PAPERS

Meta-analysis of efficacy ofquinine for treatment ofnocturnal legcramps in elderly people

Malcolm Man-Son-Hing, George Wells

AbstractObjective-To assess quantitatively the efficacy of

quinine (as quinine sulphate) compared with placeboin the treatment ofnocturnal leg cramps.Design-A meta-analysis of six randomised,

double blind, crossover trials.Setting-Randomised trials that were available as

ofApril 1994.Subjects-A total of 107 general ambulatory

patients who suffered from regular nocturnal legcramps from six clinical trials.Results-Data from individual patients were used

to calculate point estimates and 95% confidenceintervals for each of the outcome measures reportedby these studies. Treatment with quinine resulted ina significant reduction in the number ofcramps for afour week period compared with placebo (8.83 fewercramps; 95% confidence interval 4*16 to 13.49).Treatment with quinine reduced the number ofnights with cramps by 27.4% (24.0% to 30/8%)compared with placebo. Treatment did not producea significant change in the severity or duration ofindividual nocturnal leg cramps. Side effects wereuncommnon.Conclusions-The results indicate that quinine

can prevent nocturnal leg cramps in general ambu-latory populations. Given the possible serious sideeffects of treatment with quinine, the benefits andrisks in patients taking this drug should be closelymonitored.

IntroductionNocturnal leg cramps are painful involuntary

muscle cramps that occur when the patient is recum-bent. They are an extremely common complaint inelderly people. In one survey over 70% of elderlypeople had leg cramps at night at one time or another.'Many treatments, both non-pharmacological andpharmacological, have been attempted for this con-dition. Non-pharmacological treatments includedwalking, stretching, and massage.2 Pharmacologicaltreatments that have been reported include calciumchannel blockers,3 vitamin E,4 and quinine (as quininesulphate).

Quinine has been suggested as the most effectivepharmacological treatment available.5 The first reportof beneficial effects of quinine was in 1940.6 In fact,most of the trials investigating drug treatment fornocturnal leg cramps in elderly people have studied theefficacy of quinine. Interestingly, the results of thesestudies have been mixed despite similar patient popu-lations. Moreover, there have been increasing numbersof reports of side effects including pancytopenia,7cinchonism,' and visual toxicity.9 We therefore under-took a meta-analysis of the efficacy of quinine for thetreatment of nocturnal leg cramps in ambulatorypeople.

MethodsIDENTIFICATION OF RELEVANT CLINICAL STUDIES

To identify all published studies we carried outa computerised literature search by using MEDLINE(January 1966 to April 1994) and EMBASE (January1975 to April 1994) databases. The key words quinine,muscle cramps, and legs were used to locate relevantarticles. We then searched Current Contents fromJanuary to April 1994 for further trials. We alsoreviewed the references of all relevant articles found byour search, studied relevant textbooks, and spoke toauthorities about any published and unpublished workthat they might be aware of.

Before this search we decided to include in the meta-analysis only those studies that met the followingcriteria: randomisation of patients; double blind,placebo controlled, crossover design; and a generalambulatory population (that is, non-dialysis patients).A crossover design was part of the inclusion criteria fortwo related reasons: firstly, by removing differencesbetween subjects it allows analytical techniques thatincrease the statistical power of the analysis; and,secondly, before we started this study the only relevantrandomised trials we were aware of had a crossoverdesign.With access only to photocopies of the methods

section of each article, potentially eligible trials wereassessed by four independent people blinded to thestudy for fulfilment of the above inclusion criteria. Forthe clinical trials that met all inclusion criteria butdid not include data on individual patients in theirpublished reports we contacted the respective authorsin an attempt to obtain these data.

DATA EXTRACTION

We obtained from each study the following informa-tion: number of patients, sex, age range, criteria foreligibility, setting, dose of quinine, length of treatmentperiod, presence of a washout period, presence of sideeffects, and outcome measures used. Data extractionwas performed by two independent assessors. Anypoints of disagreement were settled by collaborativereview.

