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Reproductive Toxicology
journal homepage: www.elsevier.com/locate/reprotox
Use of ondansetron during pregnancy and the risk of major congenitalmalformations: A systematic review and meta-analysis
Yusuf Cem Kaplana,b, Jonathan Luke Richardsonc,⁎, Elif Keskin-Arslana,b, Hilal Erol-Coskuna,b,Debra Kennedyd,e
a Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkeyb Izmir Katip Celebi University School of Medicine, Department of Pharmacology Izmir, Turkeyc The UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UKdMothersafe, The Royal Hospital for Women, Sydney, New South Wales, Australiae School of Women’s and Children’s Health University of New South Wales, Australia
A R T I C L E I N F O
Keywords:OndansetronPregnancyNausea and vomiting of pregnancyCongenital abnormalitiesBirth defectsHyperemesis gravidarum
A B S T R A C T
Aims: To investigate whether ondansetron use during pregnancy is associated with increased rates of major orsubgroups of malformations.Methods: PubMed/MEDLINE, Cochrane and Reprotox® databases were searched. Observational studies com-prising an exposed and control group (healthy and/or disease-matched) were included.Results: No significant increased risk for major malformations, heart defects, orofacial clefts, genitourinarymalformations or hypospadias were identified in our primary analysis. A significant heterogeneity existed forisolated cleft palate. Elevated point estimates and altered statistical significances were present for some of theoutcomes among secondary analyses.Conclusions: Ondansetron use during pregnancy was not associated with a significant increase in rate of major orselected subgroups of malformations in our primary analysis. However, results of the secondary analyses warrantthe need for continued surveillance. These results may be reassuring for pregnant women in whom ondansetronuse is clinically indicated since the absolute risks of possible concerns appear to be low.
1. Introduction
Nausea and vomiting of pregnancy (NVP) affects about 70% of allwomen during their pregnancy [1,2]. Symptoms usually start early inthe first trimester (4–6 weeks), peak between 8–12 weeks and end bythe 16th week of pregnancy in the majority of women [3,4]. NVP hasthe potential to adversely affect the patient’s quality of life, socialfunctioning and occupational performance [5,6]. The most severe form,hyperemesis gravidarum (HG), may affect up to 2% of pregnant womenby leading to significant weight loss, dehydration and electrolyte im-balance necessitating hospitalization [3]. Refractory NVP may evenlead to pregnant women considering termination of an otherwisewanted pregnancy [6].
Ondansetron is a serotonin 5-HT3 receptor antagonist, a pharma-cological class which was originally developed to control che-motherapy-induced emesis [7]. Current NVP treatment guidelinessuggest that its use may be considered if first-line drugs such as VitaminB6 (pyridoxine), doxylamine/Vitamin B6, diphenydramine,
dimenhydrinate, meclizine, metoclopramide and their combinationshave failed to suppress maternal symptoms [4,8]. However, studiesinvestigating the safety of maternal ondansetron use during pregnancyhave reported inconsistent findings. Although the major congenitalmalformation rate was not suggested to be increased in any of theparticular studies to date [9–15], two prospective cohort studies havereported an increase in risk of heart defects [12,13] while one case-control study identified a significant increase in the risk of isolated cleftpalate [16], and another reporting conflicting findings for this outcomein two different datasets [17].
Given that NVP is the most common medical condition duringpregnancy which overlaps with the period of organogenesis and thatondansetron’s off-label prescription rate to pregnant women has beenon the rise [10,13,18], it is important to investigate the safety of on-dansetron use during pregnancy. Our objective while undertaking thisfirst meta-analysis of the controlled epidemiological studies to date,was to assess whether ondansetron use in pregnancy is associated withan increase in the rate of major congenital malformations. Our
https://doi.org/10.1016/j.reprotox.2019.03.001Received 17 September 2018; Received in revised form 27 February 2019; Accepted 4 March 2019
⁎ Corresponding author at: The UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.E-mail address: [email protected] (J.L. Richardson).
Reproductive Toxicology 86 (2019) 1–13
Available online 05 March 20190890-6238/ © 2019 Elsevier Inc. All rights reserved.
T
secondary objective was to analyze the rates of subgroup of mal-formations such as heart defects, orofacial clefts and isolated cleft pa-late, genitourinary malformations and hypospadias.
2. Methods
2.1. Search strategy
Searches were conducted by the study authors in PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotoxdatabases from inception to 21 st September 2016 using the followingsearch terms and their combinations with BOOLEAN operators by thestudy authors: ondansetron, pregnancy, congenital malformations,congenital abnormalities, birth defects, cardiovascular malformationsand heart defects. We applied no language or date restrictions. Amanual search has also been held through the reference list of theprevious systematic reviews in order to identify other potentially eli-gible studies. The study identification and inclusion flow chart wasprepared in compliance with the Preferred Reporting Items forSystematic Reviews and Meta-Analyses (PRISMA) [19] and is presentedin Fig. 1. Our findings are reported in adherence with the Meta-Analysisof Observational Studies in Epidemiology (MOOSE) guidelines [20].
2.2. Inclusion and exclusion criteria
Observational cohort and case-control studies investigating majorcongenital malformations after maternal use of ondansetron in preg-nancy were included in this meta-analysis. A study was consideredeligible if it met the following criteria: [1] Exposure to ondansetronduring pregnancy was reported [2]; A healthy or disease-matchedcontrol (either nausea and vomiting of pregnancy or hyperemesisgravidarum) group was included. These control groups should be un-exposed to ondansetron but they might be exposed to either non-ter-atogenic drugs or antiemetics other than ondansetron; [3] Either thetotal number of exposure and outcome events or point estimates werereported [4]; The data reported were not overlapping with anotherstudy. If an overlap between two studies was detected, we preferred toinclude the one that received higher score regarding methodologicalquality. However, a sensitivity analysis including each of the over-lapping studies at a time was also conducted. The exclusion criteriawere case reports and series, animal studies, editorials and reviews.
2.3. Quality assessment
The Newcastle-Ottawa scale [21] was used for quality assessment ofthe study methodologies. The authors were not blinded to the authornames, institutions, results or journals of the publications. Any dis-agreements were resolved through subsequent discussion with another
Fig. 1. PRISMA flow diagram.
