 6 months of conception, reduced B-cell number was seen in 39% of newborns, all of which return to normal level within 6 months. ⁹

This case demonstrates the occurrence of delayed-onset neutropenia in infants exposed to rituximab in utero. When evaluating a fever of unknown origin in such infants, it is utmost important to obtain cell blood counts as neutropenic fever could be the culprit of these cases. It highlights the importance of monitoring the exposed infants, both clinically and serologically during the first 3–4 months after birth. In these cases, it is reasonable to monitor total blood cell count and B and T cells. If B-cell depletion is identified, live-attenuated vaccines should not be administered until there is full B-cell reconstitution. Inactivated vaccines do not need to be delayed, but boosters may be considered at a later time in those children who had reduced B-cell numbers and did not achieve protective antibody titers. Additional studies should be performed, and guidelines should be developed to optimize management of newborns in these situations.