Thalidomide and Congenital Abnormalities

Letter

By: W. G. McBride

Date: December 16, 1961

Source: McBride, W. G. "Thalidomide and Congenital Abnormalities." Letter to the Editor. The Lancet 2 (December 16, 1961): 1358.

About the Author: Born in Sydney, Australia, in 1927, gynecologist and obstetrician William G. McBride brought the link between the drug thalidomide and birth defects to the attention of the medical world. In 1962, he was designated "Australian of the Year" for this achievement. Other honors followed and he used some of his prize money to set up Foundation 41, a research institute for the study of birth defects. However, in 1987, he was accused of scientific fraud over his claims that another drug, Debendox, causes birth defects and was struck off the medical register. Later, his position as an obstetrician was restored.

INTRODUCTION

Thalidomide was first synthesized in 1953 and became popular as a sedative prescribed for the morning sickness often associated with pregnancy. By 1958, thalidomide was being heavily advertised and promoted around the world. However, in April 1961, obstetrician William McBride began to notice cases of a rare birth defect involving shortened or absent limbs in babies whose mothers had used thalidomide in pregnancy. At the Crown St. Women's Hospital in Sydney, Australia, where McBride practiced, he soon persuaded the hospital to stop using the drug and wrote of his concerns to Distillers, the company that sold the drug in Australia. At about the same time, pediatrician and geneticist Widukind Lenz noted many similar cases in Germany, where thalidomide was available without prescription.

At this time, physicians assumed that the placenta was impervious to any drugs the expectant mother ingested—unless the drug actually killed her. This belief persisted despite experimental evidence to the contrary. Since thalidomide was not fatal in overdose, it was deemed safe. When thalidomide was approved, drugs were not tested in pregnant animals for their teratogenic effect—that is, for their ability to cause developmental abnormalities in the fetus. McBride wrote the letter below to a leading medical journal, The Lancet, to alert the medical community to the dangers of thalidomide.

PRIMARY SOURCE

THALIDOMIDE AND CONGENITAL ABNORMALITIES

Sir,—Congenital abnormalities are present in approximately 1 5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide ('Distaval') during pregnancy, as an anti-emetic or as a sedative, to be almost 20%.

These abnormalities are present in structures developed from mesenchyme—i.e., the bones and musculature of the gut. Bony development seems to be affected in a very striking manner, resulting in polydactyly, syndactyly, and failure of development of long bones (abnormally short femora and radii).

Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy?

Hurstville, New South Wales.

                                      W. G. McBride.

SIGNIFICANCE

McBride's warning concerning the teratogenic effects of thalidomide saved countless babies from being born with birth defects. However, the drug remained on the market for some time following McBride's warning, which accounts for the fact that there are still some 8,000 thalidomide survivors in the world today.

The observations of McBride and Lenz were to have far-reaching effects on the pharmaceutical industry. They were astute enough to notice rare and unusual conditions occurring in their patients and to spot patterns and connections with factors such as drug exposure. After thalidomide, it became mandatory to test new drugs on pregnant animals. Doctors became far more aware of the potential teratogenic effect of drugs and were more careful about the drugs they prescribed to pregnant women.

In general, the drug regulatory authorities acquired more sweeping powers after the thalidomide tragedy. One important development was the establishment of systems for post-market drug surveillance. That is, once a drug is on the market, it is monitored for any new side effects that emerge in the general population. These new side effects are reported through the physician. As a result of these post-marketing surveillance efforts, several drugs have been withdrawn on safety grounds. Unanticipated drug side effects still occur and they still harm or even kill vulnerable people. However, tighter regulation has undoubtedly improved patient safety.

Meanwhile, thalidomide has enjoyed something of a resurgence as a treatment for leprosy and multiple myeloma. However, it is no longer prescribed to women who are pregnant or who may become pregnant. Scientists now know that other drugs are as dangerous to an unborn child as thalidomide is. One such drug is isotretinoin, which is used in the treatment of severe acne. A woman actually needs to provide proof of a negative pregnancy test before she can be prescribed isotretinoin, according to the U.S. Food and Drug Administration. While on the drug, she must use an effective method of contraception. The fetus is most vulnerable to medication exposure through the placenta in the first three months of pregnancy. In the thalidomide case, one in five women who had taken the drug between thirty-seven and fifty-four days of pregnancy gave birth to a child with birth defects.

FURTHER RESOURCES

Books

Lock, Stephen, John M. Last, and George Dunea, eds. The Oxford Illustrated Companion to Medicine. Oxford: Oxford University Press, 2001.

Web sites

James Lind Library.org. "Thalidomide: An Unexpected Adverse Effect." 〈http://www.jameslindlibrary.org/trial_records/20th_Century/1960s/mcbride/mcbride_commentary.html〉 (accessed November 21, 2005.