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Planning a pregnancy: managing MS treatments

Further to several decades of mistaken beliefs concerning the risks posed by pregnancy in female MS patients, data from large-scale prospective studies such as PRIMS (1998) have made it possible to establish the facts and advise such patients on a solid scientific basis. 

Nowadays, it is clearly stablished that MS patients should not established discouraged from getting pregnant.

Nevertheless, the postpartum period remains critical in terms of the resurgence of disease activity, which returns to its pre-conception levels and may therefore be fairly high in the case of forms very active prior to pregnancy. It is consequently
important that this period be covered with effective therapy, an appropriate lifestyle and adequate periods of rest. We therefore suggest that family planning be discussed at an early stage with MS patients, especially in connection with the choice of background treatment, as a number of them are contraindicated during pregnancy and therefore need to be stopped, hence the importance of discussing the patients’ wish to become pregnant as soon as the first treatment is set up, and of bringing up the subject regularly (at least each time medication is changed)
. Such pre-conception talks are essential if the patient is to be able to make informed choices.

In the event of a pregnancy, should a treatment need to be stopped, it is essential to do so at the right time. In such cases, a patient may find herself going without treatment for almost or even over a year. The decision to cover the pregnancy with a compatible background treatment chiefly depends on the risk of a flare-up during the pregnancy – especially in the case of the very active forms – but also on the increase of that risk postpartum. It so happens that few treatments are immediately effective in such a way as to cover this crucial time as soon as they are administered once more.

