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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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allergic encephalomyelitis.
24,25
The anti-inflammatory effects
appear to be mediated by estrogen nuclear receptors alpha
(ERα) and beta (ERβ), which are expressed by regulatory
CD4+CD25+ T cells, regulatory B cells, and dendritic cells.
E2 neuroprotective effects on experimental allergic
encephalomyelitis seem to be mediated by binding to the
membrane G-protein-coupled receptor 30 (GPR30).
Progesterone appears to play a role in axonal protection and
remyelination. Testosterone is thought to work by either
binding to androgen receptors or after its conversion to
estrogen, through estrogen receptors or GPR30. It can restore
synaptic transmission deficits in the hippocampus.
Additionally, androgens may induce remyelination by acting
on neural androgen receptors.
26-28
As a result, current research
efforts are aimed at studying hormones as therapeutic agents,
which may have implications for add-on therapy.
MRI During Pregnancy
significantly surpasses other imaging modalities with respect
to its positive predictive value.
29-31
MRI is also used in
pregnancy for maternal assessment and fetal prenatal
diagnosis. Its use is often times avoided in the first trimester
because of theoretical risks associated with an increase in body
temperature and acoustic noise exposure to a developing fetus.
However, when indicated and necessary, MRI should be used
regardless of gestational age. The use of gadolinium-contrast
agents is generally avoided in pregnancy, mainly because of a
lack of safety data in humans.
30
Vitamin D During Pregnancy
Vitamin D deficiency has been linked to the development of
MS in offspring by two distinct mechanisms—autoimmunity
with an increase in proinflammatory T cell populations and
lipid effect on myelinogenesis. 32 In a recent Finnish study,
Munger et al compared maternal vitamin D levels during
pregnancy with those of controls. The authors found that
offspring of mothers with hypovitaminosis D during their
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pregnancy had a nearly twofold increase in risk of developing
MS when compared with children born to mothers with
nondeficient levels. One limitation of this study was the
relatively young cohort of children, ranging from 18 to
27 years of age, which may have contributed to an inflated
relative risk because the average age of MS diagnosis is
30 years. 33 A dietary study performed in the United States
found a similar association, although two smaller Swedish
studies did not.
34-36
Medications During Pregnancy
Fortunately, relapse, which is defined as a worsening of
neurologic symptoms lasting more than 24 hours, 12 is less
likely to occur in pregnancy. However, glucocorticoids can be
used to reduce the severity and duration of relapses during
pregnancy. Corticosteroids, which are often used in pregnancy
to treat other autoimmune diseases such as systemic lupus
nephritis and rheumatoid arthritis, are generally considered
safe in pregnancy. Short-term, high-dose regimens are
recommended, because prolonged glucocorticoid exposure can
cause neonatal adrenal suppression and maternal glucose
intolerance and increase the risk of preterm delivery and
premature rupture of membranes. 7 If a relapse occurs in the
first trimester, the preferred treatment is prednisolone, as it is
inactivated in the placenta and therefore fetal passage is much
less than with dexamethasone. Primary or secondary
progressive MS was previously treated with
immunosuppressants such as cyclophosphamide or
methotrexate. These medications are contraindicated in
pregnancy because of their teratogenicity and associated
adverse pregnancy outcomes and are not commonly used. The
only FDA-approved treatment for primary progressive MS is
ocrelizumab, which is a monoclonal antibody with limited
safety data in pregnancy.
37
Medications that are not recommended in pregnancy owing to
teratogenicity concerns include fingolimod, alemtuzumab,
mitoxantrone, ocrelizumab, and teriflunomide. Most
physicians recommend that women discontinue treatment with
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these disease-modifying drugs for MS before attempting to
conceive, and often times a “washout” period is recommended
before attempting conception. The length of time
recommended for these medications to wash out before
attempting conception differs according to the medication
type. For example, most providers recommend that a patient
wait 4 months after alemtuzumab and a 6-month washout
period is recommended for rituximab and ocrelizumab. For
teriflunomide, patients who are attempting to conceive
undergo an elimination procedure, which involves taking
cholestyramine or activated charcoal for up to 2 weeks. Of
note, men taking teriflunomide and attempting to conceive
with a partner are advised not to be on this medication during
that period. See Table 15.1 for the washout periods for
commonly used medications.
