European Journal of Clinical Pharmacology

https://doi.org/10.1007/s00228-017-2385-1

PHARMACOEPIDEMIOLOGY AND PRESCRIPTION

Exposure to cox-2 inhibitors (coxibs) during the first trimester

and pregnancy outcome: a prospective observational cohort study
Katarina Dathe 1 & Stephanie Padberg 1 & Stefanie Hultzsch 1 & Luisa-Maria Köhler 1 & Katja Meixner 1 &
Anne-Katrin Fietz 1 & Tatjana Tissen-Diabaté 1 & Reinhard Meister 2 & Christof Schaefer 1

Received: 29 August 2017 / Accepted: 26 November 2017

# Springer-Verlag GmbH Germany, part of Springer Nature 2017

Abstract
Purpose Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned
pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further
data on coxibs and their effects on embryogenesis are needed.
Methods This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January
2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected
cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens.
Results The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI
0.34–3.42; OR adjusted 0.96, 95% CI 0.28–3.26). The cumulative incidence of spontaneous abortions was nonsignificantly
lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51–1.58; HR adjusted, 0.87; 95% CI, 0.49–1.56). Elective
terminations of pregnancies (ETOP), mainly for ‘social’ reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR,
2.31; 95% CI, 1.26–4.24; HR adjusted 2.12, 95% CI 1.13–3.97).
Conclusions Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence
basis on coxib exposure during pregnancy, well-established alternatives should be preferred.

Keywords Cox-2 inhibitors . Coxibs . Pregnancy outcome . Birth defects . Spontaneous abortions . Pharmacovigilance

Introduction cyclooxygenase (cox)-2, coxibs as selective cox-2 inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely
used in patients requiring analgesic, anti-pyretic and anti-
inflammatory therapy. Since anti-inflammatory as well as an-
algesic effects are mainly achieved by the inhibition of
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00228-017-2385-1) contains supplementary
material, which is available to authorized users.
* Katarina Dathe
katarina.dathe@charite.de
1
Charité Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin
Institute of Health, Pharmakovigilanz- und Beratungszentrum für
Embryonaltoxikologie, Institut für Klinische Pharmakologie und
Toxikologie, Augustenburger Platz 1, 13353 Berlin, Germany
2
Beuth Hochschule für Technik - University of Applied Sciences,
Berlin, Germany
are potent drugs for the treatment of various pain symptoms
and rheumatic diseases. However, due to severe adverse ef-
fects including cardiovascular toxicity and artherothrombotic
events, their prescription has been restricted to defined indica-
tions taking into account individual risk factors [1–3].
Pregnant women may be exposed to coxibs for different
reasons, either intentional or inadvertently in an unplanned not
yet recognised pregnancy. However, it should be emphasised
that coxibs do not belong to the analgesics or anti-phlogistics
of choice during pregnancy because their effect on pregnancy
outcome is not well-studied. During the third trimester,
NSAIDs including coxibs should not be used. Their cox inhi-
bition may cause prostaglandin antagonistic premature closure
of the ductus arteriosus botalli and compromised foetal renal
function resulting in oligo- or anhydramnios [4–7].
Currently, data are scarce to assess possible teratogenic risks
after the use of coxibs in the first trimester which is the sensitive
period for disturbances of embryogenesis. There is no prospec-
tive or retrospective study with a particular focus on coxibs in

