Journal of Perinatology

https://doi.org/10.1038/s41372-018-0237-1

PERSPECTIVE

Hyaline membrane disease (HMD): an historical and Oslerian

perspective
Michael H. Malloy1 John P. McGovern1
●

Received: 19 July 2018 / Accepted: 14 September 2018

© Springer Nature America, Inc. 2018

Abstract
Hyaline membrane disease (HMD) offers an illustration of a disease discovered during the lifetime of William Osler and
effectively treated in the twentieth century—the perspective that suggests that there was a straightforward progressive
identification of the disease process, a discovery of the underlying biochemical agent responsible for the pathophysiology,
and the pharmacological refinement of that agent to be used to treat the disease is illusory. By reviewing the timeline from
the earliest pathological description of what was to be later termed HMD to the discovery of surfactant and its impact on
infant mortality, this narrative will demonstrate how various random historical events served to affect the progress of
1234567890();,:
1234567890();,:

developing a treatment for HMD; how the marked reduction in deaths due to HMD may have set the stage for unrealistic
expectations; and how the humanities have warned us of the potential for excessive optimism in our understanding of nature.

Hyaline membrane disease (HMD): an First World War evolved and Osler lost his son, Revere to
historical and Oslerian perspective the war, Osler’s optimism for “man’s redemption of man”
darkened and he spoke of the “barbarism they had all
HMD, also referred to as respiratory distress syndrome succumbed to,” and that “it has yet to be determined
(RDS) and contemporarily often referred to as surfactant whether Science, as the embodiment of a mechanical force,
deficiency [1], provides an excellent paradigm to relate to can rule without invoking ruin.” [5]
the lifetime and hopes of William Osler [2]. Its pathology In reviewing the evolution of HMD, some perspective
was first described during Osler’s lifetime in 1903 [3]; it from the basic schools of thought on understanding disease
relates to Osler’s enthusiasm for the promise of science; from an historical perspective is necessary. First, the
it seemingly demonstrates the systematic progressive nature historical-conceptionalist approach takes concepts of dis-
of science; yet it may pose as a cautionary tale for the ease as objects of historical study and these concepts can
optimism that is often associated with overblown expecta- only be understood within the social and cultural context
tions for humanities’ ultimate control of nature. of a specific period [6]. Thus, for example, the death of
Osler, in his 1910 address to the students of the Uni- a prematurely born infant 200 years ago would only
versity of Edinburgh entitled 'Man’s Redemption of Man', be understood as an infant death, which would not have
synthesized the dream that science would be man’s greatest been an uncommon event in 1818. The death would
contribution to allow for “the final conquest of nature out of have simply been attributed to “natural causes.” In contrast,
which has come man’s redemption of man.” [4]. As the the naturalist-realist approach takes modern disease con-
cepts as the mirror of natural reality [6]. Thus, the realist
would take the discovery of a case diary or file from
200 years ago describing a prematurely born infant that
died at 24 h of age manifesting signs of difficulty breathing
This work was presented in part at the annual meeting of the American
Osler Society, Pittsburgh, PA, 16 May 2018. as a probable case of HMD.
For HMD this narrative takes a conceptionalist approach
* Michael H. Malloy aided by the observation that with the development of
mmalloy@utmb.edu
pathological medicine that originated in France [7] at the
1
Department of Pediatrics, The University of Texas Medical end of the eighteenth century, it became possible to require
Branch, , Galveston, Texas 77550, USA as “cause of death” a proximate pathological assignment for
 M. H. Malloy, J. P. McGovern

Fig. 1 Timeline for the

discovery of hyaline membrane
disease, surfactant, and therapy.
See text for specific references

