Galactorrhoea, hyperprolactinaemia, and protease inhibitors

For personal use only. Reproduce with permission from The Lancet Publishing Group.

472 THE LANCET • Vol 357 • February 10, 2001

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COMMENTARY

Glucose tolerance in adults after prenatal exposure to famine

Sir—My former colleagues at theAcademic Medical Center (AMC) inAmsterdam and David Barker’s groupin Southampton were co-workers on areport on glucose tolerance in 1998.1 Iwas the initiator of the study, and I wasconcerned by several ethical andscientific issues raised by the report.Particularly disturbing was the failureto note that the study findings did notagree with the original studyhypothesis. Initially I refrained fromwriting, but these issues are notresolved and I feel compelled to callattention to them.

The Amsterdam study is importantbecause it affords a rare opportunity tostudy the potential effects of maternalnutrition on cardiovascular disease(CVD) risk in adulthood. Ifdocumented, this effect could havesubstantial scientific and policyimplications. For ethical and practicalreasons, suitable experimental studiescan probably never be done in humanbeings. In the absence of experimentaldata, the circumstances of the Dutchfamine provide a rare opportunity toinvestigate these relations in variousnutritional exposures not normally seenin human populations.

I set up a study in the 1980s at theAMC in Amsterdam, with severalcolleagues from the neonatologydepartment experienced in the follow-up of infants born in the hospital. Thestudy included 1067 singleton womenborn in 1944–46, and assessed thelong-term effects of maternal under-nutrition in specific trimesters ofpregnancy on size at birth and onsubsequent reproductive perfor-mance.2,3 We established that manyfamine-born infants could be identified,traced, and interviewed after a follow-up period of 43 years or more. Lossesto follow-up were at a minimum andparticipation in health interviews washigh. In all, more than 700 womenwere interviewed.

In 1991, I approached Barker inSouthampton to inquire about hisinterest in collaborating in a study ofCVD risk in this population. Thesampling frame was expanded toinclude men and more controls without

prenatal famine exposure. I alsoexpanded the Amsterdam team ofcollaborators, and together with theSouthampton team started preparationsfor the new study. The work wascompleted by my colleagues inAmsterdam, after I left the Netherlandsfor the USA. Based on earlier reportedassociations of specific phenotypes atbirth with cardiovascular risk factorsfrom Barker’s group, we drew up thehypothesis that exposure to nutritionaldeprivation in early to mid gestationwould be related to the risk in adult lifeof non-insulin-dependent diabetesmellitus, hypertension, hypertriglyceri-daemia, and insulin resistance. Theproposal was funded in 1994 by theMedical Research Council in London,UK, with a grant awarded to threeinvestigators: one from Amsterdam,one from Southampton, and myself.We assessed around 740 people.

The 1998 report1 was the firstpublication from this study. Glucoseconcentrations were increased 2 h aftera standard glucose load and werehighest for people who had beenprenatally exposed in mid and lategestation. These findings challengedthe original fetal programminghypothesis and it is, therefore,important that they be confirmed inother populations.

There are some problems with thereport. In the published form, thefindings seem to be from a new study,although the women came from theexisting and previously studied Dutchfamine birth cohort. The original studyhypothesis was not specified in thereport, and therefore it was not obviousthat the findings provided no supportfor the a priori hypothesis but rather fora hypothesis formulated later. Thispresentation of the findings isdisappointing and misleading, since Iset up the study to test several explicithypotheses about the relation betweenfetal nutrition and CVD risk.

Additional complications arisebecause the analyses are based onexposure groups that are differentlyspecified from previous studies of thiscohort, and the data are not presentedseparately for men and women.

Consequently, direct comparisons withearlier work, to which relevantreferences are missing, are not possible.Unfortunately, I could not correctthese omissions, because the paper waspublished with my name in theacknowledgments but without myknowledge. The MRC deemed thisaction a breach of publication ethics.Moreover, in the contributions section,four of the investigators claim that theydesigned the study. This statement isfalse and needs correction.

An additional report on infant birthsize was later submitted by theinvestigators with my name as a co-author, but without my knowledge orapproval. Again, the MRC deemed thisaction a breach of publication ethics.The manuscript was withdrawn fromconsideration after I contacted theeditor of the journal concerned andinformed him that the investigatorswere unwilling to consider anyamendments in the text. Other reportsfrom the group have been publishedunder similar circumstances, withoutappropriate acknowledgments, regardfor existing work, or for a priorihypotheses.4,5

Although the data in the 1998 reportare important, they should be analysedwith scientific rigor and integrity, andcrucial insights from previous work onthe famine should not be ignored.

L H LumeyEpidemiology Division, Mailman School of PublicHealth, Columbia University, 600 West 168Street, New York, NY 10032, USA(e-mail: [email protected])

1 Ravelli ACJ, van der Meulen JHP, Michels RPJ, et al. Glucose tolerance inadults after prenatal exposure to famine.Lancet 1998; 351: 173–77.

2 Lumey LH, Ravelli ACJ, Wiessing LG,Koppe JG, Treffers PE, Stein ZA. TheDutch famine birth cohort study: designvalidation of exposure, and selectedcharacteristics of subjects after 43 yearsfollow-up. Paediatr Perinat Epidemiol 1993;7: 354–67.

3 Lumey LH. Reproductive outcomes inwomen prenatally exposed toundernutrition: a review of findings from theDutch famine birth cohort. Proc Nutr Soc1998; 57: 129–35.

4 Ravelli ACJ, van der Meulen JHP, Osmond C, Barker DJP, Bleker OP. Obesity at the age of 50 years in men and


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women exposed to famine prenatally. Am JClin Nutr 1999; 70: 811–16.

5 Roseboom TJ, van der Meulen JHP,Osmond C, Barker DJP, Ravelli ACJ, Bleker OP. Plasma lipid profiles in adultsafter prenatal exposure to the Dutch famine.Am J Clin Nutr 2000; 72: 1101–06.

Sir—L H Lumey and The Lancet areboth aware that the a priori hypothesisfor our 1998 Lancet report1 waspublished 3 years previously.2 Lumeyleft Amsterdam in 1993 and wasexcluded from authorship under theVancouver guidelines, to which TheLancet subscribes.

O P Bleker, J H P van der Meulen, A C J Ravelli, T J Roseboom, R P J Michels,*D J P Barker, C N Hales, C OsmondAcademic Medical Centre, University ofAmsterdam, Netherlands; *MRC EnvironmentalEpidemiology Unit, University of Southampton,Southampton SO16 6YD, UK; and Departmentof Clinical Biochemistry, University ofCambridge, UK

1 Ravelli ACJ, van der Meulen JHP,Michels RPJ, et al. Glucose tolerance inadults after prenatal exposure to famine.Lancet 1998; 351: 173–77.

2 Barker DJP. Fetal origins of coronary heartdisease. BMJ 1995; 311: 171–74.

Editor’s reply

In July, 1997, The Lancet altered itsauthorship policy. The journal switchedto a contributor system,1 requiring allsubstantive research contributions to belisted. In the January, 1998, paper fromA C J Ravelli and colleagues,2 thecontributors section begins, “AnitaRavelli, Jan Van der Meulen, CliveOsmond, and David Barker designedthe study”. On the original MRC grantapplication, there are three names:Clive Osmond, Jan H P Van derMeulen, and Lambert H Lumey. Thecontributors statement published inThe Lancet is, therefore, incorrect.

Furthermore, publication of Lumey’sname in the acknowledgments sectionbut without his permission—he wasthanked for his “help” only—breaches,at the very least, norms of scientificcourtesy. The allegations concerning asecond journal, adjudicated on by theMRC, go unanswered by O P Bleker and colleagues, as do Lumey’scomments about several otherpublished reports.

Lumey also argues that the study aspublished in The Lancet was unclearsince “the findings provided no supportfor the a priori hypothesis but rather fora hypothesis formulated later”. Barkerand colleagues point out that the paper asserting the new hypothesis3

was cited in The Lancet report. It is truethat this new hypothesis was cited(reference 15), but I regret that, forreaders with a less intimate knowledge

of the fetal origins hypothesis thanBarker and colleagues, the sharp shiftin thinking between the 1993/1994MRC grant application and the 1995report published in the British MedicalJournal was not made more explicit inthe paper’s introduction.

1 Horton R. The signature of responsibility.Lancet 1997; 350: 5–6.

2 Ravelli ACJ, van der Meulen JHP, Michels RPJ, et al. Glucose tolerance inadults after prenatal exposure to famine.Lancet 1998; 351: 173–77.

3 Barker DJP. Fetal origins of coronary heartdisease. BMJ 1995; 311: 171–74.

Laparoscopiccholecystectomy

Sir—McMahon and colleagues (Nov11, p 1632)1 portray a picture oflaparoscopic cholecystectomy over thepast 20 years in Scottish NationalHealth Service hospitals thatrepresents only part of the story. Lackof correlation between surgicalworkload and significant gallstonedisease is even more striking than theysuggest.

