Response to ACC criticism of a study finding DEHP in medical devices increases likelihood of liver problems in premature infants

July 31, 2009 at 5:27 pm | Posted in Analysis | 2 Comments
It's not easy finding pictures to illustrate PVC-related posts. Image (c) Stefan gara

Image (c) Stefan Gara

Thanks to John Newby, PhD for substantial input.

Recently, the journal Pediatrics published a very important study finding an association between the use of PVC in total parenteral nutrition (TPN) infusion systems and an increased risk of developing a liver disorder, cholestasis.

The American Chemistry Council (ACC) was quick to respond to the study, questioning the validity of the conclusions on the grounds of confounding factors and the limitations of epidemiological studies.

At H&E we disagree with the ACC assessment on a number of points and believe it to be worthy of response because they are dismissing, on scientifically dubious grounds, a study which clearly identifies a risk factor which if eliminated could substantially improve patient welfare.

Previously, researchers have measured chemical exposures during medical treatment, and even determined the various risk factors relating to development of cholestasis (TPN featuring strongly here).

This study is a vital addition to the literature because it pinpoints the specific material used in the TPN infusion equipment (PVC containing DEHP) as an additional risk factor in cholestasis.

In their response to the study, the ACC argues that:

“the finding that ‘DEHP load caused by polyvinylchloride infusion systems for TPN constitutes an important factor in the occurrence of Cholestasis’ are not supported by the data.”

suggesting that:

“the study does not answer whether the development of Cholestasis in these seriously troubled infants was related to the presence of DEHP in the vinyl tubing, or to the more severe underlying conditions of the infants prior to initiation of TPN.”

The ACC also suggest that the study does not show any direct cause and effect, but rather includes a multitude of confounding factors.

In general we are unhappy with the response, but would like to highlight two important errors.

Firstly, since this was an epidemiological study the elucidation of a direct cause and effect is highly unlikely: no epidemiological study will provide evidence of a direct cause and effect.

Secondly, there is the issue of the so-called “confounding factors”. This is the most important error in the ACC critique, where they treat recognised additional risk factors as being on a par with confounding factors.

Cholestasis is very likely to be multifactorial in origin, rather than having just one cause. Therefore, a number of risk factors can contribute to development of the condition. The ACC argues that these risk factors are confounding factors which may bias the study and therefore invalidate the results.

This is incorrect: the authors of the study recognised the known risk factors for cholestasis and they assessed the strength of correlation for development of hepatobiliary dysfunction in the study, and put the results in Table 2. [article continues after table]

Risk factors for cholestasis. Click image to enlarge.

Risk factors for cholestasis. Click image to enlarge.

Each of the factors listed in the table increases the risk of developing cholestasis. TPN correlates with a p value of 0.04, surgical disease/intervention p <0.0001, and systemic inflammation p=0.0083.

The study finds that, on top of these existing risk factors, the use of PVC infusion systems is an additional risk factor, found to correlate with a p value of 0.0004. Risk factors such as surgical disease/intervention influence the outcome independent of DEHP-PVC, ergo it is plausible that DEHP-PVC tubing increases risk independent of other risk factors.

So, far from being “confounders”, these are additional risk factors which influence the health outcome independent of the use of PVC in the TPN equipment.

From a health perspective, this is why the study is so significant: cholestasis incidence in the PVC-free group in this study was 18% compared to 50% for the PVC group. The ACC’s swift rejection of the study is, at best, unhelpful in the ongoing effort to improve medical care.

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  1. The author’s criticism of ACC’s comments on the Pediatrics article on cholestasis suggests a misunderstanding of the importance of confounding factors in assessing the significance of scientific findings. Such factors are those that can confound, or confuse, the researchers ability to test his/her hypothesis – in this case that “use of DEHP-containing PVC tubing increases the occurrence of cholestasis in infants receiving TPN.”

    Simply put – unless the researcher can eliminate potentially confounding factors, he/she cannot really test the hypothesis. Ideally, this would be accomplished by selecting two groups of subjects that differ only in the factor that one wants to test as part of the hypothesis. Practically, however, researchers select groups that are the same for as many other risk factors for the measured effect as possible.

    The authors of the Pediatrics article have not done this. The article indicates significant differences between the two groups for two important risk factors (duration of TPN, number of TPN units) and provides no data for at least one other (drug treatment). The data presented suggest that the group receiving TPN through PVC tubing containing DEHP has more severe underlying conditions (ie., were sicker) before the TPN started, and likely more prone to cholestasis to begin with.

    Based on the data presented, there is no way to determine to what degree DEHP exposure may have contributed to the incidence of cholestasis, if it contributed at all.

    • The argument here is over whether or not the two groups in the study were similar enough to make the test fair.
      We think they are. Although there were statistically significant differences between the two study groups for duration of TPN, p = 0.0499 and transfusion units, p = 0.0002, for the other parameters (gestational age, p = 0.3152; birth weight, p = 0.5379; surgical disease, p = 0.2213; and systemic inflammation (infection) p= 0.0607), there was no statistical significance between the two groups.
      Therefore, in our opinion, it is highly unlikely that the findings of the study can be explained by underlying illnesses.

      Furthermore, the researchers recorded a precipitous drop in cholestasis incidence following replacement of DEHP-PVC tubing.

      Explaining the magnitude of this drop with confounding is very difficult, as the two study groups were as similar as it was possible to have.

      As the ACC point out in their comment, “ideally the two study groups would differ only in the factor being tested.” Practically, however, researchers can only select groups that are the same for as many other risk factors for the measured effect as possible.”

      We feel the authors of the study in Pediatrics achieved this.

      John Newby, Medical Information Scientist, Cancer Prevention and Education Society


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