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
2
Table1
Cha
racteristics
ofthestud
ies.
a.Coh
ortstud
iesinve
stigatingmajor
andorga
n-specificco
ngen
ital
malform
ationratesfollo
wingon
dansetronexpo
sure
during
preg
nanc
y
Eina
rson
etal.2
004
Colvinet
al.2
013
Pasterna
ket
al.2
013
And
ersenet
al.2
013
Dan
ielssonet
al.2
014
Fejzoet
al.2
016
Cou
ntry
Stud
yPe
riod
Design/
setting
Can
adaan
dAustralia
– Prospe
ctiveCoh
ort
Australia
2002
-200
5Reg
istry-ba
sedCoh
ort
Den
mark
2004
-201
1Reg
istry-ba
sedCoh
ort
Den
mark
1997
-201
0Reg
istry-ba
sedCoh
ort
Swed
en19
98–2
012
Reg
istry-ba
sedCoh
ort
UnitedStates
2007
-201
4Retrospective
Coh
ort
Dataso
urce
Nau
seaan
dVom
itingof
Preg
nanc
yHelplineor
Teratoge
nInform
ationSe
rvices
(TIS)at
The
Mothe
risk
Prog
ram
inTo
rontoor
TheMothe
rsafeProg
ram
inSy
dney
AustralianPh
armaceu
tical
Bene
fits
Sche
me,
Western
AustralianData
Link
ageSy
stem
,Hospital
Morbidity
DataSy
stem
,Midwives’N
otification
System
,Reg
istryof
Births
andDeaths,
Western
AustralianReg
isterof
Dev
elop
men
talAno
malies
(WARDA)
Dan
ish
Med
ical
BirthReg
istry,
Dan
ish
Nationa
lPa
tien
tReg
ister,
Dan
ish
Nationa
lPrescription
Reg
istry,
Dan
ishCen
tral
Person
Reg
ister,
Statistics
Den
mark
Dan
ish
Med
ical
BirthReg
istry,
Nationa
lHospital
Reg
ister,Dan
ishNationa
lPrescription
Reg
istry
Swed
ishMed
ical
BirthReg
ister,
Swed
ishPrescription
Reg
ister,
Birth
DefectReg
ister,
MidwifeInterview
Hyp
erem
esis
Educ
ationan
dResearchFo
unda
-tionWeb
site
(www.H
elpH
er.org)
Num
berof
participan
ts52
8preg
nant
wom
en/49
1infants
96,698
preg
nant
wom
en/
98,325
infants
608,38
5preg
nanc
ies/44
2,74
8infants
897,01
8births
1,50
1,43
4infants
1335
preg
nant
wom
en/33
96preg
nanc
ies/2
679liv
ebirts
Num
berof
even
tsOnd
ansetron
-ex
posed(First
trim
ester):
Une
xpos
ed:
NVP/
HG
contro
l:
Totalbirth:
169
MCM:6
Heart
defects:
1Oralcleft:0
Gen
itou
rina
ry:4
Ren
alde
fects:
1Hyp
ospa
dias:3
Totalbirth:
162
MCM:3
Heart
defects:
2Oralcleft:0
Gen
itou
rina
ry:1
Ren
alde
fects:
0Hyp
ospa
dias:1
Totalbirth:
160
MCM:3
Heart
defects:
1Oralcleft:0
Gen
itou
rina
ry:1
Ren
alde
fects:
1Hyp
ospa
dias:0
Total:21
1MCM:1
0Heart
defects:
a
Oralcleft:
a
Gen
itou
rina
ry:5
Ren
alde
fects:
N/A
Hyp
ospa
dias:a
Total:98
,062
MCM:3
975
Heart
defects:
641
Oralcleft:21
5Gen
itou
rina
ry:1
352
Ren
alde
fects:
N/A
Hyp
ospa
dias:3
61
Total:12
33MCM:3
6Heart
defects:
13Oralcleft:3
Gen
itou
rina
ry:8
Ren
alde
fects:
4Hyp
ospa
dias:4
Total:49
32MCM:1
41Heart
defects:
50Oralcleft:13
Gen
itou
rina
ry:2
5Ren
alde
fects:
11Hyp
ospa
dias:1
2
Total:12
34CM:5
8Heart
defects:
N/A
Oralcleft:N/A
Gen
itou
rina
ry:N
/ARen
alde
fects:
N/A
Hyp
ospa
dias:N/A
Total:89
5,91
4CM:3
1357
Heart
defects:
N/A
Oralcleft:N/A
Gen
itou
rina
ry:N
/ARen
alde
fects:
N/A
Hyp
ospa
dias:N/A
Total:13
49MCM:38
Heart
defects:
19Oralcleft:1
Gen
itou
rina
ry:4
Ren
alde
fects:
0Hyp
ospa
dias:3
Total:1,45
8,69
7MCM:42
,392
Heart
defects:
14,412
Oralcleft:N/A
Gen
itou
rina
ry:N
/ARen
alde
fects:
N/A
Hyp
ospa
dias:N/A
Total:95
2MCM:1
5Heart
defects:
5Oralcleft:1
Gen
itou
rina
ry:2
Ren
alde
fects:
0Hyp
ospa
dias:2
Total:12
86MCM:1
6Heart
defects:
9Oralcleft:2
Gen
itou
rina
ry:2
Ren
alde
fects:
1Hyp
ospa
dias:1
Total:44
1MCM:7
Heart
defects:
1Oralcleft:0
Gen
itou
rina
ry:1
Ren
alde
fects:
1Hyp
ospa
dias:0
Inclus
ioncriteria
-Allwom
enwithon
dansetron
expo
sure
who
wereless
than
threemon
thspreg
nant
atthe
timeof
calling
totheTISwithina
twoye
arpe
riod
-Allbirths
inWestern
Australianbe
tween20
02-
2005
-Allsing
leton
livebirthor
stillbirthor
ende
dwith
anyab
ortive
outcom
ein
Den
markbe
tween
Janu
ary1,
2004
-March
31,2
011
-Allwom
engiving
birth
inDen
markbe
tween
1997
and20
10
-Allliv
ebirths
inSw
eden
betw
een
1998
and20
12-Ev
ents
withrelative
lyseve
reco
ngen
ital
malform
ation
-Allwom
enwithadiag
nosisof
HG
who
recruitedto
web
site
betw
een
2007
and20
14-Sing
letonpreg
nanc
y-Treatm
entwithIV
fluids
and/
ortotalpa
renteral
nutrition/
nasoga
stricfeed
ingtube
(con
tinuedon
next
page)
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
3
Table1(con
tinued)
a.Coh
ortstud
iesinve
stigatingmajor
andorga
n-specificco
ngen
ital
malform
ationratesfollo
wingon
dansetronexpo
sure
during
preg
nanc
y
Eina
rson
etal.2
004
Colvinet
al.2
013
Pasterna
ket
al.2
013
And
ersenet
al.2
013
Dan
ielssonet
al.2
014
Fejzoet
al.2
016
Exclus
ioncriteria
N/A
-Minor
defectswithno
disfi
guring
orrequ
irem
entof
treatm
ent
-Le
ssthan
five
subjects
ineach
defectssubg
roup
were
notmen
tion
ed
-Pregn
ancies
withmissing
orim
plau
siblege
stationa
lag
eor
birth
weigh
t(for
birthweigh
tan
alysis)
-Multiplereco
rdson
overlapp
ing
dates
-The
abortion
swhich
wereoc
curred
priorthan
6thge
stationa
lweeks
-Ond
ansetron
prescription
swithin1mon
thbe
fore
preg
nanc
yon
set
-Infan
tswithch
romosom
alab
erration
s(e.g.,Dow
n’ssynd
rome)
andthose
with
know
ncauses
ofbirthde
fects(e.g.,
fetalalco
hol
synd
rome)
-Unp
airedinfantsafterprop
ensity
scorean
alysis
N/A
-Relativelyco
mmon
andclinically
less
sign
ificant
malform
ations
witha
variab
leregistration
such
uspreauricular
tags,ton
guetie,pa
tent
ductus
inpreterm
infants,
sing
leum
bilic
alartery,und
escend
edtestis,
hip(sub
)lux
ation,
andne
vus
-Dup
lications
intheprescription
register
andmidwifeinterviews
-Und
er18
years
-Living
outsidetheUnitedStates
Expo
sure
Ond
ansetron
,Other
antiem
etics;
diclectin,
metoc
lopram
ide,
phen
othiazines
and
ging
er
Ond
ansetron
Ond
ansetron
Ond
ansetron
,metoc
lopram
ide
Ond
ansetron
,meclozine
Ond
ansetron
,metoc
lopram
ide,
prom
etha
zine
Expo
sure
timewindo
wEx
posure
toon
dansetrondu
ring
firsttrim
ester
Ond
ansetron
expo
suresrepo
rted
atthefirstpren
atal
visit
Firsttrim
esterdispen
sing
wereinclud
edthean
alysis
ofmajor
birthde
fect.
