Introduction
Pregnancy is associated with anatomical and physiological changes, such as decreased
vascular resistance, increased vascular permeability and cardiac output. These are
essential to accommodate plasma volume expansion and guarantee perfusion of vital
organs. Nevertheless, fluctuations in estrogen concentration can increase coagulation
factors and lead, consequently, to an increased risk of thromboembolism. In these
situations, elevated levels of progesterone induce vasodilation, vascular stasis and
edema, which further increase the risk of thromboembolism.[1]
The risk of hypertension caused by the higher resistance in maternal systemic blood
vessels, which occurs in cases of preeclampsia, can adversely affect blood flow in
many organs (including liver, kidneys, brain and placenta).[2]
[3] Thus, women with preeclampsia and eclampsia have an increased risk of complications,
such as pulmonary edema, placental abruption, aspiration pneumonia, renal failure,
hepatic failure and stroke.[3]
[4]
Some peripheral neuropathies (carpal tunnel syndrome, peripheral facial palsy) and
some central neurological disorders (seizure, migraine, cerebrovascular malformations,
epilepsy) may be more frequent during pregnancy due to an exacerbation of a preexisting
neurological condition, or by an acute onset of a neurological disorder associated
with physiological changes engendered by pregnancy (such as headache or vascular disorders).[1]
[5]
[6]
[7]
[8]
Both peripheral and central neurological disorders can occur during the three trimesters
of pregnancy. So, an early and accurate diagnosis is essential to improve pregnancy
management, treatment and subsequent perinatal outcomes.
The aim of this review is to describe and characterize the most common peripheral
and central neurological disorders during pregnancy and subsequent management and
treatment thereof.
Results
Both peripheral and central neurological disorders can occur during the three trimesters
of pregnancy and arise from specific changes occurring in each trimester ([Table 1]).
Table 1
Summary of the characteristics of new-onset acute peripheral and central neurological
disorders in pregnancy
|
Peripheral Disorders
|
First trimester
|
Second trimester
|
Third trimester
|
Comments
|
|
Carpal Tunnel Syndrome
|
+
|
++
|
+++
|
Pregnant women:
- shorter duration of symptoms
- ↑ incidence in both hands
- weaker intensity of symptoms
|
|
Bell's palsy
|
+
|
+
|
+++
|
Rarely recurrent
|
|
Central Disorders
|
|
Headache
|
-MH is as a possible predictor of complications in pregnancy (miscarriage, preeclampsia, eclampsia, CVT, stroke, low birth weight)
↓
- Inconsistent by deficient controlled studies
|
|
MH
|
|
a) without aura
|
+++
|
++
|
+/−
|
|
b) with aura
|
+
|
++
|
+++
|
|
Cerebrovascular complications
|
- AVM typically occurs earlier (15–20 weeks of GA) and in younger women (20–25 years-old)
- Aneurysm rupture occurs later (30–40 weeks of GA) and in older women (30–35 years-old)
- SAH occurs commonly as a result of ruptured aneurysm
|
|
- CVT
|
+
|
+
|
+++
|
|
- AVM
|
+++
|
+
|
+
|
|
- Aneurysm rupture
|
+
|
++
|
+++
|
|
- SAH
|
(see comments)
|
(see comments)
|
(see comments)
|
Abbreviations: AVM, arterial-venous malformation; CVT, cerebral vein thrombosis; GA,
gestational age; MH, migraine headache; SAH, subarachnoid hemorrhage.
+ → can occur; ++ → common; +++ → very common; - → cessation; ± → unchanged; ? → unknown; Ø → inexistent.
Peripheral Neurological Disorders
Carpal tunnel syndrome and peripheral facial palsy are common examples of minor peripheral
neurological disorders in pregnancy.[7]
[8]
[9] However, factors that predispose to neuropathies should be considered in pregnant
women, including diabetes, thyroid disorders, and/or inherent neuropathies (Charcot-Marie-Tooth
disease).
