J Neurol (2013) 260:12021214
DOI 10.1007/s00415-012-6653-9
REVIEW
Multiple sclerosis and pregnancy: therapeutic considerations
Maria K. Houtchens Channa M. Kolb
Received: 22 May 2012 / Revised: 7 August 2012 / Accepted: 8 August 2012 / Published online: 25 August 2012
Springer-Verlag 2012
Abstract For women with multiple sclerosis (MS) who
become pregnant, the risks and benefits of ongoing therapy
for the health of both the mother and the fetus must be
carefully considered. Based on a literature review and our
MS centers standard practices, we provide guidance to aid
clinical decision making in the absence of clear evidence-
based clinical practice guidelines. Women seeking to
achieve pregnancy should generally discontinue disease-
modifying therapy use prior to attempting conception. For
example, the immunosuppressant mitoxantrone is terato-
genic and should be prescribed only with the assurance of
effective contraception. Conception should be discouraged
for patients on fingolimod, because of the limited infor-
mation available on human pregnancy outcomes. Current
evidence, including data from pregnancy registries for
glatiramer acetate (GA), interferon beta-1a (IFNb-1a), and
natalizumab, has not shown specific patterns of malfor-
mations suggesting teratogenicity. Pregnancy registry data
have not been published for IFNb-1b. During breastfeed-
ing, intravenous immunoglobulin and corticosteroids are
generally safe and may be associated with a reduction in
postpartum relapses; however, a washout period is rec-
ommended between corticosteroid administration and the
resumption of breastfeeding. Clinical data on the use of
IFNb, GA, and natalizumab during lactation are limited.
Mitoxantrone is contraindicated during breastfeeding, and
fingolimod should be avoided in nursing mothers, because
of a lack of data.
M. K. Houtchens (&)
C. M. Kolb
Department of Neurology, Partners Multiple Sclerosis Center,
Brigham and Womens Hospital, Harvard Medical School,
1 Brookline Place #225, Brookline, MA 02445, USA
e-mail: mhoutchens@partners.org
123
Keywords Multiple sclerosis
Pregnancy

Disease-modifying therapies
Management

Breastfeeding
Review
Introduction
Multiple sclerosis (MS) is an immune-mediated chronic
neurodegenerative disease that may result in sustained
physical and cognitive disability, reduction in quality of
life, and significant costs to families and society [14]. MS
is the most common neurologic disease among young
adults, typically starting in the third and fourth decades of
life. Women are more frequently affected than men, and
MS can impact a womans reproductive years [5, 6]. Dis-
ease-modifying therapies (DMTs) and other medications
are widely used by women of childbearing potential. Thus,
women with MS who choose to become pregnant, experi-
ence an unplanned pregnancy or elect to breastfeed their
infants must consider the benefits and risks of MS therapy.
The impact of pregnancy on MS has been reported in
various studies including the large, prospective Pregnancy in
Multiple Sclerosis (PRIMS) study. Pregnant women with
MS typically experience a gradual reduction in relapse rate
during the antenatal period, with an approximately 70 %
reduction in relapse rate during the third trimester relative to
the year before pregnancy [7]. By contrast, the relapse rate
often increases to approximately 70 % above the prepre-
gnancy rate during the first postpartum trimester and 30 %
above the prepregnancy rate during postpartum trimesters
two and three before returning to prepregnancy levels [8, 9].
While the complex mechanisms through which pregnancy
may have positive effects on MS relapses are beyond the
scope of the current review, high levels of estrogens have
been implicated in these therapeutic outcomes [10].
J Neurol (2013) 260:12021214
There is currently no compelling evidence that preg-
nancy has any adverse effects on MS progression, even in
patients who experience postpartum exacerbations [1113].
Although the impact of pregnancy on MS is well-estab-
lished, there is little published information available on the
effects of MS treatments on the mother and the fetus/
newborn. In addition, there are currently no evidence-based
clinical practice guidelines on clinical decision making and
therapeutic choices for women with MS who become
pregnant.
In the US, current National MS Society recommenda-
tions [14] suggest that women stop their medication one
full menstrual cycle prior to attempting conception. These
recommendations also allow resumption of therapy
immediately after delivery, if breastfeeding is not planned.
Women on therapy for MS who unexpectedly become
pregnant are often advised to discontinue therapy as soon
as the pregnancy is recognized [12, 14]. The European
Medicines Agency (EMA) has not issued general guide-
lines for MS care during pregnancy, but individual coun-
tries may provide guidance regarding the use of specific
medications during pregnancy. Little guidance is available
for women who wish to continue their medication during
either pregnancy or breastfeeding or who want to better
understand the possible effects of prior therapy on their
pregnancy/newborn.
The purpose of this review is first to provide an
up-to-date summary of the available data on the utilization
of DMTs and other medications for acute MS relapses
during pregnancy and breastfeeding. A second objective is
to provide data- and experience-based practical guidance
on MS management in women on DMTs who plan to
become pregnant, in women who unexpectedly become
pregnant while receiving MS treatment, and in those who
elect to breastfeed.
MS therapies and pregnancy
Therapies approved for use in MS patients
US Food and Drug Administration (FDA) and EMA clas-
sifications of pregnancy risk for medications are presented
in Table 1. The FDA has created pregnancy risk categories
for inclusion in consumer product information, while the
EMA has developed specific statements that are acceptable
for use in the pregnancy section of a product monograph
[15]. There are currently seven approved MS therapies:
glatiramer acetate (GA), subcutaneous (SC) interferon beta
(IFNb)-1a, intramuscular (IM) IFNb-1a, SC IFNb-1b, fin-
golimod, natalizumab, and mitoxantrone (Table 2). To date
there are no reports of completed, adequate, well-con-
trolled prospective human pregnancy studies for these
1203
DMTs, and none of these therapies have been placed in the
safest pregnancy risk category (Table 3) [16]. The avail-
able evidence for use of each therapy during pregnancy is
summarized below.
GA
GA is the only DMT with an FDA pregnancy category B
rating [17]. This rating is based on the results of studies in
rats and rabbits that show no adverse effects on offspring
development at up to 36 times the therapeutic human dose.
However, since well-controlled studies of human preg-
nancy are lacking [17] and animal reproduction studies do
not always predict human response, the US prescribing
information for GA states that it should only be used during
pregnancy, if clearly needed [17]. The EMA does not
provide guidance on the use of GA during pregnancy.
However, the Association of British Neurologists guide-
lines for prescribing in MS state that GA is not licensed for
use during pregnancy.
The GA manufacturers postmarketing surveillance
study, which was presented in 2003 [18] is the largest
source of data on GA safety during pregnancy. The overall
miscarriage rate (17 %) was close to the expected range in
the US population (1015 %) [19], and there was no
apparent increased risk of adverse fetal or pregnancy out-
comes. However, data on GA exposure throughout preg-
nancy are lacking, since most women discontinued
treatment during the first trimester. Another study [20]
reported a similar duration of GA exposure (median
6.9 weeks) based on registry data, with only 7 of the 31
women in the analysis (23 %) receiving GA beyond week
7. Again, GA exposure did not increase the risk for fetal
adverse effects, and birth weight was not significantly
affected. There were also no observed complications in a
Brazilian study that included 20 patients on GA during
pregnancy [21]. However, the duration of GA usage during
pregnancy and specific trimesters of exposure were not
reported. In addition, none of these studies reported patient
relapse rates during or after pregnancy.
Three longer duration observational studies followed
women on GA during pregnancy and reported MS out-
comes and relapse rates. In a retrospective assessment of 11
women with MS on GA continuously for 7 months or more
during pregnancy [22], their offspring were fully evaluated
for complications after at least 1 year of age. There were
no observed drug-related malformations, neonatal compli-
cations or developmental abnormalities. The mean patient
MS relapse rate of 1.6 in the 10 months prior to pregnancy
decreased to 0.4 (p = 0.005) during pregnancy and
remained low (0.6, p = 0.005 vs the prepregnancy rate) in
the first 6 months post partum. Salminen et al. [23]
reported analogous findings in a prospective observational
123
1204 J Neurol (2013) 260:12021214

