To the Editor. –
We read with interest Dr Rayu’s commemoration1 on WA Silverman (1917-
2004) who was a famed neonatologist around the world, and remember him as
„a highly influential figure in contemporary pediatrics”. Bill Silverman
became an indefatigable advocate of „evidence-based medicine” as well,
almost half a century before the term was created, and decades before the
principles were widely appreciated in medicine. He was also well known for
raising controversial questions about the scientific basis and ethics in
neonatology.2 His contributions to Peadiatric and Perinatal Epidemiology
began in 1987 and continued with a long series of „Fumes from the spleen”
(also written under a pseudonym, „Malcontent”). These essays have been
collected in a book – „Where’s the Evidence? Controversies in modern
Medicine”.3 In chapter 37.of this book (p.164-165) – „Non-replication of
the replicable (1996)” – professor Silverman has written: „Another
intriguing lead in the management of prematurely-born infants surfaced in
Hungary in 1973, when a group of investigators began to use d-
penicillamine (DPA) in the treatment of neonatal hyperbilirubinemia. (….)
When a very low incidence of retinopathy of prematurity (ROP) was found in
the infants so treated for jaundice, the Hungarian group began to use DPA
to prevent the retinal disorder. (….)The results in observational studies
were encouraging; and, in 1986, a randomised clinical trial of the
effectiveness of DPA was carried out.4(….) No independent efforts were
made by others to repeat this trial.” – And a sentence from his
subsequent witty remarks: „Without sceptics who are willing to undertake
the crucial work of replication, progress in scientific medicine falters
and becomes haphazard.”
Now, we greatly appreciate a pilot trial conducted by Christensen et
al. which has been published in the Journal of Perinatology5 . This work
can be considered as the first international replication of our
observation and clinical trials.
During the previous, almoust 20 year interval there were two
remarkable publications recommending DPA prophylaxis of ROP6,7 : one of
them appeared in the Pediatrics in 1988. In a recent Cochrane Review8
we wrote of the need for appropriately powered and well-designed
multicentered trials to test our promising approach.
Christensen et al.5 recognized no immediate intolerance of the prepared
solution of penicillamine given by nasogastric tube nor did they observe
any evidence of renal, hematologic, or hepatic toxicity in their five
patients approved by the FDA. The authors emphasize that long-term
adverse effects of DPA administration to pretem babies are possible and
they suggest that trials testing enteral 3-mercapto-D-valine (DPA) as a
means of reducing ROP should go forward.
We quite agree with this viewpoint and - on the basis of our previous
favorable experiences - would like to encourage other NICUs to use DPA for
the prevention of ROP. Our results suggest that DPA administration in
very low-birth-weight infants has no serious adverse effects during the
neonatal period nor during the short-term9 and long-term ( 10-11 years)10
follow-up.
Finally, we owe our gratitude to Professor Silverman with a couple of
related personal thougths:
Although the Hungarian aspects of WA Silverman’s place and date of birth
are undeniable (lots of people from Hungary are living in Cleveland and 23
October is the day of the Hungarian revolution of 1956), it is also true
that he had many close friends and admirers of Hungarian origin. To
correspond with him was a pleasure. He had informed us that Hungarian wine
-growers were present at the birth of the famous Californian wines at the
beginning of the last century. His favorite saying is worthy of notice:
„Learn from the mistakes of others! – You can’t live long enough to make
them all yourself”. We are honored to have been able to have known him.
Zsuzsanna Vekerdy M.D., Ph.D.
National Institute for Medical Rehabilitation
Departmen of Children’s Rehabilitation
Budapest XII.
Szanatórium u.19.
H-1528
Tel: +36-1-391-1956
E-mail: zs.vekerdy@rehabint.hu
Lajos Lakatos M.D. DSc
Kenezy County Hospital
Debrecen
Bartók B.u. 2-26.
H-4043
Tel: +36-52-511-760
Fax: +36-52-511-761
E-mail: lakatosl@kenezykorhaz.hu
REFERENCES
1. Raju TNK. William Sealy Gosset and William A. Silverman: Two „Students”
of Science. Pediatrics. 2005; 116:732-735
2. Chalmers I. In memoriam Bill Silverman: a personal appreciation.
Paediatric and Perinatal Epidemiology.2005; 19:82-85
3. Silverman WA. Where’s the Evidence? Debates in Modern Medicine. Oxford
University Press Oxford New York Tokyo. 1998
4. Lakatos L, Hatvani I, Oroszlan Gy, Vekerdy Zs, et.al. Controlled trial
of D-Penicillamine to prevent retinopathy of prematurity. Acta Paediatrica
Hungarica 1986; 27:47-56
5. Christensen RD, Alder SC, Richards SC, Horn JT, et al. A pilot trial
testing the feasibility of administering D-penicillamine to extremely low
birth weight neonates. J Perinatol. 2006; 26:120-124
6. Lakatos L. D-Penicillamine and Retinopathy of Prematurity. Pediatrics.
1988; 82:951-952
7. Lakatos L, Phelps DL, Watts JC. International replications, anyone?
Arch. Dis. Childh. Fetal Neonatal Ed. 1999; 80: F253
8. Phels DL, Lakatos L, Watts JL. Penicillamine for preventing retinopathy
of prematurity in preterm infants. Cochrane Database Syst Rev. 2001;
1:CD001073
9. Vekerdy Zs, Lakatos L, Oroszlan Gy, Itzes B. One year longitudinal
follow-up of premature infants treated with D-penicillamine in the
neonatal period. Acta Paediatrica Hungarica. 1987; 28:9-16
10. Vekerdy Zs, Lakatos L, Itzes B. Infants weighing 1000 g or less at
birth. Outcome at 8-11 years of age. Acta Paediatrica Sandinavica
Supplement. 1989; 360:62-71
Conflict of Interest:
None declared
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