Prenatal exposure to isotretinoin

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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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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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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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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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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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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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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(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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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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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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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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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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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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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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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

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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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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 MultipleIsotretinoin-exposed cases (N = 61) Metropolitan Atlanta (N = 12,2224)

EAR 70.50% 0.53% 133CNS 49.20% 4.88% 10CVS 32.80% 4.06% 8EAR + CNS 39.30% 0.04% 982EAR + CVS 24.60% 0.02% 1230CNS + CVS 23% 0.16% 144EAR + CNS + CVS 18% 0% N/AEAR + (CNS or CVS) 45.90% 0.07% 656

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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.

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Health & Medicine

Prenatal exposure to isotretinoin