The Increase In The Incidence Of Malformed Babies In The German Federal Republic (West Germany) During The Years 1959-1962

Charles H. Frantz, M.D.


Beginning in February of 1962, press releases in the United States reported the alarming number of congenital malformations occurring in West Germany. News stories indicated that most of these deformities were phocomelia and were thought to be caused by the ingestion of the drug thalidomide by many women during the early months (first eight weeks) of pregnancy.

The alarming increase in malformed babies caused considerable anxiety in medical circles. In September 1961, Professor Hans Rudolph Wiedemann, Professor of Pediatrics of the Children's Clinic in Kiel, published an article calling attention to the marked increase in phocomelia (1). In this presentation thirteen cases were cited, with eight photographs. Professor Wiedemann indicated that the increased incidence had grown to epidemic proportions and suggested that a toxic agent in the embryonic environment might be a factor.

Two months later on November 18, Dr. Widukind Lenz, Professor of Pediatrics and Human Genetics at the University of Hamburg, expressed the opinion that a drug was the causative agent (2). He convinced the producers (Chemie-Gruenthal) that thalidomide was the toxic factor, and on November 28, 1961, the drug was withdrawn from the market. Thalidomide was thought to be so innocuous relative to side effects that it was sold over the counter without prescription. A chronological detail of events leading to the drug's withdrawal from sale is well documented by Dr. Helen B. Taussig (3).

Thalidomide was not released in the United States, France, Switzerland, the Argentine or Spain. It was available in a number of countries under various trade names:

Japan

January 1958

Nine (9) names

England

April 1958

Distoval

Germany

May 1958

Contergan

Israel

March 1961

?

Canada

April 1961

Talimol and Kevadon

Portugal

?

Softenon

Up to the middle of August 1962, fourteen cases were known in Switzerland. Italy reported cases from Rome, Milan, Palermo and Siracusa.

The situation in West Germany presented an interesting sociological phenomenon. The great majority of these phocomelic children were born to middle-class families, i.e., businessmen, clerks, professional men (doctors, lawyers, veterinarians, dentists, etc.). Many German physicians stated that the intensely "accelerated tempo" of this group made them "pill-takers."

Itinerary

Under a grant from the National Society for Crippled Children and Adults, Inc., it was my privilege to study the effects of thalidomide in Germany at first hand. Ten large cities were visited (see Chart 1 ), including municipal hospitals, state hospitals, University centers and two large rehabilitation centers. The area traveled represented a total population of 8,320,000. Physicians in the institutions visited have seen, examined and are currently caring for 1,793 cases.

During this inspection tour, personal observations and conferences with many physicians and surgeons indicated that channels of information and exchange of statistics are not as efficient as one would expect, compared to the United States. A considerable amount of insularism seems to remain in Germany with a tendency toward lack of referral.

The German Federal Republic consists of 94,708 square miles. The population is closely estimated to be between 56 and 58 million people, an increase of almost nine million since 1950.

The Federal Republic apparently is a loosely knit federation. The individual States, i.e., Westphalia, Schleswig-Holstein, North Rhine, etc., are much more independent in their operations relative to the federal government than are the States in our country. Public announcements indicated that the federal government at Bonn did not assume any degree of responsibility in solving the existing problem. Rather, the responsibility was placed in the hands of the individual States. The Ministry of Health does not seem to fulfill a function for the country as a whole, as does its counterpart in the United States (Department of Health, Education and Welfare).

Incidence

Figures from various large clinics varied to some degree, but it was quite evident that the peak incidence of malformed children was reached in the month of September 1961 in Kiel (47 cases), October 1961 in Hamburg (44 cases), and in the middle of 1961 in Bremen (31 cases). Despite the fact that individual chiefs of orthopedic and pediatric clinics noted an increase in malformations as early as the Spring of 1959, the true situation was not generally realized until Professor Hans Wiedemann's report in September 1961 (1).

