Expert Review
org
Eclampsia in the 21st century
Michal Fishel Bartal, MD; Baha M. Sibai, MD
Definition and Incidence
Eclampsia is one of the most serious
acute complications of pregnancy, and it
carries high morbidity and mortality for
both the mother and baby.1 Eclampsia is
defined as the occurrence of 1 or more
generalized, tonic-clonic convulsions
unrelated to other medical conditions in
women with hypertensive disorder of
pregnancy. Although 10% of pregnan-
cies are complicated by hypertensive
disorders, eclampsia continues to occur
in 0.8% of women with hypertensive
disorders.2 During the past 50 years,
there has been a reduction in the rate of
eclampsia in developed countries with a
reported incidence ranging from 1.6 per
10,000 deliveries to 10 per 10,000
deliveries.3e13 In some low-resource or
developing countries, the reported rate
of eclampsia ranges from 50 to 151 per
10,000 deliveries (Figure 1).14e18
Although the rate of eclampsia and the
number of maternal deaths from hy-
pertension in pregnancy have fallen
steadily over recent years in developing
countries, hypertensive disorders still
feature among the top 6 causes of
maternal mortality in the United States
and are responsible for up to 14% of all
maternal deaths worldwide.1,19e21 Our
impression is that differences in the
incidence and complication rates be-
tween developed and developing coun-
tries result from gaps in access to care,
appropriate and early prenatal care,
From the Division of Maternal-Fetal Medicine,
Department of Obstetrics, Gynecology and
Reproductive Sciences, McGovern Medical
School, The University of Texas Health Science
Center at Houston, Houston, TX.
Received May 27, 2020; revised Sept. 14, 2020;
accepted Sept. 22, 2020.
The authors report no conflict of interest.
This paper is part of a supplement.
Corresponding author: Michal Fishel Bartal, MD.
Michal.f.bartal@uth.tmc.edu
0002-9378/$36.00
Published by Elsevier Inc.
https://doi.org/10.1016/j.ajog.2020.09.037
ajog.
The reported incidence of eclampsia is 1.6 to 10 per 10,000 deliveries in developed
countries, whereas it is 50 to 151 per 10,000 deliveries in developing countries. In
addition, low-resource countries have substantially higher rates of maternal and perinatal
mortalities and morbidities. This disparity in incidence and pregnancy outcomes may be
related to universal access to prenatal care, early detection of preeclampsia, timely
delivery, and availability of healthcare resources in developed countries compared to
developing countries. Because of its infrequency in developed countries, many obstet-
rical providers and maternity units have minimal to no experience in the acute man-
agement of eclampsia and its complications. Therefore, clear protocols for prevention of
eclampsia in those with severe preeclampsia and acute treatment of eclamptic seizures
at all levels of healthcare are required for better maternal and neonatal outcomes.
Eclamptic seizure will occur in 2% of women with preeclampsia with severe features who
are not receiving magnesium sulfate and in <0.6% in those receiving magnesium
sulfate. The pathogenesis of an eclamptic seizure is not well understood; however, the
blood-brain barrier disruption with the passage of fluid, ions, and plasma protein into the
brain parenchyma remains the leading theory. New data suggest that blood-brain barrier
permeability may increase by circulating factors found in preeclamptic women plasma,
such as vascular endothelial growth factor and placental growth factor. The management
of an eclamptic seizure will include supportive care to prevent serious maternal injury,
magnesium sulfate for prevention of recurrent seizures, and promoting delivery.
Although routine imagining following an eclamptic seizure is not recommended, the
classic finding is referred to as the posterior reversible encephalopathy syndrome. Most
patients with posterior reversible encephalopathy syndrome will show complete reso-
lution of the imaging finding within 1 to 2 weeks, but routine imaging follow-up is un-
necessary unless there are findings of intracranial hemorrhage, infraction, or ongoing
neurologic deficit. Eclampsia is associated with increased risk of maternal mortality and
morbidity, such as placental abruption, disseminated intravascular coagulation, pul-
monary edema, aspiration pneumonia, cardiopulmonary arrest, and acute renal failure.
Furthermore, a history of eclamptic seizures may be related to long-term cardiovascular
risk and cognitive difficulties related to memory and concentration years after the index
pregnancy. Finally, limited data suggest that placental growth factor levels in women with
preeclampsia are superior to clinical markers in prediction of adverse pregnancy out-
comes. This data may be extrapolated to the prediction of eclampsia in future studies.
This summary of available evidence provides data and expert opinion on possible
pathogenesis of eclampsia, imaging findings, differential diagnosis, and stepwise
approach regarding the management of eclampsia before delivery and after delivery as
well as current recommendations for the prevention of eclamptic seizures in women with
preeclampsia.
Key words: abruption, angiogenic, cardiovascular, cerebral edema, convulsions, fetal
death, fetal growth restriction, hypertensive disorder of pregnancy, magnesium sulfate,
maternal mortality, placental growth factor, posterior reversible encephalopathy syn-
drome, seizures, severe maternal morbidity, soluble endoglin, soluble fms-like tyrosine
kinase-1, vascular endothelial growth factor
surveillance and management protocols heart failure and magnesium sulfate
for timely hospitalization and delivery, prophylaxis during the peripartum
antihypertensive therapy for prevention period in women with severe
of stroke, pulmonary edema, congestive preeclampsia.22,23
FEBRUARY 2022 American Journal of Obstetrics & Gynecology S1237
Expert Review
Pathophysiology
The pathogenesis of eclamptic seizures is
not well understood. Several hypotheses
and pathologic mechanisms have been
implicated, but none has been proven.
One proposed model for eclampsia is the
alteration of autoregulation in the cere-
bral circulation similar to hypertensive
encephalopathy with blood-brain bar-
rier (BBB) disruption and passage of
fluid, ions, and plasma proteins into the
brain parenchyma. The BBB created by
the endothelial cells lining the walls of
the capillaries regulates the paracellular
(transfer of substances across an epithe-
lium by passing through the intercellular
space between the cells) and transcellular
(transfer of substances travel through the
cell, through both the apical mem-
branes) passages of molecules and sol-
utes between the cerebral vessels and the
brain. The capillary endothelium is
characterized by the presence of tight
junctions with lack of fenestrations. The
tight junctions between the endothelial
cells form a barrier, which selectively
excludes most substances from entering
the brain, protecting it from systemic
influences.24 The BBB provides not only
a stable environment for neural function
but also a combination of specific ion
channels and transporters to keep the
ionic composition optimal for synaptic
signaling function.25,26 The autor-
egulation of the cerebral circulation is a
mechanism to maintain constant cere-
bral blood flow during changes in blood
pressure. With normal response, vaso-
constriction of the cerebral vessels will
occur in response to elevated blood
pressure, whereas vasodilation occurs
when blood pressure is lowered. Cere-
bral blood flow autoregulation is medi-
ated and modulated through myogenic,
neurogenic, metabolic, or endothelial
control.27e29 Myogenic control induces
vascular smooth muscle constriction or
dilation in response to transmural pres-
sure. Neurogenic control occurs through
perivascular sympathetic and cholin-
ergic responses. Metabolic control oc-
curs in response to changes in carbon
dioxide, oxygen, and protons and is
tightly linked to neuronal activity.
Endothelial control occurs in response to
S1238 American Journal of Obstetrics & Gynecology FEBRUARY 2022
factors released from endothelial cells,
such as nitric oxide, which acts as a
vasodilator or endothelin-1, a vasocon-
strictor. With the increase in plasma
volume and cardiac output during
pregnancy, the adaption of the cerebral
circulation to pregnancy is unique from
other organs because of the need to
maintain constant flow, whereas other
organ systems undergo substantial in-
creases in blood flow.30 One mechanism
suggested for eclampsia is similar to the
pathophysiological changes described in
hypertensive encephalopathy, autor-
egulation failure in acute hypertension,
which leads to increased hydrostatic
pressure and decreased cerebral vascular
resistance, potentially damaging the
microvessels and resulting in increased
BBB permeability, microbleeds, focal
cerebral edema, neuroinflammation,
and neuronal damage.29,31e33 This the-
ory cannot explain all the cases of
eclampsia as some women with
eclampsia do not have severe hyperten-
sion (systolic blood pressure [SBP] of

160 mm Hg or diastolic blood pressure
[DBP] of
110 mm Hg) before an
eclamptic seizure. One possible expla-
nation previously suggested is a shift in
the autoregulation curve to a lower
blood pressure during pregnancy. This
mechanism can potently improve cere-
bral blood flow during hemorrhagic
hypotension but could be related to
autoregulation failure even without se-
vere range blood pressure during
pregnancy.34e36 However, recent data
did not find any difference in cerebral
blood flow or autoregulation break-
through between nonpregnant and
pregnant animal models.31,37
Furthermore, new data suggest that
BBB permeability may increase by
circulating factors found in the plasma of
women with preeclampsia, such as
vascular endothelial growth factor
(VEGF) and placental growth factor
(PlGF).38,39 One mechanism suggested
to affect the BBB includes increased
levels of oxidized low-density lipopro-
tein (oxLDL) in women with pre-
eclampsia.40,41 Increased oxidative stress
in the placental circulation during pre-
eclampsia causes oxidative conversion of
ajog.org
LDL to oxLDL. oxLDL initiates multiple
pathways in both endothelial and
vascular smooth muscle cells, mostly
through binding to its receptor lectin-
like oxLDL receptor (LOX-1).42 oxLDL
binding to LOX-1 generates complex
signaling cascades leading to the induc-
tion of the inflammatory pathway and
increase production of superoxide in
endothelial cells that can further pro-
mote vascular dysfunction.43,44 Super-
oxide decreases the concentration of
nitric oxide by binding nitric oxide to
form peroxynitrite, a stable reactive ox-
ygen and nitrogen species that has dele-
terious effects on endothelial
function.45e47 Increased BBB perme-
ability caused by oxLDL may promote
vasogenic edema formation and the
neurologic sequela.44 BBB dysfunction
has also been suggested as an important
etiologic player in seizure disorders and
has recently been described as another
suggested mechanism for seizure activity
in women preeclampsia.24,48 In this
mechanism, increased BBB permeability
will allow the passage of serum constit-
uents into the brain, subsequently
causing microglial activation. Microglial
activation has been shown to decrease
seizure threshold through the secretion
of proinflammatory cytokines in
different animal models.24,48,49
As discussed, the mechanisms by
which eclampsia occurs is not clearly
understood, but it may involve a patho-
logic process involving BBB dysfunction
with increased BBB permeability. With
imaging studies being done after
eclamptic seizures, it is impossible to
state whether vasogenic edema was pre-
sent before the seizure and is therefore a
cause or whether it is an effect of
eclamptic seizures because seizures
themselves cause disruption of the BBB
and often include hypertensive crises.
Another possible mechanism for
eclampsia previously suggested was cere-
bral overregulation and vasospasm. Ce-
rebral overregulation will occur when the
normally protective cerebral vasocon-
strictive response to acute severe hyper-
tension progresses to vasospasm.
Vasospasm is thought to cause local
ischemia, necrosis, and disruption of the
ajog.org
FIGURE 1
Rate of eclampsia and hypertensive related maternal mortality
Rate of eclampsia per 10,000 deliveries and rate of eclampsia or HDP mortality per 10,000 deliveries in developed and developing countries based on the
current published data.
HPD, hypertensive disorder of pregnancy.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
BBB, which leads to cerebral edema.50e54
If this theory was true, then a specific
cerebral vasodilator would be more
effective at relieving vasospasm (and thus
a better drug to prevent eclampsia) than
magnesium sulfate. The nimodipine
study (in which women with severe pre-
eclampsia were randomly assigned to
receive a selective cerebral vasodilator:
nimodipine vs magnesium sulfate) indi-
cated that deliberate cerebral vasodilata-
tion, which interfered with the protective
physiological vasoconstriction, actually
increased the eclampsia rate (2.6% with
nimodipine vs 0.8% with magnesium
sulfate).55 Those findings suggest that
seizures in patients with eclampsia are
more likely related to overperfusion than
vasospasm or ischemia.54
Cerebral Pathology
Cerebral pathology autopsy findings
typical in eclampsia include massive ce-
rebral edema, white matter hemorrhage,
and necrosis.56 Brain lesions assessed in
317 cases of maternal death from
eclampsia were characterized by peri-
vascular edema (68.4%), hemorrhage
(36.8%), hemosiderin (31.6%), small
vessel thrombosis (10.5%), and
parenchymal necrosis (15.8%). The le-
sions in the brain are not specific; there
are similar changes in other forms of
systemic endothelial injury, such as
thrombotic microangiopathy, atypical
hemolytic-uremic syndrome, malignant
hypertension, and antiphospholipid
antibody syndrome.56
Neurodiagnostic Tests
Several neurodiagnostic tests, such as
electroencephalography (EEG), computed
tomography (CT), magnetic resonance
imaging (MRI), and cerebral angiography,
have been studied in women with
eclampsia. In reviewing an EEG, abnor-
malities in waveform, frequency, ampli-
tude, symmetry, and reactivity patterns (ie,
slow waves or spikes or spike-wave
complexes) are documented, including
localization (focal vs diffuse or gener-
alized). A review evaluating the avail-
able medical literature concerning EEG
findings in patients with eclampsia
included 153 patients from 8 available
studies. On average, 81% of the EEGs of
women with eclampsia showed EEG
abnormalities following the seizure
with resolution of those abnormalities
in 90% of cases soon after delivery.57,58
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
The nonpathognomonic EEG findings
in patients with eclampsia were slow
waves most frequently localized in the
occipital lobe and spike discharges.59 In
addition, the abnormal EEG findings in
women with eclampsia were seen even
with appropriate administration of
magnesium sulfate. This finding may
suggest that the central anticonvulsant
activity in eclamptic seizures does not
completely explain the magnesium
sulfate mechanism of action (discussed
below).60
Abnormal neuroimaging findings in
eclampsia are similar to those found in
hypertensive encephalopathy, including
cerebral edema, infarction, and hemor-
rhage.61 The classic finding following an
eclamptic seizure is referred to as pos-
terior reversible encephalopathy syn-
drome (PRES) (Figure 2). PRES is a
reversible neurologic disorder charac-
terized by a range of neurologic signs and
symptoms, including headache,
impaired visual acuity or visual field
deficits, disorders of consciousness,
confusion, seizures, and focal neurologic
deficits.62 The distinctive neuroimaging
findings in PRES are focal or confluent
vasogenic edema with classic posterior
S1239
Expert Review ajog.org