-Ond
ansetron
dispen
sing
atan
ytimedu
ring
preg
nanc
yfor
othe
rou
tcom
es(stillb
irth,
birthweigh
tetc.)
Ond
ansetron
dispen
sing
tothewom
enin
firstda
yof
thelast
men
strual
period
throug
h12
gestationa
lweeks
foran
ymajor
birthde
fect.
-Ond
ansetron
dispen
sing
atan
ytime
during
preg
nanc
yforothe
rou
tcom
es(preterm
birth,
birthweigh
t,stillbirthan
dspon
tane
ousab
ortus)
Wom
enrede
emed
onda
nsetron
prescription
sdu
ring
first
trim
ester
Expo
sure
toon
dansetronafterlast
men
struel
period
throug
h12
gestationa
lweeks
oron
dansetron
prescribed
during
firsttrim
ester
Expo
sure
toon
dansetronan
ytime
during
preg
nanc
y.Fo
rou
ran
alysison
lyfirsttrimester
expo
sureswereextractedfrom
unpu
blishe
dda
ta.
Con
trol
Con
trolswereen
rolle
din
thesame
way
withexpo
sedgrou
p.Group
2withNVPwho
wereno
texpo
sedto
onda
nsetron,
they
hadused
othe
ran
ti-emetics
Group
3who
wereexpo
sedton
on-teratog
endrug
sor
hadno
tused
anymed
ication
Wom
enwithno
onda
nsetron
dispen
sing
inthesamepe
riod
withexpo
sedgrou
p
Wom
enwithno
onda
nsetron
dispen
sing
inthesamepe
riod
with
expo
sedgrou
p,1expo
sedinfant
match
edwith4
unexpo
sedinfants
Wom
enwithno
onda
nsetron
prescription
s
Wom
enwithno
expo
sure
toon
dansetronan
dmecliz
inedu
ring
first
trim
ester
HG
controls:Wom
enwho
suffered
from
HG
andno
texpo
sure
onda
nsetronor
expo
sedto
othe
rtreatm
ents
forNVPan
dalso
had
minim
um2follo
w-upafter27
weeks.
Healthy
controls:Wom
enwith
know
nhistoryof
norm
alna
usea/
vomitingor
nona
usea/v
omitingat
leastin
2preg
nanc
ies.
Metho
dof
cong
enital
malform
ation
diag
nosis
Stan
dardised
interview
withmothe
rsan
dthen
for
verification
ofba
by’she
alth
were
aske
dtheirph
ysicians
withletter
WARDA
classification
and5-
digitBritishPa
ediatric
Assoc
iation
Internationa
lClassification
ofDiseases,
Ninth
Rev
ision(ICD-9)system
Europe
anSu
rveilla
nce
ofCon
genitalAno
malies
(EUROCAT)
classification
,Internationa
lClassification
ofDiseases;
thetenthrevision
(ICD-10)
EUROCATclassification
Internationa
lClassification
ofDiseases
code
Structured
onlin
esurvey
swere
done
bymothe
rs
(con
tinuedon
next
page)
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
4
Table1(con
tinued)
a.Coh
ortstud
iesinve
stigatingmajor
andorga
n-specificco
ngen
ital
malform
ationratesfollo
wingon
dansetronexpo
sure
during
preg
nanc
y
Eina
rson
etal.2
004
Colvinet
al.2
013
Pasterna
ket
al.2
013
And
ersenet
al.2
013
Dan
ielssonet
al.2
014
Fejzoet
al.2
016
Cov
ariatesfor
adjustmen
tAge
,smok
ing,
alco
holstatus
and
gestationa
lag
eat
timeof
call
Materna
lag
e,prev
ious
preterm
birth,
smok
ingdu
ring
preg
nanc
y,socioe
cono
mic
situation,
parity,p
riva
tehe
alth
insuranc
e,an
dmultiplebirth,
caesarean
deliv
ery
(The
adjustmen
tweredo
neon
lyforpreterm
birth,
elective
caesareanan
dpo
stpa
rtum
haem
orrhag
ia)
Age
,place
ofbirth,
coun
tyof
reside
nce,
married
orliv
ingwith
partne
r,leve
lof
educ
ation,
inco
me,
preg
nanc
yhistory,
smok
ing,
pre-
preg
nanc
yBM
I,med
ical
history,
health
care
utilization
,use
ofothe
ran
tiem
etics(m
etoc
lopram
ide,
antiem
etic
antihistam
ines,
scop
alam
ine,
anddo
mpe
rido
ne)
Adjustm
entwas
repo
rted
butau
thorsdidno
tmen
tion
which
cova
riates
were
includ
ed.
Yearof
birth,
materna
lag
e,pa
rity,
smok
ingin
earlypreg
nanc
y,an
dbo
dymassinde
x
Ethn
icity,
educ
ation,
term
ination,
miscarriage
,age
Results
releva
ntto
this
meta-an
alys
isOR/R
R(95%
CI)or
pva
lue
Use
ofon
dans
etro
ndu
ring
first
trim
ester
MCM:
6/16
9vs
6/32
2(p
=0.52
)Hyp
ospa
dias:
3/16
9vs
1/32
2(p
=0.25
)
Use
ofon
dans
etro
nan
ytimedu
ring
preg
nanc
yAny
birthde
fect:
OR:1
.3(0.8–2
.1)
MCM:
OR:1
.1(0.6–2
.0)
Use
ofon
dans
etro
ndu
ring
firsttrim
ester
MCM:
OR:1
.2(0.6–2
.2)
Obstruc
tive
defectsof
rena
lpe
lvis
andureter:
OR:6
.2(2.0-19.5)
Use
ofon
dans
etro
ndu
ring
first
trim
ester
MCM:
aOR:1
.12(0.69-1.82
)
Use
ofon
dans
etro
ndu
ring
firsttrim
ester
MCM:
aOR:1.3(1.0-1.7)
Heart
defect:
aOR:2.0(1.3-3.1)
Use
ofon
dans
etro
ndu
ring
first
trim
ester
Any
malform
ation:
OR:0
.95(0.72–
1.26
)MCM:
OR:1
.11(0.81–
1.53
)Heart
defect:
OR:1
.62(1.04–
2.54
)
Use
ofon
dans
etro
nan
ytime
during
preg
nanc
yBirthde
fects
HG/O
ndan
setron
grou
pvs
HG/N
oOnd
ansetron
grou
p3.47
%vs
3.40
%(p
=1.0)
Qua
lity
assessmen
t(N
ewca
stle–
Ottaw
ascale)
****
/**/*-*
8**
**/**/*-*
8****/**/***
9****/–/*–
5****/**/*–
7****/**/–*
7
b.Case-co
ntrolstud
iesinve
stigatingtheassociationbe
tweenorga
n-specificmalform
ations
andon
dansetronexpo
sure
during
preg
nanc
y
And
erka
etal.2
012
Van
Benn
ekom
etal.2
016
And
erka
etal.2
012
Van
Benn
ekom
etal.2
016
Cou
ntry
Stud
yPe
riod
Design/
Setting
UnitedStates
1997
-200
4Multi-site
Popu
lation
-based
Case-co
ntrolStud
y
UnitedStates
2005
-200
919
97–2
013
Popu
lation
-based
Case-co
ntrol
Stud
y
Expo
sure
Ond
ansetron
Other
Antiemetics;
prom
etha
zine
,diph
enhy
dram
ine,
cetirizine
,dox
ylam
ineplus
pyrido
xine
,cetirizine,
phen
othiazines,proc
hlorpe
razine
,metoc
lopram
ide,
antacids,H
2bloc
kers,p
rotonpu
mpinhibitors,p
yridox
ine,
steroids,em
etrol/co
kesyrup,
herbal/n
atural
prod
ucts,
ging
er
Ond
ansetron
Dataso
urce
Nationa
lBirthDefects
Prev
ention
Stud
y(N
BDPS
)Nationa
lBirthDefects
Prev
ention
Stud
y(N
BDPS
)(200
5-20
09)
Slon
eBirthDefects
Stud
y(BDS)
(199
7–20
13)
Expo
sure
timewindo
wFirsttrim
esteruseof
onda
nsetron
Firsttrim
esteruseof
onda
nsetron
Num
berof
participan
tsCase
Con
trol
22,381
preg
nant
wom
en45
2458
59
N/A
Con
trol
Con
trol
subjects
witho
utbirthde
fectswererand
omly
selected
.Hyp
ospa
dias
analysis
done
withon
lymaleco
ntrols.