Although most neuropathies are usually reversible, associated disabilities or morbidities
can limit function and require therapy.[9]
Carpal tunnel syndrome is a group of symptoms caused by compression of the median
nerve in the carpal tunnel, characterized by numbness, tingling and weakness in the
thumb, index, middle, half of the ring finger and parts of the palm of the hand (supplied
by the median nerve). The incidence varies from 2 to 70% during pregnancy depending
on the diagnostic method and the physician.[7]
[10]
[11]
[12]
Complaints occur most commonly in the second and third trimester ([Table 1]), in the morning and at night. They are associated with venous congestion and/or
nerve compression upon wrist flexion during sleep. Hormonal changes, fluid accumulation
with a predisposition to edema, nerve hypersensitivity and glucose level fluctuations
can all increase the risk of pregnant women developing symptoms of carpal tunnel syndrome.[7] Diagnosis is clinical and could be confirmed by electrodiagnostic testing.[7]
[10]
Conservative treatment is almost always appropriate and a complete recovery after
pregnancy is the rule. In cases requiring intervention, first-line treatment includes
overnight immobilization of the wrist with a splint in a neutral position or in slight
extension. If necessary, local procedures such as an intracarpal steroid injection
and surgery (with local anesthesia) are safe for mother and fetus.[7]
[10]
[11]
[12]
Peripheral facial palsy, also called Bell's palsy, is an idiopathic facial neuropathy
named after Sir Charles Bell, who first described this condition and its link to pregnancy.
The incidence is around 28–45:100.000 pregnancies; it is rarely recurrent and it is
more common in the third trimester ([Table 1]).[8]
[9]
The most frequent symptoms are unilateral weakness of the muscles controlling facial
expressions (smiling, closing eyelids), dry eyes and mouth, hyperacusis to acute sounds
and loss of taste over the anterior two thirds of the tongue ipsilateral to the facial
weakness. It may be preceded or accompanied by ipsilateral retroauricular pain; some
studies reveal that the increased incidence in pregnancy may be related to hypertensive
disorders of pregnancy (preeclampsia, gestational hypertension).[9]
[13]
[14]
There are no specific treatments studied for peripheral facial palsy. The affected
eye must be kept patched and moist to prevent corneal abrasions. Some neurologists
prescribe a short course of steroids to minimize clinical features and increase the
probability of facial nerve recovery.[9]
[15]
Central Neurological Disorders
Headache is a common presenting complaint during pregnancy.[16]
[17] Despite the strong link between hormonal changes and headache, the recognition of
non-hormonal factors is crucial. A pulsating and unilateral headache, associated with
nausea and/or vomiting and/or photophobia or phonophobia are typical symptoms of a
migraine headache (MH).[1]
[5]
[18]
[19]
About 8% of women suffering from MH experience an increase in the attack frequency
and pain intensity of migraine during pregnancy, affecting more often those women
with MH with aura.[20] New-onset migraine arising during pregnancy usually takes place during the first
trimester.[1]
[5]
[20] If de novo MH occurs, it is more likely to occur with aura. In general, 50–75% of
women with preexisting MH without aura see an improvement or complete remission during
pregnancy. This fact suggests that high stable placental estrogen levels, mainly during
the second and third trimesters of pregnancy, could be beneficial to this pathology.[5]
[20]
[21]
Studies have shown no difference in the incidence or course of MH between primiparous
and multiparous women.[1]
[21]
[22]
The increase in estrogen levels can be the source of MH with aura in susceptible women.
In general, women with MH (with or without aura) can be assured that there are no
adverse effects on pregnancy's outcome or maternal health. Nevertheless, some retrospective
studies suggest that MH has been mentioned as a possible predictor of complications
in pregnancy, including miscarriage, preeclampsia, eclampsia, congenital abnormalities,
cerebral venous sinus thrombosis, stroke, and low birth weight; these links remain
inconsistent due to poorly controlled studies.[1]
[16]
[23]
Imaging Studies
Neuroradiology is important to exclude secondary causes of headache. Imaging findings
are usually normal in migraine. The indications for imaging testing are the same as
those for non-pregnant women. The exclusion of threatening secondary causes is essential,
especially if “red flags” are present ([Fig. 1]).
