Discomfort and Pain in Newborns With Myelomeningocele: A Prospective Evaluation

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DiscomfortandPaininNewbornsWithMyelomeningoceleAProspectiveEvaluation

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DOI 101542peds2011-1645 originally published online February 27 2012Pediatrics

Rob de JongMyrthe J Ottenhoff Ruben Dammers Erwin J O Kompanje Dick Tibboel and T H

EvaluationDiscomfort and Pain in Newborns With Myelomeningocele A Prospective

httppediatricsaappublicationsorgcontentearly20120222peds2011-1645

located on the World Wide Web at The online version of this article along with updated information and services is

of Pediatrics All rights reserved Print ISSN 0031-4005 Online ISSN 1098-4275Boulevard Elk Grove Village Illinois 60007 Copyright copy 2012 by the American Academy published and trademarked by the American Academy of Pediatrics 141 Northwest Pointpublication it has been published continuously since 1948 PEDIATRICS is owned PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly

at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

Discomfort and Pain in Newborns WithMyelomeningocele A Prospective Evaluation

WHATrsquoS KNOWN ON THIS SUBJECT Active termination of life innewborns with myelomeningocele because of assumed sufferingin these newborns has been extensively discussed However thelevel of discomfort and pain in these newborns has never beensubstantially assessed

WHAT THIS STUDY ADDS This is the first study presentingquantitative data on discomfort and pain in newborns withmyelomeningocele Therefore it can be of guidance in the choiceof treatment either active treatment or palliative care in thecontext of end-of-life decisions

abstractOBJECTIVE In a worldwide debate on deliberately terminating the livesof newborns proponents point at newborns with very severe forms ofmyelomeningocele (MMC) and their assumed suffering claiming thereare no effective means of alleviating their distress Nevertheless thedegree of discomfort and pain in these newborns has never beenassessed in a structured manner

METHODS In a prospective cohort study 28 consecutive newbornswith MMC were included over a 5-year period and were followedup throughout their hospital stay for initial treatment We created 2disease severity groups on the basis of the Lorber criteria The primaryoutcomes were discomfort and pain assessed by simultaneously scor-ing 2 validated scales the visual analog scale for pain and the ComfortBehavioral Scale for discomfort These scores were coupled to a vali-dated and evidence-based analgesia algorithm

RESULTS Overall discomfort related to pain was measured in 33 ofthe scores This percentage differed little between the preoperativeand postoperative periods and did not significantly differ between new-borns with less severe MMC and severe MMC (39 vs 28 P = 3) Themean dosage of paracetamol was 35 mgkg per day (95 confidenceinterval 32ndash39) the mean dosage of morphine was 09 mgkg perhour (95 confidence interval 06 ndash12)

CONCLUSION Over the length of their hospital stays for initial treat-ment all newborns with MMC presented with low levels of discomfortand pain independent of disease severity and time frame Pediatrics2012129e741ndashe747

AUTHORS Myrthe J Ottenhoff MSca Ruben DammersMD PhDa Erwin J O Kompanje PhDb Dick Tibboel MDPhDc and T H Rob de Jong MDa

Departments of aNeurosurgery and cIntensive Care Erasmus MCSophia Childrenrsquos Hospital Rotterdam Netherlands andbDepartment of Intensive Care Erasmus MC RotterdamNetherlands

KEY WORDSdecision-making infant newborn pain measurementsstandards spinal dysraphismtherapy

ABBREVIATIONSCImdashconfidence intervalCOMFORT-BmdashComfort Behavior ScaleMMCmdashmyelomeningoceleVASmdashvisual analog scale

All authors made substantial contributions to conception anddesign acquisition of data or analysis and interpretation ofdata drafted the article or revised it critically for importantintellectual content and all authors provided final approval ofthe version to be published

wwwpediatricsorgcgidoi101542peds2011-1645

doi101542peds2011-1645

Accepted for publication Nov 15 2011

Address correspondence to Rob T H R de Jong MD Erasmus MCSophia Childrenrsquos Hospital Department of Neurosurgery RoomSk-1200 Postbus 2060 3000 CB Rotterdam Netherlands E-mailthrdejongerasmusmcnl

