Desmopressin Acetate and Nocturnal Enuresis: How Much Do We Know?

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Desmopressin

Acetate

and

Nocturnal

Enuresis:

How

Much

Do

We

Know?

420 PEDIATRICS Vol. 92 No. 3 September 1993

M.E.K. Moffatt, MD, MSc, FRCPC; S. Harlos, MD; A.J. Kirshen, MD, FRCPC; L. Burd, MS

ABSTRACT. Objectives. Desmopress in acetate

(DDAVP) is promoted to treat nocturnal enuresis but in-dications for its use are unclear. We reviewed all random-ized controlled trials to determine (1) short- and long-term efficacy, (2) responders, (3) dose-response curve, (4) side effects, and (5) comparative efficacy with other treat-ments.

Methods. A Medline search of the English language

literature from January 1966 to August 1992,

supple-mented by contact with the drug companies, yielded 18

articles which were true randomized controlled trials (11

cross-over and 7 parallel studies).

Results. The 18 randomized controlled trials included 689 subjects for most of whom some other type of treat-ment had failed. All studies found decreased mean

fre-quency of wetting ranging from 10% to 91%, but only

24.5% of subjects achieved short-term dryness. One study

of DDAVF responders directly tested long-term dryness and 21% stayed dry. In three studies that incidentally

reported on long-term effects 5.7% stayed dry after

stop-ping DDAVP. There was wide variation in the type of

patient included. Seven studies addressed prognostic

fac-tors. Children more than 9 years old and with fewer

initial wet nights do better. Four studies seem to include almost exclusively monosymptomatic children with noc-turnal enuresis (ie, primary nocturnal enuresis, positive

family history, and no urinary symptoms). Results were

no better than those which included mixed symptoms.

Five studies attempted to address the dose-response

is-sue. Despite some methodological issues, there is

prob-ably some dose-response effect. Side effects were

infre-quent in the 589 subjects who received DDAVP as

opposed to placebo. No cases of water intoxication and no significant shifts in electrolytes were reported in the four studies which measured them. Nasal stuffiness, headache, epistaxis, and mild abdominal pain seem to be the only side effects noted, and these were uncommon.

Only one study compared DDAVP with conditioning alarms. Alarm patients had 10% fewer wet nights and a

better long-term result.

Conclusions. DDAVP reduces wet nights in children

for whom other treatments have failed but it produces complete dryness in a minority, and this is often a

tern-porary effect. The literature focuses on short-term

effi-cacy. The true role of DDAVP will be known when

sam-ples are carefully selected, prognostic factors are

examined, and more comparisons with other treatments

From the Departments of Community Health Sciences and Pediatrics, Uni-versity of Manitoba, Canada.

Received for publication Dec 21, 1992; accepted Mar 17, 1993.

This study was presented in part at the annual meeting of the Ambulatory

Pediatrics Association, Baltimore, MD, in May 1992, and at the annual

meeting of the American Academy of Pediatrics in San Francisco in October

1992.

Reprint requests to (M.E.K.M.) Department of Community Health Sciences, Faculty of Medicine, University of Manitoba, Room S100-750 Bannatyne Avenue, Winnipeg, Manitoba R3E 0W3.

are conducted focusing on long-term outcomes. On the

basis of current knowledge, DDAVP is inferior to

conditioning alarms as a primary therapy. Pediatrics

1993;92:420-425; enuresis, DDAVP, randomized controlled

trials, efficacy.

ABBREVIATIONS. DDAVP, desmopressin acetate; RCTs,

random-ized controlled trials.

In recent years, desmopressin acetate (DDAVP) has

been promoted as a therapy for nocturnal enuresis.

Reports of its efficacy date back 14 years,1 but the

impetus for wide-scale utilization has come from the

important work of a group of Danish scientists,2’3

who have further delineated the physiology of this

symptom and discovered that there are children with

nocturnal enuresis who produce a large volume of

dilute urine while sleeping and who seem to fail to

have the normal increase in secretion of antidiuretic

hormone at night. The use of DDAVP is considered a

form of hormone replacement for these children.

