Chapter 49

Neurologic Disorders
in Pregnancy
ELIZABETH E. GERARD and PHILIP SAMUELS

Epilepsy and Seizures  1031
Epilepsy and Fertility  1032
Epilepsy and Pregnancy  1032
Teratogenic Effects of Antiepileptic
Drugs  1032
Effects of Pregnancy on Anticonvulsant
Medications  1036
Pregnancy and Seizure Frequency  1037
Obstetric and Neonatal Outcomes  1037
Preconception Counseling for Women
With Epilepsy  1038
Care of the Patient During
Pregnancy  1040
Labor and Delivery  1040
New Onset of Seizures in Pregnancy and Management of Multiple Sclerosis During
in the Puerperium  1040 Pregnancy  1045
Breastfeeding and the Postpartum Breastfeeding and the Postpartum
Period  1041 Period  1046
Multiple Sclerosis  1041 Headache  1046
Multiple Sclerosis and Fertility  1042 Migraine  1046
Effect of Pregnancy on Multiple Secondary Headache in Pregnancy  1049
Sclerosis  1042 Stroke  1050
Effect of Multiple Sclerosis on Pregnancy Ischemic Stroke  1050
Outcomes  1042 Hemorrhagic Stroke and Vascular
Disease-Modifying Agents and Malformations  1051
Pregnancy  1042 Carpal Tunnel Syndrome  1051
Prepregnancy Counseling for Patients
With Multiple Sclerosis  1045

KEY ABBREVIATIONS
American Academy of Neurology AAN Intramuscular IM
American Heart Association AHA Intrauterine device IUD
Antiepileptic drug AED Intrauterine growth restriction IUGR
Arteriovenous AV Liverpool and Manchester LMNG
Arteriovenous malformation AVM Neurodevelopmental Group
Australian Register of Antiepileptic Drugs APR Magnetic resonance imaging MRI
in Pregnancy Magnetic resonance angiography MRA
Attention-deficit/hyperactivity disorder ADHD Magnetic resonance venogram MRV
Autism spectrum disorder ASD Multiple sclerosis MS
Autosomal-dominant frontal lobe epilepsy ADFLE Neural tube defect NTD
Autosomal-dominant temporal lobe ADTLE Neurodevelopmental disorder NDD
epilepsy Neurodevelopmental Effects of NEAD
Centers for Disease Control and CDC Antiepileptic Drugs
Prevention North American AED Pregnancy Registry NAAPR
Central nervous system CNS Periventricular nodular heterotopia PVNH
Cerebral venous thrombosis CVT Posterior reversible encephalopathy PRES
Cerebrospinal fluid CSF syndrome
Computed tomography angiography CTA Pregnancy and Multiple Sclerosis study PRIMS
Computed tomography CT Reversible cerebral vasoconstriction RCVS
Disease-modifying agent DMA syndrome
Electroencephalogram EEG Small for gestational age SGA
Electromyography EMG Sodium channel, voltage-gated type 1 SCN1A
Enzyme-inducing antiepileptic drug EIAED alpha subunit
European Medicine Agency EMA Subarachnoid hemorrhage SAH
Expanded Disability Status Scale EDSS Sudden unexpected death in epilepsy SUDEP
U.S. Food and Drug Administration FDA Thymus helper Th
Idiopathic intracranial hypertension IICH Tissue plasminogen activator tPA
Intelligence quotient IQ World Health Organization WHO

1030
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 Chapter 49  Neurologic Disorders in Pregnancy
EPILEPSY AND SEIZURES
Epilepsy affects approximately 1% of the general population
and is the most frequent major neurologic complication
encountered in pregnancy. It is important that the practicing
obstetrician becomes familiar with the basic treatment of epi-
lepsy and the implications for the patient and fetus. Many of
the antiepileptic drugs (AEDs) used to treat epilepsy are also
used to treat psychiatric and pain disorders and are commonly
prescribed to women of childbearing age; this makes an under-
standing of their implications for pregnancy imperative for any
clinician managing these patients.
A diagnosis of epilepsy is made in the setting of two
unprovoked seizures or one seizure in a patient with clinical
features that make a second seizure likely, such as findings
on brain magnetic resonance imaging (MRI) or electroen-
cephalogram (EEG) that are consistent with a diagnosis of
epilepsy or a family history of epilepsy. Epilepsy syndromes
can be divided into generalized and focal epilepsies. An epi-
lepsy syndrome is defined by the constellation of clinical features
of a patient’s seizures as well as their imaging and EEG findings.
It is important to note that both types of epilepsy syndromes
can present with a wide spectrum of seizure types. Convulsions
or tonic-clonic seizures, colloquially referred to as “generalized”
seizures, can occur in patients with either generalized or focal
epilepsies. It is important to work with a patient’s neurologist
to have an understanding of the patient’s epilepsy syndrome
because this has significant implications for treatment and also
sometimes gives insight into the etiology of the patient’s seizure
disorder. It may also have a role in predicting the course of the
seizure disorder during pregnancy.
Genetic generalized epilepsies, also known as idiopathic
generalized epilepsies, are presumed to be genetic in origin,
although most cases do not exhibit a mendelian inheritance
pattern or have varying degrees of penetrance; first-degree rela-
tives are often not affected. Patients with genetic generalized
epilepsy can have myoclonic, absence, or tonic-clonic seizures.
They may have only one or a combination of those seizure
types. These patients are typically treated with “broad-spectrum”
AEDs that include lamotrigine, levetiracetam, topiramate,
valproate, and zonisamide. The majority of other AEDs—
including, but not limited to, carbamazepine, gabapentin, oxcar-
bazepine, phenytoin, and pregabalin—are considered “narrow
spectrum” and can provoke myoclonic or absence seizures in
patients with genetic generalized epilepsies, even if the patient
does not have a history of these seizure types. The newest AEDs,
such as lacosamide and perampanel, are approved for treatment
of focal epilepsies but are being studied for use in generalized
epilepsies.
Focal epilepsy is the most common type of epilepsy in
adult patients. Whereas the etiology of most focal epilepsies
often remains unknown, an underlying cause must be ruled out
because they may occur secondary to an acquired abnormal-
ity such as a tumor, vascular malformation, brain injury, or
infectious or autoimmune disorder that affects the brain.
An increasing number of genetic causes of focal epilepsies have
also been identified recently, including some with autosomal-
dominant inheritance patterns. Patients with focal epilepsy may
present with focal seizures with or without loss of consciousness,
previously known as simple partial and complex partial seizures,
and/or focal seizures that progress to a tonic-clonic seizure, pre-
viously known as a secondarily generalized seizure.
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1031
The manifestations of focal seizures depend on where in the
brain the seizure begins. The most commonly encountered focal
epilepsy is temporal lobe epilepsy, which frequently presents
with focal seizures with loss of awareness. These seizures are
characterized by alteration of awareness that typically lasts 30
seconds to 2 minutes and may be accompanied by semipurpose-
ful movements of the face and hands. The break in awareness is
often underreported by patients and even their family members
because patients do not remember this part of the seizure, and
they may seem to observers to be interacting with their environ-
ment. These seizures can be preceded by an aura, such as a
feeling of fear or an “epigastric rising,” a sensation that begins
in the stomach and that may rise to the chest and head, but an
aura also may not be present or remembered. These seizures have
the potential to progress to tonic-clonic seizures. Patients with
focal epilepsy can be treated with broad- or narrow-spectrum
AEDs; however, if the diagnosis is uncertain, it is best to begin
with broad-spectrum drugs. The choice of the first AED usually
depends on characteristics of the patient and the side effects of
the drug. In women of childbearing age, the teratogenic poten-
tial of the AEDs should be a strong consideration; this will be
discussed below.
Most women with epilepsy will need to remain on AEDs
during their childbearing years and throughout pregnancy.
Exceptions include patients with childhood epilepsy, which can
remit in adulthood. In select cases of adult-onset epilepsy,
patients who have been seizure free for 2 to 4 years may attempt
to wean from seizure medications under a neurologist’s supervi-
sion. Several factors that include the patient’s seizure pattern and
MRI and EEG findings affect this decision. Seizure freedom in
the 9 months prior to pregnancy predicts a good chance of
seizure control during pregnancy.1 Thus in an appropriate
patient who wanted to stop AED therapy before pregnancy,
weaning her off seizure medication should be started at least 1
year before becoming pregnant. Unfortunately, women with
epilepsy may abruptly stop all medications as soon as they
find out that they are pregnant,2 which puts both the mother
and fetus at risk.
Uncontrolled seizures increase the risk of maternal injury
and death and potentially expose the infant to transient
anoxia.3 The direct fetal effects of seizures during pregnancy have
only been studied in a few case reports. Tonic-clonic seizures
during delivery were associated with fetal bradycardia followed
by tachycardia in two cases, although the infants were reportedly
unaffected on delivery.4 Fetal death at 33 weeks’ gestation
was associated with intraventricular hemorrhage in one patient
following a tonic-clonic seizure; the patient had had three tonic-
clonic seizures in pregnancy.5 Focal seizures with loss of con-
sciousness were associated with prolonged uterine contraction in
one patient reported by Nei and colleagues.6 The fetal heart rate
also fell from 140 to 78 beats/min. In a population-based study
from Taiwan, Chen and colleagues7 studied 1016 pregnant
women with epilepsy. Women with seizures during pregnancy
had increased risks of preterm delivery (odds ratio [OR], 1.63),
small-for-gestational-age (SGA) infants (OR, 1.37), and low-
birthweight infants (OR, 1.36) compared with women without
epilepsy. When compared with women with epilepsy but without
tonic-clonic seizures during pregnancy, patients with seizures
had an increased risk of SGA infants (OR, 1.34).
Two studies have raised significant alarm about the risk of
epilepsy in pregnancy. The U.K. confidential inquiry into mater-
nal deaths found that women with epilepsy were 10 times
1032 Section VI  Pregnancy and Coexisting Disease
more likely to die during pregnancy or during the postpar-
tum period.8 Similarly, a recent study by MacDonald and asso-
ciates9 evaluated delivery hospitalization records in the United
States and also reported a more than tenfold increase in deaths
during delivery in women with epilepsy. In the U.K. study, 3 of
14 maternal deaths appeared to be directly related to complica-
tions of seizures (drowning, hypoxia, trauma), and the other
11 were attributed to sudden unexpected death in epilepsy
(SUDEP),10 defined as the sudden and unexpected, nontrau-
matic, and nondrowning death of a person with epilepsy
without a detected toxicologic or anatomic cause of death.
Mechanisms of SUDEP are uncertain, but risk factors include
refractory and tonic-clonic seizures and noncompliance with
medications. The U.K. inquiry pointed out that 8 of the 14
women with epilepsy who died in their cohort had not been
referred to a provider with knowledge of epilepsy and had not
received prepregnancy counseling. Additionally, they noted that
one third of the women had difficult social circumstances that
may have limited their access to care. Domestic abuse was
present in at least two cases, and one patient had schizophrenia.8
The causes of maternal mortality in the U.S. population study
are not known, but it was observed that these patients had an
increased risk of major comorbidities that included diabetes,
hypertension, psychiatric conditions, and alcohol and substance
abuse.11 They were also at increased risk of preeclampsia, preterm
labor, stillbirth, and cesarean delivery.9
Whereas these two studies that describe increased mortality
in women with epilepsy point to the importance of further
research into the optimal management of pregnant women with
epilepsy and their comorbidities, they should be put into context
for women with epilepsy so as not to deter them from pursuing
pregnancy. Although the relative risk was significantly increased,
the absolute risk of maternal death in women with epilepsy in
the study by MacDonald and colleagues9 was 80 per 100,000
births (0.08%). Similarly, Edey and colleagues10 analyzed the
U.K. inquiry and estimated the rate of deaths during pregnancy
and the postpartum period among women with epilepsy to be
100 per 100,000 births (0.1%). These studies do point to the
need for close medical supervision of pregnancies in women
with epilepsy and the importance of prepregnancy counseling
and planning. The obstetrician and neurologist must work
closely together to guide the patient through her pregnancy.
Through this cooperation, the majority of pregnant women
with seizure disorders can have a successful pregnancy with
minimal risk to mother and fetus.
EPILEPSY AND FERTILITY
Epilepsy and epilepsy treatment may adversely affect fertility
in some women. Several population studies have demon-
strated that birth rates are lower in both men and women
with epilepsy compared with unaffected individuals.12-15 In
many studies these decreased birth rates were not explained by
lower marriage rates in patients with epilepsy. However, these
epidemiologic studies are unable to control for nonbiologic
factors that may affect reproduction rates, such as decreased
libido, which has been reported in patients with epilepsy, or
patients’ concerns about having a child because of fears about
the implications of the condition or their medications. Sukuma-
ran and colleagues16 prospectively followed 375 Indian women
trying to conceive and found that 38.4% were infertile after at
least 1 year of trying to conceive. Risk factors for infertility
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include taking AEDs, particularly multiple AEDs. However, age
and lower educational level also played a role in the study.
Many lines of evidence suggest that potentially, both epilepsy
and AEDs may have adverse effects on reproductive function.
Seizures, particularly temporal lobe seizures, are known to
disrupt the hypothalamic-pituitary-gonadal axis, and certain
AEDs can affect sex steroid metabolism and sex hormone
binding globulin concentrations. Increased risks of polycystic
ovarian syndrome, premature ovarian insufficiency, and hypogo-
nadotropic hypogonadism have been reported in women with
epilepsy.17,18 Miscarriage rates, however, do not seem to be
increased in women with epilepsy.19
EPILEPSY AND PREGNANCY
Teratogenic Effects of Antiepileptic Drugs
Women with epilepsy are at increased risk of having pregnan-
cies complicated by major congenital malformations. This
risk appears to be related to exposure to AEDs during preg-
nancy rather than the epilepsy.20 Not all AEDs are the same
in terms of their teratogenic potential or the patterns of malfor-
mations with which they are associated (see Chapter 8). Over
the past 15 years, prospective studies of the effects of AEDs on
teratogenesis have largely replaced older retrospective case series.
A few prospective studies of the cognitive effects of AED expo-
sure during pregnancy have also been pivotal in our understand-
ing of AED-associated risks. The most well-studied AEDs in
pregnancy are valproate, carbamazepine, and lamotrigine. Of
these drugs, valproate has been consistently demonstrated to
carry a risk of major congenital malformations significantly
greater than that of other AEDs and baseline population
rates, typically 1% to 3% depending on the study popula-
tion. It has also been clearly associated with adverse cognitive
and behavioral developmental outcomes.
Lamotrigine has been associated with relatively low rates of
teratogenesis, and although cognitive data are mostly reassuring,
this still needs further clarification. Levetiracetam is less well
studied, but promising early data have led to a dramatic increase
in its use in pregnant women and those planning pregnancy.
Lamotrigine and levetiracetam are now the most commonly
prescribed AEDs for women of childbearing age.21 Carbam-
azepine also appears to be a reasonable choice for women who
plan to conceive, although its use has been declining in this
population.21
The section below summarizes the available information on
the best-studied and most prescribed AEDs. The majority of
the information we have on structural teratogenesis is derived
from several international pregnancy registries (Table 49-1). It
is important to note that each of these registries uses slightly
different methodologies in regard to means of recruitment,
infant assessment control groups, and duration of follow-up.22
These differences account for some of the variability in results;
however, when the findings are looked at in aggregate, clear
patterns emerge regarding the relative teratogenic risk of indi-
vidual AEDs.
Valproate
Rates of major congenital malformations with first-trimester
exposure to valproate monotherapy range from 4.7% to
13.8%.23-27 In the two largest prospective cohorts from the
United Kingdom and Ireland (1290 valproate exposures)28 and
the European Registry of Antiepileptic Drugs and Pregnancy
 Chapter 49  Neurologic Disorders in Pregnancy 1033

TABLE 49-1 RATE OF MAJOR CONGENITAL MALFORMATIONS WITH INDIVIDUAL ANTIEPILEPTIC DRUGS WHEN
USED AS MONOTHERAPY
RATE OF MAJOR CONGENITAL MALFORMATIONS WITH INDIVIDUAL
ANTIEPILEPTIC DRUGS AS MONOTHERAPY*
REGISTRY STUDY CBZ GBP LTG LEV OXC PHB PHT TPM VPA
Australian Pregnancy Vajda, 2014 5.5% 0% 4.6% 2.4% 5.9% 0% 2.4% 2.4% 13.8%
Registry (346) (14) (307) (82) (17) (4) (41) (42) (253)
Danish Registry Mølgaard, 2011 1.7% 3.7% 0% 2.8% 4.6%
(59) (1019) (58) (393) (108)
EURAP Tomson, 2011 5.6% 2.9% 1.6% 3.3% 7.4% 5.8% 6.8% 9.7%
(1402) (1280) (126) (184) (217) (103) (73) (1010)
Finland National Birth Artama, 2005 2.7% 10.7%
Registry (805) (263)
GSK Lamotrigine Cunnington, 2011 2.2%
Registry (1558)
North American AED Hernandez, 2012 3.0% 0.7% 2.0% 2.4% 2.2% 5.5% 2.9% 4.2% 9.3%
Pregnancy Registry (1033) (145) (1562) (450) (182) (199) (416) (359) (323)
Norwegian Medical Veiby, 2014 2.9% 3.4% 1.7% 1.8% 7.4% 4.2% 6.3%
Birth Registry (685) (833) (118) (57) (27) (48) (333)
Swedish Medical Birth Tomson, 2012 2.7% 0% 2.9% 0% 3.7% 14% 6.7% 7.7% 4.7%
Registry (1430) (18) (1100) (61) (27) (7) (119) (52) (619)
U.K./Ireland Campbell, 2014 2.6% 3.2% 2.3% 0.7% 3.7% 9% 6.7%
pregnancy registry Mawhinney, 2013 (1657) (32) (2098) (304) (82) (203) (1290)
Morrow, 2006
Hunt, 2008
Data from Gerard E, Pack AM. Pregnancy registries: what do they mean to clinical practice? Curr Neurol Neurosci Rep. 2008;8(4):325-332.
*Numbers in parentheses indicate number of pregnancies enrolled.
AED, antiepileptic drug; CBZ, carbamazepine; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PHB, phenobarbital; PHT, phenytoin; TPM, topiramate;
VPA, valproic acid.