that leads to cerebral hyperperfusion,

FIGURE 2
with vascular leakage and vasogenic
Posterior reversible encephalopathy syndrome on MRI edema, and endothelial injury by circu-
lating endogenous or exogenous toxins,
which leads to the breakdown of the BBB
and subsequent brain edema.62,64,65 PRES
can be seen in up to 90% of women with
eclampsia but has also been described in
up to 20% of women with preeclampsia
and neurologic symptoms limited to
headache and visual disturbances.61,66e68
The clinical picture of women with
eclampsia, either with or without associ-
ated PRES, is similar. However, some
studies suggest that PRES might be
indicative of a more severe disease
process.65,69e71 The prognosis of PRES
following eclampsia is favorable, and
most patients will recover within 1 week,
although some patients can occasionally
take several weeks to achieve full recovery.
MRI of the brain reveals posterior reversible encephalopathy syndrome in a woman with eclampsia.
In rare cases, severe neurologic injury and
A, Occipital lobe hyperintensity on postpartum day 1. The arrow points at a vasogenic edema that is
fatality can occur because of intracranial
considered reversible. B, Interval improvement in vasogenic edema on postpartum day 5.
hemorrhage, posterior fossa edema with
MRI, magnetic resonance imaging.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
brainstem compression, or cerebral
infraction.64,72,73
We do not recommend neuroimaging
parietal and occipital lobe involvement. neurologic symptoms with PRES have routinely for patients with eclampsia.74
Subcortical white matter is usually shown blood vessel irregularities Neuroimaging studies could generally
involved, but even cortical gray matter consistent with reversible vasoconstric- be limited to those women who have
can be involved, depending on the tion (Figure 3). The leading theories focal neurologic signs, recurrent con-
severity of the disease.63 Some reports of regarding the pathophysiology of PRES vulsions, and prolonged coma. Imaging
MRI angiography in women with are elevation of blood pressure levels can also be considered in atypical cases,
eclampsia or preeclampsia with above the upper autoregulatory limit such as seizures that develop at or before
20 weeks of gestation and >48 hours
after delivery and for women that have
some of the signs and symptoms of
FIGURE 3
preeclampsia without the usual hyper-
Cerebral vasoconstriction on magnetic resonance angiography imaging
tension.75,76 In these patients, intracra-
nial hemorrhage and other serious
abnormalities that require specific
pharmacologic therapy or surgical
intervention must be excluded.
Most patients with PRES will show
complete resolution of the imaging
finding in 1 to 2 weeks, and others will
show widespread regression in up to 1
month.65,71 Based on our clinical expe-
rience, we recommend follow-up imag-
ing in 3 to 4 weeks only if there is
evidence for cerebral hemorrhage or
infraction or if there is ongoing neuro-
A, Normal magnetic resonance angiography imaging of a woman on postpartum day 1. B, Magnetic
logic deficit.
resonance angiography on postpartum day 6 when the patient presented with eclamptic seizure. The
Imaging studies several years
arrows indicate vasoconstriction on medium and small blood vessels.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
following an eclamptic seizure found
that white matter lesions are more

S1240 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org
common in women with previous
pregnancies complicated by preeclamp-
sia or eclampsia than in parous women
in a control group.77,78 MRI scans 7 years
after the index pregnancy of 39 women
who formerly had eclampsia were
compared with 29 control women.
Women with eclampsia demonstrated
subcortical white matter lesions more
than twice as often than controls (41% vs
17 %; odds ratio [OR], 3.3; 95% confi-
dence interval [CI], 1.05e10.61; P¼.04).
In addition, there was a positive corre-
lation between the number of seizures
and the presence of white matter lesions.
Women who had experienced 3 or more
seizures (n¼10) demonstrated white
matter lesions more than 3 times as often
as than controls.78
Risk Factors
Risk factors for eclampsia are similar to
those that have been associated with
preeclampsia or gestational hyperten-
sion. Several factors have been associated
an with increased risk of eclampsia,
including black and Hispanic race,
advanced maternal age, nulliparity,
maternal age of 20 years, multifetal
gestation, preterm delivery at <32 weeks
of gestation, and lack of prenatal
care.6,79,80 With the implementation of
protocols for magnesium sulfate pro-
phylaxis for women presenting with se-
vere hypertension, eclampsia may be
considered a preventable disease in many
of the cases. The rate of seizures in
women with severe preeclampsia not
receiving magnesium sulfate is 2.0%,
whereas it is 0.6% in those receiving
magnesium sulfate. Thus, 71 women
with severe preeclampsia need to be
treated to prevent 1 case of eclampsia.
The rate of seizures in women with
preeclampsia without severe features not
receiving magnesium sulfate is very low.
Based on data from observational studies
and the 2 randomized placebo trials, this
rate is estimated to be about 1 in 200
women.81 Therefore, it is anticipated
that the rate of eclampsia in gestational
hypertension will be lower than 1:200. A
recent national population-based retro-
spective cohort study of deliveries in
Norway, including 1387 women with
eclampsia or HELLP syndrome
(hemolysis, elevated liver enzymes, and
low platelet count), emphasizes the
importance of available obstetrics hos-
pitals. Nulliparous women living
>1 hour from any obstetrical institution
had a 50% increased risk of eclampsia or
HELLP syndrome and parous women
living >1 hour from emergency in-
stitutions had a doubled risk of
eclampsia (0.6% vs 0.3%, adjusted rela-
tive risk [RR], 2.0; 95% CI, 1.2e3.3)
compared with women living 1 hour
from an obstetrical institution.82
Presentation and Diagnosis
Several signs and symptoms may pre-
cede eclampsia, such as visual distur-
bances, epigastric pain, and severe
persistent occipital or frontal headaches,
but none can accurately predict or
exclude eclampsia.16,83e85 Visual
changes may include blurry vision,
diplopia (double vision), scotoma (par-
tial loss of vision or blind spot), pho-
topsia (flashes of light in the field of
vision), and transient cortical blind-
ness.86,87 In a systematic review of 2163
women with eclampsia and reported
symptoms, the most common symp-
toms were headache (66%), visual
disturbance (27%), and right upper
quadrant or epigastric pain (25%).88
When a woman presents with hyper-
tension, proteinuria, and convulsions,
most clinicians would agree that the
diagnosis of eclampsia is clear. However,
although hypertension is the hallmark
for the diagnosis of eclampsia, it may be
absent in up to 25% of cases. Further-
more, severe hypertension is more
common in women who developed
antepartum eclampsia than in women
with postpartum preeclampsia.89 The
American College of Obstetricians and
Gynecologists Task Force report on hy-
pertension in pregnancy, and the Inter-
national Society for the Study of
Hypertension in Pregnancy removed the
requirement of proteinuria for the
diagnosis of preeclampsia if there are
other findings suggestive of end-organ
involvement (thrombocytopenia,
elevated liver transaminases, renal
insufficiency, pulmonary edema, or
new-onset neurologic symptoms).90,91
Women with eclampsia can present
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
with proteinuria, but previous studies
have found that substantial proteinuria
(
3 on a dipstick) was present only in
48% of cases and proteinuria was absent
in 14% of cases.89
The most common finding during
the neurologic examination following a
seizure is altered mental status and
deficits of memory or visual
perception.87
Time of Onset
The onset of eclamptic convulsions can
be in the antepartum, intrapartum, or
postpartum period with 50% to 70% of
eclamptic seizures in developing coun-
tries occurring in the community and
not in the hospital.17 Up to 59% to 70%
of seizures will occur during the ante-
partum period, whereas around 20% to
30% will occur during labor and 20% to
30% in the postpartum period.16,88,89
Almost all cases of antepartum
eclampsia will occur after 28 weeks of
gestation. Eclampsia that occurs before
20 weeks of gestation is usually associ-
ated with a molar pregnancy, with or
without a coexistent fetus.75,92 Further-
more, the presence of hypertension,
proteinuria, and abnormal laboratory
tests at 20 weeks of gestation may be
owing to lupus nephritis, hemolytic-
uremic syndrome, antiphospholipid
antibody syndrome, or thrombotic
thrombocytopenic purpura. Women
presenting with eclampsia before 20
weeks of gestation should be evaluated
for these different disorders. Although
exceedingly rare, women in whom con-
vulsions develop in association with hy-
pertension and proteinuria during the
first half of pregnancy should be
considered to have eclampsia until
proven otherwise. These women should
have an ultrasound examination to rule
out molar pregnancy and an extensive
neurologic and medical evaluation to
rule out another pathologic process.
Historically, preeclampsia and
eclampsia were believed to occur only
within 48 hours following delivery.
However, retrospective data evaluating
timing of postpartum eclampsia in 29
women found that 79% had late-onset
seizures (>48 hours from delivery).93
Late postpartum eclampsia can occur
S1241
Expert Review ajog.org

TABLE 1
Differential diagnosis of seizure during pregnancy or after delivery
Potential causes of seizures in pregnancy and after delivery
Seizure disorder
Pregnancy related
B Eclampsia

B Thrombotic thrombocytopenic purpura

B Amniotic fluid emboli

Neurovascular
B Intracranial hemorrhage

B Subarachnoid hemorrhage (ruptured aneurysm or malformation)

B Arterial embolism or thrombosis

B Cerebral venous thrombosis

B Angiomas

B Space occupying lesion (benign, neoplastic, primary, metastatic)

B Posterior reversible encephalopathy syndrome

B Congenital brain defects

Metabolic
B Liver or renal failure

B Hypoglycemia

B Hyponatremia
B Hyperosmolar states (hyperosmolar nonketotic hyperglycemia)

B Hypocalcemia

Autoimmune
B Systemic lupus erythematosus
B Antiphospholipid syndrome

Infectious encephalitis or meningitis: bacterial, viral, parasitic, tuberculosis

Drug or substance overdose or withdrawal (ie, antipsychotics, tricyclic antidepressants, salicylate overdose, withdrawal from alcohol, barbiturates,
benzodiazepines, illicit drug use such as cocaine, methylenedioxymethamphetamine)
Trauma
Psychogenic nonepileptic seizures (pseudoseizures)
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.

