Supplementary Table 1a. First-line disease-modifying treatment use in pregnancy
FDA / EMA Labelling / Clinical trials and post-marketing studiesIFN-β / C / There is limited information on the use of Interferons in pregnancy.
Available data indicate that there may be an increased risk of spontaneous abortion.
Initiation of treatment is contraindicated during pregnancy
In patients with a high relapse rate before treatment has started, the risk of a severe relapse following discontinuation in the event of pregnancy should be weighed against a possibly increased risk of spontaneous abortion. / Clinical trial registry and industrial post-marketing experience
Sandberg-Wollheim (2011) Rebif Pregnancy Registry1
679 pregnancies exposed to IFN-β1a (subcutaneous injections).
459 live births, 145 spontaneous abortions (21.4%), 61 elective abortions, 7 stillbirths, 7 ectopic pregnancies. 24 cases of birth defect (major or minor) – no specific pattern. Mean exposure 28 days.
Tomczyk (2012) Avonex Pregnancy Registry (US)2
306 pregnancies exposed to IFN-β1a (intramuscular injections).
272 live births, 28 spontaneous abortions (10.8%), 5 elective abortions, 1 stillbirth. 17 cases of birth defect—no specific pattern.
No information on duration of exposure.
Coyle (2014) Betaseron Pregnancy Registry (US)3
99 pregnancies exposed to IFN- β1b.
86 live births, 11 spontaneous abortions (11.1%), 2 stillbirths, 3 unknown.
5 cases of birth defect—no specific pattern.
No information on duration of exposure.
Cohort studies
Lu (2012) Systematic review4
761 pregnancies exposed to any IFN- β.
Lower mean birth weight. Higher number of preterm deliveries (<37 weeks). No increase in the spontaneous abortion rate.
Amato (2010)5
88 pregnancies exposed to any IFN- β in Italy.
75 live births, 7 spontaneous abortions (7.9%), 5 elective abortions, 1 stillbirth.
Mean exposure 4.6 weeks (1 continued during pregnancy).
Compared to 318 non-exposed MS women: no increase in the spontaneous abortion rate, lower birth weight (3012g vs 3208g), higher percentage of pre-term deliveries (32.8% vs 20.1%)
Hellwig (2012)6
78 pregnancies exposed to any IFN- β in Germany.
Mean exposure 8.8 weeks (4 continued during pregnancy)
3 cases of birth defect—no specific pattern
Fragoso (2012)7
17 pregnancies exposed to any IFN- β.
Mean exposure 18.4 weeks. Lower birth weight—no increase in spontaneous abortion rate
Glatiramer acetate / B / There are no adequate data of the use of glatiramer acetate in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy; embryonal/fetal development, parturition and postnatal development. The potential risk for humans is unknown.
Glatiramer acetate is contraindicated during pregnancy.
A contraceptive cover should be considered whilst using this medicinal product. / Cohort studies
Lu (2012) Systematic review 4
97 pregnancies exposed to glatiramer acetate.
No difference in mean birth weight, spontaneous abortion, congenital anomalies.
Giannini (2012) 8
17 pregnancies exposed to glatiramer acetate in Italy.
16 live births, 1 spontaneous abortion. No birth defect.
Mean exposure 4.9 weeks.
Compared to 318 non-exposed women: no increase in the spontaneous abortion rate, no difference in birth weight (3357g vs 3208g), no difference in pre-term deliveries (25% versus 20.1%)
Hellwig (2012)6
41 pregnancies exposed to glatiramer acetate in Germany.
Mean exposure 6.5 weeks (1 continued during pregnancy).
2 cases of birth defect—no specific pattern
Fragoso (2012) 7
41 pregnancies exposed to glatiramer acetate.
Mean exposure 18.4 weeks. No difference in spontaneous abortion or birth weight.
Dimethylfumarate / C / There are no or limited amount of data from the use of dimethyl fumarate in pregnant women.
Animal studies have shown reproductive toxicity.
Dimethyl fumarate is not recommended during pregnancy and in women of childbearing potential not using appropriate contraception.
Dimethyl fumarate should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus. / Clinical trial registry and industrial post-marketing experience
(Gold 2014)9
44 pregnancies exposed to dimethyl fumarate
25 live births, 3 spontaneous abortions (7.0%), 10 elective abortions, 6 unknown.
