Pregnancy and Family REVIEW ARTICLE


Planning in Multiple C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE

Sclerosis
By Annette M. Langer-Gould, MD, PhD

ABSTRACT
PURPOSE OF REVIEW: This article provides practical guidance on successful
management of women with multiple sclerosis (MS) through pregnancy
and the postpartum period.
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVJua3JJgqHHlUk4MDQF1JtxPh8N4crIkwmck8KAeebLJ on 06/03/2019

RECENT FINDINGS: Recent studies indicate that most women diagnosed with
MS today can have children, breast-feed, and resume beta interferons
or glatiramer acetate per their preferences without incurring an increased
risk of relapses during the postpartum period. More than 40% of women
with mild MS do not require any treatment before conception or in the
postpartum period. Women with highly active MS can now become CITE AS:
CONTINUUM (MINNEAP MINN)
well-controlled before, throughout, and after pregnancy via highly
2019;25(3, MULTIPLE SCLEROSIS
effective treatments. Unfortunately, pregnancy does not protect against AND OTHER CNS INFLAMMATORY
relapses following the cessation of fingolimod or natalizumab, and some DISEASES):773–792.

women experience severe rebound relapses during pregnancy. Accidental

Address correspondence to
first-trimester exposure to teriflunomide or fingolimod increases the risk Dr Annette M. Langer-Gould,
of fetal harm. Kaiser Permanente Southern
California Permanente Medical
Group, 100 S Los Robles Ave,
SUMMARY: Most women with MS can have normal pregnancies and Pasadena, CA 91101, Annette.M.
breast-feed without incurring harm. Clinicians should avoid prescribing Langer-Gould@kp.org.
medications with known teratogenic potential (teriflunomide, fingolimod),
RELATIONSHIP DISCLOSURE:
known risk of severe rebound relapses (fingolimod, natalizumab), or Dr Langer-Gould receives
unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of research/grant support from
the National Multiple Sclerosis
childbearing age who desire pregnancy or are not on reliable birth control. Society and the Patient-
If a treatment needs to be resumed during breast-feeding, clinicians Centered Outcomes Research
should opt for glatiramer acetate, interferon beta, natalizumab, or Institute.

rituximab/ocrelizumab, as biologically plausible risks to the infant are UNLABELED USE OF

exceedingly low. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Langer-Gould discusses the
use of corticosteroids and
INTRODUCTION plasma exchange to treat
multiple sclerosis relapse during

T
he majority of patients with multiple sclerosis (MS) no longer need to pregnancy, gabapentin to treat
alter pregnancy or breast-feeding plans because of their underlying neuropathic pain, natalizumab
to treat multiple sclerosis during
disease. More than 40% of women are not on treatment in the
pregnancy, and rituximab to
12 months before conception and do not incur increased risk of treat multiple sclerosis.
disability.1,2 Accidental pregnancy exposure to some of the most
commonly prescribed MS treatments in the United States, glatiramer acetate and © 2019 American Academy
various interferon beta preparations, appears safe. Breast-feeding at least briefly, of Neurology.

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PREGNANCY AND FAMILY PLANNING IN MS
KEY POINT
● Multiple sclerosis does
not increase the risk of
infertility, adverse
pregnancy outcomes, or
adverse neonatal outcomes,
but some multiple sclerosis
treatments may increase
these risks.
774
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even if combined with formula feedings, neither increases or decreases the risk
of postpartum relapse,1 and breast-feeding exclusively for at least 2 months
postpartum appears to decrease the risk of postpartum relapses.3,4 Even when
relapses occur during pregnancy or the postpartum period, they do not appear to
affect long-term prognosis in most women.5 If treatment is needed during
lactation, several medications are available that pose no biologically plausible
risk to the infant if exposure occurs only via breast milk.
Thus, the good news is there are only a few pitfalls to be avoided when
managing and counseling women of childbearing potential; those with the
highest impact are pregnancies that occur while a woman is still taking
medications that are known to or potentially increase the risk of adverse
pregnancy outcome risks and pregnancies that occur shortly after cessation
of or while a woman is still taking fingolimod or natalizumab. Luckily, the
large number of treatment options available now make these issues easy
to avoid.
This article focuses on how to avoid these potentially high-impact errors
through proper counseling and treatment selection. Practical management
guidance is also provided for when a woman does get pregnant while on a risky
MS medication, including when high-risk obstetrics care and additional neonatal
care may be wise. This article also covers less common scenarios, including
fertility treatment and drugs to avoid in men who desire children.
BACKGROUND
The uncertainties and controversies in the counseling and management of
women with MS during pregnancy and the postpartum period have shifted
significantly over the past 30 years. Evidence generated in a landmark study6 laid
to rest concerns that pregnancy was not safe for women with MS. This study also
raised awareness that the risk of relapses is increased in the first 3 to 4 months
postpartum, particularly in women with very active MS before pregnancy. After
the introduction of MS disease-modifying therapies that have allowed women
to achieve improved disease control before pregnancy, the debate shifted to
whether women with MS should breast-feed or forego breast-feeding to
resume disease-modifying therapy in the hopes of preventing these early
postpartum relapses.
Simultaneously, researchers demonstrated a multitude of infant and
maternal health benefits of breast-feeding, and public health efforts have led to
significant rises in rates of prolonged breast-feeding in the general population.7
This is causing increasing concern that recommending foregoing breast-feeding
in women with MS could have long-lasting detrimental effects for the mother
and infant. This issue is particularly concerning as multiple revisions in the MS
diagnostic criteria have allowed for earlier diagnosis in patients with milder
disease. This means that today many women with MS who get pregnant may
have much milder disease than those included in the historical studies from
which the concerns of postpartum relapses arose (CASE 10-1).
In the past 5 years, evidence has been increasing in MS and other autoimmune
diseases that recommending foregoing breast-feeding is unnecessary8 and that
exclusive breast-feeding may reduce the risk of postpartum MS relapses,4
particularly in women with milder forms of MS. But a new issue has arisen:
severe relapses occurring during pregnancy following cessation of natalizumab9
or fingolimod,10,11 which were virtually unheard of before.
JUNE 2019
 Other studies have been published confirming that MS itself does not increase
the risk of infertility, adverse pregnancy outcomes, or adverse neonatal
outcomes.12,13 However, with the introduction of oral disease-modifying
therapies, particularly teriflunomide, clinicians should ensure that women are on
effective birth control to prevent fetal toxicity and that they plan their
pregnancies.14 In addition, if alemtuzumab was used before pregnancy,
neurologists should monitor the mother closely for development of autoimmune
thyroiditis, as this can result in neonatal thyroid disease and its numerous risks.

