European Journal of Clinical Pharmacology

https://doi.org/10.1007/s00228-019-02712-2

REVIEW

Risk estimation of fetal adverse effects after short-term second

trimester exposure to non-steroidal anti-inflammatory drugs:
a literature review
Katarina Dathe 1 & Stefanie Hultzsch 1 & Lucas William Pritchard 1 & Christof Schaefer 1

Received: 20 March 2019 / Accepted: 25 June 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended in the 3rd trimester of pregnancy due to known
fetal adverse effects in an advanced gestational age. This investigation was performed to assess whether there is a significant risk
of NSAIDs being used as an analgesic or antipyretic medication in the 2nd trimester.
Methods A systematic search for publications reporting 2nd trimester NSAID exposure was performed in MEDLINE. The
search focused on case descriptions reporting defined adverse effects including prenatal ductus arteriosus constriction,
oligohydramnios, neonatal renal failure, and primary pulmonary hypertension. Original articles published until February 2018
were considered for evaluation.
Results Out of 681 identified publications, 26 included relevant information on the defined adverse effects. Among these
publications, premature labor was the major reason for 2nd trimester indomethacin treatment while other clinical indications
and other NSAIDs were underrepresented. Narrowing or closure of the ductus arteriosus in the 2nd trimester was described in 33
fetuses. Only eight publications reported adverse effects after less than 7-day exposure during the 2nd trimester.
Conclusions Based on these results, short-term use of NSAIDs as analgesics or antipyretics in the 2nd trimester does not appear to
pose a substantial risk for fetal adverse effects. Long-term use in the late 2nd trimester, however, should always be monitored.

Keywords Anti-inflammatory agents, non-steroidal [MeSH] . Pregnancy trimester, second [MeSH] . “Fetus” [MeSh] .
Oligohydramnios [MeSH] . Ductus arteriosus [MeSH] . Renal insufficiency [MeSH]

Introduction pregnancy. Although there is an ongoing discussion, paracet-

Due to the high prevalence of pain and inflammatory diseases,
paracetamol and non-steroidal anti-inflammatory drugs
(NSAIDs) belong to the most frequently used drugs in
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00228-019-02712-2) contains supplementary
material, which is available to authorized users.
* Katarina Dathe
katarina.dathe@charite.de
1
Charité-Universitätsmedizin Berlin, 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
amol is used as an analgesic and antipyretic in any trimester of
pregnancy. Well-proven NSAIDs, e.g., ibuprofen, are current-
ly considered a further medication of choice in the 1st and 2nd
trimester. In the 3rd trimester, however, NSAIDs and sub-
stances acting as partial prostaglandin antagonists like
metamizole should not be used due to their known risk of
fetotoxicity. Premature closure of the ductus arteriosus
Botalli, impaired renal function leading to severe
oligohydramnios, and persistent neonatal renal failure are
dreaded adverse side effects after 3rd trimester exposure. In
particular, the likelihood for ductal constriction and related
complications increase with advancing gestational age. The
sensitivity of the ductus arteriosus to prostaglandin inhibitors
is very high in the late 3rd trimester [1]. A few case reports
even describe a complete closure of the ductus arteriosus after
single doses of NSAIDs near term [2–4].
However, there is some uncertainty whether NSAIDs may
be considered a safe analgesic or antipyretic medication in the