META-ANALYSIS

By using the data on individual patients for eachstudy we calculated a point estimate and 95% confi-dence interval for the efficacy of quinine (as quininesulphate) compared with placebo by using paireddifferences for the following outcomes: reduction innumber ofnocturnal leg cramps for a four week period;severity of nocturnal leg cramps; duration of nocturnalleg cramps; and cramp index (duration x severity of legcramps).One way analysis of variance was used to test for

homogeneity. Again with data on individual patientsrelevant studies were combined to produce a bestestimate (95% confidence interval) for each of the

BMJ VOLUME, 310 7 JANUARY 1995

Division ofGeriatricMedicine, University ofOttawa, GeriatricAssessment Unit, OttawaCivic Hospital, Ottawa,Ontario, Canada K1Y 4E9Malcolm Man-Son-Hing,assistant professor ofmedicine

Department ofMedicine,University ofOttawa,Clinical EpidemiologyUnit, Ottawa CivicHospital, Ottawa, Ontario,CanadaGeorge Wells, associateprofessor

Correspondence to:Dr Man-Son-Hing.

BMJ 1995;310:13-7

13

above outcome measures. For the outcome measure ofnumber of nights with cramps, analysis was performedby X2 tests to compare rates as data on individualpatients were not available.

ResultsSYSTEMATIC OVERVIEW

Eleven potentially eligible clinical trials were identi-fied through the computer literature search. Despiteexhaustive searching for other published and un-published relevant trials none could be found.There was cormplete agreement among the four

independent assessors on which trials met all inclusioncriteria. Five trials did not meet these criteria and wereexcluded (table I).'0-'4 The six remaining trials wereincluded in the meta-analysis.-'5-0 Three of these trialsdid not publish data on individual patients. We weresuccessful in obtaining outcome data but not demo-graphic data for individuals from the authors for two ofthese studies.

TABLE i-Trials excluded because all criteriafor inclusion not met

Criteria for eligibility

GeneralRandomised Double Drug vs ambulatory

Reference patients blinded Crossover placebo patients

Kaji eta84 8/ 8/ 8/Limnetal" -a/ - 8/ 8/Baltodano et aP° - - / - 8/Gorlichera/2 NJ 8/ -a/Roca etal" 8/ 8 - - -

Adherence to the data extraction process resulted incomplete agreement between the two assessors. TableII summarises the six trials included in the meta-analysis and relevant information about each.

META-ANALYSIS

Absolute change in number ofnocturnal leg crampsfor afour week period (fig 1)

Five of the six eligible studies reported the absolutechange in the number of cramps while the subjectswere taking quinine compared with placebo as anoutcome measure. Because each study had treatmentperiods with varying lengths of time, studies thatdid not have treatment periods of four weeks werestandardised to the number of cramps experienced in afour week period. The standardisation method usedwas to increase proportionately the number of crampsexperienced by each individual patient in a study withtreatment periods less than four weeks. For example, ifa study had a two week treatment period the number of

-.371Sidorov20 (n= 16) 1_

2 Connolly et al18 (n=27) 1 .17.56-7.37

3 Fung et all7 (n=8) .-7.4 Warburton et a!16 (n=22) 18.08

-8.83Studies 1-4 combined (n=73) 1

5 Hypothetical Jones et aPs (n=9) 1 0

(see table IV) -8.30Studies 1-5 combined (n=82)

-28 -24 -20 - 6-I2i 40 4 8 2Change in No of cramps a week

FIG 1-Absolute change in number ofcramps in patients taking quininecompared with placebo (four week period)

cramps experienced in each treatment period wasdoubled to simulate a four week treatment period. Thelongest treatment period of any relevant study was fourweeks.These data show that there are two individual trials

in which a significant reduction in the number ofcramps was obtained in patients taking quininesulphate compared with those taking placebo and twothat did not. Combination of the results of these fourtrials showed that the use of quinine resulted in asignificant reduction of 8-83 (950/o confidence interval4-16 to 13-49) nocturnal leg cramps in a four weekperiod.Data on individual patients from one study were not

available.'5 As a form of sensitivity analysis we used thepublished information provided by this clinical trialto derive a hypothetical set of results for individualpatients (tables III and IV). These results were derivedsuch that the maximum standard deviation possiblefor the given parameters of the data was created. Wethen combined this "worst case scenario" with the fourother studies. The result was similar (8-30 (3-85 to12-75) fewer nocturnal leg cramps in four weekswith quinine) to those obtained without the addition ofthe derived data.

