This study records the use of intravenous prostaglandin Ez in 23 consecutive cases of intra-uterine fetal death in the third trimester of pregnancy. The results presented are related to the causative factors of intra-uterine death and some suggestions are made in regard to the selection of patients and the method of management in these cases.S. Afr. Med. J, 48, 1941 (1974)

Gordon, H

van Iddekinge, B

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21 September 1974 S.-A. MEDIESE TYDSKRIF 1941The Value of Intravenous Prostaglandin E2after Intra-uterine DeathB. VAN IDDEKINGE, H. GORDONSUMMARYThis study records the use of intravenous prostaglandinEz in 23 consecutive cases of intra-uterine fetal death inthe third trimester of pregnancy. The results presentedare related to the causative factors of intra-uterine deathand some suggestions are made in regard to the selectionof patients and the method of management in these cases.S. Air. Med. J., 48, 1941 (1974).The interval between intra-uterine death of the fetus inthe third trimester of pregnancy and its spontaneousexpulsion is variable and unpredictable.There does appear. to be some corre:ation between thecause of fetal death and the onset of spontaneous labour.In cases of abruption of the placenta, the onset of labouris usually rapid. When placental insufficiency or rhesusiso-immunisation is responsible for intra-uterine death ofthe fetus, the delay before the spontaneous onset of labourmay be several weeks or even months, especially if deathoccurs at an early gestational age. Considering the possiblemechanisms related to the onset of labour in these cases,it may be possible to modify the form of management tosuit all groups of patients.The value of prostaglandins in the management ofintra-uterine fetal death has been shown in several studiesusing different routes of administration of the prosta-glandin. Given by intravenous infusion, prostaglandin E,(PGE,) and prostaglandin F,a (PGF,a) have been usedsuccessfully in the termination of pregnancy followingintra-uterine fetal death.'"· Given by extra-amnioticinjection, PGE, and PGEa gave good results w:th minimalcomplications in a recent series of 22 cases.' Karim hasachieved success by using a single dose of intra-amnioticprostaglandin.sAll these authors stress the desirability of deliveringthe fetus soon after the diagnosis of intra-uterine deathis made, provided it can be done safely, with the minimumof surgical interference or side-effects. There are threereasons given by different authors for expediting delivery incases of intra-uterine death. The first reason is the emo-tional and psychological effect on the parent who knowsthe fetus is dead, and the resultant loss of morale andconfidence of the patient and the difficulty in managementfrom the obstetrician's point of Vie"N. Secondly, intra-Institute of Obstetrics and Gynaecology, University of Lon-don and Hammersmith Hospital, LondonB. VAN IDDEKINGE, M.B. B.eH., F.e.O.G. (S.A.), M.R.e.O.G.H. CORDON, F.R.e.S., M.R.e.O.G.Date received: 6 May 1974.uterine infection in the presence of a dead fetus mayoccur, especially if any surgical int.rference is attempted,and this may rapidly proceed to a potentially lethalsituation. Thirdly, there is a risk of blood coagulationdisorders. This danger ;s thought to be greater the longerthe fetus is retained in utero.' O'Driscoll and Lavelle'ohave suggested that this is most likely to develop whenthe fetus is retained for 4 or more weeks after intra-uterinedeath.This study reports the use of intravenous prostaglandinE, in 23 consecutive cases of intra-uterine fetal death inthe third trimester of pregnancy. The results are presentedin terms of causative factors of the intra-uterine death,and some suggestions are made in regard to the selectionof patients and the method of management of these cases.PATIENTS AND METHODSTwenty-three patients, aged from 21 to 39 years (mean28 years), were studied. In all cases intra-uterine deathoccurred between 24 and 40 weeks' gestation (mean 29,8weeks).In 7 cases the cause of death was due to placentalinsufficiency. In 2 of these cases essential hypertensionwas present. In 1 patient seve,e pre-eclamptic toxaemiacomplicated pregnancy at 29 we~ks' gestation; in anotherpatient persistent proteinuria was present. In 3 cases nospecific cause for the placental insufficiency was found,but in 2 cases the fetus showed evidence of chronicmalnutrition at postmortem examination. In 16 cases thecause of death was rhesus iso-immunisation with resultanthydrops foetalis.The time between the occurrence of intra-uterine deathand attempted induction of labour varied from I to19 days (mean 4,6 days).A solution of prostaglandin E, 5 fLgfml in 0,9%saline was administered intravenously, using a paediatricinfusion set, calibrated to deliver 60 drops/m!.Uterine activity was monitored continuously, using anexternal tocograph (Hewlett-Packard). Temperature, bloodpressure