advanced 2nd trimester. Since NSAIDs are among the fre-
quently used and recommended drugs in pregnancy, there is
a need for well-grounded risk characterization. Therefore, the
purpose of our approach was to identify published evidence
for defined adverse events in the fetus after NSAID exposure
in the 2nd trimester. We performed a systematic literature
search to identify relevant case descriptions.
Methods
Initially, a systematic search was performed in PubMed iden-
tifying case descriptions on pre- and postnatal adverse effects
observed with 2nd trimester exposure of NSAIDs previously
published in MEDLINE. The final search approach was de-
fined after testing several search strategies (Suppl. Table 1).
The search included controlled terms for NSAID medication
(Medical Subject Headings (MeSH) terms and pharmacolog-
ical action (PA)) in pregnancy and defined adverse fetal out-
comes. All indications for NSAID use were allowed.
Restriction of the search strategy to the fetal period
(“Pregnancy Trimester, Second” [MeSH] or “Pregnancy
Trimester, Third” [MeSH]) resulted in a large number of miss-
ing relevant articles. Therefore, the PubMed search initially
covered all trimesters in order to ensure a high sensitivity.
Except for a filter for “species: humans”, no further limitations
were set. Articles were not filtered based on publication types,
publication date, or language. PubMed was searched on 17
Dec 2015 and again on 8 Feb 2018. Duplicate publications
were excluded. Subsequently, in a first step, all titles and ab-
stracts (filter 1) were independently screened by two authors
according to predefined criteria (Suppl. Table 2). Relevant
endpoints were ductus arteriosus constriction/closure, oligo-
or anhydramnios, and fetal death, as well as neonatal renal
insufficiency/failure and primary pulmonary hypertension
(PPHT) in the neonate. Publications were also included if
one author deemed the reference as potentially relevant. In a
next step, full-text articles (filter 2) were assessed using iden-
tical selection criteria. Adding filter 3, we selected publica-
tions containing details on gestational weeks (GW) at
NSAID exposure, dosage, treatment duration and indication,
and fetotoxicity observed exclusively at GW ≤ 28. The rele-
vant exposure and outcome characteristics had to be assign-
able to individual cases or at least to a defined number of
cases. Only case reports on adverse effect at GW ≤ 28 clearly
assignable to NSAID exposure fulfilled the inclusion criteria
for further evaluation. Publications may have reported on
more than one affected case. Publications (e.g., cohort studies)
in which a case-specific assignment of NSAID exposure in-
terval and an adverse event was not possible were excluded.
Two additional publications were found by scanning the ref-
erence lists of the included full-text articles. The flowchart
(Fig. 1) provides a numerical breakdown of the search
Eur J Clin Pharmacol
approach identifying relevant publications. Relevant data
were extracted from these publications and summarized indi-
vidually in evidence tables.
Results
The PubMed search resulted in 681 hits. After applying the
selection criteria, we identified 26 publications reporting cases
in which the defined study endpoints were observed after ex-
posure to NSAID at GW ≤ 28. Some publications included
more than one case description. The summary of case descrip-
tions extracted from the literature is given in Suppl. Table 3. A
short synopsis adding up the numbers of the defined pre- and
postnatal adverse events can be found in Table 1.
Nineteen of 26 (73%) of the publications on fetal side ef-
fects on 2nd trimester exposure were published between 1986
and 1999, and only 7/26 (27%) were published since 2000
[5–11].
The majority of published case descriptions (22/26) dealt
with the use of NSAIDs for obstetrical indications comprising
tocolysis and treatment of polyhydramnios and feto-fetal
transfusion syndrome. Only 3/26 publications reported on
NSAIDs used as analgesics [6, 9, 12], and in one case, a
NSAID was taken to attempt suicide [7].
The majority of the identified descriptions of 2nd trimester
fetal adverse effects were related to indomethacin treatment
for tocolysis. Only 10 pregnancies with fetotoxic effects con-
cerned other NSAIDs: acetylsalicylic acid [7], diclofenac [6,
9], ibuprofen [13], ketoprofen [14, 15], nimesulide [5, 6], and
piroxicam [12]. These reports included two affected twin
pregnancies [5, 9] and one triplet pregnancy [15].
Intrauterine narrowing or closure of the ductus arteriosus at
GW ≤ 28 associated with NSAID exposure was described in
33 fetuses [1, 6–8, 13, 16–26]. The earliest gestational age of
ductus arteriosus constriction was reported at GW 25 in five
fetuses [1, 13, 18, 25, 26]. The NSAIDs used in these cases
were ibuprofen for several weeks [13], indomethacin for a few
days [18], and a single dose of indomethacin 6 h before a mild
ductus constriction was diagnosed [25]. In two further cases,
the duration of the indomethacin treatment was not specified
[1, 26].
Oligo- or anhydramnios was associated with 2nd trimester
NSAID exposure in 10 fetuses [5, 8, 9, 12, 19, 27] including
two affected twin pairs and was observed earliest at GW 22 [9,
27].
Postnatal impaired renal function leading to oliguria or an-
uria was described in 8 infants being exposed to NSAIDs
exclusively in the 2nd trimester [14, 15, 17, 28, 29] including
affected triplets [15] and one affected donor twin in a preg-
nancy with feto-fetal transfusion syndrome [17]. In all of these
cases with extremely premature newborns, the exposure-free
interval was at most a few days.
Table 1 Synopsis of affected fetuses by study endpoints

Reference Summary of defined study endpoints ≤ GW 28 Ductus arteriosus constriction or Oligo-or Stillbirth Anuria, oliguria, renal PPHT
closure anhydramnios failure
Eur J Clin Pharmacol