(EURAP, 1010 valproate exposures),29 the malformation rates
were 6.7% and 9.7%, respectively.
In the European Surveillance of Congenital Anomalies
(EUROCAT) database, a population-based database of 14
European countries, valproate exposure was associated with an
increased risk of several specific defects.30 Compared with control
pregnancies, those exposed to valproate monotherapy were at
statistically increased risk for spina bifida (OR, 12.7), craniosyn-
ostosis (OR, 6.8), cleft palate (OR, 5.2), hypospadias (OR, 4.8),
atrial septal defects (OR, 2.5), and polydactyly (OR, 2.2). These
numbers, however, describe only relative risk and can be hard
for a patient to understand. Tomson and Battino24 compiled
the data of 22 prospective studies that reported on specific
AED-associated malformations and reported the absolute
risks of neural tube defects (NTDs, 1.8%), cardiac malforma-
tions (1.7%), hypospadias (1.4%), and oral clefts (0.9%).
In addition to significantly increasing the risk of birth defects,
valproate exposure during pregnancy has also been associ-
ated with cognitive and behavioral teratogenesis. Two pro-
spective studies of children exposed to AEDs in utero have
recently been published, the Neurodevelopmental Effects of
Antiepileptic Drugs (NEAD) study31 and a study by the Liver-
pool and Manchester Neurodevelopmental Group (LMNG).32
Both recruited women with epilepsy in the first trimester of
pregnancy and followed the development of their children until
age 6. In contrast to many earlier studies of the cognitive effects
of AEDs, both of these investigations controlled for several
important confounding variables, including maternal intelli-
gence quotient (IQ)—an important predictor of a child’s cogni-
tive performance. Of note, the two studies did overlap: 92
children from the LMNG study were also enrolled in the NEAD
study. The NEAD study ultimately evaluated 224 children at
age 6 who had been exposed to carbamazepine, lamotrigine,
phenytoin, or valproate monotherapy. The LMNG study
assessed 198 six-year-old children born to women with epilepsy
who took AED monotherapy (n = 143) or polytherapy (n = 30)
or no medication (n = 25) during pregnancy and a control group
of 210 children of the same age. In the NEAD study, exposure
to valproate monotherapy was associated with a significant
decrease in mean full-scale IQ (FSIQ) by 7 to 10 points com-
pared with children exposed to carbamazepine, lamotrigine, or
phenytoin. The LMNG found that exposure to first-trimester
doses of valproate greater than 800 mg/day was associated with
a significant decrease in FSIQ by 9.7 points when compared
with a control group.32 The mean FSIQ of children exposed to
low valproate doses (≤800 mg/day) was also lower than that of
controls, but this did not meet statistical significance. The low-
dose group, did, however, have significantly lower verbal IQ
scores and an increased need for educational intervention.32
A population study that utilized the National Psychiatric
Registry and birth registries in Denmark found that school-age
children whose mothers were prescribed valproate monotherapy
during pregnancy had a significantly increased risk of receiving a
formal diagnosis of autism or autism spectrum disorder (ASD).33
In the valproate-exposed cohort, the absolute risk of autism was
2.5%, whereas the rate in the general population was 0.48%,
and the risk of ASD was 4.42%, with a baseline risk of ASD of
1.53%. The rates of autism and ASD in children born to mothers
with epilepsy who did not take valproate during pregnancy did
not differ from baseline population rates. A recent nested study34
from the Australian Pregnancy Registry also found that of 26
children between 6 and 8 years of age who were exposed to
valproate monotherapy, one tested in the “autistic range” and
one tested in the “concern for autistic range” on a standardized
assessment. The overall risk of autistic traits was 7.7% in the
monotherapy group. In this study, the risk of autistic traits was
greatest in the valproate polytherapy group (7/15; 46.7%) and
was dose related in the valproate monotherapy group.

