Vol. 333 No. 2
`
`PREVENTION OF PREGNANCY IN WOMEN RECEIVING ISOTRETINOIN
`
`101
`
`SPECIAL ARTICLE
`
`A PREGNANCY-PREVENTION PROGRAM IN WOMEN OF CHILDBEARING AGE
`RECEIVING ISOTRETINOIN
`, M.D., C
` M. V
` B
`, M.P.H.,
`
`A
`
`LLEN
`
` A. M
`
`ITCHELL
`
`ARLA
`
`AN
`
`ENNEKOM
`
`AND
`
` C
`
`AROL
`
` L
`
`OUIK
`
`, S
`
`C
`
`.D.
`
`Abstract
`Isotretinoin is effective in treat-
`Background.
`ing severe acne, but it is also teratogenic. To minimize
`pregnancies among exposed women, the manufacturer,
`together with the U.S. Food and Drug Administration, im-
`plemented a multicomponent Pregnancy Prevention Pro-
`gram in 1988. We report the results of an ongoing survey
`designed to assess compliance with this program.
`Methods.
`Treated women enrolled in the survey
`through their physician, by filling out a form in the medi-
`cation package, or by calling a toll-free telephone num-
`ber. They were randomly assigned to be followed by tele-
`phone or by mail. Telephone interviews were conducted
`at the start of therapy, in the middle of it, and 6 months
`after it ended; mailed questionnaires were completed
`6 months after therapy ended (median duration of thera-
`py, 20 weeks).
`Results.
`Between 1989 and 1993, 177,216 eligible
`
`I
`
`N 1982, the vitamin A analogue isotretinoin (Accu-
`tane) was introduced in the United States for the
`treatment of severe recalcitrant cystic acne. Because
`studies in animals had suggested that isotretinoin
`might be teratogenic in humans, the drug was contrain-
`dicated in women who were or might become pregnant
`during therapy or in the following month. The concern
`about human teratogenicity proved well founded, be-
`cause it was soon demonstrated that approximately 25
`to 30 percent of exposed fetuses had birth defects — the
`so-called Accutane embryopathy, consisting of craniofa-
` Despite
`cial, heart, and central nervous system defects.
`1
`prominent warnings to physicians in direct mailings,
`advertisements, and the package insert, reports of preg-
`nancies in exposed women continued to accumulate,
`and by 1989 approximately 78 malformed infants had
`
`been reported.
`2
`In the spring of 1988, this issue was reviewed by an
`advisory committee to the U.S. Food and Drug Admin-
`istration. There was little debate about the teratogenic-
`ity of isotretinoin, but dermatologists and others assert-
`ed that its unique efficacy in the treatment of severe
`acne, together with its relatively short treatment course
`(15 to 20 weeks), warranted its continued availability.
`3,4
`As an alternative to removing the drug from the market
`or formally restricting its use, the manufacturer pro-
`
`From the Slone Epidemiology Unit, School of Public Health, Boston Univer-
`sity School of Medicine, Boston. Address reprint requests to Dr. Mitchell at the
`Slone Epidemiology Unit, 1371 Beacon St., Brookline, MA 02146.
`Presented in part at meetings of the International Conference on Pharmacoep-
`idemiology, Minneapolis, September 5–8, 1989; the Teratology Society, Victoria,
`B.C., Canada, June 8–12, 1990; the American Epidemiological Society, Pitts-
`burgh, March 25–26, 1993; and the American Osteopathic College of Dermatol-
`ogy, Boston, October 10–14, 1993.
`Supported by Hoffmann–La Roche.
