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Unethical Bioethics 1

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False Medical Denials about the Fatal
Omissions in the SUPPORT Consent Form


Peter Aleff, 2097 Cottonwood Drive, Vineland, NJ 08361, USA,
prevent@retinopathyofprematurity.org   April 21, 2013     

     
 

As posted on the "BioethicsConsent" page of this site, I had alerted the U.S. Office for Human Research Protections (OHRP) on May 24, 2011, about the lack of informed consent in the SUPPORT experiment of oxygen withholding from premature babies. That OHRP took almost two years to examine this simple yes-or-no question but at long last sent on March 7, 2013, a "letter of determination" to one of the 23 study centers to state that the parental consent form submitted to it had failed to disclose any information about the known and expected risks of death and serious brain damage from low oxygen.

The consumer-advocacy group Public Citizen commented on this letter on April 10 under the title "HHS-Funded Experiment Exposed Babies to Risk of Death and Blindness Without Informing Parents" at http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=3859  and requested that "HHS Secretary Should Apologize to Parents of Premature Infants Enrolled in Unethical Trial at 23 U.S. Medical Centers", adding on April 15 a request that "HHS: Suspend Enrollment in Baby Trials, Release Details of Ongoing and Earlier Experiments."

In response to the resulting media coverage, three of the SUPPORT researchers wrote a Letter to the Editor to the New England Journal of Medicine to falsely claim in the 4/17 issue that they had not expected an increase in mortality among the preemies with the lower oxygen levels. See http://www.nejm.org/doi/full/10.1056/NEJMc1304827

They also misleadingly repeated their already debunked claim that the not enrolled infants were a control group with a higher mortality rate than any of the groups in their experiment. However, as Public Citizen had pointed out already on 4/11 to one of the researchers, these non-enrolled infants had been significantly sicker than those enrolled and could therefore be expected to die at a higher rate. 

An editorial in the same issue of the NEJM, posted at http://www.nejm.org/doi/full/10.1056/NEJMe1304996 was written as if addressed to the parents of the enrolled preemies. It claimed again that

"There was no way for you as a parent of a child in SUPPORT to know what the answer would be before your child participated."

That editorial omitted to say that the parents had no way of knowing the information about the relative risks known to the researchers because these had deceptively withheld that information from them.

To point out the blatant misinformation promulgated by the researchers and their apologists, I submitted on 4/18 this response to the NEJM:


Reply to Waldemar A. Carlo, M.D., Edward F. Bell, M.D., and Michele C. Walsh, M.D.,
"Oxygen Saturation in Extremely Preterm Infants", letter to the Editor, NEJM, April 17, 2013, as posted at http://www.nejm.org/doi/full/10.1056/NEJMc1304827

To the Editor:

Drs. Carlo, Bell, and Walsh defend the ethics of the SUPPORT experiment with oxygen saturation targets for premature infants by asserting that "Death was included in the primary outcome because it competes with retinopathy, not because a difference in mortality was expected".

Contrary to this assertion, the SUPPORT authors were well aware of the added risk of death and serious brain damage to the infants receiving oxygen only in the lower half of the typical range. They cited a British report from 1973 that the routine oxygen withholding practices introduced 17 years earlier had by then led to an estimated 16 deaths for each case of blindness prevented[1]. Similarly, the authors of the NeOProM umbrella study proposal, which included the SUPPORT experiment as well as four similar studies in other countries, mentioned an estimate of 150,000 preemies killed from lack of oxygen in the first 20 years after the largest of these studies and its fatal recommendation to withhold the life-saving gas[2].

Both groups expressed the hope that better measurement techniques would meanwhile allow to improve this outcome, but the examples the SUPPORT authors cited did not back up their argument. They summarized a limited sample of studies in which lower oxygen levels had correlated with lower incidences of blinding, but for most of these the mortality had not been reported, and in at least one of them a tighter monitoring of this breathing help had increased the number of deaths by 8 to 11 per cent, depending on the birth weight group, with a probability of 94 percent that these increases were not statistical flukes[3].

