Having a child is often one of the most joyous events in a woman’s life. The priority amongst women in this stage of their life is to bring a healthy child into the world. No group feels this more strongly than women with epilepsy, since the majority of women with epilepsy taking antiepileptic drugs may have a higher risk of having a child with minor or major birth defects (fetal abnormalities) than women in the general population.

The North American AED Pregnancy Registry

Although it has long been recognized that AEDs may significantly increase the likelihood of fetal abnormalities it wasn’t until 1997 that the North American Antiepileptic Drug Pregnancy Registry was founded to explore the depth of fetal abnormalities associated with each AED. Since the inception of this hospital-based registry, 3, 633 women from the United States and Canada have enrolled. To enroll, the eligible woman herself must call the toll-free telephone number of the registry. She is interviewed 3 times including: at the time of enrollment, at 7 months’ gestation and post partum (up to 8 to 12 weeks after the expected date of delivery). Only major malformations are included in the registry and are defined as a structural abnormality of the baby with surgical, medical, or cosmetic importance.

“The registry is important, because the range of birth defects due to antiepileptic drugs has not been studied systematically. By enrolling women early in pregnancy and before any prenatal screening, the findings in their infants are relatively unbiased. We need to provide information on this risk to the women themselves and their doctors as soon as possible. Enrollment in the Antiepileptic Drug Pregnancy Registry is the best way to speed up the process,” said Dr. Lewis Holmes, Professor of Pediatrics at Harvard Medical School and Chief, Genetics and Teratology Unit, MassGeneral Hospital for Children.

Patricia Cioppa, a mother and former participant in the registry, believes the registry is crucial in better understanding the risks of birth defects from AEDs, “Having had a child with health issues we have suffered quite a bit. I believe medical research is always important because eventually it helps someone. In nine months I spent a total of 30 minutes. That’s an easy time commitment and anyone can devote such a short amount of time to such an important cause with long-term implications.”

Valproate: The Current Findings

Based on data culled from the AED registry there is strong evidence suggesting that in utero exposure to the AED sodium valproate is associated with a very significant risk in fetal abnormalities. Among 149 pregnancies during which women took valproate as monotherapy, nine infants had major malformations, including, serious heart defects, renal anomalies, limb defects and spina bifida(1). Spina bifida is a neural tube defect that happens in the first month of pregnancy when the spinal column doesn’t close completely. One infant had multiple major malformations. This rate of major malformations is approximately four to five times that seen in unexposed children(1). Holmes believes, “This risk is for a wider spectrum of major malformations than most physicians realize.”

Phenobarbital

Data from the registry published in 2004 suggested that phenobarbital is also linked to a four-fivefold increased risk of major malformations in exposed pregnancies. Among 77 pregnancies during which women took phenobarbital as monotherapy, five infants were born with major malformations including heart defects and cleft lip and palate(2). Holmes contends that the phenobarbital is a flagrant example of why the registry is so crucial, “Remember that phenobarbital was first marketed in 1912. The serious fetal effects were not identified until 80 years later (the mid 90’s).” Homes also said, “Having established the significant fetal risks phenobarbital has such as cleft lip, palate, and heart defects it is unfortunate that the low cost makes it likely to be used in developing countries.” In the article, The AED (Antiepileptic Drug) Pregnancy Registry, A 6-Year Experience, Holmes states that “on average, phenobarbital , which is on the World Health Organization’s list of essential drugs, could cost as little as $5 per person per year.” He notes too, that in addition to its risk of causing major malformations, exposure to phenobarbital in utero has been shown to cause effects on intelligence.

A Lapse in Communication

Trish Dalley, another participant in the registry was fortunate enough to find out about the registry through a colleague. She believes visibility of the registry is vital to pinpointing the AEDs that are harmful to fetal development. “I think Ob-Gyns who specialize in high risk obstetrics know about the registry as do some neurologists, but I think knowledge of the registry is not as widespread as it should be amongst health care professionals especially primary care physicians and non-specialized Ob-Gyns.” Dalley also points out, that doctors prescribe AEDs for other health issues such as migraines and psychiatric disorders. “These women, who are taking AEDs for other health problems besides epilepsy need to know the potential harm that might occur during their pregnancy,” Dalley said. Dr. Kaarkuzhali Krishnamurthy, Director of Women's Health in Epilepsy and Director of Anti-Convulsant Development of Beth Israel Deaconess Medical Center agreed with Dalley stating, “There are standard health practices which the majority of primary care physicians don’t talk about with their female patients such as taking folic acid during the child bearing years. If something as standard as this is not being discussed what about the extras like the effects of anticonvulsants?” She advises physicians to treat women with epilepsy as women first and said, “I think Epilepsy is the most common neurological condition in pregnant women. These women need to be counseled appropriately including receiving information about supplements, accurate statistics of fetal abnormalities associated with AEDs and need to be informed of the Registry.”

Looking Ahead

When asked why the continuation of the registry is so important Holmes replied, “We must do better than we have in the past. Many new drugs have been and are being marketed. Without the registry we have no way to track these new drugs and no way to learn more so that we may accurately and safely advise pregnant women with epilepsy.”

Whether you are a patient, family member of a person with epilepsy or health care professional the pregnancy registry is a link to a healthier world; a world where pregnant women taking AEDs can make informed decisions. If you would like to learn more about the registry you may go to http://aedpregnancyregistry.org.

References
1. Alsdorf RM et al: Birth Def Res: Clin Mol Ter 70:245, 2004.
2. Holmes LB, Wyszynski D, Lieberman E. The AED (Antiepileptic Drug) Pregnancy Registry A 6-Year Experience. Arch Neurology. 2004;61:673-678.