the first trimester. Only few of published studies on NSAIDs
investigating teratogenic effects reported on coxib-exposed
pregnancies within their cohorts, and if so, sample sizes were
small [8, 9]. Since published experience is insufficient for reli-
able individual drug risk assessment, we felt the need to system-
atically analyse the data collected in the German Embryotox
pharmacovigilance system. The primary aim of our study was
to evaluate the teratogenic risk of coxibs in the first trimester
with the focus on spontaneous abortions and major birth defects.
Methods
The German Embryotox Pharmacovigilance Institute in Berlin
is a well-established publicly funded institution that offers risk
assessment on drug use in pregnancy to health care provider
(HCP) and pregnant women. Using a structured approach, all
relevant data with respect to treatment indications, preexisting
chronic diseases, medication, exposure to other agents, mater-
nal characteristics and obstetrical history as well as family his-
tory are collected during the risk counselling process with the
permission of the patient. Data on drug exposure include details
on time, duration, dose and co-medication. Approximately
8 weeks after the expected date of delivery, a follow-up ques-
tionnaire is sent to the person who initially contacted our insti-
tute for risk estimation. A follow-up is not initiated in requests
obtained, e.g. by a pharmacy not directly involved in the pa-
tient’s care. Follow-up includes maternal complications during
pregnancy and delivery, data on neonatal outcome such as ges-
tational age at birth, sex, birth weight, length, head circumfer-
ence, umbilical cord artery pH, Apgar scores and, if applicable,
details of congenital anomalies and postnatal disorders. Further
queries follow in cases of missing or implausible data, or if data
recorded at initial request and follow-up are contradictory.
Medical documentations are requested by us from obstetricians
in cases with an unusual pregnancy course (e.g. stillbirth, elec-
tive termination of pregnancy) or from paediatricians if anom-
alies are reported in the infants.
Prospectively ascertained cases fulfilling the inclusion
criteria are the basis for this study. ‘Prospective’ means that
the outcome of pregnancy is not known at first contact to our
institute. In addition, the Embryotox institute serves as a na-
tional clearinghouse for suspected adverse drug reactions in
pregnancy and receives case reports for evaluation from HCP,
patients, pharmaceutical industry and the Drug Commission
of the German Medical Association. These retrospective case
reports are not included in our study cohort and considered
separately in the ‘Discussion’ section.
Study design, study criteria and definitions
All data were enrolled by the German Embryotox
pharmacovigilance system. For this single-centre observational
Eur J Clin Pharmacol
cohort study, all requests to our institute on exposure to coxibs
between January 2000 and January 2016 were considered.
Only pregnancies exposed at least between gestational week
(GW) 2 + 0 days (presumed time of conception) and GW
12 + 6 days after the first day of the last menstrual period
(LMP) were included in the analysis. Weeks of gestation were
calculated in the vast majority of cases using the ultrasound-
based estimated date of birth recorded in the maternity log, if
not available in rare cases, using the first day of the LMP.
Exposed pregnancies were included independently of the dura-
tion of treatment within the first trimester. Exposure to coxibs
may have terminated within the first trimester or may have
lasted longer. Only cases with completed follow-up were in-
