Summary for UKPID
Aspirin and non-steroidal
Anti-inflammatory agents - PREGNANCY
Phil Young, BSc (Hons) Msc MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
ASPIRIN
SUMMARY
* Prospective studies of aspirin use during pregnancy have involved
low doses (40-150 mg/day) rather than analgesic doses.
* Large retrospective studies of aspirin use in women during
pregnancy have failed to demonstrate a teratogenic effect.
* Aspirin should be avoided during the third trimester due to
possible bleeding complications and premature closure of the
ductus arteriosus, which may lead to pulmonary vasculature
abnormalities and pulmonary hypertension in the newborn.1
* In pregnancies at risk for the development of pregnancy-induced
hypertension and pre-eclampsia, and in fetuses with intra-uterine
growth retardation, low-dose aspirin (40-150 mg/day) may be
beneficial.
* Use of low dose aspirin may reduce pre-eclampsia by approximately
25%, but study findings have been inconsistent
ANIMAL STUDIES
Doses of aspirin commonly used in animal studies were in the range of
250-1000 mg/kg maternal weight. At such doses a high rate of
resorption and stillbirths was found in all species tested (rat,
mouse, rabbit, dog and sheep). Foetal malformations were common in the
surviving fetuses with 25 to 80% affected. The types of malformations
varied by species, but included cleft lip and palate, gastroschisis,
hydrocephalus, and skeletal abnormalities.2
Studies involving lower doses of aspirin, given a few days before
delivery, have shown permanent premature closure of the fetal ductus
arteriosus.2
HUMAN STUDIES
TERATOGENICITY
The Collaborative Perinatal Project recorded 9736 women with
intermediate exposure to aspirin (doses unavailable) and 5128 women
heavily exposed to aspirin during the first 17 weeks of pregnancy.
Heavy exposure was defined as aspirin taken on at least 8 days in one
of the first 4 lunar months of pregnancy. There was no increase in the
rate of malformations in either group.3
In a review of more than 16000 live births, pooled from multiple
studies, it was concluded that low doses of aspirin are not
teratogenic. Aspirin ingestion within several days of delivery may
cause premature closure of the ductus arteriosus and/or a tendency to
bleed.2
Saxen noted an association between aspirin ingestion in the first
trimester and cleft palate/lip in a retrospective, controlled study
involving 599 children.4 The incidence of combined cleft lip and
palate was 19.8%, nearly 4 times the rate in the control group.
However, the significance of these findings is unclear as
retrospective reporting is more likely to show a tendency towards
malformations even when compared to a control group.
PREGNANCY-INDUCED HYPERTENSION (PIH)
Imperiale and Petrulis 5 performed a meta-analysis of six published,
controlled, trials (one nonrandomised, two non-placebo, three
double-blind) of aspirin in PIH. They evaluated the degree of
reduction in the incidence of PIH, the reduction in severe low birth
weight infants, and adverse effects of low doses of aspirin during
pregnancy. Of 394 women studied the relative risk of pregnancy-induced
hypertension in women who took aspirin was found to be 0.35 (95% CI;
0.22-0.55). Aspirin reduced the risk of severe low birth weight among
newborns by 44% (RR 0.56 ; CI 0.36-0.88), and reduced the risk of
caesarean section by 66% (RR 0.34 ; CI 0.25-0.48) overall, although
the specific indications for caesarean section were generally not
described. There was no effect on fetal and neonatal mortality and no
maternal or neonatal adverse were associated with aspirin use.
PRE-ECLAMPSIA
In a randomised, double-blind, placebo-controlled trial, Sibai et al6
studied the effects of a daily aspirin dose of 60 mg on the incidence
of pre-eclampsia in 3135 normotensive nulliparous women. Aspirin was
started at 13 to 26 weeks gestation for the remainder of pregnancy.
There was no significant difference in birth weight or the incidence
of fetal growth retardation, post-partum haemorrhage, or neonatal
bleeding problems between groups in the 2985 women followed up. The
incidence of pre-eclampsia was reduced in the treatment group (4.6% vs
6.3%), while abruptio placentae (premature separation of placenta from
uterus) was increased by aspirin (11/1,570 Vs 2/1,565 ; p=0.01).