`
`women enrolled in the survey. Interviews with 24,503
`women within one month of enrollment revealed that 99
`percent had been told to avoid pregnancy. At that time, ap-
`proximately 54 percent were not sexually active (of whom
`37 percent used contraception) and 42 percent were sex-
`ually active (of whom 99 percent used contraception);
`4 percent were infertile. Among 124,216 women with com-
`pleted telephone or mail follow-up results, there were 402
`pregnancies during therapy (3.4 per 1000 courses of iso-
`tretinoin); 72 percent of the pregnant women had elective
`abortions, 16 percent spontaneous abortions, 3 percent
`ectopic pregnancies, and 8 percent live births.
`Conclusions.
`The pregnancy rate among women re-
`ceiving isotretinoin therapy was substantially lower than
`that in the general population and was compatible with
`the characteristics and behavior of the enrolled women.
`(N Engl J Med 1995;333:101-6.)
`
`posed an aggressive program designed to reduce the
`risk of pregnancy among women taking the drug. The
`committee recommended that the major components
`of this program be implemented, and the manufactur-
`er’s Pregnancy Prevention Program commenced in the
`fall of 1988.
`The program was targeted at both prescribers and
`patients. In late 1988, materials were distributed to ev-
`ery dermatologist and to all nondermatologists identi-
`fied as prescribers of isotretinoin in the United States.
`The materials included guidelines for physicians (in-
`structing them, for example, to warn patients of risks,
`obtain negative pregnancy tests, and delay therapy un-
`til the second or third day of the next normal menstru-
`al period). They also included a patient-qualification
`checklist, an information brochure for patients, contra-
`ceptive information, information about and the neces-
`sary forms for a contraception referral program (in
`which the manufacturer would reimburse patients for a
`visit to another physician for contraceptive counseling),
`and a consent form. In addition, in mid-1989 the man-
`ufacturer replaced traditional medication bottles with a
`10-capsule blister pack that contained information di-
`rected specifically at women: the package included
`warnings about the risks of becoming pregnant while
`taking isotretinoin or during the month after treat-
`ment, an “avoid pregnancy” icon behind each capsule,
`and line drawings of malformations associated with iso-
`tretinoin. The program was reinforced by periodic
`communications directed at prescribers and pharma-
`cists.
`We designed and conducted a survey to assess the
`compliance of physicians and patients with the pro-
`gram and to identify the rate of pregnancy during
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on May 27, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`PAR1029
`IPR of U.S. Patent No. 8,731,963
`Page 1 of 6
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`102
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`July 13, 1995
`
`treatment with isotretinoin and during the month after
`treatment.
`
`M
`ETHODS
`The subjects were women of childbearing age (12 to 59 years of
`age) who were being treated with isotretinoin. To identify compliance
`with the program and the occurrence of pregnancy, the survey cov-
`ered the treatment period and the subsequent six months, a period
`long enough to allow identification of pregnancies occurring as late
`as the first month after discontinuation of treatment. Thus, for exam-
`ple, women treated for a typical 5-month course would be followed
`for 11 months.
`To maximize the proportion of treated women who participated,
`we provided multiple opportunities for enrollment. In addition to the
`materials described above, the program also included survey-enroll-
`ment consent forms; physicians were asked to encourage women to
`use these forms to enroll at the time isotretinoin was prescribed. A
`second opportunity was provided directly to the women through an
`enrollment-consent form that was included in each medication pack-
`age. In 1990, a toll-free telephone number that women could call to
`enroll was added to the form. All forms indicated that participants
`would receive a $10 payment.
`To minimize memory loss and biased recall, we collected informa-
`tion on the behavior of physicians and patients at the start of therapy
`as well as during treatment. However, inquiries at these times might
`have transformed the survey, which was intended to be observational,
`into a form of intervention. Therefore, we randomly assigned the
`women to be followed by one of two approaches. The first involved
`telephone contact during and after therapy, providing prospective in-
`formation on physicians’ and patients’ behavior. Since the telephone
`calls might themselves enhance compliance with the program, we
`used a second approach with other participants: a questionnaire
`mailed after therapy that identified the occurrence of pregnancy and
`obtained retrospective information on contraceptive practices.
