Isotretinoin is a novel treatment for severe, recalcitrant nodular acne sold under the brand names Accutane®, Amnesteem®, Claravis®, and Sotret®. It is the most widely used teratogenic drug in the United States. From a population based perspective, women and men use the drug in near equal proportions but the risks are exponentially greater for women of childbearing years. Serious developmental abnormalities have displayed a high tendency to occur in clusters in fetuses exposed to isotretinoin. This review of medical literature focuses on the public health implications of isotretinoin use and develops a case for continued risk management. Reduction of fetal isotretinoin exposure is contingent upon effective programming and continued adherence to strict standards.

1. Prenatal Exposure to Isotretinoin
Running Head: PRENATAL EXPOSURE TO ISOTRETINOIN
Prenatal Exposure to Isotretinoin:
Diagnosis, Outcomes, and Clinical Management
Lindsay K. Meyer
University of Notre Dame
BIOS 30303-01
Professor Kohlberg
November 16, 2007
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2. Prenatal Exposure to Isotretinoin
Abstract
Isotretinoin is a novel treatment for severe, recalcitrant nodular acne sold under the brand names
Accutane®1
, Amnesteem®2
, Claravis®3
, and Sotret®
.4
It is the most widely used teratogenic drug
in the United States. From a population based perspective, women and men use the drug in near
equal proportions but the risks are exponentially greater for women of childbearing years.5
Serious developmental abnormalities have displayed a high tendency to occur in clusters in
fetuses exposed to isotretinoin.6
This review of medical literature focuses on the public health
implications of isotretinoin use and develops a case for continued risk management. Reduction
of fetal isotretinoin exposure is contingent upon effective programming and continued adherence
to strict standards.
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3. Prenatal Exposure to Isotretinoin
Prenatal Exposure to Isotretinoin:
Diagnosis, Outcomes, and Clinical Management
In the twenty-five year interval since the 1982 introduction of isotretinoin, over 2000
pregnancies in the United States have been affected by this teratogen (Abroms, Maibach, Lyon-
Daniel & Feldman, 2006). Risk management initiatives are now in their relatively mature third-
stage with the launch of iPLEDGE™ in March 2006. The failure of two previous campaigns7
was accompanied with congenital defects occurring in rates higher than 20%.8
The late twentieth century emphasis on preventative medicine did little to preclude
isotretinoin-exposed pregnancies. Despite widespread efforts to educate women about the
dangers of pregnancy while using Accutane®
, female patients using the drug continued to
become pregnant. The phenomenon continues today, with the consequences of the recently
implemented iPLEDGE™ program yet to be observed or benchmarked. An abbreviated
literature review9
was conducted to gain additional insight into the following questions:
1. What is the epidemiology associated with the isotretinoin embryopathy?
2. What is the risk profile for prenatal isotretinoin exposure?
3. What is the prognosis for isotretinoin-exposed fetuses?
4. What risk management programming has been developed to reduce isotretinoin-
exposed pregnancies?
Until statistical evidence suggests significant decreases in birth defects, it is critical that
physicians and pharmacists continue to exercise the highest ethic in steering patients towards an
appropriate treatment for acne which seeks to identify target candidates for Accutane®
therapy
via comprehensive pre-screens, educational initiatives, and oversight consistent with the
iPLEDGE™ program.
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4. Prenatal Exposure to Isotretinoin
What is the epidemiology associated with the isotretinoin embryopathy?
Congenital Defects
Work done by Lynberg et al. (1990) was very systematic in grouping defects into organ
system by ear, central nervous system, and cardiovascular system. Abnormalities of the ear
included absence of stricture of auditory canal, absence of auricle, and microtia. The cascade of
central nervous system defects included hydrocephalus, microcephalus, and reduction
deformities of the brain. Common truncus, transposition of the great vessels, septal defects,
aortic arch abnormalities and Fallot’s tetralogy were defects of the cardiovascular system.
Further studies by Sladden and Harman (2007), suggested that spina bifida, craniofacial
abnormalities (cleft palate, hypertelorism, depressed nasal bridges) and thymic defects (ectopia,
hypoplasia and aplasia) were also characteristic of the embryopathy. The mechanism for
teratogenicity is unclear according to Benifla, Ville, Imbert, Thomas & Pons (1995) but “may be
due to an exaggeration in the normal process of physiologic cell death during embryonic
development due to the vitamin A-induced release of lysosomal cell enzymes” (p. 190).
