Liability for Misdiagnosis of Headaches During Pregnancy and the Peripartum

This article gives an overview of headaches in pregnancy and considers the diagnostic challenges of separating benign from life-threatening conditions.

Approximately 90% of headaches in pregnancy are primary headaches – migraine or tension-type headaches. Primary headaches may present for the first time or the frequency or characteristics of the headache may differ in pregnancy. Pregnancy also leads to an increased risk of certain secondary headaches. The key causes of headache in pregnancy are outlined below:

Key causes of headache in pregnancy

Primary

• Migraine
• Tension headache

Secondary

• Hypertension
• Subarachnoid hemorrhage
• Drug-related, e.g. nifedipine, medication overuse
• Postdural tap
• Meningitis
• Cerebral venous thrombosis
• Anemia
• Idiopathic intracranial hypertension
• Stroke
• Arteriovenous malformation (can enlarge/bleed in pregnancy)
• Enlargement of a pituitary tumor
• Enlargement of a hormone-sensitive tumor, e.g. meningioma
• Bleeding into a pre-existing tumor
• Cerebral metastasis of choriocarcinoma

Postdural puncture headache

• Puncture of the dura occurs in 0.5–2.5% of epidurals
• If accidental dural puncture occurs with an epidural needle there is a 70–80% chance of a postdural puncture headache
• The headache is usually in the fronto-occipital regions and radiates to the neck. It is characteristically worse on standing and typically develops 24–48 hours post-puncture
• Conservative management includes hydration and simple analgesics
• Untreated, the headache typically lasts for 7–10 days but can last up to 6 weeks
• Epidural blood patch has a 60–90% cure rate

Red flag features for potential secondary headache

• Thunderclap: rapid time to peak headache intensity (seconds to 5 minutes), e.g. with a subarachnoid hemorrhage
• Focal neurological symptoms (e.g. limb weakness, aura <5 minutes or >1 hour)
• Non-focal neurological symptoms (e.g. cognitive disturbance) – seen in central venous thrombosis
• Change in headache frequency, characteristics or associated symptoms
• Abnormal neurological examination
• Headache that changes with posture – a sign of high or low cerebrospinal fluid pressure
• Headache awakening the patient – associated with migraine and raised intracranial pressure
• Headache precipitated by physical exertion or Valsalva maneuver – consider subarachnoid hemorrhage or raised intracranial pressure
• Patients with risk factors for cerebral venous thrombosis
• Jaw claudication or visual disturbance – associated with giant cell arteritis (women over 50 years)
• Fever – consider meningitis
• Neck stiffness – indicative of meningeal irritation
• New onset of headache in a patient with a history of HIV infection
• New-onset headache in a patient with a history of cancer

Differential diagnosis of headache in pregnancy

In the initial clinical assessment of a pregnant or postpartum woman with headache, a history and neurological examination often allows the correct cause for the headache to be identified. The history alone often distinguishes the benign and more sinister causes of headache, particularly by eliciting the presence or absence of ‘red flag’ features. Duration, location, frequency, severity, family history, associated symptoms and relationship to this and previous pregnancies should all be established. It is often helpful, to the patient and doctor, to ask what the patient believes to be the cause of the headache.

A severe or atypical headache may, after this clinical assessment, need to be discussed with a neurologist and then urgent imaging considered. Neurological conditions are one of the main causes of maternal death so obstetricians must be aware of these conditions and when to involve neurological expertise.

Neurological examination

A neurological examination is usually essential and needs to include the following:

• fundoscopy – looking for papilledema, a sign of raised intracranial pressure

Papilledema. Look for pinkness of the disc with blurring and heaping up of its margins. There is loss within the disc of the normal pulsation of the retinal veins. The disc becomes engorged and its vessels dilated.

• cranial nerve assessment, in particular:

– pupil reaction to light and accommodation

– visual fields – looking for lesions affecting visual processing, such as pituitary

tumors

– eye movements – a sixth nerve palsy presents with binocular horizontal diplopia

with in-turning of the eye and decreased lateral movement; a third nerve palsy,

with or without pupillary dilatation, can point to an aneurysm in the posterior

communicating artery

– speech and swallowing

• tone, power, reflexes and coordination in all four limbs
• plantar response (an upward extensor plantar response is seen in upper motor neuron lesions)
• assessment of gait, including heel–toe walking.

Blood pressure, proteinuria and clonus should be assessed and pre-eclampsia considered, especially after 20 weeks of gestation.