Baker et al. 1993 Ductus arteriosus constriction/closure, GW 25 x

Bivins et al. 1993 Ductus arteriosus constriction/closure, GW 27 (earliest) x
Buderus et al. 1993 Ductus arteriosus constriction/closure, GW 28 x
Anuria, oliguria, renal failure x
Gouyon et al. 1991 Anuria, oliguria, renal failure x
Harada et al. 1997 Ductus arteriosus constriction/closure, GW 25 (earliest) x
Hickok et al. 1989 Oligo−/anhydramnios, GW 22 x
Holmes et al. 2000 Oligo−/anhydramnios, GW 27 + 5 x (2 fetuses, twins)
Jaqz-Aigrain et al. 1993 Anuria, oliguria, renal failure x
Kirshon et al. 1991 Ductus arteriosus constriction/closure, GW 26 + 0 x
Oligo−/anhydramnios, GW 26 + 3 x (2 fetuses)
Levy et al. 1999 Ductus arteriosus constriction/closure, GW 27 (earliest) x (4 fetuses)
Llanas et al. 1996 Anuria, oliguria, renal failure, GW 26 x (3 newborn, triplets)
Lopes et al. 2016 Ductus arteriosus constriction/closure, GW 27 and GW28 x (2 fetuses)
Luchese et al. 2003 Ductus arteriosus constriction/closure, GW 27 x (2 fetuses)
Moise et al. 1988 Ductus arteriosus constriction/closure, GW 28 (earliest) x (2 fetuses)
Moise et al. 1993 Ductus arteriosus constriction/closure, GW 25, GW 26 and 28 x (3 fetuses)
Nishikubo et al. 1994 Anuria, oliguria, renal failure, GW 24 + 6 and GW 27 + 2 x (2 newborn)
Pratt et al. 1997 Ductus arteriosus constriction/closure, GW 27 + 5 x
Respondek et al. 1995 Ductus arteriosus constriction/closure, GW 26 x
Savage et al. 2007 Ductus arteriosus constriction/closure, GW 26 + 1; oligo−/anhydramnios, x x
GW 22 + 3
Scherneck et al. 2015 Oligo−/anhydramnios, GW 21 + 3 x (3 fetuses, twins
incl.)
Shehata et al. 2006 Stillbirth, GW 27 x
Tarcan et al. 2004 PPHT, GW 27 x
Truter et al. 1986 Ductus arteriosus constriction/closure, GW 26 x
van den Veyver et al. 1993 Ductus arteriosus constriction/closure, GW 24 + 1 x
Vermillion et al. 1997 Ductus arteriosus constriction/closure, GW 24 + 1 (earliest), GW 26–28 x (10 fetuses)
Voyer et al. 1994 Oligo−/anhydramnios, GW 28 x
Sum 33 10 1 8 1

Legend: GW, gestational week; PPHT, primary pulmonary hypertension.

 Eur J Clin Pharmacol

Fig. 1 Flow chart of PubMed

search and selection of
publications. Some of the relevant
publications (n = 26) describe
more than one case with the
defined study endpoints at GW ≤
28. Therefore, the overall number
of affected cases is higher than
n = 26. All included case
descriptions are summarized in
Suppl. Table 3. The number of
defined study endpoints pub-
lished in the relevant literature is
added up in Table 1.