and pulse rate were recorded every half hour.The infusion was started using 0,125 ml (0,625 fLg)min,and maintained at this rate for 60 minutes. If satisfactoryuterine contractions were not obtained, the infusion ratewas increased at hourly intervals to 0,5 ml (2,5 fLg)/min,and then to 1 ml (5 fLg)jmin.The infusion was not continued for more than 24 hours.The membranes were not artificially ruptu~ed during theprocedure. Analgesics were prescribed when necessary.After expulsion of the fetus, ergometrine 0,5 mg withoxytocin 5 IU was given by intramuscular injection.1942 S.A. MEDICAL JOURNAL 21 September 1974RESULTSIn the 7 cases where intra-uterine death was due toplacental insufficiency, all the cases were successfullydelivered by intravenous PGE, iufusion at the first attempt(Table I). The average period of gestation at the time ofTABLE I. SEVEN CASES OF INTRA-UTERINE DEATH DUE TOPLACENTAL INSUFFICIENCY (Intravenous PGE2 0,625J.Lg - 5,0 fLgfmin)intra-uterine death was 31,6 weeks. The mean intra-uterine death-induction interval was 6,9 days. The averageduration of infusion was 9,1 hours, and the mean total doseof PGE, required was 0,83 mg.In the 16 cases where intra-uterine death was due torhesus iso-immunisation, 13 cases were successfullydelivered by intravenous PGE, infusion at the firstattempt (Table Ill). The average period of gestation atthe time of intra-uterine death was 28,4 weeks, and themean death-induction interval was 3,4 days. The averageTABLE 11. SIDE-EFFECTS RELATED TO TABLE I (7 CASES)TABLE 11/. INTRA-UTERINE DEATH DUE TO RHESUSISO-IMMUNISATION. SUCCESSFUL INDUCTION WITHINTRAVENOUS PGE2 0,625 fL9 - 5,0 fLgfmin AT FIRSTATTEMPT (13 CASES)Pyrexia 37,5°CTachycardia > 120 beats/minNausea and/or vomitingDiarrhoeaPhlebitis ...IUD = intra-uterine death.PGE, = prostaglandin E,.31535TABLE V. PGE2 INDUCTION FAILURE AT FIRST ATTEMPT(3 CASES -- ALL RHESUS ISO-IMMUNISATION)Induction/deliveryGestation Duration Total interval Totalat of dose (to infusionIUD IUD PGE2 nearest time(weeks) Parity (days) (mg) hour) (hours)28 1 + 0 6 3,50 81 2931 2 + 0 6 1,27 28 1427 4 + 0 11 2,25 6 4228,7 7,7 2,34 58,3 28,3In Table V the 3 cases tabulated were those notdelivered with a single infusion of PGE,. In 2 of thesethe' infusion was discontinued before the 24-hour limit,because progress was slow. When infusion was restarted,delivery was completed within a few hours. In the thirdcase a second infusion lasting 18t hours was requiredduration of infusion was 12,5 hours and the mean totaldose of PGE, required was 1,42 mg.The amount of PGE, required for successful inductionof labour in the group where intra-uterine death was dueto rhesus iso-immunisation (Table Ill), was significantlygreater than the amount used in the group where intra-uterine death was related to placental insufficiency(P<0,02).There was no statistically significant difference in theduration of intra-uterine death between the two groups.There was also no significant difference in the period ofgestation at which IUD occurred.Taking parity as previous gestations beyond 28 weeks,there was a significantly higher parity in the rhesus group.In correlating the dose required, the 3 cases in whichinduction of labour failed at the first attempt (Table V)(all due to rhesus iso-immunisation) were not included.TABLE IV. SIDE-EFFECTS RELATED TO TABLE 11/ (13 CASES)Pyrexia 37,5°CTachycardia >120 beats/minNausea and/or vomiting ...DiarrhoeaPhlebitis ...1nil112Induction/deliveryinteNal (tonearesthour)55101295189,1Induction/deliveryinteNal (tonearesthour)189223812181110158101812,5TotaldosePGE2 (mg)0,550,150,751,251,270,501,320,83TotaldosePGE2 (mg)2,250,992,110,631,380,831,351,501.821,500,931,491,61i,42Durationof IUD(days)1914371046,9Durationof IUD(days)32339522623223,4Parity0+00+22 + 01 + 02 + 00+00+00,7Parity2 + 02 + 04 + 32 + 32 + 02+12+11 + 03 + 02 + 03 + 01 + 02+12.2Gestationat IUD(weeks)33242924312430242831283330Mean 28,4Gestationat IUD(weeks)33363029292440Mean 31,621 September 1974 S.-A. MEDIESE TYDSKRIF 194324 hours after the initial induction.The side-effects listed in Tables 11 and IV relate toTables I and HI respectively. Generally, these side-effectsappeared to correlate with the infusion rate and concen-tration of PGE,.There were some individual variations not directlyrelated to infusion rate and solution concentration. Noaccurate prediction of side-effects could thus be made for·a .particular case before commencement of the infusion.However, sensitivity to low doses of PGE, were uncommon.Nausea and/or vomiting were the most common side-effects, but were only severe in 2 cases, both requiringhigh-dose infusion rates. Diarrhoea occurred occasionally,but was only troublesome in 3 cases. Phlebitis occurredfrequently, but was only noted in 7 cases before delivery.In 1 case it was necessary to transfer the infusion toa large vein in the opposite arm. Other cases of phlebitis(only recorded in the