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Fetal Retinoid Syndrome
Fetal retinoid syndrome is a characteristic pattern of
physical and mental birth defects that results from a
mother’s use of retinoids during pregnancy, usually
during the first three months. Retinoids are medications
made of artificial forms of vitamin A. Vitamin A is very
important for healthy eyes, skin, hair, and mucous
membranes. A mucous membrane is one of four major
types of thin sheets of tissue that line or cover various
parts of the body.
Accutane is a type of retinoid.
FEATURED BOOK: The Retinoids: Biology, Biochemistry, & Disease
The most well-known retinoid is the prescription medication, isotretinoin (also known as
Accutane). Isotretinoin is used to treat severe cystic acne that resists other forms of
treatment and it clears the skin of most affected individuals for prolonged periods. Cystic
acne is a severe disfiguring form of acne that affects hundreds of thousands of people
and causes scarring and multiple inflamed cysts. A cyst is an abnormal lump, swelling, or
sac that contains fluid, a part solid material, or a gas, that is covered with a membrane. A
membrane is a thin layer of flexible tissue that covers something.
WHAT ARE THE SIGNS AND SYMPTOMS OF FETAL RETINOID SYNDROME?
As mentioned above, fetal retinoid syndrome is associated with physical and mental
effects. However, the range of severity of these abnormalities will vary from case to
case. Some characteristic abnormalities include slowed growth before and after birth,
abnormal formation of the skull and facial bones, and abnormalities of the brain, spine,
heart, or urinary system. The urinary system is the structures in the body that are
important for urine production and output.
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One side of the face can appear out of proportion to the other in
fetal retinoid syndrome. Structures in the middle of the face can
appear underdeveloped, a condition known as midfacial hypoplasia.
The outer part of the ear can be abnormally small, abnormally
formed, or missing. The ear canal (also known as the auditory
canal), which is the passageway inside the ear, can also be
reduced in size or missing. The child can be born deaf or blind.The
eyes can appear abnormally small and cataracts can occur. A
cataract is a darkening of the lens in the eye. The lens is an organ
located between the colored part of the eye that bends light as it
enters the eye. The jaw may be underdeveloped, a condition known
as micrognathia.
There may also be cleft palate, in which there is a deep groove or space in the roof of the mouth that is
present from birth. There can be underdevelopment or absence of the thymus. The thymus is an organ
located in the upper part of the chest and is very important in producing substances that protect the body
against disease.
Regarding heart defects, abnormalities (such as underdevelopment) of the aortic arch are common. The
aorta is the largest artery of the body. An artery is a blood vessel that carries blood away from the heart.
The aorta splits into four areas, one of which is the aortic arch. The aortic arch gives rise to the other
sets of arteries. Coarctation of the aorta can occur, which is a localized narrowing of the aorta.
Another heart defect observed in fetal retinoid syndrome is a ventricular septal defect. A ventricular septal
defect is when one or more holes are present in the ventricular septum. The ventricular septum is the
muscular wall that separates that right and left ventricles of the heart. The ventricles are the chambers on
the bottom of the heart. The left ventricle has been known to be underdeveloped in fetal retinoid
syndrome. Transpositions of the great vessels can occur, which is an abnormal condition since birth
characterized by the aorta and other major blood vessels of the heart being switched around, which leads
to abnormal blood circulation.
Another heart abnormality that occurs in fetal retinoid syndrome is known as double outlet of the right
ventricle (DORV). DORV is when the aorta and pulmonary artery arise almost entirely or mostly from the
right ventricle. The pulmonary artery is a type of artery that supplies blood to the lung from the heart.
DORV is almost always associated with ventral septal defects (see last paragraph).
Another common heart defect in fetal retinoid syndrome is a conotruncal heart defect. A conotruncal heart
defect is a type of heart defect that causes improper circulation of blood. It is caused by a defect in the
conotruncus, which is a wall that divides the lower area of the heart. Large blood vessels can also be
damaged in fetal retinoid syndrome.
Fetal retinoid syndrome can cause microcephaly with hydrocephalus. Microcephaly is a rare condition in
which the head is abnormally small. Hydrocephalus is a condition in which there is an abnormal increase
in cerebrospinal fluid (CSF) inside the head. CSF is the cushiony fluid that protects the brain and spine
and helps distribute nutrients to these structures. Hydrocephalus in fetal retinoid syndrome is thought to be
due to bleeding in the ventricles of the brain soon after birth. Ventricles are openings inside the brain that
produce and hold CSF.