A multicentre study (CLASP 7) looked at aspirin administration for
the prophylaxis of pre-eclampsia, prophylaxis and treatment of
intrauterine growth retardation (IUGR), and treatment of pre-eclampsia
in 9364 women. Women between 12 and 32 weeks gestation were randomly
assigned 60 mg aspirin daily or placebo. Aspirin was associated with a
12% reduction in the incidence of proteinuric pre-eclampsia, which was
not significant. There were no significant differences in the
incidence of IUGR (1.4% with aspirin Vs 1.7% with placebo) or
stillbirth and neonatal death (2.7% Vs 2.8%), but the likelihood of
preterm delivery was significantly reduced (19.7% Vs 22.2%, p=0.003).
Aspirin was not associated with a significant increase in placental
haemorrhage or in bleeding during preparation for epidural anaesthesia
(0.4% Vs 0.6%), but there was a slight increase in the use of blood
transfusion after delivery 4.0% Vs 3.2%). Low-dose aspirin was
generally safe for the fetus and newborn infant, with no evidence of
an increase in bleeding.
INTRAUTERINE GROWTH RETARDATION
The efficacy of low-dose aspirin in preventing fetal growth
retardation was studied by Uzan et al in a multicentre study.8 Women
with a history of fetal growth retardation and/or fetal death or
abruptio placentae in at least one previous pregnancy were randomly
allocated to receive placebo, aspirin 150 mg/day, or aspirin 150
mg/day plus dipyridamole 225 mg/day, for the remainder of pregnancy.
In the first phase of the trial all actively treated patients (n=156)
were compared with the placebo group (n=73). Mean birthweight was
significantly higher in the treated group. The frequency of fetal
growth retardation doubled in the placebo group and the frequencies of
stillbirth and abruptio placentae were also higher. There was no
excess of maternal or neonatal side-effects in the aspirin-treated
group.
The Italian Study of Aspirin in Pregnancy 9 assessed the efficacy of
low-dose aspirin in women judged to be at moderate risk of IUGR and
PIH. Women were randomly assigned treatment with 50 mg aspirin (n=583)
or no treatment (n=523) until delivery. There were no differences
between the two groups in the numbers of spontaneous or therapeutic
abortions, stillbirths, perinatal mortality, mean birthweight,
proportion of infants with birthweights below the 10th centile, or
births before 37 weeks' gestation. The frequency of PIH with or
without proteinuria was unchanged.
DUCTUS ARTERIOSUS PATENCY
The fetal circulation is dependent on a patent ductus arteriosus,
allowing blood to bypass the lungs. Prostaglandins (PGE2 and
prostacyclin) are the most important mediators of vasodilation of the
ductus arteriosus during fetal life. Maternal ingestion of drugs which
inhibit the formation of prostaglandins (e.g. aspirin and
non-steroidal antiinflammatory agents) during the third trimester of
pregnancy has been associated with intrauterine closure of the fetal
ductus arteriosus,10 leading to fetal and neonatal pulmonary
hypertension and the syndrome of persistent fetal circulation.11
There have been no reports of premature closure of the ductus
arteriosus with the maternal use of aspirin.
Prostaglandins are required for maintaining renal artery patency.
Inhibition of prostaglandins in pregnant women may lead to reduced
fetal renal blood flow and resultant fall in urine output.
Oligohydramnios (a reduction in amniotic fluid) may theoretically
result with subsequent fetal malformations as protection from uterine
wall pressures is reduced. There have, however, been no reports of
oligohydramnios with maternal use of aspirin.
ASPIRIN OVERDOSE IN PREGNANCY
High doses of aspirin are known to be teratogenic in rats, causing
facial clefts and cranial and neural tube defects. Several large
studies have not found an increased incidence of congenital
abnormalities in humans associated with high dose aspirin. However,
few data are available on the likely fetotoxicity of aspirin overdose.
