Congenital Heart Defects Associated With Fetal Valproate Syndrome

Introduction

Fetal Valproate Syndrome consists of a spectrum of symptoms that can occur to a developing fetus if exposed to valproic acid.

Valproate acid is a known medication used to treat various neurological and psychiatric disorders most commonly epilepsy.

It is normally contraindicated for pregnant mothers to take valproic acid. If for any reason the mother was taking it during pregnancy, valproic acid can cross the placenta and attain fetal blood circulation. 

The Fetal valproate syndrome is associated with skeletal malformations, orofacial clefts, urogenital malformations, neural tube defects, congenital heart diseases, neurodevelopmental delay and autism spectrum disorder.¹

With a 10% risk of a major malformation or 30–40% with a neurodevelopmental disorder,² fetal valproate syndrome can to a considerable extent affect the quality of life of infants born with this disorder and their families.

In this article, we will focus on the congenital defects associated with fetal valproate syndrome.

Congenital heart defects in fetal valproate syndrome

One of the consequential teratogenic effects of valproic acid is congenital heart defects. They can present in various types and can affect to a great extent the overall health of the child and his quality of life. The increased risk of developing heart defects in the fetus is increased with first-trimester exposure to sodium valproate.³

Types of congenital heart defects associated with FVS

Atrial septal defect (ASD)

The human heart is a vital organ composed of four chambers. It consists of two atria and two ventricles. 

Blood flows from the right atrium to the right ventricle through the mitral valve and from the left atrium to the left ventricle through the tricuspid valve. 

The atrial septal defect occurs when there is a defect in the closure of the communication between the left and right atria. Small atrial septal defects go unnoticed but large ones can cause symptoms such as palpitations, cardiac dysrhythmias, pulmonary hypertension and increased mortality.⁴

Usually small ASD close spontaneously but larger ones require closure through surgery.      

Ventricular septal defect (VSD)

A ventricular septal defect is a heart condition with an abnormal defect between the right and left ventricles. This will allow blood from the right ventricle to mix with the left ventricle.

The right ventricle contains deoxygenated blood coming from the body and the left ventricle contains oxygenated blood coming from the lungs destined to supply the body with oxygenated blood. Small defects usually close spontaneously but large defects will require surgical intervention. These defects result in the mixing of oxygenated and deoxygenated blood. It also leads to a decrease in the quantity of oxygenated blood destined to supply the whole body. 

Large defects can also lead to complications such as pulmonary hypertension, ventricular dysfunction and an increased risk of cardiac dysrhythmias.⁵

Tetralogy of fallot (TOF)

Tetralogy of Fallot is a heart malformation with four different defects t: an overriding aorta, ventricular septal defect, right ventricular outflow obstruction and right ventricular hypertrophy. It produces an alteration in the normal blood flow in the heart and the whole body.

Tetralogy of Fallot can be diagnosed before birth with an ultrasound. After birth, babies with tetralogy of Fallot can develop cyanosis, and blue colouration of their skin due to the decreased level of oxygen in their blood. It is usually diagnosed early in childhood as it can lead to obvious symptoms such as bluish discolouration of the skin, shortness of breath, getting tired easily and trouble gaining weight.⁶

Other less common defects

Pulmonary valve atresia 

The pulmonary valve t is present between the right ventricle and the main pulmonary artery. It prevents the backflow of blood from the pulmonary artery to the right ventricle. Pulmonary valve atresia is a condition in which the pulmonary valve does not develop.  There is an obstruction of blood flow from the right ventricle to the pulmonary artery. 

Symptoms develop early and include bluish discolouration of the skin, poor feeding and breathing problems. Treatment can include surgery during which doctors create a passage for blood between the right ventricle and the pulmonary artery. ⁷

Hypoplastic right heart

The hypoplastic right heart is a very rare heart malformation in which structures of the right heart (right ventricle, tricuspid valve, pulmonary artery) are underdeveloped which leads to decreased blood flow to the heart and this affected heart cannot dispense a satisfactory amount of blood to the body. This disorder is commonly associated with atrial septal defect.⁸

Prevention and risk mitigation

Prevention of fetal valproate syndrome is a paramount aspect to consider. 

Considering the severity of the effects fetal valproate syndrome can cause accounting for physical, and neurodevelopmental delays which include congenital malformations, cognitive impairment and increased risk of autism spectrum disorders. Fetal valproate syndrome can greatly affect the quality of life of the child and his family.

Here are some aspects we should consider to prevent fetal valproate syndrome occurrence:

Alternatives to valproate during pregnancy

The management of fetal valproate syndrome by switching to a safer medication before pregnancy. This requires a multidisciplinary approach where obstetricians and neurologists should be involved in the choice of the most suitable medication and its doses during pregnancy. 

Folic acid supplementation can be very helpful as folic acid is known to decrease the risk of many complications, especially neural tube defects.⁹

Counselling and risk assessment

Counselling and risk assessment of fetal valproate syndrome is an essential part of preventing it. 

Patient education is of utmost importance. All women of childbearing age taking valproic acid should be educated and provided with clear and understandable information about fetal valproate syndrome. They should be made aware of the prevention by exploring alternate drug options if planning for a pregnancy.. They should also be properly informed about effective contraception plans if not planning a pregnancy.

This can be achieved by offering genetic counselling for more detailed risk assessment and discussing and exploring the potential genetic factors that may predispose to fetal valproate syndrome.

Summary

Congenital heart malformations are a consequential concern in Fetal Vaproate Syndrome. Affectation of the heart which is one of the most vital organs in the human body, congenital heart malformations account for one of the most serious potential outcomes of this syndrome.

Although not very common, Fetal Valproate Syndrome should be taken seriously. 

Prevention and risk mitigation are among the most important actions to be taken in the management of FVS and compromise a thorough education on the syndrome, the potential dangers of sodium valproate during early pregnancy and potential long-term effects on the affected individual. Management should also include a multidisciplinary team involving neurologists, obstetricians and paediatricians in the care plan.

Also, an emphasis should be put on clinical research of FVS and congenital heart malformations to better understand the risks and to enable better prevention strategies.

FAQs

Can FVS be diagnosed before birth?

Yes, fetal valproate syndrome can be diagnosed before birth. By ultrasound, a healthcare professional can detect fetal anomalies in the heart and other organs which may suggest FVS. 

Also, the detection of alpha fetoprotein, a tumour marker in the maternal serum and a history of valproic acid usage during the pregnancy can be highly suggestive of a fetal affectation.

Are there alternatives to valproic acid for women desiring fertility?

Yes, there are alternatives to sodium valproate which can be safer during pregnancy. Women taking valproic acid should be acknowledged for the teratogenic effects of this drug and should be advised to discuss it with their healthcare professionals when planning a pregnancy. Depending on her condition, an alternative drug should be prescribed to her.

Does the dose of sodium valproate acid matter?

Yes, taking higher doses, especially during the first trimester of pregnancy is associated with higher risks of fetal affection.

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Sadie Mahamat Habib Doutoum

MBBch, Obstetrics & Gynecology resident, Stellenbosch University

Sadié is a Medical Doctor and is currently specializing in Obstetrics & Gynecology.

She has several years of clinical experience and is also passionate about medical writing. Sadié uses her medical background to write understandable and engaging medical content to educate and empower people.

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