By contrast with the present situation there were only three malformed infants per 1,000 births in Hamburg (a City-State) in 1961. In Schleswig-Holstein there were two to five cases per 1,000 births. In Bremen (a City-State) there were two cases per 1,000 births. The rise in the incidence is dramatically shown by the analysis of 266,599 births from 1949 to 1956, a six-year study obtained from a population of 2,000,000 people (4):

2500 spinal anomalies (block vertebrae, klippel feil, spina bifida)
2 amelia
7 acheiria
7 hemimelia
5 micromelia
7 peromelia (incomplete phocomelia)
3 phocomelia
29 hypoplasia, or deformity of long bones

In Schleswig-Holstein 30%, of mothers who had malformed babies were Primiparae.

This report includes nine documented cases of twins, some of whom died. Dr. Taussig reported six dizygotic cases, four of which had identical malformations. The total cases of twinning is not known to date. There undoubtedly are more.

The incidence curve began to fall off in the Spring (April and May) of 1962. The drop from May to June was dramatic. It was expected that no new cases would occur after July 25. However, a few sporadic cases did occur in August 1962.

During the third week in August, the Ministry of Health at Bonn officially reported 5,000 malformed babies had been born since 1959. The mortality rate was 50%, either stillborn or dying during the first few months of postnatal life. These figures indicated that 2,500-2,600 children were living and would need continuing orthopedic and/or prosthetic treatment. These figures are probably not final, as there is a discrepancy in reporting. Cases are reported to the Landesarzt (State physician), but this is not mandatory. People in villages may be reluctant to register their children, having in mind that in the past registries were utilized to eliminate the malformed and the afflicted aging by the centralized federal government.

In many instances, Roman Catholics accepted the malformed babies as an "Act of God". So it is felt that children in scattered rural areas are not reported.

Types of Cases

As of August 31, 1962 statistics were incomplete. Hospital clinics for the most part were unable to produce complete breakdowns and enumerate the total number of cases based on diagnostic evidence. This will require more time. It is hoped that eventually there will be a central source of information where totals of the various types of malformations will be available. This must be initiated by a well organized bureau within the Ministry of Health. No one knows how soon this will come about.

One clinic has analyzed its cases quite carefully, and the incidence figures are indicative of the general situation. Of 513 cases, only arms were involved in 50% of the children. Of 117 cases carefully studied and recorded, there were 97 with combinations of upper involvement. These were: Radial hemimelia, with or without floating thumb, 44 (45%) (Fig. 1 and Fig. 1A ); Three-fingered hands, 21; Phocomelia, 15 (15.5%) (Fig. 2 and Fig. 2A ); Triphalangeal thumb, 14 (Fig. 3 ); Hypoplasia of the thenar eminence, 9; Syndactylism, 5.

There were 40 lower extremity involvements (in combination) as follows: Dislocation of the hip, 16 (12 bilateral), 40% (Fig. 4 and Fig. 4A ); Paraxial tibial hemimelia, 8 (4 bilateral) (Fig. 5 and Fig. 5A ); Proximal femoral focal deficiency, 9 (2 bilateral) (Fig. 4A ); Aplasia of the femur, 7 (3 bilateral) (Fig. 5B and Fig. 5C ); Phocomelia, 6; Polydactylism, 5; Absent hallux (great toe), 4; Amelia, 3.

Visceral malformations: Ear -Microtia, 17 (Fig. 9A and Fig. 9B ); Anotia, 15 (Fig. 8 ); Eye - Micropthalmia with or without coloboma, 7 (Fig. 9A ); Absence of eyeball, 1; Cardiac anomalies, 26; Multicystic kidneys (death) (?).

The orthopedic hospital at Dortmund reported one case of cyclops. The child died in the early weeks of postnatal life.

