Young women taking isotretinoin still conceive: Role of physicians in preventing disaster

Gordana Atanackovic, MD; Gideon Koren, MD, FRCPC

February, 1999

Isotretinoin was introduced for clinical use 16 years ago as effective treatment for severe cystic acne, and more than 100000 female patients are exposed to isotretinoin yearly in the United States.¹ Because preclinical studies of laboratory animals showed isotretinoin to be teratogenic,² and because the elimination half-life was relatively short (14.7 hours) in healthy volunteers,³ the drug was contraindicated for women who were or might become pregnant during therapy and in the month following discontinuation of therapy. It soon became apparent, however, that women conceived while receiving the medication, and rates of teratogenicity were high.

The patterns of retinoic acid embryopathy are well-known today. They include central nervous system, cardiovascular, craniofacial, and thymic malformations.⁴ Cognitive deficits in more than half the children exposed in utero have also been reported in follow-up studies to 5 years of age.⁵

Because standard labeling of the medication was not shown to prevent fetal exposure to isotretinoin, a Pregnancy Prevention Program for isotretinoin was developed by the manufacturer and the United States Food and Drug Administration. The program includes printed material for prescribing physicians to use in educating female patients about the serious risk for birth defects⁶ and instructions for physicians to obtain negative pregnancy test results before prescribing the drug and to delay therapy until the second or third day of the next normal menstrual period. The program strongly suggests simultaneous use of two forms of contraception in an attempt to further reduce the likelihood of fetal exposure. In addition, female patients are asked to sign a consent form acknowledging that they have been instructed through the Pregnancy Prevention Program, that they are aware of the need for contraception during isotretinoin therapy, and that they will undergo pregnancy testing before, during, and after isotretinoin therapy.^7,8

Despite these precautions, the Motherisk Program's teratogen information service in Toronto still records new cases of fetal exposure to isotretinoin every year.⁹ We recently published four new cases of isotretinoin exposure during pregnancy to highlight continuing problems in implementing the Pregnancy Prevention Program because of patients' and physicians' noncompliance.⁹

Case 1

A 17-year-old woman in her first pregnancy gave birth following exposure to 60 mg/d of isotretinoin from 3 months before conception to the end of her first trimester. Her physician verbally advised her that, while receiving therapy with this medication, she should not conceive and that, if she became sexually active, she should use contraception. She also received pamphlets on isotretinoin. Although she fully understood the meaning of the information provided, she chose not to use contraception because "she did not intend to have sex."

Her pregnancy was diagnosed at 23 weeks' gestation. She was informed about the option of terminating the pregnancy and was offered the telephone number of an appropriate clinic. She decided to continue the pregnancy. Level 2 ultrasound examination did not reveal any abnormalities.

A male infant of 3000g was born after full-term pregnancy by normal vaginal delivery. The infant, who did not cry at birth, experienced neonatal respiratory distress. His Apgar score was 1/5 (1 min/5 min, respectively). His head was microcephalic (32cm, <3%), and his facial features included a cupped thickened helix, a depressed nasal bridge, a cleft of soft and hard palate (without family history), and micrognathia. On two-dimensional echocardiographic examination, a small patent ductus arteriosus was detected.

Case 2

A 20-year-old woman in her second pregnancy took 20 10-mg tablets of isotretinoin during the first 4 weeks of an unplanned pregnancy. The medication had been prescribed the previous year for cystic acne by a dermatologist, but she had not taken it at that time. The woman was informed verbally by her physician about the teratogenic effects of isotretinoin and advised about proper contraception. She was not informed about the Pregnancy Prevention Program and did not receive any printed material. She reported using birth control pills, but not regularly.

Even though she was informed about the increased risk of having a baby with major malformations, she decided to continue the pregnancy. She did not know the date of her last menstrual period, and ultrasound examination at 17 weeksí gestation did not show fetal abnormalities. She delivered a full-term baby by cesarean section. At birth, apart from hydrocele, the infant appeared normal.

Case 3

A 16-year-old adolescent was prescribed 40 mg of isotretinoin daily for cystic acne by her dermatologist. She was told she should not conceive while receiving therapy, and a blood test was done to exclude pregnancy before initiation of therapy. She did not receive the Pregnancy Prevention Program or any other written material. She visited her family physician, who prescribed birth control pills. She started isotretinoin treatment before results from the pregnancy test were obtained. Results were positive. In the meantime, she had taken three isotretinoin tablets. Because she did not remember the date of her last period, ultrasound examination was performed to determine the exact time of exposure, which turned out to be at 9 weeksí gestation. She was counseled by her physician and she contacted the Motherisk Program regarding the risks associated with isotretinoin exposure. After counseling she decided to continue the pregnancy until ultrasound examination results were obtained.

