Case study: how soon to start ocrelizumab post-partum?
My obstetrician is happy for me to have the infusion of ocrelizumab after delivery, but my neurologist has advised me to wait for 3-4 weeks before restarting ocrelizumab. What would you recommend?
Case study
I have been on ocrelizumab for close to four years. I am pregnant and will give birth via a planned caesarian section in 10 weeks. I will not have had an ocrelizumab infusion for over 12 months when I deliver my baby. I am beginning to feel like my MS is becoming active, and I am concerned about having a post-partum rebound. My obstetrician is happy for me to have the infusion of ocrelizumab after delivery, but my neurologist has advised me to wait for 3-4 weeks before restarting ocrelizumab. What would you recommend?
Prof G’s response
High-dose steroids
I am sure you know you will likely have some B-cell repletion because you have not had ocrelizumab for over a year. This means you are at risk of having an infusion reaction due to B-cell lysis and therefore covered with high-dose steroids. Although only one dose of steroids is required, the dose may impact wound healing and put you at a higher risk of infections. Please note steroids are only a relative contraindication to not having ocrelizumab immediately post-partum.
Rebound post-partum
The treatment effect of anti-CD20 therapies lasts much longer than 12 months and probably longer than 18 months. In the phase 2 ocrelizumab extension study, fewer patients had MRI activity despite having their last dose of ocrelizumab more than 18 months earlier (see image below). This data is the main driver for exploring ocrelizumab as an IRT (immune reconstitution therapy). Therefore it is doubtful that you will have rebound disease activity if you wait 3-4 weeks longer before recommending ocrelizumab treatment.
In general, rebound post-partum is not that common anymore because most women continue DMTs during pregnancy or start DMTs soon after delivery.
Breastfeeding
I am on record stating that monoclonal antibodies and ocrelizumab are safe during breastfeeding as little gets into the breast milk, and the small amounts that do get into the breast milk will be metabolised in the baby’s gastrointestinal tract (see MS-Selfie newsletter from 2-Feb-2023). The exception is in the first 2-3 weeks post-partum when your breasts produce colostrum, and the newborn’s intestinal tract is immature and can transfer antibodies across the intestinal surface.
Colostrum, or first milk, is produced immediately after the newborn's delivery and for about 2-3 weeks after delivery. Colostrum is especially high in antibodies and other factors to protect the newborn against disease and infection. As the newborn’s gastrointestinal tract is immature, many of the proteins in colostrum are absorbed and will have systemic immune effects.
Most of the antibodies in colostrum are IgA and IgM produced by plasma cells in the breast. Therefore I suspect that circulating IgG, including ocrelizumab, will only get transferred into breast milk in small amounts. However, the breast epithelial cells express the so-called neonatal Fc-receptor, the molecular shuttle for transporting antibodies into milk. In addition, this neonatal Fc receptor shuttle is also expressed in the newborn intestine. So the molecular mechanisms are in place to potentially increase your developing baby’s exposure to ocrelizumab.
So if you plan to breastfeed, which I recommend, you would want to avoid ocrelizumab when your breasts produce colostrum. I suspect this is why your neurologist suggested you wait 3-4 weeks before recommencing ocrelizumab.
There are no black-and-white answers to any problem in MS. However, I think the reasons for delaying recommencing ocrelizumab treatment for a few weeks post-partum outweigh the chances of rebound disease activity. I suggest you discuss this further with your consultant neurologist. If you have any questions, please feel free to ask them.
Finally, thank you for allowing me to discuss your case. There is a clear need to study whether or not high levels of ocrelizumab are found in colostrum and breast milk. Are you aware of the SOPRANINO study (see paper below)? It is now recruiting patients to answer at least the second part of the question. I recommend you find out if your centre is participating in this study or, if not, whether you can be referred to a participating centre.
MINORE and SOPRANINO Studies
Background: Most disease-modifying therapies (DMTs) approved for the treatment of multiple sclerosis (MS) are not recommended during pregnancy, and discouraged while breastfeeding. However, discontinuation of some DMTs before pregnancy can leave women vulnerable to MS relapses. Although available data on ocrelizumab suggest no increased risk in terms of pregnancy or neonatal outcomes, it is unknown whether ocrelizumab transfers across the placenta or is absorbed through breastmilk; and if so, whether infant B cell development, immune responses or growth and development are affected. This manuscript describes two studies designed to address these uncertainties.
Methods/design: MINORE and SOPRANINO are multicentre open-label studies. MINORE, which addresses placental transfer, will recruit 44 women with MS or clinically isolated syndrome (CIS) exposed to ocrelizumab between 6 months before the last menstrual period (LMP) to the end of the first trimester. It will evaluate pharmacodynamic effects of potential in utero exposure through the proportion of infants with B cell numbers below lower limit of normal (LLN) at week 6 of life (primary endpoint); as well as through vaccine-induced antibody responses (reflecting B cell function) during the first year of life. Placental transfer will be assessed through measurement of ocrelizumab concentrations in paired samples at delivery (maternal blood as well as umbilical cord blood), and infant serum at week 6 of life. SOPRANINO, which evaluates breastmilk transfer, will recruit 20 women with MS or CIS who resume or initiate ocrelizumab treatment while breastfeeding. The effect of potential exposure through breastmilk will be assessed through the proportion of infants with B cell levels below LLN at 30 days after the mother's first post-partum ocrelizumab infusion (co-primary endpoint). Infant exposure via breastmilk will be assessed through ocrelizumab average daily infant dose in breastmilk over 60 days after the same infusion (co-primary endpoint). Vaccine-induced responses will be measured as in MINORE. Both studies will also measure infant growth and development over the first year of life and safety outcomes in both mothers and infants. All analyses will be descriptive, under an estimand framework.
Discussion: Both studies are designed to mimic real-world clinical practice. Treatment decisions for ocrelizumab are independent from study participation; as such, these studies will recruit women who decide, along with their physicians, to continue their pregnancies despite potential in utero exposure (for MINORE); or to breastfeed while under ocrelizumab treatment (for SOPRANINO). MINORE is the first prospective study to measure placental transfer of any DMT in MS, and to perform comprehensive assessments in infants and mothers. Results may inform the optimal contraception period for women treated with ocrelizumab who are planning a pregnancy. Similarly, SOPRANINO is the first prospective study to measure pharmacodynamic effects of ocrelizumab in breastfed infants in addition to pharmacokinetic parameters in breastmilk. SOPRANINO may establish whether breastfeeding is safe for infants whose mothers received treatment with ocrelizumab.
Conclusion: By collecting detailed pharmacokinetic, pharmacodynamic and safety information, MINORE and SOPRANINO will contribute to understanding the risk/benefit of ocrelizumab in pregnant and lactating women with MS.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
Dear Professor Giovannoni,
I am a 21 year old man recently diagnosed with multiple sclerosis. I wanted to know if you can dedicate a case study directed toward young men with multiple sclerosis. There is not a lot of material out there specifically for young men with MS. I often see material directed towards women with MS on topics such as pregnancy. Meanwhile as a man with MS I wonder if I can even find love anymore. Thank you sir.
Fantastic information!!! Once again, thank you.🙏