Periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in offspring: protocol for a systematic review and meta-analysis
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Talo icM, e al. BMJ Open 2017;7:e014637. doi:10.1136/bmjopen-2016-014637
Open Access
Abs Ac
In oduc ion P egnancy is associa ed wi h se e al
ho monal changes which in luence he de eloping
e us. Va ia ions in ma e nal endogenous ho mones and
p ep egnancy use o ho monal p epa a ions ha e been
linked o as hma and alle gy in he o sp ing, bu indings
a e inconsis en . We plan o unde ake a sys ema ic e iew
o syn hesise he e idence on he associa ion be ween
endogenous and exogenous ma e nal sex ho mones and
he isk o as hma and alle gy in he o sp ing.
Me hods and analysis We will sea ch Medline, Embase,
Coch ane Lib a y, Ins i u e o Scien i ic In o ma ion Web
o Science, Cumula i e Index o Nu sing and Allied Heal h,
Scopus, Google Schola , Allied and Complemen a y
Medicine Da abase, Global Heal h, Psychological
In o ma ion (PsycINFO), Cen e o Ag icul u e and
Bioscience (CAB) In e na ional and WHO Global Heal h
Lib a y om incep ion un il 2016 o iden i y ele an
s udies on he opic. Addi ional s udies will be iden i ied
by sea ching da abases o 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 ical epidemiological s udies. Two
esea che s will independen ly sc een iden i ied s udies,
unde ake da a ex ac ion and assess isk o bias in
eligible s udies, while a hi d e iewe will a bi a e any
disag eemen . We will use he E ec i e Public Heal h
P ac ice P ojec ool o assess he isk o bias in he
s udies. We will pe o m a andom-e ec s me a-analysis
o syn hesise he e idence. We will use he G ading
o Recommenda ions Assessmen , De elopmen and
E alua ion app oach o a e he s eng h and quali y o he
o e all e idence wi h espec o each ou come.
E hics and dissemina ion E hical app o al is no
equi ed since he s udy is a sys ema ic e iew o
published li e a u e. Ou indings will be epo ed in a
pee - e iewed scien i ic jou nal.
PROSPERO egis a ion numbe CRD42016048324
In oduc Ion
P egnancy is associa ed wi h nume ous adjus -
men s ha occu in he endoc ine sys em,
which a e no mal and necessa y adap a ions
ha adequa ely accommoda e he e us.1–5
These adjus men s include oes ogen and
p oges e one ho monal changes, which see
s eady le els o inc ease and a e essen ial in
supp essing he hypo halamic axis and he
mens ual cycle.1–5 Human cho ionic gonad-
o opin also inc eases and helps o sus ain
he p oduc ion o p oges e one by he co pus
lu eum.4 5 P olac in le els inc ease as a esul
o he ma e nal pi ui a y gland. Ad enal
ho mones such as co isol and aldos e one
inc ease, as do pa a hy oid ho mones, which
lead o g ea e up ake o calcium in he gu
and eabso p ion in he kidney.1–5
Oes ogen plays a key ole in he well-being
and de elopmen o he e us.4 5 Inc eases in
he le els o p oges e one p oduc ion help
o elax b onchiola smoo h muscle and a e
associa ed wi h an inc ease in minu e en ila-
ion, which can ise o up o 50% g ea e han
p ep egnancy le els.4 5 Bo h oes ogen and
p oges e one a e hough o ac as immuno-
s e oids, al hough he e ec on he di ec ion
Pe iconcep ion endogenous and
exogenous ma e nal sex s e oid
ho mones and isk o as hma and
alle gy in o sp ing: p o ocol o a
sys ema ic e iew and me a-analysis
Me hunisa Talo ic,1 Aziz Sheikh,1 Nicola McClea y,1 Maijaliisa E kkola,2
Minna Kaila,3 Su i M Vi anen,4,5,6,7 B igh I Nwa u1,4
o ci e: Talo icM,
SheikhA, McClea yN, e al.
Pe iconcep ion endogenous
and exogenous ma e nal sex
s e oid ho mones and isk o
as hma and alle gy in o sp ing:
p o ocol o a sys ema ic e iew
and me a-analysis. BMJ Open
2017;7:e014637. doi:10.1136/
bmjopen-2016-014637
►P epublica ion his o y and
addi ional ma e ial o his
pape a e a ailable online. To
iew hese iles please isi he
jou nal online (h p:// dx. doi.
o g/ 10. 1136/ bmjopen- 2016-
014637).
