Episode 6: Neuropathy in Pregnancy and Postpartum

Ann is a busy mom of three kids - but can she really be "too busy" to notice that half of her face is not moving? In this episode we discuss Bell's Palsy and other "high yield" neuropathies that can occur in pregnancy and postpartum. Featuring obstetrical medicine and infectious disease expert Dr. Erica Hardy, and neuromuscular expert Dr. Kara Stavros. Dr. Julie Roth hosts.

Key Takeaways:

• Bell's Palsy is characterized by weakness or paralysis of one side of the face - both the upper and lower face - with reduced eye blinking, sometimes with impaired taste and hearing. Patients can get numbness, tingling and pain in the face or behind the ear.
• A short course of steroids is evidence-based in nonpregnant patients with Bell's Palsy, although less is known about the use of steroids in pregnancy and postpartum period for this condition.
• Carpal Tunnel Syndrome (CTS) is the most common peripheral neuropathy in pregnancy; it presents with achy wrist and arm pain and tingling in the fingers, worse at night, relieved by shaking out the hand. It can be managed conservatively with wrist splints during pregnancy and symptoms usually resolve after delivery.
• An enlarged uterus can compress nerves and the lumbosacral plexus in the pelvis during pregnancy, and prolonged labor and delivery is also a risk factor for some lower limb neuropathies. A careful history and exam can make the diagnosis of these neuropathies, and treatment is supportive, including physical therapy and where needed, pain control. 
• The overall prognosis for recovery from pregnancy- and postpartum-related neuropathies is very good.

Written Case: Bell's Palsy and Other Neuropathies in Pregnancy and Postpartum

Stephanie Chang, MD’19, Dr. Niharika Mehta and Dr. Julie Roth

A 37 year old G3P3 woman presents to her internist at two weeks postpartum with complaints of numbness, pain and weakness of the left side of the face. Onset of symptoms was within one week prior to delivery. She had noticed that the left side of her face was mildly numb, and she had attributed this to stress. She underwent caesarian section for breech presentation. Her pregnancy was otherwise uncomplicated. After delivery, she noticed mild weakness of the left face, worsening in the few days prior to presentation, with pain behind the left ear. Her husband told her that she was not blinking the left eye normally. She also noticed that when she drank water, it would dribble down her chin.

What are the diagnostic considerations in this case? And how would you differentiate?

Muscle weakness on one side of the face raises concern for paralysis of cranial nerve VII, also known as the facial nerve. Facial muscle paralysis can result from injury anywhere along the path from the cerebral motor cortex to the corticobulbar tract, and on to the facial nucleus and CN VII itself.  It is therefore important to differentiate between central lesions involving the brain, such as stroke or tumor, and peripheral causes affecting the nerve, such as Bell’s Palsy.

Central causes often present with an upper motor neuron pattern of symptoms, including paralysis of the contralateral lower muscles of facial expression only, with muscles on the forehead left intact. Also, although these patients will lack voluntary control of facial muscle movement, they will exhibit spontaneous movement in response to emotional input. Thirdly, patients with central causes of facial paralysis may also demonstrate other neurological findings – the arm or leg might be involved, speech might be affected, and vision might be affected, depending on the location of the lesion.  If a stroke is suspected, neuroimaging and appropriate work-up must be performed ASAP.

Bell’s Palsy is a peripheral cause of unilateral facial paralysis that affects the facial nerve itself. Typically, patients with Bell’s Palsy present with isolated facial weakness that progresses to complete paralysis within a few days.[1] While the facial nerve is not responsible for sensation, it is not unusual for these patients to have a subjective feeling of tingling or numbness of the face (with no sensory deficit on neurological exam), and with pain that is often localized to or around the ear. A lower motor neuron pattern of facial weakness is seen, defined as complete paralysis of one side of the face – forehead included.  Patients will lack both voluntary and spontaneous movement of the facial muscles, and may also demonstrate increased sensitivity to loud sounds in one ear and loss of taste from the anterior two-thirds of the tongue. An important clue to the clinician diagnosing Bell’s Palsy is reduced (or absent) blinking on the side of the facial paralysis – a finding not typically seen in stroke or other central nervous system causes.

In encountering a patient with Bell’s Palsy, other diagnostic considerations include herpes zoster, Ramsay Hunt (varicella zoster affecting the 7th and typically also the 8th cranial nerve), Lyme disease, HIV, tumors, mass lesions, Guillain-Barre, sarcoidosis, Sjogren Syndrome, and a rare condition known as the Melkersson-Rosenthal syndrome, in which a single patient may be prone to multiple bouts of Bell’s Palsy.  A careful exam, paying particular attention to the presence of vesicles in the ear canal, masses in the parotid gland, systemic symptoms such as fever, and the presence of other neurological findings, can help to rule out these causes.

On exam, she has impaired movement of the left upper and lower face, reduced blink rate of the left eye, and incomplete closure of the left orbicularis oculi. Hearing is intact to finger rub, and sensation is normal – though there is some subjective numbness and pain in the cheek and around the ear. The remainder of the cranial nerve exam is normal, as is the remainder of the neurological exam. She is afebrile. After a lower motor neuron pattern of weakness is identified, the patient is diagnosed with Bell’s palsy.

What testing is needed, if any?

In the general population, Bell’s Palsy is often attributed to an infectious etiology, which then causes an inflammatory reaction and demyelination of the facial nerve. Reactivation of latent herpes simplex virus, infection with Lyme disease, and varicella zoster have been implicated. Testing for Lyme can be performed if the patient lives in an endemic area and presents at a time of year that the disease is present. For example, In the northeastern United States, Lyme disease is a major cause of Bell’s Palsy, and so it is common clinical practice to send Lyme titers on patients who present with acute Bell’s Palsy both at presentation, and sometimes repeat testing six weeks after onset if initially negative.

For an isolated Bell’s Palsy without systemic symptoms, lumbar puncture is not necessary. Systemic symptoms like fever, joint pain, or other cranial nerve involvement would warrant lumbar puncture.

How is this condition treated?

Corticosteroids (prednisone, prednisolone) are typically administered early. Steroids may help relieve associated pain, and in nonpregnant patients with Bell’s Palsy, they have been shown to improve the chances of complete recovery.[2] Their  use in pregnancy, however, is less well established. The addition of empiric antiviral therapy (acyclovir, valacyclovir) for Bell’s Palsy does not appear to confer additional benefit.[3]

If a causative condition like Lyme disease is diagnosed, appropriate treatment such as antibiotics would be indicated. In pregnancy, amoxicillin can be used, whereas outside of pregnancy, doxycycline is used.[4]

Supportive treatment during this time can include methylcellulose eye drops (artificial tears), temporary patching to prevent corneal abrasions, and physical therapy to prevent muscle contracture.[5]

Why might this patient be at risk for Bell’s Palsy?

The incidence of Bell’s Palsy in pregnancy is up to six times higher than the incidence in the general population, with the majority of cases occurring during the third trimester or early post-partum period.[6] The reason for the increased incidence of the disorder is unknown, although it is hypothesized to result in part from immune and hormonal factors, as well as the increase in total body water (and resultant extracellular fluid) that occurs during pregnancy.

During the third trimester and early postpartum period, women have the highest extracellular fluid content, and it is hypothesized that edema, fluid retention and venous congestion compress the facial nerve within the stylomastoid foramen and fallopian (facial) canal, resulting in a compression neuropathy.  This hypothesis is supported by the fact that pregnant patients with Bell’s Palsy also have significantly higher rates of gestational hypertension and preeclampsia, two states also associated with increased pressure and fluid overload.[7]

Other hypotheses include  hypercoagulability leading to focal ischemia of the nerve.[8] In any case, the facial nerve and other peripheral nerves of pregnant women may be at higher risk for injury. 

What other peripheral neuropathies can occur in pregnancy and the postpartum period?

Carpal tunnel syndrome is the most frequent mononeuropathy in pregnancy, and is hypothesized also to be due to fluid retention and edema.  Symptoms often do not resolve immediately after delivery, but the majority will spontaneously resolve one to three years post-partum.[9] Treatment is conservative and includes wrist splints or rest, physical therapy, and local injections.

Some neuropathies, like Bell’s Palsy and carpal tunnel syndrome, may appear towards the end of pregnancy without a clear inciting cause, while other mononeuropathies, particularly involving the lower limbs, may result from direct compression of the nerve during the pregnancy itself or in labor and delivery.[10] In the absence of a clear cause, entrapment neuropathies should prompt clinicians to look for other features of preeclampsia, a pregnancy specific condition characterized by hypertension and proteinuria, which can present with significant edema, including swelling in the nerve sheath leading to entrapment.

Lower extremity neuropathies are also common in the postpartum period, and are associated with nulliparity and a prolonged second stage of labor.[11] After delivery, these neuropathies may need to be differentiated from spinal or epidural anaesthesia-related factors. Differentiation begins with a detailed history – including anaesthesia, details of the pregnancy, labor and delivery, and clinical symptoms of pain, weakness, parethesias and sensory loss. A neurological exam can pick up a specific pattern of abnormal motor weakness, sensation and reflexes. The most common of these lower limb compression neuropathies are listed below.

During pregnancy, the lateral femoral cutaneous nerve can be entrapped at the anterior iliac spine or through the inguinal ligament, resulting in sensory symptoms such as burning, numbness, tingling, and pain in the anterior and lateral thigh.  This is often due to weight gain and is more common in patients with diabetes or a large fetus. This condition is also called meralgia paresthetica, and treatments for the pain (if severe) might include neuropathic pain medications such as low-dose tricyclic antidepressants (TCAs), gabapentin, or even injection to the nerve (lateral femoral cutaneous nerve block), administered by a trained clinician.

Femoral neuropathy can result from prolonged periods of time in the lithotomy position, tight clothing, and excess weight.  In addition to experiencing sensory symptoms in the anterior thigh and medial lower leg, patients may also experience weakness of hip flexion and knee extension, resulting in leg buckling, weakness, and falls. Hip abduction and adduction is preserved, and there is no foot drop in this condition. The patellar reflexes (knee jerk) might be reduced or absent.

Peroneal neuropathy can be bilateral due to its superficial location, and is especially common in thin people or while holding legs back during delivery.  It can result in sensory symptoms in the lateral aspects of the lower leg and foot, as well as foot drop, or a “slapping gait.” The hip girdle muscles are unaffected.

The obturator nerve can be compressed between the child’s head and the pelvis, and can result in numbness and pain in the groin and medial thigh as well as weakness in abduction or internal rotation of the thigh. Extension and flexion at the knee and movement of the foot would be unaffected.

For such neuropathies, bracing, physical therapy, and topical pain medications are treatment, as most will resolve spontaneously. EMG/NCS testing can be considered if symptoms are very prolonged. This testing involves thin needles placed into muscles and electrical impulses applied to nerves; the testing itself can be uncomfortable for patients. Though EMG/NCS is considered safe in pregnancy, the diagnosis of these neuropathies is usually made clinically wherever possible. However, if signs and symptoms deviate from the typical compression mononeuropathy patterns described above, including an atypical or more prolonged course, this might suggest a more widespread problem such as a lumbosacral radiculopathy related to anesthesia (multiple nerves and nerve roots affected), or lumbosacral plexopathy due to compression in the pelvis. In these cases, MRI of the lumbar spine would be advised, possibly in addition to pelvic imaging such as CT or MRI to exclude hematoma or mass compressing the lumbosacral plexus, and EMG/NCS to evaluate for a more extensive lumbosacral plexopathy.

Additionally, isolated palsies of other cranial nerves have been documented in pregnancy, including palsies of CN III, V, VI,[12] and XII,[13] some in the context of preeclampsia. Because these particular neuropathies are very rare, the workup for these conditions should include brain MRI or skull base CT to exclude a compressive mass along these nerves.

Are there labor and delivery implications for women with Bell’s Palsy or peripheral neuropathy during pregnancy?

