BMJ Open 2012;2:e000719 doi:10.

1136/bmjopen-2011-000719 Anaesthesia

Parenteral Pethidine for labour pain relief and substance use disorder: 20-year followup cohort study in offspring
1. Robert Rodrigues Pereira1,2,3, 2. Humphrey Kanhai4, 3. Frits Rosendaal5, 4. Paula an !ommelen", 5. !i#$ %&aab', ". (ri$ Rodrigues Pereira), '. *en an de +etering, - Author A..iliations 1. 2. 3. 3. 6. 6. 7. ;. 9.
1.

1 2

Department of aediatri!"# Maa""tad$ie%en&'i"# (otterdam# t&e )et&er*and" Bo'man Menta* +ea*t& ,are# (otterdam# t&e )et&er*and" 3 Department of re-ention and ,are )et&er*and" .n"tit'te of /pp*ied 0!ien!e" 1)O# 2eiden# t&e )et&er*and" 3 Department of Ob"tetri!"# 2eiden 4ni-er"it5 Medi!a* ,enter# 2eiden# t&e )et&er*and" 6 Department of ,*ini!a* 7pidemio*o85# 2eiden 4ni-er"it5 Medi!a* ,enter# 2eiden# t&e )et&er*and" 6 Department of "tati"ti!"# )et&er*and" .n"tit'te of /pp*ied 0!ien!e" 1)O# 2eiden# t&e )et&er*and" 7 )et&er*and" .n"tit'te for )e'ro"!ien!e# an .n"tit'te of t&e 9)/:# /m"terdam# t&e )et&er*and" ; ,entra* Offi!e for Motor <e&i!*e Dri-in8 1e"tin8 =,B(># /m"terdam# t&e )et&er*and" 9 Bo'man Menta* +ea*t& ,are# (otterdam# t&e )et&er*and" /orresponden#e to !r Robert Rodrigues Pereira0 pereirar1maasstad2ie$enhuis.nl Re#ei ed 5 !e#ember 2311 A##epted 1 4ay 2312 Published 33 4ay 2312

Abstract

Objective 5o determine &hether use o. intrapartum Pethidine pain analgesia in#reases the ris$ .or substan#e use disorder in adult o..spring. Design Analysis o. data .rom a #ohort study. Setting A#ademi# hospital in 6eiden, the 7etherlands. Participants 133 #ases and 1"4 #ontrol indi iduals, aged 1)823years at .ollo&9up. ain outco!e !easure :n#iden#e o. substan#e use disorder or use o. al#ohol and toba##o. "esults 5he li.etime use o. addi#ti e substan#es in #hildren e;posed to intrapartum Pethidine analgesia &as 45< o. 133 #hildren ersus 4)< o. 1"4 not9e;posed sub=e#ts >ad=usted ?R@3.',, ,5< /: 3.4) to 1.2,A. Re#ent use o. al#ohol, toba##o and hard drugs sho&ed no statisti#al di..eren#e either. #onclusion Pethidine .or labour pain medi#ation appears not to be asso#iated &ith substan#e misuse or smo$ing in later li.e.

Article su!!ary
Article focus

Resear#h BuestionC does perinatal Pethidine .or labour pain relie. lead to substan#e use disorder in later li.eD :s it possible to #on.irm the published data on an ?R o. around 5D +e hypothesise that there is no relationship.

$ey !essages

+e #annot #on.irm earlier data on the ris$ o. substan#e use disorder a.ter perinatal analgesia. +e did not .ind a ris$ .or smo$ing and drin$ing al#ohol either. Perinatal Pethidine analgesia appears not to be asso#iated &ith substan#e misuse in later li.e.

Strengths and li!itations of this study

5his is a &ell9designed large #ohort study on long9term e..e#ts o. perinatal Pethidine analgesia. 5he main limitation is the relati ely lo& response and the possible sele#ti e response.