N/A
(con
tinuedon
next
page)
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
5
Table1(con
tinued)
b.Case-co
ntrolstud
iesinve
stigatingtheassociationbe
tweenorga
n-specificmalform
ations
andon
dansetronexpo
sure
during
preg
nanc
y
And
erka
etal.2
012
Van
Benn
ekom
etal.2
016
And
erka
etal.2
012
Van
Benn
ekom
etal.2
016
Num
berof
onda
nsetro
nex
posu
resin
case
vsco
ntro
lgrou
pOR/R
R(95%
CI)
Cleft
lipwithor
witho
utpa
late
7/93
3vs
44/4
,009
aOR:0
.88(0.38–
2.00
)Cleft
palate
11/5
25vs
44/4
009
aOR:2
.37(1.18–
4.76
)Neu
raltube
defects(N
TDs)
4/71
1vs
44/4
,016
aOR:0
.60(0.21–
1.68
)Hyp
ospa
dias
5/65
5vs
18/1
956
aOR:0
.57(0.20–
1.60
)
Cleft
palate
NBD
PSaO
R:1
.5(0.9-2.5)
BDS
aOR:0
.4(0.2-0.8)
Ren
alag
enesis/d
ysplasia
BDS
aOR:2
.3(1.3-4.0)
Hyp
oplastic
left
heartsy
ndro
me
NBD
PSaO
R:1
.5(0.7-3.1)
Diaph
ragm
atic
hern
iaNBD
PSaO
R:1
.7(0.9-3.5)
Metho
dof
cong
enital
malform
ationdiag
nosis
Materna
linterviewsin
thebirthde
fectssurveilla
nce
system
sClin
ical
gene
ticistsreview
edinform
ationof
casesfrom
med
ical
andco
nfirm
edthecases
N/A
Inclus
ioncriteria
-Infan
tswho
sefollo
w-upinterviewswere
availablean
dexpe
cted
datesof
deliv
ery
werebe
tween
Septem
ber24
,199
7an
dDecem
ber31
,20
04.
-Allinfantswho
reside
inthestud
yareas
-Ane
ncep
haly,cran
iorach
isch
isis,spina
bifida
,oren
ceph
aloc
elewereinclud
edfor
NTD
s-Onlyinfantswithseve
rehy
pospad
ias
N/A
Cov
ariatesfor
adjustmen
tMaterna
lag
e,race/ethnicity
anded
ucation,
parity,
plurality,
prev
ious
miscarriage
,any
smok
ingin
themon
thbe
fore
conc
eption
throug
hthefirsttrim
ester,
body
mass
inde
x,infant
sex,
any
folic
acid
usein
themon
thbe
fore
conc
eption
throug
hthe
firsttrim
ester,
useof
unkn
ownan
tiem
etic,s
ite,
and
expe
cted
year
ofde
livery
Adjustm
entwas
repo
rted
but
authorsdidno
tmen
tion
edwhich
cova
riates
wereinclud
ed.
Exclus
ioncriteria
-Cases
withreco
gnized
orstrong
lysuspectedch
romosom
eab
norm
alitiesor
sing
le-gen
eco
nditions
-Infan
tswithclefts
seco
ndaryto
anothe
rde
fect
(e.g.,ho
loprosen
ceph
alyor
amniotic
band
sequ
ence)
-Unc
onfirm
edorofacialclefts
afterbirth
-First-deg
reehy
pospad
ias(urethralop
ening
ontheglan
sor
corona
)-For
evalua
tion
family
history,
caseswith
samebirthde
fectswithapa
rent,s
iblin
gor
halfsiblingwereexclud
ed-Wom
enwithpre-existing
diab
etes
and
infantswithmorethan
onemajor
birth
defect
N/A
Qua
lity
assessmen
t(N
ewca
stle–
Ottaw
ascale)
****/**/-**
8****/*-/-*-
6
Abb
reviations
areas
follo
ws:Not
available(N
/A),no
trep
orted(N
R),co
ngen
ital
malform
ation(C
M),major
cong
enital
malform
ation(M
CM),na
usea
andvo
mitingdu
ring
preg
nanc
y(N
VP),h
yperem
esisgrav
idarum
(HG).
aAutho
rs’sinstitutiondo
esno
tallow
topu
blishsamplesizesless
than
5.Abb
reviations
areas
follo
ws:
Not
available(N
/A),no
trepo
rted
(NR),co
ngen
ital
malform
ation(C
M),major
cong
enital
malform
ation(M
CM).
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
6
author (Y.C.K.).
2.4. Outcome measures
The main outcome of interest for this meta-analysis was overallmajor congenital malformations. The secondary outcomes of interestwere heart defects, orofacial clefts, isolated cleft palate, genitourinarymalformations and hypospadias.
2.5. Data extraction
Two authors (E.K-A. and H.E-C.) independently reviewed the stu-dies. The data were extracted by using a standardized data extractionform and presented in Table 1. We communicated through e-mail withColvin et al., [10] and Fejzo et al., [14] regarding the details of themalformations in their studies. We also communicated with Danielssonet al. through a correspondence about an inconsistency in the reportedpoint estimate and confidence limits regarding heart defects in theirstudy [13]. First trimester exposures, if available, were considered. Anydisagreements were discussed and resolved by consulting with anotherauthor (Y.C.K.). The authors were not blinded to the details of thepublications.
