JNNP: Efficacy and safety of natalizumab during pregnancy, Italian cohort of women with multiple sclerosis

Multiple sclerosis (MS) mainly affects women of childbearing age, raising the question of
how these patients get pregnant.
According to pioneering studies by Confavreaux et al.
1 and several subsequent confirmatory studies, it is now generally accepted that pregnancy, particularly in the third trimester, reduces clinical recurrence
.
However, this general observational study cannot be applied to MS patients
treated with natalizumab (NTZ).
NTZ is a monoclonal antibody against β1–β7 integrin α4 subtle, licensed for high-activity relapse-remitting MS (RRMS).

Although NTZ has a high efficacy, due to its pharmacokinetics, from the eighth week after the last infusion, NTZ's protection against disease reactivation begins to decrease
.

Women who interrupt NTZ due to family planning have an increased risk of relapse before or during pregnancy due to rapid immune reconstitution following interruption of treatment, which is not mitigated
by pregnancy-induced immunomodulation.
It is no longer recommended in clinical practice to stop using NTZ
before pregnancy.

Currently, given the potential safety concerns of newborns, much of the debate in the scientific community focuses on how long
NTZ should be maintained during pregnancy.
Some studies have explored the effects of prolonged treatment after conception, but the validity of their results is limited
by small sample sizes.
In this study, data from 29 Italian MS centers were collected with the aim of evaluating the effect of
continuing NTZ during pregnancy versus stopping NTZ before and near pregnancy.

In addition, we describe the results
of newborns exposed to NTZ before birth.
This article was published in the Journal of Neurology, Neurosurgery & Psychiatry
.

Maternal clinical and radiological outcomes, as well as obstetric and fetal outcomes, were collected retrospectively and compared between groups (NO_EXP not pregnant, SHORT_EXP pre-pregnancy, LONG_EXP during pregnancy).

Predictors
of clinical and radiological recurrence were studied by univariate and multivariate analysis.
The following patient information is collected: duration of illness, date of NTZ onset, date of last NTZ infusion, date and type
of drug (DMD) to treat the disease after delivery.
To assess clinical and radiological outcomes, the following variables were collected: number and date of recurrence in 12 months before conception, during pregnancy, and 12 months after delivery, Extended Disability Status Scale Score (EDSS) last available closest to 12 months before conception and after delivery, cumulative number of new T2 and gadolinium-enhanced (Gd+) injuries detected in MRI scans according to standardized procedures (1.
5T magnets) at 12 months before pregnancy and 12 months after delivery
。 MRIs performed within 1 month after LMP are considered to be performed
one year before conception.
The following obstetric data were collected: age at conception, date of LMP, use of assisted reproductive technology (ART), pregnancy-related adverse events, type of delivery classified as caesarean section or spontaneous birth, gestational age at birth or miscarriage (weeks), length of birth (cm), birth weight (g), head circumference (cm), congenital anomalies classified according to the European Surveillance for Congenital Anomalies (EUROCAT), occurrence of anaemia or other haematological abnormalities (Yes/No), need for blood transfusion after delivery (Yes/No), Breastfeeding (Yes/No).

Research process

To assess risk factors for recurrence during pregnancy and postpartum and for new Gd+ lesions in the postpartum period, a logistic regression analysis was performed, including pregnancy management, age at conception, course of disease, baseline EDSS, new T2 and new Gd+ lesions In a multivariate model, the number of recurrences in the year before pregnancy, breastfeeding (for postpartum only), and NTZ treatment (for maternal only) were independent covariates
.
Where appropriate, adjust the p-value for multiple tests using Tukey-Kramer correction
.

170 eligible pregnancies
from 163 women from 29 multiple sclerosis centres in Italy were included.
During pregnancy, the annual recurrence rate (ARR) of LONG_EXP (n=66, 0.
02 (0.
001–0.
09)) was significantly lower than that of NO_EXP (n=31, 0.
43 (0.
21–0.
75), p=0.
002) and SHORT_EXP (n=73, 0.
46 (0.
30–0.
66), p=0.
0004), while LONG_EXP (0.
12 (0.
05–0.
24)) was associated with postpartum SHORT_ XP (0.
30 (0.
17–0.
50), p=0.
008) is significantly lower than NO_EXP
.
After delivery, there were fewer
gadolinium-enhanced (Gd+) lesions LONG_EXP (n=6/50, 2.
00%) compared with NO_EXP (n=9/21, 42.
86%) and SHORT_EXP (n=17/49, 34.
69%, p=0.
010).

Delayed NTZ recovery after delivery significantly increased the risk of recurrence (OR=1.
29 (95% CI 1.
07 to 1.
57), p=0.
009) and Gd+ lesions (OR=1.
49 (95% CI 1.
17 to 1.
89, p=0.
001).

After adjusting for confounders, there were no differences
in weight, height, head circumference, and gestational age between groups.
Four LONG_EXP newborns were followed for
anaemia.
The rate of congenital anomalies is within the expected range
in the population of untreated MS.

Annual recurrence rate (ARR) before, during, and after pregnancy

Comparing three different management methods, i.
e.
interruption of treatment during pregnancy (LONG_EXP), before pregnancy (NO_EXP), and before pregnancy (SHORT_EXP), we found that of 66 (1.
5%) LONG_EXP patients, only one had at least one recurrence during pregnancy, compared with 23% and 22%
of NO_EXP and SHORT_EVP patients, respectively.
Similarly, we found that LONG_EXP significantly reduced
ARR during pregnancy compared to the other two strategies.
Notably, there was no significant reduction
in ARR in the SHORT_EXP group compared to the NO_EXP group.

The findings suggest that in multiple sclerosis patients treated with NTZ before conception, continued use of NTZ throughout pregnancy and early resumption of NTZ use after delivery reduce the risk of
clinical and radiation recurrence.
This approach has no significant effect
on the prognosis of newborns.

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