Assis ed ep oduc i e echnology and
isk o as hma and alle gy in he
o sp ing: p o ocol o a sys ema ic
e iew and me a-analysis
B igh I Nwa u,
1,2
Nicola McClea y,
2
Maijaliisa E kkola,
3
Minna Kaila,
4
Su i M Vi anen,
5,6,7,1
Aziz Sheikh
2
To ci e: Nwa u BI,
McClea y N, E kkola M, e al.
Assis ed ep oduc i e
echnology and isk o
as hma and alle gy in he
o sp ing: p o ocol o a
sys ema ic e iew and me a-
analysis. BMJ Open 2016;6:
e010697. doi:10.1136/
bmjopen-2015-010697
▸P epublica ion his o y and
addi ional ma e ial is
a ailable. To iew please isi
he jou nal (h p://dx.doi.o g/
10.1136/bmjopen-2015-
010697).
Recei ed 27 No embe 2015
Re ised 22 Janua y 2016
Accep ed 11 Feb ua y 2016
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
B igh I Nwa u; b igh .
nw[email p o ec ed]
ABSTRACT
In oduc ion: The use o assis ed ep oduc i e
echnology (ART) p ocedu es has inc eased globally o e
he las h ee decades. Recen obse a ional s udies
sugges ha child en concei ed h ough ART may be a
inc eased isk o as hma and a opic disease compa ed
wi h child en concei ed na u ally, bu indings a e mixed.
We aim o syn hesise he e idence on he impac o ART
on he isk o as hma and a opic disease in he o sp ing.
Me hods and analysis: We will iden i y ele an
s udies by sea ching MEDLINE, EMBASE, Coch ane
Lib a y, ISI Web o Science, CINAHL, Scopus, Google
Schola , AMED, Global Heal h, PsychINFO, CAB
In e na ional and he WHO Global Heal h Lib a y om
1978 o 2016. We will loca e addi ional s udies h ough
sea ching da abases o he p oceedings o in e na ional
con e ences, con ac ing in e na ional expe s in he ield,
and sea ching he e e ences ci ed in iden i ied s udies.
We will include analy ic obse a ional s udies (coho
s udies, case–con ol s udies and c oss-sec ional
s udies) ha ha e in es iga ed he impac o any ype o
ART on o sp ing’s as hma and a opic disease. Sc eening
o iden i ied eco ds, da a ex ac ion om eligible s udies
and isk o bias assessmen o eligible s udies will be
independen ly unde aken by wo e iewe s, wi h
a bi a ion by a hi d e iewe . The E ec i e Public Heal h
P ac ice P ojec will be employed o isk o bias
assessmen . Es ima es om s udies judged o be
clinically, me hodologically and s a is ically homogeneous
will be syn hesised using andom-e ec s me a-analysis.
E hics and dissemina ion: As his s udy is based
solely on he published li e a u e, no e hics app o al is
equi ed. We will publish ou indings in a pee - e iewed
scien i ic jou nal and p esen he esul s a na ional and
in e na ional scien i ic con e ences.
P o ocol egis a ion: We will egis e a de ailed
p o ocol o he e iew wi h he In e na ional P ospec i e
Regis e o Sys ema ic Re iews (PROSPERO) p io o
s a ing he e iew.
INTRODUCTION
Since i s incep ion in 1978, he use o
assis ed ep oduc i e echnology (ART) has
d ama ically inc eased globally.
1–6
I is now
es ima ed ha ART accoun s o be ween 1%
and 4% o all bi hs, pa icula ly in indus ia-
lised socie ies, bu anecdo al da a sugges
ha i s use is ising in low-income and
middle-income coun ies as well.
1–6
Un il
ecen ly, in i o e ilisa ion cons i u ed he
majo i y o ART me hods, bu he use o
in acy oplasmic spe m injec ion has s eadily
inc eased in ecen imes, and is now
belie ed o comp ise up o 70% o all ART
p ocedu es; he use o o he p ocedu es,
such as esh and ozen emb yo ans e s
and in au e ine insemina ion, is s eadily
inc easing.
12
O e he yea s, he e ha e been conce ns
abou he sho - e m and long- e m isks o
child en concei ed h ough ART compa ed
wi h hose o na u ally concei ed chil-
d en.
