EXPERT REVIEW OF NEUROTHERAPEUTICS

2022, VOL. 22, NO. 4, 301–312

https://doi.org/10.1080/14737175.2022.2057224

REVIEW

Status epilepticus in pregnancy: a literature review and a protocol proposal

Roberta Robertia*, Morena Roccab*, Luigi Francesco Iannonea, Sara Gasparinic,d, Angelo Pascarella c,d, Sabrina Neric,d,
Vittoria Ciancic, Leonilda Biloe, Emilio Russo a, Paola Quaresimaf, Umberto Aguglia c,d,g, Costantino Di Carloe
and Edoardo Ferlazzoc,d,g
a
Science of Health Department, School of Medicine, Magna Græcia University, Catanzaro, Italy; bObstetrics and Gynecology Unit, “Pugliese-ciaccio”
Hospital of Catanzaro, Catanzaro, Italy; cRegional Epilepsy Centre, Great Metropolitan “Bianchi-Melacrino-Morelli” Hospital, Reggio Calabria, Italy;
d
Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy; eDepartment of Neuroscience, Reproductive and
Odontostomatological Sciences, Federico II University, Naples, Italy; fDepartment of Experimental and Clinical Medicine, Magna Græcia University
of Catanzaro, Catanzaro, Italy; gInstitute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Status epilepticus (SE) in pregnancy represents a life-threatening medical emergency for Received 22 January 2022
both mother and fetus. Pregnancy-related pharmacokinetic modifications and the risks for fetus Accepted 21 March 2022
associated with the use of antiseizure medications (ASMs) and anesthetic drugs complicate SE manage­ KEYWORDS
ment. No standardized treatment protocol for SE in pregnancy is available to date. Antiseizure medications;
Areas covered: In this review, we provide an overview of the current literature on the management of eclampsia; seizures;
SE in pregnancy and we propose a multidisciplinary-based protocol approach. magnesium sulfate;
Expert opinion: Literature data are scarce (mainly anecdotal case reports or small case series). Prompt benzodiazepines
treatment of SE during pregnancy is paramount and a multidisciplinary team is needed.
Benzodiazepines are the drugs of choice for SE in pregnancy. Levetiracetam and phenytoin represent
the most suitable second-line agents. Valproic acid should be administered only if other ASMs failed
and preferably avoided in the first trimester of pregnancy. For refractory SE, anesthetic drugs are
needed, with propofol and midazolam as preferred drugs. Magnesium sulfate is the first-line treatment
for SE in eclampsia. Termination of pregnancy, via delivery or abortion, is recommended in case of
failure of general anesthetics. Further studies are needed to identify the safest and most effective
treatment protocol.

1. Introduction
Epilepsy is a common neurological condition in women world­
wide, affecting 3 to 7 per 1000 pregnant patients [1]. During
pregnancy, the physiological variation in estrogen levels may
negatively affect seizure activity [2]. Pregnancy-related mod­
ifications such as increased volume of distribution increased
hepatic metabolism and increased renal excretion may alter
anti-seizure medications (ASMs) pharmacokinetics, as summar­
ized in Table 1 [3–5]. Moreover, decreased gastrointestinal
motility and increased gastric pH, together with malaise and
vomiting frequently occurring in early pregnancy, may alter
ASMs absorption [3]. Pharmacokinetic changes impact on total
or free serum concentrations of ASMs, which may differ than
those expected. Moreover, pregnancy-related clearance
increase of some ASMs (e.g. lamotrigine, levetiracetam, topir­
amate, oxcarbazepine, phenytoin) has been widely demon­
strated [6]. Therefore, dosage adjustments and a careful
interpretation of total drug levels may be needed [7].
Maintaining a constant and in-range ASMs (especially for
first-generation drugs) serum concentration during pregnancy,
is crucial to avoid both seizure recurrence and dose-
dependent consequences of fetal drug exposure [8]. Indeed,
it is well known that ASMs can transfer through the placenta
and some of them have well-recognized teratogenic effects
[9]. On the other hand, adequate ASMs doses are required to
prevent fetal and maternal risks associated with uncontrolled
seizures (e.g. fetal hypoxia or fetal loss, maternal injuries and
death) [8,10,11].
SE is a neurologic and medical emergency with substantial
related morbidity and mortality. SE is currently defined as ‘a
condition resulting either from the failure of the mechanisms
responsible for seizure termination or from the initiation of
mechanisms, which lead to abnormally prolonged seizures,
which can have long-term consequences, including neuronal
death, neuronal injury, and alteration of neuronal networks,
depending on the type and duration of seizures’ [12].
According to the International League Against Epilepsy
(ILAE) Task Force classification [12], SE can present with or
without prominent motor symptoms. The first category
includes convulsive SE, myoclonic SE, focal motor SE, tonic
status and hyperkinetic SE, whereas the latter corresponds to
non-convulsive SE [12]. Prompt and aggressive treatment has
been recommended especially for convulsive (tonic-clonic) SE.
SE duration represents an unfavorable prognostic factor and

CONTACT Costantino Di Carlo cdicarlo@unicz.it; Edoardo Ferlazzo ferlazzo@unicz.it Science of Health Department, School of Medicine, Magna Græcia
University, Catanzaro, Italy
*
These authors equally contributed to this work.
© 2022 Informa UK Limited, trading as Taylor & Francis Group
302 R. ROBERTI ET AL.