Recei ed 16 Oc obe 2016
Re ised 15 May 2017
Accep ed 24 May 2017
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
Me hunisa Talo ic;
me hunisa. alo ic@ gmail. com
P o ocol
S eng hs and limi a ions o his s udy
►This is he i s sys ema ic e iew examining he ole
o endogenous and exogenous ma e nal sex s e oid
ho mones and isk o as hma and alle gy in he
o sp ing and hus will con ibu e o knowledge on
he e al o igin o alle gy and as hma.
►We will iden i y s udies om majo heal hca e
da abases wi hou using geog aphical o language
limi a ions, as well as including an ex ensi e
e iew on all o he cu en li e a u e, ongoing and
unpublished s udies and will employ eplicable
me hods.
►Exis ing s udies may be he e ogeneous, hus making
i di icul o de i e pooled es ima es om included
s udies.
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Open Access
o shi in he T cells is no en i ely clea .4 5 Howe e , i
has been sugges ed ha he obse ed changes in le els
o ma e nal endogenous sex s e oid ho mones, including
oes ogen, p oges e one and es os e one, du ing p eg-
nancy may in luence subsequen isk o as hma and
alle gy in he o sp ing.6–9
P ep egnancy use o o al con acep i e pills, including
combined pills and p oges in-only pills, has been pos u-
la ed o modula e he isk o as hma and alle gy in he
o sp ing h ough possible dis up ion o he immunolog-
ical balance.10–16 Wjs and Dold we e he i s o pos ula e
ha he use o con acep i e pills be o e p egnancy may
in luence subsequen isk o as hma and alle gy in he
o sp ing.10 Acco ding o hei hypo hesis, he e ec
o con acep i e pills may las o se e al yea s e en
a e discon inua ion; howe e , he dosage, equency
and iming o use o o al con acep i e pills which may
ins iga e he immune e ec ha can esul in inc eased
o sp ing as hma and alle gy isks a e unclea .10
Al hough se e al s udies ha e now in es iga ed he ole
o bo h endogenous and exogenous sex s e oid ho mones
du ing p egnancy in he de elopmen o as hma and
alle gy in he o sp ing, indings a e inconsis en . To
cla i y he unde lying e idence base, we plan o unde -
ake a sys ema ic e iew o iden i y, c i ically app aise and
syn hesise s udies on he ole o changes in endogenous
sex s e oid ho mones du ing p egnancy and he ole o
exogenous s e oid ho mone use be o e p egnancy in he
de elopmen o as hma and alle gy in he o sp ing.
Me hods
This p o ocol is epo ed ollowing 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 .17
eligibili y c i e ia
Types o s udies
All analy ical obse a ional epidemiological s udies:
coho s udies, case con ol s udies and c oss-sec ional
s udies on he opic a e eligible o inclusion. Animal
s udies, case se ies, case s udies and e iews will be
excluded.
Pa icipan s
We a e in e es ed in he ole o changes in endogenous
sex ho mones and in he use o exogenous sex ho mones
in he yea be o e p egnancy and du ing p egnancy. We
will he e o e include women du ing p econcep ion and
p egnancy and hei o sp ing o any age.
Yea s conside ed
We will include s udies published om he incep ion o
each da abase sea ched un il he end o 2016.
Language
We will ha e no language es ic ions and we will
endea ou o ansla e li e a u e published in languages
o he han English whene e his is possible.
In o ma ion sou ces
Da abase sea ches and o he sou ces o iden i y s udies
To iden i y ele an s udies, we will sea ch Medline,
Embase, Coch ane Lib a y, Ins i u e o Scien i ic In o ma-
ion (ISI) Web o Science, Cumula i e Index o Nu sing
and Allied Heal h, Scopus, Google Schola , Allied and
Complemen a y Medicine Da abase, Global Heal h,
Psychological In o ma ion (PsycINFO), Cen e o Ag i-
cul u e and Bioscience (CAB) In e na ional and WHO
Global Heal h Lib a y. Addi ional e e ences will be iden-
i ied by sea ching he e e ences ci ed in eligible s udies;
by 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 Science, Ze oc B i ish Lib a y's
Elec onic Table o Con en s (ZETOC) and by con ac ing
a panel o in e na ional expe s and au ho s who ha e
published in he ield. 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
We ha e p epa ed a sea ch s a egy using he O id in e -
ace o Medline (see online supplemen a y appendix 1)
o iden i y and e ie e ele an s udies. We will adap his
sea ch s a egy when sea ching he o he da abases.
s udy eco ds
Da a managemen
We will use Endno e Lib a y o managing he e e ences
iden i ied om he da abases. All eco ds will be expo ed
o Endno e Lib a y o onwa d s udy sc eening, de-dupli-
ca ion and o e all managemen o he e ie ed eco ds.
