Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case–control study in Denmark, 1996–2016

• Published in: Pharmacoepidemiology and drug safety 2023-04, Vol.32 (4), p.496-505
• Main Authors: Sirirungreung, Anupong, Hansen, Johnni, He, Di, Huang, Xiwen, Ritz, Beate, Heck, Julia E.
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Brain tumors; Cancer; Case-Control Studies; Central nervous system; Central Nervous System Neoplasms - chemically induced; Child; Childhood; childhood cancer; Children; Denmark; Denmark - epidemiology; Drugs; Female; Fetuses; Humans; Leukemia; Lymphatic leukemia; Nervous system; Neuroblastoma; Neuroblastoma - chemically induced; nitrosatable drug; Nitroso Compounds - adverse effects; N‐nitroso compound; Perinatal exposure; Precursor Cell Lymphoblastic Leukemia-Lymphoma - chemically induced; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - epidemiology; Prescriptions; Risk Factors; Tumors
• ISSN: 1053-8569; 1099-1557
• DOI: 10.1002/pds.5557

Background Nitrosatable drugs can be synthesized to N‐nitroso compounds in human stomach. In a pregnant woman, N‐nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. Methods A matched case‐control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty‐five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. Results Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04–1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34–2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07–1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. Conclusion Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.