use) a second-line treatment with IV ASMs, including pheny­

Article highlights
● Prompt treatment of status epilepticus in pregnancy is paramount
and a multidisciplinary team (i.e. experts in neurocritical care, epi­
lepsy, gynecology) is needed.
● Available evidence on SE management in pregnancy are scarce and
mainly derive from case reports and small case series.
● Magnesium sulphate is the first-line treatment during SE in
eclampsia.
● Benzodiazepines are the drugs of choice for SE in pregnancy outside
eclampsia. The most appropriate second-line agents are levetirace­
tam and phenytoin.
● Additional evidence is needed to propose a definite comprehensive
approach.
mortality appears to be higher if treatment is delayed [13,14].
The relevance of SE duration has been emphasized by the
recent ILAE Task Force proposed classification, which identi­
fies two crucial time points for clinical approach and manage­
ment of SE: t1, indicating the time beyond which the seizure
should be regarded as SE and treatment should be started,
and t2, indicating the time at which long-term consequences
may be expected. Based on the available evidence, for con­
vulsive SE, t1 has been set at 5 minutes, t2 at 30 minutes [12].
SE has been classified into five stages according to timing
and suggested approach [15]. In both pre-hospital (stage 1)
and intra-hospital (stage 2) early phases, the preferred treat­
ment is represented by intravenous (IV) benzodiazepines
(BDZs). In definite SE (stage 3) (e.g. SE persisting after BDZ
toin (PHT), lacosamide (LCM), levetiracetam (LEV) or pheno­
barbital (PB), is suggested. If seizures persist despite the
above-mentioned ASMs, the SE is named refractory (RSE)
(stage 4) requiring general anesthesia (by mean of IV midazo­
lam, propofol, thiopental, or ketamine). If seizures continue
24 h or more after the onset of anesthetic drugs, SE is defined
as super-refractory (SRSE) (stage 5) [15].
SE in pregnancy needs to be promptly identified and
treated since it may compromise placental blood flow and
cause fetal hypoxia with severe neurodevelopmental delay
or death [1,16,17]. SE may be due to etiology not related
to pregnancy status (ASM withdrawal, recurrence in the
context of known epileptic syndromes), to conditions that
are favored by pregnancy (inadequate ASMs dosage, cere­
bral venous thrombosis, autoimmune encephalitis, reversi­
ble cerebral vasoconstriction syndrome), or to pregnancy-
specific conditions (mainly eclampsia) [18–20].
Unfortunately, no standardized protocols for SE treatment
in pregnancy are available to date, and data mostly gen­
erated from small observational studies, individual or case
series reports. SE management during pregnancy is further
complicated by the lack of safety data on intravenous use
of ASMs and anesthetic drugs (IVADs) in this popula­
tion [17].
We herein review the literature on convulsive SE manage­
ment in pregnancy. We also attempt to propose a useful multi­
disciplinary-based protocol approach, which might ensure
effectiveness in SE control and reduce maternal and fetal risks.

Table 1. Relevant pregnancy-related physiological changes that affect drugs’ pharmacokinetics [3–5].
Pharmacokinetic
parameter Patho-physiological changes Pharmacokinetic consequences Clinical significance
Absorption # Gastric pH # Cmax and Tmax An impaired drug absorption would result in #
bioavailability and potential reduced efficacy (but
rarely of clinical significance)
# Gastric emptying
# GI motility
Malaise and vomiting in early
pregnancy
Distribution " Blood volume Altered Vd # Total serum concentrations
" Body water and fat stores " Vd due to alteration of fat/water ratio Overall effects of pregnancy-induced alterations in Vd
differ between individuals, but generally with
limited effect on active ASMs serum concentrations
# Albumin # Total (bound plus unbound) serum concentrations Total plasma concentrations of highly bound drugs
of highly bound drugs (e.g. phenytoin, valproic could underestimate the effective concentration and
acid), with relatively small changes in unbound the fetal exposure; free fraction monitoring could be
drug concentrations more useful to establish dosage adjustments
Metabolism " CYP (i.e. CYP2B6, 2C8, 2C9, " Clearance for drugs with high hepatic extraction # Serum concentrations, notably for ASMs
2D6, 2E1, 3A4) and UGT (i. ratios metabolized through glucuronidation (e.g.
e. UGT1A4 and 2B7) lamotrigine, MHD, valproate)
activity
" Hepatic blood flow
# CYP1A2, CYP2C19 activity # Clearance for drugs with high hepatic extraction Overall, a large interpatient variability is observed in
ratios the impact of pregnancy on ASMs metabolism; TDM
should be considered to adjust dosage
Elimination " Renal blood flow and GFR " Clearance for drugs mainly excreted by the Dosage adjustments might be needed for ASMs mainly
kidneys excreted by renal route (e.g. ethosuximide,
gabapentin, pregabalin, vigabatrin levetiracetam,
and topiramate)
ASMs, antiseizure medications; CYP, cytochrome P450; Cmax, peak concentration; GFR, glomerular filtration rate; GI, gastrointestinal; MHD, monohydroxycarbazepine; TDM,
therapeutic drug monitoring; Tmax time of peak concentration; UGT, uridine diphosphate glucuronosyltransferase; Vd, volume of distribution; " , increased; # ,
decreased.
 EXPERT REVIEW OF NEUROTHERAPEUTICS 303

