Fetal trimethadione syndrome

Overview

Fetal Trimethadione Syndrome (FTS) is a rare congenital disorder resulting from prenatal exposure to the anticonvulsant drug trimethadione, which was historically used to treat absence seizures. The syndrome is associated with a high risk of miscarriage, stillbirth, and a range of severe birth defects in surviving infants. FTS is considered one of the most teratogenic (harmful to fetal development) effects of antiepileptic drug exposure and is now rarely seen due to the decline in the use of trimethadione in favor of safer alternatives.

Causes

FTS is caused by fetal exposure to trimethadione or its active metabolite, dimethadione, during pregnancy. These substances cross the placenta and interfere with normal embryonic development. The drug’s teratogenic effects are most harmful during the first trimester, when major organs and structures are forming. Risk factors include:

• Use of trimethadione during pregnancy, particularly in the first 8–10 weeks of gestation.

• Higher dosage or prolonged use of the medication.

• Lack of alternative seizure control methods during early pregnancy in women with epilepsy.

Symptoms

Infants affected by Fetal Trimethadione Syndrome often display multiple congenital anomalies. Common features include:

Craniofacial Abnormalities

• Microcephaly (small head size)

• Midfacial flattening

• Short, upturned nose

• Low-set or malformed ears

• Cleft lip and/or palate

Growth and Developmental Issues

• Intrauterine growth restriction (IUGR)

• Failure to thrive after birth

• Developmental delays

• Intellectual disability

Organ Malformations

• Congenital heart defects

• Renal (kidney) anomalies

• Genitourinary malformations

Neurological and Skeletal Abnormalities

• Seizures

• Hypotonia (poor muscle tone)

• Limb malformations or joint contractures

Diagnosis

Diagnosis of FTS is based on clinical evaluation, prenatal drug exposure history, and the presence of characteristic congenital anomalies. Diagnostic steps may include:

• Maternal medical history: Confirmation of trimethadione use during pregnancy.

• Physical examination: Assessment of craniofacial, cardiac, renal, and skeletal features in the newborn.

• Prenatal ultrasound: May detect some malformations before birth, such as growth restriction or structural anomalies.

• Echocardiogram and renal ultrasound: To identify internal organ malformations.

• Genetic testing: Used to rule out other syndromes with similar presentations.

Treatment

There is no cure for Fetal Trimethadione Syndrome. Treatment is supportive and tailored to manage the specific anomalies and functional impairments. Management strategies include:

• Surgical correction: For cleft palate, heart defects, and other structural abnormalities.

• Developmental therapies: Including physical therapy, occupational therapy, and speech-language therapy.

• Educational support: Special education services for intellectual and learning disabilities.

• Medical management: For seizures and organ-specific complications.

• Multidisciplinary care: Coordination among pediatricians, cardiologists, neurologists, surgeons, and developmental specialists.

Prognosis

The prognosis for individuals with Fetal Trimethadione Syndrome is generally poor due to the severity of congenital anomalies and developmental impairments. Many affected pregnancies result in miscarriage or stillbirth. Surviving infants often face significant lifelong challenges, including physical disabilities, intellectual disability, and medical complications. Prevention is crucial, trimethadione should be avoided during pregnancy, and women with epilepsy should consult their healthcare providers for safer alternatives.