Diagnosis
Lynberg et al.’s 1990 work included a mathematical model (p. 516) for isotretinoin
embryopathy diagnosis in populations. In this multivariate algorithm, required inputs include the
probability of exposure in the population, the probability of any defect in an unexposed
population, sensitivity (the proportion of malformed isotretinoin-exposed fetuses with the given
defect pattern), specificity (the proportion of malformed fetuses without the teratogenic exposure
who do not have the pattern of defects), and an attack rate. While not directly applicable to
individual patients, the expected outcomes are useful for epidemiologists attempting to monitor
the isotretinoin-related birth defects.
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5. Prenatal Exposure to Isotretinoin
High level diagnosis of prenatal isotretinoin exposure is a simple cause and effect
relationship in which women taking isotretinoin become pregnant and in the process exposes the
fetus to the drug (illustrated in Figure 2). Research by Boucher and Beaulac-Baillargeon (2006)
showed that common explanations for pregnancy among isotretinoin users were driven by:
unprotected intercourse (N=3), failure to use two methods of contraception at all times during
treatment (N=34), failure to use two methods of contraception one month after treatment (N=21)
and failure to wait until next menstrual period to begin treatment (N=8).10
Individual diagnosis
of defects related to the isotretinoin embryopathy occur concurrent with normally accepted
practices and timeframes for the specific disruption, deformation, or syndrome.
The National Teratology Information Service recommends that women who choose to
continue their pregnancy after exposure have alpha-fetoprotein testing at 16 to 19 weeks
gestation. A targeted ultrasound scan is suggested at 20 to 21 weeks. These tests indicate risks
of structural malformations (Sladden and Harman, 2007).
Statistics
Data on the incidence of specific defects or clusters of defects is extremely limited.
While efforts have been made by Roche to enroll female patients in voluntary studies in
accordance with their 1988 Pregnancy Prevention Program (“PPP”), individual outcomes to
isotretinoin exposure have varied significantly (Honein, Paulozzi & Erickson, 2001). As efforts
to decrease prenatal isotretinoin exposure have intensified in the past decade, birth defects have
fallen, shrinking the data universe commensurate with decreases in isotretinoin exposures.
Elective abortions have also severely limited the amount of available data on individual
outcomes.
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6. Prenatal Exposure to Isotretinoin
The Lynberg et al. sensitivity and specificity studies of isotretinoin-exposed pregnancies
provide a snapshot of incidences of craniofacial (“ear”), central nervous system (“CNS”), and
cardiovascular (“CVS”) birth defects and their respective combinations. Among the trends to
note:
- A combination of ear and cardiovascular defects was seen in 24.6% of infants,
making the pair 1230 times more likely to occur in isotretinoin-exposed pregnancies
than in the general population.
- A combination of ear and central nervous system defects was seen in 39.3% of
exposed infants, making the pair 982 times more likely to occur in isotretinoin-
exposed pregnancies than in the general population.
- Isotretinoin-exposed pregnancies resulted in ear, CNS, and CVS defects 70.5%,
49.2%, and 32.8% of the time, respectively, making them 133, 10, and 8 times more
likely than in the general population.
What is the risk profile for prenatal isotretinoin exposure?
Isotretinoin is a class X medication11
for the duration of the first trimester according to a
study of potentially teratogenic medications by Schwarz, Postlethwaite, Hung & Armstrong
(2007). One in six women had a potentially teratogenic medication filled at some point during
2001 (p. 374) and only half were counseled about concurrent use of contraceptives. Given that
half of the pregnancies in the United States are unintended, women of childbearing age can be
generalized as “at risk” for isotretinoin exposed pregnancies (p. 375).
Demographically, research by Dai et al. conducted in 1992 showed that nearly 60% of
isotretinoin-exposed pregnancies occur in females between 20 and 29. An additional 25% of
exposed pregnancies occur in the 14 to 19 year old age bracket. This is significant because
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7. Prenatal Exposure to Isotretinoin
women younger than 20 were more likely to carry exposed pregnancies to term (49%) versus
those older than 20 (28%). This suggests that teenage mothers do not fully understand all of the
risks associated with an isotretinoin-exposed pregnancy. Unfortunately, due to their young age,
these mothers are emotionally and economically ill equipped to deal with the array of
unfavorable outcomes.