We reviewed the literature on this subject focusing

only on randomized clinical trials, convinced that

knowledge about efficacy and subjective side effects

can only be obtained reliably from controlled studies

with random assignment to groups. The primary

ob-jectives of the review were to determine: (1) the

short- and long-term efficacy, (2) the characteristics of

responders, (3) whether a dose-response relationship

exists, (4) the frequency of side effects, and (5) the

relative efficacy compared with other forms of

treat-ment (specifically conditioning alarms and tricyclic

antidepressants). We also had two secondary

objec-tives: to describe the quality of the research methods

used and to make recommendations for future

stud-ies.

METHODS

A literature search was performed on the Medline database for the period January 1966 to August 1992, using Silver Platter’s CD-ROM, the National Library of Medicine in Ottawa, and

Knowledge Index tapes. Key words used included DDAVP,

des-mopressin, enuresis, incontinence, random allocation, randomized clinical trial, and controlled clinical data. The bibliographies of all papers found were searched, and the pharmaceutical companies that distribute DDAVP in the United States (Phone Poulenc Rorer) and Canada (Ferring Canada, Inc) were contacted.

Studies were accepted for review if they met two criteria. The subjects entered had to have nocturnal enuresis and the study had to be a randomized clinical trial. We imposed no age limits on the

subjects. A total of 18 trials was recovered.’-42#{176} Four of these

studies were not indexed in Medline.7-13-14-2#{176} They were found in

the bibliographies of papers found through the Medline search but

were not available in usual medical library channels, and they

were obtained either directly from the author7 or from the con-tracted research agency.’3-’4-2#{176}

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

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Subject Selection

Mixed

FamHX 31%

PrevRX 1#{176}& 2#{176}

Dose Duration Mean No. of

wet nights 14 days

p D

32 7-15 0.9:1 20

No.

Totally Dryf

30 8.8 3.0 6/17 13.0

14 11.0 4.2 5/22 17.5

14 9.9 6.9 2/17 20.5

14 8.8 7.9 N/S 15.5

Alladjem1#{176} Birkasova1 Dimso&6 Ferrie8 Fjellestad-Paulsen11 Janknegt6 7 Post18 Ramsden#{176} Sukhai’2 Terho4 Tuvemo15 Wille19 Besselar13 Besselar14 Besselar#{176} Rittig7

14 8.0 4.3 8/21

14 5.8 3.8 14/24

42+ 9.4 5.0 15

28 8.0 3.2 8/18

16.5 16.0 14.0 19.5 16.0 18.0 19.0 19.0 14.0 11.0 11.0 15.0 102 7-14 77 7-14 98 6-15 20 40 20 40 40 N/S N/S N/S N/S

161 6.7 0.6

6.7 1.8

6.7 3.3

24/28 19.0

* DDAVP, desmopressin acetate; FamHx, positive family history of enuresis in most; PrevRx, most subjects have failed on imipramine,

alarms, and psychotherapy; N/S, not stated, Rx, treatment; GU Sx, genitourinary symptoms present other than enuresis; Mono, no

daytime GU Sx; P0, per Os; IN, intranasal; 1#{176},primary nocturnal enuresis subjects; 2#{176},secondary nocturnal enuresis subjects; D, DDAVP;

I, placebo.

fTotally dry for 2 weeks unless the study follow-up was shorter. Numbers in the denominators are not always equal to total N due to

losses of patients and, in parallel studies, only those who received DDAVP were included. A qualitative review of the literature was conducted according

to the criteria of Chalmers et al.21 An independent party numbered each paper and removed the authors and affiliations, the journal reference markings, the bibliography, and any other identifying marks. Each of the four reviewers then independently reviewed each paper assigning a score of 0 or I to each item. Additional qualitative information on types of subjects, enrollment

proce-dures, the number of subjects who became completely dry for a

period of at least 2 weeks, and the number who remained dry after the study medication was stopped, was tabulated by each re-viewer. Because these items were usually not primary variables or outcomes, extracting this information required careful reading of the entire paper including the introduction and discussion sec-tions. After the review, a consensus conference was held in which reasons for ratings were discussed and clarified. When consensus was not reached, differing scores were retained. Final score was achieved by averaging the scores of the four observers.