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1034 Section VI  Pregnancy and Coexisting Disease
The LMNG also found an increased risk of behavioral abnor-
malities in their antenatally recruited cohort at 6 years of age.
Because of the relatively smaller numbers in this cohort, the
study examined the aggregate risk of several different neuro-
developmental disorders (NDDs) in exposed children, includ-
ing autism and ASD, attention-deficit/hyperactivity disorder
(ADHD), and dyspraxia as based on diagnoses received from
professionals outside of the study. An NDD was diagnosed in
12% of 50 children exposed to valproate monotherapy and in
15% of 20 children exposed to valproate in polytherapy.35 These
rates were significantly elevated compared with an NDD rate of
1.87% in the 214 control children.
Carbamazepine
In its 2009 guidelines, the American Academy of Neurology
(AAN) stated, “Carbamazepine probably does not substan-
tially increase the risk of major congenital malformations
in the offspring of women with epilepsy.”36 This conclusion
was based on one class I study37 from the United Kingdom and
the Ireland Pregnancy Registry that did not find a difference
between the rate of malformations in carbamazepine-exposed
pregnancies and those of an internal control group. At the time,
carbamazepine was the only medication that the AAN felt had
strong enough evidence to support this conclusion. Across seven
pregnancy registries, rates of major malformations in pregnan-
cies exposed to carbamazepine monotherapy have ranged from
2.6% to 5.5%.23-29 The two largest studies, the United Kingdom
and Ireland Pregnancy Registries (n = 1657) and the EURAP
registry (n = 1402) reported rates of 2.6% and 5.6%, respec-
tively. Of note, the two registries that reported higher rates of
major anomalies with carbamazepine exposure—the Australian
and EURAP registries—both follow the exposed infants to 1
year and beyond, whereas the other registries performed the last
assessment for malformations at birth or 3 months.22 In the
EURAP registry, malformations that were most likely to be
picked up between 2 and 12 months were cardiac, hip, and renal
malformations.24 The rates of anomalies increased for several
drugs at the later assessment, but rates with carbamazepine were
most affected.
In the EUROCAT database, carbamazepine exposure was
specifically associated with an increased risk of NTDs compared
with unexposed controls (OR, 2.6; 95% confidence interval
[CI], 1.2 to 5.3).38 However, the risk of spina bifida with car-
bamazepine exposure was still significantly lower than the risk
with valproate (OR, 0.2; 95% CI, 0.1 to 0.6) and was not dif-
ferent from the risk of exposure to other AEDs when valproic
acid was excluded. The EUROCAT study did not find a specific
association between carbamazepine exposure and other major
malformations that included oral clefts, diaphragmatic hernia,
hypospadias, and total anomalous venous return.38 In the com-
piled registry data prepared by Tomson and Battino,24 the abso-
lute risks of certain anomalies with exposure to carbamazepine
monotherapy were reported for NTDs (0.8%), cardiac malfor-
mations (0.3%), hypospadias (0.4%), and oral clefts (0.36%).
Early studies of carbamazepine’s effect on cognitive develop-
ment were conflicting, and many were limited by retrospec-
tive design or did not control for important confounders. A
Cochrane review39 of prospective studies published prior to
2014 concluded that the reported effects of carbamazepine on
developmental scores were largely accounted for by variability
between studies and identified no clear risk of delayed develop-
ment in infants and toddlers exposed to carbamazepine. The
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meta-analysis also reported no evident adverse effect of carba-
mazepine exposure on the IQ of school-age children.39 In the
NEAD study, no specific effects of carbamazepine exposure on
IQ were identified when this group of children was compared
with the lamotrigine- and phenytoin-exposed cohorts at age 6.31
The recent LMNG study also found no difference in the adjusted
mean IQ scores between the 6-year-old carbamazepine-exposed
children and controls, but verbal IQ was 4.2 points lower in
the exposed children. Additionally, the relative risk of having an
IQ below 85 was significantly increased in the carbamazepine
cohort.32 Both the NEAD and LMNG studies demonstrated
that, compared with valproate exposure, prenatal carbamazepine
exposure was less likely to be associated with adverse cognitive
effects.31,32
The LMNG found no increased risk for formally diagnosed
NDDs at 6 years in the carbamazepine-exposed children when
compared with controls.35 The large Danish population study
by Christensen and colleagues33 also found no increased risk of
autism or ASD in teenagers and children with prenatal carbam-
azepine exposure. An earlier study in Aberdeen, Scotland
reported that two of 80 (2.5%) of carbamazepine-exposed chil-
dren had an ASD, which is above the population rate (0.25%)
but lower than that of the valproate group (8.9%).40 These find-
ings are limited by the small number of cases, the absence of a
control group, and retrospective recruitment of only 41% of the
original AED-exposed cohort, which potentially introduced a
selection bias. The more recent study34 of autistic traits from the
Australian Registry also recruited mothers retrospectively from
the prospectively identified cohort (63% enrollment). This study
reported scores consistent with autism in one of 34 children
exposed to carbamazepine and scores that raised “concern for
autism” in another child based on a standardized assessment.
The overall rate of autistic traits was 5.9%. The authors advise
that this increase should be interpreted with caution because no
discernable dose-effect of carbamazepine and no increased risk
were seen in pregnancies exposed to polytherapy regimens that
excluded valproate. The majority of these polytherapy regimens
did include carbamazepine.34
Lamotrigine
Rates of major malformations with lamotrigine exposure
have been consistently low and range from 2% to 4.6%,
across eight prospective registries.24-29,41,42 Initially, the North
American AED Pregnancy Registry (NAAPR) reported a tenfold
increased risk in oral clefts with lamotrigine monotherapy expo-
sure. However, with a larger sample size, this risk was reevaluated
and reported as a fourfold increased risk (absolute risk with
lamotrigine, 0.45%).26 A case-control study,43 however, found
no specific increased risk of oral clefting with lamotrigine, and
other registries have reported much lower rates of clefting with
lamotrigine exposure (0.1% to 0.25%).37,41,44 The absolute risks
of clefting reported by Tomson and Battino24 was 0.15%. The
composite risk of other specific malformations in this review
were 0.6% for cardiac defects, 0.12% for NTDs, and 0.36% for
hypospadias.24
In two independent cohorts from the United Kingdom,
developmental scores of infants prenatally exposed to
lamotrigine did not differ from those of controls.45,46 In
the LMNG cohort, at 6 years of age, the IQ scores of the
lamotrigine-exposed children did not differ from those of con-
trols.32 Additionally, in the NEAD study, FSIQ scores in chil-
dren exposed to lamotrigine were significantly higher than those
 Chapter 49  Neurologic Disorders in Pregnancy
of valproate-exposed children and did not differ from those
of carbamazepine- or phenytoin-exposed children.31 However,
both valproate and lamotrigine exposure were associated with
decreased verbal IQ relative to nonverbal IQ.31 In a Norwegian
population-based mail survey, parents of lamotrigine-exposed
infants also reported impaired language functioning and an
increase in autistic traits observed in their children.47 Parental
ratings of the 6-year-old children prenatally exposed to lamotrig-
ine in the NEAD study suggested that they may be at increased
risk for ADHD, but the teacher ratings in a subgroup of these
children did not substantiate this finding, and no tendency
toward social impairment was detected.48 In contrast to these
parental observations, the LMNG found no increased risk of
formally diagnosed NDDs in lamotrigine-exposed children,35
and the population study by Christensen and colleagues33 found
no increased risk of autism or ASD.
Levetiracetam
Levetiracetam is a relatively new AED, and to date, just over
1000 pregnancies have been reported across eight prospective
registries, which have each recruited relatively small cohorts. The
major malformation rates across these registries range from 0%
to 2.4%.24-27,29,41,49 Developmental effects of levetiracetam have
been assessed in one study of 51 levetiracetam-exposed children
recruited from pregnancies identified in the U.K. Epilepsy and
Pregnancy Register.50 At 36 to 54 months, the developmental
scores of the exposed children did not differ from those of con-
trols but were better than a group exposed to valproate. Because
this is the only investigation of developmental outcomes with
levetiracetam exposure, it will need to be replicated in future
studies.
Phenytoin
Despite the fact that phenytoin is one of the oldest AEDs still in
use, little certainty exists in regard to its teratogenic implications.
In 1975, Hanson and Smith51 described a specific fetal hydan-
toin syndrome associated with in utero phenytoin exposure.
They noted growth and performance delays and craniofacial
abnormalities that included clefting and limb anomalies, includ-
ing hypoplasia of nails and distal phalanges. They later reported
that this was present in 11% of 35 exposed infants and that
31% of exposed infants had some aspects of the syndrome.52
Yet other studies have not substantiated this. In 1988, Gaily and
colleagues53 reported no evidence of the hydantoin syndrome in
82 women exposed in utero to phenytoin. Some of the patients
had hypertelorism and hypoplasia of the distal phalanges, but
none had the full hydantoin syndrome. The true prevalence of
this syndrome and contributing factors has not been established,
and it has largely fallen out of current literature.
The more recent pregnancy registries have not focused on the
description of syndromes. Of note, the major malformations
studied in these registries do not include many of the skeletal
abnormalities included in the fetal hydantoin syndrome. Rates
of anomalies in these registries have ranged from 2.4% to 6.7%
across five registries,24,26,27,29,37 but only 761 pregnancies have
been enrolled in these studies, and the individual cohorts are
small. The largest cohort studied in the NAAPR published a
major malformation rate of 2.9% among 416 phenytoin-exposed
pregnancies.26 Tomson and Battino24 reported the rates of spe-
cific malformations with phenytoin exposure: 0.4% for
cardiac malformations, 0% for NTDs, 0.2% for oral clefts,
and 0.5% for hypospadias.
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1035
The cognitive implications of phenytoin exposure have only
been evaluated in a few prospective studies. The 2014 Cochrane
review39 found that the methodologies of these studies were too
disparate to perform a meta-analysis. The review concluded that
phenytoin exposure was associated with better developmen-
tal and cognitive outcomes than valproate exposure and that
no discernable differences between phenytoin and carba­
mazepine exposure were present in terms of development and
IQ. In the NEAD study, average FSIQ and verbal IQ scores of
the phenytoin-exposed children were significantly higher than
those of the valproate-exposed cohort and were not different
from those of children exposed to carbamazepine or lamotrigine.
Because the study did not include an unexposed control group,
it is unknown whether the phenytoin group would differ from
unexposed children.31 In terms of behavioral effects, Vinten and
associates54 reported no difference between parentally assessed
adaptive behaviors in the phenytoin-exposed Norwegian chil-
dren when compared with unexposed controls born to mothers
with epilepsy.
Phenobarbital
Phenobarbital is rarely used as a first-line AED in developed
countries given its adverse cognitive and metabolic side
effects and the availability of alternative medications with
fewer adverse effects. It is very difficult to wean patients
from phenobarbital, however, and this process often leads to
worsened seizure control. Thus, unless pregnancy is planned
well in advance, many women previously taking phenobarbital
may remain on it. In the NAAPR, phenobarbital was associated
with a risk of major malformations of 5.5% in 199 pregnancies,
and cardiac malformations were the most frequent malforma-
tion reported. In a pooled analysis of 765 barbiturate-exposed
pregnancies, Tomson and Battino24 reported a rate of 3.5%
for cardiac malformations and a 1% risk or oral clefts. The
absolute risk of NTDs and hypospadias in this analysis was 0.2%
for each.
Retrospective studies of the effect of phenobarbital on cogni-
tive and educational outcomes of exposed children have reported
mixed results.55-58 The largest prospective study59 of phenobar-
bital and cognitive outcomes evaluated a cohort of 114 Danish
men who had been exposed to phenobarbital in utero between
1959 and 1961. The most common indication for phenobarbital
was pregnancy-related hypertension, and mothers with epilepsy
were not evaluated. Thus the exposure to phenobarbital was
likely shorter in duration than in the children of mothers with
epilepsy. The phenobarbital-exposed group had significantly
lower IQ scores compared with controls, and children exposed
in the third trimester were most affected. In a subset of 33 sub-
jects, this effect was driven by lower verbal IQ compared with
children exposed to other AEDs in monotherapy. In a prospec-
tive study, Thomas and colleagues60 also found lower IQs in a
group of 12 phenobarbital-exposed children. None of the studies
to evaluate the cognitive effects of phenobarbital have accounted
for the maternal IQ, which is an important predictor of the
child’s IQ.
Other Antiepileptic Drugs
A paucity of data is available to describe the teratogenic risks
of other AEDs commonly used to treat epilepsy. The rate
of major malformations with oxcarbazepine exposure among
393 prospective cases in the Danish birth registry was 2.8%.
Other cohorts are smaller.41 In the NAAPR study,61 no major
1036 Section VI  Pregnancy and Coexisting Disease
anomalies were reported in a cohort of 98 pregnancies exposed
to zonisamide monotherapy, but this was interpreted with
caution given the small sample size. The study did demonstrate
an increased risk of low birthweight with both zonisamide and
topiramate exposure. Recently, concern has been raised that
topiramate is a significant teratogen, although sample sizes are
still small. In the NAAPR study, the risk of major anomalies was
4.2% in 359 pregnancies.26 The registry also reported a tenfold
increased risk of oral clefts in the topiramate cohort com-
pared with that of an external control group; this corre-
sponded to an absolute risk of 1.4%,26 which resulted in the
U.S. Food and Drug Administration (FDA) reclassification
of topiramate from class C to class D for pregnancy. This
concern has been corroborated by subsequent cohorts
and meta-analyses.62,63 Studies of the effect of oxcarbazepine,
zonisamide, and topiramate on cognitive and behavioral devel-
opment are limited.
Little useful information is available on the effect of human
in utero exposure to other AEDs that include benzodiazepines,
eslicarbazepine, ethosuximide ezogabine, felbamate, gabapentin,
lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin.
The manufacturers of lacosamide, a recently introduced AED,
caution that it is known to antagonize the collapsin response
mediator protein 2, which is involved in axonal growth and
neuronal differentiation and appears to have adverse effects on
brain development in rodents.64
Effect of Antiepileptic Drug Dose
The risk of major malformations has been shown to be dose
related for several AEDs. In the EURAP registry, for example,
valproate monotherapy was associated with a malformation risk
of 5.6% with preconception doses of less than 750 mg/day and
a risk of 24.6% with doses greater than 1500 mg/day.29 Similar
correlations between the risk of birth defects and preconception
AED dose were also noted for carbamazepine, lamotrigine, and
phenobarbital. Additionally, dose effects on cognitive and behav-
ioral development have been noted for valproate,32,34,65 although
more data on the relationship between cognitive teratogenesis
and dose of both valproate and other AEDs are needed. Further
research is also required on the relevance of serum concentra-
tions, instead of dose, because of the substantial differences in
AED metabolism among individuals. For now, preparing a
woman with epilepsy for pregnancy involves trying to identify
the minimum therapeutic dose and corresponding drug level to
control her seizures.
Polytherapy
It was previously thought that AED polytherapy always
posed more of a teratogenic risk than monotherapy and that
polytherapy should be avoided whenever possible. This con-
clusion was based on several prior studies that demonstrated a
higher rate of major malformations with polytherapy. However,
a recent study from the NAAPR suggested that the results of
these prior studies were largely driven by polytherapy combina-
tions that included valproate. Within the NAAPR, Holmes and
colleagues66 reported that the risk of major anomalies with
lamotrigine and valproate therapy was 9.1%, whereas it was
2.9% for the combination of lamotrigine and any other AED.
Similarly, they reported that carbamazepine and valproate poly-
therapy was associated with a major malformation risk of 15.4%,
which was much higher than the 2.5% risk seen with the com-
bination of carbamazepine and any other AED. The authors also
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highlighted similar findings that had been reported in the United
Kingdom Epilepsy and Pregnancy Registry37 and the Interna-
tional Lamotrigine Pregnancy Registry.42 Studies on cognitive
development have suggested the same trend. In an Australian
cohort, Nadebaum and colleagues65 found that in utero exposure
to valproate polytherapy was associated with significantly lower
FSIQ and verbal comprehension scores than exposure to valpro-
ate monotherapy or polytherapy combinations without valpro-
ate. The LMNG also reported that only polytherapies that
included valproate were linked to decreased mean FSIQ and
verbal IQ in school-age children.32
The mainstay of epilepsy therapy, especially in women of
childbearing age, is still to try to find the one AED that best
controls a patient’s seizures at the minimum therapeutic dose
or level. However, in certain cases, polytherapy may be pref-
erable to monotherapy. For example, women with idiopathic
generalized epilepsies have a limited number of AEDs that are
appropriate for their condition. Valproate is an effective option
for this type of epilepsy but is a poor choice for these women.
When one AED—such as levetiracetam or lamotrigine—is inef-
fective for these patients, the combination of the two may some-
times be effective and likely carries a reduced risk of teratogenesis
when compared with valproate monotherapy. Given the emerg-
ing information on the relationship between AED dose and
malformation risk for most AEDs, more research is needed to
determine whether polytherapy combinations that involve low
doses of two AEDs are ever preferable to a single non-valproate
AED at a high dose.
Effects of Pregnancy on
Anticonvulsant Medications
Although most pregnancy studies to date have focused on AED
dose, AED levels are probably far more important and should
be studied in the future. Although drug manufacturers and labo-
ratories publish standard therapeutic windows for individual
AEDs, these large ranges have little relevance for a given patient
with epilepsy. AED metabolism varies greatly by individual,
and each patient has her own therapeutic drug level at which
seizures are best controlled. This is typically within the stan-
dard window but may be above or below it. Therefore it is
important to understand and establish this drug level prior
to pregnancy whenever possible, because levels of anticon-
vulsant medications can change dramatically during preg-
nancy, and in many cases, decreasing AED levels have been
associated with loss of seizure control. When prepregnancy
levels have not been obtained, they should be drawn as early as
possible in the first trimester. Whereas a trough level is ideal, it
is usually not practical or safe for women to hold medications
for a blood draw. It is more important that they have levels
drawn at a convenient and roughly standard time relative to their
AED dose. For certain AEDs, including phenytoin and some-
times carbamazepine and valproate, free (unbound) drug levels
are available and preferable.
Many factors—including altered protein binding, delayed
gastric emptying, nausea and vomiting, changes in plasma
volume, changes in the volume of distribution, and even folic
acid supplementation—can affect the levels of anticonvul-
sant medications. Additionally, changes in AED metabolism
can be dramatically altered by the pregnant state.
Lamotrigine is the most common AED prescribed in preg-
nancy, and it is utilized to treat both epilepsy and bipolar disor-
der. It is also the best example of the substantial effects of
 Chapter 49  Neurologic Disorders in Pregnancy
pregnancy on AED metabolism. Lamotrigine clearance depends
heavily on glucuronidation, a process induced by the increases
in estrogen during pregnancy. Over the course of a pregnancy,
lamotrigine clearance increases by over 200% in the majority
of women with epilepsy.67 Lamotrigine doses need to be
increased substantially over the course of a pregnancy in
order to maintain prepregnancy levels and seizure control.
Doses of 600 to 900 mg/day are not uncommon by the end of
pregnancy. Lamotrigine metabolism decreases rapidly after
delivery and returns to baseline within 3 weeks of delivery. To
avoid toxicity, it is important to give patients a postpartum
dosing plan to taper their dose starting immediately after deliv-
ery. A common practice is to decrease the dose by two thirds of
the increase over pregnancy in the first week after delivery and
then decrease back toward the baseline dose. Leaving a patient
on slightly more than her prepregnancy dose is also common,
especially in patients with brittle seizure control who may be
especially susceptible to the effects of sleep deprivation.
Although less well studied, oxcarbazepine clearance is also
dependent on glucuronidation.68 In the EURAP registry, patients
taking oxcarbazepine or lamotrigine during pregnancy were
noted to have poorer seizure control than those taking other
AEDs.69,70 Less than half of those using lamotrigine or oxcar-
bazepine had their doses adjusted, which suggests therapeutic
drug monitoring may not have been regularly performed. In
contrast, levels of free and total carbamazepine—as well as a
metabolite of carbamazepine—are relatively stable throughout
pregnancy,71 and seizure control appears to be better in patients
taking carbamazepine.72,73 Given the interindividual variation
in AED metabolism and susceptibility to changes during
pregnancy, checking AED drug levels monthly is recom-
mended for all AEDs.
Pregnancy and Seizure Frequency
For the majority of women with epilepsy (54% to 80%),
seizure frequency will remain similar to their baseline seizure
frequency. Across several studies, seizure frequency increased in
15.8% to 32% of women and decreased in 3% to 24%.1,69,74,75
Seizure freedom for 9 months prior to pregnancy is associ-
ated with an 84% to 92% chance of remaining seizure free
during pregnancy.1 Genetic generalized epilepsies seem to be
associated with less of a risk of seizures during pregnancy than
focal epilepsies, although both groups of patients are at increased
risk of seizures in the peripartum and postpartum periods.1,69,76
A recent study from the Australian Register of Antiepileptic
Drugs in Pregnancy (APR) suggested that the AEDs taken
during pregnancy might predict seizure control.73 The authors
reported that the risk of seizures was lowest with valproate
(27%), levetiracetam (31.8%), and carbamazepine (37.8%),
whereas an increased risk of seizures was seen with lamotrigine
(51.3%). Phenytoin (51.2%) and topiramate (54.8%) were also
associated with a relatively higher risk of seizures, but the sample
sizes of these groups were small. As mentioned above, the
EURAP registry has also reported a higher risk of seizures in
patients taking lamotrigine or oxcarbazepine.69,70 In contrast to
the APR, a small study by Reisinger and colleagues72 found a
relatively high risk of seizure deterioration in patients treated
with levetiracetam monotherapy (47%) when they compared
seizures during pregnancy to each patient’s baseline. The NAAPR
also notes that rates of seizures during pregnancies managed with
levetiracetam were similar to the rates in patients treated with
lamotrigine.26 The increasing metabolism and falling AED levels
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1037
of many of the newer AEDs including lamotrigine likely play
an important role in the variable seizure control reported. Both
the APR and EURAP registries reported that lamotrigine dosing
had been increased in fewer than 50% of cases analyzed.69,73
Future prospective studies, during which therapeutic drug mon-
itoring and appropriate dose adjustments are made, will be
necessary to understand whether AED metabolism is the prin-
cipal reason for worsening seizure control with certain AEDs or
if other factors play a role.
Obstetric and Neonatal Outcomes
Women with epilepsy may be at increased risk for obstetric
complications. Historically, studies on obstetric complications
had yielded mixed results. A 2009 evidence-based review from
the AAN reported that insufficient evidence was available to
support or refute an increased risk of preeclampsia or gestational
hypertension in women with epilepsy. They also stated that
preterm labor was probably not increased, at least not to moder-
ate levels (1.5 times the baseline risk) except in women with
epilepsy who smoked.1 Since then, population studies from the
United States and Norway have associated epilepsy with a mild
to moderate risk of preeclampsia (OR, 1.59 to 1.7) and preterm
labor (OR, 1.54 to 1.6) when compared with that of women
without epilepsy.9,77 Preterm labor was defined as labor before 34
weeks in the Norwegian study and before 37 weeks in the U.S.
study. In the Norwegian study by Borthen and colleagues,78 the
risk of these complications in women with epilepsy who did not
take AEDs was not increased. However, the possibility that these
patients may have had milder epilepsy must be considered.
Borthen and colleagues78 also studied 205 epileptic women from
a single Norwegian hospital and found an increased risk of severe
preeclampsia in these patients compared with unaffected women.
Epilepsy and AED use are typically not indications for
cesarean delivery (CD); however, CD may be more common
in women with epilepsy. The reasons for this association are
unclear and has not been seen consistently across all studies.9,77-79
In their hospital-based study, Borthen and colleagues78 found no
significant increased risk of CD if preterm labor was accounted
for. Induction of labor may also be more common in women
with epilepsy.9,78 Prospective studies are needed to determine the
reasons for labor induction and CD in women with epilepsy. It
is unclear if this is related to other complications in these women
or physician or patient concern about seizures during late preg-
nancy or delivery.
Bleeding complications at delivery may also be increased
in women with epilepsy, although again studies have been
conflicting on this point.79 Population studies from Norway
and the United States both suggest a small but significantly
increased risk of postpartum hemorrhage.9,80
According to the 2009 AAN literature review and recom-
mendations, evidence was sufficient to suggest a near twofold
increased risk of SGA infants born to epileptic women taking
AEDs, but the group felt data were inadequate on the risk of
intrauterine growth restriction (IUGR).36 A recent study from a
prospective registry in Norway studied 287 children born to
women with epilepsy and found that they had an increased risk
of being SGA and having a ponderal index below the tenth
percentile.81 AED exposure was the strongest predictor of a low
ponderal index, but seizure frequency was not controlled for. In
yet another Norwegian study,25 topiramate was specifically asso-
ciated with SGA infants, and in an investigation from the
NAAPR, both topiramate and zonisamide were associated with
1038 Section VI  Pregnancy and Coexisting Disease
lower birthweights in exposed infants.61 A Taiwanese study by
Chen and colleagues found that seizures during pregnancy were
associated with an increased risk of SGA.
The recent U.S. population study found a mild but signifi-
cantly increased risk of stillbirth in women with epilepsy (OR,
1.27; 95% CI, 1.17 to 1.38).9 Two other population studies
from Denmark and Norway found a trend toward an increased
stillbirth risk of similar magnitude, but the effect was not statisti-
cally significant.82,83 Little else about fetal outcomes of infants
born to women with epilepsy is known. The AAN did conclude
that the offspring of women using AEDs were at greater risk for
a low 1-minute Apgar score.84
Preconception Counseling for Women
With Epilepsy
Ideally, preconception counseling for a woman with epilepsy
should begin at the time of diagnosis and with prescription
of the first AED. Unfortunately, this is not always possible.
For most patients, the obstetrician must stress that the patient
has a greater than 90% chance of having a successful pregnancy
that results in a normal newborn. A detailed history of medica-
tion use, seizure types, and seizure frequency should be obtained.
The patient must be informed that if she has frequent seizures
before conception, this pattern will probably continue. Further-
more, if she has frequent seizures, in most cases, she should
be encouraged to delay conception until control is optimized.
The obstetrician must stress that controlling seizures is of pri­
mary importance. For patients with seizures that have been
refractory to one to two medications, inpatient video EEG
monitoring is often indicated to determine whether the patient
is a surgical candidate. Inpatient video EEG monitoring is
also recommended in intractable cases or in any patient with
atypical features to rule out a diagnosis of nonepileptic seizures.
It can be very difficult to diagnose nonepileptic seizures
based on clinical history, but some features that should raise
suspicion of this diagnosis are closed eyes during a seizure, long
duration of seizure activity that waxes and wanes, and a history
of abuse.
Valproate is a poor first choice as an AED for any woman of
childbearing age. In addition to the adverse effects on pregnancy,
valproate is associated with weight gain, hirsutism, and signs of
polycystic ovarian syndrome (PCOS). Lamotrigine and leveti-
racetam are better choices and are quickly becoming the
most commonly prescribed drugs for women of childbearing
age. They are often used in both focal and generalized epilepsies.
Carbamazepine is also a reasonable option for women with
focal epilepsy. If these medications are not effective, however, a
woman may need to be switched to an AED with higher tera-
togenic risk or undefined risk. In these cases the patient should
be counseled on the available information and unknowns, but
again, the importance of seizure control should be stressed. In
some women with genetic generalized epilepsies, valproate is the
only drug that effectively controls their seizures. Valproate
therapy is not a reason to terminate pregnancy, and despite the
relatively increased risks of teratogenesis, the majority of women
taking valproate will have healthy children. For all AEDs, pre-
pregnancy counseling should include trying to find the minimum
therapeutic dose/level needed. This is of utmost importance in
women taking valproate.
As discussed above, it is important to establish baseline
AED levels prior to pregnancy in order to set a target for dose
adjustment during pregnancy. A minimum of two levels taken
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at a similar time of day is advisable to establish a given indi-
vidual’s therapeutic range.
Unfortunately, the majority of pregnancies in women with
epilepsy are unplanned,85 which emphasizes the need for appro-
priate selection of an AED for women of childbearing age and
the need for early preconception counseling. Changing AEDs
once a woman is already pregnant is usually not recom-
mended. Structural teratogenesis occurs early in the first trimes-
ter, and the potential effects of exposure are likely already
underway by the time a woman learns she is pregnant. Addition-
ally, switching drugs during the first trimester exposes the fetus
to polytherapy and potentially breakthrough seizures during this
critical time. Given the increasing knowledge of the adverse
cognitive effects of valproate, which are mostly thought to occur
in the third trimester, some specialists have switched women off
valproate typically to levetiracetam. No available evidence sup-
ports or refutes this approach, but it should only be considered
in select patients whose history suggests that they may have a
good chance of responding to a different drug and are in the
care of an epilepsy specialist who can monitor them closely.
If the patient has had no seizures during the past 2 to 4
years, an attempt may be made to withdraw her from anti-
convulsant medications. This is usually done over a 1- to
3-month period, slowly reducing the medication, and should
not be done close to or during pregnancy. Up to 50% of patients
relapse and need to start their medications again. This with-
drawal should be attempted only if the patient is completely
seizure free and has a normal EEG, and it should only be done
with the help of a neurologist. Based on a patient’s history, many
neurologists will recommend that the patient refrain from
driving for a period of time during and after the wean.
Genetic Counseling
A detailed family history should be taken in the process of
counseling women with epilepsy. A history of congenital mal-
formations in the family increases the chances of having an
affected child. In particular, in women taking valproate, those
who have had prior pregnancies complicated by a malformation
have a significantly increased risk of having a second child with
a malformation, regardless of whether they were taking valproate
at the time of the prior pregnancy.86
It is also important to take a family history that includes
seizure disorders, including febrile seizures, and intellectual dis-
ability. Many patients are concerned about the risk of passing
epilepsy on to their child. Only a few epidemiologic studies have
looked at the inheritance patterns of epilepsy. For most patients
with epilepsy, the risk of passing it on to their children is
higher than the approximate 1% to 2% risk in the general
population; however, the absolute risk remains low. Factors
associated with a low risk are late onset of epilepsy in the parent
and a known acquired cause of epilepsy such as a vascular mal-
formation, stroke, or trauma. Patients with an early onset of
epilepsy, epilepsy of unknown cause, and a family history of
epilepsy—particularly in a first-degree relative—have a higher
risk. Epilepsy associated with intellectual disability may also be
more likely to be genetic. Across many studies, the “genetic”
generalized epilepsies or idiopathic generalized epilepsies have a
higher risk of inheritance than focal epilepsy. Interestingly, a
consistent finding in several epidemiologic studies is that
mothers with epilepsy have a much higher chance of having
a child with epilepsy than do fathers with epilepsy. The most
recent large population study from Rochester, Minnesota
 Chapter 49  Neurologic Disorders in Pregnancy 1039

