our necropsy and prostatectomy series supports the concept
`that carcinoma seen at necropsy, clinically detected
`carcinoma, and metastatic carcinoma represent different
`phases along the biological continuum of a single type of
`cancer. The apparent unpredictability of behaviour in
`prostate cancer need not imply the existence of a second type
`that is innately innocuous or "latent". It may be mainly a
`function of the large proportion of tumours under 1 ml in
`volume which would probably remain clinically silent for a
`very long time. It has been suggested that this unusual
`volume distribution may simply be the result of a slow growth
`rate for this tumour in its early phases There is no evidence
`that carcinoma in the prostate is in any other way
`substantially different from or less predictable than that of
`any other organ.
`
`The volume distribution of histological differentiation
`further supports the concept that progression in the
`acquisition of malignant characteristics with time and
`increasing volume is an important feature of the biology of
`prostate cancer. The only likely explanation for these data is
`that the great majority of prostate cancers are at least
`moderately differentiated at first and subsequently lose.
`differentiation. That this phenomenon is similar but not
`identical for all tumours is implied by the range of
`differentiation found in even the smallest tumours, as well as
`the age differences and possibly racial differences found
`among larger tumours. The reported poor prognosis for
`prostate cancer among black men15 may be largely explained
`by a greater tendency toward loss of differentiation with
`increasing volume.
`
`Our data indicate that carcinoma of the prostate follows a
`predictable natural history and that precise determination of
`volume and capsule invasion should improve the estimation
`of prognosis in the individual patient. In both our series, the
`highest category of either volume or capsule penetration
`identified the cases with metastasis at least as accurately as did
`the presence of seminal vesicle invasion. Unlike seminal
`vesicle invasion, volume and capsule invasion are continua,
`and the division points and ranges of probable greatest
`significance along these continua have been identified here,
`though the numerical values we have defined may change as
`we study more cases and accumulate data from long-term
`follow-up. The ranges of greatest interest are potentially
`within reach of measurement by in-vivo imaging techniques.
`Though the significance of capsule penetration has been
`debated, 16,17
`it has been clarified here by precise
`determination of both depth and extent of penetration of the
`capsule.
`
`The predictive value of histological grade was
`unexpectedly low in both series, even though for all 9
`metastatic carcinomas either primary or secondary grade was
`4. Poor differentiation became prevalent in a volume range
`considerably below that at which metastasis was first seen,
`and in the necropsy series 5% oftumours under 0 - 46 ml were
`grade 4. This suggests that grade 4 tumours may be a
`heterogeneous group in terms of their biological malignant
`potential; we are currently investigating this possibility.
`Attempts to improve the predictive value of histological
`grading should be specifically directed toward finding
`morphological features of differential prognostic significance
`within the grade 4 category. Improvements here combined
`with estimation of cancer volume and extent of complete
`capsule penetration by in-vivo imaging could achieve a
`
`63
`
`degree of accuracy in estimation of prognosis of prostate
`cancer at least equal to that of any other malignant disorder.
`We thank Dr Lincoln E. Moses for help with statistical analyses. This work
`was partly supported by grants from the Richard M. Lucas Cancer Foundation
`(J. E. McN.) and the National Institute of General Medical Sciences grant
`GM07781 (D. G. B.).
`Correspondence should be addressed to J. E. McN., Department of
`Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
`
`’
`
`REFERENCES
`
`1. Whitmore WF. The natural history of prostatic cancer. Cancer 1973; 32: 1104-12.
`2. Stamey TA. Cancer of the prostate: an analysis of some important contributions and
`dilemmas. Monogr Urol 1982; 3: 67-94.
`3. Franks LM Latent carcinoma of the prostate. J Pathol Bacteriol 1954; 68: 603-16.
`4. Gleason DF. Histologic grading and clinical staging of prostatic carcinoma. In:
`Tannenbaum M, ed. Urologic pathology: the prostate. Philadelphia: Lea and
`Febiger, 1977.
`5. McNeal JE. Origin and development of carcinoma in the prostate. Cancer 1969; 23:
`24-34.
