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Abstracts / Reproductive

Results: Pregnant animals were sacrificed on 17th ges-ational day. Foetuses were collected and observed undertereomicroscope. Foetuses with minor birth defects selectedor this study were embedded in paraffin and standard his-ological techniques were employed to assess the extent ofevelopment and developmental abnormalities of the craniofa-ial area. Histological observations of the examined foetusesreated with all-trans retinoic acid showed varying degreesf orofacial malformations, such as cleft lip and palatallefts and eye malformations such as exophthalmia. Foetusesreated with 3′-azido-3′-deoxythymidine (AZT), showed milderacial clefts while exophthalmia was also observed. Foetusesreated with corn oil and untreated control fetuses showedo craniofacial abnormalities. Histological observations on thexophthalmia showed an interesting retina defect, presented asetina folding which was distinct at fetuses treated with 3′-azido-′-deoxythymidine (AZT).

Discussion: Previous guidelines for HIV-infected pregnantomen have recommended 3′-the second and third trimestersf pregnancy to prevent foetal HIV infection. New guidelinesuggest that women should continue or be offered combina-ion antiretroviral therapy (including protease inhibitors) duringregnancy. Nevertheless, little animal or human toxicity datanderlie these recommendations. The results of this study pro-ides further evidence that craniofacial malformations, althoughinor in morphology and successful for the neonate’s survival;

s facial clefts and exophthalmia can be caused from 3′-azido-′-deoxythymidine (AZT) and all-trans retinoic acid. Althoughhose birth defects can be the most of them manipulated withlastic surgery and ocular surgery treatment after birth at neona-al, postnatal and childhood life, they can be causatives forroblems and low quality of life in children and their families.

Conclusion: From our results we conclude that the applied forhis study antiretroviral and chemotherapeutic drugs can induceeversible defects, such as orofacial clefts and irreversible dam-ge on embryonic/foetal organs such as retina malformationsuring development. This damage, although several times butot always can be repaired surgically, can cause problems at theuality of life to both, the newborn child and the total family.

oi:10.1016/j.reprotox.2007.04.058

irst trimester itraconazole exposure: Neonatal and preg-ancy outcome

arco De Santis 1, Anna Franca Cavaliere 2, Elena Diianantonio 2, Gianluca Straface 1, Elena Cesari 1, Guidombrosini 3, Maurizio Clementi 2

Department of Obstetrics and Gynecology, Telefono Rosso-eratology Information Service, Rome, Italy; 2 CEPIG, Clinicalenetics, University of Padua, Italy; 3 Department of Reproduc-

ion Sciences, University of Padua, Italy

Itraconazole is a systemic antifungal agent, similar to keto-onazole and fluconazole. In mouse and rat models it iseratogenic with an increased incidence of cleft palate and limbefects at high oral doses. This teratogenicity is mediated by

aro(

ology 24 (2007) 57–80 77

drenal effects not expected at the clinical dosage used in humans1]. Regarding the human data we have few and limited studiesith a normal rate of major malformations and without specificattern of anomalies. The rate of spontaneous abortion and fetaleath is not different from the general population [2].

We report our experience as a cohort prospective study onregnancies exposed to itraconazole in the first trimester of preg-ancy compared to a similar and contemporary control group.he data were collected by two Italian TISs in Rome and Paduaetween 2002 and 2006.

We enrolled 221 women exposed to itraconazole during therst trimester of pregnancy and 229 controls who were exposed

o various substance known to be non teratogenic drugs. Thexposed group has the same characteristics of age, parity andravidity of the control group.

The rate of congenital anomalies in the exposed group was.8%, compared with 2.35% in the control group. We had a liveirth rate of 74.6%, that is lower than control group (91.7%)ecause we had 1 intrauterine death in the exposed group and anigher rate of both spontaneous and induced abortion (15.38%ersus 4.8% and 9.5% versus 3.5%). Birth weight at term, meanestational age at delivery, pregnancy and neonatal complica-ions did not differ between the groups.

Our study supports previous data [3] that itraconazole duringrst trimester does not increase the rate of congenital anomalies.

This study is financially supported by the “Ministeroell’Istruzione, dell’Universita e della RicTherca”prot n◦004063099-002.

eferences

1] Reprotox Catalogue. Available on: www.reprotox.org.2] Sobel JD. Use of antifungal drugs in pregnancy: a focus on safety. Drug Saf

2000;23:77–85.3] Bar-Oz, et al. Pregnancy outcome after in utero exposure to itraconazole: a

prospective cohort study. Am J Obstet Gynecol 2000;183:617–62.

oi:10.1016/j.reprotox.2007.04.059

oloprosencephaly in the Kyoto collection of humanmbryos: Phenotypic variability and epidemiologic charac-eristics

ohei Shiota, Shigehito Yamada, Chigako Uwabe

Department of Anatomy and Developmental Biology and Con-enital Anomaly Research Center, Kyoto University Graduatechool of Medicine, Kyoto, Japan

Holoprosencephaly (HPE) became a new target of researchor clinical geneticists and dysmorphologists since the first casesf HPE with mutations in the SHH gene were reported in 1996.n a large collection of human embryos at Kyoto University,ore than 200 cases of HPE embryos have been found. Theajority of the cases were obtained from healthy women with

n uneventful course of pregnancy. Although HPE is a ratherare malformation in newborns (1/15,000–20,000 births), it isne of the most common anomalies in early human embryos>1/250). An intrauterine life-table analysis revealed that more