Brandy Parker-McFadden had always considered herself one of the lucky ones, and by any measure she was. Diagnosed with epilepsy at age 15 after her first convulsive seizure, Parker-McFadden, now 40, has had just three seizures in the 25 years since. "I took my medications faithfully and went on with my life," she says. "I grew up, I got married, and I had a baby,  and then two more. Through it all, my epilepsy was well controlled with medication. From the outside, it was almost as though I didn't have it."

This was thanks in large part to valproate, an antiseizure medication prescribed by her neurologist that is often used to treat epilepsy and bipolar disorder and to prevent migraines. So when her neurologist instructed her obstetrician to increase the dosage during her first pregnancy to ensure that the medicine remained at a therapeutic level within her body, Parker-McFadden didn't question it.

That was 12 years ago, in 2003. Parker's firstborn, Samuel, is now 11.

"Samuel was born right around the time we got the first information on cognitive risks to babies exposed to valproate in utero," says Kimford J. Meador, MD, a professor of neurology and neurological sciences at Stanford University Medical Center in California, clinical services director of the Stanford Comprehensive Epilepsy Program, and a Fellow of the American Academy of Neurology (FAAN). "There were hints in the epilepsy pregnancy registries [online databases cataloging the experiences of pregnant women taking epilepsy drugs], but what wasn't fully known until 2004 is that one in 10 children exposed to valproate in utero will have a major complication—plus a 7- to 10-point drop in IQ. Verbal intelligence, in particular, is affected."

Ignorant of the Odds

Born six weeks early, Samuel had developmental delays typical of children exposed to valproate in utero and was subsequently diagnosed with autism. "His limitations don't completely define him," says Parker, "but I feel immensely guilty that my medication forever altered his life. The findings on valproate were new at the time I became pregnant, but that doesn't stop me from wishing I'd dug more."

Samuel was born just as the data were being gathered from Dr. Meador's Neurodevelopmental Effect of Antiepileptic Drugs (NEAD) study—an observational, multicenter study that recruited pregnant women with epilepsy taking the antiepileptic drugs carbamazepine, lamotrigine, phenytoin, or valproate from 1999 to 2004. The first set of results, published in the New England Journal of Medicine in 2009, revealed that children exposed to valproate in utero had significantly lower IQ scores at age three than kids exposed to the other antiepileptic drugs. Three years later, research published in The Lancet Neurology showed that those same children were less verbally adept at age six than kids exposed to the other antiepileptic drugs.

It was largely this research that led the US Food and Drug Administration (FDA) to give valproate a "D" classification for treating epilepsy, indicating that the benefits may outweigh the risks in certain situations, especially for the small minority of women whose epilepsy can only be controlled with valproate. (See "Medications: How Safe Are They for Baby?" below.) For women with migraines, which can be treated with many other equally effective, less risky medications, valproate was given an "X" classification, an indication that proven fetal risks outweigh any potential benefit.

Women who live with epilepsy or other neurologic conditions such as migraines or multiple sclerosis want nothing more than to keep themselves and their babies healthy during their pregnancies. The challenge is choosing the safest way forward.

That is why Parker-McFadden, now a mom of three and living in Nashville, founded My Epilepsy Story. Dr. Meador serves as chair of the board of this education and advocacy foundation, which was established to provide a resource for women with epilepsy and to encourage them to take an active role in their health care. "I can't change what happened to me and to Samuel, but I can help change what happens to other families like ours," says Parker-McFadden. She switched from valproate to levetiracetam (Keppra) after Samuel was born; his two younger siblings were unaffected by the medication. "Information and collaboration are the keys," she says. "Given the research restraints posed by pregnancy, the only way forward is together."