No birth defect reported.
Teriflunomide / X / There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animals have shown reproductive toxicity. Teriflunomide may cause serious birth defects when administered during pregnancy. Teriflunomide is contraindicated in pregnancy.
Women of childbearing potential have to use effective contraception during treatment and after treatment as long as teriflunomide plasma concentration is above 0.02 mg/l.
For women receiving teriflunomide treatment, who wish to become pregnant, the medicine should be stopped and an accelerated elimination procedure is recommended in order to more rapidly achieve concentration below 0.02 mg/l / Clinical trial registry and industrial post-marketing experience
(Kieseier 2014)10
70 pregnancies exposed to teriflunomide.
26 live births. Rate of spontaneous abortion similar to general population.
Median birth weight and gestational age similar to mothers without MS.
No birth defect.
22 pregnancies in partners of males exposed to teriflunomide.
16 live births.
No birth defect.
Supplementary Table 1b. Second-line disease-modifying treatment use in pregnancy
Fingolimod / C / Animal studies have shown reproductive toxicity including fetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect. Furthermore, the receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis.
There are very limited data from the use of fingolimod in pregnant women.
Before initiation of treatment in women of childbearing potential a negative pregnancy test result needs to be available.
While on treatment, women should not become pregnant and active contraception is recommended.
If a woman becomes pregnant while taking fingolimod, discontinuation of fingolimod is recommended.
Because it takes approximately 2 months to eliminate fingolimod from the body on stopping treatment, the potential risk to the fetus may persist and contraception should be continued during that period. / Clinical trial registry and industrial post-marketing experience
(Karlsson 2014)11
74 pregnancies exposed to fingolimod.
28 live births, 9 spontaneous abortions (12.2%), 24 elective abortions, 1 unknown, 4 ongoing.
5 cases of abnormal fetal development: 1 tibial malformation, 1 acrania, 1 Fallot tetralogy, 1 spontaneous intrauterine death, 1 failure of fetal development.
Duration of exposure between 8 and 12 weeks in the majority of cases.
Natalizumab / C / There are no adequate data from the use of natalizumab in pregnant women.
Studies in animals have shown reproductive toxicity.
The potential risk for humans is unknown.
Natalizumab should not be used during pregnancy unless the clinical condition of the women requires treatment with natalizumab.
If a woman becomes pregnant while taking natalizumab, discontinuation should be considered. / Clinical trial registry and industrial post-marketing experience
(Cristiano 2012)12
375 pregnancies exposed to natalizumab.
286 live births, 34 spontaneous abortions, 13 elective abortions, 1 stillbirth, 8 unknown, 41 ongoing.
Malformations were isolated, no drug-related pattern reported.
Cohort studies
Hellwig (2011)13
35 pregnancies in German women exposed to natalizumab.
29 live births, 5 spontaneous abortions (14.3%), 1 elective abortion.
1 birth defect (hexadactily).
Exposure: 6 had last infusion prior to last menses, 29 others were exposed for a mean of 22.6 days.
Lower birth weight (3,159g) than children born from MS mothers without DMD (3,406g).
Portaccio (2014)14
28 pregnancies in Italian women exposed to natalizumab.
20 live births, 6 spontaneous abortions (21.4%), 2 elective abortions.
1 birth defect (Down syndrome).
Mean birth weight (2904g).
Ebrahimi (2014)15
102 pregnancies in German women exposed to natalizumab, 98 followed prospectively.
77 live births, 17 spontaneous abortions (17.3%), 4 elective abortions.
3 birth defects (1 atrial septal defect, 1 hernia, 1 hexadactily). 1 neuroblastoma diagnosed later after birth.
Exposure: 0–13 weeks.
Lower birth weight in children born from mother threated with natalizumab or other DMD, compared to children born from MS mothers without DMD.
Haghikia (2014)16
13 pregnancies exposed to natalizumab in the third trimester.
Mild to moderate hematologic abnormalities in 10 newborns, thrombocytopenia and anemia. Natalizumab detectable in all 5 children tested.
Alemtuzumab / C / There is a limited amount of data from the use of alemtuzumab in pregnant women. Alemtuzumab should be administered during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Human IgG is known to cross the placental barrier; alemtuzumab may cross the placental barrier as well and thus potentially pose a risk to the foetus.