They openly admitted in their clinical paper that the safety of the infants in their trial was not assured:

"Although data from these studies suggest that maintenance of oxygenation at ranges lower than those previously used may decrease the incidence of retinopathy of prematurity, the safety of low target levels of oxygen saturation remains a concern.” [4]

However, they did not mention this safety concern on the parental consent forms which were initially unavailable to the NIH's Freedom of Information Office but were belatedly given to the Office of Human Research Protection after I had pointed out to that OHRP the unacceptable absence of these legally mandated forms.

Moreover, the authors of the NeOProM umbrella study proposal, which included the SUPPORT experiment as well as four similar studies in other countries, stated:

“… none [of these five trials] individually will be able to exclude the possibility that the expected valuable short term benefits associated with giving babies less oxygen are not associated with a small but significant 4 per cent increase in death or serious neurosensory disability in survivors.”[5]

The SUPPORT result of 23 "extra" deaths in the low-oxygen group amounted to 3.5 percent of that group, so the researchers' prediction had been fairly accurate and confirmed their well-informed expectation.

Yet, this expected risk of death and serious brain damage for the infants was not mentioned on the parental consent forms either.

Indeed, no parent could legally have agreed to enroll their child in a study with this risk of death, merely for an unproven hope of reducing the risk of blindness which is a non-lethal condition. Risking death to prevent eye damage is clearly not in the interest of any child, and the Nuremberg Code as well as subsequent declarations of medical ethics specifically forbid all researchers to expose their subjects to any  risk of death from their research. For instance, Articles 5 and 7 of that Code state clearly:

“No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur” and “Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.”

The designers of this oxygen-withholding experiment were fully aware of the impossibility to obtain any parent's informed consent for their experiment. They had suggested already in 2003, in their initial proposal for the experiment, to skip the informed consent formality because this “defensive documentation” would be likely to reduce enrollment or make it impossible to begin with if its risks had to be explained to the parents. They offered this suggestion obliquely and indirectly because it was clearly illegal, so they discussed “the wisdom of collecting only the relevant, necessary data” and then quoted approvingly this analysis from a 1998 article on the future of clinical trials: 

“Requirements for large amounts of defensive documentation imposed on trials by well intentioned guidelines . . . may, paradoxically, substantially reduce the reliability with which therapeutic questions are answered, if their indirect effect is to make randomized trials smaller or even to prevent them starting.” [6]

This passage clearly reveals the researchers’ intention to ignore the requirement for informed consent because only this “defensive documentation” imposed by “well intentioned guidelines” could have prevented many or all parents from volunteering their babies for that potentially fatal experiment.

The lack of information about these fatal risks on the parental consent forms was therefore not due to any ignorance of those risks on the part of the researchers, or to their alleged incertitude about them, but rather to their planned obfuscation of the known risks because revealing these honestly would have kept their knowingly patient-harming experiment from starting.

[1] Support Study Group of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: "Target Ranges of Oxygen Saturation in Extremely Preterm Infants", posted May 16, 2010, on the website of the New England Journal of Medicine, see page 2 left at http://www.nejm.org/doi/full/10.1056/NEJMoa0911781

[2] Askie LM, Brocklehurst P, Darlow BA, et al.: “NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol”, BMC Pediatrics, January 17, 2011, see page 7 for the death toll estimate for an unspecified area, as posted at http://www.biomedcentral.com/content/pdf/1471-2431-11-6.pdf;
[3]
Bancalari E, Flynn J, Goldberg RN, Bawol R, Cassady J, Schiffman J, Feuer W, Roberts J, Gillings D, and Sim E. Influence of Transcutaneous Oxygen Monitoring on the Incidence of Retinopathy of Prematurity. Pediatrics, May 1987, 79: 5: 663-669,

[4] Support Study Group of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: "Target Ranges of Oxygen Saturation in Extremely Preterm Infants", as posted May 16, 2010, by the New England Journal of Medicine at http://www.nejm.org/doi/full/10.1056/NEJMoa0911781 

[5] Askie LM, Brocklehurst P, Darlow BA, et al.: “NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol”, BMC Pediatrics, January 17, 2011, as posted at

http://www.biomedcentral.com/content/pdf/1471-2431-11-6.pdf

[6]  http://pediatrics.aappublications.org/content/
112/6/1415.full.pdf. See page 1418 left

For more information about the flaws of this SUPPORT experiment and the entire unscientific doctrine of oxygen withholding, see the four pages that begin at http://retinopathyofprematurity.org/UnethicalBioethics1.htm as well as the rest of that site.