DEVELOPMENT OF BEST PRACTICE RECOMMENDATIONS

The recommendations presented herein were developed for use by neurologists
and pharmacists practicing in Kaiser Permanente Southern California by the
author and the MS specialists group. They balance the mother’s risk of disability

A 24-year-old woman with multiple sclerosis (MS) presented to discuss CASE 10-1
pregnancy and breast-feeding. She had been diagnosed with MS at age
20 when she presented with optic neuritis and met McDonald criteria for
MS by brain MRI. She was started on a modestly effective disease-
modifying therapy but stopped after 6 months. She had not had any
further relapses.
Her neurologic examination was normal. Her brain MRI showed a
single new nonenhancing periventricular lesion since diagnosis.
She was worried about the risk of postpartum relapse and her ability
to care for a baby. She was reassured that her disease was quite mild and
that if a postpartum relapse occurred, it would also likely be mild and
treatable like her past relapses; exclusive breast-feeding was also
recommended.
In the next 3 years, she had two children and remained relapse-free
and untreated. Both pregnancies were uncomplicated, both infants were
breast-fed exclusively until 6 months of age, and she planned to
continue to breast-feed her 1-year-old child. She was not sure whether
she wanted more children and was not on birth control.

This case illustrates an increasingly common scenario as the MS diagnostic COMMENT

criteria undergo revisions allowing women to be diagnosed earlier and with
milder disease. Recommending this patient resume a disease-modifying
therapy before or shortly after pregnancy, particularly if it meant she
could not breast-feed, was not necessary as she did not have frequent
relapses, significant accumulation of new lesions on MRI, or disability
from previous relapses. Supporting her in her desire to breast-feed was
appropriate. Now that she may be done having children, it would be
appropriate to check another noncontrast brain MRI to assess for lesion
progression. If she has new or enlarging lesions, starting glatiramer acetate
or interferon beta would be compatible with breast-feeding and the
possibility that she may become pregnant accidentally before
discontinuation of treatment.

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PREGNANCY AND FAMILY PLANNING IN MS
KEY POINTS
● Potential risks not
captured by US Food and
Drug Administration
pregnancy categories
include neonatal
immunosuppression,
impaired early-life
neurocognitive
development, delayed
toxicities in the child (eg,
cancer), and risks incurred
from severe rebound
relapses in pregnancy.
● It is important to assess
whether the patient’s
disease activity is
adequately controlled
before counseling about
pregnancy. First decide
whether patients with
multiple sclerosis need to
be on highly effective or
modestly effective
disease-modifying therapy
to control their disease
activity, then consider the
possibility of pregnancy
when choosing a disease-
modifying therapy.
776
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with risks to the infant and practical considerations, including the mother’s
preferences and simplicity. Where clear evidence in humans is available, it
takes precedence over animal data. When solid data in humans are lacking,
which is usually the case with newer drugs, we rely on biological plausibility
obtained by considering the combination of animal data, pharmacologic
properties, mechanism of action, and case series in humans. Both risks captured
by the US Food and Drug Administration (FDA) risk categories (fertility,
fetotoxicity, major malformations) and those not captured by those categories
are considered. These additional risks include the impact on the infant’s
developing immune system and vaccine responses, potential neurologic sequelae
that can result directly from drugs or from increased risk of preterm labor or
low birth weight, later-life cancers or other delayed offspring toxicities, and
risks incurred from severe rebound relapses during pregnancy. When the
evidence is mixed, the author recommends caution and counseling women
regarding the uncertainties. In areas where the risks are high and the evidence
is rapidly evolving, the author recommends consulting a neurologist who is an
expert in MS and pregnancy for the most up-to-date guidance.
Women have strong preferences regarding family planning, breast-feeding
choices, and use of drugs during pregnancy and lactation. Thus, only in rare
circumstances would the author strongly recommend treating with disease-
modifying therapy until conception or during pregnancy or resuming disease-
modifying therapy shortly after delivery. In most scenarios, we openly
discuss the pros and cons with the mother and support her decision,
while monitoring for disease activity should she choose a very risk-averse
approach.
Incorporating Family Planning in Starting, Stopping, or Switching Multiple
Sclerosis Treatments
FIGURE 10-1 describes best practice recommendations for how to incorporate
family planning when starting, stopping, or switching MS treatment plans. The
first decision for any patient with MS to make is whether to start a highly or
modestly effective disease-modifying therapy. If patients are already on a
disease-modifying therapy, the question is whether their MS is well controlled
and, if not, whether they should be switched to another disease-modifying
therapy to reduce risk of long-term disability.
The author recommends a risk-stratified treatment approach for all patients
with MS that considers their underlying risk of long-term disability when
deciding whether to start or switch to a highly effective disease-modifying
therapy. The strongest risk factors for long-term disability are progressive disease
course and, in patients with relapsing-remitting MS, sphincter involvement with
or without motor involvement (ie, spinal cord), incomplete recovery from
relapses, and frequent relapses early in the disease course.15 In these patients, the
author recommends starting or switching to a highly effective disease-modifying
therapy. For patients who have continued disease activity on modestly effective
disease-modifying therapies (defined as relapses or unequivocally new lesions on
MRI scans after ≥6 months on disease-modifying therapy), the author also
recommends escalating to a highly effective disease-modifying therapy rather
than switching to another modestly effective agent.
Highly effective disease-modifying therapies are defined as those that have
demonstrated superiority to a modestly effective disease-modifying therapy in
JUNE 2019
FIGURE 10-1
Starting, stopping, or switching multiple sclerosis disease-modifying therapies in women of
childbearing potential. This figure depicts best practice recommendations to balance
optimal disease control while minimizing risks to the offspring in women who want to get
pregnant or are of childbearing age and not on reliable contraception. Teriflunomide is
highly teratogenic (US Food and Drug Administration [FDA] pregnancy Category X) and should
be rapidly eliminated in women who desire pregnancy before stopping contraception.
Fingolimod and natalizumab cessation can cause rebound relapses; thus, the author
recommends switching women to rituximab before stopping contraception. Rituximab
infusions before conception appear safe, but data on risk of spontaneous abortions are
lacking. Dimethyl fumarate exposure in animal models is not safe and human data are
lacking, thus the author recommends stopping before conception. Alemtuzumab frequently
causes autoimmune thyroiditis and subclinical antithyroid antibody formation, which, in
turn, could result in adverse pregnancy/infant outcomes, although human data are scarce.
© 2018 Kaiser Permanente.