Bell’s palsy in pregnancy has no particular implications when it comes to a labor and delivery plan. Compression neuropathies that occur during labor and delivery can be hard to avoid, but it is important to note that a prolonged labor, or remaining in one position, may put women at risk.

The patient notes that after delivery, her face gradually improved to baseline over the course of a few weeks.

What do you tell her if her symptoms had not resolved within three months?

Nerves regrow at a speed of 0.3-1mm/day – thus the speed and totality of recovery from Bell’s Palsy is variable. Over 50% of women will have full recovery within a few months, and another 35% will recover within one year.[14] If function has not returned in 6-16 months, surgery (hypoglossal-facial nerve anastomosis, for example) can restore partial function.

REFERENCES:

[1] Vrabec JT, Isaacson B, Van Hook JW. Bell’s palsy and pregnancy. Otolaryngology - Head and Neck Surgery 2007; 137(6): 858-61.

[2] Sullivan FM, Swan IRC, Donnan PT et al. Early Treatment with Prednisolone or Acyclovir in Bell's Palsy. New England Journal of Medicine 2007; 357:1598-1607.

[3] Engstrom M, Bert T, Stjernquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell's Palsy: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurology 2008 Nov;7(11):993-1000.

[4] Walsh CA, Mayer EW, Baxi LV. Lyme Disease in Pregnancy: Case Report and Review of the Literature.2006. Obstetrical & Gynecological Survey. Vol 62, No. 1, pp. 41-50.

[5] Cohen Y. Bell Palsy Complicating Pregnancy: A Review. Obstetrical & gynecological survey 2000; 55(3): 184 - EOA.

[6] Klein A. Peripheral nerve disease in pregnancy. Clinical obstetrics and gynecology 2013; 56(2): 382 - EOA.

[7] Katz A, Sergienko R, Dior U, Wiznitzer A, Kaplan DM, Sheiner E. Bell's palsy during pregnancy: Is it associated with adverse perinatal outcome? The Laryngoscope 2011; 121(7): 1395-8.

[8] Cohen Y. Bell Palsy Complicating Pregnancy: A Review. Obstetrical & gynecological survey 2000; 55(3): 184 - EOA.

[9] Padua L, Pasquale AD, Pazzaglia C, Liotta GA, Librante A, Mondelli M. Systematic review of pregnancy-related carpal tunnel syndrome. Muscle & Nerve 2010; 42(5): 697-702.

[10] Massey EW and Guidon AC. Peripheral neuropathies in pregnancy. (Neurology) Continuum (Minneap Minn) 2014; 20(1):100-114.

[11] Klein A. Peripheral nerve disease in pregnancy. Clinical obstetrics and gynecology 2013; 56(2): 382 - EOA.

[12] Gilca M. Multiple Concomitant Cranial Nerve Palsies Secondary to Preeclampsia. Journal of neuro-ophthalmology 2015; 35(2): 179 - EOA.

[13] Femia G, Parratt JDE, Halmagyi GM. Isolated reversible hypoglossal nerve palsy as the initial manifestation of pre-eclampsia. Journal of Clinical Neuroscience 2012; 19(4): 602-3.

[14] Klein A. Peripheral nerve disease in pregnancy. Clinical obstetrics and gynecology 2013; 56(2): 382 - EOA.

Episode 5: Pseudotumor Cerebri and Secondary Causes of Headache in Pregnancy

When is a headache more than just a headache? Amanda's headaches started with a twinge, but when she started to lose her vision, her doctors sent her to the ER. Were Amanda's doctors overreacting? Featuring expert interviews with obstetrical medicine specialist Dr. Niharika Mehta, neurosurgeon Dr. Petra Klinge, maternal fetal medicine specialist Dr. Erika Werner, and neurooncologist Dr. Alexander Mohler. Dr. Julie Roth hosts.

Key Takeaways:

• Secondary causes of headache warrant workup in pregnancy if a patient screens in with the "SNOOP" acronym - systemic/secondary, neurologic, onset, older, and prior headache history - or positional headaches.
• Neuroimaging modality should be based on how acute the symptoms are - CT is indicated for headaches less than 24 hours, stroke-like symptoms, or sudden onset first or worst headache of life; MRI/A/V without gadolinium is indicated for secondary headaches over 24 hours.
• Treatment of pseudotumor cerebri during pregnancy is indicated to relieve symptoms and to preserve the vision; visual loss is the major risk of this disorder.
• Labor and delivery methods in individuals with elevated intracranial pressure depends on the cause. In pseudotumor cerebri, if patients are symptomatic around the time of delivery, passive second stage (passive descent) with operative delivery should be considered as an alternative to caesarian section; Valsalva during vaginal delivery can increase the intracranial pressure.

Written Case: Pseudotumor Cerebri and Secondary Causes of Headache in Pregnancy

Dr. Niharika Mehta and Dr. Julie Roth

A 26 year old woman, currently pregnant at 29 weeks gestation, presents for evaluation of headaches. She had never had headaches before the pregnancy. Beginning in her second trimester, she began to have constant, throbbing, posterior head pain, worse in the morning and when lying down. She also developed floaters in her visual fields, particularly when changing position.

What concerns do you have in a pregnant patient with this headache pattern?

Headaches account for a third of all neurologic issues encountered in pregnancy. More than 80% of women in the reproductive age group experience headache at some point, making it a common occurrence in pregnancy[1]. While primary headaches (such as migraine, tension and cluster headaches, chronic daily headaches or medication overuse headaches) account for majority of the cases of headache seen in pregnancy, the presence of certain clinical features should prompt a thorough examination of possible differential diagnoses. The American Headache Society offers the mnemonic  SNOOP[2] to identify red flags in a headache history, that can help differentiate primary and secondary headaches:

-SYSTEMIC SYMPTOMS (fever, weight loss) or SECONDARY RISK FACTORS (HIV, systemic cancer);

- NEUROLOGIC SYMPTOMS or abnormal signs (confusion, impaired alertness or consciousness);

-ONSET: sudden, abrupt, or split-second;

- OLDER: new onset and progressive headache, especially in middle age >50 yr (giant cell arteritis); and

-PREVIOUS HEADACHE HISTORY: first headache or different (change in attack frequency, severity, or clinical features; and POSITIONAL component).

Applying the above mnemonic in this patient should prompt the clinician to consider secondary causes of headache (New onset, associated visual phenomena and positional component).

While the brain itself feels no pain, the pain-sensitive structures inside the head include the scalp, the skull, the blood vessels and the meninges. Any irritability or direct injury to one of these structures may result in headache pain. For example, headaches worse lying down or waking a patient from sleep at night can be due to elevated intracranial pressure. Sudden onset headaches, especially with neurological symptoms, can suggest rupture of a vascular anomaly such as aneurysm or arteriovenous malformation. And systemic symptoms, secondary risk factors, and older age can be risk factors for either inflammatory, infectious, or gradually expanding (such as neoplastic) lesions that irritate or damage these pain-sensitive structures over a longer period of time.

What is the differential diagnosis to consider in this patient presenting with suspected secondary headache in pregnancy?

When considering causes of headache in a pregnant woman, it helps to classify conditions into three categories: those that are specific to pregnancy; those that are exacerbated by or associated with pregnancy; and those that are unrelated to pregnancy.

Conditions specific to pregnancy include preeclampsia, a condition characterized by new onset of hypertension, proteinuria and multi-organ involvement, in the second half of pregnancy (after 20 weeks gestation). Patients with preeclampsia may progress to eclampsia (seizures) with subsequent development of PRES (posterior reversible encephalopathy syndrome) evident on MRI. Both preeclampsia and PRES present clinically with headaches.

Conditions exacerbated by or associated with pregnancy include arteriovenous malformations (AVMs) that might experience increased blood-flow and possibly increase in size due to pregnancy-related cardiovascular changes and blood volume expansion. Sinus headaches are also more frequently seen in pregnancy due to increased vascularity and mucus production, resulting in sinus congestion. In patients with pituitary adenomas, particularly macroadenomas, tumor growth can occur with pregnancy progression[3], and may present as headache. Pregnancy is a hypercoagulable state and although ischemic stroke is rare, cerebral vein thrombosis can be seen in pregnancy, particularly in the third trimester and postpartum period[4].

In pregnancy, an increase in intracranial pressure can result from increased intraabdominal pressure and subsequent reduced cerebral venous outflow, as well as hormonal effects with increased circulatory volume. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, shows a predilection for young, obese women of childbearing age and although no definite association[5] has been found between pregnancy and IIH in case control studies[6], this condition is an important consideration in pregnant patients – especially as weight gain and increased circulatory volume are normal features of pregnancy.

Conditions unrelated to pregnancy include trauma, tumors, and infections, although it is important to consider listeria in the differential when treating meningitis in a pregnant patient.

Does this patient’s headaches warrant further evaluation? What sort of evaluation?

Yes. When it comes to headaches in pregnancy, the clinical history and examination – including vital signs, neurological exam, and funduscopic exam – are of utmost importance. A longstanding history of headaches, predictable semiology and normal exam findings would be reassuring factors. Any new-onset headache in pregnancy, and headaches accompanied by new neurological phenomena (visual, sensory, motor, or cognitive, for example), focal features on neurological exam, or abnormal fundoscopy would require neuroimaging. A physical examination of the patient should include a neurological exam to assess for abnormal motor or sensory findings (especially weakness or sensory loss in one or two limbs), gait instability, coordination difficulties (finger to nose test), or abnormal cranial nerve findings, most importantly: papilledema on funduscopic exam, abnormal visual fields, abnormal eye movements or pupillary responses, or facial asymmetry. Funduscopic exam can reveal retinal vasospasm or serous retinal detachment in cases of severe preeclampsia. Hyperreflexia is also noted in this condition and is a precursor of eclamptic seizures.

In pregnant patients with headache and associated neurologic features that have lasted over 24 hours, MRI (and possibly non-contrast MRA and MRV) should be considered. While gadolinium (MRI contrast agent) should be avoided in pregnancy whenever possible, the MRA and MRV do not require contrast. MRA can detect vascular malformations such as aneurysm and arteriovenous malformation. MRV dcan detect cerebral venous sinus thrombosis. A noncontrast MRI provides detailed imaging of the brain parenchyma and can detect causes of elevated intracranial pressure including cerebral edema (focal or diffuse) and hydrocephalus. Although gadolinium cannot be administered to pregnant patients, the lack of edema seen on the T2/FLAIR MRI images would argue strongly against a mass or tumor as the source of the pain. MRI is preferable to CT, both from a safety and sensitivity standpoint, but in an emergency (headache less than 24 hours, stroke-like symptoms, or sudden onset first or worst headache of life), CT is considered the standard of care. CT poses minimal radiation risk to the fetus. If fundoscopy is abnormal (papilledema, signaling raised intracranial pressure), neuroimaging should precede lumbar puncture.

The patient was found on physical exam to have bilateral papilledema but an otherwise unremarkable neurological exam, and was sent to the emergency room. She underwent a brain MRI, which was unremarkable.

What other testing is important at this point?

If neuroimaging is normal, lumbar puncture (LP) should be done for opening pressure and routine analysis. Routine labs include cell count and differential (to screen for infection), protein, glucose, gram stain and culture. A lumbar puncture can be safely performed in pregnancy in any gestation.

What is the most likely diagnosis? What other causes of headache should be explored?

The most likely cause of the headache in this patient is idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri. 