>48 hours but <6 weeks after
delivery.87,93e95 Based on our experience
and review of literature, we recommend
that after delivery, any woman with
convulsions >48 hours after delivery
who is hypertensive or has either pro-
teinuria or symptoms of preeclampsia
should be considered eclamptic, while
other causes are being ruled out.75
Differential Diagnosis
The clinical presentation and symptoms
of eclampsia may overlap with other
medical and surgical conditions. When a
woman is presenting with convulsions
that develop in association with hyper-
tension or proteinuria during pregnancy
or immediately postpartum, the most
common etiology is eclampsia.75 Alter-
native diagnoses should especially be
considered in the following scenarios:
normal blood pressures with absence of
proteinuria, focal neurologic deficits,
onset before 20 weeks of gestation or
>48 hours after delivery, or prolonged
loss of consciousness.96 The differential
diagnosis of seizures that should be taken
into consideration is listed in
Table 1.97,98 When an alternative diag-
nosis is considered, the path toward the
diagnosis of a seizure in pregnant
women will begin with a thorough his-
tory and physical examination. Under-
lying causes, including medications,
substance abuse, and medical comor-
bidities, should be evaluated. Although
not routinely recommended, complete
blood count, blood glucose, electrolyte
panels, urinary analysis for protein,
lumbar puncture, and toxicology studies
may be helpful based on clinical cir-
cumstances. Brain imaging with CT scan
or MRI for further assessment should be
done.99 The distinction of etiology is
critical, because therapy must be
directed at the underlying disorder.
Maternal and Neonatal Complications
Eclampsia is associated with a slightly
increased risk of maternal death in
developed countries, but the maternal
mortality rate may be as high as 7% in
developed countries.17,100 In a recent
cross-sectional study from 29 countries
including Africa, Asia, Latin America,
and the Middle East, the risk of death in
women with eclampsia increased expo-
nentially (adjusted OR [aOR], 42.38;
95% CI, 25.14e71.44) compared with
the risk of death in women without
preeclampsia. Furthermore, in
eclampsia, the risk of life-threatening
conditions involving the central

S1242 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org Expert Review

nervous system, such as coma or loss of

consciousness lasting 12 hours, stroke, TABLE 2
status epilepticus, or total paralysis, were Acute maternal complications in eclampsia
up to 60 times more frequent than those Complication %
in women without preeclampsia.101 Death 0.0e1.0
Maternal adverse outcomes and death
Cerebrovascular disease 2.0e4.0
from a complication related to pre-
eclampsia are most common among Heart failure 3.0e9.5
women who are older than 35 years, Cardiomyopathy 1.0
foreign-born Hispanic and African Cardiac arrest 0.5
American women, at 20 to 28 weeks of
Aspiration pneumonia 2.0e4.0
gestation, have multiple gestations, and
among women with the first live Pulmonary edema 3.0e12.0
birth.1,5,102 In a retrospective review of all Placental abruption 7.0e12.0
preeclampsia-related deaths identified by Acute renal failure 3.0e8.8
the California Pregnancy-Associated
Disseminated intravascular coagulation 6.0e7.0
Mortality Review from 2002 to 2007,
there were 333 pregnancy-related Venous thromboembolism 4.7
maternal deaths in California. Of these, Blood transfusion 24.0
54 (16%) were associated with pre- Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
eclampsia, whereas eclampsia occurred in
36% of cases.1
Beyond the increased risk of mortality, about 25%, with higher risk if the onset cardiovascular morbidity during de-
eclampsia is associated with substantial of eclampsia was in the second trimester livery hospitalization. Eclampsia was
acute maternal complications (Table 2). of pregnancy. The rate of recurrent associated with a 12-fold increased risk
Women with eclampsia have increased eclampsia is about 2%.105,106 of cardiovascular morbidity, such as
risk of severe maternal complications, Beyond the acute morbidities in myocardial infarction, cerebrovascular
such as placental abruption, HELLP, those with eclampsia, there is the po- disease, acute heart failure, cardiomy-
disseminated intravascular coagulation, tential for long-term sequela. A recent opathy, or cardiac arrest.107 The risk of
pulmonary edema, aspiration pneu- retrospective cohort study of 569,900 a future seizure disorder following
monia, cardiopulmonary arrest, and women, of whom 39,624 had hyper- an eclamptic seizure was evaluated in
acute renal failure (Figure 4).3,5,89,103 tensive disorder of pregnancy and 319 a large retrospective database of
Women in whom eclampsia developed (0.06%) had eclampsia, evaluated 1,565,733 births, of whom 1615 women
at 32 weeks of gestation have a re-
ported higher incidence of placental
abruption, HELLP syndrome, and acute FIGURE 4
renal failure than those in whom Chest X-ray revels pulmonary edema in a woman presenting with
eclampsia developed later.89 eclampsia
Perinatal mortality and morbidity
remain high in eclamptic pregnancies.
The reported perinatal death rate ranges
from 5.6% to 11.8%.6,103 Most perinatal
death cases are related to placental
abruption, fetal growth restriction, or
extreme prematurity.104 Neonates of
women with eclampsia are at increased
risk of being small for gestational age
(SGA) and having complications related
to prematurity, such as respiratory
distress syndrome and neonatal death.6,13

Long-term Maternal Prognosis

Women with a history of eclampsia are at A, A large volume of pink-tinged frothy fluid from the trachea in a woman intubated following an
increased risk of preeclampsia in a sub- eclamptic seizure. B, Chest X-ray indicates bilateral pulmonary edema.
sequent pregnancy. The rate of pre- Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
eclampsia in subsequent pregnancies is

