Neurological Problems of Pregnancy

Diseases of the nervous system develop and continue despite pregnancy. The good neurologist maintains a broad perspective, balancing the needs of the woman, her fetus, and her loved ones. Insofar as this audience creates an atmosphere for performance, the clinician may feel like a stage character prompted by cues from scattered, incomplete, and occasionally contradictory findings reported in the literature. Still, neurologists who enjoy drama find gratification in caring for the pregnant woman with neurological disease.

Neurological Complications of Contraception

The neurologist can help a woman with pre-existing neurological disease to plan a pregnancy. The expected burden of her neurological disease must be balanced against her perceived need for procreation. Asking her to consider the effect of a child on her life and how her illness might affect the child can be beneficial. For instance, a patient who is wheelchair enabled with spinal muscular atrophy (SMA) or muscular dystrophy may have difficulty with breathing during the later stages of pregnancy, may need a cesarean section to deliver the baby, and may have great difficulty lifting the baby as it grows. The neurologist might discuss prenatal genetic testing with women affected by inherited neurological disease. To address controversy concerning the best use of amniocentesis, chorionic villus sampling, or preimplantation genetic diagnosis, a geneticist’s help can be enlisted. One retrospective study suggested an increased relapse rate in women with multiple sclerosis (MS) undergoing an abortion, a procedure potentially preventable with the effective use of contraception ( ). Many women welcome the neurologist’s calming opinion.

While sterilization, such as with tubal ligation, is a consideration, sterilization often is irreversible and performed usually for indications other than neurological disease. Approximately 4% of women with epilepsy of reproductive age report having had a tubal ligation. Sterilization is not discussed in this section.

Oral contraceptives containing more than 80 μg of estrogen are linked to increased incidence of stroke. Physicians have considered that risks of hormonal contraception (HC) nevertheless are lower than the risks associated with pregnancy. Parsimonious use of estrogen in modern preparations as low as 20 μg have demonstrably increased safety. Exclusively progestogen agents do not increase stroke risk. No progestogen preparation is safer than another. Progestogens also have been used successfully in the treatment of migraine, according to a meta-analysis ( ) and possibly have been associated with improved seizure control. Hormonal oral contraceptives, either progestogens or combined oral estrogen and progestogen contraceptives (COCs), do not cause increased seizures in a cohort study ( ), although a retrospective registry study concluded that COCs increase risk ( ). Earlier studies on the use of COCs containing less than 50 μg of estrogen in nondiabetic, nonhypertensive patients indicate that these agents pose no additional risk or at most a true relative risk of ischemic stroke of no more than 2.5 ( ). In recent studies, this increased relative risk may be as low as 1.3 (95% confidence interval [CI] 1.1–1.6) ( ). Given the very low annual incidence of ischemic stroke (≈11.3 per 100,000 in the normal population of women 15–44 years of age), this small or nonexistent added risk can be considered safe. When women taking this dose smoke cigarettes, the risk for hemorrhagic stroke increases the odds ratio (OR) to 3.64, with a 95% CI of 0.95–13.87. Discussion of stroke in pregnancy and the puerperium occurs later in the chapter.

Contraception, Migraine, and Stroke Risk

Effect on Stroke Risk

The effect of COCs on stroke incidence in patients with migraine remains incompletely clear. Retrospective data from a US Nationwide Healthcare Claims Database published in 2017 add to previous case-control and cohort studies ( ; ; ; ) to show that migraine with and without aura are both associated with increased stroke risk that further is exacerbated by COCs ( ). Patients aged 15–50 suffering an ischemic stroke are nearly twice as likely to have had a history of migraine than those without ischemic stroke ( ) ( Table 112.1 ).

TABLE 112.1

Absolute Risk of Ischemic Stroke in Women Aged 20–44 Years in Relation to the Use of Hormonal Contraception and Migraine Status

From Sacco, S., Merki-Feld, G.S., Ægidius, K.L., Bitzer, J., Canonico, M., Kurth, T., et al. 2018. Correction to: Hormonal contraceptives and risk of ischemic stroke in women with migraine: A consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). J. Headache Pain. 19(1), 81 .

	No Migraine	Migraine With Aura	Migraine Without Aura
Without hormonal contraception	2.5/100,000	5.9/100,000	4.0/100,000
With hormonal contraception	6.3/100,000	14.5/100,000	10.0/100,000

Expected incidence of ischemic stroke in women aged 15–44 (strokes per 100,000 women per year) has been measured in large studies and ranges from 10/100,000 to 11/100,000. This figure is age dependent, as illustrated in Fig. 112.1 .

Fig. 112.1, Average Yearly Cumulative Incidence of Ischemic Stroke, 2006–12.