TABLE s--Information used in meta-analysis from double blindcomparison of quinine sulphate and placebo carried out in 1983 byYones and Castleden"

Detail Quinine Placebo

Average No ofcramps over two weeks 3-6 5 6Range 0-20 1-15Distribution Four patients had -

no cramps

Total No ofcramps over two weeks 3-6 x 9 5-6 x 9patients patients-32-4 -50 4

TABLE II-Relevant characteristics oftrials included in meta-analysis

Outcome measures

Sex Mean age Length of No of No ofNo of (range) Dose (mg) treatment Washout cramps/ Severity of Duration nights with

Reference (year) patients Men Women years Eligibility Setting ofquinine period period unit time cramps ofcramps cramps

Jones et al (1983)' 9 ? ? ? (elderly) >Two General 300 At Two weeks 8f / 8/ /cramps a practice bedtimeweek

Warburtonetal(1987)'6 22 6 16 78 (SD8) >Two General 300At Threeweeks - ./ * *cramps a practice bedtimeweek

Fungetal(1989)' 8 1 7 63 (47-81) >Two Intemal 200At Fourweeks 8/ / / 8/ -cramps a medicine bedtimeweek clinic

Connollyetal(1992)8 27 27 0 59 (38-73) > Six cramps General 200 supper Four weeks / >/ / - 8/on survey medicine 300 At

clinic bedtimeDunn (1993)' 25 ? (about ? (about 67 (51-82) Received General 300/day 30 Days - - - -/

equal) equal) regular practicequinine

Sidorov (1993)20 16 2 14 585 (29-85) >Two Intemal 200 At Two weeks 8/ / 8/ 8-cramps a medicine bedtimeweek clinic

*Severity and duration ofcramps combined into measure called cramp index.

BMJ voLuM 310 7JANuARY 1995

............... ......

.H

TABLE tv-Data for individual patients derived from infornationgiven in study ofJones and Castleden." Values are numbers ofcramps

StandardisationDifference over to four week

two weeks treaunent periodPatient Quinine Placebo (quinine-placebo) (quinine-placebo)

1 20 1 19 382 9-4 1 84 1683 1 1 0 04 1 1 0 05 1 1 0 06 0 1 -1 -27 0 14-4 -14-4 -28-88 0 15 -15 -309 0 15 -15 -30

Total 32-4 50-4Mean -2-0 -4 0

*See also table III.

Change in severity ofindividual nocturnal leg cramps(fig 2)

Five studies used the severity of nocturnal legcramps as an outcome measure. One study, however,combined the reporting of severity and duration intoone measure called the "cramp index" and thusindividual severity scores were not available.'6 Also, asstated before, individual results from one study couldnot be obtained.'5 Therefore, three studies were avail-able to assess the efficacy of quinine to reduce theseverity ofindividual cramps.

Sidorov20 (non-rounded)(n= 16)20 , I0.060.125

Sidorov20 (rounded)(n= 16)20 0.0

Connolly et ai18 (n=27) -0.677 0

Fung et all7 (n=8) 1 * I0.0048

Combined (non-rounded)(n=51)-)Combined (rounded)(n=5) 02

-1.0 -0.5 0 0.5Severity scale (0-3)

FIG 2-Change in severity of cramps in patients taking quininecompared with placebo

Methods of determining severity of cramp differedbetween studies. One study used a 10 cm visualanalogue scale, and the other two used a 3 point scale(1-mild, 2-moderate, 3-severe). To allow us tocombine data on severity from each of these threestudies we used two standardisation methods toconvert the 10 cm visual analogue data to a 3 pointscale: non-rounded-mean cramp severity for indi-vidual patients was divided by 3-33 and the pointestimate (95% confidence interval) calculated; androunded-the mean cramp severity for each patientwas converted to numerical values correspondingto mild, moderate, or severe (that is, mean visualanalogue scores from 0 to 3-3 were assigned a value of1,3-4 to 6-6 assigned 2, and 6-7 to 10 assigned 3).There was no significant change (-0-048 units

(-0-314 to 0-218) on a 3 point visual analogue scale) inthe mean severity of individual leg cramps withquinine compared with placebo. The difference inthe results was negligible when we used either thenon-rounded or rounded method of standardisation.Sensitivity analysis including hypothetical data fromJones and Castleden'5 had no significant effect on thisresult.