Data are available for all NHScholecystectomies done in Scotlandsince 1961. Initially, numbers ofoperations soared by 133% until 1977,which is the year with the highest totalto date. The number fell gradually by21% until 1988, after which there wasa further 20% rise until 1999–2000.The actual prevalence of gallstones didnot change at all until after 1974, whennumbers, standardised for age and sex,increased significantly.2

In the 1960s, with no change ingallstone-disease prevalence, surgicalrates rose sharply. The rise might beexplained by greater enthusiasm forsurgery, which was perhaps perceivedas safer, and a large number ofsurgeons were active. Some of the risein the 1970s could relate to theincreased frequency of gallstonedisease, but this increase could not bethe whole explanation, nor can itexplain the decline in the 1980s. Thedecline could have reflected a deeperunderstanding of the lack of clinicalimportance of most gallstones, orperhaps overconfidence in non-surgical dissolution management. Therise in cholecystectomy rates in the1990s almost certainly reflectsenthusiasm for the laparoscopictechnique, as has been previouslynoted.3

Changes in operative techniques areof lesser importance than thedetermination of the need for surgery

in the first place, and the evidencesuggests we have not yet got it right.

M C BatesonBishop Auckland General Hospital, BishopAuckland, County Durham DL14 6AD, UK(e-mail: [email protected])

1 McMahon AJ, Fischbacher CM,Frame SH, MacLeod MCM. Impact oflaparoscopic cholecystectomy: apopulation-based study. Lancet 2000; 356:1632–37.

2 Bateson MC. Gallstones andcholecystectomy in modern Britain.Postgrad Med J 2000; 76: 700–03.

3 Lam C-N, Murray FE, Cuschieri A.Increased cholecystectomy rate after theintroduction of laparoscopiccholecystectomy in Scotland. Gut 1996; 38: 282–84.

Galactorrhoea,hyperprolactinaemia, andprotease inhibitors

Sir—Jane Hutchinson and colleagues(Sept 16, p 1003)1 report four patientswho presented with galactorrhoea andhyperprolactinaemia in associationwith protease-inhibitor treatment.Although hyperprolactinaemia hasbeen frequently noted in HIV-1-infected patients, the circumstances ofits presence remains poorly under-stood.2,3

Prolactin is a comitogen factor thatstimulates lymphocyte proliferation inresponse to antigen and mitogens.Immune cells secrete prolactin, andpituitary production of this substanceis partially under the control ofproinflammatory cytokines.4 Prolactinmight, therefore, act as a cytokine, andthe question arises as to whether raisedserum concentrations of prolactin aremore likely to prevail when HIV-1-infected patients develop clinicallyactive concomitant infections.5

To address this issue, we studiedserum prolactin concentrations in 46HIV-1-infected patients (33 men) andin 17 seronegative controls (12 men).20 of the 46 HIV-1-infected patientswere receiving antiretroviral treatmentwith zidovudine, lamivudine, andindinavir. 14 HIV-1-infected patientshad stage III disease and, the othersstage IV disease. 18 of the 32 withstage IV disease presented withconcomitant active infections, and allthe other 28 patients were symptom-free. We separated patients into twogroups according to whether they hadconcomitant infection or not; thegroups did not differ for age, sex, andantiretroviral treatment and itsduration.

Serum prolactin concentrationswere significantly higher among HIV-1-infected patients (p=0·022). Hyper-



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viral load. Medicina (B Aires) 2000; 60:427–30.

4 Montero A, Giovanoni AG, Sen L.Immunological properties of prolactin.Medicina (B Aires) 2000; 60: 515–20.

5 Hooghe R, Delhase M, Vergani P, Malur A,Hooghe-Peters EL. Growth hormone andprolactin are paracrine growth anddifferentiation factors in the haemopoieticsystem. Immunol Today 1993; 14: 212–14.

Sir—Jane Hutchinson and colleagues1

report the cases of four womenpresenting with hyperprolactinaemiaand galactorrhoea associated withprotease inhibitors. They deduce thatthis effect may have arisen from theuse of protease inhibitors, directlythrough hypothalamic stimulation orindirectly through the p450 system.They also state that although three ofthe four women were concurrentlytaking metoclopramide or fluoxetine,both of which are associated withhyperprolactinaemia and, hence,galactorrhoea, the incidence of theseside-effects are rare.

These side-effects for these drugsare documented in the British NationalFormulary and are widely known,since they were assessed as potentialtreatments to increase low milksupply.2 As such, the effects might beunder-reported. P Lissoni andcolleagues3 state that metoclopramiderepresents the classic stimulatory testfor prolactin secretion. T Brown andcolleagues4 saw prolactin releaseinduced by metoproclamide, but thiseffect was affected by parity. Thepossible effect of these drugs onprolactin and subsequently on milksecretion cannot, therefore, beignored.

T Murata and colleagues,5 however,assessed the use of an oral proteasecomplex to lessen the symptoms ofbreast engorgement in breastfeedingwomen, for which it was effective.They had assumed that this drug actedat a local level to reduce mammaryinflammation and increase vascularflow. If the conjecture of Hutchinsonand colleagues is subsequently verified,the effect seen by Murata andcolleagues might be explained by adirect effect of the protease complex atthe level of the pituitary gland.

*Helen Snowden, Mike Woolridge,Mary RenfrewMother and Infant Research Unit, University ofLeeds, Leeds LS2 9LN, UK

1 Hutchinson J, Murphy M, Harries R,Skinner CJ. Galactorrhoea andhyperprolactinaemia associated withprotease-inhibitors. Lancet 2000; 356:1003–04.

2 Renfrew M, Woolridge M, Ross McGill H.Enabling women to breastfeed. London:Stationery Office, 2000.

3 Lissoni P, Mandala M, Rovelli F, et al.Paradoxical stimulation of prolactinsecretion by L-dopa in metastatic prostatecancer and its possible role in prostate-cancer-related hyperprolactinaemia.Eur Urol 2000; 37: 569–72.

4 Brown TE, Fernandes PA, Grant LJ,Hutsul JA, McCoshen JA. Effect of parityon pituitary prolactin response tomeoclopramide and domperidone:implications for the enhancement oflactation. J Soc Gynecol Invest 2000; 7:65–69.

5 Murata T, Hanzawa M, Nomura Y. Theclinical effects of ‘protease complex’ onpostpartum breast engorgement (based onthe double blind method). J Japan ObstetGynaecol Soc 1965; 12: 139–47.

Sir—I am a paediatrician interested infurthering breastfeeding for preterminfants, and have some queries aboutJane Hutchinson and colleagues’report.1 They conclude thatgalactorrhoea in four women wasassociated with the use of proteaseinhibitors. Two of the four womenwere also treated with meto-clopramide, and in the other two it isnot stated that they definitely did notreceive this drug. In view of the side-effects of nausea and vomitingassociated with the use of proteaseinhibitors, the need for someantiemetic therapy is to be expected.

Hutchinson and colleagues statethat during a period of 28 years, only67 cases of galactorrhoea have beenreported associated with the use ofmetoclopramide. Although this side-effect might be undesirable, the drug is frequently used therapeutically for just this effect, to promote theproduction of breastmilk in motherswhose milk production is in-adequate.2,3 Its use is associated with asignificant increase in basal prolactinconcentrations. The galactorrhoeamight not, therefore, be totallyunexpected in patients receivingmetoclopramide.

If the other two patients inHutchinson and colleagues’ series alsoreceived metoclopramide, this drugcould be a contributory factor to thegalactorrhoea. It would be useful toknow whether this side-effect ofmetoclopramide is increased byprotease inhibitors.

Anne Marie Oudesluys-MurphyDepartment of Paediatrics, Medisch CentrumRijnmond-Zuid, locatie Zuider, 3075 EARotterdam, Netherlands(e-mail: [email protected])

1 Hutchinson J, Murphy M, Harries R,Skinner CJ. Galactorrhoea andhyperproloactinaemia associated withprotease-inhibitors. Lancet 2000; 356:1003–04.

2 Encrenkranz RA, Ackerman BA.Metoclopramide effect on faltering milkproduction by mothers of premature

prolactinaemia (>21 �g/L) was seen inten HIV-1-infected patients, but in noseronegative control. Four of the tenhyperprolactinaemic paients and 16 ofthe 36 patients with normal prolactinconcentrations were receiving proteaseinhibitors. When we compared serumprolactin concentrations in the 20treated with those for the 26 non-treated patients, they did not differsignificantly.3

Serum prolactin concentrations inrelation to the presence of activeinfections were significantly higher inthe group with secondary infectionsthan among symptom-free patients.Hyperprolactinaemia was present inten of 18 patients having concomitantinfections, but in only two of the 28symptom-free patients (figure).

Taken together, our results showthat hyperprolactinaemia was notrelated to protease-inhibitor-basedantiretroviral treatment but to thepresence of secondary activeopportunistic infections in AIDSpatients.