127
Child en concei ed h ough ART
a e belie ed o pheno ypically and biochem-
ically di e om hose concei ed na u ally,
bu he mechanisms unde lying hese di e -
ences and he subsequen heal h implica-
ions a e unclea .
2
Amids conflic ing
S eng hs and limi a ions o his s udy
▪As he use o assis ed ep oduc i e echnology
becomes mo e common, cla i ying i s impac on
disease isk in o sp ing, such as isk o as hma
and alle gy, is essen ial o decision-making.
▪This is he i s sys ema ic e iew o he impac
o assis ed ep oduc i e echnology on as hma
and alle gy in o sp ing, and i will p o ide a
comp ehensi e syn hesis o he unde lying e i-
dence base.
▪The iden i ica ion o s udies om leading
medical and public heal h da abases, wi h no
geog aphical o language limi a ions, will
ad ance impo o his e idence syn hesis ac oss
se ings.
Nwa u BI, e al.BMJ Open 2016;6:e010697. doi:10.1136/bmjopen-2015-010697 1
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findings, some s udies ha e sugges ed ha ART child en
a e a inc eased isk o key pe ina al ou comes, includ-
ing congeni al mal o ma ions, p ema u i y, low bi h
weigh , hype ensi e disease, diabe es, pe ina al mo al-
i y, imp in ing diso de s and ce ain cance s.
1–6
Howe e , some in es iga o s sugges ha hese obse a-
ions may be a consequence o po en ial biases inhe en
in obse a ional epidemiological s udies, unde lying
ma e nal ac o s such as sub e ili y, age and pa i y, o a
combina ion o hese ac o s and ART, and no necessa -
ily he ART p ocedu e alone.
127
Recen ly, some s udies ha e in es iga ed he ela ion-
ship be ween ART and he isk o as hma and a opic dis-
o de s in child en concei ed h ough ART compa ed
wi h ha in child en concei ed na u ally, bu findings
a e conflic ing.
8–15
While he possible biological mech-
anism o hese associa ions, as in o he pe ina al ou -
comes, has no been clea ly add essed, some a gue ha
he obse ed associa ions may be a ibu ed o ma e nal
sub e ili y, esidual con ounding, o o he immune
modi ying ma e nal ac o s du ing p egnancy, such as
p e-exis ing condi ions including bu no limi ed o
as hma and alle gy, o o he ex insic ac o s such as med-
ica ions and smoking.
16
Fu he mo e, i has been sug-
ges ed ha , since women unde going ART p ocedu es
a e gene ally o highe socioeconomic s a us, and ha e
highe body mass wi h inc eased p e alence o me abolic
diso de s, hei o sp ing may be a an inc eased isk o
ad e se ou comes.
16
The high p e alence o me abolic
impai men in he in e ile pa ien popula ion may he e-
o e ha e long- e m ansgene a ional impac , ei he
h ough gene ic o epigene ic mechanisms as a esul o
emb yo cul u e and he po ency o he e ili y d ugs
used o ea ing esul an o a ian hype s imula ion.
16 17
Gi en he inc easing numbe o s udies ela ing ART
o as hma and a opic disease in he o sp ing and mixed
findings now being obse ed, a comp ehensi e syn hesis
o hese s udies is essen ial in o de o clea ly app ecia e
he unde lying e idence ela ing ART o he ae iology
and ou comes o as hma and a opic disease in he o -
sp ing. A syn hesis o he e idence base will also help o
iden i y ele an gaps in esea ch in his a ea and
sugges key s eps in add essing hese gaps. The e o e, in
his s udy, we aim o iden i y, c i ically app aise and syn-
hesise he e idence on he use o ART, and he isk o
as hma and a opic disease in he o sp ing.
METHODS
We ha e ollowed he ecommenda ions o he P e e ed
Repo ing I ems o Sys ema ic e iew and Me a-Analysis
P o ocols (PRISMA-P) checklis in epo ing his
p o ocol.
18
Eligibili y c i e ia
Types o s udies
We will include all analy ic obse a ional epidemio-
logical s udies (coho s udies; case–con ol s udies; and
c oss-sec ional s udies) ha ha e been conduc ed on he
opic. We will exclude e iews, case s udies and case
se ies and animal s udies.
