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    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 ▀-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 weeksť 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

    REFERENCES

    1.    Hertz-Picciotto I. Epidemiologic Reviews 1990 ; 12 : 108-148

    2.    Roubenoff R et al. Sem Arth Rheum 1988 ; 18(2) : 88-110

    3.    Slone D et al. Collaborative Perinatal Project Lancet 1976 June
          26 : 1373-1375

    4.    Saxen I. Int J Epidemiol 1975 ; 4 : 37

    5.    Imperiale TF and Petrulis AS. JAMA 1991 ; 266(2) : 261-65

    6.    Sibai BM et al. N Engl J Med 1993 ; 329 : 1213-8

    7.    CLASP Collaborative Group Lancet 1994 ; 343 : 619-299

    8.    Uzan S et al. Lancet 1991 ; 337 : 1427-31

    9.    Parrazzini F et al. Lancet 1993 ; 341 : 396-400

    10.   Van den Veyver et al. Obstet Gynecol 1993 ; 82 : 500-3

    11.   Manchester D. Am J Obstet Gynecol 1976 ; 126 : 467-9

    12.   Lewis RB & Schulman JD. Lancet 1973 ; 2 : 1159 

    13.   Garretson LK et al. Clin Pharmacol Ther 1974 ; 17 : 98

    14.   Lynd PA et al. Clin paediatr 1976 ; 15 : 912

    15.   Bove KE et al. Arch Pathol Lab Med 1979 ; 103 : 187

    16.   Rejent TA, Baik S. J Forens Sci 1985 ; 30 : 942

    17.   Agapitos M et al. Pediatr Pathol 1986 ; 6 : 309

    18.   Norton ME et al. N Engl J Med 1993 ; 329 : 1602-7

    19.   Keirse MJNC. Indomethacin tocolysis in pre-term labour.

    20.   In : Pregnancy & childbirth module (Eds. Enkin MW, Keirse MJNC,

    21.   Renfrew MJ, Neilson JP), "Cochrane database of systematic
          reviews" :  Review No. 04383, 14 August 1992. Published through
          "Cochrane updates on disk", Oxford : Update Software, 1994, Disk
          Issue 1

    22.   Van den Veyvver I et al. Obstet Gynecol 1993 ; 82 : 500-3

    23.   Moise JK. Am J Obstet Gynecol. 1993 ; 168 : 1350-3

    24.   Goldenberg RL et al. Am J Obstet Gynecol 1989 ; 160 1196-7

    25.   Uslu et al. International Journal of Clinical Pharmacology,
          Therapy and Toxicology        1992 ; 30(7) : 230-232

    26.   Kirshon B et al. American Journal of Perinatology 1991 ; 8(2) :
          86-88

    27.   Folb PI and Dukes MNG (Eds). Drug Safety in Pregnancy. Elsevier :
          Oxford, 1990 : 115-129

    28.   Ostensen M. Clin Pharmacokin 1994 ; 27(6) : 486-503

    29.   Shepard TH (Ed.) Catalog of teratogenic agents. Johns Hopkins.
          1989 : 342

    30.   Adams SF, Bough RG, Cliffe EE, Lessel B, & Mills RSN. Absorption
          distribution and toxicity of ibuprofen. Toxicol Appll Pharmacol
          1969 ; 15:310-330

    31.   Randall J, Becker HC & Anton RF. Effect of ibuprofen on alcohol
          induced teratogenesis in mice. Alcoholism : Clin Ex Res 1991 ;
          15:673-77

    32.   Kazuo Momma K and Harumitsu Takeuchi . Voltaren 1983 ; 26(4) :
          631-643

    33.   Barry WS, Meinzinger MM, & Howse CR. Ibuprofen overdose and
          exposure in utero: Results from a postmarketing voluntary
          reporting system. Ibuprofen symposium. Am J Med July 13, 1984 :
          35-39

    34.   Schardein JL. Chemically Induced birth defects. New York : Marcel
          Dekker, 1985 : 113

    35.   Hallesley EW, Shot LD, & Hill R. Comparative toxicology of
          naproxen.

    36.   Scand J Rheumatol. Suppl 2. 1973 : 20-28

    37.   Montenegro MA & Palomino H. Induction of cleft palate in mice by
          inhibitors of prostaglandin synthesis. J Cranial Fac Genet Dev
          Biol. 1990 ; 10 :83-94

    38.   Wilkinson AR et al. Arch Dis Child 1979 ; 54 : 942-945

    39.   Gilstrap LC & Little BB. (Eds). Drugs and pregnancy. Elsevier.
          1992 : 353

    40.   Reprorisk (R) System : Mefenamic acid (TERIS (R) Document) in
          Dabney BJ (Ed.) : TERIS (R) System. Micromedex, Inc., Denver,
          Colorado (Edition expires 31.5.96)

    41.   Reprorisk (R) System : Mefenamic acid (REPROTEXT (R) Document) in
          Dabney BJ (Ed.) : REPROTEXT (R) System. Micromedex, Inc., Denver,
          Colorado (Edition expires 31.5.96)