*Antonio Montero, Oscar A Bottasso,María R Luraghi, Adria G Giovannoni,Luisa Sen*Consejo de Investigaciones, UniversidadNacional de Rosario, 2000-Rosario, Argentina;Central Laboratory and Internal MedicineDepartment, Hospital de Emergencias “DrClemente Alvarez”, Rosario; and Laboratorio deBiología Celular y Retrovirus, Buenos Aires(e-mail: [email protected])

1 Hutchinson J, Murphy M, Harries R,Skinner CJ. Galactorrhoea andhyperprolactinaemia associated withprotease-inhibitors. Lancet 2000; 356:1003–04.

2 Montero A, Fernández MA, Cohen JE,Luraghi MR, Sen L. Prolactin levels in thecerebrospinal fluid of patients with HIVinfection and AIDS. Neurol Res 1998; 20:2–4.

3 Montero A, Giovannoni AG, Sen L.Hyperprolactinemia is a frequent finding inHIV-infected, but it does not correlate with

Ser

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100

90

50

40

20

30

10

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Serum prolactin concentrations in HIV-1-infected patients by presence orabsence of concomitant infection



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infants. Pediatrics 1986; 78: 614–20.3 Gupta AP, Gupta PK. Metoclopramide as a

lactogogue. Clin Pediatr 1985; 24: 269–72.

Authors’ reply

Sir—Antonio Montero and colleaguessuggest that hyperprolactinaemia isdue to opportunistic infections in HIV-1-seropositive patients. They do notcomment on the presence ofgalactorrhoea as a consequence of thiseffect.

In the two HIV-1-seropositivepatients in our series, the timing of thedevelopment of hyperprolactinaemiaand galactorrhoea was coincident withother infections. Patient one had achest infection when she presentedwith a 1-week history of galactorrhoea.She was treated with azithromycin for3 days as an outpatient. Patient twodeveloped galactorrhoea a few daysafter being discharged from a hospitalstay for Streptococcus pneumoniainfection. In these two patientsconcomitant infection might havecontributed to their raised prolactinconcentrations.

However, concomitant infections donot account for hyperprolactinaemia inthe two patients who were HIV-1seronegative (and otherwise wellduring the period of galactorrhoea),which we believe can be adequatelyexplained by only one of the twomechanisms proposed in our paper.

We accept that in the postpartumperiod metoclopramide can promotelactation,1 as stated by Snowden andcolleagues and Oudesluys-Murphy andcolleagues, galactorrhoea is rarelyreported when metoclopramide is usedas an antiemetic.

In response to Oudesluys-Murphy’squery, only the two women whoreceived protease inhibitors as part ofpostexposure prophylaxis in our seriesalso received metoclopramide. Theother two women, who were HIV-1-seropositive and received proteaseinhibitors as part of highly activeantiretroviral therapy, did not receivemetoclopramide. 4 months before theonset of galactorrhoea, one of the lattertwo women did, however, start takingfluoxetine, which also causeshyperprolactinaemia. We agree thatone of the possible mechanisms for theobservation of hyperprolactinaemiaand galactorrhoea in these women mayincrease this known side-effect ofmetoclopramide and fluoxetine relatedto protease-inhibitor use. We suggestalso that the effect is related toinhibition of the cytochrome p450system. Alternatively, we propose that

this phenomenon might be due to anew endocrine abnormality caused bythe action of protease inhibitors, theexact mechanism of which remains tobe elucidated.

*Jane Hutchinson, Maurice Murphy,Rachel Harries, Celia J SkinnerMedical and Emergency Directorate, Infectionand Immunity Speciality Group,St Bartholomew’s and the London NHS Trust,London EC1A 7BE, UK

1 Gupta AP, Gupta PK. Metoclopramide as alactogogue. Clin Pediatr 1985; 24: 269–72.

Sir—One of the possible mechanismsenounced by Jane Hutchinson andcolleagues1 in their report ofgalactorrhoea and hyperprolactinaemiain four HIV-1-infected patientsreceiving protease inhibitors was adirect toxic effect of these drugs. Wedescribe an unususal case ofgalactorrhoea and hyperprolactinaemiaassociated with systemic symptoms ina patient receiving nevirapine therapy.

A woman aged 37 years withsymptomless HIV-1 infection startedtaking stavudine, didanosine, andnelfinavir, which led to undetectableHIV-1 viral load (<200 copies/mL) upto month 14. At that time, nelfinavirwas switched to nevirapine, inincreasing doses up to 400 mg per day,because of fat-tissue distributionabnormalities, hypercholesterolaemiaand hypertriglyceridaemia. 1 monthlater, the woman presented a flu-likesyndrome. Because of the persistenceof the symptoms, despite a 7-daycourse of cefadoxil, she was re-admitted to the treatment unit.

The patient’s temperature was37·8ºC, and physical examinationshowed no lymphadenopathy or rash.Laboratory assessment showed raisedalanine aminotransferase (five timesnormal values), aspartate amino-transferase (four times normal), and �-glutamyltransferase (20 timesnormal serum concentrations).Neviparine was continued undermedical supervision. 15 days later,continuous galactorrhoea occurredwithout amenorrhoea. Repeatedmeasurement of prolactin plasmaconcentrations through a permanentcatheter for 4 h yielded values of 107,97, 66, and 394 �g/L (normal<25 �g/L). Plasma concentrations ofcortisol, thyroid hormones, oestradioland � human chorionic gonadotropinwere within normal values. Cerebralmagnetic resonance imaging showed anormal pituitary gland. Extensiveresearch for other drugs or substancestaken by the patient was negative. Wesuspected a toxic effect of nevirapineand switched the patient to efavirenz.2

Systemic symptoms disappeared

rapidly, as did hyperprolactinaemia2 weeks later, and galactorrhoea andhepatitis 1 month later.

The most common physiological,pharmacological, and tumoural causesof hyperprolactinaemia, includingpregnancy, primary hypothyroidism, use of neuroleptics, and pituituarytumour were ruled out.3 Thechronology of the clinical andbiological manifestations suggested anassociation with the initial change to ahighly active antiretroviral regimen.Protease inhibitors induce gynaeco-mastia resulting from breast glandularadipocyte tissue redistribution.4 Weknew of no interaction with theprolactin endocrine axis before weread Hutchinson and colleagues’report. In our patient, galactorrhoeaseems to have been related to the usenevirapine rather than to interruptionof protease-inhibitor use.

The mechanism of galactorrhoeaand hyperprolactinaemia is unknown.Nevaripine may act directly on thecentral nervous system and neuro-endocrine regulation since it belongsto the dipyridodiazepinone family,whose compounds have intracerebralreceptors. This mechanism does not,however, clearly explain the otheradverse manifestations in our patient;they could be part of a systemicimmunoallergic syndrome that hasbeen previously well described fornevirapine.2 Also, increased con-centrations of prolactin have beendetected in other non-HIV-relatedimmunological diseases and weassume that, in the present case,hyperprolactinaemia can be integratedinto a systemic immunoallergicmechanism of nevirapine.5

*Xavier Duval, Etienne Larger,Pascale Longuet, Catherine Leport,Jean-Louis VildeService des Maladies Infectieuses etTropicales et d’Endocrinologie, Hôpital BichatClaude Bernard, 75877 Paris, Cedex 18,France(e-mail: [email protected])

1 Hutchinson J, Murphy M, Harries R,Skinner CJ. Galactorrhoea andhyperprolactinemia associated withprotease-inhibitors. Lancet 2000; 356: 1003–04.

2 Bourezane Y, Salard D, Hoen B, Vandel S,Drobacheff C, Laurent R. DRESS (drugrash with eosinophilia and systemicsymptoms) syndrome associated withnevirapine therapy. Clin Infect Dis 1998; 27:1321–22.

3 Biller BM. Diagnostic evaluation ofhyperprolactinemia. Br Reprod Med 1999;44: S1095–99.

4 Caeiro JP, Visnegarwala F,Rodriguez-Barradas MC. Gynecomastiaassociated with indinavir therapy. Clin InfectDis 1998; 27: 1539–40.

5 Neidhart M. Prolactin in autoimmunediseases. Proc Soc Exp Biol Med 1998; 217:408–19.



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sewage and river water furthercontributed to quantitative features ofenvironmental pollution by oralvaccination programmes.

The well known high mutation rateof picornaviruses (10�3 to 10�4),initially quantified with coxsackievirusA9,2 and the implications for sheddingless-attenuated or virulent poliovirusafter oral vaccination of even anindividual has been studied andreviewed by P Minor and colleagues3

and many others. One feature of theissue should not be neglected. Sometime ago, H Knolle4 and myself5

postulated on possible contaminationof drinking water by vaccine-derived,less-attenuated polioviruses. Incountries with limited water resourcesespecially, shortcuts between sewageand drinking water cannot beexcluded and might result indistribution of contaminated waterinto dense and rapidly growingpopulations.

These considerations do notquestion the current poliomyelitiseradication programmes, but point toa possible risk.

Hans J EggersInstitut für Virologie der Universität zu Köln, D-50935 Köln, Germany

1 Yoshida H, Horie H, Matsuura K,Miyamura T. Characterisation of vaccine-derived polioviruses isolated from sewageand river water in Japan. Lancet 2000; 356:1461–63.