Lewis and Schulman 12 reviewed case reports of 103 women who took
more than 3g of aspirin per day for rheumatoid arthritis during at
least the last 6 months of pregnancy. No fetal or neonatal effects
were reported, but there was evidence of prolonged spontaneous labour,
increased frequency of premature labour and longer gestations. There
have also been numerous single case reports of exposure to high doses
of aspirin in pregnancy (See Table 1).
The treatment of pregnant women following overdose with aspirin should
not differ from that in non-pregnant women. Overdose during the third
trimester may lead to premature closure of the ductus arteriosus.
Aspirin may cause a reduction in fetal renal output leading to
oligohydramnios and possible malformation. The incidence and duration
of bleeding both in the fetus and mother during delivery may be
increased by aspirin ingestion close to term.
The National Teratology Information Service has follow-up data on 76
cases of aspirin poisoning during pregnancy. There were 56 normal
babies, 1 maternal and fetal death, 2 spontaneous abortions, and 15
elective terminations of pregnancy, and 2 abnormalities (one with
pyloric stenosis at 8 weeks, and one with a clicking right hip). These
data do not suggest that aspirin overdose has major adverse fatal
consequences.
Despite the small number of case reports of aspirin overdose in
pregnancy, it is likely that there have been many more which remain
unreported.
NON-STEROIDAL ANTI-INFLAMMATORY AGENTS (NSAID)
SUMMARY
* There is no evidence that NSAIDs are teratogenic when used in
normal doses. The use of NSAIDs during pregnancy is not, however,
without potential problems.
* The use of NSAIDs, even for short periods, after the 32nd week of
pregnancy should be avoided due to a high incidence of premature
closure of the ductus arteriosus.
* The use of NSAIDs particularly during the third trimester of
pregnancy may cause a reduction in fetal urine output and
consequent oligohydramnios resulting in fetal malformations.
TABLE 1 : OUTCOMES OF SINGLE CASE REPORTS OF HIGH DOSE ASPIRIN INGESTION IN PREGNANCY
Reference Number Dose Duration Foetal/neonatal Maternal
of cases effects complications
13 1 6.5g/day Whole of None reported Bleeding prior to labour,
pregnancy Abruptio placentae
14 1 Unknown 1 month Poor feeding, None reported
prior to irritability,
delivery hypertonia,
agitation, blood
gases normal, no
hyperpnoea
15 1 19g Single Diffuse metanephric None reported
overdose at adenoma
8 weeks
16 1 30g Single Foetal death at Spontaneous delivery
overdose at 18-20 hours Level 568 mg/L
32-34 weeks after admission on admission, time of
ingestion not known
17 1 4g/day First 3 months Stillborn. Polyhydramnios
of pregnancy Microcephaly with in late pregnancy
cyclopia
* NSAIDs may increase the incidence and duration of bleeding both
in the fetus and mother during delivery. Inhibitors of
prostaglandin production decrease natural prostaglandin induced
uterine contractions and may, therefore, prolong pregnancy and
labour.
* If a NSAID is required during pregnancy ibuprofen is the agent of
choice. NSAIDs should be avoided in the last trimester of
pregnancy.
INDOMETHACIN
SUMMARY
* There is no evidence that indomethacin is teratogenic in human
pregnancy.
* The use of indomethacin during the third trimester has been
associated with the potentially serious complications of
oligohydramnios and premature closure of the ductus arteriosus.
* The use of indomethacin in the last trimester of pregnancy should
be avoided.
ANIMAL STUDIES
Indomethacin transfer across the placenta has been demonstrated. In
doses of 4 to 15 mg/kg it increases in utero fetal mortality and
central nervous system cell necrosis. Premature closure of the ductus
arteriosus seems to occur even at low doses (2.5 mg/kg, equivalent to
175 mg for a 70 kg human) in both rats and rabbits.2 Indomethacin
(given towards the end of gestation) has been shown to prolong
gestation without causing fetal toxicity. An abnormal effect on
fertility has been demonstrated in deermice living in field conditions;
a progressive decrease in litter size and frequency was noted when
indomethacin was added to their diet. Similar effects were shown for
rats and rabbits at doses of 1 to 4 mg/kg.