reviewed the medical records of all 660 probands with epilepsy

born between 1935 and 1994 and all their first-degree relatives.87
This study also found that epilepsy was more likely to be inher-
ited from the mother, although when analyzed separately, this
effect was only true for focal epilepsies, not generalized epilep-
sies. When all types of epilepsy were considered, the cumulative
incidence to age 40 of epilepsy in a child of a woman with
epilepsy was 5.39%, which correlates to a fivefold increased risk
from the baseline population. The authors recommended taking
the standard error into account and counseling women that on
average, the risk of passing on epilepsy is 2.69% to 8%. In
children of women with generalized epilepsy, the incidence was
8.34% (1.36% to 15.36% risk, considering standard error), and
if the mother had focal epilepsy, the incidence was 4.43%
(1.43% to 7.43%).
This type of epidemiologic data can be useful for patients with
epilepsy of unknown cause, but they should not be used to
counsel all patients indiscriminately. It is critical that the neu-
rologist and obstetrician take a patient’s individual clinical and
family history into account before advising on the risks of
passing on epilepsy.
An increasing number of epilepsy genes and familial syn-
dromes have been discovered that can substantially alter the risk
of inheriting an epileptic disorder.88 Autosomal-dominant forms
of epilepsy, such as autosomal-dominant frontal lobe epilepsy
(ADFLE) and autosomal-dominant temporal lobe epilepsy
(ADTLE), are highly penetrant familial epilepsies that should
be considered in a patient with one or more first-degree relatives
with a similar epilepsy syndrome. Mutations in the sodium
channel, voltage gated, type 1 alpha subunit (SCN1A) gene have
variable penetrance and expressivity, and they can present with
a range of manifestations. Even within one family, some indi-
viduals with the mutation will be unaffected, some will have
simple febrile seizures or a mild epilepsy syndrome that persists
into adulthood, whereas others can have Dravet syndrome, a
severe epileptic encephalopathy. Preimplantation genetic testing
for these disorders is available only for some syndromes and is
controversial. However, recognizing these family syndromes
definitely changes the counseling on the risk of inheriting epi-
lepsy. Other genetic syndromes associated with epilepsy have
more serious complications. For example, bilateral periventricu-
lar nodular heterotopia (PVNH; Fig. 49-1) is an uncommon
cause of focal epilepsy. Approximately 50% of female patients
with PVNH will have a mutation in the filamin A gene.89 This
is an X-linked–dominant mutation that is typically lethal in
males in the third trimester or in the immediate postnatal
period. Female patients may have no manifestations other than
the periventricular nodules, which represent aberrant neuronal
migration, and epilepsy. An echocardiogram is recommended in
these women, because they can have cardiac anomalies. Other
examples of critical genetic diagnoses are mitochondrial disor-
ders that can present with epilepsy. Whereas a comprehensive
review of the genetics of epilepsy is beyond the scope of this
chapter, genetic counseling is an important option for many
prospective parents with epilepsy, and certain clinical find-
ings or key features in a family history, such as other affected
relatives or frequent miscarriages, make specialized counsel-
ing essential.
Folic Acid Supplementation
The 2009 AAN practice guidelines recommend folic acid
supplementation of 0.4 to 4 mg/day for all women of
FIG 49-1  Bilateral periventricular nodular heterotopia (PVNH). Magnetic
resonance imaging (MRI) of a 28-year-old primigravida with intractable
focal epilepsy who presented for neurologic evaluation at 24 weeks’
gestation. Her prior MRI demonstrated bilateral PNVH (white arrows
point to abnormal cortical tissue lining the ventricles bilaterally). In up
to 50% of women, this syndrome is associated with an X-linked
dominant mutation in the filamin A gene that is often lethal in male
fetuses in the third trimester or the first few postnatal days. In
females, this mutation is associated with the above migrational abnor-
malities and focal seizures. Female patients may have normal or
slightly low intelligence quotients (IQs). This case illustrates the
importance of early prepregnancy neurologic evaluation and genetic
counseling.
childbearing age who take AEDs.90 These recommendations
are largely extrapolated from studies that have demonstrated that
folic acid supplementation reduces the risk for NTDs in the
general population.91 Additionally, low first-trimester serum
folic acid levels have been correlated with an increased risk for
congenital malformations in the offspring of women with epi-
lepsy, and several AEDs are known to lower folic acid levels.92,93
Little direct evidence is available to suggest that folic acid reduces
the risk of major anomalies in women taking AEDs, although
the AAN practice guidelines state that prior studies might have
been underpowered to detect a benefit.90 One study by Pittsch-
ieler and colleagues94 suggested that folic acid may reduce the
risks of miscarriage in women with epilepsy. The NEAD study31
also found an association between higher IQs in children of
mothers with epilepsy who took periconceptional folic acid
supplementation (≥0.4 mg). It is unclear whether this effect was
specific to AED use because similar beneficial effects on cogni-
tive development have been noted in the general population.
The optimal dose of folic acid for women taking AEDs is not
known. A recent study of women without epilepsy found delayed
psychomotor development in children of women exposed to
doses greater than 5 mg compared with women who took doses
of 0.4 to 1 mg, which raises concerns about the practice of high-
dose supplementation.95 More research is needed to determine
the optimal dose of folic acid in women with epilepsy. In the
meantime, supplementation with 0.4 to 1 mg in all women

