In this study, we did not find statistical evidence for an association between maternally-reported CAs and infant leukemia. Previous studies have suggested that several types of CAs confer an increased risk for leukemia. However, not all previous studies have excluded individuals with Down syndrome from their analyses [11
]. In studies that have excluded these individuals, non-significant associations have generally been reported between leukemia (AML, ALL, or total) and any congenital anomaly [13
], major congenital anomalies [30
], and heart defects [13
], while significant associations have been reported for birthmarks (ALL and AML) [12
], heart abnormalities (ALL) [12
], and pancreas or digestive tract abnormalities (ALL) [12
]. Our finding of no overall association between CAs and infant leukemia is consistent with that of most previous studies that have excluded Down syndrome.
Our finding of a twofold increase risk of infant leukemia in association with large or multiple birthmarks in females is intriguing in light of reports by four previous studies (two of childhood cancer and two of childhood leukemia) that have reported significant positive associations for birthmarks [12
]. Mertens et al. [12
] reported significant increased risks for large or multiple birthmarks overall in the index child but not their siblings for both ALL (OR=1.3; 95% CI 1.1-1.7) and AML (OR=1.9; 95% CI 1.2-3.1). Roganovic et al. [31
] reported significant excesses of pigmented nevi and café-au-lait spots in children with hematological malignancies, while Johnson et al. [32
] and Merks et al. [33
] reported increased frequencies of birthmarks and port-wine stains respectively in childhood cancer cases compared to non-cases. Similar to the results of our study, Johnson et al. [32
] also reported a female excess in cases with birthmarks. A biological explanation for these findings is unclear as none of these studies have included cases that were reported to have neurofibromatosis type 1 that is characterized by the presence of café-au-lait spots and an increased risk of leukemia [3
Intriguingly, four studies have reported significant positive associations between rib abnormalities and leukemia [7
]. However, only two of these studies reported excluding children with Down syndrome, which has previously been noted to be associated with an excess of rib abnormalities [34
]. Two controls and no cases had reported rib abnormalities in our study, a lower than expected frequency [8
], that is likely due to under-reporting since mothers may not be aware of rib abnormalities in the absence of their child having undergone a chest X-ray.
One previous study has suggested that children born with a CA are at greater risk for cancer in the first year of life than children born without a CA [11
] implicating the infant period as being the most vulnerable to development of malignancy. The risk for leukemia was mainly due to chromosomal anomalies (including Down syndrome) and not other defects, which is consistent with our findings.
This study has strengths and limitations. Our study is the largest study to date to examine risk factors for infant leukemia specifically, and included a nearly population-based source of cases diagnosed in the United States and Canada through the COG [35
]. In addition, all data were collected systematically by trained interviewers. A limitation of our study is that CAs were ascertained by maternal interview, which may miss CAs that are minor or not clearly visible. We were also limited by low statistical power to detect modest effect sizes. For example, we had 80% power to detect an increased OR of 1.7 for the overall association between CAs and infant leukemia. Recall or reporting bias could have affected our results if the maternal reporting accuracy of CAs varied by cancer status. Positive bias could result if mothers over-reported CAs in case children. However, this seems unlikely to have occurred since associations between sibling CAs and infant leukemia were near unity. Selection bias may also have affected our results since our controls were different on several respects from cases and the general population as previously reported [14
]. However, adjustment for factors that differed between cases and controls did not materially change the results.
In conclusion, this study does not provide evidence for a strong association between CAs and infant leukemia.