RESULTS

The characteristics and results of the 18 papers

reviewed are summarized in Table I. Altogether, 741

subjects are listed in these trials, but the study by

Post et al18 includes 52 subjects who were part of a

larger trial,20 so the total number is 689. The rationale

for including the Post study is that it gives valuable

information on total dryness and long-term

effective-ness that was not available in the report on the larger

study. Five of the studies were parallel designs, four

of which included 108 subjects who received only

placebo10’13’14’17 or conditioning alarm)9 In total

then, 581 subjects were treated with DDAVP. These

studies were remarkably similar in design. Nearly all

the studies concentrated on the short-term outcome

of mean percentage decrease in wet nights, usually

during a 2-week period. For the purpose of easy

comparison, we have recalculated the numbers in

those papers that used other than a 2-week interval.

Of the 18 studies reported, only three had significant

variations in design. These included: one comparing

DDAVP plus conditioning alarm with placebo plus

conditioning alarm,12 one open trial comparing

DDAVP with conditioning alarms during a 3-month

TABLE 1. Some Characteristics of 18 Randomly Controlled Trials Using DDAVP for Nocturnal Enuresis*

First Author and Ref.

10 & 2#{176} Failed Rx Mixed Prey Rx FamHyx PrevRx PrevRx Mono? PrevRx

1#{176}& 2#{176} PrevRx GU Sx PrevRx Mono FamHx Mono? 1 /2FamHx 1#{176}noct Mixed FamHx Mixed FamHx Mixed PrevRx Mono PrevRx DDAVP responders

N Age,y Sex

Ratio M:F

22 4-12 1.8:1 10

40(5)

17 6-13 4.7:1 20

22 9-16 1.8:1 20

30 6-15 2:1 20 in

200 po

22 6-16 4.5:1 20

40

37 9-15 N/S 10

20

52 6-16 3.3:1 40

24 >18 0.3:1 20

28 7-16 3:1 20 +

alarm

52 5-13 2.1:1 20

18 6-12 N/S 20

50 6-? N/S 20 vs

N/S

alarm

28 8-45 0.9:1 10/20

30 40 28 9.0 9.0 60 10.6 10.6 31 7.7 7.7 14 10.0 84 Baseline DDAVP Alarm 28 11.1 11.1 28 11.1 11.1 28 10.6 5.6 3/29 6.4 6.8 N/S 7.6 5.0 4/25 5.0 7.8 6 9.8 13.8 I .6 9.1 7.6 10.0 8.4 8.1 Methods Score

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Wet Nights

Per

14

Days

oPlacebo

12-loUIzI*IIIII

2 #{149}DDAVP

0.

*Estimated from a graph

422 DDAVP AND NOCTURNAL ENURESIS

period with cross-over of failures,19 and a single

long-term study comparing DDAVP for 21 weeks

with an additional 3-week block of placebo inserted

randomly.7 This latter study included only DDAVP

responders. The remaining 15 studies all compared

short, 2- to 6-week courses of DDAVP with placebo,

and all used decrease in number of wet nights as the

outcome of interest. No study used complete dryness

as the outcome of interest.

The studies were awarded scores ranging from 11

to 20.5 out of a possible 26 indicating moderate

at-tention to description of important methodological detail. Crohnbach’s a for interrater reliability before

consensus conference was 0.66. Some of the

method-ological items that were rated as well or poorly done are listed in Table 2.

Efficacy

There were 14 distinct studies which compared DDAVP with placebo only and all of them found a

decrease in wet nights when DDAVP was used (see

Fig. 1). All but one8 of these decreases reached

sta-tistical significance. Therefore, there is no doubt that

DDAVP decreases the frequency of wetting. In spite

of the broad range, we felt that there was insufficient information on patient selection to justify the perfor-mance of meta-analysis statistical techniques.

A more pertinent outcome for the patient and the

clinician is whether the child stops wetting

complete-ly. We were able to extract that information from 11 of

the studies1’4’5’2’15-18 involving 326 subjects, 80

(24.5%) of whom became dry during a 2-week

pe-nod.