cluded. Cases with maternal co-medication considered as po-
tent teratogens or fetotoxicants were excluded. Further criteria
for study inclusion and exclusion are shown in the flow chart
(Suppl. Fig. 1). The exposed cohort was compared to a random-
ly selected comparison cohort of prospectively ascertained
pregnancies neither exposed to the study medication and other
NSAID nor to established teratogens. Controls were matched
by year of case identification in an approximate ratio of 1:3.
Spontaneous abortion (SAB) was defined as spontaneous
pregnancy loss of an embryo or a foetus with a weight less
than < 500 g (definition used in Germany) or before 24 + 0
GW if the weight was not known. Preterm delivery was de-
fined as less than 37 completed GW.
Classification of birth defects was performed according to
EUROCAT [10]. Genetic and chromosomal disorders were
classified as separate entity. The assessment and classification
of birth defects were carried out by two experts blinded for
exposure status. In cases with inconsistent classification of a
birth defect, a third expert was involved in the final decision.
Statistical analysis
Descriptive statistics of maternal and neonatal characteristics
were generated for the treatment and comparison cohort.
For examining the effect of coxibs on spontaneous abor-
tions, hazard ratios (HRs) and 95% confidence intervals (CI)
were estimated using Cox proportional hazards models.
Cumulative incidences of SAB and elective termination of
pregnancy (ETOP) were assessed using event history analysis
for cause-specific sub-distributions of competing risks while
accounting for left truncation due to varying times of gestation
at enrolment [11]. For cumulative incidences, pregnancies
where coxibs start before GW 5 + 0 days were included in
the analysis to avoid immortal time bias [12, 13].
Furthermore, analysis was conditioned on survival to at least
GW 5 + 0 days for all survival models.
Crude birth defect rates were calculated by dividing the
total number of infants and foetuses with birth defects by the
number of all live-born infants plus the number of pregnancy
losses and elective terminations with birth defects. Birth
Eur J Clin Pharmacol
defects with genetic aetiology were considered separately.
Logistic regression analyses were used to obtain unadjusted
and adjusted odds ratios (OR) for risks of birth defects and
preterm birth.
To address confounding, all final regression analysis in-
volved either covariate adjustment or propensity score (PS)
adjustment by using the logit of the PS [14]. Covariate adjust-
ment was applied in the Cox proportional hazard model and
PS adjustment for all other endpoints using the same set of
covariates. The PS was estimated using boosted regression
trees based on the covariates maternal age, alcohol consump-
tion, smoking habits, number of previous foetal losses, num-
ber of previous deliveries and number of previous children
with anomalies [15].
For all analyses including covariates, missing values were
addressed using multiple imputation by chained equation as-
suming that the data were missing at random [16]. Twenty
imputed data sets were generated per outcome including the
respective outcomes and the covariates used for PS estima-
tion. For each imputed data set, analyses were performed as
described above. Results were then combined using Rubin’s
rule [17]. Additional investigations on patterns of missing
values are summarised in Suppl. Fig. 2. To avoid suppression
of potential signals, no adjustment for multiple testing has
been applied. Statistical analyses were performed with R
Version 3.3.1 (R Development Core Team) in parts using the