While current studies suggest that estrogen increases the disproportionate stroke risk for women with migraine, consensus recommendations and authority opinions differ. American College of Obstetrics and Gynecology (ACOG) guidelines issued in 2010 reinforce a notion that continuous or extended-cycle COCs, transdermal estrogen patch, and depot-medroxyprogesterone acetate “may afford relief of headaches for some women” based on uncontrolled studies and theoretical support ( ). ACOG simultaneously offered that due to the devastating consequences of a stroke, physicians “should consider” alternative means of contraception to COCs for women with migraine and “focal neurological signs,” women who smoke, or women over the age of 35 ( , Bulletin 110). Echoing this approach in 2017, reviewers suggested that more studies are needed. However, “any form of hormonal therapy should be avoided” in patients with aura lasting longer than 60 minutes, aura with multiple neurological symptoms, including migraine with brainstem aura and hemiplegic migraine; such therapy should be discontinued for any patient without the latter symptoms but who develop aura for the first time or have worsening migraine. These patients should be monitored for worsening cardiovascular risk factors. For patients with simple aura, an individualized approach is suggested ( ).

In 2017, European medical societies issued a more restrictive consensus statement recommending that physicians avoid the prescription of COCs when used for contraception in women with migraine. The European Headache Federation and the European Society of Contraception and Reproductive Health advised that they are placing foremost values of caution and safety. Additional qualifications include the application of an estimated relative risk of COCs of 2.52, higher than the observed risk of low-dose COCs in some studies ( ), the elimination of age as a variable, but qualified that the evidence on which the recommendations are based is of low to medium quality. The societies issued 13 recommendations—4 strong and 9 weak ( ). Perhaps most important is that the recommendations emphasize that the amount of estrogen in each of the preparations varies and should be taken into account. A proscription against the use of any COC for any patient experiencing migraine with aura is stated. Instead, authors suggest initially using or switching to the use of condoms, intrauterine devices (IUDs), permanent methods, or progestogen-only contraception, with a goal to lower the risk of ischemic stroke while balancing the woman’s need to limit procreation with reasonably effective methods.

For women suffering migraine without aura associated with additional risk factors (smoking, hypertension, obesity, history of cardiovascular disease, previous history of venous thrombosis or thromboembolism) progestogen-only or non-hormonal contraception is suggested. For those women with migraine without aura and without additional risk factors, COCs containing less than or equal to 35 μg DMS of ethinylestradiol are recommended as a “possible” contraceptive option with monitoring of migraine frequency and characteristics. The consensus statement suggests that physicians planning to use COCs or progestogens to treat polycystic ovary syndrome or endometriosis should continue as clinically indicated, regardless of migraine type. When used for contraception, the statement suggests that COCs be discontinued with the development of migraine with or without aura and alternative contraceptive methods employed.

Investigators have reported migrainous infarction associated with the use of postcoital contraception when regimens containing estrogen are used within 24 hours in patients who have a history of migraine with aura ( ). For women with either type of migraine seeking emergency contraception, authors of the consensus statement recommended the use of levonorgestrel DMS 1.5 mg orally, ulipristal acetate 30 mg orally DMS, or the copper-bearing IUD rather than estrogen-containing products. For any woman with non-migrainous headache seeking hormonal contraception, low-dose hormonal contraception was advised.

Researchers bemoan conflicting messages from physicians received by women with migraine seeking contraceptive advice. The problem lies partially in the incompleteness of the information on actual risk and considerations with regard to how much risk is reasonable given the availability of nonestrogen contraceptive methods as alternatives.

Effect on Migraine

The effect of COCs on migraine frequency and severity is variable and difficult to investigate, worsening in 18%–50%, improving in 3%–35%, and without change in 39%–65%, in a review article ( ). Those women suffering migraine with aura were more negatively affected than those without aura. Attacks occur most frequently during the pill-free week. Continuing the administration of a hormonally active pill reduces migraine severity and frequency ( ). A history of purely perimenstrual migraine makes sensitivity to COCs more likely, although this effect may be minor ( ) and may be helped by shortening the pill-free drug regimen from 7 to 4 days ( ).

Contraception and Epilepsy

The risk of teratogenic effects of antiepileptic drugs (AEDs) or neurocognitive deficits in gestationally exposed children often prompt neurologists to advise safe contraceptive methods for women taking these medications. Nevertheless, contraceptive failure occurs more frequently in women with epilepsy About half of women with epilepsy discontinue oral contraception and about a quarter discontinue an IUD ( ). Reports of increasing safety of IUDs for both nulliparous and multiparous women suggest that IUDs are an obvious and superior alternative to pharmaceutical contraception in appropriately selected women taking anticonvulsants. Still, the prescription of AEDs and hormonal contraception is common. When AEDs and hormonal contraceptives are taken together, some drug interactions cause physicians to worry over risks of uncontrolled epilepsy and unplanned pregnancy. Physicians prescribing AEDs to women taking hormonal contraceptives need both general and theoretical approaches, given the introduction of newer AEDs, newer hormonal agents with lower amounts of ethinyl estradiol (20–35 μg DMS), and the use of AEDs for indications other than epilepsy, such as the treatment of neuropathic pain, migraine, anxiety, and bipolar disorder (see Table 112.2 ).

TABLE 112.2

Bi-Directional Drug Interactions Between Hormonal Contraceptives and Antiepileptic Drugs

From Reimers, A., Brodtkorb, E., Sabers, A., 2015. Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. Seizure 28, 66–70 .

