Overview

During pregnancy, there are certain restrictions on food consumption and medication exposure, due to the potential effects on the developing foetus; phenytoin is one such example. It is an antiseizure medication which is classed as a teratogen (a substance which interferes with foetal development). If taken during pregnancy, it can cause issues with the development of the foetus in approximately 5-10% of cases.¹ The collection of symptoms caused by phenytoin is described as ‘foetal hydantoin syndrome’, and it affects people equally, regardless of gender.

Foetal hydantoin syndrome includes both congenital issues and developmental issues, which become apparent later in life. This syndrome occurs because some antiseizure medications, including phenytoin, can pass from a pregnant person to their foetus via the placenta.²

Most foetuses exposed to phenytoin do not experience foetal hydantoin syndrome. However, because there is a notable risk, the choice of medications should be carefully considered, and the pregnancy should be diligently monitored by healthcare providers. That being said, you should not stop taking medications without first consulting a healthcare provider, as this can also be dangerous for you and the developing foetus. Furthermore, taking multiple antiseizure medications simultaneously can increase the risk of developing foetal hydantoin syndrome.

This article focuses on the neurodevelopmental outcomes of foetal hydantoin syndrome. The impacts of foetal hydantoin syndrome on child brain development will be discussed. It is worth noting that there are other issues associated with foetal hydantoin syndrome, such as abnormalities of the skull and facial features, growth deficiencies, cardiovascular issues, and underdeveloped nails of the fingers and toes, but this article doesn’t aim to develop these aspects.^1,3

What is phenytoin?

According to the NHS, phenytoin is an antiseizure medication commonly prescribed for epilepsy. Phenytoin stops seizures by slowing down the abnormal bursts of electrical activity in the brain, which are characteristic of seizures. Phenytoin is also prescribed as a remedy for trigeminal neuralgia - a type of nerve pain which affects the face.

Phenytoin is considered teratogenic because it can interfere with the normal development of a foetus, posing a risk to pregnant users. Phenytoin is often prescribed with other antiseizure drugs and medications that may influence the development of the disorder.

It is currently unclear whether the adverse effects of phenytoin during foetal development are entirely caused by the drug itself, or by the by-products of phenytoin metabolism. In addition, the potential role of other factors remains unclear, such as genetic variations which affect phenytoin metabolism.

Pathophysiological changes in foetal hydantoin syndrome

Phenytoin, once present into the bloodstream, travels to the foetus via the placenta. The exposure of the foetus to the medicine is significant, because the developing foetus processes the drug differently than the mother. This exposure is more dangerous (5 to 10% risk of having foetal hydantoin syndrome) if the drug is administered in the first trimester of pregnancy.

Only a few cases of foetuses exposed to phenytoin experience foetal hydantoin syndrome. Genetics may influence or increase the risk of some foetuses, making them more predisposed to the condition. For example, maternal and foetal genotypes can affect placental transport, absorption and metabolism of compounds.⁴

There are several mechanisms by which phenytoin can impair brain development:

Phenytoin interferes with the metabolism of folate, which is crucial for DNA synthesis and cell division. Folate deficiency can lead to defects in the neural tube (the structure that eventually develops into the brain and spinal cord). As a result, women taking phenytoin are commonly advised to take folic acid supplements.⁵

Phenytoin can interfere with the migration of neurons to the correct positions in the developing brain. This disruption can lead to cortical dysplasia (the abnormal development of the cerebral cortex) and other structural brain abnormalities.⁶ This can cause neurological deficits when the child is born.

Phenytoin can also affect the specialisation process of neural progenitor cells (multipotent neural stem cells) into mature neurons.⁷ When this process is disrupted, it can impair the proper formation of neural circuits in the brain, which can also cause neurological problems when born.

Phenytoin metabolism produces radical oxygen species, leading to oxidative stress as free radicals can damage neurons in the brain. The foetal brain has limited antioxidant defenses, making it particularly vulnerable to oxidative damage.⁸

Neurodevelopmental outcomes in foetal hydantoin syndrome

Foetal hydantoin syndrome can affect cognitive, psychomotor and speech abilities in the infant due to the deleterious effects of phenytoin on the developing brain of the foetus.⁹ 

Cognitive development

• IQ levels and intellectual disability: children with foetal hydantoin syndrome often have IQ levels below the average for their age. The exact severity of intellectual disability varies case by case¹⁰ 
• Specific learning disabilities: many children with foetal hydantoin syndrome experience dyslexia and dyscalculia

Language and communication

Delayed speech: Verbal skills are often delayed in children with foetal hydantoin syndrome, meaning that these children start to speak later than their peers and do not achieve language-related milestones at the same rate as healthy children.

Motor skills and coordination

The cerebellum is an area of the brain crucial for balance and motor coordination. Phenytoin exposure can lead to cerebellar hypoplasia, where the cerebellum is smaller than normal due to a lack of functioning neurons.¹¹ As a result, cerebellar hypoplasia causes delays in milestones such as sitting, crawling, walking, and running due to difficulties with balance and coordination.

Diagnosis of foetal hydantoin syndrome

Healthcare providers diagnose foetal hydantoin syndrome at birth or during early childhood when the child displays signs characteristic of the condition, such as those mentioned previously. Healthcare providers will use the biological mother’s medical history, especially to check for phenytoin use, to aid with the diagnostic process. There are no diagnostic tests specific to foetal hydantoin syndrome, so diagnosis relies on clinical observation and medical histories.

Prognosis and long-term outcomes

The prognosis and long-term outcomes for those with foetal hydantoin syndrome are influenced by the severity of their physical and cognitive impairments. Despite many affected individuals facing significant challenges, early intervention, tailored educational programs and consistent medical care can improve outcomes and enhance quality of life.

Learning disabilities

Persistent learning disabilities, such as difficulty reading, writing, and doing mathematics, often require special education services and tailored learning strategies throughout schooling. Such difficulties are long term, but these children may be entitled to reasonable adjustments such as extra time during school exams.

Motor development 

Delays in gross and fine motor skills can continue to affect daily activities and occupational tasks. Physical and occupational therapy can help improve motor function but are unlikely to resolve all issues.

Coordination and balance

Persistent issues with coordination and balance can impact participation in sports and other physical activities, potentially leading to a preference for less physically demanding hobbies.

Speech and language

Speech and language delays may improve with therapy but can continue to affect social interactions and academic performance. Some individuals may require long-term speech therapy.

Summary

• Foetal hydantoin syndrome is caused by taking phenytoin during pregnancy
• It is important that a pregnant woman does not stop taking phenytoin unless advised to by a healthcare provider, because the return of seizures can also be damaging to both the foetus and the pregnant person
• Foetal hydantoin syndrome does not affect all foetuses exposed to phenytoin
• Phenytoin can impair neurodevelopmental outcomes in the child, due to the impact of phenytoin on the developing brain of the foetus
• The severity of the syndrome varies case by case
• Phenytoin can cause issues with coordination and development, IQ, language, communication, and difficulties in learning
• The neurological deficits are irreversible. However, functions such as speech and coordination can be improved through therapy. Additionally, educational support can be provided to support the patient with any learning difficulties experienced