Pa icipan s
Eligible pa icipan s will include women wi h e idence
o concep ion his o y and hei o sp ing o any age.
Yea s conside ed
Gi en ha he fi s ART p ocedu e was unde aken in
1978,
12
we will conside all e idence emana ing om
his da e up o 2016.
Language
The e will be no language es ic ions and, whe e pos-
sible, we will ansla e he li e a u e published in lan-
guages o he han English.
In o ma ion sou ces
Da abase sea ches and o he sou ces o iden i y s udies
We will sea ch MEDLINE, EMBASE, Coch ane Lib a y,
ISI Web o Science, CINAHL, Scopus, Google Schola ,
AMED, Global Heal h, PsychINFO, CAB In e na ional
and he WHO Global Heal h Lib a y. The da abases will
be sea ched o s udies indexed om 1978 un il 2016.
We will loca e addi ional e e ences h ough sea ching
he e e ences ci ed in iden ified s udies; h ough
sea ching da abases o he p oceedings o in e na ional
con e ences, such as ISI Con e ence P oceedings
Ci a ion Index ia Web o Knowledge, ZETOC (B i ish
Lib a y); and by con ac ing a panel o in e na ional
expe s and au ho s who ha e published in he field. We
will sea ch ial egis ies, such as Cu en Con olled
T ials (h p://www.con olled- ials.com), ClinicalT ials.
go (h p://www.clinical ials.go ) and Aus alian and
New Zealand Clinical T ials Regis y (h p://www.anzc .
o g.au), o iden i y ongoing s udies.
Sea ch s a egy
Using he O id in e ace o MEDLINE, we ha e de el-
oped a highly sensi i e and comp ehensi e sea ch s a -
egy (see online supplemen a y appendix 1) o iden i y
and e ie e ele an and eligible s udies. This sea ch
s a egy will be adap ed in sea ching he o he da abases.
S udy eco ds
Da a managemen
The e ie ed eco ds om all da abases will be expo ed
o Endno e Lib a y, which will be used h oughou he
e iew o s udy sc eening, deduplica ion and o e all
managemen o he e ie ed eco ds.
Selec ion p ocess
Ti les and abs ac s o e ie ed a icles will be sc eened
and ull ex copies o po en ially eligible s udies
assessed by wo independen e iewe s; a hi d e iewe
will a bi a e any disc epancies. S udies ha do no ulfil
he inclusion c i e ia will be excluded.
2Nwa u BI, e al.BMJ Open 2016;6:e010697. doi:10.1136/bmjopen-2015-010697
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Da a ex ac ion
Two e iewe s will independen ly ex ac ele an s udy
da a om eligible s udies on o a cus omised da a ex ac-
ion o m; a hi d e iewe will a bi a e any disc epan-
cies. Be o e using he o m o all s udies, we will pilo
he da a ex ac ion o m wi h a selec ed sample o
s udies in o de o e alua e he abili y o he o m o
cap u e he ele an s udy da a o in e es .
Da a i ems
Desc ip i e summa y ables will be p oduced o summa -
ise he li e a u e and we will abula e all ele an s udy
da a. In addi ion o o he ele an s udy da a as may be
a ailable om each s udy, we aim o cap u e, as a
minimum, he ollowing da a i ems om each s udy:
s udy au ho ; coun y o s udy; yea o publica ion; ype o
s udy design; s udy size; sou ce o s udy popula ion; ype
o ART (and compa ison g oup) and me hod o assess-
men ; single on e sus mul iple p egnancy; leng h o
ollow-up ( o ollow-up s udies); key po en ial con oun-
de s (ma e nal age, pa i y, sub e ili y, his o y o as hma/
alle gy, ma e nal smoking du ing p egnancy and sex o
child); s udy ou comes and me hods o assessmen ; ana-
lysis me hods; and key esul s. The PRISMA checklis will
guide he epo ing o he sys ema ic e iew.
