NORD gratefully acknowledges Mariana Bundra Todosiev, PharmD, RPh, and Dr. Kelly-Ann Eastwood, Academic Clinical Lecturer in Obstetrics and Gynecology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, for assistance in the preparation of this report.
Fetal retinoid syndrome is a pattern of mental and physical birth defects (congenital malformations) that can result from a mother taking retinoids during pregnancy. The absolute risk of congenital malformations following oral isotretinoin therapy is currently unclear. Overall malformation rates in live-born infants from prospectively reported pregnancies range from 5% to 20%.
Retinoids are the synthetic (man-made) forms of vitamin A used to treat various skin (dermatological) conditions. The most well-known retinoid is isotretinoin (commonly referred to by one of its former brand names, Accutane or Roaccutane, a drug used to treat severe cystic acne. Isotretinoin and its commercially available brands, although effective in the treatment of acne, can cause developmental abnormalities in the fetus (teratogenic effects) and therefore should not be used during pregnancy due to the risk of birth defects. The range and severity of associated abnormalities are variable. However, characteristic features may include growth delay before and after birth (intrauterine growth restriction and postnatal growth retardation); malformations of the skull and facial (craniofacial) region; central nervous system (CNS) abnormalities; heart abnormalities; and/or additional physical findings. Additional anomalies may include renal, thymus gland abnormality and parathyroid gland abnormalities.
Characteristic features of infants with fetal retinoid syndrome include abnormalities of the craniofacial region, CNS, and cardiovascular system. The specific symptoms and physical findings can vary from one infant to another. Affected infants may not have all of the symptoms listed below.
Some affected infants may display small, low-set ears (microtia) with narrowing (stenosis) of the ear canals or are born missing ears. Abnormalities of the middle and inner ears may also be present including hearing loss. Additional craniofacial findings include widely spaced eyes (hypertelorism), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), and/or underdevelopment of the middle area of the face (midface hypoplasia). Some affected infants may experience paralysis (palsy) of certain facial nerves.
Potential cardiovascular abnormalities following retinoid exposure include structural (anatomical) malformations of the heart such as transposition of the great vessels; hypoplastic left heart syndrome; ventricular septal defects (VSDs); and tetralogy of Fallot.
Hypoplastic left heart syndrome is characterized by underdevelopment of the left ventricle, the aortic and/or mitral valves, and the ascending aorta.
VSDs are abnormal openings that may occur in any portion of the ventricular septum, the fibrous partition that divides the heart’s two lower pumping chambers (ventricles). The size and location of the defect will determine the severity of symptoms. Small VSDs may close without treatment or become less significant as affected infants mature and grow. If a moderately-sized defect is present, the heart may be unable to pump blood effectively, resulting in an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), and/or failure to grow and gain weight at the expected rate (failure to thrive). In some children, without appropriate treatment, large VSDs may cause life-threatening complications during infancy.
Tetralogy of Fallot is a rare form of cyanotic heart disease. Cyanosis is the abnormal bluish discoloration of the skin and mucous membranes (lips and tongue) that occurs due to low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs due to an abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis); a displaced aorta that causes blood to flow into the aorta from both the right and left ventricles; and abnormal enlargement of the right ventricle.
Some infants with fetal retinoid syndrome may develop CNS abnormalities, including hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Excess fluid can increase pressure on the brain and can cause the head to swell. Infants with fetal retinoid syndrome may have below average intelligence, experience learning disabilities, and exhibit delays in reaching developmental milestones such as sitting or crawling. In some children, the forebrain (prosencephalon) may fail to develop resulting in holoprosencephaly.
Affected infants may also develop a condition known as microcephaly, where the head circumference is smaller than would be expected for their age and gender due to developmental issues. This can result in developmental and intellectual disabilities. Additional complications that may arise due to microcephaly including balance and coordination problems as well as seizures.
Infants with fetal retinoid syndrome may experience abnormalities of thymus function. The thymus gland is located below the thyroid gland in the neck in front of the chest and is the primary gland of the lymphatic system. The thymus gland makes white blood cells needed to protect the body from infection.
Additional abnormalities that may occur in some children include webbing of the fingers (syndactyly), skeletal malformations affecting the legs and spine, and/or low muscle tone (hypotonia). Some infants may also develop eye problems such as microphthalmia, a condition where one or both eyeballs are very small, leading to possible vision loss. Some infants are born with their eyes missing (anopthalmia).
Maternal use of synthetic vitamin A (retinoids) such as isotretinoin (Accutane) during pregnancy can result in multiple effects on the developing embryo and fetus including miscarriage, premature delivery and a variety of birth defects. Commercially available isotretinoin brand products include, Absorica, Amnesteem, Claravis, Myorisan, and Zenatane; as well as various types of generics available globally.
There is debate in the medical literature as to the specific risks for individual pregnancies following retinoid exposure. However, it is known that there is an increased risk of birth defects in women who become pregnant while taking retinoids such as isotretinoin. It is estimated that a 35% risk of fetal retinoid syndrome exists in infants of women who take isotretinoin beyond the 15th day following conception. Some researchers believe that birth defects do not occur in women who discontinue isotretinoin one month before conception. It is also unknown what specific dosage of retinoids may result in birth defects. More research is needed to determine the specific risks and long-term effects when women are inadvertently exposed to retinoids during pregnancy.
Fetal retinoid syndrome affects males and females in equal numbers. The exact incidence of fetal retinoid syndrome is unknown and because many children with fetal retinoid syndrome often go unrecognized. The disorder is under-diagnosed, making it difficult to determine the true frequency of the disorder in the general population.
There is no diagnostic testing that can identify fetal retinoid syndrome. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of retinoid exposure during pregnancy.
Prenatal diagnosis may be possible by ultrasound where fetal abnormalities such as central nervous system and heart abnormalities may be detected.
Due to the severity of the birth defects that an infant may develop following retionoid exposure, use of oral retinoids is strictly prohibited during pregnancy. Women should be counselled carefully regarding the risks of isotretinoin treatment and should be screened and monitored for pregnancy while on the medication. Throughout the course of isotretinoin therapy, two forms of contraception are recommended and pregnancy should be avoided until the isotretinoin therapy has been discontinued.
Continual use of birth control (contraception) is needed for safety precautions during isotretinoin therapy in women of childbearing age. Evidence from medical literature states that contraception use should be started one month before isotretinoin therapy and continued for three months after therapy has been stopped.
The treatment of fetal retinoid syndrome is directed toward the specific problems affecting each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and additional health care professionals may need to systematically and comprehensively plan an affected child’s treatment. Other treatment is symptomatic and supportive.
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