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they haveno financial relationships relevant to this article to disclose

FUNDING No external funding

PEDIATRICS Volume 129 Number 3 March 2012 e741

ARTICLE

at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

Myelomeningocele (MMC) is a birthdefect resulting from incomplete fusionof the neural folds and is thereforecategorized as a neural tube defect Therecommended treatment is surgicalclosure of the defect and insertion ofa ventriculoperitoneal shunt if hydro-cephalus is diagnosed1 However sur-gery does not always seem feasiblebecause some forms of MMC are con-sidered to be too severe to be treatedCriteria for determining whether toproceed with treatment were deve-loped by Lorber in the 1970s2 Thesecriteria are still being used today todistinguish between severe and lesssevere cases of MMC2 as improvementsin care have allowedmany patients withMMC to reach their adult years witha nearly normal quality of life3ndash5 Despitethese improvements decision-makingon initiation of treatment in very se-vere forms of MMC even prenatally6

may be difficult Even more difficult maybe deciding on palliative treatment oractive termination of life when surgicaltreatment is not started

In 2005 a total of 22 cases of deliberatetermination of life of newborns in theNetherlands were reported over theperiod 1997 to 20047 These 22 new-borns were all born with MMC and suf-fered unbearably without any propermedical means to alleviate their con-dition This serious condition of thesenewborns was expected to continue onthe long-term without hope for thefuture7 This debate was then extrapo-lated to all newborns with very severeconditions In the Netherlands this ledto the development of The GroningenProtocol89 which evoked an extensive in-ternational discussion10ndash19 This protocolcontains directives and criteria underwhich physicians can decide to deliber-ately terminate the lives of newbornswithout the prospect of legal prosecutionIt was adopted by the Dutch Society ofPediatrics and was accepted by the DutchPublic Prosecution Service Proponents

of The Groningen Protocol used the as-sumption of unbearable and hopelesssuffering in newbornswith a very severeform of MMC as an argument in theirfavor7ndash9 Opponents argued that new-borns with MMC certainly can feel painbut that any discomfort andor pain canbe alleviated effectively and that new-borns are not able to suffer to beginwith13ndash162021

Most of these publications howeverare of an ethical legal or philosophicalnature Quantifying the assumed suf-fering therefore seems to be very im-portant not only in the light of thedebate on deliberate termination of thelife of newborns with MMC per se butalso of newborns with severe con-ditions in general However sufferingshould not be considered as an out-come measure for the following rea-sons (1) suffering is a subjective termwhich cannot be measured and (2) suf-fering also includes future suffering interms of hospital dependency predictedinability to communicate future qualityof lifeandpredictedself-sufficiency Thisbroad idea of suffering cannot be ex-periencedbynewborns Furthermore ifone suspects a newborn is currently suf-fering thus excluding the future prospectof this distress one should determinetheactual causes for thesuffering suchas discomfort or pain Objective andvalidated scales are now available tomeasure both discomfort and painthese tools include the Comfort Be-havioral Scale (COMFORT-B) and thevisual analog scale (VAS)22 In additionthe degree of discomfort and pain innewborns with MMC has never beenassessed to our knowledge We there-fore conducted The Rotterdam Study onDiscomfort and Pain in Newborns withMyelomeningocele whichwe report here

METHODS

Study Design Patients and Setting

We performed a prospective cohortstudy to characterize the discomfort

and pain profiles of newborns withMMC The study was approved by thelocal medical ethical review board ofthe Erasmus University Medical CenterRotterdam the Netherlands Newbornswith MMC were included when theywere admitted for initial treatment toour hospital between January 1 2005and January 1 2010 Patients were ex-cluded when they were born with ad-ditional gross congenital anomalies orchromosomal anomalies not associ-ated with MMC

Patient DemographicCharacteristics and Lorber Criteria

Routinely collectedparameters includedgender postnatal and postmenstrualage and the anatomic level of the MMCIn addition clinical symptoms of men-ingitis active hydrocephalus requiringsurgical intervention and the presenceof a retention bladder were assessedalong with types and doses of analge-sics administered