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S1243

Expert Review
were previously affected by eclampsia.
A future seizure disorder (defined as more
than 30 days after the index birth
discharge date and not more than 20
weeks of gestation in a subsequent preg-
nancy) was more likely after a pregnancy
with eclampsia (4.58 per 10,000 person-
years) than a pregnancy without a hy-
pertensive disorder of pregnancy (0.72 per
10,000 person-years; crude RR, 6.09; 95%
CI, 2.73e13.60). Although the RR of a
seizure disorder is higher than unaffected
women, the absolute risk is extremely low
(approximately 1 seizure per 2200 person-
years).108
Moreover, women who suffered
eclampsia may report more long-term
cognitive difficulties related to memory
and concentration years after the index
pregnancy.109e112 A study evaluating 123
women 6 to 24 months after an
eclampsia noted that 51% of women had
at least 1 persistent symptom, 10% of
women reported persistent amnesia,
22% reported loss of memory, 11% re-
ported visual disturbances, 10% had
vertigo or balance problems, and 18%
reported ongoing headaches.112 Another
study evaluating subjective cognitive
functioning several years after a preg-
nancy complicated with eclampsia
(n¼30), women with a history of
eclampsia, reported impaired cognitive
functioning compared with healthy
parous women. In addition, women who
experienced multiple eclamptic seizures
reported greater cognitive impairment
than those who experienced 1 seizure.109
One study has evaluated visual fields and
the presence of brain white matter le-
sions on MRI in 47 women who had
experienced eclampsia-related PRES.
Women with a history of eclampsia re-
ported worse vision-related quality of
life compared with women who had
normotensive pregnancies. Further-
more, 36% of women had white lesions
on MRI, but none of them had visual
field defects on MRI. The lower vision-
related quality of life was associated
with the presence of cerebral white
matter lesions; however, these lesions did
not seem to induce visual field loss.113
Although women with history of
eclampsia may report subjective cogni-
tive dysfunction, data do not
S1244 American Journal of Obstetrics & Gynecology FEBRUARY 2022
demonstrate impaired cognitive func-
tioning using objective neurocognitive
assessments.105,114,115 A recent study
evaluated the cognitive functioning with
an average follow-up of 7 years in
women who had preeclampsia and
eclampsia using neurocognitive tests and
self-reported cognitive dysfunction and
measures of anxiety and depression.
Aside from minor slowing in motor
speed, no differences were seen in
objective measures of visual perception,
working memory, long-term memory,
attention, and executive functioning in
women with eclampsia (n¼46) or pre-
eclampsia (n¼51) compared with con-
trols. Women with eclampsia and
women with preeclampsia reported
more cognitive failures in daily life and
scored higher for anxiety and depres-
sion. Women with eclampsia did not
demonstrate worse cognitive or motor
performance than women with
preeclampsia.114
Prevention of Eclampsia
Primary prevention aims to prevent
disease or injury before it ever occurs.
For primary prevention of eclampsia,
low-dose aspirin (dosage ranging
60e150 mg daily) has been proven to
reduce the risk of preeclampsia by 10%
to 15%.116e119 Low-dose aspirin is rec-
ommended to women with a history of
preeclampsia, multifetal gestation,
chronic hypertension, type 1 or 2 dia-
betes, renal disease, and autoimmune
disease (ie, systemic lupus erythemato-
sus, antiphospholipid syndrome). Low-
dose aspirin should also be considered
if the patient has more than 1 of the
following risk factors: nulliparity,
obesity, family history of preeclampsia,
sociodemographic characteristics (Afri-
can American race, low socioeconomic
status), age of
35 years, and personal
history factors (low birthweight or SGA,
previous adverse pregnancy outcome,
more than 10-year pregnancy inter-
val).120 Secondary prevention will
include intervention for early detection
of the disease and reducing the impact of
a disease. Secondary prevention of
eclampsia will include weekly moni-
toring for women with gestational hy-
pertension or preeclampsia, use of
ajog.org
antihypertensive medications for blood
pressure regulation, timely delivery, and
prophylactic use of magnesium sulfate
during labor and immediately after de-
livery in women with preeclampsia with
severe features.120 We recommend that
women with gestational hypertension or
preeclampsia will have weekly follow-up
with close monitoring of blood pressure,
weekly laboratory test (complete blood
count, serum creatinine, aspartate
aminotransferase [AST], alanine trans-
aminase [ALT]), serial ultrasound to
determine fetal growth every 3 to 4
weeks, and weekly antepartum testing. If
there is no progression to preeclampsia
with severe features, induction of labor
at 37 weeks of gestation is recom-
mended. If there are signs or symptoms
for preeclampsia with severe features (ie,
SBP of
160 mm Hg or DBP of
110
mm Hg, thrombocytopenia, impaired
liver function, renal insufficiency, pul-
monary edema, new-onset headache, or
visual disturbances), the patient should
be admitted to the hospital and managed
according to the guidelines for pre-
eclampsia with severe features (discussed
below). It is important to emphasize that
about 20% to 40% of women with
eclampsia do not have any preceding
symptoms before the onset of the con-
vulsions. In fact, in up to 60% of cases,
seizure is the first sign of
preeclampsia.121,122
There is substantial evidence
regarding the use of magnesium sulfate
to prevent convulsions in women with
preeclampsia with severe features.2,55
Magnesium sulfate was found to be su-
perior to phenytoin, diazepam, or
nimodipine for the prevention of
eclampsia in women with preeclampsia
and is the drug of choice for the pre-
vention of a seizure.55,123e126 The largest
randomized controlled trials of magne-
sium sulfate for the prevention of
eclampsia are listed in Table 3. In a meta-
analysis, magnesium sulfate more than
halves the risk of eclampsia in women
with preeclampsia (RR, 0.41; 95% CI,
0.29e0.58), with a nonsignificant
reduction in maternal death (RR, 0.54;
95% CI, 0.26e1.10), with no clear dif-
ference in serious maternal morbidity
(RR, 1.08; 95% CI, 0.89e1.32), and with
ajog.org
TABLE 3
Large randomized controlled trials of magnesium sulfate in severe preeclampsia
Magnesium sulfate
First author, year dosing
Lucas et al,123 1995 LD, 10 mg IM
MD, 5 mg/4 h
Altman et al,2 2002 LD, IV 4 g or IM 10 g
MD, IV 1 g/h or IM 5 g/4 h
Coetzee et al,126 1998 LD, 4 g
MD, 4 g/4 h
Belfort et al,55 2003 LD, IV 6 g or 4 g
MD, IV 2 g/h or 1 g/h
IM, intramuscular; IV, intravenous; LD, loading dose; MD, maintenance dose, NC, not calculated; PO, per orem.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
a number needed to treat of 102 (95%
CI, 72e173) compared with placebo.125
It is currently not clear for how long
magnesium sulfate should be continued
after delivery and whether there is a
benefit to continue magnesium sulfate
for 8, 12, or 24 hours after delivery for
women that received magnesium sulfate
during labor. The current randomized
studies addressing the length of treat-
ment after labor and the associated risk
of eclampsia had small sample sizes,
which are inadequate to evaluate the risk
of eclampsia.127e132 The largest ran-
domized controlled study assessing
whether there is benefit for continuing
magnesium sulfate following delivery
included women with severe pre-
eclampsia who received magnesium
sulfate loading dose of 4 g and mainte-
nance dose of 1 g/h for 8 hours before
delivery. A total of 1113 women were
enrolled and randomized either to
continue the infusion of magnesium
sulfate for 24 hours after delivery or
stopping the magnesium sulfate infusion
immediately after delivery. The primary
outcome was the incidence of eclampsia
at the first 24 hours after delivery. There
was no difference in the rate of eclampsia
between the groups; there were 1 of 555
cases of eclampsia (0.18%) in the 24-
hour magnesium sulfate group vs 2 of
558 cases of eclampsia (0.35%) when
magnesium sulfate was stopped at de-
livery (RR, 0.7; 95% CI, 0.1e3.3; P¼.50).
Comparison
group
Phenytoin
LD, IV 1000 mg
MD, PO 500 mg after 10 h
Placebo
Placebo
Nimodipine, 60 mg/4 h
Although this randomized control study
was well conducted with a sample size
calculation for a noninferiority study,
the major limitation of this study is the
sample size. The sample size was based
on a much higher eclampsia rate than
observed in the study in the control
group (2% vs 0.38%), this sample size
calculation was based on the reported
rate of eclampsia without magnesium
sulfate. The rate of eclampsia in this trial
was only 0.35% in women who dis-
continued magnesium sulfate after la-
bor, but this rate was still 50% higher
than women who continued magnesium
sulfate for 24 hours after delivery.128
Therefore, until further evidence de-
velops; we recommend continuing
magnesium sulfate for 24 hours after
labor for women with preeclampsia with
severe features.
A few studies have described the use of
magnesium sulfate for women with pre-
eclampsia without severe features.133e135
Because of the limited number of pa-
tients in all published studies, the current
evidence does not support the use of
magnesium sulfate prophylaxis for
women with preeclampsia without severe
features.
Tertiary prevention aims to soften the
impact of an ongoing illness or injury
that has lasting effects. For women with
eclampsia, tertiary prevention will
include magnesium sulfate for the pre-
vention of recurrent seizures. For
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
Rate of seizures
Magnesium Control, Relative risk (95%
sulfate, n/n (%) n/n (%) confidence interval)
0/1049 (0.00) 10/1089 (0.92) NC
40/5055 (0.80) 96/5055 (1.90) 0.42 (0.29e0.60)
1/344 (0.30) 11/340 (3.20) 0.09 (0.01e0.69)
7/831 (0.80) 21/819 (2.60) 3.20 (1.10e9.10)
women with eclampsia, magnesium
sulfate reduced the risk of maternal
death (RR, 0.59; 95% CI, 0.37e0.94) and
recurrence of seizures (RR, 0.44; 95% CI,
0.34e0.57) compared with diaz-
epam.124,136 Magnesium sulfate also re-
duces the risk of further seizures
compared to phenytoin (RR, 0.31; 95%
CI, 0.20e0.47), or to lytic cocktail
(usually chlorpromazine, promethazine,
and pethidine) (RR, 0.09; 95% CI,
0.03e0.24).137
Although the effectiveness of magne-
sium sulfate in treating and preventing
eclampsia has been established, its
mechanism of action remains unclear.
Several possible mechanisms of action
have been proposed, including acting as
a vasodilator (either peripherally or in
the cerebral circulation to relieve vaso-
constriction), protecting the BBB to
decrease cerebral edema formation, and
acting as a central anticonvulsant.138,139
Magnesium sulfate is a calcium antago-
nist that acts both intracellularly and
extracellularly on calcium channels in
vascular smooth muscle, resulting in
a decrease in intracellular calcium with
a vasodilator effect.140e142 However, a
vasodilator, such as magnesium sulfate,
would seem to be a paradoxical treat-
ment choice for hypertensive encepha-
lopathy in which acute elevations in
blood pressure cause increased BBB
permeability and cerebral edema.
Further studies have suggested that
S1245
Expert Review
FIGURE 5
Protocols for the treatment of severe hypertension
SBP of
160 mm Hg or a DBP of
110 mm Hg and persistent for 15 minutes.
DBP, diastolic blood pressure; IV, intravenous; SBP, systolic blood pressure.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
magnesium sulfate causes
concentration-dependent vasodilation
in both cerebral and mesenteric resis-
tance arteries, with mesenteric arteries
more sensitive to magnesium sulfate.143
Other studies have found that magne-
sium sulfate did not change cerebral
blood flow, large cerebral artery diam-
eter, or middle cerebral artery veloc-
ity.144,145 It seems that the magnesium
sulfate vasodilator effect may prevent
eclampsia by reducing peripheral
vascular resistance and lower systemic
blood pressure and not by a vasodilator
effect on the cerebral blood flow.138
Another suggested mechanism of mag-
nesium sulfate is decreasing cerebral
edema formation. This could be
explained by magnesium sulfate’s action