Even though results were negative for major malformations at 18 weeksí gestation, she decided to terminate the pregnancy. Pathologic findings after termination revealed no obvious internal or external abnormalities.

Case 4

A 21-year-old woman in her first pregnancy was treated for cystic acne with 40 mg of isotretinoin daily by her dermatologist. She was informed about the teratogenic effects of isotretinoin, received the Pregnancy Prevention Program, and signed the consent form. For contraception she chose condoms. Six weeks after discontinuing the drug, she found out she was pregnant. Because she did not know the date of her last menstrual period, ultrasound examination was performed. It showed she had conceived around the date she discontinued therapy. She delivered a full-term baby by cesarean section. At birth the infant was healthy and had no evident malformations.

Discussion

Half the pregnancies in North America are unplanned and might result in inadvertent fetal exposure to drugs.¹⁰ In 1994, we documented the demographic characteristics and pattern of use of contraceptives of Canadian women prescribed synthetic retinoic acids whose contraceptive methods failed. Our data showed that isotretinoin-exposed women were younger than their nonexposed controls, tended to be adolescents, and sought counseling later in gestation. The Pregnancy Prevention Program for isotretinoin was reasonably used by prescribing physicians in the first years, as documented by a trend to more appropriate use of contraception by patients counseled with the entire program.⁷

During the last 6 months, the Motherisk Program has recorded four new cases of isotretinoin exposure during pregnancy. All four patients were younger than 22 years, and all four pregnancies were unplanned. This might indicate that the potential risk was not considered seriously by this group. The three who used contraception used a single method (Table1), which is not the intent of the program.

All the women were verbally advised by their dermatologists not to conceive while receiving therapy and, if they were sexually active, to use contraception. Only one, however was given the full Pregnancy Prevention Program and signed the consent form. In case 3, the dermatologist did not follow the program guideline and did not wait until obtaining pregnancy test results, which led to starting isotretinoin after the patient was already pregnant.

It could be argued that these four cases do not necessarily reflect widespread physician noncompliance with the program. A recent letter from a Canadian dermatologist practising in British Columbia, however, substantiates our suspicions that these cases stem from widespread noncompliance by dermatologists, who are supposed to be the only specialists prescribing isotretinoin in Canada.¹¹

The best prevention program is doomed to fail if physicians do not adhere to it. Our cases indicate that full compliance is still an issue, as in case 4. Regulatory agencies, manufacturers, and especially prescribing physicians should ensure that fetal exposure to isotretinoin is prevented. Continuous failure to implement the Pregnancy Prevention Program and, in particular, to ensure contraception strongly suggests that prescription of isotretinoin should be coupled with referral to professional contraception counseling. Very often, young teenagers have little sexual experience and poor understanding of birth control methods, which substantially increases the risk of fetal exposure to isotretinoin.⁸ In addition, an educational program for physicians is needed to heighten awareness of this serious problem.

References

1. Dai WS, La Braico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26:599-606.
2. Kochhar DM. Teratogenic activity of retinoic acid. Acta Pathol Microbiol Scand 1967:70:398-404.
3. Colburn WA, Gibson DM. Isotretinoin kinetics after 80 to 320 mg oral doses. Clin Pharmacol Ther 1985;37:411-4.
4. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Broun JT, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41.
5. Teratology Society. Recommendations for isotretinoin use in women of childbearing potential. Teratology 1991;44:1-6.
6. Pastuszak AL, Koren G. The Retinoid Pregnancy Prevention Program. In: Koren G, editor. Retinoids in clinical practice. The risk-benefit ratio. New York, NY: Marcel Dekker; 1993. p. 147-75.
7. Pastuszak AL, Koren G, Rieder JM. Use of the retinoid pregnancy prevention program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Rep Toxicol 1994;8:63-8.
8. Koren G, Feldman Y, Shear N. Motherisk: a new approach to antenatal counseling of drug/chemical exposure. Vet Hum Toxicol 1986;28:563-5.
9. Atanackovic G, Koren G. Failure of the Pregnancy Prevention Program for isotretinoin: analysis of recent Canadian cases. Can Med Assoc J. In press.
10. Skrabanek P. Smoking and statistical overkill. Lancet 1992;340:1208-9.
11. Gregory WB. Isotretinoin and teratogenicity [letter]. Can J Clin Pharmacol 1997;4(3):3.

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto and edited by Dr G. Koren, Professor of Pediatrics in Pharmacology, Pharmacy, and Medicine at the University of Toronto.

Table 1. Compliance with the Pregnancy Prevention Program in the four cases

* Patient did not intend to be sexually active.

Ü Used oral contraceptives but irregularly.

á Oral contraceptives were started before isotretinoin, but woman was already pregnant, as was later confirmed by blood test.

** Condoms were used.