all those cases formerly classified as “natural causes.” [8]. [15, 16]. This event may have provided the serendipitous
Thus, prior to the early part of the twentieth century HMD random occurrence that moved research into HMD/RDS
would contextually have been considered a “natural cause into high gear.
of death” among preterm infants. From the early twentieth What was the social and cultural impact of Patrick
century to the 1960s it would become a pathological diag- Kennedy’s death? President Kennedy and his immediate
nosis, i.e., the presence of hyaline membranes at autopsy, family were deeply affected. Even prior to Patrick’s death,
and from the end of the twentieth century to the present a the Kennedy family had been deeply interested in infant
disease appreciated as a developmental biochemical phe- developmental issues as a function of the presence of JFK’s
nomenon associated with a deficiency of surfactant. developmentally affected sister, Rose Marie, who probably
The historical narrative of the discovery and treatment of experienced an asphyxiating incident at birth and was later
HMD can be demonstrated figuratively (Fig. 1). The time- even more devastated by a prefrontal lobotomy [17]. With
line presented in this figure is not all inclusive, but a the encouragement of JFK’s sister, Eunice Shriver, JFK had
selection of those events that seemed most important. pushed for the development of The National Institute of
Looking at the timeline, the first pathological description of Child Health and Human Development (NICHD), which
hyaline membranes in the lung of a dead infant came from came into being in 1962 [18]. Within 2 months of Patrick’s
the German literature in a report by Hochheim in 1903 [3]. death JFK signed into law a grant authorizing $256 million
The first English report did not follow until 1923 by in research funding primarily directed toward combating
Johnson [9]. An attempt to conceptualize the cause of the mental retardation through provision of prenatal maternity
presence of hyaline membranes was not put forward until and infant care [19]. In addition, through NICHD
1932 when Farber and Wilson proposed that they (hyaline $1,283,000 was being funded for the study of preterm birth,
membranes) occurred as a function of inhaled amniotic of which $800,000 was to be devoted to focus on HMD in
fluid debris [10]. Not much further activity or progress in the preterm infant [20].
understanding HMD occurred until around 1950, when By 1968, there was good evidence that the funding had
Miller and Jennison described well the clinical presentation stimulated an abundance of research directed toward
of neonates dying of HMD [11]. In 1955 Pattel discovers understanding and developing a therapy for HMD/RDS.
surfactant [12]; in 1957 Clements further elucidates sur- According to a review by Scarpelli in 1968, there were 350
factant properties [13]; and in 1959 Avery and Mead references to surfactant in the literature, 250 that occurred
demonstrate surfactant deficiency in infants dying of HMD since Patrick Kennedy’s death in 1963 [21].
[14]. Then in the early 60s there begins a flurry of activity. Going back to the timeline, early attempts at prolonging
A great deal of this activity may be ascribed to the death life among preterm infants that were considered terminal
of Patrick Bouvier Kennedy, the son of the President, John were reported by Delivoria-Papadopoulis in Toronto using a
F. Kennedy (JFK), in August 1963. Patrick was born at very crude Bird Mark 8 ventilator in 1964 [22]. Further
34 weeks gestation, weighed 2098 g, and died at 39 h of life refinement of ventilators continued and the impact of
Hyaline membrane disease (HMD): an historical and Oslerian perspective

Nevertheless, there are a number of skeptics, particularly

among non-physician medical historians. Charles Rosen-
berg states, “A variety of scholars have begun to think of
science as a set of generation- and place specific practices,
and not accumulations of knowledge advancing ineluctably
– if sometimes erratically – toward a deeper understanding
of nature.” [32].
Still some non-medical historians appreciate the progress
made in medical practice. Michael Bliss, a biographer of
Osler, stated,