	AED May Be Reduced by COC	Ethinyl Estradiol May Be Reduced by AED	Progestin May Be Reduced by AED
Carbamazepine	n.a.	Yes	Yes
Eslicarbazepine	n.a.	Yes	Yes
Felbamate	n.a.	Yes	Yes
Gabapentin	n.a.	No	No
Lacosamide	No	No	No
Lamotrigine	Yes	No	Yes
Levetiracetam	No	No	No
Oxcarbazepine	n.a.	Yes	Yes
Peram panel	n.a.	No	Yes ∗
Phenobarbital	n.a.	Yes	Yes
Phenytoin	n.a.	Yes	Yes
Pregabalin	n.a.	n.a.	n.a.
Retigabine/ezogabine	No	No	No
Rufinamide	No	Yes	Yes
Stiripentol	n.a.	n.a.	n.a.
Topiramate	n.a.	Yes ∗	No
Valproate	Yes	No	No
Zonisamide	No	No	No

AED, Antiepileptic drug; COC , combined oral contraceptive; n.a ., no data available.

∗ Dose dependent.

Effect of Antiepileptic Drugs on Contraception

Further prospective studies are needed to confirm and refine registry data that found a more than doubled risk of spontaneous fetal loss when women with epilepsy experience unintended pregnancy. This information is coupled with findings that 65% of women with epilepsy have pregnancies that are unplanned, compared to about 45%–51% in the general US population. About one-third of women with unintended pregnancy and epilepsy engage in contraceptive methods that are known to be relatively ineffective (barrier, withdrawal, or combination), about one-third use no contraception, and about 20% use systemic hormonal contraception in combination with enzyme-inducing AEDs, which may double pregnancy risk ( ).

Anticonvulsants do not affect the efficacy of medroxyprogesterone. Although an IUD may be superior overall, medroxyprogesterone may be the contraceptive pharmaceutical of choice in women with seizure disorders. Based on theoretical considerations, some investigators recommend administering medroxyprogesterone injections every 10 weeks rather than every 12 weeks for women taking anticonvulsants that induce hepatic microsomal enzymes.

Unwanted pregnancies with levonorgestrel have occurred in women taking phenytoin and in women taking carbamazepine. Some researchers advise against the use of levonorgestrel in patients taking liver enzyme–inducing drugs of any kind, including enzyme-inducing anticonvulsants (carbamazepine, eslicarbazepine, felbamate, oxcarbazepine, phenobarbital, phenytoin, rufinamide, topiramate, perampanel). Usual-dose COCs, progestogen-only pills, medroxyprogesterone injections, and levonorgestrel implants have no known interactions and can be used in patients receiving valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide, and benzodiazepines. Failure of COCs with oxcarbazepine is reported in incomplete studies. A World Health Organization Working Group recommended against use of COCs, transdermal patch, vaginal ring, and progesterone-only pills for women taking phenytoin, carbamazepine, barbiturates, primidone, topiramate, or oxcarbazepine due to reduced contraceptive effect ( ). Enzyme-inducing AEDs affect emergency contraception for unintended pregnancy. Doubling the first dose of levonorgestrel to 1.5 mg DMS has been recommended. However, we lack studies on efficacy of this regimen and also on the use of ulipristal ( ).

Effect of Contraception on Antiepileptic Drugs

In a small prospective study, researchers find no substantial effect on AED levels for women with epilepsy using a progestogen IUD ( ). The study included the use of lamotrigine, levetiracetam, oxcarbazepine, carbamazepine, lacosamide, valproate, and clobazam.

Some neurologists advise female epileptic patients taking microsomal enzyme-inducing anticonvulsants to increase the dose of estrogen in their contraceptives to at least 50 μg ( ). Although this adjustment may increase contraceptive effectiveness, the efficacy of the regimen is untested. The result is that barrier, spermicidal, or other contraceptive measures often are recommended for use simultaneously or exclusively.

In a careful study of small numbers of women, COCs lowered levels of lamotrigine by about 33%. This same study demonstrated that the lamotrigine levels of women in mid-luteal menstrual phase and not taking COCs dropped by about 31% ( ). Other studies report that when women take COCs, lamotrigine levels may decrease by half and some patients may suffer an increase in seizures. This effect is not seen when additional anticonvulsants are used with lamotrigine. Manufacturers of lamotrigine recommend that physicians increase that medication when patients taking lamotrigine monotherapy are placed on COCs. Adjustment of lamotrigine dose is unnecessary with progestogens.

Valproic acid (VPA) levels were lowered up to 23% with use of COCs in one small study. For patients taking VPA, an AED known to have teratogenic and neurocognitive effects on the fetus, contraception may be particularly important. An IUD may be the contraceptive of choice, and dual use of barrier methods may be advised for patients taking VPA.

Miscellaneous Conditions

Estrogen-containing oral contraceptive agents may worsen chronic inflammatory demyelinating polyneuropathy (CIDP) and moyamoya disease, unmask systemic lupus erythematosus (SLE), worsen migraine, and produce chorea in patients with antiphospholipid antibody syndrome (APS). For young women taking COCs, the low risk for stroke in this age group approximately doubles. Some physicians advise that an individually tailored contraceptive approach may include the recommendation of COCs in antiphospholipid antibody–negative patients with inactive or moderately active stable SLE ( ). The heightened risk for cerebral venous thrombosis (CVT) in women taking oral contraceptive agents increases with prothrombin or factor V gene mutations. Routine screening for prothrombin gene mutation before initiating hormonal contraception probably is not useful ( ). Some neurologists recommend against the use of hormonal contraceptives in women with activated protein C resistance.