19
Types o exposu es
We will include all s udies ha ha e in es iga ed he ole
o any ype o ART (in i o e ilisa ion, in au e ine
insemina ion, in acy oplasmic spe m injec ion, zygo e
in a allopian ans e , game e in a allopian ans e ,
medicinal and su gical in e ili y ea men s) in compa i-
son wi h na u al concep ion o any o he compa ison
g oup as epo ed in he s udies.
Ou comes and p io i isa ion
Ou p ima y ou comes will include: objec i ely measu ed o
sel - epo ed as hma, a opic de ma i is/eczema, alle gic
hini is, anaphylaxis, u ica ia, angio-oedema and ood
alle gy. The seconda y ou comes will include: a opic sensi-
isa ion as defined ei he by skin p ick es o aised an igen-
specific IgE; objec i e and subjec i e measu es o disease
se e i y and impac on quali y o li e, including as hma
exace ba ions, use o as hma medica ions, hospi alisa ion
o as hma, wheeze as defined by sel - epo o objec i e
diagnosis; indica o s o ai way unc ion (including peak
expi a o y flow, o ced expi a o y olume in 1 s, o ced i al
capaci y, o ced expi a o y flow a e o al e na i e age app o-
p ia e pulmona y unc ion es s (oscillome y o exhaled
ni ic oxide analysis)); and measu es o pa ien - epo ed
heal h- ela ed quali y o li e ela ed o as hma o alle gy.
Risk o bias in indi idual s udies
Risk o bias in eligible s udies will be assessed by wo
e iewe s; a hi d e iewe will a bi a e any disc epan-
cies. We will assess he isk o bias by using he E ec i e
Public Heal h P ac ice P ojec (EPHPP) ool (h p://
www.ephpp.ca). We will g ade he ollowing componen s
o each s udy: sui abili y o he s udy design o he
esea ch ques ion; isk o selec ion bias; exposu e meas-
u emen ; ou come assessmen ; and gene alisabili y o
findings. F om hese componen -specific assessmen s, we
will de i e an o e all g ading o each s udy.
Da a syn hesis
To summa ise he o e all e idence, we will unde ake a
na a i e syn hesis o he da a. Addi ionally, o clinically,
me hodologically and s a is ically homogeneous s udies,
we will pe o m me a-analyses using andom-e ec s
models o quan i y a pooled es ima e o he e ec o spe-
cific ypes o ART on he isk o as hma and a opic
disease in he o sp ing. Me a-analyses will be unde aken
sepa a ely o each specific s udy design. In compa ison
wi h fixed-e ec me a-analysis, using andom-e ec s
models o compu e he pooled es ima es p esen s a mo e
conse a i e op ion, as he unde lying assump ion o
andom-e ec s me a-analysis o non-common e ec
ac oss s udies is mo e ealis ic when in ol ing s udies
ob ained solely om he published li e a u e.
20
The
andom-e ec s model also akes in o accoun po en ial
he e ogenei y be ween s udies when compu ing he
pooled es ima es.
20
We will quan i y he he e ogenei y
be ween s udies using he I
2
s a is ic. We will unde ake
he ollowing subg oup analyses: by age o o sp ing a
onse /diagnosis o ou comes (whe e possible using he
ollowing age g oups: <5 yea s, 5–12 yea s, >12 yea s);
single on e sus mul iple p egnancy; single e sus double
emb yo ans e s; pa i y; and leng h o sub e ili y. We will
unde ake a sensi i i y analysis by he g ading o s udy
quali y in o de o e alua e he obus ness o ou find-
ings. The me a-analyses will be pe o med using he S a a
14 s a is ical package (S a aCo p. 2015. S a a S a is ical
So wa e: Release 14. College S a ion, TX: S a aCo p LP).
Publica ion bias
We will e alua e he po en ial o publica ion bias by
using unnel plo s and Begg and Egge es s.
21 22
P o ocol egis a ion
A de ailed p o ocol o he e iew is egis e ed wi h
he In e na ional P ospec i e Regis e o Sys ema ic
Re iews (PROSPERO): 2016:CRD42016035966 (h p://
www.c d.yo k.ac.uk/PROSPERO/display_ eco d.asp?
ID=CRD42016035966).
