Male babies in the womb during the peak of the 1918-1919 flu pandemic were at increased risk of heart disease when they reached their 60s, 70s and 80s, researchers said.
In those men, the rate of heart disease was more than 23 percent higher than among those whose mothers were not pregnant during the pandemic's virulent phase in the fall of 1918, according to Dr. Caleb Finch, of the University of Southern California, and colleagues.
The main factor in the increase was a 32.7 percent rise in the rate of ischemic disease, Finch and colleagues reported online in the Journal of Developmental Origins of Health and Disease.
The 1918 pandemic was the most deadly on record, with mortality estimated as high as 100 million people worldwide.
But Finch said he and colleagues are concerned that even milder flu may have long-term consequences for the children of women pregnant during an outbreak.
"Our point is that during pregnancy, even mild sickness from flu could affect development with longer consequences," Finch said in a statement. "There is particular concern for the current swine flu, which seems to target pregnant women."
Other experts said the study appears to be solid, but cautioned against using it to draw conclusions about the current pandemic.
"I'd be extremely reluctant to infer anything about the 2009 swine flu outbreak from these findings," said Philip Alcabes of City University of New York.
Among other things, the study showed that heart disease was more common among all those who were in utero at the time, and not those whose mothers were actually infected with the flu, said Alcabes, who is the author of Dread: How Fear And Fantasy Have Fueled Epidemics From The Black Death To Avian Flu.
Since many women who were pregnant at that time either died or lost their babies, he said, "it could be that heart disease developed preferentially in offspring of women who were not infected, possibly because of some other exposure."
Dr. Howard Markel of the University of Michigan called the study "fascinating" but added that it only shows an association between later heart disease and in utero exposure.
"As compelling as the data is," he said, "there is no definitive proof that the latter caused the former."
But both Markel and Alcabes added that it's still important for pregnant women to avoid getting either seasonal or pandemic flu, if possible.
"This is why pregnant women are high on the priority list for vaccine once it is ready and they should get it," Markel said.
The study used data from the National Health Interview Surveys from 1982 through 1996, focusing on the 101,068 men and women who were ages 60 through 82 during those surveys.
Those people were born between 1915 and 1923, which allowed Finch and colleagues to compare the incidence of disease between the cohort in utero during the peak of pandemic and those whose mothers were pregnant with them before and after.
"They were able to compare babies born only months apart who differed only in whether they were in utero during the 1918 flu," said Jennifer Beam Dowd, also of City University of New York.
That makes the causal link relatively strong, she said.
On the other hand, she said, generalizing to current strains -- at a time when overall medical care of women and their unborn babies is much better -- would be "speculation at this point."
The study is the second to suggest such a link, according to Dr. Mohammad Madjid of Houston's Texas Heart Institute.
A Brazilian scientist reported similar findings in a 2004 issue of the institute's journal, he said, adding, "there are two main questions: Is this a true relationship, and if true, what are the underlying mechanisms?"
Madjid and colleagues have published a series of studies showing that influenza infection can cause inflammation in the cardiovascular system, which might cause acute effects such as heart attack.
On the other hand, this study suggests a long-term effect whose mechanism is not clear, he said.
"Potential mechanisms could include an uncontrolled immune response, inflammatory response, change in chronic risk factors, socio-economical effects, and most likely a combination of these," he said.
John Barry, author of The Great Influenza: The Epic Story of the Deadliest Plague in History, said the study is additional confirmation of the virulence of the 1918 flu.
"The 1918 virus was very nasty," he said. "And novel H1N1, though mild in the overwhelming majority of cases, seems to be creating similar problems, though fortunately only in very few instances."
In the study, Finch and colleagues found that men and women born in the first quarter of 1919 -- those whose mothers were pregnant with them during the peak of the pandemic -- reported a 10.9 percent excess in heart disease later in life.
Most of the increase was accounted for by a 25.4 percent excess of ischemic disease, also known as coronary artery disease.
There was no significant excess of hypertensive or rheumatic disease, the researchers found.
But the differences were driven almost entirely by disease among men, the researchers said.
This article was developed in collaboration with ABC news.