HEADACHE IN PREECLAMPSIA : REVIEW ARTICLE

Mulia Dian Sumbawati 1, Hanik Badriyah Hidayati 2, Ernawati 3

1
Faculty of Medicine Univeritas Airlangga
2
Department of Neurology, Faculty of Medicine, Universitas Airlangga
3
Department of Obstetrics And Gynecology, Faculty of Medicine, Univeritas Airlangga

Correspondence Author:
Hanik Badriyah Hidayati
Email: hanikhidayati@fk.unair.ac.id
https://orcid.org/0000-0002-6825-1311

ABSTRACT

Preeclampsia is a multisystem disease that causes systemic disturbances in maternal endothelial

function. It is a vascular disease that causes symptoms such as arterial hypertension and impaired
function of organs such as the kidneys, liver and brain. Headache is pain felt in the head region or an
uncomfortable sensation felt in the head region. Headaches during pregnancy can be caused by primary
causes such as migraine, but can also be a symptom of secondary causes such as preeclampsia which
can be life-threatening. High blood pressure in pregnant women is associated with a 17-fold increased
risk of secondary headaches. Pregnancy and labour can be affected by headaches in preeclampsia and
can lead to higher risks and complications. Headache in preeclampsia can predict the occurrence of
eclampsia/seizure with a sensitivity of 56% and specificity of 83%. Research in Indonesia shows a
picture of the degree of headache in preeclampsia mostly experiencing severe headache as much as
65.2%, moderate headache 19.6%, mild headache 13%, and no headache 2.2%. Therefore, based on the
existing literature, this article intends to collect scientific data regarding headache pain in preeclampsia
patients.
Keywords: Headache, Preeclampsia, Hypertension, Maternal mortality
Artikel Highlight:
1. Headache in preeclampsia is a type of secondary headache.
2. Elevated blood pressure in pregnant women is associated with a 17-fold increased risk of
secondary headaches.
3. Typical preeclampsia headache is progressive, bilateral (frontal or occipital), throbbing,
associated with visual changes, worsens with higher blood pressure, aggravated by physical
activity, and unresponsive to over-the-counter medications.