`6. McNeal JE. The prostate gland: morphology and pathobiology. Monogr Urol 1983; 4:
`3-33.
`7. Foulds L. The experimental study of tumor progression: a review. Cancer Res 1954; 14:
`327-39.
`8. Nowell PC. The clonal evolution of tumor cell populations. Science 1976; 194: 23-28.
`9. Fidler IJ, HartIR. Biologic diversity in metastatic neoplasms: origins and implications.
`Science 1982; 217: 998-1003.
`10. Poste G, Greig R. On the genesis and regulation of cellular heterogeneity in malignant
`tumors. Invasion Metastasis 1982; 2: 137-76.
`11. Goldie JH, Coldman AJ. A mathematical model for relating the drug sensitivity of
`tumors to their spontaneous mutation rate. Cancer Treat Rep 1979; 63: 1727-31.
`12. McNeal JE. Regional morphology and pathology of the prostate. Am J Clin Pathol
`1968; 49: 347-57.
`13. Moses LE, Emerson JD, Hosseini H. Analyzing data from ordered categories. N Engl J
`Med 1984; 311: 442-48.
`14. Hollander M, Wolfe DA. Nonparametric statistical methods. New York: Wiley, 1973.
`15. Ernster VL, Wilkenstein W, Selvin S, Brown SM. Race, socioeconomic status and
`prostate cancer. Cancer Treat Rep 1977; 61: 187-91.
`16. Jewett HJ. The case for radical perineal prostatectomy. J Urol 1970; 103: 195-99.
`17. Myers RP, Fleming TR. Course of localized adenocarcinoma of the prostate treated by
`radical prostatectomy Prostate 1983; 4: 461-72.
`
`PERCUTANEOUS TRANSLUMINAL
`VALVULOPLASTY OF ACQUIRED AORTIC
`STENOSIS IN ELDERLY PATIENTS: AN
`ALTERNATIVE TO VALVE REPLACEMENT?
`
`ALAIN CRIBIER
`NADIR SAOUDI
`JACQUES BERLAND
`Service des Soins Intensifs Cardiologiques et des Explorations
`Hémodynamiques Cardiovasculaires, Centre Hospitalier et
`Universitaire, Hôpital Charles Nicolle, Rouen, France
`
`THIERRY SAVIN
`PAULO ROCHA
`BRICE LETAC
`
`Summary
`
`Percutaneous transluminal balloon catheter
`aortic valvuloplasty (PTAV) was carried out
`in three elderly patients with acquired severe aortic valve
`stenosis. Transvalvular systolic pressure gradient was
`considerably decreased at the end of the procedure, during
`which there were no complications. Increased valve opening
`was confirmed by angiography and echocardiography.
`Subsequent clinical course showed a pronounced functional
`improvement. PTAV is recommended as a simple alternative
`to aortic valve replacement in elderly and/or high-risk
`patients.
`
`Introduction
`PERCUTANEOUS transluminal balloon catheter angioplasty
`is a recognised treatment for peripheral and coronary artery
`stenoses. This technique has also been used successfully in
`certain forms of coarctation of the aorta,’ pulmonary
`stenosis,2-6 congenital aortic valve stenosis,7,8 and mitral
`stenosis,9 but not previously in adults with acquired aortic
`valve stenosis. It might be thought impossible to dilate such
`long-standing and usually calcified lesions; if feasible,
`
`Edwards Exhibit 1028, pg. 1
`
`

`
`64
`
`however, percutaneous transvalvular aortic valvuloplasty
`(PTAV) would be an appropriate alternative treatment
`whenever surgical valve replacement proved impracticable.
`We have now carried out PTAV in 3 adults with isolated
`severe calcific aortic stenosis; in all 3 cases, severity of
`progression made valve replacement appear both mandatory
`and urgent. We elected to attempt valvuloplasty, however,
`because advanced age and poor physical condition made the
`operative risk very high in 2 patients, while the third refused
`to contemplate surgery.