Table 1 US and EU pregnancy risk classifications for medications

FDA pregnancy risk categories
Category Description

A Adequate studies in pregnant women have failed to show a risk to the fetus in the first trimester, and there is no evidence of risk in
later trimesters
B Animal studies have failed to show a risk to the fetus, but there are no adequate studies in pregnant women or animal studies have
shown an adverse effect, but human studies have not shown a risk to the fetus in the first trimester, and there is no evidence of risk
in later trimesters
C Animal studies have shown an adverse effect on the fetus and there are no adequate studies in humans, but the benefits may outweigh
the risks or there are no adequate human studies
D There is positive evidence of human fetal risk, but the benefits may outweigh the risks
X Animal or human studies have shown fetal abnormalities or toxicity, and the risk outweighs the benefits
EMA pregnancy risk statements [15]
1. Based on human experience (specified), Drug X is suspected to cause congenital malformation (specified), when administered during
pregnancy
2. Drug X should not be used during pregnancy (trimester specified), unless the clinical condition of the woman requires treatment with Drug X
3. A moderate amount of data on pregnant women (between 300 and 1,000 pregnancy outcomes) indicates no malformative or feto/neonatal
toxicity for Drug X
4. No effects during pregnancy are anticipated, since systemic exposure to Drug X is negligible
FDA US Food and Drug Administration, EMA European Medicines Agency

case series of 13 women with highly active relapsing-
remitting MS who were taking GA during pregnancy. The
9 women who received GA throughout the antenatal period
all had live births with no reported birth defects. Finally,
Hellwig and Gold [24] followed 3 women taking GA
throughout pregnancy and post partum. One case of penile
hypospadias was reported. With respect to disease activity,
no subjects had a relapse in the year before pregnancy,
during pregnancy or in the first 6 months post partum.
In summary, published open-label observations appear
to confirm preclinical studies and suggest that GA is not
associated with teratogenicity or a higher rate of miscar-
riage [11, 18, 2024]. Although the potential relapse
reduction with GA during pregnancy is interesting, there
are only a small number of reported cases, and pregnancy
is normally associated with fewer MS relapses, particularly
during the third trimester. These observations should
therefore be interpreted with caution; current evidence
supports no definitive conclusions about the therapeutic
efficacy of GA in pregnant women.
IFNb
In primates, administration of up to 100 times the recom-
mended weekly human dose of IFNb (based upon a body
surface area comparison) was not associated with terato-
genicity or adverse effects on fetal development [2527].
In spite of these data, the FDA has given IFNb drugs a
pregnancy category C rating based on experimental pri-
mate studies showing abortifacient activity at 2100 times
the corresponding human dose. The EMA guidance also
states that initiation of IFNb treatment is contraindicated
during pregnancy and that discontinuation of therapy
should be considered for women who become pregnant
while taking IFNb.
In contrast, data from several large registry studies
suggest that IFNb-1a does not increase the human spon-
taneous abortion rate. Preliminary results from a pregnancy
registry study of IM IFNb-1a treatment (the Avonex
pregnancy exposure registry [28]) that enrolled a total of
329 patients showed that the spontaneous abortion rate
(10.5 %) was in line with reported rates for the US general
population (1015 %) [19], with no increase in the pro-
portion of births with major/serious malformations or
overrepresentation of specific malformations. Consistent
findings were reported for an SC IFNb-1a pregnancy reg-
istry that included 1,022 cases of exposure to SC IFNb-1a
and 679 documented outcomes [29]. In cases for which
information was available, the mean duration of fetal
exposure before treatment discontinuation was 28 days.
Among prospectively studied pregnancies, 11.5 % resulted
in spontaneous abortions which is similar to the US rate
[19] and live birth major congenital anomalies were also in
line with the general population. Relapse rates were not
reported in these registry studies. It should be noted that
registries to date have only been published for IM and SC
IFNb-1a, similar large-cohort data are not currently avail-
able for IFNb-1b.
Other reports also suggest that IFNb has no effect on
fetal abnormalities and spontaneous abortions [21, 24, 30,
31]. One study [30] evaluating data on 396 pregnancies in
388 women (mean exposure 4.6 weeks) reported an 8 %

