Mac olides and Congeni al Mal o ma ions
1
P ena al Exposu e o Mac olides and Risk o Congeni al Mal o ma ions: A
Me a-Analysis
Na meen MALLAH, MS1,2, Hamid Reza TOHIDINIK, Ph.D1,3,4, Mahya ETMINAN,
Pha mD, MS5, Adol o FIGUEIRAS, Pha mD, Ph.D1,2, Bahi TAKKOUCHE, MD,
Ph.D1,2
A ilia ions: 1Depa men o P e en i e Medicine, Uni e si y o San iago de Compos ela,
San iago de Compos ela, Spain; 2Cen o de In es igación Biomédica en Red de
Epidemiología y Salud Pública (CIBER-ESP), Mad id, Spain; 3HIV/STI Su eillance
Resea ch Cen e , and WHO Collabo a ing Cen e o HIV Su eillance, Ins i u e o Fu u es
S udies in Heal h, Ke man Uni e si y o Medical Sciences, Ke man, I an; 4Depa men o
Epidemiology and Bios a is ics, School o Public Heal h, Teh an Uni e si y o Medical
Sciences, Teh an, I an; and 5Eye Ca e Cen e , Uni e si y o B i ish Columbia, Vancou e ,
Canada.
Add ess co espondence o: Bahi Takkouche, Depa men o P e en i e Medicine,
Uni e si y o San iago de Compos ela, San iago de Compos ela, Spain
R/ San F ancisco, s/n, 15782, [bahi.[email p o ec ed]], +34-881-812-268
ORCID: 0000-0002-0739-2241
Sho i le: Mac olides and Congeni al Mal o ma ions
Mac olides and Congeni al Mal o ma ions
2
Abs ac
In oduc ion: Mac olides a e widely used du ing p egnancy; howe e , hei e al sa e y
emains unce ain. We pe o med a me a-analysis o assess he ela ion be ween p ena al
exposu e o mac olides and occu ence o congeni al mal o ma ions.
Me hods: We sea ched MEDLINE, EMBASE and o he da abases un il June 12 h, 2019. We
assessed he quali y o he s udies and checked o he e ogenei y and publica ion bias. We
pe o med 3 di e en analyses and compa ed he e ec o mac olides o each o he
ollowing unexposed popula ions: G oup 1: babies unexposed o any medicine be o e bi h,
G oup 2: babies exposed o non-mac olides an ibio ics/non- e a ogens, and G oup 3: mixed
popula ion o he i s and second compa a o s.
Resul s: A weak associa ion be ween mac olides and congeni al mal o ma ion o any ype
was obse ed when mac olides we e compa ed o he mixed popula ion [ORg oup 3: 1.06
(95%CI 1.01, 1.10)]. Subg oup analysis showed ha his weak associa ion is es ic ed o
e us exposu e in he i s imes e o p egnancy [OR: 1.06 (95%CI: 1.01, 1.11)] and o
coho s udies [OR: 1.07 (95%CI: 1.02, 1.13). Diges i e sys em mal o ma ions we e ound o
be sligh ly associa ed wi h p ena al exposu e o mac olides [ORg oup 3: 1.14 (95%CI: 1.02,
1.26)]. Musculoskele al sys em was also ound o be po en ially a ec ed [ORg oup 2: 1.21
(95%CI: 1.08, 1.35) and ORg oup 3: 1.15 (95%CI: 1.05, 1.26)]. Eu opean s udies showed a
sligh ly s onge associa ion han Ame ican s udies in hese wo compa isons.
Conclusions: Ou s udy sugges s a weak associa ion o mac olides’ p ena al use and
congeni al mal o ma ions, limi ed o exposu e in ea ly p egnancy, and musculoskele al and
diges i e sys ems. In addi ion o s udies wi h a la ge con ol o con ounding, isk-bene i
esea ch is needed o de e mine he use ulness o mac olides du ing p egnancy.
Key wo ds: mac olides, congeni al mal o ma ions, me a-analysis, e al sa e y.
Mac olides and Congeni al Mal o ma ions
3
Key Poin s
• Mac olides a e widely used du ing p egnancy, howe e knowledge abou hei e al
sa e y is unce ain.
• This me a-analysis shows ha mac olides in ake du ing p egnancy is associa ed wi h a
weak inc ease in he odds o congeni al abno mali ies, limi ed o some subg oups.
• These indings along wi h addi ional assessmen o he isks and bene i s o mac olides
a e c ucial o de e mine hei use ulness du ing p egnancy.
Mac olides and Congeni al Mal o ma ions
4
1. In oduc ion
Congeni al abno mali ies a e mal o ma ions o o gans o body pa s du ing o ganogenesis,
which mainly ake place in he i s imes e o p egnancy [1,2]. Some mal o ma ions may
also occu in he second and hi d imes e s o p egnancy as he issues and o gans con inue
o de elop [2].
Bi h de ec s a e he leading isk ac o o in an s’ mo ali y wo ldwide [1, 3-5]. Howe e he
causes o he occu ence o hese de ec s a e no well de e mined [1]. Acco ding o he Global
Repo on Bi h De ec s, he p opo ion o mal o ma ions due o gene ic ac o s is small
compa ed o he p opo ion o abno mali ies due o exposu e o e a ogenic in a-u e ine
ac o s such as ce ain medicines [6]. I is ema kable ha 97.7% o he d ugs app o ed by
he FDA be ween 2000 and 2010 ha e ‘‘unde e mined’’ e a ogenic isk in human p egnancy
[7]. An ibio ics a e equen ly p esc ibed du ing p egnancy, mainly o ea u ina y in ec ions.
Indeed, a ound one- ou h o p egnan women ecei e an ibio ics du ing p egnancy,
comp ising he eby 80% o all p esc ip ions [8]. Some an ibio ics used o his pu pose we e
ound o ha m e al o ma ion [9].
Mac olides a e among he mos consumed an ibac e ial medicines [10-12]. The majo ypes
o mac olides include e y h omycin, azi h omycin, cla i h omycin and oxi h omycin. Da a
abou he associa ion o p ena al exposu e o mac olides wi h bi h de ec s a e inconclusi e
[9, 13-16]. Fo ins ance, when used in ea ly p egnancy, e y h omycin was associa ed wi h
anencephaly, ans e se limb de iciency, pylo ic s enosis and o he congeni al mal o ma ions,
[9, 13] while no ela ion was ound be ween cla i h omycin and he isk o e al
mal o ma ions [16].
Excep o a me a-analysis aimed a assessing gene al ad e se child ou comes, which
included a limi ed numbe o o iginal s udies, no comp ehensi e e iew was ca ied ou on
his opic so a [17]. The e o e, o de e mine i he e is an e ec o mac olides´ p ena al
Mac olides and Congeni al Mal o ma ions
5
exposu e on congeni al abno mali ies and o s udy whe he his e ec a ies acco ding o he
ype o mac olide and o he exposu e p egnancy e m, we ca ied ou a sys ema ic e iew
and me a-analysis.
2. Me hods
2.1. In o ma ion sou ces and sea ch s a egy
We e ie ed published s udies on he use o mac olide an ibio ics du ing p egnancy and he
de elopmen o congeni al mal o ma ions, by sea ching MEDLINE om 1966 un il June
12 h, 2019. To iden i y he ele an a icles, we used he ollowing syn ax:
(mac olide* OR e y h omycin OR oxi h omycin OR cla i h omycin OR azi h omycin OR
mac olide[MeSH Te ms]) AND (((bi h de ec *) OR (congeni al) OR "congeni al
abno mali ies"[MeSH Te ms] OR e al OR e us)))). The sea ch was exclusi e o s udies
in ol ing humans. Ou sea ch was no limi ed o any language o publica ion.