Registering Risk

The gold standard for medical research is the double-blind study, in which both the participants and the researchers involved are unaware of which patients have received the experimental medication or procedure. But because of the risks, pregnant women are largely excluded from double-blind studies of any sort, including those testing medications for neurologic conditions. This creates a "huge evidence gap," says Gary Gronseth, MD, FAAN, a professor of neurology at the University of Kansas in Kansas City, a member of the Neurology Now editorial advisory board, and an expert on best practices and guidelines for physicians. "We end up relying on animal studies and on observational evidence—the personal, anecdotal experiences that show up in the registries," he says. "That evidence is weaker, but it is accumulating. And with it, the knowledge is, too."

Here's what is known: A drug's effect on a fetus is determined largely by the drug's potency and dosage, as well as the age of the fetus when it is first exposed, explains Joseph I. Sirven, MD, FAAN, chair of the department of neurology at the Mayo Clinic in Scottsdale, AZ, editor-in-chief of the Epilepsy Foundation's website, and a member of the Neurology Now editorial advisory board. When exposure occurs before the 20th day after fertilization, drugs typically have an all-or-nothing effect, killing the embryo or not affecting it at all, says Dr. Sirven. If exposure occurs as the organs are forming, at about 20 to 56 days after fertilization, several events may occur: The woman may have a spontaneous abortion; the fetus may develop a congenital malformation or a metabolic or functional defect that may appear later in life; or the fetus may be fine. Exposure to a drug once the organs have formed, in the second and third trimesters, may alter the growth and function of normally formed fetal organs and tissues.

Valproate was first approved for use as an anticonvulsant in France in 1967. Nowadays, lamotrigine (Lamictal) is probably the most widely prescribed drug for epilepsy in the United States, Dr. Sirven says. But before evidence began mounting against it, valproate or valproic acid (Depakote, Depakene) was likely the most widely prescribed antiepileptic drug worldwide—which means a lot of observational evidence exists concerning its benefits and risks.

"To get large enough patient samples for any given drug used during pregnancy, you need two decades' worth of women on the registries," says Dr. Sirven. "For older drugs like valproate, the available patient samples are large. Newer drugs, such as lacosamide (Vimpat) and perampanel (Fycompa), haven't been around as long and haven't been as widely prescribed. So you weigh what you know against what you don't know."

Inching Toward Certainty

Of course, neurologists still don't know what's safe in every case, and even minimal uncertainty can be unnerving. "It used to be that women with neurologic conditions were told, simply, that they couldn't have children, that pregnancy would make their conditions worse," recalls Dr. Gronseth. "Now we know better. We even know how to stratify the risks for both mother and child. There are still many questions, of course. But now we have some answers."

We posed some of those questions to experts on epilepsy, migraine, and multiple sclerosis to find out what women need to know to assess their medical readiness for a healthy pregnancy and to nurture their bodies and babies during those nine months. Here are their answers.

Epilepsy

Does pregnancy make epilepsy worse? "Pregnancy in and of itself doesn't alter epilepsy too much," says Dr. Sirven. "However, the changes in blood volume that accompany pregnancy can make drug levels fall below a therapeutic level, putting women at a higher risk of seizures." Since seizures pose a serious risk to both the mother and her child, expectant women need to work with their obstetricians and neurologists to keep medication at a therapeutic level throughout the pregnancy, he says.

Can epilepsy drugs harm the baby? "Most women who take antiepileptic drugs do well," says Dr. Sirven, "but the risk of a problem increases for women taking valproate."

Cynthia Harden, MD, system director of epilepsy services with Mount Sinai Health System in New York City, agrees. "Alternatives to valproate should almost always be used in women of child-bearing potential with epilepsy," she says. "The exception is when valproate is the safest option, specifically because it is the only medication able to stop severe and frequent seizures. Women who must be on valproate should work with their neurologists to achieve the lowest effective dose, since higher doses are associated with an increased risk of major congenital malformations."

Dr. Harden also recommends avoiding phenobarbital because "exposure in utero carries one of the highest rates of physical malformations, primarily heart defects," she says. The anticonvulsant topiramate (Topamax) has been linked to oral cleft lip and palate as well, she adds. Lamotrigine and levetiracetam are two antiepileptic drugs with the most favorable profiles based on the current data, says Dr. Meador, but both are category C, which means risks cannot be ruled out due to a lack of data in humans.

