Unexpected pregnancy in a patient with AQP4-IgG + NMOSD after treatment with inebilizumab: a case report

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammatory demyelinating lesions affecting the optic nerve and spinal cord. As a rare condition, its clinical management—particularly in special populations such as pregnant patients—remains challenging. Inebilizumab, a B-cell-depleting biological agent used in aquaporin-4 immunoglobulin G-positive(AQP4-IgG+) NMOSD treatment, has demonstrated efficacy in disease control. However, no prior clinical reports have described its use in pregnant patients or the associated long-term maternal, fetal, and disease outcomes, leaving a critical gap in evidence. This case report, therefore, aims to address this knowledge deficit by presenting the first detailed account of an unexpected pregnancy in a patient receiving inebilizumab maintenance therapy, alongside the subsequent management strategies and outcomes.

Case presentation

We report a female patient with AQP4-IgG + NMOSD who experienced an unexpected pregnancy during three cycles of inebilizumab maintenance therapy. A multidisciplinary team (neurologists, obstetricians, and immunologists) collaborated to develop an individualized treatment plan. Following confirmation of pregnancy, her therapy was adjusted to low-dose methylprednisolone combined with azathioprine. During pregnancy, monitoring revealed persistently low B-cell counts, with low serum AQP4-IgG titers in the second trimester. The patient achieved a safe delivery and promptly resumed inebilizumab post-partum. Notably, no NMOSD recurrence was observed during the pre-conception, pregnancy, or post-partum periods.

Conclusions

This study is the first to report the successful management of an unplanned pregnancy in AQP4-IgG + NMOSD patient receiving inebilizumab. It confirms the efficacy and safety of preconception targeted B-cell depletion, individualized immunotherapeutic maintenance under multidisciplinary guidance during pregnancy, and timely resumption of targeted therapy postpartum, providing important clinical references for optimizing perinatal treatment strategies in reproductive-aged AQP4-IgG + NMOSD patients.

Background

NMOSD is a group of central nervous system demyelinating diseases primarily characterized by autoimmune-mediated involvement of the optic nerve and spinal cord, Approximately 80% of patients have detectable AQP4-IgG in their serum [1]. In recent years, novel biologics targeting B cell depletion, blocking the interleukin-6 signaling pathway, and inhibiting the complement system have significantly changed the treatment landscape for AQP4-IgG + NMOSD. However, managing AQP4-IgG + NMOSD during pregnancy remains a clinical challenge, as previous studies have indicated that pregnancy may increase the risk of disease relapse, and continuous immunosuppressive therapy is crucial for maintaining disease stability [2]. Inebilizumab, a B-cell-depleting biological agent used in AQP4-IgG + NMOSD treatment, has demonstrated efficacy in disease control. However, no prior clinical reports have described its use in pregnant patients or the associated long-term maternal, fetal, and disease outcomes, leaving a critical gap in evidence. This case report, therefore, aims to address this knowledge deficit by presenting the first detailed account of an unexpected pregnancy in a patient with AQP4-IgG + NMOSD receiving inebilizumab maintenance therapy, alongside the subsequent management strategies and outcomes.Through multidisciplinary collaboration, an individualized treatment plan was developed, successfully achieving a relapse-free pregnancy and safe delivery, offering valuable insights for using biologics in unique patient populations.

Case presentation

The patient is a 27-year-old woman who experienced a decline in vision in her right eye to light perception, limb weakness, sensory disturbances, and urinary and fecal incontinence in January 2020.

