Preventive Medicine 45 (2007) 243–244www.elsevier.com/locate/ypmed

Letter to the Editor

Table 1Patient compliance to prescription information sheet of the drug (35/52 cases(67.3%)) a

Questionsbeforepregnancy,preconceptional

Questionsduringpregnancywithout drugexposure

Questionsduringpregnancywith drugexposure

Total

Acute cystic acne 7/9 17/21 1/5 25/35Information onteratogenicity

8/9 18/21 4/5 30/35

Pregnancy test priorto therapy

2/9 9/21 2/5 13/35

Use of contraception1 month prior,during, and 1month aftertherapy

6/9 14/21 0/5 20/35

Therapy begun 2ndand 3rd day ofmenstruation

5/9 5/21 0/5 9/35

a All prescriptions were made by a dermatologist.

The need for restricted prescription of retinoic acidderivative isotretinoin to prevent retinoid teratogenicity

Isotretinoin is a derivative of vitaminA used in the treatment ofacute cystic acne resistant to other conventional therapies. Variousstudies have shown that the exposure to 0.5–1.5 mg/kg/day ofisotretinoin in the first weeks of pregnancy, and in particular in thecritical period of the 2nd to the 5th weeks after conception, cancause a 40% rate of spontaneous abortion and a 26% risk ofmalformative syndrome (Lammer et al., 1985; Dai et al., 1992).

We sought to evaluate whether the systems of controlcurrently in use in Italy regarding the prescription of isotretinointo women of child bearing age are effective in preventingaccidental exposure during pregnancy and the resulting cases ofcongenital malformation syndrome for retinoids.

From July 2002 until October 2005 we enrolled all 52patients with isotretinoin exposure who contacted TelefonoRosso, a specialized phone service for teratological counselingand teratogenic risk evaluation and a member of the EuropeanNetwork of Teratology Information Services (ENTIS) (www.entis-org.com). At consultation, all patients were required toanswer specific questions in order to ascertain whether thewarnings contained on the prescription information sheet of thedrug had been respected.

At the time of counseling, 19 of those consulted (36.5%)were in the period of preconception, and we informed themabout the waiting period of 1 month before conception; 29(55.8%) were pregnant; and 4 involved paternal exposures. Inthe 4 paternal exposures and in 19 cases out of 29 pregnantwomen for whom the therapy was suspended for more than 1month before conception, we did not mention an increased riskof malformation. However, in the remaining 10 cases, for whomexposure had occurred during pregnancy or less than 1 monthbefore conception the increased risks of teratogenicity werespecifically conveyed to these women.

Among the latter 10 women, 4 cases were lost to follow-up.In the remaining 6 cases there was 1 spontaneous abortion at the8th week to a woman exposed until the 6th week of pregnancy;3 voluntary abortions due to exposure at the 2nd, 5th, and 6thweeks; and 2 live births without major birth defects, the firstborn at 39 weeks weighing 3450 g to a woman exposed until the3rd week prior to conception, and the second born at 40 weeksweighing 3800 g to a woman exposed to a single dose at the 4thweek. In addition, during this period, in our hospital one childwith a complex cardiopathy and bilateral anotia was born to awoman exposed to isotretinoin until the 5th week of pregnancy.

0091-7435/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.ypmed.2007.04.010

Our evaluation of the type of information received about thedangers associated with the use of the drug and the precautions tobe taken to avoid pregnancy is based on 35/52 (67.3%) cases withcomplete data (Table 1). The results show that even though thedrug was always prescribed by a dermatologist, in 10 women(28.6%) the indications were not followed correctly; 5 women(14.3%) claimed not to have received clear and precise informa-tion regarding the teratogenicity of the drug; 13 women (37.1%)took a pregnancy test before starting the therapy; 9 women(25.7%) began the therapy on the 2nd or 3rd day of menstruation;and 20 women (57.1%) indicated that they used contraception 1month before, during, and 1 month after the therapy.

These findings indicate that despite the dangers of teratogenic-ity of isotretinoin and the fact that themedication is only prescribedby a specialist, there have been cases in Italy of exposure to thedrug during pregnancy and that the rigorous implementationstandards of the pharmaceutical companieswere not followed. Ourservice responds to approximately 7000 calls a year nationwide, ofwhich 2% involve cases where exposure to a teratogenic agentis reported. Although this represents a relatively small number ofour case records, we believe that neither a single case of birthdefects is acceptable nor are the cases of legal termination ofpregnancy due to the risk of elevated exposure to a teratogen.

It is essential to provide further controls in the prescriptionand the ingestion of the drug. A rigorous program to ensure

244 Letter to the Editor

adequate control in the administration of isotretinoin to womenof child bearing age does not currently exist in Italy except inthe form of a drug information sheet providing the warningsbased on a European program for the prevention of pregnancyfrom 2003 (www.emea.eu.int/index/indexhl.htm). This year, theItalian Drug Agency (AIFA) has issued a set of regulationsregarding the prescription of isotretinoin. Educational materialfor doctors, pharmacists, and patients and a follow-up form forpossible pregnancies which may occur during the course of thetherapy will be provided as part of these measures. There willalso be an information sheet and a consent form to be signedby the patients. Notwithstanding, we firmly believe thatfurther precautionary measures along the lines of IPLEDGEenacted by the US Food and Drug Administration (FDA) inDecember 2005 (www.ipledgeprogram.com) must be adopted.This system was adopted after prevention programs developedby Hoffman-La Roche Inc. (Accutane Pregnancy PreventionProgram, created in 1988, and System to Manage Accutane-Related Teratogenicity, begun in 2002) turned out to be inade-quate and revealed a lack of compliance on the part of thepatient (Brinker et al., 2005).

IPLEDGE is a computer-based risk management programwhich states that no doctor can prescribe the drug and nopharmacist can distribute the drug without prior enrollment inthe program and that all patients who take isotretinoin mustregister in the program. All doctors, before prescribing the drug,must enter the relative information on pregnancy testing and thetype of contraception used and provide counseling to each

individual patient. We aspire towards a procedure of this kind inItaly and in Europe as only a single centralized control of eachand every case of prescription can guarantee adherence to safetyprotocols and ensure follow-up of all possible cases ofpregnancy during the course of therapy.

References

Brinker, A., Kornegay, C., Nourjah, P., 2005. Trends in adherence to a revisedrisk management program designed to decrease or liminate isotretinoinexposed pregnancies. Arch. Dermatol. 141, 563–569.

Dai, W.S., LaBraico, J.M., Stern, R.S., 1992. Epidemiology of isotretinoinexposure during pregnancy. J. Am. Acad. Dermatol. 26 (4), 599–606(Apr).

Lammer, E.J., Chen, D.T., Hoar, R.M., Agnish, N.D., Benke, P.J., Braun, J.T.,Curry, C.J., Fernhoff, P.M., Grix, A.W., Lott, I.T., et al., 1985. Retinoic acidembryopathy. NEJM 313 (14), 837–841.

Available online at www.entis-org.com (accessed on 27/11/06).Available online at www.emea.eu.int/index/indexhl.htm (accessed on 28/11/05).Available online at www.ipledgeprogram.com (accessed on 28/11/05).

Marco De Santis*Gianluca Straface

AnnaFranca CavaliereElena Nobili

Allesandro Caruso

Catholic University of Sacred Heart, Italy

E-mail address: marcodesantis@rm.unicatt.it.*Corresponding author.