Letters to the Editor

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LETTERS TO THE EDITOR 151 avenues of influence ought to receive more attention.

JOHN E. STRAWBRIDGE, PHD

Department of Psychology

Memorial University of Newfoundland

St John’s, Newfoundland, Canada

REFERENCES

1. Rush D, Stein Z, Susser M: A randomized controlled trial of

prenatal nutritional supplementation in New York City.

Pediatrics 65:683, 1980

2. Miller DJ, Ryan EB, Short EJ, et al: Relationships between

early habituation and later cognitive performance in infancy.

Child Dec 48:658, 1977

3. Maccoby EE, Dowley EM, Hagen JW, et al: Activity level and intellectual functioning in normal preschool children.

Child Dec 36:761, 1965

To the

Editor.-On the basis of 13 premature births to mothers who were given cans of protein-rich supplement, Rush et al

(Pediatrics 65:683, 1980) conclude that “. .. the

supple-ment produced growth retardation.” The data do not

support this conclusion.

The authors calculate that women on the protein

sup-plement actually increased their mean daily caloric

in-takes by only 261 calories to 2,326-still below the

Rec-ommended Daily Allowances (RDA) for the average

preg-nant women (AND the malnourished one). Furthermore,

those 13 women on protein supplemention who delivered

prematurely were noted to have further reduced their calories to a mean of 1,523 daily, or only two thirds of the RDA. I suggest that it was not protein supplementation that produced growth retardation, but rather calorie mal-nutrition.

Not only do Rush et al say that protein

supplementa-tion is “dangerous,” but they also conclude that any

further “human intervention studies be resumed at a later stage,” as if calorie supplementation was also, somehow, “dangerous.” This is also not supported by their data.

The calorie-supplemented women had an incidence of

only 11.7% of infants weighing under 2,500 gm while the

unsupplemented women had an increase of 16.3% of

un-derweight babies. This difference was not significant, in part because of small numbers in the study and control groups. In part, however, the lack of result was due to the fact that supplementation was not adequate.

The canned supplements were not the type of food

poor black women like to eat. These women will eat more

foods from their own range of dietary choices, foods that they fmd tasty. My experience in a similar study was that

the women knew their urine was being checked to see

whether they drank the formula, and so they simply

drank some on the morning of their appointments. They

gave the rest of the canned supplement to their malnour-ished toddlers, or they used it in cooking as a soup base or in macaroni and cheese, or they gave it to poor

neigh-bors and friends.

Other, better-designed studies have shown that supple-mentation improves outcomes of infants among impov-erished women.’6 This study involved inadequate sup-plementation, poor compliance measures, and utterly

baseless conclusions. If effective supplementation

pro-grams pay heed to this study, it will be a blight on science.

REFERENCES

MADELEINE H. SHEARER, RPT

Editor

Birth and the Family Journal

1 10 El Camino Real Berkeley, CA 94705

1. Mora JO, et al: Nutritional supplementation and the out-come of pregnancy. III. Obstet Gynecol Surv 34:437, 1979 2. Lechtig A, et al: Effect of food supplementation during

pregnancy on birthweight. Pediatrics 56:508, 1975

3. Adams SO, et al: Effect of nutritional supplementation in

pregnancy. J Ajiz Diet Assoc 72:144, 1978

4. Habicht JP, et al: Evidence for fetal malnutrition in the human: An intervention study. Nutr Rep Int 7:533, 1973 5. Edozien JC, et a!: Medical evaluation of the special

supple-mental food program for women, infants and children. Am J Clin Nutr 32:677, 1979

