Sister Jean Ward, phototherapy, and jaundice: a unique human and photochemical interaction

Subjects

The story

We do not know how long phototherapy has been used for the treatment of newborn jaundice, although Lucey1 suggests that midwives in India might have placed naked jaundiced infants in the sun. We do know that we owe the discovery of contemporary phototherapy to Sister Jean Ward, a British nurse in charge of the premature nursery at Rochford General Hospital in Rochford, Essex, UK, and to a subsequent serendipitous observation at the same hospital. As described by R.H. Dobbs,2 a consultant pediatrician, and Richard Cremer, his registrar (resident) at the time, Sister Ward (Figure 1) ‘… on warm summer days would wheel the more delicate infants out into the courtyard, sincerely convinced that the combination of fresh air and warm sunshine would do them much more good than the stuffy overheated atmosphere of an incubator.’2 In 1956, during a ward round, the pediatricians saw a preterm infant who looked ‘…pale yellow except for a strongly demarcated triangle of skin very much yellower than the rest of the body.’ When asked about this, the Sister explained that this was a jaundiced baby who had been exposed to sunlight. A corner of the sheet had covered an area of the baby’s skin and it was, as the Sister noted, ‘… the rest of the body that seems to have faded.’ Only a few weeks later, an exchange transfusion was performed on an infant and the tube that contained the pre-exchange blood sample was mislaid. When it was eventually located on a window sill, the serum was ‘…green instead of yellow and the bilirubin content was far below what was expected…There was no escaping the fact that while exposed to sunlight there had been a reduction in the bilirubin content of the sample.’ In what can only be described as a classic example of British understatement, Cremer notes, ‘It seems that we had stumbled on something that might have a practical application.’ But how could Cremer know that these observations would lead to the worldwide use of phototherapy in, perhaps, some 150 million infants?

Figure 1
figure1

Sister Jean Ward in 1956 with one of the earliest infants given phototherapy at Rochford General Hospital. From Dobbs, Cremer3 with permission.

Cremer and RW Perryman, a biochemist, went on to demonstrate that, when exposed to daylight, sunlight and artificial light, bilirubin levels in icteric sera decreased rapidly and, in 1958, they published their seminal observations 3 demonstrating that both sunlight and blue light (delivered by their home-made phototherapy unit consisting of eight 40-W ‘light blue’ fluorescent tubes) would decrease bilirubin levels in jaundiced newborns (Table 1). Indeed, after a hiatus of some 56 years, sunlight is again being used to treat hyperbilirubinemia.4 Later the same year, Franklin5 described his experience with 12 jaundiced infants and 13 controls. The bilirubin levels declined in the jaundiced infants but Franklin stopped using phototherapy because, as he noted, ‘… there is no information about the nature or toxicity of the material elaborated from bilirubin by the action of these light waves; and secondly, because it seems unlikely that the quantitative effect will be great enough to be a substitute for exchange transfusions.’

Table 1 Effect of sunlight and fluorescent light on jaundiced newborns

Nevertheless, pediatricians in Brazil, Uruguay, and Chile, and subsequently in Italy, France, and England, were bold enough to continue Cremer’s experiment. In September 1960, Ferreira et al.6 described their experience with 77 jaundiced infants and were the first to coin the term ‘phototherapy.’ Following the 1958 publications of Cremer et al.3 and Franklin5 no less than 21 papers, largely case series, were published documenting the efficacy of phototherapy in jaundiced newborns, but it was not until 1968 that Lucey et al.7 published the first US phototherapy study. Why did it take 10 years for this to happen? One might expect that, following documentation in a prestigious, peer-reviewed journal of an effective, simple, noninvasive and cheap(!) method for treating jaundiced newborns, neonatologists in the USA would want to confirm or refute these findings. That they did not is almost certainly because, of the 21 papers published following Cremer’s 1958 study, only one8 was in English. Whatever those of us in the USA are celebrated for, it is not for our facility with other languages. As a result, the papers documenting the efficacy of this intervention were neither read nor appreciated by US pediatricians.

There was also some skepticism regarding this new treatment. Dr. Jerold (Jerry) Lucey, the ‘father’ of US phototherapy, told me that, soon after the publication of Cremer’s observations, he was giving a talk in Maine and, when asked about phototherapy, expressed the opinion that ‘it was not scientific and just wouldn’t work.’ In the latter part of the 1960s, however, Lucey attended a meeting in Portugal where he met a young Chilean physician, Mario Ferreiro, and agreed to have him come to do a neonatal fellowship in Vermont. Soon after his arrival, the new fellow wanted to know why there was no phototherapy in the neonatal intensive care unit (NICU), something that had been used in Chile for years. Intrigued, Lucey, who had already published extensively on the jaundiced newborn, dispatched Ferrreiro to dig up all of the relevant phototherapy references and, with the help of the Chilean as his translator, soon realized that this was a therapy that deserved his attention. Lucey then set about constructing a phototherapy device and demonstrating, in the first randomized controlled trial of this therapy, that it was a highly effective method for preventing hyperbilirubinemia in the preterm infant7 (Figure 2). In his paper he notes that Obes-Polleri had recently published a similar controlled trial of 152 infants and that ‘his experience now includes observations on over 1000 infants with hyperbilirubinemia of different etiologies and he has observed no toxic effects over this 5 year period.’7