Migraine

Migraine is more common in women, with the highest prevalence rates during the childbearing years. It is classified by the presence or absence of aura. Pregnancy can alter migraine aura and trigger attacks of aura without headache as a result of high plasma concentrations of estrogen. Women may present with aura for the first time in pregnancy, leading to concern regarding intracranial disease. Typically, aura involves fully reversible phenomena of vision, sensation, motor power, balance and speech. The symptoms include flickering lights, spots, zigzag lines (fortification spectrum), tingling, numbness and visual holes (scotoma). Symptoms evolve over more than 5 minutes and resolve within 60 minutes and may occur in succession. A neurologist can be of assistance in recognizing this typical pattern of aura presentation.

A migraine is classically:

• unilateral
• pulsating
• builds up over minutes to hours
• moderate to severe in intensity
• associated with nausea and/or vomiting and/or sensitivity to light and/or sensitivity to sound
• disabling
• aggravated by routine physical activity.

Pre-eclampsia

Pregnant women who experience migraines have a more than two-fold increased risk of pre-eclampsia compared with women who do not. Women need to be aware to consult a health professional if their headache is different from their usual migraine, and have their urine and blood pressure checked. A population-based analysis also found migraine was associated with a 17-fold increased risk of stroke and a four-fold increased risk of acute myocardial infarction.

The International Headache Society diagnostic criteria for headache attributed to pre-eclampsia are described below.

Diagnostic criteria for headache attributed to pre-eclampsia or eclampsia

1. Headache in a woman who is pregnant or in the puerperium fulfilling criterion C
2. Pre-eclampsia or eclampsia has been diagnosed
3. Evidence of causation demonstrated by at least two of the following:
   1. Headache has developed in temporal relation to the onset of the pre-eclampsia or eclampsia
   2. Either or both of the following:
      1. a) headache has significantly worsened in parallel with worsening of the pre-eclampsia or eclampsia
      2. b) headache has significantly improved or resolved in parallel with improvement in or resolution of the pre-eclampsia or eclampsia
   3. Headache has at least two of the following three characteristics:
      1. a) bilateral location
      2. b) pulsating quality
      3. c) aggravated by physical activity
4. Not better accounted for by another diagnosis

Headache is the most common prodromal symptom prior to a seizure.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension is a rare condition but more prevalent in obese women of childbearing age. It may present for the first time in pregnancy and pre-existing disease tends to worsen during pregnancy. The headache is generalized, non-throbbing, aggravated by coughing or straining and is associated with diplopia (38%) and visual loss (31%) with papilledema. Diagnosis requires excluding other causes and finding abnormally elevated cerebrospinal fluid pressure (>20 cmH2O) on lumbar puncture.

Management includes monitoring of the visual fields and visual acuity because of the risk of optic nerve infarction. Women should be encouraged to limit weight gain. Treatment with therapeutic lumbar puncture or acetazolamide (500 mg twice daily) is directed towards improving the headache and preventing visual loss.

Reversible cerebral vasoconstriction syndrome

Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular disorder associated with multifocal arterial constriction and dilation. It has a significant association with the postpartum period. RCVS is characterised by recurrent sudden onset and severe headaches over 1–3 weeks, often accompanied by nausea, vomiting, photophobia, confusion and blurred vision. Diagnosis requires the demonstration of diffuse arterial beading on cerebral angiography with resolution within 1–3 months. It is in the differential of a postpartum thunderclap headache often made after subarachnoid haemorrhage has been excluded but the headaches recur. Treatment is currently based on neurological consultation including the use of calcium channel blockers, high-dose corticosteroids and magnesium sulphate.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) is a clinical–neuroradiological entity associated with pre-eclampsia. It is characterised by headache, vomiting, visual disturbances, seizures and altered mental state, with radiological findings of edema in the posterior circulation of the brain.

PRES classically demonstrates parietal and occipital lobe cortical and subcortical signal change which are hypotense on T1 and hyperintense on T2 and FLAIR sequences caused by vasogenic edema. Infarcts and hemorrhages are relatively uncommon but occur in approximately 15% of cases.

Cerebral blood flow is maintained despite changes in blood pressure by an autoregulatory mechanism facilitated by changes in vascular resistance. In PRES, this autoregulatory response is impaired, leading to breakdown of the normal blood–brain barrier and culminating in vasogenic brain edema. Because of a partial lack of sympathetic innervation of the vasculature that emerges from the basilar artery, edema tends to occur in the posterior regions of the central nervous system. Edema leads to progressive brain compression within the skull and the symptoms of headache, nausea, vomiting and seizures. So why does pre-eclampsia lead to a breakdown in this autoregulation? Cases of PRES without hypertension have been reported associated with immunosuppressant drug use, nephrotic states, sepsis and systemic lupus erythematosus. In these cases a common etiological pathway leading to vasogenic edema is endothelial damage. Endothelial dysfunction is associated with the pathophysiology of pre-eclampsia. Studies have also shown that pregnancy alone predisposes the brain to the neurological complications of eclampsia by promoting hydrostatic brain edema when blood pressure is acutely elevated.