No one child has a single deformity. There is multiple limb involvement with varying formulae. The most frequent deficiency in all clinics is bilateral radial hemimelia (absence). This implies a small floating thumb or no thumb. The elbow joint is markedly limited in motion during the first few months of life. However, it gains an acceptable range of motion. This group of children usually does not have other abnormalities. Comparatively speaking, this is a minor handicap, as the limbs are functional; the children will be able to dress and feed themselves. They comprise approximately 25%, of the total.

A more severe degree of deformity is the bilateral incomplete phocomelia. In this situation there is attenuation of the humerus with a short forearm. The hand may lack one or more digits. The elbow is limited in flexion (see Fig. 5 ).

The true or complete phocomelia is bilateral. This is the classical picture as physicians understand it. The hand arises directly from the shoulder girdle. There may be no humerus, radius or ulna. The hand may lack two, three or four digits. The fingers present have weak extensor power and no significant intrinsics. Many of these children have upper extremity involvement only (see Fig. 4 ).

Quadrimembral phocomelia is the most severe handicap (see Fig. 7 ). In this syndrome the legs are markedly attenuated. There may be a very small vestige of the femur, or no femur. The tibia is absent and the fibula foreshortened. The feet are rotated externally and the plantar surface faces the perineum. These children face a difficult future with respect to function.

The phocomelic infants have a brachy-cephalic skull, an arcuate concave nose (not the classical saddle nose) and a midline hemangioma extending from across the forehead down the bridge of the nose and across the upper lip (see Fig. 1 and Fig. 7 ). The hemangioma disappears in from twelve to twenty-four months. The eyes are widely separated. The phocomelics are estimated to be 30% of the total (see Fig. 2 ). It must be remembered that these figures are not accurate and may change.

Microtia and micropthalmia occur in conjunction with a facial paralysis (Fig. 9C ) and paralysis of the extraocular muscles (Fig. 9A and Fig. 9C ). These children cannot hear well and are unable to move their eyes naturally. Some pediatricians are concerned that these children may be ataxic. Most of the patients in this group do not have significant extremity deformities. A small percentage of them are thought to be mentally deficient.

The classical clubbed foot accompanies lower extremity abnormalities (see Fig. 6 ). Visceral abnormalities are common. Cardiac anomalies include auricular defects, pulmonary stenosis, septal defects and dextrocardia. Many of these babies have died. A few are still living.

Malrotation of the gut, cystic kidney, esophageal atresia and duodenal atresia are not uncommon. Many babies have had imperforate anus, atresias and hernias corrected. Undescended testicles are a common accompanying anomaly with quadrimembral phocomelia. In some instances the testes cannot be palpated in the canal. Recto-vaginal fistula has been encountered.

Microcephaly and cleft palate and harelip are rare. Of the total cases in this report, only nine cases of cleft palate and harelip have been encountered (Fig. 6 ). The geneticists believe these deformities to be incidental.

Dr. Lenz of Hamburg has attempted to compute the critical time element relative to certain deformities. His critical period from day to day has been plotted from the last day of menstruation.

Anotia (complete absence of the ears - see Fig. 8 ): Ten carefully documented cases were studied. This anomaly was produced when thalidomide was taken on the 35th day. In no instance was the anomaly reported when the drug was taken before the 35th day, and no cases when the drug was taken after the 35th day. Impression: the 35th day seems to be the critical period for anotia.

Microtia (hypoplastic auricles): The critical period seemed to be longer: the 36th to the 46th day.

Upper amelia: In twelve documented case histories, the critical period seemed to be from the 39th to the 41st days. One case began ingestion on the 44th day, but the date of the last menstrual period was in doubt.

Lower amelia (4 cases): The critical period seemed to be from the 41st to the 44th days.

Upper phocomelia (21 documented cases): The critical period seemed to be from the 38th to the 52nd days. The peak incidence was reported to be between the 43rd and the 50th days. This, however, is not too well documented. There were some discrepancies of dates in some histories.

