474 Current Drug Metabolism, 2012, 13, 474-490

Use of Non-steroidal Anti-inflammatory Drugs in Pregnancy: Impact on the Fetus

and Newborn

Roberto Antonucci1*, Marco Zaffanello2, Elisabetta Puxeddu3, Annalisa Porcella4, Laura Cuzzolin5, Maria
Dolores Pilloni6 and Vassilios Fanos3

1
Division of Neonatology and Pediatrics, “Nostra Signora di Bonaria” Hospital, San Gavino Monreale, Italy; 2Section of Pediatrics,
Department of Life and Reproduction Sciences, University of Verona, Verona, Italy; 3Neonatal Intensive Care Unit, University of
Cagliari, Cagliari, Italy; 4Division of Neonatology, “San Camillo” Hospital, Sorgono, Italy; 5Department of Public Health & Com-
munity Medicine-Section of Pharmacology, University of Verona, Italy; 6Family Planning Clinic, San Gavino Monreale, ASL 6 San-
luri (VS), Italy

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in pregnancy to treat fever, pain and inflammation.
Indications for chronic use of these agents during pregnancy are inflammatory bowel or chronic rheumatic diseases. Since the seventies,
NSAIDs have been used as effective tocolytic agents: indomethacin has been the reference drug, delaying delivery for at least 48 hours
and up to 7-10 days. Additionally, self-medication with NSAIDs is practiced by pregnant women.
NSAIDs given to pregnant women cross the placenta and may cause embryo-fetal and neonatal adverse effects, depending on the type of
agent, the dose and duration of therapy, the period of gestation, and the time elapsed between maternal NSAID administration and deliv-
ery. These effects derive from the action mechanisms of NSAIDs (mainly inhibition of prostanoid activity) and from the physiological
changes in drug pharmacokinetics occurring during pregnancy.
Increased risks of miscarriage and malformations are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs
after 30 weeks’ gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Fe-
tal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been
reported after prenatal exposure to NSAIDs.
NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for
the shortest duration possible.
This article discusses in detail the placental transfer and metabolism of NSAIDs, and the adverse impact of prenatal NSAID exposure on
the offspring.
Keywords: Non-steroidal anti-inflammatory drugs, NSAIDs, indomethacin, tocolysis, pregnancy, adverse effects, embryo, fetus, newborn.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND
PREGNANCY
1. NSAID USE DURING PREGNANCY: INDICATIONS AND
EPIDEMIOLOGICAL DATA
Non-steroidal anti-inflammatory drugs (NSAIDs) are among
the most common drugs prescribed to pregnant women to treat
fever, pain and inflammation [1]. Indications for a chronic use of
NSAIDs during pregnancy are inflammatory bowel diseases [2] and
chronic rheumatic diseases such as rheumatoid arthritis and spondy-
larthropathy. On the other hand, obstetrical indications for NSAID
administration include the management of premature labor (indo-
methacin), the prevention of gestosis, and the treatment of polyhy-
dramnios and antiphospholipid syndrome [1].
The frequency of NSAID use during pregnancy is not easily
countable, considering that some of these drugs are available over
the counter (OTC) and thus can be easily purchased without medi-
cal prescription. Unpublished data of EUROCAT-registration
Northern-Netherlands revealed that NSAID exposure during preg-
nancy was due to 60% on prescription and 35% OTC [3]. Insuffi-
cient information about OTC-use of NSAIDs may lead to underes-
timating their actual use. Furthermore, the consumption of NSAIDs
in early pregnancy may occur due to unawareness of the pregnant
state, or through ignoring the composition of self-medication drugs
that are being used [4,5].
*Address correspondence to this author at the Division of Neonatology and
Pediatrics, "Nostra Signora di Bonaria" Hospital, San Gavino Monreale,
Italy; Tel: +39 070 9378263; Fax: +39 070 9378260;
E-mail: roant@tiscali.it
A recent study has documented that in the majority of pregnan-
cies (75.6%) NSAIDs and/or acetylsalicylic acid (ASA) were pre-
scribed during the first trimester, resulting in an overall first trimes-
ter exposure of 2.9%. Part of the first trimester exposure would be
due to unawareness of pregnancy by the women [3]. Epidemiologi-
cal studies from Canada [6], Denmark [7], and Sweden [8] reported
an exposure to NSAIDs during the first trimester of pregnancy of
2,9%, 3%, and 3,4 %, respectively. On the other hand, third trimes-
ter prescribing of NSAIDs and/or ASA was found to be low (0.6%).
This fact was to be expected due to guidelines stating not to pre-
scribe these agents during the third trimester [3].
This review article includes a general overview of NSAID use
during pregnancy, with special emphasis on the mechanism of ac-
tion, placental transfer and metabolism of these medications; then,
the embryo-fetal and neonatal adverse effects related to the antena-
tal use of NSAIDs are discussed in detail.
2. MECHANISM OF ACTION OF NSAIDS
Prostanoids belong to a family of biologically active lipids,
including prostaglandins, prostacyclins, and thromboxanes. Prosta-
noids are synthesized as needed in three steps. The first step is the
release of arachidonic acid from membrane phospholipids through
the action of phospholipase-A2. In the second step, cyclooxygenase
enzyme first oxidizes arachidonic acid to form prostaglandin G2
(PGG2) through a cyclooxygenase process and then peroxidizes
PGG2 to PGH2. Finally, this highly instable compound is converted
into five major prostanoids, namely prostaglandin E2 (PGE2),
PGF2
, PGD2, PGI2 and thromboxane A2 (TXA2) by specific PG
synthase enzymes [9].