To investigate whether the discomfortand pain profile was dependent on theseverity of the MMC we distinguishedbetween less severe MMC and severeMMC by using the Lorber criteria andaccordingly created 2 groups labeledthe nonndashLorber group and the Lorbergroup respectively Newborns wereassigned to the Lorber group when 1or more of the following conditionswere met thoracolumbar lesion se-vere paraplegia (grade 5 paraplegia[at most the hip flexors acting] orgrade 4 paraplegia [at most the hipadductors and the quadriceps acting inaddition to the hip flexors]) gross en-largement of the head (2 cm abovep90) kyphosis additional gross con-genital anomalies andor major birthinjuries2

Discomfort and PainMeasurements

The COMFORT-B scale was applied toassess discomfort the VAS was used to

e742 OTTENHOFF et al at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

assess pain Purpose-trained ICU andpediatric nurses applied both scales inall patients for the duration of theirtreatment These nurses previouslydemonstrated acceptable interraterreliability (linearly weighted Cohenrsquosk$065) with an already qualified scorerin 10 consecutive scoring sessions22

The COMFORT-B scale measures dis-comfort by observation of behavior23

The scale was validated by researchersat Sophia Childrenrsquos Hospital22 TheCOMFORT-B scale includes 6 behaviorswhose intensities are rated on a scalefrom 1 to 5 alertness calmnessagitation respiratory response inmechanically ventilated patients or cry-ing in spontaneously breathing new-borns body movement muscle toneand facial tension Rating is performedafter 2 minutes of bedside observationAt the end of the observation perioda limb is carefully lifted to assess mus-cle tone The scores on all 6 items aresummed to produce a total score be-tween 6 and 30 A COMFORT-B score$17indicates discomfort that should be al-leviated24

The VAS is a standard method of as-sessing pain in clinical settings and isgenerally considered as an overall as-sessment of pain It is applied after the2-minute COMFORT-B observation TheVAS is a 10-cm line on which the ob-server places a mark to rate pain from0 (ldquono painrdquo) to 10 (ldquoworst possiblepainrdquo) A VAS score $4 is classified asldquopainrdquo and is an indication for (addi-tional) analgesic treatment2225

Protocolized Pain Management

A series of studies at our institution haveresulted in a validated algorithm formonitoring and treating discomfort andpain in newborns222426ndash30 in line withnationwide guidelines31 These guide-lines have not changed in the last decade

This algorithm is basedon the combinedCOMFORT-B and VAS scores for the fol-lowingreasonWhenonly theCOMFORT-B

scale exceeds a cutoff point the dis-comfort could be caused by eventsother thanpain suchashungerorawetdiaper However when both COMFORT-Band VAS scores exceed their cutoffpoints simultaneously the discomfortis most likely caused by the pain whichshould then be treated

Because suffering is not an objectiveparameter we considered this vali-dated algorithm most suitable to as-sess thedegreesofdiscomfort andpainof newbornswithMMCbefore and afterclosure of the defect Therefore theprimary outcome of this study was theconcurrent COMFORT-B and VAS scores

Statistical Analysis

Patient demographic characteristicsare presented as mean values and 95confidence intervals (CIs) or as fre-quencies and percentages where ap-propriate The continuous variables ofthe Lorber group and the nonndashLorbergroup were compared by using un-paired Studentrsquos t test when the varia-bles were normally distributed or aMann-Whitney U test otherwise Dis-crete variables were compared by us-ing the x2 test or Fisherrsquos exact testwhen at least 1 of the expected countsof the variable values was 5

COMFORT-B VAS scores and combinedCOMFORT-B and VAS scores that excee-ded the previous cutoff points are pre-sented as frequencies and percentagesThese percentages are treated as con-tinuous variables and do not seem to benormally distributed To evaluate time-dependent or surgery-related distresswe compared discomfort and pain dur-ing various time periods (preoperativewithin 24 hoursrsquo postoperative 24ndash48hoursrsquo postoperative and 48 hoursrsquopostoperative) by using a Wilcoxonsigned rank test