123
 Table 2 DMTs currently approved for use in MS
Generic (brand) name
GA (Copaxone, Teva Pharmaceutical Industries,
Petach Tikva, Israel)
IM IFNb-1a (Avonex, Biogen Idec, Weston, MA,
USA)
SC IFNb-1a (Rebif, Merck Serono, Geneva,
Switzerland)
IFNb-1b (Betaseron/Betaferon, Bayer
HealthCare Pharmaceuticals,
Pine Brook, NJ, USA; Extavia, Novartis, Basel,
Switzerland)
TM
Fingolimod (Gilenya , Novartis)
Natalizumab (Tysabri, Biogen Idec)
Mitoxantrone (Novantrone, EMD Serono,
Darmstadt, Germany)
DMT disease-modifying therapy, MS multiple sclerosis, GA glatiramer acetate, FDA US Food and Drug Administration, MRI magnetic resonance imaging, ABN association of british
neurologists, IM intramuscular, IFNb interferon beta, EMA European Medicines Agency, SC subcutaneous
a
Some indications may be country-specific. Please refer to country-specific guidelines for individual medications
123
Indication(s)a
FDA: To reduce relapse frequency in patients with relapsing-remitting MS and patients who have experienced a first clinical episode and
have MRI features consistent with MS
ABN guidelines: For the treatment of patients with a diagnosis of active MS with relapsing onset (relapsing-remitting MS) to reduce
relapses, active disease is defined by two clinically significant relapses in the previous 2 years, other patient categories can be
considered
FDA: To slow accumulation of physical disability and decrease frequency of clinical exacerbations in patients with relapsing forms of MS
and patients who have experienced a first clinical episode and have MRI features consistent with MS
J Neurol (2013) 260:12021214
EMA: For the treatment of (1) patients diagnosed with relapsing MS, to slow the progression of disability and decrease the frequency of
relapses, and (2) patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant
treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if the patients are determined to be at high
risk of developing clinically definite MS
FDA: To slow the accumulation of physical disability and decrease the frequency of clinical exacerbations in relapsing forms of MS
EMA: For the treatment of (1) patients with a single demyelinating event with an active inflammatory process, if alternative diagnoses
have been excluded and if the patients are determined to be at high risk of developing clinically definite MS, and (2) patients with
relapsing MS
FDA: To reduce the frequency of clinical exacerbations in patients with relapsing forms of MS and patients who have experienced a first
clinical episode and have MRI features consistent with MS
EMA: For the treatment of (1) patients with a single demyelinating event with an active inflammatory process, if it is severe enough to
warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if the patients are determined to be
at high risk of developing clinically definite MS, (2) patients with relapsing-remitting MS and two or more relapses within the last
2 years and (3) patients with secondary progressive MS with active disease, as evidenced by relapses
FDA: To reduce the frequency of clinical exacerbations and delay accumulation of physical disability in patients with relapsing forms of
MS
EMA: As monotherapy for adult patients with highly active relapsing-remitting MS despite treatment with a beta-interferon or with
rapidly evolving, severe relapsing-remitting MS, as defined by two or more disabling relapses in 1 year and one or more gadolinium-
enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI
FDA: As monotherapy for relapsing forms of MS, to delay accumulation of physical disability and reduce frequency of clinical
exacerbations
EMA: As monotherapy for adult patients with highly active relapsing-remitting MS despite treatment with a beta-interferon or with
rapidly evolving, severe relapsing-remitting MS, as defined by two or more disabling relapses in 1 year and one or more gadolinium-
enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI
FDA: To reduce neurologic disability and/or the frequency of clinical relapses in secondary (chronic) progressive, progressive relapsing,
or worsening relapsing-remitting MS
EMA: Not approved for MSa
1205
1206
spontaneous abortion rate with IFNb-1a. An observational
study of 7 patients on IFNb throughout pregnancy and in
the postpartum period [24] also reported no increase in
spontaneous abortions or malformations. Unexpectedly,
disease activity increased, although these data should be
interpreted cautiously given the small number of patients.
No other studies to date have directly examined the impact
of IFNb on relapse rate during pregnancy.
In contrast to large registry and observational studies,
some smaller studies have found higher rates of sponta-
neous abortion in patients treated with IFNb preparations
[20, 32, 33]. Sandberg-Wollheim et al. [32] examined
individual patient data from eight clinical trials with SC
IFNb-1a. Of the 41 pregnancies with in utero IFNb expo-
sure (B16 weeks, with most women discontinuing at
B4 weeks), 19.5 % (8 of 41) spontaneously aborted.
Boskovic et al. [33] followed 16 women (23 pregnancies)
and reported a spontaneous abortion rate of 39 % with
IFNb exposure (any formulation) versus 5 % in healthy
non-MS controls; however, the duration of IFNb exposure
during pregnancy was not reported. Two major malfor-
mations (Down syndrome and an abnormal X chromo-
some; 8.7 %) were reported in the IFNb group and one
malformation (5.0 %) among healthy controls. By contrast,
Weber-Schoendorfer and Schaefer [20] found that IFNb-1a
(SC or IM) was not associated with an increase in spon-
taneous losses. However, a higher miscarriage rate was
reported with IFNb-1b [28 % (5 of 18)] than with IFNb-1a
[5 % (2 of 42); p = 0.02] or GA [4 % (1 of 26); p = 0.02]
or in healthy non-MS controls [9 % (138 of 1,515);
p = 0.03]. No malformations were reported for patients
taking IFNb-1a. Although important, these results should
be considered together with the results from the larger trials
described above.
Three of the studies mentioned above also indicated that
IFNb may be associated with a lower birth weight com-
pared to unexposed control patients [20, 30, 33]. Con-
versely, other studies found no effect on birth weights [24,
26, 31, 34]. In women taking IFNb (n = 7) or GA (n = 3)
throughout pregnancy, birth weights were slightly higher in
the IFNb-exposed pregnancies [24], but other small studies
found no statistical difference in birth weight with IFNb
exposure [34]. A retrospective analysis of 7 women who
became pregnant, while taking IFNb also did not detect an
effect of IFNb on birth weight [31]. None of these studies
distinguished among the different IFNb formulations.
Taken together, this information indicates that IFNb is
not teratogenic. Collectively, reports on over 1,500 preg-
nant women [21, 24, 2831] indicate that IFNb exposure is
not associated with an increased risk of spontaneous
abortion. Other observational studies or analyses involving
fewer than 120 patients treated with IFNb yielded
123
J Neurol (2013) 260:12021214
somewhat conflicting findings [20, 32, 33]. There is
inconsistent information as to whether IFNb leads to a
reduction in birth weight some studies found a reduction,
while others reported no such effect. Women who become
pregnant or plan to become pregnant, while taking IFNb
should be informed of these findings and the risks and
benefits of treatment should be discussed.
Fingolimod
The FDA has given fingolimod a pregnancy category C
rating based on experimental rat and rabbit studies showing
developmental toxicity including teratogenicity (in rats),
and embryolethality following fingolimod administration to
pregnant animals [35]. EMA product information recom-
mends that women of childbearing potential be counseled
regarding the potential for serious risk to the fetus and the
need for effective contraception during treatment with
fingolimod [36]. The sphingosine-1-phosphate receptors
affected by fingolimod have established functions in vas-
cular formation during embryogenesis. The most common
fetal visceral malformations in rats included ventricular
septal defect and persistent truncus arteriosus, in which a
single arterial trunk arises from the two cardiac ventricles
by means of a single semilunar valve. The highest no-effect
dose in rat studies (0.03 mg/kg/day) was less than the
recommended human dose of 0.5 mg/day on a body sur-
face area (mg/m2) basis, while in rabbit studies, the no-
effect dose (0.5 mg/kg/day) was approximately 20 times
the recommended human dose.
A pregnancy registry has been established to collect
information on fingolimod use during pregnancy. As of
January 2011, 47 pregnancies were reported in patients
who were receiving or had received fingolimod therapy
[35]. Among the 35 known outcomes, there were 5 spon-
taneous abortions (14 %), 14 elective abortions, and 16
successful births. One infant was born with unilateral
congenital posteromedial bowing of the tibia, and there was
one elective abortion following detection of tetralogy of
Fallot, the most common congenital cyanotic heart defect,
and one case of acrania in an ongoing pregnancy. The
reported number of pregnancies is not sufficient to draw
any definitive conclusions from these registry data.
Fingolimod (at a 0.5 mg dose) does not significantly
impact the pharmacokinetics of oral contraceptives and
does not compromise contraceptive efficacy [37]. Based on
the potential risk of fetal harm with fingolimod, which may
take approximately 2 months to be completely eliminated
from the body (Table 3), the US prescribing information
advises women of childbearing potential to use effective
contraception to avoid pregnancy during and for 2 months
after stopping fingolimod treatment [35].
J Neurol (2013) 260:12021214 1207

Table 3 DMTs currently approved for use in MS: general characteristics and pregnancy and lactation risks
Generic (brand) name Chemical structure T FDA EMA Lactation
(elimination) categorya statementb categoryc

GA (Copaxone, Teva Pharmaceutical L-glutamic acid polymer with *20 h B 2 L3

Industries) L-alanine, L-lysine, L-tyrosine,
molecular weight 59 kDa
IM IFNb-1a (Avonex, Biogen Idec) 166-aa glycoprotein, molecular *10 h C 2 L3
weight 23 kDa
SC IFNb-1a (Rebif, Merck Serono) 166-aa glycoprotein, molecular 69 37 h C 2 L3
weight 23 kDa
IFNb-1b (Betaseron/Betaferon, Bayer 165-aa protein product, molecular 8 min4.3 h C 2 L3
HealthCare Pharmaceuticals; Extavia, weight 19 kDa
Novartis)
TM
Fingolimod (Gilenya , Novartis) 2-amino-2-[2-(4-octylphenyl) ethyl] 69 days C 2 L4
propan-1,3-diol hydrochloride,
molecular weight 344 kDa
Natalizumab (Tysabri, Biogen Idec) Recombinant humanized IgG4j 11 4 days C 2 L3
monoclonal antibody, molecular
weight 149 kDa
Mitoxantrone (Novantrone, EMD Serono) Synthetic anthracenedione 23215 h D 2 L5
C22H28N4O6
2HCl, molecular weight
517 kDa
DMT disease-modifying therapy, MS multiple sclerosis, T half-life, FDA US Food and Drug Administration, EMA European Medicines
Agency, GA glatiramer acetate, kDa kilodaltons, IM intramuscular, IFNb interferon beta, aa amino acid, SC subcutaneous, IgG4j immuno-
globulin G4j
a
Based on risk of teratogenic effects, medications are classified by the FDA and listed in each drugs respective package insert as pregnancy
category A, B, C, D or X; please see each drugs respective package insert [16, 2426, 34, 38, 46]
b
Indicates the statement in Table 1 most similar to the statement in the product insert regarding pregnancy risk
c
Lactation risk categories are currently not listed in drug package inserts; DMT classifications based on lactation risk as L1 (safest), L2 (safer),
L3 (moderately safe), L4 (possibly hazardous) or L5 (contraindicated) are from Hale et al. [16]

