Introduction

Fetal hydantoin syndrome (FHS) is a combination of birth defects in babies when exposed in the womb to the anti-epileptic drug (AED) phenytoin during pregnancy. The term “Fetal Hydantoin Syndrome” was first introduced by Hanson and Smith in 1975.¹  Phenytoin (also known as hydantoin or DPH) has been used to manage epilepsy since 1938.² Even though seizure control in pregnant women with epilepsy is essential for both mother and baby, phenytoin use during pregnancy carries a greater risk of birth defects.¹ Although most children born to women who took phenytoin throughout pregnancy do not have structural or behavioral problems, a small proportion (5–10%) of babies develop all the classical features of fetal hydantoin syndrome, and about one-third (33%) of them show fewer effects.^3,4,5

What causes fetal hydantoin syndrome?

FHS develops only when the fetus is exposed to phenytoin medicine in the womb. The U.S. FDA identifies phenytoin as a Category D medicine, as it can cause serious harm to a developing fetus.^2,4 

Monotherapy vs polytherapy

Anti-epileptic drugs (AEDs) such as phenytoin, valproic acid, and carbamazepine carry the highest risk of birth defects, especially when taken together. ⁴ The rate of birth defects is about 3.7% for babies exposed to a single AED and up to 6% when multiple AEDs are used.⁶ Therefore, if you are taking any anti-epileptic drugs during pregnancy, a single drug (monotherapy) is safer than two or more AEDs (polytherapy).^1,2,6

Dosage 

High doses of anti-epileptic drugs carry an increased risk of birth defects than low doses of the same medicine.⁶

Other factors

Not all babies exposed to phenytoin in the womb are affected, which indicates the additional role of genes, the mother’s age, and the gestational age (stage of pregnancy) in causing phenytoin-induced birth defects.^1,6

Craniofacial abnormalities

The facial and skull abnormalities seen in fetal hydantoin syndrome consist of:

Fascial Dysmorphism Spectrum

• Abnormal facies/craniofacial dysmorphia: the unusual appearance of facial features^1,3,4
• Microcephaly: a rare presentation of small head size^1,7,3
• Midfacial hypoplasia: an underdeveloped middle part of the face^7,2
• Short nose with anteverted nostrils: a short nose with nostrils turned forward⁷
• Broad deep nasal bridge: a flattened appearance of the septum of the nose^1,7,2
• Long and indistinct philtrum: the vertical distance between the base of the nose and the middle part of the upper lip is elongated and poorly defined^2,7
• Bowed upper lip: an upper lip that has a curved shape⁷
• Hypertelorism: a wide space between the eyes^2,4
• Pseudohypertelorism: an appearance of widely spaced eyes due to a broad nasal bridge, even if the actual distance between the eyes is normal²
• Ocular defects: problems with the eyes, including drooping eyelids (ptosis), crossed eyes (strabismus), folds at inner eye corners, and watery eyes^7,3,2
• Coarse scalp hair: rough or thick-textured hair⁸
• Hirsutism: Excessive hair growth⁸
• Low-set hairline: the hairline on the forehead is positioned lower than the normal²

Oral and dental malformations

• Cleft lip and/or palate: babies exposed to phenytoin in the womb are much more likely to have a cleft lip or palate (about five times more often than other babies)^1,2,7
• Broad alveolar ridges: the jawbones that hold the teeth are wider than normal²
• High arch palate: the roof of the mouth that is unusually high and narrow²
• Soft tissue abnormality on palate/Indistinct submucosal palatal cleft: a hidden opening in the roof of the mouth as the soft tissue fails to fuse properly during pregnancy²

Ear abnormalities

• Low-set and/or malformed ears: an unusual shape or lowered positioning of ears^1,2,4

These features can present alongside other abnormalities, and the pattern may appear differently in all the affected babies, which could be due to genetic differences.^2,7

Mechanisms underlying craniofacial abnormalities

Activation of retinoic acid receptor (RARs)

Phenytoin increases the activity of retinoic acid receptors (RARα, RARβ, RARγ) in developing facial tissues. Retinoic acid supports growth and formation of facial structures; imbalances can lead to malformations (cleft palate, malformed ears, or small eyes). The drug may lower retinoic acid levels, signaling the body to increase RAR activity in response. Phenytoin may also directly activate RARs, changing gene expression during the stages of facial development.⁷

Growth factors and extracellular matrix proteins 

On gestational day 11, phenytoin exposure increases the activity of growth factors (IGF-2, TGF-α, and TGF-β1) and the proteins found outside the cells, called extracellular matrix proteins (Lamininb1), which are the essential components for the formation of the roof of the mouth. These changes in growth factor activity continued into the later stages of development, including when the mouth roof was nearly formed, further indicating that phenytoin altered the mechanisms responsible for the proper functioning of growth factors.⁷

Other genes affected by phenytoin

Decreased levels of protein-making genes like brain-derived neurotrophic factor and cellular fos during the earliest stages of pregnancy may delay proper development and closure of soft tissues. Increased glutamate receptors (GRIA-2 and GRIA-5) and the activity of sodium ion channel genes are also noted on gestation days 12 and 14.⁷

All these molecular changes seen post-exposure to phenytoin may contribute to the formation of craniofacial abnormalities found in fetal hydantoin syndrome (FHS).⁷

How is it diagnosed?

