MJA: Chan et al., Oral retinoids and pregnancy

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Oral retinoids and pregnancy

Annabelle Chan, Marshall Hanna, Malcolm Abbott and Rosemary J Keane

MJA1996; 165: 164-167

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Introduction - Adverse reactions - Teratogenicity - Prescribing guidelines - Compliance - Pregnancy prevention programs - Recommendations - Conclusions - Acknowledgements - References - Authors' details

The oral retinoids isotretinoin and etretinate are uniquely effective in the treatment of severe cystic acne and keratinisation disorders. Because of their known teratogenicity, there are strict prescription guidelines, but exposure during pregnancy still occurs. A dedicated effort by women and their clinicians is required, involving patient selection, education and informed consent, detailed contraceptive counselling, and careful monitoring and management, including pregnancy testing before commencement of therapy. (MJA 1996; 165: 164-167)

Introduction

T he Australian Drug Evaluation Committee lists only five drugs in Medicines in pregnancy ¹ as Category X -- drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. The oral retinoids isotretinoin (Roaccutane, Roche) and etretinate (Tigason, Roche) are two of the five listed. The newly released acitretin (Neotigason, Roche) should also be included.

These synthetic retinoids closely resemble naturally occurring vitamin A, essential for the maintenance of visual and reproductive function and for proliferation and differentiation of epithelial tissues. ² They were released in the United States and Europe in 1982 and in Australia towards the end of 1985. Acitretin was released in Australia in late 1995 to replace etretinate, as it is more rapidly eliminated from the body. Isotretinoin is uniquely effective in severe cystic acne, and etretinate and acitretin in severe psoriasis and other keratinisation disorders which have proved recalcitrant to all other therapies. This accounts for their availability on prescription despite their teratogenicity .

Adverse reactions

The commonly reported adverse reactions (which are largely dose-related, of early onset and reversible on discontinuation) include dryness of the lips, mouth and eyes, hair loss and pruritus. ³ Less common but more severe, probably idiosyncratic, reactions (which may occur after weeks or months of therapy) include altered vision, headache, joint and muscle pain, abnormally raised serum transaminase levels, serum lipid changes, as well as increases in serum triglyceride and chol esterol levels and an increase in low density : high density lipoprotein ratio. Rare reactions include mental depression, severe hepatitis, diffuse hyperostosis of the spine and benign intracranial hypertension.

Teratogenicity

The most serious side effect, teratogenicity, was foreshadowed by animal studies, so that, at the time the drugs were released, strong warnings against exposure during pregnancy were given. The retinoids are believed to interfere with the activity and migration of cranial neural crest cells during development and thus cause craniofacial, thymic, conotrun cal heart and central nervous system malformations ^4,5 (Box 1). Intellectual deficits in more than half the children exposed in utero have also been reported in follow-up studies to five years of age. ⁶

Isotretinoin Any fetal exposure during the first trimester within the therapeutic dose range of isotretinoin may be teratogenic. ⁷ Isotretinoin has a short elimination half-life of about 20 hours and the recommended contraception period after cessation of therapy is one month. Estimates from prospectively reported (i.e., before outcome was known) exposed pregnancies place the risk of teratogenicity for isotretinoin for first trimester exposure at around 28%, ⁷ reducing to around 4% for pregnancies occurring within one month of cessation of treatment ⁸ (Box 2).

Etretinate Birth defects associated with etretinate include meningomyelocele, craniofacial and skeletal abnormalities and brain defects. ^4,5 Etretinate is readily taken up into adipose tissue and slowly released from it. Thus, it has a long elimination half-life (120 days or more ² ) and the recommended contraception period after therapy is two years. The best estimate from the literature of the risk of teratogenicity for exposure to etretinate during pregnancy is about 26%, ⁹ but the risk is likely to be less, as the pregnancies considered probably include retrospectively reported ones (in which there is a tendency to under-report normal outcomes). The risk for pregnancies occurring within two years of cessation of treatment appears to be considerably less, about 2%. All estimates are based on relatively few pregnancies (Box 2).