Selec ion p ocess
Two e iewe s (MT and NM) will independen ly sc een
he i les and/o abs ac s and ull ex s o po en ially
eligible s udies. A hi d e iewe (BN) will a bi a e any
disag eemen s.
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, while a hi d e iewe will a bi a e any
disc epancies. The da a ex ac ion o m will be pilo ed
using a selec sample o he eligible s udies p io o use in
ex ac ing da a om all s udies.
Da a i ems
We will p oduce desc ip i e summa y ables o summa ise
eligible s udies. All ele an s udy da a will be abula ed
and as a minimum he ables will include he ollowing:
s udy au ho , coun y o s udy, yea o publica ion, s udy
design, size o s udy popula ion, sou ce o s udy popula-
ion, ype o exposu e s udied (endogenous s exogenous
sex ho mones and he speci ic ypes) and me hod o
assessmen , ime be o e p egnancy and imes e du ing
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Talo icM, e al. BMJ Open 2017;7:e014637. doi:10.1136/bmjopen-2016-014637
Open Access
p egnancy exposu e was asce ained, leng h o ollow-up
( o ollow-up s udies), con ounding ac o s conside ed,
s udy ou comes and me hods o assessmen , analysis
me hods and key esul s. The PRISMA checklis will guide
he epo ing o he sys ema ic e iew.18
Types o exposu es
We will include s udies ha ha e in es iga ed he ole o
all ele an endogenous sex s e oid ho mones (including
oes ogen, p oges e one, es os e one) and exogenous
sex ho mones (including oes ogen only, p oges e one
only and combined o al con acep i es).
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, angioedema and
ood alle gy. The seconda y ou comes will include: a opic
sensi isa ion as de ined ei he by skin p ick es o aised
an igen speci ic 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 de ined by sel - epo
o objec i e diagnosis; indica o s o ai way unc ion
including (peak expi a o y low, o ced expi a o y
olume in 1 s, o ced i al capaci y, o ced expi a o y low
a e o al e na i e age app op 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. We will also assess he impac
o sex ho mones on any alle gic o espi a o y ou come.
Risk o bias in indi idual s udies
Two e iewe s (MT and NM) will independen ly e alua e
he isk o bias in eligible s udies and consensus will be
eached h ough discussion; a hi d e iewe (BN) will
a bi a e any disc epancies. We will use he E ec i e
Public Heal h P ac ice P ojec ool (EPHPP) (www. ephpp.
ca) o app aise he isk o bias in s udies. The EPHPP ool
allows o he g ading o key componen s o he s udies,
including: sui abili y o he s udy design o he esea ch
ques ion; isk o selec ion bias; exposu e measu emen ;
ou come assessmen (gi ing a highe g ade o objec i ely
de ined ou comes han subjec i ely de ined ou comes)
and gene alisabili y o indings. F om hese compo-
nen -speci ic g adings, we will de i e an o e all g ading
o each s udy.
Da a syn hesis
All analyses will be unde aken sepa a ely o s udies
on exogenous ho mones and s udies on endogenous
ho mones. We will syn hesise he da a bo h na a i ely and
quan i a i ely. Fo quan i a i e syn hesis, we will pe o m
andom-e ec s me a-analysis o combine he es ima es
om s udies judged o be clinically, me hodologically
and s a is ically homogeneous. He e ogenei y be ween
s udies will be quan i ied using he I2 s a is ic. Fo anal-
yses in es iga ing he ole o endogenous sex ho mones,
da a syn heses will be unde aken by p egnancy imes e .