What if women go off medications entirely while pregnant? "They increase their risk of having a seizure and all its consequences—a fall, an injury, even oxygen deprivation, none of which is good for the mother or the fetus," says Dr. Sirven.

How else can women protect their babies? Take a daily multivitamin that includes 1 mg of folic acid (folate), says Dr. Meador. "The NEAD study showed that taking folate during the period from before conception through early pregnancy is associated with higher IQs in children whose mothers took antiepileptic drugs during pregnancy, so it may be protective against cognitive deficits." Studies suggest that this is also true for women without epilepsy, he adds.

Are babies likely to inherit their mother's epilepsy? Not necessarily. "The origins of epilepsy depend on several factors—they can be acquired or genetic," says Dr. Sirven. "Plus, there are numerous genes that can play a part, and simply having a gene doesn't mean you'll get epilepsy. The complex interplay between genes and the environment is what determines if someone will develop epilepsy."

Migraine

Does pregnancy make migraines worse? "The hormonal changes that occur during pregnancy make some women's migraines better during pregnancy, but this is less likely if they have migraine with aura," says Teshamae Monteith, MD, chief of the headache division of the University of Miami Miller School of Medicine and a member of both the AAN and the Neurology Now editorial advisory board. "The problem often arises when a woman is doing well on a particular drug regimen and then has to stop treatments because of the risk to the fetus. Even so, I don't know of any neurologist who recommends women with migraines avoid pregnancy altogether."

Once the baby arrives, women may experience changes in hormone levels, sleep cycles, and lifestyle, as well as sleep deprivation and stress, all of which can trigger migraines, says Dr. Monteith, who recommends establishing a postpartum support system—soliciting help from a partner, spouse, family, or a caregiver—and a treatment plan.

Does breastfeeding make migraines worse? "A few studies suggest that breastfeeding may reduce the frequency of migraines," says Dr. Monteith. "While the relationship isn't well established, it's possible that stable estrogen levels during lactation combined with the absence of menstruation may help to prevent migraines."

Can migraine drugs harm the baby? "Valproate and topiramate [which is associated with oral cleft malformations] should never be the first medication prescribed during pregnancy," says Dr. Monteith. The same is true for opioid painkillers such as codeine, hydrocodone bitartrate/acetaminophen (Vicodin), meperidine (Demerol), oxycodone/acetaminophen (Percocet), and hydromorphone (Dilaudid), she adds. "The extended-release and long-acting opiates have warnings for neonatal opioid withdrawal syndrome (NOWS). Risks for the mother include abuse, addiction, increased sensitivity to pain, overdose, and even death."

Alternative drugs to consider include anti-nausea and anti-vomiting medications metoclopramide (Reglan), diphenhydramine (Benadryl), and ondansetron (Zofran). "These classes of drugs are considered relatively safe," says Dr. Monteith. She also suggests using greater occipital nerve blocks—injections of lidocaine to the back of the head—to treat prolonged migraines with vomiting, as well as tricyclic antidepressants like amitriptyline, beta blockers such as propranolol, oral magnesium, and riboflavin (vitamin B2).

How else can women safely treat migraines? "A pain psychologist can help with non-pharmacological interventions such as biofeedback, cognitive behavioral therapy, and relaxation therapy, which may help to prevent and lessen the impact of migraine attacks," says Dr. Monteith. "Also, drinking more water might be very helpful, since dehydration can be a trigger for migraines and more vomiting." Other non-pharmacological treatments such as acupuncture, supraorbital transcutaneous stimulation (20 minutes a day of nerve stimulation to the forehead with a headband-like device), aromatherapy, and application of menthols may help, too.