Fetal retinoid syndrome can also cause abnormalities of the posterior fossa, such as cysts. The posterior
fossa is an indented area of bone in the lower, back part of the skull. A cyst is an abnormal lump, swelling,
or sac that contains fluid, a part solid material, or a gas, and is covered with a membrane. A membrane is
a thin layer of flexible tissue that covers something. Fetal retinoid syndrome can cause neural tube
defects. A neural tube defect is a birth defect that is the result of the brain or spinal cord failing to develop
normally in an embryo. An embryo is a fertilized egg from the time of conception until the 8th week of
pregnancy. Holoprosencephaly can be caused by caused by fetal retinoid syndrome. Holoprosencephaly
is a birth defect caused by the failure of the brain to divide into two hemispheres (halves).
Fetal retinoid syndrome can cause spina bifida. Spina bifida is a birth defect in which part of the bones
that surround the spinal cord do not form properly, leaving part of the spinal cord exposed. Fetal retinoid
syndrome can cause occasional hemivertebrae, which is an abnormal condition characterized by the
failure of a vertebrae to develop completely since birth. Vertebrae are bones that form an opening in which
the spinal cord passes.
Fetal retinopathy can cause facial nerve paralysis and oculomotor paralysis. Facial nerve paralysis is a
loss of voluntary control of muscles of the face, usually on one side. Oculomotor paralyis is partial or
complete lack of movement of the eye muscles due to injury to the third cranial nerve (also known as the
oculomotor nerve). The oculomotor nerve is a nerve in the brain that helps control eye movements.
Metopic synostosis can be caused by fetal retinoid syndrome. Metopic synostosis is when the bones that
run down the middle of an infant’s forehead prematurely fuse together, resulting in the appearance of a
triangular forehead.
Abnormalities of the stomach and intestine can occur in fetal retinoid syndrome. Inguinal hernia can also
result from fetal retinoid syndrome. Hernia is when a part of a structure sticks out through the tissues that
normally contain it. Inguinal hernia is when an organ or tissue sticks out through the inguinal canal. The
inguinal canal is a passage in the lower part of the abdominal wall.
Occasionally, syndactyly and clubfoot can result from fetal retinoid syndrome. Syndactyly is a birth defect
in which webs appear between the fingers and toes. Clubfoot is a birth defect in which the foot is twisted
out of shape or position. The femur can be underdeveloped in fetal retinoid syndrome. The femur is the
long bone of the leg that runs from the hip to the knee. The radius can be deformed in fetal retinoid
syndrome. The radius is one of the bones of the forearm. Sirenomelia can occur, which is when the legs
are joined together, with a partial or complete joining together of the feet.
Fetal retinoid syndrome can cause underdevelopment of the kidneys and renal tubular acidosis (RTA).
RTA is a syndrome in which the kidney tubules are not able to adequately remove acids from the blood
and release them into the urine. The kidneys are two organs located on each side of the spine that filter
(remove) wastes from the blood. Each kidney is made up of over a million tubules. The tubules help
reabsorb some essential chemical components and allow others to flow back to the center of the kidney.
The body’s immune (defense) system may be underdeveloped in patients with fetal retinoid syndrome.
Underdevelopment of the adrenal gland can also be caused by fetal retinoid syndrome. The adrenal glands
are a pair of glands that play an important role in metabolism and help the body respond to physical and
emotional stress by releasing certain hormones. Glands are organs in the body made of special cells that
form and release materials such as fluid. Hormones are natural chemicals produced by the body and
released into the blood that have a specific effect on tissues in the body. Metabolism is the chemical
actions in cells that release energy from nutrients or use energy to create other substances.
HOW DOES ISOTRETINOIN CAUSE BIRTH DEFECTS?
Isotretinoin appears to prevent cells from moving to their proper places during early development as an
embryo. This prevention of cell movement is what leads to birth defects in fetal isotretinoin syndrome.
TELL ME MORE ABOUT ISOTRETINOIN?
Isotretinoin was first introduced in September 1982 by Roche Pharmaceuticals under the brand name,
Accutane. Accutane was and still is marketed as a medicine to treat severe cystic acne that is resistant
to other forms of treatment. Prior to its release in 1982, the manufactures knew that the drug was an
animal teratogen, which means it is a substance that causes birth defects in animal fetuses. A fetus is an
unborn living being. In animals, the drug caused high rates of abnormalities in the brain and spine as well
as deformities of the face after exposure to it during pregnancy. Because of these observed defects, the
Food and Drug Administration (FDA) listed isotretinoin as a Category X drug, meaning that it should not be
used during pregnancy. A statement about this was included in the package insert.
