Results
Study selection and
characteristics
The study identification and inclusion flow chart were prepared in
compliance PRISMA guidelines.32Fig.1 showed the PRISMA
flowchart. Our search yielded 1558
records of which 39 proved potentially eligible on the basis of titles
and abstracts (see Supplementary Table S2 for the reasons and lists of
references excluded in full-text screening) and 19 articles proved
eligible.33-51 There were 11 cohort
studies,33-435 case-control
studies,44-48 2 case report
studies49-50 and 1 case series
study.51 Supplementary Table S2 showed the excluding
studies.
Ten of the including studies originated from USA, three from Canada, two
from Sweden, other apart from Turkey, Australia, Canada, Denmark and
Israeli. The eligible studies also used different types of control
groups which included chlorpromazine, unexposed, other anti-emetics,
metoclopramide, NTE, meclizine and RxAE. Both approaches aimed to rule
out confounding by indication. Colvin et al., Berard et al., Asker et
al., Dormuth et al., Lemon et al., Huybrechts et al., Suarez et al.,
Pasternak et al., Werler et al., Zambelli-Weiner et al. had one control
group, unexposed for comparison. ÖZDEMİRCİ et al had one control group,
Chlorpromazine for comparison. Fejzo et al. and
Einarson et al. had two different
control groups, diseased-matched and unexposed, for comparison. Parker
et al. had two different control groups, RxAE and unexposed, for
comparison. Sakran et al. evaluated the rates of malformations in the
metoclopramide-exposed pregnancies within the same cohort as the
ondansetron exposed group, while Danielsson et al. also took a similar
aprroach and asessed the outcomes of the meclizine-exposed pregnancies.
There were also two case report studies and one case series study. Table
1 presents the characteristics of 19 studies.
Methodological quality of individual
study
Most (94.74%,18/19) of the eligible studies were categorized as being
high methodological quality by assessment of with the Newcastle-Ottawa
scale, and the only one (5.26%) low quality study was received by
Einarson et al..40 Three cohort studies33,35,40 and three case-control
studies44,46,48 at high risk of bias for assessment of
exposure because they did not report any information or citations on the
validity of the ondansetron measure or measured only at
baseline. Ten cohort studies at
high risk of bias for comparability of cohorts on the basis of the
design or analysis34-43, and three case-control
studies44,47-48 at high risk of bias for study
controls for any additional factor. Four (36.36%) cohort
studies33-34,37,40 at high risk of bias for assessment
of outcome. One cohort study42 at high risk of bias
for adequacy of follow up of cohorts. Two case-report studies and one
case-series report study did not assess the risk of bias. Supplementary
Fig S1 showed the risk of bias of
the including studies.
Overall congenital
malformations
Nine studies assessing total
number of 293,134 ondansetron-exposed and 8,443,119 control infants
reported congenital malformations in this
analysis.35-36,38-39,41,43,45,47-48 No significant
increase in the rate of overall congenital malformation was detected
following ondansetron use during pregnancy (OR=1.10,95% CI:0.94–1.29,
Low certainty) in our primary analysis (Fig 2). We observed no
suggestion of a subgroup effect (Supplementary Fig S2).
No statistically significant
publication bias was found for overall congenital malformations
(p =0.60) (Supplementary Fig S3). Sensitivity analysis by
excluding anyone study showed similar results.
Heart defects
Five studies assessing a total
number of 104,763 ondansetron-exposed and 2,687,298 control infants
reported heart defects in this analysis.39,41,45,46,48Significant increase in the rate of heart defects was detected following
ondansetron use during pregnancy (OR=1.06,95% CI:1.02–1.11, Moderate
certainty) in our primary analysis (Fig 3). To confirm the types of
heart disease, we conducted subgroup analyses of the different types of
congenital heart disease (Fig S4). Further research showed that
significant increase only in the rate of other circulatory defects was
detected following ondansetron use during pregnancy (OR=1.11,95%
CI:1.02–1.20). For heart defects, the pooled effect of studies with ORs
was not different from those with RRs (Supplementary Fig S5).
Sensitivity analysis by excluding anyone study showed similar results.
Cleft palate
Three studies assessing a total number of 100,837 ondansetron-exposed
and 2,656,466 control infants reported cleft palate in this
analysis.41,45,48 No significant increase in the rate
of cleft palate was detected following ondansetron use during pregnancy
(OR=0.78,95% CI:0.37–1.64, Very Low certainty) in our primary analysis
(Fig 4). For cleft palate, the pooled effect of studies was all with
ORs. The sensitivity analysis lines were identical after excluding any
of the studies.
Other organ malformations
Three studies assessing a total number of 78,307 ondansetron-exposed and
2,299,834 control infants reported other organ malformations in this
analysis.45,47,48 Significant increase in the rate of
other organ malformations was detected following ondansetron use during
pregnancy (OR=1.09,95% CI:1.03–1.16, Moderate certainty) in our
primary analysis (Fig 5). To confirm the types of organ malformations,
we conducted subgroup analyses of the different types of organ
malformations (Fig S6).
Significant increase in the rate
of craniosynostosis, diaphragmatic hernia, laryngeal cleft, relatively
severe malformation and other defects were detected. The pooled effect
of studies was all with ORs. The sensitivity analysis lines were
identical after excluding any of the studies.
Stillbirth or Miscarriage
Six studies assessing a total number of 190,193 ondansetron-exposed and
4,034,373 control infants reported stillbirth or miscarriage in this
analysis.33,35,38,42,43,46 Significant decrease in the
rate of stillbirth or miscarriage was detected following ondansetron use
during pregnancy (OR=0.60,95% CI:0.40–0.91, Low certainty) in our
primary analysis (Fig 6). For stillbirth or miscarriage, the pooled
effect of studies with ORs was not different from those with RRs/HRs
(Supplementary Fig S6). No statistically significant publication bias
was found for stillbirth or miscarriage (p=0.62) (Supplementary Fig S7).
The sensitivity analysis lines were identical after excluding any of the
studies.
Preterm birth
Three studies assessing a total number of 4,661 ondansetron-exposed and
9,102 control infants reported preterm birth in this
analysis.33,42,43 No significant increase in the rate
of cleft palate was detected following ondansetron use during pregnancy
(OR=0.78,95% CI:0.37–1.64, Low certainty) in our primary analysis (Fig
7). For stillbirth or miscarriage, the pooled effect of studies with ORs
was not different from those with HRs (Supplementary Fig S8).
Sensitivity analysis by excluding anyone study showed similar results.
Other pregnancy outcomes
Three studies assessing a total number of 3,842 ondansetron-exposed and
104,778 control infants reported other pregnancy outcomes in this
analysis.35,42,43 No significant increase in the rate
of other pregnancy outcomes was detected following ondansetron use
during pregnancy (OR=1.08,95% CI:0.92–1.27, Low certainty) in our
primary analysis (Fig 8). To confirm the types of other pregnancy
outcomes, we conducted subgroup analyses of the different types of other
pregnancy outcomes (Fig S9). Significant increase in the rate of birth
length were detected. For other pregnancy outcomes, the pooled effect of
studies with ORs was not different from those with HRs (Supplementary
Fig S10). Sensitivity analysis by excluding anyone study showed similar
results. The included case-report studies reported the outcomes included
ALT/AST, pharmacokinetic changes, intrauterine growth retardation
[IUGR], transient tachypnea, a mild hydrocele and extrarenal pelvis.