Last updated:
2/3/2026
Years published: 1993, 2001, 2015, 2018, 2026
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders for assistance in the preparation of this report.
Summary
Fetal hydantoin syndrome (FHS) is a condition that may occur in children who were exposed to the anti-seizure medication phenytoin, also known by the brand name Dilantin, in the womb.1 This exposure before birth can affect physical growth and development. Common features include differences in facial appearance, slower growth before and after birth, underdevelopment of fingernails and toenails (nail hypoplasia), and mild developmental delay, such as with learning, speech or motor skills. Other possible findings include cleft lip (a split in the upper lip due to the upper lip not fully fusing during fetal development) and/or cleft palate (an opening in the roof of the mouth), a smaller than average head size (microcephaly), and abnormalities of the fingers or hands.1,2
Studies suggest that about 5-10% of pregnancies exposed to phenytoin result in fetal hydantoin syndrome. 3
Treatment focuses on the specific medical needs of the individual and may include surgical procedures to correct certain birth differences, as well as supportive therapies.
Introduction
The term fetal hydantoin syndrome was first introduced in 1975 by researchers Hanson and Smith to describe a group of birth differences observed in infants born to mothers who used the anti-seizure medication phenytoin during pregnancy.4
Anti-seizure medications, including the drugs from the hydantoin group (such as phenytoin), are commonly prescribed to women of childbearing age. Some of these medications are known to be teratogenic, which means they can interfere with normal fetal development and increase the risk of birth defects when taken during pregnancy.4,5 A teratogen is an exposure in pregnancy that interferes with the development of the fetus. Exposure to these anti-seizure medications before birth can result in a recognizable pattern of congenital (present at birth) differences, especially involving the face and head.5,6
Although phenytoin has long been associated with a specific pattern of effects on fetal development, research has shown that many anti-seizure medications can cause similar or overlapping features. This has led to the broader concept of fetal anticonvulsant syndromes, which refers to a group of related conditions caused by different anti-seizure medications taken during pregnancy.5, 6
It is important to note that not all anti-seizure medications care the same level of risk. Some medications, such as valproate, are associated with a higher risk of developmental and learning difficulties compared with phenytoin.7, 8, 9
Although individual drug-specific syndromes like fetal hydantoin syndrome are uncommon, the overall risk of birth defects related to anti-seizure medication use during pregnancy is clinically important and not rare.4, 6
Fetal hydantoin syndrome (FHS) is most often associated with prenatal (before birth) exposure to phenytoin, also known by the brand name Dilantin, which belongs to the hydantoin family of anti-seizure medications (anticonvulsant drugs).
The signs and symptoms of fetal hydantoin syndrome can vary widely from person to person. Some features may not be noticeable at birth and may become more apparent as the child grows and develops.1 Understanding the full range of effects is limited by the small number of long-term studies available.6 The following signs and symptoms have been described: 1, 2, 6, 8-10
Other possible medical findings include:
A possible increased risk of certain tumors has been suggested, but current evidence is not sufficient to confirm a direct cause-and-effect relationship.11
Fetal hydantoin syndrome occurs when a developing fetus is exposed to the medication phenytoin (which is part of the drug class hydantoins) during pregnancy. Phenytoin is considered a teratogen, an exposure in pregnancy that interferes with the development of the fetus. There is no known dose of phenytoin that has been shown to be completely safe from causing developmental effects.3 The risk of developing this condition may be higher when phenytoin is used together with other anti-seizure medications (a treatment approach known as polytherapy) than when used alone (monotherapy) and may also be influenced by genetic factors in both the pregnant individual and the fetus. 4, 5, 12
Research on how phenytoin affects fetal development suggests that when the body breaks down (metabolizes) the medication, it can form reactive byproducts. These byproducts can cause oxidative stress, a process in which unstable molecules damage cells. This kind of cellular damage may affect important cells and tissues during early fetal development, when organs and body systems are forming.