`The enrollment forms were screened on receipt to exclude enroll-
`ments that were apparently fraudulent, men, and previously enrolled
`women. The eligible women were assigned, at random, to be followed
`by one of the two methods. Within two days, they were sent $10 and
`told when to expect contact. Each week, 100 women were randomly
`assigned to the group interviewed by telephone. They were contacted
`three times: at the start of therapy (within one month after enroll-
`ment), when we inquired about the patients’ understanding of the
`hazards of isotretinoin and compliance with the program; in the mid-
`dle of therapy (between two and four months after the start of iso-
`tretinoin), when we inquired about continued understanding of the
`hazards of isotretinoin and compliance with the program; and six
`months after the completion of therapy, when we asked about the oc-
`currence of pregnancy during or after treatment. Women who could
`not be reached by telephone within specified intervals were trans-
`ferred to the group followed up by mail.
`Women not randomly assigned to the telephone group were sent a
`brief questionnaire six months after starting isotretinoin to determine
`the date on which they had completed or were expected to complete
`therapy. They were then mailed a questionnaire six months after that
`date, which included the same questions as the third telephone inter-
`view. Nonrespondents were contacted by air courier and, if this failed
`to elicit a response, by telephone.
`Women who were pregnant at the time they began treatment, or
`who became pregnant during treatment or in the month after it end-
`ed, were interviewed by telephone regarding the pregnancy and its
`outcome; permission was sought to obtain relevant medical records
`and for our teratologist to examine all liveborn infants.
`The protocol was approved by the Boston University Medical Cen-
`ter Institutional Review Board for Human Research. The survey be-
`gan January 1, 1989, and is continuing at the present time.
`R
`
`ESULTS
`
`Enrollments
`Between January 1, 1989, and December 31, 1993,
`177,216 eligible women enrolled in the survey. The
`
`number increased from 21,267 in 1989 to 43,265 in
`1993. Twenty percent enrolled through the form pro-
`vided to physicians, 77 percent through the form in-
`cluded in the medication package, and 3 percent by
`telephone.
`
`Follow-up
`Telephone Interviews
`Overall, 26,986 women were assigned to telephone
`follow-up. Because of start-up problems, we completed
`first telephone interviews of only 72 percent of the
`women assigned to the telephone group in the first year
`of the survey; this proportion subsequently increased to
`96 percent. For the five-year study period, first tele-
`phone interviews were completed for 24,503 women.
`By June 30, 1994, the third telephone interview had
`been completed by 17,960 women (92 percent of the
`19,621 eligible women — that is, those who had com-
`pleted therapy at least six months before that date).
`
`Mailed Questionnaires
`Follow-up by mail involved 150,230 women assigned
`randomly to the mail group and 4420 women trans-
`ferred from the telephone group. Of the 126,251 wom-
`en eligible for the second mailed questionnaire by June
`30, 1994, responses had been received from 84 percent
`by that date.
`The ages and geographic distributions were similar
`among women assigned to telephone follow-up and
`those assigned to mail follow-up and among women with
`incomplete and those with complete follow-up (data not
`shown).
`
`Characteristics of Women and Behavior of Physicians at
`Start of Therapy
`Among the 24,503 women who completed first tele-
`phone interviews, the median age was 26 years (the
`10th and 90th percentiles were 17 and 39, respective-
`ly), the median number of years of education was 14
`(i.e., 2 years beyond high school), and the median du-
`ration of acne was 8 years. Dermatologists were the
`prescribing physicians for 92 percent of the patients.
`Past treatments for acne (data unavailable for 1989) in-
`cluded oral antibiotics (96 percent of the patients), tret-
`inoin (Retin-A) (82 percent), benzoyl peroxide (74 per-
`cent), and orally administered vitamin A (11 percent).
