Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation

Abstract

Objective: To determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods.

Methods: Eleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period.

Results: The mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1).

Conclusion: We determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.

Keywords: breastmilk; lactation; multiple sclerosis; natalizumab; natalizumab concentration; neurofilament light chain; pregnancy.

Conflict of interest statement

UP received speaker fee from Merck, Biogen and Bayer and personal compensation from Biogen and Roche for consulting service. RH has received travel compensation from Celgene and Sanofi. HI received speaker fee from Roche. KA received personal compensation from Roche, Sanofi, Alexion, Teva, Biogen and Celegene for consulting service. TZ reports consulting or serving at speaker bureaus for Biogen, Celgene, Roche, Novartis, Celgene, Merck and Sanofi as well as research support from Biogen, Novartis, Merck and Sanofi.

Copyright © 2021 Proschmann, Haase, Inojosa, Akgün and Ziemssen.

Figures

Figure 1

NAT concentration in breastmilk and serum samples of nursing mothers. NAT concentrations (µg/ml) in breastmilk (●) and serum () samples of patients 1,3,4 and 5 from delivery (d0) up to 302 days postpartum with up to 10 maintenance NAT infusions (↓).

Figure 2

NAT concentration in breastmilk and serum samples of nursing mothers. NAT concentrations (µg/ml) in breastmilk (●) and serum () samples of patients 7-10 from delivery (d0) up to 150 days postpartum with up to five maintenance NAT infusions (↓).

Figure 3

Median NAT serum trough levels across pregnancy. Median NAT trough concentrations (µg/ml) and range in serum samples prior pregnancy, during each trimester and up to six months postpartum. Data were analyzed by general linear mixed models for repeated measures.

Figure 4

Mean sNfL levels across pregnancy. SNfL mean levels ± SD prior pregnancy, during each trimester and up to six months postpartum. Pre-pregnancy sNfL value in patients having received at least six NAT infusions prior conception was defined as individual steady state value. A relevant increase of sNfL was defined as sNfL value ≥ SS ± 2xSD. A relevant sNfL increase is labeled in purple.