Safety of Haloperidol and Penfluridol in Pregnancy: A Multicenter, Prospective, Controlled Study

Orna Diav-Citrin, M.D.; Svetlana Shechtman, Ph.D.; Shani Ornoy, B.A.; Judy Arnon, Ph.D.; Christof Schaefer, M.D.; Hanneke Garbis, B.Sc.; Maurizio Clementi, M.D.; and Asher Ornoy, M.D.

Objective: To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy.

Method: The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001.

Results: We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)--78.2% (of 206) were in the first trimester--and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls.

Conclusion: This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

(J Clin Psychiatry 2005;66:317-322)

Received June 20, 2004; accepted Sept. 13, 2004. From the Israeli Teratogen Information Service, Jerusalem, Israel Ministry of Health (Drs. Diav-Citrin, Shechtman, Arnon, and A. Ornoy and Ms. S. Ornoy); Pharmakovigilanz-und Beratungszentrum für Embryonaltoxikologie, Berlin, Germany (Dr. Schaefer); Teratology Information Service, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands (Ms. Garbis); Servizio di Informazione Teratologica, Padova, Italy (Dr. Clementi); and the Hebrew University Hadassah Medical School, Jerusalem, Israel (Dr. A. Ornoy).

Previously presented at the 14th European Network of Teratology Information Services (ENTIS) meeting, September 6-7, 2003, Elsinore, Denmark.

The authors report no financial affiliation or other relationship relevant to the subject matter of this article.

Corresponding author and reprints: Asher Ornoy, M.D., The Israeli Teratogen Information Service, Department of Anatomy and Cell Biology, Laboratory of Teratology, The Hebrew University Hadassah Medical School and Israel Ministry of Health, P.O. Box 12272, Jerusalem 91120, Israel (e-mail: ornoy@huji.ac.il).