as a calcium antagonist at the level of the
endothelial cell actin cytoskeleton
(composed of actin filaments, interme-
diate filaments, and microtubules) while
decreasing calcium cell contraction, tight
junction permeability, and the para-
cellular movement of solutes, thereby
limiting edema formation and
improving clinical outcomes in
eclampsia.138,146 The third possible
S1246 American Journal of Obstetrics & Gynecology FEBRUARY 2022
mechanism of magnesium sulfate is as a
central anticonvulsant. Seizures are
thought to be mediated at least in part by
stimulation of glutamate receptors, such
as the N-methyl-D-aspartate (NMDA)
receptor. Magnesium sulfate has been
found to have a central action on
NMDA-induced seizures in different
animal models.147e149 The possible
anticonvulsant activity of magnesium
sulfate may be related to its role in
increasing the seizure threshold by
inhibiting NMDA receptors. Finally, one
of the suggested mechanisms of
eclampsia described before involves
increased BBB permeability, subse-
quently causing microglial activation
and secretion of proinflammatory cyto-
kines causing decrease seizure threshold.
The newer anti-inflammatory theory for
magnesium sulfate mechanism of action
suggests that the effect of magnesium
sulfate may be related to a direct effect on
microglial activation, as opposed to
limiting BBB permeability. Magnesium
sulfate may limit lipopolysaccharide-
induced microglial secretion of proin-
flammatory cytokines, such as TNF-a
and interleukin (IL)-6 in a cell culture.
ajog.org
This action is thought to be mediated
through the inhibition of L-type calcium
channels and subsequent reduction in
downstream signaling of nuclear factor
kappa B, a transcription factor involved
in inflammatory pathways.48,150
Management of Severe Hypertension
In a retrospective analysis of 465 women
with severe hypertension, timely man-
agement (within 60 minutes) of
confirmed diagnosis of severe maternal
hypertension was associated with a 72%
reduction (1.9% vs 6.4%; P¼.02) in RR
of severe maternal morbidity (defined as
prolonged hospital stay, readmission,
admission to the intensive care unit
[ICU], or transfusion of
4 units of
packed red blood cells).151 A standard-
ized approach for treatment with intra-
venous blood pressure medication and
magnesium sulfate for sustained severe
maternal blood pressures (SBP of
160
mm Hg or DBP of
110 mm Hg)
resulted in a marked reduction in severe
maternal morbidity.8 Antihypertensive
drugs for treatment of severe hyperten-
sion include intravenous hydralazine or
labetalol or oral nifedipine in doses
described in Figure 5.152
Management of Eclampsia
The management of eclampsia requires
the availability of a medical ICU, and
women with eclampsia at term should
be cared for only in a level II or III
hospital with adequate medical ICU.
For women with eclampsia remote
from term, referral should be made to a
tertiary care center. Before transferring
a patient with critical illness, it is
important to stabilize blood pressure
and control convulsions. The patient
should be given a loading dose of
magnesium sulfate and fetal moni-
toring should be undertaken (Figure 6).
Patients should be sent in an ambu-
lance with medical personnel in atten-
dance for proper management in the
event of subsequent convulsions.
Acute care during a seizure
During or immediately after the acute
convulsive episode, supportive care
should be given to prevent serious
maternal injury, assessing and
ajog.org
establishing airway patency, ensuring
oxygenation, and avoiding aspiration.
During this time, the bedside rails
should be elevated and padded. We do
not recommend holding the patient
down or trying to stop their movement.
To minimize the risk of aspiration, the
patient should lie in the lateral decubitus
position, and oral secretions should be
suctioned as needed. Adequate oxygen-
ation should be maintained during the
convulsive episode. Although the initial
seizure usually lasts only a few minutes,
it is important to maintain oxygenation
by supplemental oxygen administration
through a facemask at 8 to 10 L/min.
Pulse oximetry can be used for moni-
toring. Arterial blood gas analysis will be
required only if the pulse oximetry re-
sults are abnormal (oxygen saturation of
92%). After the convulsion has ceased,
the patient typically begins to breathe
again, and oxygenation is rarely an issue.
However, maternal hypoxia may develop
in women who have repetitive convul-
sions, aspiration pneumonia, or pul-
monary edema.
Maternal hypoxia and hypercarbia can
cause fetal heart rate and uterine activity
changes during and immediately after a
convulsion. Fetal heart rate changes may
reveal bradycardia, late decelerations,
decreased variability, or compensatory
tachycardia. Uterine contractions can
increase in frequency and tone. These
changes usually resolve within 3 to 10
minutes after the termination of con-
vulsions and correction of maternal
hypoxia (Figure 7).153 As discussed
before, the patient should lie in the
lateral decubitus position; if possible,
supplemental oxygen should be admin-
istered, but we do not recommend giving
fluid for fetal heart rate resuscitation.
The patient should not be rushed to an
emergency cesarean delivery based on
these findings, especially if the maternal
condition is stable.
Treatment of convulsions
The next step in the management
would be to prevent recurrent seizures
as discussed before. Magnesium sulfate
is the drug of choice to prevent subse-
quent convulsions in women with
eclampsia.136 A loading dose of 6 grams
FIGURE 6
Emergency treatment algorithm for eclamptic seizure
ICU, intensive care unit; IV, intravenous.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
over 15 to 20 minutes is recommended,
followed by a maintenance does of 2
grams per hour as a continuous IV so-
lution. Maintenance infusion of 2 g/h
following either a 4- or a 6-g loading
dose has a higher likelihood of pro-
ducing the mean therapeutic concen-
tration of magnesium sulfate with
fewer fluctuations during the period of
administration compared with 1 g/
h.154e156 In women without an avail-
able intravenous access, magnesium
sulfate can be administered by intra-
muscular (IM) injection, 10 grams
initially as a loading dose (5 g IM in
each buttock), followed by 5 g every 4
hours. Overall, the serum concentra-
tion fluctuates much more with this
regimen than with continuous IV regi-
mens described above, and serum level is
less consistent.154,157 About 10% of
women with eclampsia may have a second
convulsion after receiving magnesium
sulfate.136 In this case, a second bolus of 2
g of magnesium sulfate can be given
intravenously (IV) over 3 to 5 minutes.
In the occasional scenario of recurrent
convulsions while receiving adequate
and therapeutic doses of magnesium
sulfate, recommended treatment is lor-
azepam 4 mg IV over 3 to 5 minutes.
Because magnesium sulfate is excreted
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
almost exclusively in the urine, if renal
function is impaired, serum magnesium
levels will increase quickly, placing the
patient at risk of adverse effects. There-
fore, in patients with a serum creatinine
of >1.2 mg/dL or oliguria (<30 mL
urine output per hour for more than 4
hours), the loading dose of 4 to 6 g
should be followed by a maintenance
dose of only 1 g/h.156
The adverse effects of magnesium sul-
fate (ie, respiratory depression and car-
diac arrest) come largely from its action as
a smooth muscle relaxant. Deep tendon
reflexes are lost at a serum magnesium
level of 9 mg/dL (7 mEq/L), respiratory
depression occurs at 12 mg/dL (10 mEq/
L), and cardiac arrest occurs at 30 mg/dL
(25 mEq/L). Patients at risk of impending
respiratory depression may require intu-
bation and emergency correction with
calcium gluconate 10% solution, 10 mL
IVover 3 minutes. As such, provided deep
tendon reflexes are present, the likelihood
for more serious toxicity is extremely low.
We recommend monitoring magnesium
levels every 4 to 6 hours only in women
with renal dysfunction (creatinine >1.2
mg/dL or urine output was <30 mL/h for
more than 4 hours) or in women with
signs concerning magnesium toxicity. If
the serum level exceeds 9.6 mg/dL (8
S1247
Expert Review
FIGURE 7
Uterine activity and fetal response during a seizure on fetal heart tracing
A, Uterine activity and recurrent late decelerations during a seizure. B, Uterine activity and fetal heart
rate following resuscitation of the patient.
Fishel Bartal. Eclampsia in the 21st century. Am J Obstet Gynecol 2022.
mEq/L), the infusion should be stopped,
and serum magnesium levels should be
determined at 2-hour intervals. The
infusion can be restarted at a lower rate
when the serum level decreases to <8.4
mg/dL (7 mEq/L).120,156
Management of the eclamptic patient
after a seizure
The presence of eclampsia would be an
indication for delivery but is not an
indication for cesarean delivery.158,159
The decision to perform a cesarean de-
livery should be based on gestational age,
fetal condition, presence of labor, and
cervical bishop score. Once the maternal
and fetal status are stable, and the patient
is alert and oriented to person, place, and
time, induction should be started. We
believe that induction is reasonable as
long as the patient is in the active phase
within 24 hours.
Based on the available data and our
experience, patients with eclampsia
before 30 weeks of gestation who are not
S1248 American Journal of Obstetrics & Gynecology FEBRUARY 2022
in labor with an unfavorable cervix
(Bishop score of <5) have very low
(<10%) success rate in induction of labor,
and cesarean delivery is recommended.
On admission, we recommend
obtaining the following laboratory test:
complete blood count with platelets,
serum creatinine, AST, and ALT. If the
patient presented with abruption, severe
bleeding, or severe liver dysfunction, we
recommend obtaining a fibrinogen level.
If the first laboratory results are normal,
we do not recommend repeating them.
We recommend repeating the laboratory
assessment in 6 hours if there is evidence
of thrombocytopenia (<100,000/mL) or
elevated creatinine (>1.0 mg/dL). In a
stable woman who is not bleeding, we
recommend platelet transfusion if the
platelet count is <50,000/mL before a
cesarean delivery or <20,000/mL for a
vaginal delivery.160
Maternal pain relief during labor and
delivery can be provided by epidural
anesthesia. Regional anesthesia is
ajog.org
contraindicated in the presence of coa-
gulopathy or severe thrombocytopenia.
A recent retrospective review, including
573 patients with a platelet count
<100,000/mL who received a neuraxial
technique, noted that the risk of epidural
hematoma from neuroaxial anesthesia is
<0.2% with platelet count of more than
70,000/mL.161 In women with eclampsia,
general anesthesia increases the risk of
aspiration and failed intubation because
of airway edema. Women with airway or
laryngeal edema may require awake
intubation under fiberscope observation
with availability of immediate
tracheostomy.162
Following delivery, women with
eclampsia should receive close moni-
toring of vital signs, input, output, and
symptoms for at least 72 hours. Women
with eclampsia, especially those with
abnormal renal function, are at increased
risk of pulmonary edema, and careful
attention to fluid status is essential.163
Magnesium sulfate should be
continued for 24 hours after delivery and
at least 24 hours after the last convulsion.
Angiogenic Factors and Eclampsia
An important area of research is whether
we can predict severe maternal out-
comes, such as eclampsia in women with
preeclampsia. Angiogenic factors,
including PlGF and soluble fms-like
tyrosine kinase-1 (sFlt-1), have been
the dominant focus of placental
biomarker studies in preeclampsia over
the past 15 years.164e166 PlGF, a proan-
giogenic member of the VEGF family,
normally increases during pregnancy as
a function of gestational age. A reduction
in PlGF is observed in women with
preeclampsia, which precedes the onset
of disease and reflects the underlying
placental dysfunction. Therefore, several
studies have examined the utility of
PlGF-based tests for predicting
preeclampsia.167e168 A large United
Kingdom pragmatic multicenter ran-
domized controlled trial that aimed to
determine whether knowledge of the