Figure 2
figure2

Effect of phototherapy initiated within 12 h of birth on infants <2500 g birthweight. Redrawn from Lucey et al.7

How it works

The utter simplicity and efficacy of this treatment now gained widespread acceptance, although there were some who remained concerned about its safety.9, 10, 11 But exactly how phototherapy worked had yet to be elucidated. Through the 1970s and 1980s, many investigators worked on this question, but those most responsible for elucidating the mechanisms of phototherapy include Donald Ostrow,12 David Lightner,13 Shoju Onishi14 and Tony McDonagh.15 Initially postulated to be an oxidative reaction during which the tetrapyrrole bilirubin was converted by light to polar, colorless mono or dipyrroles,15 it was ultimately the work of McDonagh and Lightner13, 16, 17 that finally demonstrated that when bilirubin in the skin and subcutaneous tissues absorbs light it undergoes several photochemical reactions that generate yellow stereoisomers of bilirubin and colorless derivatives of lower molecular weight that can be excreted in bile or urine without the need for conjugation (Figure 3).18 We do not know exactly how much each of these reactions contributes to the elimination of bilirubin, but most studies suggest that photoisomerization is more important than photodegradation. Not only did Tony McDonagh elucidate phototherapy’s basic mechanisms but, with his unique clarity of expression, he was able to explain these mechanisms to the practitioner so that we had some understanding of what we were doing.19

Figure 3
figure3

Mechanism of Phototherapy. The absorption of light by the normal form of bilirubin (4Z,15Z-bilirubin) generates transient excited-state bilirubin molecules. These fleeting intermediates can react with oxygen to produce colorless products of lower molecular weight, or they can undergo rearrangement to become structural isomers (lumirubins) or isomers in which the configuration of at least one of the two Z-configuration double bonds has changed to an E-configuration. (Z and E, from the German zusammen (together) and entgegen (opposite), respectively, are prefixes used for designating the stereochemistry around a double bond. The prefixes 4 and 15 designate double-bond positions.) Only the two principal photoisomers formed in humans are shown. Configurational isomerization is reversible and much faster than structural isomerization, which is irreversible. Both occur much more quickly than photooxidation. The photoisomers are less lipophilic than the 4Z,15Z form of bilirubin and can be excreted unchanged in bile without undergoing glucuronidation. Lumirubi isomers can also be excreted in urine. Photooxidation products are excreted mainly in urine. Once in bile, configurational isomers revert spontaneously to the natural 4Z,15Z form of bilirubin. The graph, a high-perfomance liquid chromatogram of serum from an infant undergoing phototherapy, shows the prescence of several photoisomers in addition to the 4Z,15Z isomer. Photoisomers are also detectable in the blood of healthy adults after sunbathing. With permission from Maisels and McDonagh.18

How many infants have received phototherapy?

Worldwide, there are about 135 million annual live births, and hospital-based studies in the industrialized world report that some 0.5 to 4% of term, early term and late preterm infants receive phototherapy before discharge from the nursery20, 21, 22 and an equal number are readmitted for phototherapy after discharge. In limited resource countries, however, it is likely that a far smaller proportion are treated. If we can assume that the total worldwide incidence of phototherapy is only about 2%, some 2.7 million infants are treated annually and, since 1970, perhaps as many as 119 to 120 million have received phototherapy.

What has phototherapy accomplished?

As the only effective alternative to phototherapy for infants with severe hyperbilirubinemia is exchange transfusion, one measure of the efficacy of phototherapy is the dramatic reduction in the number of exchange transfusions performed in term and preterm infants,23 an effect strikingly apparent in very low birth weight infants.23, 24, 25 Prior to the introduction of phototherapy, as many as one in three infants with birth weights <1500 g received at least one exchange transfusion,23 whereas in the recent Neonatal Research Network study only 5/1974 (0.25%) infants with birth weights 1000 g were subjected to this procedure.25 Some of this decrease in term infants is also attributable to the treatment of Rh-negative mothers with anti-D immune globulin as well as to changes in the recommended threshold levels for exchange transfusions.

One important benefit of phototherapy, perhaps not recognized by most clinicians, has been its impact on our understanding of bilirubin metabolism. In his encyclopedic work on bilirubin,26 David Lightner entitled one section ‘Bilirubin chemistry reawakened thanks to jaundice phototherapy’ and recalls that phototherapy unleashed ‘…a small torrent of interest among those with training in the molecular sciences.’

Is phototherapy safe and does it prevent kernicterus?