One neonate twin born in GW 27 was diagnosed with
primary pulmonary hypertension (PPHT) after only two doses
of indomethacin within 16 h before birth [11]. Another ex-
posed pregnancy with feto-fetal transfusion syndrome treated
with indomethacin from GW 20 to 27 resulted in a stillbirth in
GW 27 of one twin, and the autopsy revealed a thrombotic
occlusion of the ductus arteriosus [10]. In another case, intra-
uterine death occurred in GW 31 due to hydrops fetalis most
likely secondary to chronic ductus arteriosus constriction
since GW 26. Indomethacin was given for tocolysis between
GW 16 and 24 [24].
In the majority of the identified publications, 2nd
trimester fetal adverse events occurred after NSAID ex-
posure of at least 7 days, often even longer. Not all
publications report on the duration of NSAID treatment
in detail. However, there are single reports of fetal side
effects after NSAID exposure of less than 7 days [6, 11,
14, 17, 21, 22, 28, 29]. Among these, constriction of
the ductus arteriosus was reported after diclofenac expo-
sure for 6 days [6] and after indomethacin treatment for
6 days [17], 3 days [29], and 30 h [22].
Discussion
Can well-studied NSAIDs be considered a safe medication
against acute pain or fever in the 2nd trimester? Taking into
account the high number of requests dealing with this topic
that we receive at the Berlin Embryotox Institute daily, this
question is highly relevant. By reviewing the published liter-
ature, we focused on the question of whether there is evidence
Eur J Clin Pharmacol
for fetal adverse effects, in particular ductus arteriosus con-
striction and oligohydramnios at GW ≤ 28.
In the fetus, the ductus arteriosus shunts the output of the
right fetal heart from the pulmonary trunk directly to the de-
scending aorta, bypassing the pulmonary circulation. Severe
narrowing or even complete closure of the fetal ductus
arteriosus may result in right ventricular overload, heart fail-
ure, and, without further intervention, fetal death.
Only a few (7/26) of the relevant publications on fetal ad-
verse effects of 2nd trimester NSAID exposure have been
published since 2000. The majority of identified literature
was published two decades ago and reports fetal adverse ef-
fects after indomethacin treatment for tocolysis (Suppl.
Table 3). Since the 1990s, other tocolytics with different
risk-benefit profiles, e.g., betamimetics, atosiban, and partic-
ularly nifedipine, are increasingly used [30]. The findings of
the studies on indomethacin for tocolysis may not be applica-
ble to short-term analgesic or antipyretic NSAID use. As
tocolytics are usually administered under close ultrasound
monitoring, detection of reduced amniotic fluid or constriction
of fetal ductus arteriosus as adverse drug effects is more likely
in these cases. In contrast, temporary 2nd trimester analgesic
or antipyretic NSAID medication is usually not monitored by
fetal ultrasound. Therefore, at least transient fetal effects may
be missed.
Overrepresentation of indomethacin for tocolysis in the
identified literature may be explained by a larger number of
exposed pregnancies, stronger toxicity of this NSAID, longer
treatment duration for tocolysis than for other indications, or a
detrimental effect of the treatment indication, i.e., premature
labor. After birth, indomethacin is a well-established and po-
tent drug in the pharmacological treatment of hemodynami-
cally relevant patent ductus arteriosus (PDA) in the newborn
[31, 32]. Interestingly, recent meta-analyses have shown that
high-dose ibuprofen (and even paracetamol) seems equally
effective for PDA closure in preterm infants after birth
[33–35].
During pregnancy, the likelihood of ductal constriction in
the fetus increases with advancing gestational age in the 3rd
trimester with a significantly higher responsiveness to prosta-
glandin inhibitors from GW 31 to term [1, 26]. Depending on
gestational age and other treatment characteristics, indometh-
acin tocolysis was associated with ductus arteriosus constric-
tion ranging from 6.5 to 86% [8, 16, 21, 36]. Usually, ductus
arteriosus constriction normalizes after cessation of NSAID
exposure [23].
Interestingly, Van den Veyver et al. reported that indometh-
acin levels had no predictive power in their study after an
adjustment of relevant factors. Higher fetal serum levels did
not correlate with higher rates of prenatal ductus arteriosus
constriction [25]. In contrast, investigations of different
NSAIDs on ductus arteriosus constriction performed in full-
term pregnant rats showed that substances differ substantially.
Acidic NSAIDs comprising indomethacin, ibuprofen,
diclofenac, and naproxen were more potent and led to a
dose-dependent constriction if administered in doses equiva-
lent to human anti-inflammatory doses [37, 38].
Intrauterine constriction of the ductus arteriosus may occur
spontaneously, i.e., independent of drug exposure. Some of the
publications, identified for our investigations, shed light on this
phenomenon. Luchese et al. reported on 20 fetuses with ductus
constriction mainly during the 3rd trimester of which 13 were
idiopathic and seven occured after maternal NSAID exposure.
Two of the NSAID-exposed cases were observed at GW ≤ 28
[7]. Leal et al. described five fetuses with ductus closure includ-
ing three occurring spontaneously and two after 3rd trimester
indomethacin exposure [39]. In a retrospective cohort study
from a fetal cardiology unit, Lopes et al. reported 29/45 fetuses
with ductus constriction or closure associated with NSAID ex-
posure, two of them at GW ≤ 28. In 8/45 fetuses, a previous
exposure to other drugs or agents was reported, and in further
8/45, the ductus constriction was classified as idiopathic [6]. No
reliable population-based data on the incidence of idiopathic
ductus arteriosus constriction in the fetus are currently avail-
able, but the observations above suggest a substantial propor-
tion occurring spontaneously. As yet, there is no evidence that
premature contractions, i.e., the treatment indication for
(indomethacin) tocolysis itself, trigger ductus arteriosus con-
striction or vice versa. It is unlikely that ductus arteriosus con-
striction and related conditions play a major causal role for
premature contractions and the decision to start tocolysis.
Severe ductus constriction leading to elevated right ventric-
ular pressure may result in irreversible pulmonary vascular
changes causing PPHT in the newborn [40, 41]. Our literature
search identified one case description of PPHT in a neonate
twin born in GW 27 having been exposed to indomethacin
within only 16 h before delivery. He died within the first two
days of life. The second twin showed only mild respiratory
distress [11]. The causative role of NSAID exposure in this
case must be critically questioned. There are estimates that
PPHT in newborns is idiopathic in about 23% [42].
In two cases of the identified literature with 2nd trimester
NSAID exposure, fetal death was described, which may have
resulted from an undiagnosed ductus constriction; one of them
occured before GW 28. [10, 24].
Amniotic fluid production depends on proper fetal renal
function. Thus, oligohydramnios might be the result of
NSAID-induced fetal renal damage. Cohorts exposed to indo-
methacin in the 2nd and 3rd trimester particularly for preterm
labor report oligohydramnios rates between 7.3 and 89% [8,
16, 43–47]. Long-persisting severe oligohydramnios may lead
to limb positioning defects, Potter facies, and lung hypoplasia
with respiratory failure after birth. Our literature search limited
to NSAID exposure at GW ≤ 28 revealed 10 affected preg-
nancies. The earliest diagnosis of oligohydramnios in NSAID-
exposed pregnancies was in GW 22 and concerned three