Summary Recommendations

For patients with migraine and epilepsy an IUD may be the contraceptive method most broadly acceptable due to its rate of efficacy, low discontinuation rate, minimal effect on the disease process, and safety associated with usual therapeutics. Medroxyprogesterone injection may be the pharmaceutical of choice for these patient groups or, in selected patients, an oral progestogen.

Due to risk of contraceptive failure, women taking liver enzyme–inducing AEDs in general should avoid COCs, etonogestrel, or levonorgestrel implants. Levonorgestrel-containing IUDs are safe and effective.

When COCs are used for patients with epilepsy, careful attention to levels of lamotrigine and valproic acid may be needed.

The use of COCs in patients with migraine increases stroke risk. Caution should be exercised with mixed recommendations from medical societies.

In general, COCs should not be used for patients with migraine when alternatives are easily available and acceptable. If they are employed, low-dose estrogen COCs are preferred for women with migraine without aura, and avoided for women with migraine with aura.

Ethical Considerations

Partially settled and unresolved ethical difficulties complicate care of the gravid woman with neurological disease. In nearly every instance, physicians juggle competing responsibilities to, and differing goals of therapy for, the mother and fetus. In complex situations, multiple interested parties may demand a determining say, including the husband, the father (if not the husband), the family, the state, legal representatives, and political and religious groups.

When a diagnosis of maternal death by neurological criteria is confirmed for a woman carrying a fetus considered to be nonviable, judicial review in the state of Texas, a state whose laws favor fetal preservation, confirms that medical interventions need not be continued ( ). No consensus exists as to the conditions under which such medical interventions must be offered by physicians when the fetus is considered viable or marginally viable. Researchers reviewed 30 retrospective cases reported over 28 years of pregnant women diagnosed as dead by neurological criteria ( ). In this retrospective study, detailing a select fraction of those seen in medical practice, 12 infants were delivered. Medical documentation from six of these at 24 months did not include a notation of medical problems. Maternal organ procurement could be confirmed as having taken place in 10 of these patients with an “excellent” graft survival at 1 year.

Confronted with this situation, physicians who decide to offer continued medical interventions turn to the ethically appropriate surrogate(s) or legally recognized healthcare decision maker, sometimes one for the mother and one for the fetus, to discuss foreseeable possible futures in a process of shared decision making. Advice from a Committee on Bioethics or an ethics consultant is recommended in current literature ( ). In some states, the physician helps select surrogates. In others, a statute-driven “hierarchy” exists. Some states prohibit an appropriate surrogate from permitting the termination of pregnancy for an incapacitated patient but not when the patient is dead. Advising pregnant women to execute advance directives for medical care seems an unlikely and incomplete solution, particularly given that half the states in the United States contain some restrictions on a pregnant woman’s documented preference for end-of-life care and healthcare decisions ( ).

Imaging

Computed tomography (CT) scanning employs ionizing radiation with known risks of teratogenesis, mutagenesis, and carcinogenesis. In general, physicians avoid ionizing radiation during pregnancy, particularly between 8 and 15 weeks, the gestational period most sensitive to ionizing radiation. However, the risk is not as high as perceived by some medical professionals, and several authors urge an approach balanced to the diagnostic needs of the woman and fetus. Researchers estimate the average woman receives background radiation less than 0.1 rad over 9 months. Risks of fetal malformation demonstrably increase with radiation doses above 15 rad. Induced miscarriages and major congenital malformations occur at negligibly increased risk with doses to the fetus under 5 rad. Estimated radiation dosage from a typical CT scan of the brain is less than 0.050 rad when employing precautionary lead shielding. Lumbar spine CT delivers some 3.5 rad. Acting on anxiety attributed by some to physician advice, women have opted for pregnancy termination after receiving low-dose diagnostic radiation during early gestation ( ). Iodinated contrast media used for radiological procedures has the potential to depress fetal thyroid production. Most states mandate routine newborn thyroid screening; this is especially important in infants receiving iodinated contrast agents in utero.

In general, when circumstances require urgent neuroimaging, CT remains the most appropriate tool during pregnancy ( ) and, when contrast is required, iodinated CT contrast agents are likely safer than gadolinium-based contrast agents ( ). That said, some authors provide recommendations during pregnancy for imaging specific conditions, such as the use of noncontrasted magnetic resonance venography when CVT is suspected, MRI with or without contrast to demonstrate the pachymeningeal pathology associated with intracranial hypotension syndrome, and the relative help from both MRI and CT techniques in characterizing pituitary apoplexy ( ).

Magnetic resonance imaging (MRI) without contrast can be used selectively to scan the brain and the venous and arterial circulations and is useful during pregnancy. No study or clinical observation has detailed harmful effects to mother or child, but detailed longitudinal studies on children exposed in utero to MRI are lacking. Limited information involves the use of 1.5-T MRI while data detailing the safety of 3.0-T magnets are unavailable. Despite the observations by the American College of Obstetricians and Gynecologists and the American College of Radiology ( ; ; ) that there is no known adverse effect of MRI on the fetus, only two human studies on this point existed at that time, neither of which was of a design adequate to detect adverse effects that may be significant ( ). A more recent retrospective study of a Canadian provincial database ( ) also may have been underpowered to detect rare events. The authors found that in their series, MRI during the first trimester of pregnancy was not associated with increased risk of harm to the fetus or easily detectable in early childhood. Although current safety information is optimistic, restriction of maternal brain MRI, balancing the importance of diagnostic yield to the rare but uncertain fetal risk of MRI, especially during the first trimester, continues to be prudent.

