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Beyond thalidomide: birth defects explained=

By Dr Janet McCredie AM

Between 1958 and 1962, thousands of babies across the Western world were unaccountably born with a plethora of physical deformities, including short or absent limbs, ears and eyes, holes in the heart, blocked intestines, and/or absence or duplication of other internal organs.

At first glance, longitudinal reduction of limbs was the most obvious feature, but more serious, often lethal defects were hidden in other organs. Vital organs such as the ear, eye, heart, gut, and/or kidney were deformed or completely absent. The perinatal mortality rate of these babies was an alarming 40 percent.

Striking patterns emerged in the geography of this alarming epidemic. West Germany had thousands of deformed babies, while East Germany had none: they simply stopped at the Iron Curtain. Canada had over 150, but the USA had almost none. They stopped at the 49th parallel. Britain had over 400 cases, and the British Commonwealth was afflicted, for example Australia had 46 known cases.

Doctors began searching for the cause of this frightening phenomenon. One of them, Dr Widukind Lenz, a Hamburg paediatrician, found that 41/46 mothers of phocomelic babies had taken a thalidomide preparation in early pregnancy. He presented his findings at a conference in Düsseldorf on 18 November, 1961, and published them in a German medical journal four days later. On 16 December 1961, a letter in the Lancet from Dr William McBride, a Sydney obstetrician, voiced similar suspicions. It was quickly becoming clear that thalidomide was the cause of the catastrophic birth defects in these children. These two independent reports from different sides of the world forced the companies concerned to withdraw thalidomide from European and British markets. Eight months later, the epidemic suddenly ceased.

History of the drug

Thalidomide (Contergan) was invented at Chemie-Grünenthal GmbH, a German cosmetics manufacturer that was diversifying into pharmaceuticals. Thalidomide was originally marketed as a light sedative for adults and children. The claim of no lethal dose was a strong selling point for a sedative in the days of fatal barbiturate or narcotic overdosage. Claiming to be safe and non-toxic, thalidomide captured 40 percent of the German sedative market from 1956. However, it soon became evident that people taking thalidomide encountered a dangerous side effect – sensory peripheral neuropathy in their longest nerves (those to feet and hands) – which left many victims permanently disabled. Chemie-Grünenthal strenuously denied adverse reports and settled legal threats out of court. German state health authorities transferred thalidomide from “over the counter” sales to “on prescription only”. Consequently, profits slumped. Chemie-Grünenthal found a new market for the drug – pregnant women with morning sickness. The drug was successfully marketed as a morning sickness drug from 1957, in Germany and overseas.

During the long period of postwar austerity, the British government taxed alcohol to the limits, impacting the giant Scotch whisky producer, Distillers Co., who decided to diversify into medicines, particularly sedatives. When they bought the rights to sell thalidomide to the British Commonwealth, they thought that Chemie-Grünenthal had done appropriate tests. So a German cosmetics manufacturer and a Scottish whisky producer were now selling a drug for human consumption. Both were motivated to improve profits by diversifying into human pharmaceuticals, an industry in which they were both inexperienced. The consequences of these forays were terrible.

The aftermath

The disastrous effects of Thalidomide resulted in mass litigation and compensation for its victims in the 1960s and 70s. In Aachen, Germany, parents of the German “Contergan kinder” collectively sued Chemie-Grünenthal for compensation towards medical and other expenses foreseen for these very disabled youngsters. The worst afflicted of the victims – some of whom were eyeless, earless, or limbless – had to be institutionalised. The less-disabled could live at home, but needed constant care and maintenance: wheelchairs, prostheses, chairlifts on stairs, and around-the-clock carers to assist with all ordinary daily activities.

This was the first time that a drug company had been charged with liability for intra-uterine damage. The German litigation went through a decade-long legal labyrinth to establish that thalidomide caused the defects. But Chemie-Grünenthal management was never found criminally guilty. Adverse media publicity surrounding the case forced the company to compensate German victims. The Contergan case was the second most expensive and longest litigation in German legal history – exceeded only by the Nuremburg trials.

Thalidomide was a disaster for Distillers Co., who as a consequence, left the pharmaceutical industry forever. They offered to compensate the victims, but the Sunday Times editor, Harold Evans, was outraged at Distillers’ inadequate offer of compensation. His paper campaigned to extract a better deal for the children based on ethics rather than legalese. In taking the moral high ground, the Sunday Times eventually won the day. The children were first helped financially by a benevolent fund; and later supported by The Thalidomide Trust, established by Distillers Co.

Thalidomide opened a new chapter in legal liability and compensation law worldwide. Many countries initiated new legislation to regulate the growing pharmaceutical industry and to protect the public. Following the long German litigation, compensation became available worldwide from 1971. The children (aged 9–12 years) were assessed to equate the amount of compensation to the degree of disability. Large sums of money attracted new claimants, some with no proven exposure to the drug. Some mothers who had denied taking the drug now confessed to it.
There was considerable shuffling in the queues for damages.

The first task of the assessors was to determine which children were true thalidomide victims and thus the responsibility of the drug companies – and which were not. I was asked by Dr McBride if X-rays might help in determining which children should be rightfully compensated. When I first looked at the X-ray films, I was frankly shocked. I had never seen such grossly abnormal bones and joints.

