What Is Fetal Hydantoin Syndrome?

Introduction

Fetal hydantoin syndrome (FHS) is a complex disease that consists of a distinct pattern of physical and developmental differences that can affect babies when their mothers take certain anticonvulsant medications during pregnancy.^1,2 These medications are used to manage seizures, but they can have adverse effects on a baby's development in utero.^1,2 FHS is not a single symptom, but a collection of traits that vary from one child to another.^1,2

Importance of understanding fetal hydantoin syndrome

Expectant mothers should be made aware of the potential risks of using certain anticonvulsant medications during pregnancy. It is essential to make informed decisions and work closely with healthcare providers to ensure the well-being of both the mother and the developing baby. For the general public, awareness of FHS helps promote support for families dealing with this condition. By learning about FHS, we can collectively contribute to a more empathetic and supportive environment for the individuals and their families experiencing this condition. 

Causes of fetal hydantoin syndrome

Fetal hydantoin syndrome can occur when a developing baby is exposed to certain anticonvulsant medications while in the womb, most notably, phenytoin.^1,2 These medications are used to manage seizures in adults but when taken during pregnancy, they can sometimes result in a baby affected by FHS.^1,2

Maternal seizures

It has been proposed that in addition to the anticonvulsants, the developmental problems observed in babies with FHS could be linked to seizures the mother experiences during pregnancy.¹ The stress caused by seizures might negatively impact a baby's development.¹ 

Medication effects

Phenytoin is a common anticonvulsant used to treat epileptic seizures. However, this drug can also be teratogenic meaning it can negatively affect fetal development. This drug is commonly linked to FHS as it is estimated that 11% of pregnant people taking phenytoin will have babies with FHS.¹ Many children with FHS will only suffer from mild impairments with no severe effects, but the extent of the disease varies substantially.¹ It is likely that the dosage used, and the specific mix of anticonvulsant medications used can cause these wide variations in the disease presentation.¹ Other medications like barbiturates and carbamazepine can also play a role.¹ 

Epoxide hydrolase

When phenytoin and similar medications are used, they produce substances called epoxides which cross the placenta to the developing baby.¹ These substances can react and interfere with development which can impair fetal growth.¹ Epoxide hydrolase, a molecule in the body, helps break down reactive epoxides into safer forms.¹ In babies exposed to medications linked to FHS, there are lower levels of epoxide hydrolase which means that more reactive epoxides are present, that can interfere with development.¹

Possible genetic influence

It is also believed that some babies might have genetic differences that affect how well their bodies break down epoxides.¹ This could make them more susceptible to the harmful effects of these substances. Some research indicates that specific genes related to epilepsy might increase the chance of FHS.¹ These genes could be passed from the epileptic mother taking anticonvulsants to the child, increasing the risk of FHS. However, further research is needed to determine the role of epileptic genes in FHS development.

Other mechanisms

In addition to the epoxide-related theory, other mechanisms might also be at play. Some researchers have looked into the impact of disturbances in folate metabolism or specific homeodomain transcription factors, both of which have been shown to influence how babies develop in utero.¹

Signs and symptoms

FHS is associated with a range of physical and developmental differences that can vary significantly from one child to another. While some effects may not be apparent at birth, they may become more pronounced as the child grows.² Not all children with FHS express the same symptoms and likely will not present with all possible symptoms.^1,2 If you have concerns about your child's development or if they present with any of these features, it is advisable to speak to a medical professional. A doctor can provide guidance and support based on you and your child's unique situation.

Physical features

• Facial structure: Children with FHS might have unique facial features, including  a flat and broad bridge of the nose, a shorter than usual nose, and eyes that are farther apart than usual.^1,2
• Eyes and mouth: Some children may have crossed eyes, droopy eyelids, and/or a large mouth.² They might also have a gap (cleft) in the upper lip or roof of the mouth, known as a cleft lip or cleft palate.²
• Toes and fingers: The fingers and toes might be stiff and tapered, or their toes might more closely resemble fingers.² Nails on the fingers and toes may also be underdeveloped or misshapen.²
• Additional features: Some infants could have extra body and facial hair and they might also have more fingerprint arches on their hands.²

Developmental delays

• Growth issues: Babies with FHS might be smaller at birth due to growth problems which can be mild to moderate.²
• Learning milestones: Some infants and children might take longer to reach developmental milestones like sitting up or crawling.² Children usually catch up as they grow older but they may still be a bit behind their peers.²
• Intellectual challenges: In some cases, children with FHS might have mild intellectual and learning difficulties.² They may find certain things harder to understand or learn than other children their age.²

Other possible symptoms

• Head size: Their head might be smaller than expected (microcephaly).²
• Behavioural differences: Some children might exhibit neurodivergent behaviours, such as attention deficit hyperactivity disorder (ADHD).²
• Heart and kidney: In some cases, children could be born with heart problems or kidney abnormalities.²
• Hernias: Children might also have hernias, which are when parts of the intestines push through muscles in the stomach or near the belly button.²
• Possible tumour risk: There have been suggestions that children with FHS might have a slightly higher chance of developing certain cancerous tumours, like neuroblastoma or Wilms tumour, but further research needs to be conducted to test this theory.²