Change in number ofnights with cramps (fig 3)Two trials measured the number of nights with

cramps. Because Dunn used a 30 day treatment periodin his trial'9 his results were standardised to a four weektreatment period by using the same method describedearlier. Each trial individually showed a significantreduction in the number of nights with leg cramps, andthe combination of the two trials showed similar results

(-27-5% (-30-6% to -24-4%) change in the numberofnights with cramps).

Change in duration ofindividual nocturnal leg crampsDuration of individual nocturnal leg cramps was an

outcome measured in four studies. Again, individualdata were not available from Warburton et al as severityand duration were combined into one index'6 and datafrom Jones and Castleden were not available.'5

Sidorov20 and Fung'7 found a -4-2 minute (-22-8 to14-5) and - 54-0 minute (- 121-3 to 13-3) change induration of an individual leg cramp, respectively, withquinine compared with placebo. The results of com-bining these data show no significant change (-20-8minutes (-43-7 to 2-1) in duration of individual legcramps with quinine versus placebo. Sensitivityanalysis including hypothetical data for Jones andCastleden'5 did not significantly change this result.

Change in Cramp IndexWarburton et al combined the results of cramp

severity and duration into a single result they called thecramp index.'6 The cramp index was based on theproduct of the total duration of leg cramps for eachperiod and the mean severity of the cramps. Threeother studies measured both severity and duration.Cramp index scores for each study were derived fromthese data. To allow combination of data on crampseverity from individual studies the same methods asdescribed above were used to calculate respectivecramp indices.

Results from individual studies showed a changein the cramp index as follows: Sidorov -2-87 units(- 13-86 to 8.07)20; Fung et al - 37-87 units (- 68-80 to-6-95)'7; and Warburton et al 26-84 units (-0-95 to54.64).16 Combination of the data for the individualpatients from these three trials showed no significantchange (5-25 units (-10-43 to 20-93)) in the crampindex with quinine or placebo. Inclusion of hypo-thetical data for Jones and Castleden" did not signifi-cantly change this result.

Side effects oftreatment with quininePooling of the descriptive data on side effects

reported by the six studies (n- 107) showed that onlyone person in any of the studies experienced seriousside effects. This person experienced nausea, myalgia,leucopenia, and thrombocytopenia that resolved threedays after discontinuation of quinine. Only a smallminority of patients reported any side effects at allwhile taking quinine.

DiscussionThere is current uncertainty about whether pre-

scribing quinine for patients who complain of frequentnocturnal leg cramps is beneficial. Treatment withquinine is not without risk as there have been severalreports of serious adverse effects. Many studieshave tested the efficacy of quinine sulphate for thiscondition since 1976. Overall, the results of thesestudies have not been definitive. We conducted thismeta-analysis to attempt to clarify whether quinineis more efficacious than placebo in providing relief forsufferers ofnocturnal leg cramps.

Connolly et al18 (n=26)

Dunn19 (n=25)

Comined(n=5 1)

-23.9

-30.9

-27.4

-40 -30 -20 -10 0Percentage change

FIG 3-Percentage change in number of nights with cramps in patientstaking quinine compared with placebo

BMJ VOLUME 310 7jANuARY 1995 15

Pooling of data from the six eligible trials, all ofwhich had strong methodological designs, indicatedthat quinine does reduce the number of nocturnal legcramps suffered by patients and also reduces thenumber of nights on which they actually have cramps.Quinine did not seem to reduce the severity or durationof a cramp once it had occurred, though the confidenceintervals were wide. Serious side effects of treatmentwith quinine were uncommon in these trials, thoughtreatment periods were not long enough to excludelong term complications. The inability to obtain dataon individual patients from one of the eligible studiesdid not have any significant effect on our results.We therefore believe that treatment with quinine isefficacious in the prevention of nocturnal leg cramps ingeneral ambulatory populations.

