Introduction

Definition of foetal hydantoin syndrome (FHS) 

Foetal hydantoin syndrome (FHS) is recognised as a spectrum of defects associated with in-utero exposure to any hydantoin product or derivative.¹ In this case, the most available hydantoin product used in medicine is phenytoin, which is primarily used as an antiepileptic drug (AED).¹

Overview of phenytoin and its ise as an anticonvulsant 

Antiepileptic medications are used to treat epilepsy as well as a broad range of other medical conditions, including bipolar disorder, migraines, and neuropathic pain.² Most women with epilepsy still require the use of antiepileptic drugs (AEDs) to control their seizures during pregnancy.² These medications include phenytoin or phenytoin derivatives which are derived from the hydantoin component and are primarily used to treat epilepsy, with minimal sedative effects.²  

Teratogenic effects of phenytoin on foetal development

Irrespective of the route of administration, phenytoin has been shown to have adverse effects on the embryo, thereby compromising the embryogenesis process.

Importance of studying cardiac defects in FHS 

Prevalence and clinical significance 

Cardiac malformations are the most common abnormalities observed as a result of in-utero exposure to AEDs, followed by hypospadias and facial clefts, which are also among the most common congenital anomalies in the general population.² FHS affects both genders equally.³ The exact prevalence of FHS is unknown, but studies indicate that approximately 10-15% of infants exposed to phenytoin during pregnancy will develop FHS.³

Overview of cardiac development and potential disruptions

Prenatal exposure to anticonvulsant/antiepileptic drugs has a teratogenic effect on humans, leading to the appearance of congenital malformations in their offspring.⁴

An overview of FHS

Mechanism of action of phenytoin 

Phenytoin readily transfers across the placenta, either from maternal or foetal circulation and accumulates in placental tissue.⁵ 

Phenytoin has a direct action on cardiac ion channels. Phenytoin has the potential to block the three ion channels (sodium, potassium, and calcium) involved in generating cardiac action potentials in embryos.⁶ The blockage of any one of these channels places the embryo at risk of embryonic bradycardia, as observed with in vitro phenytoin.⁶

Phenytoin also interferes with the body's ability to absorb folic acid, which is a vital component in embryogenesis. The inadequate folic acid supply increases the risk of major developmental abnormalities.⁷

Teratogenic potential and risk factors 

The risk of developing oral clefts and cardiac defects in cases of hydantoin exposure is five times higher than for other abnormalities.⁷ Irrespective of the route of administration of phenytoin, it has adverse effects on the embryo. Despite our awareness of phenytoin’s teratogenic effects, the exact mechanism remains unknown.² However, it is believed that an arene oxide metabolite produced by cytochrome P450 enzyme activity during the bioactivation of phenytoin may be the potential teratogenic molecule.² The teratogenicity of phenytoin can also be influenced by different environmental variables, which may increase the possibility of damage to the developing embryo.² Of note, there is no safe dose of any AED taken during pregnancy which can provide therapeutic efficacy without potential developmental risk to the infant.² 

Clinical features (foetal hydantoin syndrome)

Craniofacial abnormalities 

• Cleft lip: A gap or cleft in the tissue of the upper lip.
• Cleft palate: A gap or cleft in the tissue of the palate.
• Crossed eyes (strabismus)
• Large, wide mouth
• Malformed ears
• Drooping eyelids (ptosis)
• Microcephaly 

Limb defects

• Skeletal malformations of the fingers and hands 
• Underdeveloped fingers and toes
• Toes resembling fingers (digitised toes)
• Underdeveloped toenails and fingernails

Developmental delays

Growth deficiencies: Infants may be smaller than expected at birth due to growth deficiencies during development. The severity can range from mild to moderate and may continue into the newborn period.³

Cardiac anomalies: Anomalies such as congenital heart defects and cardiac rhythm disturbances can be found in people with FHS. 

Ventricular septal defect (VSD) 

Ventricular septal defect (VSD) is a common condition present at birth in many children, while in adults, it is typically secondary to heart attacks. Phenytoin intake/use during pregnancy increases the risk of developing VSD.⁸ The incidence of VSD in newborn children is approximately 0.3%. A curved wall called the interventricular septum separates the two ventricles of the heart. When this septum fails to develop and fuse, it results in the formation of a shunt or hole.⁸ VSD results from an abnormal communication between the right and left valves thus developing a shunt/hole formation.⁸ Though very common, spontaneous closure of the shunt or hole is observed in many cases, though some cases progress to become severe.

Atrial septal defect (ASD)

This occurs when the communication between the right and left atria fails to close. This allows for defects resulting in a lack of communication between the right and left atria.⁹ Small defects have the potential to close up spontaneously. However large defects may need surgical intervention to close the communication between the two atrias and prevent further complications.

Tetralogy of fallot (TOF)

It describes a cardiac defect characterised by a combination of 4 anatomical alterations of large a ventricular septal defect which is misaligned anteriorly, the presence of an overriding aortic root (which causes right ventricular hypertrophy) and narrowing of pulmonary and subpulmonary valves.¹⁰ In children and neonates TOF causes cyanosis clinically.