2. Methods hospital-based sources and hence, evidence on pre-hospital

SE management is lacking.
For this narrative review, the source references were identified
A total of 39 women developing SE during pregnancy were
by some of the authors (EF, ER, RR, LFI) using PubMed and
found in the literature, with only a single large published
Google Scholar until November 2021, by means of the terms
cohort reporting data about 17 pregnant women (Table 2)
(‘antiepileptic drugs’ OR ‘AED’ OR ‘anti-seizure medications’ OR
[17–19,21–33]. Thirty-three out of 39 (84,6%) women had
‘ASM’) AND (‘status epilepticus’ OR ‘seizures’ OR ‘SE’) in various
a good outcome in terms of recovery to baseline; eighteen
combinations with ‘pregnancy’ ‘new-born,’ ‘eclampsia,’ ‘gesta­
(48.6%) fetuses were delivered at term and twelve (31.6%)
tion.’ Furthermore, the searches combined the generic names
fetuses at preterm. Death was reported in two women and
of each drug used to treat SE with the terms (‘pharmacoki­
two fetuses. However, data about the fetus’ safety and the risk
netics’ AND ‘pregnancy’); (‘fetal risk*’ OR ‘teratogenicity’ OR
of teratogenicity of ASMs administered for SE are not men­
‘malformation*’). Search results were reviewed and original
tioned in those studies and the available evidence on these
studies, systematic reviews and meta-analyses related to
issues comes essentially from studies and registers including
ASMs and anesthetic drugs used in SE during pregnancy
epileptic pregnant women chronically treated with ASMs.
were selected. No date limits were applied. Only articles in
English language were selected.
3.1. Pharmacological treatments: general considerations
The occurrence of respiratory depression associated with IV
3. Results
drugs’ administration should be carefully considered [34]. The
Available evidence on SE management in pregnancy is scarce limited available data suggest that the drugs commonly used
and mainly derives from anecdotal case reports and small case for SE during pregnancy seem to be relatively safe for both
series. Of note, the majority of relevant data came from mother and fetus. An ASM effective for SE in pregnancy might

Table 2. Literature reports on SE during pregnancy.

N° of
Reference Study Design patients Etiology of SE Drugs Outcome
Dam et al., 2003 Case report 1 Eclampsia DZP, MgSO4, TP, PHT, PPF SE termination after PFF
[27] administration
Schulze-Bonhage Case report 1 Vitamin B6 deficit PHT, PB, MDZ, SE termination after pyridoxine
et al., 2004 administration
[28]
Engelhardt et al., Case report 1 Porphyria LOR, PHT, LEV, TP, GPN SE stopped after pregnancy
2004 [29] interruption
Gunduz et al., Case report 1 HSV encephalitis CBZ, PHT, DZP SE termination (following antiviral
2006 [30] therapy)
Aladdin et al., Case report 1 Cavernous angioma PHT, LOR, CLB, CBZ, PPF SE stopped after pregnancy
2008 [31] interruption
Legriel et al., Case report 1 RCVS, PRES MgSO4, MDZ SE stopped only after cesarian
2011 [32] delivery
Jeong et al., 2011 Case report 1 Unknown, PT affected by epilepsy due MDZ, LEV, PHT, PB SE stopped only after cesarian
[33] to focal cortical dysplasia delivery
Lu et al., 2016 Retrospective 7 ASMs withdrawal (n = 1), CVT (n = 2), OXC, VPA, PB, PPF, LEV, TPM, MDZ, SE termination in 5/7 (71%),
[19] study limbic encephalitis (n = 2), MgSO4, LTG, CLB, CLZ, PHT death in 2/7 (28.5%)
autoimmune encephalophathy
(n = 1), anti NMDAR encephalitis
(n = 1)
Rajiv et al., 2017 Prospective cohort 17 eclampsia (n = 4), PRES (n = 6), CVT LOR, MDZ, PHT, VPA, PB, LEV, PPF, 13/17 (76%) had good outcome,
[18] study (n = 3), SHA (n = 1), NMDA MgSO4 4/17 (57%) had poor outcome
encephalitis (n = 1)
Talahma et al., Case report 1 ASMs withdrawal LOR, PPF, KT, MgSO4 SE termination after KT
2018 [21] administration
Alibas et al., 2019 Case report 2 Preeclampsia (PT1), ASMs withdrawal MDZ, LEV, PPF, TP, LCM, TPM, SE termination after cesarian
[22] (PT2) mPRED, VPA delivery
Jbili N et al., 2019 Case report 1 Schizencephaly MDZ, DZP, PB, CLB, LTG, TP SE termination after TP
[23]
Shi H et al., 2019 Case report 1 POLG-related epilepsy MDZ, LCM, LEV, PHT, CLB, KT, SE termination
[24] MgSO4
Park Sh et al., Case report 1 Schizencephaly LOR, LEV, PB, MDZ, TP SE termination after TP and MDZ
2021 [25] (after cesarian delivery)
Carrasco et al., Case report 1 Eclampsia LOR, LEV, MDZ, PFF, PHT, LCM, KT, SE termination after cesarian
2021 [17] PB, VPA, PN delivery
Poggiali et al., Case report 1 Eclampsia/PRES MgSO4, MDZ SE termination
2021 [26]
Legend: ASM, anti-seizure medication; CBZ, carbamazepine; CLB, clobazam; CLZ, clonazepam; CVT, cerebral venous thrombosis; DZP, diazepam; GPN, gabapentin;
HSV, herpes simplex virus; KT, ketamine; LCM, lacosamide; LEV, levetiracetam; LOR, lorazepam; MDZ, midazolam; MgSO4, magnesium sulfate; mPRED, methyl­
prednisolone; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PN, pyridoxine; PPF, propofol; PRES, posterior reversible encephalopathy syndrome; PT,
patient; RCVS, reversive cerebral vasocontriction syndrome; SE, status epilepticus; SHA, subarachnoid hemorrhage; TP, thiopental; TPM, topiramate; VPA, valproic
acid.
304 R. ROBERTI ET AL.