1-/12 $58.00+.00 © 2012 Bentham Science Publishers

Impact of Prenatal NSAIDs on the Offspring
The key enzyme in the prostaglandin synthesis is prostaglandin
endoperoxide synthase (PGHS) or cyclooxygenase (COX). This
bifunctional enzyme possesses two catalytic sites, namely a cy-
clooxygenase active site and a peroxidase active site. We now know
that there are two major isoforms of COX, coded by two distinct
genes, and referred to as COX-1 and COX-2. COX-1, which has
been designated as “constitutive” because of its distribution in vir-
tually all tissues under basal conditions, is responsible for the pro-
duction of prostaglandins with general “housekeeping” functions,
such as gastric cytoprotection, vascular homeostasis, platelet aggre-
gation, and kidney function. On the other hand, COX-2 has been
termed “inducible” because of its more restricted basal expression
and its upregulation during inflammation and cellular transforma-
tion. It is noteworthy that COX-2 is expressed constitutively in the
fetal and adult kidney, and in the perinatal brain. Some years ago,
Chandrasekharan et al. [10] identified a COX-1 splice variant, des-
ignated as COX-3, in the canine cerebral cortex. This new COX
isoform, absent in the fetal CNS tissue but abundantly expressed in
the mature brain, regulates fever and pain sensitivity.
The three-dimensional structure of COX-1 was determined by
Picot et al. [11]. This enzyme comprises three independent folding
units: an epidermal growth factor-like domain, a membrane binding
motif and an enzymatic domain. The site for peroxidase activity is
adjacent but spatially distinct from the site for cyclooxygenase ac-
tivity. The conformation of the membrane-binding motif strongly
suggests that the enzyme is a monotopic membrane protein. Three
of the helices of the structure lie at the entrance to the cyclooxy-
genase channel and their insertion into the membrane could allow
arachidonic acid to reach the active site from the interior of the
bilayer [12]. The COX active site is a long, hydrophobic channel,
and Picot et al. [11] have provided evidence that some aspirin-like
drugs, such as flurbiprofen, inhibit COX-1 by excluding arachi-
donic acid from the upper portion of the channel. Tyrosine 385 and
serine 530 are at the apex of this active site [12].
The three dimensional structure of COX-2 has also been de-
scribed [13]. This structure closely resembles that of COX-1, except
that the COX-2 active site is slightly larger and can accommodate
larger structures than those which are able to fit the COX-1 active
site. A secondary internal pocket contributes significantly to the
larger volume of the active site of COX-2, even though the central
channel is also bigger by 17%. Selectivity for COX-2 inhibitors is
dependent on the replacement of histidine 513 and isoleucine 523
of COX-1 with arginine and valine, respectively.
A number of NSAID mechanisms of action have been de-
scribed. In 1971, Vane [14] proposed that the action mechanism of
the aspirin-like drugs (i.e., NSAIDs) was through the inhibition of
PG synthesis, and this theory is generally accepted today. Prosta-
glandin inhibition by aspirin is due to the irreversible acetylation of
the COX site of PGHS, while the peroxidase activity of the enzyme
is unaffected. In contrast to this irreversible action of aspirin, other
NSAIDs such as indomethacin or ibuprofen cause reversible COX
inhibition by competing with the substrate, arachidonic acid, for the
active site of PGHS.
Aspirin differs from other NSAIDs because of its irreversible
inhibition of both COX isoforms [1]. In the case of COX-2, how-
ever, the efficiency by which serine 530 is trans-acetylated by aspi-
rin, resulting in enzyme inhibition, is at least 10-fold less than for
COX-1 isoform.
Furthermore, the action mechanisms and effects of aspirin vary
with dose. Low doses (75-81 mg/day) are able to irreversibly acety-
late COX-1 serine 530 [15,16], thus inhibiting thromboxane A2
platelet production and resulting in an antithrombotic effect. Inter-
mediate doses (650 mg-4 g/day) inhibit COX-1 and COX-2, thus
blocking prostaglandin production, and have analgesic and antipy-
retic effects. Finally, high doses (4-8 g/day) of aspirin have anti-
Current Drug Metabolism, 2012, Vol. 13, No. 4 475
inflammatory effects, which may not be entirely attributable to
direct COX inhibition [16].
Classical NSAIDs (e.g., diclofenac, ibuprofen and naproxen)
are nonselective COX inhibitors that inhibit both COX-1 and COX-
2 isoforms in different degrees. On the other hand, the more recent
drugs celecoxib and rofecoxib belong to the highly selective COX-2
inhibitors (COXIBs).
Although NSAIDs clearly inhibit the synthesis and release of
prostaglandins, these actions are not sufficient to explain all the
antiinflammatory effects of NSAIDs.
In vitro, some NSAIDs such as indomethacin, diclofenac, keto-
profen, and aspirin, have been shown to strongly inhibit the neutro-
phil-endothelial cell attachment, which is a critical step in the in-
flammatory response. The underlying mechanism of this NSAID-
induced effect has been attributed to a rapid reduction in the expres-
sion of L-selectin on the neutrophil surface [17].
It is well-known that nitric oxide (NO) formation is increased
during inflammation, and that several classic inflammatory symp-
toms (erythema and vascular leakiness) are reversed by nitric oxide
synthase (NOS) inhibitors [18,19]. Moreover, cytokines and other
proinflammatory mediators induce inducible NOS (iNOS), conse-
quently leading to increased inflammation [20]. Amin et al. [21]
have documented that the inhibition of iNOS expression and func-
tion represents another action mechanism for aspirin (if not for all
aspirin-like drugs), and that these effects are exerted at the level of
translational/posttranslational modification and on the catalytic
activity of iNOS.
Recently, Suleyman et al. [22] have shown that some NSAIDs,
namely indomethacin, diclofenac sodium, ibuprofen, nimesulide,
tenoxicam, and aspirin, produce significant anti-inflammatory ef-
fects in intact rats but insignificant effects in adrenalectomized rats.
Therefore, the Authors have concluded that anti-inflammatory ef-
fects of these agents are related to adrenalin and cortisol.
3. CYCLO-OXYGENASE INHIBITORS AND TOCOLYSIS
The molecular mechanisms underlying the onset and mainte-
nance of labor at term have not been fully established, but it is cer-
tain that prostaglandins (PGs) are strongly implicated [23]. Fur-
thermore, PGs are important mediators in delivery, stimulating
uterine contraction and enhancing cervical ripening. The expression
of COX-2, but not of COX-1, in fetal membranes and myometrium
increases in association with labor, and thus this COX isoform is
likely to play a role in the increased prostaglandin synthesis ob-
served in the uterus at term [24-27]. These findings could explain
why the COX inhibitors administered in the last trimester of preg-
nancy prolong gestation both in animals and in humans [1].
In a Cochrane review [28], when compared to conventional
tocolytics (betamimetics and magnesium sulphate), cyclo-
oxygenase inhibitors (mainly indomethacin, but also sulindac, ke-
torolac, nimesulide and rofecoxib) resulted in a reduction in the
number of women delivering prior to 37 weeks’ gestation and fewer
maternal side-effects. Moreover, a trend toward a reduction in the
number of women delivering before 48 hours after initiation of
treatment was observed, while no difference was shown at 7 days.
In a recent meta-analysis [29], prostaglandin inhibitors (indometha-
cin, sulindac, ketorolac, mefenamic acid, nimesulide, celecoxib,
rofecoxib) resulted superior to the other tocolytic agents (be-
tamimetics, calcium-channel blockers, magnesium sulphate, oxyto-
cin receptor antagonists and nitrates) providing the best combina-
tion of delayed delivery and tolerance. Compared to placebo, all
tocolytic agents were able to delay delivery by 48 hours and 7 days.
However, a detailed data analysis demonstrated that prostaglandin
inhibitors may be considered the optimal first-line agents before 32
weeks’ gestation to delay delivery for 48 hours and 7 days (lower
rate of failure events, higher proportion of patients tolerating treat-
ment and achieving outcomes), whereas calcium-channel blockers
476 Current Drug Metabolism, 2012, Vol. 13, No. 4
were superior first-line tocolytic agents to delay delivery until 37
weeks’ gestation [29].
Since the seventies, NSAIDs have been used as effective toco-
lytic agents. Indomethacin (INDO) has been the reference drug,
delaying delivery for at least 48 hours and up to 7-10 days [30]. The
placenta is readily permeable to INDO, allowing similar maternal
and fetal concentrations of the drug [31]. However, its use is lim-
ited by fetal and neonatal severe adverse effects, as well as an in-
creased risk of perinatal death. The exact incidence of such side
effects is still being debated [32,33].
Preferential or selective inhibitors of COX-2 (particularly su-
lindac, nimesulide and celecoxib) have been proposed for the
treatment of preterm delivery, expecting less fetal and maternal side
effects. Clinical and pharmacological data on the perinatal use of
selective COX-2 inhibitors are limited: nevertheless, these drugs
appear as effective as INDO in preventing preterm delivery in hu-
mans and animals, with similar side effects [28, 29, 34-38].
4. PLACENTAL TRANSFER AND METABOLISM OF
NSAIDS
During pregnancy, physiological changes occur that can affect
the pharmacokinetics of drugs. Most of these changes begin early in
gestation and are more pronounced in the third trimester [39].
Absorption of drugs administered orally is delayed because of
slow gastric emptying and reduced intestinal motility, largely due to
progesterone action on smooth muscle activity [40]. The volume of
distribution of drugs increases during pregnancy, as by the 6th to 8th
week of gestation plasma volume has expanded and continues to
increase until approximately 32 to 34 weeks’ gestation. The con-
centration of plasma albumin decreases during pregnancy, while
plasma concentrations of
1-acid glycoprotein are relatively un-
changed [39]. The metabolic activity of the liver is increased, ac-
celerating the metabolism of lipophilic drugs: progesterone as well
as other placental hormones can be responsible for hepatic enzy-
matic activity changes [39]. Renal filtration is increased, leading to
enhanced renal elimination of water-soluble drugs. These modifica-
tions are generally responsible for reduced plasma concentrations
and reduced half-life of most drugs [40].
The distribution of a drug from the maternal circulation into the
placenta is the first step for its transfer across the placenta and is
mainly a function of both uterine blood flow and permeability of
the placental membrane [41].
The major function of the placenta is to transfer nutrients and
oxygen from the mother to the fetus, to synthesize hormones and
peptides vital for a successful pregnancy, and to remove waste
products. The impression that the placenta forms an impenetrable
obstacle against drugs is widely regarded as false. Nearly all drugs
administered during pregnancy enter the circulation of the fetus and
a variety of pharmacokinetic variables, including transplacental
transport and metabolism, determine the degree of maternal-to-fetal
drug transfer and exposure. Placental transfer of drugs occurs pri-
marily through passive diffusion, so the physicochemical properties
of drugs such as polarity, molecular weight < 500 D and liposolu-
bility influence the rate of transfer. In addition, some drugs are
pumped across the placenta by various transporters, while facili-
tated diffusion appears to be a minor mechanism and pinocytosis is
considered too slow to have any significant effect on fetal drug
concentrations [41].
The extent of drug transfer may also be affected by its own
degree of binding to plasma proteins (mainly albumin or
1-acid
glycoprotein), since the complex drug-protein is too large to cross
the placenta. However, this binding is a transient phenomenon and
when the drug separates from the protein it is able to cross the pla-
centa establishing an equilibrium between maternal and fetal circu-
