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Multiple sclerosis
Original research
Disease activity and neonatal outcomes after exposure to natalizumab throughout pregnancy
  1. Sandra Thiel,
  2. Nastassja Litvin,
  3. Sabrina Haben,
  4. Ralf Gold,
  5. Kerstin Hellwig
  1. Universitätsklinik für Neurologie der Ruhr-Universität Bochum, Katholisches Klinikum Bochum Sankt Josef-Hospital, Bochum, Nordrhein-Westfalen, Germany
  1. Correspondence to Dr Sandra Thiel, Universitätsklinik für Neurologie der Ruhr-Universität Bochum, Katholisches Klinikum Bochum Sankt Josef-Hospital, Bochum, Nordrhein-Westfalen, Germany; Sandra.Thiel{at}ruhr-uni-bochum.de

Abstract

Background After natalizumab discontinuation severe relapses can occur despite pregnancy, but third trimester exposure is associated with neonatal haematological abnormalities (HA). The best time point for stopping natalizumab during pregnancy is unclear.

Methods Prospective, observational cohort with 350 natalizumab exposed pregnancies from the German Multiple Sclerosis and Pregnancy Registry. Clinical disease activity and neonatal outcomes are compared between women with natalizumab discontinuation during (1st Trim-group) versus after the first trimester (maintaining-group) and for subgroup analysis before (<30-subgroup) or after (≥30-subgroup) the 30th gestational week (gw).

Results Baseline characteristics did not significantly differ between the 1st Trim-group (n=179; median exposure duration: 2.60 gw, IQR 1.30–3.60) and the maintaining-group (n=171; median exposure duration: 30.9 gw, IQR 26.9–33.3). Fewer relapses occurred during pregnancy and the postpartum year in the maintaining-group (25.7%) compared with the 1st Trim-group (62.6%; p<0.001). Women in ≥30-subgroup had a significantly lower relapse risk in the first 6 months postpartum (relapse rate ratio: 0.36, 95% CI: 0.15 to 0.84). In total, 7.5% retained meaningful disability 12 months postpartum. No significant effect on neonatal outcomes were observed, but anaemia (OR: 2.62, 95% CI: 1.12 to 6.52) and thrombocytopaenia (OR: 2.64, 95% CI: 1.15 to 6.46) were significantly more common in the ≥30-subgroup. 21.8% of all neonates were born small for gestational age, independent of the timing of natalizumab discontinuation.

Conclusion Continuing natalizumab during pregnancy after gw 30 decreases the relapse risk postpartum going along with a higher risk for HA in the newborns. These results add relevant knowledge as a basis for informed risk–benefit discussion.

  • MULTIPLE SCLEROSIS

Data availability statement

Data are available upon reasonable request. Anonymised data that support the findings of this study will be shared, upon reasonable request and if compatible with data protection policies.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jnnp-2023-332804

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The discontinuation of natalizumab due to family planning can lead to severe relapses and permanent disability accrual, but as monoclonal antibodies are actively transferred over the placenta during pregnancy, the continuation might affect newborns with haematological abnormalities (HA) as anaemia or thrombocytopaenia. To what extent natalizumab exposure throughout pregnancy impacts clinical disease activity and disability during pregnancy and postpartum as well as neonatal outcomes including HA and the best time point to stop natalizumab during pregnancy, with the lowest possible risk for mother and child is unknown.

    WHAT THIS STUDY ADDS

    • In this prospective cohort study including 350 pregnancies, the maintenance of natalizumab during pregnancy beyond the 30th gestational week (gw) reduced the relapse and disability risk during pregnancy and postpartum, especially when coupled with early (28 days) treatment restart postpartum, but was also associated with a higher number of newborns with HA.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • These results should lead to a distinct risk–benefit-discussion between neurologist and natalizumab treated women who are considering maintaining natalizumab beyond gw 30 and restart in the first 4 weeks after delivery to reduce relapse activity and disability accumulation just prior to or after birth.

    Introduction

    Natalizumab (NTZ) is an effective disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS) but the discontinuation has been associated with severe rebound.1 2 Planning a pregnancy is a common reason to discontinue NTZ. In contrast to DMT untreated women,3 women with high disease activity do not necessarily experience a decrease in relapse rate during pregnancy, and studies observed an increased relapse and disability risk after NTZ discontinuation.4–8 This reinforces the importance of an effective and safe treatment during pregnancy in patients with highly-active RRMS.

    The European Medicines Agency did not rate a higher malformation risk after NTZ first trimester exposure,9 but the active transfer of the monoclonal antibody after treatment throughout pregnancy was measured in newborns cord blood and yielded haematological abnormalities (HA), usually as thrombocytopaenia or anaemia.10 First observations described abnormalities that were mostly mild and reversible,10 11 but the cohorts were very small.

    Treating pregnant women with RRMS requires careful risk−benefit-consideration taking maternal and fetal health into account. Therefore, the aim for this study was twofold, to analyse: (1) clinical disease activity during pregnancy and up to 1-year postpartum; and (2) neonatal outcomes including HA in newborns of mothers with NTZ exposure throughout pregnancy.