be potentially continued during all pregnancy and thereafter, Table 3. Pregnancy-related pharmacokinetic modifications of the drugs used for
and this should be taken in account when choosing an ASM SE.
for SE. Pregnancy-related pharmacokinetic
modifications References
Data from the Australian Register of Antiepileptic Drugs in
First line
Pregnancy showed a small (but not statistically significant) treatment
increase in the risk of intrauterine death in pregnant women Benzodiazepines
exposed to ASMs compared with unexposed ones (3.44% vs Diazepam " FF [41,56]
" terminal half-life
0.59%) [35]. EURAP data reported that 632/7055 pregnancies Lorazepam -
exposed to ASMs monotherapy ended in intrauterine deaths, Midazolam " CYP3A4 activity as pregnancy progresses [42,78]
with similar rates across the different monotherapies (8.2%; " AUC, # Cl and Vd, in active labor
Clonazepam -
95% CI 7.5%–8.9%). In the multivariable analysis, the only Magnesium # Cl in preeclampsia [43]
treatment-related factor affecting the risk of intrauterine sulfate
death was ASMs polytherapy [36]. However, the type of ASM Second-line
treatment
chosen is likely more important than whether it is used in Phenobarbital # Total and unbound plasma [44,45]
mono- or polytherapy [37]. Gestational age represents another concentrations on average by 50%
variable potentially influencing ASMs effects on fetus. In fact, " Cl (125% total, 143% unbound)
Phenytoin " Cl [45,46]
organogenesis spans the first trimester of gestation and, after # Free and total concentrations (31% and
this time, teratogenic drugs may not have a major effect on 56%, respectively)
malformation risk. Nevertheless, the risk of cognitive dysfunc­ " FF by 40% (3rd trimester)
Levetiracetam " Cl [6,47]
tion related to prenatal exposure to AMSs may still persist, as # Total plasma concentrations by 40%-60%
cerebral development, synaptogenesis and neuronal migra­ Lacosamide Limited and contrasting data [48,49]
tion largely occur during the second and third trimester [38]. Valproic acid # Total CDR ~ by 50% in the last trimester [50–52]
# Protein binding
As regards anesthetic drugs, most of them seem to have Third line
a good safety profile during pregnancy and without major treatments
risks for spontaneous abortion. The short time (acute admin­ Propofol " Cl [53]
# Elimination half-life
istration) of exposure to those drugs also could reduce that Thiopental " Apparent Vd, and elimination half-life [54]
risk [39]. Ketamine # Cl [120]
Mechanisms of action and pharmacokinetic characteristics Table 3 legend: AUC, area under the concentration–time curve; CDR, concentration–
of the drugs used for SE have been reviewed elsewhere [40]. dose ratio; Cl, clearance; CYP, cytochrome P450; FF, free fraction; MCMs, major
congenital malformations; SGA, small for gestational age; Vd, volume of distribu­
Pregnancy-related pharmacokinetic modifications of the drugs tion; " ;, increased; # , decreased.
used for SE are summarized in Table 3.

3.1.1. Fetal risks with first-line treatments
3.1.1.1. Benzodiazepines. Benzodiazepines (BDZ) (i.e. diaze­
pam, lorazepam, midazolam and clonazepam) are the first line
drugs for SE, but their use is also common in RSE and SRSE.
The use of BDZs outside the acute seizures emergencies is
limited by tolerance, sedative or behavioral effects. For these
reasons, except for clobazam (not described in this section),
they do not represent drugs of choice in chronic epilepsy
treatment [55]. As lipid-soluble drugs, they easily and rapidly
cross biological membranes, including the blood brain barrier
and human placenta [56,57], and may accumulate in the fetal
circulation, reaching levels up to three times higher than
maternal ones [58].
Conflicting data exist on BDZs safety during pregnancy. In
a nested case-control study, a dose-dependent increased risk
of miscarriage (adjusted OR [aOR]:1.85; 95% confidence inter­
val [CI]: 1.61–2.12) was observed among early pregnancies
with incident exposure to BDZs (with an aOR ranging from
1.13 for flurazepam hydrochloride to 3.43 for diazepam) [59].
An increased risk of adverse neonatal outcomes was reported
also in previous studies [60–62]. Notably, a population-based
study showed a 50% higher risk (OR 1.5) of miscarriage in
women with depression or anxiety taking BDZs during the
first trimester of pregnancy, compared with those who dis­
continued medication use [61].
Data from observational studies in the 1970s suggested
that diazepam use during pregnancy was associated with an
increased risk for orofacial clefts [63,64], albeit no higher risk
for any major congenital malformations (MCMs) was observed
in a subsequent case-control study [65] and in a study cohort
from United Kingdom [66]. Furthermore, no increase in MCMs
risk in women exposed in the first trimester of pregnancy to
10 mg of diazepam bis in die for hyperemesis gravidarum [67],
or to extremely high doses (up to 800 mg) for suicide attempts
was found [68]. However, occurrence of floppy infant syn­
drome in the new-born after high-dose diazepam administra­
tion (such as in the treatment of eclampsia, for which doses up
to 100 mg IV could be needed) has been reported [56]. Other
studies on diazepam safety require the assessment of recall
bias [69,70]. As an example, in a matched case-population
control paired analysis, a higher risk for limb malformations,
rectal–anal stenosis/atresia, cardiovascular malformations and
multiple congenital abnormalities was found, but increased
risk did not resulted if considering only patients taking exclu­
sively diazepam, suggesting a lower proportion of maternal
self-reported intake in the control group [69].
There are small sample size reports of higher risk of anal
atresia [71], pulmonary valve stenosis (non-adjusted odds ratio
[OR]: 4.1; 95% CI: 1.2–14.2) and gastroschisis (OR: 3.5; 95% CI:
0.9–13.7) after in utero exposure to lorazepam [72]. Therefore,