`Selected information related to the behavior of phy-
`sicians is shown in Table 1. Virtually all the women
`were told of the importance of avoiding pregnancy; 85
`percent were told of the importance of using effective
`contraception for one month before starting isotreti-
`noin. In 1989–1990, 78 percent were told to wait for
`pregnancy-test results and 63 percent to wait until the
`next menstrual period before starting isotretinoin. For-
`ty-six percent of the women reported having serum
`pregnancy tests before starting treatment; 60 percent
`had had some type of pregnancy test. These findings
`prompted the manufacturer, in late 1990, to introduce
`a new medication package with certain points high-
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on May 27, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`PAR1029
`IPR of U.S. Patent No. 8,731,963
`Page 2 of 6
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`Vol. 333 No. 2
`
`PREVENTION OF PREGNANCY IN WOMEN RECEIVING ISOTRETINOIN
`
`103
`
`Table 1. Selected Information Obtained from Telephone Interviews with Women of
`Childbearing Age Conducted at the Start of Therapy with Isotretinoin.
`*
`
`S
`
`URVEY
`
` Q
`
`UESTION
`
`URVEY
`
` Y
`
`EAR
`
`N
`
`N
`
`N
`
`N
`
`N
`
`N
`
`1993
`⫽
`5014)
`
`
`ALL
`⫽
`23,740)
`
`(
`
`99
`84
`
`87
`
`77
`
`56
`69
`
`99
`85
`
`82
`
`70
`
`51
`64
`
`these, 122,582 (99 percent) reported
`taking isotretinoin for less than 365
`days; except where otherwise noted,
`analyses are restricted to the latter
`group.
`The median duration of therapy
`for women followed by telephone
`was 141 days, and for those followed
`by mail, it was 140 days. There were
`45,773 person-years of isotretinoin
`exposure. Pregnancies during thera-
`py were reported by 402 women (0.3
`percent); 46 were pregnant when
`therapy began, and 356 became
`pregnant during therapy. The preg-
`nancy rate for the survey population
`(Table 3) was 3.4 per 1000 20-week
`courses of isotretinoin (the annual-
`ized rate was 8.8 per 1000 person-
`years) (Fig. 1). (Among 1382 wom-
`en who took isotretinoin for one to
`two years, there were 1727 person-
`years of exposure and 19 pregnancies, for a rate of 11.0
`per 1000 person-years.) The pregnancy rates were 3.1
`and 3.4 per 1000 20-week courses for the women in the
`telephone and mail groups, respectively. Among the
`138 women in the telephone group who were warned
`not to continue isotretinoin therapy without taking
`steps to avoid pregnancy (69 of whom reported nonsur-
`gical infertility), 2 subsequently became pregnant (1 of
`whom had reported being infertile); exclusion of this
`group did not appreciably affect the pregnancy rate
`among women followed by telephone. Data for 1989 to
`1993 suggest a decrease in the pregnancy rate over
`time, though continuing follow-up for the most recent
`cohorts may produce slight changes in these rates.
`Overall, 46,249 women reported not using birth con-
`trol (on the basis of telephone data, approximately 99
`
`1989
`⫽
`4308)
`
`(
`
`1990
`⫽
`5016)
`
`(
`
`S
`1991
`⫽
`4685)
`
`(
`
`1992
`⫽
`4717)
`
`(
`
`(
`
`percentage of women answering yes
`
`Did your doctor tell you the
`importance of
`Avoiding pregnancy?
`Using effective contracep-
`tion for 1 month before
`starting isotretinoin?
`Waiting for pregnancy-test
`result before starting
`isotretinoin?
`Waiting until next men-
`strual period before
`starting isotretinoin?
`Did you have a pregnancy
`test before starting
`isotretinoin?