lations. Although plasma protein binding could alter the total con-
Antonucci et al.
centration of drugs in the maternal and fetal plasma, the free con-
centrations in the mother and fetus will not differ [42].
The extent to which drugs cross the placenta is also modulated
by the actions of placental phase I and II drug-metabolizing en-
zymes, which are present at fluctuating levels throughout preg-
nancy. Cytochrome P450 (CYP) enzymes have been well character-
ized in the human placenta [41]. The type and amount of expressed
CYPs vary depending on the period of gestation and maternal
health status. More CYP isoforms are expressed in the first trimes-
ter than at term gestation: it has been hypothesized that during the
early development of the fetus the expression of CYPs is maximal
in order to counteract the effects of teratogens while, later, the
CYPs not needed for fetal well-being are switched off [43].
CYP1A1, CYP2E1, CYP3A4, CYP3A7 and CYP4B1 have been
detected in the term placenta [44]. Much less is known about phase
II enzymes in the placenta. Uridine diphosphate glucuronosyltrans-
ferases, which are involved in the conjugation of xenobiotics with
glucuronic acid, are present in the placenta throughout gestation
suggesting a significant role of these enzymes in placental drug
detoxification [45]. Moreover, sulfation in the placenta may be a
significant biotransformation pathway for some drugs [41].
Several studies have documented that NSAIDs cross the human
placenta. Placental transfer of aspirin [46], indomethacin, sulindac,
naproxen [47], and diclofenac [48] has been shown both in placenta
perfusion models and in placenta and fetal tissues of women admit-
ted for termination of pregnancy [49].
Because of their lipid solubility, salicylates and aspirin were
demonstrated to cross the human placenta and widely distribute to
the fetus and extrafetal fluids, but equilibrium is achieved slowly.
In pregnancy, the lower concentration of plasma albumin is associ-
ated with a lower binding of salicylate and an increase in volume of
distribution. However, the low levels in fetal plasma are not due to
differences in protein binding but rather to the lower pH of fetal
blood. From limited data, it appears that the clearance of salicylate
is increased during pregnancy [1,50].
Placental transfer of indomethacin seems to be unrelated to the
gestational age in the human fetus. This drug distributes in fetal
tissues and achieves equilibrium in about 6 hours post-dose [1,51].
The half-life of the drug is much longer in the fetal circulation (14.7
h) than in the maternal circulation (2.2 h) [31].
Sulindac, a pro-drug, readily crosses the placenta. Its active
sulfide metabolite, formed through maternal hepatic metabolism,
may cross the placenta and reach the fetal circulation. Transplacen-
tal passage seems to be low after a single, oral dose of sulindac in
pregnant women (24-36 weeks of gestation). However, the human
placental perfusion model showed that sulindac sulfide reached the
fetus in a high concentration [49,52].
Naproxen achieves a drug concentration in fetal serum compa-
rable to that in maternal serum after repeated dosing [53].
Transplacental transfer of the COXIBs has to be expected due
to their low molecular weight. Rofecoxib has been shown to cross
the placenta in rats and rabbits [1,53].
MATERNAL EXPOSURE TO NSAIDS DURING PREG-
NANCY AND ADVERSE EFFECTS ON THE OFFSPRING
Adverse effects on the fetus and newborn have been reported
after prenatal exposure to COX inhibitors as a result of the transpla-
cental passage of these agents [28,54,55].
The major pharmacological action of NSAIDs on the fetus
might be mediated through the inhibition of the prostaglandin syn-
thesis pathway, that influences blood circulation in various organs.
Recent studies have not demonstrated any differences in neonatal
outcomes when comparing the maternal administration of non-
selective COX inhibitors with COX-2 inhibitors [1,28]. This obser-
Impact of Prenatal NSAIDs on the Offspring
vation could be explained by considering that COX-2 is expressed
in a variety of fetal tissues [1].
NSAID effects on the fetus and newborn are different depend-
ing upon the period of pregnancy in which the drugs have been
administered to the mother. Women who are treated with NSAIDs
during early pregnancy may be at a greater risk of having children
with congenital anomalies [6]. On the other hand, premature closure
of the ductus arteriosus has been observed in fetuses of mothers
treated with NSAIDs during the third trimester of gestation [56].
Both the duration of maternal NSAID therapy and the distance
between maternal administration and the delivery have been re-
ported as important factors in the development of adverse effects on
the fetus. Major et al. [57] documented that antenatal indomethacin
exposure occurring within < or = 24 hours of delivery and of at
least 48 hours' duration was associated with an increased incidence
of necrotizing enterocolitis in low-birth-weight neonates. Another
study demonstrated that antenatal indomethacin treatment for
longer than 2 days, with a daily or cumulative dosage >/=150 mg,
correlated with a significantly higher incidence of grade I-II intra-
ventricular hemorrhage. Furthermore, a combined ante- and postna-
tal exposure, a cumulative antenatal exposure >/=150 mg, and a
duration of antenatal exposure of more than 2 days were associated
with necrotizing enterocolitis, and a cumulative exposure with sep-
sis [58].
A recent study has reported that prenatal indomethacin expo-
sure (duration > 48 hours between the last dose given to the mother
and delivery) could be associated with an increased risk of periven-
tricular leukomalacia [59].
Prenatal NSAID administration was also found to have terato-
genic effects on the fetus. Two recent studies have reported an ad-
justed odds ratio (OR) of 1.04 and 2.21, respectively, for any con-
genital malformation in infants whose mothers had used NSAIDs in
early pregnancy [6,8]. In 1990, Montenegro and Palomino [60]
documented that the exposure to prenatal NSAIDs (naproxen, su-
lindac, indomethacin, diclofenac, and mefenamic acid) induced
cleft palate in the mouse offspring, with sulindac being the most
teratogenic. In vitro, each drug under study prevented the fusion of
the palatine processes in treated explants, and the degree of inhibi-
tion was dependent on the stage of development at the time of ex-
plantation. In both in vivo and in vitro experiments, the drugs pre-
vented medial epithelial cell breakdown that normally occurs in the
medial secondary palatal epithelium. The findings of this study
suggest that prostaglandins may play an important role in the nor-
mal differentiation of the developing palatine region [60]. More
recently, Burdan et al. [61] have reported that gastroschisis is the
only congenital ibuprofen-related malformation that was proved in
large epidemiological human studies. Other congenital anomalies
associated with maternal ibuprofen ingestion, and reported in avail-
able literature, have not been established in epidemiological studies.
The adverse effects of antenatal NSAIDs on the embryo, fetus
and newborn are described organ by organ in the following sec-
tions.
1. MISCARRIAGE
Prenatal use of NSAIDs was found to increase the risk of mis-
carriage [1], although conclusive evidence on this point is lacking.
Nielsen et al. [62] reported a significant association between the
use of prescribed NSAIDs and miscarriage, with odds ratios that
ranged from 1.3 for NSAID use 10-12 weeks before miscarriage to
7.0 for NSAID use one week before miscarriage. However, this
study had several limitations. In particular, no information on pa-
tient compliance, or about the gestational age at time of miscarriage
was available. Furthermore, the results of this study did not exclude
the possibility of confounding by indication (as an example, the
prescribing of a pharmacological agent to treat pain that may have
been a precursor of miscarriage). More recently, a population-based
Current Drug Metabolism, 2012, Vol. 13, No. 4 477
cohort study by Li et al. [63] documented that antenatal NSAID
administration was associated with an 80% increased risk of mis-
carriage after adjustment for potential confounders. Moreover, the
association was stronger if the initial NSAID use was around the
time of conception, or if NSAID use lasted more than a week, sug-
gesting a dose-response relationship. Similarly, antenatal aspirin
use was associated with an increased risk of miscarriage. As sug-
gested by the authors, the probable mechanism underlying this ef-
fect of NSAIDs in pregnant women is the suppression of prosta-
glandin biosynthesis in the tissues of the reproductive system: this
could lead to abnormal embryo implantation that predisposes to
miscarriage. The above-mentioned mechanism is supported by the
findings of some animal studies showing that prostaglandins are
important mediators in the process of embryo implantation into the
uterus wall [64-67]. In addition, through the suppression of prosta-
glandin production, NSAIDs may have an adverse effect on placen-
tal perfusion and circulation, thus increasing the risk of fetal demise
[63].
On the other hand, it should be considered that NSAIDs are also
prescribed to pregnant women to treat antiphospholipid antibody
syndrome, which itself increases the risk of miscarriage. In women
with this syndrome, pregnancy was found to be more successful
with the treatment. Heparin, moderate-to-high dose of prednisone
and low dose aspirin are the most commonly used drugs [68].
2. CELOSOMY
The term “celosomy” indicates a group of congenital anomalies
characterized by opening of the somatic wall with evisceration,
including gastroschisis, omphalocele and umbilical cord hernia
[69]. Gastroschisis is a defect in the abdominal wall, lateral to the
umbilical cord, which is considered to be a vascular problem,
probably due to an intrauterine interruption of the omphalomesen-
teric artery [70]. Recent reports indicate that gastroschisis is in-
creasing in prevalence, while omphalocele has remained steady;
this finding suggests that environmental factors may play a role in
the pathogenesis of abdominal wall defects [69].
Some studies conducted in rat fetuses documented that aspirin
increases the risk of abdominal wall defects, unlike other non-
selective COX inhibitors [71] and selective COX-2 inhibitors [71,
72].
Over the last 20 years, many human studies showed a higher
risk of gastroschisis in newborns of pregnant women treated with
NSAIDs, particularly aspirin [73-77].
In 2002, Werler et al. [77] conducted a retrospective study to
evaluate the relation between maternal use of cough/cold/analgesic
drugs and risk of gastroschisis. Risks of gastroschisis were found to
be elevated for maternal use of aspirin (OR = 2.7), pseudoephedrine
(OR = 1.8), acetaminophen (OR = 1.5), and pseudoephedrine com-
bined with acetaminophen (OR = 4.2). Furthermore, fever, upper
respiratory infection, and allergy were not associated with gastro-
schisis risk. These findings confirm that aspirin use in early preg-
nancy increases the risk of gastroschisis; they also raise questions
about interactions between drugs and about the possible role of an
infectious agent in affecting this risk.
In another more recent study, Werler et al. [78] evaluated the
associations between maternal vasoactive exposures in pregnancy,
as possible markers of vascular disruption, and the risk of gastro-
schisis. Compared to mothers of non-malformed newborns, mothers
of newborns with gastroschisis were more likely to report use of
non-aspirin NSAIDs (OR = 1.4, 95% CI = 1.1-1.7). Furthermore,
the odds ratios for use of non-aspirin NSAIDs were greatest in the
older women. The findings of this study, as noted by the authors,
suggest that vasoactive risk factors play a minor role in the etiology
of gastroschisis and raise the question of whether inherent maternal
factors might influence the risk.
478 Current Drug Metabolism, 2012, Vol. 13, No. 4
3. CARDIAC EFFECTS
Over the last decade, many studies documented the relationship
between antenatal maternal use of NSAIDs and the development of
congenital cardiac malformations [8,62,72,79-82]. The occurrence