PlGF levels would reduce time to diag-
nosis and maternal and perinatal adverse
outcomes in women with suspected
preeclampsia was recently published.
This study included 1035 women with
ajog.org
suspected preeclampsia; 576 (56%)
women were assigned to the intervention
(revealed PlGF testing) group, and 447
(44%) women were assigned to receive
usual care with additional concealed
testing (concealed PlGF testing group).
Suspected preeclampsia in this study was
defined as new-onset or worsening of
existing hypertension, dipstick protein-
uria, epigastric or right upper quadrant
pain, headache with visual disturbances,
fetal growth restriction, or abnormal
maternal blood tests that were suggestive
of the disease (such as thrombocyto-
penia or hepatic or renal dysfunction).
The documented diagnosis of pre-
eclampsia was defined according to the
International Society for the Study of
Hypertension in Pregnancy 2014 state-
ment.169 The main finding from this
study was that the availability of PlGF
results substantially reduced the time to
clinical confirmation of preeclampsia
(1.9 vs 4.1 days; time ratio, 0.36; 95%
CI, 0.15e0.87; P¼.027) and reduced
severe maternal adverse outcomes (4%
vs 5%; aOR, 0.32; 95% CI, 0.11e0.96;
P¼.043) compared with the concealed
testing group. There were 5 serious
events (2 eclamptic seizures, 2 strokes,
and 1 cardiac arrest in 4 women, all of
whom had low PlGF concentrations) in
the concealed testing group, whereas
there were no similarly serious events in
the revealed testing group. Further-
more, a higher proportion of women in
the concealed testing group received
blood products transfusion (3% vs 2%)
compared with the revealed testing
group.170 A secondary analysis of the
prospective multicenter Preeclampsia
Triage by Rapid Assay Trial that enrolled
women with suspected preeclampsia171
evaluated whether abnormal PlGF
level is associated with adverse neonatal
and maternal outcomes. The parent
trial included women with hyperten-
sion, proteinuria, laboratory abnor-
malities, excessive maternal weight
gain, fetal growth restriction, or clinical
symptoms (such as headache, epigastric
pain, and nausea and vomiting). For the
secondary analysis, 1112 participants
with a singleton pregnancy between 20
and 41 weeks of gestation were
included, whereas plasma PlGF was low
in 742 (67%) of them. Low PlGF levels
(100 pg/mL) at the time of clinical
presentation were associated with a
higher risk (6.2% vs 1.9%; aRR, 3.6;
95% CI, 1.7e8.0) of maternal compli-
cations attributable to preeclampsia
(death, eclampsia, HELLP syndrome,
pulmonary edema, placental abruption,
receipt of a third antihypertensive
agent, or occurrence of other rare
maternal complications, such as acute
renal failure, myocardial infarction,
hypertensive encephalopathy, cortical
blindness, retinal detachment, stroke,
disseminated intravascular coagulation,
microangiopathy acute fatty liver of
pregnancy, or liver hematoma or
rupture). In this analysis, there were 3
cases of eclampsia in the PlGF of 100
pg/mL group compared with no cases in
the PlGF of >100 pg/mL group. The
difference in eclampsia rate did not
reach statistical significance.172
Furthermore, excessive production of
sFlt-1 leads to a binding of circulating
VEGF and inhibition of its function.
Although there is a lack of data signifying
the clinical utility of sFlt-1 in the clinical
setting, there is some evidence that the
mean serum level of sFlt-1 in eclampsia
is higher than in noncomplicated pre-
eclampsia cases (298.375.2 vs
128.136.5; P<.001).173 Eclampsia was
also found to be associated with higher
maternal circulating concentrations of
soluble VEGF receptor 1 and soluble
endoglin and lower concentrations of
PlGF than normal pregnancy but with
similar concentrations to severe pre-
eclampsia. These findings strengthen the
assumption that eclampsia shares a
common pathogenic pathway with se-
vere preeclampsia.174
Although recent data suggest that
PlGF levels are superior to clinical
markers in the prediction of adverse
pregnancy outcomes, including
eclampsia in preeclamptic women, ran-
domized trials are still required to
determine their value as clinical markers
and utility in clinical decision making,
such as the need for admission, follow-
up, and medical therapy for the pre-
vention of eclampsia in women pre-
senting with hypertension during
pregnancy.
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
Summary and Future Directions
Because eclampsia is a rare but life-
threatening condition, protocols should
be in place for education and imple-
mentation of antenatal and postpartum
care for women presenting with seizure.
As discussed above, the pathophysiology
of eclampsia is poorly understood, and
25% of women will not have hyperten-
sion before an eclamptic seizure.
Although new data are emerging
regarding the biomarker to identify
women at risk, blood pressure moni-
toring and assessment of clinical symp-
toms remain the most effective methods
to diagnose preeclampsia and eclampsia,
thereby providing the opportunity for
expeditious intervention and preventa-
tive strategies. There are needs to (1)
determine the optimal duration for
magnesium sulfate prophylaxis after
delivery for women with preeclampsia
with severe features; (2) assess whether
women presenting with late postpartum
preeclampsia with severe features (>48
hours after delivery) will benefit from
magnesium sulfate prophylaxis; (3) bet-
ter understand long-term neurologic
complications for women with a history
of eclampsia; (4) prospectively study
obstetrical complications in subsequent
pregnancies following eclampsia; and (5)
evaluate cost-effectiveness and clinical
utility of postpartum follow-up for
women with preeclampsia, including the
frequency of blood pressure monitoring,
symptoms evaluation, and prevention of
significant maternal complications, such
as eclampsia. -
REFERENCES
1. Main EK, McCain CL, Morton CH, Holtby S,
Lawton ES. Pregnancy-related mortality in Cali-
fornia: causes, characteristics, and improve-
ment opportunities. Obstet Gynecol 2015;125:
938–47.
2. Altman D, Carroli G, Duley L, et al. Do women
with pre-eclampsia, and their babies, benefit
from magnesium sulphate? The Magpie Trial: a
randomised placebo-controlled trial. Lancet
2002;359:1877–90.
3. Ghulmiyyah L, Sibai B. Maternal mortality
from preeclampsia/eclampsia. Semin Perinatol
2012;36:56–9.
4. Thornton C, Dahlen H, Korda A, Hennessy A.
The incidence of preeclampsia and eclampsia
and associated maternal mortality in Australia
S1249
Expert Review
from population-linked datasets: 2000-2008.
Am J Obstet Gynecol 2013;208:476.e1–5.
5. Zhang J, Meikle S, Trumble A. Severe
maternal morbidity associated with hypertensive
disorders in pregnancy in the United States.
Hypertens Pregnancy 2003;22:203–12.
6. Liu S, Joseph KS, Liston RM, et al. Incidence,
risk factors, and associated complications of
eclampsia. Obstet Gynecol 2011;118:987–94.
7. Hitti J, Sienas L, Walker S, Benedetti TJ,
Easterling T. Contribution of hypertension to
severe maternal morbidity. Am J Obstet Gynecol
2018;219:405.e1–7.
8. Shields LE, Wiesner S, Klein C, Pelletreau B,
Hedriana HL. Early standardized treatment of
critical blood pressure elevations is associated
with a reduction in eclampsia and severe
maternal morbidity. Am J Obstet Gynecol
2017;216:415.e1–5.
9. Callaghan WM, Creanga AA, Kuklina EV.
Severe maternal morbidity among delivery and
postpartum hospitalizations in the United States.
Obstet Gynecol 2012;120:1029–36.
10. Schaap TP, Knight M, Zwart JJ, et al.
Eclampsia, a comparison within the International
Network of Obstetric Survey Systems. BJOG
2014;121:1521–8.
11. Knight M; UKOSS. Eclampsia in the United
Kingdom 2005. BJOG 2007;114:1072–8.
12. Centers for Disease Control and Prevention.
Rates in severe morbidity indicators per 10,000
delivery hospitalizations, 1993e2014. 2019.
Available at: https://www.cdc.gov/reproductive
health/maternalinfanthealth/smm/rates-severe-
morbidity-indicator.htm 2019. Accessed July,
2020.
13. Jaatinen N, Ekholm E. Eclampsia in Finland;
2006 to 2010. Acta Obstet Gynecol Scand
2016;95:787–92.
14. Eke AC, Ezebialu IU, Okafor C. Presentation
and outcome of eclampsia at a tertiary center in
South East Nigeria–a 6-year review. Hypertens
Pregnancy 2011;30:125–32.
15. Miguil M, Chekairi A. Eclampsia, study of
342 cases. Hypertens Pregnancy 2008;27:
103–11.
16. Cooray SD, Edmonds SM, Tong S,
Samarasekera SP, Whitehead CL. Character-
ization of symptoms immediately preceding
eclampsia. Obstet Gynecol 2011;118:995–9.
17. Vousden N, Lawley E, Seed PT, et al. Inci-
dence of eclampsia and related complications
across 10 low- and middle-resource
geographical regions: secondary analysis of a
cluster randomised controlled trial. PLoS Med
2019;16:e1002775.
18. Ratsiatosika AT, Razafimanantsoa E,
Andriantoky VB, et al. Incidence and natural
history of preeclampsia/eclampsia at the uni-
versity maternity of Antananarivo, Madagascar:
high prevalence of the early-onset condition.
J Matern Fetal Neonatal Med 2019;32:3266–71.
19. Say L, Chou D, Gemmill A, et al. Global
causes of maternal death: a WHO systematic
analysis. Lancet Glob Health 2014;2:e323–33.
20. Davis NL, Smoots AN, Goodman DA.
Pregnancy-related deaths: data from 14 US
S1250 American Journal of Obstetrics & Gynecology FEBRUARY 2022
maternal mortality review committees,
2008e2017. 2019. Available at: https://www.
cdc.gov/reproductivehealth/maternal-mortality/
erase-mm/mmr-data-brief.html 2019.
Accessed July, 2020.
21. Clark SL, Belfort MA, Dildy GA, Herbst MA,
Meyers JA, Hankins GD. Maternal death in the
21st century: causes, prevention, and relation-
ship to cesarean delivery. Am J Obstet Gynecol
2008;199:36.e1–5. discussion 91-2.e7e11.
22. Sibai BM. Disparity in the rate of eclampsia
and adverse pregnancy outcome from
eclampsia: a tale of two countries. Obstet
Gynecol 2011;118:976–7.
23. Moodley J. Hypertensive emergencies in
pregnancies in underresourced countries. Curr
Opin Obstet Gynecol 2008;20:91–5.
24. Marchi N, Tierney W, Alexopoulos AV,
Puvenna V, Granata T, Janigro D. The etiological
role of blood-brain barrier dysfunction in seizure
disorders. Cardiovasc Psychiatry Neurol
2011;2011:482415.
25. Abbott NJ, Patabendige AA, Dolman DE,
Yusof SR, Begley DJ. Structure and function of
the blood-brain barrier. Neurobiol Dis 2010;37:
13–25.
26. Cipolla MJ, Sweet JG, Chan SL. Cerebral
vascular adaptation to pregnancy and its role in
the neurological complications of eclampsia.
J Appl Physiol (1985) 2011;110:329–39.
27. Armstead WM. Cerebral blood flow autor-
egulation and dysautoregulation. Anesthesiol
Clin 2016;34:465–77.
28. Hamner JW, Tan CO. Relative contributions
of sympathetic, cholinergic, and myogenic
mechanisms to cerebral autoregulation. Stroke
2014;45:1771–7.
29. Jones-Muhammad M, Warrington JP. Ce-
rebral blood flow regulation in pregnancy, hy-
pertension, and hypertensive disorders of
pregnancy. Brain Sci 2019;9:224.
30. Cipolla MJ. The adaptation of the cerebral
circulation to pregnancy: mechanisms and
consequences. J Cereb Blood Flow Metab
2013;33:465–78.
31. Cipolla MJ, Bishop N, Chan SL. Effect of
pregnancy on autoregulation of cerebral blood
flow in anterior versus posterior cerebrum. Hy-
pertension 2012;60:705–11.
32. van Veen TR, Panerai RB, Haeri S,
Griffioen AC, Zeeman GG, Belfort MA. Cerebral
autoregulation in normal pregnancy and pre-
eclampsia. Obstet Gynecol 2013;122:1064–9.
33. Friedman A, Kaufer D, Heinemann U. Blood-
brain barrier breakdown-inducing astrocytic
transformation: novel targets for the prevention
of epilepsy. Epilepsy Res 2009;85:142–9.
34. Chapman AC, Cipolla MJ, Chan SL. Effect
of pregnancy and nitric oxide on the myogenic
vasodilation of posterior cerebral arteries and the
lower limit of cerebral blood flow autoregulation.
Reprod Sci 2013;20:1046–54.
35. Cipolla MJ. Cerebrovascular function in
pregnancy and eclampsia. Hypertension
2007;50:14–24.
36. Cipolla MJ, Vitullo L, McKinnon J. Cerebral
artery reactivity changes during pregnancy and
ajog.org
the postpartum period: a role in eclampsia? Am J
Physiol Heart Circ Physiol 2004;286:H2127–32.
37. Euser AG, Cipolla MJ. Cerebral blood flow
autoregulation and edema formation during
pregnancy in anesthetized rats. Hypertension
2007;49:334–40.
38. Amburgey OA, Chapman AC, May V,