Natalizumab (natalizumab) Pregnancy Exposure Registry (TPER) sug-

The FDA has given natalizumab a pregnancy category C
rating based on a guinea pig study showing a small
reduction in pup survival, when the drug was administered
at 30 mg/kg (7 times the human dose based on body
weight). In addition, a primate study showed hematologic
effects on the fetus (mild anemia, reduced platelet count,
increased spleen weight, and reduced liver and thymus
weights) when the drug was administered at 2.3 times the
human dose [3840]. These hematological effects resolved
following natalizumab discontinuation. Both studies
revealed no evidence of teratogenic effects at seven times
the human dose (30 mg/kg) [4042].
The EMA guidance on natalizumab use during preg-
nancy states that data on the use of natalizumab in pregnant
women are currently inadequate and that natalizumab
should not be used during pregnancy unless the clinical
condition of the woman requires natalizumab treatment
[43].
Although there are no well-controlled studies of natal-
izumab efficacy and safety in pregnant women, a pre-
liminary review of data from the prospective Tysabri
gests that treatment has no apparent adverse effect on
pregnancy outcomes in humans [44]. As of 23 May 2011, a
total of 341 pregnant patients were enrolled prospectively
in TPER, there were 277 known pregnancy outcomes. The
reported 11 % preliminary rate of spontaneous abortions
[44] is consistent with the expected US population rate of
15 % for spontaneous pregnancy loss in recognized preg-
nancies at \20 weeks gestation [19]. Malformations
occurred in 23 pregnancy outcomes in 21 of 277 women.
Malformations of the male genitalia, umbilical hernias,
plagiocephaly, hemangioma, and cardiovascular defects
(ventricular septal defect, patent ductus arteriosus, and
tetralogy of Fallot) were recorded, but these cases were
isolated and some were confounded by other risk factors,
they did not suggest any drug-related pattern [44].
Data from this registry are consistent with other findings
reported in a small number of pregnant women with
natalizumab exposure. Hoevenaren et al. [45] reported on
the pregnancy outcomes of 2 women with MS. One patient
used natalizumab, while trying to become pregnant and the
other received natalizumab prior to becoming pregnant and
throughout gestation. The newborns did not have any

123
1208
abnormalities at birth and showed normal development at
6 weeks follow-up. The patient who received continuous
natalizumab experienced no MS relapses during preg-
nancy. In another recently published article, Hellwig et al.
[46] followed 35 women with MS who accidentally
became pregnant, while taking natalizumab. All patients
stopped natalizumab as soon as they became aware of their
pregnancy. Patients included in the study had received
natalizumab for at least 8 weeks prior to their last menses.
The proportion of spontaneous abortions was 14 % (5 of
35), which is similar to what was seen in the natalizumab
registry [40] and is in line with the US population rates
[19]. All of the remaining 29 pregnancies were healthy
newborns, except for a boy born with hexadactyly.
Although the babies from natalizumab-exposed pregnan-
cies tended to have a lower mean birth weight than those
from a non DMT-treated control group (3,159 vs 3,406 g),
all newborns had birth weights within the normal range.
Interestingly, after natalizumab was withdrawn, MS
activity did not rebound either during pregnancy or post
partum. Furthermore, natalizumab-exposed women tended
to have fewer relapses than non DMT-exposed women
during pregnancy, while the number of relapses after
pregnancy did not differ significantly between the two
groups.
Three cases of first-trimester exposure to natalizumab
were recently reported [47, 48]. All three pregnancies
developed without any complications, with normal fetus
growth and full-term delivery (one spontaneous birth and
two cesarean births). Two of the women experienced
relapses in the immediate postpartum period, but reinitia-
tion of treatment with natalizumab stopped disease activity.
In addition, 2 patients from the authors clinic were
exposed to natalizumab during the first 6 weeks of preg-
nancy. One pregnancy resulted in a healthy delivery, the
other ended in miscarriage (M. Houtchens, unpublished
data). Collectively, there are only a few published cases on
the usage of natalizumab during pregnancy. Monitoring
patients through the prospective natalizumab pregnancy
registry should provide needed information on the safety of
natalizumab exposure during pregnancy.
Mitoxantrone
Mitoxantrone is a cytotoxic chemotherapeutic agent
approved for the treatment of secondary progressive MS. It
intercalates with DNA and inhibits topoisomerase II, and it
is considered a potential human teratogen. The FDA has
given mitoxantrone a pregnancy category D rating, and the
products US package insert states that women who are
pregnant or are trying to become pregnant should not use
mitoxantrone [49]. The EMA has not approved mitoxan-
trone for the treatment of MS. Adverse effects on the
123
J Neurol (2013) 260:12021214
developing fetus have been observed with structurally
related agents [49].
In preclinical models, administration of mitoxantrone to
rats during the organogenesis period of pregnancy was
associated with fetal growth retardation at doses of
[0.1 mg/kg/day (0.01 times the recommended human dose
on a mg/m2 basis) [49]. Similarly, when pregnant rabbits
were treated during organogenesis, mitoxantrone treatment
increased the rate of premature delivery at doses of
[0.1 mg/kg/day (0.01 times the recommended human dose
on a mg/m2 basis). Although no teratogenic effects were
observed in these studies, the maximum doses tested were
well below the recommended human dose (0.02 and 0.05
times the recommended human dose on a mg/m2 basis in
rats and rabbits, respectively).
Just three case reports on clinical outcomes during
pregnancy with mitoxantrone have been published, and
only two of these were in women with MS [5052]. In the
first case, a woman with MS received mitoxantrone until
the 29th week of her pregnancy [50]. Fetal growth was
restricted; however, the baby had no evidence of fetal
malformations. In the second case, a patient with MS was
exposed to mitoxantrone during the conception period and
delivered a child with Pierre Robin sequence, a syndrome
characterized by glossoptosis, micrognathia, and cleft pal-
ate [50]. The authors concluded that a causal relation with
mitoxantrone could be possible. In the third case, involving
a non-MS patient with acute myeloid leukemia, the new-
born showed no congenital malformations [51].
As a consequence of the available information with
mitoxantrone, the US prescribing information states that all
women of childbearing potential should have a pregnancy
test performed prior to each dose of the drug and should be
advised against becoming pregnant while taking this
cytotoxic agent.
Effects of approved MS therapies on fertility
The potential influence of DMTs for MS on fertility was
also reviewed. GA has no known effects on human fertility.
In a multigeneration reproduction and fertility study in rats,
GA at SC doses of up to 36 mg/kg (18 times the human
therapeutic dose on a mg/m2 basis) had no adverse effects
on reproductive parameters including fertility [16]. Simi-
larly, IFNb-1a has no known effects on human fertility.
Subcutaneously administered IFNb-1a showed no adverse
effects on fertility in rhesus monkeys at approximately nine
times the recommended human dose [25, 26]. Following
administration of oral fingolimod (0, 1, 3 or 10 mg/kg/day)
to male and female rats prior to and during mating, and
continuing to day 7 of gestation in females, no effect on
fertility was observed up to the highest fingolimod dose
tested (10 mg/kg, which is approximately 200 times the
J Neurol (2013) 260:12021214
recommended human dose on a mg/m2 basis) [35]. With
natalizumab, reductions in female guinea pig fertility have
been observed at dose levels of 30 mg/kg, but not at the
10 mg/kg dose level (2.3 times the clinical dose) [42].
Natalizumab did not affect male guinea pig fertility at
doses up to seven times the recommended human dose. No
controlled studies have reported the effects of natalizumab
on human fertility [40]. Finally, in four randomized, con-
trolled clinical trials of mitoxantrone in MS patients,
infertility and amenorrhea in female patients were among
the most frequently reported short-term adverse events
[53].
Therapies not approved for use in MS patients
A number of therapeutic agents are used off-label for the
treatment of MS including intravenous immunoglobulin
therapy, immunosuppressants, and monoclonal antibodies.
These agents are generally approved for the treatment of
other conditions and have been or are being investigated
for MS. As such, they are typically utilized with patients
who have failed to adequately respond to an approved
DMT. Table 3 summarizes the FDA pregnancy risk cate-
gory and EMA pregnancy risk statement for each thera-
peutic. There are only a few clinical reports on the use of
these agents during pregnancy that specify adverse out-
comes. Data on the effects of these agents on fertility in
MS patients are also not yet available.
Corticosteroid therapy for acute relapse treatment
In MS, intravenous corticosteroids are frequently used for
the treatment of acute relapses. Adequate human repro-
duction studies have not been performed with corticoste-
roids. However, they are broadly used in obstetric medicine
to treat fetuses at risk of preterm birth to prevent respira-
tory distress syndrome and to aid lung maturity [54]. Their
use in this context does not appear to be associated with a
negative impact on the development of the fetus [55], and
intravenous corticosteroids are thus probably safe in the
second and third trimesters of pregnancy. Steroids cross the
placental barrier and may increase the risk of cleft palate
when used in the first trimester [56] or may cause low birth
weight [55], and they could in theory delay healing for the
mother after birth. Therefore, corticosteroids should prob-
ably be reserved for treatment of serious acute exacerba-
tions. Prednisone, prednisolone, and methylprednisolone
can be administered with low levels of fetal exposure
and may be preferred for use during pregnancy [55, 56].
These agents are metabolized to inactive forms by 11-b-
hydroxysteroid dehydrogenase in the placenta, allowing
less than 10 % of the maternal dose to reach the fetus. In
contrast, betamethasone and dexamethasone, which have
1209
fluorine at the 9a position, cross the placenta with minimal
metabolism, leading to likely direct full-dose effects on the
fetus [56].
Intravenous immunoglobulin (IVIG) administration has
been reported to reduce the MS relapse rate during preg-
nancy and post partum, allowing concomitant breastfeed-
ing with no serious adverse effects on the infant [57]. The
Gammaglobulin Post Partum (GAMPP) study investigated
two IVIG doses (avoiding placebo control, because of
ethical concerns) and concluded that IVIG application
likely had beneficial effects, since the relapse rate did not
increase post partum [58]. More recently, Hellwig et al.
[59] have assessed the comparative efficacy of IVIG
application, treatment with other immunomodulatory
compounds and no treatment on the postpartum relapse
rate. The reduction in relapse rate showed a trend in favor
of the IVIG-treated women. However, analyzing the
expected number of relapses, IVIG-treated patients had
significantly fewer postpartum relapses than the untreated
control group matched for disease activity before and
during pregnancy (Chi-square test, p = 0.013).
MS therapies and breastfeeding
Breastfeeding is not contraindicated in women with MS.
Most studies have reported that breastfeeding has no effect
on MS relapses [9, 6063]. In other studies by Langer-
Gould et al. [64] and Hellwig et al. [65, 66], exclusive
breastfeeding in the postpartum period actually reduced the
risk of postpartum relapses. A detailed discussion of the
potential influence of breastfeeding on postpartum MS
relapses is beyond the scope of the current review, which
focuses on MS drug exposure and pregnancy.
Although a 24-h suspension of breastfeeding has his-
torically been recommended following exposure to intra-
venous contrast agents such as gadolinium-based agents as
a precautionary measure, because of the lack of data on
levels of gadolinium excreted in breast milk and the risk to
newborns, recent evidence-based guidelines for the use of
computerized tomography, magnetic resonance imaging
(MRI), and contrast media during pregnancy state that it
seems to be safe to continue breastfeeding immediately
after receiving iodinated contrast or gadolinium [67, 68].
Therefore, the mother should generally be allowed to
choose, whether or not to breastfeed based on her personal
preference as long as her illness has not been particularly
aggressive prior to conception. In women who were taking
a DMT before pregnancy, we advise not resuming therapy
until after the mother has finished breastfeeding her infant
[14]. In a woman with difficult-to-control disease prior to
pregnancy, an argument can be made in favor of rapid
reintroduction of immunomodulating therapy in order to
123
1210 J Neurol (2013) 260:12021214