postnatal notes) were mild and notrecorded as significant side-effects.Pyrexia over 37,5°C occurred in 4 cases, but neverexceeded 38,5°C. In one case a temperature rise to39°C was recorded on 3 successive attempts to infusePGE, on different occasions. An infusion rate of 0,625Jig/min produced a marked elevation of temperaturewithin 15 minutes, and attempts at PGE, induction wereabandoned. This case has not been included as no truetrial of prostaglandin could be carried out. The intra-uterine death in this case was related to rhesus iso-immunisation.Postpartum haemorrhage (over 600 ml of blood) wasnot recorded in any of the cases.Evacuation of the uterus after delivery was necessaryin 2 cases. One of these was complicated by a secondarypostpartum haemorrhage.There were" no cases of puerperal infection and nocoagulation disorders occurred.DISCUSSIONThe value of prostaglandin in the management of intra-uterine death is now well established.'" This is supportedby the results obtained in our series of 23 cases. However,the most suitable method of administration of the prostag-landin has not yet been established.The disadvantages of intravenous prostaglandins are thesystemic side-effects which arise, and which increase inseverity as the infusion concentration and rate areincreased. The dose level necessary to obtain the desiredeffect may therefore not be practical or acceptable incases where concentration and dose are high. Theadvantage of this method is that labour can be accuratelymonitored and the dose level regulated to prevent hyper-stimulation or to diminish side-effects.The advantage of extra-amniotic or intra-amnioticprostaglandin is that at the dose levels referred to'" the11systemic side-effects were fewer when comparable resultswere obtained. The disadvantages of these methods arethat they require some form of surgical intervention witha high risk of infection, especially if the induction shouldfail or if infection is introduced at the time of induction.In addition, the dose may be more difficult to regulate,and in the third trimester this may be dangerous if thefetus lies in a transverse or abnormal position, which maybe difficult to diagnose clinically after intra-uterine death.The important factor which has emerged in this seriesis that the amount of prostaglandin necessary to inducelabour in cases of intra-uterine death does depend on thecause of death. In this series only 2 groups, placentalinsufficiency and rhesus iso-immunisation, were comparedand they showed a statistically significant difference indose level of PGE, required.In view of this, and if side-effects are related to thedose of prostaglandin, then it would suggest that casesshould be selected for the most suitable method ofinduction of labour after intra-uterine death. When thecause of death is related to placental insufficiency, signi-ficantly smaller doses of prostaglandins can achieve deli-very of the fetus and an intravenous route will be themethod of choice. However, in cases of rhesus iso-immunisation, where larger doses of prostaglandin arerequired, with correspondingly more severe side-effects,the extra-amniotic route may be preferable.As more knowledge is gained of the factors involvedin the initiation of labour in these cases, selection ofmethods and patients may become more clear. Until suchtime it is suggested that when termination of pregnancyafter intra-uterine death is considered, selection of themethod used should be modified in relation to the indi-vidual as well as to the cause of death of the fetus.In this series only placental insuffic:ency 2nd rtesusdisease are discu,sed, and more work will be required todetermine the method, of choice in groups where fetaldeath is due to other factors.We should like to thank Upjohn Limited, for the supply ofprostaglandin E, and their assistance in this project.REFERENCESI. Karim, S. M. M. (1970): Brit. Med. J .. 3. 196.2. Karim, S. M. M. and Trussell, R. R. (1971): East AIr. Med. J. 48. 1.3. Filshie, G. M. (1971): J. Obstet. Gynaec. Br.t. Cwlth. 78. 87.4. Miller, A. W. F., Calder, A. A. and Macnaught"". M. C. (1972):Lancet, 2, 5.5. Pederson. P. H .. Larsen. F. J. and Sorensen. B. (1972): Prostag-landlos, 2, 135.6. Gordon, H. and Pipe, N. J. G. Unpublished data.7. Embrey, M. P., Salder, A. A. and Hillier, K. (1974): J. Obstet.Gynaec. Brit. Cwlth, 81, 47.8. Karim, S. M. M .. ed. (1972): The Proscaglandills-Progress ill Re-search, pp. 110 - 112. London: \Viley Interscience.9. Hodgkinson, G. P., Margulis, R. R. and Luzarde. S. H. (1954): 1.Amer. Med. Assoc .. 154. 557.10. O'Oriscoll, O. T. and Lavelle, S. M. (1955): Lancet, 2. 1169.

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The value of intravenous prostaglandin E2 after intra-uterine death

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The value of intravenous prostaglandin E2 after intra-uterine death

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