Regular use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with a reduced risk of many adult cancers (Gonzalez-Perez et al, 2003; Bosetti et al, 2006; Elwood et al, 2009). Two studies of adult leukaemia suggested a protective effect with aspirin (Kasum et al, 2003; Weiss et al, 2006), but no effect with non-aspirin NSAIDs, and a possible increased risk with acetaminophen (Weiss et al, 2006). For childhood leukaemia, results are inconsistent with regard to maternal analgesic use (Wen et al, 2002; Shaw et al, 2004; Schuz et al, 2007), although many of these drugs are known to cross the placenta (Alano et al, 2001).

Given the paucity of risk factors identified for infant leukaemia, the strong evidence of an in utero origin, and the potential for possible effects on the developing fetus, we examined non-prescription maternal analgesic use and the risk of infant leukaemia.

During phase I of recruitment, controls were identified using random digit dialling, and frequency matched to cases on year of birth. Interviews were completed for 254 of 430 potentially eligible controls (59% field response rate). In phase II, controls were identified through a sample of state birth registries. Controls were frequency matched to cases on year of birth and region of residence based on the distribution of cases enrolled during phase I. Interviews were completed for 71 out of 267 potentially eligible controls (27% field response rate). The two control groups were found to be similar based on both maternal and infant characteristics (Puumala et al, 2009), and thus were combined into one control group for this analysis.

Informed consent was obtained from all participants. Information on maternal and infant characteristics was collected through computer-assisted telephone interviews with the biological mother. Analgesic questions included maternal use of aspirin, acetaminophen and non-aspirin NSAIDs, both before and after knowledge of pregnancy, including the frequency of use during these two time periods. The frequency of use categories before knowledge of pregnancy included fewer than 5 times, 5–25 times, and more than 25 times. For the period after knowledge of pregnancy through the end of the pregnancy, the categories were less than 10 times, 10–50 times, and greater than 50 times. Detailed reports on leukaemia cell cytogenetics and molecular abnormalities were obtained for cases and included leukaemia subtype (ALL, AML) and MLL gene translocation status (MLL+, MLL−, undetermined). Data on analgesic use during pregnancy were missing for two cases and one control. Few women reported using any type of analgesic more than 25 times before knowledge of pregnancy or more than 50 times after knowledge of pregnancy, which precluded examining frequency of use. Instead, for each type of analgesic, we created two variables: one for any use during the specified period and a second to indicate regular use (more than 5 times before knowledge of pregnancy or more than 10 times after knowledge of pregnancy).

We also evaluated the distribution of cases and controls with regard to analgesic use across selected potential confounders for the two pregnancy periods (data not shown). Before knowledge of pregnancy, acetaminophen was the most commonly (63%) used analgesic, followed by non-aspirin NSAIDs (31%) and aspirin (9%). Compared with non-regular users (5 times), regular users were more likely to smoke during pregnancy and less likely to have completed education beyond high school or to report an annual household income greater than $75000. Regular aspirin or non-aspirin NSAID users were more likely to be Caucasian and to drink during pregnancy, whereas regular acetaminophen users were less likely to use multivitamins before knowledge of pregnancy, compared with non-regular users. After knowledge of pregnancy, acetaminophen use increased (69%), whereas the use of aspirin and non-aspirin NSAIDs decreased (3 and 9%, respectively); only 19 case mothers and 13 control mothers used aspirin or non-aspirin NSAIDs regularly (10 times).

Possible associations between infant leukaemia and maternal analgesic use, assessed both before and after knowledge of pregnancy, are shown in Table 2. There was no association between any use or regular use of aspirin, non-aspirin NSAIDs or acetaminophen with infant ALL, in either pregnancy period. However, for AML, there was a statistically significant or borderline significant reduced risk associated with any use of non-aspirin NSAIDs (OR=0.60, CI: 0.37–0.97) and acetaminophen (OR=0.66, CI: 0.43–1.01), respectively, but not with aspirin (OR=0.55, CI: 0.24–1.26); regular use of each analgesic did not reflect further reduction in risk. These inverse associations were observed only before knowledge of pregnancy, whereas they were attenuated toward the null after knowledge of pregnancy.

Aspirin use had no effect on infant leukaemia risk in either pregnancy period. However, aspirin is not recommended during pregnancy, especially during the last trimester, although 10–30% of women may use aspirin in the first trimester before they are aware of their pregnancy (Werler et al, 1989; Kozer et al, 2002). In our study, aspirin was used by 10.5% of controls and 8.5% of cases before knowledge of pregnancy, and by 3.7% of controls and 3.3% of cases after knowledge of pregnancy.

Two out of three studies found no association between maternal analgesic use and risk of leukaemia in children 0–14 years of age (Wen et al, 2002; Schuz et al, 2007). In contrast, one study reported a borderline significant two-fold increased risk of childhood ALL associated with prescription or over-the-counter anti-inflammatory drug use during pregnancy (Shaw et al, 2004). These three studies, however, included few women who used these medications during pregnancy. In addition, associations may have been diluted owing to broad medication groupings and few details on specific medications used.

Strengths and weaknesses of our study are relevant. This is the largest infant leukaemia study to date and included availability of MLL gene status. Identification of cases through COG provided a nearly population-based study population, as COG institutions see ~100% of leukaemia cases aged 0–4 years (Ross et al, 1996). We evaluated different classes of analgesics, but not their doses. The small sample size for some subgroup analyses warrants caution in interpretation of the relevant associations. In particular, given the low frequency of aspirin use, especially after knowledge of pregnancy, we had limited power to evaluate aspirin effects. Recall bias is a concern in case–control studies, but it is unlikely that mothers with ALL infants would recall their exposures differently from mothers with AML. Further, the early age of onset helped to limit the recall period. There is also some concern with regard to selection bias. We found that use of analgesics varied by race, income, educational attainment, and smoking or alcohol consumption during pregnancy. Although we adjusted for maternal race, ethnicity, income, and alcohol consumption during pregnancy, residual confounding may remain.