`
`Case 1
`
`Case-reports
`
`A 77-year-old woman had been treated for 10 years for angina
`pectoris. In August, 1984 several syncopal attacks on mild exertion
`led to the discovery of aortic stenosis. Angina and exertional
`dyspnoea severely limited physical activity. Physical examination
`showed a mid-systolic grade 3/6 murmur at the aortic area, radiating
`to the cervical vessels, an absent second heart sound, and a grade 1/6
`diastolic murmur. Electrocardiogram (ECG) showed pronounced
`left ventricular hypertrophy, and the left ventricle was moderately
`enlarged on the chest radiograph. Two-dimensional (2D) echo-
`cardiogram showed severe aortic stenosis with calcifications and
`satisfactory left ventricular function. In view of the severity of
`symptoms, cardiac catheterisation was proposed for preoperative
`evaluation, but the patient withheld her consent for a year, during
`which symptoms steadily worsened, with nocturnal angina and two
`episodes of syncope at rest.
`Left ventricular catheterisation showed left ventricular pressures
`of 245/28 mm Hg and aortic pressures of 155/70 mm Hg (systolic
`pressure gradient 90 mm Hg). Aortic valve cusps were moderately
`calcified. Selective left ventricular angiography showed a normal
`diastolic volume (73 ml/m2), with normal left ventricular function
`(ejection fraction 77%) and clearly thickened walls. Post-stenotic
`dilatation of the ascending aorta and slight aortic regurgitation were
`seen on aortic angiography. Selective coronary arteriography did
`not show any significant coronary lesions. The patient gave
`informed consent for PTAV as an alternative to surgical valve
`replacement and this was done three weeks later.
`
`Case 2
`A 68-year-old woman had had aortic stenosis diagnosed 15 years
`previously. Her clinical status deteriorated progressively over the
`years (New York Heart Association functional class III) and angina
`appeared and became progressively worse. Admission for further
`investigation was precipitated by an attack of severe chest pain
`when walking against the wind, followed by syncope. Physical
`examination on admission showed a grade 3/6 systolic murmur at
`the base, absent second heart sound, and a grade 2/6 diastolic
`murmur. There were clearcut signs of left ventricular hypertrophy
`on ECG and the chest radiograph showed slight cardiomegaly. 2D
`echocardiogram showed severe calcific aortic stenosis with normal
`left ventricular function.
`Cardiac catheterisation demonstrated ventricular pressures of
`230/22 mm Hg and aortic pressures of 100/50 mm Hg (systolic
`pressure gradient 130 mm Hg). The aortic valve was massively
`calcified. Right heart pressures and cardiac index were normal. Left
`ventricular angiography showed a normal end-diastolic volume
`(94 ml/m2) with slightly reduced ejection fraction (54%) and
`thickened walls. The ascending aorta was moderately dilated, and
`aortic regurgitation was insignificant. Selective coronary arterio-
`gram was normal.
`Severity of both symptoms and haemodynamic data led us to
`propose immediate valve replacement, but the patient would not
`contemplate surgery. However, she accepted PTAV, which was
`done a month later.
`
`Case 3
`A 79-year-old man who had complained of progressive exertional
`dyspnoea for 10 years was admitted after three syncopal attacks
`
`brought on by mild exertion. Aortic stenosis was diagnosed.
`Physical examination on admission showed a grade 4/6 mid-systolic
`murmur at the base, with an absent second heart sound. ECG
`showed severe left ventricular hypertrophy and the chest
`radiograph mild cardiomegaly and signs of mild pulmonary
`hypertension. 2D echocardiogram showed severe aortic stenosis
`with considerable valve calcification and severe left ventricular
`dilatation with impaired ventricular function. Two days after
`admission, the patient had an episode of acute, massive pulmonary
`oedema which was brought under control with difficulty by high
`doses of frusemide.
`At cardiac catheterisation, left ventricular pressure was 140/28
`mm Hg (systolic pressure gradient 60 mm Hg) and the aortic valves
`were massively calcified. Left ventricular angiography confirmed
`left ventricular dysfunction, with an increased diastolic volume
`(190 ml/m2) and greatly decreased ejection fraction (20%). Selective
`coronary arteriography showed major multiple vessel lesions with
`proximal left-anterior-descending occlusion. These findings made
`us reluctant to recommend valve replacement and, with informed
`consent, we decided to attempt PTAV.