6. Higgins AC, et al: Nutrition and the outcome of pregnancy.

In Proceedings of the Fourth International Congress of

Endocrinology, 1972. Washington International Congress

Series No. 273. Princeton, NJ, Excerpta Medica, pp 1071-1077

In

Reply.-Dr Strawbridge says that in our summary paper de-scribing a randomized controlled trial of prenatal nutri-tional supplementation’ we draw conclusions not demon-strable by the conventions of statistics and logic. We can

only reply that levels of significance must be understood to be no more than conventions: they cannot substitute for scientific coherence and judgment. Strawbridge fails to distinguish between the strength or magnitude of an association and its statistical significance. Significance is

a function both of magnitude, and of the number of

observations. Thus, when numbers are large, effects of very small magnitude, and of ultimately trivial impor-tance, can be highly significant. Conversely, with small

numbers strong effects of great biologic importance may

not reach conventional levels of statistical significance. What Strawbridge claims we said, and what we actually

said, are not the same. With regard to premature

deliv-eries and neonatal deaths, life table curves afford, we think, the most appropriate comparisons. (We do not

anywhere refer to the perinatal deaths mentioned in Strawbridge’s letter.) In these comparisons, it is true, in the supplement group neither the excess of very early premature delivery nor neonatal death attained the con-ventional significance level of P < 0.05. To reiterate,

significance levels are conventions. They can be used to suit differing interpretations as is demonstrated by the data in our table 4: in a different and less sophisticated analysis, the excess of neonatal death in the supplement group is in fact significant. The association can therefore well be described-in our words-as “at the margins of statistical significance.” Given the magnitude and impor-tance ofthe result, as well as its coherence with the highly

significant depressed birth weight among the entire pre-mature group on high protein supplement, we chose to

interpret it as unlikely to have arisen by chance, and

certainly as a caution against high protein supplementa-tion. Likewise, we reported that the relationship between the balanced protein-calorie complement and length of gestation was not a strong one. Strawbridge implies we are inconsistent in doing so. This difference, too, however,

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152 PEDIATRICS Vol. 68 No. 1 July 1981

was not significant in the comparisons between the life

tables of delivery rates among the three treatment groups. This is not to deny a possible, if small, beneficial effect of such supplementation.

We did not “claim” that the prematurely born in the

supplement group were significantly lighter, as

Straw-bridge says we did, but merely reported the relevant

observations with the appropriate statistics. We wonder

whether Strawbridge sees the data otherwise, and if so, how?

As to the relation of a history of past low birth weight delivery and birth weight, the numbers of past low birth

weight deliveries among multiparae were correlated with

birth weight, by treatment, as follows: in the supplement group, r = -.32 (P < .001); in the complement group, r = -.23 (P < .01); and in the control group, r = -.20

(P < .05). These correlations taken together with the results in our figure 4, suggested to us that “This risk was

exacerbated in the supplement group,” and we still find that conclusion a reasonable one.

With regard to the potential significance of the effects of high protein supplementation on aspects of perform-ance at 1 year of age, we in no way intended to underplay

the findings. Indeed, we were disappointed that none of

the commentaries published with the paper commented

on the result, and we are pleased that at least in this

matter Strawbridge has drawn attention to a finding that we believe could have profound significance. We hope that significance will be tested in future studies.

Strawbridge argues that we are not justified in stating that the high protein supplement retarded fetal growth among premature infants. Strawbridge does not escape the issue by his argument. Excepting failures of random-ization (which there is little to suggest) and flaws of execution, differences in the dietary behavior ofthe

moth-ers who delivered prematurely that may account for the growth retardation must, by the canons of experimental logic, be imputed to the treatment assignment.

Both Strawbridge and Shearer misread our data on

dietary intake. There were not 13 but 51 women who delivered prematurely in the supplement group (our

fig-ure 3). The 13 women are those who had delivered very

prematurely (before 33 weeks gestation) and for whom we had diet recalls. They took the supplement, but di-minished their total dietary intake. We infer that very early delivery could have followed lowered dietary intake, with anorexia caused by the protein supplementation. However, fetal growth retardation in the supplement group was consistent and significant at all stages of

premature delivery, up to and including delivery near

term. Between 33 and 36 weeks’ gestation, fetal growth retardation occurred in the absence of any reported sup-pression of total caloric intake. Thus, whereas low caloric

intake could be implicated in the excess of very early

delivery and neonatal death, it could not be implicated in the growth retardation among later premature deliveries. These data are more fully presented in our recently published monograph.2 A calmer reading of our paper and the monograph might also persuade Shearer that we do not think that any hazard attaches to calorie supple-mentation.