IIH presents with symptoms/signs attributed to increased intracranial pressure (e.g., headache, papilledema, transient visual obscurations or “dim-outs,” and pulsatile tinnitus). The incidence of IIH is 2 to 20 times higher in the primary risk group: overweight women of childbearing years. Its diagnosis in pregnancy is no different than outside of pregnancy; the characteristic findings are normal neuroimaging with elevated opening pressure on LP. Making the diagnosis is important to avoid permanent visual loss, which can occur in about 25% of IIH patients. Sending the patient for a visual field and dilated eye examination is crucial. Visual fields can be tracked over time to determine resolution or progression. About 2-12% of pregnancies are affected by IIH.[7]

Intracranial hypertension can sometimes be a secondary finding – in the case of cerebral venous sinus thrombosis, for example, elevated intracranial pressure can occur because of increased venous congestion, even without an associated venous infarct or hemorrhage in the vicinity. This finding might go unseen on a standard MRI, and therefore, MRV is recommended to image the cerebral venous sinuses. Outside of pregnancy, elevated intracranial pressure can also be caused by excess vitamin A (or vitamin A derivatives), antibiotics (tetracycline family, for example), steroids or hormone-based contraception, or underlying disorders like obstructive sleep apnea, endocrinopathies, infections (lyme disease, for example) and systemic lupus erythematosus (SLE).

The patient is diagnosed with idiopathic intracranial hypertension (IIH) based on imaging results. Lumbar puncture was encouraged, but the patient was too anxious to perform the testing, although it was offered on several occasions.

How is IIH treated? What are the risks of treatment in pregnancy?

Treatment is geared toward maintaining limited weight gain, low salt diet and diuretics—especially acetazolamide. Although the complete safety of acetazolamide during pregnancy is not known, therapeutic doses of acetazolamide during pregnancy are unlikely to pose a substantial teratogenic risk. Metabolic acidosis is a recognized complication of acetazolamide therapy in adults and transient neonatal metabolic acidosis has been reported in premature infants whose mothers were treated with acetazolamide[8]. Outside of pregnancy, topiramate and furosemide can be used to treat this condition; however, these drugs should be avoided in pregnancy whenever possible. If vision is threatened, frequent lumbar punctures can temporize while a more definitive procedure is arranged. Procedures used to treat this condition when medical therapy fails include: optic nerve sheath fenestration, venous stenting, or placement of a ventriculoperitoneal shunt. Optic nerve sheath fenestration is performed less commonly than the other two procedures, although all three can be effective. However, in pregnancy, these invasive procedures are usually avoided unless absolutely necessary – especially if the increased weight gain in pregnancy is felt to be the major player in the development of symptoms, because resolution after delivery may occur.

IIH is not associated with adverse pregnancy outcomes[9]. Delivery method should remain unaffected due to IIH, with obstetrical indications governing the decision to perform a cesarean section. However, where there is concern for visual loss, an assisted delivery with forceps or vacuum may be warranted to limit further increases in intracranial pressure with Valsalva/expulsion efforts.[10]

On acetazolamide, visual symptoms and headache completely resolved. Visual field testing was normal. Funduscopic exam in the office was normal. She underwent MRV, which showed mild narrowing of the transverse and sigmoid sinuses on both the right and left side. Thrombus was ruled out.

What are the implications of the MRV findings?

While the MRV in patients with IIH is often normal, the narrowing of sinuses on this patient’s MRV corroborate the diagnosis of IIH. The MRV definitively ruled out cerebral venous sinus thrombosis. Moreover, the narrowing of the sinuses is a finding – along with “empty sella” – that is often seen in IIH. It is unknown if congenitally narrow sinuses prevent venous outflow, leading to pressure buildup in the head – a process that might be exacerbated in states of increased total body fluid, like pregnancy – or if the pressure of the brain on the sinuses themselves is the cause of the narrowing. Outside of pregnancy, a patient with venous sinus narrowing and a lack of response to medical therapy might be a candidate for venous stenting, a procedure usually done endovascularly.

At 36 weeks gestation, the patient called to report that her symptoms had returned, including posterior headaches and floaters in her vision. She described her vision as “foggy” or as if she was looking through a smoky room. She also had periods in which she would temporarily lose her vision when she was bending over, blowing her nose, or during bowel movements. She had had no abnormalities on visual field testing throughout pregnancy to date.

What is the significance of these symptoms? What are the next steps?

In a situation in which the symptoms of elevated intracranial pressure return in a patient with high level of suspicion for IIH, the medication (acetazolamide) can be titrated to effect. Also, in this particular case, the diagnosis of IIH is assumed – in spite of no opening pressure on lumbar puncture to confirm. Therefore, lumbar puncture should again be offered – not only to measure the opening pressure, but also to remove some cerebrospinal fluid and hopefully reduce the symptoms. Repeating visual field testing can be useful for more constant visual symptoms, but episodic symptoms such as those described above can sometimes be missed.

The patient finally agreed to lumbar puncture in spite of extreme anxiety. She was given a dose of alprazolam, a benzodiazepine, in order to complete the procedure, which she ultimately tolerated well. She reported that her visual symptoms improved markedly after the lumbar puncture, but the headache remained – and in fact, worsened. Surprisingly, the opening pressure was normal (10 cmH20). Therefore, no cerebrospinal fluid was removed. After the lumbar puncture, her vision improved, but her headaches developed the opposite positional pattern – they were worse standing or sitting up and better lying down. She developed severe nausea when standing as well. Blood pressure was normal, and there was no proteinuria.

What are some other causes for intractable, severe headaches towards the end of pregnancy? And what is the implication of the “reverse positional” headache?

Preeclampsia and PRES were discussed previously, and should always be high on the list in a patient with suspected secondary causes of headache later in pregnancy. In this patient, normotension and the lack of proteinuria would argue against this diagnosis. She has already had neuroimaging, and so a new mass lesion or inflammatory or infectious lesion would be very unlikely. Aneurysm rupture would present suddenly, not gradually.

Finally, she has a new (reverse) positional feature to the headaches. They are better lying down than standing or sitting. Especially after lumbar puncture, these are the features of a spinal – or “low-pressure” – headache. In a patient who has not had a lumbar puncture, this “reverse positional” patter is also important to ascertain, because it can occur in a spontaneous low-pressure headache due to a dural leak. Treatment of low-pressure headaches – including a spinal headache – includes caffeine, aggressive fluid repletion (either oral or intravenous), and when conservative methods fail, another procedure known as a blood patch. A blood patch involves repeating the lumbar puncture – but with the intent of injecting some of the patient’s own blood into the subdural space, presumably to seal any leakage.

Are there labor and delivery implications? Can she push?

If there are clear signs of elevated intracranial pressure, pushing during vaginal delivery should be avoided. For example, in a patient with visual changes bending over or with Valsalva, pushing should be avoided to prevent a more permanent loss of vision. In this case, the patient’s headaches and visual symptoms worsened with Valsalva or bending over. Caesarian section can also contribute to fluctuations in blood pressure and therefore possibly to intracranial pressure. There is a third option – known as passive second stage with operative delivery, or passive descent. In this case, natural labor is planned but with the use of vacuum or forceps rather than pushing as the baby descends through the birth canal. This option minimizes or avoids “pushing” (Valsalva) while reducing the operative risks typically associated with caesarian section.

Anesthesiology goals should involve minimizing increases in intracranial pressure, primarily through pain reduction. Because patients with IIH do not have an obstructive process leading to a pressure differential between the cranial and spinal compartments, not only is dural puncture safe, but in symptomatic patients, it can be therapeutic.

Although a patient with spinal headache due to low intracranial pressure may be reluctant to pursue spinal anesthesia, there is no specific anesthesia risk in a patient with low pressure headaches. Blood patch can be administered as a treatment for this condition.

However, headaches remained severe in spite of treatment of the “spinal headache.” Vision impairment never returned, but due to severe headache pain and emotional distress, her baby was delivered at 38 weeks by caesarian section due to breach presentation. Following delivery, she had no signs of postpartum preeclampsia, and over 8 weeks, headaches gradually subsided.

Are there any additional tests she needs after delivery?

In this case, the etiology of the headaches remains a mystery. The papilledema and MRV findings support a diagnosis of IIH, and it is possible that the usual fluctuations of intracranial pressure, coupled with the timing of the acetazolamide she was taking and effects of the benzodiazepine she took prior to the lumbar puncture led to a falsely low opening pressure. Ideally, a repeat lumbar puncture would be useful to follow up on this finding, but the patient declined this test. Visual field testing should be repeated as a way to wean the patient off acetazolamide. Neuroimaging may be repeated to follow up on a finding such as narrowing of the venous sinuses, but it is not always necessary if symptoms resolve.

REFERENCES:

[1] Marcus DA, Scharff L, Turk D. Longitudinal prospective study of headache during pregnancy and postpartum. Headache 1999(39); 9:625-632

[2] Available at https://americanheadachesociety.org/wp-content/uploads/2016/07/Primary_OR_Secondary_ Headache.pdf. Last accessed on July 22,2017

[3] Molitch ME, Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25(6):885

[4] Martinelli I. Cerebral vein thrombosis . Thromb Res. 2013 Jan;131 Suppl 1:S51-4.

[5] Thurtell MJ, Bruce BB, Newman NJ, Biousse V. An Update on Idiopathic Intracranial Hypertension. Rev Neurol Dis. 2010 Spring-Summer;7(2-3):e56-68

[6] Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology. 1991;41(2 ( Pt 1)):239

[7] Hopkins A, Alshaeri T, Akst SA, et al. Neurologic disease with pregnancy and considerations for the obstetric anaesthesiologist. Seminars in Perinatology 38 (2014) 359-369.

[8] Merlob P, Litwin A, Mor N: Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol. 1990 Apr;35(1):85-8

[9]Tang RA, Dorotheo EU, Schiffman JS, Bahrani HM. Medical and surgical management of idiopathic intracranial hypertension in pregnancy. Curr Neurol Neurosci Rep. 2004;4:398–409. 

[10] Bagga R, Jain V, Das CP, Gupta KR, Gopalan S, Malhotra S. Choice of therapy and mode of delivery in idiopathic intracranial hypertension during pregnancy. MedGenMed. 2005 Nov 10;7(4):42

Episode 4: Preeclampsia and Cerebrovascular Consequences - RCVS and PRES

Grace is 26 years old and just delivered a healthy baby girl... then suddenly, days later, severe pain hits her head like a thunderclap. What is the workup for "thunderclap headache" in the postpartum period? We talk with obstetrician Dr. Jane Sharp, maternal fetal medicine specialist Dr. Erika Werner and stroke specialist Dr. Shadi Yaghi. Dr. Julie Roth hosts.

Key Takeaways:

• Preeclampsia is a multisystem, vascular disorder of pregnancy defined by the new onset of hypertension and proteinuria after 20 weeks of gestation. However, preeclampsia can also occur in the early postpartum period.
• Neuroimaging is indicated in any individual experiencing the "first or worst" headache of one's life, to exclude subarachnoid hemorrhage as can be seen in cerebral aneurysm rupture.
• There is substantial overlap between reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES); both neurological disorders reflect abnormal cerebral vasculature and both can be seen within or outside of pregnancy and the postpartum period. 

Written Case: Preeclampsia and Its Cerebrovascular Consequences - RCVS and PRES

By Dr. Niharika Mehta and Dr. Julie Roth

A 26 year old G1P0 woman experiences hypotension and presyncope during pregnancy, with mild peripheral edema shortly before delivery; her pregnancy is otherwise normal and she delivers a healthy baby girl at full term. Three days after delivery, she returns to the ER after experiencing a sudden-onset, severe, “thunderclap headache.” Her blood pressure in the ER is 170/90, normal liver function tests, serum creatinine of 1.2. She is diagnosed with postpartum preeclampsia and treated with intravenous magnesium, which quickly resolves the headache. Her blood pressure returns to normal within 24 hours and she is discharged.

QUESTIONS:

What is preeclampsia? How is it clinically defined, and what is the pathophysiology?