R packages ‘etm’ [16], ‘survival’ [18] and ‘mice’ [19].
Power considerations
The primary endpoints are major birth defects and spontane-
ous abortion. For major birth defects, the sample size allows to
detect an approximately 3.5-fold risk increase of major birth
defects with a power of 80% at a significance level of 5%
given a baseline risk of 2%. Therefore, results of major birth
defects are qualified as exploratory. For SAB, the study is
sufficiently powered to detect an HR of approximately 2.
Results
Overall, 523 requests on coxibs were received by the German
Embryotox Pharmacovigilance Institute during the study pe-
riod. One hundred seventy-four pregnancies met the inclusion
criteria of the prospective study cohort of maternal exposure to
coxibs in the first trimester (Suppl. Fig. 1).
Maternal characteristics
Maternal characteristics of the study cohort (n = 174) and
comparison cohort (n = 521) are shown in Suppl. Table 1.
There were only slight differences between the cohorts in
most of the parameters. However, the exposed women tended
to have a lower educational level (academic study 23.7 vs.
42.6%) and higher nicotine consumption (> 5 cig/day 19.3
vs. 10.3%). In addition, the attitude towards pregnancy was
more critical in the exposed cohort (indifferent, 11 vs. 9.4%;
primarily not wanted, 5.5 vs. 0.7%).
A case by case illustration of coxib exposure intervals is
summarised in Suppl. Fig. 3. The daily dosage is known in
101/174 (58%) of cases. Of these, 98 were in the range of the
recommended daily dose. In 45.2% of cases, the exposure
interval ranged between 1 and 7 days. Women who started
coxib medication already preconceptional tended to have a
longer exposure interval during pregnancy. Suppl. Fig. 1 (low-
est box) shows the number of cases per coxib substance. In
about 40% of our patients, coxibs were used to treat rheumatic
diseases such as rheumatoid arthritis or ankylosing spondylitis
and in 30% localised pain symptoms due to injuries, sinusitis,
tooth infections or postoperative pain. Further information on
treatment indications is presented in Suppl. Table 2.
Pregnancy outcome
Table 1 gives an overview on pregnancy outcomes and cumu-
lative incidences in both cohorts. The cumulative incidence of
SAB was lower in the exposed cohort (14.3 vs. 20.0%).
However, the estimated risk for SAB does not significantly
differ between the cohorts (HR, 0.90, 95% confidence inter-
val, CI, 0.51–1.58; HR adjusted (adj) 0.87; 95% CI, 0.49–
1.56). In contrast, ETOPs were significantly more frequent
in the exposed cohort than in the comparison cohort (17.5
vs. 7.0%; HR, 2.31; 95% CI, 1.26–4.24; HRadj 2.12, 95%
CI 1.13–3.97). Focusing on ETOPs for social or personal rea-
sons, 16/19 cases were observed in the coxib and 19/23 cases
in the comparison cohort (HR, 2.33; 95% CI, 1.20–4.53;
HRadj 2.12, 95% CI 1.07–4.21).
Neonatal characteristics
The median gestational age of live-born children was 39 + 0 in
the coxib cohort and 39 + 4 in the comparison cohort. Birth
length, weight and head circumference were all unremarkable.
For an overview of neonatal characteristics, see Suppl.
Table 3.
Birth defects
In the cohort exposed to coxibs, 4/139 (2.9%) live-born in-
fants presented with a major birth defect. All four infants were
affected by a congenital heart defect; see details in Table 2.
There were no major birth defects observed in pregnancies
ending in SAB, stillbirth or by ETOP. In the comparison co-
hort, major birth defects were reported in 12/451 (2.7%) live-
born infants. Of these birth defects, 5/12 were congenital heart
defects and the other 7/12 affected different organ systems
 Eur J Clin Pharmacol