Fortunately, most MRI studies relevant to neurological disease do not require the use of gadolinium. However, definitive studies detailing the safety of gadolinium-based magnetic resonance contrast agents during pregnancy and lactation are lacking. Gadolinium crosses the placenta, finds its way into amniotic fluid, and is swallowed by the fetus. Fetal developmental delay occurs in animals receiving high doses of gadolinium. No reports of mutagenic or teratogenic effects in humans appear in reviews of available literature ( ). A small prospective study of 26 women who received gadolinium inadvertently during the periconceptional period and first trimester yielded a single child with a minor congenital anomaly ( ). A larger retrospective study ( ) found that gadolinium-enhanced MRI at any time in pregnancy was associated with an increased fetal risk of rheumatological, inflammatory, or infiltrative skin conditions and stillbirth or neonatal death. While a theoretical risk of nephrogenic systemic fibrosis exists, no known cases have yet been reported ( ).

Breastfeeding

A small percentage of iodinated contrast medium is excreted into breast milk and absorbed by the infant gut. The amount is calculated to be so small as to make it reasonable to declare maternal iodinated contrast material injection to be safe without a need to interrupt breastfeeding ( ). Optional interruption of breastfeeding may be suggested to last a period of 12–24 hours, but without value stopping for longer than 24 hours. Preparatory storage of milk before the contrast and discarding of milk pumped within 24 hours following contrast has been advised.

Some authorities recommend that a woman abstain from breastfeeding for 24 hours after receiving iodinated contrast agents, including gadolinium ( ). Others, citing the tiny amount of contrast entering breast milk and the minute amount absorbed from the baby’s gut, suggest that the potential risks are insufficient to warrant a recommendation to interrupt breastfeeding ( ; ). Reasoning that only a small percentage of gadolinium-based contrast medium is excreted into milk and absorbed by the infant gut, no interruption of breastfeeding is recommended by the American College of Radiology ( ) which provides recommendations for those women wishing to further reduce risk identical to those above for CT contrast imaging while breastfeeding.

Headache

Tension Headache

Headache during pregnancy is common. Usually a patient visits the neurologist to receive reassurance that no serious medical problem is apparent. Of the headaches that occur during pregnancy, benign tension headaches are seen most often (see Chapter 102 ). No known association exists with hormones and, specifically, no association with the hormonal changes of pregnancy. Treatment for mild headaches often includes cognitive behavioral therapy, adequate rest, moist heat, massage, exercise (pregnant and postpartum women should accrue 150 minutes weekly of moderately intense aerobic activity, ), avoidance of triggering factors, and use of acetaminophen. Attempts to link in utero exposure to acetaminophen to attention-deficit/hyperactivity disorder (ADHD) and asthma have been inconclusive according to the US Food and Drug Administration (FDA), and it can be considered safe in usual doses ( ; ). For severe headaches, the use of a tricyclic antidepressant such as amitriptyline or nortriptyline may be helpful. No evidence of embryopathy occurs with amitriptyline, and preschool children exposed in utero to tricyclic antidepressants have normal global IQs, language, and behavioral development. Fluoxetine may cause uncommon but serious fetal risks ( ; ; ).

Migraine Headache

More than 80% of women with migraine clearly show improvement during pregnancy, but 15% continue to have headaches, and in 5% headaches worsen. The prognosis for women with migraine without aura is better than that for women with migraine with aura. Headaches were more likely to persist with diagnosed menstrual migraine, hyperemesis, or a “pathological pregnancy course” in a prospective study. For women anticipating pregnancy, the physician may discontinue or reduce the dose of all migraine medications to lower the risk of possible fetal damage and offer vigorous treatment with behavioral therapy, moist heat, and the judicious use of acetaminophen or opioid preparations. Migraine usually lessens during the second and third trimesters. The diagnosis of complicated migraine or de novo migraine with aura during pregnancy requires a thorough consideration of other diagnoses. Migraine may increase the risk for preeclampsia, especially for patients with prepregnancy obesity ( ) and may increase the risk for peripartum stroke ( ). While small increased incidences of low birth weight, preterm birth, and cesarean section were noted in an Asian population (odds ratios 1.16, 1.24, and 1.16, respectively), the single large study did not control for the use of medications in this population, where the authors noted equivocal clarity in the database diagnosis of migraine ( ). Other studies and retrospective reviews suggest that women with migraine can expect an increased risk of gestational hypertension, preeclampsia, preterm birth, dyslipidemia, ischemic heart disease, and thromboembolic disease. While these findings lead some to suggest that pregnancy in a patient with migraine should be considered “high risk” with increased monitoring and physician visits ( ), the absence of prospective carefully designed studies to clearly define and confirm these risks may account for the lack of policy endorsing such an approach.

