Children born to mothers who had urinary or genital tract infections during pregnancy appear to have an increased risk for childhood leukemia, say researchers reporting a Danish registry analysis that may point to preventive strategies for the disease.
The research was published online today in JAMA Network Open.
The team studied more than 2.2 million children born in Denmark over more than three decades, linking their records across multiple national registries to examine both later cancer risk and maternal infection rates.
They found that, overall, at least one maternal infection during pregnancy was associated with a 35% increased risk for leukemia in the children, rising to 65% for urinary tract infections, and 142% for genital infections.
“The findings of this large population-based cohort study suggest that maternal urinary and genital tract infections during pregnancy are associated with a higher risk of childhood leukemia in offspring,” said lead author Jian-Rong He, DPhil, Division of Birth Cohort Study, Guangzhou Women and Children’s Medical Center, Guangzhou, China.
However, he added that “the associated absolute risk remained small given the rarity” of the disease. In absolute terms, the risk difference between exposed and unexposed children was 1.8 cases per 100,000 person-years for any infection, 3.4 cases per 100,000 person-years for urinary traction infection, and 7.1 cases per 100,000 person-years for genital tract infection.
Maternal infections during pregnancy may be associated with chromosomal and immunologic alterations in the fetus, the authors speculate.
“Given that little is known about the etiology of childhood leukemia,” these results “suggest an important direction for research on the etiology of childhood leukemia as well as development of potential preventive measures,” they write.
In many countries, pregnant women are tested for urinary tract infection and bacterial vaginosis, and treated with antibiotics in antenatal care, as these infections are linked to adverse perinatal outcomes, they pointed out.
The team conducted a large population-based study that included all live births in Denmark between 1978 and 2015.
After exclusions, they gathered information on 2,222,797 children, linking data from several national registries, including the Danish Medical Birth Register, the
Danish National Patient Registry, and the Danish National Cancer Registry, to identify cases of childhood cancers and maternal infection during pregnancy.
The results were then validated by comparing them with those in 2.6 million live births in Sweden between 1988 and 2014, for whom similar data was available through linkage with several Swedish registries.
The Danish cohort were followed up for a mean of 12 years per person, yielding a total of 27 million person-years. Just over half (51.3%) were boys.
Cancer was diagnosed in 4362 children before 15 years of age, of whom 1307 had leukemia (1050 had acute lymphocytic leukemia), 1267 had a brain tumor, 224 had lymphoma, and 1564 had other cancers.
At least one infection during pregnancy was diagnosed in 81,717 mothers (3.7%). Urinary tract infections were the most common (in 1.7% of women), followed by genital tract infection (in 0.7%), digestive system infection (in 0.5%), and respiratory tract infection (in 0.3%).
Women with any infection during pregnancy were more likely to be younger and primiparous than women who did not have infections, and they were also more likely to have fewer years of education, higher pre-pregnancy BMI, diabetes, and to smoke during early pregnancy.
Preterm delivery and low-birth-weight infants were also more common in women with infections during pregnancy.
Cox proportional hazards regression models revealed that, after adjustment for confounders, any maternal infection was associated with a hazard ratio of childhood leukemia of 1.35.
Further analysis revealed that the association was driven by genital tract infection, at a hazard ratio for childhood leukemia of 2.42, and urinary tract infection, at a hazard ratio 1.65.
Moreover, children born to women who had a sexually transmitted infection during pregnancy had a hazard ratio for developing leukemia of 3.13 compared with unexposed children.
There were no associations between other maternal infections and childhood leukemia.
The patterns of association between maternal infections and childhood leukemia were similar when looking at disease subtypes, as well as in the Swedish validation cohort, they add.
When interpreting the results, the researchers caution that, as data on maternal infection were drawn from hospital data, “milder infections and those not
diagnosed or treated in specialized health care facilities were not captured.”
“Also, some infections could be captured because the mother sought care for other, more serious conditions, which might bias the association of maternal infections and childhood leukemia.”
The study was supported by grants from the China Scholarship Council–University of Oxford; National Natural Science Foundation of China; Danish Council for Independent Research; Nordic Cancer Union; Novo Nordisk Fonden; and the Swedish Council for Working Life and Social Research. Dr He reported receiving a PhD scholarship from the China Scholarship Council during the conduct of the study. Several other co-authors have disclosures; the full list can be found with the original article.
JAMA Network Open. Published online February 20, 2023. Full text
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