lorazepam (which is not available in all countries) should be
prescribed with caution.
The exposure to midazolam during the first trimester of
pregnancy seems not to be associated with an increased risk
of MCMs [73]. However, preclinical studies raised growing
concern about the detrimental effects on the developing
brain after the use of some IVADs, including midazolam, in
the third trimester of pregnancy, which led the United States
Food and Drug administration to issue a warning in this
regard in 2016 [74,75]. Furthermore, when midazolam is admi­
nistered as IVAD for RSE and SRSE, attention should be paid to
maternal hemodynamic effects. Midazolam causes a mild
reduction in systemic vascular resistance, a decrease in systolic
arterial pressure and a small increase in heart rate [76]. Severe
cardiorespiratory adverse events are more likely to occur when
midazolam is administered too rapidly or at high doses [77].
Moreover, respiratory depression of the infant can occur when
midazolam is administered immediately before cesarean sec­
tion [78].
The exposure to clonazepam (mostly during the first trime­
ster of pregnancy) did not increase MCMs risk [79] and did not
affect mean head circumference of new-borns [80].
3.1.1.2. Magnesium sulfate. Magnesium sulfate was intro­
duced in the clinical practice in the 1920s. Although it is not
usually considered to be an ASM, it resulted more effective
than traditional ASMs for the prevention and treatment of
eclamptic seizures [81,82].
In a Cochrane Review, Duley et al. demonstrated that,
compared with diazepam, magnesium sulfate was associated
with a reduced risk of maternal death (RR: 0.59; 95% CI: 0.38–
0.92) and of recurrence of seizures (RR: 0.43; 95% CI: 0.33–0.55)
[83]. As regards fetal and new-born outcomes, in eclamptic
women treated with magnesium sulfate, better Apgar scores
and fewer neonates needing intubation were detected; how­
ever, no differences in perinatal mortality, neonatal mortality
and in admission to a special care nursery resulted after
diazepam or magnesium administration [83]. Overall, the
administration of magnesium sulfate for maternal or fetal
neuroprotection was not associated with increased risk of
perinatal death or other adverse outcomes for babies [84].
3.1.2. Fetal risks with second-line treatments
3.1.2.1. Phenobarbital. An increased risk of small head cir­
cumference (but not microcephaly) was reported after in-utero
exposure to ASMs polytherapy or monotherapy with primi­
done and PB [85,86].
In the network meta-analysis of Veroniki and colleagues,
infants/children who were exposed to PB showed an increased
risk for MCMs (OR: 1.83; 95% CI: 1.35–2.47) [9]. Similar results
were reported in a Cochrane review, in which children
exposed to PB were at a higher risk of malformation compared
with those born to women without epilepsy (RR: 2.84; 95% CI:
1.57–5.13) [87].
Data from the North American Antiepileptic Drug
Pregnancy Registry (NAAPR) showed an increased prevalence
of SGA infants exposed to ASMs compared with unexposed
ones. The prevalence of SGA differed according to the type of
EXPERT REVIEW OF NEUROTHERAPEUTICS 305
ASM and was particularly high for PB (aRR: 2.4; 95% CI: 1.6–3.6)
[88]. In this same registry, the prevalence of MCMs for PB was
5.5% (95%CI: 3.1–9.6) [89], whereas in the EURAP registry was
6.5% (95% CI: 4.2–9.9) [90]. Furthermore, a dose-dependent
effect was identified; in the multivariable analysis of the
European data, the prevalence of MCMs was significantly
higher for PB >80 mg/day compared with low-dose lamotri­
gine (≤325 mg/day) [90]. EURAP data showed also a rate of
intrauterine death of 8.5% (95% CI: 5.4–12.5), similar to that of
other ASMs monotherapies [36]. As concerns the type of
MCMs, pooled data from 32 cohort studies showed that bar­
biturates were associated with an increased risk of cardiac
malformations [91]. However, other factors such as parental
history of MCMs and individual susceptibility can affect MCMs
risk and should be taken into account [8].
Finally, children exposed prenatally to PB (especially during
the third trimester) had significantly lower verbal intelligence
scores (approximately −0.5 SD) than those predicted basing
on data from control subjects [92].
3.1.2.2. Phenytoin. The teratogenicity of PHT has been
established since more than 40 years, when data from pro­
spective and case controlled studies showed a high percen­
tage of children prenatally exposed developing at least some
clinical features compatible with the fetal hydantoin syndrome
(i.e. facial dysmorphisms, digital hypoplasia, intrauterine
growth restriction and intellectual disability) [93].
In more recent data, children exposed to PHT were at
increased risk of MCMs compared with children born to
women without epilepsy (RR: 2.38; 95% CI: 1.12–5.03) and to
women with untreated epilepsy (RR: 2.40; 95% CI: 1.42–4.08)
[87]; the OR for MCMs relative to unexposed patients was 1.67;
95% CI: 1.30–2.17 [9]. In EURAP and NAAPR registries, the
prevalence of MCMs was 6.4% (95% CI: 2.8–12.2) and 2.6%
(95% CI: 1.5–4.5), respectively [89,90]. In a prospective obser­
vational study, serious adverse outcomes occurred in 10.7% of
pregnancies exposed to PHT monotherapy, of which 3.6%
(n = 2/56) were fetal deaths [94].
In a study evaluating the effects of ASMs on psychomotor
development in preschool children, a subtle but significant
reduction in the scores for locomotor development was
found in children prenatally exposed to PHT compared with
those unexposed (mean scores: 98 vs 106: 95% CI for the
difference in mean scores from −14.0 to −0.4) [95]. However,
in a Cochrane review, the in utero exposure to PHT did not
appear to negatively affect early developmental skills (e.g.
language skills, motor functioning) in infancy [96]. In the
NEAD study, groups exposed to PHT had higher intelligence
quotient (IQ) scores than those exposed to VPA and compar­
able with those exposed to carbamazepine or lamotrigine; no
dose-response relationship between PHT dose and poorer
neurodevelopmental outcome was found [97]. When PHT is
administered IV, the warning label about the cardiovascular
risk associated with rapid infusion should be kept in mind [98].
3.1.2.3. Levetiracetam. Regardless of time of pregnancy, the
in utero exposure to LEV was not associated with a significant
