Study of Premature Babies Failed to Inform Parents of Risks

Several prestigious universities, including Stanford, Duke and Yale, conducted a research study on behalf of the federal government to examine which of two levels of oxygen given to extremely premature babies was better at preventing blindness without increasing the risk of brain damage or death. The purpose and execution of the study were solid; the ethics weren’t.

As widely reported, including by the New York Times, the universities failed to inform the parents of the 1,300 hundred babies that the risks of being in either group included blindness and death. The federal Office for Human Research Protections, whose job is to protect people participating in government-financed studies, detailed the ethical breach last month in a letter to the University of Alabama, Birmingham, the study’s lead site of the 23 universities involved. The babies’ families, says The Times, have yet to be notified of what the government learned.

The consumer advocacy organization Public Citizen found out about the letter, and informed the media of it on Wednesday. Public Citizen wrote a letter to HHS Secretary Sebelius asking her to step up the discipline of the universities involved, and to personally and publicly apologize to the families of the 1,300 babies.

The study, published in the New England Journal of Medicine, occurred from 2004 to 2009, and involved babies born from 24 to 27 weeks of gestation-full term babies gestate for 39 to 40 weeks. Such premature infants are extremely fragile and at high risk of death and eye disease.

Babies in the study who received the higher level of oxygen were more likely to develop the eye disease, called retinopathy of prematurity, and blindness; those who got less were more likely to die. Of the 654 low-oxygen babies, 130 died; 91 of 509 high-oxygen babies developed the eye ailment.

“The researchers,” according to the letter, “had sufficient available information to know, before conducting the study, that participation might lead to differences in whether an infant survived, or developed blindness, in comparison to what might have happened to a child had that child not been enrolled in the study.”

The consent form the parents were given to sign so their babies could participate in the study noted only the risk of abrasion of the infants’ skin by an oxygen monitoring device, and that the possible benefit to participating was a decreased need for eye surgery, depending on the group the infant was assigned to. (To learn more about informed consent, see our backgrounder.)

The vice president for research at the University of Alabama, Birmingham, told The Times that the study kept the infants within the standard band of treatment for oxygen levels. But the letter from the Office for Human Research Protections, which is an agency of the Department of Health and Human Services, found the consent form wanting, and that the risks of participating in the trial “were not the same as those receiving standard care.”

The consent form, it said, should have explained that “there is significant evidence from past research indicating that the oxygen provided to an infant can have an important effect on many outcomes including whether the infant becomes blind, develops a serious brain injury or even possibly whether the infant dies.”

The consent form, said The Times, had been approved by all of the participating universities.

Consent forms generally cover every possible adverse event because the institutions conducting research are careful not to expose themselves to legal liability. But as Dr. Arthur Caplan told The Times, parents often rely more on what doctors say in deciding whether to participate than on the fine print of a consent form. Caplan is the medical ethicist at New York University Langone Medical Center.

Treating extremely premature infants has always been challenging. Administering oxygen is indicated because preemies’ lungs are underdeveloped and they struggle for air. But the higher oxygen levels that were thought to improve their odds of survival led to many cases of blindness. So doctors usually make treatment decisions based on each individual, often in consultation with parents, and nothing having to do with such tiny babies is without risk.

The researchers said their approach also was flexible and that the infants in the study weren’t necessarily confined to rigid bands of oxygen levels. But because they wanted to determine the effects of two different levels, they tried to keep half the subjects in the low zone and half in the high zone. Also, they said a similar group of infants born around the same time in the same hospitals who did not participate in the study, but were eligible, died at higher rates than those in the low-oxygen group..

Still, assuming risk is not a unilateral decision to be made by practitioners. It’s unconscionable that parents were deprived of knowing all the concerns in their childrens’ participation in this study.

Some readers of The Times’ story, however, had a more nuanced appreciation of the ethical breach.

“Death or blindness is a terrible choice,” said one. “The retrospective finding that similar patients (in the same hospital at the same time) who did not participate in the study suffered more deaths and blindness illustrates the dire nature of the patients’ condition and the extra care bestowed on them by the researchers. Also that oxygen delivery to the infants was appropriately adjusted by the researchers-evidence that their clinical care was not adversely affected in any way by the research. Nevertheless, the federal agency is right that the parents should have been given all the available information before they signed the consent.”

Another, who identified herself as a health researcher who has written consent forms, said “This is an explanation of how research ethics works, I am not making a judgment about whether the concept of this study was right or wrong.

“Many readers are expressing anger that parents were not informed in the consent form about the risk of death and blindness with oxygen treatment. These are extremely preterm babies, who without treatment would likely die and even with treatment, may die or face a lifetime of complications. If oxygen treatment is standard of care, then any competent physician treating this baby would tell the parents about the risk of death and blindness before starting the treatment. The key question here is whether participating in the study increased these risks. If the risk of blindness and death with oxygen treatment for babies in the study is the same as babies receiving oxygen treatment and not in the study, then there would be no requirement to mention those risks again in the consent form. If there was increased risk of these outcomes due to participating in the study, then the consent form would be required to mention it. Researchers are not obligated to mention the risks of a procedure that the person has already made a decision to participate in. It is the responsibility of the consulting physician and the hospital to make sure the parents are informed of the risks of that procedure before agreeing to undergo it.”

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