Preeclampsia is a heterogeneous, multisystem disorder of pregnancy defined by the new onset of hypertension and proteinuria after 20 weeks of gestation. The ACOG[1] recommends the following diagnostic criteria to establish diagnosis of preeclampsia:

New onset BP elevation after 20 wks:  >/= 140/90 on at least 2 occasions 4 hours apart or >/=160/110 confirmed by 2 measurements a few minutes apart

AND

Proteinuria: >300mg in 24 hours or UPCR >/=0.3 or Urine Dipstick with 1+ proteinuria

OR (in the absence of proteinuria, New onset HTN and any of the following)

1. Thromboctyopenia: Plt <100k/ml
2. Renal insufficiency: Creat >1.1mg/dl
3. Impaired liver function: Liver enzymes at least 2x upper limit of normal
4. Pulmonary edema
5. Cerebral or visual symptoms

Preeclampsia is felt to result from an imbalance between proangiogenic and antiangiogenic factors in the placenta resulting in systemic endothelial dysfunction. Production of placental anti-angiogenic factors, specifically soluble fms-related tyrosine kinase 1 and soluble endoglin, have been shown to be upregulated in preeclampsia. These placental anti-angiogenic factors are released into the maternal circulation; their actions disrupt the maternal endothelium. Clinical features of preeclampsia can be explained by this endothelial dysfunction[2]: hypertension results from disturbed endothelial control of vascular tone, proteinuria and edema are caused by increased vascular permeability, and coagulopathy is the result of abnormal endothelial expression of procoagulants.

Risk factors for preeclampsia include older age (>34 years), nulliparity, preeclampsia in prior pregnancy, family h/o preeclampsia, multiple gestation, preexisting medical conditions including diabetes, hypertension, renal disease, SLE, antiphospholipid antibody syndrome, obesity[3].

Endothelial damage resulting from preeclampsia may explain subsequent increased risk of cardiovascular and end stage renal disease in these women.

What screening tests are performed throughout pregnancy?

In the first half of pregnancy, antenatal management consists of risk factor identification and treatment with low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia (USPSTF recommendation)[4] . Many experts recommend checking levels of creatinine, liver enzymes, platelets and a urine protein-to-creatinine ratio (UPCR) in the first trimester, to identify any abnormalities at baseline that might confuse the picture later on in pregnancy when preeclampsia is suspected.

A BP check and screening for proteinuria with dipstick is performed at every antenatal visit and management of abnormal values is guided by the gestational age. Before 20 weeks, an elevated BP is usually the result of a chronic or pregnancy-unrelated cause and management is guided by suspected diagnosis. After 20 weeks gestation, the finding of hypertension should prompt a search for proteinuria or other features of preeclampsia as listed above. 

During pregnancy, how is preeclampsia managed?

Once preeclampsia is identified, close monitoring to establish severity of disease and rate of progression is important. Delivery is the only definitive treatment for preeclampsia. Timing of delivery is dictated by presence of “severe features”- which include severe hypertension (>160/110), pulmonary edema, HELLP syndrome, severe intractable headache, seizures or altered mental status, progressive renal insufficiency (creatinine >1.1 mg/dl). Intravenous magnesium for seizure prophylaxis is initiated in these patients as soon as severe preeclampsia is identified and is continued until 24 hours after delivery.

In the absence of severe features, conservative management with close in-patient or out-patient monitoring with frequent lab evaluation (CBC, LFTs, Creatinine, UPCR), treatment of hypertension, assessment of fetal wellbeing and growth is indicated. For patients managed conservatively, delivery is indicated at 37 weeks of gestation or as soon as they develop preeclampsia with severe features.

What is postpartum preeclampsia? Why might it occur?

Occasionally, preeclampsia/eclampsia can present in the postpartum period. Delayed postpartum preeclampsia can be defined as signs and symptoms of the disease leading to readmission more than two days but less than six weeks after delivery[5]. Most patients tend to present in the first week after delivery and have no antecedent diagnosis of hypertensive disorders of pregnancy.  It is unclear whetherthe pathology of preeclampsia in the postpartum period is different from those that occur in the antepartum and the peripartum periods. One proposed pathophysiologic mechanism for postpartum preeclampsia includes the presence of circulating placental factors in maternal blood that have yet to be cleared.

Following resolution of her headache, she returns home and does well initially. However, 24 hours later, she notes a gradual buildup of bifrontal throbbing pain, which becomes increasingly severe (to 10/10) in spite of treatment at home with acetaminophen and ibuprofen. She has a history of rare, mild headaches prior to her pregnancy that resolved on their own, but no strong history of migraine. Her headaches fail to respond to acetaminophen.

What concerns are there in this patient with known postpartum preeclampsia who presents with severe headache? What further workup is needed?

While the overwhelming majority of postpartum headaches are from benign causes such as migraine or tension headaches exacerbated by lack of sleep and fatigue, certain features in presentation should prompt further work up for secondary causes.  Post dural puncture (“spinal”) headache should be considered in women who received epidural analgesia or spinal anesthesia for delivery and who present with positional variance in headache – in other words, worse standing up and resolved when lying down. However, the opposite pattern (worse lying down and improved standing up) suggests a secondary cause of headache, possibly related to increased intracranial pressure. Severe, sudden onset headache – sometimes called “thunderclap headache” – can be the result of intracranial hemorrhage from ruptured blood vessel anomaly like aneurysm or arteriovenous malformation or associated with other pathology such as cerebral venous thrombosis or pituitary apoplexy. Two other causes of headache in pregnancy and the postpartum period include reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES), which will be discussed further, below.

It is therefore important to pursue neuroimaging in patients who present with severe headache in the postpartum period with concerning features in their clinical history.

Definitive management of preeclampsia is delivery. Therefore in a patient presenting in the postpartum period with preeclampsia, the management is only supportive. Blood pressure control to reduce stroke risk with severe hypertension is recommended. Typical agents used to control blood pressure include IV labetalol or hydralazine or PO nifedipine.  A magnesium drip is started for seizure (eclampsia) prophylaxis and continued for 24 hours.

The patient underwent MRI/A/V, which revealed a high convexity subarachnoid hemorrhage in the right hemisphere. There was no evidence of aneurysm or arteriovenous malformation on MRA, later confirmed on CTA, and the MRV demonstrated no thrombus. There were no space-occupying lesions.

What are the possible causes of subarachnoid hemorrhage in the postpartum patient? 

It is unclear whether the risk of bleeding from brain arteriovenous malformations is higher during pregnancy, delivery, or puerperium, with various cohort studies from different geographical regions showing conflicting results[6],[7],[8]. Risk of rupture of aneurysms is also felt to be low/not impacted by pregnancy. However these remain important in the differential diagnosis of a patient presenting with severe, sudden-onset “thunderclap” headache. In a patient presenting with “thunderclap” headache, or worst headache of her life, aneurysm rupture should be excluded urgently by MRA or CTA. Conventional angiogram is the gold standard for diagnosis – and also for management of aneurysm rupture, as the vascular malformation can be treated with the placement of endovascular coils. Aneurysm rupture usually causes subarachnoid hemorrhage around the deep structures or base of the brain, because most aneurysms are found around the Circle of Willis. A “high convexity” (or along the upper surface of the brain) subarachnoid hemorrhage in a young individual can suggest trauma, and therefore, screening for signs of head injury is also important. In an elderly individual, cerebral amyloid angiopathy can also cause subarachnoid hemorrhage in this location, but this would not be expected to occur in a young, postpartum woman.

Finally, reversible cerebral vasoconstriction syndrome (RCVS) can also present as sudden onset, severe (“thunderclap”) headache and hypertension in postpartum women. Also known as postpartum angiopathy, RCVS, can cause acute, spontaneous subarachnoid hemorrhage in postpartum women, in the absence of an aneurysm or underlying vascular anomaly. In RCVS, hemorrhage is typically in the “high convexity” of the brain. This was the diagnosis in this particular patient.

RCVS occurs when there is focal narrowing of the blood vessels of the head (vasoconstriction). This finding can be seen on vascular imaging like MRA and CTA, and it is also detected on transcranial Doppler (TCD) ultrasound as elevated cerebral flow velocities. In addition to severe headaches and subarachnoid hemorrhage, cerebral ischemia, and seizures.[9] Outside of pregnancy, RCVS can be due to the use of vasoactive medications, including stimulants, allergy nasal sprays, serotonergic medications such as those used for depression, and triptan (migraine) medications. It can also be seen in patients with known hypertension or with migraine. In pregnancy and the postpartum period, RCVS can be seen in the context of preeclampsia/eclampsia, as the shared pathophysiology of this disorder is abnormal cerebral vasoconstriction. However, it can also in patients (pregnant or postpartum) who otherwise do not meet the aforementioned criteria for preeclampsia – but nonetheless have cerebral vasoconstriction. Treatment for RCVS involves calcium channel blockers like verapamil and nimodipine, and occasionally oral magnesium supplementation,[10] as well as pain control.

Another vascular cause of headache in pregnancy is known as posterior reversible encephalopathy syndrome (PRES); headaches due to PRES are usually gradual in onset and accompanied by vision changes. The pathophysiology of PRES involves cerebrovascular leakage and resultant edema in the white matter of the brain. As PRES progresses, confusion (encephalopathy) and seizures can occur. The pathognomonic MRI finding for PRES is confluent or patchy T2/FLAIR hyperintensities in the posterior white matter of the brain. Treatment of PRES is supportive and involves treating the underlying condition. 

How do RCVS and PRES relate to pregnancy?

Both RCVS and PRES are known to be associated with pregnancy. The underlying pathology of PRES is felt to result from disordered (cerebral) vascular autoregulation and endothelial dysfunction – the 2 hallmarks of preeclampsia pathogenesis. Some experts consider this condition as criteria for eclampsia diagnosis even in the absence of hypertension and proteinuria[11].  The clinical features of PRES parallel those along the preeclampsia/eclampsia spectrum, and PRES-like MRI findings would be typical for a patient with known eclampsia.

Although RCVS can occur spontaneously, at least half the cases occur in the postpartum period, with or without preeclampsia/eclampsia. Posterior reversible encephalopathy syndrome and RCVS share many clinico-radiographic features, suggesting overlapping or similar pathophysiological mechanisms.  That overlap occurs within and outside of pregnancy; between 8 and 38% of cases of RCVS also show signs of PRES on neuroimaging.[12] Similar to PRES (and therefore related to preeclampsia), RCVS is also felt to result from a transient disturbance in the control of cerebrovascular tone and is characterized by transient brain edema (endothelial dysfunction -> leaky vessels), vasoconstriction, focal infarction and hemorrhage.

The patient was transferred to the neurology intensive care unit (NICU) and treated with intravenous magnesium and calcium channel blockers, as well as aggressive pain management. Symptoms improved over 24 hours. She was discharged from the hospital with a prescription for magnesium oxide 400mg/day and verapamil 240mg/day. She remained headache free through an 8-week follow-up appointment with her neurologist, who then weaned her off the verapamil by 3 months postpartum.

How long does it usually take for postpartum preeclampsia to resolve after diagnosis? And RCVS?

Both RCVS and postpartum preeclampsia typically resolve within 3 months.

Any advice for future pregnancies?

Whether RCVS is likely to recur in future pregnancies is unclear, as there is no data currently available in the literature. However, preeclampsia can recur in subsequent pregnancies and low dose aspirin during pregnancy is recommended in these patients to reduce the risk of recurrent Preeclampsia [13].  

What do you tell her about breastfeeding?

For most calcium channel blockers, including verapamil, nimodipine and nifedipine, the amount of drug secreted in breastmilk is small and not expected to cause any adverse effect on the nursing infant. Similarly, magnesium oxide supplements at 400mg/day are generally considered acceptable in breastfeeding.

REFERENCES:

[1] Taskforce on hypertension in pregnancy. Accessed at https://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy. Last accessed on 8/1/17

[2] Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda). 2009 Jun;24:147-58.