To compare the discomfort and painscores of the Lorber and the nonndashLorber groups the COMFORT-B VASscores and combined COMFORT-B and

VAS scores were treated as a discretevariable Variables were compared byusing the x2 test or Fisherrsquos exact test

Statistical analysiswas performedwithSPSS 170 for Windows (SPSS Inc Chi-cago IL)

RESULTS

Patient Characteristics

We included 28 consecutive newbornswith MMC One patient was born withtrisomy 18 (Edwardrsquos syndrome) andwas excluded Twenty were born in theSophia Childrenrsquos Hospital 8 were ad-mitted within 48 hours of birth Of the28 included patients 14 were boys and14 were girls The mean gestationalage was 391 weeks (95 CI 383ndash399)with a range of 311 to 423 weeks Themean birth weight was 3178 g (95 CI3041ndash3315) The Lorber group con-tained 8 newborns and the nonndashLorbergroup 20 newborns MMC at the lum-bosacral level was most frequent (17patients) Twenty-six patients (929)had either congenital hydrocephalusor acquired hydrocephalus which waseventually treated with a ventriculoper-itoneal shunt One patient developedmeningitis postoperatively which wastreated with antibiotics with good re-sults None of these variables differedsignificantly between the Lorber andnonndashLorber group except level of MMC(Table 1) All patientswere found to havea retention bladder that needed cathe-terization After counseling of the par-ents and having obtained parentalconsent surgical closure of the defectwas performed mostly in collaborationwith a plastic surgeon

COMFORT-B and VAS scores were col-lectedoverameanof 317hours (95CI210ndash424) Individual follow-up timesranged from 8 to 1160 hours The meanICU stay for postoperative surveillancewas 103 hours (95 CI 14ndash190) Four-teen patients were discharged fromthe ICU within 36 hours The follow-up

ARTICLE

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time and the time spent in the ICU didnot differ significantly between the 2

groups (Table 1)

COMFORT-B and VAS Scores

Overacumulative follow-up timeof9082hours we collected 1258 scores ofwhich 87were concurrent COMFORT-Band VAS scores Numbers and percen-tages of collected COMFORT-B VAS andconcurrent scores are displayed perindividual case in Supplemental Table 4and per follow-up period in Supple-mental Table 5

Overall 79 of the COMFORT-B scoreswere $17 37 of VAS scores were$4 Overall 33 of all concurrentCOMFORT-B and VAS scores exceededboth cutoff points These percentagesvaried over time (Table 2) COMFORT-Bscores exceeded their cutoff pointsignificantly less frequently during the24- to 48-hour postoperative periodcompared with all other time periodsVAS and concurrent scores exceededtheir cutoff points significantly lessfrequently during the 24- to 48-hourpostoperative period compared with

the 0- to 24-hour postoperative periodonly

Percentages of COMFORT-B VAS andconcurrent scores exceeding theircutoff points in the Lorber group werehigher than in the nonndashLorber groupwith no significant differences (P =13 P = 08 and P = 3 respectivelyTable 3)

Administration of Analgesics

All patients received paracetamol viarectal administration to alleviate painat some time 21 patients receivedmorphine via infusion (75) Paracet-amol and morphine were being ad-ministered594and139respectivelyof the total follow-up time Paracetamolwas administered most often duringthe 24- to 48-hour postoperative period(828) which corresponds to thehighest mean dosages in this period(Table 2) followed by the 48-hourpostoperative period (598) Morphinewas more frequently administeredduring the 0- to 24-hour postoperativeperiod (646) which corresponds tothe highest mean dosage of all periodsfollowed by the 24- to 48-hour post-operative period (189)