Dr. Lenz offered this opinion: "A pregnant mother can ingest thalidomide at the 55th day of her pregnancy and ingest the drug each day thereafter during her pregnancy, and the child at term will have no skeletal discrepancies." No opinion was offered as to the fate of the viscera under these conditions.

As of the middle of August, seven cases were known where a second child has been born normal whose sibling last year was phocomelic (from thalidomide). During this second pregnancy the mother took no drugs.

Treatment

Orthopedic

Information secured from the hospitals and clinics visited indicated that none of the registered children have wanted for care. The pediatric, surgical and orthopedic facilities are well organized and staffed by competent physicians and surgeons. The outpatient clinics are active and well equipped. Many children are on the active rolls of outpatient clinics and are seen at regularly specified intervals. A large number of children are in hospitals under active surgical, orthopedic, and physical and/or occupational therapy regimes. The physicians and surgeons in Germany have taken positive and definitive action in analyzing individual problems and have initiated early corrective measures.

Pediatric wards (both medical and surgical) are light, airy and well equipped with nursing personnel. These units are immaculately clean. From personal observation, nurses and attendants shower abundant "tender loving care" during hospital stays.

It is quite obvious that the children under care are receiving excellent treatment with modern methods. There may be many children who have had no care due to the reluctance of reporting as noted earlier. In Northern Germany, orthopedic facilities are somewhat lacking, especially in the field of prosthetics. Statements have been made that these patients would be referred to Dr. Oskar Hepp at Muenster for their prosthetic care. This proposed approach to the problem will offer great difficulties. The orthopedic and prosthetic services at Muenster are well organized but overloaded, and must receive help from other organized centers in handling the patient-load.

The presenting deformity of radial hemimelia (absent radius) is the so-called "clubbed hand" which bends toward the elbow. Orthopedic surgeons have applied corrective plaster-of-paris casts early. After a series of corrective casts, the hands are gradually corrected to an almost anatomical position. When this goal is reached, the children are exercised both passively by the mother (following instruction by physical therapists) and by "play." Night splints are worn to maintain the correction. Characteristically the children with this condition grasp small objects between the fourth and fifth fingers in lieu of absent thumbs (see Fig. 10A ). Dysplastic hips are placed in corrective abduction hip splints. Dislocated hips are gently reduced and held in plaster-of-paris hip spicas.

Clubbed feet have been corrected very early in life. In the first week or weeks, a series of corrective plaster-of-paris casts are applied. When satisfactory positions have been obtained, therapists teach the mothers to obtain active contraction of dorsiflexors and evertors (peroneals) of the feet. In the city of Dortmund a high degree of skill has been obtained in correcting and activating clubbed feet "early". Professor Guenter Imhaueser has treated over 450 cases, both new and recurrent types.

Supernumerary digits (extra fingers or toes) have been removed surgically. Syndactylism (webbed fingers) are being exercised. At the ideal time (later in childhood), these webbed fingers will be separated.

The aforementioned types of cases may be said to be strictly orthopedic in nature. They have been handled intelligently, correctly, and at an early date, an axiom for children's work in this specialty.

Prosthetic

It is interesting to note that West Germany is slightly larger than the State of Oregon. There are many amputees from both World Wars, and the art of prosthetics is well developed. There are 600 prosthetic and orthotic (brace) shops, both large and small. In Germany children have been fitted with prostheses for many years. However, it apparently was not a universal practice until recent years, when this special field for children was stimulated by Dr. Oskar Hepp of Muenster (5) (6).

From a functional standpoint the complete phocomelic upper extremity offers many difficulties. There is little of the extremity afforded for a prosthetic socket and no significant power source is present. Here, the prosthetic techniques utilized are:

Plastic shoulder caps are tailored to fit over the child's shoulder with an upper arm (humeral) section. In some clinics, cables utilized to operate the hook and elbow devices will be anchored to belt-bands or to straps encircling the thighs. This technique, which is standard in the United States, Canada and England, demands that the child understand the somewhat complicated system of activating the artificial limbs. The control "tricks" cannot be mastered too well by toddlers. The system requires an excess of body motion to obtain elbow flexion or extension, and a considerable amount of energy is expended.