`
`Methods
`The same procedure for PTAV was followed in all 3 patients.
`Premedication consisted of intravenous atropine sulphate 1 mg,
`clorazepate 50 mg, and heparin 100 u/kg bodyweight. A surgical
`team was on standby.
`For continuous aortic pressure monitoring, a 5F catheter was
`inserted into the descending thoracic aorta. In addition, a Swan-
`Ganz thermodilution catheter was inserted into the pulmonary
`artery in patients 2 and 3 for measurement of cardiac output. Left
`ventricular catheterisation was carried out via the brachial approach
`which made it easier to cross the stenosed aortic orifice (and was also
`necessitated by the short length [60 cm] of the dilatation catheters
`available in our laboratory). A 7F Sones catheter was inserted into
`the aorta and then in the left ventricle. After simultaneous left
`ventricular and aortic pressure recording, right-anterior-oblique
`angiograms of the left ventricle and of the aortic root were done. A
`Cordis straight guidewire, diameter 0 - 38 mm, length 270 cm, was
`inserted into the left ventricle via the Sones catheter to enable its
`replacement by the dilatation catheter.
`We used 9F balloon catheters designed for dilatation of congenital
`valve stenosis (Meditech, Waterton, Massachusetts). Two radio-
`opaque markers gave the positions of the distal and proximal ends of
`the balloon, thus ensuring correct transvalvular positioning which
`was also confirmed by narrowing of the balloon where it crossed the
`stenosis during inflation (fig 1). The balloons were 40 mm long.
`Inflations were carried out by injecting 10 ml of a 50/50 mixture of
`saline solution and contrast medium, up to pressures of 6-8 atm.
`Three inflations, lasting 20-60 s, were successively done with three
`balloons whose maximum inflatable diameters were 8, 10, and
`12 mm, respectively. In order to stabilise the balloon in its
`transvalvular position, the guidewire was left in the ventricular
`cavity during inflation.
`ECG and aortic pressure were continuously recorded during the
`procedure. Ventricular and aortic pressures were simultaneously
`measured after each series of inflations. At the end of the procedure,
`an aortic root angiogram was done to assess valve opening and
`residual aortic regurgitation.
`
`Results
`The haemodynamic and clinical response to the inflations
`was good. There was no loss of consciousness when the
`balloon was inflated in transvalvular position. The first
`patient complained of moderate chest pain after 15-20 s of
`inflation, at the same time as ST-segment depression was
`noted in the antero-lateral precordial leads. In patients 2 and 3
`the three inflations each lasted 1 min without any ill-effects.
`During inflation, the aortic pressure never decreased below
`60 mm Hg (fig 2). The obstruction caused by the inflated
`balloon was therefore incomplete; this was confirmed by
`manual injection of a few ml of contrast medium into the
`
`Edwards Exhibit 1028, pg. 2
`
`

`
`65
`
`EARLY INFLATION
`FULL INFLATION
`Fig 1-Correct position of the balloon centred across the stenotic aortic valve during early and full balloon inflation to a diameter of 10 mm.
`Indentation from the stenotic valve is clearly seen at early inflation and disappears at full inflation. The guidewire is placed in the left ventricle to stabilise the
`balloon during inflation.
`
`ventricular cavity during one inflation (via the angioplasty
`catheter with guidewire removed). A few premature
`ventricular contractions occurred infrequently during the
`inflations.
`In the first patient, transvalvular gradient was 90 mm Hg at
`the start of the procedure and remained unchanged after the
`first two series of inflations, with the 8 and 10 mm balloons.
`After a series of three inflations with the 12 mm balloon, it
`decreased to 40 mm Hg (fig 3). In the second patient, the
`initial gradient was found to be 80 mm Hg (rather than the
`130 mm Hg measured during the initial catheterisation) and
`decreased to 70, 60, and finally 30 mm Hg after each series of
`inflations. In the third patient, improvement of systolic
`gradient was very similar-from 60 mm Hg to 50, 40, and
`finally 30 mm Hg. In patients 2 and 3 in whom cardiac output
`was measured before and after valvuloplasty, valve surface
`calculated according to Gorlin’s formulalo increased from
`0-46 cm’ to 0-96 cm2 and from 0-50 cm2 to 0-75 cm2,
`respectively.
