Pregnancy outcome following exposure to ocrelizumab in multiple sclerosis

1. Introduction

Ocrelizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody that selectively targets CD20-expressing B cells which has been increasingly used in the treatment of multiple sclerosis (MS). ¹ Whilst it is a highly efficacious disease modifying drug, the data regarding its safety in pregnancy is very limited.

Ocrelizumab is administered intravenously every six months. The average terminal half-life of ocrelizumab is 26 days. ² The drug is estimated to be eliminated from the body by approximately 4.5 months following the last administration. ³ It is important to note that IgG1 antibodies such as ocrelizumab do not cross the placenta in first trimester of pregnancy. ⁴

In animal studies, the drug has been shown to cause neonatal B cell depletion, bone marrow, renal and testicular toxicity as well as perinatal deaths at doses similar to or greater than those used clinically. ² The current recommendation is to avoid pregnancy for 6 months (Food and Drug Administration) to 12 months (European Medicine Agency) following the last ocrelizumab infusion.^2,5 However, these recommendations do little to address the arguably greater risk of significant and potentially disabling MS relapse in some patients without disease modifying therapy during pregnancy.

The use of ocrelizumab in pregnancy carries a potential risk of prolonged B-cell depletion, thereby possibly increasing the risk of maternal systemic infections or chorioamnionitis, leading to miscarriages, preterm birth, or stillbirths. As transient reduction in neonatal B-cells and lymphocytes has been reported in another anti-CD20, rituximab in pregnancy, ⁶ this has also become a concern with ocrelizumab. This is especially true when the fetus is exposed to ocrelizumab after transplacental transfer of IgG1 takes place at around 16th week of gestation. ⁴

Data from 267 pregnancies in patients with MS treated with ocrelizumab did not suggest an increased risk of adverse outcomes. ³ However, a recent study reported an increased risk of preterm births in a group of patient with neuroimmunologic disorders who were exposed to either ocrelizumab or rituximab after conception. ⁷

The objective of our study is to report the pregnancy outcome in a group of MS patients exposed to ocrelizumab during pregnancy.

2. Methods

We retrospectively identified 14 pregnancies of 12 MS patients from a specialty clinic in Western Australia, who had been exposed to ocrelizumab within 6 months prior to conception or at any time during pregnancy between 2018 and 2020.

We reviewed the medical records of our patients and their infants. Details of adverse pregnancy outcomes were recorded. This included low birthweight (less than 2500 g), stillbirths (death or loss of baby after 20 weeks completed pregnancy weeks), preterm delivery (less than 37 weeks gestational age) and major malformations as well as maternal complications such as chorioamnionitis or systemic infections. We were also interested in the risks of relapse in the cohort as evidenced by development of new neurotological symptoms or MRI lesions throughout pregnancy and within 3 months postpartum.

Approval for data collection was granted from the ethics committee. Written informed consent was obtained from all patients.

3. Results

4. Discussion

We did not identify any concerning major safety signals among the patients who were exposed to ocrelizumab prior to conception or during the first trimester of pregnancy. There was no report of serious maternal infection or chorioamnionitis during pregnancy.

In contrast to a recently published study which reported an increased risk of premature births in a group of patients with neuroimmunologic disorders including MS who were exposed to either ocrelizumab or rituximab, we have not found such an association. ⁷

One patient (M1, Pregnancy 1) had an elective termination of pregnancy following detection of fetal anomalies related to triploidy 69 XXY. Triploidy is a chromosomal abnormality which occurs sporadically in 1% to 3% of pregnancies^8,9 and cannot be attributed to the use of ocrelizumab.

M7 developed placental insufficiency during pregnancy without any identifiable risk factors. The cause of placental insufficiency in this case was unclear, and it remained uncertain as to whether ocrelizumab could have any direct effect on the placenta. To our knowledge, there is no report of ocrelizumab causing placental insufficiency to date, but a larger scale study is required to further investigate this.

We believe that the neonatal sepsis in M7's infant was not related to the use of ocrelizumab as the mother received ocrelizumab 8 weeks prior to conception, and the drug would have been eliminated from the body before it could cross the placenta after the 16th week of gestation.

Importantly, our study found that six-monthly ocrelizumab prior to pregnancy and withholding the infusion during the pregnancy can result in a stable disease course. As the suppression of CD19 B cells has been shown to correlate with therapeutic response of anti-CD20 monoclonal antibody therapy such as rituximab, ¹⁰ we monitored CD19 B cells in these patients to predict the need for a bridging therapy during pregnancy and to determine the timing to restart ocrelizumab post-delivery. A majority of our patients did not require any additional therapy as their B cells remained suppressed throughout pregnancy. We did not observe any relapses despite a prolonged ocrelizumab treatment-free interval of up to 105 weeks. Some patients even managed to complete breastfeeding for at least 6 months before ocrelizumab therapy was re-commenced. Studies investigating extended-interval dosing of ocrelizumab is scarce, but the median time to B-cell repopulation for ocrelizumab had been suggested to take approximately 62 weeks after 3 treatment cycles and 72 weeks after 4 treatment cycles. ¹¹ Interestingly, one MS treatment-naïve patient (M10) who received only a half-dose (300mg) of ocrelizumab pre-pregnancy remained protected from disease activity throughout pregnancy despite a treatment interruption interval of 40 weeks. Her CD19 B lymphocytes taken one week postpartum remained suppressed with no evidence of relapse despite being given only a single half-dose of ocrelizumab.

In patients like M7 who developed repopulation of B cells as the pregnancy approached term, we suggest for timely re-dosing of ocrelizumab soon after delivery to prevent a relapse. On the other hand, if reconstitution of B cells occurs at an early stage of pregnancy, our approach is to transition to an alternative high efficacy DMT which is considered safe in pregnancy. We chose to switch M8 to natalizumab after considering the significant risk of an MS relapse in this patient. There have been reports suggesting that the use of natalizumab in the first trimester of pregnancy is safe.^12–16 We continued M8 on natalizumab until the 32nd week of gestation, according to our own experience, ¹⁷ and in line with the UK consensus on pregnancy in MS ¹⁸ to reduce the risk of transient fetal haematological abnormalities with third trimester exposure to the drug. ¹³

With regard to the potential risk of neonatal B-cell depletion, none of our patients were exposed to ocrelizumab after the second trimester when transplacental ocrelizumab transfer occurs, and hence we did not anticipate any of our neonates to have B cell depletion.

Only minimal amounts of ocrelizumab are detectable in breastmilk, ² and there is no published evidence that has demonstrated significant risk to the infant. Only four of our patients received ocrelizumab during breastfeeding, and there were no reported adverse effects in the infants.

The main limitation of our study was the retrospective nature which predisposes to a number of potential confounders and the small number of participants included. With the potential ethical implications, prospective studies or randomized controlled trials in MS patients during pregnancy will be difficult.

5. Conclusion

We did not observe increased adverse events in our cohort of patients who were exposed to ocrelizumab prior to conception or during the first trimester of pregnancy. Our data suggests that patients with MS who had been treated with ocrelizumab before pregnancy experienced a stable MS disease course throughout pregnancy and during postpartum period despite a prolonged period of treatment interruption. Future observational studies incorporating larger patient cohorts will be required to provide more robust data.