Failure to regularly use two sources of contraception vastly increases the risk of
pregnancy in fertile women taking isotretinoin. Dai et al’s 1992 study demonstrated that nearly
half of women between 14 and 24 did not use any form contraception. This further qualifies
young age as a risk factor. However, Bérard et al. rejected this generalization in 2006 with the
assertion that, “There are no population-based risk estimates of pregnancy, abortion, miscarriage
or birth defect while one isotretinoin … all previous studies have had low participation rates and
small sample sizes” (p. 197). While debatable12
, science suggests that there is no safe time for
isotretinoin usage during pregnancy and that no specific groups exhibit higher predispositions to
exposure.
What role has advertising for prescription acne treatment influenced women’s decisions
to investigate Accutane®
therapy? The January 21, 2000 edition of the Center for Disease
Control’s Morbidity and Mortality Weekly Report (“MMWR”) included data that noted 50% of
women in California with isotretinoin-exposed pregnancies had viewed an advertisement before
taking isotretinoin. The MMWR also reported that over half of these respondents sought this
treatment from their physician, displaying the prominence of advertisements produced by
pharmaceutical companies (p. 29). More alarming however, was the 2006 discovery of Boucher
and Beaulac-Baillargeon that without awareness of its teratogenicity, some women may have
interpreted the symbols on the drug packaging to mean that isotretinoin could prevent pregnancy
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8. Prenatal Exposure to Isotretinoin
(p. 341). Special attention must be paid to marketing programs and package-specific content as
it has been seen to adversely affect exposed pregnancies and perceptions of isotretinoin’s
primary indication.
What is the prognosis for isotretinoin-exposed fetuses?
In addition to the major birth defects described on page 4, empirical research by Dai,
LaBraico & Stern (1992) showed that miscarriage or stillbirth occurs in one third of exposed
pregnancies (p. 603). The risk of a premature delivery is doubled for mothers who have taken
isotretinoin and the overall poor prognosis for isotretinoin-exposed pregnancies has lead to
induced abortions in as many as 72% of isotretinoin-exposed pregnancies (Robertson et al.,
2005).
Some women are willing to accept the risks inherent in carrying isotretinoin-exposed
fetuses to term and have metaphorically “beaten the odds” with normal pregnancies marked by
the delivery of healthy infants. However, with limited research available about the long term
growth trajectories of healthy (unaffected) infants, it is overly presumptuous to assert their
freedom from developmental problems later in life (Sladden and Harman, 2007). Problems in
cognitive performance occur in 40% of exposed pregnancies, even when no structural defects are
present (Robertson et al., 2005).
Alpha-fetoprotein testing and targeted ultrasound scans can assist parents in planning
support services, should they become necessary. In a limited number of instances, in utero
intervention is a possibility, depending on the type and severity of malformation.
What risk management programming has been developed to reduce isotretinoin-exposed
pregnancies?
The first generation approach and Pregnancy Prevention Program (“PPP”)
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9. Prenatal Exposure to Isotretinoin
Within one year of FDA approval of Accutane®
, Roche had received seven reports of
fetal malformations related to the drug (Abroms, Maiback, Lyon-Daniel & Feldman, 2006).
Initial steps were taken to place boldfaced warnings on the package insert about the
teratogenicity of the product. Warning letters were sent to prescribers and both pharmacists and
wholesalers received red warning stickers to place on the drug bottles. In spite of these efforts,
reports of fetal malformations continued and in 1988 the FDA mandated a stronger risk
management program (“RMP”). This PPP required a patient consent form, negative pregnancy
test and two reliable forms of birth control13
(Abroms et al., 2005).
While the PPP was believed to have reduced exposure rates from four per 1000
pregnancies to two per 1000 pregnancies over a ten year period (Honein, Lindstrom & Kweder,
2007), there was no mechanism to enforce the requirements of the program. The FDA
concluded that this RMP was ineffective in influencing the contraceptive behavior of women and
in reducing the number of exposed pregnancies (Abroms et al, 2005).