The overall mean dosage of para-cetamol was 35 mgkg per day (95 CI32ndash39) with a range of 0 to 102 mgkgper day Unfortunately the upper limitof this range indicates an overdosewhich reflects a single 33 mgkg dos-age over 6 hours followed by 3 single23 mgkg distributed over the rest ofthe day in 1 patient This finding isconsidered a calculation error duringthe treatment of this newborn as therewere no high COMFORT-B or VAS scoresat the time This was the only overdoseregistered in our study The overallmean dosage of morphine was 09mgkg per hour (95 CI 06ndash12) with arange of 0 to 25 mgkg per hour Themean analgesic dosages are pre-sented according to follow-up periodin Table 2

TABLE 1 Patient Characteristics

Characteristic Lorber Group P

Less Severe (n = 20) Severe (n = 8)

Gender n ( male) 10 (500) 4 (500) 99a

Birth weight mean (95 CI) g 3160 (2993ndash3330) 3214 (2922ndash3507) 72b

Gestational age mean (95 CI) wk 393 (382ndash403) 387 (372ndash401) 49b

Follow-up mean (95 CI) h 261 (194ndash327) 442 (97ndash787) 71c

Time in ICU mean (95 CI) h 68 (5ndash131) 180 (2104 to 464) 14c

Level of MMC n 001ad

Thoracic 0 1Thoracolumbar 0 4Lumbar 5 1Lumbosacral 15 2

Hydrocephalus n () 19 (950) 7 (778) 22a

Meningitis n () 0 (0) 1 (111) 31a

a P value calculated by using Fisherrsquos exact testb P value calculated by using an unpaired t testc P value calculated by using a Mann-Whitney U testd Thoracic and thoracolumar levels compared with lumbar and lumbosacral levels

TABLE 2 Scores and Analgesics Outcome According to Follow-up Period

Variable Period Total

Preoperative 0- to 24-hPostoperative

24- to 48-hPostoperative

48-hPostoperative

VASMedian (interquartile range) 0 (0ndash0) 0 (0ndash1) 0 (0ndash0) 0 (0ndash0) 0 (0ndash0)Scores $4 n () 10 (43) 11 (67a) 1 (13) 21 (30) 43 (37)

COMFORT-BMedian (interquartile range) 11 (10ndash13) 10 (9ndash11) 11 (10ndash12) 11 (11ndash13) 11 (10ndash13)Scores $17 n () 19 (76a) 10 (61a) 1 (13) 66 (92a) 96 (79)

Concurrent VAS and COMFORT-BscoresScores $4 and $17 n () 9 (39) 10 (61a) 1 (14a) 17 (26) 37 (33)

Paracetamol dosage mgkgdMean (95 CI) 28 (20ndash36) 30 (19ndash42) 48 (40ndash55) 36 (32ndash41) 35 (32ndash39)Median (interquartile range) 0 (0ndash57) 25 (0ndash67) 53 (52ndash60) 54 (0ndash62) 53 (0ndash60)

Morphine dosage mgkghMean (95 CI) 02 (201 to 04) 36 (20ndash52) 1 (01ndash18) 08 (04ndash12) 09 (06ndash12)Median (interquartile range) 0 (0ndash0) 2 (0ndash63) 0 (0ndash0) 0 (0ndash0) 0 (0ndash0)

a Significantly higher percentage compared with 24- to 48-hour phase Corresponding P values are shown in SupplementalTable 6

e744 OTTENHOFF et al at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

Newborns in the Lorber group didnot consume significantly more para-cetamol than newborns in the nonndashLorber group (P = 21) but they didconsume significantly more morphine(P = 02) However the median mor-phine dosage in both groups was 0mgkg per hour with an interquartilerange of 0 to 0 (Table 3)

Figure 1 illustrates the mean dosagesof paracetamol and morphine over thefollow-up period compared between

the 2 groups Only in the preoperativeperiod did the Lorber group consumemore paracetamol than the nonndashLorber group (P = 01) in the48-hourpostoperative period the Lorber groupconsumed significantly less para-cetamol (P = 003) As for the dailymorphine dosage the Lorber grouprequired significantly more in the 24- to48-hour period and the 48-hourpostoperative period (P = 007 and P =002 respectively)