head-to-head randomized controlled trials or have demonstrated potency in

randomized controlled trials via testing only high-risk patients (alemtuzumab,
fingolimod, natalizumab, rituximab/ocrelizumab). Modestly effective agents are
defined as those that failed to demonstrate superiority in efficacy in head-to-head
randomized controlled trials (glatiramer acetate, interferon beta, dimethyl fumarate,
teriflunomide). The author does not use mitoxantrone because of cardiac toxicity
and secondary malignancies, although this would be classified as highly effective
for potency as it demonstrated efficacy in patients with very aggressive disease.

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PREGNANCY AND FAMILY PLANNING IN MS

Once a patient has been assessed and it is determined whether a highly

effective treatment should be started or continued to reduce her risk of long-term
disability, it is time to inquire about her plans to start a family and birth control.
I ask my patients of childbearing age, “Are you planning on having children in
the next 2 years?” If the answer is no, I ask, “What kind of birth control are you
using?” If they are not on reliable birth control, I explain that this influences
which medication I would recommend for them. Reliable birth control is defined
as hormonal contraceptives, an intrauterine device, surgical sterilization, or
same-sex partnership. The withdrawal method, spermicide gel, and statements
such as “I don’t have a boyfriend” and “I can’t get pregnant” (unless infertility
is documented by an obstetrician) are not reliable forms of birth control.
Discussing how contraception choice impacts disease-modifying therapy
selection is important in helping patients make an informed decision. In some
instances, women will opt to start reliable birth control so they can take an oral
disease-modifying therapy or natalizumab.
It is important to ask patients about changes in pregnancy plans and
contraceptive use regularly, particularly women on oral disease-modifying
therapies or natalizumab. For women using oral contraceptives, the author
recommends checking to make sure they are refilling their contraceptive
prescriptions at the same time they request refills on their oral disease-modifying
therapies, in addition to inquiring at clinic visits. Unplanned pregnancies in
women with MS are common, even in randomized controlled trials, most of
which require that patients use at least two forms of birth control. In the author’s
practice, teriflunomide is almost never prescribed to women of childbearing
potential for three reasons: (1) the relatively high risk of teratogenicity with
accidental pregnancy exposure (FDA pregnancy Category X), (2) the availability
of safer alternatives, and (3) the acknowledgment that continuously assuring use
of reliable birth control is laborious and not fail-proof.16 The author also avoids
use of teriflunomide in men who could potentially father a child because the drug
is secreted in the semen, thereby potentially exposing the fetus.

Multiple Sclerosis Treatment for Women Trying to Conceive or Not on

Reliable Birth Control
Contemporary population-based studies show that more than 40% of women
with MS who became pregnant were not on any MS disease-modifying therapy
in the 12 months before conception (K. Fink, MD, written communication,
August 2018).2,16 Being untreated increased neither their risk of relapses during
pregnancy nor postpartum relapses.4 This is consistent with the preference of
many women to avoid even the slightest risk of adverse outcomes for their
babies. Being untreated before and during pregnancy and during the postpartum
period is seen most often in women with a history of mild MS disease activity,
which is defined as having little to no disability, infrequent relapses, and low
lesion burden load on MRI, or those who required only modestly effective
disease-modifying therapies to control their disease activity in the past. Thus, if
a woman with mild MS informs her neurologist that she wishes to get pregnant
and avoid all fetal risks, the author reasons that the most prudent approach is
to stop her modestly effective disease-modifying therapy at the time she stops
contraception. The one exception is if the patient is taking teriflunomide; if so,
the patient should continue her contraception until a rapid elimination procedure
has been undertaken and the drug is no longer detectable.17 In the author’s