`Serum test
`Any test
`
`99
`85
`
`79
`
`64
`
`48
`62
`
`98
`85
`
`77
`
`63
`
`45
`58
`
`98
`88
`
`83
`
`74
`
`54
`67
`
`99
`84
`
`85
`
`75
`
`54
`66
`
`lighted in large, bold print. These included warnings
`about the need to have a negative blood pregnancy test
`before starting therapy; to wait until the next menstru-
`al period before starting therapy; and to use effective
`birth control one month before starting therapy, during
`therapy, and one month after completing it. During the
`next three years, compliance with the first two behav-
`ioral recommendations increased (by approximately 10
`to 25 percent, as gauged by responses to questions 3, 4,
`and 5 in Table 1).
`Overall, 96 percent of the women interviewed indi-
`cated that they were not sexually active or that they
`were using birth control. Early in 1992, the question-
`naire was modified to allow more complete information
`to be obtained regarding sexual activity and birth con-
`trol; among 9593 women interviewed since then, 3.7
`percent were infertile (3.3 percent because of hysterec-
`tomies and 0.4 percent for other reasons) and in 0.3
`percent the risk of pregnancy was unknown. The larg-
`est proportion, 54 percent, were not sexually active (20
`percent used birth control and 34 percent did not),
`whereas 42 percent were sexually active (41 percent
`used birth control and 0.6 percent did not). (For sexu-
`ally active women who did not use birth control, the
`survey staff intervened by reading to them a warning
`about the risk of birth defects and by requesting per-
`mission to inform the prescribing physician.)
`Information about the women’s contraceptive status
`at the start of therapy is shown in Table 2 according to
`age. Methods are classified according to the schema
`used in the 1988 National Survey of Family Growth, a
`periodic survey that identifies reproductive factors in a
`
`nationally representative sample of U.S. women.
`5
`
`Outcomes
`As of June 30, 1994, 124,216 women had completed
`final telephone interviews or mailed questionnaires. Of
`
`*The table excludes data on 763 women who reported having undergone hysterectomy or being postmenopausal.
`
`Table 2. Contraceptive Status of the Women, as Ascertained by
`Telephone Interviews at the Start of Therapy, According to Age.
`*
`
`C
`
`ONTRACEPTIVE
`
` S
`
`TATUS
`
`⬍
`25
`⫽
`11,220)
`
`(
`
`N
`
`(
`
`N
`
` (
`
`GE
`
`A
`25–34
`⫽
`8287)
`
`YR
`
`)
`
`35–44
`⫽
`4299)
`
`(
`
`N
`
`⭓
`⫽
`
`45
`697)
`
`(
`
`N
`
`Not practicing contraception
`Not sexually active
`Sexually active
`Practicing contraception†
`Tubal ligation or hysterectomy
`Vasectomy
`Birth-control pill
`Intrauterine device
`Diaphragm
`Condom
`Rhythm method
`Other
`Nonsurgically sterile
`Unknown
`
`56
`55
`1
`44
`⬍
`1
`⬍
`1
`35
`⬍
`1
`1
`4
`⬍
`1
`3
`⬍
`1
`⬍
`1
`
`percentage
`
`19
`19
`⬍
`1
`80
`12
`10
`39
`1
`5
`8
`⬍
`1
`4
`⬍
`1
`⬍
`1
`
`12
`12
`⬍
`1
`85
`35
`20
`12
`2
`4
`6
`⬍
`1
`4
`2
`⬍
`1
`
`13
`11
`3
`78
`49
`16
`2
`2
`2
`3
`⬍
`1
`3
`5
`3
`
`*Totals may not equal 100 percent, because of rounding.
`†The primary method was determined with the use of the schema of the National Survey of
`Family Growth.
`5
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on May 27, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`PAR1029
`IPR of U.S. Patent No. 8,731,963
`Page 3 of 6
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`104
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`July 13, 1995
`
`Outcome
`
`Elective termination
`Other
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`During
`treatm ent
`
`1 M o after
`treatm ent
`
`2 M o after
`treatm ent
`
`3 M o after
`treatm ent
`
`4 M o after
`treatm ent
`
`Pregnancy Rate per 1000
`
`Person-Years
`
`Figure 1. Pregnancy Rates and Outcomes during and after Ther-
`apy with Isotretinoin in 122,582 Women, 1989 to 1993.