POSSIBLE ERRORS IN METHODS

As with all meta-analyses, publication bias is a

possible source of error in this study. As the medicalcommunity has genuine uncertainty about the efficacyof quinine sulphate in the treatment of nocturnal legcramps, however, all well designed clinical trialsinvestigating quinine for this condition are likely to bepublished, regardless of their final results.Another source of possible error is the method of

standardisation used to allow combination of the datafrom different studies. Standardisation was necessary

as different studies used different lengths of treatmentperiods. We chose to standardise all studies to a fourweek treatment period as two of the studies used thislength of treatment period and it was the longesttreatment period length in any study measuringthe number of cramps for individual patients.Interestingly, the two studies with four week treatmentperiods showed treatment with quinine significantlyreduced the number of cramps compared with treat-ment with placebo. Studies with shorter periods oftreatment were not able to show such significantbenefit. In fact, the longer the treatment period thegreater the point estimate of benefit for quininesulphate. Considering this result, treatment periods ofless than four weeks may be insufficient to show benefitof treatment. We therefore believe that our method ofstandardising the data takes a conservative approach inestimating the probable efficacy of quinine.The inability of quinine to affect the severity or

duration of individual cramps suggests that this drugmust be taken on a regular as opposed to an as neededbasis.The test for homogeneity with respect to reduction

in the number of nocturnal leg cramps with data fromthe four studies in which information on individualpatients was available was significant, indicating thatthe absolute reduction was not constant across thesefour studies. Inspection of the absolute reductions withtheir confidence intervals indicated that the study byConnolly et al'8 is responsible for the heterogeneity.When we reviewed the data on individual patients fromthis study we found four extreme sets of results (range- 83 to - 62 fewer cramps with quinine compared withplacebo). These were the four sets of results thatshowed the greatest efficacy of quinine. As a formof sensitivity analysis we removed these four setsof results from our analysis, which would have theeffect of reducing the estimate of efficacy of the meta-analysis results. The absolute reduction in cramps stillremained significant, and the test for homogeneitybecame non-significant (P=0-41). To further our

sensitivity analysis, when we then excluded the datafrom Connolly et al'8 altogether and repeated theanalysis we found that the absolute reduction remainedsignificant, and the three remaining studies satisfiedthe assumption of homogeneity. Considering that thestudy of Connolly et al also showed the greatest

absolute reduction in leg cramps for quinine comparedwith placebo,'8 we chose to combine the data of all fourstudies in which data for individual patients wereavailable.The study of Connolly et al was also the only one that

used only male subjects. We were unable to find any

reference to suggest or confirm that nocturnal legcramps are different from a physiological or epidemio-logical perspective in men and women. All other trialsincluded in this meta-analysis included more women.Unfortunately, data on the sex of individual patientswere unavailable.There was one study which met all inclusion criteria

except that of crossover design.'8 In this study subjectswere randomised to one of three arms: quinine alone,quinine and aminophylline, or placebo. The resultsshowed that treatment with quinine alone produced asignificant reduction in the number of nocturnal legcramps compared with treatment with placebo. Tofurther our sensitivity analysis we modified the protocolof the meta-analysis to allow inclusion of this trial. Byanalysing the data for individual patients while theyreceived quinine compared with placebo for the firsttreatment period of each crossover study, we con-

tinued to find a significant reduction in nocturnal legcramps in patients receiving quinine (12-85 fewercramps in a four week period; 95% confidence interval4-26 to 21-44). Thus, modifying the protocol of thismeta-analysis to allow inclusion of the study of Gorlichet all8 would slightly change the point estimate ofefficacy for quinine sulphate but not the significance ofits results.

Gorlich et al'8 and another German study2' studiedthe combination of quinine and aminophylline. Bothof these studies showed significant benefit for thiscombination.

In conclusion, our results show that quininesulphate is efficacious in the treatment of nocturnal legcramps on ambulatory patients. As quinine may haveconsiderable side effects, however, patients starting itfor nocturnal leg cramps should undergo a therapeutictrial with close monitoring of its benefits and risks.These data suggest that patients should receive quinineon a regular basis and for a period of at least four weeksbefore conclusions about its efficacy are made. Giventhe possible risks and benefits of quinine an n of 1 trialmay be indicated for individual patients.

We thank Drs J Sidorov, P Connolly, and E Shirley forkindly allowing us access to data on individual patients fromtheir respective studies. We also thank Drs H Brown, AByszewski, W B Dalziel, and Mr L Kelly for performing theblinded assessments and Janet Brennan for the production ofthe tables.