Is there anything new in the research? A recently published analysis of six studies that included more than 4,000 infants of women who took sumatriptan or other triptans while pregnant revealed no increased risk of major spontaneous abortions, congenital malformations, or prematurity. (Triptans are part of a family of tryptamine-based drugs typically taken at the onset of a migraine to stop it.) "I'm still not suggesting patients treat their migraines with triptans during pregnancy, since observational evidence can be weak and more research is needed," says Dr. Monteith. "But if a patient of mine took them before knowing she was pregnant, I would tell her she probably shouldn't worry."

Taking sumatriptan while breastfeeding isn't significantly risky, either, due to the low levels of the drug that are secreted in breast milk and the fact that women use the drug infrequently, says Dr. Monteith.

Multiple sclerosis 

Does pregnancy make multiple sclerosis (MS) worse? "The normal symptoms of MS, such as tiredness and urinary frequency, can be exacerbated by pregnancy, which tends to cause the same symptoms," says Barbara Giesser, MD, FAAN, a professor of clinical neurology and clinical director of the Multiple Sclerosis Program at the David Geffen School of Medicine at the University of California, Los Angeles, and a member of the Neurology Now editorial advisory board. For women whose symptoms escalate with pregnancy, Dr. Giesser advises trying to manage them without medication—by stretching to improve muscle spasticity, for instance, and conserving energy to prevent fatigue.

But there can be an upside to pregnancy. "The rate of MS attacks typically goes down by about two-thirds during pregnancy," she says. "Unfortunately, the rate spikes up three to six months postpartum. But the medical literature tells us that a good predictor of postpartum relapse is how active the disease was before pregnancy."

How does pregnancy affect MS relapses? "MS is an attack of the immune system on the nervous system," explains Dr. Giesser. "We use MS drugs to tamp down the body's immune response. But pregnancy is an immune-modulating state because a baby, half of whose proteins come from its father, is a half-foreign object in the womb. Normally our bodies reject foreign proteins, but pregnancy initiates a different immune response so that the mother's body doesn't reject the growing fetus. This is called 'immunomodulation,' and it also mutes the immune activity in MS. It's why women have fewer relapses while they're pregnant."

Can MS drugs harm the baby? "We use two categories of medicines for MS: disease modifiers and those for symptom management," says Dr. Giesser. "We don't use disease-modifying drugs during pregnancy because pregnancy itself seems to naturally protect against MS." Twelve disease-modifying therapies have been approved by the FDA, and most of these are in category C, which means either no adequate animal or human studies have been conducted, or adverse fetal effects have been shown in animals, but no human data are available, she explains.

"Interferon is [in category] C because it's been associated with problems in animal studies and is possibly linked with low birth weight. The new oral medications—fingolimod (Gilenya) and dimethyl fumarate (Tecfidera)—are C, too. The exceptions are glatiramer acetate (Copaxone), which is category B, meaning animal studies show no risk to the fetus but no controlled human studies have been conducted, and teriflunomide (Aubagio), which is category X, because of its known association with birth defects. Plus, teriflunomide can persist in the body for up to two years after a woman or man stops taking it (teriflunomide is also present in the semen of men with MS who are taking it), so women and men who have been prescribed this drug should discontinue it well before they plan to get pregnant.

Since most of the medicines used for managing symptoms—treating pain, spasticity, or bladder symptoms, for instance—are category C, says Dr. Giesser, "we tend to treat these symptoms with non-pharmacologic strategies."

Does breastfeeding make MS worse? "We don't know whether disease-modifying drugs cross into breast milk," Dr. Giesser says, "so we discourage disease-modifying therapy while breastfeeding. But while the evidence is mixed, some research indicates that breastfeeding may be associated with a decreased postpartum relapse rate." A German study published in JAMA Neurology in August that looked at data collected from 2008 to June 2012 in the German MS and pregnancy registry showed that women with MS who intended to breastfeed exclusively for two months had a lower risk of relapse in the first six months after giving birth than women with MS who either did not breastfeed or combined breastfeeding with supplemental feedings—perhaps indicating a link between the return of menstruation and MS relapse, the study authors suggest.