Animal studies have shown reproductive toxicity.
It is not known whether alemtuzumab can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity.
Serum concentrations were low or undetectable within approximately 30 days following each treatment course. Therefore, women of child bearing potential should use effective contraceptive measures when receiving a course of treatment with alemtuzumab and for 4 months following that course of treatment. / Clinical trial registry
(McCombe 2014)17
139 pregnancies exposed to alemtuzumab.
67 live births, 24 spontaneous abortions (17.3%), 14 elective abortions (including 2 foetal defects), 1 stillbirth, 4 unknown, 29 ongoing.
133 out of 139 pregnancies started more than 4 months after the last infusion.
Cohort studies
(Tuohy 2014)18
87 patients treated with alemtuzumab
15 pregnancies in 12 women after a mean of 26 months (range: 1–86 months).
No birth defects.
9 pregnancies in partners of 7 males treated with alemtuzumab after a mean of 14 months (range: 8–44).
1 spontaneous abortion.
1 congenital heart defect.
Mitoxantrone / D / There are no adequate and well-controlled studies in pregnant women. Mitoxantrone should not normally be administered to patients who are pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus.
Women of childbearing potential and their partners should be advised to avoid becoming pregnant and use effective contraception during therapy and for at least 6 months after cessation of therapy. / Cohort studies
(Le Page 2011)19
802 French patients treated with mitoxantrone.
No exposed pregnancies.
32 normal pregnancies in 27 women, 1–7 years after the last infusion.
20 normal babies fathered by 15 men.
Supplementary Table 1c. Off-label disease-modifying treatment use in pregnancy
Azathioprine / D / No EMA statement – licenced by national health authorities
UK labelling
Azathioprine must not be used during pregnancy without careful assessment of risks and benefit.
In animal studies, azathioprine was teratogenic and embryotoxic.
Azathioprine and its metabolites have been found in low concentrations in fetal blood and amniotic fluid after administration to the mother. Leucopenia and/or thrombocytopenia have been reported in a number of neonates whose mothers received azathioprine during pregnancy. Extra care in haematological monitoring of the mother and a dose reduction in case of leucopenia is advised during pregnancy. Contraceptive measures must be taken by both male and female patients of reproductive age during, and for at least three months after the end of azathioprine therapy.
Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices. Therefore it is recommended to use other or additional contraceptive measures.
After in utero exposure to azathioprine in combination with prednisone, a temporary reduction of immune function is observed. Intra-uterine growth retardation and premature birth have been reported in cases of treatment with azathioprine together with prednisolone. The long-term consequences of these properties of azathioprine are not known, but many children exposed to the substance in utero have now reached the age of ten years without any problems being reported.
French labelling (additional mention)
In humans, hundreds cases of pregnancies exposed to azathioprine to date allow the ruling out of the hypothesis of a risk of birth defects / No data available in patients with MS.
Cyclophosphamide / D / Cyclophosphamide should not normally be administered to patients who are pregnant or to mothers who are breast feeding. Alkylating agents, including cyclophosphamide, have been shown to possess mutagenic, teratogenic and carcinogenic potential. Pregnancy should therefore be avoided during cyclophosphamide therapy and for 3 months thereafter. / Cohort studies
(Patti 2014)20
105 Italian women in childbearing years treated with cyclophosphamide.
No exposed pregnancies.
10 live births, 1 elective abortion.
No birth defects.
Mean delay of pregnancy 3.7 years (range: 0.33–5.9)
Methothrexate / X / Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women.
Women of childbearing potential should not receive methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 6 months following cessation of methotrexate therapy. / No data available in patients with MS.
Mycophenolate mofetil (MMF) / D / It is recommended that MMF therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning MMF therapy, during therapy, and for six weeks following discontinuation of therapy. Patients should be instructed to consult their physician immediately should pregnancy occur.
The use of MMF is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. MMF should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.
There is limited data from the use of MMF in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to MMF in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to MMF.
Studies in animals have shown reproductive toxicity. / No data available patients with MS.
Rituximab / C / IgG immunoglobulins are known to cross the placental barrier. B cell levels in human neonates following maternal exposure to rituximab have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women; however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies. For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Owing to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with rituximab. / No data available in patients with MS.
References