fetuses: one twin pregnancy was exposed in a long-term man-
ner to diclofenac [9] and in another case the fetus was exposed
to indomethacin for 1 week [27]. In most cases describing
oligohydramnios, amniotic fluid normalized after discontinu-
ation of the medication. Nevertheless, the causal role of
NSAIDs on amniotic fluid is difficult to assess given the het-
erogeneity of possible reasons for oligohydramnios. This ap-
plies in particular to situations with short-term medication and
without an improvement after discontinuation.
Prenatal renal damage caused by NSAID may result in
renal failure in the newborn presenting with oliguria or anuria.
Some publications report on renal histologic changes suppos-
edly caused by NSAIDs [48]. We identified reports on preterm
newborns affected by renal failure and maternal NSAID ex-
posure at GW ≤ 28 shortly before birth [14, 15, 17, 28, 29].
Such extremely preterm infants present, however, complex
clinical problems. Since renal impairment may be related to
prematurity, causality of NSAIDs is difficult to assess.
Although particularly ibuprofen is recommended world-
wide against pain, fever, or inflammatory diseases up until
the beginning of the 3rd trimester, published data on the de-
fined fetal adverse events after short-term NSAID exposure in
the 2nd trimester are scarce. Either there is no significant risk
particularly of short-term use or related fetal side effects are
reversible. In contrast to the 3rd trimester, ultrasound is not
regularly recommended along with such treatment in the 2nd
trimester. Thus, a certain number of transient adverse fetal
effects may remain unrecognized. It is therefore difficult to
estimate the true risk of such adverse effects based on the
available data.
Conclusions
Apart from the well-known risk in the 3rd trimester of preg-
nancy, NSAID use may cause ductus arteriosus constriction
and oligohydramnios also in the 2nd trimester. In cases of
long-term NSAID use, fetal monitoring is recommended, in
particular from GW 20 onward. However, short-term analge-
sic or antipyretic NSAID treatment not exceeding 1 week does
not seem to carry a noteworthy fetal risk of cardiovascular or
renal impairment during the 2nd trimester. Prospective studies
focusing on 2nd trimester NSAID exposure are highly desir-
able for further assessment of drug safety.
Acknowledgments We thank Luisa Maria Köhler and Verena
Linsenmeier who helped to obtain the required full-text publications.
Part of the literature review will be included in the thesis of Lucas
William Pritchard.
Authors’ contributions KD and CS developed the approach. KD and
LWP developed the search strategy and conducted the literature search.
KD, LWP, and SH screened the articles. KD and SH extracted the data
from the relevant literature and created the evidence tables. All the listed
Eur J Clin Pharmacol
authors participated in the result interpretation. KD and CS wrote the first
draft of the manuscript, and all authors critically revised subsequent man-
uscript drafts and contributed essential discussion points. LWP edited the
manuscript. All the listed authors approved the final manuscript.
Funding This work was funded by the German Federal Institute for
Drugs and Medical Devices (BfArM).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest. The funder had no role in the study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
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