Long-term efficacy after the DDAVP was stopped,

was specifically addressed in one study by Rittig et

al.7 His study included only DDAVP responders and

each received DDAVP at doses between 20 and

40 ig (the lowest dose providing maximal response)

for 21 weeks. Dryness was maintained 12 weeks after

stopping DDAVP in 6 (21.4%) of 28 subjects who

achieved dryness while on the medication. Three

ad-ditional studies gave long-term results in the

dis-10 ‘ 1 ‘16 ‘ 8 ‘11 6 17 9 4 5 15 13 14 20

Study Reference Number

Figure. Maximal mean decrease in wet nights. Fourteen

random-ized controlled trials of desmopressin acetate (DDAVP) vs placebo.

cussion section. These studies incorporated 123

sub-jects, selected by various means, but not specifically

selected for DDAVP response. Only 7 (5.7%) of those

subjects were dry 6 months after DDAVP. They had

received courses of DDAVP ranging from 48 to 60

days for study purposes. One other study11

men-tioned that 9 of 30 subjects remained dry after

dis-continuance of DDAVP, but the authors did not state

how long they observed these children and it was not

clear that this number had become dry while on

DDAVP, so these subjects were not included.

Characteristics of Responders

Seven studies4’6’7’10’’16’18 considered prognostic

indicators for response to DDAVP which included

age, sex, baseline wetting frequency, and ability to

concentrate urine while on DDAVP. Four7’10’16’18

found a better response in older children (9 or 10

years of age or more), but three studies1’4’6 found no

correlation. Four studies5’6’17’18 found a correlation between fewer baseline wet nights and superior

re-sponse, but one study did not. Two studies6’11 found

better response in subjects able to concentrate their

TABLE 2. Methodological Issues That Were Well

Desmopressin Acetate Trials

Addressed and Poorly Described in Existing

Issue Well Addressed Poorly Described

Description of #{149}Age range

subjects #{149}Sex ratio #{149}Numbers

#{149}Source

#{149}Socioeconomic status #{149}Daytime urgency

#{149}Inclusion and exclusion criteria #{149}Monosymptomatic

#{149}Number of eligibles #{149}Selection from eligibles #{149}Reasons for withdrawals

Study #{149}Description of intervention

structure #{149}Binding

#{149}Method of randomization #{149}Placebo equivalence

#{149}Comparability of subjects and controls in parallel studies

#{149}Equal comorbidity

#{149}Acceptability of treatment to parents and children

Outcomes #{149}Clearly specified

#{149}Method of measuring outcome

#{149}Reporting of all side effects #{149}Long-term follow-up

Analysis #{149}P value significance #{149}Confidence intervals

#{149}Appropriate handling of dropouts

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morning urine to greater than 1000 mosm/L while

on DDAVP. Sex was examined in two studies4’18 and

not found to correlate. Weight4’6 did not predict

re-sponse. One study examined each of the following

characteristics and found no correlation: heredity,

birth rank,18 birth weight,18 maternal age and

pan-ty18 and broken vs intact homes.16

The term monosymptomatic nocturnal enuresis

was used in the literature to refer to patients who wet

the bed while sleeping but do not have bladder

symptoms such as urgency, frequency or dysunia, or

daytime wetting. Only the study of Rittig et al7 used

this criterion for entry. Four studies appear to have

entered mostly monosymptomatic subjects,’7

al-though it was not a stated criterion for admission.

When the paper by Rittig et al is eliminated from the

monosymptomatic group because only responders

were included in that study the mean decrease in wet

nights per fortnight in the other three studies was 4.0

± 0.3. The decrease for 11 studies which included a

variety of types of subjects was 3.2 ± 1 .8. The

stan-dard deviation was much larger in the latter group,

indicating wide variability. However, we emphasize

that one of the major weaknesses in this literature is

the absence of a clear description of the subjects.

Dose-Response Relationship

Five studies6’13’14’17’18 attempted to address the

is-sue of whether more is better. Janknegt and Smans6

assigned 22 subjects to randomly allocated blocks of

4 weeks each on placebo, 20 pg and 40 pg. Both doses

reduced wet nights more than placebo, but there was

no difference in the amount. In fact the lower dose

had a slightly better record. Three other studies13’14’18

used multiple single-dose levels, randomly assigned,

and found the higher dose to be more effective.

Ped-erson et al17 used two doses, 10 and 20 pg. and found

the higher dose to be slightly better.

Side Effects

All 18 studies mentioned measuring side effects.

Eight1’4’5’9’10’15’17’18 reported no adverse effects.