Table 15.1
Recommended Washout Periods for Various Disease-Modifying
Therapies Before Attempting Pregnancy
38-40
DiseaseModifying
Drug
Washout Period (months)
Glatiramer
acetate
0
Interferons 0-1
Dimethyl
fumarate
0-1
Natalizumab 1-3
Fingolimod 2
Alemtuzumab 4
Ocrelizumab 6
Rituximab 6
Teriflunomide Requires a washout protocol using oral cholestyramine or
activated charcoal to reduce plasma level to <0.02 mg/L
A systematic review of disease-modifying MS therapies
during pregnancy, by Lu et al, found associated pregnancy
outcomes with several commonly used medications. The study
found that interferon beta exposure was associated with lower
birthweight and preterm delivery but not with any congenital
anomalies. Glatiramer acetate exposure did not have any
adverse effects on birthweight or gestational age at delivery
and also did not have any associated congenital anomalies.
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Natalizumab was also not found to have any associated
adverse effects on neonates. 41 See Table 15.1 for a list of the
most common MS medications and their current pregnancy-
related advisories. Importantly, in 2015, the FDA discontinued
the use of pregnancy risk categories (A, B, C, D, X) and it has
been replaced by the FDA Pregnancy and Lactation Labeling
Rule (PLLR). This rule requires narrative text to describe risk
information, clinical considerations, and background data for
the drug. Examples of these narratives are included in Table
15.2.
42
Table 15.2
Pregnancy Precautions and Mechanisms for Commonly Used DiseaseModifying MS Medications
43
Medication Mechanism of
Action
Pregnancy Precautions
Glatiramer acetate T cell activation Based on animal studies, no
increased risk of congenital
anomalies. Case reports of
successful pregnancies in humans
Interferon-beta-1a,
beta-1b
Cytokine that
modulates immune
responsiveness
Interferons at high exposure levels
have been shown to cause adverse
pregnancy outcomes in animal
studies, but there are case reports of
successful pregnancy in humans. Not
adequate data in humans
Natalizumab Monoclonal
antibody
Not adequate data in humans, but
based on animal data, may cause
fetal harm, but not associated with
congenital anomalies. May be
associated with increased risk of
miscarriage
Alemtuzumab Monoclonal
antibody
Not adequate data in humans, but
based on animal data, may cause
fetal harm
Ocrelizumab Monoclonal
antibody
Not adequate data in humans, but
based on animal data, may cause
fetal harm. In some humans, has
been found to cause
lymphocytopenia in neonates
Rituximab Monoclonal
antibody
Not adequate data in humans, but
based on animal data, may cause
fetal harm. In some humans, has
been found to cause
lymphocytopenia in neonates and is
associated with preterm delivery
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Medication Mechanism of
Action
Pregnancy Precautions
Mitoxantrone Inhibits DNA and
RNA synthesis
Not adequate data in humans, but
based on animal data, may cause
fetal harm. No controlled studies on
pregnancy effects
Dimethyl fumarate Immunomodulator No adequate human data. Found
toxic to animal embryos at very high
levels (three times higher than dose
used in humans)
Teriflunomide Immunomodulator,
anti-inflammatory
Based on animal data, may cause
major birth defects. Contraindicated
in pregnancy. However, there are
also reports of normal human infants
born after exposure
Fingolimod Anti-inflammatory Not adequate data in humans, but
based on animal data, may cause
fetal harm. Associated with
decreased fetal viability and caused
malformations in animals at doses
lower than those used clinically
Cyclophosphamide Alkylating agent,
decreases DNA
synthesis
Cyclophosphamide has been
associated in experimental animal
studies and human case reports with
adverse effects on fertility and
embryo development
Glucocorticoids
(e.g., prednisolone,
dexamethasone)
Anti-inflammatory Considered safe in pregnancy. Small
association found with use and fetal
facial clefts (OR, 1.16) but not
reproduced in all studies
Azathioprine Blocks DNA
synthesis
Most studies did not find
azathioprine-associated risk of
congenital anomalies after
pregnancy exposure; however, one
study found an increase in atrial and
ventricular septal defects and in
preterm delivery. Neonatal
hematologic and immune
impairment were reported in some
exposed infants
IV
immunoglobulin
Immunomodulator Limited human data but based on
animal studies, no increased risk of
fetal anomalies
IV, intravenous; MS, multiple sclerosis; OR, odds ratio.