306 R. ROBERTI ET AL.
increased risk of MCMs [9,87,99]. Likewise, in the EURAP study,
MCMs’ risk associated with LEV, was within the range reported
in the literature for children unexposed to ASMs [90], whereas
the rate of intrauterine death did not differ than other ASMs
monotherapies [36].
However, it should be considered that the available data on
newer ASMs are relatively fewer compared with that on older
ASMs [87]. Moreover, LEV may be not available in all countries.
3.1.2.4. Lacosamide. There is lack of data on both maternal
and fetal outcomes associated with LCM administration. In
three cases of maternal exposure to LCM, a good level of
efficacy and safety during pregnancy was suggested, arguing
against teratogenic or toxic potentialities [100].
3.1.2.5. Valproic acid. VPA is associated with the highest
number of adverse outcome (i.e. fetal death or major malfor­
mations) in pregnancy [94] as compared to other ASMs, while
the rate of intrauterine death seems not differ from other
ASMs (8.1%; CI: 6.6–9.8) [36]. VPA is characterized by a dose-
dependent relationship with MCMs and neurodevelopmental
disorders [90,96,101]. In particular, the dose-dependent rela­
tionship with MCMs appears more evident when VPA is used
during the first trimester, whereas correlation with neurode­
velopmental disorders is more evident when used during
the second or third trimesters of pregnancy [102]. VPA
assumption induced MCMs in the 6.7–10.3% of pregnant
women [103]. Compared with unexposed, first trimester use
of VPA was associated with increased risks for spina bifida (OR:
12.7; 95%CI: 7.7–20 · 7), craniosynostosis (OR: 6.8; 95%CI: 1.8–
18.8), cleft palate (OR: 5.2; 95%CI: 2.8–9.9), hypospadias (OR:
4.8; 95%CI: 2.9–8.1), atrial septal defect (OR: 2.5; 95%CI: 1.4–
4.4), and polydactyly (OR: 2.2; 95%CI: 1.0–4.5) in a large case-
control study [104]. Subsequent pooled data confirm the
increased risk for MCMs associated with VPA (OR: 2.93; 95%
CI: 2.36–3.69) [9]. Compared with children born to women
without epilepsy, those exposed to VPA showed a higher risk
of malformations (RR: 5.69; 95%CI: 3.33–9.73), including neural
tube defects, cardiac, orofacial/craniofacial clefts, and skeletal
and limb malformations [87]. A significantly lower IQ (mean
score 97) was also found in children of women taking VPA
compared with those taking carbamazepine (IQ 105), lamotri­
gine (IQ 108), or PHT (IQ 108) [97]. Furthermore, fetal VPA
exposure has dose-dependent associations with reduced cog­
nitive abilities (e.g. verbal ability, non-verbal ability, memory
and executive function), which appear to persist at least until
the age of six [97]. Among neurodevelopmental disorders,
repetitive behaviors, impaired communication, social isolation
[96,105,106], as well as autistic-like trait [107,108] could affect
children exposed in utero to VPA.
3.1.3. Fetal risks with third-line treatments
3.1.3.1. Propofol. Propofol is often used in combination
with midazolam IV for RSE and SRSE. The use of propofol in
pregnancy has not been formally evaluated and data regard­
ing propofol administration during pregnancy are limited.
Although maternal hypotension is a common adverse effect
of propofol, the umbilical blood flow seems to be
appropriately maintained [109]. Concerns about neonatal
depression are limited to the close to delivery administration,
especially at high doses [110]. Propofol readily crosses the
placenta and fetal concentrations are half of maternal concen­
trations in minutes with a minimal placental metabolism of
propofol that do not concentrate in the amniotic fluid
[111,112]. No impaired fertility or fetal harm have been
observed in preclinical studies using doses 6-fold higher than
those recommended in humans [113].
3.1.3.2. Thiopental. Thiopental has been routinely used as
an anesthetic induction agent for cesarean section since the
1930s. Following thiopental administration for induction of
anesthesia for elective cesarean section, a transient increase
in plasma concentration was observed at delivery. The use of
thiopental has been associated with a decreased maternal
arterial pressure that, combined with a long induction time,
could reduce the Apgar score [114].
3.1.3.3. Ketamine. Ketamine is emerging as an important
therapeutic option when other IVADs are not suppressing sei­
zures or are causing serious cardiocirculatory impairment [115].
However, it is not recommended in women with arterial hyper­
tension, since it can increase maternal blood pressure and heart
rate up to 40% [116]. When used for induction in cesarean
section, ketamine may initially cause lower Apgar scores com­
pared with thiopental [117]. On the other hand, when the rate-
pressure product (obtained by multiplying systolic blood pres­
sure and heart rate) is assessed, a lower increase is observed
with ketamine than with thiopental (30 vs 60%) [118].
Preclinical data suggest the potential neurotoxicity of fetal
exposure to ketamine. The mechanisms involved include the
increasing risk of neuronal apoptosis and the alteration of
a NOTCH signaling pathway in neural crest development. This
latter leads to the inhibition of Notch targeted genes expression,
resulting in a greater risk of congenital disorders in humans [119].
Considering these growing concerns and the paucity of data on
the safety of ketamine prolonged use, it should be avoided (if
possible) during the third trimester of pregnancy [120].
3.1.3.4. Midazolam. Data on midazolam safety in pregnancy
are reported above.
3.2. Management according to etiopathogenesis
3.2.1. SE in pregnancy (outside eclampsia)
Limited data exist on SE management in pregnancy and ther­
apeutic choices mainly derive from literature on SE management
in the overall population [121]. BDZs bolus (diazepam: 0.15–
0.2 mg/kg, max 10 mg IV; lorazepam: 0.05–0.1 mg/kg, max
4 mg IV; midazolam: 10 mg IM or IV) is the first choice for initial
management of SE [122]. Diazepam is a highly lipophilic BDZ,
rapidly entering into the brain but rapidly redistributing into
peripheral fatty tissues. This pharmacokinetic property is respon­
sible for its faster but shorter anticonvulsant effect as compared
to IV lorazepam [123]. In the pre-hospital treatment of SE,
Alldredge et al. demonstrated that both IV lorazepam and IV
diazepam were effective in inducing SE termination (59.1% vs