Before Pregnancy

Pregnancy and the anticipation of pregnancy complicate usual migraine therapy. Valproic acid causes fetal malformations. FDA labeling contraindicates the use of valproic acid for fertile women with migraine unless no substitute can be found. This contraindication may make sense in the context of an unplanned pregnancy rate in the United States that approximates 50%. For fertile women taking prophylactic valproic acid whose migraine has been unresponsive to other therapy, folic acid supplementation is advised (see the section Epilepsy and Its Treatments). Discussion of reliable contraceptive measures and the risks for fetal malformation is essential. During pregnancy, physicians advise avoidance of valproic acid to treat headache. Topiramate is fetally toxic in animals, and the magnitude of teratogenic risk of topiramate is incompletely determined in humans. When prescribing topiramate, unintended fetal exposure during the early first trimester may occur with unplanned pregnancy. Canadian labeling advises that physicians restrict therapeutic topiramate for migraine to those fertile women using reliable contraception.

The calcitonin gene–related peptide (CGRP) monoclonal antibodies used to treat migraine have long half-lives. They cross the placenta in increasing amounts throughout pregnancy in animal models. CGRPs play a theoretical role in regulating uteroplacental blood flow, myometrial uterine relaxation, and the maintenance of gestational blood pressure. Blockade of CGRP conceivably may increase the potential for gestational hypertension, preeclampsia, and eclampsia. Adverse events in animal reproduction studies were not observed with fremanezumab, galcanezumab, and erenumab. Given the absence of human pregnancy safety data, some advocate for the use of registries to help to confirm safety, to avoid the use of CGRP monoclonal antibodies in women who are planning pregnancy, and to advise contraception for women taking these medications simultaneous with their prescription ( ). Whether these antibodies enter breast milk is unknown.

During Pregnancy

Acute treatments

Authorities suggest that opioids and antiemetics, specifically prochlorperazine (oral or suppository) and meperidine, are the drugs of choice for migraine during pregnancy ( ). Some physicians simultaneously treat with diphenhydramine to reduce the potential for dystonic reaction with prochlorperazine. Metoclopramide and acetaminophen are unassociated with fetal risk and are of benefit. Emergency physicians in New York commonly order a combination of acetaminophen and metoclopramide as initial treatment ( ). Although sometimes employed, the addition of diphenhydramine to metoclopramide to treat headache has been shown to be ineffective for migraine ( ).

Opioids used chronically for pain are associated with birth defects, poor fetal growth, stillbirth, and preterm delivery. However, these risks are not known to occur with occasional acute treatment of migraine, and, while of uncertain risk, opioids may provide significant benefit when initial treatment is ineffective.

The use of occasional, single-dose naproxen sodium orally or ketorolac intravenously is relatively safe throughout pregnancy, although safest when used during the first two trimesters. In the past, researchers reported possibly increased risk of miscarriage for women using nonsteroidal antiinflammatory drugs (NSAIDs) longer than 1 week during pregnancy. Larger, more recent studies were unable to support this claim. Manufacturers recommend avoiding NSAIDs altogether after 30 weeks’ gestation, and cautious use during breastfeeding, primarily due to fetal cardiovascular risks.

Physicians commonly employ the use of intravenous fluids, such as normal saline over 1–2 hours, to treat acute migraine, a treatment safe during pregnancy. Data to support its use are wanting ( ).

For triptans, data are incomplete and their general use is inadvisable. Limited information suggests a low or no teratogenic potential ( ). This reassuring but qualified news has led some to suggest that prescription of a triptan may be acceptable in pregnant women who suffer physiologically and psychologically disabling migraine, whose headaches respond to a triptan, and in whom safer medications have failed ( ). A prospective, cohort study suggests relative safety of sumatriptan without endorsing the use of other triptans ( ).

During pregnancy, ergotamine and dihydroergotamine cause high rates of fetal malformation and are contraindicated. Canadian Headache Society guidelines ( ) recommend against the use of dexamethasone, magnesium sulfate, tramadol, and acetaminophen for any adult presenting with acute migraine. American Headache Society guidelines ( ) find level A evidence for the use of acetaminophen and level B evidence for the use of magnesium sulfate in general migraine pharmacotherapy in adults. During pregnancy, intravenous magnesium sulfate used daily for 5 days is known to result in serious bony fetal abnormalities. The occasional use for migraine likely is safe and some physicians continue to employ magnesium when other therapies have failed. Butalbital was found to lack evidence for efficacy in the treatment of adults with migraine in American Headache Society guidelines. The safety of butalbital during pregnancy has been investigated incompletely. One study hints at a possible increased risk of serious cardiac defects ( ).

Migraine prophylaxis

Rare case reports describe fetal toxicity associated with propranolol, atenolol, and other beta-blockers. Although often safe during pregnancy, these drugs usually are discontinued or usage is reduced to the lowest effective dose. Prolonged use of atenolol to treat hypertension during pregnancy is associated with an increased risk of intrauterine growth restriction (IUGR) and current guidelines describe atenolol as contraindicated during pregnancy ( ). When physician and patient are convinced that prophylactic therapy is required, the benefit of metoprolol or verapamil may outweigh risks. Incomplete data are available for lithium usage in humans. In animals, lithium is teratogenic. Physicians commonly advise that patients avoid lithium to treat headache during pregnancy.