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1040 Section VI  Pregnancy and Coexisting Disease
of childbearing age taking AEDs should be recommended.
Many clinicians increase the dose to 4 mg of folic acid when a
patient is trying to conceive or is pregnant.
Vitamin D deficiency is also common in women with
epilepsy. This occurs because anticonvulsants may interfere
with the conversion of 25-hydroxycholecalciferol to 1,25-
dihydroxycholecalciferol, the active form of vitamin D. Ideally,
25-hydroxyvitamin D levels should be checked and opti-
mized prior to pregnancy. A supplemental dose of 1000 to
2000 IU of vitamin D3 in addition to a prenatal vitamin is
reasonable during pregnancy. Additionally, because folic acid
supplementation can mask the hematologic effects of vitamin
B12 deficiency, B12 levels should also be checked in women with
epilepsy.
Care of the Patient During Pregnancy
Once the patient becomes pregnant, it is of the utmost impor-
tance to establish accurate gestational dating. This will prevent
any confusion over fetal growth in later gestation. AED levels
should be checked as soon as possible and then monthly.
Adjustments should be made to keep the patient’s AED level
around her prepregnancy or early pregnancy level.
An early anatomic ultrasound at 14 to 15 weeks’ gestation
can identify signs suggestive of NTDs in women at high risk
(see Chapter 9). At approximately 16 weeks’ gestation, the
patient should undergo blood testing with maternal serum
alpha-fetoprotein screening in an attempt to detect any NTD.
Coupled with ultrasonography, these data result in a detection
rate of more than 90% for open NTDs (see Chapter 10). At 18
to 22 weeks, the patient should undergo a specialized,
detailed anatomic ultrasound to determine whether congeni-
tal malformations, including NTDs, are present. If adequate
views of the fetal heart are not obtained, a fetal echocardio-
gram can be performed at 20 to 22 weeks’ gestation to detect
cardiac malformations, which are among the more common
malformations in women taking any antiepileptic medica-
tions. In the United States, no official recommendations have
been made on the use of fetal cardiac echo studies in women
with epilepsy, but the 2009 Italian guidelines do advise this
examination for all women taking AEDs.96
As previously noted, there appears to be an increased risk for
IUGR in fetuses exposed in utero to anticonvulsant medica-
tions. If the patient’s weight gain and fundal growth appear
appropriate, regular ultrasound examinations to assess fetal
weight are probably unnecessary. If, however, if poor fundal
growth is suspected or if the patient’s habitus precludes adequate
assessment of this clinical parameter, serial ultrasonography for
fetal weight discernment can be performed.
Antepartum fetal evaluation with nonstress testing is not
necessary in all mothers with seizure disorders, but it should
be considered for patients who have active seizures in the
third trimester.
Vitamin K Supplementation
Third-trimester vitamin K supplementation in women taking
certain enzyme-inducing AEDs (EIAEDs) is a historic practice
based on a concern for an increased risk of intracranial neonatal
hemorrhage and clotting factor deficiencies associated with
EIAED exposure reported in early case studies.97,98 EIAEDs
include phenobarbital, phenytoin, carbamazepine, and oxcar-
bazepine. A more recent study of 662 women with epilepsy
taking EIAEDs did not find any increased risk of bleeding
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in the neonate if the infant received 1 mg of vitamin K intra-
muscularly at birth.99 This problem is rare today because most
neonates are given vitamin K at birth. The 2009 AAN guidelines
state that evidence is insufficient to recommend for or against
the practice of peripartum vitamin K supplementation.90
Another recent study evaluated the risk of maternal postpartum
hemorrhage in women with epilepsy and also found no signifi-
cant difference in the risk of bleeding in women taking EIAEDs
versus controls.100 There was also no difference in the risk of
bleeding in women taking EIAEDs who supplemented with
vitamin K and those who did not.
Labor and Delivery
Although epidemiologically there may be an increased risk
of induction of labor and CD in women with epilepsy, these
interventions should not be recommended to women with
epilepsy without specific additional obstetric, medical, or
neurologic indications. Most women with epilepsy have suc-
cessful vaginal deliveries. Although no evidence exists to support
or challenge epidural analgesia in patients with epilepsy, it is
typically utilized to decrease stress and allow the mother to rest
during a long labor.
The risk of seizures during labor in women with epilepsy is
3.5% or less, and seizures are most common in patients who
have had seizures during pregnancy.69,70 Whenever a seizure
occurs, acute seizure management involves assessing the patient’s
clinical stability, including respiratory and circulatory function.
Nothing should be put in the mouth of a seizing patient, but
supplemental oxygen should be provided, and suctioning of
secretions can be performed if possible. Ideally, the patient
should be turned on her left side to increase blood supply to the
fetus. Short-acting benzodiazepines, typically lorazepam 0.1 mg/
kg to 0.2 mg/kg with a maximum of 10 mg, are the mainstay
of acute seizure treatment. If the seizure does not resolve within
2 minutes, lorazepam should be given. In most cases this is fol-
lowed by intravenous (IV) fosphenytoin or phenytoin if seizures
persist. Status epilepticus is defined by seizures that last more than
5 minutes. In the rare case of tonic-clonic status in pregnancy,
intubation and stabilization with anesthesia may be required.
Fetal monitoring should begin as soon as possible after a seizure,
if it is not already in place. Transient fetal heart rate changes may
be seen and can be tolerated temporarily, but if fetal bradycardia
persists, the clinician must assume fetal compromise or placental
abruption and must proceed with CD.
New Onset of Seizures in Pregnancy
and in the Puerperium
Occasionally, seizures are diagnosed for the first time during
pregnancy, which may present a diagnostic dilemma. If the
seizures occur in the third trimester, they are eclampsia until
proven otherwise and should be treated as such until the
physician can perform a proper evaluation. The treatment of
eclampsia is delivery, but the patient must first be stabilized (see
Chapter 31). Magnesium sulfate, instead of AEDs, is the treat-
ment of choice for eclamptic seizures. It is often difficult,
however, to distinguish eclampsia from an epileptic seizure. The
patient may be hypertensive initially after an epileptic seizure
and may exhibit some myoglobinuria secondary to muscle
breakdown, which will test as proteinuria on a routine urinalysis.
The diagnosis becomes clearer over time, but in either case, rapid
thoughtful action must be undertaken. The first physician to
attend a patient after a seizure may not be an obstetrician/
 Chapter 49  Neurologic Disorders in Pregnancy
gynecologist, and magnesium sulfate may not be started acutely;
this should be remedied as soon as possible.
If the patient develops seizures for the first time at an
earlier gestational age, she should be evaluated and started
on the proper medication. The physician must look for acquired
causes of seizures that include trauma, infection, metabolic dis-
orders, space-occupying lesions, central nervous system (CNS)
bleeding, and ingestion of drugs such as cocaine and amphet-
amines. Blood samples should be obtained for electrolytes,
glucose, ionized calcium, magnesium, renal function studies,
and toxicologic studies while IV access is being established. If
the patient experienced a tonic-clonic seizure and the attending
physician believes, based on clinical history, that this is probably
new-onset epilepsy with a high likelihood of recurrence, she
should be started on the appropriate anticonvulsant medication
while awaiting the results of any laboratory studies. Although
lamotrigine is one of the most commonly prescribed drugs
for women planning pregnancy, it is typically not practical
to start it when epilepsy presents in pregnancy. The lamotrig-
ine titration schedule is at least 6 weeks because of an increased
risk of a Stevens-Johnson reaction in patients taking this drug,
especially if it is titrated quickly. In addition, accelerated
lamotrigine metabolism in pregnancy makes it virtually impos-
sible to achieve a therapeutic level in a pregnant woman over a
reasonable time period. Similar considerations apply to oxcar-
bazepine. For new-onset epilepsy, levetiracetam is often used
first because it can be started quickly and does not carry a
high risk of rash. An unfortunate side effect of levetiracetam,
however, is an increase in depressed mood or irritability; this
should be assessed in women starting this drug.
Any patient who experiences seizures for the first time during
pregnancy without a known cause should undergo an EEG and
intracranial imaging. In studying only eclamptic patients, Sibai
and colleagues101 found that EEGs were initially abnormal in
75% of patients but normalized within 6 months in all women
studied. Although this group found no uniform abnormalities
on computed tomography (CT) in this series of eclamptic
patients, they did find that 46% and 33% had some abnormal
findings on EEG and CT, respectively. Most of the findings were
nonspecific and were not helpful in diagnosis or treatment. An
MRI is indicated in most cases of new-onset seizures and may
be helpful if eclampsia is suspected.
Breastfeeding and the Postpartum Period
The levels of anticonvulsant medications must be monitored
frequently during the first few weeks postpartum (see Chapter
23) because they can rise rapidly. If the patient’s medication
dosages were increased during pregnancy, they will need to
be decreased over the 3 weeks after delivery to levels at or
slightly higher than that of the prepregnancy period. As dis-
cussed above, this is especially important for lamotrigine.
The benefits of breastfeeding have been well established and
include the promotion of mother-infant bonding (see Chapter
24).102 Whereas AEDs taken by the mother are present in
breast milk to varying degrees, few data suggest neonatal
harm from exposure through breast milk. The NEAD study103
found that infants exposed to carbamazepine, lamotrigine, phe-
nytoin, and valproate in breast milk had higher IQs and lan-
guage scores at 6 years than those infants whose mothers did not
breastfeed. An improvement in parent-reported developmental
abilities of children was also noted in breastfed infants in a
Norwegian cohort of AED-exposed children at 6 and 18 months,
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1041
although the effect was not sustained at 36 months.104 Neither
study found adverse effects on developmental outcomes related
to breast milk exposure for the studied drugs (carbamazepine,
lamotrigine, phenytoin, and valproate). Although further pro-
spective studies of AED exposure via breast milk are necessary,
for most AEDs, the theoretic concern of prolonged infant expo-
sure likely does not outweigh the known benefits of breastfeed-
ing. Some experts advise caution with AEDs with longer
half-lives, such as phenobarbital and zonisamide, although again
the concern is largely theoretic.
Postpartum Safety
Breastfeeding should be supported and encouraged for most
women with epilepsy; however the sleep deprivation associated
with trying to feed a newborn may put her at risk for seizures.
A key part of managing a pregnancy in women with epilepsy
is discussing seizure safety with her and her family. Partners
or other members of a patient’s support system should assist with
night feedings with either pumped milk or formula so that the
patient can get a stretch of uninterrupted sleep, typically 6 to 8
hours depending on the patient. The patient may have to pump
milk additional times during the day to maintain this supply.
Other safety recommendations include giving baths only in the
presence of another adult and changing diapers on a pad on the
floor instead of on a changing table. Avoiding stairs when pos-
sible and using a stroller, rather than an infant carrier strapped
to the mother, should also be considered. The importance of not
allowing infants to sleep in the parents’ bed should also be
emphasized. Lastly, women with epilepsy are at increased risk
for postpartum depression, a topic that should be discussed with
the patient and her family prior to delivery and after.
Contraception
Contraceptive counseling is an important part of preconception
and postpartum planning in women with epilepsy, and drug-
drug interactions are numerous between AEDs and hormonal
contraception. Both the Centers for Disease Control and Pre-
vention (CDC) and the World Health Organization (WHO)
have released evidence-based reviews on the use of specific types
of contraception in women taking AEDs.105,106 The most reliable
form of reversible contraception is the intrauterine device (IUD),
and this is considered the contraceptive method of choice for
most women with epilepsy. Both the copper and levonorgestrel
IUD are appropriate. If hormonal methods are considered, the
physician should review the considerations laid out by the CDC
and WHO before initiating treatment.
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a chronic autoimmune demyelinat-
ing disease that affects women more often than men, and the
ratio of affected females to males has been increasing over
time.107 The onset of symptoms usually occurs between the
ages of 20 and 40 years, and thus it commonly affects women
of childbearing age. The diagnosis of MS is often made years
after the initial onset of symptoms. Common presenting symp-
toms include weakness, paresthesias or numbness of one or both
lower extremities, visual complaints that include optic neuritis,
and loss of coordination. MS primarily affects the white matter
of the CNS, and lesions may involve the spinal cord, brainstem,
cerebral hemispheres, and optic tracts. The hallmark of diagnosis
is that it causes lesions “disseminated over space and time.” The
1042 Section VI  Pregnancy and Coexisting Disease
most common form of the disease, relapsing remitting MS,
is characterized by periodic exacerbations with complete or
partial remissions. Only 10% to 15% of patients show steady
progression at the time of onset, but over time, the majority of
patients with MS will develop secondary progressive MS with
continuing accumulation of neurologic deficits and disability.
Because symptoms of an MS attack can be subtle, it is often
easy to attribute them to pregnancy. Many pregnant women
complain of being more awkward or having some weakness. If
these symptoms are persistent or progressive, they should not be
ignored, and the patient should be referred for neurologic con-
sultation. An MRI of the brain and sometimes an MRI of the
spinal cord are necessary to make the diagnosis of MS. Gado-
linium contrast is helpful to identify acute demyelinating lesions,
but it should not be administered to pregnant women. Even
without contrast, an MRI can be valuable in evaluating a patient
with suspected MS or new symptoms in the setting of a prior
diagnosis of MS.
Multiple Sclerosis and Fertility
The relationship between MS and fertility is unclear. Similar to
women with epilepsy, women with MS are less likely to have
children than are unaffected women.108,109 However, it is not
completely clear whether this is due to biologic reasons or to the
reproductive decisions of women with MS. Other factors may
play a role, such as sexual dysfunction, which is common in MS
patients. Translational studies have suggested that women with
MS may have reduced ovarian reserve based on elevated follicle-
stimulating hormone (FSH) and decreased anti-Müllerian
hormone (AMH) levels; AMH is a marker of ovarian reserve.110,111
Additionally, women with MS are also more likely to utilize
assisted reproductive technology (ART).112 It should be noted,
however, that in vitro fertilization (IVF) procedures that utilize
gonadotropin-releasing hormone (GnRH) agonists have been
shown to increase MS disease activity, particularly if the cycle is
not successful.113-115
Effect of Pregnancy on Multiple Sclerosis
The risk of MS relapses is reduced during gestation but may
increase transiently in the postpartum period. Convincing
evidence shows that the risk of MS attacks is decreased during
the course of pregnancy. It is hypothesized that the lower rate
of disease activity during gestation may be attributable to a
pregnancy-induced shift from thymus helper 1 (Th 1) cyto-
kines to Th 2 cytokines to facilitate immune tolerance (see
Chapter 4). The Pregnancy and Multiple Sclerosis (PRIMS)
study prospectively followed 269 pregnancies in 254 women
with MS across 12 European countries.116,117 They found that
the annual rate of relapse declined during pregnancy, especially
in the third trimester. A rebound of disease activity was noted
in the first 3 months postpartum, but subsequently the relapse
frequency returned to baseline. Of note, the rate of relapse over
the entire pregnancy year—9 months gestation plus 3 months
postpartum—did not differ from the baseline rate, and only
28% of patients experienced a postpartum relapse. Most impor-
tantly, no change in disability progression was noted over
the duration of the study.117,118 A meta-analysis of 13 studies
published prior to 2011 found that the annualized relapse rate
significantly decreased from a baseline of 0.43 per year to 0.26
per year during pregnancy.119 In the year following delivery, the
average annualized rate of relapse increased to 0.7 per year.
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Despite the transient increase in postpartum relapses seen
in women with MS, pregnancy likely has a neutral effect on
long-term disease progression. Weinshenker and colleagues120
showed no association between long-term disability and (1) total
number of term pregnancies, (2) the timing of pregnancy rela-
tive to the onset of MS, or (3) the worsening of MS in relation
to a pregnancy. Verdru and associates121 studied 200 women
with MS and found that pregnancy delays the onset of long-term
disability. As an index of progression, they used the length of
time from onset of disease until wheelchair dependence. In
patients with at least one pregnancy after diagnosis, the mean
time to wheelchair dependence was 18.6 years compared with
12.5 years for other women. Similarly, Runmarker and Ander-
sen122 observed a decreased risk of MS onset in parous women
compared with nulliparous women and reported that women
who were pregnant after the onset of MS had a decreased risk
of developing progressive disease. A recent retrospective study of
1317 Canadian women with MS also found that pregnancy
slowed the rate of conversion to irreversible disability based on
the Expanded Disability Status Scale (EDSS).123 However, in
terms of long-term risk of conversion to secondary progressive
MS—as judged by an EDSS of 6, when a walking aid is
required—women who had been pregnant had a lower risk, at
trend levels, of converting to this form of the disease at 5 years
but an increased risk at 10 years postpartum. These longer-term
effects were not statistically significant and require further study.
The apparent slowed progression of disability may also be influ-
enced by the fact that women with more severe disease are less
likely to conceive after the onset of MS. A population-based
study of 2105 women, also from Canada, found that when
confounding variables such as age at disease onset were consid-
ered, pregnancy had no effect on the time to progress to an
EDSS score of 6.124
Effect of Multiple Sclerosis
on Pregnancy Outcomes
Although more data are needed, MS does not seem to have any
significant effect on the course of pregnancy or fetal out-
comes. Some early studies had suggested that MS may affect
fetal birthweight, but important confounders were not assessed.
The largest study to date by van der Kop and colleagues125 also
controlled for important confounders such as parity and prior
preterm births but found no association between MS and
preterm birth or newborn birthweight.
Disease-Modifying Agents and Pregnancy
The field of MS therapy is rapidly evolving, and unfortunately,
information on the risks related to MS therapies during preg-
nancy and lactation is sorely lacking. The mainstay of treat-
ment for acute MS relapses is corticosteroids or, rarely, other
immunomodulatory treatments. Corticosteroids are used
symptomatically to lessen the severity and hasten recovery from
acute neurologic symptoms, but they do not seem to alter the
course of the disease. In 1993, the first disease-modifying agent
(DMA), interferon-β, was introduced. Since then, a steady
increase has occurred in available DMAs. These therapies are
utilized to reduce relapse rates; decrease MRI progression,
one marker of MS disease activity; and lessen cumulative
disability in patients with MS. They are not used to treat
acute MS relapses. DMAs are divided into first-line and second-
line agents (Table 49-2). Second-line therapies are usually
 Chapter 49  Neurologic Disorders in Pregnancy 1043

TABLE 49-2 DISEASE-MODIFYING AGENTS FOR MULTIPLE SCLEROSIS: TERATOGENIC RISK AND RECOMMENDED
WASHOUT PERIOD
DISEASE
MODIFYING AGENT ANIMAL STUDIES HUMAN STUDIES RECOMMENDED WASHOUT
First-Line Disease-Modifying Agents
Glatiramer acetate No concerns raised No concerns, although studies were small 1 month
Interferon-β Increased spontaneous abortion No changes in rates of conception, 1 month
spontaneous abortion, or MCM; may be
associated with preterm birth and
decreased birthweight and length
BG-12/dimethyl fumarate Embryo toxicity, spontaneous No increased risk of MCM or spontaneous 1 month
abortion, neurobehavioral issues abortion in 69 pregnancies
Fingolimod Embryolethality and fetal In humans, spontaneous abortion rate 24% 2 months
malformations (ventricular (slightly increased from baseline) in 89
septal defect, persistent truncus pregnancies; “abnormal fetal
arteriosus) development” also noted in 7.6%
Teriflunomide Embryotoxic and teratogenic No increased risk of spontaneous abortion 24 months; “washout protocol”
effects or MCM in 83 pregnancies where recommended to achieve plasma
mother was exposed concentrations less than 0.02 mg/mL
Second-Line Disease-Modifying Agents
Natalizumab Increased risk of spontaneous No increased risk of MCM in 101 2 to 3 months, although some advise
abortion pregnancies; hematologic issues in infants continuation to conception
exposed in third trimester
Alemtuzumab Increased risk of fetal death Limited data, no increased risk of 4 months
spontaneous abortion in 134 pregnancies
Mitoxantrone Limited data Decreased weight, increased prematurity 6 months; consider fertility preservation
(may cause amenorrhea)
MCM, major congenital malformation; MS, multiple sclerosis.

reserved for patients who have failed a first-line agent and those
who have very active disease.
Given that few data are available on the safety of DMAs
in pregnancy and the fact that MS attacks are usually less
frequent in pregnancy, most experts recommend stopping
DMAs prior to conception. Highly effective contraception is
also recommended for women who utilize these therapies. It is
worth noting that many of the observational reports of MS,
including the prospective PRIMS study, took place before
DMAs were available. Since then, a few studies have suggested
that use of DMAs prior to conception or during gestation
decreases the risk for postpartum relapses.118,126,127 Postpartum
relapse rates are also lower in patients whose MS activity had
been well controlled in the year prior to pregnancy.126,128 Decid-
ing which DMA is best for a woman with MS who is of repro-
ductive age, as well as the appropriate time to stop the drug and
contraception when trying to conceive, is a complex decision
based on the patient’s disease burden, the specific drug she is
taking, and her personal concerns. These decisions should be
made in consultation with her treating neurologist. Available
information on the various DMAs available are summarized
below and in Table 49-2.
First-Line Agents
First-line DMAs include interferon-β, glatiramer acetate,
dimethyl fumarate, and teriflunomide. The Food and Drug
Administration (FDA) also considers fingolimod a first-line drug
for the treatment of MS, although the European Medicine
Agency (EMA) does not. Of the first-line therapies, experts
agree that interferon-β and glatiramer acetate can be contin-
ued up to the time that contraception is stopped. Some have
suggested that they can even be continued until a pregnancy
is confirmed.118 In some rare cases, glatiramer acetate is contin-
ued during pregnancy.
Interferon-β formulations (interferon beta-1a and interferon
beta-1b) are subcutaneous or intramuscular (IM) injections used
at intervals that range from daily to every other week based on
the formulation. These were among the first DMAs introduced
for the treatment of MS, yet a relative paucity of information
remains concerning the use of interferon-β therapy in preg-
nancy. However, lately, the number of available studies on this
topic has increased.
Of note, interferons are large molecules that must be trans-
ferred across the placenta by active transport, and this process
likely does not occur until after the first trimester.129 Animal
studies had suggested an increased risk of spontaneous abortions
with interferon-β exposure; however, this has not held up in
observational human studies. Sandberg-Wollheim and col-
leagues130 dissected data on 1022 cases of interferon beta-1a
exposure during pregnancy. To avoid bias, they only included
outcomes for prospective data (n = 425) and found 324 normal
infants were delivered at term (76.2%), 4 infants were born with
malformations (0.9%), 4 third-trimester stillbirths occurred
(0.9%, 1 with anomalies), along with 5 ectopic pregnancies
(1.2%), 49 (11.5%) first-trimester spontaneous abortions, and
39 (9.2%) elective abortions. The authors reported that these
results are not dissimilar to the general population, but no
control group was included. Amato and colleagues131 investi-
gated first-trimester exposure to interferon β-1a or -1b. They
compared these patients with those who were never treated or
who discontinued treatment at least 4 weeks before conception.
Of the 88 exposed fetuses, no increase was found in spontaneous
abortion, malformations, or developmental abnormalities over a
median follow-up of 2.1 years, although the incidence of low
birthweight was increased and infants were shorter at birth. In
a systematic review of reports of DMA exposure in preg-
nancy, Lu and colleagues132 summarized that prospective
cohort studies of fair to good quality have found that