HUMAN STUDIES
PRE-TERM LABOUR
Norton et al reviewed 57 infants delivered at or before 30 weeks
gestation whose mothers had been treated at various stages of
pregnancy with indomethacin for preterm labour and matched them with
57 infants not exposed to indomethacin. There were no significant
differences between the two groups in birth weight and Apgar scores.
More indomethacin exposed infants had a patent ductus arteriosus (62%
Vs 44%, p=0.05), intracranial haemorrhage (28% Vs 9%, p=0.02), and
necrotizing enterocolitis (29% Vs 8%, p=0.005).18 Further trials show
indomethacin to be more effective than placebo in delaying delivery
for 48 hrs, for 7-10 days, and beyond 37 weeks. The incidence of low
birth weight was significantly reduced in the indomethacin treated
group, but there was no difference in the incidence of fetal death,
neonatal death, and respiratory distress syndrome.19
CONSTRICTION OF DUCTUS ARTERIOSUS
A study of 25 pregnancies showed that the constrictive effect of
maternal indomethacin ingestion on the fetal ductus arteriosus begins
as early as 27 weeks gestation.20
Moise 21 retrospectively reviewed patients presenting with premature
labour (n=35) or hydramnios (n=9) treated with indomethacin (25 mg six
hourly). Almost 50% of fetuses showed impairment of ductal flow at 32
weeks gestation.
RENAL VASOCONSTRICTION AND OLIGOHYDRAMNIOS
Goldenberg 22 described a 28 year old woman with a previous history of
two neonatal deaths following spontaneous premature labour. She was
admitted at 20 weeks gestation with contractions and received
indomethacin 200 mg daily initially and 100 mg daily once contractions
were controlled over a period of 12 weeks. Indomethacin administration
was associated with oligohydramnios which did not carry adverse fetal
effects.
Uslu et al 23 reviewed 28 patients with suspected premature labour
(26 to 34 weeks gestation) treated with indomethacin 75 mg four times
a day for 2 days. Oligohydramnios developed in 25 of the women. No
premature ductus arteriosus closure, pulmonary hypertension, bleeding
disorders or renal failure was reported.
Kirshon et al 24 looked at amniotic fluid levels in 6 pregnancies
prior to and during indomethacin therapy (25 mg six hourly) for
preterm labour. Fetal urine output fell and oligohydramnios developed
within 15 to 28 days of commencing indomethacin therapy. The
indomethacin dose was reduced in one mother due to premature ductus
arteriosus closure.
A single case report suggested a link between perinatal death in a
female infant born with Potter's facies and anuria after prolonged
intrauterine exposure to indomethacin.25 The infants mother had
received ß-adrenergic agonists and indomethacin in order to stop
preterm uterine contractions. There was severe oligohydramnios in late
pregnancy and slowing of the fetal heart rate; death was due to
uraemia and respiratory failure.
There has been one case report of possible indomethacin induced
phocomelia and agenesis of the penis.25
OVERDOSE
No specific details on indomethacin overdose in pregnancy could be
found. The National Teratology Information Service has no follow-up
data available.
DICLOFENAC
SUMMARY
* There is little information on the use of diclofenac in human
pregnancy, however, anecdotally it is widely used without
apparent harmful effects in early pregnancy.
* In common with other NSAIDs, diclofenac has the potential to
cause premature closure of the ductus arteriosus and
oligohydramnios, so its use in the third trimester of pregnancy
should be avoided.
ANIMAL STUDIES
In studies of pregnant rats, antenatal exposure to diclofenac has been
shown to cause constriction of the fetal ductus arteriosus in a dose-
dependent fashion.25
HUMAN STUDIES
There are few published reports on the use of diclofenac in human
pregnancy and no controlled trials. One study looked at 9 patients
with premature labour treated with diclofenac 75 to 150 mg/day for 3
to 45 days (gestation range between 28 and 35 weeks at exposure). No
adverse fetal effects attributable to drug treatment were observed.26
OVERDOSE
No specific details on diclofenac overdose in pregnancy could be
found. The National Teratology Information Service has follow-up data
on 3 cases. There were 2 normal babies and one elective termination.