We excluded c oss sec ional s udies om ou sea ch due o he impossibili y o his design o
in e any causal e ec . We also conduc ed a sea ch using he ollowing e ms as ee ex
wo ds: bi h de ec s, congeni al mal o ma ion, congeni al abno mali ies, p egnancy,
mac olides, coho , case-con ol and incidence. We adop ed simila s a egies o sea ch
EMBASE om 1980 un il 2019; he i e egional bibliog aphic da abases o he Wo ld
Heal h O ganiza ion (WHO): A ican Index Medicus (AIM), La in Ame ican and Ca ibbean
Heal h Science Li e a u e Da abase (LILACS), Index Medicus o he Eas e n Medi e anean
Region (IMEMR), Index Medicus o Sou h-Eas Asia Region (IMSEAR), Wes e n Paci ic
Region Index Medicus (WPRIM); as well as he Open Access Thesis and Disse a ions
(OATD). We also sea ched o abs ac s o scien i ic mee ings using he Con e ence
P oceedings Ci a ion Index om incep ion in 1990 un il June 2019. Finally, we manually
examined he e e ences o all ob ained a icles as well as hose o ela ed sys ema ic e iews.
Mac olides and Congeni al Mal o ma ions
6
All sea ches we e ca ied ou independen ly by wo epidemiologis s (N.M. and B.T.) and he
esul s we e me ged.
We egis e ed he e iew p o ocol o his s udy in he In e na ional p ospec i e egis e o
sys ema ic e iews PROSPERO (Re e ence: CRD42017055131) [18].
2.2. Eligibili y c i e ia and s udy selec ion
We included s udies ha ul illed he ollowing eligibili y c i e ia: (1) epo ing o iginal da a
om andomized clinical ials, case-con ol o coho s udies; (2) examining he associa ion
be ween p ena al exposu e o mac olides and he de elopmen o congeni al mal o ma ion;
(3) p o iding es ima es o ela i e isk (RR) o odds a ios (OR) and hei co esponding 95%
con idence in e als (CIs) o p esen ing enough da a o calcula e hem. Due o hei limi a ion
in in e ing causal ela ionships, c oss-sec ional s udies we e excluded. We es ic ed ou
analysis o congeni al mal o ma ions in li e bi hs only. We excluded a icles on d ugs ha
could be assimila ed o mac olides such as i e mec in, nys a in and na amycin and limi ed
ou s udy o ue mac olides. We also excluded s udies ha in es iga ed he pos na al
ma e nal and/o in an exposu e o mac olides. Duplica e s udies we e de ec ed by iden i ying
he s udy popula ion. Only he mos upda ed s udy was included in he me a-analysis. In
addi ion, o publica ions abou di e en mac olides ha we e ca ied ou by he same
in es iga o in he same popula ion, we calcula ed he pooled RRs o ORs o hese di e en
publica ions and p esen ed hem as a single s udy. When e ec measu es o ma e nal
exposu e o di e en ypes o mac olides and/o du ing dis inc e ms o p egnancy we e
epo ed in he same s udy, we analyzed each ou come sepa a ely.
2.3. Da a ex ac ion
We scanned he i les and abs ac s o he collec ed a icles in o de o exclude he i ele an
ones, and subsequen ly e iewed he ull ex s o he emaining a icles o check hei
Mac olides and Congeni al Mal o ma ions
7
eligibili y. We eco ded he ollowing in o ma ion om he eligible s udies: (1) s udy name
and sou ce; (2) publica ion yea ; (3) s udy design (coho s udy and case-con ol s udy); (4)
s udy pe iod; (5) sample size (numbe o cases and con ols o case-con ol s udies, o
numbe o cases and coho size o coho s udies); (6) ype o con ol (unexposed o any
d ug, exposed o non-mac olides an ibio ics o o non- e a ogens, o a mix u e o he
unexposed and non-mac olide exposed e uses), (7) s udy coun y; (8) asce ainmen o
mac olides exposu e; (9) exposu e dose; (10) exposu e pe iod; (11) e ec measu es and 95%
con idence in e al; (12) adjus men , ma ching, and es ic ion a iables; (13) pe cen age o
d op-ou s in coho s udies; (14) esponse a e in case-con ol s udies; (15) ype o mac olide;
and (16) use o indi idual o a mix u e o mac olides.
2.4. Quali y assessmen
We assessed he quali y o he s udies by using a se en-poin scale ex ac ed om he
Newcas le O awa scale acco ding o he equi emen s o his me a-analysis [19]. We
assessed he ollowing c i e ia: Mac olide exposu e asce ainmen : based on a clinical his o y
o any o he documen ed p oo (1 poin ), else (0 poin s). Con ounding assessmen : esul s
adjus ed o ma e nal age and u ina y ac in ec ions (2 poin s, 1 poin each), else (0 poin s).
Exposu e desc ip ion: epo ed du a ion (1 poin ) and de e mined dose (1 poin ), else (0
poin s). To assess me hodological issues ha we e no common o coho s udies and case-
con ol s udies, we used he ollowing c i e ia: d op-ou a e o losses o ollow up in coho
s udies: < 20% (2 poin s), be ween 20% and 40% (1 poin ), and > 40% o no explained (0
poin s) and pa icipa ion a e in case-con ol s udies: > 80% (1 poin ), < 80% o no epo ed
(0 poin s). We ca ied ou a pooled analysis on s udies sco ing mo e han 4 poin s and
compa ed he esul s wi h hose o s udies wi h a lowe quali y sco e.
Mac olides and Congeni al Mal o ma ions
8
Bo h da a ex ac ion p ocess and quali y a ing we e independen ly pe o med by wo
epidemiologis s [N.M. and H.T.] and disc epancies we e esol ed h ough discussion wi h a
hi d pa y [B.T.].
2.5. Da a syn hesis
We ex ac ed he adjus ed odds a ios and hei 95% CI om he s udies included in ou me a-
analysis. We used he c ude ORs i no adjus ed es ima e was p o ided o compu ed hem
om he da a p o ided by he au ho s. Subsequen ly, we weigh ed he log RRs and log OR
o coho and case-con ol s udies, espec i ely, by he in e se o hei a iance o ob ain a
pooled OR and i s 95% CI. Odds Ra ios we e conside ed unbiased es ima es o he Rela i e
Risk [20].
We ca ied ou h ee di e en analyses acco ding o he cha ac e is ics o he unexposed
popula ion. In he i s app oach, we included all s udies ha used e uses unexposed o any
d ug as a compa a o (compa ison g oup 1). The second app oach encompassed s udies ha
compa ed he e ec o mac olides pa en al exposu e o exposu e o non-mac olides o
non e a ogenic d ugs (compa ison g oup 2). The hi d analysis in ol ed he combina ion o
he s udies o he wo app oaches desc ibed abo e (compa ison g oup 3).
We p esen ed bo h ixed and andom e ec s pooled es ima es. We checked o he e ogenei y
using De Simonian and Lai d’s Q es . We quan i ied he he e ogenei y by calcula ing he
p opo ion o he o al a iance due o be ween s udy a iance (Ri) [21]. La ge alues (>0.75)
o Ri indica e la ge amoun o he e ogenei y, alues be ween 0.4 and 0.75 sugges a mode a e
amoun while small alues (<0.4) indica e low he e ogenei y. Subsequen ly, we es ic ed he
analysis o subg oups de ined by s udy cha ac e is ics such as adjus men ac o s, exposu e
pe iod, ana omical loca ion o congeni al mal o ma ions and s udy design. P io o da a
analysis, we con ac ed he au ho s in o de o know whe he abs ac s e ie ed in ou sea ch
Mac olides and Congeni al Mal o ma ions
9
we e published la e as a ull pape and o ha e mo e in o ma ion abou he compa ison g oup
used in he s udies [14, 16, 22-25]. We epea ed he same analysis o he h ee ca ego ies o
compa ison popula ions.
