The Anecdotal History of Screening for Congenital Hypothyroidism

Jean H. Dussault

Research Unit in Human Genetics, CHUQ–Pavillon CHUL, Ste-Foy, QC G1V 4G2 Canada

Address correspondence and requests for reprints to: Research Unit in Human Genetics, CHUQ–Pavillon CHUL, 2705 boul. Laurier, Ste-Foy, QC G1V 4G2 Canada.


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 Introduction
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THIS YEAR marks the 25th anniversary of the establishment of the first screening program for congenital hypothyroidism in April 1974 in Quebec. Since then, more than 150,000,000 newborns have been tested, thus, around 42,000 detected. It is estimated that one million newborns are tested yearly and 2800 detected. New programs are being established regularly in developing countries, a good example being the Mexican experience (1). The American Office of Technology Assessment (2) concludes that screening for congenital hypothyroidism is one of the few programs in preventive medicine that has an impact on public health with a positive cost to benefit ratio (10:1). This is the anecdotal history of screening for congenital hypothyroidism for this special issue of the journal.

My interest in fetal and neonatal thyroid physiology and pathology originated with my first research project as a fellow of the Canadian Medical Research Council with Dr. Robert Volpe at the University of Toronto in late 1960. We studied the placental transfert of T3 in the human (3). To pursue further our investigation on the subject, we moved to Dr. D.A. Fisher’s laboratory at UCLA Harbor General Campus using the sheep as a model (3). At the same time and place, our friend and colleague, Inder J. Chopra, was developing RIA for T3 and T4 (4). On our departure to Quebec in 1971, we were given antibodies for both these hormones and TSH.

During the same period, Raiti and Newns (5) and Klein et al. (6) published data showing that if congenital hypothyroidism was treated early (within 3 months after birth) those infants developed normally intellectually. On the other hand, Jacobsen and Brandt (7) later determined that only one third of the newborns were diagnosed during that period. Klein et al. (8) showed that serum measurements of thyroid hormones (T4-TSH) in cord blood could detect hypothyroidism in the neonatal period. Because we had a disease that was difficult to diagnose clinically with deleterious effect on mental development but reversible if treated early, a treatment, synthetic L-thyroxine, thus an ideal disease for mass screening if a method for detection was available.

On our arrival at the Centre Hospitalier de l’Université Laval in Quebec city, the laboratory space allotted to us was situated near the provincial laboratory of the Quebec Network for Genetic Medicine, which was screening for phenylketonuria and tyrosinemia using filter paper blood samples. Why not T4! We, thus, developed a RIA for the measurement of T4 from the eluate of filter paper blood spots in late 1971 and early 1972.

Our abstract was not accepted by The Endocrine Society for the 1972 International Meeting and was first presented at a Quebec Clinical Investigation Society in September 1972 (9) and at a national meeting of the Canadian Society for Clinical Investigation in January 1973 (10). That same year, supported by the Quebec Network for Genetic Medicine, we did a pilot study on 30,000 samples and detected four cases of congenital hypothyroidism. Our preliminary report on mass screening for congenital hypothyroidism was not accepted for publication by Clinical Chemistry or The New England Journal of Medicine, which judged the report irrelevant! A year later they published an editorial on the importance of the subject (11). Thus, our first report was published in French in 1973 (12). In April 1974, mass screening for congenital hypothyroidism was incorporated with phenylketonuria and tyrosinemia and available to every newborn of the Province of Quebec. In the fall our preliminary report was presented at The American Thyroid Association, but as the last paper of the last session of the meeting (13)! Very rapidly the screening laboratory was computerized by Jean Morissette and we developed a tight relationship with two pediatric endocrinologists, Jacques Letarte at Ste. Justine and Harvey Guyda at the Montreal Children’s Hospital. Detected cases were referred to those two centers and in Quebec City. The four of us met frequently to establish treatment protocols, clinical examination techniques that lead to a hypothyroid clinical index, confirmation procedures for the diagnosis (serum levels of TSH-T4), thyroid scan, bone age, and follow-up.

After our publication in the Journal of Pediatrics (14) we received numerous inquiries on the subject, and other programs were established, particularly in New England, Oregon, and France. Concomitantly we developed a TSH (15) and T4-binding globulin (16) assay for filter paper blood to minimize the number of false positive results.

