Taking antibiotics for long periods after the age of 40 may be linked to increased risk of heart attack or stroke in older women, according to the results of a study published yesterday in the European Heart Journal.
The results are the latest observations to be gleaned from the Nurses' Health Study (NHS), an ongoing study of registered US nurses that began in 1976 and uses biennial questionnaires to investigate risk factors for major chronic diseases in women. Analyzing questionnaire data from 2004 through 2012, researchers found that women who took antibiotics for more than 2 months during middle age or late adulthood were 28% and 32% more likely, respectively, to develop cardiovascular disease (CVD) than women who took no antibiotics.
The results also showed that women who took antibiotics for more than 15 days after age 40 had increased risk of coronary heart disease (CHD).
Gut microbiome could play a role
The research team, led by Lu Qi, MD, PhD, director of the Tulane University Obesity Research Center, was interested in looking at the relationship between durations and life-stage of antibiotic use and CVD because previous research has found associations between certain classes of antibiotics and cardiovascular health. Fluoroquinolones, for example, have been linked to prolongation of the QT interval, a syndrome that causes irregular heart rhythms, and use of macrolide antibiotics has been associated with sudden cardiac death.
Qi said this connection might have something to do with how antibiotics affect the gut microbiome—the complex community of bacteria that live in the digestive tract. Although the relationship between gut microbiota and health is not completely understood, recent research has suggested alterations in the balance of gut bacteria may affect metabolism and play a role in atherosclerotic cardiovascular disease. When people take antibiotics, particularly broad-spectrum antibiotics that wipe out both good and bad bacteria, that balance is disrupted.
"Because antibiotics affect gut microbiota, we assume that antibiotic use may also affect diseases related to the microbiota, including cardiovascular diseases," Qi told CIDRAP News.
But a connection between antibiotic use and long-term cardiovascular events has yet to be established, and no longitudinal study examining the relationship between duration of antibiotic use in different stages of adulthood and CVD incidence has been conducted.
To investigate the relationship, Qi and his colleagues started with the first year (2004) that the NHS assessed antibiotic use in respondents. In that questionnaire and subsequent ones over the next 8 years, the women were asked to indicate the total time using antibiotics during young (age 20 to 39), middle (age 40 to 59), and late (age 60 and older) adulthood. The researchers categorized respondents into those who never took antibiotics and those who took them for less than 15 days, 15 days to 2 months, and 2 months or longer. Women who had previous history of CVD and cancer were excluded.
A total of 36,429 women over the age of 60 were included in the study, and 1,056 of them developed CVD over the course of the study. After adjusting their analysis to account for age and a variety of factors that increase risk of CVD—including demographics, diet, lifestyle factors, body mass index, reasons for antibiotic use, other diseases, and use of other medications—the researchers found that use of antibiotics for more than 2 months was significantly associated with increased risk of CVD during late adulthood (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.03 to 1.70) and middle adulthood (HR, 1.28; 95% CI, 0.95 to 1.70) compared with women who didn't take antibiotics.
No risk was observed in younger women who took antibiotics for more than 2 months.
In addition, women over 40 who used antibiotics for 15 days to 2 months (HR, 2.30; 95% CI, 1.21 to 4.38) or for longer than 2 months (HR, 2.00; 95% CI, 1.05 to 3.79) had an increased risk of CHD compared to non-users. The researchers also found that the association between long-term antibiotic use and CVD risk was stronger in women with higher body mass indices .
The most common reason provided by respondents for their antibiotic use was a respiratory infection, with urinary tract infections and dental uses also listed as common indications. Information on classes of antibiotic or doses were not provided.
Although the information on antibiotic use was self-reported, the fact that all participants were nurses suggest the information provided about antibiotics and other medications was more likely to be accurate than if the participants were members of the general population. "This is a major strength of the study," Qi said.
While Qi stressed that these findings are observational and do not establish a causal link between antibiotic use and CVD, he said he wasn't surprised by the results, given his hypothesis about antibiotics, the gut microbiome, and disease. He said the next step is to look more closely at how antibiotics impact the gut microbiome so they can determine whether antibiotics are responsible for the increased risk.
"We didn't directly analyze the relationship between antibiotic use and gut microbiota, so we can't provide direct evidence. It's just a hypothesis," he said. Future studies, he added, "should directly assess the effect of antibiotic use on this potential mechanism."
He also noted that, since the study only involved women, researchers need to determine if there's a similar relationship between antibiotic use and CVD in men.
While Qi and his colleagues have no way to determine whether the antibiotics used by the women were appropriate or not, he says the findings reinforce the idea of antibiotic stewardship for both clinicians and patients. "The take home message is that we should be very careful in prescribing antibiotics, and use them only when they are absolutely needed," he said.
Apr 25 Eur Heart J study