Symptom Management During Pregnancy
Although it is generally recommended that most MS
medications be tapered or discontinued in pregnancy, patients
may still experience symptoms that interfere with daily life
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and therefore require treatment. For example, issues with
chronic pain, neuropathy, muscle spasticity, and specific
neurologic issues such as seizures and trigeminal neuralgia,
which is characterized by recurrent episodes of sudden, severe
stabbing pain in the distribution of the fifth cranial nerve, may
necessitate continuation of medical treatment during
pregnancy. 12 Although safety data in pregnancy are limited,
chronic pain and neuropathy have been treated during
pregnancy with short courses of opioid medications or
gabapentin
44-47
and trigeminal neuralgia can be treated with
carbamazepine or baclofen. 48 If the patient needs chronic
opioid medication, a discussion regarding neonatal concerns,
such as need for respiratory support and treatment for neonatal
symptoms of withdrawal, as well as prolonged stay in the
neonatal intensive care unit, should be had with the patient.
49-
52
In case reports, baclofen and tizanidine, which are both
muscle relaxants, have been used to treat muscle spasms in
pregnant patients
53,54
and no adverse pregnancy outcomes
have been reported, although human data largely are
unavailable. 55 There have been case reports of good
pregnancy outcomes with intrathecal administration of
baclofen in patients with MS. 56 Antiepileptic medications that
have been used in pregnancy are lamotrigine, carbamazepine,
and levetiracetam, which can also be used to treat other
neurologic and psychiatric disorders as well as prevent
seizures. 57 Antidepressants that are commonly used in
pregnancy but carry an increased risk of persistent pulmonary
hypertension of the newborn include selective serotonin
reuptake inhibitors (SSRIs), such as citalopram, escitalopram,
and fluoxetine, and norepinephrine-dopamine reuptake
inhibitors, such as buproprion. 58 There has been a concern
about congenital cardiac defects with the use of SSRIs, but
studies have shown that the increase in risk of cardiac defects
is not substantial. 59 Discontinuation of antiepileptic and
antidepressant medications can cause the recurrence of
seizures and an exacerbation of depression, respectively,
which can be detrimental not only to the pregnant mother but
also to the developing fetus. Additionally, owing to an increase
in total body fluid volumes and enhanced glomerular filtration
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in pregnancy, drug levels need to be monitored carefully and
doses need to be adjusted accordingly.
60-62
Treatment of Relapse in Pregnancy
Pregnancy undoubtedly adds a layer of complexity to the
management of MS. Women who experience an MS
exacerbation during pregnancy typically report progressive
neurologic deficit over the course of several days. Optic
neuritis, asymmetric numbness, weakness, and ataxia are
common presenting symptoms. Pain is very rarely a symptom
of an MS relapse.
Generally, interferons can be continued up to attempting
pregnancy. However, some routinely used therapies are
contraindicated in pregnant women, as they are known to be
teratogenic. In fact, many providers avoid using drugs such as
teriflunomide in women of childbearing age who are not using
reliable contraception. Most physicians suggest that their
patients with MS discontinue disease-modifying drugs when
they are planning to conceive and during pregnancy.
As with many medications, the risk versus benefit must be
weighed for each patient. Although there are only limited data
on the safety profile of these therapies in pregnancy, some
argue that in the setting of a lower relapse rate in pregnancy,
women should strongly consider stopping their medications.
Others argue that despite the uncertain fetal risks, there are
often times profound benefits to the mother.
41,63
An acute MS attack during pregnancy is often treated with
intravenous glucocorticoids, which are not teratogenic but can
be associated with neonatal adrenal suppression, maternal
glucose intolerance, and an increased risk of preterm
premature rupture of membranes. As a result, most authors
recommend high-dose, short-term regimens. Glucocorticoids
should be used if indicated and necessary, regardless of
gestational age.
Management of MS relapse in pregnancy also includes the
consideration of many disease-modifying therapies,
particularly if a certain drug has worked successfully for a
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patient in the past. These include glatiramer acetate,
interferons, alemtuzumab, dimethyl fumarate, fingolimod, and
natalizumab. A systematic review, published in Neurology in
2012, likely provides the highest quality of evidence in regards
to the use of disease-modifying therapies for women with MS
in pregnancy. Fifteen studies were included in the review and
evaluated pregnancies exposed to interferons (n = 761),
glatiramer acetate (n = 97), and natalizumab (n = 35).