A quandary: dysmorphology without pathology?

While examining the X-rays of these children, however, I became riveted by another set of questions altogether: how does thalidomide do this to the embryo? What is its target? What is its mode of action? These fundamental questions remained unanswered despite a decade of research. Typically, radiologists match images to pathology. But there was no known pathology underlying these skeletal defects and the skeletal histology was normal. Absence of pathology is unacceptable to a radiologist. It seemed likely that there was pathology somewhere, but where? Unintentionally, I had joined the search for the target cell and the mechanism of action of thalidomide.

I was provided with the radiographs of five Australian thalidomide children. These were proven thalidomide cases, where the original prescriptions or pill bottles were kept. When I examined their radiographs, I kept getting the same answer: that thalidomide was damaging the sensory nerves in the embryo. The radiographs kept saying that the longitudinal reduction deformities of the limbs were due to absence of segments of nerve supply.

There was evidence of sensory neuropathic osteoarthropathy occurring in the embryo, with skeletal manifestations such as Charcot’s joints and neuropathic bones, similar to those seen in older patients with long-standing sensory neuropathy due to diabetes, syringomyelia, tabes, leprosy, etc. Thalidomide was a known sensory nerve toxin, causing neuropathy in adults. It might well target the sensory nerves of the embryo – the same cell as in the adult. Looking at the X-rays, this seemed an obvious solution.

I wondered why nobody had thought of nerves as a possible cause of the embryonic deformities, and deduced several reasons. Firstly, nobody had analysed the X-rays, therefore the clues that the bone deformity was secondary to sensory nerve injury remained unread. Researchers had examined the bone and cartilage damage, but found no sign of disease, without examining nerve tissue.

Secondly, embryology text books state that there are no nerves in embryonic limb buds. This statement dates to 1901, when light microscopy was not powerful enough (mag 1000x) to view nerve axons (diameter 2–5 nm). In 1974, we had the electron microscope, which magnifies 100,000 times. Dr John Cameron photographed thousands of axons in the undifferentiated limb buds of rabbit embryos. The embryology textbooks had been wrong!

Thirdly, much of the research had been done on animal subjects, and animals cannot complain of pain, tingling or numbness. A complaint requires language to communicate that something feels wrong. No laboratory scientist gets any clue to the presence of sensory neuropathy from an animal. So nobody had looked at the right tissue – the nerves.

Consultation in England

I decided to discuss my diagnosis with an expert in the UK during study leave, so I wrote to Sir Howard Middlemiss, Professor of Radiology in Bristol, author of papers on the radiology of tropical diseases such as leprosy, a disease of the nerves. He invited me to Bristol.

At the Royal Society of Medicine Library, London, I made an exciting discovery: I found publications proving that limb regrowth in amphibia is dependent upon sensory nerves – the phenomenon of sensory neurotrophism. I wondered if I had stumbled across neurotrophism in the human embryo, and I decided to discuss my theory with Professor Middlemiss. We compared radiographs of his lepers with my thalidomide children, and he declared that my interpretation was correct, and that birth defects were an expression of sensory neuropathy in the embryo. This was the first time, he said, that radiology had established the nature of a disease before pathology. He met me in London a week later to read my first draft.

While I was in London I viewed an excellent collection of X-ray films of British thalidomide children, where I analysed radiographs of 50 cases that confirmed my conclusions from the five Australian cases. What I had observed in Australia was not a fluke, but a consistent pattern. Back in Sydney, I joined the Department of Surgery, Sydney University, and began full time research in Professor JG McLeod’s neurology laboratory.

Consequent research

My research team found quantitative neuro-pathology in newborn rabbits. We looked at peripheral nerves in legs of control and thalidomide-treated pups. Kathryn North and Gillian Dunlop found reduction in the population of large calibre axons in foetal rabbits exposed to thalidomide in utero. If the nerve deficit was severe, a skeletal defect resulted. But the nerve lesion came first.

In Germany, radiographs of over 200 thalidomide children had been retained by Dr Hans-Georg Willert, professor of orthopaedics in Göttingen. He and his colleague Dr Lothar Henkel had discovered the pattern of thalidomide deformities of the limbs. They could not explain the mechanism behind the pattern. Using his X-ray material and my method, we established that skeletal malformations are due to injury to one or more sensory nerve segments. Segmental nerve injury explained the longitudinal disease pattern that Willert and Henkel had shown, with an exact correlation in 80 percent.

This research found that thalidomide targets sensory neurons. In the embryo, this is the neural crest. Neurotrophic function fails at the damaged level, and growth within that area of segmental nerve supply fails. The result is a longitudinal defect in the limb. It follows that anatomically similar, non-genetic birth defects are due to sensory and/or autonomic neuropathy after neural crest injury.

You can read about thalidomide in more detail in Janet McCredie’s book Beyond thalidomide: birth defects explained and watch an interview with Janet McCredie.

And another one right here.

Dr Janet McCredie AM is Honorary Fellow of the University of Sydney.

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