*

The NEJM's submission form for Letters to the Editor did not accept this comment because it exceeded the 175-word limit for such comments by 976 words. I therefore resubmitted my letter to the person who had directed me towards that submission form and added in my cover letter:

I hope you can bypass the rigidity of your submission system that does not allow me to properly document my comment. On the other hand, I will also understand if your editor may be reluctant to publish my recapitulation of the facts in your Journal because it shows that the NEJM editor involved in publishing the initial SUPPORT paper was complicit in the lack of informed parental consent evident from that paper: the authors stated openly that they were concerned about the safety of the infants in their low-oxygen group. Any alert editor, bound to assure compliance with the official codes of medical ethics, would therefore have had to ask how the researchers could have obtained any parental consent at all for exposing the premature babies to their potentially unsafe research.

*

It is also important to point out that the above cited assertion by some SUPPORT researchers reveals a profound ignorance of basic medical ethics. They said:

"Death was included in the primary outcome because it competes with retinopathy, not because a difference in mortality was expected".

The very idea that death could compete with blindness is contrary to medical ethics, to common ethics, and to common sense. Article 6 of the Nuremberg Code states clearly that

"The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment".

In other words, you don't risk killing the babies to save them from mere blindness. This staple of medical ethics was recently cited again as a matter of course by the Presidential Commission for the Study of Bioethical Issues.

The concept that death could be weighed against blindness illustrates a "better dead than blind" attitude among the SUPPORT researchers that shows the various declarations of medical ethics and relevant federal regulations are mere window-dressing, designed to reassure the public about the alleged protections for human research subjects, but without any intention to actually abide by them or, heaven forbid, to enforce them against violators.

Nursery doctors mislead by their blind and blinding faith in the pediatric doctrine continue therefore the approach of the eugenicists who designed the original oxygen-blaming experiment. Those doctors from over half a century ago intentionally eliminated the babies most likely to become blind, as documented on the page oxygenstudyfrauds and in my letter to the Bioethics Commission which is posted at Bioethics1955oxygen. Meanwhile, their modern successors who ran the SUPPORT experiment as well as the medical editors who approve such statements need urgently a refresher course in basic medical ethics to learn that death is not on the same level of risk as blindness.

*

To comply with the NEJM's 175-word limit for letters to the editor, and to not give its editors the excuse that they could not read a submission outside their standard form, I submitted through their system on 4/28 the following Letter to the Editor:

"Apologists for the SUPPORT experiment of lowering oxygen levels for premature infants claim they did not alert the parents to the potentially fatal risk because they had not expected a difference in mortality for the low-oxygen group. [i],[ii]

However, the SUPPORT authors had cited earlier examples of increased mortality from restricting oxygen to reduce the risk of retinopathy of prematurity, and they stated in their paper that “
the safety of low target levels of oxygen saturation remains a concern[iii] Similarly, the designers of the umbrella study had admitted that none of the five parallel experiments “
will be able to exclude the possibility that (…) giving babies less oxygen [is] not associated with a small but significant 4% increase in death or serious neurosensory disability in survivors.”[iv]

Some researchers had advised that “defensive documentation” would be likely to reduce enrollment or make it impossible if its risks had to be explained to the parents.[v] This “defensive documentation” could only mean the Informed Consent which they deemed less important than their potentially fatal experiment on humans.


[i] Waldemar A. Carlo, M.D., Edward F. Bell, M.D., and Michele C. Walsh, M.D.,"Oxygen Saturation in Extremely Preterm Infants", letter to the Editor, NEJM, April 17, 2013, as posted at http://www.nejm.org/doi/full/10.1056/NEJMc1304827

[ii] Jeffrey M. Drazen, M.D., Caren G. Solomon, M.D., M.P.H., and Michael F. Greene, M.D.: “Informed Consent and SUPPORT”, editorial NEJM, April 17, 2013, as posted at http://www.nejm.org/doi/full/10.1056/NEJMe1304996

[iii]Target Ranges of Oxygen Saturation in Extremely Preterm Infants”,  SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, N Engl J Med 2010; 362:1959-1969 May 27, 2010, as posted at http://www.nejm.org/doi/full/10.1056/NEJMoa0911781#t=articleTop

[iv]NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol”, Lisa M Askie, Peter Brocklehurst, Brian A Darlow, Neil Finer, Barbara Schmidt, William Tarnow-Mordi, for the NeOProM Collaborative Group, as posted at http://www.biomedcentral.com/content/pdf/1471-2431-11-6.pdf

[v] Cole, et al.: “Resolving Our Uncertainty About Oxygen Therapy”, Pediatrics 2003; 112:6 1415-1419, see page 1418 left, as posted at http://pediatrics.aappublications.org/content/112/6/1415.full.pdf.