Interferon beta exposure was associated with lower mean
neonatal birth weight, shorter mean neonatal birth length, and
preterm birth at less than 37 weeks’ gestation; however, it was
not associated with an increased risk of spontaneous abortion,
fetal congenital anomaly, cesarean delivery, or neonatal birth
weight less than 2500 g. Glatiramer acetate and natalizumab
exposure were not associated with any observed increased
risks. Notably, there were no studies reporting exposure to
alemtuzumab, dimethyl fumarate, fingolimod, teriflunomide,
or mitoxantrone during pregnancy. 41 Fragoso et al later
published a study that compared women with MS who were
exposed to disease-modifying drugs for at least 8 weeks during
pregnancy with those who were not. Although this was a
retrospective, nonrandomized study, the authors found that the
use of these medications was associated with a significantly
lower rate of postpartum relapse and disease progression.
64
Additionally, some authors recommend restarting prophylactic
treatment with disease-modifying therapies immediately
postpartum and considering the administration of immune
globulin in those patients who report a history of severe
postpartum exacerbation.
65
Pregnancy Outcomes
The available data on the effect of MS on pregnancy suggest
that maternal disease is associated with an increased rate of
cesarean delivery and lower neonatal birth weight. The largest
study in the United States analyzed a database with an
estimated 15 million deliveries from 2003 to 2006, including
4730 women with MS. MS was associated with a small but
statistically significant increase in the risk of cesarean section
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(odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.4)
and fetal growth restriction (OR, 1.7; 95% CI, 1.2-3.3).
66
A large retrospective study in Norway noted that mothers with
MS were more likely to have small for gestational age infants
and were more likely to undergo induction of labor with an
assisted second stage. 67 Lastly, a report from Taiwan
compared women with MS with healthy controls and found
that maternal disease was associated with an increased risk for
preterm birth and infants who were small for gestational age.
68
It is important to counsel women with MS that many of them
can achieve a healthy full-term pregnancy, often times
avoiding the use of any disease-modifying therapies; however,
their risk of operative delivery and fetal growth abnormalities
is not insignificant.
Anesthesia Considerations
There are limited studies addressing the use of anesthetic
techniques for pregnant women with MS. For regional
anesthesia, spinal or epidural, the lowest effective
concentration is always recommended to minimize any
potential risk of local anesthetic crossing into the
cerebrospinal fluid with the theoretical risk of neurotoxicity to
demyelinated nerves. Although most authors favor the use of
epidural when feasible, spinal anesthesia is also thought to be
safe in patients with MS. The decision regarding neuraxial
anesthesia for labor analgesia and cesarean delivery should be
made based on clinical factors, such as coagulopathy and
infection, urgency of the situation, and patient preferences.
69
The literature on the safety of general anesthesia in pregnant
women with MS is also sparse; however, current opinion
suggests it to be safe. There exists a higher risk of aspiration,
lost airway, and desaturation, particularly in patients with
bulbar involvement. Antenatal consultation with an obstetric
anesthesiologist is of utmost importance so as to make an
informed plan for a safe delivery.
69,70
MS in the Puerperal Period
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Contraception
Oral contraceptives contain a form of progesterone with or
without a form of estrogen. Studies have found that users of
oral contraceptives had a lower incidence of MS than
nonusers; however, other studies have not found this
relationship.
71,72
Another study found that the incidence of MS
was 40% lower in oral contraceptive users compared with
nonusers, which further supports the theory that oral
contraceptives are protective against MS. 73 Intrauterine
devices, intravaginal progesterone rings, subcutaneous
progesterone implants, and depoprogesterone injections have
not been well studied in MS, but they are not contraindicated
for patients with MS. There is also no evidence that oral
contraceptives lower the efficacy of disease-modifying
therapies; however, modafinil (which is used to treat fatigue in
MS) may reduce oral contraceptive efficacy. 74 Patients on
disease-modifying therapies are counseled to use
contraception to avoid unplanned pregnancy, especially if their
disease is not well controlled. Long-acting reversible
contraceptives, such as the levonorgestrel-containing
intrauterine device (Mirena IUD) or the etonogestrel implant
(Implanon), are especially good options for patients with MS.
Breastfeeding
There are imperfect data on breastfeeding in women with MS,
with conflicting results regarding disease activity.
75,76
Most
studies have suggested either no effect or more commonly
suppressed disease activity in women who breastfeed;
however, many of these studies did not stratify outcomes
based on prepregnancy disease activity and are confounded by
mixing patients who exclusively breastfed and those who
supplemented with formula.
32,75-79
Exclusive breastfeeding
results in a prolonged secondary lactational amenorrhea with
ovarian suppression, hyperprolactinemia, and low nonpulsatile
luteinizing hormone levels, thereby leading to decrease in
disease activity. 80 Exclusive breastfeeding likely lends some
protective effect, although it is certainly not clear whether
disease suppression is as pronounced as it is with disease-
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