`Aortic root angiography showed no worsening of the aortic
`regurgitation. Valve motion, which was considerably
`impaired before the procedure, was greatly improved,
`especially in the second patient. These results were
`supported by the findings of 2D echocardiography done 24 h
`later: in the parasternal long-axis view, opening of the aortic
`valve increased from 0-45 to 0 - 77 cm in the first case; from
`0 - 41 to 0 - 72 cm in the second (fig 4); and from 0 - 32 to 0 - 48
`cm in the third. In the cross-sectional view, valve opening was
`also clearly improved, mainly in the second patient.
`Clinical course during the eight days in hospital after the
`procedure was uneventful in the first two patients, and before
`discharge both climbed three flights of stairs without any pain
`or dyspnoea-a striking functional improvement. At four
`weeks follow-up, the improvement persisted: there had been
`no syncope, no pain, and very little dyspnoea, even though
`the patients had by then resumed a normal lifestyle. Follow-
`up of the third patient has been shorter, but it was uneventful
`after fifteen days, with no more functional signs, including
`dyspnoea.
`
`Discussion
`To our knowledge, the 3 patients reported here are the first
`to undergo PTAV of adult acquired aortic stenosis.
`Immediate results appear very encouraging, since the
`dilatation resulted in a change from severe to moderate aortic
`stenosis according to the usual haemodynamic criteria-a
`pronounced decrease in the ventriculo-aortic systolic
`pressure gradient, with a residual gradient of 40 mm Hg in
`one patient, and of 30 mm Hg in the other two.
`From the angiographic and echocardiographic data,
`improvement in the gradient is a consequence of better
`systolic valve opening. The balloon inflations probably
`resulted in a partial tear of the stenosed valve. Although the
`valve orifice is often hard to cross in severe adult calcific aortic
`stenosis, we experienced no technical difficulty in passing the
`dilatation catheters via the aortic orifice and in reaching a
`good transvalvular position. The excellent patient tolerance
`of the inflations is worth emphasising, since we had feared
`that inflation of the balloon in a stenosed aortic orifice might
`lead to syncopal circulatory arrest. During the inflations, the
`aortic pressure remained satisfactory, suggesting that the
`
`Fig 2-ECG (lead V5) and aortic pressure continuous recording
`during a 40 s balloon inflation-deflation cycle.
`Inflation was associated with a slight decrease in systolic aortic pressure
`from 85 to 70 mm Hg. There was no change in heart rate and only one
`premature ventricular contraction.
`
`Edwards Exhibit 1028, pg. 3
`
`

`
`66
`
`Fig 3-Simultaneous recording of left ventricular and aortic
`pressures before (left) and at the end ofPTAV (right) in case 1.
`Transvalvular systolic gradient decreased from 90 to 40 mm Hg.
`
`inflated balloon was not totally occlusive, probably due to the
`irregular shape of the aortic orifice. There were no
`complications during or after the procedure, although
`calcium embolism could be considered a risk. 11 1
`It is too early to predict the possible place of PTAV in the
`treatment of severe adult acquired aortic stenosis from so few
`patients. Nevertheless, our 3 cases illustrate the feasibility of
`the procedure, its good patient tolerance, and the resulting
`haemodynamic and clinical improvement. Although the
`results are unlikely to compare in quality with those of valve
`replacement, PTAV can offer a simple therapeutic alternative
`to patients, mostly elderly, in whom surgery would be too
`risky or impossible.
`We thank Dr N. Moore for his help in translation of the typescript.
`Correspondence should be addressed to A. C., Service des Soins Intensifs
`
`Fig 4-2D echocardiogram (parasternal long axis view) in case 2 before (left) and 24 h after (right) PTAV.
`Maximum aortic valve opening (arrows) increased from 0’41 to 0-72 cm. Ao =aorta; LA=left atrium; LV=left ventricle.