The System to Manage Accutane®
Related Teratogenicity (“SMART™”) program14
Work by Bensouda-Grimaldi et al. (2005) indicated cross-border parallels to
programming efforts in France between 1999 and 2002. Poor patient compliance with
contraception agreements made the complete elimination of exposed pregnancies impossible (p.
416). The 2002 launch of the SMART™ program in the United States attempted to prevent
pregnant women from taking Accutane®
and prevent pregnancies among existing Accutane®
users (Brinker, Kornegay & Nourjah, 2005). The SMART™ program required patients to pass
an initial pregnancy screen, a pregnancy test seven days after initiation of treatment. The
program enhanced education about the teratogenic effects of Accutane®
and involved counseling
on the selection of two reliable forms of birth control. When all qualifications were met, patients
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10. Prenatal Exposure to Isotretinoin
received a special prescription for a 30-day supply of the medication. The use of a qualification
sticker on the prescription also attempted to hold pharmacies more accountable for dispersal
(Brinker et al., 2005).
Roche established goals for assessing the SMART™ program. First, they aimed for a
60% participation rate in a voluntary Accutane® patient survey, one year after the
implementation of SMART™. Second, they aimed for a 90% qualification sticker rate on
dispensed Accutane®
prescriptions. Brinker et al. (2005) concluded:
The usefulness of the results derived from surveys designed to evaluate the SMART™
program is limited by the lack of reliability and validity of the survey instruments and
questionable generalizability to all female recipients of isotretinoin. The presence of a
qualification sticker may not have an impact in pregnancy testing or compliance with
effective birth control behavior as outlined in the SMART™ program. (p. 563)
iPLEDGE™: The newest RMP frontier
Abroms et al. (2006) report that iPLEDGE™, the third phase of RMP’s is the “most
rigorous risk management program in history for such a widely prescribed drug, involving
patients, physicians, pharmacies and wholesales” (p. 1978). This RMP requires all recipients of
isotretinoin – male and female to be registered in the iPLEDGE™ system. Females of
childbearing potential must re-qualify every month to receive a new prescription. The
qualification process requires the confirmatory pregnancy pre-screen established by SMART™
and monthly follow up tests. Confirmation by the patient and prescriber of agreed upon
contraception must be independently entered into the system. The records must match. Monthly
contraceptive counseling during patient visits is required. Patients must also correctly answer
questions intended to reinforce key messages about the RMP.
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11. Prenatal Exposure to Isotretinoin
This aggressive approach has added real value by allowing real time updates of
pregnancy tests results that can be linked to the dispensing of the medicine (Honein et al., 2007).
It is anticipated that the 12% of fetal exposures to isotretinoin that occurred as a result of women
being pregnant at the time of isotretinoin initiation will be eliminated with the new rigorous
standards. The iPLEDGE™ program streamlines all RMP’s associated with generic forms of
isotretinoin into a single program, making it easier for pharmacists to manage (see Footnote 14).
The system also offers the supreme advantage of being self-scrutinizing central database for
public health experts to analyze program effectiveness. A pregnancy registry will also allow the
FDA to finally gain a realistic picture of outcomes in exposed pregnancies (Honein et al., 2007).
The primary challenge presented by iPLEDGE™ is that prescribing physicians may not
be specialists on counseling patients about contraceptive use (Abroms et al., 2006). The teenage
isotretinoin population may also be reluctant to communicate with their physician about sexual
activity. According to Abroms et al. (2006), many people will find ways to obtain isotretinoin
outside of the “iPLEDGE™ map” (p. 1981). In addition, the program was hurriedly approved
without sufficient testing and was not developed with complete input from the patients,
prescribers, pharmacies and wholesales affected most by the changes. Bearing these challenges
in mind, modifications to the program will likely be required for operational enhancements
(Honein et al., 2007). None the less, the system has vast potential to make positive contributions
to public health.