Table 4 DMTs not currently approved for use in MS

Generic (brand) name Approved indication(s) FDA EMA Lactation
categorya statementb categoryc

Antibodies
Alemtuzumab (Campath/MabCampath, Genzyme Corporation, B cell lymphocytic leukemia C 1 L4
Cambridge, MA, USA)
Daclizumab (Zenapax, Hoffmann-La Roche, Basel, Switzerland) Prophylaxis of organ rejection in C 1d Unknown
renal transplants
Rituximab (MabThera, Hoffmann-La Roche; Rituxan, Non-Hodgkin lymphoma, C 1 L3
Biogen Idec) follicular lymphoma, RA
Immunoglobulin therapy
Intravenous immunoglobulin (various) Immune deficiencies, autoimmune C 2 L2
disorders, acute infections
Immunosuppressants
Azathioprine (Imuran, GlaxoSmithKline, London, UK; Azasan, Autoimmune diseases, RA, D 1 L3
Salix Pharmaceuticals, Morrisville, NJ, USA) prevention of organ and tissue
rejection
Cyclophosphamide (Endoxan, Baxter Oncology, Halle Malignancies, bone marrow D 1 L5
Westfalen, Germany; Cytoxan, E.R. Squibb and Sons, transplantation
Plainsboro, NJ, USA; Neosar, Pfizer, New York, NY,
USA; Procytox, Baxter Corporation, Mississauga,
TM
Ontario, Canada; Revimmune , Accentia Biopharmaceuticals,
Tampa, FL, USA)
Methotrexate (Rheumatrex, Dava Pharmaceuticals, Fort Lee, NJ, Neoplastic diseases, psoriasis, RA X 1 L3
TM
USA; Trexall , Duramed Pharmaceuticals, Pomona, NY, USA)
Mycophenolate mofetil (Cellcept, Genentech, South San Prophylaxis of tissue graft D 1 L4
Francisco, CA, USA) rejections
DMT disease-modifying therapy, MS multiple sclerosis, FDA US Food and Drug Administration, EMA European Medicines Agency,
RA rheumatoid arthritis
a
Based on risk of teratogenic effects, medications are classified by the FDA and listed in each drugs respective package insert as pregnancy
category A, B, C, D or X; please see each drugs respective package insert [17, 2527, 35, 40, 49]
b
Indicates the statement in Table 1 most similar to the statement in the product insert regarding pregnancy risk
c
Lactation risk categories are currently not listed in drug package inserts; DMT classifications based on lactation risk as L1 (safest), L2 (safer),
L3 (moderately safe), L4 (possibly hazardous) or L5 (contraindicated) are from Hale et al. [16]
d
The marketing authorization for Zenapax has been withdrawn at the request of the marketing authorization holder

avoid the compounded risk of postpartum exacerbation and
a rapid return to an active prepregnancy disease state.
Approved DMTs and breastfeeding
Lactation risk categories are not currently included in US
or EMA drug package inserts. As an alternative, the lac-
tation risk categories for each approved DMT were
obtained from the authoritative resource Medications and
Mothers Milk [16] and are presented in Table 3. Excretion
of GA, IM IFNb-1a, SC IFNb-1a or SC IFNb-1b in human
milk is not well established [17, 2527]. The molecular
weight of these compounds may limit their transfer to
maternal milk [24] and they are likely to be depolymerized,
if ingested orally so toxicity is unlikely [23]. In one recent
report [69], systematic assessment of IM IFNb-1a transfer
to human breast milk in 6 women receiving IM IFNb-1a
30 lg/week showed that even using the highest value
measured in breast milk (179 pg/mL), the estimated rel-
ative infant dose would be 0.006 % of the maternal dose.
No side effects were noted in any of the breastfed infants
[69]. These data suggest only subclinical levels of IFNb-1a
levels in human milk following IM dosing.
However, clinical data on the use of GA or other IFNb
formulations during breastfeeding are limited. Fragoso
et al. [22] reported on 9 mothers who breastfed their babies
for a mean period of 3.6 months while taking GA. No
infections, signs of inadequate digestion or other significant
ill effects were observed in these breastfed children during
or after breastfeeding. Hellwig and Gold [24] followed
3 mothers taking GA and 1 mother taking IFNb during
breastfeeding, again without any noticeable problems.
Although approved injectable DMTs are unlikely to have a
negative effect during breastfeeding, the decision on using

123
J Neurol (2013) 260:12021214 1211

Table 5 Author recommendations on the use of MS therapies during pregnancy and breastfeeding
Guidance for physicians counseling women receiving MS treatment who want to become pregnant