of congenital heart defects in animal fetuses antenatally exposed to
NSAIDs is suggested by literature data. Cappon et al. [72] docu-
mented that inhibition of COX-1 may be involved in the disruption
of heart development, whereas the selective inhibition of COX-2
appears to have no effect on heart development in rats and rabbits.
The findings of another study on pregnant rats suggest that prenatal
exposure to non-selective COX inhibitors, but not to selective
COX-2 inhibitors, could increase the risk of ventricular septal de-
fects (VSD) when compared to historic controls [81]. A recent ret-
rospective analysis revealed a higher incidence of VSD in rat off-
spring prenatally exposed to various COX inhibitors, especially
aspirin and ibuprofen. All detected defects were limited to the
membranous part of the septum and the effect was treatment-
related, with the incidence and severity of VSD being significantly
higher in the high dose group than in the low dose group [83].
The critical period for the ventricular septal development seems
to be between gestational day (GD) 8 and GD 16 (embryonic age),
and includes the development of the primordial endocardium (GD
8.25-8.5), then the origin of endocardial cushion (GD 13), and fi-
nally the formation of the membranous part of the ventricular sep-
tum [84]. On this subject, it should be clarified that, in embryology,
gestational age (also termed fertilisation age or embryonic age) is
the time elapsed since conception. On the other hand, in human
obstetrics, gestational age is generally defined as the time elapsed
since 14 days prior to conception. This is approximately the dura-
tion between the first day of the last normal menstrual period and
the day of delivery [85].
COX-1 is the only COX isoenzyme detected during the whole
embryonic and fetal period, and could regulate prostaglandins,
prostacyclin and thromboxane synthesis [86]. In contrast, COX-2
expression was found only in the heart of fetuses aged
GD 16
[86], when interventricular septation is completed [84]. Accord-
ingly, the prenatal COX-1 blockade and the resulting disturbances
in eicosanoid physiology could explain the VSD occurence in ani-
mals antenatally exposed to NSAIDs [83]. These findings have
been partially confirmed in human studies. A Swedish study
showed an increased prevalence of VSD among infants whose
mothers had used nonsteroidal anti-inflammatory drugs (namely
diclofenac, ibuprofen, or naproxen) in early pregnancy, reporting an
OR of 1.86 for these cardiac defects [8]. Recently, Ofori et al. [6]
have found that women prescribed NSAIDs during early gestation
may be at a greater risk of having children with congenital anoma-
lies, with an adjusted OR of 3.34 (95% CI = 1.87-5.98) for the
anomalies related to cardiac septal closure. These findings were
confirmed by other studies [80,87-89], but contrasting data were
also reported [62,79,90,91]. This apparent contrast can be explained
by considering that, in most of the studies, the main indication for
NSAID use was maternal fever [62,80,90-92] and that hyperthermia
itself may alter septal development [93,94].
4. VASCULAR EFFECTS
4.1. Effects on the Ductus Arteriosus
The ductus arteriosus is a vessel connecting the main pulmo-
nary trunk with the descending aorta. It is essential during fetal life
to shunt blood away from the high resistance pulmonary circula-
tion, so much so that the ductal closure in utero may lead to fetal
demise or pulmonary hypertension. Fetal patency of the ductus, and
its spontaneous closure after birth, is the result of a balanced inter-
action of locally produced and circulating mediators (of which pros-
taglandins seem to play a major role), and the particular structure of
the vessel wall [95]. In healthy term newborns, the functional clo-
sure of the ductus occurs within 96 hours after birth. On the other
hand, complete anatomic closure with fibrosis takes up to 2-3
Antonucci et al.
weeks. The ductus normally constricts due to the postnatal drop in
circulating prostaglandin E2 levels, as well as the rise in systemic
oxygen tension, which induce a cytochrome P450-dependent in-
crease in endothelin-1 in ductal smooth muscle cells [96]. The fail-
ure of this closure process with the continued patency of this fetal
channel is called patent ductus arteriosus (PDA); it is inversely
proportional to gestational age occurring in almost 60% of very low
birth weight infants [95]. Persistent PDA with significant left to
right shunt in preterm infants can result in serious hemodynamic
changes causing respiratory, gastrointestinal, cerebral, and renal
morbidities, and increasing mortality if not promptly treated. Early
closure of the ductus arteriosus may be achieved pharmacologically
using cyclooxygenase inhibitors, or by surgery. Indomethacin and
ibuprofen are the prostaglandin inhibitors mainly used to treat pat-
ent ductus arteriosus in preterm infants.
Both COX-1 and COX-2 are expressed in endothelial and
smooth muscle cells of the ductus arteriosus [1,34]. Therefore, con-
striction or premature closure of the ductus is a risk of all antenatal
NSAIDs [97], including COXIBs [98]. In the literature, prenatal
closure of the ductus arteriosus is reported after maternal admini-
stration of most of the NSAIDs during pregnancy. Two animal
studies have found that aspirin and indomethacin administered dur-
ing pregnancy constrict fetal ductus arteriosus [97,99]. In addition,
experimental studies documented that naproxen, similar to other
NSAIDs, readily passed the placental barrier and caused constric-
tion of the ductus arteriosus [89]. Two studies reported a case of
prenatal closure of the ductus arteriosus following maternal di-
clofenac therapy during the third trimester of gestation [56,100].
Paladini et al. [101] observed 10 cases of constriction of the fetal
ductus arteriosus occurring after maternal self-medication with just
one or two oral doses of nimesulide. On account of these data, the
monitoring of the fetal ductus state and velocities by fetal echocar-
diography in women treated with NSAIDs seems to be appropriate
[100]. Moreover, each fetus should be evaluated by echocardiogra-
phy in case of multiple gestations, because the ductal response may
vary between individual fetuses [102].
Circulating PGE2 is considered to play a role in the patency of
lamb ductus arteriosus. Therefore, the constrictive effect of
NSAIDs might be due to the inhibitory effect of PGE2 synthesis
[103]. In an animal study, Takizawa et al. [104] documented that
the increased ductal responsiveness to PGE2 in newborn rats was a
common response after maternal treatment with aspirin and ibupro-
fen, but the catabolism of PGE2 in the lungs did not always con-
tribute to this response. Human studies documented a fetal ductus
arteriosus constriction when aspirin [105] or other non-selective
COX inhibitors were given to pregnant women to treat preterm
labor [106]. Recently, a retrospective analysis of fetal and neonatal
echocardiographic databases by Gewillig et al. [107] revealed pre-
mature fetal closure of the arterial duct in 12 cases. Eight of 12
cases were diagnosed prenatally, and in 3 out of these 8 cases the
mothers had received NSAIDs during pregnancy; in particular, 2
mothers had been treated with NSAIDs in the third and one in the
second trimester. Since NSAIDs are known to cause the constric-
tion of the ductus arteriosus if ingested late in pregnancy, the
authors hypothesized that this might have been the case in at least 2
patients.
Several studies using fetal echocardiography found that the
effect of indomethacin on the constriction of the ductus arteriosus
was independent of the fetal serum concentration of this drug [108-
110]. The rate of indomethacin-induced constriction of the ductus
arteriosus seems to be related to gestational age, increasing from
0% before week 27 of gestation to 61% during 31-34 weeks of
gestation [109]. For this reason, indomethacin should not be used
beyond 31 weeks of gestation [111]. In addition, the constriction
seems to reverse frequently within 24-48 hours after cessation of
therapy [1].
Impact of Prenatal NSAIDs on the Offspring
Conflicting opinions are reported in the literature about antena-
tal NSAIDs and their effects on the ductus arteriosus in the neonate.
In 1990, Baerts et al. [112] documented a lower incidence of PDA
in infants exposed in utero to indomethacin when compared with
those not exposed. Two recent metanalysis, aimed at assessing the
effects of tocolysis with indomethacin on neonatal outcomes, have
revealed no significant differences in the rates of patent ductus
arteriosus between infants exposed to indomethacin antenatally and
those not exposed [59,113], confirming the findings of previous
studies [32,114,115]. In infants antenatally exposed to indometha-
cin, other authors [116,117] documented a surprisingly higher inci-
dence of PDA and a higher postnatal PDA severity. This was char-
acterized by a symptomatic PDA requiring postnatal therapy with
indomethacin [117] or surgical ligation because of a lack of initial
response or ductal reopening after postnatal indomethacin therapy
[116]. These data were confirmed in several animal studies that
demonstrated a delayed postnatal closure of the ductus arteriosus in
mice, sheep, and rats that had been exposed to nonselective COX
inhibitors during the last period of gestation [118-121] and in mice
lacking both COX genes [119,120,122]. The recent study conducted
on rats by Momma et al. [121] documented that the delay in closure
of the ductus arteriosus induced by indomethacin was dose-
dependent and temporary, with recovery 3 days or more after expo-
sure. A timing evaluation revealed a maximum delay with the ad-
ministration of indomethacin 2 days before birth and a minimum
delay with the administration of the drug 5 days before. The authors
suggested that the delay was induced by a decreased stimulus to the
prostaglandin EP(4) receptor system in the last 2 days in utero.
Nevertheless, the mechanism underlying this paradoxical response
is not entirely clear. In utero COX inhibition may probably contrib-
ute to delayed closure by increasing NO [118,123] or decreasing
hyaluronic acid production in the ductus [124]. Specific compo-
nents of ductal contractility are involved in the postnatal closure of
the ductus arteriosus, namely smooth muscle calcium channels,
potassium channels [125-129], Rhokinase– related calcium sensitiz-
ing pathways [125,130-132], mature myosin isoforms [133], and
cytoskeletal proteins [134]. In the literature, it has been suggested
that events or drugs that interfere with these pathways can lead to
delayed postnatal ductus closure [130,131,135-137]. In a recent
study, Reese et al. [138] have speculated that prostaglandins may
regulate the development of one or more of these contractile path-
ways and hypothesized that in utero inhibition of COX activity may
alter the development of contractile apparatus, leading to a persis-
tent PDA after birth. They examined the effects of prostaglandin
exposure and inhibition on the fetal mice and sheep ductus, and
found that PGE2 increased the CaL- and K+-channel genes expres-
sion (which regulate oxygen-induced constriction) and the phos-
phodiesterase expression (which decreases the sensitivity of the
ductus to cAMP- or cGMP-dependent vasodilators). On the con-
trary, chronic in utero exposure to COX inhibitors decreased these
expressions. These findings could explain the increased risk of
PDA after in utero COX inhibition. In fact, PGE2 seems to have
two complementary roles during ductus development: maintaining
ductus patency for fetal well-being, and promoting the expression
of pathways necessary for its oxygen-induced closure after delivery.
The paradoxical effects of acute and chronic COX inhibition seem
to be consistent with the existence of these two roles [138]. Clyman
et al. [118] hypothesized that the ductus arteriosus resistance to
postnatal indomethacin of newborn infants exposed to antenatal
indomethacin could be due to ductus constriction in utero, with
subsequent remodelling of the vessel. A study by these authors
documented an increase of the thickness of the avascular zone and a
constriction of the ductus after infusion of fetal lambs with indo-