`
`isotretinoin; thus, five infants (38 percent) were judged
`to have defects compatible with the isotretinoin embry-
`opathy. Birth records available for four additional in-
`fants revealed no defects. Parental reports, available
`for 13 of the remaining 15, identified 1 infant as having
`cerebral palsy and developmental delay and 1 who died
`from defects involving the ear, eye, heart, kidney, and
`liver.
`
`Table 3. Pregnancy Rates during Isotretinoin Treatment, Based on Completed
`Follow-up by Telephone and Mail.
`*
`
`percent were not sexually active at the beginning of
`therapy or during it). Eighty-eight became pregnant
`during treatment (1.9 per 1000 20-week courses). In
`comparison, among the 76,149 women who practiced
`contraception, 268 became pregnant (3.6 per 1000 20-
` On the basis of the primary
`week courses) (P<0.001).
`6
`contraceptive method being used at the start of treat-
`ment (reported in the third telephone interview or the
`second mailed questionnaire), we estimated method-
`specific pregnancy rates during therapy. Among women
`using nonsurgical means of contraception, rates for the
`most commonly used methods were 3.2 pregnancies
`per 1000 20-week courses for birth-control pills (39,053
`women), 10.3 for condoms (7686 women), and 8.1 for
`diaphragms (3023 women). The rates among women
`who had had tubal ligations or whose male partners
`had had vasectomies were 0.4 (4 of 10,949 women) and
`0.3 (2 of 7394 women), respectively.
`There were 136 pregnancies that were conceived
`during the month after discontinuation of therapy, for a
`rate of 13.4 per 1000 person-years (Fig. 1). Pregnancy
`rates were also calculated for the next three months,
`when pregnancy was no longer discouraged by the pro-
`gram; these were 29.0, 37.1, and 43.2 per 1000 person-
`years, respectively.
`Of the 402 women with pregnancies conceived during
`treatment with isotretinoin, 290 (72 percent) had elec-
`tive terminations, 63 (16 percent) had spontaneous
`abortions, 13 (3 percent) had ectopic pregnancies, none
`had stillbirths, 32 (8 percent) had live births, and in 4 (1
`percent) the outcome could not be determined. Among
`the 136 pregnancies occurring during the month after
`therapy, a smaller proportion (55 percent) were elective-
`ly terminated and a larger proportion (28 percent) were
`carried to term or were continuing at the time of analy-
`sis. For pregnancies occurring in the subsequent three
`months, 23 percent were terminated and 61 percent
`were carried to term or were continuing.
`Among the 32 liveborn infants, 13 had been exam-
`ined by the survey teratologist by January 1995. Six had
`no defects, one had major anomalies (ear, eye, cranio-
`facial, and brain), and six had minor anomalies (ear in
`two, ear and craniofacial in two, and hypoplastic scro-
`tum and confluent eyebrows in one each). The examin-
`er, who knew the exposure status of the mothers, did
`not consider the latter two defects to be associated with
`
`V
`
`ARIABLE
`
`1989
`
`1990
`
`1991
`
`1992
`
`No. of women
`Pregnancies reported†
`Person-years of isotreti-
`noin exposure
`Rate per 1000 20-wk
`courses of isotretinoin
`
`18,075
`73
`7,045
`
`28,757
`102
`10,759
`
`29,639
`91
`11,093
`
`30,048
`90
`11,190
`
`4.0
`
`3.6
`
`3.1
`
`3.1
`
`D
`ISCUSSION
`Among women enrolled in this survey, understand-
`ing of the teratogenic risks of isotretinoin and of the
`need to avoid pregnancy was virtually universal. Com-
`pliance with other aspects of the program was less
`complete, although in no case did compliance for any
`measure decline during the study period. Apart from
`ensuring that the women understood the risks, perhaps
`the most important aspect of the program was the rec-
`ommendations that women ensure that pregnancy tests
`were negative, that they wait until menses had begun
`before initiating isotretinoin therapy, and that they
`use effective birth control preceding, during, and im-
`mediately after treatment. Information from the first
`months of the survey revealed incomplete compliance
`with these guidelines. As a result, the manufacturer re-
`inforced physician education about these three recom-
`mendations and changed the medication package to
`highlight their importance. Within months after distri-
`bution of the new package, compliance with these rec-
`ommendations, though still incom-
`plete, improved.