Table 1 Pregnancy outcomes in

the study cohorts and cumulative Cohorts Coxibs Comparison
incidences
n Cumulative incidence n Cumulative incidence
%(95% CI) %(95% CI)

Pregnancies 174 521

Spontaneous abortion 16 14.3 (9.0–22.5) 50 20.0 (15.1–26.1)
ETOP 19 17.5 (11.2–26.9) 23b 7.0 (4.6–10.4)
Voluntarily/social reasons (16) (19)
Embryopathology – (3)
Medical reasons due to maternal (2)a
disease
Unknown reason (1) (1)
Stillbirth – – 4 –
Live birth 139 68.2 (59.1–76.9) 444c 73.1 (67.2–78.6)
Live-born infants 139 451

ETOP elective termination of pregnancy, n number of cases, CI confidence interval, reported for cumulative
incidences over the full pregnancy period
a
The two medical indications were cytomegalovirus infection and somatoform chronic pain disorder
b
One twin pregnancy included
c
Seven sets of twin pregnancies included

according to the EUROCAT subgroups (2× limb, 1× digestive
system, 1× nervous system, 1× oro-facial clefts, 2× other
anomalies/syndromes). The overall rate of major birth defects
(2.9 vs. 2.7%, OR, 1.08; 95% CI 0.34–3.42; ORadj 0.96, 95%
CI 0.28–3.26) was similar in both cohorts (Table 3).
Discussion
Our study covering 174 pregnant women exposed to coxibs
during the first trimester shows that even though coxibs are
not being considered medication of choice for pregnant wom-
en [20, 21], exposure occurs nonetheless.
In our study, the rate of major birth defects was similar
between the exposed and comparison cohort (2.9 vs. 2.7%)
and in the same range as the European population based prev-
alences published by EUROCAT [22]. All four major birth
defects in the exposed cohort affected the heart (Table 2). In
two cases, an atrial septal defect type II was diagnosed and
two infants were affected by a transposition of the great ves-
sels, in one of them associated with a ventricular septal defect.
Therefore, we cannot exclude that coxibs may specifically
disturb proper heart development. However, this observation
should be interpreted with caution due to the small cohort size
and low number of observed birth defects.
Some previous studies focussing on pregnancy outcome
after NSAID exposure did show an elevated risk for congen-
ital heart defects [9, 23, 24], whereas others did not [8, 25–27].
Ofori et al. (2006) found a significant association for defects
related to cardiac septal closure (ORadj 3.34, 95% CI 1.87–
5.98) primarily based on ibuprofen prescriptions [9]. An
increased risk for cardiac defects was also reported by
Ericson and Källén [23]. They did not observe any drug spec-
ificity in their NSAID cohort and the overall rate of congenital
malformations was not suspicious. Based on only two affected
cases, van Gelder et al. (2011) discussed an association be-
tween exposure to multiple NSAIDs during pregnancy and
septal heart defects [24].
Heart anomalies are the most prevalent anomalies among
congenital birth defects. According to EUROCAT, congenital
heart defects occur with a prevalence of 0.65%. Atrial and
ventricular septal defects as well as combined septal defects
account for the majority (0.48%) of heart defects, whereas a
transposition of the great vessels is rare (0.03%) [22]. Three of
the children with congenital heart defects described in our
study cohort were exposed to coxibs in GW 3 to 4, i.e. within
the first 2 weeks after fertilisation and before the human heart
starts to develop. Therefore, a causal association with the sep-
tal defects and the transposition of great vessels is rather un-
likely. In the fourth case, the drug exposure time window (up
to GW 8 + 5) includes the critical period of heart development.
In addition to our prospective study cohort, we screened
our retrospective case registry for reports with prenatal expo-
sure to coxibs. High numbers of adverse drug reactions, in
particular with a distinct phenotype or affecting a specific
organ system, indicate a signal of prenatal toxicity. A lack of
such reports suggests the contrary. During the study period,
we received five retrospective reports of coxib-exposed preg-
nancies; three of them were exposed in the first trimester.
These reports do not indicate a specific risk for heart defects.
A higher SAB rate was reported after maternal exposure to
NSAIDs in early pregnancy [28, 29] but others did not support
Eur J Clin Pharmacol

Table 2 Description of major birth defects in the cohort exposed to coxibs

Case Exposure Active Treatment Pregnancy Major birth defects; additional Co-medication or co-exposurea in first trimester
to coxibs substance indication outcome, GW minor birth defects and remarks (peri-conceptional included)
(GW) at birth,
weight, sex

1 3 to 4 Rofecoxib Pain due to Live born, Atrial septal defect type II Doxycycline (GW 3 to 4), smoking (approx. 10
sinusitis GW 40 + 0, cig/day)
3750 g,
female
2 3 + 2 to Rofecoxib Low back pain Live born, Transposition of the great vessels Piritramide (GW 0 to 2), tramadol (GW 1 to 2),
4+0 GW 36, x-ray lumbar spine (GW 3 + 2), x-ray
2520 g, abdomen (GW 6 + 2), smoking (approx. 20
male cig/day in early pregnancy)
3 3 to 4 Etoricoxib Pain not Live born, Atrial septal defect type II; mild Diclofenac (cutaneous, GW 1 + 5 to 4 + 5)
otherwise GW 27 + 1, pulmonary artery stenosis,
specified 875 g, pylectasis left, amniotic
female infection syndrome
4 0 to 8 + 5 Celecoxib Pain due to Live born, Transposition of the great vessels, Tetrazepam (GW 0 to 8 + 5), ibuprofen (GW 0 to
spondylolisth- GW 41 + 1, ventricular septal defect 8 + 5), fluticasone/salmeterol (by inhalation,
esis 3640 g, entire pregnancy), salbutamol (by inhalation,
male GW 0 to 11 + 6, if required), smoking (approx.
10 cig/day, GW 0 to 8 + 5)