2 Eggers HJ, Tamm I. Coxsackie A9 virus:mutation from drug dependence to drugindependence. Science 1965; 148: 97–98.

3 Minor P. Picornaviruses. In:Topley WWC, Wilson GS, Collier LH,eds. Topley and Wilson’s microbiology andmicrobial infections, vol I. London:Arnold, 1998: 485–509.

4 Knolle H. Uebertragung der Poliomyelitisdurch Trinkwasser und das Problem derAusrottung. Gesundheitswesen 1995; 57:351–54.

5 Eggers HJ. Kommentar zur Arbeit“Uebertragung der Poliomyelitis durchTrinkwasser und das Problem derAusrottung”. Gesundheitswesen 1995; 57:349–50.

Sir—The reports by Hiromu Yoshidaand colleagues1 and Chushi Koroiwaand colleagues2 refer to some of thecryptic issues during the final phase ofpoliomyelitis eradication.

Yoshida and colleagues areconcerned by the existence ofpotentially neurovirulent recombinanttype poliovirus strains in the rawsewage and river water in Toyama,Japan. The neurovirulent strains insewage or river water affluent in Japanor elsewere might not pose muchdanger to the local community per se.Nevertheless, unexpected incessanttorrential rains with unrelentingflooding of river water or natural

negatively affected because scarceresources were allocated to thenational immunisation days but tookthis to be a temporary issue. Inter-viewed scholars perceived immu-nisation days as a vertical approachhaving a major negative, and possiblylong-lasting, effect on the overallimmunisation programme. Documentanalysis supported this: polio vaccinecoverage in India decreased from95% in 1994 (before nationalimmunisation days wereimplemented) to only 73% in 1998;and measles coverage decreased from87% to 66% (www.who.int/vaccines-s u r v e i l l a n c e / c o u n t r y / i n d i a . p d faccessed Feb 6, 2001). Data from thestudy district for 1999 showed acoverage of 73·5% for polio and only42·5% for measles; in 1996 and 1998,the number of fully immunisedchildren had plummeted.

Our findings show that polioeradication in India will require moreintervention than additional nationalimmunisation days. Constructivecommunication is needed at all levelsof the health system; in particular,concerns of all parties involved,including mothers, need to be takenseriously. In view of decreasing polioimmunisation coverage, the routineexpanded programme onimmunisation should be rein-vigorated, which might requireadditional donor commitment tomake up for resources shifted tointensified polio eradication efforts.2

Action is urgently needed becauseeradication in one region may turnout to be reversed if it is not achievedin neighbouring regions and,ultimately, worldwide.

Dr Liyanage was enrolled in a communityhealth and health management MSc course atHeidelberg University on a scholarship fromGerman Academic Exchange Service.

*Oliver Razum, Jayantha Liyanage,K R Nayar*Department of Tropical Hygiene and PublicHealth, Heidelberg University, 69120Heidelberg, Germany; Department of PublicHealth, Colombo Municipal Council, SriLanka; and Centre of Social Medicine andCommunity Health, School of Social Sciences,Jawaharial Nehru University, New Delhi, India(e-mail: [email protected])

1 Kuroiwa C, Vongphrachanh P, Chosa T,et al. Risk of poliomyelitis importation andre-emergence in Laos. Lancet 2000; 356:1487–88.

2 Dietz V, Cutts F. The use of masscampaigns in the expanded program onimmunization: a review of reportedadvantages and disadvantages. Int J HealthServ 1997; 27: 767–90.

Sir—The paper by Hiromu Yoshidaand colleagues (Oct 28, p 1461)1 onvaccine-derived type 3 polioviruses in

Difficulties in polioeradication

Sir—Chushi Kuroiwa and colleagues(Oct 28, p 1487)1 warn of a possiblere-emergence of poliomyelitis in Laosnow that the western Pacific regionhas been declared free of wildpoliovirus. They report an increasingrisk of polio importation from theneighbouring southeast Asia regionand low polio vaccine coverage inmany districts. The latter observationraises particular concern.

The strategy for polio eradicationrelies on a functioning expandedprogramme on immunisation,complemented by mass vaccinationcampaigns and intensifiedsurveillance. If, with this strategy,polio coverage remains low, questionsarise as to what underlying constraintsthere may be, and whether thisstrategy is optimum for polio-endemiccountries such as India.

India remains one of the majorglobal poliovirus reservoirs because ofits large, dense population and intensevirus transmission. All three wildpoliovirus types are still transmitted inseveral foci, mainly in the states ofUttar Pradesh and Bihar. India iscurrently engaged in a majoracceleration of eradication, com-prising activities such as, additionalrounds of national immunisation days(www.polioeradication.org/global_status.html accessed Feb 6, 2001).We interviewed health policy-makers,care providers, mothers, and public-health scholars to identify managerialand social constraints of polioeradication in a rural district of UttarPradesh in May and June, 2000.

District health staff assigned highpriority to polio eradication andnational immunisation days; theymentioned irregular vaccine supplyand ignorance of the mothers as majorconcerns. Contrary to what healthworkers believe, mothers are wellinformed about polio vaccination(albeit not about the programme onimmunisation as a whole). Theycomplained that frequently novaccine, or only polio antigen, wasavailable at the health posts.Interviews with policy makers andscholars revealed completelycontradicting interpretations of thepresent situation. Policy makersviewed national immunisation days asa successful strategy contributing topolio eradication, and argued that thenumber of reported polio cases inIndia has been decreasing since 1998.They conceded that the expandedprogramme on immunisation was



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disasters could lead to a shortage ofsafe drinking water, exposure toinfected water, or both. Thepoliovirus-seronegative populationwould certainly then be exposedto a risk of recombinant-poliovirus-induced acute flaccid paralysis.

Kuroiwa and colleaguesrecommend increased surveillance foracute flaccid paralysis and highcoverage with oral poliovirus vaccineafter the polio eradication in thewestern pacific region. They arealarmed by the potential increase insusceptible people after the end ofmass live vaccination campaigns. Therise would not be confined to childrenor adolescents but would involveadults and elderly. With almost nopoliovirus circulation and a regularuse of inactivated rather than oralpoliovirus vaccine, the number ofpeople lacking antibody to threepoliovirus strains would bephenomenal.

A close watch on declining antibodyin adults and elderly, includingdrug users or on immunosuppressivetherapy after organ transplants couldprevent such eventuality. There was awidespread lack of poliovirus antibodyin young drug addicts at the SanPatrignano rehabilitative communityat Rimini, Italy. Seronegativity of 27%for type 1 poliovirus, 27% for type 2,34% for type 3, and 11% for all threetypes was highest among the HIV-1-positive drug addicts.3 Furthermore,in 16 adult recipients of bone-marrowtransplants in Finland, a decline inantibody titres against poliovirusresulted in a loss of protection againstpoliomyelitis.4

Immunisations with inactivatedrather than live poliovirus vaccine inpolio-free countries,1 surveillance forpatients with acute flaccid paralysis,2

and serosurveillance for susceptibleindividuals should ensure freedomfrom poliovirus-induced episodes ofacute flaccid paralysis globally.

Subhash C AryaCentre for Logistical Research and Innovation,M-122 (of part 2), Greater Kailash-II, NewDelhi 110048, India (e-mail: [email protected])

1 Yoshida H, Horie H, Matsuura K,Miyamura T. Characterisation of vaccine-derived polioviruses isolated from sewageand river water in Japan. Lancet 2000; 356:1461–63.

2 Kuroiwa C, Bongphrachanh P, Chosa T,et al. Risk of poliomyelitis importation andre-emergence in Laos. Lancet 2000; 356:1487–88.

3 Pregliasco F, Minolfi V, Boschin A,Andreassi A, Prefota ML. Aseroepidemiologic survey of immunityagainst poliomyelitis in a group of HIVpositive and HIV negative drug addicts.Eur J Epidemiol 1995; 11: 693–95.

4 Parkkali T, Ruutu T, Stenvik M, et al.Loss of protective immunity to polio,diphtheria and Haemophilus influenzae typeb after allogeneic bone marrowtransplantation. APMIS 1996; 104:383–88.

Sir—The report by Hiromu Yoshidaand colleagues1 provides importantand somewhat concerning infor-mation. They genotyped 29 isolates oftype 3 poliovirus from environmentalwater samples. All of the isolates werevaccine-derived, since wild polio-viruses have been absent in Japansince 1980.

Among the isolates, 13 wereneurovirulent because of back-mutation from vaccine-like(nucleotide U at position 472 in the 5�non-coding region) to wild-like (C atposition 472). Each of the 13 isolateshad more than 80% 472-C revertants.Another cluster of 13 strains wereclearly vaccine-like, with fewer than0·25% revertants. Three strains wereintermediate, with 2–65% revertants.Thus, most strains fell in two polarclusters, either with the vaccinereference strain (F313) or with thewild prototype strain (Leon), insteadof being intermediate. Yoshida andcolleagues did not explain why. I offeran explanation.