Shearer suggests that the study might have turned out

as she would have expected if supplementation had been

adequate. She points out that the intake of 2,326 calories per day reported by the supplement group is lower than the current Recommended Daily Allowance (RDA). This does not explain worse outcome in the supplement group

than control group: ifthe RDA of 2,400 calories is optimal, the 2,326 calories taken by the supplement group should

certainly produce better results than the 2,065 calories

taken by the control subjects, which it did not. Like Jacobson in the commentary3 that accompanied our report, Shearer thinks that the cans of supplement beverage might have been diffused among others, and

therefore might not have had the desired effect. We

argued previously that any diffusion-unlikely as it was

given the type of supplement and the precautions we took against it-would tend to minimize the differences be-tween groups, and could not be implicated to explain adverse outcome.4 Shearer also states that women would

modify their behavior with the knowledge that urine was

being checked and that our reliance on this measure of compliance was misplaced. In fact, our analyses for ribo-fiavin were done on urine collected for routine clinical

purposes; the laboratory assay of riboflavin concentration as a marker of intake was not announced to participants. But in any event, we did not rely on any single measure for monitoring intake, and several were used.

Shearer’s reference to the existence of other, better designed studies with differing results is, in our opinion, not supportable. We have reviewed both the study de-signs and the results of published studies that were ade-quately controlled. A statement will be found in the final chapter of our book on the project2 and has been further

extended in a more recent review.5 As to design, on

objective grounds we think that, given limited if reason-able resources, the technical aspects of our own study design could not, at the time of launching, have been much improved on. For instance, no other study combines the several crucial design features of a double-blind ap-proach with mutiple methods of monitoring intake (in-eluding biochemical) and a sample size capable of detect-ing an increment in birth weight in the range that is coherent with the likely effects of maternal nutrition on fetal growth. As to results, what is remarkable is the consistency of our results with those of other studies of strong design (as judged by objective standards of exper-imental procedure about which there can be little argu-ment). None of these yields results that differ from ours in any essential respect. This correspondence applies even to the untoward effects of high protein supplementation on birth weight, as well as to the rather small favorable effect on birth weight that one can anticipate from bal-anced protein-calorie supplements. (This is illustrated in the Table in our previous reply,4 in which the references were omitted-printer’s error.)

For example, the well designed study of Mora et al6 found only a difference of 51 gm birth weight with sup-plementation, not statistically significant on a two-tailed test, and quite comparable with our results. The results of Higgins’ work and Adams et al were similar to ours. We have recently completed an evaluation of the effect of Higgins’ program on birth weight7 and have found a significant, but small, difference in birth weight between those receiving dietary services and a group of compara-ble public patients matched on several characteristics.

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LETTERS TO THE EDITOR 153 The magnitude of difference, 40 gm, is nearly identical

with the nonsignificant difference between our comple-ment group and the control group. Adams et al8 used the

supplements developed for our study. Although they

could only study a very small population and results were not statistically significant, they too found, with supple-ment, depressed birth weight (45 gm), and with comple-ment, an increment (92 gm).

We have previously noted our reservations concerning the study of Edozien et al.4’5 In the Guatemalan study of

Habicht et al, levels of supplementation were at the

choice of the subject, and the rigor of studies that permit this bias of self-selection is not as great as studies in which the investigator determines to which subjects sup-plementation is to be given.9 An overestimate is the more

likely in the Guatemalan study because length of

gesta-tion was not closely controlled in the analysis of the dose-effect of supplementation: thus, the later the delivery, the more the dietary intake and the higher the birth

weight-and vice versa. We do not know how much confounding

resulted, but in our view there is bound to be an overes-timate of the nutritional effect.

The results of our study controvert many of our own

starting assumptions and initial hypotheses. We expected, and would certainly have preferred, a different outcome. We tested and reanalyzed our results in many ways before we committed ourselves to them.

