Paediatric and Prrinntal Epidemiology 1995,9,250-255

From our own correspondents

Fumes from the spleen

Each time we learn something new and surprising, the astonishment comes with the realization that we were wrong before . . . In truth, whenever we discover a new fact it involves the elimination of old ones. We are always, as it turns out, fundamentally in error.

Lewis Thomas

An American ophthalmologist, Theodore Terry, described the first known instance of retinopathy of prematurity (ROP) in 1942,’ and he speculated that ‘ . . . some new factor has arisen to produce such a condition.’ Fifty years later, John Watts has carried out a rigorous review of the evidence that has accumulated in efforts to solve the 5-decade-old mystery.2 There has been a persistent hope that Terry’s single ‘new factor’ will be uncovered and an expectation that ROP-blindness in prematurely-born infants will be completely eliminated. But this optimism, Watts makes it clear, is unwarranted. ’“lot only are we still severely limited in our ability to prevent, treat or even understand the disease’, he writes, ’but the problem may be increasing’.

What stands out in the search for a sblution to the puzzle presented by the unique retinopathy, is how disjointed the pursuit has been. There have been many leads, but very few have been tested rigorously in large-scale experimental trials. For example, only two large multicentre randomised trials were carried out in the 50-year history of the disorder. The first of these exercises was conducted in the US in 1953-54: to evaluate the effect of modifying the accepted liberal policy of administering oxygen in the care of prematurely-born infants (’routine‘ use of high concentrations of the life-sustaining gas to all infants weighing less than 1.5 kg at birth). The trial demonstrated that the relative risk of cicatricial retinal lesions could be reduced by about two-thirds by using the gas ‘only as needed’; but the curtail- ment of oxygen did not totally eliminate the risk of blindness.

The second multicentre randomised trial, carried out thirty-two years later: tested the safety and efficacy of transscleral cryotherapy in halting the progression of moderately advanced acute ROP in infants weighing less than 1.25 kg at birth. The ablative procedure reduced the expected rate of unfavorable retinal outcome by one-half; but, again, the intervention did not completely eliminate the risk of blindness.

An early example of fhe kind of endless speculation about the sole necessary and sufficient cause of ROP is the on-going debate about the putative role of light; it began with Terry in 1942. A number of studies have been carried out to determine

0 10% Blackwell Science Ltd. 250

From OUT own correspondents 251

whether or not exposure to the high level of ambient fluorescent light commonly found in present-day nurseries increases the risk of ROP, but the studies have been much too small and the study-designs have been too weak to provide reliable estimates of the size of a purported light-effect. Despite five decades of interest and repeated claims about the causal role of light, the matter remains completely unsettled. And the same must be said about all other plausible-but-never-fully- tested influences on the origin and the course of ROP.

The 45-year-old history of the testable-notion that vitamin E might prevent ROP is another unhappy example of the never-fully-tested problem that has resulted in such intractable uncertainty. In 1949, Owens and Owens suspected that a relative lack of vitamin E might play a causal role in the development of the retinopathy, and they began a small, open (not masked) trial of prophylactic treatment using concurrent untreated control^.^ The early trend in favour of vitamin E was so impressive the senior advisors in the department of ophthalmol- ogy ordered the young husband and wife team to abandon the trial; and prophylac- tic vitamin E was then given to all premature infants admitted to the premature nursery. Several observational studies in other centres were unable to confirm the earlier results indicating a protective effect of vitamin E; soon all interest in this agent evaporated. In the 1980s, there was renewed interest in the efficacy of vitamin E (now it was the antioxidant property of this substance that captured the imagin- ation of researchers). Again, only single-centre trials were conducted, and the results were contradictory. In 1986, a committee of the Institute of Medicine met in Washington to review the evidence then extant (in six parallel-comparison trials) concerning the effectiveness of vitamin E.6 The committee concluded that the data from these prospective studies did not warrant a recommendation for the routine use of vitamin E to prevent or modify ROP. They noted that 'a multicentre clinical trial would be necessary to provide a sufficiently large study population for definitive information on the efficacy of vitamin E in ROY. But the cooperative action necessary to obtain this 'definitive information' has not yet been taken; and 45 years of frustrating uncertainty remains unresolved.

In the past few years, there has been an upsurge of interest in the 'oxygen paradox' (the mechanism of post-hypoxic re-oxygenation injury by oxygen free- radicals) to explain the pathogenesis of ROP and several other neonatal disorder^.^ And there is interest in ways and means of increasing the relatively poor anti- oxidant defenses of infants born prematurely8 For example, Sullivan has pointed to the low iron-binding-capacity (and the resultant elevated concentrations of ionic iron capable of catalysing the formation of toxic oxygen free-radicals) in these neonates as the deficit which may explain why they are so prone to damage by oxygen. He has urged that the preventive effect of parenteral human apotrans- ferrin in premature infants susceptible to ROP should be subjected to formal study? No-one has acted on this approach that might shed light on a most

,

0 1995 Blackwell Science Ltd. Paediarrir and Peritiota/ Epideemioloyy, 9, 250-255

252 From our own correspondents intriguing question: Why do most infants who develop ROP improve spontaneously?

In 1986, encouraging initial results of use of an antioxidant (d-penidlamine) were confirmed in a randomised trial conducted in a single centre in Hungary.lo Once more, no effort has been made to organise an independent multicentre trial to find out whether or not the favourable results with penidlamine can be replicated. And the uncertainty about the use of this approach is unresolved.