There are small patchy slightly hyperintense T2 signals with positive enhancement in the right optic nerve. Linear hypointense T1 and hyperintense T2 signals with positive enhancement are observed in the medulla oblongata and the spinal cord corresponding to cervical vertebrae C1-C3. The AQP4-IgG + titer was 1:320 in serum by cell-based assay(CBA), leading to a diagnosis of AQP4-IgG + NMOSD. After treatment with high-dose methylprednisolone combined with cyclophosphamide and rehabilitation, the patient’s limb weakness, urinary and fecal incontinence, and sensory disturbances gradually returned to normal. However, her right eye vision remained impaired, recovering only to a distance of 30 cm. Subsequently, she was placed on oral methylprednisolone 8 mg once daily combined with mycophenolate mofetil 0.5 g twice daily for relapse prevention. Despite this, the patient experienced four relapses characterized by vision decline in her right eye, each time treated with high-dose methylprednisolone and intravenous immunoglobulin, which restored her vision to pre-relapse levels. The last relapse occurred on September 19, 2023.On September 25, 2023, optic nerve MRI revealed that the right optic nerve exhibited hypointensity on T1WI and hyperintensity on T2WI, with mild enhancement noted on contrast-enhanced sequences (Fig. 1). Due to the frequency of relapses, inebilizumab was administered at a dose of 300 mg on three occasions: November 10, 2023 (Dose 1), November 30, 2023 (Dose 2), and June 6, 2024 (Dose 3). The patient maintained sustained remission following inebilizumab therapy. During this period, the patient’s CD19 + B cell percentages, monitored on September 24, 2023, November 8, 2023, November 10, 2023, November 27, 2023, November 29, 2023, and May 20, 2024, were 13.9%, 13.63%, 0.06%, 0.14%, 0.23%, and 0.02%, respectively (Fig. 2). An unplanned pregnancy was confirmed on July 30, 2024, with the last menstrual period (LMP) on June 25, 2024. The patient was then regularly monitored in a multidisciplinary outpatient clinic consisting of neurology, obstetrics and gynecology, and clinical pharmacy.

Fig. 1.

The MRI of optic nerve revealed that the right optic nerve exhibited hyperintensity on T2WI (A, arrows), with mild enhancement noted on contrast-enhanced sequences (B, arrows)

Fig. 2.

Longitudinal measurements of AQP4-IgG titer in serum and the percentage of CD19 + B cells before, during, and after pregnancy demonstrating declining serum AQP4-IgG titer and near complete B-cell depletion, along with inebilizumab infusions and other medication from 2023 to 2025

Pregnancy process

After discussions among the departments of neurology, obstetrics and gynecology, and the clinical pharmacy, a treatment plan was established. During pregnancy, the patient received 4 mg of methylprednisolone daily along with 50 mg of azathioprine twice daily. Throughout the pregnancy, low levels of B cell depletion were maintained (Fig. 2). In mid-pregnancy, serum AQP4-IgG was measured at a titer of 1:32, and a three-dimensional ultrasound showed no structural abnormalities in the fetus, with normal growth and development. The patient requested a cesarean section and underwent successful delivery at 38⁺⁵ weeks of gestation, with both the mother and neonate in good condition.

Infant and maternal outcomes

The infant’s appearance, facial expressions, pulse, activity, and respiratory scores were normal, with a birth weight of 2.8 kg. Routine blood tests showed normal counts of white blood cells, platelets, red blood cells, and lymphocytes.The infant was born with hypospadias and showed moderate jaundice on the second day, which normalized after ten days. The patient opted for artificial feeding. Follow-up at 3 months postpartum, the infant had a normal growth curve, had completed routine vaccinations as scheduled, and no abnormalities were observed during vaccination.

As for the mother, she experienced an uneventful postnatal course without complications, including postpartum hemorrhage. She was in good health, with stable examination results. On the tenth day postpartum, her percentage of CD19 + B cells was 0.2%, the AQP4-IgG + titer was 1:320 in serum, and on the following day, she received 300 mg of inebilizumab treatment. Sixteen days after treatment, her percentage of CD19 + B cells further decreased to 0.01% (Fig. 2). Follow-up at 3 months postpartum, there were no relapses or infections during the entire pregnancy and three months postpartum.

Discussion and conclusions

AQP4-IgG + NMOSD is an autoimmune disease primarily involving the optic nerve and spinal cord, with perinatal management in reproductive-aged women remaining a clinical challenge. Pregnancy and the 3-month postpartum period are high-risk for relapse — patients with a prior relapse within 1 year have a 3.5-fold higher recurrence risk [2]. High disease activity pre- or during pregnancy increases miscarriage risk, potentially linked to AQP4 antibody-mediated placental inflammation [3]. Thus, maintaining perinatal disease stability and reducing relapse risk is key to improving maternal and neonatal outcomes.