2.6. Assessmen o publica ion bias
We assessed publica ion bias isually using unnel plo s a i s , and hen, mo e o mally,
using Egge ´s eg ession es [26]. Fu he mo e, we used he im-and- ill me hod o co ec
o po en ial publica ion bias.
We also pe o med a sensi i i y analysis by assuming ha he esul s o case-con ol s udies
a e he leas likely o be published when hei esul s show no e ec . Acco dingly, we
ecalcula ed he pooled OR assuming ha (1) he case-con ol s udies e ie ed in ou sea ch
ep esen only hal o he s udies e e conduc ed, (2) he unpublished s udies ound a null
associa ion (OR = 1) be ween mac olides p ena al exposu e and congeni al mal o ma ion, and
(3) he unpublished s udies ound he same p e alence o congeni al mal o ma ion as he
a e age o he published s udies. We e-calcula ed he pooled odds a io unde hese ex eme
assump ions.
All subg oup analyses, including ana omic loca ion o he mal o ma ion, ype o mac olides
and p egnancy e m, we e planned a p io i and we e iden i ied and published in he p o ocol
egis e ed in PROSPERO.
All analyses we e ca ied ou using he so wa e HEpiMA e sion 2.1.3 [27], and STATA
e sion 12 (S a a Co p, College S a ion, Tex).
Mac olides and Congeni al Mal o ma ions
16
ch omosomal congeni al abno mali ies in p e ious s udies and could ep esen po en ial
con ounde s [9, 46]. Howe e , i is wo h men ioning ha he esul s a e es ic ion o he
analysis o he ully adjus ed s udies did no di e om ha o he incomple ely adjus ed
s udies.
Misclassi ica ion o he ou come is highly imp obable o occu o such a diagnosis.
Misclassi ica ion o exposu e o mac olides is also unlikely as i was well documen ed in
mo e han hal (13 ou o 21) o he included s udies in which he co esponding da a we e
collec ed h ough medical eco ds. In addi ion, al hough i is unlikely ha ecall bias may
ha e a ec ed ou esul s, we ecalcula ed he pooled OR by excluding he s udies ha
assessed exposu e using a ques ionnai e o an in e iew (and no medical eco ds), and he
esul s emained unal e ed. Howe e , exposu e o mac olides migh be misclassi ied i some
women did no ac ually ake he mac olides ha we e p esc ibed.
Due o he absence o da a in he o iginal s udies, he esul s o ou me a-analysis a e limi ed
by he absence o dose- esponse analysis. In addi ion, due o una ailabili y o da a, we did
no conside mal o ma ion ou comes in abo ions o s illbi hs. The e o e, we canno ule ou
a mu agenic e ec o mac olides ha could ha e caused abo ions o s illbi hs.
5. Conclusion
In summa y, ou me a-analysis showed ha he inc ease in he odds o bi h de ec s among
women who consumed mac olides du ing hei p egnancy is e y low. Howe e , a ha m ul
e ec o mac olides canno be uled ou , especially o he musculoskele al and diges i e
sys ems. Risk-bene i esea ch is needed o add ess he ques ion o whe he mac olide
p esc ip ion should be es ic ed du ing p egnancy.
Mac olides and Congeni al Mal o ma ions
17
Au ho s´ con ibu ions
Concep ion and design o he s udy: Bahi Takkouche and Mahya E minan.
Concep ualiza ion o he manusc ip and e iew and syn hesis o he li e a u e: Na meen
Mallah. Da a ex ac ion: Na meen Mallah and Hamid Reza Tohidinik. Coo dina ion and
supe ision o da a ex ac ion and analysis: Bahi Takkouche and Adol o Figuei as. All
au ho s made subs an ial con ibu ion o he in e p e a ion o da a, c i ically e iewed he
manusc ip and app o ed i s submission o publica ion.
Compliance wi h E hical S anda ds:
Funding Sou ce: No speci ic unding o his wo k. D Takkouche’s and D Figuei as’ wo k
is unded by a g an om he Regional Minis y o Educa ion, Uni e si ies and Voca ional
T aining, San iago de Compos ela, Spain, ED431C 2018/20.
Con lic o In e es : Na meen Mallah, Hamid Reza Tohidinik, Mahya E minan, Adol o
Figuei as, and Bahi Takkouche decla e ha hey ha e no con lic o in e es .
Da a Sha ing: All da a gene a ed o analyzed du ing his s udy a e included in his published
a icle and i s supplemen a y in o ma ion ile (Online Resou ce 1).
Re e ences
1. Wo ld Heal h O ganzia ion. Congeni al anomalies. Wo ld Heal h O ganiza ion. 2016.
h p://www.who.in /mediacen e/ ac shee s/ s370/en/. Accessed 19 Feb 2019.
2. Cen e s o Disease Con ol and P e en ion. Bi h De ec s 2018.
h ps://www.cdc.go /ncbddd/bi hde ec s/ ac s.h ml. Accessed 19 Feb 2019.
3. Pe ini J, Damus K, Russell R, Poschman K, Da ido MJ, Ma ison D. Con ibu ion
o bi h de ec s o in an mo ali y in he Uni ed S a es. Te a ology. 2002;66 Suppl
1:S3-6. h ps://doi.o g/10.1002/ e a.90002
4. Kochanek KD, Mu phy SL, Xu JQ, A ias E. Mo ali y in he Uni ed S a es, 2016.
NCHS Da a B ie . 2017. Repo No.: 293.
Mac olides and Congeni al Mal o ma ions
18
5. Janz T, Na aneelan T, Pea son C. Dea hs om congeni al anomalies in Canada, 1974
o 2012. Heal h a a Glance. S a is ics Canada. 2016. Ca alogue No.: 82-624-X.
6. Ch is ianson A, Howson CP, Modell B. Global epo on bi h de ec s. The hidden oll
o dying and disabled child en. Whi e Plains (NY): Ma ch o Dimes Bi h De ec s
Founda ion. 2006. h ps://www.ma cho dimes.o g/global- epo -on-bi h-de ec s- he-
hidden- oll-o -dying-and-disabled-child en- ull- epo .pd . Accessed 02 Ap 2019.
7. Adam MP, Poli ka JE, F iedman JM. E ol ing knowledge o he e a ogenici y o
medica ions in human p egnancy. Am J Med Gene C Semin Med Gene .
2011;157C(3):175-82. h ps://doi.o g/10.1002/ajmg.c.30313
8. Books a e PB, Bland CM, G i in B, S o e KR, Eiland LS, McLaughlin M. A
e iew o an ibio ic use in p egnancy. Pha maco he apy. 2015;35(11):1052-62.
h ps://doi.o g/10.1002/pha .1649
9. C ide KS, Cle es MA, Ree huis J, Be y RJ, Hobbs CA, Hu DJ. An ibac e ial
medica ion use du ing p egnancy and isk o bi h de ec s: Na ional bi h de ec s
p e en ion s udy. A ch Pedia Adolesc Med. 2009;163(11):978-85.
h ps://doi.o g/10.1001/a chpedia ics.2009.188
10. B aue R, Ruigómez A, Downey G, Ba e A, Rod iguez LAG, Hue a C e al.
P e alence o an ibio ic use: a compa ison ac oss a ious Eu opean heal h ca e da a
sou ces. Pha macoepidemiol D ug Sa . 2016;25(sup 1):11 - 20.
h ps://doi.o g/10.1002/pds.3831
11. Lin KJ, Mi chell AA, Yau WP, Louik C, He nandez-Diaz S. Sa e y o mac olides
du ing p egnancy. Am J Obs e Gynecol. 2013;208(3):221 e1-8.
h ps://doi.o g/10.1016/j.ajog.2012.12.023
12. San os F, Sheehy O, Pe eaul S, Fe ei a E, Be a d A. T ends in an i-in ec i e d ugs
use in p egnancy. J Popul The Clin Pha macol. 2012;19(3):e460-5.