Con idence in he cumula i e es ima e
We will e alua e he s eng h o he o e all e idence
h ough assessmen o he clinical and me hodological he -
e ogenei y ac oss s udies and on he basis o he isk o bias
assessmen in included s udies. We will conside hese lines
o impac on he o e all e idence in eaching a conclusion
on he impo o findings and in ecommending o u u e
di ec ionin hefield. Fu he mo e, we will g ade he
s eng h and quali y o he o e all e idence by using he
G ading o Recommenda ions Assessmen , De elopmen
and E alua ion (GRADE) app oach.
23
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CONCLUSION
The inc easing use o ART and i s po en ial implica ion
o inc eased isk o as hma and a opic disease in he
o sp ing now equi es a comp ehensi e e idence syn-
hesis, which will p o ide us wi h he oppo uni y o
app ecia e he unde lying e idence base and assess i s
policy, p ac ice and public heal h implica ions. In add-
i ion, his e idence syn hesis p o ides he oppo uni y
o iden i y he esea ch gaps in s udies linking ART o
he de elopmen o as hma and a opic disease in he
o sp ing. We aim o epo he findings om his
e iew by au umn 2016.
Au ho a ilia ions
1
School o Heal h Sciences, Uni e si y o Tampe e, Tampe e, Finland
2
As hma UK Cen e o Applied Resea ch, Cen e o Medical In o ma ics,
Ushe Ins i u e o Popula ion Heal h Sciences and In o ma ics, The Uni e si y
o Edinbu gh, Edinbu gh, UK
3
Depa men o Food and En i onmen al Sciences, Uni e si y o Helsinki,
Helsinki, Finland
4
Depa men o Public Heal h, Uni e si y o Helsinki, Helsinki, Finland
5
Nu i ion Uni , Depa men o Li es yle and Pa icipa ion, Na ional Ins i u e o
Heal h and Wel a e, Helsinki, Finland
6
Tampe e Cen e o Child Heal h Resea ch, Tampe e Uni e si y Hospi al,
Tampe e, Finland
7
Science Cen e o Pi kanmaa Hospi al Dis ic , Tampe e Uni e si y Hospi al
and Uni e si y o Tampe e, Tampe e, Finland
Con ibu o s BIN concei ed he idea o his wo k and is he gua an o . AS
con ibu ed subjec expe ise o he de elopmen o he p o ocol. The p o ocol
was d a ed by BIN and hen e ised a e se e al ounds o c i ical commen s
om AS and addi ional eedback om ME, MK, SMV and NM. All he au ho s
will be in ol ed in he sys ema ic e iew p ocess.
Funding This wo k is unded by a ellowship awa d o BIN om he Ins i u e
o Ad anced Social Resea ch, wi h addi ional suppo om he School o
Heal h Sciences, Uni e si y o Tampe e, Finland. Addi ional suppo was also
p o ided by he As hma UK Cen e o Applied Resea ch, The Uni e si y o
Edinbu gh, UK.
Disclaime The iews p esen ed he e a e hose o he au ho s and no
necessa ily hose o he Uni e si ies o Tampe e and Edinbu gh.
Compe ing in e es s None decla ed.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h
he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license,
which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-
comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided
he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p://
c ea i ecommons.o g/licenses/by-nc/4.0/
REFERENCES
1. Talaulika VS, A ulkuma an S. Rep oduc i e ou comes a e assis ed
concep ion. Obs e Gynecol Su 2012;67:566–83.
2. Sa age T, Peek J, Ho man PL, e al. Childhood ou comes o
assis ed ep oduc i e echnology. Hum Rep od 2011;26:2392–400.
3. de Mouzon J, Goossens V, Bha acha ya S, e al. Assis ed
ep oduc i e echnology in Eu ope, 2006: esul s gene a ed om
Eu opean egis e by ESHRE. Hum Rep od 2010;25:1851–62.
4. Basa emu E, Su cli e A. Follow-up o child en bo n a e ART.
Placen a 2008;29:S135–40.
5. Schie e LA, Fe e C, Pe e son HB, e al. Pe ina al ou come among
single on in an s concei ed h ough assis ed ep oduc i e echnology
in he Uni ed S a es. Obs e Gynecol 2004;103:1144–53.