    Methods

    Study design, setting and participants

    We included women voluntarily enrolled during pregnancy between November 2006 and January 2022 in the German Multiple Sclerosis and Pregnancy Registry (DMSKW), with the following inclusion criteria: available minimal data set (last menstrual period (LMP), end of pregnancy date, enrolment date, DMT stop date during pregnancy) and NTZ treatment between LMP and end of pregnancy. As this analysis focuses on clinical disease activity and neonatal outcomes, pregnancies with a duration less than 22 weeks or with NTZ stop and restart during pregnancy were excluded (figure 1).

    Figure 1
    Figure 1

    Inclusion criteria, pregnancy and neonatal outcomes. Depicted are pregnancies fulfilling the inclusion criteria as well as neonatal outcomes. Proportions of preterm births and twin pregnancies are calculated with the total number of live births as denominator; small for gestational age, congenital abnormalities and neonatal deaths with the total number of neonates (maintaining-group: n=172; first Trim-group: n=182) as denominator. Proportions of other neonatal outcomes are calculated with the total number of pregnancies and haematological abnormalities with the number of available blood counts for every specific variable as denominator. 1st Trim-group stopped natalizumab during the first trimester (completed gestational week 12) of pregnancy, maintaining-group maintained natalizumab after the first trimester of pregnancy. The maintaining-group was further stratified by latest natalizumab exposure prior to completed gestational week 30 (<30-subgroup) or after/at completed gestational week 30 (≥30-subgroup). Natalizumab stop and restart during pregnancy was defined as a therapy break of at least 12 weeks during pregnancy. Haematological abnormality: Any kind of haematological abnormality in the infant’s blood count immediately after birth. Anaemia: Haemoglobin under the days-of-life specific standard value lower range.15 Thrombocytopaenia: Platelets under the days-of-life specific standard value lower range.15 Leucocytosis: over the days-of-life specific standard value upper range.15 High LDH level: LDH over the days-of-life specific standard value upper range.16 High GPT/ALT level: GPT/ALT over the days-of-life specific standard value upper range.16 ALT, alanine aminotransferase; DMT, disease modifying therapy; GPT, glutamic pyruvic transaminase; LDH, lactate dehydrogenase; LMP, last menstrual period; MCA, major congenital abnormality; n, number of cases; NTZ, natalizumab; SGA, small for gestational age.

    Data were collected via standardised, telephone-administered questionnaires at each remaining trimester after enrolment and up to 12 months postpartum.12 Self-reported relapses were confirmed and Expanded Disability Status Scale (EDSS) obtained from the treating neurologist by phone during the postpartum follow-up period. Infant’s blood cell counts immediately after birth were collected from delivery hospitals, if available. 193 pregnancies included in this analysis have been previously analysed with regard to various objectives.8 10 13 14

    Outcomes

    Clinical MS disease activity outcomes: relapses, glucocorticosteroid-treatments and EDSS values were collected between 1 year prepregnancy and up to 1-year postpartum. To asses disability, we used the established definition for disability progression (defined as a worsening of at least 1.5 EDSS points if baseline EDSS=0, at least 1 point for baseline EDSS 1–5.5 and 0.5 point for baseline EDSS ≥6.0)4 and the Severe Relapse Disability Composite Score (SRDCS, defined as any relapse during pregnancy or post partum leading to either (1) an increase of 2 EDSS points, (2) new ambulatory impairment in those without significant prepregnancy ambulatory impairment (EDSS increase from ≤3.5 to ≥4.0 points) or (3) significant worsening in women with at least some pre-existing ambulatory impairment (EDSS increase from ≤5.5 to ≥6.0 points (cane or worse); 6.0 to ≥6.5 points (walker or worse); 6.5 to ≥7.0 points (wheelchair or worse); and 7.0 to ≥8.0 points (bedbound with some arm function or worse))).8 We defined neonatal outcomes preterm births (before completed gestational week (gw) 37), small for gestational age (SGA, birth weight under the 10 national age-specific and sex-specific percentile), major congenital abnormalities (according to the European network of population-based registries for the epi- demiological surveillance of congenital anomalies (EUROCAT)-guidelines), neonatal death (during the first 28 completed days of life) and birth weight as previously described.12 HA were defined as follows: haemoglobin,15 platelets,15 haptoglobin16 under the days-of-life specific standard value lower range; or leucocytes,15 lactate dehydrogenase (LDH),16 aspartate aminotransferase (AST),16 alanine aminotransferase (ALT),16 bilirubin total16 over the days-of-life specific standard value upper range.

    Statistical analyses

    For the analysis of clinical disease activity during pregnancy and neonatal outcomes, we compared NTZ discontinuation during (1st Trim-group) or after the first trimester (maintaining-group). For the analysis of HA and postpartum clinical disease activity, the maintaining-group was stratified by latest NTZ exposure before (<30-subgroup) or after 30th gw (≥30-subgroup). Descriptive statistics include Kruskal-Wallis test, Fisher/χ2 test and t-test.12

    Annualised relapse rates (ARR) per trimester between the prepregnancy year (baseline) and 1-year postpartum were calculated using a multivariable mixed-effects Poisson-regression model; groups and subgroups were compared with relapse rate ratios (RRR with 95% CIs).

    We used multivariable logistic/linear regression to estimate ORs (OR)/β-coefficients with 95% CIs to compare for clinical disease activity during pregnancy and postpartum and neonatal outcomes with the covariables ‘gw of last NTZ during pregnancy’ (linear), ‘extended dosing interval’ (yes/no), ‘number of NTZ infusions during pregnancy’ (linear), ‘NTZ exposure after 1st trimester’ (yes/no) and ‘NTZ exposure after 30th gw’ (yes/no).