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1044 Section VI  Pregnancy and Coexisting Disease
interferon-β exposure may be associated with preterm deliv-
ery (before 37 weeks), as well as lower weight and length at
birth, but did not find an association between interferon
exposure and birthweight below 2500 g, major malforma-
tions, or spontaneous abortion. Recently, the manufacturers
of interferon β-1b released information on the largest prospec-
tive cohort of pregnancies exposed to this interferon from their
international pharmacovigilance database.133 Among 1045 preg-
nancies, no increased risk of spontaneous abortions or major
anomalies was reported compared with expected population
rates. They also detected no change in preterm birth or SGA
infants. It should be noted that the majority of patients in these
studies had limited exposure to interferon-β (average of 4 to 8
weeks), and no conclusions can be reached about exposure
throughout pregnancy or long-term effects.
Glatiramer acetate is also used to treat frequent relapses in
those with relapsing remitting MS. It is a large macromolecule
that likely does not pass the placenta.129 Preclinical studies did
not demonstrate adverse effects of glatiramer acetate on off-
spring of exposed animals, and thus it received a class B designa-
tion from the FDA. Studies of glatiramer acetate in pregnancy
are based on small cohorts, but two studies have evaluated
women exposed to the drug throughout pregnancy. Salminen
and coworkers134 prospectively followed 13 women exposed to
glatiramer from preconception through pregnancy and the post-
partum period and found no congenital anomalies, and the
treatment was well tolerated. Fragoso and colleagues135 retro-
spectively evaluated 11 women who used glatiramer continu-
ously for at least 7 months during pregnancy. Children were
followed for at least 1 year after birth. No congenital anomalies,
neonatal complications, or developmental abnormalities were
seen in the children. Postnatal MS relapse rates remained sig-
nificantly lower than antenatal rates in these women.135 Although
data are significantly limited by the small sample sizes, most
experts feel that glatiramer acetate is the DMA of choice if
one must be used during pregnancy, although the patient’s
history of response to this drug must also be considered.
Dimethyl fumarate, teriflunomide, and fingolimod are oral
agents that have been recently introduced and have been shown
to reduce relapse rates, as well as disability scores, in patients
with MS. They are popular given that they are oral formulations.
Animal studies have raised concern for embryolethality and tera-
togenicity of these medications, and clinical experience with
these drugs in human pregnancy is limited to accidental expo-
sures in clinical trials and postmarketing surveillance. It is rec-
ommended that effective contraception be used with each of
these drugs and that they not be continued in pregnancy. In
addition, given the long-term effects and half-lives of some of
these oral agents, it is recommended that they be stopped prior
to discontinuation of contraception (see Table 49-2). A special
“washout” protocol is advised for teriflunomide.
In animal studies of dimethyl fumarate, an increased risk of
spontaneous abortion and adverse fetal outcome (decreased fetal
weight and delayed ossification) were seen at supratherapeutic
doses and were thought to be due to maternal toxicity.136 Neu-
rodevelopmental effects were observed in animals at all doses
tested. No increased risk of spontaneous abortion or fetal abnor-
malities was noted in 69 reports of human pregnancies exposed
to dimethyl fumarate in clinical trials or postmarketing
surveillance.137
Teriflunomide has been associated with embryotoxicity and
teratogenicity in animals.138 In 83 pregnancies of women with
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MS and 22 pregnancies of partners of men with MS taking teri-
flunomide, the risks of spontaneous abortions or fetal abnor-
malities were not increased.139 Because of the concern of
teratogenesis, as well as the long half-life of teriflunomide, con-
traception is recommended during and after treatment. A
“washout” protocol with activated charcoal or cholestyramine is
recommended for women who plan to conceive and for those
who become pregnant while taking the drug. In a systematic
review, an international multidisciplinary consortium recom-
mended that for teriflunomide, “Conception should be tied to
plasma concentration levels less than 0.02 mg/mL rather
than to the 5 maximal half-lives algorithm for exponential
decay.”140 Because teriflunomide is also present in the sperm of
men who take the drug, a similar protocol is recommended for
men planning to conceive.
Animal studies of fingolimod have demonstrated embryo­
lethality and teratogenic effects with doses lower than those
recommended in humans.141 In a report of 89 pregnancies that
occurred during the clinical studies of the drug, the rate of spon-
taneous abortions was 24% (slightly higher than the expected
baseline rate of 15% to 20% according to the authors), and
five cases of “abnormal fetal development” were reported that
included one case of each of acrania, bowing of the tibia, tetralogy
of Fallot, intrauterine death, and failure of fetal development.142
Second-Line Agents
Natalizumab is a humanized monoclonal immunoglobulin (Ig)
G4 antibody to human α4 integrin that works against many
processes involved in human development. However, it is a large
molecule that should not cross the placenta. Wehner and col-
leagues143 set out to examine postnatal development in monkeys
exposed to this medication. In the first cohort of monkeys, an
increase in spontaneous abortions occurred. However, the rate
in the control group was low (7%). In the second cohort studied,
the spontaneous abortion rates were equivalent in both groups.
These researchers found no adverse effects on the general health,
survival, development, or immunologic structure or function of
the newborn monkeys whose mothers were treated with natali-
zumab. Ebrahimi and colleagues144 reported on 101 pregnancies
in patients who received natalizumab during pregnancy or up
to 8 weeks before the last menstrual period. The patients were
ascertained from a prospective registry of MS patients and were
paired with disease-matched controls. The authors found no
significant difference in the presence of malformations, low
birthweight, or preterm birth between the two groups. In a case
series of 13 pregnancies in 12 women with highly active MS
who were treated with natalizumab in the third trimester,
Haghikia and colleagues145 reported mild to moderate hemato-
logic abnormalities, including thrombocytopenia and anemia,
in 10 of 13 infants. In most children, the abnormalities resolved
without consequence within 4 months of delivery. One child
had subclinical bleeding and another was born with a cystic
abnormality in the thalamic region thought to be due to prior
hemorrhage, although no developmental consequences were
obvious at 2 years of age. No consensus has been reached on
when to stop natalizumab prior to conception. Some experts
recommend, based on the above data, that the drug can be
continued up to the time of conception, checking pregnancy
tests before each infusion.118 Others believe waiting 1 to 3
months before conceiving is appropriate.129 The antibody can be
removed from the blood with a series of plasma exchanges, but
this is rarely thought to be necessary.
 Chapter 49  Neurologic Disorders in Pregnancy
Alemtuzumab is another humanized monoclonal antibody
approved as a second-line drug for MS in 2013. It is directed
against CD52 and causes a long-lasting depletion of lympho-
cytes. It is given as a yearly infusion and can be complicated by
immune-mediated thyroid disease in one third of patients.
Animal exposure to alemtuzumab during gestation increased the
risk of fetal death in rodents.138 Limited data are available in
humans. In the only clinical abstract,146 139 pregnancies in 104
patients were reported. The rate of spontaneous abortion was
17%, which the authors stated was comparable to that of the
general population. Eleven adverse events without a clear pattern
were also reported, along with one case of thyrotoxic crisis.
Contraception is therefore recommended for 4 months after
discontinuing alemtuzumab.138
Mitoxantrone is a second-line agent for the treatment of
MS, and cyclophosphamide is occasionally used for severe
cases. Both treatments can cause amenorrhea in one third of
patients, and cyclophosphamide is associated with ovarian
toxicity.138 In animals, cyclophosphamide has been shown to
cause genetic abnormalities in female germ cells; however, very
little is known about the effects of mitoxantrone and cyclophos-
phamide during pregnancy. The risks of both are felt to outweigh
potential benefits of both in pregnancy. It is recommended that
contraception be continued for 6 months after mitoxantrone
and 3 months after cyclophosphamide have been stopped.
Prepregnancy Counseling for Patients
With Multiple Sclerosis
Women with MS should be counseled about reproductive
choices at the time of diagnosis and before starting a DMA. The
topic should also be revisited regularly. Patients should be reas-
sured that the vast majority of women with MS can have
healthy pregnancies and that MS in the mother does not pose
an adverse risk to the fetus. Additionally, they should be told
that pregnancy will likely reduce the risk of MS flares temporar-
ily, and although they may worsen in some women in the
postpartum period, pregnancy likely does not have any adverse
effect on long-term disease course. The decision of whether to
start a DMA and which DMA to start depends on the patient’s
disease burden and timeline for conception.
Timing of conception is very important for a woman with
MS, given that disease burden prior to conception may affect
the course of the pregnancy. For a woman with very active
disease, a neurologist might recommend treatment with a DMA
for 1 year to obtain better disease control before conception.
Of course, given uncertainties around ovarian function in
women with MS, the patient’s age and an assessment of fertility
may also be considered. Women who require treatment with
drugs such as cyclophosphamide or mitoxantrone may want to
consider fertility preservation prior to beginning treatment.
Women should be counseled on the recommended timeline to
continue contraception following discontinuation of a DMA
(see Table 49-2).
Some women with MS may be concerned about the risk of
passing the disease on to their children. MS is a polygenic dis-
order and combined effects of genetic susceptibility and environ-
ment determines an individual’s risk. The risk of developing
MS in a child with a single parent with MS is 2% to 2.5%.147
Whereas this is a twentyfold increase from the baseline popula-
tion risk, the absolute likelihood that a mother will pass MS on
to her child is still very low and usually is not a reason to avoid
pregnancy.118
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1045
Women with MS should also receive general prenatal coun-
seling that includes stressing the importance of supplementa-
tion with a prenatal vitamin. Vitamin D deficiency is gaining
more attention as an environmental factor that affects suscepti-
bility to MS and MS relapses. Vitamin D deficiency in a mother
may also affect her child’s subsequent risk of developing MS. In
a small open-label trial, pregnant women with MS and low
vitamin D levels were randomized to 50,000 IU of vitamin D3
a week, starting at weeks 12 to 16 of gestation, or routine care.148
The group of six who received “high-dose” vitamin D had
normal postpartum levels of vitamin D, whereas the nine
patients who received routine care did not. No adverse effects
of supplementation were reported during pregnancy or 6 months
postpartum, although no conclusions can be made about long-
term fetal effects. Patients who received the high-dose vitamin
D appeared to do better in terms of EDSS and relapse rate, but
these data are limited by the small sample size and open-label
methodology. The optimal dose of vitamin D in pregnancy is
not known, but a consortium of experts recommended that
1000 to 2000 IU daily should be safe.140 Ideally, the vitamin D
level should be checked and optimized before pregnancy, and a
dose of 1000 to 2000 IU can be continued in pregnancy.
Management of Multiple Sclerosis
During Pregnancy
No specific changes in routine obstetric care are recom-
mended for women with MS. Women with disturbances in
bladder function may be more prone to urinary tract infections
and need to be monitored more frequently. Urinalysis and
culture should be checked in the setting of new or worsening
symptoms because infections can often exacerbate the presenta-
tion of MS.
If an acute and severe MS relapse occurs during pregnancy,
treatment with corticosteroids may hasten recovery. The typical
regimen is 1 g of methylprednisolone daily for 3 to 7 days,
which can be given intravenously or orally; no oral taper is used.
Methylprednisolone or the equivalent dose of prednisolone and
prednisone are recommended if steroids are needed because less
than 10% of these steroids pass across the placenta. When pos-
sible, it is recommended that steroid use be minimized in preg-
nancy, and ideally, it should be avoided in the first trimester.
Safety information on the fetal effects of steroids is limited but
some older studies associated steroid exposure with an increased
risk of cleft lip and palate (see Chapter 8).140 Questions were
also raised by studies that suggested low birthweight and prema-
ture delivery as a result of steroid use. IV immunoglobulin
(IVIG) can be used as an alternative to steroids or when steroids
fail, but safety data on IVIG is also limited.140 Monthly IVIG
or steroids can also be considered for women with active disease
during pregnancy to decrease the risk of relapses.
Labor and Delivery
In the past, anesthesiologists had been concerned that epidural
analgesia might somehow worsen the disease or promote relapses.
In both the PRIMS study116,117 and a large Italian cohort,149 only
18% to 19% of women with MS received epidural analgesia. In
the PRIMS study, a trend was seen toward a higher relapse rate
in the first 3 months postpartum in women who received epi-
durals, but this effect did not reach statistical significance. In
the Italian study by Pastò and colleagues,149 no increase was
seen in relapse rate or EDSS score 1 year after delivery in
women with MS who had received epidural anesthesia.
1046 Section VI  Pregnancy and Coexisting Disease

Perceptions of the risk of anesthesia may have changed. A more onset of action of these first-line therapies is delayed, typically
recent population-based study performed in Canada found that by 2 months, and even if they are started immediately postpar-
nulliparous women with MS received epidural or spinal anes- tum, they may not provide protection from relapses in the
thesia at a rate similar to that of the general population. However, immediate postpartum period. Pulse doses of IVIG155-157 or
multiparous women with MS were more likely to receive epidu- methylprednisolone158 have been tried to prevent relapses in the
ral analgesia.150 postpartum period, but differing results and methodologic limi-
Cesarean delivery is usually not indicated in women with tations make it difficult to draw firm conclusions about the
MS. Only in rare cases of severe or active disease that affects the benefit of this approach.118
spinal cord may MS affect a patient’s ability to labor safely. Postpartum, women with MS will often need help with their
Across five studies assessed in a recent meta-analysis, cesarean own care and the care of their infant. This depends greatly on
delivery rates varied from 9.6% to 42%,119 which likely reflects the patient’s level of disability and whether she experiences a
the variability of practice among different cultures and practi- relapse. For all patients who are pregnant or considering preg-
tioners. Pastò and colleagues149 found no association between nancy, it is helpful to discuss the need for support from friends
cesarean delivery and relapse rate or disability scores in Italian and family members in the postpartum period as well as to
women with MS. prepare a contingency plan for infant care in the event of a
disabling MS relapse.
Breastfeeding and the Postpartum Period
Breastfeeding in women with MS is a controversial and
actively debated topic. Some studies have suggested that breast- HEADACHE
feeding has a protective effect on MS relapses, whereas others Headache disorders can be divided into two classes, primary and
report no effect on disease activity. The PRIMS study found secondary. Primary headache disorders include migraine and
that breastfeeding had no effect on the rate of MS relapses tension-type headaches as well as cluster headaches, although the
in the first 3 months postpartum.116,117 A more recent study of latter are rare in women. Both migraine and tension-type head-
302 pregnant women with MS treated at Italian MS centers also aches improve in pregnancy, although some may persist. The
found no effect of breastfeeding on disease activity. The authors biggest challenge in evaluating headache is to rule out secondary
noted that breastfeeding may not be possible for women headache disorders (Fig. 49-2), which are symptomatic of under-
with high disease burden.128 Other studies have suggested, how­ lying and potentially deleterious pathologies. Most patients with
ever, that breastfeeding—particularly exclusive breastfeeding— primary headaches such as migraine have a prior history of a
may reduce the likelihood of MS relapses in the postpartum similar headache pattern. Any new symptoms or headache
period.151,152 A 2012 meta-analysis of 12 studies of MS and pattern and all new-onset headaches, even if they have a migrain-
breastfeeding found that women who did not breastfeed were ous quality, should prompt evaluation for underlying causes. It
nearly twice as likely to have at least one relapse in the postpar- is also important to be aware of the appropriate treatments for
tum period.153 This result was significant but was limited by the these conditions.
variability of the studies available. The authors cautioned that it
is not possible to completely control for the possibility that Migraine
women with more benign disease may also be more likely to Headaches are extremely common in women, and the majority
breastfeed. of migraine headaches occur in women of childbearing age.
The decision to breastfeed is made more complicated by a Migraines are associated with vasodilation of the cerebral
woman or her doctor’s desire for her to resume DMAs. Most
experts state that DMAs should not be resumed while a
woman is breastfeeding.118,129,138 However, this recommenda- Headache
tion is based on a lack of evidence about the safety of these
drugs in breastfeeding rather than evidence of harm. Unfor-
tunately, this conservative approach will likely prevent the ability
Subacute Chronic
to gather important data on the safety of some of these therapies Acute
persistent intermittent
during breastfeeding, as has been done with AEDs, and may
make patients more reluctant to breastfeed.
Both interferons and glatiramer acetate are large molecules Subarachnoid
Cerebral
that are not orally bioavailable. It is unlikely that they pass into venous Migraine
hemorrhage
thrombosis
breastmilk, although this has not been studied systematically.
Interferon β-1a transfer into breastmilk was assessed in six Stroke/ Idiopathic
women, and the relative infant dose was estimated at 0.006%. Tension
intracerebral intracranial
headache
No adverse effects were noted in the infants who were exposed hemorrhage hypertension
through breastmilk.154 In another small study of glatiramer
acetate and breastfeeding, no problems were noted in nine Medication
Pituitary Cluster
overuse
infants exposed through breastmilk for an average of 3.6 apoplexy
headache
headache
months.135 Nevertheless, official recommendations continue
to state that all DMAs should be held in women who plan to Reversible
Eclampsia/
breastfeed, and thus most women must make a choice between cerebral
PRES
breastfeeding and resuming a DMA. A minority of physicians vasconstriction
are comfortable with patients breastfeeding while taking glat- FIG 49-2  Differential diagnosis of headaches in pregnancy. PRES, pos-
iramer acetate.129 It is important to note, however, that the terior reversible encephalopathy syndrome.