IBUPROFEN
SUMMARY
* There is little information on the use of ibuprofen in human
pregnancy.
* In common with other NSAIDs, ibuprofen has the potential to cause
premature closure of the ductus arteriosus and oligohydramnios,
so its use in the third trimester of pregnancy should be avoided.
ANIMAL STUDIES
No evidence of teratogenicity was found in rats and rabbits treated
throughout pregnancy.27,28,29
HUMAN STUDIES
Reports of ibuprofen in 105 human pregnancies in dosages varying
between 1200 to 2400 mg daily relate to its use as a tocolytic agent.
No congenital malformations have been described, but mild constriction
of the ductus arteriosus was found in 4 of 61 fetuses exposed to
ibuprofen. In two studies ibuprofen caused reduction in fetal urinary
output and oligohydramnios which normalised after withdrawal of the
drug.30 Barry et al31 reported 50 case reports of ibuprofen exposure,
and 43 were prospectively followed up. Outcomes were obtained on 25
cases, of which there were 23 normal infants, 1 spontaneous abortion,
and 1 stillbirth.
OVERDOSE
No specific details on ibuprofen overdose in pregnancy could be found.
NTIS has prospective follow up data on 41 pregnancies in which
overdoses of ibuprofen occurred. Twenty-two took ibuprofen only, and
19 took ibuprofen plus other drugs also. There were 17 overdoses in
the first trimester, 12 in the second trimester and 12 in the third
trimester.
1st trimester exposure: 9 normal infants (1 set of twins),
(n=17) 1 spontaneous abortion and 8 ETOP.
2nd trimester exposure: 10 normal infants, 1 premature baby
(n=12) delivered at 28 weeksœ and 1 ETOP
3rd trimester exposure: 11 normal infants, 1 infant with
(n=12) a soft palate defect
* Overdose of 12 x 200mg tablets at 25 weeks. Spontaneous labour 18
days after the overdose, baby delivered by LSCS. No malformations, but
the baby died at 7 weeks of age.
*Overdose of 16 tablets ibuprofen (strength not known) + 12.5g
paracetamol at 26-28 weeks, therefore palatal defect not causally
related.
NAPROXEN
SUMMARY
* There are no published reports of naproxen induced congenital
abnormalities.
* In common with other NSAIDs, naproxen has the potential to cause
premature closure of the ductus arteriosus and oligohydramnios,
so its use in the third trimester of pregnancy should be avoided.
ANIMAL STUDIES
Naproxen has not been demonstrated to be teratogenic in mouse, rat or
rabbit.32 However, two studies in rats have shown a dose dependant
increase in fetal death,33,34 and one of these also showed an
increased risk of cleft palate.34
HUMAN STUDIES
There are no reports of congenital abnormalities attributable to
naproxen in the literature despite its probable use during pregnancy
in some instances.
Wilkinson et al 35 reported three cases (a twin and a singleton) born
at 30 weeks gestation with very low plasma prostaglandin E levels,
pulmonary hypertension and severe hypoxaemia resulting from closure of
the ductus arteriosus. Abnormalities in blood clotting, renal
function, and bilirubin metabolism were also found, one infant died.
In each case the mother received naproxen in an attempt to delay
parturition.
OVERDOSE
One case of naproxen overdose during pregnancy has been reported.36
Approximately 8 hours after ingestion of 5 grams of naproxen at 35
weeks gestation, non-specific and supportive therapy was given.
Spontaneous labour developed, and a preterm infant was delivered who
developed hyponatraemia and water retention. The infant recovered and
had no other apparent problems.
The National Teratology Information Service has follow-up data on 4
cases. All infants were normal and delivered at full-term.
MEFENAMIC ACID
SUMMARY
* There are no published reports of mefenamic acid induced
congenital abnormalities.