Two6’7 reported headache in four subjects, and one

reported stomach ache in three subjects. Body

weight and blood pressure were measured

repeat-edly in 13 studies.4-9,11,13-16,20 Rittig et al7 reported

one subject with borderline hypertension and

fluc-tuating weight. This subject had obesity as a pretrial

state. Fjellestad-Paulsen et aP1 reported

treatment-related weight gain only in subjects receiving 400 pg

orally in the dose-response part of their study. All

other studies showing weight gain while on

treat-ment were able to attribute it to growth rather than

treatment. Four studies measured serum sodium

re-peatedly7’9’11’15 Fjellstad-Paulsen et al11 during a

study comparing oral (200 jig) with nasal (20 jig),

reported 3 of 30 subjects with serum sodium

de-creasing to the 125 to 130 mmol/L range. The other

three authors reported no changes. No cases of

wa-ten intoxication were reported in these studies.

Episodes of epistaxis were reported by two

au-thors.8’19 Both these studies were performed using a

nasal pipette which could have been responsible for

trauma. Will&9 reported nasal stuffiness in 13% of

his subjects.

Comparison with Other Treatments

Two of the clinical trials involving DDAVP

incor-porated another form of therapy, although many of

the subjects had previous treatment failures with

conditioning alarms or imipramine. The study of

Sukhai et aP2 did not compare the two, but rather

compared alarm plus placebo with alarm plus

DDAVP. A single study by Wille15 compared alarms

with DDAVP. He found a quicker response in the

DDAVP group, but after 6 weeks on treatment, the

alarm-treated subjects consistently had more dry

nights than those on DDAVP; and after 14 weeks of

treatment, when both therapies were withdrawn, the

relapse rate in the DDAVP group was significantly

higher.

No studies have compared DDAVP with tricyclic

antidepressants.

DISCUSSION

We reviewed randomized clinical trials because we

believed that that is the only way to obtain

informa-tion about the efficacy of any treatment. Information

on the types of patients who will respond to a

med-ication can be obtained from other types of studies.

Some might argue that it is difficult to do long-term

studies with DDAVP in the form of a randomized

controlled trial (RCT), but we believe that this would

be feasible if the comparison group received one of

the other commonly used treatments. There is a vast

literature on the conditioning alarm, reviewed in

sev-eral useful papers,2224 which shows that it is

effec-tive in 70% of children and that relapse rates can be

reduced to about 10% to 15% if ovenlearning is used.

We believe that a long-term study comparing these

two treatment modalities would be feasible if

sub-jects who were failures on treatment with either

mo-dality were considered as failures and crossed over to

the opposite treatment at the point when they are

considered failures. In the design of future studies,

careful consideration should be given to some of the

methodological issues which we found to be

per-formed poorly (see Table 2). The literature produced

thus far does not show DDAVP to be a cure for

enuresis when given for 2 to 21 weeks. At least two

uncontrolled studies have used DDAVP in this

man-ner for periods of 12 months or longer.25’26 These two

inadequately describe subject selection to determine

who responds. They both had a higher response rate

than any of the RCTs, and thus probably represented

a selected sample of enuretic children. More than half

the children became completely dry, and

complica-tions were rare in these long-term subjects.

Unfortu-nately, it is impossible to generalize from

uncon-trolled studies. However, these studies provide some

rationale for the development of RCTs which use

long-term DDAVP as one treatment choice.

The reduction in wet nights that has been used in

all the studies thus far as the major outcome does not

seem to be the most clinically relevant outcome.

When achievement of complete dryness is examined

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424 DDAVP AND NOCTURNAL ENURESIS

it appears that only one quarter of the children

in-cluded in the studies reviewed achieved this. The

studies appear to have included a wide variety of

types of subjects, many of whom had failed with

other forms of treatment. At least thre&’16’18 included

some subjects with secondary enuresis who would

probably not be expected to respond. Generally, they

were also not well enough described, particularly in

terms of their daytime voiding habits and bladder

capacity. Some of the subjects included probably had

small bladder capacities and difficulty with daytime

voiding control which could make them unsuitable

candidates for DDAVP therapy.

The narrow range of scores on the methodology

scale reflects the high degree of uniformity in these

studies. It seems that most of these studies were done

with the goal of satisfying pharmaceutical regulating

agencies about short-term efficacy and safety. There

is a clear need for more studies to be done with

clinical relevance in mind, such as the ones by Wille19

and Rittig et al.7

Safety is an issue in this research. In the group as a

whole, side effects seem to have been fairly minor

and infrequent. They consisted of headache,

abdom-inal pain, nasal stuffiness, and epistaxis. The latter

has only been reported in studies which

adminis-tered the drug intranasally with a polyethylene

cath-eter. This may have been responsible for trauma.