    We considered the following adjustments in the regression models, depending on outcomes (see online supplemental tables and figure legends): maternal age, body mass index (BMI) and disease duration at conception; gw at enrolment and birth; relapse and EDSS prior to pregnancy; relapses, high-dose glucocorticosteroids, EDSS, antibiotics, gynaecological complications or tobacco/alcohol during pregnancy; newborns gender; DMT restart, early NTZ restart in the first 28 days and exclusive breastfeeding postpartum. Covariates were checked for possible correlation with the correlation coefficient of Pearson or with Cramer’s V.

    Supplemental material

    All analyses were performed at a two-sided significance level of α=0.05 and conducted with R V.4.1.2 (R Core Team 2021).

    Results

    Study population

    We identified 390 pregnancies with NTZ treatment in the first trimester or beyond (figure 1). Spontaneous abortions (n=37, 9.5%), ectopic pregnancies (n=1, 0.3%), elective abortions (n=2, 0.5%; 1 in gw 26 due to trisomy 13 and 1 in gw 13 due to trisomy 21) were excluded for this analysis.

    As no stillbirths were observed, baseline characteristics of 350 pregnancies with live births in 320 women are shown in table 1, stratified by NTZ cessation during (n=179; 1st Trim-group) or after (n=171; maintaining-group) the first trimester. Most enrolled during the first trimester (median gw 9.9, IQR 6.7–15.5), with women in the maintaining-group enrolling statistically significantly earlier (table 1).

    View this table:
    Table 1

    Characteristics of the study sample

    The maintaining-group was treated until median gw 30.9 (IQR 26.9–33.3). The majority of women for whom the dosing frequency was available (137/159; 86.2%) were on extended dosing intervals ranging from 6 to 8 weeks, and receiving a median number of 5 (IQR 5–6) NTZ infusions during pregnancy. Women in the maintaining-group, who reintroduced NTZ post partum, had a median therapy break of 69.5 days (IQR 49.0–100.0). Most (75.7%) restarted NTZ during the first 4 weeks, with 18 breast feeding under NTZ. Women in the 1st Trim-group decided more often to breast feed (64.0%), four under NTZ treatment, and fewer (42.7%) started NTZ early postpartum (table 1).

    Clinical disease activity during pregnancy and postpartum

    Statistically significant fewer relapses occurred during pregnancy and postpartum in the maintaining-group (44/171, 25.7%) compared to the 1st Trim-group (112/179, 62.6%; p<0.001). Out of 10/171 (5.9%) women in the maintaining-group suffering from a pregnancy relapse, only 3 were treated with high dose corticosteroid treatments during pregnancy. Of note, we still observed 22.8% postpartum relapses in the maintaining-group, but statistically significantly fewer in the ≥30-subgroup (13.3%), especially during the first postpartum trimester (8.6%, table 2). Only 8/79 (10.1%) in the ≥30-subgroup who restarted during the first 28 days postpartum had a postpartum relapse.

    View this table:
    Table 2

    Clinical disease activity and disability during pregnancy and the postpartum year

    Figure 2 demonstrates statistically significant lower ARRs in the maintaining-group during pregnancy and postpartum (RRR: 0.35, 95% CI: 0.23 to 0.53) than in the first Trim-group. Highest relapse rates were observed during the first trimester post partum in both groups, but statistically significantly lower in the maintaining-group (RRR: 0.57, 95% CI: 0.36 to 0.92). Subgroup analysis demonstrated statistically significant lower ARRs in the ≥30-subgroup during the first 6 months postpartum (RRR: 0.36, 95% CI: 0.15 to 0.84) than in the <30-subgroup. Online supplemental table 1 gives a summary of all ARRs per time frame.

    Figure 2
    Figure 2

    Course of annualised relapse rates during pregnancy and postpartum. Depicted are mean annualised relapse rates as estimated by Poisson regression stratified by timing of natalizumab cessation (A) during (1st Trim-group) or after (maintaining-group) the first trimester or (B) before (<30-subgroup) or after (≥30-subgroup) gestational week 30. Error bars represent 95% CIs. Adjustment for (A) maternal age at conception, disease duration and gestational week at entry into the cohort and (B) maternal age at conception, disease duration, gestational week at entry into the cohort, relapse during pregnancy, exclusive breast feeding and early natalizumab restart in the first 28 days post partum. ARR, annualised relapse rate; tri, trimester.

    16 (10%) relapses reached the SRDCS at the end of pregnancy, all in the 1st Trim-group (table 2). In total, 24 fulfilled the SRDCS criteria up to 1-year postpartum (figure 3), but only 2 (2.70%) in the ≥30-subgroup who restarted during the first 28 days postpartum. Online supplemental table 2 gives an overview of the 12 most severe relapses, with an EDSS increase ≥3 during pregnancy or postpartum, only 1 in the ≥30-subgroup with NTZ restarted during the first 28 days post partum (stop in gw 30, restart 8 days postpartum). Pregnancy relapses were treated with high-dose and one with intrathecal corticosteroids or an additional apheresis treatment, respectively. Only two women recovered to the baseline EDSS at 12 months post partum.