%ntroduction
Analgesia during labour is #ommon &orld&ide. 4ethods used in#lude barbiturates, nitrous o;ide, opioids, epidural analgesia, trans#utaneous ele#tri# ner e stimulation, psy#hoprophyla;is and hypnosis. :n the 7etherlands, opiates had been used in '<815< o. all deli eries bet&een 2333 and 233', &hi#h is in 15333833333 mothers a year.1 :n the 1,'3s,

intramus#ular PethidineE &as the most #ommon drug .or pain relie. during labour. :n re#ent years, a rise in the use o. epidural or spinal analgesia and in P/A >patient9#ontrolled analgesiaA &ith ery short a#ting opiates intra enously is obser ed. Ho&e er, PethidineE is the most #ommonly used opioid &orld&ide be#ause it is #heap and easy to administer. /on#erns ha e been raised about its e..e#ti eness and potential maternal, .etal and neonatal side e..e#ts.2 A.ter parenteral therapy in the mother, the opiates #an be dete#ted in #ord blood &ith a plasma le el o. 53< o. that o. the mother. A.ter birth, the #hild is o.ten sleepy and slightly respiratory depressed .or a .e& hours.3 4 :n 1,)', the issue o. de elopment o. substan#e use disorders >%F!sA and beha ioural problems in the o..spring a.ter perinatal analgesi# medi#ation &as addressed.5 5he authors reported ?Rs o. 4.' #ompared &ith indi iduals &ho did not re#ei e perinatal analgesi# drugs. 5hese results &ere deri ed .rom #ase8#ontrol studies in patients &ith %F!."8) 5he %F! &as attributed to the Gimprinting hypothesisH and &as .irst published in the *4I in 1,,3 by Ia#obson et a*.' 5he brain, &hen e;posed to a no;e during a &indo& in time be.ore or during birth, #ould be a..e#ted permanently by #hanging neurotransmitter re#eptors, synaptogenesis, myelination, proli.eration, apoptosis, migration o. neuronal #ells or by stunting o. dendrite gro&th.,812 An epidemiologi#al and #lini#al study sho&ed that #annabis e;posure be.ore birth is asso#iated &ith impulsi e and psy#hiatri# disorders in later li.e.13 /on.li#ting results ha e been publishes about the asso#iation o. autism spe#trum disorders, de elopmental delay and learning disorders in o..spring a.ter peripartum e;posure to analgesi#s.1481' 7o long9term .ollo&9up study in #hildren born a.ter opioid use o. the mother during pregnan#y or a.ter opioid labour analgesia has been published. A re#ent /o#hrane Re ie& has been published loo$ing at the e..e#ti eness and side e..e#ts o. intrapartum parenteral opioids.1) %hort9term .ollo&9up studies did not sho& seBuelae in #hildren in their de elopment up to 5years.1,822 +e in estigated the asso#iation bet&een PethidineE use and the ris$ on smo$ing, drin$ing al#ohol or drug abuse in o..spring 23years a.ter birth.

ethods
Sa!ple and study design
Power calculation /onsidering the pre alen#e o. drug abuse, smo$ing and drin$ing al#ohol, &e needed 1"3 parti#ipants in ea#h group. :n total, )5 indi iduals in ea#h group &ere su..i#ient to dete#t an ?R o. 4.' or more bet&een the groups &ith )3< po&er and a type : error o. 3.35,' assuming a pre alen#e o. ma=or drug abuse in the #ontrol group o. 5<.1 *e#ause o. the mu#h more .reBuent use o. toba##o and al#ohol, this sample si2e &as su..i#ient to dete#t ?Rs around t&o. !ata about li.etime pre alen#e and re#ent substan#e use are a ailable .or (urope23 and .or the 7etherlands24 >table 1A.