778 JUNE 2019

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experience, many of the women who stopped disease-modifying therapies with KEY POINTS
prior pregnancies and want to have subsequent children opt to remain untreated
● It is important to ask
and may not even seek neurologic care between pregnancies. patients with multiple
In practice, glatiramer acetate and interferon beta are the author’s preferred sclerosis about pregnancy
modestly effective disease-modifying therapies for women who are planning a plans and contraception
pregnancy within the next 2 years or not on reliable birth control. This is because regularly.
accidental first-trimester exposure with glatiramer acetate or interferon beta
● Many patients with
appears safe and both disease-modifying therapy types are easy to use in general multiple sclerosis have
practice settings, as interferon beta requires only minimal additional safety adequately controlled
monitoring and glatiramer acetate requires none. For glatiramer acetate, disease without any
accidental first-trimester pregnancy exposure has now been firmly established as treatment or only modestly
effective disease-modifying
safe, with more than 4000 exposed human pregnancies.18 Accidental interferon therapies. If these patients
beta exposure is similarly safe, with more than 1200 exposed human pregnancies, start trying to conceive,
although a slight risk of decreased infant birth weight has not been fully excluded.19,20 discontinuing treatment, if
Thus, if a woman is very risk averse, stopping glatiramer acetate or interferon any, is prudent.
beta at the time of stopping contraception can be recommended, but she should ● Glatiramer acetate and
be reassured that if she does get pregnant accidentally on either of these drugs, interferon beta are the
there is no reason for alarm. In women who are not so risk averse, glatiramer preferred modestly
acetate and interferon beta can be safely continued until they find out they are effective disease-modifying
therapies for women who
pregnant. No additional obstetric or neonatal care is required (FIGURE 10-2).
are not on reliable birth
Rarely, a clinician may continue glatiramer acetate (or interferon beta) control.
throughout a patient’s pregnancy. The author does not recommend this for two
reasons. First, no disease-modifying therapy has been shown to be safe for use ● Consider a B-cell–
throughout pregnancy. Second, it seems illogical, because the protective effect depleting drug if a highly
effective disease-modifying
of pregnancy on MS disease activity far outweighs the effect of glatiramer acetate therapy is needed for a
or interferon beta in both historical6 and contemporary cohorts.1,4 woman who is trying to get
The author recommends stopping dimethyl fumarate at the time of stopping pregnant or not on reliable
contraception because of the uncertain but plausible risks. Human data are too birth control. Assess for
pregnancy before each
sparse to draw conclusions (known pregnancy outcomes in 58 of 104 exposed infusion and do not infuse
pregnancies).21 Animal studies show that first-trimester exposure caused delayed the medication if the patient
development, including small birth size, spontaneous abortions, and delayed is currently pregnant.
ossification, and exposure during the third trimester and lactation caused
decreased fetal viability, decreased fetal growth, and impaired learning and
memory, albeit at twice the recommended human dose.22
In women who require a highly effective disease-modifying therapy to control
their disease while trying to get pregnant or not on reliable birth control,
rituximab is the author’s preferred choice because (1) it is not associated with
rebound disease activity, (2) it has prolonged protective effects even after the
medication has been eliminated, (3) it is easy to avoid accidental pregnancy
exposure by asking about last menstrual period and, if necessary, performing
a urine pregnancy test shortly before each infusion, and (4) it does not appear to
be teratogenic or otherwise adversely affect pregnancy outcomes, although
data here are from less than 400 exposed pregnancies (K. Fink, MD, AM
Langer-Gould, MD, PhD, unpublished data, August 2018).23,24
The typical rituximab dose used in Sweden and in Kaiser Permanente
Southern California (through a collaborative Patient-Centered Outcomes
Research Institute [PCORI] observational study) is 500 mg or 1000 mg for the
first infusion and 500 mg every 6 months thereafter, because clinical experience
in Sweden showed that a 500 mg maintenance dose was equally effective and
safer than 1000 mg every 6 months.25 The author recommends checking a urine

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PREGNANCY AND FAMILY PLANNING IN MS

FIGURE 10-2
Recommendations for additional maternal, fetal, and neonatal monitoring if first-trimester
exposure to multiple sclerosis (MS) disease-modifying therapy has occurred. This figure
depicts how to monitor for potential pregnancy and neonatal complications in the event a
woman finds out she is pregnant after first-trimester exposure to MS disease-modifying
therapy has already occurred. Teriflunomide should be stopped and a rapid elimination
procedure initiated immediately; the mother should be counseled about the increased risk of
teratogenicity. A high-risk obstetrics specialist should follow the patient. Fingolimod should
be stopped immediately and pregnancy monitored for maternal rebound disease activity and
malformations in the infant. If a steroid-refractory rebound relapse occurs, the author
recommends contacting a neurologist who is an expert in MS and pregnancy to aid in
treatment decisions. The author also strongly recommends contacting a neurologist who is an
expert in MS and pregnancy if a woman gets pregnant on natalizumab to aid in the decision of
stopping treatment or continuing at prolonged dosing intervals through the second trimester
of pregnancy. If natalizumab is continued, a neonatologist should be present at delivery to
monitor for hematologic abnormalities and their complications (eg, thrombocytopenia and
bleeding). Little is known about the risks of accidental first-trimester rituximab exposure, but
it is plausible that it could result in infant B-cell depletion. Thus, the author recommends
neonatal screening for B-cell depletion and pancytopenia; if present the Centers for Disease
Control and Prevention (CDC) should be contacted to determine whether the infant
vaccination series should be adjusted.
© 2018 Kaiser Permanente.