Acitretin In spite of a shorter elimination half-life of 50 hours, a two-year contraception period after therapy has also been recommended for acitretin, as in some women there is conversion of acitretin to etretinate during therapy. ^2,3,9 Up to 1994, there had been no exposures to acitretin during pregnancy reported prospectively to the manufacturer (Roche) with known outcomes; of three reported retrospectively, one aborted fetus had characteristic defects, one baby had high frequency hearing loss and a third was normal. None of the 32 prospectively reported pregnancies conceived in the two-year period after therapy has resulted in an infant with a birth defect (S Weber, Roche Products Medical Information Department, personal communication).

Prescribing guidelines

In Australia, authority to prescribe oral retinoids for specified conditions needs to be obtained under the Pharmaceutical Benefits Scheme, and they can only be prescribed by dermatologists (except in regions where there is no derm atologist available and a specialist physician may have authority to prescribe under State law). However, in the United States and Canada, ¹⁰ general practitioners and physicians may also prescribe these drugs.

Roche recommends that:

The possibility of pregnancy must be ruled out by a pregnancy test within two weeks before commencing treatment.
Treatment should be commenced on the second or third day of the next normal menstrual period.
An effective form of contraception should be used for at least one month before treatment, during treatment and for at least one month after cessation of treatment with isotretinoin, and for two years after treatment with etretinate and acitretin.
Women should be effectively counselled about the risks to a fetus, and if pregnancy does occur they should immediately stop taking the drug and seek medical advice.
To increase understanding of the implications of treatment, a specially designed consent form should be signed by the patient before commencing treatment.
Breastfeeding should not occur while a woman is taking oral retinoids. The drugs should not be given to others, and should be kept out of reach of children.

The manufacturer has also made available to dermatologists patient information pamphlets (also in several languages other than English), contraceptive guidelines and a special consent form for treatment. A warning that the product causes birth defects is carried on the drug package as well as the dispensed product. The Australasian College of Der matologists has provided comprehensive guidelines for prescription, focusing on signed informed consent for treatment, the performance of tests for pregnancy, liver function and lipid levels before treatment, and the importance of regular review.

Compliance

Despite these measures, exposure to the drugs during pregnancy has occurred both in Australia ^11,12 and in other countries. While most women have been advised of the teratogenicity of the drugs, there has been less strict compliance with pregnancy tests and signed consent before initiation of treatment, with 4% of dermatologists in the Netherlands, ¹³ 73% in the United States ¹⁴ and 80% in Australia ¹¹ undertaking pregnancy tests, and 59% in the United States ¹⁴ obtaining signed consent for therapy. About a third of the women in the United States and Canada with exposure during pregnancy were already pregnant at the time therapy was commenced; ^4,7 33% in one study ⁴ and 40% in the other ⁷ were not using contraception, while 26% were using less reliable methods and 65% of those taking oral contraception reported using contraception irregularly. ⁷ Women under 25 years showed the poorest compliance (50%) with contraceptive use. ⁷ Use of oral retinoids for other than the specified indications has been reported, ^13,14 as well as prescription by unauthorised doctors, ¹² and use of drugs left over from previous prescriptions or obtained from friends or relatives. ⁷

Pregnancy prevention programs

Pregnancy prevention programs ^15,16 instituted in 1988 by the manufacturer and the US Food and Drug Administration included additional features such as a check list of selection criteria for suitable patients, a self-evaluation test for patients, drug packages with drawings of associated birth defects and "avoid pregnancy" icons, a contraception referral program with reimbursement for the first visit by the manufacturer, a recommendation to use two forms of contraception simultaneously, ¹⁶ and periodic communications with prescribers and pharmacists. Encouraging outcomes were achieved among participants, such as a low pregnancy rate of 3.4 per 1000 courses of treatment with isotretinoin, ¹⁵ and a trend towards more appropriate use of contraception among women who were counselled with the entire program. ¹⁶ Even so, compliance with the guidelines, such as pregnancy testing (64% ¹⁵ ), waiting until the next menstrual period before commencing therapy (70% ¹⁵ ) and use of effective contraception, was still incomplete.

Recommendations

While the search continues for safer drugs, how can we reduce the risk of pregnancy in women taking oral retinoids while achieving maximum benefits from this unique group of drugs? (see Box 3).

Conclusions

A recent study ²⁰ has provided further support for the teratogenicity of preformed vitamin A in dosages of 10 000 IU or more daily in the form of supplements. The recommended daily amount of vitamin A for women in Australia is 2500 IU and supplements exceeding this or heavy consumption of liver and liver products ² should be avoided, particularly during therapy with oral retinoids, as well as during pregnancy.