Counsel all women of childbearing age on family planning and conception planning
Provide expedited referral to infertility specialists, if a woman is unable to conceive and is remaining off therapy for extended periods of
time while attempting pregnancy
Consider monthly intravenous high-dose steroid treatment to coincide with the menstrual period in a woman who is attempting conception
and is off standard DMTs
IFNb and GA therapies should be discontinued for 1 month (elimination half-life 8 min4.5 days) prior to attempting conception. A longer
period (at least 23 months; elimination half-life 615 days) is recommended for natalizumab, fingolimod, and mitoxantrone. (See Table 1)
Women who wish to continue taking a DMT during pregnancy should avoid mitoxantrone and fingolimod. For the other DMTs, women and
their clinicians should weigh up the risks and benefits based on the following information:
Preliminary data on GA, IFNb, and natalizumab exposure and pregnancy outcomes have not shown any specific patterns of malformations
suggestive of teratogenicity, but there is currently insufficient evidence for definite conclusions
Among the IFNb formulations, IM or SC IFNb-1a is preferred due to the availability of safety data from pregnancy registries, which are
lacking for IFNb-1b
Limited preclinical data and findings in a limited number of patients suggest that IFNb may be associated with an increase in the rate of
spontaneous abortions. However, this effect was not seen in over 1,500 women enrolled in pregnancy registries and other studies
GA and natalizumab may be associated with reduced relapses during pregnancy, according to limited evidence. Comparable data are not
available for IFNb. Natalizumab should be used during pregnancy only, if the potential maternal benefit justifies the potential risk to the
fetus
Intravenous prednisone, prednisolone, and methylprednisolone are moderately safe in the second and third trimesters of pregnancy for the
treatment of serious acute exacerbations
Reassure patients that methods of obstetrical anesthesia and mode of delivery (vaginal versus cesarean section) are not related to the
likelihood of postpartum relapse [78, 79]
Guidance for physicians counseling women receiving MS treatment who unexpectedly become pregnant
Women should be advised to discontinue their DMT treatment if they unexpectedly become pregnant. This particularly applies to
mitoxantrone and fingolimod. Women taking GA and IFNb should be counseled that preliminary data on GA, IFNb, and natalizumab
exposure and pregnancy outcomes have not shown any specific patterns of malformations suggestive of teratogenicity, but there is currently
insufficient evidence for definite conclusions
If there is documented exposure to high-risk approved or off-label compounds in the first trimester, the patient should be expeditiously
referred to a high-risk maternal fetal medicine specialist for ongoing pregnancy follow-up
The same recommendations outlined in the section above apply to those who unexpectedly become pregnant and wish to continue taking
their DMT
Guidance for physicians counseling women with MS treatment who wish to breastfeed their infant
The transfer of GA into breast milk is unlikely, and IFNb was reported to be present only in extremely small quantities [66]. Natalizumab
has also been detected in human breast milk [38]. However, clinical data on the use of these drugs during breastfeeding and potential effects
on infants are currently lacking. Therefore, women considering taking one of these agents during breastfeeding should weigh the potential
risks as well as the benefits
In patients with a high risk of postpartum relapse, intravenous immunoglobulin is safe during breastfeeding and may be associated with
reduction in postpartum relapses [56, 80, 81]
Corticosteroids are moderately safe for women experiencing an acute relapse while breastfeeding, and they may reduce relapse rates when
used as monthly high-dose infusions. However, a washout period should be applied
For high intravenous doses, mothers should pump and discard breast milk for 2448 h after their infusion before resuming nursing
Fingolimod and mitoxantrone should be avoided during breastfeeding
It is safe to continue breastfeeding after receiving iodinated or gadolinium-contrast agents for MRI [64, 65]
DMT disease-modifying therapy, IFNb interferon beta, GA glatiramer acetate, IM intramuscular, SC, subcutaneous, MRI magnetic resonance
imaging

IFNb or GA during lactation should be made jointly by the
neurologist and the obstetrician, and the current practice
standards advise against the use of any injectable MS
therapies in breastfeeding mothers.
There is some evidence that other approved agents
(fingolimod, natalizumab, and mitoxantrone) are excreted
into milk [35, 40, 49]. For fingolimod, the evidence for
excretion into milk comes from experiments in treated rats
[35]. For mitoxantrone and natalizumab, excretion into
milk has been observed in humans [40, 49]. As mitoxan-
trone is a cytotoxic agent, it has a high risk of causing
significant negative effects on the infant and its use is
contraindicated during lactation. The use of fingolimod
during breastfeeding should also be avoided, given that it is