`Whatever attention is directed to
`the education and compliance of pa-
`tients and physicians, the most rele-
`vant measure of the effectiveness of
`efforts to prevent pregnancies is the
`pregnancy rate. Among U.S. women
`15 to 44 years of age, the pregnancy
`rate is approximately 109 per 1000
` For women in the
`person-years.
`7
`same age group in the survey popu-
`lation, the rate during isotretinoin
`
`1993
`
`16,063
`46
`5,686
`
`A
`
`LL
`
`122,582
`402
`45,773
`
`3.1
`
`3.4
`
`*The table excludes data on 1634 women who reported taking isotretinoin for one year or more and includes 78 reports
`of pregnancies awaiting confirmation.
`†Values include 46 women who were pregnant at the time they began taking isotretinoin.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on May 27, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`PAR1029
`IPR of U.S. Patent No. 8,731,963
`Page 4 of 6
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`Vol. 333 No. 2
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`PREVENTION OF PREGNANCY IN WOMEN RECEIVING ISOTRETINOIN
`
`105
`
`exposure was 8.8 per 1000 person-years, or approxi-
`mately 8 percent of that of the general population.
`The program sought to exclude from isotretinoin
`treatment women who were at high risk of becoming
`pregnant. The prevalence of sexually active women not
`using contraception was low (0.6 percent), and among
`those practicing contraception the use of oral contra-
`ceptives (one of the most effective methods) was high
`(49 percent) as compared with the respective propor-
`tions (7 and 28 percent) in the National Survey of Fam-
` Irrespective of method, major factors as-
`ily Growth.
`5
`sociated with successful contraception include duration
`of use, education, and motivation.
` We have only re-
`8
`cently collected information on duration of use, but we
`know that the enrolled population was relatively well
`educated and that motivation was likely to have been
`quite high, given knowledge of the risks. Furthermore,
`pregnancy had to be avoided for only six months, on av-
`erage. Thus, the observed low rates are compatible
`with the demographic and other characteristics of these
`women. Though a causal link between implementation
`of the program and low rates of pregnancy cannot be
`proved by observational study, such an effect is likely,
`given the frequency of reported compliance with com-
`ponents of the program.
`In a survey based on self-reports, one must ask
`whether the information is valid. Follow-up rates were
`high in both the telephone and mail groups, and re-
`sponses regarding knowledge, behavior, and compli-
`ance were similar whether elicited at the start of treat-
`ment (in the first telephone interview) or six months
`after its completion (in the second mailed question-
`naire) (data not shown). The low pregnancy rates dur-
`ing isotretinoin treatment and the increase in preg-
`nancies in the four months afterward are consistent
`with intentional avoidance of pregnancy during the
`period of teratogenic risk. The high proportion of
`women having therapeutic abortions during treatment
`and the low proportion having them during the subse-
`quent four months further support the validity of these
`data. Although some underreporting of pregnancies
`and therapeutic abortions is likely, we believe that the
`survey design and study population minimize this
`problem.