Fig. 1 Approach to evaluation of headache in pregnant patient. Abbreviations: CT, computed
tomography; MRA, magnetic resonance angiogram; MRV, magnetic resonance venogram; PE,
preeclampsia; PH, primary headache; SAH, subarachnoid hemorrhage.
Magnetic resonance imaging (MRI) is safe during pregnancy; However, the use of gadolinium
in pregnant women is controversial because it can cross the placenta (although it
has not been shown to cause birth defects).[16]
[21] Magnetic resonance imaging is recommended to assess the posterior fossa, while magnetic
resonance arteriography (MRA) and magnetic resonance venography (MRV) are indicated
to exclude vascular causes of headache.[21] Computed tomography (CT) scan without contrast is an imaging option in pregnancy
in selected cases; however, the risk of in utero exposure to ionizing radiation limits
its use.[16]
[21]
When imaging studies are indicated, MRI should be used due to its higher resolution,
increased sensitivity, and lack of ionizing radiation. The use of CT scan should be
considered in selected cases, due to its wider availability and lower cost. Contrast
agents should be avoided, unless absolutely necessary.[16]
[24]
Symptomatic Treatment
Medical therapy should be selected taking into consideration adverse effects on the
fetus. Symptomatic treatment during pregnancy is challenging and a detailed discussion
of the risks and benefits of each medical treatment is essential ([Table 2]). First-line therapy includes an analgesic and an antiemetic drug.[1]
[25]
[26] The pain management options for use during pregnancy described below are in accordance
with the US Food and Drug Administration (FDA) recommendations.
Table 2
Symptomatic drugs used during pregnancy
|
Drug
|
First Trimester
|
Second Trimester
|
Third Trimester
|
|
Acetaminophen/Paracetamol (≤4 g)
Metamizol (Dipyrone)**
|
ID
|
ID
|
Avoid
|
|
Aspirin (≤100 mg/day)
Ibuprofen
Diclofenac
Naproxen
|
()
|
()
|
Avoid
|
|
Metoclopramide
Promethazine
Ondansetron
Prochlorperazine*
Chlorpromazine*
Prednisolone*
|
()
|
()
|
()
|
|
Ergotamine
|
CI
|
CI
|
CI
|
|
Almotriptan
Eletriptan
Frovatriptan
Zolmitriptan
|
ID
|
ID
|
ID
|
|
Naratriptan
Rizatriptan
Sumatriptan
|
?
|
?
|
?
|
Abbreviations: CI, contraindicated; ID, insufficient data; ?, limited data, but
probably safe.
,
no
evidence of
harm
; () data suggest
unlikely
to cause
harm
.
*, for
emergency treatment
of migraine
not responding
to standard measure
**, contraindicated in the US market. Available in some European and Latin-American countries.
Analgesics
Acetaminophen (category B for intravenous administration) is the analgesic of choice
for short-term relief of mild to moderate pain during pregnancy,[25]
[27] and it is considered a safe drug at therapeutic doses of ≤ 4 g per day for an adult.[28] An analgesic dose of acetylsalicylic acid (100mg/day) is safe in the first and second
trimesters, but it should be used with caution near term (category D) due to its effect
on platelet function, causing an increased risk of prolonged labor, postpartum hemorrhage,
neonatal bleeding and premature closure of the fetal ductus arteriosus.[25] Metamizol/dipyrone (category C), by oral or intravenous route, has been demonstrated
to be effective in the treatment of migraine attacks, but the risk of agranulocytosis,
renal failure and hypotension limits its use.[29]
[30] Also, it has been associated with Wilms tumor, with risk of infant leukemia and
there are several case reports suggesting its association with oligohydramnios and
closure of the ductus arteriosus when used in the third trimester.[30]
[31]
[32]
[33] It was taken off the US market, but it is still available in some European and Latin
American countries.[27]
Non-Steroidal Antiinflammatory Drugs (NSAIDS)
Studies do not satisfactorily support their use during pregnancy, except for ibuprofen
(category C prior to 30 weeks and category D ≥ 30 weeks). Moreover, persistent exposure
to NSAIDs, or any level of exposure to them after 30 weeks, is associated with an
increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios
due to its inhibitory effect on prostaglandin activity.[25]
[34]
[35]
Triptans
In contrast to analgesics, the efficacy of triptans is due to the specifically targeted
pathogenesis of MH.[36] The safety of triptans during pregnancy is still questionable and their sustained
use is discouraged unless no other treatment is successful. Sumatriptan and rizatriptan
(category B) have not been associated with congenital abnormalities or adverse outcomes[25]