methacin for 48 hours. These modifications in turn induced the
expression of vascular endothelial growth factor, endothelial nitric
oxide synthase (due to ingrowth of vasa vasorum), neointima for-
mation, and loss of smooth muscle cells. Furthermore, this study
documented that moderate degrees of ductus constriction in utero
Current Drug Metabolism, 2012, Vol. 13, No. 4 479
increased NO production, which inhibited ductus contractility,
while marked degrees of ductus constriction decreased tissue dis-
tensibility and contractile capacity. The authors concluded that
ductal patency was no longer controlled primarily by prostaglandins
once the ductus had been exposed to indomethacin in utero [118].
4.2. Persistent Pulmonary Hypertension of the Newborn
(PPHN)
Exposure of the fetus to NSAIDs and the resulting closure of
the ductus arteriosus in utero has been suggested to be one possible
cause of persistent pulmonary hypertension of the newborn
(PPHN). PPHN is a neonatal disorder characterized by elevated
pulmonary resistance and altered pulmonary vasoreactivity that lead
to a failure of the pulmonary circulation to adapt to extrauterine
life. This results in a right to left blood shunt across the foramen
ovale and the ductus arteriosus (if it is patent), thus causing severe
hypoxemia. NSAIDs are COX inhibitors that can block the synthe-
sis of prostaglandins and thromboxane, which are involved in main-
taining ductal patency and regulation of pulmonary vasculature
[139]. Since 1976, animal experiments demonstrated that indo-
methacin produced constriction or closure of the ductus arteriosus
with subsequent primary pulmonary hypertension due to elevated
pulmonary vascular resistance [140]. Three years later, Levin et al.
[141] documented that antenatal indomethacin administration
caused ductal constriction, pulmonary arterial hypertension, and
right ventricular damage in the fetus. In the newborn infant, this
mechanism may be one cause of persistent pulmonary hypertension
due to vasoconstriction and increased pulmonary arterial smooth
muscle.
In fetal lambs, pulmonary hypertension due to antenatal me-
chanical ligation of the ductus arteriosus caused partial musculari-
zation of the intraacinar pulmonary arteries [142]. In other animal
studies, the antenatal exposure to NSAIDs has been shown to pro-
duce ductal constriction, an increase in pulmonary arterial smooth
muscle thickness, and pulmonary arterial hypertension [143-147].
These results were not confirmed in two other studies that could not
reproduce functional and structural changes of PPHN in newborn
lambs after antenatal administration of indomethacin [148,149].
Ohara et al. [150] examined whether or not closing the ductus arte-
riosus of fetal lambs by the administration of indomethacin in utero
could produce the functional and structural changes of PPHN. The
results of this study suggested that, in newborn lambs, pulmonary
hypertension due to constriction of the ductus arteriosus by antena-
tal indomethacin produced only a part of the structural changes of
the pulmonary vascular bed in fatal PPHN, and it failed to repro-
duce the postnatal hemodynamics of PPHN.
In a case-control interview study by Van Marter et al. [151],
maternal intake of NSAIDs and aspirin during pregnancy or the
conditions leading to the use of these drugs were shown to contrib-
ute to an increased risk of PPHN.
It has been documented that not only long-term indomethacin
therapy but also administration of this drug even hours before de-
livery can significantly affect the ductus arteriosus and the pulmo-
nary vasculature, leading to pulmonary hypertension in the prema-
ture newborn [111].
To our knowledge, only one case-control study documented
that indomethacin tocolysis was not associated with a higher inci-
dence of pulmonary hypertension of the newborn [32].
Other NSAIDs, namely aspirin [151], diclofenac [152,153],
naproxen sodium [154], ibuprofen [61], and niflumic acid [155]
were reported to be associated with an increased risk of PPHN
when administered to the mother during pregnancy. Zenker et al.
[152] found that pulmonary hypertension following an antenatal
maternal treatment with diclofenac only responded to high and
prolonged treatment with inhaled NO, suggesting a structural altera-
tion of pulmonary vasculature induced by this drug. In 2001, Alano
480 Current Drug Metabolism, 2012, Vol. 13, No. 4
et al. [4] conducted a study to detect fetal exposure to NSAIDs by
meconium analysis and to determine the relationship between fetal
exposure to NSAIDs and PPHN development. The findings of this
study confirmed the results of previous studies, demonstrating that
the use of NSAIDs during pregnancy, in particular aspirin, ibupro-
fen, and naproxen, is underestimated by maternal history and is
significantly associated with PPHN.
5. EFFECTS ON THE BRAIN
Many literature studies have documented the effects of antena-
tal NSAID administration on the central nervous development and
the neural activity. Joschko et al. [156] investigated the effects of
salicylic acid on the developing nervous system in rats in vitro,
demonstrating that the neural tube was especially vulnerable and
frequently failed to close, while cellular and ultrastructural exami-
nation revealed extensive cell death in the neuroepithelium. The
authors suggested that the extensive cell necrosis in the developing
neuroepithelium at the site of neural tube fusion might be involved
in failed neurulation, while necrosis at other sites in the cranial
neuroepithelium might be linked with previously reported intellec-
tual and behavioural abnormalities. A more recent study reported a
decrease in the total brain weight, cerebrum and cerebellum length
and width in rats antenatally exposed to high dose of aspirin [157].
A pronounced neuron loss in cornu ammonis and dentate gyrus of
the hippocampus was observed in a diclofenac sodium-treated
group of rats, probably due to the neurotoxicity of this drug on the
developing hippocampal formation [158]. Another study showed
that the total number of Purkinje cells in the offspring of diclofenac
sodium-treated rats was significantly lower than in the offspring of
control animals, suggesting that the Purkinje cells of a developing
cerebellum might be affected by the administration of this drug
during the prenatal period [159]. These data are in contrast with the
findings of Odaci et al. [160] that documented an increased number
of Purkinje cells in the cerebellum of a developing female rat prena-
tally exposed to the same drug.
A recent study by Marret et al. [161] has shown that low-dose
aspirin given during pregnancy is not significantly associated with
cerebral lesions, cerebral palsy, or global cognitive impairment in
5-year-old children. Moreover, the results of this study have sug-
gested that aspirin could be associated with a reduction in neurobe-
havioral difficulties.
The effects of NSAIDs on the development of peripheral nerves
are still not clarified. A recent study by Canan et al. [162] has
shown that the axon number of sciatic nerve and mean axon cross-
sectional area, but not average myelin sheet thickness, are signifi-
cantly decreased in rats antenatally exposed to diclofenac sodium
compared with the control group; moreover, electron microscope
analysis has revealed a deterioration of myelin sheaths. Accord-
ingly, the authors have suggested that the prenatal administration of
diclofenac sodium impairs peripheral nervous system development.
Decreases in fetal blood pressure stimulate homeostatic stress
responses which help the blood pressure to return to normal values.
In the fetus, hypothalamus-pituitary-adrenal (HPA) axis responses
to hypotension are mediated by chemoreceptor and baroreceptor
reflexes and central nervous system ischemia [163]. HPA response
is controlled by prostaglandins generated within the fetal brain
[164]. Indomethacin, a nonselective inhibitor of prostaglandin en-
doperoxide synthase (PGHS)-1 and -2, attenuates the HPA response
to hypotension in the fetal sheep [165]. Very recently, Wood et al.
[163] have demonstrated that the activity of PGHS-2 in the brain is
a necessary component of the HPA response to cerebral hypoperfu-
sion in the sheep fetus. Furthermore, the blockade of N-methyl-d-
aspartate (NMDA) receptors seems to reduce the fetal ACTH re-
sponse to cerebral hypoperfusion. A recent study has shown that the
generation of prostanoids via the action of PGHS-2 in the fetal
brain increases the fetal HPA axis response to NMDA-mediated
glutamatergic stimulation [164].
Antonucci et al.
The mechanisms underlying the endothelium-dependent regula-
tion of cerebral circulation in human newborns are not clear due to
the lack of experimental data [166]. Chemtob et al. [167] docu-
mented that prostaglandins exert significant effects on the cerebral
circulation of newborn piglets. These mediators are essentially
cerebral vasodilators, except for PGE1 which produces vasocon-
striction at low dose. A subsequent study demonstrated that total
cerebral blood flow decreased significantly after the administration
of indomethacin, a prostaglandin H-synthase inhibitor, in newborn
piglets [168]. Parfenova et al. [166] found that COX activity in
cultured endothelial cells from microvessels from the autopsy
specimens of neonatal human cerebral cortex and cerebellum led to
vasodilator prostanoids, prostacyclin, and PGE2 production and that
both COX-1 and COX-2 contributed to endothelial prostanoid syn-
thesis in the neonatal human brain.
COX-2 has been shown to be the predominant form of COX
and the main catalyst of prostaglandin synthesis in the neonatal
brain. An animal study by Li et al. [169] demonstrated a key role
for COX-2 in the regulation of PGE2 and PGF2alpha receptors and
their functions in the neonatal cerebral vasculature. Najaran et al.
[170] documented that high levels of PGs in the nervous tissue,
specifically PGE2 acting apparently via EP2 receptors, seemed to
contribute to the preservation of electrophysiological neural func-
tion in newborn pigs subjected to hypoxic events in the perinatal
period. This effect of PGE2 was unrelated to improvements in cere-
bral blood flow. The same study revealed that ibuprofen and di-
clofenac were able to decrease brain PG levels. On the basis of their
results, the authors suggested that the reduction in PG levels would
enhance the posthypoxic deterioration in neural function of the
perinate. Other authors [33, 171,172] compared the effects of in-
domethacin and ibuprofen on cerebral hemodynamics in preterm
infants: ibuprofen did not significantly reduce cerebral perfusion
and oxygen availability, while indomethacin affected cerebral blood
flow velocity.
5.1. Cystic Periventricular Leukomalacia (cPVL)
Cystic periventricular leukomalacia (cPVL), the principal
ischemic brain injury in premature infants, is characterized by the
necrosis of white matter in the periventricular region and represents
the major neuropathology for spastic motor deficits in cerebral
palsy or epilepsy. Recent reports strongly suggest that the brain
injury associated with cPVL may have already occurred in utero
[173].
Antenatal NSAIDS are reported to increase the risk of cPLV in
many studies.
In an old study, the incidence of periventricular leukomalacia
was found to be increased among infants born before 30 weeks’
gestation and exposed to any tocolytic agent, and cystic lesions
occurred more commonly in those exposed to indomethacin [112].
More recent studies, which were conducted in cohorts of pre-
mature infants, confirmed this finding and showed that antenatal
exposure to indomethacin increased the risk of cPVL occurrence by
2-3 times. These data support a growing consensus that cPVL is
often the result of maternal and fetal factors as well as antenatal
treatments [59,173].
5.2. Periventricular/Intraventricular Hemorrhage (PVH/IVH)
Periventricular/intraventricular hemorrhage (PVH/IVH) is a
multifactorial pathological condition which is frequently associated
with neurological morbidity and mortality in very low birth weight
premature infants, and therefore its prevention is particularly impor-
tant.
Predisposing factors include an immature vasculature of germi-
nal matrix, a pressure-passive cerebral circulation, and hemody-