[3] Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005 Mar 12; 330(7491): 565

[4]https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication. Last accessed 8/8/17

[5] Al-Safi Z, et al. Delayed postpartum preeclampsia and eclampsia: demographics, clinical course, and complications. Obstet Gynecol 2011; 118(5):1102

[6] Relative risk of hemorrhage during pregnancy in patients with brain arteriovenous malformations. Int J Stroke. 2017 Jan 1:1747493017694387. doi: 10.1177/1747493017694387

[7] Hemorrhage Risk of Brain Arteriovenous Malformations During Pregnancy and Puerperium in a North American Cohort. Stroke. 2017 Jun;48(6):1507-1513

[8] Known and unknown cerebral arteriovenous malformations in pregnancies: haemorrhage risk and influence on obstetric management. Neuroradiol J. 2017 Jan 1:1971400917712264.

[9] Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 2(1):91

[10] Mijalski C, et al. Magnesium for Treatment of Reversible Cerebral Vasoconstriction Syndrome: Case Series. Neurohospitalist. 2016 Jul; 6(3): 111–113.

[11] Raps EC, Galetta SL, Broderick M, Atlas SW. Delayed peripartum vasculopathy: cerebral eclampsia revisited. Ann Neurol. 1993;33(2):222

[12] Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012; 11:906-17. 

[13] 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(2):110.

Episodes RSS

Episode 3: Epilepsy and Seizures in Pregnancy

Sara is 29 years old with a history of epilepsy since childhood, and ready to start a family. How will you keep her seizure-free while protecting her baby? Our experts this time are sisters: Dr. Gina Deck and Dr. Tina Yarrington. Dr. Julie Roth hosts.

Key Takeaways:

• Epilepsy is defined as a tendency to have seizures; the treatment for epilepsy is anticonvulsant therapy.

• Anticonvulsants have been linked with birth defects and neurocognitive problems in the developing fetus - but not all drugs have equal risk!

• The primary goal in pregnancy is to keep the patient seizure-free on the lowest possible dose of medicine. 

• Checking levels can be a useful way to track progress in pregnancy, because there are a number of physiological changes that contribute to altered drug levels in pregnancy.

• Safety precautions after the baby is born may include strategies to reduce sleep deprivation, avoiding diaper changes on raised surfaces, no baths for mom or the baby when home alone, and be careful about heights.

Written Case: Seizures and Epilepsy in Pregnancy

Dr. Julie Roth and Dr. Niharika Mehta

A 29 year old woman with a longstanding history of absence epilepsy since age 16 presents for pre-pregnancy counseling. Her seizures are characterized by staring spells lasting one minute duration, and she has been treated with lamotrigine extended release formulation 200mg/day. She has been seizure-free, to her knowledge, for at least 5 years. However, in the past, when she tried to discontinue lamotrigine, she had breakthrough seizures.

What pregnancy-related considerations warrant discussion with women with epilepsy who are of childbearing age? What important points should be discussed at this office visit with a patient presenting for preconception counseling?

All anticonvulsants, also known as antiepileptic drugs (AEDs), have been linked with major congenital malformations (MCMs) among offspring exposed in utero. However, seizures in pregnancy are also risky. Therefore, all women of childbearing age should be counseled on the possibility of birth defects and seizure-related risks, should they become pregnant.

Because 50% of pregnancies are unplanned, discussion of pregnancy concerns should occur in all women with epilepsy who are of childbearing age. This should include a candid discussion about folic acid supplementation as well as birth control methods. While birth control methods are often reviewed by obstetricians/gynecologists in routine office visits, it is important for specialists treating chronic diseases in women, including epilepsy, to gain comfort with contraception discussions, particularly in situations in which medications used to treat these conditions may have teratogenic implications, and where drug-drug interactions with hormone-based contraception may be a factor in unplanned pregnancies. This is certainly true for anticonvulsants. For example, combined hormonal contraceptive methods can lower lamotrigine levels due to glucuronidation. Other anticonvulsants that are hepatically metabolized through CYP450, and in particular, enzyme-inducing anticonvulsants like phenytoin, carbamazepine, topiramate, phenobarbital among others, can reduce levels of the exogenous hormones in the bloodstream. The downstream effect of increased enzyme induction makes hormone-based birth control less effective and increases the risk of unintended pregnancies. Long-term reversible birth control methods such as intrauterine devices and contraceptive implants have low rates of unintended pregnancies, and some of these methods have low likelihood of conflict with anticonvulsants.[i]

Are some anticonvulsants riskier in pregnancy than others?

Although anticonvulsants have known teratogenic risks, these drugs can be separated into low, intermediate or unknown, and high risk categories. Lamotrigine is among the safest anticonvulsants used in pregnancy, with a risk of MCMs of approximately 2.0% (compared to 1-2% of the general population). Levetiracetam is another common anticonvulsant used on pregnancy because of its relatively low risk of MCMs (2.4%).[ii] In spite of prior predictions, two older, hepatic enzyme inducing anticonvulsants had lower than expected rates of MCMs: phenytoin (2.9%) and carbamazepine (3.0%). It is worth noting that at the North American Pregnancy Registry[iii] and other world-wide registries continue to enroll women with epilepsy, the exact numerical values of these rates, as well as confidence intervals, change. Higher risk anticonvulsants include valproic acid, phenobarbital, and topiramate. Phenobarbital carries a risk of MCMs of 5-6%, and Topiramate 4-5%. There is some evidence of low birth weight among babies exposed in utero to topiramate and to some extent, zonisamide.[iv]

Valproic acid has the highest risk for MCMs of all anticonvulsants, between 9 and 10% and is contraindicated in pregnancy except in extenuating circumstances (i.e., the seizures can only be controlled on this drug). Adverse neurocognitive effects of valproic acid have also been identified in one-third of cases within a cohort of children exposed to anticonvulsants and followed since birth.[v] Other anticonvulsants studied in this cohort did not pose increased neurocognitive risk compared to the unexposed control group. Valproic acid is controversial for use in young women of childbearing age in general, especially for alternative indications such as migraine and bipolar disorder due to these risks.

Most other anticonvulsants are considered to be "intermediate” or unknown risk, in which teratogenic risk (between 0 and 4% risk of MCMs) is balanced against the number of cases documented in the North American AED Pregnancy Registry[vi] and many other international registries. Most anticonvulsants - and most medications, for that matter - are listed as Category C for use in pregnancy, associated with some evidence of risk in animals but not enough human data to support an alternative category. Important exceptions to this rule are valproic acid, topiramate and phenobarbital, all of which are listed as Category D (clear evidence of risk to human fetuses) in pregnancy.

Folic acid may help offset risk in pregnant women by protecting specifically against neural tube defects, which are among the most severe of these birth defects. However, there is no consensus on the appropriate dose of folic acid.[vii] Experts recommend between 0.4mg and 10mg per day. Common doses in the United States include between 1 and 5mg/day, and agreement on the proper dose is typically reached through discussion among the patient, the neurologist, and the obstetrician. 

Finally, a pre-pregnancy baseline drug level should be checked if the opportunity arises, preferably on a yearly basis. In a seizure-free individual, the pre-pregnancy baseline provides a point of comparison in order to keep the patient seizure-free during pregnancy.[viii]

What are the risks of having a seizure during pregnancy? Should she remain on lamotrigine throughout the pregnancy?

The risks associated with seizures in pregnancy are difficult to quantify but in part relate to trauma resulting from a seizure – this can lead to placental abruption or even miscarriage. Other risks include acidosis, reductions in uterine blood flow and associated hypoxia. It is generally accepted among neurologists and obstetricians that preventing seizures in pregnancy outweighs the significantly lower risk of teratogenicity of anticonvulsants. A 2009 nationwide, population-based study in Taiwan identified a higher risk of preterm labor and delivery as well as a risk of intrauterine growth restriction (IUGR) and delivery of infants who are small for gestational age (SGA) among women with uncontrolled, frequent seizures in pregnancy.[ix] Therefore, the need to continue anticonvulsants throughout pregnancy should be emphasized to a woman at risk for such. Epilepsy continues to be an important indirect cause of death for a minority of women. Based on the 2011 report of the United Kingdom Confidential Enquiries into Maternal Deaths, 14 deaths were epilepsy-related, of which 11 (79%) were sudden and unexpected (SUDEP)[x].

A long seizure-free interval might predict a seizure-free pregnancy, and the majority of women find that seizure frequency does not change significantly in pregnancy.[xi] Progesterone and its derivatives can have an anticonvulsant effect on the brain, while in some circumstances, estrogen is felt to promote seizures. During pregnancy, both hormones are steadily on the rise. The response of seizures to pregnancy, therefore, is unpredictable. In this particular patient, tapering her lamotrigine in the past resulted in breakthrough seizures, placing her at higher risk for recurrence.

These issues were discussed with the patient, and she, her neurologist and obstetrician opted to continue the lamotrigine at the current dose and preferred a dose of 4mg/day of folic acid in preparation for pregnancy. A pre-pregnancy lamotrigine level was 3.5 - on the lower end of the therapeutic spectrum (between 3.5-15). A few months later, she learned she was pregnant. An urgently scheduled follow-up appointment was made for her.

What counseling should be provided to a woman with epilepsy who has recently discovered she is pregnant? What are the next steps? 

Typically, pregnancy-related issues are emphasized once again in a more urgently scheduled visit - ensuring medication compliance and folic acid supplementation. All seizures and auras should be reported to the neurologist. A first-trimester drug level should be checked to ensure stability compared to the pre-pregnancy baseline.

What physiological factors contribute to alteration of anticonvulsant levels in pregnancy? And what is the clinical relevance?

Anticonvulsant levels can plummet during pregnancy due to physiologic alterations that occur from trimester to trimester. This is due to several discrete pregnancy-related physiological factors: an increase in maternal circulatory volume leading to reduced blood concentrations; an increase in the glomerular filtration rate leading to more rapid clearance of the drugs; and the increase in hepatically synthesized proteins altering concentrations of protein-bound drugs as well as metabolic pathways that are influenced by hormones. Nausea and vomiting in pregnant women also contributes to poor absorption of anticonvulsants.

Lamotrigine is extensively metabolized through glucuronidation - a process that is enhanced by sex hormones. More commonly than not, lamotrigine levels drop by up to 50% within the first trimester of pregnancy, with this process beginning before a woman knows she is pregnant, and leaving her less protected from seizures. Therefore, it is possible that pregnancy may present as a cluster of breakthrough seizures. Fortunately, this is the exception rather than the rule! Even the levels of drugs with low protein binding and high renal clearance (rather than hepatic metabolism), like levetiracetam, can drop during pregnancy due to the increased glomerular filtration rate. Because the complex interaction of pharmacology with pregnancy-related physiology is complicated, a good rule of thumb is to check at least once level per trimester and in the last month of pregnancy.[xii] If the level drops, then an appropriate increase in dose and "re-check" of the level is advised. Women should be counseled that it is more common than not to end up on a higher dose of anticonvulsant during pregnancy than they had been taking previously, because of these factors. After delivery, physiologic and metabolic changes return to the pre-pregnant state at different speeds. Glucuronidation, for example, normalizes within two weeks, and therefore for drugs like lamotrigine, a more rapid taper of the drug to slightly higher than the pre-pregnancy dose over this period is advised.[xiii] It is preferable to be proactive with medication adjustments in response to changing levels in a pregnant woman rather than reacting to seizures and auras, but levels may be prohibited by cost or not be readily available in all institutions. In these cases, clinicians should consider drugs that are more stable from trimester to trimester, drugs with a low toxicity profile even at higher levels (like levetiracetam), or more frequent visits to screen for clinical seizures, auras and signs of toxicity among patients. 

Lamotrigine levels throughout the pregnancy ranged from 2.7 to 4.6. She felt well until 29 weeks gestation, when in the context of work stress, sleep deprivation with insomnia, she felt “spacy.” She could not tell if she was having true absence seizures. The pros and cons of a medication increase were reviewed, and she decided to make no changes and wait a little longer. Within 6 weeks, she had several recurrent absence seizures and the medication was increased to 400mg/day, which resolved the symptoms. She also took time off work to relieve stress and promote improved sleep – two major seizure triggers. She was seen again at 37 weeks – the final neurology visit before delivery. 

What are the next steps?