    Figure 3
    Figure 3

    Disability development during pregnancy and the postpartum year using the SRDCS in 320 pregnancies with available EDSS (A) in the total cohort, (B) stratified by natalizumab exposure during (1st Trim-group) or after (maintaining-group) the first trimester of pregnancy and (C) with stratification of the maintaining-group by natalizumab maintenance ≥30th gestational week and early restart during the first 28 days postpartum. EDSS, Expanded Disability Status Scale; GW, gestational week; SRDCS, Severe Relapse Disability Composite Score.

    In the adjusted logistic regression model, having a later timing of the last NTZ infusion during pregnancy (covariable: GW of last NTZ during pregnancy) was statistically significant associated with fewer pregnancy (OR: 0.93, 95% CI: 0.90 to 0.96) and postpartum relapses (OR: 0.97, 95% CI: 0.95 to 0.99) as well as fewer disability progression (OR: 0.94, 95% CI: 0.90 to 0.97) and reaching the SRDCS during pregnancy (OR: 0.85, 95% CI: 0.71 to 0.93; table 3), while having an extended dosing interval did not (online supplemental table 3).

    View this table:
    Table 3

    Adjusted logistic regression of clinical disease activity and neonatal outcomes

    Regarding postpartum relapses, an early NTZ restart during the first 28 days postpartum was associated with a reduced risk (OR: 0.26, 95% CI: 0.13 to 0.50), whereas exclusive breast feeding was not (OR: 1.24, 95% CI: 0.62 to 2.44). In addition, pregnancy relapses were associated with reaching the SRDCS postpartum (OR: 4.05, 95% CI: 1.34 to 12.3).

    Neonatal outcomes

    Neonatal outcomes were similar between groups (figure 1). In total, 11.7% preterm births (median 35.3 gw; IQR 34.1–36.3) were observed. In 354 neonates (4 twin pregnancies) we observed 4.0% congenital abnormalities, without a specific pattern (online supplemental table 4). Two extremely preterm newborns (gw 24+3 and 26+1, respectively) died within the first week after delivery. 21.8% neonates were born SGA in the total cohort (figure 1), but mean birth weights did not differ between groups. 2/77 (2.6%) SGA neonates were twins and 8 were also born preterm.

    In the adjusted regression models, neither NTZ exposure after the first trimester (tables 3,4), nor the dosing scheme (online supplemental tables 3 and 5) had a statistically significant effect on any neonatal outcome. Next to the known predictors for negative pregnancy outcomes (maternal BMI, tobacco and alcohol consumption), high-dose glucocorticosteroid treatment during pregnancy was statistically significantly associated with preterm birth (OR 9.43, 95% CI: 3.07 to 30.8), but not with lower mean births weight (β −23, 95% CI: −181–136) or SGA (OR: 0.59, 95% CI: 0.19 to 1.55).

    View this table:
    Table 4

    Adjusted linear regression of neonatal outcomes

    Haematological abnormalities

    We received blood cell counts immediately after birth from 121/172 (70.3%) neonates in the maintaining-group of which 74/121 (61.2%) were born with HA, mainly with anaemia (42/114, 36.8%) or thrombocytopaenia (43/117, 36.8%; figure 1). Anaemia, thrombocytopaenia and leucocytosis were statistically significantly more common in the ≥30-subgroup (table 3). High LDH and ALT were rare; high total bilirubin, AST and low haptoglobin were not observed.

    At least one follow-up blood count was available in 30/74 (40.5%) neonates with HA. After a median of 2 days (IQR 1–4), 7/30 (23.3%) were reversible. Only 2/42 (4.8%) neonates with anaemia received a specific treatment and substituted iron orally.

    Five neonates with first trimester exposure and available blood cell count showed no HA.

    The earliest gw of last NTZ infusion we observed an HA (thrombocytopaenia) was in gw 13.

    Discussion

    In our pregnancy cohort study, pregnancy and postpartum relapses were much rarer in women maintaining NTZ (25.7%), compared with those who stopped in the first trimester (62.6%). The early 3 months postpartum relapse risk was lower (8.6%), when NTZ was last administered after gw 30, and lowest in the combination with an early restart of NTZ postpartum (6.3%). In total, 7.5% reached the SRDCS 12 months postpartum, but only 2.7% in the ≥30-subgroup with NTZ restart during the first 28 days post partum. Our results indicate that relapses after NTZ discontinuation can be mostly prevented by maintaining treatment during pregnancy and starting shortly after delivery. Adverse neonatal outcomes were not more common with the continuation of NTZ, except for HA occurring in 61.2% of all newborns. Another important finding of our study is that independent of NTZ discontinuation the number of newborns with SGA is nearly doubled compared with German newborns. The results of our study add relevant knowledge of fetal and maternal risks after NTZ long-term pregnancy exposure, as a basis for informed risk-benefit discussion between neurologists and patients with MS, who plan a pregnancy.

