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

Abstract

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.

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population‐based cohort study in Taiwan, 2004 to 2015

“…44 Furthermore, doxycycline is considered a nitrosatable drug, and maternal prescriptions of nitrosatable drugs have also been associated with childhood ALL. 15 While our findings should be considered exploratory, they suggest associations between the prescription of beta-lactam antibacterials (excluding penicillin) during pregnancy and the occurrence of childhood hepatoblastoma. In contrast, a cohort study conducted in Denmark and Sweden found no associations between maternal prescriptions of other beta-lactam antibacterials and the risk of childhood cancers (HR = 0.88; 95% CI: 0.50-1.57).…”

“…Notably, doxycycline, a commonly used drug from the tetracycline group, has been found to increase the average number of megakaryocytes and the periportal leukocytic infiltration in liver cells, as well as causing DNA damage, in a study on rat embryonic development 44 . Furthermore, doxycycline is considered a nitrosatable drug, and maternal prescriptions of nitrosatable drugs have also been associated with childhood ALL 15 …”

“…13,14 Furthermore, many antibiotics are considered nitrosatable drugs, which have been associated with certain types of childhood cancer. 15 On the other hand, several studies explored the potential links between maternal infections during pregnancy and the risk of childhood brain and nervous system tumors, which represent the second most common type of childhood cancer. However, findings have been inconclusive due to limited statistical power.…”

“…Certain types of antibacterials, such as some quinolones and metronidazole, have been shown to act as carcinogens or genotoxins in animal studies 13,14 . Furthermore, many antibiotics are considered nitrosatable drugs, which have been associated with certain types of childhood cancer 15 …”

Nitrate in drinking water and pregnancy outcomes: A narrative review of epidemiological evidence and proposed biological mechanisms

“…with poor oral health), more alkaline stomach pH (facilitating bacterial proliferation) and with a high intake of other sources of amines (red meat or certain drugs) and low intake of NOC inhibitors (polyphenols, vitamin C). Pregnant women can experience physiological changes that may make them more prone to endogenous formation of NOC [65,66]. While it would be unethical to randomise pregnant women to conditions that could put them or their baby at risk, future studies could investigate these biological mechanisms in non-randomised observational studies of pregnant women or randomised control trials of non-pregnant volunteers.…”