Questions on the Vitamin E Study

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LETTERS TO THE EDITOR 327

port), there were 18 hemorrhages in control patients and 16 hemorrhages in treated patients. There were no dif-ferences between groups in the distribution of hemor-rhages among grades I through IV. I question why differ-ent diagnostic methods were reported on the same

pa-tients in the two different published reports. This and

the exclusion of outborn patients is especially relevant inasmuch as computed tomographic scans indicated that 16 treated patients had hemorrhages whereas ultrasound findings (with outborn patients excluded) indicated that only ten treated patients had hemorrhages, and in the control group, 18 patients had hemorrhages indicated by computed tomographic scans but 24 patients had hem-orrhages indicated by ultrasonography. These changes create, in the present report, an increased number of

hemorrhages in control patients and a decreased number

of hemorrhages in the treated patients; therefore, statis-tical significance is achieved.

In such cases where statistical significance so critically

depends upon what data are being used for analysis, I too

remain unconvinced of the efficacy of vitamin E in de-creasing the incidence or severity of intraventricular hemorrhage in very low-birth-weight neonates.

REFERENCES

ROBERT D.JANSEN, MD

Department of Pediatrics

Indiana University Medical Center

Indianapolis, IN 46223

1. Speer ME, Blifeld C, Rudolph AJ, et at: Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: Evidence for efficacy of early intramuscular vitamin E administration. Pediatrics 1984;74:1107

2. Phelps DL: Vitamin E and CNS hemorrhage. Pediatrics

1984;74:1113

3. Hittner HM, Speer ME, Rudolph AJ, et at: Retrolental fibroplasia and vitamin E in the preterm

infant-Compari-son of oral versus intramuscular:oral administration.

Pedi-atrics 1984;73:238

In

Reply.-Regarding the efficacy of a few early intramuscular injections of vitamin E to decrease the incidence and

severity of intraventricular hemorrhage reported by

Speer et al,’ Jansen adds his concerns to those already

expressed in the commentary by Phelps.’

The intraventricular hemorrhage data were a retro-spective study, the inborn and outborn infants were not randomly separated into control and treatment groups, and the small numbers resulted in some nonsignificant

differences between control infants and treated infants.

It was not suggested that the reduction in severe intra-ventricular hemorrhage in the inborn infants was respon-sible for the decreased mortality reported in the total

group by Hittner et al.’

Of the 26 inborn patients who died, 12 infants (eight control infants and four infants who were treated) had one or more real-time ultrasound examinations at least two days prior to death as well as a postmortem

exami-nation. In no instance was a new or progressive

intraven-tricular hemorrhage found at autopsy. Another five

in-fants (four control infants and one treated infant) died

after day 14, and the ultrasound diagnosis determined whether an intraventricular hemorrhage was present. The remaining nine infants (six control infants and three infants who were treated) had either a postmortem ex-amination or an ultrasound examination at the time of death. If these nine patients are excluded from consid-eration, the statistical differences of decreased incidence and severity of intraventricular hemorrhage in the infants treated with vitamin E remains significant (x’ = 5.91, P

= .015; and

x2

= 5.07, P = .024; Yates correction, respec-tively). Therefore, we do not feel that the postmortem findings unduly increased the incidence or severity of intraventricular hemorrhage in the control group.

Jansen correctly points out that all patients were eval-uated for the presence of intraventricular hemorrhage

using cranial ultrasound. Thus, in the Hittner report,

“computed tomography” should have read “cranial

ultra-sound.” However, there are no conflicting data regarding the infants in the Hittner and Speer reports. The project

performed at the Texas Children’s Hospital in 1982 en-rolled 168 infants and had four subsets of infants weigh-ing 1,500 g at birth: (1) Subset 1 included 26 inborn infants (18 control and eight treated infants) who

sur-vived less than 5 weeks of life. (2) Subset 2 included

seven outborn infants (four control and three treated infants) who survived less than 5 weeks of life. (3) Subset 3 included 108 inborn infants (52 control and 56 treated

infants) who survived more than 1 1 weeks of life. (4) Subset 4 included 27 outborn infants (15 control and 12

treated infants) who survived more than 11weeks of life. Hittner et at3 reported on subsets 3 and 4, which are applicable to retinopathy of prematurity as severe reti-nopathy of prematurity develops only a few months after

birth (survived 10 weeks: 67 control and 68 treated

infants). Speer et al’ reported on subsets 1 and 3, and

their findings are most applicable to intraventricular hemorrhage as intraventricular hemorrhage usually de-velops in the first four days of life (inborn infants only:

70 control and 64 treated infants).