[29] and, to date, the risk of major malformations has been reported to be equal to the
baseline risk in the general population (1% to 3%).[36]
Antiemetics
Metoclopramide (category B) is commonly used in pregnancy for its antiemetic and gastric
prokinetic effects.[25]
[26] Extrapyramidal reactions are the most common acute side effect of metoclopramide
with a reported incidence of 0.2%.[37]
[38] Promethazine (category C in the first trimester and B thereafter) and prochlorperazine
(category C) are dopamine receptor antagonists and can be used combined with NSAIDs
or opioids;[39] the latter may be associated with congenital heart defects and cleft palate.[19] Ondansetron (category B) should not be used as first-line treatment. Beginning the
treatment after 10 weeks of gestational age (GA) minimizes the risks of teratogenicity.[40]
Cerebrovascular disorders are uncommon in reproductive-aged women. Pregnancy-induced
physiological changes increase the risk of cerebral venous thrombosis, as also do
the existence of preeclampsia/eclampsia and thrombophilia.[39]
[41]
[42]
[43]
Cerebral venous thrombosis
Most pregnancy-related cerebral venous thrombosis (CVT) occur in the third trimester
of pregnancy and puerperium ([Table 1]), accounting for 27 to 57% of all pregnancy-related strokes.[44]
[45] Common presenting complaints include headache (typically sub-acute), focal neurological
deficits, seizures, altered mental status and signs of high intracranial pressure
such as papilloedema.[22]
[46] History of a previous extracerebral venous thrombotic event is also associated with
adverse pregnancy outcomes and has a 3–4-fold higher risk of venous thrombotic event
during subsequent pregnancies.[44] Headache with focal neurological signs or seizures should raise the suspicion of
CVT.[2]
[21] Diagnosis is based on neuroimaging, with MRI being preferable to CT scan because
of its higher resolution, sensitivity, and lack of ionizing radiation.[16]
[21]
[24] In most cases, CT results will show nonspecific edema or infarction. Fetal outcomes
after a CVT seem to be favorable and have low mortality rates.[43]
[44]
[47]
[48] Pregnancy and the puerperium are periods of high-risk for thrombotic complications,
particularly the third trimester of pregnancy and the first four weeks postpartum.[49]
[50]
[51]
[52]
Anticoagulation during pregnancy must be individualized according to the co-existence
of risk factors.[13]
[43]
[47] Evidence suggests the use of maintenance anticoagulation for a period of 3 months
in presence of high risk factors, and for at least 6–12 months in patients with idiopathic
cases (potential etiologies include paroxysmal atrial fibrillation, patent foramen
ovale, atherosclerotic plaques of the aortic arch, congenital and acquired prothrombotic
states) and women with mild hereditary thrombophilia (heterozygous factor V Leiden
or prothrombin G20210A mutation). Indefinite anticoagulation should be reserved to
patients with idiopathic cases, recurrent episodes, and to those with high-risk thrombophilia
(antithrombin, protein C or protein S deficiency, homozygous factor V Leiden or prothrombin
G20210A mutation, antiphospholipid antibodies and combined abnormalities).[52]
[53]
[54]
[55]
Hemorrhagic disorders
Bleeding of an arteriovenous malformation (AVM) is a cerebrovascular complication
that is noticeable in younger women (20–25 years-old) and earlier in pregnancy (15–20
weeks of GA); in contrast, aneurysm rupture occurs more commonly in older women (30–35
years-old) and between 30–40 weeks of GA.[6]
[56] Possible mechanisms include hormonal changes (that lead to a predisposition to the
development, enlargement and rupture of an aneurysm), increase in cardiac output by
60% in the second trimester and higher blood volume in the third trimester, which
all increase the risk of aneurysm rupture. Women generally present with an abrupt
onset of a severe and unusual headache (thunderclap headache), nausea and vomiting,
photophobia, syncope and focal neurological deficits. If brain CT without contrast
does not provide a diagnosis, a lumbar puncture should be performed.[57] For hemorrhagic AVM, cerebral angiography is necessary. An unruptured AVM in pregnancy,
with no bleeding risk factors (aneurysm, venous ectasia), should be followed conservatively.[6]
[56]
[58] In contrast, an emergency surgery is necessary for a bleeding cerebral AVM, particularly
if the existence of a hematoma causes worsening of neurological symptoms or cerebral
