In Vitro Fertilization and Multiple Sclerosis

Fertility treatments are increasingly used to support the family planning goals of people living with multiple sclerosis (MS). Currently available treatments include not only assisted reproductive techniques such as in vitro fertilization (IVF) but also fertility preservation, intrauterine insemination, embryo transfer from donor eggs, and ovarian stimulation using oral agents. As fertility treatments evolve, so must our understanding of how to stabilize disease activity and optimize neurologic outcomes in patients with MS undergoing these interventions.

In this edition of Neurology®, Mainguy et al.¹ performed a retrospective cohort study leveraging routinely acquired healthcare data to evaluate the relationship between IVF and severe MS relapses. In contrast to the 5 case series published before 2017, and in line with the most recent report,² the authors found that there was no elevated risk of disease activity after IVF cycles. Furthermore, annualized relapse rate (ARR) after IVF was lower in patients prescribed disease modifying therapy (DMT) during IVF compared with that in those for whom DMT had not been prescribed. The findings of this study are of prime importance to both patients with MS considering assisted conception and to their clinicians.

Studying 338 IVF procedures in 225 women, the authors provide the largest cohort of people with MS undergoing IVF to date. By including the overwhelming majority of French patients with MS having fertility treatment between 2010 and 2015, this study overcomes some of the limitations in previous work.² Using routinely acquired healthcare data from an entire country advances our understating from case series and single-center studies, which are subject to particular forms of bias. Using each participant as her own control is facilitated by the time-restricted nature of IVF—the time of exposure is relatively well-delineated, and the time of effect can also be modeled. Furthermore, the authors attempt to overcome some of the time-dependent biases that may result from a choice to perform IVF during relative disease remission by using a “control” period 12 months before IVF in a sensitivity analysis. Finally, by considering 4 outcomes—ARR, proportion of IVF with relapse, difference in the number of relapse “after–before,” and the time from IVF to the first relapse—the authors provide a robust and comprehensive examination of any potential relationship between fertility treatment and inflammatory activity.

Using routinely acquired healthcare records for this research is not without complexity. Such records are not designed to capture either MS-specific information or reproductive interventions and outcomes; therefore, prescription and other data are used as surrogate measures. While these surrogate outcomes have been validated for use in the study population, each needs to be carefully considered. It was only possible to include relapses requiring steroids or hospitalizations due to the nature of the data set, so a number of milder relapses may have been missed. Further confounding this risk of bias is the possibility that prescription decisions could have been influenced by IVF itself. Given a historical concern about the risk of cleft palate associated with steroid use during the first trimester, this could have resulted in undertreatment of relapses during this period.

The population in the study conducted by Mainguy et al. was drawn from patients receiving IVF between 2010 and 2015. Treatments for fertility and MS have evolved substantially since then. Thankfully, so too has management of patients with MS undergoing fertility treatments. There has been an increasing use of both highly active MS therapies and induction therapies such as cladribine, alemtuzumab, and anti-CD20 therapies to stabilize disease activity preconception. This is likely to have reduced relapse rate at a population level, potentially obscuring a relative effect of assisted reproductive technology (ART). In addition to increasing the use of more effective DMTs, there has been more judicious discontinuation of DMTs before pregnancy, with evolution in practice informed by increasing real-world and physiologic data. Further driving this change has been a recognition of the risks of rebound disease activity in the context of discontinuing sphingosine-1-phosphate receptor modulators and natalizumab for pregnancy planning purposes. These changes are unlikely to have affected the biological effect of IVF exposure, although the effect of stopping DMT around the time of assisted conception cannot be ignored. Changes to IVF protocols, to achieve controlled ovarian hyperstimulation, have resulted in a shift away from GnRH agonists (historically, more strongly associated with post-ART relapse risk in MS) and toward GnRH antagonists, which could also reduce inflammatory activity after ART.

Many questions continue to arise about the effect of fertility treatments on MS disease activity, beyond the important findings of Mainguy et al.¹ As fertility treatments continue to expand with changing reproductive technologies, so too will the need for additional data. One could hypothesize elevated risks associated with controlled ovarian hyperstimulation protocols for egg freezing (i.e., not followed sequentially by embryo transfer and the immunotolerant state of pregnancy). We might also expect different risks from cycles consisting of “just” embryo transfer from stored embryos or donor eggs—or from intrauterine insemination and clomiphene-induced ovarian stimulation. Furthermore, the data set used by Mainguy et al. did not enable an analysis of the potential inflammatory effect of the substantial physical and psychological burden that facing infertility and undergoing assisted conception places on individuals and family units. A prospective collection of serial noncontrast-enhanced MRIs before and after fertility treatments could provide greater sensitivity than clinical relapse data alone.

MS incidence seems to be increasing; the number of people with MS considering family planning and facing challenges to these plans is likely going to continue to increase. Historically, the use of fertility treatments has been primarily in those with subfertility; they are now increasingly used to support conception in sexual and gender minority groups. Studies such as the current one by Mainguy et al. provide vital information to all these patients. Perhaps the most actionable clinical insight from this study is that patients with an elevated risk of inflammatory activity should be treated for their MS—those undergoing fertility treatments should be offered treatment with effective MS DMTs that carry little risk of placental transfer, teratogenicity, or rebound disease activity.

• Received June 2, 2022.
• Accepted in final form July 18, 2022.

• © 2022 American Academy of Neurology