The introduction of Accutane, which is a drug taken by mouth, was a major treatment advance because of
its effectiveness against severe cystic acne. However, within months after the drug was released, severe
birth defects were reported in the infants of women who had taken the drug. In fact, soon after its release,
a high number of birth defect cases from throughout the country were reported to the FDA. By 1983, the
FDA had publicly reported on birth defects associated with isotretinioin use during pregnancy.
It was known that a woman is at high risk to deliver a child with severe birth defects if she gets pregnant
while taking isotretinoin, even if the doses are small and are taken for a short period of time. Despite this,
use of the medication rapidly increased and it began to be inappropriately prescribed to patients with less
severe forms of acne. For example, in 1997, an international survey of isotretinoin users found that only
45% had a condition that the drug was officially labeled to treat.
Isotretinoin became known as a human teratogen, which is a substance that causes birth defects in
human fetuses. In fact, isotretinoin is considered the strongest human teratogen in existence today. This
is important information since a high percentage of people who take isotretinoin are women in their child-
bearing years. In fact, 38% of isotretinoin users are between ages 13 and 19. The highest risk for severe
complications, sometimes resulting in death of the embryo, is between two and five weeks after
conception. Of course, many women do not yet know they are pregnant at this point. Isotretinoin can
cause miscarriages or premature delivery if the pregnancy continues.
One hundred and fifteen pregnant volunteer women treated with Accutane had reported to Roche
Pharmaceuticals before the outcome was known. Of these women, 18% had spontaneous abortions.
There were 94 live babies born, the mothers of which were almost all treated with Accutane during the first
three months of pregnancy. Of these 94 babies, 28% had at least one major birth defect. The dosages
taken ranged from 0.2 to 1.5 milligrams. A milligram is a thousandth of a gram. Birth defects even occurred
in babies whose mothers were treated for less than a week in the first three months of pregnancy.
A follow-up study was conducted with 31, five-year old children born to women who had taken Accutane
during the first 60 days of pregnancy. Of these children, 47% performed in the subnormal range on
standard intelligence test. Of 12 children who had a major birth defect, six had an IQ less than 70, which is
in the mentally retarded range. Of these six children, four had major brain or spine abnormalities. An IQ of
70 is at the 2nd percentile, meaning that 98% of other children performed better on the IQ test than they
did.
Four of the children had an IQ between 70 and 85. Only 2 of the 12 children had an IQ over 85. There
were 19 children born without any major birth defects. Of these children, six had an IQ between 70 and
85. Thus, even children without any major birth defects who are exposed to isotretinoin during pregnancy
can have low intelligence. The remaining thirteen children had an IQ over 85.
In another follow-up study of pregnant mothers using isotretinoin, 8 of 36 pregnancies were spontaneously
aborted in the first three months of pregnancy. One pregnancy resulted in a stillborn infant. A stillbirth is
the birth of a dead infant after the 28th week of pregnancy. Four of the 36 pregnancies resulted in infants
born with at least one major birth defect. Twenty-three of the 36 pregnancies resulted in infants without
major malformations. This study found a 25.6% risk of birth defects associated with isotretinoin use during
pregnancy. Another study found that about 40% of children exposed to isotretinoin during the first three
months of pregnancy will have major birth defects. Yet another study found a risk of birth defects in about
35% fetuses who were exposed to isotretinoin. A 1999 study at Boston University showed that 3 in every
1000 women who took isotretinoin became pregnant.
Because of the risk of birth defects, the standard recommendation by physicians is that women should
stop taking isotretinoin at least one month before conceiving a child. Since traces of isotretinoin leave the
body within 10 days of the last dose, a one month time frame should provide enough of a safety net so
that women can safely conceive if following the above recommendations of physicians. Physicians also
recommend that women be on two forms of birth control when using isotretinoin. Women should always
consult with their physicians if they believe they may be pregnant and are considering using isotretinoin.
CAN ISOTRETINOIN BE STORED IN CELLS AND CAUSE BIRTH DEFECTS MONTHS TO YEARS
AFTER THE LAST DOSE?