namic perturbations in sick premature infants. Intact cerebral
autoregulation has been documented in stable premature infants; by
Impact of Prenatal NSAIDs on the Offspring
contrast, it functions within a limited blood pressure range and is
likely to be absent in the sick hypotensive infant, thus increasing
the risk for PVH/IVH with perturbations in blood pressure. The risk
for PVH/IVH is markedly increased in the absence of antenatal
glucocorticoid exposure in intubated infants with birth weight less
than 1000 g affected by respiratory distress syndrome [174].
The role of antenatal use of NSAIDs on the incidence of neona-
tal PVH/IVH remains to be elucidated.
Vermillion et al. [32] documented that maternal indomethacin
exposure immediately before delivery was not associated with an
increased risk for grade III/IV intraventricular hemorrhage in in-
fants delivered between 24 and 32 weeks' gestation. This finding
was confirmed in a more recent study showing that indomethacin
tocolysis was not associated with an increased risk for intraven-
tricular hemorrhage [175]. On the other hand, Ojala et al. [58]
documented that antenatal indomethacin treatment for longer than 2
days, with a daily or cumulative dosage >/=150 mg, was correlated
with a significantly higher incidence of grade I-II intraventricular
hemorrhage in infants of gestational ages between 23 and 32 weeks.
Furthermore, Doyle et al. [115] showed that the incidence of grades
III to IV IVH was significantly higher in VLBW infants exposed to
antenatal indomethacin as compared to the non-exposed infants;
moreover, antenatal indomethacin exposure was significantly asso-
ciated with an increased incidence of IVH after controlling for an-
tenatal corticosteroids, maternal pre-eclampsia, gestational age and
birth weight.
Some studies have shown that antenatal aspirin is associated
with an increased incidence of intracranial hemorrhage. In particu-
lar, the use of aspirin in the last 3 months of pregnancy has been
suggested to be highly questionable [176,177]. Nevertheless, it
should be considered that aspirin use during pregnancy is particu-
larly useful for the prevention of intrauterine growth restriction
(IUGR) and preeclampsia, and for the treatment of antiphospholipid
antibodies syndrome (APAs). In the pathogenesis of both IUGR
and preeclampsia, the activation of platelets seems to play an im-
portant role, and therefore an antiplatelet agent such as aspirin may
be useful in preventing these two pregnancy complications [1].
Additionally, low-dose aspirin combined with low-molecular-
weight heparin has been found to be the most effective treatment
for pregnant women with APAs [178]. The aspirin mechanism of
action is related to its ability to increase the level of prostacyclins
and to reduce the level of thromboxane, the platelets prothrombotic
factor, thus preventing placental thrombosis which is a possible
complication of antiphospholipid syndrome [179].
The exact pathophysiology of IVH related to the antenatal ex-
posure to NSAIDs is unclear. In pregnant women undergoing toco-
lysis with indomethacin, Parilla et al. [180] have documented that
this drug does not significantly affect fetal cerebral blood flow.
Based on this finding, the authors have concluded that, if antenatal
indomethacin in the preterm fetus increases the risk of intraven-
tricular hemorrhage, it seems to be due to another mechanism.
5.3. Neurodevelopmental Outcome
There are limited data on the long-term neurodevelopmental
outcome of premature infants exposed to antenatal indomethacin. In
a follow-up study, Salokorpi et al. [181] reported that antenatal
indomethacin was not significantly associated with abnormal neuro-
logical outcome in premature infants when evaluated at 18 months
corrected age. Similarly, in a small retrospective cohort study, Al-
alaiyan et al. [182] found that there were no effects of antenatal
indomethacin on neurodevelopmental outcome at 12 months of age.
Recently, a retrospective cohort study by Amin et al. [183] was
conducted to evaluate if the exposure to antenatal indomethacin was
associated with abnormal neurological outcome. The findings of
this study showed that indomethacin, used as a tocolytic agent, was
not associated with adverse neurodevelopmental outcome at 16–24
months corrected age in infants
29 weeks’ gestational age; fur-
Current Drug Metabolism, 2012, Vol. 13, No. 4 481
thermore, antenatal indomethacin exposure might be associated
with an improved neurological outcome. It is noteworthy that Sa-
lokorpi et al. [181] performed their study when antenatal steroids
were not routinely used, while the study by Al-alaiyan et al. [182]
failed to account for possible confounders. Conversely, the strength
of the study by Amin et al. [183] consists in the evaluation of the
effect of antenatal steroids and the adjustment for possible con-
founders. In fact, the beneficial effects of antenatal steroids should
be considered as well, since these effects might outweigh the risk
associated with the use of antenatal indomethacin. Moreover, pre-
vious findings have shown that the benefits of antenatal indometha-
cin for tocolysis outweigh the potential risks to the newborn at ges-
tational ages < or = 32 weeks [184].
6. EFFECTS ON THE KIDNEY
Renal function in postnatal life is affected by prenatal environ-
mental and genetic determinants. The number of pregnant women
who are receiving drugs administered when fetal glomerulogenesis
is still occurring is increasing [185]. Several drugs have been shown
to produce adverse effects on the kidneys, mainly when exposure
occurs during active nephrogenesis [186]. Mothers of infants that
showed neonatal acute renal failure had received more nephrotoxic
drugs during pregnancy and delivery [187]. Such adverse effects
may occur particularly when fetuses are exposed to NSAIDs [188].
A review article by Bavoux [189] reported the renal effects of ante-
natal NSAIDs (acute renal failure with edema, oliguria, hyponatre-
mia and hyperkalemia) in 23 neonates, 8 of whom died. Drukker et
al. [190] have recommended close attention to the use of NSAIDs
during pregnancy because these agents impair renal structure and
function in the unborn fetus.
The nephrotoxic effects of NSAIDs are related to the block of
prostaglandin synthesis through the inhibition of cyclooxygenase-2
[191]. Prostaglandin E2 (PGE2) modulates both intrarenal vascular
tone and salt and water excretion. In particular, PGE2 contributes to
regulate renal perfusion and glomerular filtration rate in virtue of its
vasodilating properties, by counteracting the action of vasoconstric-
tive substances such as angiotensin II, catecholamines, vasopressin
and endothelin [9].
Several cases of severe and sometimes irreversible renal failure
have been reported in neonates exposed to indomethacin prenatally
[191]. In a case of twin-to-twin transfusion syndrome, renal tubular
dysgenesis-like lesions and hypocalvaria which were found in twins
were attributed to indomethacin treatment of the mother for acute
polyhydramnios [192]. Infants whose mothers had received indo-
methacin tocolysis were shown to be at risk of developing renal
impairment [193, 194]. Jacqz-Aigrain et al. [195] reported that 22%
of live-born neonates of pregnant women receiving indomethacin
for treatment of premature labor or polyhydramnios developed
renal insufficiency. Van der Heijden et al. [196,197] reported 6
anuric neonates exposed to indomethacin in utero. In 5 infants,
cystic dilatations of superficial nephrons were associated with
ischemic changes of the deep cortex.
Comparative studies are available in the literature. Renal func-
tion was measured during the first 4 postnatal days in 9 preterm
neonates exposed to indomethacin during the last 2 days of preg-
nancy and compared with controls. Inulin clearance was lower and
serum creatinine was higher in patients than in controls [198]. Pre-
term infants whose mothers had been treated with indomethacin for
preterm labor, matched with infants whose mothers had not re-
ceived indomethacin, had a lower urine output and higher serum
creatinine concentrations during the first three days after delivery
[116]. Similarly, the study by Butler-O'Hara et al. [193] found that
infants whose mothers had received indomethacin for tocolysis
were more likely to have elevated serum creatinine than matched
controls. Van Den Anker et al. [199] documented the negative ef-
fect of prenatal indomethacin administration on the renal function
of preterm infants in the first days of life. In particular, they found
482 Current Drug Metabolism, 2012, Vol. 13, No. 4
that prenatal exposure to this agent resulted in a significant and
transient reduction in glomerular filtration rate (GFR) values at 3
days after birth. On the other hand, Vieux et al. [200] found low
GFR values at 7 days of life in a group of very preterm infants
treated with ibuprofen during the first week of life. To document
postnatal trends and covariates of creatininemia, George et al. [201]
linked maternal characteristics, characteristics at delivery and dur-
ing neonatal stay (postnatal ibuprofen among others) with creatin-
inemia observations in 151 extremely low birth weight (ELBW)
neonates in the first 6 weeks of life. ELBW infants exhibited trends
similar to heavier neonates, but peak creatininemia was higher (val-
ues above the 75th percentile) and the subsequent decrease was
slower (values remained elevated until day 28). With the monovari-
ate analysis, raised creatininemia in ELBW infants was shown to
reflect immaturity (lower gestational age), morbidity (lower Apgar
score, longer postnatal ventilation and oxygen need, higher inci-
dence of retinopathy of prematurity and intraventricular hemor-
rhage) and drug treatments (ibuprofen, postnatal steroids). With
regard to the latter, a negative effect of ibuprofen exposure on peak
creatininemia was reported, with an impact on creatinine clearance
that lasted beyond the days of ibuprofen treatment. Moreover, when
all risk factors were entered in a multiple regression model, ibupro-
fen treatment and immaturity remained the predominant independ-
ent covariates of creatininemia.
The neonatal and neurodevelopmental outcome of fifteen pre-
term infants exposed antenatally to indomethacin was investigated
by comparison with 15 controls not exposed to antenatal indo-
methacin. No neonatal complications attributable to the antenatal
use of indomethacin were reported; in particular, mean creatinine,
BUN, and urine output for the first 3 days of life were similar in the
two groups [182].
No data are available on the nephrotoxic effect of antenatal
ibuprofen in the fetus and newborn. Administration of ibuprofen to
preterm neonates on the first day of life to enhance closure of an
asymptomatic PDA was shown to reduce amikacin and vancomycin
clearance in the first month of postnatal life [202]. Recently, Iaco-
belli et al. [203] have investigated maternal and neonatal factors
affecting postnatal changes in serum creatinine in preterm infants
with gestational age <32 weeks. Lower gestational age (P<0.0001)
and ibuprofen-treated patent ductus arteriosus (P<0.0001) were the
main analyzed factors independently associated with higher serum
creatinine peak during the first week of life. In infants with hemo-
dynamically significant PDA, the authors found that serum creatin-
ine before ibuprofen administration was higher compared to gesta-
tional age matched controls, thus suggesting that a renal impairment
due to PDA and/or associated conditions existed before the initia-
tion of NSAID therapy. On the other hand, it has been shown that
ibuprofen treatment markedly reduces (59.4%) urinary PGE2 and
may alter renal function in preterm infants with PDA [204].
Maternal consumption of nimesulide has been shown to be
responsible for neonatal renal failure [194]. Several case reports
showed acute, reversible and irreversible renal failure in term and
preterm newborns whose mothers had received therapeutic doses of
nimesulide during the last weeks of pregnancy [205,206]. A case of
neonatal renal failure associated with maternal ingestion of nimesu-
lide in the third trimester of pregnancy was reported by Ali et al.
[207]. In particular, this newborn presented with metabolic acidosis