Outborn patients were not included in the Speer report in order to minimize the number of variables that might influence the development of intraventricular hemor-rhage. It is inappropriate to compare two groups of dis-similar patients. The obstetrical management and resus-citation of the outborn infants varied tremendously and

thus could not be compared with those of the inborn

patients. Additionally, the outborn infants were not

transported by the same personnel or equipment. It is unrealistic to anticipate that vitamin E can protect the microcirculation from injury if an intraventricular hem-orrhage has already occurred prior to hospital admission. Furthermore, ultrasound evaluations were not performed upon admission of an outborn infant to the intensive care unit. Therefore, the outborn patients were excluded. Nev-ertheless, the intraventricular hemorrhage data provided in the Table include the outborn patients. The previously observed difference in incidence and severity is obscured by the large percentage of outborn infants in the treat-ment group with intraventricular hemorrhage of grade II or higher versus findings for inborn infants who were treated (5/15 = 33.3% compared with 4/64 = 6.3%).

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*Treatment group v control group, P > .05.

5

4

#{163}=Chiswick (treatment) n=21

. = Speer (treatment) n=64 0 = Speer (controls) n70 L =Chiswick (controls) n23

3

Suggested

F.D.A.

Maximum

2

1

20 mg/kg Ephynal#{174}(Basel) IM (ASAP

after birth. 24. 48, and 72 hours later)

15 mglkg Ephynal#{174}(Nutley) IM (ASAP

after birth; 10 mg/kg IM on days 2,

4, and 6; 100 mg/kg tocopheryl acetate

ORALLY (every day) in MCT oil

100 mg/kg tocopheryl acetate

ORALLY (every day) in MCT oil

Unsupplemented 0

0

1 2

3

328 PEDIATRICS Vol. 76 No. 2 August 1985

Further, we attempted to make our data base compa-rable to that of Chiswick et al, who also reported only inborn patients and used the intramuscular route of administration ofvitamin E. We felt that this comparison was important despite the fact that there are at least five

differences between the studies of Speer et al and Chis-wick et at: (1) The Speer et al study utilized Ephynal (Hoffman-LaRoche, mc, Nutley, NJ) which is free to-copherol; the Chiswick et at study utilized Ephynal (Hoff-man-LaRoche, mc, Basel, Switzerland) which is

toco-pheryl acetate and must be hydrolyzed to free tocopherol. Evidence for rapid elevation of plasma-free tocopherol levels by administration of either product is demon-strated in the Figure. (2) The plasma vitamin E levels

reported by Speer et al are described in milligrams per deciliter; Chiswick et al reported vitamin E levels in micromoles per liter; 1 mg/dL is equivalent to 23.2 mol/

L. Conversion of the Chiswick et at data (1 mg/dL = 23.2

mol/L) and their relationship to the data of Speer et al are shown in the Figure. (3) The enrollment criterion for infants in the study of Speer et at was a birth weight 1,500 g; Chiswick et al used 1,750 g. (4) The control group in the study of Speer et at received oral vitamin E supplementation; the control group in the study of Chis-wick et at received no vitamin E supplementation (see

Figure). (5) The reporting of intraventricular hemorrhage in the study of Speer et al includes grades I to IV intraventricular hemorrhage; the reporting of intraven-tricular hemorrhage in the study of Chiswick et at in-cludes only grades II to IV, with grade I intraventricular hemorrhage as subependymal hemorrhage only.

A definitive prospective controlled, double-blind, ran-domized study is underway in London (M. L. Chiswick, personal communication). Speer et al’ concluded that the

TABLE. Incidence and Severity of Intraventricular Hemorrhage (IVH) in Control and Treatment Groups

Total IVH Grade I Grade II Grade III Grade IV

Control group (n = 89) 35 (393%)* 15 12 5 3

Inborn (n = 70) 24 (34.3%) 10 11 2 1

Outborn (n = 19) 11 (57.9%) 5 1 3 2

Treatment group (n = 79) 20 (25.3%) 11 4 4 1

Inborn (n = 64) 10 (15.6%) 6 2 1 1

Outborn (n = 15) 10 (66.7%) 5 2 3 0

E

0 0

C)

E

w

C

E

>

E

U)

CD

Days

of Life

Figure. Plasma vitamin E (free tocopherol) levels of preterm infants enrolled in

con-trotted, double-masked, randomized clinical trials studying use of a few initial intramus-cular injections of vitamin E to prevent intraventricular hemorrhage. Symbols used are: solid triangles, treated infants in study of Chiswick et at who received intramuscular

Ephynal from Beset, Switzerland (dl-a-tocopheryl acetate); solid circles, treated infants

in study of Speer et at who received intramuscular Ephynat from Nuttey, NJ (dl-a-tocopherol), plus oral dl-a-tocopheryl acetate in medium-chain triglycerides (MCT oil);

open circles, control infants in study of Speer et at who received oral dl-a-tocopherol

acetate in MCT oil; open triangles, control infants in study of Chiswick et al who received

no vitamin E supplementation.

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LETTERS TO THE EDITOR 329

use of early intramuscular vitamin E “appears to be prudent. . .(although). . .further prospective studies

should be performed to confirm our findings.”