Each virus isolate is probably theprogeny of an extremely small numberof virions in the original inoculum. Ifeach isolate is derived from a singleviable virion in the sample, theprogeny will resemble the parent,which might be 472-U genotype or its472-C revertant. Thus, 13 virions inthe water samples would have beenvaccine-like and another 13revertants. Mutations do occur duringreplication of polioviruses, even in cellculture, since their genome consists ofRNA, which cannot proofread andcorrect errors. Therefore, each virusisolate will be a mixture, as illustratedby these 26 strains, with most of thevirions resembling the parent, and asmall proportion consisting ofmutants with the oppositecharacteristic. This pattern explainsthe polar clustering. The three strainswith 2–65% 472-C revertants mighthave been derived from more than oneparent virion in the inoculum, andduring replication one genotype mighthave grown faster than the other.

Many workers might not haverealised that the type 3 vaccinereference strain itself could contain asmall proportion (0·4%) of 472-Cneurovirulent revertant.1 Albert Sabinhad plaque-purified each vaccine virustype, ensuring that each was theprogeny of a single virion. Yet whenthe strain is grown in culture, a small

number of mutants would appear.Since most progeny viruses wouldresemble the parent virion, thevaccine strain will consist mostly ofvaccine-like genotype, and will alsopass the monkey neurovirulence test.2

A vaccine recipient might developvaccine-induced polio because of thiscontamination with revertants. Whena contact of a vaccinated childdevelops vaccine-induced polio, thevirus could have reverted toneurovirulence during passage in thetwo people. WHO have clearlywarned all countries using the livevaccine that the negative monkeyneurovirulence test is not proof ofits innocuity,3 and wanted allcountries using the live vaccine toestablish surveillance to detect andmeasure the frequency of vaccine-induced polio. Many countriesneglected to do this.

The risk of people acquiringinfection from environmental watermight be negligible in Japan, but notin many other countries with denselypopulated communities that havepoor hygiene and sanitation. In caseof infection from the environment, therevertant virus could have thepotential for transmission similar tothe wild virus. Therefore, there iswisdom in the conclusion of Yoshidaand colleagues that completeeradication may require replacing thelive vaccine with the inactivatedvaccine, which, according to WHO issafe and provides individual andcommunity protection.3 Knowing thepotential risk from the vaccine viruses,we ought to redefine polio eradicationas the absence of any polioviruses inhuman beings and the environment,instead of the currently populardefinition as the absence of only wildpolioviruses.

T Jacob John439 Civil Supplies Godown Lane,Kamalakshipuram, Vellore, TN 632 002, India(e-mail: [email protected])

1 Yoshida H, Hitoshi H, Matsuura K,Miyamura T. Characterisation of vaccine-derived polioviruses from sewage and riverwater. Lancet 2000; 356: 1461–63,

2 Chumakov KM, Powers LB, Noonan KE,Roninson IB, Levenbook IS. Correlationbetween amount of virus with alterednucleotide sequence and the monkey testfor acceptability of oral poliovirus vaccine.Proc Natl Acad Sci USA 1991; 88:199–203.

3 WHO Consultative Group. The relationbetween acute persisting spinal paralysisand poliomyelitis vaccine. Bull WorldHealth Organ 1982; 60: 231–42.

Sir—Hiromu Yoshida and colleagues1

report that no wild type 3 polioviruseswere isolated from samples of sewageand river water collected in Toyama



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few revertant VDS will cause disease,there is no need to abandon the use ofOPV after the elimination of wildpolioviruses in a country. Althoughseveral more-developed counties haveswitched from OPV to inactivatedpoliovaccines, this approach wouldnot be feasible in less-developedcountries.

The establishment of new orimprovement of existing poliosurveillance systems in variouscountries will have a key role in theglobal eradication of poliomyelitis.Only an excellent surveillance in thepostimmunisation era will give theanswers on how successul the globaleradication was.

John Furesz20 Driveway, #805, Ottowa, Ontario K2P 1C8,Canada

1 Yoshida H, Horie H, Matsuura K,Miyamura T. Characterisation of vaccinederived polioviruses isolated from sewageand river water in Japan. Lancet 2000; 356:1461–63.

2 Chumakov KM, Powers LB, Noonan KE,Roninson IB, Levenbook IS. Correlationbetween amount of virus with alterednucleotide sequence and the monkey testfor acceptability of oral poliovirus vaccine.Proc Natl Acad Sci USA 1991; 88:188–203.

3 Furesz J, Armstrong RE, Moreau P,Yarosh W, Nagler FP. Antigenic studies onSabin types 1 & 3 poliovaccine virus during1 to 7 passages in the human intestinaltract. Am J Epidemiol 1966; 83: 501–08.

4 Contreras G, Dimock K, Furesz J, et al.Genetic characterization of Sabin types 1and 3 poliovaccine virus following serialpassage in the human intestinal tract.Biologicals 1992; 20: 15–26.

prefecture, Japan, between October,1993, and September, 1995. All 29type 3 polioviruses isolated from thesesources were vaccine-like, sinceroutine oral vaccine administrationwas done yearly in May and October.

By use of the genetic marker test(mutant analysis by PCR andr e s t r i c t i o n - e n z y m e - c l e a v a g e[MAPREC]) developed by K MChumkov and colleagues,2 Yoshidaand co-workers showed that 13 ofthese strains maintained theirattenuated phenotypes, but 16 (55%)strains were classified as virulent.Since MAPREC assay and themonkey neurovirulence test correlatewell, the classification virulent refersto monkey neurovirulence.

These findings do not necessarilypredict human neurovirulencebecause a large proportion of AlbertSabin oral polioviruses isolated fromthe human intestinal tract a few daysafter vaccination show reversion tomonkey virulence without causing anyclinical symptoms in human beings.For example, when monovalent type 3oral poliovirus vaccine (OPV) wasserially passaged in 1960, seven timesin infants aged 8–12 months, bycontact exposure or by feedinginfants’ stool virus to infants, the virusexcreted by the first-passage infant 4days after vaccination already showedan increased monkey neurovirulencethat was sustained during theremaining six human passages.3,4 Thenucleotide-sequence analysis of thesehuman-passage strains by theMAPREC test confirmed the monkeyneurovirulence test results. None ofthe infants showed symptoms ofdisease.4 The wild-type 3 Leon strainthat was isolated from a fatalbulbospinal poliomyelitis case in 1937and used by Sabin for developing theattenuated type 3 vaccine, showed thelowest monkey neurovirulence amongthe four wild strains used as controlsin the test.4 Thus the correlation ofpoliovirus neurovirulence betweenmonkeys and humans is limited.3

In light of the success of WHO’sGlobal Poliomyelitis EradicationProgram, which that is in its finalstage, Yoshida and colleagues’overemphasis of the environmentalrisk of vaccine-associated paralyticpoliomyelitis should be accepted withcaution. After the elimination of wild-type polioviruses from variouscommunities by the large-scale use ofOPV, the continuous circulation ofvaccine-derived strains (VDS) in thepopulation should be anticipated aslong as OPV programmes are in place.Since the risk of vaccine-associatedpoliomyelitis is very low and only a

Fetal stimulation andactivity state

Sir—The conclusion of C F vanHeteren and colleagues (Sept 30,p 1169)1 that fetal habituation rateis linked to learning and memoryprocesses is dubious. 18 (24%) of 75recordings had to be disregarded,which brings into question the validityof the stimulator they used as ahabituation tool.

The fetuses might have beendisturbed in a way similar to thatwhich we have shown for otherintense stimuli (electrolarynx).2

Moreover, there are discrepanciesbetween the text and figure. Theminimum number of stimuli in theinitial test is given as one and threein the upper and lower panels,respectively, and at least four insteadof one habituated more slowly 24 hlater. Most importantly, van Heterenand colleagues did not take intoaccount that responsiveness toexternal stimuli can depend on theunderlying fetal behavioural state.

Hab

ituat

ion

rate

(nu

mbe

r of

stim

uli)

50

40

30

20

10

0

1F day 1 2F day 2 2F day 1 1F day 2

State

Fetal habituation rate during states 1Fand 2F on first and second day

Term fetuses alternate mainly betweenquiet sleep (1F) and active (2F) sleepstates, which represent differentmodes of brain activity, and last about25 min and 60 min, respectively.3

We studied habituation to repeatedvibroacoustic stimulation with anelectric toothbrush in 15 healthy termfetuses, observed ultrasonographicallyduring stimulation on two occasions24 h apart, once in state 1F and oncein state 2F. 50 5 s stimuli werepresented every 20 s. We definedhabituation as absence of fetal trunkmovement for five successive stimuli.Overall, habituation was significantlyfaster in state 1F than in state 2F(median 4 [IQR 0–10] vs 14 s stimuli[2–31]), with no effect of experimentalsequence (figure). Non-respondingoccurred on both days (figure). Theoverall habituation rate was similaron both days stimuli (7 [0–31] vs8 s stimuli [0–11]).

