Source: Kaijser M, Akre O, Cnattinggius S, et al. Preterm birth, low birth weight, and risk of esophageal adenocarcinoma. Gastroenterology. 2005;128:607–609.Gastroesophageal (GE) reflux is a common condition in infants, especially those who are premature.1 Adult GE reflux is a strong risk factor for adenocarcinoma.2 As part of a cohort established for the study of perinatal exposures for malignancies, these authors from Stockholm, Sweden established a cohort of 3364 subjects born prematurely (<35 weeks gestation) or with a low birth weight (girls <2000g or boys <2100g) at 4 major Swedish delivery units from 1925 to 1949. They also established a cohort of 3569 controls born at the same units during the same period. The Register of Population and Population Changes was used to follow the subjects from January 1, 1958 to December 31, 1998. Esophageal cancer occurrence was ascertained from the Swedish Cancer Registry. The standardized incidence rate ratio for esophageal adenocarcinoma was increased more than 7-fold in the cohort, and in infants <2000 grams was associated with a more than 11-fold increase in risk. Eight esophageal cancers were found among the subjects. Four were adenocarcinomas, the cancer associated with reflux in adults. The expected incidence of adenocarcinoma for this group was 0.55, yielding a standardized incidence ratio of 7.27 (95% CI, 1.98–18.5). Of interest, there were 3 squamocellular carcinomas (a cancer not associated with GE reflux) when 1.62 squamocellular carcinomas should have been expected, and 1 anaplastic carcinoma.Dr. Kawatu has disclosed no financial relationships relevant to this commentary. Dr. Leleiko has disclosed no financial relationships relevant to this commentary.This report suggests yet another adult morbidity associated with prematurity and low birth weight. The authors clearly state that the associations may be spurious, but one potential explanation for their findings is that increased GE reflux during infancy among infants born preterm and/or small for gestational age may predispose to the later development of esophageal adenocarcinoma.Since prematurity and low birth weight are common, finding this association in other populations would satisfy one of the principles of establishing causal association, namely consistency. The other principles include strength of association, biological gradient, effect of intervention, temporal order, biological plausibility, and coherence of results among studies.3 The authors speculate that the esophageal mucosa in premature and low birth weight babies may be predisposed to malignant changes if exposed to gastric refluxate during infancy. This would seem to satisfy the criteria for a temporal order relationship between exposure and outcome. It is biologically plausible since esophageal adenocarcinomas essentially develop after a diagnosis of Barrett’s esophagus, whose principal risk factor is GE reflux.As the authors have stated, this study has merely generated a hypothesis. It would be premature to make any recommendation based on this report other than the need for additional, more rigorous studies. These studies would need to address obvious coherence and specificity issues in order to confirm the association. For example, prematurity and low birth weight are both much more common in African Americans, yet in this population esophageal adenocarcinoma is relatively uncommon.4,5 Finally, although not statistically significant, there was more than the expected number of squamocellular carcinomas. This cancer has not been associated with GE reflux. This raises the possibility that the suggested association between GE reflux in infancy and esophageal adenocarcinoma may be confounded by other factors associated with prematurity and low birth weight.We publish the study’s summary as much for its flaws and limitations as for the relationship it suggests, but at this point certainly cannot prove. The suggested association seems to us more inflammatory than plausible given the small number of cases and the homogeneity of the study population increasing the likelihood of confounding.