123
1212
orally bioavailable and takes a long time to clear. Although
natalizumab is not orally bioavailable, it has been detected
in breast milk [40] and the effects of exposure on new-
borns/infants are unknown, so caution is required.
Other therapies and breastfeeding
The lactation risk categories for other common therapies
that are not approved for MS are summarized in Table 4.
Of these therapies, intravenous immunoglobulin may be
particularly useful during breastfeeding to reduce post-
partum relapse rate without causing adverse effects to the
infant [57, 58, 70]. A double-blind, randomized trial in
Europe investigated intravenous immunoglobulin in 168
postpartum mothers with MS [57]. Mothers who breastfed
for 3 months or longer while taking this therapy were more
likely to be relapse-free during the study than those who
did not breastfeed or who breastfed for less than 3 months.
No adverse effects on the breastfed infants were reported.
In addition, a case series in 43 breastfeeding women with
MS who received intravenous immunoglobulin within
3 days of delivery and monthly thereafter found that the
relapse rate was lower in the studied patients than in his-
torical controls [71]. The only reported adverse effect was
a transient rash, possibly caused by the administration of
immunoglobulin. The potential benefits of postpartum
intravenous immunoglobulin on relapse rate have also been
seen in another smaller study [72].
Breastfeeding by women on glucocorticoid therapy is
generally considered safe, and there appears to be minimal
excretion of corticosteroids into breast milk [7375]. In one
study, it was calculated that small-to-moderate doses of
corticosteroids ingested from milk (e.g., prednisolone
80 mg daily) would add, at most, 10 % to the infants
endogenous corticosteroid production, which was expected
to have little clinical significance [74]. However, since
steroids can cause adverse events in children including
growth retardation [55], a washout period should be
applied between dosing and nursing. Steroid levels in
breast milk peak 2 h after administration and decline rap-
idly thereafter. Therefore, exposure may be minimized, if
nursing is performed 4 h after a low-to-moderate dose is
taken [55]. For higher intravenous doses (e.g., of monthly
methylprednisolone), it may be prudent for mothers to wait
2448 h after their infusion before nursing, using a breast
pump in the interim. These women should be instructed to
plan ahead and save breast milk ahead of time to continue
to use it, while they are transiently unable to nurse.
In the postpartum period, pulses of monthly intravenous
methylprednisolone for 6 months led to a reduced rate of
relapses relative to an untreated group (p = 0.018), sug-
gesting a beneficial effect for this therapy in this setting
[76]. A similar approach can be utilized in women who are
123
J Neurol (2013) 260:12021214
at high risk for postpartum exacerbation, but choose to
breastfeed their infants and are not comfortable returning to
their platform prepregnancy therapy while nursing.
Conclusions
Historically, women with MS were discouraged from
having children based on unsubstantiated concerns about
the potential effects of pregnancy on the mothers disease
and the potential effects of MS on the fetus. Mounting
evidence has shown that pregnancy has no long-term
negative effects on disease course and that maternal MS is
not associated with an increased risk of birth defects or
developmental delays [6, 7780]. Though data on the
efficacy and/or safety of MS treatments during pregnancy
and breastfeeding remain limited, completed or ongoing
registry studies are providing essential real-world data
allowing healthcare professionals and patients to weigh the
benefit of specific MS treatments against the potential risks
to the fetus. Based on data from these registries, other
published studies and analyses, and our own clinical
experience, we have developed clinical considerations on
the use of DMTs and corticosteroids during pregnancy and
breastfeeding (Table 5). Ultimately, the treating physician
and the patient involved must carefully consider the deci-
sion to either discontinue or continue using a particular
agent during pregnancy or breastfeeding.
Acknowledgments Medical writing assistance was provided by
Christopher Barnes and editorial support was provided by Joshua
Safran, both of Infusion Communications. Their work was funded by
Biogen Idec Inc. The authors were not compensated and retained full
editorial control.
Conflicts of interest Dr. Houtchens has served on scientific advi-
sory boards and received compensation for her work as a consultant
for EMD Serono, Biogen Idec, Novartis, Acorda, and Teva Pharma-
ceutical Industries. Dr. Kolb has received compensation as a paid
consultant for Teva Neuroscience.
References
1. Grima DT, Torrance GW, Francis G, Rice G, Rosner AJ,
Lafortune L (2000) Cost and health related quality of life con-
sequences of multiple sclerosis. Mult Scler 6:9198
2. Naci H, Fleurence R, Birt J, Duhig A (2010) Economic burden of
multiple sclerosis: a systematic review of the literature. Phar-
macoeconomics 28:363379
3. Asche CV, Singer ME, Jhaveri M, Chung H, Miller A (2010) All-
cause health care utilization and costs associated with newly
diagnosed multiple sclerosis in the United States. J Manag Care
Pharm 16:703712
4. Naci H, Fleurence R, Birt J, Duhig A (2010) The impact of
increasing neurological disability of multiple sclerosis on health
utilities: a systematic review of the literature. J Med Econ
13:7889
J Neurol (2013) 260:12021214
5. Weinshenker BG, Bass B, Rice GP et al (1989) The natural
history of multiple sclerosis: a geographically based study I.
Clinical course and disability. Brain 112:133146
6. Confavreux C, Aimard G, Devic M (1980) Course and prognosis
of multiple sclerosis assessed by the computerized data pro-
cessing of 349 patients. Brain 103:281300
7. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire
P, Moreau T (1998) Rate of pregnancy-related relapse in multiple
sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med
339:285291
8. Vukusic S, Hutchinson M, Hours M et al (2004) Pregnancy and
multiple sclerosis (the PRIMS study): clinical predictors of post-
partum relapse. Brain 127:13531360
9. Vukusic S, Confavreux C (2006) Pregnancy and multiple sclerosis:
the children of PRIMS. Clin Neurol Neurosurg 108:266270
10. Niino M, Hirotani M, Fukazawa T, Kikuchi S, Sasaki H (2009)
Estrogens as potential therapeutic agents in multiple sclerosis.
Cent Nerv Syst Agents Med Chem 9:8794
11. Stenager E, Stenager EN, Jensen K (1994) Effect of pregnancy on
the prognosis for multiple sclerosis: a 5-year follow up investi-
gation. Acta Neurol Scand 90:305308
12. Dhooghe MB, Nagels G, Uitdehaag BM (2010) Long-term
effects of childbirth in MS. J Neurol Neurosurg Psychiatry
81:3841
13. National MS Society (2011) Pregnancy, delivery, and the post-
partum period: information for women with MS to share with
their physicians. http://www.nationalmssociety.org/living-with-
multiple-sclerosis/healthy-living/pregnancy/index.aspx. Accessed
12 August 2011
14. Coyle PK, Christie S, Fodor P et al (2004) Multiple sclerosis
gender issues: clinical practices of women neurologists. Mult
Scler 10:582588
15. Davis DB (2010) Drugs in pregnancythe issues for 2010.
J Popul Ther Clin Pharmacol 17:e332e335
16. Hale TW (2010) Medications and mothers milk, 14th edn. Hale
Publishing, Amarillo
17. Copaxone (glatiramer acetate) prescribing information (2011)
http://www.sharedsolutions.com/pdfs/
prescribinginformation.aspx. Accessed 4 November 2011
18. Coyle P, Johnson K, Pardo L (2003) Pregnancy outcomes in
patients with multiple sclerosis treated with glatiramer acetate
(Copaxone). 19th Congress of the European Committee for
Treatment and Research in Multiple Sclerosis (ECTRIMS),
Milan, 1720 September 2003
19. Ventura SJ, Curtin SC, Abma JC (2012) Estimated pregnancy
rates and rates of pregnancy outcomes for the United States,
19902008. Nat Vital Statistics Rep 60:122
20. Weber-Schoendorfer C, Schaefer C (2009) Multiple sclerosis,
immunomodulators, and pregnancy outcome: a prospective
observational study. Mult Scler 15:10371042
21. Finkelsztejn A, Fragoso YD, Ferreira ML et al (2011) The Bra-
zilian database on pregnancy in multiple sclerosis. Clin Neurol
Neurosurg 113:277280
22. Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR et al (2010)
Long-term use of glatiramer acetate by 11 pregnant women with
multiple sclerosis: a retrospective, multicentre case series. CNS
Drugs 24:969976
23. Salminen HJ, Leggett H, Boggild M (2010) Glatiramer acetate
exposure in pregnancy: preliminary safety and birth outcomes.
J Neurol 257:20202023
24. Hellwig K, Gold R (2011) Glatiramer acetate and interferon-beta
throughout gestation and postpartum in women with multiple
sclerosis. J Neurol 258:502503
25. Rebif (subcutaneous interferon beta-1a) prescribing information
(2011) http://www.emdserono.com/cmg.emdserono_us/en/images/
rebif_tcm115_19765.pdf. Accessed 4 November 2011
1213
26. Avonex (intramuscular interferon beta-1a) prescribing informa-
tion (2011) http://www.avonex.com/pdfs/pi-powder.pdf. Accessed
4 November 2011
27. Betaseron (interferon beta-1b) prescribing information (2011)