The question has been raised as to whether isotretinoin can be stored in certain cells in the body. The
fear is that since the medication is present in the cells, it may still have the potential to cause birth defects
months to years after the last dose was taken, should a pregnancy occur. This question has yet to be
answered. However, Roche Pharmaceuticals reported on 101 pregnancies that resulted days to weeks
after the last Accutane dose. Of these pregnancies, there was no increase in birth defects or
miscarriages. An additional study reported on 88 women who became pregnant within 2 to 60 days after
the last dose of Accutane. Again, there was no increase in birth defects or miscarriages.
IS ISOTRETINOIN USED TO TREAT OTHER SKIN DISEASES?
Yes, isotretinoin is used to treat other skin diseases besides severe acne. However, the use of
isotretinoin to treat many of these other diseases or conditions has not been approved by the FDA.
Examples of such diseases or conditions are gram-negative folliculitis, pyoderma faciale, cutaneous lupus
erythematosus, rosacea that does not respond to treatment, generalized lichen planus, psoriasis, acne
fulminans, squamous cell carcinomas, keratosis follicularis, ichthyosis dermatoses, palmoplantar
pustulosis, and leukemias. A brief description of each of these diseases and conditions follows:
Gram negative folliculitis is folliculitis (inflammation of hair follicles) caused by gram negative bacteria.
Hair follicles are pouch-like depressions (such as the openings in the skin) through which hair grows.
Gram negative bacteria are bacteria that do not absorb a violet stain (known as Gram's stain) that
scientists use to characterize bacteria and other microorganisms. A microorganism is a tiny organism
made of one cell that is usually too small to be seen without using a microscope.
Pyoderma faciale is an unusual skin condition occurring in young adult women. It is characterized by the
sudden onset of deep areas of damaged tissue on the surface of the skin and tends to occur in the center
of the face. Cutaneous lupus erythematosus is a type of skin disease seen in people with lupus
erythematosus. Lupus erythematosus is a long-term disease in which the connective tissues throughout
the body are inflamed because the body's defense system attacks these tissues as if they were foreign
substances.
Rosacea is a skin disease characterized by various forms of facial redness due to enlargement and
widening of blood vessels beneath the surface of the skin. Generalized lichen planus is a non-cancerous
skin condition characterized by small, shiny, flat bumps on the skin that vary in color from pink to red to
violet. Psoriasis is an abnormal, non-contagious skin condition that causes scales to form. Acne fulminans
is a severe form of acne that can result in severe scars and skin ulcers (open sores).
Squamous cell carcinoma refers to carcinoma of the squamous cells. Squamous cells are flat, scale-like
cells. A carcinoma is any malignant cancer that arises from cells in the covering surface layer or
membrane (outer covering) that lines an organ of the body. When describing cancer, malignant means that
the newly formed tissues are made of abnormally structured and primitive-looking cells that grow
uncontrollably, spread throughout the body, and invade surrounding tissues.
Keratosis follicularis is a group of several skin disorders characterized by overgrown, thickened, small,
solid skin lesions (less than one centimeter wide) that come together to form black or brown, crusted,
wartlike patches. A wart is a growth on the body caused by a virus. Ichthyosis dermatoses are skin
conditions in which the skin is dry, thickened, and resembling fish scales. Palmoplantar pustulosis is an
eruption of pustules on the palms of the hands and soles of the feet. Pustules are distinct raised areas of
the skin that contain pus. Pus is a yellow or green creamy substance sometimes found at the site of
infections.
Leukemia is a type of cancer in the blood in which bone marrow (a tissue that fills the openings of bones)
is replaced by early forms of white blood cells. Cancer is a group of diseases in which symptoms are due
to an abnormal and excessive growth of cells in one of the body organs or tissues. White blood cells help
protect the body against diseases and fight infections.
IS THERE A CREAM FORM OF RETINOIDS AVAILABLE?
There are cream forms of retinoids available that can be applied to the skin, known as Retin-A, Renova,
and Differin (adapalene). Depending on the type, the cream forms are used to treat acne, wrinkled skin,
and skin damaged by the sun. Very little of the medicine gets absorbed into the body when it is applied on
the skin because the skin breaks it down. Because of this, studies to date have shown that the topical
treatments do not appear to result in an increased risk of birth defects. Nevertheless, to be safe, most
doctors agree that it is best to avoid the topical form during pregnancy. This is because there have been a
few reports of birth defects in babies of women who used the topical forms during pregnancy.