INTRODUCTION while secondary headache is headache that is

Headache according to the International
Association For The Study Of Pain is a painful
and disabling neurological condition that has
forms such as migraine, tension-type headache,
cluster headache, primary stabbing headache,
primary sex headache, or rarer conditions such
as idiopathic persistent facial pain. There are
two types of head pain: primary and secondary
headache. Primary headache is pain that is not
accompanied by structural organ abnormalities,
accompanied by organ dysfunction :. Pregnancy
is a risk factor for secondary headache
disorders. Hypercoagulability, hormonal
changes, and anaesthesia during delivery are
just some of the various factors that contribute
to the high incidence of secondary headache
during pregnancy. Category red flags and
caution should be exercised if the headache is
accompanied by abnormal signs such as
confusion, impaired alertness and decreased
consciousness 2. Preeclampsia is defined as
hypertension occurring after 20 weeks'
gestation and proteinuria >300 mg/24 hours 3.
Preeclampsia is a multisystem disease that
causes systemic disturbances in maternal
endothelial function. It is a vascular disease that
causes symptoms such as arterial hypertension
and impaired function of organs such as the
kidneys, liver and brain 4.
A recent study by Robbins et al. 5 found
35% secondary headache in 140 pregnant
women with acute headache Hypertensive
disorders of pregnancy accounted for 51% of
these cases (about 18% of the total), with
preeclampsia as the leading cause, followed by
reversible posterior leukoencephalopathy
syndrome (PRES, eclampsia). Research in
Indonesia showed that the degree of headache
in preeclampsia mostly experienced severe
headache as much as 65.2%, moderate
headache 19.6%, mild headache 13%, and no
headache 2.2% 6. Headache in preeclampsia can
affect pregnancy, labour and lead to a higher
risk of complications. Headache in
preeclampsia can predict the occurrence of
eclampsia/seizure with a sensitivity of 56% and
specificity of 83% 7. Therefore, this study was
created to collect scientific data on headache
pain in preeclampsia.
REVIEW
Definition
Pain is an unpleasant sensory and
emotional condition associated with actual or
potential damage to a tissue 8. Headache is pain
felt in the head region or is an uncomfortable
sensation felt in the head region. Headache
without any danger signs is a low-risk headache
and tends towards primary headache, whereas if
there are danger signs, namely prolonged pain,
seizures or neurological symptoms, one of
which appears, it is necessary to conduct
laboratory tests related to the headache 9.
Women who have headache or migraine
complaints during pregnancy have poorer
health-related quality of life than those who do
not. Headache during pregnancy has a
significant impact on the quality of life of
pregnant women 10.
Preeclampsia is a disorder of pregnancy
associated with the onset of hypertension,
which most commonly occurs after 20 weeks of
gestation and often near term 11. Preeclampsia is
defined as hypertension occurring after 20
weeks' gestation and proteinuria >300 mg/24
hours 3. Preeclampsia is a multisystem disease
that causes systemic disturbances in maternal
endothelial function. Vascular disease leads to
symptomatic manifestations such as arterial
hypertension and end-organ involvement such
as the kidneys, liver and brain 4.
Characteristics and Causes of Headache in
Pregnancy
1. Primary Headache
Primary headaches in pregnancy are common
and about 5% of pregnancies are affected by
new attacks, migraine-type headaches are the
most common 12. Headaches that occur in early
pregnancy are more common due to primary
headaches, in addition to migraine type, tension
type headaches are quite common in pregnancy.
In late pregnancy the frequency and severity of
migraine headaches tend to decrease as there is
a shift in the ratio between maternal oestrogen
and progesterone 13. Pregnancy is associated
with physiological changes that affect
neurological function and may cause different
neurological symptoms 5. Clinically the most
significant primary headaches consist of
migraine, tension-type headache and cluster
headache.
2. Secondary Headache
Secondary headaches often associated with
pregnancy caused by cerebrovascular disease
especially in the late stages of pregnancy 14.
Pregnancy is associated with cerebrovascular
disorders that can cause headache. Research on
the description of headache in pregnancy, the
most common cause is secondary headache at
86% 12. According to Robbins et al. (2018) 15
Frequent headache in pregnancy is primarily
caused by preeclampsia. Clinically, the causes
of secondary headache consist of preeclampsia,
eclampsia, idiopathic intracranial hypertension,
cerebral venous thrombosis, subarachnoid
haemorrhage, ischaemic stroke, reversible
cerebral vasoconstriction syndrome, posterior
reversible enchepalopathy syndrome.
Pathogenesis of Headache in Preeclampsia
Elevated blood pressure in pregnant
women is associated with a 17-fold increased
risk of secondary headaches 15. The occurrence
of hypertensive disorders will be higher in
women with a history of migraine 16. Ibu
Pregnant women with headache pain and
hypertension with signs and symptoms
associated with headache pain (i.e., altered
mental status, fever, thunderclap attacks, etc.)
should be evaluated immediately. There is a
need for closer monitoring of pregnant women
with a history of hypertension including disease
progression and symptoms experienced as these
women are an at-risk population 17.
Various neurological problems are
caused by preeclampsia, including headache,
visual disturbances, seizures, posterior
reversible encephalopathy syndrome, and
haemorrhagic stroke. Typical preeclampsia
headaches are progressive, bilateral (frontal or
occipital), throbbing, associated with visual
changes, worsen with higher blood pressure,
aggravated by physical activity, and
unresponsive to over-the-counter medications.
Symptoms can also be vague and typical of
tension-type headaches. Typical posterior
reversible encephalopathy syndrome headaches