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pregnancy test in women of childbearing potential before rituximab infusion and
holding infusions during pregnancy. As with other monoclonal antibody drugs,
active transport across the placenta of rituximab will begin in the second
trimester and increase rapidly through the remainder of pregnancy. With an
estimated half-life of 18 to 22 days, rituximab should be cleared by 90 to 110 days
after the last dose. Thus, the author recommends waiting 1 month after each
infusion to ensure that the drug is cleared before placental transfer begins in the
second trimester, although should a woman become pregnant even within 1 week
after the last infusion, there is no cause for alarm. The author does not use
rituximab during pregnancy unless absolutely necessary (ie, a severe relapse), as it
causes infant B-cell depletion,23,24 which could theoretically increase the risk of
neonatal infections and inadequate vaccine responses. It should be noted that the
FDA label recommends stopping rituximab 1 year before conception but provides
no rationale for this.26 The author does not recommend such a long washout, as
it may increase the risk of return of MS disease activity in the postpartum year.
Some insurance carriers do not cover rituximab; in these instances, the author
recommends using the lowest effective dose of ocrelizumab or other similar
anti-CD20 B-cell–depleting agent. Human experience with ocrelizumab and
pregnancy is scant,27 and animal data raise concern that infusion during
pregnancy at currently recommended ocrelizumab doses may result in more fetal
harm than reported with rituximab in humans. The FDA package insert states,
“Following administration of ocrelizumab to pregnant monkeys at doses similar
to or greater than those used clinically, increased perinatal mortality, depletion
of B-cell populations, renal, bone marrow, and testicular toxicity were observed
in the offspring in the absence of maternal toxicity.”28
The author does not recommend fingolimod in women who are not on reliable
birth control, primarily because of increased risk of adverse fetal outcomes
with accidental exposure. During the clinical development program, major
malformations/fetal toxicities were detected in 6 of 41 women (14.6%) who
attempted to carry their pregnancies to term, which far exceeds the expected
rate of 3% to 4%. The fetal toxicities observed resulted in four pregnancy
terminations and were consistent with animal model studies, including tetralogy
of Fallot, failure of fetal development, and intrauterine death, including a baby
with acrania, a severe neural tube defect.29 The manufacturer has an ongoing
pregnancy registry with more than 800 pregnancies, but outcomes are known for
less than 400. The manufacturer concludes that there is no increased risk of
major malformations but reports outcomes only on live births, not those that
were terminated because of major malformations or intrauterine death.30
Thus, until high-quality, reassuring data are available, the author continues to
recommend continuing effective contraception until 2 months after cessation
of fingolimod.
In the rare instance in which a woman continues to have uncontrolled central
nervous system inflammation while treated with natalizumab and again when
switched to rituximab/ocrelizumab, the author would consider using
alemtuzumab before pregnancy. Alemtuzumab is also a monoclonal antibody;
negative pregnancy tests are required before each infusion, thereby minimizing
risk of fetal exposure. The main concern with prepregnancy exposure to
alemtuzumab is the relatively common risk of autoimmune thyroiditis
(approximately 40%). Maternal thyroiditis can result in increased fetal risks,
including low birth weight, preterm birth, preeclampsia, and neurocognitive

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PREGNANCY AND FAMILY PLANNING IN MS

impairment. Even in euthyroid women, antithyroid antibodies are frequently

detected, which could result in neonatal Graves disease via transplacental
transport of maternal autoantibodies. Severity of neonatal Graves disease can
range from mild self-limited illness to neurocognitive impairment and even
death. The onset of autoimmune thyroiditis following alemtuzumab varies
widely, usually starting at 6 months and peaking 36 months after the first
infusion.31 Thus, the author recommends thyroid hormone and autoantibody
screening before pregnancy and frequent monitoring during pregnancy and the
early postpartum period. The author recommends that patients treated with
alemtuzumab should delay conception until at least 12 months after the last dose,
because the development of other autoimmune diseases that may require
treatments incompatible with pregnancy peak around this time.32

CASE 10-2 A 26-year-old woman with relapsing-remitting multiple sclerosis (MS)

presented in follow-up. She had been diagnosed with MS at the age of 18;
multiple modestly effective disease-modifying therapies were
prescribed but failed to control her MS, and she had frequent relapses
and new lesions on MRI. At age 20, she was started on natalizumab. After
2 years of being relapse-free and having no new lesions on MRI
(FIGURE 10-3A), she accidentally became pregnant. Natalizumab was
stopped, with her last dose at approximately 8 to 10 weeks of gestation.
During the late second trimester (4.5 months after her last dose of
natalizumab), she had a relapse with significant unilateral leg weakness
requiring her to use a cane. She was treated with IV methylprednisolone
with some improvement; this was the most severe relapse she had ever
had. In her early third trimester (1 month later), she had a second
pregnancy relapse (optic neuritis) that was treated with IV
methylprednisolone with complete resolution. She had a normal labor
and delivery. Her baby had normal Apgar scores but was small for
gestational age. She resumed natalizumab within 2 weeks following
delivery and remained relapse-free. She breast-fed for only 3 weeks. An
MRI obtained 1 month postpartum showed a dramatic increase in lesions
(FIGURE 10-3B).
At 4 years of age, her child had met all normal neurocognitive
milestones. The mother’s Expanded Disability Status Scale (EDSS) score
was 2.5, and she was limited by fatiguing weakness in her leg.

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Risk of Rebound Relapse After Cessation of Fingolimod or Natalizumab
It has recently become clear that pregnancy does not protect against the risk of
return of disease activity or rebound relapses after cessation of fingolimod or
natalizumab, although the magnitude of this risk is uncertain. Return of disease
activity in the year following cessation of fingolimod or natalizumab is common,
occurring in more than 40% of patients; in some instances, it can be very severe,
even life-threatening.9,33 Severe rebound relapses during pregnancy have been
reported as early as 1 month after stopping fingolimod10,11 and 3 to 4 months after
stopping natalizumab.9 In nonpregnant patients, disease activity usually returns
4 to 7 months after natalizumab cessation.34
Cases of severe rebound disease activity, particularly during pregnancy, are
frightening (CASE 10-2), yet it remains unclear how many women are at risk.

FIGURE 10-3
Sagittal fluid-attenuated inversion recovery (FLAIR) MRIs of the patient in CASE 10-2 showing
natalizumab rebound disease activity during pregnancy. A, Prepregnancy; MRI shows minimal
signs and the patient had no disability and an Expanded Disability Status Scale (EDSS) score of
1.5. B, 1 Month postpartum; the patient had unilateral leg weakness and an EDSS score of
4.0. C, 10 Months postpartum; the patient had fatiguing leg weakness and an EDSS score of 2.5.

This case illustrates that pregnancy does not protect against natalizumab COMMENT
rebound relapses and that multiple relapses can occur. The severity of
relapses in this patient was not catastrophic, and they responded to
corticosteroid treatment. But exposing a baby to multiple courses of
corticosteroids has been associated with low birth weight, which, in turn,
has been associated with multiple complications. Had her relapses not
responded to corticosteroids, resuming natalizumab during pregnancy may
have been necessary. Resuming natalizumab as soon as possible after
delivery restored her excellent disease control. A brain MRI obtained
10 months postpartum showed lasting damage (FIGURE 10-3C), and some leg
weakness persisted. The optimal approach would have been to switch her
to rituximab before conception to prevent return of disease activity
following cessation of natalizumab.