The first controversy to arise on screening for congenital hypothyroidism was about the sample collection, cord blood, or serum (17) vs. filter paper heel blood taken between 3 and 5 days of age. The argument was quickly resolved because all the programs piggy-backed T4 determination done on filter paper for logistical and economical reasons.

The second controversy, and still alive, was on the detection method: T4 vs. TSH. The question was really specificity vs. sensitivity. In theory, TSH was more specific to diagnose hypothyroidism, but one must remember that in those days TSH assays were of the first generation and not very sensitive. On the other hand, T4 was more sensitive, but less specific detecting cases of hypo-T4-binding globulin emia and secondary hypothyroidism, but also cases of the low T4 syndrome of the prematures. The camps were divided between North America (T4) (18) and Europe (TSH) (19).

In the early 1980s, we measured both hormones on the same sample and obtained similar results for false negative with both assays (20). Numerous programs in the United States (New England, Oregon, and Texas) are still using T4 as a first tier method with great efficacy.

In 1979, screening for congenital hypothyroidism became of age with the First International Meeting on neonatal thyroid screening held in La Malbaie, Quebec. Speakers, interested physicians, and scientists came from all over the world to discuss various aspects involved in screening for congenital hypothyroidism: methodology, treatment follow-up, and so on. A book containing the presentations and discussions was published the following year with, most importantly, the first published recommendations on how a screening program should be set and run (21). Two more International Meetings where also held, but with less impact in Tokyo in 1982 (22) and in Brussels in 1988 (23). That First International Meeting was also responsible for establishing strong bonds between the Quebec program and the New England program. For the next 15 yr, all the participants of those programs met annually in either Quebec or New England to discuss specific problems encountered by their program and results obtained in specific studies.

In the late 1970s, with the help of a psychologist, we began to assess prospectively the intellectual development of the detected newborns and presented our first results at the Western Society for Pediatric Research (24), not knowing that this would lead to another controversy that raged through the 1980s. Indeed, with the detected newborns with congenital hypothyroidism getting older and the psychological assessment more precise, we were able to determine a subpopulation (15%) that did not score as well as the others (25). They were characterized by a very low T4 level at diagnosis and a retarded bone age due to the severity of the disease and not the treatment since there was no difference between the two groups on the age at initiation of treatment and T4 levels during treatment (26). These results were not confirmed by the New England program in similar studies undertaken simultaneously (27), although it was confirmed by other programs in France (28), Italy (29), England (30), and in Canada (31). A prospective study on the effect of the initial dosage of L-thyroxine on the intellectual development might shed more light on this discrepancy (32).

Another crisis arose in the mid-1990s with the start of early hospital discharge within 24 h after delivery. Because of the physiological surge of TSH and T4 at birth, samples taken at that time for screening purposes were of less value because of the inherent increase of false positive numbers, which were unacceptable (33). A meeting was organized to study the impact of such a policy on screening programs, and recommendations from this meeting included not to discharge mothers and newborns before 24 h, to modify the cut-off for recalls, to measure both TSH and T4 to minimize the number of false positives, and finally, to require a second sample (34). These recommendations were accepted by pediatric societies both in the United States and Canada, and the number of early discharges has almost disappeared now.

One cannot conclude this anecdotal history of screening for congenital hypothyroidism without speaking about its influence on monitoring maternal thyroid function. We have studied a thyroid function of over 250 mothers of hypothyroid infants and found that 20% had one abnormality or another (suppressed TSH, antimicrosomial antibodies), with more than 7% being hypothyroid (35). Thus, we recommend to screen every mother of detected newborns. Also, in the same group of women we were able to determine in the majority of cases of transient hypothyroidism and the presence of TSH-blocking antibodies in both mothers and newborns (36). Finally, a recent study by the New England program (37) tends to show that undiagnosed hypothyroidism in pregnant women may adversely affect their future in regard to their mental development; therefore, screening for thyroid deficiency during pregnancy may be warranted. Data from our own normal pregnant women population in which more than 10% have thyroid antibodies would support this recommendation.

Thus, screening for congenital hypothyroidism may eventually lead to screening pregnant women for autoimmune thyroid diseases.

Received September 28, 1999.

Accepted September 30, 1999.


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 Introduction
 References
 

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