ARE THERE OTHER RETINOIDS THAT CAN CAUSE FETAL RETINOID SYNDROME?
Yes. Isotretinoin is not the only medication that can cause fetal retinoid syndrome. All oral retinoids pose
a significant risk of birth defects and should be avoided during pregnancy. For example, fetal retinoid
syndrome has been observed after pregnant mothers have used etretinate (also known as Tegison). This
medication, which is also manufactured by Roche Pharmaceuticals, was approved by the FDA in 1986 to
treat severe psoriasis that does not respond to other forms of treatment. Psoriasis is an abnormal, non-
contagious skin condition that causes scales to form.
Etretinate is also labeled as a category X drug and thus should not be used during pregnancy. Unlike other
retinoids, Etretinate is so strong that it has been measured in the blood at therapeutic levels seven years
after the last dose was taken. The risk of birth defects after etretinate is used lasts for an indefinite period
of time after the last dose is taken. Any woman who has used etretinate in the past should discuss with
her doctor if and when it may be safe to attempt pregnancy.
Soriatane (acitretin) is a newer type of oral retinoid marketed by Roche pharmaceuticals that has
replaced etretinate. This medication is used to treat severe psoriasis. This drug is known to cause birth
defects of the skull, heart, spine, arms, and legs. This medication remains in one’s body for an extended
period of time after treatment. The current recommendation by physicians is that this medication should
not be used by women who plan to become pregnant within three years after stopping treatment with it.
Also, women who take Soriatane are advised by their physicians not to drink alcoholic beverages while
taking the drug or for two months afterwards because this combination will turn the drug into etretinate,
which may remain in the body longer.
Another retinoid named Vesanoid (tretinoin) is used to treat a form of leukemia known as acute
promyelocytic leukemia (APL). Remember from above that leukemia is a type of in the blood in which bone
marrow is replaced by early forms of white blood cells. APL is characterized by the presence of abnormal
promyelocytes, a type of white blood cell. For Vesanoid, doctors recommend a pregnancy test two months
before starting treatment and two reliable forms of birth control during treatment and for one month after
stopping the drug.
A major concern is that that the patent the drug manufacturers had on Accutane has expired. This means
that other drug manufactures are able to sell the isotretinoin under different names. When the patent
expired, three new forms of the medication were rapidly introduced (Amnesteem, Sotret, and Claravis) in
the United States. There are now over thirty different generic forms of isotretinoin available throughout the
world, several of which are approved by the FDA. A generic drug is an identical or nearly identical form of
the drug, sold by a different company.
The introduction of new forms of isotretinoin will likely further increase the use of this drug among sexually
active young women. All generic versions of Accutane pose the same risk of birth defects as Accutane
and should never be used by pregnant women. The FDA requires that all drug companies producing
generic versions of Accutane follow the same guidelines as Roche Pharmaceuticals in how the drugs are
prescribed and given to women of childbearing age.
There are also a number of new retinoids being tested for their effectiveness in treating and preventing
various forms of cancer. These drugs appear to cause cancer cells to appear to act like normal cells. If
these drugs prove successful, women and their physicians will need to pay careful attention to the risks of
birth defects when using them.
CAN HIGH DOSES OF VITAMIN A CAUSE BIRTH DEFECTS?
Yes, high doses of vitamin A taken by the mother while she is pregnant can cause birth defects. Daily
supplements of vitamin A that exceed 5,000 International Units (the standard measuring dose) can result
in birth defects. A 1995 study found that women who took more than 10,000 International Units of Vitamin
A in the first two months of pregnancy had more than twice the risk of having a baby born with birth
defects that are similar to the birth defects described above. Ten thousand International Units of vitamin A
is more than four times the recommended amount of 2300 International Units by the Institute of Medicine’s
Recommended Dietary Allowance (RDA).
There have been other studies that have shown that Vitamin A doses under 25,000 International Units
probably does not cause birth defects. The lowest dose in which vitamin A causes birth defects is
unknown. The body makes its own Vitamin A from substances in certain foods such as yellow and green
vegetables. This form of vitamin A is considered by doctors to be completely safe and healthy during
pregnancy. However, it should be noted that much of the vitamin A people consume is preformed vitamin A
(an earlier form of it), which, in excessive amounts can cause birth defects. Preformed vitamin A can be
found is some vitamin supplements, meats (especially liver), eggs, dairy products, and fortified breakfast
cereals.