and non-oliguric renal failure on the second day of life, and showed
histopathological evidence of renal tubular dysgenesis.
Maternal administration of niflumic acid, a COX-2 inhibitor,
during the last days of gestation was demonstrated to induce fetal
and neonatal renal failure [208].
Voyer et al. [209] reported the case of a female neonate, born at
37 weeks of gestation, who presented with respiratory distress syn-
drome, right pneumothorax and anuria. Family history was unre-
markable, except that her mother had received piroxicam at about
Antonucci et al.
26 weeks of gestation; moreover, a sonogram at 28 weeks of gesta-
tion had shown oligohydramnios. Peritoneal dialysis was started on
the 14th day of life because of renal insufficiency, but the neonate
died on the 33rd day. Renal histopathology showed crowded
glomeruli and only few differentiated proximal convoluted tubules
in the inner cortex, abnormally differentiated microcystic tubules
and microcystic glomeruli in the outer cortex. Electron microscopy
revealed the presence of brush border remnants and other proximal
tubular characteristics.
Acute kidney failure was observed at birth in a premature neo-
nate and in twin infants prenatally exposed to ketoprofen during the
last days of pregnancy [210,211].
Coadministration of drugs, such as aminoglycosides and
NSAIDs, can worsen the outcome of nephrotoxicity. The risk of
drug interactions between aminoglycosides and NSAIDs appears to
be greater in young children than in neonates and infants [212,213].
In addition to functional adverse effects, the intrauterine expo-
sure to NSAIDs may affect renal structure itself and produce renal
congenital abnormalities, including cystic dysplasia, tubular dys-
genesis, ischemic damage and a reduced number of nephrons
[188,190].
Balasubramaniam [214] reported the case of a male neonate
who presented with oliguria and renal failure from birth, but with-
out any respiratory distress. Family history revealed that his mother
had received nimesulide from week 30 of pregnancy, for 8 weeks.
Peritoneal dialysis was started on the fourth day of life. Although
there was an increase in urine output over the next few days, renal
failure persisted. Needle biopsy of the kidneys, which was done on
the eighth day, showed partial abnormal tubular differentiation with
subacute tubulointerstitial nephritis.
An unusual case of neonatal anuria owing to renal tubular dys-
genesis with atypical histology was reported after in utero exposure
to naproxen sodium [215].
The measurement of urinary biomarkers in preterm and term
infants might constitute a novel approach for the prevention and
early detection of NSAID-induced nephrotoxicity [9,216,217].
7. EFFECTS ON THE LUNG
Postnatal indomethacin administration was shown to alter lung
structure in rats: in particular, diminished alveolar air, increased
alveolar duct air, increased mean linear intercept (gas-exchanging
wall distance), diminished gas-exchanging surface area and surface-
to-volume ratio, increased septal wall thickness, diminished number
of alveolar crests, and an increased number of lamellar bodies in
alveolar type II cells were found [218]. A recent study has docu-
mented that the use of prophylactic indomethacin in newborns with
a birthweight lower than 1250 grams increases the risk of develop-
ing bronchopulmonary dysplasia (BPD) [219]. Conflicting opinions
are reported on the association between the antenatal indomethacin
administration and the risk of bronchopulmonary dysplasia devel-
opment [116,220].
8. EFFECTS ON THE SKELETON
It has been reported that NSAIDs suppress bone repair and
remodeling, but only mildly inhibit bone mineralization at the ear-
lier stage of the repair process. In 1999, Ho et al. [221] conducted a
study on fetal calvaria to investigate whether NSAIDs affected the
proliferation and/or differentiation of osteoblasts and whether these
effects were prostaglandin-mediated. The results of this study sug-
gested that the inhibitory effect of ketorolac on osteoblastic prolif-
eration contributed to its suppressive effects on bone repair and
remodeling in vivo, and that the effects of ketorolac and indometha-
cin on cell proliferation and differentiation could not be mediated
by the inhibition of the synthesis of PGE1 or PGE2. Furthermore,
PGEs and NSAIDs seemed to be involved in matrix maturation and
Impact of Prenatal NSAIDs on the Offspring
biologic bone mineralization in the earlier stage of osteoblast dif-
ferentiation.
More recently, Chang et al. [222] have investigated the influ-
ences of NSAIDs on cell cycle kinetics, cytotoxicity, and cell death
pattern in osteoblast cultures from rat fetal calvaria. They docu-
mented that NSAIDs arrested cell cycle at the G(0)/G(1) phase and
induced cytotoxicity and cell death of osteoblasts, contributing in
this manner to the suppressive effect on bone formation. Among
studied NSAIDs, piroxicam showed the least effect in producing
osteoblastic dysfunction. Moreover, the cytotoxic and apoptotic
effects of NSAIDs on osteoblasts did not seem to be prostaglandin-
related.
In another study conducted on fetal rats, the effects of non-
selective NSAIDs (indomethacin, ketorolac, diclofenac and piroxi-
cam) and COX-2 selective inhibitors (celecoxib and DFU, an ana-
log of rofecoxib) on cell proliferation and death were investigated
in cultured epiphyseal-articular chondrocytes. Therapeutic concen-
trations of non-selective NSAIDs were found to cause proliferation
suppression and cell death of chondrocytes by PG-independent
mechanisms. As suggested by the authors, these adverse effects
may be one of the reasons that could explain the delay in the en-
dochondral bone formation observed in previous studies. On the
other hand, COX-2 selective inhibitors exhibited less adverse ef-
fects on chondrocytic proliferation and death [223].
In 2008, Burdan et al. [224] showed a decrease of vertebra
mineralization in fetuses of rats prenatally exposed to COX inhibi-
tors. Unlike DFU, which is a selective COX-2 inhibitor, the exam-
ined nonselective COX inhibitors were shown to decrease fetal
bone mineralization when administered in high maternal toxic
doses. A decrease in fetal length has been the only sign of toxicity
found after exposure to DFU [225]. Other authors [226] reported an
inhibitory effect of parecoxib, a COX-2 selective inhibitor, on the
mineralization of fracture callus after a tibial fracture in rats, with
this effect persisting for a longer period compared to indomethacin.
Recently, maternal toxicity has been found to be an important
factor affecting prenatal skeletal development during in utero expo-
sure to NSAIDs [225].
Finally, dose-related skeletal anomalies, including fused rib,
incomplete ossification of the cervical arch, absent/hemicentric
body of thoracic or lumbar vertebra, deformation of lumbar arch,
and absent sacral arch, have been described in rats prenatally ex-
posed to acetylsalicylic acid [227].
9. EFFECTS ON THE GASTROINTESTINAL TRACT
9.1. Spontaneous Intestinal Perforation (SIP)
Spontaneous intestinal perforation (SIP) commonly occurs in
extremely low-birth-weight (ELBW) infants. Early postnatal indo-
methacin exposure was identified as one of the risk factors for SIP
[228-230]. This drug seems to play a causative role in the etiology
of SIP through its effects on ileal trophism and motility [229], by
decreasing mesenteric blood flow, blocking autoregulation of ter-
minal ileum oxygen consumption and altering defense mechanisms
in the neonatal gastrointestinal tract [231-234].
Watterberg et al. [235] conducted a multicentric trial to evalu-
ate the effect of postnatal low-dose hydrocortisone therapy to pre-
vent BPD in extremely premature infants, assuming that the in-
creased inflammation observed in infants developing BPD may
partly reflect inadequate adrenal function. Hydrocortisone-treated
infants who received indomethacin were found to be more likely to
experience apparently spontaneous gastrointestinal perforation
compared with placebo-treated infants who received indomethacin,
suggesting an interactive effect. The incidence of perforation in
hydrocortisone-treated infants who did not receive indomethacin
was similar to that of the placebo group. On the other hand, this
study did not reveal any relationship between prenatal indometha-
cin exposure and perforation.
Current Drug Metabolism, 2012, Vol. 13, No. 4 483
In 1988, Vanhaesebrouck et al. [236] reported three preterm
infants antenatally exposed to indomethacin who developed a char-
acteristic syndrome consisting of renal failure and ileal perforation
in the first postnatal days. A recent analysis suggests that antenatal
indomethacin may be a risk factor for SIP, particularly when given
close to birth [229]. In addition, antenatal indomethacin has been
found to be more likely associated with spontaneous intestinal per-
foration rather than NEC [237]. In contrast, a prospective preva-
lence study by Sharma et al. [238] has revealed that VLBW infants
prenatally exposed to indomethacin do not show an increased rate
of neonatal gut injury.
9.2. Necrotizing Enterocolitis (NEC)
Necrotizing enterocolitis (NEC) is an acquired gastrointestinal
disease associated with significant morbidity and mortality in pre-
maturely born neonates [239]. There are conflicting opinions con-
cerning the role of antenatal NSAIDs in the pathogenesis of NEC.
Many studies have reported that antenatal indomethacin expo-
sure is not associated with a significant increase in the incidence of
necrotizing enterocolitis [32,113-115]. Other studies have shown
that antenatal indomethacin may be associated with an increased
risk of necrotizing enterocolitis in premature infants [59,116].
Major et al. [57] documented that the incidence of NEC in
newborns delivered within 24 hours of maternal indomethacin ther-
apy for tocolysis was 20% compared with 9% in the non-exposed
group (p = 0.005). In the same study, the incidence of NEC in neo-
nates with more than 48 hours of antenatal indomethacin exposure
was 26.4% compared with 4.1% in those with less than 48 hours of
indomethacin exposure. The authors concluded that antenatal in-
domethacin exposure occurring within < or = 24 hours of delivery
and of at least 48 hours' duration was associated with a significant
increase in the incidence of necrotizing enterocolitis in low birth
weight neonates.
10. EFFECTS ON LYMPH NODES
A dose-dependent retardation in the formation of main struc-
tures of the mesenteric lymph nodes was documented in rats ante-
natally treated with indometacin [240,241]. In particular, a retarda-
tion in the development of capsule, sinuses and reticular fibers of
the node was observed, as well as a decrease in lympho- and plas-
mocytopoiesis [241].
CONCLUSIONS
Non-steroidal anti-inflammatory drugs are among the common-
est drugs prescribed to pregnant women. In general, fever, pain and
inflammation are frequent indications for NSAID treatment during
pregnancy. In addition, these agents are used in pregnant women
not only to treat inflammatory bowel diseases and chronic rheu-
matic diseases, but also in the management of obstetrical complica-
tions such as preterm labor and polyhydramnios. The real consump-
tion of NSAIDs during pregnancy remains unknown, considering
that self- medication is possible as some of these drugs are available
over the counter.
Several studies have provided evidence that NSAIDs can cross
the human placenta, and so reach the fetal circulation. Accordingly,
a spectrum of adverse effects may occur in the offspring of women
treated with NSAIDs during pregnancy (Table 1). These effects are
dependent on the type of agent, the dose and duration of therapy,
the period of gestation, and the time elapsed between maternal
NSAID administration and delivery. The main pharmacological
action of these drugs on the fetus seems to be mediated by the inhi-
bition of prostaglandin synthesis.
The period of gestation in which NSAIDs are given is a major
factor in influencing embryo-fetal effects. For example, miscarriage
and congenital anomalies (particularly cleft palate, congenital heart
defects and abdominal wall defects) have been described after
484 Current Drug Metabolism, 2012, Vol. 13, No. 4 Antonucci et al.