`Evaluation of the representativeness of a survey
`based on voluntary enrollment requires information on
`both the total number of women of childbearing age
`who are treated with isotretinoin and the differences
`between enrolled and unenrolled women. Unfortunate-
`ly, the number of treated women is not known. Avail-
`able estimates, based on complex and unvalidated as-
`sumptions, suggest that the numbers of women of
`childbearing age for whom isotretinoin was prescribed
`were approximately 76,094 in 1991, 83,887 in 1992,
`and 90,390 in 1993 (Bylancik A, Hoffmann–La Roche:
`personal communication). If these estimates are cor-
`rect, we can assume on the basis of their 95 percent
`confidence intervals that the 117,652 women who en-
`rolled in the survey represented 44 to 52 percent of the
`
`women treated with isotretinoin. Whether participants
`differed in pregnancy risk from women who did not en-
`roll is not known. We assumed, a priori, that the wom-
`en who did not enroll were more likely to be noncom-
`pliant and at high risk for pregnancy; on the other
`hand, women may not enroll specifically because they
`are infertile or in other ways not at risk for pregnancy.
`Despite its limitations, we believe that our design
`was as successful as could be expected in a setting of
`voluntary participation. Alternative designs cannot en-
`sure representativeness, and because of the need for
`patient consent, the potential for selection bias is ines-
`capable.
`Before the introduction of isotretinoin, the unique is-
`sues related to teratogenic drugs were not adequately
`considered — such drugs were either removed from use
`or left on the market with no pregnancy-prevention
`program. The isotretinoin program offers a novel ap-
`proach that seeks to keep the drug available while min-
` The results suggest
`imizing the teratogenic hazard.
`4
`that the program encourages communication between
`physicians and patients regarding the drug’s teratogen-
`ic risk and the need to prevent pregnancy, promotes the
`selection of patients at low risk for pregnancy, and is as-
`sociated with low pregnancy rates. These benefits oc-
`curred in a particular context: physicians and patients
`were highly committed to using the drug, pregnancy
`had to be avoided for only a limited time, and the phy-
`sicians belonged largely to a single specialty (dermatol-
`ogy), enhancing the feasibility of the educational cam-
`paign.
`Whether similar benefits could be achieved with
`drugs used for other purposes remains unclear, but this
`question may soon require resolution. Thalidomide ap-
`pears to be an effective treatment for various medical
` as does methotrexate,
` prompting in-
`conditions,
`9-11
`12,13
`terest in making these teratogenic drugs more widely
`available.
` The experience gained with isotretinoin
`10,13-15
`can serve as a basis for considering how such drugs
`should be used and monitored, with a view to ensuring
`that pregnancies and malformations are reduced to an
`absolute minimum.
`
`We are indebted to the following members of the Slone Epidemi-
`ology Unit Accutane Advisory Committee, who provided independ-
`ent and critical advice in the design, analysis, and interpretation of
`this survey: P. Stolley, M.D. (chair), E. Decker, Pharm.D., K. McKoy,
`M.D., J. Melski, M.D., P. Pochi, M.D., R. Stern, M.D., C. Catz, M.D.
`(National Institute of Child Health and Human Development liai-
`son), J. Cordero, M.D. (Centers for Disease Control and Prevention
`liaison), W. Dai, M.D., Dr.P.H., and J. LaBraico, M.D. (Hoffmann–
`La Roche liaison); to D. Gute, M.P.H., Ph.D., for his assistance in the
`initial survey design; to E. Lammer, M.D., for conducting the infant
`examinations; to J. Trussell, Ph.D., for guidance in assessing contra-
`ceptive efficacy; to the American Academy of Dermatology for its
`support; to the Slone Survey staff; to S. Shapiro, M.B., for his support
`and advice; and to the many physicians and patients who participat-
`ed in the survey.
`
`R
`
`EFERENCES
`
`1. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl
`J Med 1985;313:837-41.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on May 27, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`PAR1029
`IPR of U.S. Patent No. 8,731,963
`Page 5 of 6
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`

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`106
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`THE NEW ENGLAND JOURNAL OF MEDICINE
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`July 13, 1995
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