One of the key questions the findings raises is whether the same factors that cause babies to be born preterm and small also set the developing brain on an autistic path or whether, more disturbingly, some of the medical interventions that kept them alive somehow triggered the disorder.
Either way, the number of babies who develop autism - as well as cerebral palsy, mental retardation, vision, hearing, and other problems - due to low birth weight is likely to increase in coming years, said Jennifer Pinto-Martin, a professor at Penn's nursing and medical schools and lead author of the study.
"This is a big public-health hit," she said. "A lot of kids will be coming down the pike who will need special-education services . . . and whose families will need special support."
Between 1985 and 2007, the number of low-birth-weight babies born in the United States rose more than 40 percent - three times the increase for all births - while their mortality rate in the first year of life was halved, federal statistics show.
Still, those babies represent only about 8 percent of all newborns. (The birth weights in the autism study, which used definitions that are smaller than the current standard, make up 3 percent of newborns.)
Most autistic children were normal size at birth. The cause of the disorder is unknown. Scientists believe multiple environmental factors, perhaps during pregnancy or shortly after birth, trigger various genes that then push the developing brain off course.
The resulting spectrum of disorders is characterized by problems with social interaction, communication, and repetitive behaviors. Some people make it through college - and even excel in certain areas - with support. Others may never speak.
Jacob Diamond, 21, is in the latter category. He spends much of his day watching television in his parents' Chestnut Hill home. The Diamonds are among a growing number of families nationwide who reach the almost complete end of government services when their children grow beyond school age.
"There is no funding initiative at the state or national level to support adults with autism" and what little is currently available is vulnerable to deficit-reduction efforts, said Roy Diamond, president of Autism Living and Working, a nonprofit that works to provide housing, employment, and other services to autistic adults.
The new findings, published Monday in the journal Pediatrics, were not a surprise. But other experts said the study was more significant than previous research because it relied on actual diagnoses rather than screening tools that are intended to find people at risk. The team tracked down 189 of the low-birth-weight babies 21 years later, and most were then evaluated at a Princeton satellite clinic of Children's Hospital of Philadelphia.
"One of the questions is: Is it something that was developmentally going wrong in the first place?" said Irva Hertz-Picciotto, an environmental epidemiologist at the University of California, Davis, "or all these interventions going on for all these babies" that had an impact?
Some babies are born small because their growth was restricted for various reasons in utero. Others are delivered prematurely, the result of myriad ills that are more likely when the mother is older or in poor health.
"We know very little, actually, about the causes of preterm delivery," said Lisa Croen, director of autism research at Kaiser Permanente Northern California. Neither she nor Hertz-Picciotto was involved with the Penn study.
Croen is analyzing the records of 180,000 babies born in the Kaiser health system over eight years to try to flesh out the reasons. She will also look at the smallest babies' medical problems in neonatal intensive care units and how doctors intervened to help them.
Respiratory distress, for example, is common in low-birth-weight babies, and mechanical ventilation has been linked to later problems. Kaiser's records will also indicate whether their mothers received antibiotics during pregnancy, Croen said; some kinds of infections as well as certain drugs may cause developmental difficulties.
The new paper reports on the latest in a series of studies based on what began with 1,105 low-birth-weight babies born in Middlesex, Monmouth, and Ocean Counties between 1984 and 1987. The children were reassessed at ages 2, 6, 9, and 16 years, resulting in findings for cerebral palsy, behavioral disorders, school performance, and psychiatric problems (all influenced by birth weight). The studies have received about $20 million in federal funding.
Autism wasn't on the radar screen until a decade or so ago, which is why the researchers supplemented the earlier assessments with in-person evaluations at age 21. Some milder cases had never been diagnosed.
Pinto-Martin, the lead researcher, directs the Center for Autism and Developmental Disabilities Research and Epidemiology in Penn's School of Nursing. Established in 2001 and with a current roster of 14 researchers and staff, it is often overshadowed by Children's Hospital's far larger autism center.
The center has distinct missions determined by the federal government, its sole funding source. Estimating the prevalence of autism spectrum disorders is one of them, and its local data contributed several years ago to the national estimate that about 1 percent of children are affected.
Another mission is public awareness. A study that looked at using nurses as what Pinto-Martin called "developmental advocates" in primary-care practices led to a nursing school program that began last month to train nurse specialists in autism.
American Academy of Pediatrics guidelines instruct pediatricians to screen all children for developmental problems but many don't, researchers say, because of time pressure and other reasons. Although there is no cure for autism and many children don't respond to current therapies, the earlier the disorder is detected and therapy started, the greater the chance for improvement.
An important message of the new study, Pinto-Martin said, is that pediatricians must regularly screen low-birth-weight children.
Alycia Halladay, environmental sciences research director for Autism Speaks, a major funding source that was not involved with this study, emphasized that parents of children who were born small or premature should make regular visits to the pediatrician.
"They should make sure that their child receives close developmental evaluations from childhood to adolescence," Halladay said.
Contact staff writer Don Sapatkin at 215-854-2617 or email@example.com.