`
`Edwards Exhibit 1028, pg. 4
`
`

`
`Cardiologiques et des Explorations Hemodynamiques Cardlovasculaires,
`Centre Hospnalier et Universitaire, Hopital Charles Nicolle, 1 rue de
`Germont, 76031 Rouen Cedex, France.
`
`Addendum
`Follow-up in the three patients described here has now
`been uneventful for 15, 10, and 9 weeks respectively. In
`addition, PTAV has been carried out in another eleven
`patients with similar results.
`REFERENCES
`
`1 Cooper RS, Ritter SB, Golinko RJ. Balloon dilatation angioplasty: Nonsurgical
`management of coarctation of the aorta. Circulation 1984; 70: 903-07.
`2 Kan JS, White RI, Mitchell SE, Anderson JH, Gardner TJ. Percutaneous transluminal
`balloon valvuloplasty for pulmonary valve stenosis. Circulation 1984; 69: 554-60.
`3 Lababidi Z, Wu JR Percutaneous balloon pulmonary valvuloplasty. Am J Cardiol
`1983; 52: 560-62
`4 Pepine CJ, Gessner IH, Feldman RL Percutaneous balloon valvuloplasty for
`pulmonic valve stenosis in the adult. Am J Cardiol 1982; 50: 1442-45.
`5 Rey C, Marache P, Matina D, Mouly A Valvuloplastie transluminale percutanée des
`sténoses pulmonaires A propos de 24 cas. Arch Mal Coeur 1985; 78: 703-10.
`6 Rocchini AP, Kveselis DA, Crowley D, Dick Mac D, Rosenthal A. Percutaneous
`balloon valvuloplasty for treatment of congenital pulmonary valvular stenosis in
`children. J Am Coll Cardiol 1984; 3: 1005-12.
`7 Lababidi Z, Wu JR, Walls JT. Percutaneous balloon aortic valvuloplasty: Results in 23
`patients Am J Cardiol 1984, 53: 194-97.
`8 Walls JT, Lababidi Z, Curtis JJ, Silver D. Assessment of percutaneous balloon
`pulmonary and aortic valvuloplasty. J Thorac Cardiovasc Surg 1984; 88: 352-56.
`9. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of
`transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc
`Surg 1984, 87: 394-402
`10 Cohen MV, Gorlin R Modified orifice equation for the calculation of mitral valve area.
`Am Heart J 1972, 84: 839-40.
`1 1 Brockmeier LB, Adolph RJ, Gustin BW, Holmes JC, Sacks JG. Calcium emboli to the
`retinal artery in calcific aortic stenosis. Am Heart J 1981; 101: 32-37.
`
`COMPARISON OF TWO METHODS OF
`PREDICTING OUTCOME IN PERINATAL
`ASPHYXIA
`
`M. I. LEVENE
`HELEN GRINDULIS
`
`CAROLINE SANDS
`J. R. MOORE
`Department of Child Health, University of Leicester School of
`Medicine, and Leicester Royal Infirmary
`
`Summary
`
`In a follow-up study of 122 full-term infants
`in whom postasphyxial encephalopathy
`occurred the incidence of death or severe handicap was 1 in
`1000 deliveries. The abilities of two methods of diagnosing
`intrapartum asphyxia to predict outcome at a median age of
`2· 5 years were compared. A decision matrix calculation was
`undertaken to assess the sensitivity and specificity of low
`Apgar score and postasphyxial encephalopathy. A 10 min
`Apgar score ≤5 was the most sensitive of six different Apgar
`ratings in predicting adverse outcome (sensitivity 43%,
`specificity 95%) but even this was much less sensitive than
`the presence of moderate or severe encephalopathy in
`predicting death or severe handicap (sensitivity 96%).
`Introduction
`ASPHYXIA is the most common cause of major cerebral
`birth injury in the perinatal period; its incidence in full-term
`infants varies between 2’9 and 9-0 cases per thousand.l-6
`There have been several attempts to relate either low Apgar
`scores or abnormal neurological findings after asphyxia 3,1-9
`to outcome. If we are to use an assessment of asphyxia at birth
`to predict neurological sequelae, the ability of the method to
`evaluate prognosis should be tested.