Our findings, therefore, do notsupport van Heteren and colleagues’conclusion that the fetus has long-term memory, nor that non-responding to stimulation suggestsimmediate recognition of stimuli,since they and others have previouslyshown that fetuses with major central-nervous-system malformations(encephalocele, anencephaly, micro-cephaly) are non-responders.4,5

Although there have been manystudies on fetal habituation during thepast 20 years, its importance is stillcontroversial. We believe that thestate-dependent habituation rate wesaw made a difference to van Heterenand colleagues’ results. If they hadanalysed the data in relation to fetalbehavioural state and in comparablestates, their data might have lentvalidity to the conclusions for short-term and long-term memory.

*E J H Mulder, P G Robles de Medina,M E W Beekhuijzen, D E Wijnberger,G H A Visser

Department of Obstetrics, Neonatology, andGynaecology, University Medical Centre,3584 EA Utrecht, Netherlands



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Guiding hands of ourteachers

Sir—As clinicians we appreciate thedifficulties associated with frequenthand cleansing, and note in the reportof Didier Pittet and colleagues (Oct 14,p 1307)1 that doctors were theprofessional group most resistant tochange of practice.

We believe you cannot teach olddogs new tricks. To address this issue in the University of Liverpool,

we start in the first week of study to teach students to use alcoholhandrub so that it becomes secondnature for them before any contact withpatients. Furthermore, the correctapplication of hand washing is anintegral part of the assessments thatstudents undertake in clinical skills.Many clinical teachers, however, do notencourage this practice by example andeven complain when it features inclinical examinations.

We believe our students are the onlyoperators for changes, but until themost senior doctors accept theimportance of this simple procedureand set examples, it will be hard fornew students to establish the standardof care they desire.

*Richard D Griffiths, Paul Bradley*Department of Medicine (Intensive Care) andthe Clinical Skills Resource Centre, Faculty ofMedicine, University of Liverpool, LiverpoolL69 3GA, UK(e-mail: [email protected])

1 Pittet D, Hugonnet S, Harbarth S, et al,and members of the infection controlprogramme. Effectiveness of a hospital-wideprogramme to improve compliance withhand hygiene. Lancet 2000; 356:1307–12.

Sir—Didier Pittet and colleagues1

describe a successful intervention toimprove hygiene practices thatcoincided with a reduction ofnosocomial infection. The subject ofreport and the accompanying comm-entary by Christina Vandenbroucke-Grauls (Oct 14, p 1290)2 is that of ourmission to improve handwashingbehaviour in health-care workers andour promotion of the use of alcoholhandrub to overcome several commonbarriers to hand hygiene (time,facilities, and skin allergy).

Pittet and colleagues’ report partly validates this suggestion, but acknowledges that use of alcohol handrub was but onecomponent of a multifacetedintervention that included observation,feedback, posters, and institutionalsupport.

Pittet and colleagues andVandenbroucke-Grauls note thelimitations of hand-hygiene studies:lack of randomisation, the Hawthorneeffect, insufficient power, and theconfounding effect of other infectioncontrol practices when attributinglower infection rates to improved handhygiene. Indeed, during the study, arigorous control programme formeticillin-resistant Staphylococcusaureus (MRSA), was started3 whichmay also have influenced the decline inMRSA.

The commentary dwelt on the needfor health-care workers to have

latter all responded initially. Theabnormal fetuses never responded,even when tested again after 1 or 2weeks.2,3

14 (19%) of our 75 experimentswere uninterpretable because fetusesshowed alternate responses and non-responses, which prompted Mulderand colleagues to question the validityof our stimulator. Most fetusesexhibited regular responses, however,to repeated stimulation and we thinkthat the stimulator was valid. Weexcluded data for conformity with thedefinition of habituation that we used.

To study fetal habituation, thestimulus must reach the fetus andrepeated stimulation results in regularfetal responding. Attention should befocused on the duration, maximumnumber of stimuli, and place ofstimulation to account for possiblefetal disturbance.4 To diminish therisk of fetal disturbance we stimulatedfor 1 s every 30 s over the fetal legswith a maximum of 21 stimuli.

*Cathelijne F van Heteren, P Focco Boekkooi, Henk W Jongsma, Jan G Nijhuis*Department of Obstetrics and Gynaecology,University Medical Centre, 6500 HB Nijmegen,Netherlands, and Department of Obstetricsand Gynaecology, University Hospital,Maastricht, Netherlands

1 Van Heteren CF, Boekkooi PF, Jongsma HW, Nijhuis JG. Fetalhabituation to vibroacoustic stimulation inrelation to fetal states and fetal heart rateparameters. Early Hum Dev (in press).

2 Mulder EJH, Robles de Medina PG,Beekhuijzen MEW, Visser GHA. Fetalhabituation to vibro-acoustic stimulation:the effect of behavioural state. In: Abstractsof the Fetal and Neonatal PhysiologicalSociety. Netherlands: Fetal and NeonatalPhysiological Society, 1999: 84.

3 Van Heteren CF, Boekkooi PF, Jongsma HW, Nijhuis JG. Responses tovibroacoustic stimulation in a fetus with anencephalocele compared to responses ofnormal fetuses. J Perinat Med 2000; 28: 306–08.

4 Visser GHA, Mulder HH, Wit HP, Mulder EJH, Prechtl HFR. Vibro-acousticstimulation of the human fetus: effect ofbehavioural state organization. Early HumDev 1989; 19: 285–96.

1 van Heteren CF, Boekkooi PF,Jangsma HW, Nijhuis JG. Fetal learningand memory. Lancet 2000; 356: 1169–70.

2 Visser GHA, Mulder HH, Wit HP,Mulder EJH, Prechtl HFR. Vibro-acousticstimulation of the human fetus: effect onbehavioural state organization. Early HumDev 1989; 19: 285–96.

3 Nijhuis JG, Prechtl HFR, Martin CB,Bots RSGM. Are there behavioural statesin the human fetus? Early Hum Dev 1982;6: 177–95.

4 van Heteren CF, Boekkooi PF,Jongsma HW, Nijhuis JG. Responses tovibroacoustic stimulation in a fetus with anencephalocele compared to responses ofnormal fetuses. J Perinatal Med 2000; 28:306–08.

5 Leader LR, Baillie P, Martin B,Vermeulen E. Fetal habituation in high-riskpregnancies. Br J Obstet Gynaecol 1982; 89:441–46.

Authors’ reply

Sir—There is a difference between thefigure in our report and the text. Weexcluded the data from sixexperiments of the second test andfrom six of the third, and, therefore,the data from 19 experimentsremained for these tests. The upperpanel of the figure includes the data offetuses with only two interpretabletests, whereas the lower panel isrestricted to that of 17 fetuses withthree interpretable tests. After 24 h,16 of 19 fetuses habituated morerapidly and three fetuses more slowly,with two of them exhibiting persistentresponses (p=0·042).

We may have missed the effect offetal behavioural states on habituation,but, in a previous study we saw noeffect.1 This finding can be explainedby the fact that vibroacousticstimulation arouses the fetus, whichresults in a state transition to an activestate during testing in most fetuses.1

Therefore, the influence of statebefore stimulation can probably beneglected.

Moreover, we think that E Mulderand colleagues’ data should beinterpreted with caution, since 57% ofthe fetuses in state 1F on day 1 did notrespond.2 In our study all 25 fetusesresponded in the first test. Therefore,we think that the stimulator they haveused is unsuitable for testing fetalhabituation.

In our study, although all fetusesresponded in the first test, four did notrespond in the second test, and one inthe third test. We propose non-response is a result of immediaterecognition of the stimulus. Thedifference between non-responderswith brain or chromosomal anomaliesand the normal fetuses that did notrespond to repeated testing is that the



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behavioural or educational inter-ventions will improve compliance.Thames Valley University’s systematicreview of handwashing5 calls for trials ofsuch interventions, reinforcing theearlier call by our group.5 Pittet andcolleagues’ report, with its emphasis onuse of alcohol handrub and feedback ofcompliance is an important pointer tothe way forward. To reflect thisstrategy, we have changed our namefrom the Handwashing to the Hand-hygiene Liaison Group.

The other members of the group are Carole Fry,Dinah Gould, Annette Jeaves, Liz Jenner, Dee May, Ann Pallett, Martin Schweiger, andGeoff Scott.

*Sheldon Stone, Louise Teare,Barry Cookson, for the Hand-hygieneLiaison Group*Department of Geriatric Medicine, Royal FreeCampus, Royal Free and University CollegeMedical School, London NW3 2PF, UK;Chelmsford Public Health Laboratory Service,Chelmsford; and Laboratory of HospitalInfection, Central Public Health Laboratory,London(e-mail: [email protected])

1 Pittet D, Huggonet S, Harbath S, et al, andmembers of the infection controlprogramme. Effectiveness of a hospital-wideprogramme to improve compliance withhand hygiene. Lancet 2000; 356: 1307–12.

2 Vandenbroucke-Grauls CMJE. Clean handscloser to the bedside. Lancet 2000; 356:1290–91.

3 Harbarth S, Martin Y, Rohner P, Henry N,Auckenthauler R, Pittet D. Effect of delayedinfection control meaures on a hospitaloutbreak of methicillin resistantStaphylococcus aureus. J Hosp Infect 2000;46: 43–49.