42.6%, respectively) [124]. Intravenous lorazepam was better
than IV diazepam for reducing the risk of persisting SE (RR:
0.64; 95% CI: 0.45–0.90) and had a lower risk for continuation of
SE requiring a different drug or general anesthesia (RR: 0.63; 95%
CI: 0.45–0.88) [123]. According to the American Epilepsy Society
Guideline, no significant difference in effectiveness has been
demonstrated between lorazepam and diazepam in adults with
convulsive SE [34]. In the comparison between IM midazolam
and IV lorazepam in the pre-hospital treatment of SE, a lower rate
of endotracheal intubation and recurrent seizures with IM mid­
azolam was observed [125].
When BDZs are unsuccessful, a second-line treatment
should be started [126]. There is no single best second-
line IV ASM; LEV, PHT and fosphenytoin (not available in all
countries) are the most employed drugs, while VPA should
be administered only in pregnant woman unresponsive to
other ASMs [103,127,128], preferably not during the first
trimester pregnancy due to its teratogenic risk [123]. IV
PHT (15–18 mg/kg) should be infused via separate venous
access in a large vein to reduce the risk of phlebitis, with
continuous monitoring of heart rate and arterial pressure
[34]. IV LEV at 60 mg/kg (max 4500 mg) [34] is a valid
alternative and it is widely used in clinical practice due to
its safety and effectiveness. Prasad et al. demonstrated that
LEV is effective as lorazepam in aborting seizures (RR: 0.97;
95%CI: 0.44–2.13). VPA (40 mg/kg; max 3000 mg) is recom­
mended by most guidelines, keeping in mind the well-
known dose-dependent teratogenic risk [129–131].
In patients with RSE or SRSE, continuous IVADs (midazolam,
propofol, thiopental or ketamine) infusion [123,132] is needed.
There is no general consensus regarding which IVAD should
be used, especially in pregnant women [17]. Each woman with
SE treated with IVADs needs a continuous electroencephalo­
graphic monitoring [34,133]. The use of midazolam (0.1–
0.3 mg/Kg, max 4 mg/min followed by 0.2–0.6 mg/kg/h) and
propofol (bolus 1–2 mg/kg, followed by continuous infusion at
2–12 mg/kg/h) is favored by their short half-life, cardiovascular
stability, and lower risk of hepatotoxicity compared with thio­
pentone (1–3 mg/kg in bolus, followed by continuous infusion
at 3–5 mg/kg/h) [15,121]. Ketamine (0.5–4 mg/kg bolus, then
infusion at 0.3–5 mg/kg/h) may be a potential and effective
alternative therapy for RSE in pregnant patients [120], with
a success rate ranging from 32 to 73% [133], without any
impairment on feto-maternal outcomes [134]. Overall, not­
withstanding the lack of safety data on fetal exposure to
ketamine, its use may be justified by the maternal and fetal
risks associated with RSE and SRSE [120]. Termination of preg­
nancy, via delivery or abortion, should be considered if the
prolonged exposure to multiple antiepileptic strategies is not
able to solve SE [17,19,22,33]. The most suitable timing for
pregnancy termination is unclear and its therapeutic choice in
the first two trimesters imposes ethical and medico-legal con­
siderations [22]. Within 23 weeks of gestation the fetus has not
any life expectancy; after 23 weeks, fetal survival and neonatal
outcomes are directly proportional to gestation epoch. Thus,
after a firstly attendance time, the termination option should
be considered and discussed with patient’s family [22]. The
EXPERT REVIEW OF NEUROTHERAPEUTICS 307
therapeutic effect of termination can be attributed to re-
alteration of neuronal excitability, re-constitution of immunity
and reestablishment of hormonal balance [22].
3.2.2. SE in eclampsia
Eclampsia is a rare but serious complication occurring in
0.8% of pregnant women with hypertensive disorders
[135]; it is defined as the occurrence of coma or of one or
more generalized, tonic-clonic seizures unrelated to other
medical conditions in pregnant women with signs and
symptoms of preeclampsia (hypertension, ankle edema, pro­
teinuria). Status epilepticus in eclampsia is related to high
feto-maternal morbidity and mortality. Key-factors are con­
trolling SE, maintaining treatment to prevent further sei­
zures minimizing and treating fetus-maternal
complications, optimizing the timing of birth [83].
Specifically, acute maternal complications are placental
abruption, Hemolysis, Elevated Liver enzymes and Low
Platelets (HELLP) syndrome, disseminated intravascular coa­
gulation, pulmonary edema, aspiration pneumonia, cardio­
pulmonary arrest, and acute renal failure, whereas a high
perinatal mortality and morbidity risk (5.6–11.8%) is due to
placental abruption, fetal growth restriction, or extreme
prematurity [135,136]. Indeed, newborns are at increased
risk of being SGA and having complications related to pre­
maturity, such as respiratory distress syndrome and neona­
tal death [135,136].
Magnesium sulfate is the treatment of choice in women
with eclampsia and SE [135]. A loading IV dose of 4 to 6 g
over 15 to 20 minutes is recommended, followed by
a maintenance dose of 2 g per hour as a continuous IV
infusion. If a safe IV access is not available, an IM injection
of magnesium at the loading dose of 10 g (5 g IM in each
buttock) should be exerted, followed by 5 g every 4 hours
[135]. Duration of treatment should not normally exceed
24 hours [83]. Magnesium sulfate has a dose-response
effect on smooth muscle which may lead to respiratory
depression and bradycardia or even to respiratory or car­
diac arrest, so a careful clinical monitoring has to be
exerted [83]. During or immediately after the acute epi­
sode, supportive care (airway patency, ensuring oxygena­
tion, and avoiding aspiration) should be given to prevent
serious maternal injury [135]. Moreover, fetal monitoring
should be undertaken.
As regards comparative efficacy, magnesium sulfate was
better than phenytoin (RR: 0.34; 95% CI: 0.24–0.49) and nimo­
dipine (RR: 0.33; 95% CI: 0.14–0.77) in reducing recurrence of
seizures and maternal death, and in improving neonatal out­
come [137].
About 10% of women with eclampsia may have a seizure
recurrence after receiving magnesium sulfate [138]. In this
case, a second bolus of 2 g of magnesium sulfate can be
given IV over 3 to 5 minutes [135]. If SE persists, IV BDZ
bolus is needed [135]. If BDZ bolus is ineffective, continues
IV infusion of midazolam or other anesthetic agents (see
chapter 3.2.1), are needed [27,139–141].
308 R. ROBERTI ET AL.