2.6. Classification of malformations
Most of the studies had already classified the malformations theyinvestigated, therefore relevant point estimates or event numbers wereused to pool the data. The malformations which were retrieved bypersonal communication through e-mail with Colvin et al., [10] Fejzoet al. [14] were classified independently by the study authors (Y.C.K.,J.L.R., E.K-A. and H.E-C.) and consensus was achieved through dis-cussion with another author (D.K.). Because the malformations wereclassified using the Malformation Coding Guides of European Surveil-lance of Congenital Anomalies (EUROCAT) [22,23], as major andminor, JRC-EUROCAT Central Registry was also consulted through e-mail in case of any disagreements among the authors regarding theclassification. The authors were not blinded regarding whether themalformations belonged to exposed or control groups during the clas-sification of malformations.
2.7. Meta-analytic methods
For pooling the events, data were extracted from eligible studies andarranged in a 2 by 2 table. The odds ratios (OR) and 95% confidenceintervals (CI) for the dichotomous outcomes of interest were calculatedusing Mantel-Haenszel method and outcome data was combined byusing a random-effects model with RevMan 5.3 (Review Manager 5.3;Cochrane Collaboration, Oxford, UK). For pooling the point estimates,we extracted ORs (or aORs where available from eligible studies). Forthe study by Einarson et al., [9] Colvin et al. [10] and Fejzo et al. [14]we calculated the ORs for the outcomes of interest from the data ac-cordingly. The log odds ratios (log [OR]) and standard errors (SE) werecombined using generic inverse variance method and random-effectsmodel in RevMan 5.3 (Review Manager 5.3; Cochrane Collaboration,Oxford, UK) [24]. Heterogeneity was assessed utilizing the Q and I-square statistic. An I-square value between 25%–50% signified lowheterogeneity, between 50%–75% moderate and> 75% signified highheterogeneity [25]. A funnel plot was not utilized to assess publicationbias since it is suggested to have low power for detecting asymmetrywith good accuracy if the number of included studies is below ten [26],which was the case with our meta-analysis.
3. Results
The study identification and inclusion flow chart was prepared incompliance PRISMA guidelines [19] and is presented in Fig. 1 below.
Seven cohort studies [9–15] and two case-control studies [16,17]were identified as eligible for this meta-analysis; (details presented inTable 1). Four of the cohort studies [11–13,15] originated from Scan-dinavian registries (two from Denmark and two from Sweden) whiletwo were from North America (Canada and the U.S.) [9,14] and onewas undertaken in Australia [10]. Because the two Danish studies,Pasternak et al. [11], and Andersen et al. [12], investigated largelyoverlapping data and yielded conflicting results, we undertook a sen-sitivity analysis and presented two different forest plots for the out-comes of interest by including each Danish study one at a time. Ofimportance, the study by Andersen et al. [12] was published as anabstract which provided very limited details that led to a relativelylower methodological quality score (Table 1), and as such, the study byPasternak et al. [11] was included in the primary analysis. The study byAsker et al. was also excluded since it did not report the details of thecontrol group and had overlapping data (Swedish Medical Birth Reg-ister) with the study by Danielsson et al., which was much more recent(1995–2002 vs 1995–2012, respectively).
The studies by Pasternak et al. [11] and Andersen et al. [12] and theAustralian study by Colvin et al. [10] used relevant birth and electronicregistries for the data, while the Canadian study, by Einarson et al. [9]utilized data collected through calls to a teratology information service(Motherisk). The study from the U.S., by Fejzo et al. [14] used datafrom a larger investigation regarding hyperemesis gravidarum. Al-though the eligible studies mostly consisted of pregnant women withondansetron exposure during the first trimester, the rates of first tri-mester exposure differed between the studies. Nevertheless, we focusedon exclusively the first trimester exposures while pooling the data.Pasternak et al. [11] and Andersen et al. [12] considered only firsttrimester ondansetron exposure, while about 70% of the exposures inDanielsson et al. [13] and Colvin et al. [10] occurred during the firsttrimester. Fejzo et al. [14] described higher rates (> 90%), and Ei-narson et al. [9] reported that most of the exposures in their studyoccurred between 4 and 9 week of pregnancy, but no rate was quan-tified.
The eligible studies also used different types of control groups.Andersen et al. evaluated the rates of malformations in the metoclo-pramide-exposed pregnancies within the same cohort as the ondanse-tron exposed group [12], while Danielsson et al. also took a similaraprroach and asessed the outcomes of the meclizine-exposed pregnan-cies [13]. Both approaches aimed to rule out confounding by indication.Pasternak et al. [11] and Colvin et al. [10] used a non-exposed controlgroup whereas Einarson et al. [9] and Fejzo et al. [14] had two differentcontrol groups, diseased-matched and unexposed, for comparison. Be-cause such differences on the selection of the control group exists, wedecided to undertake a sensitivity analysis by limiting the combinationof results to studies which included control groups with similar char-acteristics.
There were also two case-control studies. Anderka et al. used theNational Birth Defects Prevention Study (NBDPS, 1997–2004) data toassess the link between the drugs used in the first trimester for NVP andpossible malformations [16]. Van Bennekom et al. [17] used two dif-ferent datasets; Slone Birth Defects Study (BDS 1997–2013) and theNational Birth Defects Prevention Study (NBDPS) (2005–2009). Ofimportance, this study retrospectively evaluated the link between sev-eral different classes of drugs used for NVP and several organ specificmalformations [17].
The methodological quality assessment of the eligible studies withthe Newcastle-Ottawa scale indicated high quality. The lowest scorewas received by Andersen et al. [12] since it was only published as anabstract. Therefore Pasternak et al. [11] was considered as eligible forour primary analysis among the overlapping Danish studies since itreceived a much higher quality score.
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
7
3.1. Meta-analysis of major and organ-specific congenital malformationrates in ondansetron-exposed vs healthy controls
3.1.1. Overall major congenital malformationsSix studies assessing a total number of 5148 ondansetron-exposed
and 2,459,053 control infants were considered eligible for inclusion inthis analysis [9–14]. Because two of the studies were overlapping,Andersen et al. [11] was excluded in our primary analysis leaving atotal of 3914 ondansetron-exposed and 1,563,139 control infants. Nosignificant increase in the rate of overall major congenital malformationwas detected following ondansetron use during pregnancy (OR, 1.16;95%, CI 0.92–1.45) in our primary analysis (Fig. 2). However, thesensitivity analysis (including Andersen et al. [12] instead of Pasternaket al. [11] 3915 exposed vs 2,454,121 control infants, slightly elevatedthe point estimate and altered the statistical significance (OR, 1.23;95%, CI 1.02–1.48) (Fig. 2). No significant heterogeneity among thestudies were present for either analysis (incl. Pasternak et al. [11]P=0.95, I-square= 0%, and incl. Andersen et al. [12] P= 0.91,I²= 0%).
3.1.2. Heart defectsThe same six studies were eligible for the analysis of heart defect
risk [9–14]. In the extraction of the data from the primary sources, wedetected an inconsistency in the reported point estimate and confidencelimits in one of the studies [13]. Subsequent communication with theauthors revealed a typing error in the upper limit of the reportedconfidence interval for heart defects (OR, 1.62; 95%, CI 1.04–2.14). Theauthors, in their recent erratum [27], corrected the upper confidencelimit as 2.54 instead of 2.14. Considering this correction, the combinedodds ratio for overall heart defect risk following ondansetron use wasnot significant (OR, 1.26; 95%, CI 0.90–1.77) (Fig. 3). Similar to themajor congenital malformation analysis above, the sensitivity analysisregarding the heart defects elevated the point estimate and altered thestatistical significance (OR, 1.59; 95%, CI 1.14–2.21) (Fig. 3). No sig-nificant heterogeneity existed for the investigated outcomes (incl.Pasternak et al. [11] P=0.50, I-square= 0% and incl. Andersen et al.[12] P=0.35, I²= 9%).