BMJ VOLUME 310 7 JANUARY 1995

Key messages

* Nocturnal leg cramps are a commoncomplaint, occurring in more than 70% ofelderly people at one time or another* The results of this meta-analysis show thatquinine sulphate is more effective than placeboin reducing the number of cramps experiencedby patients* This analysis also suggests that dosing iscumulative, therefore a trial of at least fourweeks of quinine may be necessary to show abeneficial effect* Quinine should be taken on a regular asopposed to as needed basis as it could not beshown definitively to reduce the severity orduration of an individual cramp

1 Hall AJ. Cramp and salt balance in ordinary life. Lancet 1947;ii:231-3.2 Daniell HW. Simple cure for noctumal leg cramps. N Engl Y Med 1979;301:

216.3 Peer G, Blum M, Aviram A. Relief of hemodialysis-induced muscular cramps

by nifedipine. Dialysis and Transplantation 1983;12:180-1.4 Ayres S, Mihan R. Noctumal leg cramps (systremma) and 'restless legs'

syndrome: response to vitamin E. South Medy 1974;67:1308-12.5 McGee SR. Muscle cramps. Arch Intern Med 1990;159:51 1-8.6 Moss HK, Herrmann LG. The use of quinine for relief of night cramps in the

extremities.JAMA 1940;115:1358-9.7 Maguire RB, Stroncek DF, Campbell AC. Recurrent pancytopenia, coagulo-

pathy, and renal failure associated with multiple quinine-dependent anti-bodies. Ann Intern Med 1993;119:215-7.

8 Bateman DN, Blain PG, Woodhouse KW, Rawlins MD, Dyson H, HeyworthR, et al. Pharmacokinetics and clinical toxicity of quinine overdosage: lackof efficacy of techniques intended to enhance elimination. Q J Med1985;214:125-31.

9 Bacon P, Spalton DJ, Smith SE. Blindness from quinine toxicity. Br JOphthalmol 1988;72:219-24.

10 Baltodono N, Gallo BV, Weidler DJ. Verapamil vs quinine in recumbentnocturnal leg cramps in the elderly. Arch Intern Med 1988;148: 1969-70.

11 lim SH. Randomized double-blind trial of quinine sulphate for noctumal legcramps. BrJClin Psact 1986;40:462.

12 Gorlich HD, von Gablenz E, Steinberg HW. Treatment of noctumal legcramps. A multi-center, double blind, placebo controlled comparison

between the combination of quinine and theophylline ethylene diamine withquinine. Arzneimittelforschung 1991;41:167-75.

13 Roca AO, Jarjoura D, Blend D, Cugino A, Rutecki GW, Nuchikat PS, et al.Dialysis leg cramps. Efficacy of quinine versus vitamin E. ASAIO J1992;38:481-5.

14 Kaji DM, Ackad A, Nottage WG, Stein RM. Prevention of muscle cramps inhaemodialysis patients by quinine sulphate. Lancet 1976;ii:66-7.

15 Jones K, Castleden CM. A double blind comparison of quinine sulphate andplacebo in muscle cramps. AgeAgeing 1983;12:155-8.

16 Warburton A, Royston JP, O'Neill CJA, Nicholson PW, Jee RD, DenhamMJ, et al. A quinine a day keeps the leg cramps away? Br Jf Clin Pharmacol1987;23:459-65.

17 Fung MC, Holbrook JH. Placebo-controlled trial of quinine therapy fornocturnal leg cramps. WestJMed 1989;151:42-4.

18 Connolly PS, Shirley EA, Wassen JH, Nierenberg DW. Treatment ofnocturnal leg cramps. A crossover trial of quinine vs vitamin E. Arch InternMed 1992;152:1877-80.

19 Dunn NR. Effectiveness of quinine for night cramps [letter]. Br J Gen IPract1993;43:127-8.

20 Siderov J. Quinine sulfate for leg cramps: does it work? J Am Geriatr Soc1993;41:498-500.

21 Moerl H, Dieterich HA. Noctumal leg cramps: their causes and treatment.MedKin 1980;75:40-5.

(Accepted 4 November 1994)

MRC EnvironmentalEpidemiology Unit,University ofSouthampton,Southampton GeneralHospital, Southampton,S016 6YDC H D Fall, clinical scientistM Vijayakumar, researchfellowD J P Barker, directorC Osmond, statisticianS Duggleby, researchassistant

Correspondence to:Dr Fall.