The successful implementation of a pregnancy prevention program during oral retinoid therapy could be viewed as a pregnancy rate no greater than the failure rate of the recommended contraceptive method. If this is taken as 0.3 per 100 woman-years for the combined oral contraceptive pill ¹⁸ (with the potential to be less with the simultaneous use of another method), then the pregnancy rate during therapy with isotretinoin, with an average contraception period of six months per woman per course (four months for treatment ¹¹ and one month before and after therapy), ideally should not exceed 1.5 per 1000 courses of treatment. The estimated rates of 3.1 terminations per 1000 courses of treatment with isotretinoin ¹² and 3.4 pregnancies per 1000 courses of treatment ¹⁵ recently reported are relatively low but can be reduced further. This requires the wholehearted commitment of women and their clinicians.

Acknowledgements

We are grateful to the staff of the South Australian Health Commission Library for helping us to obtain the references and many others not listed, and to Roche Products Medical Information Department for additional references and statistics on exposed pregnancies.

References

Australian Drug Evaluation Committee. Medicines in pregnancy. An Australian categorisation of risk of drug use in pregnancy. 2nd ed. Canberra: AGPS, 1992.
Chalmers RJG. Retinoid therapy -- a real hazard for the developing embryo. Br J Obstet Gynaecol 1992; 99: 276-278.
Saurat J-H. Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992; 27: S23-S28.
Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837-841.
Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986; 33: 355-364.
Teratology Society: recommendations for isotretinoin use in women of childbearing potential. Teratology 1991; 44: 1-6.
Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26: 599-606.
Dai WS, Hsu M-A, Itri LM. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 1989; 125: 362-365.
Geiger J-M, Baudin M, Saurat J-H. Teratogenic risk with etretinate and acitretin treatment. Dermatology 1994; 189: 109-116.
Hogan DJ, Strand LM, Lane PR. Isotretinoin therapy for acne: a population-based study. Can Med Assoc J 1988; 138: 47-50.
Lee M, Cooper A. Survey of Australian isotretinoin prescribing. Australas J Dermatol 1991; 32: 13-16.
Chan A, Keane RJ, Hanna M, Abbott M. Terminations of pregnancy for exposure to oral retinoids in South Australia, 1985-1993. Aust N Z J Obstet Gynaecol 1995; 35: 422-426.
Eurocat. Surveillance of the retinoic acid embryopathy: a pharmacy based study. Eurocat Newsletter December 1992; 6(4).
Doering PL, Araujo OE, Frohnapple DJ, et al. Patterns of prescribing isotretinoin: focus on women of childbearing potential. Am Pharmacother 1992; 26: 155-161.
Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 1995; 333: 101-106.
Pastuszak A, Koren G, Rieder MJ. Use of the retinoid pregnancy prevention program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 1994; 8: 63-68.
Kovacs G. Oral contraceptives -- can we make them more effective? Med J Aust 1993; 159: 224-225.
Ceyrac DL, Serfaty D, Lefrancg H. Retinoids and contraception. Dermatology 1992; 184: 161-170.
Sturkenboom MCJM, de Jong-van den Berg LTW, van Voorst-Vader PC, et al. Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment. Br J Clin Pharmacol 1994; 38: 229-235.
Rothman K, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995; 333: 1369-1373.

Authors' details

South Australian Health Commission, Public and Environmental Health Service, Adelaide, SA.
Annabelle Chan, FAFPHM, Senior Medical Consultant, Pregnancy Outcome Unit; and South Australian Birth Defects Register, Women's and Children's Hospital, North Adelaide, SA. Malcolm Abbott, AUA, FSHP, Pharmacist, Therapeutic Goods Section; currently Rural Pharmacist, Territory Health Services, Katherine District, NT.
Rosemary J Keane, RN, RM, Midwife, Pregnancy Outcome Unit.
Flinders Medical Centre, Adelaide, SA.
Marshall Hanna, FRACP, FACD, Senior Visiting Dermatologist, Department of Dermatology.
Reprints and Correspondence: Dr A Chan, South Australian Health Commission, Public and Environmental Health Service, PO Box 6, Rundle Mall, Adelaide, SA 5000.