Inebilizumab is a humanized IgG monoclonal antibody targeting CD19 that depletes the full spectrum of B cells — spanning from B progenitor cells to terminally differentiated plasma cells — via antibody-dependent cellular cytotoxicity (ADCC). By reducing AQP4-IgG production at the source and inhibiting immune-mediated damage to the central nervous system (CNS) [4, 5], it has now been approved for the treatment of AQP4-IgG + NMOSD patients. In this case, the patient completed three doses of inebilizumab prior to pregnancy, with serum AQP4-IgG titer declining from 1:320 to 1:32 and CD19 + B cells persistently sustained at low levels — a finding closely aligned with inebilizumab’s mechanism of action. Multiple studies endorse pre-pregnancy CD20-targeting B-cell depleting therapies (including ocrelizumab, ofatumumab, and rituximab) as preferred disease-modifying therapy (DMT) options for patients with multiple sclerosis(MS)/NMOSD who are planning pregnancy [6–10]. Discontinuing such therapy during pregnancy and resuming it postpartum not only effectively mitigates the risk of disease relapse but also minimizes fetal exposure(IgG molecules do not cross the placenta in the first trimester), thereby lowering the risk of fetal B-cell depletion. As a B-cell depleting agent of the same class, inebilizumab has a terminal half-life of approximately 18 days [4, 5, 11]. The patient conceived one month after the last dose; by the end of five half-lives (approximately 90 days) — preceding the second trimester — maternal serum drug concentration was exceedingly low. Combined with the absence of placental crossing in early pregnancy, this translated to an extremely low actual risk of fetal exposure.

The pregnancy outcomes associated with inebilizumab treatment remain unclear, and experience with anti-CD20 agents may serve as a reference [12]. Current evidence indicates that prenatal exposure to B-cell depleting agents does not increase the risk of birth defects [13–16]. Guidelines from multiple countries permit the continued use of rituximab during pregnancy for patients with AQP4 + NMOSD and inadequate disease control, particularly when no satisfactory alternative therapies are available or when maternal benefits outweigh potential fetal risks [17–23]. The international Delphi consensus on AQP4 + NMOSD recommends that the use of inebilizumab during pregnancy may be guided by the experience with rituximab [17]. Similarly, the Polish guidelines suggest that inebilizumab can be continued in pregnancy if maternal benefits outweigh the potential fetal risks [18].

The discontinuation of inebilizumab during pregnancy in this case was primarily driven by the paucity of data on its use as a single agent in pregnancy and concerns that exposure in the second and third trimesters might lead to fetal B-cell depletion. However, current guidelines do not recommend discontinuing DMT only because of pregnancy. Given the patient’s history of recurrent optic neuritis prior to pregnancy — which carries a high risk of disability — the adjustment to azathioprine combined with maintenance of low-dose glucocorticoids during pregnancy aligns with the consensus on perinatal management [18, 22–24]. Azathioprine and glucocorticoids prevent recurrence through inhibiting lymphocyte activation and proliferation. While azathioprine is recommended by guidelines from multiple countries for the maintenance treatment of AQP4 + NMOSD during pregnancy [18, 22, 23], its metabolite, 6-mercaptopurine, may exhibit embryotoxicity [25]. Hypospadias was identified in the neonate of this case; although no direct evidence establishes a causal relationship with azathioprine, the relatively low incidence of hypospadias in the general population necessitates cautious interpretation of this adverse outcome.

Following B-cell depletion, re-differentiation and maturation rely on bone marrow hematopoietic stem cells — a process that typically spans several months to one year, with substantial interindividual variability in recovery kinetics [26, 27]. The therapeutic effect of a single treatment course can persist for a prolonged duration. As illustrated in this case, for AQP4-IgG + NMOSD patients who achieved sustained B-cell depletion and disease stability through pre-pregnancy inebilizumab therapy, additional azathioprine or steroids may be unnecessary during pregnancy to mitigate maternal and fetal risks. This proposition requires further investigation; clinically, CD19 + B-cell count could serve as a reference for determining the initiation of additional medication in future practice.