Since the drug is now administered by a metered

dose aerosol, this may no longer be a problem. The

absence of serious side effects in these 741 subjects,

however, does not rule out the possibility of rare

cases of more serious side effects. The one that is

most feared is water intoxication. In healthy children

and adults this is probably rare, but it is more likely to happen in children with problems of

osmoregula-tion (eg, brain-damaged children) or those with

elec-trolyte-losing disorders such as cystic fibrosis. If the

use of this drug becomes more widespread, it will

inevitably be administered to children who fall into

these categories, and water intoxication may be

re-ported more frequently.

The rationale for using DDAVP is based on the

important discovery by Norgaard and colleagues,2

that some children with nocturnal enuresis produce

high volumes of urine with low osmolality at night,

and do not have an increase in their night-time

se-cretion of antidiuretic hormone. To date we do not

have population-based studies which have

deter-mined how common this pattern is, and we do not

know whether it is only these patients who respond

to DDAVP. Much more research needs to be done in

this area. Important as this discovery is in explaining

the physiology of nocturnal enuresis, considering

this to be the cause of enuresis is an

oversimplifica-tion of a complex problem. When discussing the

pathophysiology of bedwetting with parents and

children, we use a two-factor model. To wet the bed, a child has to both overifil his bladder capacity and be

unable to arouse from sleep to the stimulus of a full

bladder. This latter is the natural state of infants and

is probably resolved by a learning or a

developmen-tal process. We feel that conditioning alarms assist

this learning process in children who have otherwise

been unable to achieve it spontaneously. There is no

scientific proof for this model, but it matches clinical

experience. Research directed at determining the

prevalence of antidiuretic hormone secretion pattern

abnormalities, the response of such children to

con-ditioning, and the changes in their antidiuretic

hor-mone pattern or their bladder capacity with

treat-ment would help clarify this issue.

In summary, the RCT literature on DDAVP has

indicated that it is effective in reducing the number

of wet nights, but that only about one quarter of the

subjects studied became completely dry. A small

pro-portion of responders remained dry after the

medi-cation was withdrawn. Thus, DDAVP as used in

these studies seems to be a symptomatic treatment.

There are not enough studies that used lengthy

courses of DDAVP to know whether this is a

reason-able and safe way to relieve the symptom until it

spontaneously resolves, or whether long courses

could result in a reset of regulation of the

hypotha-lamic-pituitary axis resulting in a more normal

an-tidiuretic hormone secretion pattern. Side effects to

date appear to be infrequent and minor, but rare

serious side effects will only be known after much

longer and wider experience. Dose-response

rela-tionships probably exist but more work needs to be

performed in this area. There are a number of

meth-odological issues which need to be addressed in

fu-ture studies (see Table 2). There is no justification for

more short-term studies. DDAVP should be

com-pared carefully with other effective treatments,

espe-cially conditioning, in longer trials with families who

are willing to undergo randomization.

ACKNOWLEDGMENTS

The corresponding author (M.E.K.M.) was supported by the Manitoba Medical Services Foundation (MMSFI) through a

Clin-ical Research Professorship. Research support was provided by

the Children’s Hospital of Winnipeg Research Foundation and

MMSFI.

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PEDIATRIC EDUCATION IN COMMUNITY SETTINGS

CALL FOR PAPERS

Papers describing educational experiences are being solicited for a manual on

pediatric education in community settings. Submissions, not to exceed 5 pages,

should identify strengths in one or more of the following areas: structure, faculty,

development, evaluation, and financial support. Creative and innovative

ap-proaches are encouraged. Submit papers by September 30, 1993 to Thomas G.

DeWitt, MD, Department of Pediatrics, University of Massachusetts Medical

Cen-ten, 55 Lake Avenue North, Worcester, MA 01655. Additional information may be

obtained from either Dr. DeWitt (508-856-2294) or Kenneth B. Roberts, MD

(508-856-3590).

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1993;92;420

Pediatrics

M. E.K. Moffatt, S. Harlos, A. J. Kirshen and L. Burd