herniation.[14]
[56]
[58]
Endovascular embolization for cerebral AVM in pregnancy should be performed per clinical
manifestations and angiographic features. Several studies reported that this procedure
during pregnancy is safe and effective.[56]
[59]
[60] The radiation dose of endovascular and stereotactic radiotherapy during pregnancy
is also safe.[16] However, non-radiation procedures are preferred during pregnancy. In cases of unruptured
AVM, vaginal delivery or caesarean section should depend on obstetric criteria.[56]
[61]
Subarachnoid hemorrhage (SAH) occurs most commonly because of ruptured aneurysm or
AVM. The frequency of SAH in pregnancy is 5.8:100.000 deliveries in the United States
of America.[62] The most common symptom is severe headache. Computed tomography scan is the diagnostic
exam of choice as it can identify hyperdense signal provided by the extravasated blood
in the basal cisterns.[24]
[57] It is unclear whether the risk of SAH is increased during pregnancy and the puerperium
and there are no formal studies to support optimal obstetric management of pregnant
women with SAH. Mode of delivery is based solely on obstetric criteria.[58]
[61]
[62]
[63]
Discussion
Pregnancy is associated with a risk of thromboembolism and can lead to neurological
disorders. So, women who present with acute neurological symptoms require a meticulous
diagnostic evaluation[1]
[2]
[3]
[64] Carpal tunnel syndrome and peripheral facial palsy are common examples of peripheral
neurological disorders, which occur more often in the third trimester due to physiologic
changes during pregnancy.[7]
[10]
[11]
[65]
[66] Generally, surgery is not required and medical treatment is satisfactory.[10]
[11]
[65] However, some women can maintain symptoms in the first three years post-partum.[10]
[12]
Central nervous system disorders are more complex. The acknowledgment of symptoms
and imaging testing, if necessary, are extremely important to attain the correct diagnosis.
Magnetic resonance imaging is safe during pregnancy and CT scan should be avoided
and used only if absolutely necessary.[16]
[21] Both diagnosis and management of headache in pregnant women present several challenges.
Migraine is the most common and well-studied type of headache and it is divided in
two main subtypes: with aura, occurring predominantly in the third trimester; and
without aura, most common in the first trimester, improving in the third trimester.[1]
[5]
[20] In contrast, ∼ 8% of women experience increased frequency or intensity of MH during
pregnancy.[5] Data showed no difference in the incidence or course of MH between primiparous and
multiparous women.[1]
[21]
[22] Symptomatic treatment during pregnancy is challenging and should be selected taking
into consideration adverse effects on the fetus. The literature is consensual that
analgesic (such as acetaminophen) and antiemetic drugs (such as metoclopramide) are
the first-line therapy of choice.[25]
[27] Recently, a preliminary study with recommended doses of acetaminophen was performed
to investigate the potential effect of perinatal exposure on metabolic function in
mice offspring. The authors concluded that acetaminophen may be associated with impaired
glucose metabolism, increased plasma insulin level, and reduced liver glycogen content;
however, further investigation is warranted to demonstrated this potential association.[67] Generally, acetaminophen is considered a safe drug at therapeutic doses. However,
acetaminophen overdose remains the most common cause of acute liver failure in the
western world,[68] and women must be warned that safe dosage needs to be respected. Some triptans (sumatriptan
and rizatriptan) can be used, although their safety in pregnancy remains unknown.[25]
[29]
[36] Non-steroidal anti-inflammatory drugs should be avoided mainly in the third trimester
due to its association with premature closure of the foetal ductus arteriosus, oligohydramnios
and risk of postpartum hemorrhage.[25]
[34]
[35] For all these facts, medical treatment has to be conscientious, maintaining doses
as low as possible, individualized to each woman. The prognosis of migraine (with
or without aura) is favorable and literature does not provide evidence of complications.[5]
[20] Nevertheless, perinatal adverse outcomes can occur in women with no evidence of
remission or amelioration of migraine attacks.[69]
[70] So, MH should be considered a potential risk factor in obstetric care and has to
be managed by a multidisciplinary team.