The first 1–3 months postpartum constitute a high-risk period for AQP4-IgG + NMOSD relapse [11]. In this case, the patient resumed inebilizumab therapy on postnatal day 11, which resulted in a further reduction in CD19 + B-cell count and no relapse within 3 months postpartum — a finding that confirms the importance of timely reinitiation of B-cell depleting therapy [7, 10]. Additionally, comprehensive management delivered by a multidisciplinary team (encompassing neurology, obstetrics, and clinical pharmacy) provided critical support for treatment regimen adjustments, prenatal monitoring, and the protection of maternal and fetal safety. This approach aligns with the perinatal multidisciplinary management model for NMOSD recommended by the French Multiple Sclerosis Society [23].

This study has several limitations. First, studies demonstrate that administration of B cell-depleting agents during the second and third trimesters of pregnancy is associated with transient B cell depletion in neonates [26]. the follow-up duration was only 3 months postpartum, which precluded the assessment of long-term maternal disease control and neonatal immune function. Specifically, neonatal CD19 + B-cell counts and immunoglobulin levels were not monitored—only lymphocyte counts were documented as normal—and future investigations should extend the follow-up period to more than 1 year to address this gap. Second, the neonate in this case did not receive breastfeeding, resulting in a lack of direct data regarding the compatibility of inebilizumab with breastfeeding. Third, the FCGR3A polymorphism was not monitored to assess the therapeutic efficacy of the medication.Finally, as a single-case report, the conclusions have limited generalizability to the broader population. Larger-sample clinical studies are therefore warranted to further validate the safety and efficacy of inebilizumab in the perinatal management of patients with AQP4-IgG + NMOSD.

In conclusion, this study presents the first report of successful management of an unplanned pregnancy occurring during inebilizumab treatment in a patient with AQP4-IgG + NMOSD. It validates the efficacy and safety of a three-component strategy: pre-pregnancy targeted induction of B-cell depletion, individualized immune maintenance under multidisciplinary oversight during pregnancy, and timely reinitiation of targeted therapy postpartum. This case offers valuable clinical insights for optimizing perinatal treatment paradigms in reproductive-aged patients with NMOSD. Nevertheless, the clinical utility of immunosuppressants during pregnancy and their potential association with adverse neonatal outcomes necessitate further elucidation through large-scale cohort studies.

Abbreviations

NMOSD

Neuromyelitis optica spectrum disorder

AQP4

Aquaporin-4

AQP4-IgG+

Aquaporin-4 immunoglobulin G-seropositive

LMP

Last menstrual period

DMT

Disease-modifying therapy

MS

Multiple sclerosis

CBA

Cell-based assay

CNS

Central nervous system

ADCC

Antibody-dependent cellular cytotoxicity

Authors’ contributions

Feiyan Wan; Conceptualization; Data curation; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.Xia Wu: Conceptualization; Data curation; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.Yuanyuan Tan: Conceptualization; Data curation; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.Yuefei Guo: Data curation; Formal analysis.Yuge Wang; Data curation; Formal analysis.Wei Qiu: Data curation; Conceptualization; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.Yaqing Shu: Data curation; Conceptualization; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.Li Xiao: Data curation; Conceptualization; Formal analysis; Methodology; Writing - original draft; Writing - review \& editing.

Funding

This work was supported by National Natural Science Foundation of China (82071343, 82371354) and the Third Affiliated Hospital of Sun Yat-Sen University, Clinical Research Program (QHYH202501).

Data availability

The datasets used during the study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki Ethical Principles and was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University (CR2025-014-01). Written informed consent for study participation was obtained appropriately for the two participants (one adult patient, one infant): the adult provided consent directly, while the infant’ s consent was obtained from their parents (legal guardians).

Consent for publication

Written informed consent for the publication of de-identified data and images in this report was obtained in accordance with ethical standards: the adult patient provided direct written informed consent, and the infant’s parents (legal guardians) provided written informed consent on the infant’s behalf (as the infant is aged < 16 years).

Competing interests

The authors declare no competing interests.