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PREGNANCY AND FAMILY PLANNING IN MS

Recent studies from the German Multiple Sclerosis and Pregnancy Registry
and the Italian multicenter cohort suggest that following cessation of natalizumab,
pregnancy relapses that require treatment with steroids are common (42% in the
German Multiple Sclerosis and Pregnancy Registry35 and 36.5% in the Italian
multicenter cohort33), and severe relapses with resulting permanent disability
occur in less than 15% (K. Hellwig, MD, written and oral communication, August
2018). These are likely overestimations of the true risk in community-based
settings, as both studies recruited women with more severe disease activity.
For women treated with fingolimod, much less is known about the incidence of
pregnancy-related relapses aside from case series affirming that they can be
catastrophic.10,11 Recent findings from the German Multiple Sclerosis and
Pregnancy Registry suggest that the risk of relapses occurring during pregnancy
following cessation is 27%.36 In Kaiser Permanente Southern California and Sweden,
we have too few women who were on fingolimod around the time of conception to
draw conclusions. Rare use of fingolimod in women of childbearing potential seems
to reflect widespread awareness among neurologists of its teratogenic potential.17
In a case series of 12 women who developed severe steroid-refractory
natalizumab rebound relapses that required resuming natalizumab infusions
during pregnancy, 10 of the 13 infants had self-limited hematologic abnormalities
or hyperbilirubinemia, or both, including one case of thrombocytopenia with an
asymptomatic intracranial hemorrhage. Most of these women had stopped
natalizumab when they found out they were pregnant.9 These hematologic
abnormalities are consistent with the mechanism of action of natalizumab and
high likelihood of fetal exposure with second- and third-trimester infusions.

Preventing Rebound Relapses

For women who are currently well-controlled on fingolimod or natalizumab and
want to get pregnant, the author recommends switching them to rituximab
before stopping their birth control to prevent rebound disease activity37 and
minimize risk to the child. Although the magnitude of risk of incurring a severe
relapse during pregnancy is uncertain (currently estimated at 10%),38 treating
relapses during pregnancy with high-dose corticosteroid infusions, resuming
natalizumab, or starting rituximab all appear to carry higher risks than prepregnancy
exposure to rituximab. With this approach, fewer than 1% of pregnancies occur
annually while a woman is still treated with fingolimod or natalizumab.16
For women who accidently become pregnant on natalizumab, the author
recommends consulting with a neurologist who is an expert in MS and pregnancy
as the evidence of balancing maternal and fetal risk is rapidly evolving
(FIGURE 10-2). Natalizumab exposure during early pregnancy does not appear to
be fetotoxic and should not be a cause for alarm. A natalizumab exposure
pregnancy registry tracked outcomes in 96.2% of 369 pregnancies and found
that accidental first-trimester natalizumab exposure is associated with a slightly
higher risk of major and minor malformations (5.05%) but without a clear
pattern.39 This is consistent with the lack of fetotoxicity in animals as well.
The expert may recommend continuing natalizumab at 6- to 8-week extended
intervals, with the last dose occurring at less than 30 weeks, or stopping it,
considering a woman’s prenatalizumab disease severity, prior attempts to
stop natalizumab, and her preferences. For women who accidentally become
pregnant on fingolimod, the author recommends immediate cessation of the
drug because of potential teratogenic effects.

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 It is important to remember that steroid-refractory rebound relapses KEY POINTS
during pregnancy or the postpartum period are treatable. The author has
● Pregnancy does not
seen two cases, and is aware of other reports, in which the treating neurologists protect against the risk of
were unaware of this and the patients died.40,41 Treatment options for severe return of disease activity or
steroid-refractory rebound relapses occurring during pregnancy include rebound relapses after
plasma exchange and, if necessary, resuming natalizumab or starting rituximab. cessation of fingolimod or
natalizumab.
The author strongly recommends consulting a neurologist who is an expert
in MS and pregnancy to provide the most up-to-date treatment options. ● To prevent return of
For women who are very risk averse and do not want to incur the low but disease activity or rebound
uncertain risks of prepregnancy rituximab treatment, the author recommends relapses during pregnancy
stopping natalizumab or fingolimod and continuing contraception until the risk after cessation of
fingolimod or natalizumab,
of rebound relapse has passed (6 to 12 months) before trying to conceive. Rituximab consider switching women
could be started if a rebound relapse occurs during this washout period. It is to a B-cell–depleting
important to note that other treatments, including glatiramer acetate, interferon therapy before conception.
beta,42 and dimethyl fumarate,43,44 do not appear to reduce the risk of
● Fingolimod and
rebound relapses. natalizumab rebound
relapses are treatable, even
Breast-Feeding, Postpartum Relapses, and Multiple Sclerosis if they occur during
Disease-Modifying Therapies pregnancy.
The plethora of short- and long-term infant health benefits, particularly with
● Encourage and support
prolonged and exclusive breast-feeding, include reduced risk of infections, breast-feeding for optimal
asthma, obesity, and type 1 and type 2 diabetes mellitus.7 Maternal health benefits infant and maternal health.
of breast-feeding include reduced risk of obesity, type 2 diabetes mellitus,
breast and ovarian cancer, and metabolic syndrome.7 These benefits have become ● Glatiramer acetate and
interferon beta pose
clear over the past 20 years, during which women with MS had been actively exceedingly low risk to
discouraged to breast-feed by many clinicians in order to resume infants via breast milk
disease-modifying therapies,1 causing the rates of breast-feeding to drop in exposure and can be
women with MS compared with their contemporaries.1,3,4 This overly resumed when desired.
conservative approach was adopted by most clinicians because of the FDA’s
official position that breast-feeding is not recommended while the patient is on
any disease-modifying therapy because of the lack of human data, in many
instances without any biologically plausible reason. Some clinicians also believed
that resuming disease-modifying therapies would reduce the risk of relapses in the
early postpartum period.1 Over the past decade, it has become increasingly clear
that this approach is flawed for several reasons:

u No evidence has shown that breast-feeding increases the risk of postpartum relapses,
even when compared to women who resume medications1,4,45
u Exclusive breast-feeding appears to reduce the risk of postpartum MS activity, even when
compared to women who do not breast-feed or resume disease-modifying therapies4
u Resuming glatiramer acetate or interferon beta early in the postpartum period does not
reduce the risk of relapses within the first 6 months4,45,46
u Exceedingly low biological plausibility exists that glatiramer acetate and interferon beta
exposure through breast milk would adversely affect the infant47,48
u Low biological plausibility exists that natalizumab,49,50 rituximab,51 or ocrelizumab
exposure through breast milk would adversely affect the infant52

In addition, it is not clear whether the risk of early postpartum relapses

described in a group of women who were diagnosed with highly active disease
before pregnancy6 in the 1980s and early 1990s remains in today’s women, who,

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PREGNANCY AND FAMILY PLANNING IN MS

TABLE 10-1 Factors That Determine Compatibility of Multiple Sclerosis Disease-

Modifying Therapies With Breast-Feeding and Summary Recommendation

Disease- Compatible
Modifying Detectable in Transluminal Expected Effects With
Therapy Description Breast Milk? Transfer?a With Infant Exposureb Lactation?
Large molecules

Glatiramer Large molecule Not done, unlikely Yes, as with any None Yes
acetate (4.7–13 kDa) amino acid
heterogeneous
strings of amino acids

Interferon beta Large molecule, 0.0006% relative Exceedingly low Flulike symptoms Yes
protein infant dose

Monoclonal
antibodies

Natalizumab IgG4 <1:200 of maternal Exceedingly low Infections,c impaired Yes, if

serum level; 2–5% vaccine responses or needed
relative infant dose disseminated disease
from live vaccines,c
hepatitis,c anemiac

Rituximab IgG1 Approximately Exceedingly low B-cell depletion, Yes, if

1:240 of maternal infections,c impaired needed
serum level vaccine responses or
disseminated disease
from live vaccinesc

Small molecules

Dimethyl Immediately Animals yes/ High Neurocognitive No

fumarate metabolized to humans not done impairment,
monomethyl fumarate but highly likely in lymphopenia,
(129 Da), low protein high amounts gastrointestinal upset,
binding infections,c vaccine
responsesc

Fingolimod Highly protein bound, Animals yes/ Moderate Infections,c vaccine No

long half-life humans not done responses,c
but highly likely in cardiovascular
low amounts effects,c pulmonary
toxicity,c hepatitisc

Teriflunomide Inhibits pyrimidine Animals yes/ High Pancytopenia, No

synthesis, highly humans not done infections, vaccine
protein bound, very but highly likely responses,c
long half life hepatotoxicity, later-
life neoplasmsc

IgG = immunoglobulin G.
a
Likelihood of transfer of disease-modifying therapy from infant’s gut into its circulation assuming a large amount of disease-modifying therapy is
present in breast milk.
b
Assumes large amounts of the disease-modifying therapy have entered the infant’s circulation.
c
Plausible but unknown risk.
© 2018 Kaiser Permanente.

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in general, are diagnosed earlier and have milder disease. Other than rebound KEY POINT
relapses, most postpartum relapses, if they occur, do not appear to affect
● Natalizumab and
long-term prognosis.5 rituximab have very low
TABLE 10-1 summarizes the biological plausibility of excretion of disease- theoretical risks to infants
modifying therapies into human breast milk, transluminal transfer from the with breast milk exposure
infant’s gut into its bloodstream, and the potential effects on the infant if a only and may be resumed
during lactation if
significant amount were to enter the infant’s circulation and provides a
necessary.
recommendation based on this information. Several factors influence a drug’s
potentially harmful effects on the infant if exposure occurs through breast milk
only (ie, no pregnancy exposure):

u The possibility of excretion in significant amounts into the breast milk, as is likely
for small-molecule disease-modifying therapies (eg, fingolimod, dimethyl fumarate,
teriflunomide), particularly those with low protein binding (eg, dimethyl fumarate).48
u The possibility of transport from the infant’s gut into its bloodstream. This is common
for oral agents (fingolimod, dimethyl fumarate, teriflunomide), whereas transluminal
transport is exceedingly unlikely for IgG drugs (rituximab, ocrelizumab, natalizumab),
particularly in full-term infants.52
u The potentially harmful effects on the developing systems of the infant in addition to
the known toxicities in adults. Given the highly plausible effects of the oral agents on
the infant’s developing neurocognitive, immune, cardiovascular, or pulmonary systems
and safer alternative disease-modifying therapies, the author never recommends
the use of oral disease-modifying therapies during breast-feeding.