Does MS worsen after the baby is born? "Fatigue is the most common symptom of MS, so a new mother might have a double whammy of it," says Dr. Giesser. As for MS relapses worsening after the baby arrives, she says, "women who had more active disease and more relapses before they became pregnant are more at risk for a relapse postpartum. Those women may be advised to resume their disease-modifying therapy as soon as possible after the baby is born."

Your Birth Strategy

• Plan ahead. "Fifty percent of all pregnancies in the United States today are unplanned, and for anyone on medication, that's a situation to actively avoid," says Joseph I. Sirven, MD, FAAN, chair of the department of neurology at the Mayo Clinic in Arizona, editor-in-chief of the Epilepsy Foundation's website, and a member of the Neurology Now editorial board. "In the case of epilepsy, the drugs that cause problems do so in the first trimester. Make sure you plan your pregnancy in close consultation with your neurologist."
• Discuss contraception with your doctor. Many medications interact with birth control drugs and can even render them ineffective, says Gary Gronseth, MD, FAAN, a professor of neurology at the University of Kansas in Kansas City and a member of the Neurology Now editorial board.
• Field a team. "Make sure your obstetrician and your neurologist communicate regularly and weigh all risks and benefits from both their perspectives," says Dr. Gronseth. And include your baby's future pediatrician, advises Cynthia Harden, MD, system director of epilepsy services with the Mount Sinai Health System in New York City.
• Consider IVF. "If you and your team agree that you should curtail your medication prior to and during your pregnancy, you might consider in vitro fertilization, just to increase your chances of getting pregnant right away and minimize the amount of time that you're off your drugs," says Mary Angela O'Neal, MD, director of the Brigham and Women's Hospital women's neurology program in Boston.
• Be your own best advocate. "Educate yourself and ask questions. If your doctor doesn't want to hear it, find another doctor," says Brandy Parker-McFadden, founder of My Epilepsy Story, an epilepsy advocacy and education foundation.
• Take a daily multivitamin that includes folic acid. "While it may not ward off major birth defects, folic acid does appear to protect against cognitive deficits," says Kimford J. Meador, MD, FAAN, director of the Stanford Comprehensive Epilepsy Center.
• Join a registry, a clinical trial, or both. "We are miles ahead of where we were just 15 years ago, but we still have so much more to find out," says Dr. Meador. He encourages women to add to the knowledge and be a part of the collaboration.

Medications: How Safe Are They for Baby?

Last summer, the Food and Drug Administration (FDA) revised its longtime classification system for drugs taken during pregnancy. The old rating system, still used by doctors and all physicians quoted in this article, sorted drugs into five lettered classes—A, B, C, D, and X—based on the potential of the drug to cause fetal birth defects if taken during pregnancy. A sixth letter—N—was used to signify a drug the FDA hadn't yet classified. But the letters provided an overly simplified view of a medication's risk, so the FDA is phasing them out.

All new drugs applying for FDA approval must comply with the new system, which replaces the letters with summaries of any known risks and the data behind them in these categories: Pregnancy, Lactation, and Males and Females of Reproductive Potential. The labeling for older drugs is required to comply with the new system over the next three to five years. But in the meantime, drugs may still be referred to by the FDA's old letter classification, as follows:

A  Controlled human studies show no fetal risk. These are the safest drugs for use during pregnancy.

B  Animal studies show no risk to the fetus, but no controlled human studies have been conducted. Or, animal studies show a risk to the fetus, but well-controlled human studies do not.

C  No adequate animal or human studies have been conducted. Or, adverse fetal effects have been shown in animals, but no human data are available.

D  Evidence of human fetal risk exists, but benefits may outweigh the risks in certain situations (such as life-threatening disorders or serious disorders for which safer drugs cannot be used or are ineffective).

X  Proven fetal risks outweigh any possible benefit.