April 21, 2021

expert reaction to rat study looking at antioxidant treatment in pregnant rats and memory in adult rat offspring

A study published in FASEB J looks at maternal antioxidant treatment during pregnancy and memory function in adult rat offspring.

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“The study in rats in this research is informative and useful, but the implication in the press release that we might be near to having a treatment in human mothers than can deal with memory problems in their children is very misleading indeed.  What the researchers actually did is to carry out work in rats that clarifies the mechanisms in the body by which low oxygen in the womb might affect memory function in offspring, and to show that a particular intervention using vitamin C as an antioxidant with the rat mothers could prevent those mechanisms from operating.  But this is still a long way from a treatment that could work in human mothers.  Also, the evidence that the vitamin C treatment has an effect in the cognitive tasks that some of the baby rats did, to test their learning, memory, exploration behaviours, and anxiety-related behaviour, is not strong statistically.  On one of the two tasks used, no clear differences were found at all between rats whose mothers had different treatments.  On the other, despite what the press release says, there seems to be no evidence that rats from pregnancies with low oxygen levels took longer to perform the memory task, though there is a certain amount of evidence that they did not remember as well, and that this effect could be removed to some extent by giving the mother vitamin C.  The evidence on differences in the brains of the offspring is statistically stronger and clearer.

“So how far is this study from something that might be used as a treatment in humans?  A long way, in my view.  I’m a statistician, and cannot comment on how similar the relevant aspects of the rats’ physiology would apply in humans – though that’s clearly relevant to how easy it will be to translate the findings to humans.  But the experimental conditions that were applied to the rats do look fairly extreme.  The rats in low-oxygen (hypoxic) conditions breathed oxygen at a concentration corresponding to the air at about 13,000 feet above sea level.  That’s pretty high.  There are mountains in the Alps higher than that, though people don’t spend their pregnancies at the top of them.  Some people in the Andes or the Himalaya do live that high, and the researchers give reasons in their paper why data on this kind of restriction of oxygen in the mothers’ air can be relevant to some other causes of low oxygen in the womb, but what happens in humans subject to these other causes of low oxygen would need to be investigated properly before a useable treatment could be established.  Also, the amount of Vitamin C that the mother rats were given to drink is very high, compared to what humans might take for pretty well any purpose. Weight for weight, the daily dose for the rat mothers corresponds to about 37 grams of vitamin C a day in humans – that’s 37 of those big 1,000mg high-dose vitamin C tablets every day.  As the researchers and the press release point out, that couldn’t possibly be used in humans because of the risk of adverse effects (such as kidney stones, for example), and they have no evidence that lower vitamin C doses could have the same effects.  The researchers suggest that other antioxidants could be used instead, but so far they appear not to have evidence that they will work in rats in the way that these very large vitamin C doses did, let alone in humans.

“So in summary, this looks like a good piece of research that might in the end lead to a useful treatment in humans, but it’s a very long way from actually providing evidence for such a treatment, and doesn’t even make it clear in detail what that treatment might be.”

Prof Dominic Dwyer, Professor in the School of Psychology, Cardiff University, said:

“This is a very promising study concerning the mechanisms of hypoxic brain damage and potential means to prevent or ameliorate it – however, several of the claims in the press-release (and the paper itself) go beyond the evidence provided.  In particular, the claim that vitamin C treatment during pregnancy in rats protected against later cognitive deficits requires that there was a deficit in performance on the cognitive task produced by oxygen restriction during pregnancy, and that this deficit was not seen in the offspring of rat mothers treated with vitamin C – that is a claim based on the presence of an interaction between the oxygen restriction manipulation, and the vitamin C treatment, and no such interaction is present in the data (in contrast, this critical interaction is present in the analysis of measures of brain health and placental function).  Also, the claim that the effects of hypoxic brain damage (and its amelioration by vitamin C treatment) are not due to factors such as exposure to excess glucocorticoid exposure or foetal growth restriction are based on an absence of evidence as opposed to evidence of absence.

“The press release and paper do note important limitations of the work (e.g. the fact that the vitamin C dose in rats was higher than would be safe in humans, and only male rat offspring were tested).  There are also several other limitations – such as the fact that vitamin C treatment was given throughout the period of oxygen restriction, and the offspring were raised by the same rat mothers which mean that it is not possible to determine from the current study when the treatment was effective, or by what mechanism (or mechanisms).

“In summary, this is very promising work on an important topic that but it will require extensive follow up before the promise of a treatment for foetal oxygen restriction can be delivered.  It should not be relied on to promote treatment strategies in humans in the absence of such additional research.  There is simply no basis for generalising to human treatment as the work currently stands.  This research in rats raises the possibility that antioxidant treatment may ameliorate hypoxic brain damage, and is valuable in doing so – but without further investigation of the mechanisms involves, and translational research aimed at generalising to humans, it is premature to speculate about potential human interventions based on this work alone.

Does the press release accurately reflect the science?

“Broadly speaking, yes.  But several specifics are incorrect and others overstated (see below).

Is this good quality research?  Are the conclusions backed up by solid data?

“This is high quality lab-based research.  However, some of the data is less conclusive than it is presented to be (in both the paper and the press release (see below).

How does this work fit with the existing evidence?

“Regarding hypoxia and vitamin C (i.e. antioxidant treatment) – this is outside my area of expertise.  Regarding brain function and cognitive function – the apparent link between hippocampal dysfunction and a deficit on the navigation task used is in line with prior research.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“Some issues are noted (in particular the fact that the vitamin C dose used in rats is higher than would be safe in humans; and the fact that only male rat offspring were tested), others were not (see general comments above about the lack of ability to determine when and how the vitamin C treatment might be effective).

What are the implications in the real world?  Is there any overspeculation?

“There is simply no basis for generalising to human treatment as the work currently stands.  This research in rats raises the possibility that antioxidant treatment may ameliorate hypoxic brain damage, and is valuable in doing so – but without further investigation of the mechanisms involves, and translational research aimed at generalising to humans, it is premature to speculate about potential human interventions based on this work alone.”

Prof Andrew Shennan, Professor of Obstetrics, King’s College London, said:

“It is well established that the environment inside the womb is important for long term health to the baby in later life.  A poorly functioning placenta causing low oxygen to the baby, can result in adverse effects, including to brain function.

“This study in fetal rats suggest that by giving vitamin C some of these effects, in this case poor memory, could be improved in rats.  Vitamin C has failed to show benefits in other conditions in human pregnancy with similar placental disease, such as pre-eclampsia, so this work would need to be replicated in humans.”

‘Maternal antioxidant treatment protects adult offspring against memory loss and  hippocampal atrophy in a rodent model of developmental hypoxia’ by Emily J. Camm et al. was published in FASEB J at 00:01 UK time on Wednesday 21 April 2021.

DOI: 10.1096/fj.202002557RR

Declared interests

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  However, my quote above is in my capacity as an independent professional statistician.”

Prof Dominic Dwyer: “I can confirm I have no conflict of interest.”

Prof Andrew Shennan: “No conflicts to declare.”