The obviously more practical prosthetic technique for phocomelics is the use of external power. In Heidelberg, Professors Kurt Lindemann and Ernst Marquardt have fitted prostheses with external power (see Fig. 11 ) during the past ten years. The source of power is carbon dioxide gas under pressure. The gas is in a small tank which is carried in a sling. From this tank are miniature plastic or rubber tubes leading to small pressure-control valves. These valves release gas which operates the elbow in flexion and extension and opens or closes the terminal device.

Children as young as eighteen months have been fitted with this technique (fifteen to date). Their initial maneuvers are, of course, crude and clumsy, but under the instruction of well trained occupational therapists, they soon come to learn what the devices can do for them. The opening or closing of the valves is accomplished by a slight pressure by one or two small phocomelic fingers. The valves rest on the shoulder caps immediately under a window for the fingers. The external power is available for elbow activation and the opening and closing maneuver of the hand without excessive body motion, which in the older techniques almost amounted to gyrations of the body trunk.

Phocomelic children with involvement of four extremities offer more difficult problems (see Fig. 2 ). The application of lower extremity artificial limbs articulated to the pelvic wall offers a poor possibility of independent ambulation unless there are good arms to handle crutches (see Fig. 11 ). With the absence of upper limbs the difficulties are compounded. The orthopedic surgeons and prosthetists are working on this phase, hoping to develop more satisfactory appliances.

Incomplete phocomelics have short arm segments which may be suitable for prosthetic sockets. These children have deficient muscle power (absent deltoid, biceps and triceps musculature). In these situations modified types of standard above-elbow and shoulder disarticulation types of prostheses are utilized. The phocomelic fingers are used to operate the positive-locking elbow units located in the humeral section of the appliance. This technique is well developed at the University of Muenster and is standard practice in the United States.

Surgical

Visceral anomalies are corrected when diagnosed. The pediatric services work in close cooperation with surgical departments. General surgeons and pediatric surgeons have proceeded with skill. In Kiel, Hamburg, Bremen, Heidelberg, Cologne and Munich, infants were seen who had undergone surgery for esophageal atresia, duodenal atresia, imperforate anus and the bowel. In Munich the pediatric surgeon at the University Kinderklinik had successfully operated fifteen cases of imperforate anus, three esophageal atresia cases, and two cases of duodenal atresia.

Children with microtia have been seen by the otologists, and imperforate external auditory canals have been opened. In some instances X-rays failed to reveal the inner ear structures. What can be done for the children with extraocular muscle paralysis and facial paralysis remains to be seen. The few cases of harelip and cleft palate are being corrected.

As is universally practiced, these children will be followed regularly throughout their growing period in offices, clinics and hospitals. The status of many of these children three or four years from now would make a very worthwhile study. The magnitude and universal interest in the multiple problems will certainly lead to well documented and complete records.

Parental Social-Emotional Reactions

As one would expect, the birth of a malformed child into a family is received with some emotional shock, mostly on the part of the mother. In upwards to three months, most mothers gradually became resigned to the fact that they had a problem and responded more objectively than emotionally. A few uneducated mothers had the feeling that this catastrophe was a curse from God and that they would have to bear the judgment. Other mothers in this group blamed the doctor for the "pills" and the company that manufactured them. In some instances these reactions made medical management difficult. One surgeon in Cologne stated: "The more religion in the family, the more rational the acceptance of the problem." Suicides were reported.

After medical examinations and counseling by pediatricians, many mothers in Northern Germany expressed relief that their babies were the result of an extraneous factor (drug) and pot hereditary. Their worries were also lightened when reassured that the baby was not mentally deficient.

Very rarely was an infant rejected by the family. Mothers with one or more older children in the family adjusted more rapidly to the new baby than did mothers of a firstborn. Euthanasia was not mentioned in Germany. One clinician stated that there had been no "talk" of this nature in North Germany.