13. Kallen BA, O e blad Olausson P, Danielsson BR. Is e y h omycin he apy
e a ogenic in humans? Rep od Toxicol. 2005;20(2):209-14.
h ps://doi.o g/10.1016/j. ep o ox.2005.01.010
14. Lund M, Pas e nak B, Da idsen RB, Feens a B, K ogh C, Diaz LJ e al. Use o
mac olides in mo he and child and isk o in an ile hype ophic pylo ic s enosis:
Na ionwide coho s udy. BMJ. 2014;348:g1908. h ps://doi.o g/10.1136/bmj.g1908
15. Dinu AB, Ko en G, Ma ok I, Wizni ze A, Uziel E, Go odische R e al. Fe al sa e y
o mac olides. An imic ob Agen s Chemo he . 2013;57(7):3307-11.
h ps://doi.o g/10.1128/AAC.01691-12
16. Ande sen JT, Pe e sen M, Jimenez-Solem E, B oedbaek K, Ande sen NL, To p-
Pede sen C e al. Cla i h omycin in ea ly p egnancy and he isk o misca iage and
mal o ma ion: A egis e based na ionwide coho s udy. PLoS One.
2013;8(1):e53327. h ps://doi.o g/10.1371/jou nal.pone.0053327
17. Fan H, Li L, Wijlaa s L, Gilbe RE. Associa ions be ween use o mac olide
an ibio ics du ing p egnancy and ad e se child ou comes: A sys ema ic e iew and
me a-analysis. PLoS One. 2019;14(2):e0212212.
h ps://doi.o g/10.1371/jou nal.pone.0212212
18. P ospe o In e na ional P ospec i e Regis e o Sys ema ic Re iews. 2017.
h ps://www.c d.yo k.ac.uk/p ospe o/display_ eco d.php?Reco dID=55131.
19. Wells GA, Shea B, O'Connell D, e al. The Newcas le-O awa Scale (NOS) o
assessing he quali y o non andomised s udies in me a-analyses.
h p://www.oh i.ca/p og ams/clinical_epidemiology/ox o d.asp. Accessed 19 Feb
2019.
Mac olides and Congeni al Mal o ma ions
19
20. Ro hman KJ, G eenland S, Lash TL. Measu e o e ec and measu es o associa ion.
In: Lippinco W, Wilkins, edi o s. Mode n epidemiology. 3 d edi ion. Philadelphia:
Lippinco , Williams and Wilkins. 2008. pp. 61
21. Takkouche B, Cada so-Suá ez C, Spiegelman D. E alua ion o old and new es s o
he e ogenei y in epidemiologic me a-analysis. Am J Epidemiol. 1999;150(2):206-15.
22. Kallen B, Danielsson BR. Fe al sa e y o e y h omycin. An upda e o swedish da a.
Eu J Clin Pha macol. 2014;70(3):355-60. h ps://doi.o g/10.1007/s00228-013-1624-3
23. Mahon BE, Rosenman MB, Kleiman MB. Ma e nal and in an use o e y h omycin
and o he mac olide an ibio ics as isk ac o s o in an ile hype ophic pylo ic
s enosis. J Pedia . 2001;139(3):380-4. h ps://doi.o g/10.1067/mpd.2001.117577
24. Wol gang P, Schloemp S, S e zik K, S oz F, edi o s. Does oxi h omycin a ec
emb yo de elopmen ? 33 d Annual Con e ence o he Eu opean Te a ology Socie y;
3 - 7 Sep, 2005; Haa lem, The Ne he lands: Rep oduc i e Toxicology.
25. Lê Nguyên T, A aujo M, Hu aul -Dela ue C, Lac oix I, Damase-Michel C, Somme
A. e a ogenic isk o mac olides du ing he i s imes e o p egnancy: a s udy wi h
wo complemen a y app oaches wi hin he e eme is da abase. Clinical The apeu ics.
2017; 39 (8)Sup:e11-e12
26. Egge M, Da ey Smi h G, Schneide M, Minde C. Bias in me a-analysis de ec ed by
a simple, g aphical es . BMJ. 1997;315(7109):629-34.
27. Cos a-Bouzas J, Takkouche B, Cada so-Sua´ ez C, Spiegelman D. HEpiMA: so wa e
o he iden i ica ion o he e ogenei y in me a-analysis. Compu Me hods P og ams
Biomed. 2001;64:101-7.
28. Ba -Oz B, Webe -Schoendo e C, Be lin M, Clemen i M, Di Gianan onio E, de V ies
L e al. The ou comes o p egnancy in women exposed o he new mac olides in he
i s imes e : A p ospec i e, mul icen e, obse a ional s udy. D ug Sa .
2012;35(7):589-98. h ps://doi.o g/10.2165/11630920-000000000-00000
29. Romo en M, Lindbaek M, No deng H. P egnancy ou come a e ges a ional exposu e
o e y h omycin - a popula ion-based egis e s udy om no way. B J Clin
Pha macol. 2012;74(6):1053-62. h ps://doi.o g/10.1111/j.1365-2125.2012.04286.x
30. Coope WO, He nandez-Diaz S, A bogas PG, Dudley JA, Dye SM, Gideon PS e al.
An ibio ics po en ially used in esponse o bio e o ism and he isk o majo
congeni al mal o ma ions. Paedia Pe ina Epidemiol. 2009;23(1):18-28.
h ps://doi.o g/10.1111/j.1365-3016.2008.00978.x
31. Ba -Oz B, Dia -Ci in O, Shech man S, Tellem R, A non J, F ance ic I e al.
P egnancy ou come a e ges a ional exposu e o he new mac olides: A p ospec i e
mul i-cen e obse a ional s udy. Eu J Obs e Gynecol Rep od Biol. 2008;141(1):31-
4. h ps://doi.o g/10.1016/j.ejog b.2008.07.008
32. Chun JY, Han JY, Ahn HK, Choi JS, Koong MK, Na a-Ocampo AA e al. Fe al
ou come ollowing oxi h omycin exposu e in ea ly p egnancy. J Ma e n Fe al
Neona al Med. 2006;19(3):189-92. h ps://doi.o g/10.1080/14767050500439657
33. Sa ka M, Woodland C, Ko en G, Eina son AR. P egnancy ou come ollowing
ges a ional exposu e o azi h omycin. BMC P egnancy Childbi h. 2006;6:18.
h ps://doi.o g/10.1186/1471-2393-6-18
34. Eina son A, Phillips E, Mawji F, D'Alimon e D, Schick B, Addis A e al. A
p ospec i e con olled mul icen e s udy o cla i h omycin in p egnancy. Am J
Pe ina ol. 1998;15(9):523-5. h ps://doi.o g/10.1055/s-2007-994053
35. Coope WO, G i in MR, A bogas P, Hickson GB, Gau am S, Ray WA. Ve y ea ly
exposu e o e y h omycin and in an ile hype ophic pylo ic s enosis. A ch Pedia
Adolesc Med. 2002;156(7):647-50. h ps://doi.o g/10.1001/a chpedi.156.7.647
Mac olides and Congeni al Mal o ma ions
20
36. Wil on LV, Pea ce GL, Ma in RM, Mackay FJ, Mann RD. The ou comes o
p egnancy in women exposed o newly ma ke ed d ugs in gene al p ac ice in England.
B J Obs e Gynaecol. 1998;105(8):882-9.
37. Muanda FT, Sheehy O, Be a d A. Use o an ibio ics du ing p egnancy and he isk o
majo congeni al mal o ma ions: A popula ion based coho s udy. B J Clin
Pha macol. 2017;83(11):2557-71. h ps://doi.o g/10.1111/bcp.13364
38. Czeizel AE, Rockenbaue M, Olsen J, So ensen HT. A case-con ol e a ological
s udy o spi amycin, oxi h omycin, oleandomycin and josamycin. Ac a Obs e
Gynecol Scand. 2000;79(3):234-7.