In Australian studies, it has been shown that pregnant women commonly (20%–48%) seek alternative therapies ( ; ). A variety of products are available without prescription. One systematic review concluded that DMS riboflavin 400 mg daily taken prophylactically is well tolerated, inexpensive, and has demonstrated efficacy in reducing the frequency of migraine in adults ( ). The daily allowance of riboflavin recommended by the Institute of Medicine Food and Nutrition Board during pregnancy and lactation is DMS 1.4 and DMS 1.6 mg, respectively ( ). The safety and efficacy of riboflavin to treat migraine during pregnancy remains unexplored.

Magnesium oxide 400–600 mg DMS daily has been found to be effective migraine prophylaxis in nonpregnant subjects, although the effect is modest. Daily allowance recommended by the Institute of Medicine in pregnant women aged 19–30 and 31–50 is 310 DMS and 360 mg DMS, respectively; and 310 and 320 mg daily DMS while breastfeeding.

Lack of safety data and known potential risks during pregnancy has led some authors to advise against the use of Petasites (butterbur) during pregnancy ( ). Evidence-based guidelines published by the American Academy of Neurology (AAN) in 2012 including the use of nutraceuticals in nonpregnant adults were retired over Petasites safety concerns ( ; personal communication).

Postpartum

Breastfeeding reduces migraine recurrence ( ), but postpartum falls in estrogen are thought to trigger migraine. In general, the breastfeeding woman with migraine should avoid ergotamine and lithium. NSAIDs are safe for mothers breastfeeding healthy infants. Cautious use of triptans and some antidepressants is accepted. Sumatriptan by injection may be an ideal way to deal with disabling migraine in this period ( ). When beta-blockers are called for during lactation, some authors favor the use of propranolol ( ).

For some drugs, in the absence of empiric safety data, the American Academy of Pediatrics offers recommendations for breastfeeding based on the milk-to-plasma ratio of the drug, considering that when this relative infant dose ratio is less than 10%, some drugs can be considered to be safe, and possibly unsafe when over 25% ( ). Approaches sometimes include pumping and discarding breast milk associated with the use of a medication. Guidelines from manufacturers of CGRP antagonist monoclonal antibodies advise that a decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

When a woman presents with severe puerperal headache, physicians may derive some comfort that 34% of women with a history of migraine will develop headache during the first postpartum week, commonly between 4 and 6 days and usually benign. However, the puerperium also is the time serious illness may present with sudden severe or “thunderclap” headache (see Chapter 102 ). The differential diagnosis includes migraine, cerebrospinal fluid (CSF) hypovolemia including postdural puncture headache, CVT, preeclampsia/eclampsia, subarachnoid hemorrhage, stroke syndromes, posterior leukoencephalopathy syndrome, postpartum cerebral angiopathy, pituitary apoplexy, Sheehan syndrome, and lymphocytic hypophysitis ( ). A careful history detailing whether and how the current headache differs in character from a woman’s previous migraine may be helpful toward accurate diagnosis.

Leg Muscle Cramps

Between 5% and 30% of pregnant women experience painful leg cramps, which do not adversely affect the fetus but bother the patient. The condition resolves rapidly postpartum. Typically, cramps occur in the morning or evening during the last trimester of pregnancy. Changes in the ionic concentrations of potassium, magnesium, sodium, and calcium may be important in the pathogenesis. Magnesium lactate or magnesium citrate tablets (122 mg DMS in the morning and 244 mg DMS in the evening) relieve or considerably lessen symptoms in approximately 80% of patients. Placebo is similarly effective in 40%. A randomized, double-blind, placebo-controlled prospective trial in Thailand using magnesium bisglycinate chelate 100 mg three times daily DMS led to a 50% reduction of cramp frequency in about 86% of those on the medication and 61% of those on placebo. The study also found those in the magnesium group noted a similar reduction in cramp severity without additional side effects ( ). Some physicians report successful therapy with oral calcium carbonate or gluconate, 500 mg DMS three or four times daily. A randomized small study of calcium supplementation found a reduction in the frequency but not the severity of muscle cramps in an Iranian patient population ( ). Passive stretch and massage are helpful for the acute cramp, while daily preventive stretching before sleep has been helpful in nonpregnant adults.

Myasthenia Gravis

Before Pregnancy

Fertility is unaffected by myasthenia gravis, and oral contraceptive agents do not weaken these patients. No single study offers certainty with regard to the cumulative risk pregnancy causes in the patient with known myasthenia gravis ( ). Conditions may remain stable, improve, worsen, or both improve and worsen at different stages of pregnancy. Approximately two-thirds of patients report some worsening at some time during pregnancy or the puerperium. The puerperium and first trimester are times of greatest risk. The course of myasthenia gravis for a future pregnancy is not predictable by the course of previous pregnancies. A consensus group advises that physicians should reassure the majority of their patients with stable disease that their myasthenia gravis likely will remain stable through pregnancy ( ).