4 Rotter ML. Semmelweiss’ sesquicentennial:a little noted anniversary of Handwashing.Curr Opin Infect Dis 1998; 11: 457–60.

5 Thames Valley University EAC guidelines:evidence based practice in infection control.J Hosp Infect 2001 (in press).

Sir—Didier Pittet and colleagues1 showthat it is possible to produce sustainedimprovement in compliance withhandwashing. They identify potentiallimitations related to observation biasand the Hawthorne effect fromobservations made by infection-controlnurses. Despite improvement in overallcompliance of hospital staff, however,compliance among doctors did notimprove with time.

We did an observational study in theOxford Kidney Unit to assess whetherhandwashing practice could beimproved. A junior doctor counted the number of times hands were washed on ward rounds led by a registrar or consultant, withouttheir knowledge or any previousdiscussion about handwashing practices.The frequency of handwashing on therenal ward over a 1-week period was58% (24 of 41 observed opportunities).

We presented this result, togetherwith a summary of relevant publishedreports, to the medical staff at an audit meeting and invited suggestionsof ways to improve handwashingpractice. It was agreed that cliniciansshould wash their hands after physicalexamination of all patients, and that all members of the medical andnursing staff involved in ward roundswould remind any doctor who forgot todo so. After 1 month, the observerreaudited handwashing practice for 1week, again without the knowledge of the clinicians. The handwashing rate had increased significantly to 86%(30 of 35 opportunities, p=0·019).

Although handwashing frequency islow among doctors2 compared withother healthcare workers,3 no study hasshown an improvement in handwashingcompliance among doctors. We showthat with little expense, handwashingcompliance of doctors in a specialistunit can improve through self-reminders and encouragement. Weplan to maintain this improvement byrepeated audit and feedback ofcompliance rates.

Lok B Yap, *Ian C J W Bowler,Patrick H MaxwellOxford Kidney Unit, Churchill Hospital,Headington, Oxford; and *Department ofMicrobiology, John Radcliffe Hospital, OxfordOX3 9DZ, UK

1 Pittet D, Hugonnet S, Harbarth S, et al,and members of the infection controlprogramme. Effectiveness of a hospital-wideprogramme to improve compliance withhand hygiene. Lancet 2000; 356: 1307–12.

2 Daniels IR, Rees BI. Institution UniversityHospital of Wales, Cardiff. Handwashing:simple, but effective. Ann R Coll Surg Engl1999; 81: 117–18.

3 Pittet D, Mourouga P, Perneger TV.Compliance with handwashing in a teachinghospital. Ann Intern Med 1999; 130: 126–30.

evidence that handwashing ordecontamination between contact withpatients reduces infection rates. Wesuggest that the evidence is muchstronger than that presented. Withexclusion of studies done before andafter intervention, which have a weakerexperimental design, and those studiesthat seem not to measure handwashing,we identified nine studies (threerandomised controlled trials, fivecontrolled trials, and one crossoverstudy), in various settings (community,school, and neonatal, obstetric, andintensive care departments), in whichhandwashing adherence has beenmeasured by direct observation or useof consumables, or enforced by studyinvestigators (table). All these studiesshow significant reductions ininfection-related outcomes. Someworkers might argue, thatSemmelweiss’s study4 was not set up asa controlled trial, but his raw datasupport our contention that it can beclassified as such.

These settings might not all seemcomparable to general hospital wards orgeneralisable to the level of hospital-acquired infection. However, the effectattributable to improved hand hygienewas seen both in settings with a highrate of infection in critically ill patientsand in relatively well populations withlow rates of infection.

The issue is no longer whether handdecontamination is effective. Theevidence for this is clear, as is that toshow that direct contact with patientsresults in hand contamination. Alcoholhandrub is the most effective agent toremove such organisms, unless there isphysical soiling, when soap and water isindicated. The issue, therefore, is which

Study Design Setting (country) Unit comparison Outcome attributable to handdisinfection

Semmelweiss, 1861 CT Obstetric department Department Reduction of mortality from 11%(Austria) to 1%

Mortimer E, et al. BMJ 1966 CT Neonatal nursery Cohort of babies Reduction of S aureus acquisition(USA) from 43% to 10%

Black RE, et al. Am J Epidemol RCT Community (USA) Child day-care 47% reduction in diarrhoea1981 centres (USA)Khan MU. Trans R Soc Med CT Community Family 67% reduction in ShigellosisHyg 1981 (Bangladesh)Stanton and Clemens. Am J RCT Community Urban community 26% reduction in diarrhoeaEpidemiol 1987 (Bangladesh)Conley JM, et al. Am J Crossover Medical ITU (USA) · · Reduction nosocomial infectionInfect Control 1989 from 33% to 12%Butz AM, et al. Am J Infect RCT Community (USA) Family day-care OR 0·35 (95% CI 0·20–0·56) forControl 1990 homes vomiting. OR 0·715 (95% CI

0·54–0·72) for diarrhoeaShahid S, et al. J Diarrhoeal CT Community Periurban village Relative risk diarrhoea 0·38Dis Res 1996 (Bangladesh) (95% CI 0·33–0·43)Masters D, et al. Fam Med CT School (USA) Classroom Relative risk of enteric infection1997 0·43 (95% CI 0·25–0·73) and of

all infection 0·75 (95% CI0·60–0·95)

CT=controlled trial; RCT=randomised controlled trial.

Outcome of trials of handwashing



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Guidance on rosiglitazonefor type 2 diabetesmellitus

Sir—The National Institute forClinical Excellence’s (NICE)Guidance on rosiglitazone1 is acarefully worded appraisal ofrosiglitazone based on public evidence.This evidence does not, however,include any outcome data formicrovascular and macrovasculardisease in type 2 diabetes. Theevidence for the use of rosiglitazone inparticular, and probably thiazolidi-nediones in general, hinges thereforeon surrogates, of which the mostimportant is glycosylated haemoglobin(HbA1c).

Agents that lower HbA1c concentra-tions as monotherapy or combinedtherapy are likely to reducemicrovascular disease and probablymacrovascular disease.2,3 The thiazol-idinediones certainly lower HbA1c, andthe evidence is, therefore, that theycould be offered as an alternative toinjected insulin in patients who cannottake metformin and sulphonylurea.The logic of that is irrefutable.However, the NICE guidelines (para1.3) suggest that such patients “shouldbe offered rosiglitazone combinationtherapy as an alternative to injectedinsulin”. Is there not a differencebetween what could be done and whatshould be done? There is no evidenceto suggest that the thiazolidinedionesare more effective than insulin in thelong term.

In contrast to the generally soberand evidence-based tone of the NICEGuidelines, the UK Department ofHealth letter of Friday Aug 18, 2000(ref 0485) is less constrained.Apparently “it is thought thatrosiglitazone may give better protectionthan insulin against damage to bloodvessels”. Where is the evidence forsuch a statement? We are informedthat “it is also easier to monitorwhether rosiglitazone is working” thaninsulin. Is there something built intothe structure of thiazolidinediones thatmakes them easier to monitor? Couldwe encourage the Department ofHealth to let us know what this easymonitoring entails? Meanwhile I shallcontinue to use HbA1c.

David R MatthewsOxford Centre for Diabetes Endocrinology andMetabolism, Radcliffe Infirmary, Oxford OX2 6HE, UK

1 Technology Appraisal Guidance, No 9.London: NHS National Institute forClinical Excellence, August 2000.

2 UK Prospective Diabetes (UKPDS) Group.Intensive blood-glucose control withsulphonylureas or insulin compared with

conventional treatment and risk ofcomplications in patients with type 2diabetes (UKPDS 33). Lancet 1998; 352:837–53.

3 UK Prospective Diabetes (UKPDS) group.Effect of intensive blood-glucose controlwith metformin on complications inoverweight patients with type 2 diabetes(UKPDS 34). Lancet 1998; 352:854–65.

Correspondent’s reply

Sir—I am gratified that DavidMathews considers that NICEguidance on Rosiglitazone is “a carefully worded appraisal”. I hope he also agrees that the guidance represents the best approachto current practice with thistechnology. The absence of anyoutcome data in the appraisal for directeffect of rosiglitazone on microvascularand macrovascular complications intype 2 diabetes simply reflects thepaucity of a relevant evidence base.The evidence for efficacy ofrosiglitazone, therefore, relates to theimprovements in glycaemic controlthat are achieved.

This approach reflects the outcomedata for this endpoint published underthe auspices of the United KingdomProspective Diabetes Study (UKPDS),which shows the clinical and costeffectiveness of maintaining goodglycaemic control for patients with type2 diabetes, especially on reducedincidence of diabetic complications.1,2

Interestingly, the evidence from trialson rosiglitazone of its effects onsurrogates for major cardiovascularendpoints such as LDL and HDLcholesterol blood concentrations isneutral.

The NICE guidance urges patientsand their clinical advisers to considerrosiglitazone as an alternative toinjected insulin to improve glycaemiccontrol after the failure of othertreatments. Whether the words couldor should best reflect this advice mustremain a matter of opinion. In eithercase, the principle is the same.

I am not in a position to commenton the letter from the Department ofHealth.