39. Louik C, We le MM, Mi chell AA. E y h omycin use du ing p egnancy in ela ion o
pylo ic s enosis. Am J Obs e Gynecol. 2002;186(2):288-90.
h ps://doi.o g/10.1067/mob.2002.119718
40. Czeizel AE, Rockenbaue M, So ensen HT, Olsen J. A popula ion-based case-con ol
e a ologic s udy o o al e y h omycin ea men du ing p egnancy. Rep od Toxicol.
1999;13(6):531-6. h ps://doi.o g/10.1016/S0890-6238(99)00046-5
41. Bulska M, Szcześniak P, Pię a-Dolińska A, Oszukowski P, O szulak-Michalak D. The
placen al ans e o e y h omycin in human p egnancies wi h g oup B s ep ococcal
in ec ion. Ginekol Pol. 2015;86(1):33-9.
42. Danielsson BR, Skold AC, Aza bayjani F. Class III an ia hy hmics and pheny oin:
e a ogenici y due o emb yonic ca diac dys hy hmia and eoxygena ion damage. Cu
Pha m Des. 2001;7(9):787-802.
43. Go elik E, Masa wa R, Pe lman A, Ro shild V, Muszka M, Ma ok I. Sys ema ic
e iew, me a-analysis, and ne wo k me a-analysis o he ca dio ascula sa e y o
mac olides. An imic ob Agen s Chemo he . 2018;62(6).
h ps://doi.o g/10.1128/AAC.00438-18
44. Can ield MA, Mai CT, Wang Y, O'Hallo an A, Ma engo LK, Olney RS e al. The
associa ion be ween ace/e hnici y and majo bi h de ec s in he uni ed s a es, 1999-
2007. Am J Public Heal h. 2014;104(9):e14-23.
h ps://doi.o g/10.2105/AJPH.2014.302098
45. Goossens H. An ibio ic consump ion and link o esis ance. Clinical Mic obiology and
In ec ion. 2009;15(Sup 3):12 - 5.
h ps://doi.o g/10.1111/j.1469-0691.2009.02725.x
46. Hollie LM, Le eno KJ, Kelly MA, DD MC, Cunningham FG. Ma e nal age and
mal o ma ions in single on bi hs. Obs e Gynecol. 2000;96(5 P 1):701-6.
h ps://doi.o g/10.1016/S0029-7844(00)01019-X
Figu es
Fig. 1 Flow cha o sc eening o li e a u e abou mac olides’ p ena al exposu e and
congeni al mal o ma ion
Fig. 2 S udy speci ic and pooled odds a ios o p ena al exposu e o mac olides and
congeni al mal o ma ions
Fig. 3 Funnel plo o p ena al mac olides’ exposu e and any congeni al mal o ma ion
Mac olides and Congeni al Mal o ma ions
21
Supplemen al In o ma ion
Online Resou ce 1 (Table ESM_1). Da ase o ex ac ed and calcula ed OR o gene al and
speci ic congeni al mal o ma ions classi ied by he compa a o g oup, con inen , OR
adjus men s a us, quali y assessmen sco e, body sys ems, exposu e pe iod and ype o
mac olide.
Online Resou ce 2 (Table ESM_2): ep esen s he cha ac e is ics o coho s udies o
mac olides´ in ake and congeni al mal o ma ions
Online Resou ce 3 (Table ESM_3): ep esen s he cha ac e is ics o case-con ol s udies
o mac olides´ in ake and congeni al mal o ma ions
Mac olides and Congeni al Mal o ma ions
22
Table 1 Pooled Odds Ra ios (ORs) and 95% Con idence In e als (CIs) o mac olides’ in ake and congeni al
mal o ma ions (compa ison g oup 1: e uses no exposed o any d ug)
Numbe
o s udies
OR (95% CI)
Fixed e ec s
OR (95% CI)
Random e ec s
Ri*
Q es
(p alue)
Any congeni al
mal o ma ion
All s udies
14
1.05 (0.99, 1.12)
1.05 (0.99, 1.12)
0.00
0.81
S udy Design
Coho
11
1.07 (0.99, 1.15)
1.07 (0.99, 1.15)
0.00
0.90
Case-con ol s udies
3
1.02 (0.92, 1.14)
1.01 (0.88, 1.17)
0.39
0.21
Ana omic loca ion
Ca dio ascula
8
1.03 (0.93, 1.14)
1.05 (0.90, 1.22)
0.48
0.07
Head and Neck
4
1.27 (0.94, 1.72)
1.27 (0.94, 1.72)
0.00
1.00
Musculoskele al sys em
5
1.06 (0.91, 1.24)
1.06 (0.85, 1.31)
0.33
0.27
Diges i e sys em
8
1.13 (0.97, 1.31)
1.12 (0.9, 1.33)
0.18
0.30
U ogeni al sys em
5
1.00 (0.80, 1.24)
0.98 (0.71, 1.35)
0.43
0.17
Ne ous sys em
4
1.14 (0.86, 1.52)
1.12 (0.81, 1.55)
0.19
0.28
Adjus men
Full
2
1.04 (0.94, 1.15)
1.04 (0.94, 1.15)
0.00
0.50
Incomple e
12
1.06 (0.98, 1.15)
1.06 (0.98, 1.15)
0.00
0.75
Quali y sco e
≥ 4
7
1.04 (0.95, 1.14)
1.04 (0.95, 1.14)
0.00
0.78
< 4
7
1.06 (0.98, 1.16)
1.06 (0.98, 1.16)
0.00
0.56
Mac olide exposu e pe iod
Fi s imes e
11
1.07 (1.00, 1.14)
1.07 (1.00, 1.14)
0.00
0.93
Thi d imes e
3
1.00 (0.79, 1.28)
1.08 (0.73, 1.59)
0.60
0.11
Geog aphic loca ion
Eu ope
6
1.10 (0.98, 1.23)
1.10 (0.98, 1.23)
0.00
0.71
No h Ame ica
6
1.03 (0.96, 1.12)
1.03 (0.96, 1.12)
0.00
0.45
Type o ea men
E y h omycin
7
1.05 (0.97, 1.15)
1.05 (0.97, 1.15)
0.00
0.46
Azi h omycin
2
1.15 (0.97, 1.36)
1.15 (0.97, 1.36)
0.00
0.37
Cla i h omycin
2
1.10 (0.88, 1.38)
1.10 (0.88, 1.38)
0.00
0.84
Roxi h omycin
2
2.03 (0.75, 5.48)
2.03 (0.75, 5.48)
0.00
0.79
*Ri: P opo ion o o al a iance due o be ween-s udy a iance.