Abortion is not a topic of general conversation in the medical profession. This operation is illegal in Germany, and the laws are patterned as they are in the United States. A medical board may authorize the interruption of a pregnancy if the life of the mother is endangered. Two cases of abortion quite late were authorized in North Germany in the interests of the mental health of the mothers. Both feti were normal. The possibility of a deformed baby is a completely new concept and no doubt will be the subject of debate in medical and legal circles. North Germany has a majority of Protestant denomination (Evangelical). One pediatrician discussed changes in the laws governing abortions, expressing the opinion that the law should be broadened. In Southern Germany, where Roman Catholicism predominates, one investigating doctor stated that because abortion was illegal he did not mention it to families during questioning because this operation is "against the law".

Two organizations of interested parents have been formed. One has a membership of 450 parents as of August 1962. This group included the parents of five sets of twins. A young lawyer is guiding these groups. His second child is phocomelic, and his sister has one phocomelic child. The main objective of this group is the interchange of ideas in various communities. Discussion of mutual problems, stimulation of interest, and funds for the special care of the children when they reach school-age are also objectives. There is some degree of animosity against the Chemie-Gruenthal Company. It is too early to determine how far legal activities will proceed.

Generally, it appears that the families have adjusted well to the problems. They return to clinics and are grateful for the positive approach being pursued by the medical profession.

It must be repeated again that there are undoubtedly many unreported cases in that people of certain religious faiths have accepted the deformities as an Act of God or are reluctant because of former social and political practices to present their child to a physician or a clinic knowing he will be registered as a "case". Under these circumstances, it is expected that more cases of two- and three-year-old children may be reported as time goes on. The political implications in Germany indicate that States are maintaining political independence as a result of former experiences under the old strongly centralized federal government.

The Future

German physicians do not expect additional malformed infants resulting from the ingestion of thalidomide. It is possible that in some places there may still be uninformed individuals who will accidentally take a tablet from a medicine cabinet unaware of what they take. The German press has featured numerous articles in many cities describing this problem and its consequences. There have been few or no photographs, and the level of reporting has been far from the tabloid type of sensationalism.

The medical profession is well aware of its present responsibilities in caring for these children (now toddlers) and have met their problems as one might expect in a modern Western European country. The clinics continue to care for the children in a progressive manner. Corrected extremities are being followed in clinics, children are being referred to prosthetic centers for fitting and training to a certain degree, and it is expected that this practice will expand.

The State of Hanover has already planned for two treatment and school centers in Hanover and Debstedt. These units will offer thirty beds each for the severely handicapped when the time arrives for schooling. Two more such centers are being planned.

The Village of Volmarstein is south of Dortmund. In this area there is a large Evangelical Rehabilitation Unit under the direction of a well trained and mature orthopedic surgeon. There are 900 beds in this complex as well as 250 hospital beds and modern operating rooms. Courses in iron-working, tool-and-die making, metallurgy, electric and arc welding, shoe-making, dressmaking, upholstering, bookkeeping, office management, bookbinding and typing, plus electronics (radio and television) are offered. There are 250 young handicapped people under training at present. Seventy handicapped children are obtaining primary and secondary formal schooling.

In Cologne, within the orthopedic complex, there is a well equipped, well staffed orthopedic school, patterned in the same manner as our own units. There is a ISO bed convalescent unit for handicapped children, complete with a training program and prosthetic shop. Muenster boasts a well organized orthopedic department and prosthetic training center.

Other cities have counterparts of these facilities. Such modern facilities in the area of total rehabilitation will play a part in the future of the severely malformed children (now two and three years of age).

Financial help is available not only through benevolent fund raising, but through state governments. Social insurance, in part compulsory, will aid in relieving the financial load of many parents. Voluntary insurance programs may broaden their disability benefits in order to meet some of the costs of prosthetic appliances. The contribution of the federal government is sadly lacking, and it apparently does not realize the severity of the future implications in the care of these children.