GW gestational week
a
Excluding routine supplementation, e.g. folic acid

this finding [30]. In our study, the cumulative incidence of
SAB did not significantly differ between the study cohorts
(14.3 vs. 20.0%; HRadj 0.87; 95% CI, 0.49–1.56). In contrast,
ETOPs were more frequent in the exposed cohort than in the
comparison cohort (17.5 vs. 7.0%). Various reasons may have
influenced decisions for or against ETOP. Women in the ex-
posed cohort tended to be more critical regarding their preg-
nancy at the first contact to our institute. Fears of negative
effects on the embryo caused by the use of a not well-
studied medication during pregnancy or the severity of the
underlying disease might herein play a role.
Our study is based on data obtained during individual risk
counselling. One limitation is that the Embryotox cohort may
not be representative of the general pregnant population.
Counselling requests of exposed women often focus on new
drugs with insufficient experience, drugs suspected to cause
developmental toxicity or known teratogens/fetotoxicants.
Furthermore, the level of educational achievement is higher
among women who seek advice at Embryotox [31]. Since
higher-educated women presumably are better informed of
pregnancy risk factors and use prenatal care more regularly,
their risk for adverse pregnancy outcome may be lower than in
the general population with similar medication. In addition,
the underlying disease in the exposed cohort may have influ-
enced pregnancy outcome. An internally established set of
covariates used for adjustment aims to minimise potential
confounding effects. Due to our limited cohort size, results
on major birth defects should be interpreted cautiously.
Our approach has several advantages with respect to reli-
able information on start and duration of drug exposure and
outcome of pregnancy. In contrast to many population studies
based on prescription data and diagnoses from health care
databases, Embryotox studies are based on a case by case
plausibility test of exposure and outcome data followed by

Table 3 Rates of birth defects in

the study cohorts Coxibs Comparison OR OR adjusted
n, 174 n, 521 (95% CI) (95% CI)

Live-born infants, n 139 451

Major birth defects, n (%) 4/139 (2.9)a 12/451 (2.7) 1.08 (0.34–3.42) 0.96 (0.28–3.26)
Genetic anomalies, n (%) – 7/454 (1.5)b – –

n number of cases (denominators vary due to the different outcomes of pregnancies as live-born infants, sponta-
neous abortions or ETOPs), OR odds ratio, CI confidence interval
a
See Table 2 for a detailed description of major birth defects
b
Including one SAB and two ETOPs. Birth defects were classified according to the EUROCAT guidelines

callbacks to the attending HCPs when necessary. Follow-up
procedure after birth is similar across exposed and control
cohorts and therefore minimises exposure dependent biases.
Conclusion
Our study results support the assumption that coxibs are not
major teratogens. Pregnant women seeking advice after the
use of coxibs in the first trimester should be reassured. A
thorough prenatal ultrasound investigation may be offered to
confirm normal foetal development. Considering the still lim-
ited experience on coxibs during the first trimester, well-
established alternatives should be preferred.
Acknowledgments We would like to thank our colleagues from the
German Embryotox Pharmacovigilance Institute for counselling patients
and their attending physicians. The thorough documentation of each case
is an indispensable prerequisite to obtain a high data quality of the study
population. This study is part of the thesis of Luisa-Maria Köhler.
Contribution of authors KD, SP, SH, RM and CS designed the study.
KD, SP, LMK and KM validated and analysed the data. AKF and TTD
performed the statistical analyses and RM provided expert interpretation
of the analyses. KD, SP, SH, CS, AKF, TTD, RM, KD and CS partici-
pated in the result interpretation. KD and CS wrote the first draft of the
manuscript and all authors critically revised subsequent manuscript drafts
and contributed essential discussion points. The listed authors approved
the final version of this manuscript and they are responsible for the accu-
racy of this work.
Funding This work was supported by the German Federal Institute for
Drugs and Medical Devices (BfArM). The funder had no role in study
design, data collection and analysis, decision to publish or preparation of
the manuscript.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
Ethics approval Ethics approval was obtained from the ethics commit-
tee of the Charité Universitätsmedizin Berlin, Germany (no. EA4/029/
16). The study was registered in the German Clinical Trials Register (no.
DRKS00011140).
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