6. Schie e LA, Rasmussen SA, Buck GM, e al. A e child en bo n a e
assis ed ep oduc i e echnology a inc eased isk o ad e se heal h
ou comes? Obs e Gynecol 2004;103:1154–63.
7. Lambe RD. Sa e y issues in assis ed ep oduc i e echnology:
ae iology o heal h p oblems in single on ART babies. Hum Rep od
2003;18:1987–91.
8. Jäde be g I, Thomsen SF, Ky ik KO, e al. A opic diseases in wins
bo n a e assis ed ep oduc ion. Paedia Pe ina Epidemiol
2012;26:140–5.
9. Guibas GV, Moschonis G, Xepapadaki P, e al. PD44-In i o
e ilisa ion is posi i ely associa ed wi h p e alence o as hma in
childhood. Clin T ansl Alle gy 2014;4:P44.
10. Sicignano N, Beydoun HA, Russell H, e al. A desc ip i e s udy o
as hma in young adul s concei ed by IVF. Rep od Biomed Online
2010;21:812–18.
11. Ca son C, Sacke A, Kelly Y, e al. As hma in child en bo n a e
in e ili y ea men : indings om he UK Millennium Coho S udy.
Hum Rep od 2013;28:471–9.
12. Källén B, Finns öm O, Nyg en KG, e al. As hma in Swedish
child en concei ed by in i o e ilisa ion. A ch Dis Child
2013;98:92–6.
13. Guibas GV, Moschonis G, Xepapadaki P, e al. Concep ion ia in
i o e iliza ion and deli e y by Caesa ean sec ion a e associa ed
wi h paedia ic as hma incidence. Clin Exp Alle gy 2013;43:1058–66.
14. Ce inkaya F, Gelen SA, Ke ancioglu E, e al. P e alence o as hma
and o he alle gic diseases in child en bo n a e in i o e ilisa ion.
Alle gol Immunopa hol 2009;37:11–3.
15. Kleme i R, Se ón T, Gissle M, e al. Heal h o child en bo n as a
esul o in i o e iliza ion. Pedia ics 2006;118:1819–27.
16. Da ies MJ. In e ili y ea men a he edge: disco e y and isk
con e ge a he limi s o knowledge. A ch Dis Child 2013;98:89–90.
17. Shio a K, Yamada S. In au e ine en i onmen -genome in e ac ion
and child en’s de elopmen (3): assis ed ep oduc i e echnologies
and de elopmen al diso de s.J Toxicol Sci 2009;34(Suppl 2):
SP287–91.
18. Shamsee L, Mohe D, Cla ke M, e al. P e e ed epo ing i ems o
sys ema ic e iew and me a-analysis p o ocols (PRISMA-P) 2015:
elabo a ion and explana ion. BMJ 2015;349:g7647.
19. Mohe D, Libe a i A, Te zla J, e al. The PRISMA G oup. P e e ed
epo ing i ems o sys ema ic e iews and me a-analyses: he
PRISMA s a emen . PLoS Med 2009;6:e1000097.
20. Bo ens ein M, Hedges LV, Higgins JPT, e al. A basic in oduc ion o
ixed-e ec and andom-e ec s models o me a-analysis. Res Syn h
Me hods 2010;1:97–111.
21. Begg CB, Mazumda M. Ope a ing cha ac e is ics o a ank
co ela ion es o publica ion bias. Biome ics 1994;50:1088–101.
22. Egge M, Smi h GD, Schneide M, e al. Bias in me a-analysis
de ec ed by a simple, g aphical es . BMJ 1997;315:629–34.
23. Guya GH, Oxman AD, Vis GE, e al. GRADE: an eme ging
consensus on a ing quali y o e idence and s eng h o
ecommenda ions. BMJ 2008;336:924–6.
4Nwa u BI, e al.BMJ Open 2016;6:e010697. doi:10.1136/bmjopen-2015-010697
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o a sys ema ic e iew and me a-analysis
as hma and alle gy in he o sp ing: p o ocol
Assis ed ep oduc i e echnology and isk o
Vi anen and Aziz Sheikh
B igh I Nwa u, Nicola McClea y, Maijaliisa E kkola, Minna Kaila, Su i M
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