The initial step towards confirming FHS is to take the medication history and find out if the mother has taken phenytoin during pregnancy.  A doctor may examine a newborn to look for any physical abnormalities.  Additionally, ultrasound scan can detect major birth defects linked to fetal hydantoin syndrome starting from the second trimester. Although this doesn’t directly diagnose fetal hydantoin syndrome, doctors may use cytogenetic tests (like chorionic villus sampling) to rule out genetic problems, especially when multiple birth defects are present.⁵

Treatment options

Treatment for fetal hydantoin syndrome requires a multidisciplinary approach where a team of specialists works together to address the individual child’s specific problem. The possible treatment options include

Surgical intervention

Some babies affected with fetal hydantoin may need to undergo surgery to correct structural problems, such as cleft lip and palate, heart defects, and orthopaedic issues.^5,4

Developmental support

Children with developmental delays or learning difficulties benefit from ongoing support, including physical, occupational, and speech therapies, to help them with everyday life activities.^2,4,6

Anaesthetic considerations

Anaesthesiologists face difficulties when treating children with fetal hydantoin syndrome. Poor development of facial and skull parts makes airway management difficult. Skeletal or heart problems may affect breathing, and some children may also have muscle weakness due to impaired nervous system. Liver and kidney problems also require careful attention when using anesthesia. In some cases, regional anaesthesia may be preferred over general anaesthesia to reduce risks associated with it. Children with spina bifida - a condition where spine and spinal cord does not close properly - need extra attention, and anaesthesia is only considered if the spinal cord is unaffected.^5,4

Postnatal monitoring

Newborns exposed to anti-epileptic drugs (AEDs) should be closely monitored for excessive sleepiness, restlessness, or poor feeding.^6,9

Vitamin K Administration

Babies are given 1 mg of vitamin K at birth to prevent early bleeding problems caused by low vitamin K levels.^5,6,9

Breastfeeding

If the mother is taking high doses of certain anti-epileptic drugs like barbiturates or benzodiazepines, formula may be advised during the first week. Breastfeeding should be paused if the baby appears unusually sleepy, especially when taking AED medications such as primidone, phenobarbital, or diazepam.^6,9

Challenges in current research and care

Unclear mechanisms

Despite the existing theories, the exact mechanism behind fetal hydantoin syndrome remains unclear.^1,5,6

Variability in clinical presentation

Fetal hydantoin syndrome shows a wide range of symptoms depending on the intensity of the action of phenytoin, making diagnosis difficult especially in mild cases.^2,8

Diagnostic challenges

Diagnosis can be challenging when families are not ready to undergo a complete set of investigations. Doctors may then rely on visible features to identify skeletal or other structural defects for confirmation.²

Challenges in therapeutic drug monitoring

Monitoring phenytoin plasma levels in pregnant women can be difficult, especially in developing countries or where regular check-ups are limited, increasing the chances of higher drug exposure.¹

FAQs 

How to prevent fetal hydantoin syndrome?

The initial steps in preventing FHS involve counseling before planning pregnancy and careful selection of anti-epileptic drugs (AEDs) and their dosage. Women of childbearing age should be informed about birth defect risks related to AEDs, seizure control needs, and possible involvement of genes.

Can I stop taking phenytoin all at once during pregnancy?

No, discontinuing AEDs suddenly can cause seizures. Consult with a neurologist to use the lowest effective dose. A single medicine (monotherapy) is preferred over multiple AEDs.

What is the role of folic acid supplementation for pregnant women with epilepsy?

Appropriate folic acid levels reduce the risk of birth defects. The CDC recommends a higher dose (4mg/day) for women with epilepsy. Start taking the medicine at least one month before conception in planned pregnancies and continue throughout the first trimester.

What preventive measures are recommended during pregnancy for women on AEDs?

Early identification of defects can be done by regular follow-up visits, checking plasma AED levels and folic acid concentrations, ultrasound scanning during pregnancy, and alpha-fetoprotein testing.

Summary 

Fetal hydantoin syndrome (FHS) occurs when multiple birth defects appear in the developing fetus due to exposure to phenytoin (an anti-epileptic medicine) during pregnancy. The AED medicine phenytoin can be taken to control epilepsy or other seizure disorders. Doctors typically prescribe phenytoin to prevent seizures during pregnancy for the protection of both the mother's and the baby’s health. The fetus gets exposed to the medicine in the mother’s bloodstream via the placenta, an organ that links the baby’s system with the mother's. Babies born with this condition show physical signs of abnormalities at birth. As they grow, these children may also face challenges with learning and development. 

Among all the physical changes observed, facial and skull features are most commonly affected. Many of these defects can be corrected through surgery or reconstructive procedures, while others, like minor external ear deformity or mild facial differences, may not require treatment if they don’t interfere with the child’s health or function. The appearance of the abnormalities differs from person to person, even between the twins.

The severity of the birth defects is due to the dosage of phenytoin, multiple anti-epileptic drugs (AEDs) usage, and heredity pattern. Treatment is mainly supportive and may sometimes require surgical intervention. Seeking developmental therapies and regular follow-ups is essential in managing symptoms and preventing further complications. Early detection and long-term care can significantly improve the quality of life of the affected babies.