Holoprosencephaly is a brain defect resulting from incomplete cleavage of the 
embryonic forebrain. It involves forebrain and facial malformations that can 
range from mild to severe. The epidemiology of holoprosencephaly is largely 
unknown. Published prevalence estimates have been derived from clinic-based case 
series, and suggested risk factors for holoprosencephaly have been identified in 
case reports, without confirmation from systematically conducted 
population-based studies. Using data from a population-based birth defects 
registry in California, we describe the epidemiologic and clinical 
characteristics of cytogenetically and phenotypically distinct types of 
holoprosencephaly. A total of 121 cases was identified among a cohort of 
1,035,386 live births and fetal deaths. The prevalence of holoprosencephaly was 
1.2 per 10,000 births (95% confidence interval 1.0-1.4 per 10,000). Of all 
cases, 41% (50/121) had a chromosomal abnormality, most commonly Trisomy 13. 
Among the 71 cytogenetically apparently normal cases, 18 had recognizable 
syndromes and the remaining 53 were of unknown cause. Among the cytogenetically 
abnormal cases, females had a greater risk than males (odds ratio = 2.3,95% 
confidence interval [1.2, 4.4]). Among the cytogenetically normal cases, 
increased risks were observed among Hispanic whites (OR = 1.8 [0.9, 3.6]) and 
cases whose mother was born in Mexico (OR = 2.2 [1.0, 4.5]). Approximately 46% 
of all cases had alobar holoprosencephaly, the most severe form of the forebrain 
malformation. The facial phenotype did not strongly predict the severity of the 
brain defect; however, severity was inversely correlated with length of 
survival. This study is the first to present findings based on such a large 
population-based series of infants/fetuses affected by holoprosencephaly, and 
demonstrates the importance of investigating the component subgroups of this 
rare phenotype.