DISCUSSION

The findings from this study show thatroutine analgesic treatment222426ndash30

resulted in low levels of discomfort andpain in all newborns with MMC in-dependent of the severity of the dis-ease and over the whole preoperativeand postoperative periods Only the 24-to 48-hour postoperative period wasdifferent as the 0- to 24-hour post-operative period showed higher percen-tages of exceeding VAS and concurrentscores compared with this period Inaddition the percentage of exceedingCOMFORT-B scores in the 24- to 48-hourperiod was lower compared with allother periods Disease severity was notassociated with paracetamol consump-tion except in the preoperative periodThe more severely affected patientsconsumed more morphine howeverNevertheless morphine was rarely ad-ministered overall as the median mor-phine dosagewas 0mgkg per hour withan interquartile range of 0 to 0

Some limitations of this study shouldbe addressed First because it was asinglendashcenter study the level of re-producibility at other centers cannot

TABLE 3 Scores and Analgesics According to Lorber Group

Scale Lorber Group P

Less Severe Severe

VASMedian (interquartile range) 0 (0ndash0) 0 (0ndash1)Scores ($4) n () 18 (29) 25 (46) 13a

COMFORT-BMedian (interquartile range) 11 (10ndash12) 11 (10ndash13)Scores ($17) n () 47 (67) 49 (95) 08a

Concurrent VAS and COMFORT-BScores ($4 and $17) n () 17 (28) 20 (39) 3a

Paracetamol dosage mgkg per dayMean (95 CI) 37 (33ndash42) 33 (28ndash38) 21b

Median (interquartile range) 52 (0ndash67) 53 (0ndash58)Morphine dosage mgkg per hMean (95 CI) 05 (02ndash07) 15 (09ndash21) 02c

Median (interquartile range) 0 (0ndash0) 0 (0ndash0)a P value calculated by using a x2 testb P value calculated by using an unpaired t testc P value calculated by using a Mann-Whitney U test

FIGURE 1Comparison of paracetamol andmorphine dosage between Lorber groups according to follow-up period P values were calculated by using a Mann-Whitney Utest

ARTICLE

PEDIATRICS Volume 129 Number 3 March 2012 e745 at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

be established However our centerhas extensive experience in the treat-ment of children with MMC for exam-ple our multidisciplinary MMC teamwas established 25 years ago Fur-thermore great attention is paid to thediagnosis and treatment of pain anddiscomfort in newborns and chil-dren222427 Second there may be someselection bias because nurses aremore likely to assess the newbornswhenever discomfort or pain is sus-pected Both inconsistencies are due todaily practice on a pediatric wardThird the follow-up ended at dischargeand the follow-up period therefore dif-fered between the children Assumingthat the length of the hospital stay isrelated to the severity and complica-tions of the disease the discomfort andpain levels could have been overes-timated Still we found no relationshipbetween these variables (P = 7) andtherefore consider our conclusions tobe valid and justified by the data

Our findings indicate that discomfortand pain in newborns with MMC canbe adequately managed In all patientsany possible level of discomfort andpain measured was treated with anevidence-basedalgorithm foranalgesictreatment except for 1 patient whoreceived a single overdose of para-cetamol Concurrent COMFORT-B andVAS scores indicated the need of extra

analgesic treatment only rarely (37ofcases) Moreover during much of thefollow-up period only paracetamol wasadministered indicating mild pain32 Inaddition surgical closure of the defectseems to be an effective means ofproducing stable well-being in thesenewborns given that pain and dis-comfort scores in the postoperativeperiods were not significantly higherthan those in the preoperative periodThe doses of morphine administered inthe postoperative periods were con-sistent with standards for newbornswho have undergone surgery2728 Inaddition severity of the congenital mal-formations had no influence on levels ofdiscomfort and pain We concludedtherefore that treatment of more se-verely affected patients is as feasible asthat of less severely affected patients

