Search strategy
PubMed, Embase, the Cochrane Library, CINAHL, CNKI, CBM, WANFANG and
ClinicalTrials.gov were searched for citations published in any language
from inception to 15 December 2021, including terms for ondansetron AND
pregnancy (see Supplementary Table S1 for detailed search strategy).
There were no restrictions on the publication language and publication
status. Additionally, we manually reviewed the reference lists from
included studies and relevant systematic reviews.
Eligibility criteria and study
selection
Eligible studies included any observational study conducted in humans
(such as prospective cohort, case-control, nested case-control, or
case-cohort design) that reported a measure of association (such as
hazard ratios or incident rate ratios for prospective studies; or odds
ratios for retrospective studies) between use of ondansetron during
pregnancy and the risk of abnormal pregnancy outcome (still birth,
preterm birth, congenital malformations, et al). A study was considered
eligible if it met the following criteria: 1) A healthy or
disease-matched control (either nausea and vomiting of pregnancy or
hyperemesis gravidarum) group was included. These control groups should
be unexposed to ondansetron but they might be exposed to either
non-teratogenic drugs or antiemetics other than ondansetron; 2) The data
reported were not overlapping with another study. If an overlap between
two studies was detected, we preferred to include the one that received
higher score regarding methodological quality. The exclusion criteria
were animal studies, editorials and reviews. One reviewer assessed
titles and abstracts of all studies identified through electronic
searches. Potentially eligible studies were reviewed independently by a
second reviewer, with discrepancies resolved by discussion; and when
necessary, a senior author was consulted to reach consensus.
Data extraction
Pairs of authors (XC and MYS) independently extracted details of the
study design, country of conduct, exposure and outcome assessment,
participant characteristics, and statistical analyses (including
adjustment for confounders) from included studies, with discrepancies
resolved by discussion. We extracted risk estimates (hazard ratio,
relative risks, or odds ratios) with their 95% confidence intervals
from the multivariable-adjusted models with the most complete adjustment
for potential baseline confounders. Authors were contacted for
additional data, when necessary.
Risk of bias of individual
study
We independently assessed the risk of bias of individual studies by
paired reviewers (XC and MYS) using a modified version of the
Newcastle-Ottawa scale on the basis of selection of study groups,
comparability of groups, and ascertainment of exposure(s) or
outcome(s).26-27 We rated each study as being of high
methodological quality(low risk of bias) and low methodological quality
(high risk of bias) based on the following criteria: 1) studies were
considered to be high methodological quality if all seven questions were
assigned to be low risk of bias, or only 1 of the 7 questions was
assessed as“definitely no”, six questions were low risk of bias, or 2
of the 7 questions were assessed as “probably no”, other five
questions were low risk of bias; 2) studies were considered to be low
methodological quality if they did not meet the criteria for high
methodological quality as detailed above. The authors were not blinded
to the author names, institutions, results or journals of the
publications. Any disagreements were resolved through subsequent
discussion with another author (QYY).
Data synthesis and statistical
analysis
We used odds ratios (ORs) and 95%
confidence intervals (CIs) as a measure of the association between
ondansetron and abnormal pregnancy outcomes. Due to the low risk of
abnormal pregnancy outcomes, hazard ratios (HRs) and relative risks
(RRs) were included in the same meta-analysis. Subsequently, we
conducted a subgroup analysis to identify possible differences between
studies using ORs and those using HRs/RRs. If an interaction test
indicated significant differences between subgroups, we used the results
from studies with ORs for assessing the association between ondansetron
and abnormal pregnancy outcomes. We pooled ORs and 95% CIs through the
inverse variance weighted method using random-effects
meta-analysis.28 To confirm the specific type of
outcomes, we classify the abnormal pregnancy outcomes. We examined
statistical heterogeneity among the studies with Cochrane’s Q test and
I2 value.29 Publication bias was
assessed using the Begg’s rank correlation test at the p <
0.05 level of significance for all meta-analyses with at least 5
studies.30 We also carried out priori sensitivity
analyses. All analysis were performed with Stata V.16.1 software (Stata
Corp, College Station, Texas, USA).
Certainty of evidence
assessment
Paired reviewers (XC, MYS) independently rated the certainty (quality)
of evidence as high, moderate, low or very low using the grading of
recommendations, assessment, development and evaluation (GRADE) approach
considering risk of bias, imprecision, inconsistency, indirectness and
publication bias.31 Any conflict was resolved through
the adjudication of a third reviewer (QYY).