The author’s recommendations to continue breast-feeding when resuming

natalizumab or rituximab in women with active disease, rather than discouraging
breast-feeding when resuming treatment, are consistent with those of many
gastroenterologists50,53 and rheumatologists.8 Large molecules, including
monoclonal antibodies, are unlikely to be excreted in breast milk in significant
amounts and, even when low levels are detectable, are exceedingly unlikely to
make it into the baby’s circulation. This is supported by limited human data
for MS disease-modifying therapies.47,50,51 In addition, a 2018 study of women
with inflammatory bowel disease treated during lactation with monoclonal
antibodies (primarily tumor necrosis factor-a antagonists) showed that low drug
levels were detectable in breast milk in some women, but no increased risk of
infections or developmental delay was seen in their babies.50 This is consistent
with the exceedingly low biological plausibility of adverse infant outcomes with
monoclonal antibody exposure during lactation.
In practice, most of the author’s patients prefer to breast-feed initially
without resuming medications. At 6 to 12 months postpartum, when breast milk is
no longer the baby’s primary source of nutrition, these women can be encouraged
to resume glatiramer acetate or interferon beta while lactating, as disease activity
usually returns by 2 years postpartum45,46 and these disease-modifying therapies
have a delayed onset of action. For women who had highly active disease in the
year before pregnancy or had a relapse during pregnancy and prefer to
breast-feed, more frequent noncontrast MRI monitoring should be considered as
they are at higher risk of postpartum relapses.1,6

Treating Relapses During Pregnancy or Breast-Feeding

Short courses of high-dose methylprednisolone are the preferred first-line
treatment option for relapses occurring during pregnancy or breast-feeding.
Because a slight increased risk of adverse fetal outcomes, including cleft palate

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PREGNANCY AND FAMILY PLANNING IN MS

and low birth weight from corticosteroid exposure, cannot be excluded,8 the
author recommends their use only for clinically significant relapses and first-
trimester exposure should be avoided, if possible.
Very small amounts of methylprednisolone are detectable in breast milk,
declining rapidly within 12 hours after infusion54; thus, it is not necessary to stop
breast-feeding. The author advises women to wait 3 to 4 hours after completion
of the infusion before nursing or, for the very risk averse, to “pump and dump”
for 24 hours after infusions.
For disabling steroid-refractory relapses, the author recommends plasma
exchange. Risks associated with plasma exchange are low (eg, thromboembolic
events) and not affected by pregnancy or lactation.55

MRI and Gadolinium Use During Pregnancy and Lactation

The author does not recommend routine MRIs during pregnancy because the
treatment plan during pregnancy would not be altered based on the MRI
results alone and gadolinium should never be given during pregnancy because
it is not safe. A study of more than 1.4 million pregnancies has shown that
MRI is safe, even in the first trimester, but gadolinium at any time during
pregnancy is not. Gadolinium increases the risk of stillbirth; neonatal death;
and a wide array of inflammatory, rheumatologic, and infiltrative skin
conditions.56
During lactation, MRI disease activity should be monitored periodically in
women with relapses during pregnancy or highly active disease before
pregnancy, but gadolinium should be avoided as it is not necessary to assess
disease activity. Small amounts of gadolinium are detectable in breast milk.
Whether infant exposure to these small amounts is safe has not been established,
although the theoretical risk is low. This has led most professional societies to
conservatively recommend pumping and dumping for 24 hours after infusion57
when gadolinium administration is required.

Symptomatic Multiple Sclerosis Treatments, Pregnancy, and Lactation

Migraines, fatigue, and neuropathic pain are quite common in young women
with MS. The fetal risks of some commonly used symptomatic medications
outweigh the fetal risks of many MS disease-modifying therapies. The use of
valproate, topiramate, methylphenidate, and amphetamines should be avoided
in women who are trying to conceive or not on reliable birth control unless
absolutely necessary. Modafinil should also be avoided as it poses an unknown
risk. When necessary, tricyclic antidepressants and selective serotonin reuptake
inhibitors (SSRIs) are generally considered safe, although infants can have
withdrawal symptoms with later pregnancy exposure. Gabapentin is a safer
alternative than carbamazepine or baclofen for neuropathic pain, and modest
caffeine intake is a safer alternative for fatigue than stimulants or modafinil.
Good clinical practice recommendations include monotherapy with the lowest
possible dose, discontinuing treatment if risk of relapse of the condition is low,
and consulting obstetrics and other specialists for other treatment options.

Multiple Sclerosis Treatments and Effectiveness of Hormonal

Contraceptives
Modafinil, but not disease-modifying therapies, may decrease the effectiveness
of hormonal contraceptives.58

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Fertility Treatments and Multiple Sclerosis
Women with MS who need fertility treatment should be treated according to the
recommendations of their reproductive specialists. Small case series had raised
concerns that gonadotropin-releasing hormone agonists (as opposed to antagonists)
may increase risk of relapse; these concerns have not been substantiated and were
most likely due to confounding, as the effect was seen only in women with higher
prepregnancy relapse rates in whom the fertility treatment was unsuccessful.59
For women who require treatment with MS disease-modifying therapies
during prolonged periods of fertility treatments, the author usually recommends
glatiramer acetate or, if a highly effective treatment is needed, rituximab.
Rituximab has been used successfully to achieve pregnancies in women with
recurrent miscarriages due to antiphospholipid antibody syndrome.60,61

Fatherhood, Multiple Sclerosis, and Multiple Sclerosis Disease-Modifying

Therapies
Teriflunomide is detectable in human semen, although it is unclear whether this
impacts fertility or fetal development. Until more is known, the FDA recommends
that males taking teriflunomide should use effective contraception.17 In
animal studies of other MS disease-modifying therapies, male fertility was not
affected. Risk factors for low sperm counts that may occur more frequently in
males with MS include marijuana use and, rarely, low testosterone from
hypothalamic involvement.

CONCLUSION
It is now possible to successfully control disease activity in the majority of
women with MS throughout pregnancy and the postpartum period while
simultaneously minimizing harm to the infant by promoting breast-feeding
and avoiding exposure to certain disease-modifying therapies. This has become
possible because of the availability of numerous disease-modifying therapies
and the efforts of many research communities. The optimal timing to resume
disease-modifying therapies in the postpartum period and how best to avoid
and treat severe relapses during pregnancy and the postpartum period is still
undetermined, particularly in women who become pregnant accidently while on
natalizumab or fingolimod. More research is needed to understand how often
this occurs and how to identify those women at highest risk. Pregnancy registries
and large health care databases should be leveraged to address these questions, as
well as to assess the safety of drugs during lactation, and to track long-term
infant and maternal health outcomes.

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