Her lamotrigine level was checked the same day as the visit. However, because laboratory tests for second generation anticonvulsant levels can take up to several weeks to return, based on location, any breakthrough seizures or auras should prompt an empiric increase in dosage rather than waiting for labs to return. Counseling on adequate sleep is also crucial, as sleep deprivation is a seizure trigger. It is noteworthy that sleep architecture becomes disrupted later in pregnancy, with pregnant women commonly experiencing insomnia and reporting less deep sleep.[xiv]

What peripartum seizure-related issues are important to discuss? Can the patient delivery vaginally (can she push)?

A history of epilepsy in the mother should not influence the mode of delivery. Although caesarean section rate has been higher in women with epilepsy, among other chronic diseases, there is little basis for this clinical trend. Epilepsy is not an indication for caesarean section, and there is no evidence that vaginal delivery would increase the risk of seizures for patients.

Labor and delivery for this patient were uneventful, and she delivered a healthy baby girl at full term. During the hospitalization, clinical questions were raised about the emergency treatment of seizures, and also about her ability to breastfeed.

What is the emergency treatment of seizures in pregnancy or the peripartum period, should they occur?

Seizures around the time of labor and delivery are rare, but when they occur, are an emergency. Patients are typically turned on their side to avoid aspiration or compromised airway, and treated aggressively with intravenous medications. Treating the seizing mother urgently is most important for both mother and baby. Most commonly used intravenous options are benzodiazepines (lorazepam, for example), and intravenous loads of phenytoin or levetiracetam. Even when “NPO” patients should be encouraged to take their anticonvulsant medications as usual around labor and delivery.

An important distinction should be made between eclamptic seizures, which are a marker of severe, acute but self-limited neurological disease, and epileptic seizures, which are the result of an underlying chronic condition characterized by a tendency towards (unprovoked) seizures. There is no role for magnesium, the mainstay of therapy in eclampsia, in patients with epileptic (non-eclamptic) seizures. The ideal anticonvulsant for eclamptic seizures should magnesium fail to prevent recurrent seizure activity are yet unknown, and the workup of new onset seizure in the peripartum period usually involves neurological consultation when the presentation does not match eclampsia.

What do you tell her about breastfeeding?

Mothers should be counseled that clinical evidence regarding breastfeeding and anticonvulsants is limited. Lamotrigine does cross into breastmilk and there is a theoretical risk of higher levels in babies due to immature glucuronidation. On the other hand, this is a medication to which babies would have been exposed in utero, and the amount in breastmilk is still quite minimal. There are many advantages to breastfeeding, which should be weighed against possible risks.[xv] Other anticonvulsants are excreted to varying degrees in breastmilk – usually inversely related to the degree of protein binding. Levetiracetam, for example, has very low protein binding and can thus be concentrated in breastmilk. However, the medication itself has a favorable side effect profile for infants and therefore no toxicity has been described. Breastfeeding should be reviewed on a case by case basis with patients. Signs of anticonvulsant toxicity in a baby (while very rare) would include excessive drowsiness.

Are there other postpartum concerns?

One concern postpartum is how quickly to taper the medications back to the pre-pregnancy dosage. Medications that are extensively glucuronidated must be tapered within 2 weeks; however, experts have proposed keeping the dose slightly above the pre-pregnancy dose to partially counteract the potential effects of sleep deprivation on seizure threshold. Other medications can be tapered within 1-3 months, but usually depend on the degree to which they were increased during the pregnancy. Some tapering is recommended to prevent postpartum anticonvulsant toxicity, which can lead to vision and balance problems and potentially falls.

Postpartum safety issues include avoiding baths for mom or the baby when alone in the house, to prevent catastrophic submersion. Heights should be avoided whenever possible – including changing tables when the baby is not strapped in. Co-sleeping should be avoided in women with epilepsy. Alternating feeds with a partner to allow for longer blocks of uninterrupted sleep are also advisable when possible. In case of an aura, the safest place for the baby is on the floor or in a crib, away from sharp or dangerous objects.

Finally, women with epilepsy are at higher risk for depression, anxiety, and other mental health conditions in general. It is unknown whether they are at higher risk for postpartum depression in particular, but they should be screened and treated accordingly.

REFERENCES:

[i] Herzog, A. G., Mandle, H. B., Cahill, K. E., Fowler, K. M., Hauser, W. A. and Davis, A. R. (2016), Contraceptive practices of women with epilepsy: Findings of the epilepsy birth control registry. Epilepsia, 57: 630–637. doi:10.1111/epi.13320

[ii] Hernandez-Diaz, S., Smith, C.R., Shen, A., Mittendorf, R., Hauser, W.A., Yerby, M., Holmes L.B. Comparative Safety of Antiepileptic Drugs During Pregnancy. Neurology
2012; 78:1692-1699

[iii] http://www.aedpregnancyregistry.org/

[iv] Hernandez-Diaz, S., Mittendorf, R., Smith, C.R., Hauser, W.A., Yerby, M., Holmes L.B. Association Between Topiramate and Zonisamide Use During Pregnancy and Low Birth Weight. Obstetrics & Gynecology 2014; 123(1):21-28

[v] Meador KJ, Baker GA, Browning N, et al. Fetal Antiepileptic Drug Exposure and Cognitive Outcomes at Age 6 Years (NEAD study): A Prospective Observational Study. Lancet Neurol. 2013 March ; 12(3): 244–252. doi:10.1016/S1474-4422(12)70323-X.

[vi] http://www.aedpregnancyregistry.org/

[vii] Harden CL, Pennell PB, Koppel BS, et al. Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009; 73(2):142-149. doi: http://x.oi.rg/0.212/NL.b013e3181a6b325

[viii] Roth JL and Bilodeau C, “Headaches and Seizures.” Rosene-Montella K, Medical Management of the Pregnant Patient. New York: Springer 2015. (219-231)

[ix] Chen YH, Chiou HY, Lin HC, Lin HL. Affect of Seizures During Gestation on Pregnancy Outcomes in Women with Epilepsy. Arch Neurol 2009 Aug;66(8):979-84. doi: 10.1001/archneurol.2009.142.

[x] S Edey,N Moran, and L Nashef. SUDEP and epilepsy-related mortality in pregnancy. Epilepsia, 55(7):e72–e74, 2014

[xi] Harden CL, Jopp J, Ting TY, et al. Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009 Jul 14;73(2):126-32. doi: 10.1212/WNL.0b013e3181a6b2f8. Epub 2009 Apr 27.

[xii] Pennell P. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology September 1, 2003. 61(6; suppl 2):S35-S42.

[xiii] Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in Pregnancy: Clearance, Therapeutic Drug Monitoring, and Seizure Frequency. Neurology 2008 May 27; 70(22 Pt 2): 2130-2136.

[xiv] Wilson DL, Barnes M, Ellett L, Permezel M, Jackson M, Crowe SF. Decreased sleep efficiency, increased wake after sleep onset and increased cortical arousals in late pregnancy. Aust N Z J Obstet Gynaecol. 2011;51(1):38

[xv] Veiby G, Bjork M, Engelsen BA, Gilhus NE. Epilepsy and Recommendations for Breastfeeding. Seizure 2015 May; 28:57-65.

Episodes RSS

Episode 2: Migraine in Pregnancy

A pregnant special ed teacher is having horrible, pounding headaches with light and sound sensitivity, nausea and vomiting, and her doctors have recommended... Tylenol? In this episode, we review migraine physiology, and pharmacological and behavioral treatment of this debilitating neurological disorder in pregnancy. Experts include neuroscientist Dr. Carl Saab, obstetrical medicine specialists Drs. Niharika Mehta and Kenneth Chen, and behavioral medicine specialist Dr. Lucy Rathier. Dr. Julie Roth hosts.

Key Takeaways:

• Migraine is a complex neurological syndrome that can be affected by a number of triggers - including sex hormones! This means there are many women whose migraines increase during pregnancy.

• Treatment of migraine in pregnancy can be tricky, because the list of SAFE medications in pregnancy does not necessarily match the list of EFFECTIVE medications.

• The Pregnancy and Lactation Labeling Rule (PLLR) offers more information about safety of drugs in pregnancy than the old FDA "letter category" classification system. Clinicians can use this as a framework to discuss medications and their risk profile in pregnancy individually with pregnant or lactating patients with migraine.

• In addition to medicines, there are a number of effective behavioral therapies that can treat migraine, which would be considered safe in pregnancy.

Written Case: Migraine in Pregnancy

Dr. Julie Roth and Dr. Niharika Mehta

A 36 year-old G2P1 pregnant woman, currently at 8 weeks gestation presents for evaluation of headaches. Her headaches are characterized by throbbing or pounding pain at one or both temples, with light sensitivity and nausea. She has a prior history of migraine since age 16, which have always been strongly hormonal. Her physical exam is normal, including funduscopic exam. Her prior pregnancy was notable for severe headaches in her first and early second trimester, characterized by a gradual buildup of throbbing pain in the forehead and around the eyes, lasting hours to all day, often on one side, with light and sound sensitivity, and rarely, with nausea.

What clues do you have regarding diagnosis and treatment? What is the most likely diagnosis for this patient’s headaches?

In a pregnant patient, a longstanding history of headaches from an early age and a normal exam (including funduscopic exam), are reassuring factors that confirm the current diagnosis of migraine in pregnancy. In this case, the patient has a history of prior pregnancy during which headaches were also a feature. It is important to consider clinical features of current prior headaches, a list of medications and treatment strategies that worked and did not work, and the patient’s understanding of headaches and medication use in pregnancy.

Workup for new onset headaches (or atypical headaches) in pregnancy will be covered in another case. In this particular patient, no further testing is indicated, as she meets criteria for episodic migraine headache. Throbbing headaches of gradual onset, lasting hours, and accompanied by sensory hypersensitivities such as photophobia and phonophobia, as well as nausea, are characteristic of migraine headaches. The International Headache Society defines migraine without aura as at least five attacks (not otherwise explained by another neurological disorder), lasting 4-72 hours untreated, with at least two of the following characteristics: unilateral location, pulsating quality, moderate or severe intensity, aggravation with physical activity or exertion, and at least one of the following characteristics: nausea (with or without vomiting) or sensitivity to light or sound.[1]

What is a migraine? And why does it occur?

Migraine pathophysiology is complicated. The primary mechanisms appear to be neuronal dysfunction with associated changes in bloodflow, and activation of the trigeminovascular system, triggering release of calcitonin gene-related peptide (CGRP), among other neuropeptides. The aura of migraine is caused by an electrical phenomenon known as cortical spreading depression of Leao (CSD) – characterized by progressive hyperpolarization of adjacent neurons throughout the cortex of the brain. Hypersensitivity of sensory neurons and the central nervous system are key elements in the perception of mild stimuli like light and sound as painful to a patient during a migraine attack.[2]

How common is migraine, and whom does it affect?

Migraine is more common in women than men (3:1) and in most cases appears to have genetic underpinnings; about 70% of migraineurs have a first degree relative with migraine. Migraine attacks are often triggered by factors that are common in pregnancy: changes in sleep, stress level, hormones, caffeine intake, and diet.2 While many women find a hormonal trigger to their migraines, in clinical practice, it can be hard to predict whether a woman’s migraines will improve or worsen in pregnancy. On the other hand, for women with hormonally triggered migraines, weaning from breastfeeding can exacerbate migraine attacks.

Migraine occurs in 11-26% of women of childbearing age, and although the prevalence of migraine specifically during pregnancy is unknown, up to one third of pregnancies are complicated by headache.[3] While not immediately life-threatening, migraines can be disabling and contribute to poor absorption and even dehydration through gastrointestinal effects. Migraines – and in particular, migraine with aura – are considered minor risk factors for stroke and cerebrovascular diseases. There are links between migraine and hypertensive disorders of pregnancy.[4] Furthermore, severe pain – including migraine – can be associated with stress, dehydration, and other factors that may adversely affect a pregnancy. Therefore, a diagnosis of migraine in pregnancy should be addressed from a medical standpoint. Several studies indicate a significant association between migraines and hypertensive disorders of pregnancy (PEC and Gestational HTN) . In addition, migraines are a risk factor for stroke in pregnancy and puerperium. 

