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 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)