Introduction

Fetal retinoid syndrome (FRS) is a rare condition which results in physical and mental birth defects (known as congenital anomalies) in foetuses when they are exposed to retinoids throughout the pregnancy period. Retinoids are a type of synthetic (man-made) derivatives of Vitamin A, which are a key ingredient in the production of skincare products. They are prescribed by a healthcare provider after a thorough consultation and may target:^1,2

• Acne
• Hyperpigmentation
• Psoriasis
• Keratosis pilaris
• Improving fine lines and wrinkles
• Improving skin texture

In the UK, it has been reported that 1 in every 45 babies was born with one or more confirmed congenital anomalies in 2020.³ Expecting mothers are advised by their GP to stop taking oral medications that contain retinoids, especially isotretinoin. This is due to the broad range of symptoms that babies exposed to retinoids in the prenatal stage may experience. These include developmental disorders, skeletal deformities, and heart defects. Therefore, it is crucial to minimise retinoid intake to ensure a healthy development for your baby.³

Retinoids

Retinoids are a class of chemicals that share structural and functional similarities with vitamin A. Because of their numerous skin advantages and anti-ageing characteristics, retinoid compounds are frequently used in cosmetics. Some of the functions include:^2,4

• Improving the skin’s elastic barrier and its function
• Stimulating the formation of new blood vessels in the skin by neutralising free radicals
• Decrease water loss 
• Reduce the loss and degradation of collagen by frequently interacting with it

Types of retinoids

Retinoid consists of different 4 types of groups:

• Retinaldehyde
• Retinol
• Retinyl esters
• Retinoic acid

Retinoic acid is the only form that our skin can absorb. Hence, to benefit from the others, they must first be converted to retinoic acid directly on the skin's surface, and the more steps it takes to convert, the weaker it will be. Although there are many different types of prescribed retinoic acid, the common ones you may have heard of are: tretinoin and isotretinoin.

Neurocognitive damage has been found in 30% to 60% of prenatally exposed children for mothers who take isotretinoin. Even if the medicine is taken for a short period, there is a possibility that the baby will have a birth defect if this occurs during the first semester (this is when the foetal organs are growing and developing).⁵

Symptoms

Symptoms for FRS vary with each individual. Some babies may be born as stillborn, be miscarried, have a birth defect, or have minimal effect. It is estimated that 20 to 35% of foetuses exposed to retinoids throughout pregnancy will have developed birth defects. These defects may include the following.¹

Cranial Abnormalities

Craniosynostosis

One common type of cranial abnormalities at birth is craniosynostosis (kray-nee-o-sin-cos-TOE-sis), where one or more of the cranial sutures (these are the fibrous connections that connect the bones of the baby's skull) close early or fuse before the baby's brain is fully developed. 

Consequently, the brain continues growing, which makes the head appear malformed. Surgery is used to treat craniosynostosis to reshape the skull and promote brain growth.⁶

Microcephaly

When a baby's head size is smaller than that of an average-sized head, the condition is known as microcephaly. It may transpire due to inadequate development in the womb or a lack of growth after birth. In severe cases, microcephaly poses health risks, including:⁷

• Seizures
• Unable to swallow during a feed
• Vision and hearing problems 

Others

Other craniofacial abnormalities may consist of:

• Vascular malformation: abnormal development of blood vessels 
• Cleft lip and palate: when the tissues of the mouth have not been formed properly, leading to a gap or split in the upper mouth or roof 
• Craniofacial microsomia: tissues on half of the face are underdeveloped 

Central nervous system abnormalities

Some birth defects which occur in the central nervous system (CNS) include:⁸

• Hydrocephalus: excess fluid around the brain 
• Intellectual disabilities: limitations in cognitive functions and other skills
• Spina bifida occulta: this is referred to when the spinal cord is not fully developed during pregnancy
• Agenesis of the corpus callosum: characterised when the corpus callosum, a structure that connects the two parts of the brain, is partially or completely missing 

Cardiovascular defects

Cardiovascular refers to your heart and blood vessels. Congenital defects in this region can pose life-threatening risks, especially if your baby has difficulty breathing. In the majority of cases, determining cardiovascular defects is difficult. Doctors may perform foetal echocardiography to look for any severe issues with the developing baby's heart walls and valve with a limited view. Among the defects are the following:⁹

• Septal defects (also known as "holes in the heart"): when there is a gap between two of the heart's chambers
• Coarctation of the aorta: when the aorta, the body's major artery, is narrower than usual
• Underdeveloped heart: this prevents sufficient blood from pumping around the chambers of the heart or the lungs
• Transposition of the great arteries: when the pulmonary and aortic valves and arteries they attach to are reversed 

Skeletal malformations

Skeletal abnormalities refer to deformities in the limbs i.e. one leg might be bigger compared to the other leg, or the arms may not be proportionate to the rest of the body. Some components in these limbs may be underdeveloped or completely missing.¹⁰

Diagnosis of FRS

Throughout your pregnancy, you will be expected to attend antenatal screening to monitor the general health of your baby. Your doctor may perform imaging techniques to detect any abnormalities; one of which is the prognosis of FRS and its symptoms. 

FRS might appear as delays in the development of the foetus’ body, indicating that you will need to have blood tests to check for the likelihood of carrying a child with particular birth problems, particularly in the central nervous system and in the cardiovascular system. Your doctor may also check for your medical history and conduct genetic testing to rule out any other diagnoses. 

Prenatal diagnosis can help parents emotionally prepare for a child with a birth defect, even if it typically does not result in a cure for the baby's problem. 

In other instances, a physical examination or a blood test that checks for several illnesses in newborns is used to detect birth abnormalities after delivery.¹¹

Prevention

The consumption of retinoid capsules is strictly prohibited during pregnancy due to the severity of birth abnormalities that a newborn may acquire after being exposed to them. 

Pregnancy should be avoided until isotretinoin treatment has stopped its course. Contraceptive methods should be maintained for a minimum of one month following the end of retinoid therapy to prevent any aftermath. You will be tested for pregnancy regularly throughout the treatment. However, if you do get pregnant during this period please seek your healthcare provider.¹²

It is worth noting that in men taking isotretinoin, the sperm is minimally affected but not enough to cause any harm to the baby.¹³

Treatment

The treatment of FRS is tailored to specific syndromes and disorders that each baby has. The extent of these side effects depends on the duration of retinoid exposure and how potent it is. A group of specialists may need to work together to organise the course of treatment. Treatment for an affected child may need to be planned carefully and thoroughly by paediatricians, surgeons, cardiologists, audiologists, eye consultants, and other medical professionals. Additional therapies may be recommended by your doctor. 

Summary

Fetal retinoid syndrome is a rare disorder that arises when the foetus in the womb is exposed to retinoids, resulting in congenital defects. Retinoids are vitamin A derivatives which can be used to treat severe acne and boost collagen production. Serious birth defects, such as craniofacial deformities, anomalies of the central nervous system, heart defects, and skeletal malformations, can result from prenatal exposure, especially during the first trimester. FRS can be avoided by abstaining from retinoid usage throughout pregnancy, and with guidance from healthcare experts, receive strict guidelines during retinoid treatment.