3.1.3. Orofacial cleftsThree studies were eligible [10,11,14]. No significant increase in
the rates of orofacial clefts following ondansteron use during pregnancywere observed (OR, 0.89; 95% CI, 0.32–2.50) (Table 2). No significantheterogeneity was present (P= 0.97, I²= 0%).
3.1.4. Isolated cleft palateThis outcome was only investigated by two case-control studies
[16,17]. Cohort studies did not report the specific numbers of the in-fants with isolated cleft palate. Van Bennekom et al. [17] reported twodifferent risk estimates from two seperate datasets which were used forthe sensitivity analysis. Isolated cleft palate risk was not significantlyassociated with maternal ondansetron use in our primary analysis (OR,1.13; 95% CI, 0.43–2.97) (Fig. 4). The issue of significant heterogeneity(P= 0.0009; I²= 86%) necessitated a sensitivity analysis whichyielded a conflicting result; pooled data from NBDPS (1997–2009) de-monstrated a significant association (OR, 1.77; 95% CI, 1.15–2.72,P= 0.30; I²= 7%) [16,17] whereas BDS (1997–2013) data showedcompletely the opposite (OR, 0.40; 95% CI, 0.20-0.80) [17] (Fig. 4).
3.1.5. Genitourinary malformationsFour studies were eligible [9–11,14]. No significant increase in the
rate of genitourinary malformation following ondansetron use duringpregnancy was detected (OR, 1.55; 95% CI, 0.89–2.69) (Table 2). Therewas no significant heterogeneity (P=0.30, I²= 0%).
3.1.6. HypospadiasFour studies were eligible [9–11,14]. There was no significant in-
crease in the rate of hypospadias following ondansetron use duringpregnancy (OR, 1.65; 95% CI, 0.69–3.75) (Table 2). No significantheterogeneity was present (P= 0.90, I²= 0%).
3.1.7. Meta-analysis of major and organ-specific congenital malformationrates in ondansetron-exposed vs disease-matched controls
Two studies were eligible [9,14] for each particular outcome in thismeta-analysis of which details are provided in Table 2b. Orofacial cleftscould not be analyzed since no events were reported in Einarson et al.[9] leaving Fejzo et al. [14] as the only study to be considered. Nosignificant increase in the rate of any particular outcome was detectedin the pooled analysis. Higher pooled risk estimates and wider con-fidence limits were present for genitourinary malformations (OR, 2.01;95% CI, 0.40–10.20, P=0.39, I²= 0%) and particularly for hypospa-dias (OR, 4.01; 95% CI, 0.40–33.52, P=0.62, I²= 0). The embryonicdevelopment periods for organ-specific congenital malformationswhich are investigated in our meta-analysis were presented in Table 3.
4. Discussion
In this meta analysis we observed that the pooled point estimates
Fig. 2. Meta-analysis of overall major congenital malformation rates in ondansetron-exposed vs healthy controls Fig. 2a. Forest plot of the primary analysis includingPasternak et al. Fig. 2b. Forest plot of the sensitivity analysis substituting Pasternak et al. with Andersen et al.
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
8
regarding overall major congenital malformation and heart defect risksincreased and became significant when we undertook sensitivity ana-lyses which substituted the results of two studies which utilised anoverlapping datasource (Andersen et al. [12] and Pasternak et al. (11)).However, the results of our primary analysis which used the studieswith the highest quality assessment score indicated that ondansetronuse during pregnancy was not associated with significantly increasedrates of overall major congenital malformations, heart defects, orofacialclefts, genitourinary malformations and hypospadias when exposedinfants were compared with healthy or disease-matched controls. Dataregarding the isolated cleft palate risk was heterogenous and con-flicting, thus precluded us to reach any conclusions. Although non-significant, the effect size and the direction of the point estimates forgenitourinary malformations and hypospadias in the ondansteron-ex-posed vs. healthy and disease-matched controls deserve attention infurther studies.
Our results regarding overall major congenital malformations inexposed vs. healthy or disease-matched controls are in line with theresults of the previous cohort studies [9–14]. No particular study todate has reported a significant increase in the rates of overall majorcongenital malformations. The highest point estimate regarding overallmajor congenital malformations was reported by Andersen et al (OR1.3, 95% CI 1.0–1.7) [12], inclusion of which in the sensitivity analysis,led to a slightly increased and significant pooled point estimate, in ourmeta-analysis.
A very important point of debate among the previous cohort studiesregarding ondansetron use during pregnancy is the consequent risk ofheart defects. The rate of heart defects was not significantly elevatedfollowing ondansetron exposure during pregnancy in our primaryanalysis. However, similar to the issue with overall major congenitalmalformations, including Andersen et al. [12] instead of Pasternaket al. [11] led to a slightly elevated and significant point estimate.Twoindependent cohorts, Danielsson et al. [13] and Andersen et al. [14]reported a significant increase in the rates of heart defects previously.Danielsson et al. [13] reported an OR of 1.62 (95% CI 1.04–2.14) forheart defects, of which the upper confidence limit is corrected as 2.54later by the authors via recently published erratum [27] triggered byour communication, and 2.05 (95% CI 1.19–3.28) for septum defects.Andersen et al. [12] reported an OR of 2.0 (1.3–3.1) for heart defectsand this OR was much different from that of Pasternak et al. (a crudeOR of 1.04, 95% CI 0.52–1.95) which used an overlapping dataset. Ofnote, a 2018 in vitro study which exposed gestational day 13 rat em-bryos to increasing doses of ondansetron identified that such exposures
decreased the embryonic heart rate in a dose-dependent manner, andeven produced some ventricular arrhythmias at the highest doses uti-lized [35]. Taken in consideration with previously published animalteratology studies, which had suggested exposure to be related witharrhythmia-related anomalies (including cardiovascular and skeletaldefects), the authors of the in vitro study suggested that the mechanismby which these anomalies may occur could be linked with cardiacHuman Ether-a-go-go (hERG) channel ondansetron inhibition [35].Whilst this plausible biological mechanism may add weight to the no-tion that ondansetron use in early pregnancy increases the risk of car-diac anomalies in humans, further epidemiological surveillance isneeded. Such research should utilise study designs and datasets whichtogether address some of the key data limitations associated with thecurrently available studies. Once such data become available, thefindings of this in vitro study may be more reliably extrapolated toinform on the human fetal risks of maternal ondansetron use in preg-nancy.