Not everyone processes phenytoin in the same way. Differences in how individuals break down and eliminate these byproducts, as well as differences in how the body repairs DNA damage, may help explain why some exposed fetuses are affected while others are not, even with similar exposure.11, 12
The effects of phenytoin on fetal development are believed to result from multiple interacting factors rather than a single identified cause. One possible contributing factor is lower folate levels during pregnancy, which may make developing tissues more vulnerable to damage.13, 14 Other factors that may increase risk include a reduced ability to detoxify (break down and remove) phenytoin from the body, interactions between anti-seizure medications taken together, maternal age, and the timing of medication exposure during pregnancy, especially during early stages when organs are developing.14
Certain genetic variations in the maternal methylenetetrahydrofolate reductase (MTHFR) gene have also been linked to an increased risk of fetal hydantoin syndrome. These genetic differences can affect how folate is processed in the body and how phenytoin is cleared, which may result in greater fetal exposure to the medication.11, 13
The exact number of people affected with fetal hydantoin syndrome (prevalence) is not known. However, studies estimate that approximately 5-10% of pregnancies exposed to phenytoin result in fetal hydantoin syndrome.3
Epilepsy affects an estimated 3 to 5 out of every 1,000 pregnant individuals. For many of these pregnant individuals, continuing anti-seizure medications during pregnancy is often medically necessary to prevent seizures, which can pose serious risks to both the pregnant individual and the developing fetus. These risks include miscarriage, high blood pressure during pregnancy (gestational hypertension), dangerously high blood pressure and signs of stress or damage to one or more organs (preeclampsia), preterm birth (babies born alive before 37 weeks of pregnancy are completed), and maternal death.14
Among infants born to individuals who used phenytoin during pregnancy, approximately 10-30% show at least some features associated with fetal hydantoin syndrome. The most commonly reported feature is underdevelopment of the fingers or toes, especially the tips (distal digital hypoplasia). However, most infants exposed to phenytoin as a single medication (monotherapy) do not develop the full combination of features required for a diagnosis of the syndrome.14
Studies that have looked at brain and developmental (neurodevelopmental) outcomes found that children whose mothers took phenytoin alone during pregnancy showed mild delays in motor development, such as reaching movement milestones (rolling over, crawling, sitting up, walking) later than expected. These delays were greater than those seen in children exposed to carbamazepine (another anti-seizure medication) in the womb and with children who were not exposed to anti-seizure medications.16, 17
There is no laboratory test or genetic test that can definitely confirm fetal hydantoin syndrome. Diagnosis is based on a medical history of phenytoin (hydantoin) use during the mother’s pregnancy and the careful identification of the physical, developmental, and neurological features associated with the syndrome.1 Importantly, most infants exposed to phenytoin in the womb do not develop the syndrome.3
Treatment
There is no single standard treatment for fetal hydantoin syndrome (FHS), and care is tailored to each individual’s needs. Management of the condition focuses on treating symptoms and supporting development. Care is typically provided by a multidisciplinary team, which may include pediatricians, neurologists (medical doctors specializing in the diagnosis and treatment of disorders of the brain and nervous system), surgeons, and developmental specialists. Early intervention services – such as physical therapy, occupational therapy, and speech therapy – are recommended to support a child’s development and improve long-term outcomes. 6
Surgical repair of cleft lip (a split in the upper lip due to the upper lip not fully fusing during fetal development) and/or cleft palate (opening in the roof of the mouth), when present, is performed using standard surgical approaches during infancy or early childhood. Ongoing medical care, educational support, and psychosocial services are often needed throughout childhood and beyond.
To reduce the risk of birth defects (teratogenic risk), using a single anti-seizure medication (monotherapy) at the lowest effective dose is recommended whenever possible before conception and throughout pregnancy.
Folic acid supplementation before and during pregnancy is recommended for all pregnant individuals, including those taking phenytoin.3, 5, 15 Most professional groups advise at least 400 micrograms (0.4 mg) of folic acid daily, while some recommend a higher dose (4 mg daily) for women at increased risk of neural tube defects (birth defects of the brain, spine, or spinal cord that happen in fetuses in early pregnancy). However, evidence supporting higher doses specifically for women taking anti-seizure medications is limited. As a result, folic acid dosing should be individualized through preconception (pre-pregnancy) and prenatal (during pregnancy) counseling.18, 19
The International League Against Epilepsy recommends that all women with epilepsy receive coordinated care involving both a neurologist and an obstetrician. Comprehensive counseling should be provided to discuss the importance of seizure control, the potential risks associated with seizures during pregnancy, and the possible effects of anti-epileptic drugs (anti-seizure medications) on fetal development.15 Preconception (pre-pregnancy) and prenatal (during pregnancy) counseling should address both seizure control and fetal risk.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportPlease complete this form to access the requested resource.