Generally, it is best to plan a pregnancy when MS has been perfectly stabilised, ideally for a period of 2 years, and for at least 12 months. In this case, when the background treatment needs to be suspended, this will at least be done during a period of stability. As well as clinical examination, an analysis of a brain MRI during the year prior to the pregnancy will supply additional information concerning the absence of new or active lesions, to confirm the absence of disease activity.
However, it frequently happens that pregnancies are not planned, in which case it is not easy to follow the advice supplied hereunder. There is no reason to panic, though. In such situations, the current treatment should be stopped immediately (unless it has been confirmed to be compatible with pregnancy) and the patient should get in touch with her neurologist, as well as her gynaecologist-obstetrician, to set up close obstetrical monitoring (including, for instance, repeated morphology ultrasounds). Finally, the fact that the pregnancy was begun under medication should be notified to the pharmacovigilance centre to ensure monitoring of its progress and outcome. If a register of pregnancies has been opened specifically for the treatment in question, it should also be notified and consulted.
The decision whether to pursue a background treatment should be taken by balancing the risk to the foetus against the risk that the mother’s MS may worsen.
This paper will discuss the maintenance or interruption of each of the background treatments, mainly in women, should they express a wish to have a baby – at the planning stage, as it were. This includes the right time to stop using contraception, the maintenance or interruption of the treatments, the resumption of the treatment postpartum, and if applicable compatibility with breastfeeding. The following recommendations have been issued by expert groups and are known as “international guidelines”. They are based on drug information leaflets, the drugs’ FDA classification, their molecular characteristics, the real-life data, etc.
First-line treatments
Beta interferons and glatiramer acetate
Neither of these drugs need be stopped prior to contraception and both can be taken throughout pregnancy and breastfeeding.
Dimethyl fumarate
Dimethyl-fumarate treatment can be continued until pregnancy is confirmed by a positive test. It should then be stopped.
This medication should not be taken when breastfeeding and its resumption should be postponed until breastfeeding has ended.
This treatment is contraindicated during pregnancy. However, it is not enough to cease taking it as it persists in the blood for several weeks (if not months). Effective contraception should therefore continue to be used after discontinuing teriflunomide and during the period of accelerated drug elimination by administration of cholestyramine 3x4g/day for 11 days. This lowers the blood level to less than 0.02 mg/l and contraception may then be discontinued. This treatment should also not be used during breastfeeding.
Ponesimod, siponimod and ozanimod
These three drugs are related to fingolimod and should not be used during pregnancy. They are also contraindicated during breastfeeding. Contraception should be continued for 7 days after the last dose of ponesimod, 10 days after the last dose of siponimod and 3 months after stopping ozanimod, in accordance with the half-lives of each of these medications.
Since there is no officially identified risk of rebound as in the case of fingolimod, the replacement of these treatments with another in the event of a planned pregnancy may be discussed case by case with the patient’s neurologist, and depends among others on disease activity during the past 24 months.
Second-line treatments
Fingolimod must not be used during pregnancy. Moreover, the patient should continue to use effective contraception for 2 months after the treatment has been discontinued. Finally, given the risk of a rebound in the inflammatory activity of the disease (in the form of a severe flare-up or increased lesional load), a switch to another background treatment compatible with pregnancy is highly recommended (to be discussed with the patient’s neurologist). Breastfeeding is also contraindicated when taking this drug.
Treatment with natalizumab may be continued until pregnancy is confirmed. Thereafter, in view of the risk of relapses when treatment is stopped (especially in the case of very active MS prior to initiation of treatment), it may be necessary to continue treatment during the first 2 trimesters of pregnancy (up to 32-34 weeks) and resume it as soon as possible after birth, in order to limit the interruption of the treatment to 8-12 weeks. Continuation or initiation of natalizumab during the third trimester should be discussed according to the severity of the disease (severe recent flare-up, for instance) and weighed against the potential haematological side effects for the foetus. It is advisable to space out doses (6 weeks between administrations instead of 4) in order to reduce drug exposure. Breastfeeding may be considered in the event of treatment with natalizumab, as concentrations of this drug in milk are very low. Moreover, it will be largely destroyed in the infant’s gastrointestinal tract.
It is recommended that ocrelizumab not be used during pregnancy. French experts recommend waiting at least 2 months between the last intravenous infusion and the discontinuation of contraception, while British experts advise that contraception may be discontinued immediately after the last infusion. This is because there is no significant transplacental transfer of this antibody during the first trimester of pregnancy. If the patient is not pregnant 6 months after her last treatment, an extension of the dose interval (from 6 to 9-12 months) may be considered in order to allow a longer period for conception. Exceptionally, this drug may be given during pregnancy if this is required to control the disease and no other satisfactory alternative can be considered.
Treatment may be resumed during breastfeeding, as transmission via breast milk is very slight, as in the case of other monoclonal antibodies. 
This drug is contraindicated during pregnancy and contraception should be used until the treatment is stopped. However, it can be given during breastfeeding, as the large size of the molecule means that little finds its way into the milk and this type of molecule is also partly destroyed in the infant’s gastro-intestinal tract. 
Cladribine is contraindicated during pregnancy. It is recommended that effective contraception be maintained up to 6 months after the last dose of medication. This recommendation also applies to male MS patients who wish to have children. However, this immune-reconstitution treatment does provide a therapeutic window for conception in view of its administration, which is intermittent and spread over 5 weeks per year for 2 consecutive years. Breastfeeding is contraindicated in patients treated with cladribine while taking the drug and for up to 1 week after the last dose.
It is recommended that alemtuzumab not be used during pregnancy. However, as this treatment is limited to patients in whom the disease is highly active, it can be assumed that pregnancy was not on the agenda when this treatment was chosen. Should this be the case, its cyclical treatment schedule (5 days of IV treatment in the first year, followed by 3 days of IV treatment in the second year) makes it easy to find a window of opportunity for conception: effective contraception is recommended for up to 4 months after the last course of treatment, and can then be discontinued if the patient wishes to become pregnant. A monthly assessment of thyroid function is recommended if the last treatment with alemtuzumab was given less than 4 years previously, in order to detect autoimmune thyroid
disease, which is frequently reported as a medium- and long-term side effect of this treatment. According to the European Medicines Agency, it is also contraindicated during breastfeeding for up to 4 months after administration. However, if the same principle is applied concerning passage into breast milk and destruction in the infant gastrointestinal tract as in the case of the other monoclonal antibodies, it could probably be started immediately.

Despite the guidelines supplied in the scientific literature during the past few years to aid neurologists in their decision-making, many of them are reluctant to continue a background treatment during pregnancy and breastfeeding, and clinical practice in this area varies widely. The purpose of this summary is to supply the clearest possible overview of the management of MS background treatments in the event of pregnancy and breastfeeding. Of course, the severity of the disease and the patients’ wishes (customised treatment) also need to be taken into account. 
Finally, these recommendations are not definitive and may change over time, depending on the real-life data collected in pregnancy registers worldwide for each drug (planned and unplanned pregnancies with permanent or temporary exposure to a treatment). Hence the importance of recording all pregnancies that occur after exposure to background treatments in pharmacovigilance registers or in observational studies.
Prof. Brigitte Capron, CHU Marie Curie, Charleroi
The references of all the studies cited are available on request from the Belgian Charcot Foundation:
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