Patent ductus arteriosus (PDA)

The ductus arteriosus is a foetal vessel that allows oxygenated blood from the placenta to bypass the foetal lungs in utero.¹¹ The ductus arteriosus functionally closes up 12-24 hours after birth in healthy and full-term babies with permanent closure obtained after 3 weeks.¹¹ The inability of the vessel to close naturally causes the patent ductus arteriosus situation which will require surgical closure alongside pharmacological intervention to manage the side effects.¹¹

Pulmonary stenosis 

Pulmonary stenosis is any obstruction to the right ventricle outflow into the pulmonary bed.¹² Pulmonary stenosis can be isolated but is most commonly associated with congenital cardiac defects.¹³ Stenosis is typically categorised into three levels: mild, moderate, and severe.

Less common cardiac defects

Coarctation of the aorta

This refers to the congenital narrowing of the proximal thoracic aorta. In neonates, this can occur with heart failure, or shock resulting from closure of the ductus arteriosus. Prenatal diagnosis of coarctation is challenging due to limited blood flow across the aortic isthmus and the presence of the ductus arteriosus.¹⁴

Transposition of the great arteries (TGA) 

This originates from the discordance between the aorta and pulmonary trunk during embryology causing the aorta to arise from the right ventricle and the pulmonary trunk arising from the left ventricle resulting in two parallel circuits not compatible with life.¹⁵ Complete transposition of the great arteries is also known as the d-TGA where d stands for dextroposition of the bulboventricular loop.¹⁶ D-TGA is one of the most common cyanotic heart defects observed in newborns, leading to a reversal of the typical blood flow pattern

Pathophysiological mechanisms

Effects of phenytoin on foetal cardiac development 

Phenytoin is known to induce embryonic arrhythmia through its capacity to inhibit potassium ion channels, leading to hypoxia and subsequent regenerative damage. It also has the potential to reduce the embryonic heart rate by crossing the placenta in sufficient amounts to cause bradycardia in the embryo.⁶

Diagnostic approach

No diagnostic approach is available in testing for FHS, however, a clinical diagnosis can be made by identifying individual symptoms affecting the infant in association with a history of AED (especially phenytoin) used during pregnancy.³

Prenatal diagnosis 

This can  be done during the period of the pregnancy through routine obstetric appointments, especially from the second trimester

Ultrasonography

Used to understand foetal cardiac anatomy and physiology, thus improving management and prognosis of congenital heart defects.

Foetal Echocardiography 

Has been in use since 1980 and can detect congenital heart defects in utero.

Postnatal diagnosis 

Physical examination and clinical presentation 

• Presence of unusual heart murmurs 
• Dyspnoea 
• Fatigue 
• Chest pain

 Imaging studies 

• Chest x-rays: checks for abnormally large hearts
• Electrocardiogram: Identifies signs of enlarged left ventricle (left ventricular hypertrophy)
• Transthoracic echocardiography: Very sensitive and can provide details such as size, location, number of defects and also information about the hemodynamics of the heart functions⁸
• Cardiac magnetic resonance imaging is used in cases with complex heart anatomy which is hard to visualise by the other conventional methods⁸

Genetic testing and counselling

Counselling helps to prepare expectant mothers and discuss the risk of seizures in the development of their embryos. 

Management and treatment

Treatment of FHS is tailored to the symptoms of the individuals. Since the FHS is congenital malformations it might require a multidisciplinary team in the treatment planning and process.

Infants with FHS can benefit from early interventions and treatment enabling the child to attain their potential.

Risk assessment and alternative anticonvulsant therapies 

Most pregnant women with epilepsy are advised to use a single treatment (monotherapy) throughout the pregnancy period as the use of multiple AEDs has a significant risk for development anomalies in utero.³ Moreover the use of phenytoin should always be associated with folic acid intake.

Monitoring foetal development 

This can be scheduled in three ways:

• Early pregnancy: Involves genetic checkups and identifying malformations. This can be achieved by invasive or non-invasive methods
• Non-invasive assessment involves cell foetal cell-based assessment and cell-free foetal DNA assessment¹⁷
• Invasive methods, such as amniocentesis, are typically used as confirmatory tests following non-invasive testing
• Late pregnancy: Interventions here are mainly to prevent foetal death. A large variety of technology is employed such as Doppler ultrasound, and Cardiotocography all are aimed at assessing foetal heart rates¹⁷
• Labour assessment: involves blood sample of the foetal skull
• Medical treatment in some cases is optional

Surgical interventions 

Most surgical interventions aim at closing the communication existing in the heart or aim to improve management and a better life without completely getting rid of the problem.

• Surgical interventions are used to close communication between the right and left atria, right and left ventricles, and closure of the PDA¹⁸
• Balloon pulmonary valvuloplasty (BPV) is a palliative treatment for children with TOF and is also used for cases of pulmonary stenosis¹⁸
• Surgical valvotomy: this used to be the treatment of choice before the BPV procedure which is less invasive¹⁸
• Surgical valve replacement

Prognosis

Echography every 2-3 years helps to evaluate the structure of the heart and if the heart is functioning well.

Summary

Cardiac defects in FHS is a rare syndrome affecting children exposed to phenytoin or its derivatives in utero. Most complications resulting from FHS can resolve on their own, though others can progress to severity. It is important to prioritise monotherapy of AED  during the full term of pregnancy and complement medications with folic acid supplement which is an important factor in embryogenesis.