Jie& this tableC :n this &indo& :n a ne& &indo& 5able 1 6i.etime pre alen#e and re#ent toba##o, al#ohol and drug use in the 7etherlands24 %dentification of the cohort variables A.ter ethi#al appro al by the 4edi#al (thi#al /ommittee o. the 6eiden Fni ersity 4edi#al /enter, the birth .iles .rom the A#ademi# Hospital 6eiden .rom 1,)" to 1,)' &ere used to #ompose t&o groups o. parti#ipantsC one #ohort &ith and the other &ithout labour analgesia by PethidineE. :n#luded &ere only healthy babies &ithout #ongenital anomalies, born at term a.ter an un#ompli#ated deli ery and &ho had not been admitted in the paediatri# &ard. :n.ormation &as a ailable on maternal #hara#teristi#s and obstetri# history in#luding medi#ation as &ell as the postpartum #ondition o. the ne&born. Data collection A.ter .inding the re#ent addresses, &e &ere able to send alidated Buestionnaires about li.etime and re#ent >last monthA use o. #igarettes, al#ohol and drugs. 5he .irst is the 7ational !rugs Kuestionnaire as a part o. the Permanent 7ational 6i.e %tyle :nBuiry that is used .rom 1,,' >&ith #omputer9assisted personal inter ie&ing or in #ase o. drug Buestions &ith #omputer9assisted sel.9inter ie&ing methodA that meet &ith the (uropean %tatisti#s /ode o. Pra#ti#e. 5he se#ond Buestionnaire is a alidated Buestionnaire .or young adults about li.e e ents, s#hooling and beha iour.25 Analysis 5he primary analysis &as a #omparison o. the pre alen#e o. substan#e abuse at adult age bet&een the PethidineE9e;posed and not9e;posed groups. %ubseBuently, the results &ere #ompared &ith the national drug monitor study that &as done in the same period. A multi ariate logisti# regression model &as used to #al#ulate ?Rs and ,5< /:s .or the out#ome measures &ith age, se;, religion and parental edu#ation as potential #on.ounders. 5he analyses &ere per.ormed &ith %P%% J.11.5 .or +indo&s >%P%% :n#A. &on-response 7on9responders re#ei ed a short Buestionnaire about yes or no li.etime or re#ent use o. al#ohol, smo$ing and drugs. 5he indi iduals &ho responded to the short Buestionnaire and those &ho only partially .illed in the Buestionnaire &ere analysed separately.

"esults
From a total o. '15 deli eries, ,1< o. the addresses &ere .ound. ?. these "51 indi iduals, 34' >53<A returned the Buestionnaires. ?ne hundred and thirty9three parti#ipants &ith and 1"4 &ithout PethidineE analgesia #ould be .ully e aluated >n@2,', 4"<A. A.ter a se#ond #all,

2" indi iduals &ith and 24 &ithout PethidineE analgesia #ompleted the Buestionnaire and ,2 >53 &ith and 3, &ithout PethidineEA #ompleted the short Buestionnaire. All together, 43, #hildren >"'< o. "51 #hildrenA &ere analysed. *oth the inde; and the #ontrol group sho&ed the same distribution o. age and se;. 5here &ere no di..eren#es in the distribution o. parental edu#ation or religion >table 2A. 5hese &ere also similar to national data. 5he peripartum data o. both groups sho&ed no di..eren#es in birth &eight, se; and Apgar s#ores. All ne&borns &ere healthy and none &as admitted in the paediatri# &ard. Jie& this tableC :n this &indo& :n a ne& &indo& 5able 2 !istribution o. parental edu#ation or religion strati.ied by PethidineE and no PethidineE groups 7o di..eren#es &ere .ound in li.etime or re#ent use o. drugs, al#ohol or toba##o use bet&een both groups. 5he ?R .or e er drug abuse &as 3.', >,5< /: 3.4) to 1.2,A and .or re#ent drug abuse 1.3) >,5< /: 3.4, to 2.3'A. +e also gathered data about al#ohol use, #annabis and smo$ing during and a.ter se#ondary s#hool. 5hese data did not sho& di..eren#es bet&een the groups either, the ad=usted ?Rs are presented in table 3. :n total, ,2 #hildren responded to the short Buestionnaire and 53 #hildren partially .illed out the standard Buestionnaire. 7o di..eren#e &as .ound in li.etime pre alen#e o. smo$ing, al#ohol and drug abuse bet&een the PethidineE and the non9PethidineE group independent o. the dose that ranged .rom '5 to 153mg. 5he ?Rs &ere all #lose to unity, arying bet&een 3.5) and 1.42. Jie& this tableC :n this &indo& :n a ne& &indo& 5able 3 6i.etime or re#ent use o. al#ohol, toba##o and drugs strati.ied by PethidineE and no PethidineE groups

Discussion
5his 239year .ollo&9up study sho&ed that labour analgesia by PethidineE did not signi.i#antly in#rease the ris$ o. %F! in o..spring. +e .ound no asso#iation .or hard drugs, tranBuilisers, hallu#inogeni#s, anaboli#s or so.t drugs >in#luding toba##o and al#ohol useA. 5his is in line &ith the results o. the study .rom the 4ayo #lini#s on the ris$ o. learning disability a.ter e;posure to peripartum analgesia.14 5he strength o. this study is that it is a large, long9term .ollo&9up study o. a healthy #ohort o. neonates.