During her prior pregnancy, she took amitriptyline up to a dose of 50mg/day, for migraine prevention. This helped somewhat. She has had several headaches so far that were severe (9 or 10/10 pain), and did not respond to acetaminophen. She wonders if she can take the sumatriptan she typically takes outside of pregnancy.

What medications can be used safely in pregnancy for acute treatment of headache? What daily preventative medications are safest? Which of these medications are most effective?

The FDA “category” system classifies medications based on levels of potential risk in pregnancy. Category A medications have demonstrated on risk in controlled, human studies (based on exposure in all three trimesters). Category B medications have demonstrated no risk in other studies, including animal studies – in other words, there has been no proof of risk in humans. Category C medications may have demonstrated some adverse effects in animal studies, but no well-controlled human data to make a recommendation.  It is noteworthy that 2/3 of all medications fall in the “C” category. For category C medications, risks and benefits must be carefully weighed. For category D medications, there has been evidence of human risk, and category X medications are contraindicated in pregnancy due to high fetal risk.

The medications considered most effective for acute treatment of migraine outside of pregnancy include: triptans, such as sumatriptan: nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, and ergotamines, which are less frequently used due to side effect profile. Of these, sumatriptan is considered category C in pregnancy, and so the risks and benefits must be discussed with patients on an individual level. Specifically, sumatriptan can raise blood pressure – which can be risky later in the third trimester. Full dose aspirin is in fact contraindicated throughout pregnancy. However, other NSAIDs such as ibuprofen are contraindicated after 20 weeks due to the potential for closure of the patent ductus arteriosus. Before 20 weeks gestation, NSAIDs can be used sparingly. Acetaminophen is a mild medication and is less commonly used for migraine outside of pregnancy; however, it is considered the safest analgesic to use in pregnancy (category B), and it can be effective if used early in a migraine, especially in conjunction with caffeine and metoclopramide, an antiemetic. Opioids are not typically used for migraine outside of pregnancy given the risks of addiction and analgesic rebound headaches; however, they are considered safe to the fetus if other methods of treatment fail.

A frequency of at least one headache per week in a nonpregnant patient usually suggests the need for a daily preventative medication. Medications used for the preventative treatment of migraine outside of pregnancy were reviewed in a 2012 AAN/American Headache Society guideline.[5][6][7] Those medications that received the highest level of evidence for efficacy (Level A or B evidence) included valproic acid and topiramate – both of which are anticonvulsants considered category D in pregnancy. For women who become pregnant while taking either of these drugs for migraine prevention, neurologists usually recommend stopping the medication in favor of a safer option. Metoprolol and propranolol received level A evidence for efficacy against migraine; both are category C in pregnancy. Amitriptyline is also category C in pregnancy and received level B evidence of efficacy against migraine.  While there are a number of other options, these three drugs are among the most popularly prescribed to pregnant women for migraine prevention, because of their favorable risk/benefit ratio. It is also worth mentioning that magnesium oxide in doses up to 400mg per day is often considered first line in pregnancy as a migraine preventative (level B evidence of efficacy) and is thought to be safe.[8] There has been recent controversy about magnesium sulfate injections – usually used for treatment of preeclampsia/eclampsia – given the potential effects of long-term use (more than 5-7 days in a row) of these injections on fetal bone health, leading to a category D designation from A.[9] However, these are two different formulations and doses of this supplement.

In 2015, the FDA changed the labeling requirements of medications in pregnancy and lactation – known as the Pregnancy and Lactation Labeling Rule, or PLLR. Each drug that is now FDA-approved will have a PLLR data sheet included, instead of a category designation. These data sheets list all animal and human studies detailing risk in pregnancy and lactation; drugs developed between 2001 and 2015 will retrospectively be given PLLR designations, a process that will be rolled out gradually. The PLLR labeling requirements are thought by many clinicians to be a more informative approach to safety in pregnancy and lactation. Other resources regarding the safety of drugs in pregnancy include TERIS and REPROTOX.

What  non-medication strategies can be used to treat migraine in pregnancy?

Nonpharmacological methods of migraine prevention include nerve blocks – occipital nerve block, for example – and complementary therapies such as physical therapy, acupuncture, and behavioral treatments. Many pregnant women prefer not to take medications in pregnancy at all, and for them, these therapies – especially behavioral therapies – are ideal. One aspect of behavioral therapy is the identification of triggers. The major migraine triggers include stress, hormones, diet (missed meals more than specific food triggers), weather, sleep changes, odors, neck pain, lighting/glare, neck pain, exercise/exertion, caffeine intake and dehydration.[10] Many of these triggers can be magnified in pregnancy. The other major aspects of behavioral therapy include relaxation strategies, biofeedback, and cognitive behavioral therapy – a restructuring of thought processes to avoid a maladaptive emotional response to migraine.[11] These strategies – in particular, cognitive behavioral therapy and thermal biofeedback (often in conjunction with autogenic relaxation), have high level evidence for efficacy against migraine, and can reduce migraines by 30-60%. These strategies are appealing to pregnant women as an alternative to medications.

Are there labor and delivery considerations for migraines in pregnancy? In the postpartum period?

There are no special labor and delivery considerations in this population. The labor and delivery process should not put women at particular risk for migraine. However, after weaning from breastfeeding, hormonally mediated migraines can worsen in women, and appropriate steps must be taken. As a general rule, medications that are deemed safe in pregnancy can also be used in lactation.

REFERENCES:

[1] International Headache Society, Diagnostic Criteria for Migraine Without Aura. 2016. https://www.ichd-3.org/1-migraine/1-1-migraine-without-aura/

[2] Roth JL and Bilodeau C, “Headaches and Seizures.” Rosene-Montella K, Medical Management of the Pregnant Patient. New York: Springer 2015. (219-231)

[3] Bushnell CD et al. Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study. BMJ. 2009;338:b664.

[4] Pearce CF, Hansen WF. Headache and neurological disease in pregnancy. Clin Obstet Gynecol. 2012;55:810-28.

[5] Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN Guideline for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines. Headache 2012;52:930-945.

[6] Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337-1345.

[7] Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. doi:10.1212/WNL.0b013e3182535d0c. (RETIRED: due to concerns about safety concerns in recommendation for butterbur.)

[8] Tepper D. Headache Toolbox: Magnesium. https://americanheadachesociety.org/wp-content/uploads/2016/06/Magnesium.pdf

[9] Magnesium sulfate use in obstetrics. Committee Opinion No. 652. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;127:e52-3.

[10] Kelman L. The triggers or precipitants of the acute migraine attack. Cephalalgia 2007 May;27(5):394-402. Epub 2007 Mar 30.

[11] Rathier L and Roth J. A Biobehavioral Approach to Headache Management. Rhode Island Medical Journal, February 2015;26-28.

Episodes RSS

Episode 1: Stroke In Pregnancy

A 30 year old woman presents to the ER with right arm weakness... and one more thing: she's pregnant. What do you do? We're talking with experts Dr. Karen Furie, Dr. Mahesh Jayaraman, Dr. Elizabeth Nestor and Dr. Niharika Mehta. Dr. Julie Roth hosts.

Key Takeaways

• Pregnant patients have three times the risk of stroke compared to non-pregnant patients, in large part due to hypercoagulability.
• The biggest risk factor for stroke during pregnancy is hypertension, including the hypertension seen in conditions like preeclampsia.
• While there are case reports of treatment of acute stroke with intravenous thrombolysis, there are no randomized controlled trials or guidelines to date; treatment is therefore determined on a case-by-case basis.
• Secondary ischemic stroke prevention is based on the suspected etiology of the stroke - either low dose (81mg/day) of aspirin or low molecular weight heparin are the typical drugs used in this condition, as both are considered safe in pregnancy.

Written Case: Stroke in Pregnancy

Dr. Danielle Goldfarb, Dr. Niharika Mehta, and Dr. Julie Roth

A 30 year-old woman, currently pregnant at 33 weeks gestation and with a past medical history of migraine with aura, presents to the office complaining of right arm weakness and clumsiness, and unsteadiness on her feet for one week. Over the past five weeks, she has had more migraines than usual, characterized by throbbing pain at the temples, with light and sound sensitivity. During her prior pregnancy, she was diagnosed with gestational diabetes and suffered from migraine with aura.  Initial examination is notable for mild right arm weakness.

Which investigation, if any, would be appropriate?

A history of focal neurological symptoms and an abnormal clinical exam require further neurological workup, and most importantly, neuroimaging. It is important to realize that underlying masses and vascular malformations can produce similar clinical features to migraine with aura, and that migraine should be a diagnosis of exclusion in the presence of focal neurological deficits. Furthermore, migraine with aura is a minor stroke risk factor. When a patient presents with over 24 hours of symptoms, MRI (up to 3 Tesla magnet field strength) is the test of choice. It has no adverse effects on the fetus and is most sensitive test to evaluate the brain parenchyma. Additional imaging of the arteries and veins of the head (MRA, MRV) can also be performed without the need for gadolinium, the MRI contrast agent. Gadolinium should be avoided if possible in pregnant women unless absolutely necessary.

Would it make a difference if this patient showed up with one hour, rather than one week, of symptoms?

Within several hours of onset of acute stroke-like symptoms, or in a patient with a “first or worst” headache who is in the emergency room, computed tomography imaging should be utilized instead of MRI, given the speed of testing. Fetal radiation exposure in computed tomography is below the threshold thought to cause fetal harm[1] and can be used when necessary in an emergency.  Such is the case for pregnant women with pulmonary embolus, who may require a rapid CT scan and even intravenous contrast for evaluation.[2] When considering which radiologic tests to perform, it is worth noting that the potential risk of birth defects due to radiation (CT, for example) are highest in the first few weeks of pregnancy within the first trimester, during which embryogenesis occurs. Risk is lower in the second and third trimesters. However, it is often the case that a pregnancy may not be discovered in those early weeks.

An MRI brain without gadolinium was completed and revealed T2 hyperintense lesion in mid pons consistent with subacute stroke, likely related to basilar artery vasospasm in setting of acute migraine. This patient was not a tPA candidate because the symptoms had been ongoing for weeks.  She was admitted to the inpatient stroke service.

 If she had presented immediately after the onset of right arm weakness, would she be a candidate for IV-tpa (tissue plasminogen activator)?

With 4.5 hours of symptom onset, IV-tPA (recombinant tissue plasminogen activator) administration is considered the standard of care in acute stroke management. However, there are no clinical trials to evaluate the use of recombinant tissue plasminogen activator in pregnant women with acute stroke, and data is limited to case reports and series. Pregnancy is considered a relative contraindication for administration, and pregnant women have been excluded from seminal studies.[3] Based on animal studies, there is no evidence of teratogenicity related to the use of IV-tPA, which is considered a category C drug.  Tissue plasminogen activator is a large molecule does not cross the placenta and has not thus far shown to negative effects on the child.[4] Complications related to tPA use in pregnant patients with acute stroke show similar complication rates as non-pregnant patients.[5] Tissue plasminogen activator is a large molecule that does not cross the placenta and has not thus far shown to negative effects on the child. On the other hand, from a physiologic standpoint, blood volume and blood flow to the uterus increase in pregnancy, conferring a theoretical risk of uterine hemorrhage, in addition to “usual” IV tPA risks of intracranial and other types of hemorrhage. Because stroke in pregnancy treated with IV tPA exist as case reports in the medical literature, there have been few known cases of symptomatic hemorrhage, including uterine hemorrhage, reported to date.

