Analysis of the sheep experiment part-funded by the British Heart Foundation

The suffering endured by the ewes, housed alone after extensive surgical mutilations, is heartbreaking to imagine. They were allowed to live for a week after their surgery, carrying inside them severely brain damaged offspring for the last 48 hours of their existence. Their babies, still in utero, were connected to numerous recording devices and an inflatable cuff was placed around their umbilical cords. This was then used to suffocate them, inducing severe foetal distress as documented by heart and blood pressure monitoring.

Professor Giussani has a track record of these kinds of gruesome experiments. Unbelievably, several years earlier, the Home Office had allowed him to perform similar experiments on pregnant ewes – in which their foetuses were deprived of oxygen via suffocation of their mothers (‘large respiratory hoods’ were placed over their heads for two and a half hours).

The experiment – Antenatal Allopurinol Reduces Hippocampal Brain Damage After Acute Birth Asphyxia in Late Gestation Fetal Sheep

Part-funded by: British Heart Foundation
Performed at: Cambridge University
Published: June 2013 in Reproductive Sciences

Stated purpose: to investigate whether the drug allopurinol, if given to pregnant ewes, helps with foetal brain damage caused by asphyxia in the womb.

Rationale: Human foetuses can suffer brain damage during labour and delivery due to compression of the umbilical cord. To date, the only established treatment for this damage is therapeutic hypothermia, which seems to help in cases of only mild to moderate severity. During foetal asphyxia, toxic metabolic products are produced. The drug allopurinol can limit this process.

According to the researchers, recent trials had shown that allopurinol given to asphyxiated human neonates had a beneficial effect on mortality and severe disabilities at four to eight years of age in moderately asphyxiated patients. The drug did not work if the time interval between asphyxia and treatment had been prolonged, or the insult was too severe. Allopurinol crosses the placenta and can therefore enter the foetal circulation. The researchers wanted to see whether, in animals, giving the drug to pregnant mothers whilst repeatedly inducing foetal asphyxia would limit the brain damage to their offspring.

Experimental protocol: Eleven Welsh Mountain sheep, four-fifths of the way through their pregnancies, were anaesthetised and their abdomens and wombs cut open. The legs of the foetuses were pulled out externally, so that various tubes could be inserted into their blood vessels. Another monitoring device was implanted inside the abdomen of the foetus. An inflatable cuff was positioned around the end of the umbilical cord. The ewes themselves had tubes placed in the main artery and vein of their left groin. The incisions were sewn up, and all the tubes and devices were put through an incision in the flank of the mother, inside a plastic pouch sewn onto the mother’s skin.

After five days of ‘recovery’, during which the ewes were given antibiotics, although there is no reference in the published scientific paper to them receiving painkillers, the cuff around the umbilical cord was inflated repeatedly, to cut off the blood supply to the foetus. Each cord compression reduced umbilical blood flow by 80-90 per cent, and after a sequence of five compressions, foetal blood sampling showed severe asphyxia. Physiological monitoring demonstrated severe foetal distress. Five ewes were given allopurinol whilst their foetuses were being suffocated – with the dosing regimen being adopted from a human study in women undergoing uncomplicated labour.

Two days later, the sheep were all killed by lethal injection, and caesarean sections immediately performed. The foetal brains were preserved with formaldehyde delivered through their carotid arteries. Subsequent tissue analysis showed that significantly more brain damage had occurred in certain areas compared with foetuses who had not undergone the procedure. The administration of allopurinol decreased the amount of damage in certain parts of the brain but not in others – leading the team to speculate that the drug may block only certain toxic chemical pathways.

Medical relevance: Highly questionable. These kinds of foetal suffocation experiments have been performed for many years, with piglets and rats being used repeatedly as well as sheep. Yet not one drug has emerged as useful for human medicine. The authors themselves point out that ‘Drugs like tetrahydrobiopterin, melatonin, neuronal nitric oxide synthase (nNOS) inhibitors, xenon, and vitamin C showed promising results in experimental studies but have not yet been translated to clinical use.’

A book published in 2013, entitled ‘Neonatal Neural Rescue – A Clinical Guide’, points out that ‘direct extrapolation of data from animal models (even those involving non-human primates) is highly speculative because of the differences in brain development, anatomy, pharmacokinetics and pharmacodynamics, as well as the duration of exposure required to produce injury’. Allopurinol had already been shown to make no difference when given to human neonates with severe injuries – yet the sheep in this experiment were grievously damaged.

The same book notes that the only therapy that has been shown to be of use in human neonates, therapeutic cooling, had been in use for many years prior to animal experiments, and enjoyed a revival of interest as a result of serendipitous observations on humans.

In addition, obvious ethical concerns are raised by the fact that a team comprising many of the same researchers who experimented on the sheep had already performed a trial of maternal administration of allopurinol in humans where foetal monitoring was abnormal. ‘Severity of foetal hypoxia, brain damage and free radical formation’ were assessed using mainly blood tests together with early clinical examination. The authors stated that their ‘preliminary results…make it worthwhile to design a larger trial’, and made recommendations for such a project. These included a trial end-point of ‘long-term neurodevelopmental outcome‘, something clearly not possible in animal studies. The 2013 paper reveals that, at the time of writing, ‘a large prospective multicenter placebo-controlled trial in the Netherlands, investigating the effect of maternal administration of allopurinol on markers of brain damage and neonatal outcome in humans has recently completed recruitment’. With this in mind, it is hard to view this repulsive animal experiment as anything other than superfluous.