Diagnosis 

There is no specific test to confirm FHS. Diagnosis is based on a medical professional identifying the above features in the affected child in combination with taking a medical history of the mother to determine if phenytoin or other causative drugs were taken during pregnancy.²

Prevention and risk management

Balancing maternal health with potential fetal risks

Although anticonvulsants, specifically, phenytoin, are the principal cause of FHS, there are considerable risks to the mother and the baby if these medications are stopped, as these drugs are required to treat epileptic individuals and prevent damaging seizures.^3,4 Some types of seizures, like focal awareness, focal impaired awareness, absence, or myoclonic seizures, generally do not harm a developing baby.⁴ However, there is a risk of the mother being injured during a seizure, which can have harmful effects on the mother or the fetus.⁴ Tonic-clonic seizures might have a more severe impact than other types of seizures and could lead to a miscarriage or severe problems for both the mother and the unborn baby.⁴ Although it is rare, there have been cases where pregnant individuals with epilepsy have passed away during pregnancy because their seizures were poorly controlled.⁴

To protect both the mother and the unborn child, it is essential to avoid seizure activity, particularly during pregnancy.⁴ Taking prescribed medications as directed is a crucial step to controlling seizures.⁴ Also, it is essential to inform your healthcare provider of any seizures or seizure disorders to ensure they provide the best care and support.⁴

Alternatives to phenytoin during pregnancy 

As it would be unsafe for a mother to stop epileptic treatment during pregnancy, there are several alternatives to phenytoin that can be used to prevent seizures. For some people, the solution could be as simple as using milder antiepileptic drugs such as lamotrigine or leveraticam, which are safe for use during pregnancy.⁵ However, these might not provide adequate seizure control for everyone, depending on the severity of their seizure disorder.³ Therefore, phenytoin and/or other anticonvulsants might have to be used.³ Many anticonvulsants, such as sodium valproate or carbamazepine, are equally or even more teratogenic than phenytoin.⁵ Therefore, the choice of medication used during pregnancy should be carefully considered, to minimise the risk of a seizure in the mother whilst avoiding FHS in the developing infant. Phenytoin and other anticonvulsants linked to FHS should be used as a last resort during pregnancy due to the risks they present to a developing fetus.³

Importance of communication with healthcare providers 

To accurately weigh the risks and benefits of using phenytoin or other anticonvulsants during pregnancy, it is necessary to seek medical advice and see a specialist if necessary.³ It is essential to have a clear view of your priorities when assessing epilepsy treatment options when you are trying to conceive or expecting, as there could be negative implications for you or your child’s health.

Folic acid 

Individuals taking phenytoin should consider taking folic acid supplements before and throughout pregnancy.^1,2,3 This can help lower the risk of FHS and the above-mentioned birth abnormalities.^1,2,3

Managing FHS: Early interventions

Multidisciplinary approach to care 

When treating FHS, the focus is on addressing each child's specific challenges.² This often involves a team of caring specialists such as paediatricians, surgeons, neurologists, psychologists, and others, all working together to create a comprehensive plan for the child's care.²

When there are challenges like cleft lip or palate, a team of experts will work together to plan treatment and rehabilitation.² Sometimes, surgeries can correct cleft lip and are often performed when the child is  young.² Additional procedures might be done later for cosmetic reasons.² A cleft palate can also be treated by using a special device (prosthesis) to cover or block the opening.² The specific treatment approach will depend on the severity of the condition.²

Through a combination of medical care, therapies, and the support of dedicated specialists, children with FHS can be given the best chance to grow and thrive in a supportive and caring environment.

Cognitive and behavioural challenges

For infants with FHS, early intervention is key. This means providing help as soon as possible to ensure these children can reach their full potential. They might benefit from occupational, physical, and/or speech therapy.² Different therapies focused on rehabilitation and behaviour could also be very helpful.² Additional social or vocational services might be needed to support their growth and development.²

Support for families and caregivers

In addition to supporting the child with FHS, the family could also benefit from emotional and practical help. Providing psychosocial support and raising awareness of FHS is crucial to help everyone through this journey.

Summary 

Fetal Hydantoin Syndrome (FHS) presents a distinct pattern of physical and developmental variations that arise when expectant mothers take phenytoin or similar anticonvulsant drugs during pregnancy.^1,2 Although intended for seizure management, these drugs can inadvertently lead to developmental challenges for the baby.^1,2 FHS encompasses a range of traits unique to each child.^1,2 Expectant mothers need to understand the potential risks associated with specific anticonvulsants during pregnancy, enabling informed decisions in collaboration with healthcare providers. The complex interplay of maternal health, genetics, and medication effects shapes the origins of FHS, creating challenges for the baby's development.^1,2 While our understanding evolves, we uncover new ways to mitigate these risks and offer comprehensive support to affected families. Early interventions, expert care, and family support give children with FHS the best chance to live a normal live.²