Pregnancy and the post-partum period represent important biological events that involve profound hormonal changes and have potential effects on MS activity and disease course [
7,
23]. Consistently with other studies [
7,
13], our research showed that the post-partum year is a phase with an increased risk of clinical relapses and MRI activity, which are conditioned by the clinical and neuroradiological activity of the pre-conception year and inversely related to breastfeeding duration. A recent meta-analysis of 24 studies that included nearly 3000 women concluded that breastfeeding is protective against post-partum relapses in MS. The association between breastfeeding and postpartum relapses appeared stronger in studies of exclusive breastfeeding for 2 months or more compared with studies including any breastfeeding in the breastfeeding group [
19]. Classically, exclusive breastfeeding is defined as at least 2 months of breastfeeding without regular replacement of any meal by supplemental feeding [
19]. With exclusive breastfeeding, an elevation in prolactin was reported and larger drops in follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol. All these hormonal changes work together to produce more prolonged amenorrhea and anovulation, with potentially beneficial immunological effects [
19]. However, exclusive breastfeeding was observed in 56% of our breastfeeding women in the first 2 months, with no effects on clinical and MRI outcomes at 12 months. However, given the retrospective nature of the study, the data on exclusive breastfeeding may be fallacious. Less post-partum clinical activity was observed in our sample in women who breastfed longer; this may not be attributable to a protective role of lactation on MS activity but rather to a milder disease course in these women. In fact, women with higher MS activity likely had to renounce or prematurely quit breastfeeding to start DMT. Thus, breastfeeding duration seems more likely to be conditioned by MS, resulting it shorter durations among subjects with clinical or neuroradiological reactivation. In addition, even though we did not identify a relationship between the choice to forego breastfeeding and pre-pregnancy MS activity, we observed a relationship tending toward statistical significance with exposure to second-line DMTs pre-conception or during pregnancy. Therefore, it is likely that these women had to give up breastfeeding to resume second-line DMTs immediately after delivery. Accordingly, regarding short-term outcomes, a relationship between post-partum MS reactivation and pre-conception second-line DMT exposure was found, indicating that these women are the most prone to the risk of disease recurrence. This may be attributable to the most active form of MS as well as to disease reactivation linked to the discontinuation of more effective therapies [
11,
24]. However, given that pre-conception second-line DMT exposure was observed only in 8.8% of pregnancies, the small sample size limits the power of this result. Recently, a study performed in MS patients that discontinued natalizumab for pregnancy-related reasons has shown that recurrence of disease activity, clinically and/or radiologically, was observed in 95% of discontinuations, although all patients showed no or limited disease activity in the year preceding natalizumab discontinuation [
25]. However, of the cases in whom conception occurred under natalizumab treatment, fewer relapses and less radiological activity were observed [
25]. Thus, continuation of treatment until conception may be a preferred strategy to prevent relapses and MRI activity in women on natalizumab treatment who want to get pregnant. In line with this new evidence, in the last few years the approach to pregnancy has changed. The most recent recommendations of the European Academy of Neurology and European Committee of Treatment of Research in MS have better addressed DMT use during conception and pregnancy [
26], especially in light of new data about drug safety. While the discontinuation of fingolimod until conception is necessary for safety reasons, treatment with natalizumab during the first two trimesters of pregnancy should be considered [
27], with immediate post-partum resumption at the expense of breastfeeding, despite preliminary evidence of its safe use during this phase [
28]. Other recommendations about more effective and recently launched DMTs are constantly evolving, making MS treatment during this biological reproductive phase increasingly centred on the patient and her MS characteristics [
29]. However, the long-term effects of pregnancy and puerperium on MS are extremely difficult to measure. A recent intriguing study by Portaccio et al. evaluated the influence of the pre-pregnancy period on long-term disability in MS and observed that the risk of long-term disability is higher among MS women with relapses in the pre-conception year [
30], reinforcing the importance of pregnancy planning and treatment optimisation during this reproductive phase. Thus, new data on long-term outcomes are urgently needed to better understand how to best orient therapeutic choices in the era of new DMTs. In line with some studies that reported lower disability scores in women with previous pregnancies compared with nulliparous women [
23,
30], our study focused on long-term outcomes and showed that having had at least one pregnancy was associated with lower EDSS score independent of other factors. More so, this effect is observed in the case of multiple pregnancies. However, although pregnancy has classically been considered a self-treatment due to the state of immunotolerance that it creates, its protective role against long-term disability progression is difficult to establish. Conversely, in other words, instead of the protective effect of pregnancy, women with more aggressive MS forms may be less willing to have or be discouraged from having children. A previous French and Italian cohort study provided an original description of the evolution of MS activity after two successive pregnancies in women with MS, showing similar (and even lower) disease activity in the second versus first pregnancy [
31]. This could be due to the fact that, if MS women were generally advised to consider pregnancy in a quiet period of the disease, women who experienced a relapse during a first pregnancy or after delivery may fear a similar outcome and be discouraged from considering a second pregnancy. In line with this, it is likely that women with MS with multiple pregnancies are also those with milder MS [
31]; assuming that higher disease activity is related to worse long-term disability, they could have better long-term clinical outcomes.
Furthermore, it should be highlighted that pregnancy is a well-circumscribed biological event in a long history of disease and that our patients had heterogeneous MS characteristics and DMT exposures before and after pregnancy, which complicates our evaluation of outcomes. Another central point is whether pregnancy in MS can have a protective effect against brain damage and, in particular, the evolution of brain atrophy, increasingly considered the final expression of MS brain injury. Khalid et al. previously performed a quantitative MRI analysis of cerebral lesions and atrophy in post-partum patients with MS and reported no WB or cortical atrophy despite increases in destructive lesions in the immediate post-partum period; thus, they emphasised the need for longer follow-up durations to verify these findings [
32]. Set in this context, our study evaluated long-term brain atrophy and found no correlation among WB, WM, and GM volumes and a history of pregnancies either before or after MS onset. Interestingly, however, our study showed that breastfeeding for > 6 months was associated with lower WM volume. This finding draws attention to the importance of the post-partum period and the choice of breastfeeding, which until very recently corresponded to the choice of postponing DMT use, exposing the woman to MS reactivation with immediate effects such as those in the post-partum period or the long term. These effects can be reversible, such as clinical relapses and MRI inflammatory activity, or permanent, such as WM atrophy, likely attributable to the inflammatory processes that occur in the post-partum period.
In addition to the previously discussed limitations mainly related to sample size and heterogeneity, other limitations require addressing. As discussed, the patients had different follow-up times, MS characteristics, and DMT exposures (previous and concomitant). These aspects may have affected the brain volume measurements in particular. Moreover, it is known that cerebral atrophy represents a complex outcome that is related with demographics, clinical aspects, and MS-unrelated factors (i.e., comorbidities and lifestyle) [
34], which were not specifically evaluated in this study. Moreover, the study was performed before the launch of some DMTs (e.g., B cell depletors, newer S1P receptor modulators), and this makes some results less generalisable.
Finally, since this study focused on MS-related outcomes, foetal risks and outcomes of the examined pregnancies were not evaluated.