Discussion
Principal findings
Our exhaustive literature search revealed inconsistent and conflicting
results regarding the risk of abnormal pregnancy outcomes with
ondansetron use during pregnancy. The majority of the published safety
studies on ondansetron exposure in early pregnancy indicates that the
risk of birth defects resulting from use of ondansetron is small. Our
results regarding overall congenital malformations in exposed vs.
healthy or disease-matched controls were in line with the results of the
previous cohort studies.52–54 Our analysis found a
significant decrease in the rate of stillbirth or miscarriage following
ondansetron use during pregnancy. However, the results of our primary
analysis which used the studies with the highest quality assessment
score indicated that ondansetron use during pregnancy was associated
with significantly increased rates of heart defects and other organ
malformations (including craniosynostosis, diaphragmatic hernia,
laryngeal cleft, relatively severe malformation and other defects) when
exposed infants were compared with healthy or disease-matched controls.
There were differences in the analysis of previously published
systematic reviews on the effects of ondansetron on abnormal pregnancy
outcomes. Kaplan et al. ’s analysis showed that no significant increased
risk for major malformations, heart defects, orofacial clefts,
genitourinary malformations or hypospadias were identified. Picot et
al.’s found that first trimester exposure to ondansetron was found to be
associated with an increased risk of ventricular septal defects (VSD)
(OR 1.11, 95% CI 1.00–1.23) and oral clefts (OR 1.22, 95% CI
1.00–1.49).53 Lavecchia et al.’s study’s secondary
analysis found an increased risk of specific defects, such as
cardiovascular defects and cleft palate were
conflicted.54 Carstairs’s analysis found that the
overall risk of birth defects associated with ondansetron exposure
appears to be low and there may be a small increase in the incidence of
cardiac abnormalities in ondansetron-exposed
neonates.55 As a result, no system review to date has
indicated an increase in the rate of
major malformations following ondansetron use during pregnancy. A very
important point of debate among the previous studies regarding
ondansetron use during pregnancy is the consequent risk of heart
defects, cleft palate and other malformations. Our meta-analysis of
observational studies regarding the heart defects and other organ
malformations detected significant increase in risk with ondansetron
used during pregnancy when exposed infants were compared with healthy
and disease matched controls, respectively.
In order to determine the specific type of malformation, we further
classified it, and the results showed that among the cardiac
malformation results, only other circulatory system malformations had a
significant increase in the incidence of abnormalities; In other organ
malformations, significant increase in the rate of craniosynostosis,
diaphragmatic hernia, laryngeal cleft, relatively severe malformation
and other defects were detected. Data regarding this domain was limited
to from Zambelli-Weiner et al. and Parker et al. two case-control
studies.45,48 The first of which compare the first
trimester exposure to ondansetron was associated with increased risk of
cardiac (OR: 1.52 95% CI:1.35–1.70) and orofacial cleft defects (OR:
1.32 95% CI: 0.76–2.28) in offspring compared to women with no
antiemetic exposure during pregnancy.45 The second
study found that modest increases in risk were observed for cleft palate
(adjusted OR 1.6, 95% CI 1.1–2.3) in the National Birth Defects
Prevention Study and renal agenesis–dysgenesis (adjusted OR 1.8, 95%
CI 1.1–3.0) in the Birth Defects Study.46 Given the
limited number of studies included in the respective analysis, this area
undoubtedly requires further exploration.
Off-label ondansetron use among pregnant women is on a steep
rise.56-57 Hyperemesis gravidarum that does not
respond to other treatments may be considered with ondansetron, but
because of the simultaneous strengthening of maternal and fetal testing.
Although these adverse findings may be the result of chance, ondansetron
should not be considered as a first-choice treatment for NVP in the
first trimester.
Strengths and limitations
Strengths of our review include the relatively large number of studies
(19) and the very large number of participants (9,440,626)
from 9 countries. This study included not only cohort studies, but also
case-control studies, taking into account case reports. At the same
time, we used the adjusted effect value, and the result was closer to
the real effect. Moreover, our review rated the certainty of evidence
for each exposure using the GRADE approach.
Our work does have limitations, the most important of these relates to
the classify of abnormal pregnancy outcomes. In our review, we only
classify the type of heart defects and other organ malformations.
Different differentiation methods may get different results, however,
due to the limited number of outcomes of the same type reported in the
studies, further classification could not be supported. For some
outcomes, the number of participants included in the study was small and
the findings may not be reliable. At the same time, our systematic
review did not process ORs/RRs/HRs conversion, so the aggregate values
may be biased.
Conclusions and implications for future
research
In conclusion, the use of ondansetron during pregnancy was not
associated with a significantly increased rate of overall major
congenital malformations, orofacial clefts, stillbirth and preterm birth
in our primary analysis. Our review raised concerns about ondansetron
exposure during pregnancy, in particular due to the risk of heart
defects (other circulatory defects in particular) and other organ
malformations (craniosynostosis, diaphragmatic hernia, laryngeal cleft,
relatively severe malformation and other defects) after prenatal
exposure to ondansetron. However, our review found that ondansetron
should not use as first-line treatment for NVP. But for sever and
incurable NVP, clinician can consider use moderate amount ondansetron to
treat NVP with close monitoring.
Based on the results of this review, ondansetron use during pregnancy
was associated with some abnormal pregnancy outcomes. However, the
published studies have not divided the basic maternal characteristics
(age, ethnicity, etc.) in detail, and the dosage of ondansetron has not
been further analyzed. There are few research data on defects in the
urinary system, nervous system and so on, and the credibility of the
results needs to be improved. Therefore, in future studies, the
corresponding parts should be supplemented and improved.
Disclosure of interests No author had any financial conflict of
interest.
Contribution to authorship XC, LG and CLL conceived the study.
all authors contributed to revisions and
approved the final version.
Details of ethics approval Not applicable.
Funding This research was not funded by any institution or
individual.