No cohort study to date has indicated an increase in the rate oforofacial clefts or isolated cleft palate following ondansetron use duringpregnancy. However, a case-control study by Anderka et al. using datafrom the National Birth Defects Prevention Study (1997–2004) reportedthat infants with cleft palate were significantly more likely to be ex-posed to ondansetron in utero than healthy control infants (aOR 2.37;95% CI, 1.18–4.76) though no association with cleft lip with or withoutcleft palate was identified [16]. A recent case-control study by VanBennekom et al. which was published first in the abstract form [17]which we used in our meta-analysis, and then published in the full textform during the submission phase of this manuscript [36], reportedopposite findings among two different datasets regarding this issue[17,36]. Ondansetron exposure among infants with cleft palate waselevated in The National Birth Defects Prevention Study (NBDPS, theabstract version covers years 2005–2009, while the full text versioncovers the years 2005–2011) [36] whereas the Slone Birth DefectsStudy (BDS, the abstract version covers years 1997–2013 and the fulltext version covers the years 1997–2014) reported a significantly de-creased exposure rate among infants with cleft palate [17,36]. Theseresults caused a significant heterogeneity in our meta-analysis leadingto a non-significant point estimate in the primary analysis. However, wedetected a significant pooled point estimate when only the data fromthe National Birth Defects Prevention Study (1997–2004; 2005–2009)were considered [16,17]. Parker et al. also could not explain this dis-crepancy, in spite of conducting a number of sensitivity analysis, intheir study [36]. This positive association might be a result of multiple
Fig. 3. Meta-analysis of heart defects in ondansetron-exposed vs healthy controls Fig. 3a. Forest plot of the primary analysis including Pasternak et al. Fig. 3b. Forestplot of the sensitivity analysis substituting Pasternak et al. with Andersen et al.
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
9
comparisons and warrants to be confirmed using a different dataset.The retrospective nature of exposure ascertainment in these type ofstudies could theoretically introduce recall bias to the dataset, whilemultiple testing for associations between various different exposuresand outcomes could introduce chance findings.
Our meta-analysis of cohort studies regarding the genitourinarymalformations and hypospadias detected no significant increase in riskwith ondansetron used during pregnancy when exposed infants werecompared with healthy and disease matched controls, respectively.However, higher pooled estimates such as 2.01 and 4.01 were com-puted in the latter analysis. Of importance, this analysis included twostudies which did not deal seriously with the issue of confounding andcomprising much smaller number of control infants. Nevertheless, thedirection and the effect size of the pooled point estimates amongcomparisons with healthy and disease-matched controls showed a trendtowards an increase. In addition, Colvin et al. [10] reported an OR of6.2 (95% CI 2.0–19.5) for obstructive defects of renal pelvis and ureterfollowing ondansetron exposure in their cohort study while Van Ben-nekom et al. [17] reported a significant association (OR 2.3, 95% CI1.3–4.0) between renal agenesis/dysplasia and ondansetron exposure intheir case-control study (Slone Birth Defects Study 1997–2013 dataset).Our pooled results, combined with these previous findings, warrantsurveillance for genitourinary malformations and hypospadias in futurestudies.
Our findings are generally in line with the systematic reviewspublished on this topic during the previous years [2,37] and the recentsystematic review by Lavecchia et al. which was published during thewriting phase of this manuscript [38]. However, our meta-analysisdiffers from all these studies in one major way that it also quantitativelypools the available data. The review by Lavecchia et al., includes oneadditional paper, a small retrospective study [39] which was not cov-ered in our choice of databases, whereas our study also differently in-cludes the study by Andersen et al. [12] which provokes further dis-cussion. In addition, our study was able to reach the raw data, andtherefore, it was possible to calculate the number of specific mal-formations in the studies by Colvin et al., [10] and Fejzo et al. [14]independently. Similarly to our study, Lavecchia et al. also emphasizedthe limitations and discrepancies regarding the current data (e.g. heartdefects and cleft palate) with no significant safety concerns regardingmajor congenital malformations [38].
Neurobehavioral outcome is an important yet understudied domainfor the studies assessing the possible effects of medication use duringpregnancy. Data regarding this domain is limited to one prospectivecohort study and a prospective case-control study, the first of whichreported no significant adverse effects in the ondansetron-exposed in-fants and children who were between 17 and 66 months of age [40]. Ofinterest, some of the infants were also exposed to promethazine besideondansetron in this study. The second study compared rates of maternalondansetron use for hyperemesis gravidarum between mothers of in-fants with neurodevelopmental delay (n= 99/138, 71.7%) and mo-thers of infants without delay (n=114/174, 65.5%), and found nostatistically significant difference (P=0.294) [41] Given the limitednumber of studies and the small number of ondansetron-exposedpregnancies included in the respective analyses, this area undoubtedlyrequires further exploration.
Off-label ondansetron use among pregnant women is on a steep rise[18]. Taylor et al. reported that the use increased from<1% of preg-nancies in 2001 to 22.2% in 2014, with much of this increment attri-butable to the development of oral ondasetron preparations which firstbecame available in 2006 [18]. Therefore, making interventions formonitoring the off-label prescriptions and outcomes, such as estab-lishing databases, may be an important source for the future studiesinvestigating the birth outcomes following maternal ondansetron use.
To mention a few strengths of our meta-analysis is important. Therewere some high quality cohort studies which adequately dealt with theissue of confounding. The sample size of the exposed and control groupsTa
ble2
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Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
10
particularly for overall major congenital malformations and heart de-fects were quite large and yielded relatively narrow confidence limits.The included studies retrieved data from three different geographicalregions (Scandinavia, North America and Australia). However, a fewimportant limitations should also be mentioned. The exact informationregarding the exposure time windows, dose and duration were not re-ported in the majority of the studies which limits our ability to discussthe exposure with regard to the sensitive periods for congenital mal-formations. In addition, characteristics of the healthy and disease-matched control groups widely differed between studies. Besides, a fewincluded studies were published as abstracts, precluding us from as-sessing the details of their methodology. Although studies retrieved thedata from three different geographical regions, 60% of the data origi-nated from Scandinavian pregnancy registries, with their inherentlimitations, discussed elsewhere [42].
In conclusion, the use of ondansetron during pregnancy was notassociated with a significantly increased rate of overall major con-genital malformations, heart defects, orofacial clefts, genitourinary
malformations and hypospadias in our primary analysis. However, theobservation of varying results regarding the statistical significance ofthe point estimates for overall major congenital malformations andheart defects depending on the studies which were included or excludedfrom combination in this meta-analysis warrants the need for continuedsurveillance. The issue with cleft palate remains to be further in-vestigated while genitourinary malformations and hypospadias shouldalso deserve attention in future studies. Future studies should also striveto include detailed information regarding gestational age, dose andduration of exposure in order to increase our ability to assess the safetymore accurately. In addition, neurobehavioral outcomes after in uteroondansetron exposure is a potential area which requires further ex-ploration for which very limited data exist currently. Future studiesshould also be designed to differentiate the increased fetal risks whichoccur as a consequence of hyperemesis gravidarum, for instance Binderphenotype in the infant through causing maternal vitamin K deficiency,to lessen the impact of confounding by indication [43]. Ondansetronshould not be used as the first choice of treatment for NVP in the first
Fig. 4. Meta-analysis of isolated cleft palate in ondansetron-exposed vs healthy controls. Fig. 4a. Forest plot of the primary analysis with significant heterogeneity.Fig. 4b. Forest plot of the sensitivity analysis using National Birth Defects Prevention Study dataset (NBDPS 1997–2009). Fig. 4c. Forest plot of the sensitivity analysisusing Slone Birth Defects Study dataset (BDS 1997–2013).