Our results fit into internationally ac-cepted consensus on the treatment ofcritically ill children as levels of dis-comfort and pain overall are low andany exceptional high levels are easilytreatable with a routine analgesic al-gorithm For example one review arti-cle concluded that ldquomulti-disciplinaryconsensus guidelines for maintenanceof sedation and analgesia in criticallyill children have been successfullyproduced and are supported by levelsof evidencerdquo32 However the authorsacknowledged the shortage of properly

designed trials in this particular groupof patients33

CONCLUSIONS

In this representative cohort of new-bornswithMMC we detected low levelsof discomfort and pain in newbornsindependent of disease severity andtime frame Any discomfort and paincould be routinely treated by usinga validated analgesic algorithm Thisstudy naturally suggests future researchAs the degree of discomfort and pain inthese 28 newborns with MMC is nowclearly described the quality of life ofthese patients in childhood adoles-cence and adulthood should be fur-ther investigated Factors in addition todiscomfort and pain that could be ex-plored include cognitive developmentmotor problems bladder dysfunctionsshunt deficiencies total number of oper-ations chronic pain and dependency onmedical andor supportive care

ACKNOWLEDGMENTSThe authors thank Hester F LingsmaPhD (Department of Public Health Di-vision of Clinical Decision SciencesErasmus MC) for statistical supportand Monique van Dijk PhD and KoHagoort MSc (Department of IntensiveCare Erasmus MC Sophia ChildrenrsquosHospital) for reviewing the manuscript

REFERENCES

1 Rintoul NE Sutton LN Hubbard AM et al Anew look at myelomeningoceles functionallevel vertebral level shunting and theimplications for fetal intervention Pediat-rics 2002109(3)409ndash413

2 Lorber J Spina bifida cystica Results oftreatment of 270 consecutive cases withcriteria for selection for the future ArchDis Child 197247(256)854ndash873

3 Tennant PW Pearce MS Bythell M Rankin J20-year survival of children born withcongenital anomalies a population-basedstudy Lancet 2010375(9715)649ndash656

4 Bowman RM McLone DG Grant JA TomitaT Ito JA Spina bifida outcome a 25-yearprospective Pediatr Neurosurg 200134(3)114ndash120

5 Sawin KJ Bellin MH Quality of life inindividuals with spina bifida a researchupdate Dev Disabil Res Rev 201016(1)47ndash59

6 Adzick NS Thom EA Spong CY et al MOMSInvestigators A randomized trial of pre-natal versus postnatal repair of myelo-meningocele N Engl J Med 2011364(11)993ndash1004

7 Verhagen AA Sol JJ Brouwer OF Sauer PJDeliberate termination of life in newbornsin The Netherlands review of all 22reported cases between 1997 and 2004 [inDutch] Ned Tijdschr Geneeskd 2005149(4)183ndash188

8 Verhagen AA Sauer PJ End-of-life deci-sions in newborns an approach from TheNetherlands Pediatrics 2005116(3)736ndash739

9 Verhagen E Sauer PJ The Groningen pro-tocolmdasheuthanasia in severely ill newbornsN Engl J Med 2005352(10)959ndash962

e746 OTTENHOFF et al at Erasmus MC - Medische Bibliotheek on February 27 2012pediatricsaappublicationsorgDownloaded from

10 Chervenak FA McCullough LB Arabin BWhy the Groningen Protocol should berejected Hastings Cent Rep 200636(5)30ndash33

11 Verhagen AA van der Hoeven MA vanGoudoever JB de Vries MC Schoutenvan-van Meeteren AY Albers MJ Hopeless andunbearable suffering and deliberate endingof life of newborn infants [in Dutch] NedTijdschr Geneeskd 2007151(26)1474ndash1477

12 Verhagen AA van der Hoeven MA vanMeerveld RC Sauer PJ Physician medicaldecision-making at the end of life in new-borns insight into implementation at 2Dutch centers Pediatrics 2007120(1) Avail-able at wwwpediatricsorgcgicontentfull1201e20

13 de Jong TH Deliberate termination of life ofnewborns with spina bifida a criticalreappraisal Childs Nerv Syst 200824(1)13ndash28 discussion 29ndash56