Doctors recommend that pregnant women make sure their multivitamins or vitamin supplements contain no
more than 5000 International Units of vitamin A and not to take any vitamin supplements beyond that
amount. Doctors also recommend that liver consumption be minimized.
HOW COMMON IS FETAL RETINOID SYNDROME?
Fetal retinoid syndrome due to Accutane use is uncommon today because so many women are counseled
by their doctors to avoid using this drug during pregnancy. However, if one becomes pregnant while
having used Accutane, the chances are high that the pregnancy will be lost or that significant birth defects
will result.
HOW LONG ARE WOMEN TREATED WITH ACCUTANCE?
Normally, women are treated with Accutane for about six months.
IS THERE A DANGER OF USING OTHER MEDICATIONS WHEN USING ISOTRETINOIN?
There is the potential for complications when women use isotretinoin with other medications such as
antibiotics or herbal preparations. For example, women taking isotretinoin should not use an herbal
preparation known as St. John’s wort because it can cause birth control pills to work less effectively,
increasing the chance of pregnancy.
CAN WOMEN BREASTFEED WHEN USING ISOTRETINOIN?
Breastfeeding while using isotretinoin is discouraged by physicians because the safety of this medication
during breastfeeding is unknown.
WHAT IF THE MAN TAKES ACCUTANE - CAN THAT CAUSE BIRTH DEFECTS?
Roche Pharmaceuticals maintains that birth defects can not be caused by the male partner using
Accutane. To our knowledge, there has been no published research that shows Accutane use in men
causes birth defects. Since the answer to this question, however, is not known for certain, some doctors
recommend that men do not get women pregnant while taking Accutane just to be on the safe side.
CAN FETAL RETINOID SYNDROME BE PREVENTED?
Yes, fetal retinoid syndrome can be prevented. In 1988, the FDA and Roche Pharmaceuticals put forth
Pregnancy Prevention Program guidelines to increase women’s awareness of the risk of birth defects
from isotretinoin and of the importance of not getting pregnant while using this medication. The guidelines
are distributed in the form of package inserts and patient information leaflets. A summary of the Pregnancy
Prevention guidelines are as follows:
• Isotretinoin should NOT be used by pregnant women or by women who may become pregnant while
taking it. Pregnancy should be avoided for two months after stopping treatment. This can be facilitated
through birth control. Two forms of birth control used at the same time are recommended to prevent
pregnancy while on isotretinoin and two months after treatment has ceased. Verbal and written warnings
about the danger of becoming pregnant while on isotretinoin should be provided.
• Pregnancy should be ruled out before treatment begins. This precaution can best be taken by obtaining a
negative pregnancy test no more than two weeks before the beginning of treatment. Treatment should
begin on the second or third day of the patient’s next normal menstrual period.
• The physician can offer a free pregnancy test to the patient and a birth control counseling session.
• Isotretinoin should only be prescribed in cases of severe acne that is disfiguring and which has not
responded to other forms of standard acne treatment. Other situations in which isotretinoin can be
prescribed is in severe psoriasis, keratosis follicularis, ichthyosis dermatoses, or palmoplantar pustulosis,
but only when they do not respond to other standard form of treatment. See above for a description of
these conditions.
• Patients and their doctors should receive a detailed consumer friendly educational guide about
isotretinoin. The guide contains warnings about the importance of preventing pregnancy while taking
isotretinoin.
• It should be determined that the patient is capable of following instructions before prescribing
isotretinoin.
• A consent form must be signed before treatment can begin stating that the patient understands the
serious risk of birth defects.
• An effective form of birth control should be used for at least one month before treatment with isotretinoin
begins.
• Women who have received isotretinoin should continue using an effective form of birth control for two
months after stopping treatment.
• The period of time during which pregnancy must be avoided after treatment with etretinate has been
discontinued has not yet been determined.
• Female patients need to be informed about the risks of major birth defects associated with exposure to
isotretinoin or etretinate during the first three months of pregnancy. Should a pregnancy occur during
treatment (or after treatment in the case of etretinate), the woman should consult with her physician on
how best to manage her pregnancy. Also, patients need to be informed not to share these medications
with friends or family members.
• Isotretinoin is packaged in special blister-packs containing warnings saying that it should never be used
during pregnancy.
• A symbol of a pregnant woman with a slash through it and the words “Avoid Pregnancy” appear very
noticeably on the package.
• A drawing should be included with the medication that represents common birth defects associated with
the use of isotretinoin during pregnancy.