Table 3Embryonic development week (s) of organ-specific congenital malformations investigated in our meta-analysis.
Congenital malformations Embryonic development week (s)
Heart defectsHeart development
From the middle of week 3 until the end of week 8 ([28])Highly sensitive period for heart is from the middle of week 3 to week 6 ([29])
Orofacial cleftsPalate development
5th to 12th week ([30])Most critical period for palate is 6th to 9th week ([30])The critical period of cleft palate is also reported as 8th to 12th week and critical period of cleft lip with or without palate is 5th to 7thweek in other studies ([31])
Genitourinary malformationsUrinary tract development
3rd to 34th week ([32])No critical or sensitive period was defined [31].
HypospadiasExternal genital organ development
11th to 16th week ([33])Critical period for hypospadias is 10th to 16th week ([31])7th to 16th-17th week ([34])Most sensitive period is defined as the middle of week 7 until the end of week 9 ([29])
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
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trimester/ period of organogenesis until more safety data is available.Nevertheless, for the pregnant women for whom it is clinically in-dicated, the results of this meta-analysis may be reassuring since theclinical significance of effect sizes for which the uncertainties existseems low. A second level fetal USG targeting particularly heart defects,orofacial clefts and genitourinary defects would be convenient fol-lowing a first trimester exposure.
After submission of this manuscript for publication, the authorsbecame aware of two new studies [44,45] which had investigated therisk of specific congenital malformations following maternal ondanse-tron use in early pregnancy. These newer studies were not included inthe present meta-analysis due to the timing of the original search anddata extraction/collection as detailed in the methods. Whilst it is con-sidered unlikely that the addition of these new study data would changethe observations regarding overall and cardiac malformation risks (seeAppendix for a brief summary), it is likely that they could have sug-gested a small but statistically significant increased risk of orofacialcleft following maternal first trimester ondansetron use. However, ourconclusion regarding the use of ondansetron in pregnant women re-mains same; ondansetron should not be considered as a first choicetreatment for NVP in the first trimester, however, since the absoluterisks seem low, its use may remain justifiable on a case-by-case basiswhere first choice medications have failed to control the maternalsymptoms.
Funding
No funding was provided for the specific purpose of the perfor-mance of this study. This study was conducted by researchers fromTerafar - Izmir Katip Celebi University Teratology Information, Trainingand Research Center, The UK Teratology Information Service andMothersafe, member organisations of the European Network ofTeratology Information Services (ENTIS). The financial support forthese organisations is provided from either national or local govern-ment funds.
Conflict of interest statement
All authors have completed the Unified Competing Interest Form(available on request from the corresponding author) and declare nosupport from any organization for the submitted work, no financialrelationships with any organizations that might have an interest in thesubmitted work in the previous 3 years and no other relationships oractivities that could appear to have influenced the submitted work.
Contribution statement
It is the opinion of the lead study author that all study authorscontributed equally to the performance of the research detailed in thismanuscript.
Transparency declaration
As lead study author Y.C.K affirms that the manuscript is an honest,accurate, and transparent account of the study being reported; that noimportant aspects of the study have been omitted; and that any dis-crepancies from the study as planned have been explained.
Acknowledgements
We sincerely appreciate Lyn Colvin and Marlena S. Fejzo for pro-viding us the unpublished data regarding their studies. We also wouldlike to express our sincere thanks to Ester Garne from JRC-EUROCATCentral Registry for providing us consultation regarding theclassification of malformations. The preliminary findings of this studywere presented in annual meeting of European Network of Teratology
Information Centers in Budapest 2017 and an abstract was published inReproductive Toxicology (2017; 72: 203–204.
Appendix
The first of the newer studies utilised data from the Truven HealthMarketScan dataset of anonymised health insurance records which wascollected in the USA between 2000 and 2014, and provided a very largesample size of over 860,000 mother-child pairs [44]. The study in-cluded up to 76,330 first trimester ondansetron-exposed mother-childpairs as defined by either prescription data or with confirmed medicaladministration, and 5557 with first trimester medical administrationonly. The study findings described statistically significant increasedrisks of cardiac malformations following ondansetron exposure as de-fined by medical administration data, specifically including septal de-fects overall, ventricular septal defects, atrial septal defects and atrio-ventricular septal defects. However, when exposure was defined byprescription and medical administration data combined, these findingsonly remained of borderline statistical significance for septal defectsoverall and atrioventricular septal defects specifically. No statisticallysignificant increased risks of orofacial clefts overall or specifically cleftlip alone, cleft palate alone, or cleft lip with or without cleft palate wereobserved. Exploratory analyses in the dataset also identified associa-tions with diaphragmatic hernia (based on both exposure defined frommedical administration alone and when also combined with prescrip-tion data), and laryngeal clefting, craniosynostosis and renal collectingsystem defects using the combined medical administration and pre-scription data to define exposure.
The second study utilised data from the Medicaid Analytic eXtract ofsocial health insurance claims data in the USA from 2000 to 2013 [45].Again the study included a very large sample of more than 1.8 millionmother-child pairs, with more than 88,000 exposed to ondansetron inthe first trimester (defined by pharmacy dispensing records) and uti-lised propensity score methods to account for a large number of pos-sible data confounders. The study results did not provide evidence ofstatistically significant increased rates of overall malformation, overallcardiac malformation or specifically ventricular septal defects, atrialseptal defects and atrioventricular septal defects in comparison witheither unexposed population or disease-matched (exposed to other anti-emetics) controls. However, small but statistically significant increasedrisks of any oral cleft were observed in comparison with both of thesecontrol groups. A further analysis of the specific types or oral cleftssuggested a possible small increased risk of cleft palate specificallywhich was statistically significant in a sensitivity analysis which utilisedproxy measures to control for confounding by indication. Exploratoryanalyses also suggested statistically significant increased risks of earand respiratory malformations.
Considering the findings relating to overall malformation risk, it isprobable that the weight of the Huybrechts et al. study would minimiseany difference in the risk estimates following the substitution of thePasternak et al. study data with that provided from Andersen et al. Assuch, it is unlikely that either the primary or secondary meta-analysiswould have identified increased risks for overall malformation rate.
Given that the findings of the two studies relating to risks of overallcardiac malformation are conflicting, the expected results from inclu-sion in a meta-analysis are less predictable. Given the slightly largersample size of the Huybrechts et al. study, it is possible that the in-creased risk suggested from the Zambelli-Weiner et al. analysis wouldhave been attenuated on combination. Furthermore, and as with theoverall malformation data, it is likely that the sample sizes of theZambelli-Weiner et al. and Huybrechts et al. studies would have limitedany differences in risk estimates with Pasternak et al. and Andersenet al. study data substitution.
Finally, as the data provided from Zambelli-Weiner et al. andHuybrechts et al. was provided from longitudinal cohort studies, thesedata would not have been suitable to pool with those provided from the
Y.C. Kaplan, et al. Reproductive Toxicology 86 (2019) 1–13
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case-control studies as described in this meta-analysis [16,17]. How-ever, it is possible that combination of the data provided from Zambelli-Weiner et al., which described a non-significant but increased risk oforofacial clefts, with that provided from Huybrechts et al., which de-scribed a small but statistically significant increased risk, may have alsodescribed a small but statistically significant increased risk of orofacialclefts overall.
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