Mac olides and Congeni al Mal o ma ions
23
Table 2 Pooled Odds Ra ios (ORs) and 95% Con idence In e als (CIs) o mac olides’ in ake and congeni al
mal o ma ions. (compa ison g oup 2: e uses exposed o non- e a ogenic d ugs/non-mac olides)
Numbe
o s udies
OR (95% CI)
Fixed e ec s
OR (95% CI)
Random e ec s
Ri*
Q es
(p alue)
Any congeni al
mal o ma ion
All s udies
13
1.06 (1.00, 1.12)
1.06 (1.00, 1.12)
0.00
0.88
S udy Design
Coho
11
1.07 (1.00, 1.15)
1.07 (1.00, 1.15)
0.00
0.86
Case-con ol s udies
2
1.03 (0.93, 1.14)
1.03 (0.93, 1.14)
0.00
0.36
Ana omic loca ion
Ca dio ascula
7
0.87 (0.81, 0.95)
0.93 (0.80, 1.07)
0.50
0.10
Head and Neck
4
1.08 (0.90, 1.29)
1.05 (0.78, 1.42)
0.54
0.12
Musculoskele al sys em
4
1.21 (1.08, 1.35)
1.21 (1.08, 1.35)
0.00
0.85
Diges i e sys em
5
1.14 (0.98, 1.33)
1.11 (0.90, 1.38)
0.44
0.15
U ogeni al sys em
4
0.89 (0.76, 1.05)
0.92 (0.60, 1.39)
0.84
0.001
Ne ous sys em
4
1.14 (0.92, 1.42)
1.05 (0.68, 1.62)
0.70
0.03
Adjus men
Full
2
1.05 (0.96, 1.15)
1.05 (0.96, 1.15)
0.00
0.48
Incomple e
11
1.07 (0.99, 1.15)
1.07 (0.99, 1.15)
0.00
0.84
Quali y sco e
≥ 4
8
1.08 (1.01, 1.15)
1.08 (1.01, 1.15)
0.00
0.74
< 4
5
1.02 (0.92, 1.13)
1.02 (0.92, 1.13)
0.00
0.86
Mac olide exposu e pe iod
Fi s imes e
9
1.05 (0.99, 1.12)
1.05 (0.99, 1.12)
0.00
0.83
Thi d imes e
2
1.33 (0.99, 1.79)
1.33 (0.99, 1.79)
0.00
0.34
Geog aphic loca ion
Eu ope
7
1.15 (1.01, 1.31)
1.15 (1.01, 1.31)
0.00
0.90
No h Ame ica
6
1.04 (0.98, 1.11)
1.04 (0.98, 1.11)
0.00
0.81
Type o ea men
E y h omycin
6
0.92 (0.86, 0.99)
0.99 (0.83, 1.18)
0.84
0.00
Azi h omycin
6
1.08 (0.98, 1.19)
1.08 (0.98, 1.19)
0.00
0.63
Cla i h omycin
4
0.92 (0.82, 1.04)
0.92 (0.82, 1.04)
0.00
0.95
Roxi h omycin
3
1.50 (0.81, 2.77)
1.74 (0.69, 4.37)
0.53
0.13
*Ri: P opo ion o o al a iance due o be ween-s udy a iance.
Mac olides and Congeni al Mal o ma ions
24
Table 3 Pooled Odds Ra ios (ORs) and 95% Con idence In e als (CIs) o mac olides’ in ake and congeni al
mal o ma ions. (Compa ison g oup 3: mixed popula ion o unexposed e uses)
Numbe
o s udies
OR (95% CI)
Fixed e ec s
OR (95% CI)
Random e ec s
Ri*
Q es
(p alue)
Any congeni al
mal o ma ion
All s udies
21
1.06 (1.01, 1.10)
1.06 (1.01, 1.10)
0.00
0.86
S udy Design
Coho
17
1.07 (1.02, 1.13)
1.07 (1.02, 1.13)
0.00
0.93
Case-con ol s udies
4
1.03 (0.95, 1.11)
1.02 (0.94, 1.12)
0.14
0.35
Ana omic loca ion
Ca dio ascula
11
0.93 (0.87, 0.98)
1.03 (0.89, 1.18)
0.71
0.002
Head and Neck
5
1.13 (0.96, 1.32)
1.12 (0.93, 1.35)
0.19
0.31
Musculoskele al sys em
6
1.15 (1.05, 1.26)
1.15 (1.05, 1.26)
0.00
0.40
Diges i e sys em
9
1.14 (1.02, 1.26)
1.10 (0.94, 1.28)
0.44
0.08
U ogeni al sys em
6
0.93 (0.81, 1.05)
0.96 (0.69, 1.34)
0.81
0.001
Ne ous sys em
5
1.15 (0.97, 1.36)
1.02 (0.72, 1.47)
0.71
0.01
Adjus men
Full
3
1.05 (0.98, 1.12)
1.04 (0.97, 1.12)
0.00
0.50
Incomple e
18
1.06 (1.00, 1.12)
1.06 (1.00, 1.12)
0.00
0.84
Quali y sco e
≥ 4
12
1.07 (1.01, 1.13)
1.07 (1.01, 1.13)
0.00
0.78
< 4
9
1.04 (0.97, 1.12)
1.04 (0.97, 1.12)
0.00
0.70
Mac olide exposu e pe iod
Fi s imes e
16
1.06 (1.01, 1.11)
1.06 (1.01, 1.11)
0.00
0.95
Thi d imes e
4
1.12 (0.93, 1.35)
1.15 (0.85, 1.56)
0.62
0.05
Geog aphic loca ion
Eu ope
10
1.12 (1.03, 1.22)
1.12 (1.03, 1.22)
0.00
0.86
No h Ame ica
9
1.03 (0.98, 1.09)
1.03 (0.98, 1.09)
0.00
0.74
Type o ea men
E y h omycin
9
0.96 (0.91, 1.01)
1.00 (0.88, 1.14)
0.79
0.00
Azi h omycin
6
1.09 (1.00, 1.19)
1.09 (1.00, 1.19)
0.00
0.73
Cla i h omycin
5
0.96 (0.86, 1.07)
0.96 (0.86, 1.07)
0.00
0.97
Roxi h omycin
5
1.63 (0.96, 2.75)
1.66 (0.95, 2.89)
0.08
0.36
*Ri: P opo ion o o al a iance due o be ween-s udy a iance.
Mac olides and Congeni al Mal o ma ions
25
Figu e 1.
Online Resou ce 2. Cha ac e is ics o coho s udies o mac olides´ in ake and congeni al mal o ma ions
Sou ce
Type o
Mac olide
Coun y
Type o
mal o ma ion
Exposu e
Pe iod
(mon hs o
p egnancy)
Compa ison Type
and OR (95% CI)
Cases/ Coho
Size
Gene al OR
(95% CI)
Adjus men , Ma ching,
and Res ic ion Fac o s
Muanda FT, e
al. 2017 [1]
azi h omycin,
e y h omycin,
cla i h omycin
Quebec
Ca diac, diges i e,
head and neck,
musculoskele al,
ne ous,
espi a o y,
u ogeni al
1 – 3
Unexposed o any
an ibio ic:
1.08 (0.95, 1.23)
Exposed o non-
mac olide an ibio ics:
1.04 (0.95, 1.14)
13, 852/139,938
1627/15469
1.05
(0.98, 1.14)
Ma e nal age, u ina y ac
in ec ions, socio-
demog aphic a iables,
ch onic ma e nal illness,
endome iosis and o he
ma e nal in ec ions,
heal hca e u iliza ion, yea
o deli e y, in an ’s gende
Lê Nguyên T,
e al. 2017 [2]
mac olides
F ance
Congeni al
mal o ma ions
1 – 3
Unexposed o any
an ibio ic:
1.02 (0.71, 1.46)
T ea ed wi h
penicillin:
0.93 (0.63, 1.37)
47/62,846
47/12,193
0.98
(0.75, 1.27)
Ma e nal age, long- e m
ma e nal illness, ges i y,
pa i y, mul iple p egnancy
Källén B, e al.
2014 [3]
e y h omycin
Sweden
Any, ca diac
1 – 3
Unexposed o any
an ibio ic:
1.14 (0.96, 1.36)
70339/1575847
1.14
(0.96, 1.36)
Ma e nal age, yea o
deli e y, pa i y, smoking,
obesi y
Lund M, e al.