    Our results on low pregnancy relapse risk (5.9%) are in line with previous studies on pregnancies maintaining NTZ during the first trimester (4%)17 or even throughout pregnancy (2%),11 and confirm an increased relapse risk in pregnancies stopping NTZ during the first trimester (32% vs 20–39%).4 8 17 In accordance with other cohorts,4 6 8 we observed highest ARR in the first 3 months postpartum, and a similar ARR during the postpartum year in maintaining-group (ARR: 0.25, 95% CI: 0.17 to 0.36) compared with the postpartum ARR (ARR: 0.12, 95% CI: 0.05 to 0.22) previously published by Landi et al.11 Smaller studies have reported a higher disability risk after NTZ discontinuation in the setting of pregnancy using various definitions (16.2–19%)4 18 compared with that observed in our larger cohort (7.5% reaching the SRDCS 12 months post partum). We recently reported 12.8% reaching the SRDCS 1-year postpartum in pregnancies stopping NTZ during the prepregnancy year or the first trimester and 1.1% catastrophic relapses.8 In contrast, we did not observe catastrophic relapses in women who continued NTZ during pregnancy. Therefore, our results indicate that maintaining NTZ beyond the first trimester may protect against disability worsening including severe relapses.

    We found the early NTZ restart to be protective against postpartum relapses, as reported previously,4 6 19 and pregnancy relapses associated with an increased postpartum relapse risk,4 6 7 especially for severe relapses. In contrast, two other large studies could not confirm a beneficial effect of early NTZ treatment8 or NTZ treatment during the postpartum year,11 which might be explained by the short NTZ therapy break in our cohort of a median of 70 days in the maintaining-group versus approximately 100 days reported by Landi et al.11 Consistent with this, the randomized 24- week Natalizumab treatment interruption study (RESTORE) reported most relapses 112 days after NTZ discontinuation.20

    In our observation, extending NTZ dosing intervals to 6–8 weeks was not associated with pregnancy or postpartum relapses, in line with the comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA) trial, which demonstrated similar disease control,21 but extending dosing intervals to 12 weeks was associated with increased clinical and MRI disease activity in other studies.22 23 A recent analysis also describes a decrease in NTZ efficacy with increasing dosing intervals, but every-6-week dosing was likely to maintain the efficacy of NTZ, particularly at body weights<80 kg,24 which applies to our study population.

    The theoretical advantage of extending dosing intervals is the reduction of fetal NTZ exposure. In our cohort we did not discover essential differences between neonatal outcomes; both preterm births and congenital abnormalities were in line with the general population.23–25 Of importance more infants were smaller than expected, with 20% being SGA. The SGA rate in European countries is specified with 10%, using national reference percentiles to avoid misclassification.25 Reassuringly, we observed no significant difference for SGA between exposure groups. Significantly lower birth weights compared with healthy14 or unexposed control groups26 and a significant birth weight reduction of 169 g27 for NTZ first trimester exposure has been previously described. However, the mean birth weight of term born neonates in our cohort (3296 g±433) was within the expected range in the German population (3362 g±557).28 Two small case series of pregnancies with third trimester NTZ exposure reported birth weights under the expected range, with mean birth weight 2723±416 g and median birth weight 2778 g (range 2100–3790), respectively,10 29 which is substantially lower than recently reported (median birth weight male: 3168 g; female: 3315 g)13 and in our study population. This birth weight reduction might be explained by the high number of relapses and glucocorticosteroid treatments during pregnancy, although high-dose glucocorticosteroid exposure was not associated with a lower mean birth weight or SGA newborns in this cohort, but has been described in the literature.30 Also, there has been a long lasting discussion on the effect of the MS disease itself on birth weight reduction in further observations.31 A recent systematic review indicates an increased risk for SGA among women with MS32 depending on three cohort studies,33–35 but the association between high disease activity and reduced birth weight has not been adequately studied so far. Thus, this finding needs further investigation, to rule out an increased risk of intrauterine growth restriction after NTZ pregnancy exposure or active MS itself, as low birth weight is a risk factor for several diseases in adult life.36

    HA, as described in cynomolgus monkeys37 and humans,10 were common in neonates exposed to NTZ after 30th gw (67% with all kinds of HA) and can be explained by the pharmacokinetic and pharmacodynamic characteristics of the substance. NTZ, as a monoclonal IgG4 antibody acting as an α4-integrin inhibitor, is actively transported over the blood–placenta barrier by the fetal Fc-receptor, which is increasingly expressed from the 22nd gw.38 Studies indicate that α4-integrins are important for the migration of erythroid progenitors and pre-B-cells beneath the stroma.39 Therefore, it is possible that NTZ interferes with fetal hematopoiesis through α4-integrin inhibition. The frequency of HA occurrence has been inconsistently described so far, from 10/13 (77%) in a small case series10 to 4/69 (6%) in a smaller cohort study.11 The difference to our finding of 36.8% of newborns with anaemia or thrombocytopaenia can most likely be explained by the median gw of last NTZ exposure in gw 34 (range 32–36)10 compared with 30.9 (IQR 26.9–33.3) in our cohort. Landi et al stated, that only a minority of their cohort was exposed to NTZ after the 30th gw.11 Different definitions for HA might also lead to an underestimation, therefore we decided to define abnormalities with days-of-life specific standard value, as especially the normal circulating concentrations of haemoglobin, platelets, leucocytes and bilirubin are known to be influenced by neonatal age.16

    Strengths and limitations

    Strengths of this study include a high enrolment rate during the first trimester of pregnancy, resulting in reliable, robust and prospective long-term data of high-quality, along with a large sample size and including a control group. By measuring the fetal HA risk in the majority of our cohort on the one hand and the maternal disability risk on the other hand, this study provides important information and supports decision-making for women with highly-active MS and their treating clinicians in the field of pregnancy planning.