I sent the above comment to Jacqueline Bono at the NEJM who had guided me through their procedure and had told me:

I was informed that it is acceptable for you to provide two versions – one that adheres to our 175-word count limit, plus the longer one, and then both can be moved to the editor. If you are still interested, please follow the instructions, to submit a 175-word letter, and the longer one can be uploaded as a “figure” file.

My cover letter said:

Thank you, Jacqueline Bono,
 
for your email. I submitted today the following Letter to the Editor of exactly 175 words plus the references cited. I would appreciate it if you could also convey to the editor the longer letter with more details that I had sent you on April 18.

I also want to draw your and that editor's attention to the "additional information" field of today's submission where I entered a link to my page http://retinopathyofprematurity.org/BioethicsLIGHT-ROP.htm. I document there another failure of U.S. medical researchers to inform the parents of premature babies about the risks from their experiment, this one called LIGHT-ROP, and also about their rigging of the protocol to falsely assert the safety of the fluorescent nursery lighting to the highly vulnerable eyes of premature babies.
 
I hope that the NEJM editor(s) will be sufficiently concerned with the unnecessary suffering of many ROP-afflicted preemies to expose this research fraud and to thereby remove this blatant falsehood from the medical doctrine.
 
Researchers as well as their peer reviewers and editors are supposed to be familiar with the relevant literature, but none of the oxygen-manipulating proponents seem to be aware or care that oxygen had been administered to preemies generously for several decades before any of them ever developed ROP. They should also have known that the first cases of ROP were observed in babies born the year after the introduction of fluorescent lamps in the U.S., and that the same parallel repeated itself after the war in other industrial countries as these lamps became available there.

Moreover, the U.S. Occupational Safety Guidelines have developed danger limits for damage-weighted retinal irradiance, and it is easy to calculate from their formulae that the blue-rich fluorescent nursery lighting accumulates in preemie eyes to this danger level within the first few minutes of their exposure to this un-womb-like brightness. There is a mountain of solid evidence that nursery lighting is the cause of ROP, but upon examination there is no scientifically valid evidence at all that ROP is due to excess oxygen which functions at most as an enhancer of the light damage.  

 
The researchers and reviewers and editors who keep ignoring these easily verified facts are violating the codes of medical ethics that mandate said familiarity with existing research, and they thereby prolong the epidemic of baby-blinding and encourage more dead-end and deadly experiments with oxygen rationing that are so dangerous that the dangers had to be hidden from the parents.
 
Thank you in advance for conveying this additional information to the editor(s) involved and to so help end the continuing epidemic of ROP and the continuing preemie asphyxiation from stubborn but useless and harmful oxygen rationing.
 
Sincerely,
Peter Aleff

Indeed, on June 12, 2013, I received the following reply to that submission:

I am sorry that we will not be able to print your recent letter to the editor regarding the Carlo, Drazen, Magnus article of 16-May-2013, 16-May-2013, 16-May-2013.  The space available for correspondence is very limited, and we must use our judgment to present a representative selection of the material received.  Many worthwhile communications must be declined for lack of space.

Thank you for your interest in the Journal.

Sincerely,

Edward W. Campion, MD
Senior Deputy Editor and Online Editor
New England Journal of Medicine
[617-734-9800; ecampion@nejm.org]

*

On May 5, 2013, JAMA published the paper about the nominally Canadian counterpart to the SUPPORT experiment, called COP, at http://jama.jamanetwork.com/article.aspx?articleid=1684963. This experiment had 25 participating hospitals in Canada, the U.S., Argentina, Finland, Germany, and Israel. See also the synopsis at http://www.eurekalert.org/pub_releases/2013-05/tjnj-eod050313.php and the comment in Pediatrics at
http://medicalxpress.com/news/2013-05-effect-oxygen-saturation-death-disability.html. The latter two leave out any mention of the study's limitations cited below which disqualify its alleged results. 
 