With these modern facilities and a basically sound economy, one would expect that the young malformed children will have every chance for habilitation and a productive life in the great majority of cases.

Orthopedic surgeons are contributing to the solution of both present and future problems as manifested by their participation in a symposium in August in Karlsruhe, involving orthopedists, regional medical officers (State), educators and rehabilitationists who discussed the problems of the future of these children. Only time will reveal how efficiently plans for the future will work out.

Discussion

The tragic occurrence of the "Thalidomide babies" in Germany has opened an entirely new field in the area of drug-testing and has challenged the ingenuity of prosthetic research.

It seems that the drug thalidomide (Alpha (N-phtalimido) glutarimide) is a teratogen for humans, the critical period being the first seven weeks of pregnancy. A total of 60% of the mothers in West Germany who took thalidomide during the critical period produced abnormal offspring. It may be that as more precise information is correlated this percentage picture will change.

All drug companies must proceed with caution when preparing a new compound for human consumption. However, this drug went through the regular procedures during its testing phase and in Britain the compound was put through very thorough tests, as their pharmacologists must do before releasing a new drug.

Pharmacological testing is performed on mice, rats, hamsters, dogs, cats and rabbits. No evidences of teratogenic effects were ever seen. The question arises: "Would this tragedy have been avoided if more testing had been carried out, for example on pregnant animals?" Thalidomide has not been shown to exert a teratogenic effect on the usual test animals.

Professor Karl Degenhardt of the University of Human Genetics in Frankfurt, who has been working on the problem since January 1962, has already probed the teratogenic possibilities of thalidomide in mice and hamsters. In hamsters, repeated litters have shown 17.7% malformations, mostly of the skull and vertebral column (normal litters). Hamster mothers on repeated doses of 100 mg. thalidomide per kilo produced litters with 13.4% malformations: less than the control. Hamster mothers on 1000 mg. per kilo produced repeated litters with 28.67, malformations. All of these malformations have been in the skull and vertebral column. The experimental figures of mice parallel the results with hamsters. Pregnant mice on 100 mg. per kilo produced litters with 24% malformations, whereas the control litters were only 18.2% malformed. The differential of 5.87, is not greatly significant.

Thalidomide does not affect the limb buds of these species.

Professor Degenhardt has repeated some of Dr. Josef Warkany's work with x-irradiation. Rats x-irradiated before pregnancy produced one upper phocomelic offspring in a litter of four (10).

Some substances known to be teratogenic in mice are not teratogenic to man. Dr. Warkany has conclusively shown that a diet deficient in riboflavin given to mice will produce a great variety of malformations of the mandible and extremities (9).

Many humans ingest salicylates in large quantities without known ill effects on their offspring. Dr. Warkany has shown that when pregnant mice are given six times the normal dose of salicylates they will produce litters exhibiting anencephaly and spinal rachischisis (9) (11).

It is now known that there are six breakdown products from thalidomide and none of these products are teratogenic in rats. It is not known at the present time just how the human body breaks down or metabolizes the compound. It may be that humans metabolize thalidomide in a different manner than do lower forms (rats or mice). It is known that Aminopterin (4-amino-pteroglutamic acid) exerts a teratogenic effect in humans when the drug fails to interrupt a pregnancy (abortion) (12) (13).

One German geneticist is now interested in the problem of the 407, of the mothers who took thalidomide during the critical period but had normal infants. Is there a genetic factor in these people which is different than in the 60% whose offspring were abnormal? Do they metabolize the drug in a different manner? Two German pediatricians are certain that there may be unknown factors that will account for the apparent immunity of the 40%.

The complex of anomalies in children of West Germany is not new. All of the malformations have been seen singly or in some combination before and are described in medical literature. The sudden volume of epidemic proportion, however, has never been encountered before. Intense interest and concern is now obvious and will stimulate the evolving science of drug-testing to better controls and broader fields of investigation.