2014 [4]
azi h omycin,
cla i h omycin,
e y h omycin,
oxi h omycin,
spi amycin,
Denma k
In an ile
hype ophic
pylo ic s enosis
• 1 – 6
• 6 – 9
Unexposed o any
an ibio ic:
1.23 (0.85, 1.76)
Exposed o non-
mac olide an ibio ics:
1.23 (0.83, 1.83)
30/315569
159/60732
1.23
(0.94, 1.60)
Bi h o de , in an ’s sex,
calenda pe iod, cu en
age o he in an
Ande sen JT, e
al. 2013 [5]
cla i h omycin
Denma k
Ca diac,
musculoskele al,
u ogeni al
1 – 3
Unexposed o any
an ibio ic:
1.03 (0.53, 2.00)
24817/705837
1.03
(0.53, 2.00)
Ma e nal age, educa ion,
numbe o p e ious bi hs,
economical s a us
Online Resou ce 2. Cha ac e is ics o coho s udies o mac olides´ in ake and congeni al mal o ma ions (con inued)
Sou ce
Type o
Mac olide
Coun y
Type o
mal o ma ion
Exposu e
Pe iod
(mon hs o
p egnancy)
Compa ison Type
and OR (95% CI)
Cases/ Coho
Size
Gene al OR
(95% CI)
Adjus men , Ma ching,
and Res ic ion Fac o s
Dinu AB, e al.
2013 [6]
azi h omycin,
cla i h omycin,
e y h omycin,
oxi h omycin
Is ael
Ca diac, diges i e
1 – 3
Unexposed o any
an ibio ic:
1.07 (0.84, 1.38)
---/105492
1.07
(0.84, 1.38)
Ma e nal age, yea o
deli e y, pa i y, e hnici y,
ch onic ma e nal illness
Ba -Oz B, e al.
2012 [7]
azi h omycin,
oxy h omycin,
cla i h omycin
• Czech
Republic
• Ge many
• Is ael
• I aly
• Ne he lands
Ca diac
1 – 3
Exposed o non-
e a ogenic agen s:
1.42 (0.70, 2.88)
32/1146
1.42
(0.70, 2.88)
Ma e nal age, smoking,
alcohol consump ion,
p e ious abo ions,
p e ious child wi h
s uc u al anomaly,
mac olide exposu e
Romø en M, e
al. 2012 [8]
e y h omycin,
azi h omycin,
cla i h omycin,
spi amycin
No way
Any, Ca diac
1 – 3
Unexposed o any
an ibio ic:
1.02 (0.86, 1.23)
Exposed o non-
mac olide an ibio ics:
1.15 (0.96, 1.38)
8865/178142
413/9069
1.08
(0.95, 1.24)
Ma e nal age, u ina y ac
in ec ions, ch onic
ma e nal illness, pa i y,
ma i al s a us, smoking,
p egnancy supplemen ,
p e ious abo ions
Coope WO, e
al. 2009 [9]
azi h omycin,
e y h omycin
Uni ed S a es
Any, diges i e, head
and neck, ne ous,
musculoskele al,
u ogeni al
• 1 – 3
• 1 – 9
Unexposed o any
an ibio ic:
0.92 (0.73, 1.16)
Exposed o non-
mac olide an ibio ics:
1.03 (0.88, 1.21)
869/30,049
589/7471
0.99
(0.87, 1.13)
Ma e nal age, yea o
deli e y, ace, u al
esidence, economical
s a us, ch onic ma e nal
illness, illing o
p esc ip ions o o he
known e a ogens
Ba -Oz B, e al.
2008 [10]
azi h omycin,
oxy h omycin,
cla i h omycin
• C oa ia
• Is ael
Ca diac
1 – 3
Exposed o non-
mac olide an ibio ics:
1.62 (0.68, 3.86)
32/1066
1.62
(0.68, 3.86)
Unadjus ed
Online Resou ce 2. Cha ac e is ics o coho s udies o mac olides´ in ake and congeni al mal o ma ions (con inued)
Sou ce
Type o
Mac olide
Coun y
Type o
mal o ma ion
Exposu e
Pe iod
(mon hs o
p egnancy)
Compa ison Type
and OR (95% CI)
Cases/ Coho
Size
Gene al OR
(95% CI)
Adjus men , Ma ching,
and Res ic ion Fac o s
Chun JY, e al.
2006 [11]
oxy h omycin
Sou h Ko ea
Majo
1 – 3
Unexposed o any
e a ogenic agen :
1.37 (0.07, 27.57)
3/187
1.37
(0.07, 27.57)
Ma e nal age, g a i y
Sa ka M, e al.
2006 [12]
azi h omycin
Canada
Majo
1 – 3
Exposed o any non-
e a ogen:
1.01 (0.20, 5.11)
6/227
1.01
(0.20, 5.11)
Ma e nal age, ges a ional
age a call, smoking,
alcohol consump ion
Wol gang P, e
al. 2005 [13]
oxi h omycin
Hunga y
Congeni al
anomalies
1 – 3
Unexposed o any
an ibio ic:
2.13 (0.75, 6.1)
15/275
2.13
(0.75, 6.1)
Ma e nal age, ges a ional
age a call
Coope WO, e
al. 2002 [14]
e y h omycin,
non-
e y h omycin,
lincomycin,
clindamycin,
cla i h omycin,
azi h omycin,
di i h omycin
Uni ed S a es
Diges i e
• 6 – 9
• 1 – 9
Exposed o non-
mac olide an ibio ics:
1.28 (0.96, 1.70)
679/260,799
1.28
(0.96, 1.70)
Ma e nal age, educa ion,
geog aphic esidence, use
o o he an ibio ics,
in an ´s gende , in an ´s
ace, bi h o de , yea o
deli e y, in an ´s pos na al
p esc ip ions o
e y h omycin
Mahon BE, e
al. 2001 [15]
mac olides
Uni ed S a es
Diges i e
1 – 9
Unexposed o any
an ibio ic:
1.19 (0.6, 2.3)
43/14,876
1.19
(0.6, 2.3)
Bi h weigh s, ges a ional
age
Eina son A, e
al. 1998 [16]
cla i h omycin
Canada
Majo
1 – 3
Exposed o non-
e a ogenic
an ibio ics:
1.1 (0.44, 2.78)
19/266
1.1
(0.44, 2.78)
Ma e nal age, smoking,
alcohol consump ion
Wil on LV, e
al. 1998 [17]
azi h omycin
Uni ed
Kingdom
Congeni al
anomalies
1 – 3
Exposed o non-
mac olide an ibio ics:
1.75 (0.01, 31.23)
14/556
1.75
(0.01, 31.23)
Unadjus ed
Re e ences
1. Muanda FT, Sheehy O, Be a d A. Use o an ibio ics du ing p egnancy and he isk o majo
congeni al mal o ma ions: A popula ion based coho s udy. B J Clin Pha macol.
2017;83(11):2557-71. h ps://doi.o g/10.1111/bcp.13364
2. Lê Nguyên T, A aujo M, Hu aul -Dela ue C, Lac oix I, Damase-Michel C, Somme A.
e a ogenic isk o mac olides du ing he i s imes e o p egnancy: a s udy wi h wo
complemen a y app oaches wi hin he e eme is da abase. Clinical The apeu ics. 2017; 39
(8)Sup:e11-e12
3. Kallen B, Danielsson BR. Fe al sa e y o e y h omycin. An upda e o swedish da a. Eu J Clin
Pha macol. 2014;70(3):355-60. h ps://doi.o g/10.1007/s00228-013-1624-3
4. Lund M, Pas e nak B, Da idsen RB, Feens a B, K ogh C, Diaz LJ e al. Use o mac olides in
mo he and child and isk o in an ile hype ophic pylo ic s enosis: Na ionwide coho s udy.
BMJ. 2014;348:g1908. h ps://doi.o g/10.1136/bmj.g1908
5. Ande sen JT, Pe e sen M, Jimenez-Solem E, B oedbaek K, Ande sen NL, To p-Pede sen C e
al. Cla i h omycin in ea ly p egnancy and he isk o misca iage and mal o ma ion: A egis e
based na ionwide coho s udy. PLoS One. 2013;8(1):e53327.
h ps://doi.o g/10.1371/jou nal.pone.0053327
6. Dinu AB, Ko en G, Ma ok I, Wizni ze A, Uziel E, Go odische R e al. Fe al sa e y o
mac olides. An imic ob Agen s Chemo he . 2013;57(7):3307-11.
h ps://doi.o g/10.1128/AAC.01691-12
7. Ba -Oz B, Webe -Schoendo e C, Be lin M, Clemen i M, Di Gianan onio E, de V ies L e al.
The ou comes o p egnancy in women exposed o he new mac olides in he i s imes e : A
p ospec i e, mul icen e, obse a ional s udy. D ug Sa . 2012;35(7):589-98.
h ps://doi.o g/10.2165/11630920-000000000-00000
8. Romo en M, Lindbaek M, No deng H. P egnancy ou come a e ges a ional exposu e o
e y h omycin - a popula ion-based egis e s udy om no way. B J Clin Pha macol.