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 Chapter 49  Neurologic Disorders in Pregnancy 1047

vasculature and typically last several hours. Onset is usually
subacute and the headache is often unilateral and pounding and
is often accompanied by photosensitivity and/or phonosensitiv-
ity and nausea. Migraines can be classified as those with aura
and those without. Migraines with aura are characterized by
reversible focal neurologic symptoms that occur before the
headache. Visual auras are common, but aphasia or unilateral
numbness or weakness may also occur, which sometimes makes
such headaches difficult to distinguish from transient ischemic
attacks. The migraine aura should be fully reversible in 5 to
60 minutes, and sometimes the aura can occur without a
headache.
Migraine symptoms tend to improve during pregnancy.
Maggioni and colleagues159 found that 80% of patients experi-
enced either complete remission or a 50% reduction in head-
aches during pregnancy. Improvement was more common after
the first trimester. Migraine type does not seem to be a prog-
nostic factor. Those with menstrual (catamenial) migraines had
the most improvement. However, 4% to 8% show significant
worsening during pregnancy. In a study by Ertresvåg and col-
leagues,160 58% of subjects with migraine reported having no
headache during pregnancy. Transient neurologic symptoms
were more common in patients with a history of migraine. Chen
and Leviton161 examined data from the large, prospective Col-
laborative Perinatal Project of 55,000 pregnancies. They found
that less than 2% of women in the sample were considered to
have migraines at their initial prenatal visit. Of the 484 (of 508)
women with a complete data set, 17% experienced complete
cessation of headache throughout pregnancy, and an additional
62% had two or fewer headaches in the third trimester. Only
21% of these women had no improvement in their headache.
The authors examined all available demographic and pregnancy
factors and could find none that could be used to predict head-
ache improvement during pregnancy.
Using a nationwide population-based database in Taiwan,
Chen and colleagues162 identified 4911 women with migraines
who delivered from 2001 to 2003. After adjusting for confound-
ers, they found an increased risk for low birthweight (OR, 1.16),
preterm birth (OR, 1.24), cesarean delivery (OR, 1.16), and pre-
eclampsia (OR, 1.34). Although these increases were not large,
they were all statistically significant.162 More research needs to
be undertaken to determine whether these increases apply to
different populations and if they are clinically significant.
Migraine treatment is divided into abortive and prophylactic
treatments (Tables 49-3 and 49-4). Given the anticipated
improvement of migraines during pregnancy, most women do

TABLE 49-3 ABORTIVE TREATMENTS FOR PRIMARY HEADACHES IN PREGNANCY

BEST STUDIED/ BREASTFEEDING
RECOMMENDED MALFORMATION RISK OTHER COMMENTS COMPATIBLE
Preferred
Nonpharmacologic Hydration, sleep, NA Yes
measures caffeine
Acetaminophen Acetaminophen No known associations with Recent concerns over associations with Yes
MCMs have been reported. behavioral abnormalities* and
asthma† have been raised, but more
research is needed.
NSAIDs Ibuprofen Possible associations were found NSAIDs must be avoided in the third Yes
with cardiac anomalies and oral trimester because of increased risk
clefts, but studies vary. of premature PDA closure and
oligohydramnios; an association
with asthma in children was
recently reported, but more
research is needed.†
Antiemetics Metoclopramide No association was found with A risk of tardive dyskinesia is present Yes
MCMs in limited studies. for the mother.
Less Preferred
Triptans Sumatriptan Data from case series suggest no Effects on later pregnancy have not Yes
increased risk of MCMs, but been well studied.
these were usually cases of
inadvertent first-trimester use.
Opiates Oxycodone Recent study links first-trimester Typically ineffective for migraine, Yes, but monitor infant for
opiates to increased risk of these agents can create dependence; sedation
certain MCMs, including heart neonatal withdrawal has also been
defects and spina bifida.‡ noted with use near term.
Avoid if Possible
Barbiturates Butalbital No data are available on butalbital Based on phenobarbital data, concern Not recommended because
in animals or humans, but exists for cognitive effects of of the long half-life and
extrapolating from butalbital exposure; risk of potential for sedation
phenobarbital data, an increased neonatal withdrawal is present with
risk of MCMs is likely. use near term.
Ergots Dihydroergotamine Data are limited. Ergots cause vasoconstriction of Not recommended because
Erogtamine uterine vessels and are potentially of nausea, vomiting, and
abortifacient; therefore use is weakness in the infant
contraindicated in pregnancy. and suppression of
prolactin in the mother.
*
Sordillo JE, Scirica CV, Rifas-Shiman SL, et al. Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. J Allergy Clin Immunol.
2015;135(2):441-448.
†
Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204(4):314.e1.
‡Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320.
MCM, major congenital malformation; N/A, not applicable; NSAID, nonsteroidal antiinflammatory drug; PDA, patent ductus arteriosus.

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1048 Section VI  Pregnancy and Coexisting Disease

TABLE 49-4 PROPHYLACTIC TREATMENTS FOR PRIMARY HEADACHE DISORDERS IN PREGNANCY

BEST STUDIED/ BREASTFEEDING
RECOMMENDED MALFORMATION RISK OTHER COMMENTS COMPATIBLE
Preferred
Nonpharmacologic Stress reduction No known association Many chronic migraneurs will not need Yes
measures Acupuncture any prophylactic migraine medications
Physical therapy in pregnancy
Magnesium Magnesium sulfate Limited data The FDA recommends upper limit of Yes
350 mg/day; may decrease risk of
eclampsia, but may have GI side
effects
Coenzyme Q10 Coenzyme Q10 Limited data May decrease risk of preeclampsia in Probably
Not recommended for use migraneurs when given after 20 weeks
prior to 20 weeks’ gestation
Less Preferred
β-Blockers Propranolol Limited data Possible fetal bradycardia, hypoglycemia, Yes
Metoprolol Possible intrauterine growth respiratory depression; stop 2 to 3 Propranolol seems to pose low
restriction days before delivery to avoid fetal risk
bradycardia and impairment of
uterine contractions
Tricyclic Amitriptyline Limited data; possible limb Drug of choice for tension-type headache Probably
antidepressants deformities, CNS effects prophylaxis in pregnancy, if needed Low levels are found in breast
with higher doses, but milk
none noted in range of 10
to 50 mg/day
Calcium channel Verapamil Limited data on high doses in Drug of choice for cluster headache Probably
blockers pregnancy prophylaxis in pregnancy if needed; Maternal doses up to
monitor maternal ECG for heart 360 mg/day are used
block every 6 months or with dose without adverse effect
changes; consider increased fetal
monitoring
Avoid if Possible
Topiramate Topiramate Increased risk of MCM, Increased risk for SGA infants, possible Possibly compatible but not
especially oral clefts cognitive effects on infant though not well studied
well studied If used, monitor infant for
metabolic acidosis,
lethargy, and overheating
Valproic acid Valproic acid Substantially increased risk of Increased risk of adverse cognitive Yes
MCMs including spina outcomes such as lower IQ and
bifida autism; contraindicated in pregnancy
for treatment of migraine
Lithium Lithium Associated with fetal cardiac Not indicated for the treatment of Possibly compatible, but
anomalies as well as migraine; used for cluster headache; caution is advised because
polyhydramnios, cardiac contraindicated for headache of hypotonia and ECG
arrhythmias, hypoglycemia, treatment in pregnancy; associated changes in infant; lithium
diabetes insipidus, and with neonatal withdrawal can be considered in
thyroid abnormalities closely monitored patients
CNS, central nervous system; ECG, electrocardiogram; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; IQ, intelligence quotient; MCM, major congenital malformation;
SGA, small for gestational age.

not need to take prophylactic treatment, and such treatment
is usually weaned prior to conception. Nonpharmacologic mea-
sures such as sleep, hydration, and relaxation techniques are the
first-line treatment for migraines during gestation. For drug
therapy, acetaminophen is initially recommended. Ibuprofen
can be used in the first and second trimester, but the use of
nonsteroidal antiinflammatory drugs (NSAIDs) should be
avoided if possible after 24 weeks’ gestation. When used for
more than 48 hours, these agents can cause oligohydramnios
and premature closure of the ductus arteriosus. Although opiates
are often prescribed during pregnancy, these are actually not
preferred for migraine treatment because they are typically inef-
fective, increase nausea, and decrease gastric motility. Antiemetic
therapy may be helpful, but barbiturates should be avoided if
possible.
Sumatriptan, a serotonin receptor agonist, is very successful
in treating migraines acutely. In a review by O’Quinn and col-
leagues,163 no untoward effects were reported in 76 first-trimester
exposures to sumatriptan. Using logistic regression, Olesen and
colleagues164 compared 34 pregnancies with sumatriptan expo-
sures with 89 migraine controls and 15,995 healthy women.
They found that the risk of preterm birth was elevated with
exposure (OR, 6.3) as was the risk of IUGR.164 They do state
that they did not control for disease severity. A larger study by
Källén and Lygner165 did not confirm these findings. In 658
infants whose mothers used sumatriptan during pregnancy,
no significant difference in prematurity or low birthweight
was noted.165 Hilaire and colleagues166 found birth defects in
3% to 5% of infants exposed to sumatriptan in the first trimes-
ter, a rate not greater than expected.
Recent studies have demonstrated that sumatriptan can be
used during pregnancy. In a large Norwegian database, no
increase in congenital anomalies or other adverse pregnancy
outcomes was reported. However, increases were seen in intra-
partum bleeding (OR, 1.5) and uterine atony (OR, 1.4). Ephross
and Sinclair167 reviewed 528 first-trimester exposures to

