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Prognosis, literally translated from its Greek roots, means "fore-knowing." It is one of the three classic responsibilities of a physician, the others being diagnosis and therapy. Although the breadth and detail of scientific evidence to support medical practice has expanded significantly in recent decades, there is a case to be made that evidence about prognosis has lagged behind evidence for physicians' other work. Clinical questions in perinatal epidemiology demonstrate several important issues related to the conduct of prognostic research. Using examples from the study of prognosis for infants born with congenital diaphragmatic hernia, a condition for which estimates of survival vary widely, we illustrate the importance of selecting and specifying appropriate prognostic categories and contexts (e.g., time and place) to promote the appropriate interpretation of prognosis. In a study of extremely preterm birth--another condition with wide variation in available survival statistics--we show why decisions made by patients and physicians need to be accounted for in prognostic research. By revealing several potential pitfalls of prognostic research, each of the projects described in this thesis also illuminates important opportunities for the better conduct and interpretation of such work. Making predictions about the future and providing this information to patients may always be difficult work for physicians. But better scientific evidence and interpretation of that evidence can at least make predictions more accurate. The aim of this thesis is to advance our knowledge about how to achieve such improvements.

Nonsyndromic orofacial clefts (OFCs) are major birth defects that include cleft lip with or without cleft palate (CL/P) and cleft palate (CP). The etiology of OFCs is thought to be multifactorial, and several gene variants and environmental exposures have been reported. Previous reports are equivocal for most environmental exposures studied, including those that examined parental exposure to pesticides or metals. The present set of three studies used data from the National Birth Defects Prevention Study (NBDPS) to examine associations between parental occupational pesticide exposures, selected maternal occupational metal exposures, and maternal multisource arsenic exposure and OFCs in offspring. NBDPS data for parental occupational exposures to insecticides, herbicides, and fungicides, alone or in combination, during the critical period of lip and palate development were compared between OFC cases and controls. Any (yes, no) and cumulative (no exposure, NBDPS data for any and cumulative maternal occupational exposures to cadmium, cobalt, nickel, and lead during the critical period of lip and palate development were compared between OFC cases and controls. Small sample sizes precluded analyses of cobalt, nickel, and combinations of metal exposure. After adjustment for relevant covariables, no significant, positive associations were observed for maternal exposure to cadmium or lead and all OFC cases combined or OFC subtypes, with most estimates near unity. Iowa NBDPS data and public water and well water testing data were used to compare maternal occupational and environmental exposures to arsenic between OFC cases and controls. Expert-rater review of maternal job histories was used to assign ratings for occupational exposure to any arsenic and inorganic arsenic only. Drinking water data for public water supplies or private wells were linked to maternal residential histories and combined with their reports of water consumption during pregnancy to estimate arsenic ingestion through drinking water. Reported concentrations of arsenic and inorganic arsenic in food were combined with maternal responses to a food frequency questionnaire to estimate arsenic consumption through diet. Positive, non-significant associations were observed for maternal occupational exposure to any arsenic or inorganic arsenic and all OFC cases combined. Also, significant, positive associations with any arsenic and inorganic arsenic and CP were observed. Associations for ingestion of arsenic through drinking water or dietary arsenic and OFCs were largely near unity. Findings suggest possible relations between paternal occupational pesticide exposure and maternal occupational arsenic exposure and OFCs. Additional epidemiologic research using methods to reduce possible sources of bias is needed to further elucidate the role of these exposures in the etiology of OFCs.