The decision to perform a cesarean delivery should be 5. Expert opinion

based on gestational age, fetal condition, presence of labor,
SE is a life-threating condition for both mother and fetus.
and cervical bishop score. Once the maternal and fetal
A multidisciplinary team (i.e. experts in neurocritical care,
status are stable, and if patient is alert and oriented, labor
epilepsy, gynecology) is required for an appropriate man­
induction should be started. Fishel Bartal et al. [135] suggest
agement [120]. Therapeutic approach depends on various
that induction is reasonable as long as the patient is in the
factors such as the period of gestation, etiology and asso­
active phase within 24 hours. In patients with eclampsia
ciated co-morbidities [141] as well as risk-benefit balance for
before 30 weeks of gestation who are not in labor with an
both mother and fetus. In all cases, the main aim should be
unfavorable cervix (Bishop score of <5), there is a very low
the rapid termination of the SE and the appropriate man­
(<10%) success rate in labor induction, so cesarean delivery
agement of the underlying etiology (e.g.: IV steroids in
is recommended [135].
women with autoimmune encephalitis or anticoagulation
in patients with cerebral venous thrombosis) [121]. Early
identification and treatment of patients represent a crucial
4. Fetal monitoring during SE point to decrease unfavorable outcome, since mortality risk
dramatically increases with prolonged duration of SE.
SE in pregnant patients can compromise placental flow, causing
The management of SE is extremely challenging in
fetal hypoxia, potentially leading to severe neurodevelopmental
pregnancy as evidence-based protocols for treatment are
delays [17]. Maternal hypoxia may develop in women with SE
currently unavailable. The rarity of this condition and the
due to aspiration pneumonia, or pulmonary edema. Maternal
scarcity of literature represent hampering factors for the
hypoxia and hypercapnia can cause fetal heart rate and uterine
formulation of a uniform evidence-based treatment proto­
activity changes during and immediately after seizures. Fetal
col. Multicenter prospective trials are needed. Based on the
heart rate changes include bradycardia, late decelerations,
available literature data, we attempt to propose a useful
decreased variability, or compensatory tachycardia. Uterine con­
multidisciplinary-based protocol approach (Figure 1) which
tractions can increase in frequency and tone. These changes
might ensure effectiveness in SE control and reduce mater­
usually resolve within 3 to 10 minutes after the termination of
nal and fetal risks.
seizures and correction of maternal hypoxia [135].
The traditional obstetric teaching is that, when managing
seizures or SE in a pregnant patient, every attempt should be
made to stabilize the mother and resuscitate the fetus in utero 5.1. SE in pregnancy (outside eclampsia)
before making a decision about delivery [142]. It has been ● Supportive care (airway patency, ensuring oxygenation,
shown that, if the fetal heart rate is normalized by maternal and avoiding aspiration) should be given.
treatment, expectant management until full term may be an ● BDZs (lorazepam, midazolam or diazepam) bolus are the
option to prevent the complications that are associated with drugs of choice for initial SE management.
premature delivery in infants [143]. ● If SE persist, LEV or PHT (or pPHT) bolus are suggested.

Figure 1. Proposed therapeutic approach for SE in pregnancy (Created with BioRender.com).


● VPA may be useful if the above mentioned ASMs fail,
preferably in the second or third trimester.
● If SE persist, IVADs are needed, with propofol and mid­
azolam as preferred drugs.
● Termination of pregnancy, via delivery or abortion, is
recommended if the prolonged exposure to multiple
drugs fail and after a care risk-benefit balance for both
mother and fetus.
5.2. SE in eclampsia
● Supportive care (airway patency, ensuring oxygenation,
and avoiding aspiration) should be given.
● Magnesium sulfate is the treatment of choice.
● If SE persists, a second IV bolus of magnesium sulfate
should be given.
● If SE continues, IV BDZ bolus is recommended.
● If SE persists, IVADs are needed are needed.
● Induction of labor may be scheduled if feto/maternal con­
ditions are stable and patient is well alert and oriented.
Cesarean delivery is recommended if maternal and fetal status
are not reassuring, if eclampsia arises before 30 weeks of
gestation, if Bishop score is low.
Declaration of interests
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Funding
This paper was not funded
ORCID
Angelo Pascarella http://orcid.org/0000-0002-0085-9494
Emilio Russo http://orcid.org/0000-0002-1279-8123
Umberto Aguglia http://orcid.org/0000-0002-4574-2951
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