`We have assessed two methods of diagnosing intrapartum
`asphyxia (low Apgar score and postasphyxial encephal-
`opathy) for their ability to identify infants with a poor
`prognosis as well as those likely to have a good prognosis. We
`have used a decision matrix10 to assess the sensitivity and
`specificity of both methods in predicting outcome. Sensi-
`tivity measures the proportion of infants with adverse
`
`67
`
`outcome detected by the method and specificity the propor-
`tion of infants predicted to have a favourable outcome. Our
`aim was to determine which method would enable clinicians
`to give the most reliable prognostic information to the parents
`of asphyxiated infants.
`Patients and Methods
`We have previously reported the incidence of encephalopathy
`after intrapartum asphyxia in our university obstetric department.
`Encephalopathy was graded as: mild (minor disturbances of tone,
`hyperalertness, and slight feeding difficulties, recovering by 48 h
`after birth); moderate (lethargy, more pronounced abnormalities of
`tone, poor feeding, and convulsions, with signs of recovery by 7
`days); and severe (coma, failure to maintain adequate ventilation,
`profound hypotonia, and seizures). The infants previously reported
`represent the population of full-term infants born in a teaching
`hospital maternity unit in the 4 years from 1980. Leicestershire
`Health District provides both obstetric and paediatric care for
`almost all the families living in the geographical area. Leicester
`Royal Infirmary undertakes care of high-risk pregnancies and at-
`risk infants, and severely handicapped children born anywhere in
`Leicestershire are subsequently assessed at the child development
`centre attached to the main hospital.
`Children surviving postasphyxial encephalopathy were regularly
`assessed. We were unable to trace 4 children (3%) for follow-up. 6
`others had moved out of Leicestershire and information on their
`developmental achievements and neurological function was
`obtained from general practitioners and health visitors. All 6
`children were reported to be functioning normally. The age at
`follow-up of the 122 children was between 1 and 5 years (median 2 - 5 5
`years). Any child with equivocal neurodevelopmental assessment or
`neurological signs was assessed by one of us. Children with
`developmental delay were further assessed by an educational
`psychologist using the Bayley scales. Severe neurological
`abnormality was defined as cerebral palsy sufficient to impair
`independent locomotion, developmental delay probably severe
`enough to warrant special education, sensorineural hearing loss,
`visual impairment, or epileptic seizures (not associated with fever)
`requiring medication. Adverse outcome was defined as one or more
`of these severe neurological deficits and/or death.
`Since the index cases for follow-up consisted of children who had
`had postasphyxial encephalopathy, we made a thorough search for
`children who might have had brain damage as the result of asphyxia
`defined on the basis of low Apgar scores but who had shown no
`evidence of encephalopathy. We examined the notes of all children
`referred to the child development centre from January, 1981, to
`June, 1985 who had been born at full-term in Leicester Royal
`Infirmary. No handicapped children were found who had had low
`Apgar scores alone without encephalopathy.
`We first attempted to correlate the duration and severity of Apgar
`score depression defined in six different ways with outcome. For
`the main analysis two hypotheses were tested: that adverse outcome
`was predicted either by moderate and severe encephalopathy or by a
`low Apgar score (the sensitivity). This can be conversely stated
`as a favourable outcome predicted by mild postasphyxial encephal-
`opathy or a normal Apgar score (the specificity). The sensitivity is
`calculated as the proportion of infants with adverse outcome
`predicted by the method (true-positives divided by true-positives
`plus false-negatives). Specificity is the proportion of infants with
`favourable outcome predicted by the method (true-negatives
`divided by true-negatives plus false-positives).9
`Results
`- During the study period there were 20 975 full-term, live
`births; postasphyxial encephalopathy developed in 126
`infants-an incidence of 6’0 per 1000.6 Follow-up
`information was obtained for 122 of the 126. 14 children died:
`7 during the first week of life from the effects of severe
`cerebral asphyxia; 6 between 8 days and 9 months, all
`showing grossly abnormal neurological behaviour before
`death; and 1 aged 1 year after cardiac surgery (she had severe
`oculomotor apraxia).
`
`Edwards Exhibit 1028, pg. 5