OBJECTIVE: High-grade intraventricular hemorrhage (IVH) is an important cause of severe cognitive and motor neurologic impairment in very low birth weight infants and is associated with a high mortality rate. The risk of IVH is inversely related to gestational age and birth weight. Previous studies have proposed a number of risk factors for IVH; however, lack of adequate matching for gestational age and birth weight may have confounded the results. The purpose of this study was to identify variables that affect the risk of high-grade IVH, using a retrospective and case-control clinical study. METHODS: From a cohort of 641 consecutive preterm infants with a birth weight of <1500 g, 36 infants with IVH grade 3 and/or 4 were identified. A control group of 69 infants, closely matched for gestational age and birth weight, was selected. Maternal factors, labor and delivery characteristics, and neonatal parameters were collected in both groups. Results of cranial ultrasound examinations, whether routine or performed in presence of clinical suspicion, were also collected. Univariate analysis and multivariate logistic regression analysis were performed. RESULTS: High fraction of inspired oxygen in the first 24 hours, pneumothorax, fertility treatment (mostly IVF), and early sepsis were associated with an increased risk of IVH. A higher number of suctioning procedures, a higher first hematocrit, and a relatively low arterial pressure of carbon dioxide during the first 24 hours of life were associated with a lower occurrence. In the multivariate logistic regression model, early sepsis (odds ratio [OR]: 8.19; 95% confidence interval [CI]: 1.55-43.1) and fertility treatment (OR: 4.34; 95% CI: 1.42-13.3) were associated with a greater risk of high-grade IVH, whereas for every dose of antenatal steroid treatment there was a lower risk of high-grade IVH (OR: 0.52; 95% CI: 0.30-0.90) and each decrease in a mmHg unit of arterial pressure of carbon dioxide during the first 24 hours was associated with a lower risk of IVH (OR: 0.91; 95% CI: 0.83-0.98). This multivariate model had a sensitivity of 77%, a specificity of 75%, and a positive predictive value of 76%. The area under the curve derived from the receiver operator characteristic plots is 0.82. CONCLUSIONS: Our results confirm that the development of IVH is associated with early sepsis and failure to give antenatal steroid treatment. We propose that fertility treatment (and especially IVF) may be a new risk factor, and more research is needed to assess its role.