David BarnettNICE Appraisals Committee, London WC2 5HR,UK

1 Stratton IM, Adler AI, Neil HA, et al.Association of glycaemia withmacrovascular and microvascularcomplications of type 2 diabetes (UKPDS35): prospective observational study. BMJ2000; 321: 405–12.

2 Gray A, Raikou M, McGuire A, et al. Costeffectiveness of an intensive blood glucosecontrol policy in patients with type 2diabetes: economic analysis alongsiderandomised controlled trial (UKPDS 41).BMJ 2000; 320: 1373–78.

Facing the biologicalweapons threat

Sir—That prevention is better than curemust be among the oldest of adages,but is especially applicable to the threatof biological warfare discussed by TaraO’Toole and Thomas Inglesby (Sept30, p 1128),1 and for which Ali Khanand colleagues (Sept 30, p 1179)2

describe US preparations.O’Toole and Inglesby end by noting

that prevention of biological warfaredemands new approaches to armscontrol. They mention in passing the1972 Biological and Toxin WeaponsConvention, which declares thestockpiling and use of biologicalweapons illegal, but seem unaware thatnegotiations to add an effectiveverification protocol to the conventionare at an advanced stage.3 This changesurely provides just the new approachrequired; it calls for regular inspectionof civil and military facilities wherebiological weapons might be produced,as well as in response to warnings ofpossible breaches of the convention.The new protocol is based on thatagreed in the 1993 Chemical WeaponsConvention, which seems to be workingadequately.4

The record of the USA for armscontrol treaties has been widelycriticised, and there are fears that it isobstructing progress on the BiologicalWeapons and Toxins verificationprotocol. This record may be becauseof resistance to inspection, withits implications for commercialconfidentiality, by the biotechnologyindustry, which is most advanced in theUS. Is this why O’Toole and Inglesbydo not mention the new protocol? Asthey note, there is doubt as to whetherterrorist groups, which are not party toconventions, could mount an effectivebiological weapons attack, and averification protocol would not entirelyremove the threat from states ofconcern (apparently downgraded fromrogue states). Its achievement, forwhich the active support of the US isessential, would, however, surely do farmore for deterrence against biologicalwarfare5 than the elaborate anduntestable public-health programme ina single country described by Ali Khanand colleagues.

Douglas HoldstockMedact, London N19 4DJ, UK

1 O’Toole T, Inglesby TV. Facing thebiological weapons threat. Lancet 2000; 356:1128–29.

2 Khan AS, Morse S, Lillibridge S. Publichealth preparedness for biological terrorismin the USA. Lancet 2000; 356: 1179–82.

3 Pearson G. Preventing deliberate disease.



CORRESPONDENCE

Med Confl Surviv 2000; 16: 42–59.4 Developments in the Organization for the

Prohibition of Chemical Weapons. CBWConvention Bull 1999; 43: 2–10.

5 British Medical Association. Biotechnology,weapons and humanity. Amsterdam:Harwood, 1999.

Authors’ reply

Sir—Douglas Holdstock refers to theefforts underway to negotiate aneffective verification protocol to the1972 Biological and Toxin WeaponsConvention, and suggests that theseefforts will provide the new approachrequired for the control of biologicalweapons. Discussion of the Biologicaland Toxin Weapons Convention andarms control for biological weapons wasbeyond the scope of our commentaryon the Centers for Disease Control andPrevention Bioterrorism ResponseProgram, but we will offer some briefobservations.

The Biological and Toxin WeaponsConvention, as an instrument to controlproliferation of biological weapons, hassubstantial shortcomings. Twosignatories to the convention, theformer Soviet Union and Iraq, havelarge biological weapons programmes;1

several additional signatories arebelieved to have offensive biologicalweapons programmes that would placethem in violation of the treaty.2 It iswidely agreed that the lack ofverification and enforcement measuresfor the convention have limited, if notdoomed, its effectiveness.

A review conference of theconvention is scheduled for 2001, atwhich time it is hoped that a protocoladdressing its existing limitations will beready for consideration. Severalimportant disputes remain to be settledbefore the review happens.3 Somepeople qustion whether the protocolsunder consideration effectively addresscurrent treaty limitations and raisequestions about the feasibility ofimplementation.4

It remains to be seen whether newprotocols to the Biological and ToxinWeapons Convention will be sufficientto address the need for arms controlthat confronts us. Whether and how thepotential to create as well as quellepidemics of fatal disease can beconstrained is not clear. What isapparent, however, is that any effectivecontrol of “biological” weapons mustinclude the sustained attention andactive participation of bioscientists,physicians, and public-healthprofessionals of all nationalities.

While we must seek the means andmuster the will to prevent thedevelopment or use of biologicalweapons, we must simultaneously

construct systems and programmes thatcould reduce the consequences ofbiological-weapon attacks shouldprevention fail.

Tara O’Toole, *Thomas V InglesbyJohns Hopkins Center for Civilian BiodefenseStudies, Johns Hopkins University, CandlerBuilding, Suite 850, 111 Market Place,Baltimore, MD 21207, USA

1 Inglesby TV, O’Toole T, Henderson DA.Preventing the use of biological weapons:improving response should prevention fail.Clin Infect Dis 2000; 30: 926–29.

2 Cole LA. The specter of biological weapons.Sci Am 1996; 275: 60–65.

3 Moodie M. Fighting the proliferation ofbiological weapons: beyond the BWCprotocol: disarmament forum.“Disarmament Forum,” UN Institute forDisarmament Research, 4th Quarter(Winter), 2000.

4 Taylor ER. Strengthening the biologicalweapons convention: illusory benefits andnasty side effects. Cato Policy Analysis, No355, 1999.

from a hospital with both approachesenthusiastically agreed to collaborateand recognised a need for an evidencebase to justify this approach.

Due to reorganisation of the fundingbody, 3 years after the initial applicationthe grant money came through. By thistime, however, the hospital no longeroffered surgical management, onlyexpectant management. To myknowledge, the data on miscarriagemanagement remain inconclusive andthe evidence base is as sparse as it was 3years ago. Researchers have writtenendlessly on how difficult it is to changeclinical practice,1,2 but I had seeminglychanged it just by writing a researchprotocol.

Psychologists use the stages of changemodel to describe changes in behavioursuch as smoking, eating, and exercisehabits.3 Individuals about to changetheir behaviour are described ascontemplators, which is followed bypreparation and action. Mostconsultants were reluctant to take partin my study because the protocol wasfar removed from current practice andwould involve much reorganisation ofcurrent thinking. These could beconsidered precontemplators. Mywould-be collaborator, however, was acontemplator. He agreed to take partbecause his behaviour was alreadymoving away from conventionalpractice. His decision to collaborate andwait for the money to come through wasa shift from the preparation to action.

Research is supposed to drivepractice, but changes in practice mightbe necessary before the research isdeemed feasible. Evidence shouldprovide the basis for best practice. Butcan evidence be gathered withoutclinicians having a view of what bestpractice is? And trials are supposed totake place in a state of equipoise. Butcan there ever be equipoise if thecollaborators are the doctors who arealready shifting their positions?

My experience suggests that therhetoric of research does not reflect thereality. Where there’s a researchprotocol, who needs the research?

Jane OgdenDepartment of General Practice, Guy’s, King’sand St Thomas’ Medical Schools, King’sCollege, London SE11 6SP, UK(e-mail: [email protected])

1 Davis D, Thomson MA, Oxman AD,Haynes B. Changing physician performance:a systematic review of the effect ofcontinuing medical education strategies.JAMA; 1995; 274: 700–705.

2 Stocking B. Promoting change in clinicalcare. Qual Health Care 1992; 1: 56–60.

3 Prochaska JO, DeClemente CC. Thetranstheoretical approach: crossingtraditional boundaries of therapy.Homewood, 12: Dow Jones Irwin, 1984.

From protocol intopractice: who needs theresearch?

Sir—Researchers know that the bestway to cure any clinical difficulty is tostudy it. Set up a project to examine theobese and all patients seeing theirfamily physician suddenly become thin,or negotiate with dermatologists toselect 50 patients a month with acommon skin disorder and it suddenlybecomes rare. My experience is thesame for clinical practice. Indeed, mereintention to study is enough to produceradical change. I call this the Ogdeneffect.

3 years ago I decided to assess thebest way to manage first-trimestermiscarriage. I spoke to several cliniciansand wrote to several hospitals andmiscarriage seemed to be managedidiosyncratically, not guided by anacceptable evidence base. Somehospitals offered surgical managementonly and could not believe that anyother option was viable. Some offeredonly expectant management, and othersoffered the two approaches. How awoman was treated depended upon thepreference of the consultants involved. Idesigned a randomised control trial andsent the trial protocol to severalconsultants in my search for a clinicalcollaborator. All agreed it was aninteresting area of study. One from asurgically oriented hospital, said that hewould not be able to get women toagree to expectant management. Onefrom a hospital with the opposite policysaid that she couldn’t justify subjectingher patients to surgery. One consultant

Galactorrhoea, hyperprolactinaemia, and protease inhibitors

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