Prompt recognition and management of PRES is required to avoid the risk of irreversible lesions. When PRES is associated with pre-eclampsia, management follows the treatment algorithm for severe pre-eclampsia with blood pressure control, prevention and/or treatment of seizures and prompt delivery of the baby.

Cerebral venous thrombosis

Headache is the most frequently (80–90%) occurring symptom in cerebral venous thrombosis and often the first symptom reported by patients. The International Classification of Headache Disorders describes the headache as having no specific characteristics but one study found the headache was usually acute or subacute in onset, localised, continuous and moderate to severe. Cases have been reported where headache is the only neurological symptom or sign but this is very rare. More often other clinical manifestations present at onset or develop during the course of the disease. These include papilledema, focal deficits, altered consciousness, seizures and cranial nerve signs, in particular diplopia caused by sixth nerve palsy. Psychosis, in conjunction with focal neurological signs, has also been reported. The development of symptoms may occur over hours, days or even weeks.

Risk factors identified for development of cerebral venous sinus thrombosis include age over 40 years, obesity, dehydration, sepsis, anemia, vomiting, congenital or acquired thrombophilias, immobility, pre-eclampsia, malignancy, chronic hypertension, and delivery by cesarean section.

The greatest risk period is the third trimester and the first 4 weeks postpartum. The incidence of CVT during pregnancy and the puerperium in Western countries ranges from 1 in 2500 to 1 in 10 000 deliveries. Thrombosis of the sagittal sinus with secondary extension into the cortical veins, or primary thrombosis of one of the cortical veins, are the most common sites of involvement in pregnancy.

Computed tomography (CT) is widely used as the initial imaging tool in patients who present with headache or focal neurological signs but a plain CT is insensitive for CVT, abnormal in only 30% of cases. Magnetic resonance imaging with T2-weighted imaging and magnetic resonance venography (MRV) is the imaging modality of choice.

When CVT is suspected prompt referral to a neurologist is advised. Treatment – usually anticoagulation with low-molecular-weight heparin – should be continued typically for 6 months.If there is neurological deterioration or coma despite medical treatment then further management can include endovascular therapy.

Compared with patients with CVT unrelated to pregnancy, CVT associated with pregnancy and the puerperium tends to have a better outcome with a lower mortality rate. A follow-up MRV at 3 to 6 months after diagnosis is suggested to assess for recanalization of the occluded cortical vein/sinuses.

Women may also be referred to a hematologist for further investigations if an underlying thrombophilia is suspected.

CVT is not a contraindication for future pregnancies but women should be counseled that they are at risk of further venous thrombotic events and will require prophylaxis with low-molecular-weight heparin during pregnancy and postpartum.

Imaging and referral

Women with headaches in pregnancy and the postnatal period may be at home, in a hospital, in an antenatal clinic at a tertiary referral center or in the emergency department. All medical staff should therefore be able to take a full history and examination and make a provisional differential diagnosis. Imaging of the brain should never be withheld because a woman is pregnant and women should be reassured that imaging is safe.

Key points: imaging of the head in pregnancy

• The accepted background cumulative dose of ionizing radiation during pregnancy is 50 mGy
• Fetal exposure for a computed tomography scan of the head is estimated at <0.005 mGy
• Magnetic resonance imaging (MRI) should be avoided in the first trimester because of the potential hazards of hyperthermia and acoustic noise, but MRI remains preferable to any studies using ionizing radiation
• Contrast media based on the element iodine should be avoided in pregnancy unless essential. If iodinated contrast media are used the neonatal thyroid function should be checked
• Gadolinium-based contrast agents appear to be safe in pregnancy
• Lactating women who receive iodinated contrast or gadolinium can continue breastfeeding without interruption

Conclusion

Doctors managing pregnancy and the postpartum period need to be aware of the symptoms, signs and appropriate response to the rarer and more severe causes of headache that continue to cause avoidable morbidity and mortality.

This article highlights the importance of broadening the differential diagnosis, considering alternative explanations, and not narrowing the focus of a seemingly obvious cause for a patient’s symptoms.