BACKGROUND: Uncertainty remains about the potential harmful effects of antihypertensive therapy on the developing fetus, especially for beta-blockers (betab). METHODS: We prospectively enrolled all singleton women with a blood pressure >/= 140/90 mm Hg during pregnancy. The main analysis included 1948 women with all forms of hypertension and compared the use of betab drugs, non-betab drugs or a combination of both, to no treatment. The primary study outcome was a composite of the diseases of prematurity, need for assisted ventilation for greater than 1 day, or perinatal death. A sub-group analysis evaluated the four treatment options among 583 singleton women with chronic hypertension before 20 weeks gestation. RESULTS: In the main analysis, no association was observed between betab use and the primary composite outcome [adjusted odds ratio (OR) 1.4, 95% CI 0.9-2.2], while an association was seen with non-betab therapy (OR 5.0, 95% CI 2.6-9.6) and combination therapy (OR 2.9, 95% CI 1.8-4.7). In the sub-group of 583 women with hypertension before 20 weeks, use of a non-betab drug (OR 4.9, 95% CI 1.7-14.2) or combination therapy (OR 2.9. 95% CI 1.1-7.7) was significantly associated with the primary composite outcome, while betab monotherapy was not (OR 1.4, 95% CI 0.6-3.4). CONCLUSIONS: Maternal use of antihypertensive medications other than betabs was associated with both major perinatal morbidity and mortality, while betab monotherapy was not. The combined use of betab and non-betab medications demonstrated the strongest association. Before definitive conclusions can be drawn, a large multicentre randomized controlled trial is needed to address the issues of both maternal efficacy and fetal safety with the use of one or more antihypertensive agents in pregnancy.