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

Abstract

ObjectiveTo 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.MethodsEleven 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.ResultsThe 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).ConclusionWe 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.

Use of natalizumab in persons with multiple sclerosis: 2022 update

“…None required specific treatment, and in most cases, the abnormalities resolved during the 4 months after birth (Haghikia et al, 2014). The transfer of natalizumab into breastmilk appears to be at a relative infant dose (a metric comparing the infant with maternal drug) far below the threshold of concern of 10% (Proschmann et al, 2021). Biological plausibility of harm is low with the use of monoclonal antibodies in pregnancy and breastfeeding (Mahadevan et al, 2019;Puchner et al, 2019).…”

Natalizumab in cerebrospinal fluid and breastmilk of patients with multiple sclerosis

“…Diffusion of natalizumab into CSF and milk has been reported (Table 2). 3,[5][6][7][8][9][10] Our newly developed assay for detection of natalizumab is easy to establish, reproducible and sensitive enough to enable measurement in two biological compartments where diffusion of monoclonal antibodies is considered low or negligible. 1 The assay was also suited to identify patients with neutralizing antibodies against natalizumab.…”

“…Matching serum samples were collected after 112 and 122 days from the first post-partum infusion (9 and 19 days after the third post-partum infusion, and before the fourth). Additional longitudinal milk samples from an independent published cohort (Universitätsklinikum Carl Gustav Carus, Dresden 3 ) were used to compare assay performance. Milk samples from the Dresden cohort were collected under the University Hospital Dresden ethical approval (EK348092014).…”

Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A Systematic Literature Review

“…The regimen used in T0 should be continued in T5 There was an inverse relationship between IFX levels and CRP in CD ( p = 0.03) After adjusting for albumin, BMI, and CRP, gestational age had a significant effect on the IFX concentrations with multivariate mixed modeling ( p = 0.02) Mobility shift assay (LLOD: 0.0074 µg/mL)[ 78 ] The IQR of T5 were extracted via WPD Steenholdt et al (2011) [ 47 ] Retrospective case report IFX N total : 1 NR IFX > 0.5 µg/mL is associated with maintained response in both CD and UC. They suggest this as a valid cut-off level for clinically relevant IFX concentrations NR Fluid-phase RIA (LLOD: 10 U/mL) All data were extracted via WPD T5: 16 and 28 weeks after T4 Vasilauskas et al (2006) [ 14 ] Retrospective case report IFX N total : 1 NR NR NR ELISA (NR) NR Vestergaard et al (2017) [ 45 ] Case report IFX N total : 1 NR NR NR ELISA (NR) NR Proschmann et al (2021) [ 54 ] Prospective cohort study NAT N total : 11 Women diagnosed with remitted relapse multiple sclerosis with highly active disease course NR Authors confirm that NAT is transferred into human breastmilk in reassuringly low amounts. The observed alteration of drug levels during pregnancy are small and unlikely to be of clinically significance regarding efficacy.…”