“A laudatory approach to medical history commonly

adopted by “amateur” medical historians in the
Fig. 2 Deaths attributable to HMD/RDS and death rate per 1000 live tradition of Sir William Osler has often been
births, United States 1969, 1995, and 2014. Left axis logarithmic scale
eschewed by professionals as faulty, feel-good
(black bars): number of deaths attributed to HMD (ICD-8, 776.1) in
1969; RDS (ICD-9, 769) in 1995; and RDS (ICD-10, P22) in 2014. history. But Osler was right in his belief that, on
Right axis rate per 1000 livebirths (gray bars) balance, the progress of medicine has been specta-
cular, that modern health care offers one of the finest
intermittent mandatory ventilation on improved survival of examples of the possibility of man’s redemption of
preterm infants born with HMD was reported by Swyer man. Written objectively, medical history is about
[23]. In 1971, Gregory et al. documented improved survival progress and achievement, and can properly be seen
with continuous positive airway pressure (CPAP) [24] as inspiring. If we mordantly or relativistically dismiss
and from 1972 to 1978 a number of studies begun using the unprecedentedly high quality of modern health,
artificial surfactants in animals [25, 26]. In 1980 Fugiwara we lose the ability to understand why citizens value it
was one of the first to show the efficacy of providing so highly, and this distorts our understanding of
surfactant to human infants. From 1981 to 1990 clinical current issues. We also lose our sense of the wonders
trials of surfactant were carried out, and finally in 1990 of human and medical achievement.” [33]
Exosurf and Survanta were given FDA approval [27].
What has been the impact of surfactant on mortality How does the perspective of a continuum of medical
attributed to HMD/RDS? In 1969, HMD/RDS became a progress affect physician as well as public expectations?
reportable disease on infant death certificates in the United Here are two examples. First, the progress in under-
States by virtue of the ICD-8 coding system. Figure 2 shows standing the human genome in the last 30–40 years has
the number of deaths attributed to HMD/RDS recorded on been astounding. The media has exploited these advances
the left Y axis and the rate per 1000 live births recorded on and exploded public expectations dramatically. Yet the
the right Y axis. Note that the scale on the left Y axis of this true deliverables and implementations of this science into
graph showing the absolute number of deaths is logarithmic. medical practice remain limited [34]. Though technologies
In 1969, there were about 10,000 deaths attributed to HMD to produce designer babies may be available, the under-
for an infant mortality rate of about 2.75 per 1000 live births standing of the ethical and social implications of these
[28]: compared to about 2000 deaths in 1995, 5 years after technologies remains uncertain [35]. Second, on an issue
the introduction of surfactant, resulting in an infant mor- more closely related to an immediate problem in Neona-
tality rate of 0.37 per 1000 live births [29], in 2014 there tology, despite the progress in reducing the infant mortality
were only 490 deaths attributed to HMD/RDS for a rate of associated with HMD/RDS and raising public expectations
0.12 per 1000 live births in 2014 [30]. that saving prematurely born infants is simply a matter of
Has progress been made in our understanding of HMD/ further scientific understanding and the development of
RDS? Based on the narrative just presented, it would seem new technologic and pharmacologic interventions, the
hard to argue that this story is not one of persistent progress progress in reducing the preterm and especially very pre-
of science and its application to the practice of medicine. term birth rate has been nil for the last 50 years. Figure 3
This is certainly how many practitioners as well as the lay shows the percent of live births born prematurely and
public view medicine. Osler certainly ascribed to the pro- the percent born very prematurely or at <29 weeks gesta-
mise of science and steady progress in his brighter days tion [36]. Given the lack of progress in decreasing the
stating that “some of the brightest hopes of humanity are extremely preterm mortality and morbidity, particularly
with medical progress. To it, not to law or theology, belong at 23–24 weeks gestation, and the fact that no new tech-
the promises.” [31]. nologic innovations in the care of these infants appear on
 M. H. Malloy, J. P. McGovern