    Our study also has several limitations. It is not population based and we cannot rule out that more severely affected women contact our registry.12 The lack of MRI data limits the conclusion on disease activity, especially in the postpartum period. Therefore, this data is in high demand. Also, the lack of blood counts in the 1st Trim-group as well as the relatively low rate of follow-up blood counts is a major limiting factor. Although a blood count monitoring is recommended for all neonates exposed to NTZ during pregnancy, only 70.3% received a blood count, of which only 40.5% had a follow-up blood count available. Given the follow-up blood count was a median of 2 days later, we cannot provide sufficient information on the duration until HAs are reversible. The reversibility has been described before,37 and is also biologically plausible as the α4-integrin inhibition is reversible as well.40 The duration should be investigated in further studies.

    Conclusion

    Overall the chance of women achieving stable MS status despite high disease activity before pregnancy has been greatly improved by continuing NTZ. We found that maintaining NTZ beyond the 30th gw week reduces the maternal relapse and disability risk. In combination with an early postpartum restart, the lowest risk was observed. Neonatal outcomes seem not to be affected by NTZ exposure throughout pregnancy, with the exception of a higher fetal risk for HA, mostly without specific treatment required. Despite the knowledge of the HA risk, only a small proportion of neonates had follow-up blood counts available, which underscores the need for improving the interaction among the members of the multidisciplinary team.

    Our finding should lead to a distinct risk–benefit-discussion between neurologist and women and highlights the importance of evaluating cohorts breastfeeding under monoclonal antibodies and examining child development in the future.13

    Data availability statement

    Data are available upon reasonable request. Anonymised data that support the findings of this study will be shared, upon reasonable request and if compatible with data protection policies.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by institutional review board of the Ruhr-University Bochum; registration number: 18-6474-BR. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank all the participants of the German Multiple Sclerosis and Pregnancy Registry (DMSKW) as well as the referring neurologists and multiple sclerosis nurses.