There is also the problem of managing the surviving severely handicapped children who are healthy from the general physical sense. The deficiencies in the extremities are so pronounced that orthopedic surgeons and prosthe-tists are unable to harness power from other limbs as done in standard practice. Our present techniques in handling the standard type of amputation with normal proximal joints which have potential power will not work.

The answer here is external power. At present the two available sources are gas and electricity (electronics). The use of external power has been investigated and is continuing to be investigated in this country, in an effort to offer the bilateral phocomelic or bilateral shoulder disarticulation amputee functional patterns with suitable prostheses without an expenditure of his own energies, far in excess of the amount of function obtained. The goal desired is the light touch of a valve or switch at an advantageous point, or the simple contracture of a muscle to set in action the complex motions of elbow flexion and terminal device (hand or hook) operation for purposeful function.

From this experience in Germany, one would expect three major efforts:

  1. Broader scope of drug testing and control.

  2. Acceleration of prosthetic research in the utilization of external power.

  3. Broadening the scope of genetic research relative to causes of malformations in humans.

Bibliography

  1. Wiedemann, Hans Rudolf: Hinweis Auf eine derzeitige Haeufung hypo-und aplastischer Fehlbildungen der Gliedmaschen. Die Medizinische Welt. September 16, 1961.

  2. Lenz, Von W.: Personal Communication. (Professor, Institute of Human Genetics, University of Kiel) and, Die Thalidomid - Embryopathie. Lenz and K. Knapp. Deutsche Medizinische Wochenschrift. June 15, 1962.

  3. Taussig, Helen B.: A Study of the German Outbreak of Phocomelia. J. Amer. Med. Assn., June 30, 1962.

  4. Degenhardt, Karl Heinz: Personal Communication. Max Planke Institute of Human Genetics, Frankfurt.

  5. Hepp, Oskar: Moeglichkeiten der Orthopaedischen Versorgung im Kindesalter. Jahrbuch der Fuersorge fuer Koerperbehinderte. Pp. 59-80, 1962.

  6. Hepp, Oskar : Die Haeufung der Angeborenen Defektmissbildungen der oberen Extremitaeten in der Bundesrepublik Deutschland . Medizinsche Klinik, pp. 419-426. March 16, 1962.

  7. Lindemann, Kurt and Marquardt, E.: Mitteilung ueber Standardprothesenversorgung bei Amrlosen Kindern. Die Rehabilitation, No. 1, pp. 33-36, August 1962.

  8. Lindemann, Kurt and Marquardt, E.: Pneumatische Armprothesen bei Kindern. Jahrbuch der Fuersorge fuer Korperbehinderte, pp. 82-90, 1962.

  9. Warkany, J. and Nelson, R.C.: Skeletal Abnormalities Induced in Rats by Maternal Nutritional Deficiency. Arch. Path. 34: 375-384. August 1942.

  10. Warkany, J. and Schraffenberger, E.: Congenital Malformations Induced in Rats by Roentgen Rays. Am. J. Roentgenol. 57: 455-463. April 1947.

  11. Warkany, J. and Takas, E.: Experimental Production of Congenital Malformations in Rats by Salicylate Poisoning. Am. J. Path., XXXV, No. 2, pp. 315-333. 1959.

  12. Warkany, J., Beaudry, P. H. and Hornstein, S.: Attempted Abortion with Aminopterin: Malformations of the Child. AMA J. Dis. Child.: 97: 274-281. March 1959.

  13. Emerson, Donald J.: Congenital Malformations due to Attempted Abortion with Aminopterin (4-aminopteroglutamic acid). Am. J. Ob. Gyn. pp. 356-357. August 1, 1962.

Charles Frantz is Medical Co-Director, The Area Child Amputee Center, Grand Rapids, Michigan and Chairman, Subcommittee on Children's Prosthetics Problems