Cerebral venous thrombosis frequently occurs during the third trimester and puerperium.[44]
[49]
[50]
[51] The literature is not consensual about the risk of recurrence of CVT. Generally,
fetal outcome of a pregnancy after a CVT seems to be favorable.[43]
[44]
[45]
[47] The risk of stroke is elevated during the first year postpartum, lowering in subsequent
years.[71] However, history of a previous extracerebral venous thrombotic event is associated
with adverse pregnancy outcome and has a 3–16-fold higher risk of venous thrombotic
event during subsequent pregnancies.[44]
[72] Cerebral venous thrombosis recurrence is 80-fold higher than the baseline risk described
in general population studies.[72] Mehraein et al[73] studied the outcomes of 21 pregnancies with a previously treated CVT. Low-dose heparin
was given subcutaneously during the course of 5 of these pregnancies, while no anticoagulation
was given during the course of the remaining 14 pregnancies and puerperium periods.
None of patients had recurrence of CVT during pregnancy and puerperium and no extracerebral
vascular thromboembolism occurred. They concluded that a history of CVT does not justify
a negative advice on pregnancy in women. Current guidelines of the Royal College of
Obstetricians and Gynaecologists[74] for the prevention of thromboembolism defend that all women should undergo a documented
assessment of risk factors in early pregnancy or pre-pregnancy and risk assessment
should be repeated intrapartum or immediately postpartum. Women with a previous episode
of thromboembolism (associated with antithrombin deficiency or with recurrent episodes
of thromboembolism) should be offered thromboprophylaxis with a higher dose of anticoagulant
therapy antenatally and for 6 weeks postpartum (or until returned to oral anticoagulant
therapy after delivery). Instead, women in whom the original episode of thromboembolism
was unprovoked/idiopathic or related to estrogen (for instance, in pregnancy) should
be offered thromboprophylaxis with anticoagulant therapy throughout the antenatal
period. In terms of the peripartum period, a recent integrated analysis of two prospective
studies concluded that antithrombin concentrate is safe and effective in reducing
venous thromboembolism if administered over an average period of 4 days.[75]
[76] As so, more studies are warranted to define the real risk of thromboembolism in
subsequent pregnancies and anticoagulation therapy to prevent complications and risk
of recurrence in future pregnancies; the risk of thromboembolism should be discussed
with women at risk and the reasons for individual recommendations explained.[13]
[43]
[47]
[51]
[54]
[55]
Arteriovenous malformation complications are more frequent in the first trimester,
contrasting to aneurysm rupture, which occurs more commonly in the second half of
pregnancy;[6]
[56] both can lead to SAH. It is consensual that imaging investigation is vital and,
during pregnancy, MRI is preferable to CT scan because of its higher resolution, sensitivity,
and lack of ionizing radiation. In addition, MRV and MRA can be performed for the
exclusion of vascular disorders and contrast agents cause adverse fetal effects and
should avoided, unless absolutely necessary for an accurate diagnosis.[16]
[21]
Data are consistent that the appropriate delivery in cases of neurological complications
remains undefined and the decision of the way should be based on obstetric criteria
if the hemorrhagic risk has been removed.[6]
[58]
[61]
[63]
After appropriate diagnosis, proper treatment and follow-up are extremely important.
In cases of cerebrovascular complications, the management and follow-up by a multidisciplinary
team is mandatory. With scientific advances, the ability to diagnose and discriminate
different causes of acute neurological symptoms is likely to progress. Because most
of these conditions are rare, an early transfer to a Reference Centre and a multidisciplinary
approach is essential to improve maternal and fetal outcomes.