More recently, two incidental associations were found in trials in which ROP was not the primary outcome of interest: in a trial of vitamin A supplementation,ll and in a trial of inositol infusions,'* ROP was less severe in infants allotted to receive the treatment under test. These encouraging observations need to be replicated by others, because they have raised hopes, again, about the possibility of finding an effective intervention to prevent all risk of ROP-blindness. If, however, the past history of proposals to eliminate this horrendous complication of prema- ture birth is any guide, it will take years before sufficient evidence has been collected to provide reliable estimates of the effect-size of each of these plausible- but-incompletely-tested interventions.

For 50 years the experience with ROP has demonstrated, over and over again, how difficult it is to determine the relationship between cause and effect in medicine when the course of a disorder is usually benign. As noted above, the majority of prematurely-born infants who develop the early changes of the unique retinopathy do not progress to blindnys (among 4099 very small infants closely examined in the largest study of the natural history of ROP ever c~nducted, '~ 2699 developed some stage of ROP; of these only 245 progressed to 'threshold disease' that made them eligible for consideration of cryotherapy, e.g. a level of severity at which the risk of blindess was predicted to approach 50% - a risk rate that was confirmed in the outcomes of untreated eyes at age 3years).l4 These features of the disorder make it mandatory that all claims of benefit must pass the toughest tests that can be devised.

Recent reports of the unprecedented survival of extremely immature infants,15 who are at the greatest risk for ROP, should serve as a reminder that coordinated, largescale, continuous campaigns to evaluate promising interventions are long overdue. The uncoordinated, episodic, piecemeal skirmishes, that have character- ised the battle to combat ROP blindness until now, are completely inadequate responses to the devastation caused by the disorder. Pocock16 recognised the weakness as a general problem in medicine. 'Until a greater effort is made to achieve larger numbers [of patients] in . . . clinical trials', he warned, 'much pub- lished clinical research remains essentially futile, since it lacks the resources to answer the clinical questions being posed'.

MALCONTENT

0 1995 Blackwell Science Ltd. Pardiarric and Perinard Epidemiology, 9,250-255

From OUT own correspondents 253

References 1 Terry TL. Extreme prematurity and fibroplastic overgrowth of persistent vascular sheath behind each crystalline lens. I. Preliminary report. Americun Journal of Ophthalmology 1942; 25:203-204. 2 Watts JL. Retinopathy of prematurity. In: Effective Cure of the Newborn. Sinclair JC, Bracken MB. Oxford: Oxford University Press, 1992; 617-639. 3 Kinsey VE. Etiology of retrolental fibroplasia and preliminary report of the Cooperative Study of Retrolental Fibroplasia. Transactions of the American Academy of Ophthalmology and Otolaryngology 1955; 59:15-24. 4 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Pedhfrics 1988; 81:697-706. 5 Owens WC, Owens EU. Retrolental fibroplasia in premature infants: I1 Studies on the prophylaxis of the disease; The use of alpha tocopheryl [sic] acetate. Americun Journal of Ophthalmology 1949; 32:1631-1637. 5 Institute of Medicine. Vitamin E and Retinopathy of Premnturify. Washington: National Academic Press, (June) 1986. 7 Saugstad OD. Neonatal oxygen radical disease. In: Recent Advances in Paediutrics. Editor: David TJ. Edinburgh Churchill Livingstone, 1992. 8 Sullivan JL, Newton RB. Serum antioxidant activity in neonates. Archives of Disease in Childhood 1988; 63748-750. 9 Sullivan JL. Iron metabolism and oxygen radical injury in premature infants. In: Iron and Human Disease. Editor: Lauffer RB. Boca Raton, Florida: CRC Press, 1992. 10 Lakatos L, Hatvani I, Oroszlan G, Balla G, Karmazsim L, Alaka 0, Kineses E, Szabo I, Lakatos Z. Controlled trial of d-penicillamine to prevent retinopathy of prematurity. Acfn Paediatrica Hungarica 1986; 27:47-56. 11 Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin A supple- menta tion in infants susceptible to bronchopulmonary dysplasia. Journal of Pediatrics 1987; 111:269-277. 12 Hallman M, Bry K, Hoppu K, Lappi M, Pohjavuori M. Inositol supplementation in premature infants with respiratory distress syndrome. New England Journal of Medicine 1992; 326: 1233-1239. 13 Palmer EA, fly^ JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB, Tung B. Incidence and early course of retinopathy of prematurity. Ophthalmology 1991; 981628-1640. 14 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy of prematurity: #-year outcome - structure and function. Archives of Ophthal- mology 1993; 111:339-344. 15 Hack M, Fanaroff AA. Outcomes of extremely immature infants -a perinatal dilemma. New England Journal of Medicine 1993; 329:164%1650. 16 Pocock SJ. Clinical Trials. Chichester: John Wiley & Sons, 1983.