BMJ 1995;310:17-9

Weight in infancy and prevalence ofcoronary heart disease in adult life

C H D Fall,M Vijayakumar, D J P Barker, C Osmond, S Duggleby

AbstractObjective-To determine whether low birth

weight and low weight at 1 year are followed by anincreased prevalence of coronary heart disease inadult life.Design-A follow up study of men born during

1920-30 whose birth weights and weights at 1 yearwere recorded.Setting-Hertfordshire, England.Subjects-290 men born and still living in East

Hertfordshire.Main outcome measure-The prevalence of

coronary heart disease, defined by the Rose/WHOchest pain questionnaire, standard electrocardio-graphic criteria, or history ofcoronary artery angio-plasty or graft surgery.Results-42 (14%) men had coronary heart

disease. Their mean birth weight, 7 9 lb (3600 g), wasthe same as that ofthe other men. Their mean weightat 1 year, 21P8 lb (9.9 kg), was 1 lb (454 g) lower (95%confidence interval 0 1 to 1-8, P=0.02). Percentagesofmen with coronary heart disease fell from 27% inthose who weighed 18 lb (8-2 kg) or less at 1 year to9°/o in those who weighed more than 26 lb (11.8 kg) (Pvalue for trend=0.03). This trend occurred in bothsmokers and non-smokers and within each socialclass.Conclusion-These findings add to the evidence

that coronary heart disease is "programmed" duringearly growth.

IntroductionRecent findings suggest that the pathogenesis of

coronary heart disease begins in fetal life and infancy.Among 10 141 men born during 1911-30 in Hertford-shire, England, whose birth weights and weights at 1year had been recorded, men with the lowest birthweights and weights at 1 year had the highest deathrates from coronary heart disease.'2 The associationwith weight at 1 year was stronger than that with birthweight, though both were significant. Reduced growthin utero and during infancy has also been shown to beassociated with an increased risk of hypertension andnon-insulin dependent diabetes and higher concen-trations of low density lipoprotein cholesterol andfibrinogen in adult life.3- These findings have led to thehypothesis that coronary heart disease originates from

early programming whereby undernutrition duringsensitive periods in early life permanently changes thebody's structure and physiology.78The Hertfordshire study was based on diagnosis of

coronary heart disease on death certificates.2 We nowpresent data on disease in living subjects. usingvalidated methods we have measured the prevalence ofsymptomatic and asymptomatic coronary heart diseasein a sample of 290 men born and still living in EastHertfordshire.

MethodsIn Hertfordshire from 1911 onwards each birth was

notified by the attending midwife, and a health visitorsaw the child periodically throughout infancy. Thechild's birth weight and weight at 1 year of age wererecorded.' We used these records to trace 5654 menwho were born as singletons in the six districts of EastHertfordshire between 1911 and 1930 and who hadboth birth weight and weight at 1 year recorded todetermine mortality from cardiovascular disease.' Ofthe total, 1186 men had died, 434 of them fromcoronary heart disease.' We subsequently approachedthe 1157 men who were born in East Hertfordshirebetween 1920 and 1930 and still lived there.3 Of these,845 men agreed to be interviewed at home. Theircurrent occupation or their occupation before retire-ent and their father's occupation at the time of theirbirth were used to determine socioeconomic classcurrently and at birth.9 Their blood pressure wasmeasured.' After the interview men were asked if theywould be willing to attend a local clinic to have bloodsamples taken, and 468 men agreed. Serum concen-trations of lipids and concentrations of plasma clottingfactors, glucose, and insulin were measured, and theresults have been reported.'46For the study reported here, we reapproached the

370 men who had complete measurements on all bloodsamples. Ofthe 370, seven had died and 1 1 had movedaway. Of the remaining 352, 290 (82%) took part. Themen were visited at home by a nurse who asked fordetails of current smoking habits. After the interviewthe subjects were asked to come to a local clinic wherethe Rose/WHO chest pain questionnaire'0 wasadministered and standard 12 lead electrocardiographycarried out according to the 1982 Minnesota protocol."IHeight was measured with a portable stadiometer and

BMJ voLuME 3310 7JANuARY1995 17