Retinoic Acid Embryopathy - An Overview

Introduction

Retinol, also known as Vitamin A, is derived from plant sources and animal products. The absorbed retinol is stored in the liver, from where it is supplied to the target cells. In those cells, through the oxidation process, retinol gets converted into its active form, retinoic acid. Retinoic acid is found in embryos as well as adults. Retinoic acid helps in cell growth and development. Retinoic acid is also known as isotretinoin.

What Is the Role of Retinoic Acid During the Development of an Embryo?

The reason behind this embryopathy is the ability of retinoic acid to cause abnormalities in the cephalic neural crest cells. Retinoic acid helps in embryonic development when its levels are optimal for growth. The different receptors present in the developing fetus recognize retinoic acid. After binding to the receptors, they regulate a group of genes called HOX genes, which control the baby's body shape. But when the levels of retinoic acid are in excess, there is a loss of genetic harmony, which results in physical and neural abnormalities in babies.

What is Retinoic Acid Embryopathy?

It is a congenital condition caused by the exposure of the developing fetus to teratogenic substances called retinoids. Retinoic acid is a man-made retinoid derivative of Vitamin A used to treat cystic acne and cancer. Females and males are equally affected. The exact incidence of the disease is unknown because of its rarity and lack of diagnosis.

What Causes Retinoic Acid Embryopathy?

Retinoic acid is used to treat cystic acne, a skin condition characterized by the accumulation of excess oil and dead skin cells deep within a hair follicle. It has the teratogenic property of causing fetal abnormalities when consumed by a pregnant woman. However, there is very limited information on the specific risk factors linked to the consumption of retinoic acid and on the exact dosage that can cause birth defects. Also, the time frame for when retinoic acid will potentially have the risk of teratogenicity is unknown.

What Are the Signs and Symptoms of Retinoic Acid Embryopathy?

This syndrome has effects on various organ systems. They are described as follows:

• Cardiovascular manifestations

  • Change of Position of Main Vessels of the Heart (Transposition): It is a rare heart condition where the position of two main arteries that carry blood from the heart is reversed. Blue-colored skin (cyanosis), poor weight gain, shortness of breath, and weak pulse are some of its symptoms.

  • Hypoplastic Left Heart Syndrome: It is a condition of incompletely and poorly developed left side of the heart. Grayish discoloration of skin and nails, fast heartbeat, feeding difficulties, a lack of energy, and sweaty, cool skin are some of its symptoms.

  • Ventricular Septal Defects: It means the presence of a cavity or hole between the heart's left and right ventricles. It causes fast heartbeat, fast breathing, fatigue, and frequent infections of the lungs.

  • Tetralogy of Fallot: It is a combination of four heart defects. They override the aorta, ventricular septal defect, pulmonary stenosis, and right ventricular hypertrophy. These conditions cause cyanosis, irritability, rapid breathing, easily tend to get tired, fainting, and failure to achieve normal weight and height according to age.

• Neural manifestations

  • Hydrocephalus: This is a condition where there is a build of excess cerebrospinal fluid in the brain spaces. This fluid accumulation puts pressure on the brain tissues. This causes enlargement of the head. Nausea, vomiting, seizures, lack of energy, sleepiness, eyes fixed looking downward direction, poor intelligence, delayed milestones like crawling, and prominent veins seen on the head region.

  • Holoprosencephaly: It is the impaired development of future forebrain prosencephalon. It might affect intellectual development and head size.

  • Microcephaly: It is the presence of a smaller head when compared to other babies of the same age. They have feeding difficulties, and babies have high-voiced cries, seizures, and trembling movements of hands and legs.

• Craniofacial manifestations

  • Microtia and Anotia: Microtia means both ears are placed inferiorly and are ill-formed. Anotia means completely missing ears. Hearing loss may also be present.

  • Stenosis of the Ear Canal: It is the external ear canals that are narrowed. It can lead to deafness.

  • Micrognathia: It is the underdevelopment of the lower jaw bone in size.

  • Ocular Hypertelorism: The horizontal distance between two eyes is greater than normal.

  • Cleft Palate: It indicated incomplete fusion of palatal bones leaving a hole in the roof of the mouth. Babies have feeding and talking difficulties if they have this birth defect.

  • Cleft Lip: There is a break in the lips of babies. Usually, the upper lip is affected.

  • Midface Hypoplasia: It is a condition of underdevelopment of lower jaw bones, cheekbones, and eye sockets.

  • Facial Nerve Paralysis:There is paralysis of the muscles supplied by the facial nerves. This causes muscle weakness on the face, inability to close eyes, salivate and produce tears.

  • Optic nerve abnormalities

• Other manifestations

  • Thymic Malformation: When the thymus doesn't grow the way it should, there is a decreased production of immune cells. So patients will get recurrent infections.

  • Muscle Hypotonia: Hypotonia means the loss of resistance to stretching in a muscle, leading to low tonicity and strength.

  • Anophthalmia and Microphthalmia: Babies born without eyes are said to have anophthalmia, and babies with one or two eyeballs decreased in size are said to have microphthalmia.

  • Syndactyly: The condition where fingers and toes are fused.

How Is Retinoic Acid Embryopathy Diagnosed?

• There is no specific diagnostic test for this birth defect.

• Clinical evaluation of the associated symptoms and a history of retinoic acid exposure by the mother during pregnancy confirms the diagnosis.

• Prenatal screening can be done using ultrasound to detect a malformed heart and central nervous system.

What Is the Treatment for Retinoic Acid Embryopathy?

The treatment plan is to manage the symptoms with the help of a coordinated team of pediatricians, oral surgeons, neurologists, cardiologists, otologists, audiologists, ophthalmologists, physiotherapists, occupational therapists, and other supportive healthcare workers. Unfortunately, since it is a congenital disease, there is no cure for this condition.

How Can Retinoic Acid Syndrome Be Prevented?

Although there is no cure for this embryonic defect, a few preventive measures can help avoid its occurrence.

• Women who are pregnant or planning to get pregnant should not take isotretinoin.

• Before taking isotretinoin therapy, women should insist on taking a pregnancy test. They should delay their pregnancy after retinoic acid therapy.

• Contraception should be taken for at least 30 days before the therapy. Also, women who have stopped taking retinoic acid should take contraception for 30 days.

• Women should look for an alternative treatment for acne instead of retinoic acid.

Conclusion

Retinoic acid embryopathy can be avoided by carefully planning a pregnancy and letting women know about the risks of taking this drug during the first trimester. There is a 35 percent risk of the fetus getting affected by this pathology if there is isotretinoin exposure for more than fifteen days following the formation of an embryo.