DAVID RUSH, MD

ZENA STEIN, MA, MB, BCH

MERVYN SUSSER, MD, BCH, DPH, FRCP(E)

Developmental Epidemiology Research Unit Division of Epidemiology

School of Public Health Columbia University 100 Haven Aye, 5A New York, NY 10032

REFERENCES

1. Rush D, Stein Z, Susser M: A randomized controlled trial of prenatal nutritional supplementation in New York City. Pediatrics 65:683, 1980

2. Rush D, Stein Z, Susser M: Diet in Pregnancy: A Random-ized Controlled Trial of Nutritional Supplements. New York, Alan R Liss, 1980

3. Jacobson HN: A randomized controlled trial of prenatal nutritional supplementation. Pediatrics 65:835, 1980

4. Rush D, Stein Z, Susser M: Controlled trial of prenatal

nutrition supplementation defended. Pediatrics 66:656, 1980

5. Rush D: Effects of changes in protein and calorie intake

during pregnancy on the growth of the human fetus, in Chalmers I, Enkin M (eds): Effectiveness and Satisfaction in Antenatal Care, Clinics in Developmental Medicine Se-ries. London, Spastics International Medical Publications, in

press 1981

6. Mora JO, de Paredes B, Wagner M, et al: Nutritional

sup-plementation and the outcome of pregnancy. I. Birth weight. Am J Clin Nutr 32: 455, 1979

7. Rush D: Nutrition services during pregnancy and

birth-weight: A retrospective matched pair analysis. Can Med

Assoc J,in press 1981

8. Adams SP, Barr GD, Huenemann RL: Effect of nutritional supplementation in pregnancy. JAm DietAssoc 72:134, 1978

9. Habicht JP, Lechtig A, Yarbrough C, et al: Maternal

nutri-tion, birth weight and infant mortality. Ciba Found Symp

27: 1974

Sepsis Screen Questioned

To the

Editor.-The article by Philip and Hewitt (Pediatrics 65:1036-1041, 1980) on the early diagnosis of neonatal sepsis was interesting, but their conclusions may be misleading. They demonstrated that when at least two of five screen-ing tests were positive (band/total neutrophils, leukocyte counts, latex C-reactive protein, erythrocyte sedimenta-tion rate (ESR), and latex haptoglobin), neonatal sepsis could be accurately predicted in 28 of 30 (93%) infants. Two or more tests were also positive for 43 of 346 (12%) infants without proven sepsis. Of the 71 infants with two

or more positive tests, 28 (39%) had proven sepsis. In

addition, Philip and Hewitt stated that when less than two tests were positive, the probability that sepsis was not present was 99% (303 noninfected infants/305 infants with <2 positive tests). This last observation was the basis of their recommendation that the tests should be used as a screen to identify noninfected infants. However, if the tests were always negative, then the probability that sepsis was not present would be 92% (346 noninfected infants/376 infants with negative tests). Obviously this is just playing a statistical game, but I submit that the predictive value of a test (eg, 92% or 99% prediction of

noninfected infants) must consider the prevalence of

dis-ease in the population-the essence of Bayes’ theorem.

PATRICK R. MURRAY, PHD

Division of Laboratory Medicine

Washington University School of Medicine 660 S Euclid Ave

St Louis, MO 63110

In

Reply.-Dr Murray is quite right to point out that some caution is required in interpreting a “sepsis screen,” but it depends

upon how one approaches the problem. Because the

prevalence (strictly speaking, the incidence) of “proven sepsis” was 8%, an increase to 40% probability of infection is a fivefold increase. The incidence of “not having proven

sepsis” was 92%, so that the increase to 99% (actually 99.5%) probability of not having infection implies only a slight improvement in our predictive capability. However, the assessment is to detect neonatal sepsis and so the probability of sepsis decreases from 8% to less than 1% (at least an eightfold decrease).

Thus, positive tests seem more helpful than negative tests in deciding who is or is not infected, when looked at in one way, but not in another. Those infants with “very probable” infection contribute to the dilemma, but (as stated in the last paragraph of the paper) the tests should “provide valuable adjunctive information in making de-cisions about antibiotics.”

ALISTAIR G. S. PHILIP, MD

Department of Pediatrics Division of Neonatology Evanston Hospital

2650 Ridge Ave

Evanston, IL 60201

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1981;68;151

Pediatrics

David Rush, Zena Stein and Mervyn Susser