Title:
Ondansetron in pregnancy revisited: Assessment and pregnancy labelling
by the European Medicines Agency (EMA) & Pharmacovigilance Risk
Assessment Committee (PRAC).
Running title:
Ondansetron in pregnancy
Per Damkier
MD, PhD
- Department of Clinical Biochemistry & Pharmacology Odense University
Hospital, Denmark
- Department of Clinical research University of Southern Denmark,
Denmark
Mail:pdamkier@health.sdu.dk
Phone: +45 65 50 37 90
Ondansetron is an effective antiemetic that is being widely used as a
second-line treatment option for severe Nausea and Vomiting of Pregnancy
(NVP) in accordance with clinical guidelines (1–4).
In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk
Assessment Committee (PRAC) released updated comprehensive assessment
report on the use of ondansetron in first trimester (5). This report is
a detailed assessment of the available published data on the subject,
including responses to supplementary questions posed to the Marking
Authorization Holder (MAH), and the authors to the two central
publications discussed below. The ensuing Summary of product
Characteristics (SmPC) was updated in November 2019 with important
changes to section 4.6 “Fertility, pregnancy and lactation” (6), which
now state that ondansetron should not be used in first trimester of
pregnancy.
We acknowledge that the EMA SmPC in principal only frames the way that
the MAH are legally allowed to market their product within the EU. It
does not bind the physician as such; they must act and adhere with
reference to the legal framework of their respective countries. We also
acknowledge that EMA operates within a given formalized set of options
on SmPC phrasings. In everyday practice however, the wording of the SmPC
has consequences for treatment options and decision support beyond those
formal to the legal ramifications of the SmPC.
We applaud the EMA for the following nuanced phrasings in the SmPC:
- Based on human experience from epidemiological studies,
ondansetron is suspected to cause orofacial malformations when
administered during the first trimester of pregnancy.
- In one cohort study including 1.8 million pregnancies, first
trimester ondansetron use was associated with an increased risk of
oral clefts (3 additional cases per 10 000 women treated; adjusted
relative risk, 1.24, (95% CI 1.03-1.48)).
- The available epidemiological studies on cardiac malformations
show conflicting results.
We believe that data from animal studies are of less relevance in these
and analogue situations with an abundance of human data available:
“Animal studies do not indicate direct or indirect harmful
effects with respect to reproductive toxicity.”
We do not believe that the most important sentence therein is
appropriately substantiated or justified:
“Ondansetron should not be used during the first trimester of
pregnancy.”
The latter statement comes with very clear and immediate consequences to
clinical practice and pregnant women suffering from NVP. Previous
somewhat contradictory data notwithstanding (7), the core of the
discussion is down to the interpretation of two extraordinarily large
sets of data. These are recent publications each comprising 80.000+
first-trimester exposed liveborn children. Previous studies with
somewhat contradictory results comprise cumulated first trimester
exposures less than 10% of these new data.
Huybrechts et al., a well-established research group within studies of
adverse pregnancy outcome following drug exposure during pregnancy with
an elite publication track-record, published their large study in
December 2018 (8). In this meticulously designed, conducted and reported
study comprising 88.000 liveborn children exposed to ondansetron in
first trimester, they reported no increased overall risk of
malformations and null associations for any or cardiac malformations and
a small increased risk for oral cleft. Compared to 1,727.000 unexposed
liveborn, propensity score adjusted relative risks were 1.01 (95% CI
0.98-1.05), 0.99 (95% CI 0.93-1.06) and 1.24 (95% CI 1.03-1.48) for
any, cardiac and oral cleft malformations, respectively. The increased
risk of oral clefts corresponds to about 3 additional cases for every
10.000-liveborn children exposed to ondansetron in first trimester.
Zambelli-Weiner et al. published their findings from a large study in
January 2019 (9). This triggered controversy and extensive discussions
among clinicians and researchers within the field.
They reported data on 82.000 liveborn children exposed to ondansetron in
first trimester. Compared to about 780.000 unexposed liveborn, their
overall analysis identified a weak but no clinically meaningful
association with cardiac effects, aOR 1.04 (95% CI 1.00-1.08) and a
weak association to orofacial clefts, aOR 1.12 (95% CI: 0.95-1.33). Ade facto subgroup analysis – defined by the authors as “primary
analysis” - restricted exposure to 5.500 women who were administered
ondansetron in hospitals (“medical administration”). The inferential
analysis substantially reinforced the overall weak signal for cardiac
effects (aOR 1.43; 95% CI 1.28-1.61) but not orofacial clefts, (aOR
1.30; 95% CI: 0.75-2.25). The technical analysis appears suboptimal as
adjustments were made as by a crude approach; i.e. the selection of
confounder variables was based on these resulting in at least 10%
change in effect estimates rather than simply including all selected
confounders in the model.