2012;74(6):1053-62. h ps://doi.o g/10.1111/j.1365-2125.2012.04286.x
9. Coope WO, He nandez-Diaz S, A bogas PG, Dudley JA, Dye SM, Gideon PS e al. An ibio ics
po en ially used in esponse o bio e o ism and he isk o majo congeni al mal o ma ions.
Paedia Pe ina Epidemiol. 2009;23(1):18-28.
h ps://doi.o g/10.1111/j.1365-3016.2008.00978.x
10. Ba -Oz B, Dia -Ci in O, Shech man S, Tellem R, A non J, F ance ic I e al. P egnancy ou come
a e ges a ional exposu e o he new mac olides: A p ospec i e mul i-cen e obse a ional s udy.
Eu J Obs e Gynecol Rep od Biol. 2008;141(1):31-4.
h ps://doi.o g/10.1016/j.ejog b.2008.07.008
11. Chun JY, Han JY, Ahn HK, Choi JS, Koong MK, Na a-Ocampo AA e al. Fe al ou come
ollowing oxi h omycin exposu e in ea ly p egnancy. J Ma e n Fe al Neona al Med.
2006;19(3):189-92. h ps://doi.o g/V347283491478V77
12. Sa ka M, Woodland C, Ko en G, Eina son AR. P egnancy ou come ollowing ges a ional
exposu e o azi h omycin. BMC P egnancy Childbi h. 2006;6:18.
h ps://doi.o g/1471-2393-6-18
13. Wol gang P, Schloemp S, S e zik K, S oz F, edi o s. Does oxi h omycin a ec emb yo
de elopmen ? 33 d Annual Con e ence o he Eu opean Te a ology Socie y; 3 - 7 Sep, 2005;
Haa lem, The Ne he lands: Rep oduc i e Toxicology.
14. Coope WO, G i in MR, A bogas P, Hickson GB, Gau am S, Ray WA. Ve y ea ly exposu e o
e y h omycin and in an ile hype ophic pylo ic s enosis. A ch Pedia Adolesc Med.
2002;156(7):647-50. h ps://doi.o g/poa10338
15. Mahon BE, Rosenman MB, Kleiman MB. Ma e nal and in an use o e y h omycin and o he
mac olide an ibio ics as isk ac o s o in an ile hype ophic pylo ic s enosis. J Pedia .
2001;139(3):380-4. h ps://doi.o g/S0022-3476(01)02879-7
16. Eina son A, Phillips E, Mawji F, D'Alimon e D, Schick B, Addis A e al. A p ospec i e con olled
mul icen e s udy o cla i h omycin in p egnancy. Am J Pe ina ol. 1998;15(9):523-5.
h ps://doi.o g/10.1055/s-2007-994053
17. Wil on LV, Pea ce GL, Ma in RM, Mackay FJ, Mann RD. The ou comes o p egnancy in
women exposed o newly ma ke ed d ugs in gene al p ac ice in England. B J Obs e Gynaecol.
1998;105(8):882-9.
Online Resou ce 3. Cha ac e is ics o case-con ol s udies o mac olides´ in ake and congeni al mal o ma ions
Sou ce
Type o
Mac olide
Coun y
Type o
mal o ma ion
Exposu e
Pe iod
(mon hs o
p egnancy)
Compa ison Type
and OR (95% CI)
Cases/Con ols
Gene al OR
(95% CI)
Adjus men , Ma ching,
and Res ic ion Fac o s
Lin KJ, e
al. 2013
[1]
Any mac olide,
e y h omycin,
non-
e y h omycin
• Canada
• Uni ed
S a es
Ca diac, diges i e,
head and neck,
musculoskele al,
ne ous, espi a o y,
u ogeni al
• 1 – 3
• 3 – 6
• 6 – 9
Unexposed o any
an ibio ic:
0.99 (0.85, 1.16)
4867/6,952
0.99
(0.85, 1.16)
Ma e nal age, calenda yea
when hey we e asce ained,
ace, educa ion, geog aphic
esidence, obesi y, amily
his o y o congeni al
mal o ma ions o diabe es
melli us, smoking,
p egnancy supplemen ,
mul iple p egnancy, u ina y
ac in ec ions, ma e nal
ch onic illness
C ide KS,
e al. 2009
[2]
e y h omycin
Uni ed S a es
Ca diac, diges i e,
head and neck,
musculoskele al,
ne ous, u ogeni al
1 – 3
Unexposed o any
an ibio ic:
1.12 (0.96, 1.32)
Exposed o non-
mac olide
an ibio ics:
1.01 (0.91, 1.13)
13155/4941
1384/516
1.04
(0.95, 1.15)
Ma e nal age, ace,
educa ion, obesi y,
ges a ional age a call,
p egnancy supplemen s,
smoking, alcohol
consump ion
Louik C,
e al. 2002
[3]
e y h omycin
• Canada
• Uni ed
S a es
Diges i e
• 1 – 6
• 6 – 9
Unexposed o any
an ibio ic:
0.81 (0.57, 1.14)
1,044/1704
0.81
(0.57, 1.14)
Ma e nal age, geog aphic
egion, s udy pe iod, pa i y,
in an ´s gende , ges a ional
age
Czeizel
AE, e al.
2000 [4] &
Czeizel
AE, e al.
1999 [5]
e y h omycin,
spi amyicn,
oxi h omycin,
oleandomycin,
josamycin,
Hunga y
Ca diac, head and
neck,
musculoskele al,
u ogeni al, ne ous,
o he s
• 1 – 3
• 1 – 9
Exposed o o he
agen s (no
mac olides):
1.19 (0.92, 1.54)
22,865/38,151
1.19
(0.92, 1.54)
Ma e nal age, u ogeni al
diso de s, bi h o de ,
ma e nal ch onic illness,
o he d ug uses
Re e ences
1. Lin KJ, Mi chell AA, Yau WP, Louik C, He nandez-Diaz S. Sa e y o mac olides du ing
p egnancy. Am J Obs e Gynecol. 2013;208(3):221 e1-8.
h ps://doi.o g/10.1016/j.ajog.2012.12.023
2. C ide KS, Cle es MA, Ree huis J, Be y RJ, Hobbs CA, Hu DJ. An ibac e ial
medica ion use du ing p egnancy and isk o bi h de ec s: Na ional bi h de ec s
p e en ion s udy. A ch Pedia Adolesc Med. 2009;163(11):978-85.
h ps://doi.o g/10.1001/a chpedia ics.2009.188
3. Louik C, We le MM, Mi chell AA. E y h omycin use du ing p egnancy in ela ion o
pylo ic s enosis. Am J Obs e Gynecol. 2002;186(2):288-90.
h ps://doi.o g/S0002937802042874
4. Czeizel AE, Rockenbaue M, Olsen J, So ensen HT. A case-con ol e a ological s udy
o spi amycin, oxi h omycin, oleandomycin and josamycin. Ac a Obs e Gynecol
Scand. 2000;79(3):234-7.
5. Czeizel AE, Rockenbaue M, So ensen HT, Olsen J. A popula ion-based case-con ol
e a ologic s udy o o al e y h omycin ea men du ing p egnancy. Rep od Toxicol.
1999;13(6):531-6. h ps://doi.o g/S0890-6238(99)00046-5