Subg oup analyses will be pe o med acco ding o 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), sex, pa i y and o analyses in es iga ing
he ole o exogenous sex ho mones, ime o exposu e
be o e p egnancy (eg, 6 mon hs s 12 mon hs be o e
p egnancy). Using he g ading de i ed om he quali y
app aisal o eligible s udies, we will pe o m sensi i i y
analyses o e alua e he obus ness o ou indings and
whe he hey a e in luenced by he isk o bias in s udies.
The me a-analyses will be pe o med using he s a is ical
package S a a V.14.
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.19 20
con idence in he cumula i e es ima e
We will e alua e and g ade he s eng h and quali y o
he o e all e idence emana ing om he e iew using he
G ading o Recommenda ions Assessmen , De elopmen
and E alua ion app oach.21
We do no en isage making clinical ecommenda ions
om his la gely and exclusi ely epidemiological e idence
base. The e may be no need o in e e e wi h p egnancy
ho mones in o he wise heal hy emales. Howe e , i
p ena al endogenous ho mones con ibu e o he isk o
alle gy and as hma in he o sp ing, unde s anding his
ole and he mechanisms h ough which hese ho mones
ope a e is essen ial o he ield, as his will con ibu e o
knowledge o he e al o igin o alle gy and as hma. Mo e-
o e , since s udies ha e now epo ed such associa ions,
wi h a ying esul s, a syn hesis o he unde lying e idence
is essen ial in cla i ying any pu a i e ole o p ena al sex
ho mones in he de elopmen o as hma and alle gy in
he o sp ing.
e hIcs and dIsseMIna Ion
We comple ed he Ushe Ins i u e o Popula ion Heal h
Sciences and In o ma ics Le el 1 e hics sel -assessmen
o m, which indica ed ha no u he e hical pe mission
was equi ed o his wo k as he s udy will only in ol e
e iew o he published li e a u e. Ou indings will be
epo ed in a pee - e iewed scien i ic jou nal.
Au ho a ilia ions
1As 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
2Depa men o Food and En i onmen al Sciences, Uni e si y o Helsinki, Helsinki,
Finland
3Depa men o Pedia ics, Public Heal h Medicine, Uni e si y o Helsinki and
Helsinki Uni e si y Hospi al, Uni e si y o Helsinki, Tampe e Uni e si y Hospi al,
Helsinki, Finland
4School o Heal h Sciences, Uni e si y o Tampe e, Tampe e, Finland
5Depa men o Li es yle and Pa icipa ion, Nu i ion Uni , Na ional Ins i u e o
Heal h and Wel a e, Helsinki, Finland
6Tampe e Cen e o Child Heal h Resea ch, Tampe e Uni e si y Hospi al, Tampe e,
Finland
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4Talo icM, e al. BMJ Open 2017;7:e014637. doi:10.1136/bmjopen-2016-014637
Open Access
7Science 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 BN 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 MT and BN and was hen e ised a e se e al ounds o c i ical
commen s om AS and addi ional eedback om MK, ME, SV and NM. All au ho s
a e in ol ed in he sys ema ic e iew p ocess.
Funding MT unde akes his wo k as pa o he equi emen o he disse a ion
o he awa d o a Mas e ’s in Public Heal h a The Uni e si y o Edinbu gh. The
wo k ecei ed no speci ic unding. BN was suppo ed by he Ins i u e o Ad anced
Social Resea ch Fellowship, Uni e si y o Tampe e, Finland; School o Heal h
Sciences, Uni e si y o Tampe e, Finland. Addi ional suppo was ecei ed om he
Fa Ins i u e and As hma UK Cen e o Applied Resea ch. 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.
E hics app o al Le el 1 e hics o m om Edinbu gh Ins i u ional Re iew Boa d was
comple ed o his s udy, which indica ed ha no e hics app o al is equi ed since i
is based only on he published li e a u e.
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/
© A icle au ho (s) (o hei employe (s) unless o he wise s a ed in he ex o he
a icle) 2017. All igh s ese ed. No comme cial use is pe mi ed unless o he wise
exp essly g an ed.
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a sys ema ic e iew and me a-analysis
as hma and alle gy in o sp ing: p o ocol o
ma e nal sex s e oid ho mones and isk o
Pe iconcep ion endogenous and exogenous
Minna Kaila, Su i M Vi anen and B igh I Nwa u
Me hunisa Talo ic, Aziz Sheikh, Nicola McClea y, Maijaliisa E kkola,
doi: 10.1136/bmjopen-2016-014637
2017 7: BMJ Open
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