+e e aluated putati e #on.ounders, su#h as so#ioe#onomi# status, se;, religion and parental edu#ation, but did not .ind di..eren#es bet&een the inde; and the #ontrol group. Fn#ontrolled #on.ounding is al&ays possible, but in this instan#e, one &ould e;pe#t these to lead to spurious positi e asso#iations and not to the absen#e o. an asso#iation. Further in estigation o. potential #on.ounders #ould be aluable. Li en the result o. the pre ious studies reporting a .i e.old in#reased ris$, our sample si2e &ith a minimal dete#table RR o. 2 &as #onser ati e. Ho&e er, this implies that &e #ould not dete#t small ris$ in#reases. 7e ertheless, the most li$ely interpretation o. our .indings, &hi#h e;#lude a ris$ in#rease o. more than 2,< o. li.etime drug abuse in #hildren e;posed to Pethidine, is the absen#e o. any asso#iation. 5he main limitation o. the study is the lo& response and the possibility o. sele#ted response. :t is not in#on#ei able that drug users responded less than others. :t is o. some #on#ern that response &as lo&er in the group e;posed during labour >54<A than in those &ho &ere not >42<A. %till, i. sele#ti e response &as only asso#iated to drug use in adult li.e, one &ould e;pe#t an attenuated e..e#t but not the absen#e o. any e..e#t. *ias &ould ha e resulted .rom a di..erential response related to opioid use during deli ery, irrespe#ti e o. drug use later in li.e. 5his seems implausible, as most young adults &ill not be a&are o. the analgeti# medi#ation o. their mothers during birth. Reassuring .or the absen#e o. ma=or bias is the .a#t that the non9respondents to the .irst Buestionnaire, &ho responded to the se#ond short Buestionnaire sho&ed the same negati e asso#iation .or %F!, drin$ing and smo$ing. 5he non9responders sho&ed an uneBual distribution in se; #ompared &ith the respondersC 41< s 5,< maleM.emale ratio. :n this large .ollo&9up study, &e #annot #on.irm the results o. pre ious studies that parenteral PethidineE .or labour pain relie. is asso#iated &ith %F! in later li.e. *e#ause o. the abo e9 mentioned limitations, .urther resear#h is needed to assess possible asso#iations bet&een other .orms o. intrapartum analgesia and %F!.

'ootnotes

(o cite: Rodrigues Pereira R, Kanhai H, Rosendaal F, et a*. Parenteral Pethidine .or labour pain relie. and substan#e use disorderC 239year .ollo&9up #ohort study in o..spring. BMJ Open 231202Ce333'1,. doiC13.113"Mbm=open923119333'1, /ontributors All authors #ontributed to the .ollo&ing #riteriaC >1A substantial #ontribution to #on#eption and design, a#Buisition o. data or analysis and interpretation o. data0 >2A dra.ting the arti#le or re ising it #riti#ally .or important intelle#tual #ontent and >3A .inal appro al o. the ersion to be published. Funding 5his resear#h re#ei ed no spe#i.i# grant .rom any .unding agen#y in publi#, #ommer#ial or not9.or9pro.it se#tors. /ompeting interests 7one. Patient #onsent ?btained. (thi#s appro al (thi#s appro al &as pro ided by 4edi#al (thi#al /ommittee o. the 6eiden Fni ersity 4edi#al /enter, the 7etherlands. Pro enan#e and peer re ie& 7ot #ommissioned0 e;ternally peer re ie&ed.

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5his is an open9a##ess arti#le distributed under the terms o. the /reati e /ommons Attribution 7on9#ommer#ial 6i#ense, &hi#h permits use, distribution, and reprodu#tion in any medium, pro ided the original &or$ is properly #ited, the use is non #ommer#ial and is other&ise in #omplian#e &ith the li#ense. %eeC httpCMM#reati e#ommons.orgMli#ensesMby9n#M2.3M and httpCMM#reati e#ommons.orgMli#ensesMby9n#M2.3Mlegal#ode.

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