http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf.
Accessed 4 November 2011
28. Richman S, Wallace K, Liu S, Sperling B (2012) Pregnancy
outcomes from the Avonex (interferon beta-1a) pregnancy
exposure registry. Neurology 78:P06.191
29. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G
(2011) Pregnancy outcomes in multiple sclerosis following sub-
cutaneous interferon beta-1a therapy. Mult Scler 17:423430
30. Amato MP, Portaccio E, Ghezzi A et al (2010) Pregnancy and
fetal outcomes after interferon-beta exposure in multiple sclero-
sis. Neurology 75:17941802
31. Patti F, Cavallaro T, Lo Fermo S et al (2008) Is in utero early-
exposure to interferon beta a risk factor for pregnancy outcomes
in multiple sclerosis? J Neurol 255:12501253
32. Sandberg-Wollheim M, Frank D, Goodwin TM et al (2005)
Pregnancy outcomes during treatment with interferon beta-1a in
patients with multiple sclerosis. Neurology 65:802806
33. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G (2005) The
reproductive effects of beta interferon therapy in pregnancy:
a longitudinal cohort. Neurology 65:807811
34. Hellwig K, Haghikia A, Gold R (2010) Parenthood and immuno-
modulation in patients with multiple sclerosis. J Neurol 257:580583
35. Gilenya (fingolimod) US prescribing information (2011)
http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf.
Accessed 4 November 2011
36. Gilenya (fingolimod) European public assessment report (2012)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/
human/medicines/002202/human_med_001433.jsp&mid=WC0b
01ac058001d124. Accessed 22 June 2012
37. Collins W, Francis G, Koren G et al (2011) Lack of interaction
between fingolimod (FTY720) and oral contraceptives, and
pregnancy experience in the clinical program of fingolimod in
multiple sclerosis. Neurology 76(Suppl 4):A609
38. Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J
(2009) Postnatal development in cynomolgus monkeys following
prenatal exposure to natalizumab, an alpha4 integrin inhibitor.
Birth Defects Res B Dev Reprod Toxicol 86:144156
39. Wehner NG, Shopp G, Oneda S, Clarke J (2009) Embryo/fetal
development in cynomolgus monkeys exposed to natalizumab, an
alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Tox-
icol 86:117130
40. Tysabri (natalizumab) prescribing information (2011) http://
www.accessdata.fda.gov/drugsatfda_docs/label/2011/125104s06
58lbl.pdf. Accessed 6 December 2011
41. Wehner NG, Shopp G, Rocca MS, Clarke J (2009) Effects of
natalizumab, an alpha4 integrin inhibitor, on the development of
Hartley guinea pigs. Birth Defects Res B Dev Reprod Toxicol
86:98107
42. Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J (2009)
Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in
male and female guinea pigs. Birth Defects Res B Dev Reprod
Toxicol 86:108116
43. Tysabri (natalizumab) European public assessment report (2011)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/
human/medicines/000603/human_med_001119.jsp&mid=WC0b
01ac058001d124. Accessed 22 June 2012
44. Cristiano LM, Bozic C, Bloomgren G (2011) Preliminary eval-
uation of pregnancy outcomes from the Tysabri (natalizumab)
pregnancy exposure registry. Mult Scler 17:S457
45. Hoevenaren IA, de Vries LC, Rijnders RJ, Lotgering FK (2011)
Delivery of healthy babies after natalizumab use for multiple
sclerosis: a report of two cases. Acta Neurol Scand 123:430433
123
1214
46. Hellwig K, Haghikia A, Gold R (2011) Pregnancy and natal-
izumab: results of an observational study in 35 accidental preg-
nancies during natalizumab treatment. Mult Scler 17:958963
47. Mattioda A, Masera S, Romagnolo A et al (2011) Healthy baby
delivery after conception during natalizumab exposure: a case
report. Mult Scler 17:S455S456
48. Totaro R, Rossi M, Casalena A, Carolei A (2011) Pregnancy,
delivery, and birth outcome after natalizumab use for multiple
sclerosis: a report of two cases. Mult Scler 17:S227S228
49. Novantrone (mitoxantrone) prescribing information (2011) http://
www.accessdata.fda.gov/drugsatfda_docs/label/2010/019297s03
3s034lbl.pdf. Accessed 4 November 2011
50. De Santis M, Straface G, Cavaliere AF, Rosati P, Batocchi AP,
Caruso A (2007) The first case of mitoxantrone exposure in early
pregnancy. Neurotoxicology 28:696697
51. Baumgartner AK, Oberhoffer R, Jacobs VR et al (2009)
Reversible foetal cerebral ventriculomegaly and cardiomyopathy
under chemotherapy for maternal AML. Onkologie 32:4043
52. Hellwig K, Schimrigk S, Chan A, Epplen J, Gold R (2011)
A newborn with Pierre Robin sequence after preconceptional
mitoxantrone exposure of a female with multiple sclerosis.
J Neurol Sci 307:164165
53. Martinelli V, Radaelli M, Straffi L, Rodegher M, Comi G (2009)
Mitoxantrone: benefits and risks in multiple sclerosis patients.
Neurol Sci 30(Suppl 2):S167S170
54. Roberts D, Dalziel S (2006) Antenatal corticosteroids for accel-
erating fetal lung maturation for women at risk of preterm birth.
Cochrane Database Sys Rev 3:CD004454
55. Hoes JN, Jacobs JW, Boers M et al (2007) EULAR evidence-
based recommendations on the management of systemic gluco-
corticoid therapy in rheumatic diseases. Annals Rheumatic Dis
66:15601567
56. Elliott AB, Chakravarty EF (2010) Immunosuppressive medica-
tions during pregnancy and lactation in women with autoimmune
diseases. Womens Health 6:431440
57. Achiron A, Kishner I, Dolev M et al (2004) Effect of intravenous
immunoglobulin treatment on pregnancy and postpartum-related
relapses in multiple sclerosis. J Neurol 251:11331137
58. Haas J, Hommes OR (2007) A dose comparison study of IVIG in
postpartum relapsing-remitting multiple sclerosis. Mult Scler
13:900908
59. Hellwig K, Beste C, Schimrigk S, Chan A (2009) Immunomod-
ulation and postpartum relapses in patients with multiple scle-
rosis. Ther Adv Neurol Disord 2:711
60. Portaccio E, Ghezzi A, Hakiki B et al (2011) Breastfeeding is not
related to postpartum relapses in multiple sclerosis. Neurology
77:145150
61. Nelson LM, Franklin GM, Jones MC (1988) Risk of multiple
sclerosis exacerbation during pregnancy and breast-feeding.
JAMA 259:34413443
62. Hellwig K, Haghikia A, Agne H, Beste C, Gold R (2009) Pro-
tective effect of breastfeeding in postpartum relapse rate of
mothers with multiple sclerosis. Arch Neurol 66:15801581
(author reply 1581)
123
J Neurol (2013) 260:12021214
63. Jalkanen A, Airas L, Marttila RJ (2011) To breastfeed or not to
breastfeed: effect of breastfeeding on postpartum disease activity
in multiple sclerosis revisited. Neurology 76(Suppl 4):A610
64. Langer-Gould A, Huang SM, Gupta R et al (2009) Exclusive
breastfeeding and the risk of postpartum relapses in women with
multiple sclerosis. Arch Neurol 66:958963
65. Hellwig K, Kuge M, Gold R, Langer-Gould A (2011) Exclusive
breastfeeding reduces the risk of postpartum relapses a prospec-
tive study from the German MS and pregnancy registry. Neu-
rology 76(Suppl 4):A273
66. Hellwig K, Haghikia A, Gold R (2011) Multiple sclerosis and
pregnancy experience from a nationwide database. Neurology
76(Suppl 4):A273
67. Webb JA, Thomsen HS, Morcos SK, Members of Contrast Media
Safety Committee of European Society of Urogenital Radiology
(ESUR) (2005) The use of iodinated and gadolinium contrast
media during pregnancy and lactation. Eur Radiol 15:12341240
68. Chen MM, Coakley FV, Kaimal A, Laros RK Jr (2008) Guide-
lines for computed tomography and magnetic resonance imaging
use during pregnancy and lactation. Obstet Gynecol 112(2 Pt
1):333340
69. Hale TW, Siddiqui AA, Baker TE (2012) Transfer of interferon
b-1a into human breastmilk. Breastfeed Med 7:123125
70. Ferrero S, Esposito F, Pretta S, Ragni N (2006) Fetal risks related
to the treatment of multiple sclerosis during pregnancy and
breastfeeding. Exp Rev Neurotherapeutics 6:18231831
71. Haas J (2000) High dose IVIG in the post partum period for
prevention of exacerbations in MS. Mult Scler 6(Suppl 2):S18
S20 (discussion S33)
72. Orvieto R, Achiron R, Rotstein Z, Noy S, Bar-Hava I, Achiron A
(1999) Pregnancy and multiple sclerosis: a 2-year experience. Eur
J Obstet Gynecol Reprod Biol 82:191194
73. McKenzie SA, Selley JA, Agnew JE (1975) Secretion of pred-
nisolone into breast milk. Arch Dis Child 50:894896
74. Ost L, Wettrell G, Bjorkhem I, Rane A (1985) Prednisolone
excretion in human milk. J Pediatrics 106:10081011
75. Greenberger PA, Odeh YK, Frederiksen MC, Atkinson AJ Jr
(1993) Pharmacokinetics of prednisolone transfer to breast milk.
Clin Pharmacol Therapeut 53:324328
76. de Seze J, Chapelotte M, Delalande S, Ferriby D, Stojkovic T,
Vermersch P (2004) Intravenous corticosteroids in the post-
partum period for reduction of acute exacerbations in multiple
sclerosis. Mult Scler 10:596597
77. Bennett KA (2005) Pregnancy and multiple sclerosis. Clinical
Obstet Gynecol 48:3847
78. Houtchens MK (2007) Pregnancy and multiple sclerosis. Semin
Neurol 27:434441
79. Jalkanen A, Alanen A, Airas L (2010) Pregnancy outcome in
women with multiple sclerosis: results from a prospective
nationwide study in Finland. Mult Scler 16:950955
80. Stuart M, Bergstrom L (2011) Pregnancy and multiple sclerosis.
J Midwifery Womens Health 56:4147
81. Ferrero S, Pretta S, Ragni N (2004) Multiple sclerosis: manage-
ment issues during pregnancy. Eur J Obstet Gynecol Reprod Biol
115:39