Bernstein IM, Cipolla MJ. Plasma from pre-
eclamptic women increases blood-brain barrier
permeability: role of vascular endothelial growth
factor signaling. Hypertension 2010;56:1003–8.
39. Schreurs MP, Houston EM, May V,
Cipolla MJ. The adaptation of the blood-brain
barrier to vascular endothelial growth factor
and placental growth factor during pregnancy.
FASEB J 2012;26:355–62.
40. Uzun H, Benian A, Madazli R,
Topçuog  lu MA, Aydin S, Albayrak M. Circulating
oxidized low-density lipoprotein and para-
oxonase activity in preeclampsia. Gynecol
Obstet Invest 2005;60:195–200.
41. Arifin R, Kyi WM, Che Yaakob CA,
Yaacob NM. Increased circulating oxidised low-
density lipoprotein and antibodies to oxidised
low-density lipoprotein in preeclampsia.
J Obstet Gynaecol 2017;37:580–4.
42. Itabe H. Oxidative modification of LDL: its
pathological role in atherosclerosis. Clin Rev Al-
lergy Immunol 2009;37:4–11.
43. Schreurs MP, Hubel CA, Bernstein IM,
Jeyabalan A, Cipolla MJ. Increased oxidized
low-density lipoprotein causes blood-brain bar-
rier disruption in early-onset preeclampsia
through LOX-1. FASEB J 2013;27:1254–63.
44. Schreurs MP, Cipolla MJ. Cerebrovascular
dysfunction and blood-brain barrier permeability
induced by oxidized LDL are prevented by
apocynin and magnesium sulfate in female rats.
J Cardiovasc Pharmacol 2014;63:33–9.
45. Cominacini L, Rigoni A, Pasini AF, et al. The
binding of oxidized low density lipoprotein (ox-
LDL) to ox-LDL receptor-1 reduces the intra-
cellular concentration of nitric oxide in endothe-
lial cells through an increased production of
superoxide. J Biol Chem 2001;276:13750–5.
46. Beckman JS, Koppenol WH. Nitric oxide,
superoxide, and peroxynitrite: the good, the
bad, and ugly. Am J Physiol 1996;271:
C1424–37.
47. Heeba G, Hassan MK, Khalifa M,
Malinski T. Adverse balance of nitric oxide/
peroxynitrite in the dysfunctional endothelium
can be reversed by statins. J Cardiovasc
Pharmacol 2007;50:391–8.
48. Johnson AC, Tremble SM, Chan SL, et al.
Magnesium sulfate treatment reverses seizure
susceptibility and decreases neuroinflammation
in a rat model of severe preeclampsia. PLoS One
2014;9:e113670.
49. Oby E, Janigro D. The blood-brain barrier
and epilepsy. Epilepsia 2006;47:1761–74.
50. Naidu K, Moodley J, Corr P,
Hoffmann M. Single photon emission and
cerebral computerised tomographic scan and
transcranial Doppler sonographic findings in
eclampsia. Br J Obstet Gynaecol 1997;104:
1165–72.
ajog.org
51. Qureshi AI, Frankel MR, Ottenlips JR,
Stern BJ. Cerebral hemodynamics in pre-
eclampsia and eclampsia. Arch Neurol 1996;53:
1226–31.
52. Demarin V, Rundek T, Hodek B. Maternal
cerebral circulation in normal and abnormal
pregnancies. Acta Obstet Gynecol Scand
1997;76:619–24.
53. Cunningham FG, Twickler D. Cerebral
edema complicating eclampsia. Am J Obstet
Gynecol 2000;182:94–100.
54. Belfort MA, Clark SL, Sibai B. Cerebral he-
modynamics in preeclampsia: cerebral perfu-
sion and the rationale for an alternative to
magnesium sulfate. Obstet Gynecol Surv
2006;61:655–65.
55. Belfort MA, Anthony J, Saade GR,
Allen JC Jr; Nimodipine Study Group.
A comparison of magnesium sulfate and nimo-
dipine for the prevention of eclampsia. N Engl J
Med 2003;348:304–11.
56. Hecht JL, Ordi J, Carrilho C, et al. The pa-
thology of eclampsia: an autopsy series.
Hypertens Pregnancy 2017;36:259–68.
57. Brussé IA, Peters NC, Steegers EA,
Duvekot JJ, Visser GH. Electroencephalography
during normotensive and hypertensive preg-
nancy: a systematic review. Obstet Gynecol
Surv 2010;65:794–803.
58. Sibai BM, McCubbin JH, Anderson GD,
Lipshitz J, Dilts PV Jr. Eclampsia. I. Observations
from 67 recent cases. Obstet Gynecol 1981;58:
609–13.
59. Osmanag aog lu MA, Dinç G,
Osmanag aoglu S, Dinç H, Bozkaya H. Com-
parison of cerebral magnetic resonance and
electroencephalogram findings in pre-eclamptic
and eclamptic women. Aust N Z J Obstet
Gynaecol 2005;45:384–90.
60. Sibai BM, Spinnato JA, Watson DL,
Lewis JA, Anderson GD. Effect of magnesium
sulfate on electroencephalographic findings in
preeclampsia-eclampsia. Obstet Gynecol
1984;64:261–6.
61. Di X, Mai H, Zheng Z, Guo K, Morse AN,
Liu H. Neuroimaging findings in women who
develop neurologic symptoms in severe pre-
eclampsia with or without eclampsia. Hypertens
Res 2018;41:598–604.
62. Fischer M, Schmutzhard E. Posterior
reversible encephalopathy syndrome. J Neurol
2017;264:1608–16.
63. Shankar J, Banfield J. Posterior reversible
encephalopathy syndrome: a review. Can Assoc
Radiol J 2017;68:147–53.
64. Fugate JE, Rabinstein AA. Posterior
reversible encephalopathy syndrome: clinical
and radiological manifestations, pathophysi-
ology, and outstanding questions. Lancet Neu-
rol 2015;14:914–25.
65. Ollivier M, Bertrand A, Clarençon F, et al.
Neuroimaging features in posterior reversible
encephalopathy syndrome: a pictorial review.
J Neurol Sci 2017;373:188–200.
66. Dong XY, Bai CB, Nao JF. Clinical and
radiological features of posterior reversible en-
cephalopathy syndrome in patients with pre-
eclampsia and eclampsia. Clin Radiol 2017;72:
887–95.
67. Mayama M, Uno K, Tano S, et al. Incidence
of posterior reversible encephalopathy syn-
drome in eclamptic and patients with pre-
eclampsia with neurologic symptoms. Am J
Obstet Gynecol 2016;215:239.e1–5.
68. Brewer J, Owens MY, Wallace K, et al.
Posterior reversible encephalopathy syndrome
in 46 of 47 patients with eclampsia. Am J Obstet
Gynecol 2013;208:468.e1–6.
69. Camara-Lemarroy CR, Escobedo-
Zúñiga N, Villarreal-Garza E, García-Valadez E,
Góngora-Rivera F, Villarreal-Velázquez HJ.
Posterior reversible leukoencephalopathy syn-
drome (PRES) associated with severe
eclampsia: clinical and biochemical features.
Pregnancy Hypertens 2017;7:44–9.
70. Xiaobo F, Yanling L, Dunjin C, et al. Ef-
fect of blood pressure on reversible posterior
leukoencephalopathy syndrome in pre-
eclampsia or eclampsia. Hypertens Res
2018;41:112–7.
71. Kastrup O, Schlamann M, Moenninghoff C,
Forsting M, Goericke S. Posterior reversible
encephalopathy syndrome: the spectrum of MR
imaging patterns. Clin Neuroradiol 2015;25:
161–71.
72. Tetsuka S, Ogawa T. Posterior reversible
encephalopathy syndrome: a review with
emphasis on neuroimaging characteristics.
J Neurol Sci 2019;404:72–9.
73. Pande AR, Ando K, Ishikura R, et al. Clin-
icoradiological factors influencing the reversibility
of posterior reversible encephalopathy syn-
drome: a multicenter study. Radiat Med
2006;24:659–68.
74. Dahmus MA, Barton JR, Sibai BM. Cerebral
imaging in eclampsia: magnetic resonance im-
aging versus computed tomography. Am J
Obstet Gynecol 1992;167:935–41.
75. Sibai BM, Stella CL. Diagnosis and man-
agement of atypical preeclampsia-eclampsia.
Am J Obstet Gynecol 2009;200:481.e1–7.
76. Zeeman GG. Neurologic complications of
pre-eclampsia. Semin Perinatol 2009;33:
166–72.
77. Wiegman MJ, Zeeman GG, Aukes AM, et al.
Regional distribution of cerebral white matter
lesions years after preeclampsia and eclampsia.
Obstet Gynecol 2014;123:790–5.
78. Aukes AM, de Groot JC, Aarnoudse JG,
Zeeman GG. Brain lesions several years after
eclampsia. Am J Obstet Gynecol 2009;200:504.
e1–5.
79. Sibai BM, Hauth J, Caritis S, et al. Hyper-
tensive disorders in twin versus singleton ges-
tations. National Institute of Child Health and
Human Development Network of Maternal-Fetal
Medicine Units. Am J Obstet Gynecol 2000;182:
938–42.
80. Esakoff TF, Rad S, Burwick RM,
Caughey AB. Predictors of eclampsia in Califor-
nia. J Matern Fetal Neonatal Med 2016;29:
1531–5.
81. Sibai BM. Magnesium sulfate prophylaxis
in preeclampsia: lessons learned from recent
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
trials. Am J Obstet Gynecol 2004;190:
1520–6.
82. Engjom HM, Morken NH, Høydahl E,
Norheim OF, Klungsøyr K. Risk of eclampsia
or HELLP-syndrome by institution availability
and place of delivery - a population-based
cohort study. Pregnancy Hypertens 2018;14:
1–8.
83. Hastie R, Brownfoot FC, Cluver CA,
et al. Predictive value of the signs and
symptoms preceding eclampsia: a system-
atic review. Obstet Gynecol 2019;134:
677–84.
84. Sperling JD, Dahlke JD, Huber WJ,
Sibai BM. The role of headache in the classifi-
cation and management of hypertensive disor-
ders in pregnancy. Obstet Gynecol 2015;126:
297–302.
85. Stella CL, Jodicke CD, How HY,
Harkness UF, Sibai BM. Postpartum headache:
is your work-up complete? Am J Obstet Gyne-
col 2007;196:318.e1–7.
86. Roos NM, Wiegman MJ, Jansonius NM,
Zeeman GG. Visual disturbances in (pre)
eclampsia. Obstet Gynecol Surv 2012;67:
242–50.
87. Shah AK, Rajamani K, Whitty JE. Eclampsia:
a neurological perspective. J Neurol Sci
2008;271:158–67.
88. Berhan Y, Berhan A. Should magnesium
sulfate be administered to women with mild pre-
eclampsia? A systematic review of published
reports on eclampsia. J Obstet Gynaecol Res
2015;41:831–42.
89. Mattar F, Sibai BM. Eclampsia. VIII. Risk
factors for maternal morbidity. Am J Obstet
Gynecol 2000;182:307–12.
90. American College of Obstetricians and Gy-
necologists. Task Force on Hypertension in
Pregnancy. Hypertension in pregnancy. Report
of the American College of Obstetricians and
Gynecologists’ Task Force on hypertension in
pregnancy. Obstet Gynecol 2013;122:
1122–31.
91. Brown MA, Magee LA, Kenny LC, et al.
The hypertensive disorders of pregnancy:
ISSHP classification, diagnosis & manage-
ment recommendations for international
practice. Pregnancy Hypertens 2018;13:
291–310.
92. Hazra S, Waugh J, Bosio P. ‘Pure’ pre-
eclampsia before 20 weeks of gestation: a
unique entity. BJOG 2003;110:1034–5.
93. Chames MC, Livingston JC, Ivester TS,
Barton JR, Sibai BM. Late postpartum
eclampsia: a preventable disease? Am J Obstet
Gynecol 2002;186:1174–7.
94. Lubarsky SL, Barton JR, Friedman SA,
Nasreddine S, Ramadan MK, Sibai BM. Late
postpartum eclampsia revisited. Obstet Gynecol
1994;83:502–5.
95. Matthys LA, Coppage KH, Lambers DS,
Barton JR, Sibai BM. Delayed postpartum pre-
eclampsia: an experience of 151 cases. Am J
Obstet Gynecol 2004;190:1464–6.
96. Morton A. Imitators of preeclampsia: a
review. Pregnancy Hypertens 2016;6:1–9.
S1251
Expert Review
97. Bollig KJ, Jackson DL. Seizures in preg-
nancy. Obstet Gynecol Clin North Am 2018;45:
349–67.
98. Hart LA, Sibai BM. Seizures in pregnancy:
epilepsy, eclampsia, and stroke. Semin Perinatol
2013;37:207–24.
99. Krumholz A, Wiebe S, Gronseth G, et al.
Practice parameter: evaluating an apparent
unprovoked first seizure in adults (an evidence-
based review): report of the Quality Standards
Subcommittee of the American Academy of
Neurology and the American Epilepsy Society.
Neurology 2007;69:1996–2007.
100. Giordano JC, Parpinelli MA, Cecatti JG,
et al. The burden of eclampsia: results from a
multicenter study on surveillance of severe
maternal morbidity in Brazil. PLoS One 2014;9:
e97401.
101. Abalos E, Cuesta C, Carroli G, et al. Pre-
eclampsia, eclampsia and adverse maternal and
perinatal outcomes: a secondary analysis of the
World Health Organization Multicountry Survey
on Maternal and newborn Health. BJOG
2014;121(Suppl1):14–24.
102. MacKay AP, Berg CJ, Atrash HK. Preg-
nancy-related mortality from preeclampsia and
eclampsia. Obstet Gynecol 2001;97:533–8.
103. Sibai BM. Eclampsia. VI. Maternal-
perinatal outcome in 254 consecutive cases.
Am J Obstet Gynecol 1990;163:1049–54. dis-
cussion 1054e45.
104. Witlin AG, Saade GR, Mattar F, Sibai BM.
Predictors of neonatal outcome in women with
severe preeclampsia or eclampsia between 24
and 33 weeks’ gestation. Am J Obstet Gynecol
2000;182:607–11.
105. Sibai BM, Sarinoglu C, Mercer BM.
Eclampsia. VII. Pregnancy outcome after
eclampsia and long-term prognosis. Am J
Obstet Gynecol 1992;166:1757–61. discussion
1761e3.
106. Sibai BM, Mercer B, Sarinoglu C. Severe
preeclampsia in the second trimester: recur-
rence risk and long-term prognosis. Am J
Obstet Gynecol 1991;165:1408–12.
107. Ackerman CM, Platner MH, Spatz ES,
et al. Severe cardiovascular morbidity in women
with hypertensive diseases during delivery hos-
pitalization. Am J Obstet Gynecol 2019;220:
582.e1–11.
108. Nerenberg KA, Park AL, Vigod SN, et al.
Long-term risk of a seizure disorder after
eclampsia. Obstet Gynecol 2017;130:1327–33.
109. Aukes AM, Wessel I, Dubois AM,
Aarnoudse JG, Zeeman GG. Self-reported
cognitive functioning in formerly eclamptic
women. Am J Obstet Gynecol 2007;197:365.