    References

    1. ↵
      2. Hellwig K ,
      3. Gold R
      . Immune reconstitution inflammatory syndrome after withdrawal of Natalizumab Neurology 2011;76:1362–3; doi:10.1212/WNL.0b013e318210e5d0
      OpenUrlFREE Full Text
    2. ↵
      2. Larochelle C ,
      3. Metz I ,
      4. Lécuyer M-A , et al
      . Immunological and pathological characterization of fatal rebound MS activity following Natalizumab withdrawal. multiple sclerosis (Houndmills. Mult Scler 2017;23:72–81. doi:10.1177/1352458516641775
      OpenUrlCrossRef
    3. ↵
      2. Vukusic S ,
      3. Hutchinson M ,
      4. Hours M , et al
      . Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-Partum relapse. Brain 2004;127(Pt 6):1353–60. doi:10.1093/brain/awh152
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      2. Portaccio E ,
      3. Amato MP
      . Pregnancy decision-making in women with multiple sclerosis treated with Natalizumab: I: II:Maternal risks. Neurology 2018;90:e832-e9. doi:10.1212/WNL.0000000000006430
    5. ↵
      2. Alroughani R ,
      3. Alowayesh MS ,
      4. Ahmed SF , et al
      . Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology 2018;90:e840–6. doi:10.1212/WNL.0000000000005065
      OpenUrlAbstract/FREE Full Text
    6. ↵
      2. Yeh WZ ,
      3. Widyastuti PA ,
      4. Van der Walt A , et al
      . Natalizumab, Fingolimod and dimethyl fumarate use and pregnancy-related relapse and disability in women with multiple sclerosis. Neurology 2021;96:e2989–3002. doi:10.1212/WNL.0000000000012084
      OpenUrlAbstract/FREE Full Text
    7. ↵
      2. Bsteh G ,
      3. Algrang L ,
      4. Hegen H , et al
      . Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria. multiple sclerosis (Houndmills. Mult Scler 2020;26:69–78. doi:10.1177/1352458518816614
      OpenUrl
    8. ↵
      2. Hellwig K ,
      3. Tokic M ,
      4. Thiel S , et al
      . Multiple sclerosis disease activity and disability following discontinuation of Natalizumab for pregnancy. JAMA Netw Open 2022;5:e2144750. doi:10.1001/jamanetworkopen.2021.44750
    9. ↵
      1. EMA
      . Tysabri® (Natalizumab) - EPAR summary of product characteristics. 2009. Available: https://www.ema.europa.eu/en/documents/product-information/tysabri-epar-product-information_en.pdf [Accessed 4 Oct 2021].
    10. ↵
      2. Haghikia A ,
      3. Langer-Gould A ,
      4. Rellensmann G , et al
      . Natalizumab use during the third trimester of pregnancy. JAMA Neurol 2014;71:891–5. doi:10.1001/jamaneurol.2014.209
      OpenUrl
    11. ↵
      2. Landi D ,
      3. Bovis F ,
      4. Grimaldi A , et al
      . Exposure to Natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis. J Neurol Neurosurg Psychiatry 2022;93:1306–16. doi:10.1136/jnnp-2022-329657
      OpenUrlAbstract/FREE Full Text
    12. ↵
      2. Thiel S ,
      3. Ciplea AI ,
      4. Gold R , et al
      . The German multiple sclerosis and pregnancy Registry: rationale, objective, design, and first results. Ther Adv Neurol Disord 2021;14:17562864211054956. doi:10.1177/17562864211054956
    13. ↵
      2. Ciplea AI ,
      3. Langer-Gould A ,
      4. de Vries A , et al
      . Monoclonal antibody treatment during pregnancy and/or Lactation in women with MS or Neuromyelitis Optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2020;7:e723. doi:10.1212/NXI.0000000000000723
    14. ↵
      2. Ebrahimi N ,
      3. Herbstritt S ,
      4. Gold R , et al
      . Pregnancy and fetal outcomes following Natalizumab exposure in pregnancy. A prospective, controlled observational study. multiple sclerosis (Houndmills. Mult Scler 2015;21:198–205. doi:10.1177/1352458514546790
      OpenUrlCrossRefPubMed
    15. ↵
    16. ↵
      2. Colantonio DA ,
      3. Kyriakopoulou L ,
      4. Chan MK , et al
      . Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and Multiethnic population of children. Clin Chem 2012;58:854–68. doi:10.1373/clinchem.2011.177741
      OpenUrlAbstract/FREE Full Text
    17. ↵
      2. Demortiere S ,
      3. Rico A ,
      4. Maarouf A , et al
      . Maintenance of Natalizumab during the first trimester of pregnancy in active multiple sclerosis. multiple sclerosis (Houndmills. Mult Scler 2021;27:712–8. doi:10.1177/1352458520912637
      OpenUrlCrossRef
    18. ↵
      2. Vidal-Jordana A ,
      3. Tintoré M ,
      4. Tur C , et al
      . Significant clinical worsening after Natalizumab withdrawal: predictive factors. multiple sclerosis (Houndmills. Mult Scler 2015;21:780–5. doi:10.1177/1352458514549401
      OpenUrlCrossRefPubMed
    19. ↵
      2. Vukusic S ,
      3. Durand-Dubief F ,
      4. Benoit A , et al
      . Natalizumab for the prevention of post-Partum relapses in women with multiple sclerosis. multiple sclerosis (Houndmills. Mult Scler 2015;21:953–5. doi:10.1177/1352458514554056
      OpenUrlCrossRefPubMed
    20. ↵
      2. Fox RJ ,
      3. Cree BAC ,
      4. De Sèze J , et al
      . MS disease activity in RESTORE: a randomized 24-week Natalizumab treatment interruption study. Neurology 2014;82:1491–8. doi:10.1212/WNL.0000000000000355
      OpenUrlAbstract/FREE Full Text
    21. ↵
      2. Foley JF ,
      3. Defer G ,
      4. Ryerson LZ , et al
      . Comparison of switching to 6-week dosing of Natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3B trial. Lancet Neurol 2022;21:608–19. doi:10.1016/S1474-4422(22)00143-0
      OpenUrlCrossRefPubMed
    22. ↵
      2. Muralidharan KK ,
      3. Steiner D ,
      4. Amarante D , et al
      . Exposure-disease response analysis of Natalizumab in subjects with multiple sclerosis. J Pharmacokinet Pharmacodyn 2017;44:263–75. doi:10.1007/s10928-017-9514-4
      OpenUrl
    23. ↵
      2. Trojano M ,
      3. Ramió-Torrentà L ,
      4. Grimaldi LM , et al
      . A randomized study of Natalizumab dosing regimens for relapsing-remitting multiple sclerosis. multiple sclerosis (Houndmills. Mult Scler 2021;27:2240–53. doi:10.1177/13524585211003020
      OpenUrlPubMed
    24. ↵
      2. Chang I ,
      3. Muralidharan KK ,
      4. Campbell N , et al
      . Modeling the efficacy of Natalizumab in multiple sclerosis patients who switch from Every-4-week dosing to extended-interval dosing. J Clin Pharmacol 2021;61:339–48. doi:10.1002/jcph.1737
      OpenUrl
    25. ↵
      2. Hocquette A ,
      3. Durox M ,
      4. Wood R , et al
      . International versus national growth charts for identifying small and large-for-gestational age newborns: A population-based study in 15 European countries. Lancet Reg Health Eur 2021;8:100167. doi:10.1016/j.lanepe.2021.100167
    26. ↵
      2. Friend S ,
      3. Richman S ,
      4. Bloomgren G , et al
      . Evaluation of pregnancy outcomes from the Tysabri(R) (Natalizumab) pregnancy exposure Registry: a global, observational, follow-up study. BMC Neurol 2016;16:150. doi:10.1186/s12883-016-0674-4
    27. ↵
      2. Portaccio E ,
      3. Amato MP
      . Pregnancy decision-making in women with multiple sclerosis treated with Natalizumab: I: fetal risks. Neurology 2018;91:851. doi:10.1212/WNL.0000000000006430
    28. ↵
      2. Voigt M ,
      3. Wittwer-Backofen U ,
      4. Scholz R , et al
      . Analysis of the German perinatal survey of the years 2007-2011 and comparison with data from 1995-1997: neonatal characteristics and duration of pregnancy. Z Geburtshilfe Neonatol 2013;217:211–4. doi:10.1055/s-0033-1361096
      OpenUrl
    29. ↵
      2. Triplett JD ,
      3. Vijayan S ,
      4. Rajanayagam S , et al
      . Pregnancy outcomes amongst multiple sclerosis females with third trimester Natalizumab use. Mult Scler Relat Disord 2020;40:101961. doi:10.1016/j.msard.2020.101961
      OpenUrlPubMed
    30. ↵
      2. Khan AA ,
      3. Rodriguez A ,
      4. Kaakinen M , et al
      . Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? A systematic review of current evidence in humans. Paediatr Perinat Epidemiol 2011;25:20–36. doi:10.1111/j.1365-3016.2010.01147.x
      OpenUrlCrossRefPubMed
    31. ↵
      2. Finkelsztejn A ,
      3. Brooks JBB ,
      4. Paschoal FM , et al
      . What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011;118:790–7. doi:10.1111/j.1471-0528.2011.02931.x
      OpenUrlCrossRefPubMed
    32. ↵
      2. Andersen ML ,
      3. Jølving LR ,
      4. Stenager E , et al
      . Maternal multiple sclerosis and health outcomes among the children: A systematic review. Clin Epidemiol 2023;15:375–89. doi:10.2147/CLEP.S392273
      OpenUrl
    33. ↵
      2. Andersen JB ,
      3. Kopp TI ,
      4. Sellebjerg F , et al
      . Pregnancy-related and perinatal outcomes in women with multiple sclerosis: A nationwide Danish cross-sectional study. Neurol Clin Pract 2021;11:280–90. doi:10.1212/CPJ.0000000000001035
      OpenUrlAbstract/FREE Full Text
    34. ↵
      2. Dahl J ,
      3. Myhr KM ,
      4. Daltveit AK , et al
      . Pregnancy, delivery, and birth outcome in women with multiple sclerosis. Neurology 2005;65:1961–3. doi:10.1212/01.wnl.0000188898.02018.95
      OpenUrlAbstract/FREE Full Text
    35. ↵
      2. Chen YH ,
      3. Lin HL ,
      4. Lin HC
      . Does multiple sclerosis increase risk of adverse pregnancy outcomes? A population-based study. multiple sclerosis (Houndmills. Mult Scler 2009;15:606–12. doi:10.1177/1352458508101937
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      2. Knop MR ,
      3. Geng T-T ,
      4. Gorny AW , et al
      . Birth weight and risk of type 2 diabetes mellitus, cardiovascular disease, and hypertension in adults: A meta-analysis of 7 646 267 participants from 135 studies. J Am Heart Assoc 2018;7:e008870. doi:10.1161/JAHA.118.008870
    37. ↵
      2. Wehner NG ,
      3. Shopp G ,
      4. Osterburg I , et al
      . Postnatal development in cynomolgus monkeys following Prenatal exposure to Natalizumab, an Alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:144–56. doi:10.1002/bdrb.20193
      OpenUrlCrossRefPubMed
    38. ↵
      2. Palmeira P ,
      3. Quinello C ,
      4. Silveira-Lessa AL , et al
      . Igg Placental transfer in healthy and pathological pregnancies. Clinical and Developmental Immunology 2012;2012:1–13. doi:10.1155/2012/985646
      OpenUrl
    39. ↵
      2. Arroyo AG ,
      3. Yang JT ,
      4. Rayburn H , et al
      . Alpha4 integrins regulate the proliferation/differentiation balance of Multilineage hematopoietic progenitors in vivo. Immunity 1999;11:555–66. doi:10.1016/s1074-7613(00)80131-4
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      2. Plavina T ,
      3. Muralidharan KK ,
      4. Kuesters G , et al
      . Reversibility of the effects of Natalizumab on peripheral immune cell Dynamics in MS patients. Neurology 2017;89:1584–93. doi:10.1212/WNL.0000000000004485
      OpenUrlAbstract/FREE Full Text