MICHAEL E. SPEER, MD

ARNOLD J. RUDOLPH, MD

HELEN M. HITTNER, MD

Departments of Pediatrics and Ophthalmology Baylor College of Medicine

Houston, TX 77030

REFERENCES

1. Speer ME, Blifeld C, Rudolph AJ, et al: Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: Evidence for efficacy of early intramuscular vitamin E administration. Pediatrics 1984;74:1107

2. Phelps DL: Vitamin E and CNS hemorrhage. Pediatrics

1984;74:1113

3. Hittner HM, Speer ME, Rudolph AJ, et at: Retrolental

fibroplasia and vitamin E in the preterm

infant-Compari-son of oral versus intramuscular:oral administration.

Pedi-atrics 1984;74:238

4. Chiswick ML, Johnson M, Woodhall C, et al: Protective effect of vitamin E (dl-alpha-tocopherol) against intraven-tricular haemorrhage in premature babies. Br Med J

1983;287:81

5. Chiswick ML, Gowland M, Sims DG: Protective effect of

vitamin E against intraventricular haemorrhage in

prema-ture babies, letter. Br Med J 1983;287:617

the characteristic amino acid pattern in caseins as corn-pared with whey proteins.’ If a formula is to be produced with a protein amino acid pattern similar to that of human milk, the quantity of protein must be decreased from that of conventional formulas in use today and the whey-casein ratio of the proteins must be modified from that of bovine milk. However, it may not be necessary to produce a whey-predominant formula. If the goal of for-mula feeding is to produce a plasma amino acid pattern

similar to that found in infants fed human milk, it may also not be necessary to have a whey-predominant

for-mula. Further investigations on the effects of quantity and quality of milk proteins on the metabolic balance of normal infants are needed. Although there are good ar-guments in favor of whey-adapted formulas, until more definite clinical evidence for a clear benefit of whey-predominant formula has accumulated, it would not seem

necessary to produce such formulas for normal term

infants.

REFERENCES

NIELS C. R. RAIHA, MD

Department of Pediatrics University of Lund S-214 01 Malm#{246},Sweden

1. Raih#{228}NCR: Nutritional proteins in milk and the protein requirement of normal infants. Pediatrics 1985;75(suppl): 136-141

2. The early feeds: Human milk versus formula and bovine

milk. Pediatrics 1985;(suppl)75:157-159

Protein

Quality

in Feeding

the Normal

Infant:

Do Whey-Predominant

Formulas

Offer

Nutritional

Advantages?

To the Editor.

-In a recently published paper, I have discussed milk

proteins and the question of protein requirement of the

normal infant.’ This paper was reviewed in a summary

in the same supplement of Pediatrics.’

Because this summary contains some statements that are not in complete agreement with those in the original paper, I would like to clarify a few points concerning the

quality of protein in infant formula.

The whey proteins make up the majority, about 70%

of proteins in human milk whereas caseins are the pri-mary proteins of bovine milk. Milk-based “nonadapted” formulas have a whey-casein ratio of about 18/82 which is similar to that of bovine milk. Modern techniques have

made it possible to add demineralized whey to the milk base and modify or “adapt” the whey-casein ratio. The majority of “adapted” or “modified” formulas on the

market today are whey-predominant and have a whey protein-casein ratio of 60/40. Whey-adaptation of a milk-based formula does not, however, necessarily mean that

the formula has to be whey-predominant. Ifwhey is added to a milk base to produce a whey-casein ratio of between 20/80 and 50/50, the formula would be whey-adapted but

not whey-predominant.

The amino acid compositions of casein-predominant and whey-predominant milk proteins are different due to

Developmental

Pediatrics:

Not Just the Care

of Children with Developmental Disabilities

To the

Editor.-I am concerned about the article by Bennett et at,’ on a training program in developmental pediatrics. Although I am in agreement with all of the contents of the training program, I am concerned about the narrow definition of developmental pediatrics as only the identification and care of children with developmental disabilities. They

state that a major goal was “. . . to differentiate

develop-mental and behavioral pediatrics despite their obvious

overlaps and shared expertise” and that the primary focus of behavioral pediatrics is on the behavioral or psycho-social aspects of pediatric practice.

It is important for pediatricians to have knowledge about the diagnosis and management of children with developmental disabilities. However, I find that the dis-tinction made between developmental and behavioral

pediatrics is imprudent. Children with developmental disabilities go through the same sequence of emotional struggles during maturation as all other children. In fact, much of the counseling of parents of children with devel-opmentat disabilities is around these issues.

For me and for many others, developmental pediatrics

is a term that includes all aspects of child development

and behavior including developmental disabilities. It is

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1985;76;327

Pediatrics

MICHAEL E. SPEER, ARNOLD J. RUDOLPH and HELEN M. HITTNER