It appears plausible that this subpopulation of pregnant women in whom
hospital treatment was deemed necessary, suffered from a more severe
presentation of NVP, a confounder that they did not accounted for. The
sensitivity analysis performed in patients assigned a diagnosis of NVP
or hyperemesis gravidarum does not satisfactorily account for this. In
almost all exposed cases, the exposure comprised a single intravenous
dose of ondansetron. It is biologically counterintuitive that a causal
relation to cardiac malformations be present based on such exposure. The
paper reports extraordinarily high rates of congenital cardiac
malformations be it among unexposed (3.7%) or exposed (5.5 and 4.1%
for intravenous and any exposure, respectively) liveborn children. These
observations are incompatible with all other reported data on the rate
of congenital cardiac malformations. The external validity of the study
findings is therefore less convincing and compromises comparisons to
other findings.
The authors did not provide satisfactory responses to additional
questions poses by PRAC during the assessment process. Five specific
questions were posed, and the authors did not address any of these. They
provided a short narrative statement that did not serve to clarify or
advance understanding of their findings (5). Not least, this paper is
severely compromised by an initially undisclosed serious conflict of
interest. The formal COI disclosure in the paper state: ”As an
organization, TTi reports receiving funds from plaintiff law firms
involved in ondansetron litigation…” The extent of this COI was
only revealed during a litigation process. The specific study received
substantial funding ($ 210.000) from plaintiffs’ representation who was
pursuing litigative damage by claiming malformations from ondansetron
use in pregnancy (10). It is the position of the undersigned and ENTIS
Scientific Committee that this study is methodologically and ethically
compromised to an extent that the results thereof cannot be
considered when assessing the totality of evidence on the safety of
ondansetron in pregnancy.
Since the PRAC recommendation two additional studies have been published
that should be considered in the overall assessment of the risk during
pregnancy.
In January 2020, Huybrechts et al. published an additional study on
intravenous administration of ondansetron in early pregnancy and risk of
congenital malformations (11). In this study, the authors revisited the
study population from their original paper, but restricted their
analysis to those women who received intravenous ondansetron in first
trimester (8). The resulting propensity-score adjusted inferential
analysis of about 24.000 pregnancies exposed to intravenous ondansetron
did not result in increased risk of cardiac malformations
(RR 0.97; 95% CI 0.86-1.10), oral
clefts (RR 0.95; 95% CI 0.63-1.43), or any congenital malformation(RR
1.02; 95% CI 0.96-1.08). Unadjusted analyses suggested a small
increased risk for cardiac and any malformation (11). These data
strongly mitigate the previous data on intravenous ondansetron (9).
Lemon and colleagues reported a small increased risk of ventricular
septal defect (VSD) following first trimester exposure to intravenous or
oral ondansetron in first trimester among 3700 pregnancies (12). Across
various methodological approaches the adjusted risk ratio varied between
1.7 and 2.1 with 95% CI ranging between 1.0 and 4.0. In an overall
analysis though there was no increased risk for any birth defect or any
heart defect, illustrating the dilemma of splitting versus lumping in
such analyses (13). In this study, there may be an issue of
ascertainment bias. Women exposed to ondansetron likely suffered from
more severe NVP and thus may have been be subject to more attention and
their newborn babies to a greater extent are subject to an
echocardiograph evaluation. VSDs may be clinically asymptomatic and ”Up
to 80% of small, muscular VSDs and 30%-50% of perimembranous defects
will close spontaneously” (14).
In summary, we believe that the abundance of most methodologically
convincing data on cardiovascular malformations is reasonably
reassuring. Even if a small excess risk may still be present,
ondansetron in first trimester should remain an option for pregnant
women with severe NVP.
It is the opinion of ENTIS that the EMA decision to explicitly
discourage first trimester treatment with ondansetron puts pregnant
women with severe NVP, physicians and health care professionals between
a rock and a hard place. We do not agree that the specific wording
against the use of ondansetron in first trimester is justified and we do
not support the conclusion of EMA/PRAC assessment report and this
section of the SmPC.
We urge the EMA/PRAC to carefully consider everyday clinical
consequences of formal regulatory decisions. In cases with likely
widespread clinical consequences, we suggest that EMA/PRAC consult
liberally with relevant patient organizations, clinicians and health
care professionals before final adoption of a recommendation.