    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors ST and KH act as guarantor for this study, have full access to the data and accept full responsibility for the work.

      ST and KH designed the study. ST and NL acquired the data. ST, SH and KH analysed the data. ST, NL, SH and KH interpreted the data. ST, NL, SH, RG and KH drafted a significant portion of the manuscript or figures. All authors critically reviewed and approved the final version. No medical writer or editor was involved in the creation of the manuscript.

    • Funding The German Multiple Sclerosis and Pregnancy Registry (DMSKW) is partly supported by the Innovation Fund of the Federal Joint Committee (Grant: 01VSF17022), Almirall, Biogen, Hexal AG, Merck, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries. The funders had no role in the study design, collection, analysis and interpretation of the data and were not involved in manuscript writing. All authors had full access to the data and had final responsibility for the decision to submit for publication.

    • Competing interests The German MS and pregnancy registry is partly supported by the Innovation Fund of the Federal Joint Committee, Almirall, Biogen, Teva Pharma, Novartis, Roche and Merck. ST received speakers' honoraria from Bayer Healthcare and Biogen GmbH, payment for manuscript writing from HEXAL AG as well as sponsorship for congress participation from Biogen GmbH. NL has nothing to disclose. SH has nothing to disclose. RG has received speaker honoraria and research support from Bayer-Schering Healthcare, Biogen-Idec Germany, Chugai, Eisai, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme and TEVA, has received consulting honoraria from CSL Behring, Baxter, Janssen and Talecris and has stock options in Bayer, Merck and Roche. KH has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Roche and Teva, has received support for congress participation from Bayer, Biogen, Merck, Roche, Sanofi Genzyme and Teva, and has served on scientific advisory boards for Bayer, Biogen, Sanofi, Teva, Roche, Novartis and Merck.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.