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 Chapter 49  Neurologic Disorders in Pregnancy
sumatriptan and 57 to naratriptan and observed an anomaly rate
similar to that of the background population; however, this
study had no control group. Evans and Lorber described all
available studies from 1990 through 2007 and also contacted
the manufacturers of seven triptan medications; they concluded
that data are sufficient to recommend the use of sumatriptan
for treatment of migraine in the first trimester and also feel
that naratriptan and rizatriptan are probably safe. Although
these medications are acceptable for use in the second and third
trimesters, little information is available regarding their use in
late pregnancy. Soldin and colleagues168 confirm these find-
ings and also stress that sumatriptan should be the triptan
of choice because more data are available concerning its use
in pregnancy.
Ergotamine should be avoided during pregnancy. Previous
reports have suggested that it may cause birth defects that have
a vascular disruptive etiology. In addition, ergots are uterotonic
and have an abortifacient potential.
Dietary factors may precipitate migraine attacks. Therefore
careful history may uncover foods that should be avoided,
including foods that contain monosodium glutamate (MSG),
red wine, cured meats, and strong cheeses that contain tyramine.
Relative hypoglycemia and alcohol can also trigger migraine
attacks. Many individuals have recommended, without support-
ing evidence, dietary supplements and vitamins for migraine
prevention. In a small study, Maizels and colleagues169 demon-
strated a possible role for riboflavin and magnesium in the
prevention of migraines.
Secondary Headache in Pregnancy
Headaches during pregnancy can be a symptom of underly-
ing intracranial pathology. Concerning causes of secondary
headache in pregnancy include idiopathic intracranial hyperten-
sion, cerebral venous thrombosis (CVT), subarachnoid hemor-
rhage, and stroke. Symptoms that should prompt further
evaluation include abrupt onset of symptoms, persistent
headache, and positional component. Any associated focal
neurologic signs or vision changes should also prompt addi-
tional investigation unless they are a typical part of a patient’s
migraine aura. Patients with primary headache disorders can
get secondary headaches, so any change in pattern or new
symptoms should also be considered evidence of a possible
underlying problem.
Idiopathic Intracranial Hypertension
(Pseudotumor Cerebri)
Idiopathic intracranial hypertension (IIH) may complicate 2%
to 12% of pregnancies.170 It had been thought to occur more
frequently in pregnant women, particularly those who are obese.
However, in a study by Ireland and colleagues,171 the incidence
in pregnant women and in oral contraceptive users was no
higher than that in control groups. The headache of IIH is
usually subacute in onset and is present daily. It may be aggra-
vated by lying down and may be worse in the morning. However,
the positional component is not always typical. More than
90% of patients with IIH have headaches, and 40% have
horizontal diplopia.170 Patients with IIH may also report tran-
sient visual obscurations that last less than one minute and may
also report pulsatile tinnitus. Papilledema is a characteristic
feature of the condition and is present in the majority of
cases. If left untreated, IIH can progress to permanent visual
loss. To establish the diagnosis, other causes of intracranial
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1049
hypertension must be excluded, such as an intracranial mass or
CVT, and elevated cerebrospinal fluid (CSF) pressure (>250 mm
H20) with normal CSF composition must be demonstrated.172
MRI and magnetic resonance venogram (MRV) of the brain
without contrast are the imaging modalities of choice and must
be performed before a lumbar puncture to avoid herniation in
the setting of a mass lesion. The pathogenesis of this disorder
is unknown, but CSF prolactin is markedly elevated. Prolactin
appears to have an affinity for receptors in the choroid plexus,
where CSF is produced. Prolactin has osmoregulatory functions
and therefore may have a role in the increased CSF production
found in IIH, although some believe that reduced CSF reabsorp-
tion is the etiology. Pregnancy outcome appears to be unaf-
fected by IIH,172 and no increase in fetal wastage or congenital
anomalies are reported.
The main objectives of treatment for IIH are relief of pain
and preservation of vision. The patient should be followed
closely with visual acuity and visual field determinations at inter-
vals indicated by the clinical condition. In patients with mild
disease, analgesics and close follow-up may be adequate. Moder-
ate weight loss is recommended. For patients without improve-
ment or those at risk for visual deterioration, acetazolamide—a
carbonic anhydrase inhibitor that reduces CSF production—is
the first-line treatment. Lee and colleagues173 treated 12 patients
with acetazolamide during pregnancy and reported no adverse
fetal outcomes. They reviewed the English language literature
and found nothing to contradict this assertion. The usual dose
of acetazolamide is 500 mg twice daily. Steroids are rarely used
for IIH; they are reserved for cases with impending vision loss
in patients awaiting a surgical intervention. Serial lumbar punc-
tures to reduce CSF pressure are rarely necessary but can effec-
tively lower intracranial pressure transiently. Surgical approaches
are reserved for refractory patients in whom rapid visual deterio-
ration occurs. The two most common procedures are optic nerve
sheath fenestration and lumboperitoneal or ventriculoperitoneal
shunt.
IIH is not usually an indication for cesarean delivery. A
review of the literature reveals that 73% of the reported patients
delivered vaginally. Although no data are available to confirm
this, the Valsalva maneuver—which can increase CSF pressure—
should be minimized when possible. Therefore the second stage
of labor should be shortened by operative vaginal delivery if
possible. Both epidural and spinal anesthesia, when expertly
administered, can be safely used in patients with IIH.
However, in patients with lumboperitoneal shunts, the anes-
thetic should be directed away from the spinal canal. Month and
Vaida174 reported a successful spinal epidural technique during
which 5 to 6 mL of CSF withdrawn at the time of analgesia
provided additional relief.
Cerebral Vein Thrombosis
In patients with cerebral venous thrombosis (CVT), the chief
symptoms are similar to those of IIH because the initial mani-
festations are due to increased intracranial pressure. Patients
typically present with a subacute, progressive, unremitting
headache that may be worse when lying down. As in IIH,
patients may have diplopia and pulsatile tinnitus. Patients with
CVT may also demonstrate papilledema. CVT can be compli-
cated by a venous infarction with or without bleeding, which
often leads to focal neurologic deficits and seizures. Severe head-
ache with vomiting can be seen and should raise concern for
acute worsening, such as associated stroke or hemorrhage. CVT
1050 Section VI  Pregnancy and Coexisting Disease
occurs most frequently during the immediate postpartum period
but can occur at any stage of pregnancy. It is often attributed to
a hypercoagulable state. An incidence of 1 in 10,000 pregnancies
was suggested in one study.175 Vora and colleagues176 reviewed
37,420 pregnancies in a Mumbai, India hospital between 2002
and 2006 and found a 0.1% incidence of thrombotic phenom-
ena. Of these, 10% were documented cortical vein thromboses,
confirming the incidence of 1 in 10,000 pregnancies.176 CVT
can be misdiagnosed as a postepidural headache, and this should
be considered in the differential diagnosis. When CVT has a
positional component, it should be worse lying and better stand-
ing, whereas a low-pressure headache often exhibits the reverse.
These patterns are not always observed in individual patients,
however; therefore CVT should be considered in the differential
of all postpartum headaches.
MRI and MRV of the brain are the diagnostic tests of
choice, and IV contrast is not needed to make the diagnosis.
Anticoagulation, typically with low-molecular-weight heparin
(LMWH), is the mainstay of treatment during pregnancy and
breastfeeding. Workup for underlying thrombophilias is indi-
cated to determine the duration of treatment. Prothrombin and
factor V Leiden mutations can be performed during pregnancy,
but other tests of hypercoagulability should be assessed 6 weeks
or more after delivery (see Chapter 45). Seizures can be treated
symptomatically with anticonvulsants, although little evidence
is available to suggest the appropriate duration of AED treat-
ment. Many neurologists and neurosurgeons advocate expectant
management and do not routinely use AEDs for these symp-
tomatic seizures. Women who have had a CVT during preg-
nancy should avoid hormonal contraception, and women
with a history of clotting while on hormonal contraception
should use prophylactic anticoagulation during pregnancy.
Subarachnoid Hemorrhage
Subarachnoid hemorrhage (SAH) usually manifests with a
sudden “thunderclap” headache that is often associated with
vomiting, stiff neck, and fluctuations of consciousness.
Patients often refer to it as the “worst headache of their life.”
This presentation is a medical emergency that necessitates an
emergency head CT scan, which is better than an MRI for
visualizing bleeding. Even if the CT scan is negative, a lumbar
puncture is indicated in patients with a suspicious history to
exclude intrathecal blood. Up to 50% of aneurysmal SAHs are
preceded by a “sentinel” bleed and a headache that should not
go undiagnosed. The rate of SAH complicating pregnancy is
approximately 1 per 10,400.177 Robinson and coworkers178 eval-
uated 26 patients with spontaneous SAH during pregnancy and
found that approximately half were caused by aneurysms and
half by arteriovenous (AV) malformations. They observed that
AV malformations are more common in patients younger than
25 years of age and usually bleed before 20 weeks’ gestation.
Conversely, aneurysms occurred in patients older than 30 years
of age and usually bled in the third trimester.
Cerebral angiography can be used to pinpoint the origin of
cerebral bleeding. SAH due to aneurysms should be treated
surgically whenever possible. In one study, SAH without early
surgery resulted in a maternal mortality of 63% and a fetal
mortality of 27%. With early surgery, the risk of mortality was
lowered to 11% and 5%, respectively.179 Surgery under hypo-
thermia or hypotension appears to cause no adverse fetal effects.
At an appropriate gestational age, the fetal heart rate should be
monitored during the procedure. If fetal bradycardia occurs, the
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patient’s blood pressure should be raised sufficiently to normalize
the fetal heart rate.
Reversible Cerebral Vasoconstriction
Reversible cerebral vasoconstriction syndrome (RCVS) can
present with a similar “thunderclap” headache. It may also
present with focal neurologic deficits, seizures, and fluctuat-
ing levels of consciousness. RCVS can be complicated by
stroke, nonaneurysmal SAH, and cerebral edema. Postpartum
angiopathy is a type of RCVS often seen in the immediate
postpartum period and is characterized by severe headaches with
reversible narrowing of the intracranial vessels. Diagnosis can
often be made by MRI and magnetic resonance angiography
(MRA) of the brain. Alternatively, computed tomographic angi-
ography (CTA) may be used for imaging or, rarely, an angiogram
is needed. Treatment with nimodipine appears to help the head-
aches.180 In a review of cerebrovascular disorders of pregnancy,
however, Feske and Singhal183 point out that postpartum angi-
opathy is on the same spectrum as eclampsia and posterior
reversible encephalopathy syndrome (PRES; see Chapter 31,
Figs. 31-13 and 31-14). Despite the lack of proteinuria in post-
partum angiopathy/RCVS, the similarities of imaging findings
suggest that they are likely mediated by the same pathologic
process. Thus the authors argue that magnesium sulfate infu-
sions similar to those used in eclampsia should be given to
women with postpartum angiopathy to control blood pressure
and seizures.
STROKE
Strokes can be divided into ischemic and hemorrhagic strokes.
Ischemic strokes are usually the result of an arterial occlusion
from cardioembolism and can also occur secondary to a CVT.
Arterial dissection is also a common cause of stroke in young
people and may be seen in pregnancy. Hemorrhagic strokes can
be secondary to a variety of causes and may occur from severe
hypertension alone or may be secondary to an underlying aneu-
rysm or vascular malformation. Ischemic strokes can also exhibit
hemorrhagic conversion. Preeclampsia and eclampsia are risk
factors for both ischemic and hemorrhagic strokes.
Ischemic Stroke
Ischemic stroke is diagnosed in 34 per 100,000 deliveries,
with 1.4 deaths per 100,000. The risk of stroke is increased
in patients older than 35 years and in black women. Del Zotto
and colleagues181 reviewed multiple worldwide databases and
showed that varied incidences between 4 and 41 per 100,000
deliveries. The highest risk was in patients with preeclampsia.
Predisposing factors such as preeclampsia, chronic hypertension,
or hypotensive episodes can be demonstrated in about one
third of these patients. Brown and colleagues182 investigated
ischemic stroke in women recruited between 1992 and 1996
and again between 2001 and 2003. They found that preeclamp-
sia was statistically associated with an increased risk of ischemic
stroke (OR, 1.59; 95% CI, 1.00 to 2.52). Of note, women with
a history of preeclampsia were more likely to eventually experi-
ence a non–pregnancy-related ischemic stroke. Half of the
pregnancy-related cases occurred during the immediate postpar-
tum period, and the remainder occurred during the second and
third trimesters.
Ischemic stroke typically presents with acute focal neuro-
logic symptoms. Headache can be present in 17% to 34% of
 Chapter 49  Neurologic Disorders in Pregnancy
cases. The workup should be done swiftly and starts with a
noncontrast CT of the head. Acute treatment of disabling
stroke due to arterial occlusion in nonpregnant patients is
with IV or intraarterial recombinant tissue plasminogen activa-
tor (tPA). Little is known about the efficacy and safety of
tPA in pregnant women because they were excluded from
the clinical trials for tPA therapy. However, in acute ischemic
strokes due to arterial thrombosis, the benefits of tPA likely
outweigh the risks, even in pregnant women. Feske and
Singhal183 reviewed the case reports of 11 women who received
IV or intraarterial thrombolysis. They concluded that 10 of
the patients had no major complications from the thrombolysis
and mentioned that the one patient who died had a major
complicating illness. Seven of the exposed fetuses were deliv-
ered without complications. One fetus died along with the
mother, two pregnancies were terminated, and one spontaneous
abortion occurred in a fetus whose mother had bacterial endo-
carditis. The authors point out that although tPA can be
considered for pregnant women with arterial occlusion, it
should probably be avoided in patients with preeclampsia/
eclampsia given the increased risk of intracranial hemor-
rhage in these cases.
Patients with acute strokes should typically be monitored in
an intensive care setting, especially if tPA was given. Tight blood
pressure control is required, and for major strokes, aggressive
management of intracranial pressure may be needed. Further
workup of ischemic stroke includes an MRI of the brain along
with MRA of the head and neck. In some cases, CTA or angi-
ography is needed. All patients with possible embolic stroke
should have a transthoracic echo with agitated saline to exclude
a patent foramen ovale. Blood tests should include a lipid panel,
hemoglobin A1C level, erythrocyte sedimentation rate, and
C-reactive protein level.
Hemorrhagic Stroke and
Vascular Malformations
Based on a review of prior epidemiologic studies, Feske and
Singhal183 estimated the incidence of hemorrhagic stroke in
pregnancy to be between 5 and 35 per 100,000 patients. The
likelihood of a hemorrhagic stroke increases more dramatically
in pregnancy than the risk for an ischemic stroke.
Evidence conflicts in regard to the effect of pregnancy on
the behavior of arteriovenous malformations (AVMs).178,185,186
Although it is uncertain whether incidental AVMs are at greater
risk of bleeding during pregnancy, one study found that in
27 women who presented with hemorrhage due to AVMs in
pregnancy, 26% had recurrent bleeding during or immediately
after pregnancy. This is higher than the annual 6% risk expected
in nonpregnant patients.187 There also appears to be a signifi-
cantly heightened risk of bleeding from an AVM on the day of
delivery.186
In considering the above information, a 2001 consensus state-
ment from the American Heart Association (AHA) recom-
mended that a woman with a known AVM should consider
treatment prior to conceiving, and when an AVM is discov-
ered during pregnancy, risks of treatment should be weighed
against the risk of hemorrhage. The committee felt that in
most cases, such a risk-benefit analysis will not support elective
treatment of AVMs during pregnancy.187 Typically, AVMs found
incidentally without hemorrhage are managed expectantly, but
surgical intervention is considered in a woman with an AVM
that has hemorrhaged.183
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1051
If the patient has undergone corrective surgery for an
aneurysm or an AVM, she should be allowed to deliver vagi-
nally. Moderate increases in blood pressure do not cause spon-
taneous hemorrhage in nonpregnant patients with intracranial
AVMs. If the aneurysm or AVM has not been surgically cor-
rected, a cesarean delivery is often recommended because of
concern about the effects of increased blood pressure and intra-
cranial pressure during delivery and prior observations of
increased bleeding on the day of delivery.178,183 However, in
truth, no direct evidence is available to show that cesarean deliv-
ery is more protective against bleeding from an AVM than
vaginal delivery.187
CARPAL TUNNEL SYNDROME
The medial border of the carpal tunnel consists of the pisiform
and hamate bones, and its lateral border consists of the scaphoid
and trapezium bones. They are covered on the palmar surface
by the flexor retinaculum. The median nerve and flexor
tendons pass through this carpal tunnel, which has little
room for expansion. If the wrist is extremely flexed or
extended, the volume of the carpal tunnel is reduced. In preg-
nancy, weight gain and edema can produce a carpal tunnel
syndrome that results from compression of the median nerve.
The association between carpal tunnel syndrome and pregnancy
was first reported in 1957. Although many pregnant women
complain of pain on the palmar surface of the hand, few actu-
ally have the true carpal tunnel syndrome. Stolp-Smith and
colleagues188 found that 50 of 14,579 pregnant patients (0.34%)
who presented between 1987 and 1992 actually met criteria
for carpal tunnel syndrome. Commonly, the syndrome con-
sists of pain, numbness, and tingling in the distribution of
the median nerve in the hand and wrist. This includes the
thumb, index finger, long finger, and radial side of the ring
finger on the palmar aspect. These symptoms/signs can be
accompanied by dysesthetic wrist pain, loss of grip strength,
and problems with dexterity. Compressing the median nerve
and percussing the wrist and forearm with a reflex hammer,
the Tinel maneuver, often exacerbates the pain. In severe cases,
weakness and decreased motor function can occur. The defini-
tive diagnosis is made by electromyography, but this test is often
unnecessary.
McLennan and coworkers189 studied 1216 consecutive preg-
nancies. Of these patients, 427 (35%) reported hand symptoms.
Fewer than 20% of these 427 affected women described the
classic carpal tunnel syndrome. No patient required operative
intervention. Most symptoms were bilateral and commenced in
the third trimester of pregnancy. Ekman-Ordeberg and col-
leagues190 found a 2.3% incidence of carpal tunnel syndrome
in a prospective study of 2358 pregnancies. The syndrome
appeared to be more common in primigravidae with general-
ized edema. Increased weight gain during pregnancy also raises
the risk.189 A recent prospective study of 639 Dutch pregnant
women found a 34% prevalence of carpal tunnel syndrome
based on a standardized questionnaire.191 Symptoms were more
likely to occur after 32 weeks’ gestation and were associated with
symptoms of fluid retention when adjusting for body mass index
(BMI), age, parity, and depression scores.
Padua and colleagues192 conducted a systematic literature
review concerning carpal tunnel syndrome in pregnancy. Of the
214 studies reviewed, only six fulfilled their criteria for inclu-
sion. Neurophysiologically confirmed carpal tunnel syndrome
1052 Section VI  Pregnancy and Coexisting Disease
ranged from 7% to 43% of those who presented with symptoms.
Clinically diagnosed carpal tunnel syndrome ranged from 31%
to 62%. Of note in 50% of cases, symptoms persisted for more
than a year, and in 30%, symptoms were still present 3 years
postpartum.
Supportive and conservative therapies are usually adequate
for the treatment of carpal tunnel syndrome. Symptoms often
subside in the postpartum period as total body water returns to
normal.193 Pain scores fall by half during the first week after
delivery and by half again during the next week. The reduction
in score is strongly correlated with loss of the weight gained
during pregnancy. However, about half of the women with
carpal tunnel syndrome during pregnancy still have some symp-
toms 1 year later. This occurs more commonly in those whose
symptoms started early in pregnancy. Carpal tunnel syndrome
that develops during breastfeeding may also last longer.193
Splints placed on the dorsum of the hand, which keep the
wrist in a neutral position and maximize the capacity of the
carpal tunnel, often provide dramatic relief. Local injections
of glucocorticoids may also be used in severe cases. Although
diuretics may help to control the symptoms of carpal tunnel
syndrome over a short period of time, their use is not recom-
mended because the symptoms return rather rapidly after the
cessation of treatment.
Surgical correction of this syndrome should not be delayed in
patients with deteriorating muscle tone and/or motor function.
Even small changes can be documented by electromyography
(EMG), which can be performed without harm during preg-
nancy. Decompression surgery for carpal tunnel syndrome is a
simple procedure that can be safely carried out during pregnancy
using local anesthesia, an axillary block, or a Bier block. With
new endoscopic approaches, the procedure is even less invasive.
Assmus and Hashemi194 describe the outcomes for 314 hands
surgically treated during pregnancy or in the puerperium for
carpal tunnel syndrome. One hundred thirty-three cases were
performed during pregnancy, most in the last trimester, and
included four who had both hands treated simultaneously; 98%
of patients reported good or excellent results. Local anesthesia
was used in all cases, and no complications were reported. These
authors recommend surgery if sensory loss is present or if motor
latency is more than 5 msec on nerve conduction studies. It is
important to warn patients that carpal tunnel syndrome can
persist for several years postpartum and can recur in future
pregnancies.192
KEY POINTS
◆ Epilepsy affects approximately 1% of the general popu-
lation and is the most frequent neurologic complication
of pregnancy.
◆ Prepregnancy counseling is imperative in the patient
with epilepsy.
◆ Valproic acid has been associated with a significantly
increased risk of major congenital malformations and
adverse cognitive outcomes, including lower IQs and
an increased risk of autism, when compared with other
AEDs and with the general population.
◆ AEDs known to have a low risk of structural
teratogenesis—such as lamotrigine, levetiracetam, or
carbamazepine—should be tried as first-line agents in
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women with epilepsy over AEDs that have been less well
studied or valproic acid.
◆ Ultimately, the AED that best controls the patient’s
seizures should be used during pregnancy. Efforts to
reach the minimum therapeutic dose should be
attempted well in advance of pregnancy.
◆ Because of the changes in plasma volume, drug distribu-
tion, and metabolism that occur during pregnancy, anti-
convulsant levels should be checked prior to conception
and monthly during pregnancy. Dose adjustments to
maintain prepregnancy levels are an important part of
seizure control for many AEDs, especially lamotrigine.
◆ Women using AEDs should take folic acid 0.4 mg to
4 mg daily prior to and throughout pregnancy. They
should also be offered a specialized ultrasound for
careful assessment of major congenital malformations.
◆ Understanding a patient’s epilepsy syndrome is neces-
sary to give appropriate counseling on the risk of inheri-
tance of epilepsy in offspring.
◆ Assisted reproductive techniques can precipitate MS
relapses.
◆ Pregnancy does not hasten the onset or progression
of MS. In fact, exacerbations are decreased during
pregnancy.
◆ DMAs used to decrease the rate of relapses and disabil-
ity in MS are typically not recommended during preg-
nancy because MS relapses tend to be less frequent
during gestation, and data on exposure risk are still
limited. A washout period is recommended for many
DMAs.
◆ Increasing data on DMA use in pregnancy is available;
for some patients, certain DMAs—such as glatiramer
acetate and interferon-β—can be used in pregnancy.
◆ Breastfeeding in MS is controversial. Exclusive breast-
feeding may reduce the risk of MS relapses, but treat-
ment with DMAs is typically not recommended for
women who are breastfeeding.
◆ Any new headache or new headache type that presents
in pregnancy requires workup for an underlying poten-
tially deleterious cause.
◆ Nonpharmacologic treatments are considered first-line
therapies for migraine in pregnancy, which typically
improves without treatment.
◆ Although opiates are commonly prescribed for migraine
in pregnancy, they are actually not very effective migraine
medications.
◆ Carpal tunnel syndrome is common in pregnancy and
usually responds to conservative splinting, glucocorti-
coid injection, or both. Surgery can be safely under-
taken if indicated during pregnancy.
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