Conclusion
The assault on isotretinoin therapy is warranted given its volatile history of severe birth
defects and spontaneous abortion. But according to Abroms et al. (2006), the “benefits accrued
to society from using isotretinoin outweigh the risks” (p. 1982). For the most part, patients who
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12. Prenatal Exposure to Isotretinoin
once suffered from acute acne are now able to avert the physical and emotional trauma
associated with this disease. In women of childbearing age, isotretinoin should be a last-line
acne treatment. Treatment with topical retinoids should precede oral isotretinoin, particularly in
light of Loureiro et al.’s 2005 conclusion that “first-trimester topical tretinoin exposure … was
not associated with an increased risk of any adverse pregnancy outcome” (p. 117). Going
forward, continued adherence to the guidelines formulated by iPLEDGE™ and subsequent
monitoring by the FDA will be the best indicators of success in reducing prenatal exposure to
isotretinoin.
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13. Prenatal Exposure to Isotretinoin
References
Abroms, L., Maibach E., Lyon-Daniel, K., & Feldman S. R. (2006). What is the best approach
to reducing birth defects associated with isotretinoin? Public Library of Science (PLos)
Medicine, 3, 1978-1982.
Benifla, J. L., Ville, Y., Imbert, M. C., Thomas, A., & Pons, J. C. (1995). Fetal tissue dosages
of retinoids. Fetal Diagnosis and Therapy, 10, 189-191.
Bensouda-Grimaldi, L., Jonville-Béra, A. P., Mouret, E., Elefant, E., Dhellot, H., Delmas, C., et
al. (2005). Isotretinoin: Compliance with recommendations in childbearing women
(Summary only). Annales de Dermatologie et de Vénéréologie, 132, 415-416.
Bérard, A., Azoulay, L., Koren, G., Blais, L., Perreault, S., & Oraichi, D. (2006). Isotretinoin,
pregnancies, abortions and birth defects: a population-based perspective. British Journal
of Clinical Pharmacology, 63(2), 196-205.
Boucher, N. & Beaulac-Baillargeon, L. (2006). Pregnancy prevention among women taking
Isotretinoin. Canadian Family Physician, 52, 339-343.
Brinker, A., Kornegay, C., & Nourjah, P. (2005). Trends in adherence to a revised risk
management program designed to decrease or eliminate isotretinoin-exposed
pregnancies. Archives of Dermatology, 141, 563-569.
Centers for Disease Control (2000). Accutane-exposed pregnancies – California, 1999.
Morbidity and Mortality Weekly Report, 49(2), 28-31.
Dai, W. S., LaBraico, J. M. & Stern, R. S. (1992). Epidemiology of isotretinoin exposure during
pregnancy. Journal of the American Academy of Epidemiology, 26, 599-606.
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14. Prenatal Exposure to Isotretinoin
Fauchère, J., Ersch, J., Grant, D. A., Zimmermann, R., Bucher, H. U., & Stallmach, T.
(2006). Acceleration of lung maturation following maternal isotretinoin intake. Biology
of the Neonate, 90, 203-206.
Honein, M. A., Lindstrom, J. A., & Kweder, S. L. (2007). Can we ensure the safe use of known
human teratogens? Drug Safety, 30(1), 5-15.
Honein, M. A., Paulozzi, L. J., & Erickson, J. D. (2001). Continued occurrence of Accutane®
-
exposed pregnancies. Teratology 64, 142-147.
Loureiro, K. D., Kao, K. K., Jones, K. L., Alvarado, S., Chavez, C., Dick, L, et al. (2005). Minor
malformations characteristic of the retinoic acid embryopathy and other birth outcomes in
children of women exposed to topical tretinoin during early pregnancy. American
Journal of Medical Genetics 136A, 117-121.
Lynberg, M. C., Khoury, M. J., Lammer, E. J., Waller, K. O., Cordero, J. F. & Erickson, D.
(1990). Sensitivity, specificity, and positive predictive value of multiple malformations
in isotretinoin embryopathy surveillance. Teratology 42, 513-519.
Roberston, J, Polifka J., Avner, M., Chambers, C., Delevan, G., Koren, G., et al. (2005). A
survey of pregnant women using isotretinoin. Clinical and Molecular Teratology 73,
881-887.
Schwarz, E. B., Postlethwaite, D. A., Hung, Y., & Armstrong, M. A. (2007). Documentation of
contraception and pregnancy when prescribing potentially teratogenic medications for
reproductive-age women. Annals of Internal Medicine, 147(6), 370-376.
Sladden, M. J. & Harman, K. E. (2007). What is the chance of a normal pregnancy in a woman
whose fetus has been exposed to isotretinoin? Archives of Dermatology, 143(9), 1187-
1188.