The effect of thymectomy on myasthenia gravis usually is delayed. The potential mother can be advised that the procedure may be helpful for a pregnancy beginning approximately 1 year after surgery. Generally in women with myasthenia who may become pregnant, the physician should use drugs other than azathioprine and cyclosporine. Mycophenolate is associated with an increased risk of congenital malformations and spontaneous abortion, prompting the manufacturers to recommend a negative pregnancy test within 1 week before beginning therapy and use of two reliable forms of contraception 4 weeks before and 6 weeks after therapy. Mycophenolate may affect the effectiveness of hormonal contraception. Rituximab crosses the placenta and higher levels in infants have been recorded than in the pregnant mothers. Hematological abnormalities, infections, and premature births are reported in infants born to inadvertently exposed mothers. Use is not recommended during pregnancy to treat nonlife-threatening myasthenia and the manufacturer recommends effective contraception during use of rituximab and for 12 months following its use. Myasthenia gravis does not influence the contractile strength of the smooth muscle of the uterus, the incidence of postpartum hemorrhage, or the occurrence of toxemia.

During Pregnancy

The medical therapy of myasthenia gravis changes little with pregnancy. Anticholinesterase agents including edrophonium (Tensilon) and plasmapheresis are relatively safe. An international consensus panel advises against the use of anticholinesterase agents intravenously to avoid the risk of uterine contractions associated with their use and to consider postponing CT scans of the chest looking for thymoma in newly diagnosed myasthenia gravis until after pregnancy ( ). Rapid drug metabolism during pregnancy may require increasing the rate or dose of anticholinesterase drugs. Corticosteroids remain the immunosuppressant drugs of choice during pregnancy, although they may increase the risk for gestational diabetes and preeclampsia. Abortion does not lessen the manifestations of myasthenia gravis. Fetal ultrasound helps to detect limb deformities known as arthrogryposis fetalis, thought to be due to the reduced fetal movement associated with circulating maternal antibodies. Although the use of intravenous human immunoglobulin (IVIG) appears safe during pregnancy, the number of myasthenic patients studied is small. In animals, azathioprine is teratogenic, and low levels cross the placenta. Physicians generally advise patients with myasthenia to discontinue azathioprine in preparation for pregnancy. A few women with myasthenia gravis receiving azathioprine during pregnancy have given birth to healthy children. Some researchers point to the uncommon reports of human teratogenicity and intimate that azathioprine might be safer than animal data suggest. Proponents declare azathioprine to be safe during pregnancy and breastfeeding with slim supportive empiric information ( ). Mycophenolate is contraindicated and rituximab relatively contraindicated during pregnancy.

Regional anesthesia is preferred for cesarean section. When the patient is taking anticholinesterase agents, metabolism of procaine is slowed and poorly predictable; in these patients, lidocaine is favored for local anesthesia. Neuromuscular blocking agents such as curariform drugs must be avoided because they may have a greatly prolonged effect in patients with myasthenia gravis. The use of magnesium sulfate as a tocolytic agent or a treatment for preeclampsia may precipitate a myasthenic crisis and is contraindicated.

Theoretical risks based on neurophysiology studies and rare case reports have led some authors to suggest that physicians should avoid phenytoin and barbiturates in the myasthenic developing toxemia of pregnancy ( ). This recommendation stands in contrast to common practice and the recommendations of an international consensus panel that phenytoin and barbiturates are acceptable and may be drugs of choice ( ; ). We lack studies specifically on the use of levetiracetam in this clinical scenario, with case reports noting efficacy.

Postpartum

Breastfeeding poses no significant difficulty, despite evidence that the antiacetylcholine receptor antibodies do pass to the baby in breast milk. Cyclosporine and azathioprine are secreted in breast milk; in general they should be avoided because of their risk for immunosuppression and tumorigenic potential. When medically necessary, the small but uncertain tumorigenic potential of azathioprine must be weighed against the known benefits of breast milk.

Corticosteroids also are secreted into breast milk but in small amounts. Large doses of anticholinesterase drugs taken by the mother may lead to gastrointestinal upset in the breastfed newborn.

Pregnancy Outcome

A retrospective Norwegian study reported an increased risk for premature rupture of amniotic membranes and double the rate of cesarean section among myasthenic women. A smaller retrospective Taiwanese study found statistically insignificant increased risk of cesarean section, infants small for gestational age, low birth weight, and no difference for preterm delivery ( ). Premature labor may be more common in women with myasthenia gravis but this varies considerably among multiple studies.

Perinatal mortality increases to 6%–8% for infants of women with myasthenia gravis, which is approximately five times that of the normal population. Approximately 2% of these are stillborn. Transient neonatal myasthenia affects 10%–20% of infants born to women with myasthenia gravis. Most infants who develop transient myasthenia gravis do so within the first day, but weakness may begin up to 4 days after delivery and usually resolves within 3–6 weeks. Neonates require careful observation for at least 4 days. An imperfect correlation exists between maternal levels of antiacetylcholine receptor antibodies and the likelihood that the neonate will develop transient myasthenia gravis. Intrauterine exposure to receptor antibodies rarely may result in arthrogryposis, which has a high likelihood of recurrence in future pregnancy. The role of intragestational plasmapheresis and immunosuppression to prevent this condition in subsequent pregnancies is unknown ( ).

Muscular and Neuromuscular Disorders

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