e1–6.
110. Postma IR, Groen H, Easterling TR, et al.
The brain study: cognition, quality of life and
social functioning following preeclampsia; an
observational study. Pregnancy Hypertens
2013;3:227–34.
111. Postma IR, Slager S, Kremer HP, de
Groot JC, Zeeman GG. Long-term conse-
quences of the posterior reversible encepha-
lopathy syndrome in eclampsia and
S1252 American Journal of Obstetrics & Gynecology FEBRUARY 2022
preeclampsia: a review of the obstetric and
nonobstetric literature. Obstet Gynecol Surv
2014;69:287–300.
112. Andersgaard AB, Herbst A, Johansen M,
Borgström A, Bille AG, Øian P. Follow-up in-
terviews after eclampsia. Gynecol Obstet Invest
2009;67:49–52.
113. Wiegman MJ, de Groot JC, Jansonius NM,
et al. Long-term visual functioning after
eclampsia. Obstet Gynecol 2012;119:959–66.
114. Postma IR, Bouma A, Ankersmit IF,
Zeeman GG. Neurocognitive functioning
following preeclampsia and eclampsia: a long-
term follow-up study. Am J Obstet Gynecol
2014;211:37.e1–9.
115. Postma IR, Wessel I, Aarnoudse JG,
Zeeman GG. Neurocognitive functioning in
women with a history of eclampsia: executive
functioning and sustained attention. Am J Peri-
natol 2010;27:685–90.
116. Sibai BM, Caritis SN, Thom E, et al.
Prevention of preeclampsia with low-dose
aspirin in healthy, nulliparous pregnant
women. The National Institute of Child Health
and Human Development Network of
Maternal-Fetal Medicine Units. N Engl J Med
1993;329:1213–8.
117. Meher S, Duley L, Hunter K, Askie L. An-
tiplatelet therapy before or after 16 weeks’
gestation for preventing preeclampsia: an indi-
vidual participant data meta-analysis. Am J
Obstet Gynecol 2017;216:121–8.e2.
118. Roberge S, Nicolaides K, Demers S,
Hyett J, Chaillet N, Bujold E. The role of aspirin
dose on the prevention of preeclampsia and fetal
growth restriction: systematic review and meta-
analysis. Am J Obstet Gynecol 2017;216:
110–20.e6.
119. Duley L, Henderson-Smart DJ, Meher S,
King JF. Antiplatelet agents for preventing pre-
eclampsia and its complications. Cochrane
Database Syst Rev 2007:CD004659.
120. American College of Obstetricians and
Gynecologists’ Committee on Practice Bulle-
tins—Obstetrics. Gestational hypertension and
preeclampsia: ACOG Practice Bulletin, number
222. Obstet Gynecol 2020;135:e237–60.
121. Sibai BM, Abdella TN, Spinnato JA,
Anderson GD. Eclampsia. V. The incidence of
nonpreventable eclampsia. Am J Obstet Gyne-
col 1986;154:581–6.
122. Katz VL, Farmer R, Kuller JA. Preeclampsia
into eclampsia: toward a new paradigm. Am J
Obstet Gynecol 2000;182:1389–96.
123. Lucas MJ, Leveno KJ, Cunningham FG.
A comparison of magnesium sulfate with
phenytoin for the prevention of eclampsia.
N Engl J Med 1995;333:201–5.
124. Duley L, Henderson-Smart DJ, Walker GJ,
Chou D. Magnesium sulphate versus diazepam
for eclampsia. Cochrane Database Syst Rev
2010;2010:CD000127.
125. Duley L, Gülmezoglu AM, Henderson-
Smart DJ, Chou D. Magnesium sulphate and
other anticonvulsants for women with pre-
eclampsia. Cochrane Database Syst Rev
2010;2010:CD000025.
ajog.org
126. Coetzee EJ, Dommisse J, Anthony J.
A randomised controlled trial of intravenous
magnesium sulphate versus placebo in the
management of women with severe pre-
eclampsia. Br J Obstet Gynaecol 1998;105:
300–3.
127. Anjum S, Goel N, Sharma R, Mohsin Z,
Garg N. Maternal outcomes after 12hours and
24hours of magnesium sulfate therapy for
eclampsia. Int J Gynecol Obstet 2016;132:
68–71.
128. Vigil-DeGracia P, Ludmir J, Ng J, et al. Is
there benefit to continue magnesium sulphate
postpartum in women receiving magnesium
sulphate before delivery? A randomised
controlled study. BJOG 2018;125:1304–11.
129. Keepanasseril A, Maurya DK,
Manikandan K, Suriya JY, Habeebullah S,
Raghavan SS. Prophylactic magnesium sul-
phate in prevention of eclampsia in women with
severe preeclampsia: randomised controlled
trial (PIPES trial). J Obstet Gynaecol 2018;38:
305–9.
130. El-Khayat W, Atef A, Abdelatty S, El-
Semary A. A novel protocol for postpartum
magnesium sulphate in severe pre-eclampsia: a
randomized controlled pilot trial. J Matern Fetal
Neonatal Med 2016;29:154–8.
131. Darngawn L, Jose R, Regi A, Bansal R,
Jeyaseelan L. A shortened postpartum magne-
sium sulfate prophylaxis regime in pre-eclamptic
women at low risk of eclampsia. Int J Gynecol
Obstet 2012;116:237–9.
132. Ehrenberg HM, Mercer BM. Abbreviated
postpartum magnesium sulfate therapy for
women with mild preeclampsia: a randomized
controlled trial. Obstet Gynecol 2006;108:
833–8.
133. Livingston JC, Livingston LW, Ramsey R,
Mabie BC, Sibai BM. Magnesium sulfate in
women with mild preeclampsia: a randomized
controlled trial. Obstet Gynecol 2003;101:
217–20.
134. Cahill AG, Macones GA, Odibo AO,
Stamilio DM. Magnesium for seizure prophylaxis
in patients with mild preeclampsia. Obstet
Gynecol 2007;110:601–7.
135. Witlin AG, Friedman SA, Sibai BM. The
effect of magnesium sulfate therapy on the
duration of labor in women with mild pre-
eclampsia at term: a randomized, double-blind,
placebo-controlled trial. Am J Obstet Gynecol
1997;176:623–7.
136. The Eclampsia Trial Collaborative Group.
Which anticonvulsant for women with
eclampsia? Evidence from the Collaborative
Eclampsia Trial. Lancet 1995;345:1455–63.
137. Duley L, Henderson-Smart DJ, Chou D.
Magnesium sulphate versus phenytoin for
eclampsia. Cochrane Database Syst Rev
2010;2010:CD000128.
138. Euser AG, Cipolla MJ. Magnesium sulfate
for the treatment of eclampsia: a brief review.
Stroke 2009;40:1169–75.
139. Zhang LW, Warrington JP. Magnesium
sulfate prevents placental ischemia-induced in-
creases in brain water content and
ajog.org
cerebrospinal fluid cytokines in pregnant rats.
Front Neurosci 2016;10:561.
140. Belfort MA, Moise KJ Jr. Effect of magne-
sium sulfate on maternal brain blood flow in
preeclampsia: a randomized, placebo-
controlled study. Am J Obstet Gynecol
1992;167:661–6.
141. Belfort MA, Saade GR, Moise KJ Jr. The
effect of magnesium sulfate on maternal and
fetal blood flow in pregnancy-induced hyper-
tension. Acta Obstet Gynecol Scand 1993;72:
526–30.
142. Naidu S, Payne AJ, Moodley J,
Hoffmann M, Gouws E. Randomised study
assessing the effect of phenytoin and magne-
sium sulphate on maternal cerebral circulation in
eclampsia using transcranial Doppler ultra-
sound. Br J Obstet Gynaecol 1996;103:111–6.
143. Euser AG, Cipolla MJ. Resistance artery
vasodilation to magnesium sulfate during
pregnancy and the postpartum state. Am J
Physiol Heart Circ Physiol 2005;288:
H1521–5.
144. Hatab MR, Zeeman GG, Twickler DM. The
effect of magnesium sulfate on large cerebral
artery blood flow in preeclampsia. J Matern Fetal
Neonatal Med 2005;17:187–92.
145. Belfort MA, Saade GR, Yared M, et al.
Change in estimated cerebral perfusion pres-
sure after treatment with nimodipine or magne-
sium sulfate in patients with preeclampsia. Am J
Obstet Gynecol 1999;181:402–7.
146. Turkoglu OF, Eroglu H, Okutan O, et al.
A comparative study of treatment for brain
edema: magnesium sulphate versus dexa-
methasone sodium phosphate. J Clin Neurosci
2008;15:60–5.
147. Hallak M, Berman RF, Irtenkauf SM,
Janusz CA, Cotton DB. Magnesium sulfate
treatment decreases N-methyl-D-aspartate re-
ceptor binding in the rat brain: an autoradio-
graphic study. J Soc Gynecol Investig 1994;1:
25–30.
148. Hallak M, Berman RF, Irtenkauf SM,
Evans MI, Cotton DB. Peripheral magnesium
sulfate enters the brain and increases the
threshold for hippocampal seizures in rats. Am J
Obstet Gynecol 1992;167:1605–10.
149. Cotton DB, Hallak M, Janusz C,
Irtenkauf SM, Berman RF. Central anticonvul-
sant effects of magnesium sulfate on N-methyl-
D-aspartate-induced seizures. Am J Obstet
Gynecol 1993;168:974–8.
150. Sugimoto J, Romani AM, Valentin-
Torres AM, et al. Magnesium decreases inflam-
matory cytokine production: a novel innate
immunomodulatory mechanism. J Immunol
2012;188:6338–46.
151. Gupta M, Greene N, Kilpatrick SJ. Timely
treatment of severe maternal hypertension and
reduction in severe maternal morbidity. Preg-
nancy Hypertens 2018;14:55–8.
152. American College of Obstetricians and
Gynecologists. ACOG Committee Opinion no.
767: emergent therapy for acute-onset, severe
hypertension during pregnancy and the post-
partum period. Obstet Gynecol 2019;133:
e174–80.
153. Paul RH, Koh KS, Bernstein SG. Changes
in fetal heart rate-uterine contraction patterns
associated with eclampsia. Am J Obstet Gyne-
col 1978;130:165–9.
154. Okusanya BO, Oladapo OT, Long Q, et al.
Clinical pharmacokinetic properties of magne-
sium sulphate in women with pre-eclampsia and
eclampsia. BJOG 2016;123:356–66.
155. Sibai BM, Graham JM, McCubbin JH.
A comparison of intravenous and intramuscular
magnesium sulfate regimens in preeclampsia.
Am J Obstet Gynecol 1984;150:728–33.
156. Alexander JM, McIntire DD, Leveno KJ,
Cunningham FG. Selective magnesium sulfate
prophylaxis for the prevention of eclampsia in
women with gestational hypertension. Obstet
Gynecol 2006;108:826–32.
157. Pritchard JA. The use of the magnesium
ion in the management of eclamptogenic toxe-
mias. Surg Gynecol Obstet 1955;100:131–40.
158. Pritchard JA, Cunningham FG,
Pritchard SA. The Parkland Memorial Hospital
protocol for treatment of eclampsia: evaluation
of 245 cases. Am J Obstet Gynecol 1984;148:
951–63.
159. Alexander JM, Bloom SL, McIntire DD,
Leveno KJ. Severe preeclampsia and the very
low birth weight infant: is induction of labor
harmful? Obstet Gynecol 1999;93:485–8.
160. Kaufman RM, Djulbegovic B,
Gernsheimer T, et al. Platelet transfusion: a
clinical practice guideline from the AABB. Ann
Intern Med 2015;162:205–13.
161. Lee LO, Bateman BT, Kheterpal S, et al.
Risk of epidural hematoma after neuraxial tech-
niques in thrombocytopenic parturients: a report
from the Multicenter Perioperative Outcomes
Group. Anesthesiology 2017;126:1053–63.
162. Parthasarathy S, Kumar VR, Sripriya R,
Ravishankar M. Anesthetic management of a
patient presenting with eclampsia. Anesth Es-
says Res 2013;7:307–12.
163. Sibai BM, Mabie BC, Harvey CJ,
Gonzalez AR. Pulmonary edema in severe
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
preeclampsia-eclampsia: analysis of thirty-
seven consecutive cases. Am J Obstet Gyne-
col 1987;156:1174–9.
164. Levine RJ, Maynard SE, Qian C, et al.
Circulating angiogenic factors and the risk of
preeclampsia. N Engl J Med 2004;350:672–83.
165. Szalai G, Xu Y, Romero R, et al. In vivo
experiments reveal the good, the bad and the
ugly faces of sFlt-1 in pregnancy. PLoS One
2014;9:e110867.
166. Zeisler H, Llurba E, Chantraine F, et al.
Predictive value of the sFlt-1:PlGF ratio in
women with suspected preeclampsia. N Engl J
Med 2016;374:13–22.
167. Yang J, Pearl M, DeLorenze GN, et al.
Racial-ethnic differences in midtrimester
maternal serum levels of angiogenic and anti-
angiogenic factors. Am J Obstet Gynecol
2016;215:359.e1–9.
168. Chaiworapongsa T, Romero R,
Whitten AE, et al. The use of angiogenic bio-
markers in maternal blood to identify which SGA
fetuses will require a preterm delivery and
mothers who will develop pre-eclampsia.
J Matern Fetal Neonatal Med 2016;29:1214–28.
169. Tranquilli AL, Dekker G, Magee L, et al. The
classification, diagnosis and management of the
hypertensive disorders of pregnancy: a revised
statement from the ISSHP. Pregnancy Hyper-
tens 2014;4:97–104.
170. Duhig KE, Myers J, Seed PT, et al.
Placental growth factor testing to assess
women with suspected pre-eclampsia: a
multicentre, pragmatic, stepped-wedge clus-
ter-randomised controlled trial. Lancet
2019;393:1807–18.
171. Barton JR, Woelkers DA, Newman RB,
et al. Placental growth factor predicts time to
delivery in women with signs or symptoms of
early preterm preeclampsia: a prospective
multicenter study. Am J Obstet Gynecol
2020;222:259.e1–11.
172. Parchem JG, Brock CO, Chen HY, et al.
Placental growth factor and the risk of adverse
neonatal and maternal outcomes. Obstet
Gynecol 2020;135:665–73.
173. Abbas AM, Fikry EM, Mostafa TS,
Shaltout AS, El-Baz MAH. Prognostic value of
serum soluble FMS-like tyrosine kinase (sFlt-1)
levels in pre-eclampsia and eclampsia; a pro-
spective cohort study. Hypertens Pregnancy
2018;37:137–43.
174. Vaisbuch E, Whitty JE, Hassan SS, et al.
Circulating angiogenic and antiangiogenic fac-
tors in women with eclampsia. Am J Obstet
Gynecol 2011;204:152.e1–9.
S1253