• Doctors should be prepared to provide verbal information to patients. To increase physicians’
knowledge, Roche Pharmaceuticals provides extensive educational training to them.
Despite the efforts Pregnancy Prevention Program guidelines, use of isotretinoin increased and continued
reports of fetuses being exposed to it during pregnancy were reported throughout the 1990s. Because of
this, additional preventative measures were suggested in 2002 in which a partnership between
physicians, pharmacists, and patients was created. These measures were added to the Pregnancy
Prevention Program, which was renamed SMART (System to Manage Accutane Related Teratogenicity).
The additional SMART requirements are as follows:
There should be two negative pregnancy tests before the first prescription of isotretinoin. The first test is
done when the physician decides to prescribe isotretinoin. The second test is performed during the first
five days of a woman’s period (or at a time recommended by her physician) right before staring treatment
with the drug.
Pregnancy tests are repeated monthly during treatment with isotretinoin before refills can be given.
A yellow sticker is attached to the prescription to confirm that the physician has authorized the
prescription of isotretinoin and that the patient is eligible to receive it.
No more than a 30-day supply is given and there are no automatic refills.
The woman must choose two reliable forms of birth control which should be used. These two forms of birth
control should be used at the same time unless abstinence (not having sex) is the chosen method. These
forms of birth control should be used for at least one month before and throughout treatment with the drug
and for at least one month after treatment with the drug has ended.
It should be noted that doctors recommend that women should avoid pregnancy for varying periods of time
when having taken any kind of oral retinoid. The time delay to get pregnant depends on the type of oral
retinoid used. For example, with Soriatane the time delay is at least three years and women are
recommended to remain on two forms of reliable birth control throughout that time and while using the
drug.
The FDA has warned that if the SMART guidelines do not reduce the number of exposures to this
medication during pregnancy, additional restrictions will need to be placed on this medication. Finally, in
February 2004, an FDA advisory committee recommended that because of ongoing safety issues, those
who prescribe and are treated with isotretinoin need to be recorded in a national registry.
ARE THERE SAFER MEDICATIONS FOR WOMEN OF CHILD BEARING AGE THAN ISOTRETINOIN?
Yes, there are many safer medications for women of child bearing age besides isotretinoin. It is important
to keep in mind that isotretinoin is only meant to be prescribed in cases where severe cystic acne has not
responded to treatment with other, more safe, medications. Many women with cystic acne do not have a
severe form of it and are not bothered by the condition. Many women with cystic acne will have this
condition respond to safer medications taken by mouth or applied to the skin (known as a topical form).
Doctors typically prescribe topical forms of antibiotics known as erythromycin or clindamycin for women
during pregnancy. Another safe medication doctors prescribe during pregnancy is the anti-bacterial
medication, benzoyl peroxide, which dries the skin. If topical medications do not resolve the problem, then
the doctor may prescribe an antibiotic taken by mouth. An example would be the oral version of
erythromycin that has not been associated with birth defects. If the woman is not planning to become
pregnant, some doctors will opt to treat the acne with birth control pills. Although it may sound strange,
there are some birth control pills that treat acne.
As was mentioned earlier, there are topical retinoids that are used to treat acne. Very little of the topical
form gets absorbed through the blood stream and studies have shown that the topical form does not
appear to cause birth defects. While topical retinoids are a far safer option than the oral retinoids during
pregnancy, most doctors agree that it is best to avoid them during pregnancy and use the safer medica
ARE SKIN DOCTORS THE ONLY PEOPLE THAT CAN PRESCRIBE ISOTRETINOIN?
No. In fact, family physicians now prescribe isotretinoin.
WHAT ELSE IS FETAL RETINOID SYNDROME KNOWN AS?
Fetal retinoid syndrome is also known as Accutane embryopathy, Accutane dysmorphic syndrome, fetal
Accutane syndrome, isotretinoin embryopathy, isotretinoin teratogen syndrome, isotretinoin dysmorphic
syndrome, and retinoic acid embryopathy.
WHAT IS THE ORIGIN OF THE TERM, FETAL RETINOID SYNDROME?
Fetal retinoid syndrome comes from the Latin word “fetus” meaning “fruitful,” the Latin word “rete” meaning
“net,” the Greek word “eidos” meaning “form,” the Greek word “syn” meaning “together,” and the Greek
word “dromos” meaning “course.” Put the words together and you have “fruitful net form together course.”