are bilateral, occipital, dull, and without
prodromal. One theory of the pathophysiology
of headache pain in preeclampsia is that the
blocking of VEGF and TGF-β causes loss of
fenestrase in the choroid plexus, resulting in
endothelial cell instability and periventricular
oedema. These changes may then trigger
seizures and posterior reversible
encephalopathy syndrome, which is defined by
neurological abnormalities with neuroimaging
findings of vasogenic oedema in the posterior
cerebral circulation distribution 18.
Changes in the brain after preeclampsia and
eclampsia
Changes in the brain after preeclampsia
and eclampsia Imaging results of the brain of
mothers who experience eclampsia show a
condition called PRES, a type of cerebral
oedema that is considered reversible without
long-term effects. However, recently there has
been a question of reversibility of the effects of
eclampsia on the brain or severe preeclampsia,
as women who have had preeclampsia before
have a higher risk of stroke, vascular dementia,
epilepsy and cognitive impairment 19. Magnetic
resonance imaging (MRI) studies have revealed
changes in brain morphology and function in
women with preeclampsia and eclampsia. For
example, women with previous pregnancies
complicated by eclampsia or severe
preeclampsia had an increased number of white
matter lesions (WML) several years after the
event 20.
Here are some types of headache disorders in
preeclampsia patients:
1. Preeclampsia and Cerebral Autoregulation
Cerebral autoregulation is the process
by which cerebral arterioles react
dynamically to changes in systemic blood
pressure to ensure constant blood flow to
the brain and prevent hyperperfusion
injury. Impaired dynamic cerebral
autoregulation is demonstrated in women
with chronic hypertension and women with
preeclampsia, but not in women with
normal pregnancy or gestational
21
hypertension .
2. Blood-Brain Barrier Dysfunction
Increased permeability of the blood-
brain barrier, this disorder can lead to
cerebral oedema which is often seen in
women with eclampsia and occasionally in
women with preeclampsia, especially those
with neurological symptoms.
Radiographically, the oedema pattern has
some similarities with reversible posterior
encephalopathy syndrome (PRES) and is
usually reversible if treated early and
aggressively 22. The mechanism of blood-
brain barrier dysfunction in preeclampsia is
not fully understood but may be mediated
in part by neuroinflammation.
Preeclampsia is associated with increased
 serum markers of inflammation, including
C-reactive protein, platelet and
complement activity, and elevated
proinflammatory cytokines including
interleukin (IL)-1β, tumour necrosis factor
(TNF)-α, and IL-17 23. Proteomic analysis
of cerebrospinal fluid (CSF) from women
with preeclampsia has shown clear
differences compared to normotensive
women, including increased markers of
neuroinflammation and binding proteins 24.
3. Migraine and Preeclampsia
Preeclampsia is more likely to occur
in patients with migraine, one retrospective
case series of pregnant women diagnosed
with migraine with a favourable phenotype
showed a preeclampsia rate of 21.3%, five
times higher than the risk in the general
population 25. The risk of preeclampsia
appears to be increased in women with
migraine regardless of the presence of aura.
Women with active or frequent migraine
attacks during pregnancy may show a
higher risk phenotype. The relationship
between migraine and preeclampsia is not
fully understood. While migraine is
considered primarily a brain disorder, there
is evidence that peripheral components,
including trigeminal nerve afferents, dural
immune cells, and vascular endothelial
cells, play a major role in the
pathophysiology of migraine pain 26. The
mechanisms that initiate migraine pain
remain elusive and are likely to be complex
and multifaceted. The overlap of
neuroinflammation, vascular endothelial
and smooth muscle cell dysfunction,
platelet dysfunction, and altered vascular
reactivity may provide a link between
migraine and preeclampsia 27.
The headache phase of migraine is
thought to involve sterile neurogenic
inflammation, leading to dural plasma
protein extravasation and increased
meningeal vascular permeability, arterial
vasodilatation, and local immune cell
activity. Trigeminal nerve activity releases
vasoactive neurotransmitters and
neuropeptides, such as substance P and
calcitonin gene-related peptide, adjacent to
the meningeal blood vessels. These
vasoactive neurotransmitters and
neuropeptides, in turn, trigger vasodilation
of the meningeal arteries, extravasation of
dural plasma proteins, and mast cell
activity and degranulation. Neurogenically
mediated dural plasma protein
extravasation following trigeminal
ganglion stimulation has been
demonstrated in animal models, and levels
of proinflammatory mast cell components
TNF-α, IL-1β, IL-10, and histamine are
elevated during migraine attacks,
supporting this hypothesis. Migraine has
many underlying aetiologies, pathologies
that can arise as a result of hormonal
treatment or as a single symptom during
the menstrual cycle or pregnancy, with
varying intensity and duration 28.
4. Posterior reversible encephalopathy
syndrome (PRES)
PRES is a neuroradiological entity
originally described as "a pathological
condition presenting with headache, visual
disturbances, seizures, and depression of
consciousness. MR imaging typically
shows evidence of vasogenic oedema in the
white matter and subcortical cortex,
predominantly involving the bilateral
parieto-occipital lobes. Like headache pain,
preeclampsia is mediated, in part, by
neuroinflammation, alterations in
angiogenic pathways, endothelial cell
dysfunction, changes in vascular reactivity,
and blood-brain barrier dysfunction.
Aberrant platelet activity has also been
demonstrated as part of the preeclampsia
syndrome, and inhibition of platelet activity
with aspirin has been shown in randomised
trials to reduce the risk of premature
preeclampsia 29.
Some of the mechanisms thought to
underlie preeclampsia-associated headache are
inflammation, vascular endothelial dysfunction,
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