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15. Prenatal Exposure to Isotretinoin
Footnotes
Roche is the manufacturer of Accutane®
2
Bertek is the manufacturer of Amnesteem®
3
Barr is the manufacturer of Claravis®
4
Ranbaxy is the manufacturer of Sotret®
5
Childbearing age is loosely defined as 15-44 years of age (Honein, Paulozzi &
Erickson, 2001).
6
These abnormalities and affect cardiovascular and central nervous systems and impair
craniofacial, thymic, and limb development (Sladden & Harman, 2007).
7
The two previous campaigns refer to Roche’s 1988 Pregnancy Prevention Program
(“PPP”) and their subsequent 2002 System to Manage Accutane®
-Related Teratogenicity
(“SMART™”) program.
8
Raw estimate based on all research studies cited in ‘Reference’ section. Actual figures
varied significantly based on number of subjects. Relative to the widely accepted metric of 3%
congenital defects for births within the United States, this estimate is significant, while still
conservative.
9
The literature review was abbreviated in that a wealth of articles exists on isotretinoin
use and risks. Articles were selected based on Journal of publication, date, and relevancy to
prenatal exposure and risk management.
10
Ntotal = 45. Results are not mutually exclusive.
11
Class X medications are contraindicated in women who are or may become pregnant.
2
An isolated instance in which late term exposure to the drug accelerated lung
development was compiled in a 2006 case report by Fauchère et al. This work showed that
15

16. Prenatal Exposure to Isotretinoin
inadvertent prenatal exposure at 22 weeks gestation accelerated lung development by 4 weeks.
This research was completely counter to all of the literature on prenatal isotretinoin exposure in
that it advocated for the use of retinoids (in tangent with glucocorticosteroid treatment) as a
therapy for advancing lung development in premature deliveries at the limits of viability.
13
According to Brinker et al. (2005), “Effective contraception consisted on concurrently
using both a primary (tubal ligation, partner’s vasectomy, intrauterine device, estrogen-
containing birth control pills, or topical, injectable, implantable, or insertable hormonal birth
control products) and a secondary method of birth control (diaphragm, latex condom, or cervical
cap, each to be used with spermicide)” (p. 564).
14
During the time that SMART™ was launched for Accutane®
, generic isotretinoin
became available. The FDA required the same RMP’s be put in place for each of these products,
but under different names. These programs were known as SPIRIT™ (Mylan), IMPART™
(Ranbaxy), and ALERT™ (Barr) (Honein et al., 2007).
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17. Prenatal Exposure to Isotretinoin
Table 1
Sensitivity of defect patterns in isotretinoin-exposed case series and specificity of defect patterns
in metropolitan Atlanta between 1968 and 1982
Defect Sensitivity Specificity Multiple
Isotretinoin-exposed cases (N = 61) Metropolitan Atlanta (N = 12,2224)
EAR 70.50% 0.53% 133
CNS 49.20% 4.88% 10
CVS 32.80% 4.06% 8
EAR + CNS 39.30% 0.04% 982
EAR + CVS 24.60% 0.02% 1230
CNS + CVS 23% 0.16% 144
EAR + CNS + CVS 18% 0% N/A
EAR + (CNS or CVS) 45.90% 0.07% 656
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18. Prenatal Exposure to Isotretinoin
Figure 1. A sample of three prominent congenital defects consistent with the isotretinoin
embryopathy. From bottom left (clockwise), a fetus displaying hypoplasia of the left side, an
infant with hydrocephalus, and an infant with spina bifida. Images located with Google Image
Search.
Figure 2. A sample cause and effect diagram represents how isotretinoin exposed pregnancies
occur. Image created by Lindsay Meyer.
A female taking isotretinoin: Becomes pregnant
Missedperiod/suspicion
Positive home pregnancy test
Positive pregnancy screen
…fails to wait to begin taking
isotretinoin until her menstrual
cycle begins
…has unprotected intercourse
…fails to utilize TWO methods
of contraception and one
contraceptive fails
Self-Diagnosed
Clinically Diagnosed
…fails to utilize TWO methods
of contraception following
completion of isotretinoin
treatment course
And is Diagnosed with
Prenatal Isotretinoin Exposure
18