The JAMA authors rewrite history and misquote their alleged source (Silverman) in saying that oxygen supplements were introduced in 1940 although Silverman devoted an entire chapter of his 1980 book on ROP to describing how oxygen had been given generously and routinely for decades before 1940 -- see also references [4] through [8] on my page http://retinopathyofprematurity.org/22oxygenslander.htm. They also claim oxygen rationing was introduced "in the 1960s" although this practice dates from 1955/56 and immediately increased the mortality among its victims. This convenient bending of the well documented facts illustrates the bias of the researchers in their efforts to link ROP to oxygen which they do again, without any evidence, in their second-last sentence:

"Because it is very difficult to maintain infants in a tight saturation target range, such recommendations may lead to increased tolerance of saturations above 95% and an increased risk of severe retinopathy."

The results of no statistically significant mortality difference between the groups, unlike the clearly higher mortality in the US and UK and Australian parallels of the low-oxygen groups, may be the result of the admitted caregiver bias of preferring to adjust the oxygen levels towards the higher limit and not to the lower, as I highlighted in their section on "limitations" of the Canadian study in their second-last paragraph, quoted below:
"Our trial has several limitations. Perfect adherence to the narrow target range of 88% to 92%, as displayed on the offset study oximeters, would have resulted in a difference of 6% between the true arterial saturations in the 2 groups. We observed barely half of this difference on days with at least 12 hours of supplemental oxygen. Caregivers may have tolerated saturations approaching the upper alarm limit more often than saturations approaching the lower alarm limit. Furthermore, we did not record exact times spent receiving supplemental oxygen for all study participants beyond the first 3 days. The distributions of saturations we report are therefore confounded by time spent breathing 21% oxygen when caregivers were unable to modify arterial saturations.
In other words, the nurses paid more attention to the visible status of the baby in giving more oxygen instead of blindly obeying the oximeter numbers, similar to the humane 1950 nurses described in the above cited reference [8] who bypassed the oxygen-rationing protocol in the first such experiment and turned up that life-saving gas when they thought the baby needed it. This means that babies in the "low-oxygen" group did not actually have the 6 percent lower average oxygen levels that would have separated them and their outcomes from the babies with more normal oxygenation, but the difference was barely half that amount. Accordingly, the elaborate statistics of the analysis don't apply although they appear more important in this and much other medical ROP research than the actual conditions.
 
The NEJM editorial about the also parallel BOOST II experiments is posted at http://www.nejm.org/doi/full/10.1056/NEJMe1305534
 
Its authors repeat again the already debunked lie that the researchers did not expect a higher mortality in the low-oxygen groups:
"The Office for Human Research Protections of the Department of Health and Human Services recently criticized the wording in the consent form for the SUPPORT trial. However, at the time these studies were initiated, there was no evidence of excess mortality or foreseeable additional risk related to caring for infants at the lower-target range."
So much for the NEJM editors' concern about truth in their journal.

*

Also, the alleged arterial oxygen saturations should be viewed with the following comment in mind, posted by a reader after the article [Macklin R., Shepherd L., Dreger A., and Asch A.: "The OHRP and SUPPORT -- Another View", New England Journal of Medicine, http://www.nejm.org/doi/full/10.1056/NEJMc1308015]

1 Reader's Comments

Arthur Strauss | Physician - Pediatric Subspecialty | Disclosure: None.

July 10, 2013

Sat targets vs actual sats

At least 2 studies that I'm aware of documented poor compliance with GA-related 02 sat targets in NICUs. We all observe alarm limits re-set at night, alarms ignored or addressed after long delays, etc. Until response to pulse oximetry alarms becomes automated, the human element of NICU care (stretched ratios, break coverage, lack of accountability, etc) confound any findings published on this issue.

 
Moreover, the continued obstinacy of the ROP researchers in trying to link ROP to arterial oxygen levels clashes with the long established finding that the oxygen supply of the retina is independent from the arterial levels of that gas, so the latter don't even have a theoretically plausible connection with the blinding.

 

 
 

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