Reports of clinically significant toxicity from phototherapy, at least in term, early term, and late preterm infants, are very rare, and we might assume that, if something bad has happened to an important segment of the ~120 million infants already exposed, we should probably have heard about it by now. Nevertheless, it is important to acknowledge that detailed, long-term follow-up studies of these infants are very limited, so that unrecognized toxicities could easily have been missed. Furthermore, the short-term studies have included only modest numbers and few low birth weight infants. One study found that subjects examined at age 3 to 30 years, who were treated as newborns with intense blue light phototherapy, had developed increased numbers of melanocytic nevi.27 A relationship has also been described between phototherapy and an increased risk for childhood leukemia28 and juvenile-onset diabetes,29 although other studies have not confirmed these observations.30, 31 In the short term, studies in human newborns have found evidence of DNA damage,32, 33, 34 alterations in cytokine levels,35, 36, 37 changes in mesenteric and cerebral blood flow,38, 39, 40 decreased cardiac output41 and renal blood flow,42 and evidence of oxidative stress.43, 44, 45 Nevertheless, the complete absence of any abnormal neurodevelopmental outcomes including visual and auditory function, school performance, and social interactions in children with the Crigler-Najjar syndrome who have received daily phototherapy for up to 21 years and escaped the consequences of hyperbilirunemia is, to some extent, reassuring46, 47

For term, early term, and late preterm infants, there is no evidence that phototherapy has ever prevented an infant from developing kernicterus. On the other hand, the question of risk versus benefit in very low birth weight infants has been addressed in the only two large, randomized controlled trials of phototherapy ever conducted.25, 48 In the first trial, 1339 newborn infants, born between 1974 and 1976 in six US centers, were enrolled.48 A total of 672 newborn infants were assigned to receive phototherapy and 667 did not receive phototherapy but received an exchange transfusion at predetermined levels. Although the details are sketchy, kernicterus was identified at autopsy in 4/37 control infants (all <1500 g birth weight and sick) and in 0/39 infants receiving phototherapy. No conclusions can be drawn from these data, however, because only 69% of the phototherapy group and 56% of the control group underwent autopsies. We also do not know why autopsies were performed on some infants and not on others.

There was one worrisome outcome, largely dismissed at the time because of its lack of statistical significance:49, 50 an overall 59% of phototherapy infants with birth weights <1000 g died vs 40% of controls, a relative risk of 1.49 (0.93 to 2.40, P=0.112), suggesting the possibility of as much as a 2.4-fold increase in mortality and a number needed to harm of 5.50 No differences were found, however, in the developmental outcome of surviving infants.51, 52 In the recent National Institute of Child Health and Human Development (NICHHD) Neonatal Network randomized controlled trial of infants born between 2002 and 2005, those with birth weights 501 to 750 g who had received aggressive phototherapy (compared with those who had received conventional phototherapy) had a 5% decrease in severe impairment among survivors but a 5% increase in mortality (relative risk (RR) for mortality 1.13 (0.96 to 1.34)). Although this increase in mortality did not achieve statistical significance, a conservative Bayesian analysis identified a 99% posterior probability of an increased mortality as well as a 99% probability of a reduction in profound impairment in these infants.50, 53 In addition, there was a significant increase in mortality in infants in this birth weight category who were receiving assisted ventilation at age 24 h (RR 1.19, 1.01 to 1.39).50, 53 Why phototherapy might increase mortality in these tiny infants is unknown, but it is likely that light penetrates more deeply through their thin, gelatinous skin, reaching the subcutaneous tissues and possibly producing oxidative injury to cell membranes54, 55 or other direct or indirect adverse effects.32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 It is, nevertheless, very encouraging to note that it might be possible to modify the use of phototherapy for these infants in a manner that maintains its efficacy in reducing bilirubin levels without risking an increase in mortality.56, 57

Conclusion

The result of a unique human and photochemical interaction—a serendipitous observation by a nurse, pursued by astute clinicians who recognized its potential benefits–phototherapy has proven to be a simple, inexpensive and effective tool in the management of the jaundiced newborn. It has almost entirely eliminated the need for exchange transfusions and been administered to millions of newborns with what currently appears to be a satisfactory safety profile in term, early term and late preterm infants. The same cannot be said, however, for the smallest and sickest infants, where an increase in mortality raises important, and as yet, unanswered questions about the risks and benefits in this population. Notwithstanding its worldwide acceptance for over four decades as the primary therapy for neonatal hyperbilirubinemia, there remains a need for additional research on the benefits as well as the short- and long-term complications of this ubiquitous therapy.

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Acknowledgements

I am grateful to Drs Jon Tyson, Tom Newman, Thor Hansen and Henk Vreman for their input and critical review of this manuscript and to Dr. Jerold Lucey for reviewing the manuscript and for many discussions over some 40 years about phototherapy and the jaundiced newborn.

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Correspondence to M J Maisels.

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Based on the Thomas E. Cone Jr, MD, Lecture on Perinatal History, given at the Section on Perinatal Pediatrics, American Academy of Pediatrics National Conference and Exhibition, Orlando, FL, 26 October 2013.

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Maisels, M. Sister Jean Ward, phototherapy, and jaundice: a unique human and photochemical interaction. J Perinatol 35, 671–675 (2015). https://doi.org/10.1038/jp.2015.56

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