Table 1. Adverse Effects of Antenatal NSAIDs on the Embryo, Fetus and Neonate (Human Studies)

Organ Adverse Effect Type of NSAID References

Heart Cardiac defects (VSD) naproxen; NSAIDs Ericson 2001; Ofori 2006

Prenatal closure of the ductus

diclofenac; nimesulide Rein 1999; Auer 2004; Paladini 2005
arteriosus

Blood vessels PDA indomethacin Norton 1993; Hammerman 1998

NSAIDs; aspirin; naproxen sodium;

PPHN Van Marter 1996; Talati 2000; Tarcan 2004; Siu 2004
indomethacin; diclofenac

PVL/cPVL indomethacin Baerts 1990; Murata 2005; Amin 2007

Brain
PVH/IVH aspirin; indomethacin Rumack 1981; Norton 1993; Ojala 2000; Doyle 2005

ketoprofen; indomethacin; niflumic Gouyon 1991; Jacqz-Aigrain 1993; Alessandri 1994; Van
Acute renal failure acid; ibuprofen; nimesulide; di- der Heijden 1994; Van der Heijden 1995; Balasubramaniam
Kidney clofenac 2000; Fieni 2004; Benini 2004; Ali 2006

piroxicam; indomethacin; nimesu- Voyer 1994; Van der Heijden 1994; Balasubramaniam 2000;
Renal congenital abnormalities
lide; naproxen sodium Robin 2000; Koklu 2006; Ali 2006

Lung BPD indomethacin Eronen 1994

Skeleton skeletal deformity aspirin Chakravarty 1993

Gastrointestinal SIP indomethacin Gordon 2008

tract NEC indomethacin Norton 1993; Major 1994; Ojala 2000; Amin 2007

Drongowski 1991; Werler 1992; Torfs 1996; Martínez-Frías

Abdominal wall Celosomy aspirin, ibuprofen
1997; Werler 2002

Eye Cyclopia aspirin Agapitos 1986

Mouth Cleft lip and/or cleft palate naproxen; NSAIDs Ericson 2001

Miscarriage NSAIDs; aspirin Nielsen 2001; Li 2003

piroxicam; niflumic acid; indo-

Voyer 1994; Alessandri 1994; Van der Heijden 1995; Benini
Oligohydramnios methacin; ibuprofen; diclofenac;
Others 2004; Fieni 2004; Balasubramaniam 2000
nimesulide; ketoprofen

Neonatal bleeding aspirin Stuart 1982

Congenital malformations NSAIDs Ofori 2006

Abbreviations
VSD, ventricular septal defect. PDA, patent ductus arteriosus. PPHN, persistent pulmonary hypertension of the newborn. PVL, periventricular leukomalacia. PVH/IVH, periven-
tricular/intraventricular hemorrhage. BPD, bronchopulmonary dysplasia. SIP, spontaneous intestinal perforation. NEC, necrotizing enterocolitis.

treatment with NSAIDs during early gestation, even though the risk
of these adverse pregnancy outcomes appears to be small; on the
other hand, renal and vascular effects (prenatal closure of the ductus
arteriosus and PPHN) have been observed in fetuses of mothers
treated with NSAIDs during the third trimester of gestation. It is
noteworthy that women attempting to conceive should not use any
prostaglandin synthesis inhibitors, because of animal data that indi-
cate that these agents block blastocyst implantation [64].
Embryo-fetal toxicity associated with antenatal NSAIDs may
affect several organ systems including the brain, cardiovascular
system, lung, skeleton and gastrointestinal tract. However, renal
involvement in the fetus and newborn is of particular concern: in
addition to functional adverse effects (neonatal renal failure), the
intrauterine exposure to NSAIDs may affect renal structure itself
and cause congenital abnormalities of the kidney. The nephrotoxic
effects of NSAIDs are related to the block of prostaglandin synthe-
sis through the inhibition of cyclooxygenase-2.
Currently, there are limited data on the use of COX-2 selective
inhibitors during pregnancy and thus these agents should be
avoided in pregnant women.
A considerable amount of caution should be used in interpreting
the results of the studies included in this review. In fact, many of
them have been performed in animal models, while no conclusive
evidence exists regarding the effects of antenatal NSAIDs on the
human fetus. Furthermore, the retrospective design of some studies
may limit the reliability of their results. Finally, prematurity and
low birth weight may be confounding factors in some of the studies
examined in this review.
In conclusion, further human studies are required to clarify the
toxic effects of antenatal NSAIDs (nonselective COX inhibitors)
and COXIBs (selective COX-2 inhibitors) on the embryo, fetus and
newborn.
Impact of Prenatal NSAIDs on the Offspring
Physicians should be aware of the possible embryo-fetal toxic-
ity when prescribing non-steroidal anti-inflammatory drugs to preg-
nant women. The judicious use of these medications is particularly
important in pregnant women at risk of preterm delivery since
NSAID-induced adverse effects on the fetus and newborn might
occur concurrently with the complications of prematurity. In addi-
tion, a correct and complete information to women who are preg-
nant, or are planning a pregnancy, is required with regard to em-
bryo-fetal and neonatal risks associated with consumption of ante-
natal NSAIDs, considering that some of these drugs are available
over the counter and thus can be easily purchased without medical
prescription.
CONFLICT OF INTEREST
The authors have nothing to disclose related to this article.
ACKNOWLEDGEMENT
Declared none.
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