14 Kodish E Paediatric ethics a repudiation ofthe Groningen protocol Lancet 2008371(9616)892ndash893

15 Kon AA We cannot accurately predict theextent of an infantrsquos future suffering theGroningen Protocol is too dangerous tosupport Am J Bioeth 20088(11)27ndash29

16 Chervenak FA McCullough LB Arabin B TheGroningen Protocol is it necessary Is itscientific Is it ethical J Perinat Med 200937(3)199ndash205

17 Gesundheit B Steinberg A Blazer S Jotko-witz A The Groningen Protocolmdashthe Jewishperspective Neonatology 200996(1)6ndash10

18 Sauer PJ Verhagen AA The GroningenProtocol unfortunately misunderstoodCommentary on Gesundheit et al TheGroningen Protocolmdash the Jewish perspective

(neonatology 2009966-10) Neonatology200996(1)11ndash12

19 Verhagen AA Janvier A Leuthner SR et alCategorizing neonatal deaths a cross-cultural study in the United States Canadaand The Netherlands J Pediatr 2010156(1)33ndash37

20 Kon AA Neonatal euthanasia is unsupport-able the Groningen protocol should beabandoned Theor Med Bioeth 200728(5)453ndash463

21 Jotkowitz A Glick S Gesundheit B A caseagainst justified non-voluntary active eu-thanasia (the Groningen Protocol) Am JBioeth 20088(11)23ndash26

22 van Dijk M de Boer JB Koot HM Tibboel DPasschier J Duivenvoorden HJ The re-liability and validity of the COMFORT scale asa postoperative pain instrument in 0 to 3-year-old infants Pain 200084(2ndash3)367ndash377

23 Ambuel B Hamlett KW Marx CM Blumer JLAssessing distress in pediatric intensivecare environments the COMFORT scaleJ Pediatr Psychol 199217(1)95ndash109

24 van Dijk M Peters JW van Deventer PTibboel D The COMFORT Behavior Scalea tool for assessing pain and sedation ininfants Am J Nurs 2005105(1)33ndash36

25 Buchholz M Karl HW Pomietto M Lynn APain scores in infants a modified infantpain scale versus visual analogue J PainSymptom Manage 199815(2)117ndash124

26 Bouwmeester NJ Anderson BJ Tibboel DHolford NH Developmental pharmacoki-netics of morphine and its metabolites inneonates infants and young children Br JAnaesth 200492(2)208ndash217

27 Bouwmeester NJ Hop WC van Dijk MAnand KJ van den Anker JN Tibboel D

Postoperative pain in the neonate age-related differences in morphine require-ments and metabolism Intensive Care Med200329(11)2009ndash2015

28 Bouwmeester NJ van den Anker JN HopWC Anand KJ Tibboel D Age- and therapy-related effects on morphine requirementsand plasma concentrations of morphineand its metabolites in postoperative infantsBr J Anaesth 200390(5)642ndash652

29 van Dijk M Bouwmeester NJ DuivenvoordenHJ et al Efficacy of continuous versus in-termittent morphine administration aftermajor surgery in 0-3-year-old infants a dou-ble-blind randomized controlled trial Pain200298(3)305ndash313

30 Ista E van Dijk M Tibboel D de Hoog MAssessment of sedation levels in pediatricintensive care patients can be improved byusing the COMFORT ldquobehaviorrdquo scale PediatrCrit Care Med 20056(1)58ndash63

31 Dutch Society for Pediatrics Guidelineassessment and treatment of pain inchildren 2008 Available at wwwnvknlKwaliteitRichtlijnenenindicatorenRichtlijnenPijnmetingenbehandelingvanaspx AccessedJanuary 24 2012

32 Playfor S Jenkins I Boyles C et al UnitedKingdom Paediatric Intensive Care SocietySedation Analgesia and NeuromuscularBlockade Working Group Consensus guide-lines on sedation and analgesia in criticallyill children Intensive Care Med 200632(8)1125ndash1136

33 Ista E van Dijk M de Hoog M Tibboel DDuivenvoorden HJ Construction of theSophia Observation withdrawal Symptoms-scale (SOS) for critically ill children In-tensive Care Med 200935(6)1075ndash1081

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