4. Osler W. Man’s redemption of man. In: Hinohara S, Niki H,

editors. Osler’s “A Way of Life” and other addresses, with com-
mentary and annotations. Durham & London: Duke University
Press; 2001. p. 355–70.
5. Osler W. The old humanities and the new science. Br Med J.
1919;2:1–7.
6. Wilson A. On the history of disease-concepts: the case of pleurisy.
Hist Sci. 2000;38:271–319.
7. Porter R. The greatest benefit to mankind: a medical history
of humanity. New York: W.W. Norton & Company; 1997.
p. 263–5.
8. Armstrong D. The invention of infant mortality. Sociol Health
Illn. 1986;8:211–32.
9. Johnson WC. Pneumonia in newborn infants with lesions
Fig. 3 Percent of US live births preterm (<37 weeks—black line) and resembling influenza. Proc NY Pathol Soc. 1923;23:138–42.
very preterm (<29 weeks—gray line) 10. Farber S, Wilson JL. The hyaline membrane in the lungs. Arch
Pathol. 1932;14:437–49.
11. Miller HC, Jennison MH. Study of pulmonary hyaline-like
material in 4117 consecutive births: incidence, pathogenesis,
the immediate horizon, the only likely way to modify and diagnosis. Pediatrics. 1950;5:7–20.
their occurrence will be to advance attempts to prolong 12. Pattel RE. Properties and function and origin of the alveolar lining
gestation. layer. Nature. 1955;175:1125–6.
13. Clements JA. Surface tension of lung extracts. Proc Soc Exp Biol
As we progress then, perhaps we should do so with
Med. 1957;95:170–2.
caution. There are many cautionary notes about the hidden 14. Avery ME, Mead J. Surface properties in relation to atelectasis
effects of progress written in great literature. In her and hyaline membrane disease. Am J Dis Child. 1959;97:
novel 'Frankenstein: Or the Modern Prometheus', Shelley 517–23.
15. Blair WM. Kennedys mourning baby son; funeral today will be
warns us of “the frightful effect of any human endeavor
private. New York Times. 10 Aug 1963.
to mock the stupendous mechanism of the Creator of 16. Patrick Ryan MS. Bouvier Kennedy: a brief life that changed
the world.” [37] the history of newborn care. Minneapolis, MN: MCP Books;
Thus, as our science speeds forward with one foot 2015.
17. Larson KL. Rosemary: The hidden Kennedy daughter. Boston:
on the accelerator, it might behove us to keep the other
Houghton Mifflin Harcourt; 2015.
foot ever so lightly on the brake. As systematic as the 18. NICHD. History of the National Institute of Child Health and
progress to surfactant appeared to be, as Kuhn suggests, Human Development. https://www.nichd.nih.gov/about/history/
most of the great leaps forward of science are random establishment.
19. United States Congress Public Law 88–156. Maternal and child
events dependent on serendipity [38]. In addition, if
health mental retardation planning amendments of 1963. US
we critically examine the discovery of HMD and Congress, 24 Oct 1963.
surfactant, we must admit that random events, such as the 20. Ryan MS. Patrick Bouvier Kennedy: A Brief Life that Changed
death of a president’s child, contributed to the rapid pro- the History of Newborn Care. Minneapolis, MN: MCP Books;
2015. Location 1415.
gress in the understanding of HMD and the development
21. Scarpelli EM. The surfactant system of the lung. Philadelphia:
of surfactant. Lea and Febiger; 1968.
22. Delivoria-Papadopoulis M, Swyer PR. Assisted ventilation in
terminal hyaline membrane disease. Arch Dis Child. 1964;39:481–4.
Compliance with ethical standards 23. Swyer PR. Results of artificial ventilation: experience at the
hospital for sick children. Biol Neonate. 1970;16:148–54.
Conflict of interest The author declares that he has no conflict of 24. Gregory GA, Kitterman JA, Phibbs RH, Tooley WH,
interest. Hamilton WK. Treatment of the idiopathic respiratory distress
syndrome with continuous positive airway pressure. N Engl J
Med. 1971;284:1333.
25. Einhorning G, Robertson B. Lung expansion in the premature
References rabbit fetus after tracheal deposition of surfactant. Pediatrics.
1972;50:58–66.
1. Wambach JA, Hamvas A. A respiratory distress syndrome in 26. Adams FH, Towers B, Osher AB, Ikegami M, Fujiwara T,
the neonate. In: Martin RJ, Fanaroff AA, Walsh MC, editors. Nozaki M. Effects of tracheal installation of natural surfactant in
Neonatal-perinatal medicine: diseases of the fetus and infant. premature lambs. I. Clinical and autopsy findings. Pediatr Res.
Philadelphia: Saunders, Elsevier Inc.; 2015. p. 1074–86. 1978;12:841–8.
2. Bliss M. William Osler: a life in medicine. New York: Oxford 27. Halliday HL. Surfactants: past, present and future. J Perinatol.
University Press; 1999. 2008;28:S47–S56.
3. Hochheim K. Ueber einige befunde in den lungen von neuge- 28. Malloy MH, Hartford RB, Kleinman JC. Trends in mortality
borenen und die beziehung derselben zur aspiration von frucht- caused by respiratory distress syndrome in the United States,
wasser. Cent Path. 1903;14:537. 1969-83. Am J Public Health. 1987;77:1511–4.
Hyaline membrane disease (HMD): an historical and Oslerian perspective

29. Malloy MH, Freeman DH. Respiratory distress syndrome mortality 34. Joyner MJ, Paneth N. Seven questions for personalized medicine.
in the United States, 1987 to 1995. J Perinatol. 2000;20:414–20. JAMA. 2015;314:999–1000.
30. Heron M. Deaths: leading causes for 2014. National vital statistics 35. Lander ES. Brave new genome. N Engl J Med. 2015;373:5–8.
reports. Vol 65, no. 5, Table 3. Hyattsville, MD: National Center 36. Curtin SC, Hamilton BE, Martin JA, Mathews TJ, Osterman MJK,
for Health Statistics; 2016. 76pp. et al. Births: final data for 2014. National vital statistics reports.
31. Bliss M, William Osler. A Life in Medicine. New York: Oxford Vol. 64 (12). Hyattsville, MD: National Center for Health Sta-
University Press; 1999. p. 197. tistics; 2015.
32. Rosenberg CE. Explaining epidemics and other studies in the history 37. Shelley M. Frankenstein: or the modern Prometheus. New York:
of medicine. New York: Cambridge University Press; 1992. 5pp. Dover Publications; 1994.
33. Bliss M. Medical exceptionalism. Perspect Biol Med. 2012; 38. Kuhn TS. The structure of scientific revolutions. International
55:402–8. Encyclopedia of Unified. Science. 1970;2:1–210.