* In common with other NSAIDs, mefenamic acid has the potential to
cause premature closure of the ductus arteriosus and
oligohydramnios, so its use in the third trimester of pregnancy
should be avoided.
ANIMAL STUDIES
Mefenamic acid has not been demonstrated to be teratogenic in rat, dog
or rabbit.37 However, an increased frequency of cleft palate has been
reported among offspring of mice treated with less than the usual
human dose of mefenamic acid during pregnancy.38
HUMAN STUDIES
There are no reports of congenital abnormalities attributable to
mefenamic acid in the literature despite its probable use during
pregnancy in some instances.
The National Teratology Information Service has follow-up data on 16
cases, 11 first trimester, 2 second trimetser, and 3 third trimester
exposures. There were 11 normal babies, 3 ETOP, 1 spontaneous
abortion, and 1 abnormality..
OVERDOSE
No specific details on mefenamic acid overdose in pregnancy could be
found. The National Teratology Information Service has follow-up data
on 15 case reports of mefenamic acid poisoning in pregnancy. There
were 8 normal babies, 5 elective terminations of pregnancy (ETOP), 1
premature infant, and 1 spontaneous abortion.
One elective termination occurred at twenty weeks gestation, following
an overdose of six mefenamic acid 250 mg tablets and ten paracetamol
500 mg tablets at 16 weeks, (scan showed an "abnormal fetus"). Two
ETOP's followed ingestions of 37 and 20-25 mefenamic acid 250 mg
tablets respectively (at 8 weeks and 12 weeks). No data was available
on scans or post mortems, however severe maternal toxicity, including
convulsions, was reported with the ingestion of 20-25 tablets. No
details were given for the other 2 ETOPs. The spontaneous abortion
occurred at approximately 3 months gestation and followed an overdose
of mefenamic acid, paracetamol, and alcohol (doses unknown) at 8
weeks. One infant born prematurely (31 weeks) following an ingestion
of four mefenamic acid 250 mg tablets at 4 weeks, had a soft systolic
murmur and a left side thyroglossal cyst. A causal relationship, in
this case, is unlikely. The normal deliveries followed ingestions of
various quantities from 6 mefenamic acid 250 mg through to 100
mefenamic acid 250 mg.
NON-STEROIDAL ANTI-INFLAMMATORY OVERDOSE IN
PREGNANCY
* The management of a NSAID overdose in a pregnant women should not
differ from that of non-pregnant women.
* There is insufficient data on NSAID overdose in pregnancy to
state the risk to the fetus. However, considering the low risk
from therapeutic exposure during the first and second trimesters,
NSAID overdose is unlikely to greatly increase the risk of fetal
abnormalities, in the absence of severe maternal toxicity.
* Overdose during the third trimester may lead to the development
of oligohydramnios and possible premature ductus arteriosus
closure.
TABLE 2 : EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON THE FOETUS AND NEONATE 26
EFFECTS OF FOETAL NEONATAL COMMENT*
ASPIRIN AND EFFECTS COMPLICATIONS
NSAIDs REPORTED REPORTED
Reduction of Reduction of fetal Impaired renal Renal function
renal function urine output, function normalises after
oligohydramnios & withdrawal of NSAID
resulting
malformations
Constriction of Premature closure Pulmonary Constriction of
ductus arteriosus of the ductus hypertension, the ductus arteriosus
arteriosus, persistent fetal in fetal life is
tricuspid circulation reversible within
regurgitation 24 hours of
cessation of therapy
Inhibition of Bleeding, increased Avoided when
platelet clotting time NSAIDs are stopped
aggregation several weeks before
delivery
* Risk of adverse effects in the neonate are greatest for intrauterine exposure to the
drug within a few hours of delivery and in premature infants
* There is a possibility of prolonged gestation in women exposed to
high doses of NSAIDs during the latter stage of pregnancy, but
this is unlikely from a single overdose.
* Exposure in late pregnancy may increase tendency to haemorrhage.
Author
Phil Young, BSc (Hons) Msc MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph was produced by the staff of the Newcastle Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National Poisons
Information Service.
Last Updated: January 1997
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