Additionally, there has been a recent paradigm shift in the treatment of acute ischemic stroke since the publication of five major studies in 2015, concluding that endovascular treatment (including mechanical thrombectomy) for strokes due to large vessel occlusion is superior to IV tPA alone, and therefore mechanical thrombectomy should be considered in the acute stroke treatment algorithm.[6] Endovascular procedures are typically performed with angiography, and therefore the impact of intravenous contrast should be weighed in pregnancy. While endovascular treatments offer a potential way to avoid complications of systemic thrombolysis in candidate pregnant women, mechanical thrombectomy is often performed in conjunction with IV tPA, and therefore pregnancy stroke registries are in their earliest stages and therefore both neurologists and emergency medicine specialists agree that reperfusion therapy for acute ischemic stroke in pregnancy should be assessed on a case by case basis.[7] [8] [9]

Though, the overall rate of stroke in pregnancy is fairly uncommon, at 34 cases per 100,000 deliveries,[10] it does carry significant morbidity and mortality, accounting for for 12% of maternal deaths and contributing to significant fetal morbidity and mortality in pregnancy-related stroke.[11] Disability from stroke can include weakness, dysphagia, aphasia, sensory and visual loss, and should therefore be recognized and treated urgently in pregnant women.

What are stroke risk factors in pregnancy?

Retrospective studies suggest a 3-fold increased risk of stroke in pregnancy compared to the nonpregnant state.[12]  Physiologic changes in pregnancy impart an increased stroke risk, although the relationship is complex and not well understood.  Underpinning the elevated stroke risk in pregnancy are hormonal factors that confer hypercoagulability, including activated protein C resistance, lower levels of protein S and increased fibrinogen, along with venous stasis and edema.  These changes peak around full term and the immediate post-partum period, presumably to prepare the pregnant women for delivery.

The leading cause of both hemorrhagic and ischemic stroke in pregnancy and post-partum is hypertension,[13] especially in the context of pre-eclampsia. Additional medical conditions that pose risks factors for stroke in pregnancy include preeclampsia/eclampsia, cesarean section, pregnancy-related hematologic disorders, migraine, gestational diabetes, primary hypercoagulable states, and smoking history.[14] Meta-analyses show that migraine with aura imparts a 2-2.5 times greater risk of ischemic stroke.[15] [16]  A recent systematic meta-analysis[17] found a stronger association between migraine and risk of ischemic stroke in pregnancy (OR range 7.9 to 30.7), particularly with active migraine. In nonpregnant patients, contraceptives containing estrogen add further risk of stroke for women with migraine with aura  - and consequently, the American College of Obstetrics and Gynecology recommends against using estrogen-containing contraception in this population.

What are the mechanisms of stroke in pregnancy?

The mechanisms of stroke in pregnancy appear to be similar to stroke in the non-pregnant, including arterial occlusions from artery-to-artery thromboembolism, cardiac embolism, and intracranial or extracranial atherothrombosis along with carotid and vertebral dissection. Preeclampsia/eclampsia is a mechanism unique to pregnancy and the postpartum period. In one retrospective study comparing pregnancy-associated stroke with stroke in non-pregnant women, pregnant women with stroke were less likely to have vascular risk factors such as hyperlipidemia and history of thromboembolism but more likely to have cerebral venous thromboses (21% vs 7%, p 5 0.02). [18]  Reversible cerebral vasoconstriction syndrome (RCVS) is a stroke mechanism that more commonly occurs in pregnancy, particularly among migraineurs and pathophysiology may have some overlap with eclampsia.

Lab studies while inpatient included lipid panel, a1c, TSH and hypercoagulable panel, which were all found to be normal.  Echocardiogram was normal, with no evidence for a right to left shunt on bubble study. She underwent MRA/V of the brain and MRA of the neck, and cardiac telemetry, all of which were normal. The patient was started on aspirin 81mg/day, and she continued this medication throughout the remainder of her pregnancy, delivering a healthy baby girl.

What medications are appropriate for secondary stroke prevention in pregnancy?  What are the risks of antiplatelet and anticoagulation therapy in pregnancy and delivery?

Treatment following a stroke is undertaken to prevent recurrent stroke. Hence, an understanding of the stroke etiology is important to guide treatment.  Though there are no randomized controlled trials to guide stroke prevention in pregnancy, a recent American Heart Association/American Stroke Association have issued recommendations for pregnant women with stroke.[19] These include unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for pregnant women needing anticoagulation due to cardioembolic source of stroke, or mechanical heart valves – with warfarin reserved for the second trimester through the middle of the third trimester (Class IIb; Level of Evidence C); and use of low dose aspirin after the first trimester of pregnancy for those without a high-risk thromboembolic condition. (Class IIb; Level of Evidence C).” In practice, UFH or LMWH is often utilized and warfarin avoided as it does cross the placenta and can have several potential deleterious fetal effects including birth defects when used in the first trimester, increased risk of pregnancy loss, fetal hemorrhagic complications. There is not enough data on novel oral anticoagulations to recommend their use in pregnancy. Regarding antiplatelet therapy, it is known that full-dose aspirin (325mg/day) is contraindicated in pregnancy due to risk of closure of the patent ductus arteriosis, oligohydramnios, and bleeding risk.[20] However, several meta-analyses have demonstrated that low-dose aspirin (60–80 mg/day) in fact can be used safely in select populations of pregnant women. Low-dose aspirin (81mg/day) is beneficial in preventing preeclampsia, gestational hypertension, and preterm birth when started earlier than 16 weeks’ gestation.[21] To date, the stroke literature confers no advantage of full-dose aspirin over low-dose aspirin, and therefore aspirin 81mg/day is sufficient for secondary stroke prevention in most cases of stroke in pregnancy. Of note, there is limited evidence on the use of clopidogrel during pregnancy and the post-partum period, and there are no formal guideline recommendations.  

Whether to treat pregnant women who have had strokes with anticoagulation or antiplatelet depends primarily on the etiology of the stroke. Those with arterial stroke who do not have a history of venous thrombosis could benefit from either antiplatelet or anticoagulation, whereas those with cerebral venous sinus thrombosis and associated infarct are typically prescribed anticoagulation (both Class IIa recommendations, Category C).[22] Specific coagulopathies warrant anticoagulation – both in pregnant and nonpregnant patients. The presence of an antiphospholipid antibody suggests that antiplatelet therapy would be reasonable, whereas a diagnosis of the antiphospholipid syndrome typically necessitates anticoagulation. Women with inherited thrombophilic conditions who develop stroke in pregnancy should be assessed for deep vein thrombosis (DVT) to determine the need for anticoagulation.

Is it safe to breastfeed while on antiplatelets and anticoagulants?

Data is limited on the use of anticoagulants in breastfeeding women, however, based on guidelines from the American College of Chest Physicians, breastfeeding may continue during treatment with unfractionated heparin, LMWH, warfarin, or aspirin.[23] Aspirin is excreted in breastmilk, and therefore, low-dose aspirin is preferable to full dose aspirin. Women taking full-dose aspirin are advised to wait two hours after taking the medicine to breastfeed, if possible.

What are the implications of stroke and the use of blood thinners for labor and delivery? Can she push?

There are no specific considerations to either vaginal delivery or caesarian section related to the stroke itself. Labor and delivery considerations following a stroke are related to the choice of the secondary stroke treatment and concern for maternal and fetal bleeding-related complications due to the combination of delivery-associated trauma and anticoagulant effects.  Per the Chest guidelines,[24] “For pregnant women receiving adjusted dose LMWH therapy and where delivery is planned, we recommend discontinuation of LMWH at least 24 h prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) rather than continuing LMWH up until the time of delivery (Grade 1B).” In general, bleeding risk is higher with caesarian section versus a vaginal delivery. However, surgery can performed if necessary in those taking antiplatelet therapy. The bigger risk to the patient relates to spinal or epidural anaesthesia. Though there is no contraindication to these procedures with aspirin, avoidance of anticoagulation at least 12-24 hours – and in practice, up to 48 hours following therapeutic dosing of anticoagulation – prior to spinal anaesthesia is recommended to reduce the risk of spinal epidural hematoma – a guideline that also pertains to lumbar puncture.[25]

Labor and delivery are successful, and the patient has a healthy baby girl. Three years later, she is pregnant again.

What medical precautions are recommended in a pregnant patient who has had a prior stroke?

She should take aspirin 81mg/day throughout the pregnancy; blood pressure should be controlled. If there is a history of migraines, then migraines should also be controlled in order to reduce stroke risk factors. There is no specific anticipatory neuroimaging that needs to be done. She should be educated about stroke warning signs – specifically, if neurological symptoms occur (facial or limb weakness, dysarthria, problems with coordination or balance, visual or speech/language symptoms, for example), she should go to the emergency room immediately for acute stroke assessment and possible therapy.

REFERENCES:

[1] Guidelines for Diagnostic Imaging During Pregnancy and Lactation. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;127:e75-80.

[2] Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M. Pulmonary embolism in pregnancy. Lancet. 2010; 375(9713):500-12. Epub 2009/11/06.

[3] NINDS Study Group. Tissue plasminogen activator for acute ischemic stroke. N Eng J Med. 1995;333(24):1581-1588

[4] Steinberg A, Moreira TP. Neuroendocrinal, Neurodevelopmental, and Embryotoxic Effects of Recombinant Tissue Plasminogen Activator. Treatment for Pregnant Women with Acute Ischemic Stroke.  Front Neurosci. 2016-2-25 10:51. 

[5] Leffert LR, Clancy CR, Bateman BT. Treatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period. American Journal of Obstetrics and Gynecology 2016-06-01; 214(6):723.e1-723.e11.

[6] Powers WJ, Derdeyn CP, Biller J, et al. AHA/ASA Guideline 2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46:000-000.

[7] Leffert LR, Clancy CR, Bateman BT. Treatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period. American Journal of Obstetrics and Gynecology 2016-06-01; 214(6):723.e1-723.e11.

[8] Demchuk AM. Yes, Intravenous thrombolysis should be administered in pregnancy when other clinical and imaging factors are favorable. Stroke. 2013; 44:864-865.

[9] Tassi R, Acampa M, Marotta G, et al. Systemic thrombolysis for stroke in pregnancy. American Journal of Emergency Medicine 2013-2-1; 31(2):448.e1-448.e3.

[10] Bushnell C, McCullough LD, Awad IA, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council for High Blood Pressure Research. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:1545–1588.

[11] Grear KE, Bushnell CD. Stroke and Pregnancy: Clinical Presentation, Evaluation, Treatment and Epidemiology. Clin Obstet Gynecol. 2013 June ; 56(2): 350–359.

[12] Hovsepian DA, Sriram N, Kamel H, Fink ME, Navi BB. Acute cerebrovascular disease occurring after hospital discharge for labor and delivery. Stroke 2014;45:1947–1950.

[13] Bushnell C, McCullough LD, Awad IA, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council for High Blood Pressure Research. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:1545–1588.

[14] James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005;106:509–516.

[15] Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 2010;123:612–624;

[16] Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine cardiovascular disease: systematic review and meta-analysis. BMJ 2009;339:b3914

[17] Wabnitz A, Bushnell C. Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature. Cephalalgia 2015;35:132–139.

[18] Miller EC, Yaghi S, Boehme AK, Willey JZ, Elkind MSV, Marshall RS. Mechanisms and outcomes of stroke during pregnancy and the postpartum period. A cross-sectional study. Neurol Clin Pract 2016;6:29–39.

[19] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Jan;42(1):227-76

[20] Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. American Journal of Obstetrics and Gynecology, vol. 187, no. 6, pp. 1623–1630, 2002.

[21] Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy. Obstet. Gynecol. 2010; 116:402–414.

[22] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Jan;42(1):227-76

[23] Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th edition). Chest. 2008;133(suppl 6):844S– 886S.

[24] Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th edition). Chest. 2008;133(suppl 6):844S– 886S.

[25] FDA Drug Safety Communication: Updated recommendations to decrease risk of spinal column bleeding and paralysis in patients on low molecular weight heparins http://www.fda.gov/Drugs/DrugSafety/ucm373595.htm

Episodes RSS