So what? But it's your choice

Talking to my daughter the other day I said - not for the first time - that I was feeling tired. Well', she said tartly, 'it's your choice', thus ensuring that I did not continue to talk about myself but went on to more interesting topics such as her job, her flat and her latest man.

But is she right? Is my exhaustion my choice or a result of external pressures

0 1995 Blackwell Science Ltd. Paediarnc nnd Pm'naral Epidcmiolcyy, 9, 250255

254 From our mn correspondents

over which I have no control? To help find out, I decided to keep a diary. If her diagnosis of my problem of chronic exhaustion turns out to be correct, I can then move on to treatment.

When one works hard - and I do think I work quite hard - weekends are an important part of life, creating space after a fraught professional week and allow- ing one to relax completely. Take last weekend. Having had my car wrecked whilst it was parked, an early appointment to have my hair cut on the Saturday morning entailed persuading the very elderly dog and the slightly elderly husband that getting to the hairdresser for 8.45 am was feasible. Back with fresh rolls for breakfast by 9 am. And now the relaxing can start. After preparing lunch for father and ourselves I go out to a Bazaar being run in aid of my local hospice, which I warmly support for many reasons of which self interest is but one. I shop on the way back, and decide to buy lottery tickets for 8 consecutive weeks in one purchase to cut down on the time spent on weekly visits to the shop as well as on the time spent on thinking about each weeks numbers.

Back home in time to put the apples in the oven with the meat and veg and start the washing. My weekend luxury comes next: a little sleep after too big a lunch. Then I attack the week's mail, pay some bills and look through the pile of unread newspapers, before giving some time after supper to working on the papers of a Committee I am to chair in the following week. Not sure why but its after midnight before I get to bed.

On Sunday morning by husband's amateur radio friend appears and the two men go upstairs to sit in front of the radio to take part in a competition which involves speaking to as many other radio amateurs as possible. Like the modern hospital, its quantity of contacts rather than quality that gets the highest marks. I dutifully supply coffee and then lunch. Lunch is served two up and two down, as daughter joins me for lunch giving us another chance to talk about her job, her flat and her latest man.

After a bit of washing up and a bit more washing its time to go and see my parents, shopping for supper for father, husband and me en route; (mum is not eating following a major stroke). Then its home for a quiet evening, dictating a set of minutes onto a tape and drafting an article. Later to bed than planned but up at the usual 6am to start another week at work.

Work is as busy and exhilarating as ever. A meeting here and a meeting there, some of which I minute afterwards. Letters and phone calls. Odd bit of recruit- ment. It's the week to start drafting our quarterly publication, Information Exchange, which is fun if time consuming: 20 pages covering topics ranging from the politics of hospice funding to reviewing the latest journals with ethics and fundraising and lots more in between. I have a couple of Committee meetings not connected with work. One is about coordinating the making and mending of holes in the road. The other is of the Committee I chair which is about improving access to the telephone for elderly and disabled people.

6 1995 Blackwell Science Ltd. Paediarrir und Pcn'naral Epidemiolqyy, 9,25&255

From our own correspondents 255

Evenings are fun too. I enjoy the Annual General Meeting of the All Party Hospice Group, and am pleased with my choice of speaker, a hospice medical director, who is very clear about the resources needed if people who wish to die at home are to receive the services they need. All Party Groups reflect British politics at its best. A group of members of all political parties and from both Houses of Parliament with an interest in a specific issue, working together. The All Party Hospice Group arranged a meeting with the junior Minister of Health responsible for palliative care only a week or two ago, enabling professionals from the adult and children’s hospice world to sit round a table with the minister, officials and Members of Parliament to discuss issues of concern. Even if major policies are not changed, the work of the All Party Hospice Group ensures that hospice and specialist care services remain on the political agenda.

Another evening is spent at the annual dinner of my support group: the Association of Chief Executives of National Voluntary Organisations. The food is dreadful but the gossip, networking and warmth ensure its success.

On the theatrical front the week begins with an enjoyable and uplifting produc- tion of Dickens’ Christmas Carol and ends with a modern, realistic and depressing interpretation of Brecht‘s Threepenny Opera which we leave at the interval, feeling that we have seen enough and that an early night might be a more valuable experience than the second half of a production everyone - except my friend and I - have praised. And Friday evening comes at last - spent relaxing at work, tidying up the office and my mind before the weekend begins, giving me the time at last to consider my daughter‘s assertion that I am tired through choice.

And now comes the opportunity to end this piece with a really deep exploration of the meaning of exhaustion and of concepts such as free will, as we11 as examining the extent to which insight facilitates change or whether self-deception remains more comfortable.

An opportunity I am too tired to take.

JEAN GAFFIN

0 1995 Blackwell Science Ltd. Pdiarrir atid Peritrczral Epidoniolo.qy, 9,250-255