EUROP. J. OBSTET. GYNEC. REPROD. BIOL., 1977,715, 325-329 0 Elsevier/North-Holland Biomedical Press

Extraamniotic prostaglandin Fza for intrauterine death and fetal abnormality J. Luengo, M.J.N.C. Keirse and J. Bennebroek Gravenhorst Department of Obstetrics and Gynecology, The Netherlands

University of Leiden,

University Hospital, Rijnsburgerweg

IO, Leiden,

___ LUENGO, J., KEIRSE, M.J.N.C. and BENNEBROEK GRAVENHORST, J. (1977): Extraamniotic prostaglandin Fzar for intrauterine death and fetal abnormality. Europ. J. Obstet. Gynec. reprod. Biol., 7/S, 325-329. Prostaglandin Fzor was administered extraamniotically for termination of pregnancy in 15 cases of intrauterine fetal death between 18 and 39 wk gestation and in 10 cases of fetal abnormality or hydatidiform mole between 16 and 28 wk gestation. Although delivery was achieved with minimal side effects in all cases, the best results were obtained in patients with intrauterine fetal death. It is concluded that discontinuous extraamniotic prostaglandin therapy constitutes a safe and effective approach for the active management of intrauterine fetal death. termination

of pregnancy; missed abortion; fetal death; stillbirth; prostaglandin

extraamniotic route of administration, initially for termination of mid-trimester pregnancy (Embrey, Hillier and Mahendran, 1972) and later for the management of intrauterine fetal death (Embrey, Calder and Hillier, 1974). This report describes our experience with extraamniotic prostaglandin F,,,GF,,) in the management of intrauterine fetal death at gestational ages ranging from 18 to 39 wk and in termination of pregnancy for fetal abnormality beyond the 16th wk of gestation.


Termination of pregnancy causes few problems when performed either during the first trimester of pregnancy when surgical evacuation of the uterus is easily achieved or toward term when the uterus has become very sensitive to the administration of oxytotin. Between these two periods termination of preg nancy is notoriously troublesome. It is often based upon fetal death or fetal abnormality both of which subject the patient to considerable mental distress; surgical evacuation is difficult and carries risks from infection and hemorrhage, whereas oxytocin infusion gives notoriously poor results. Several studies have drawn attention to the potential value of prostaglandins in the management of such cases and these have recently been reviewed (Karim and Amy, 1975; Thiery and Amy, 1975). The dosage of prostaglandins required for effective intravenous therapy, however, results in a high incidence of side effects. Embrey et al. therefore advocated the


and methods

15 cases of intrauterine fetal death between 18 and 39 wk of gestation were studied. The duration of amenorrhea and the estimated duration of fetal death in all cases are shown in Table I, which gives the relevant clinical details on all patients studied. Another 10 patients with gestational ages ranging from 16 to 28 wk underwent termination of pregnancy because 325


2 3

30 1

21 24

14 15

12 13

30 31

33 39






8 9



4 6 19

29 29

l/4 O/l 415

10 11





35 14 2 2



24 24 28 29

Estimated duration of fetal death (days)

Duration of amenorrhea (wk)








Paral gravida


Uterus myomatosus Rh isoimmunization, hydrops fetalis None Twin pregnancy Intrauterine growth retardation Rh isoimmunization (intrauterine transfusion) Idiopathic trombocytopenia; lupus erythematodes; hypertension; intrauterine growth retardation None None Rh isoimmunization (intrauterine transfusion, hydrops fetalis) Torsion umbilical cord Severe hypertension; Rh isoimmunization (plasmapheresis and intrauterine transfusion, hydrops fetalis, infarcted placenta) Intrauterine growth retardation None

Complications other than intrauterine fetal death

Intrauterine fetal death: induction of labor with extraamniotic


Patient No.


Vomiting (1X) Nausea Nausea

Incomplete Complete Incomplete 14.0 18.2 1.3

6.5 13.7 3.5

16.8 13.0

19.0 14.5

8.5 9.7

4.5 8.0

Complete Complete







Incomplete Complete

None None None None

Complete Complete Complete Complete 18.0 11.2 8.0 10.5


5.5 3.0 8.5

Nausea None

24.0 14.5

20.0 7.0


Retained placenta Complete Complete

Side effects

3rd stage


Induction delivery interval (h)


Total dose of PGF2, (mg)



390 100 400


700 150 20 270

50 265


Total blood loss (ml)


!? 2 ““0 2


l/2 o/2

O/l 214 l/2

l/2 l/2 l/2 417

21 3

4 51 6l

7 20 22 24 28

16 16 19

16 16


Duration of amenorrhea (wk)


Rubella 2 Rubella 2 Rubella ’ Rh isoimmunization: severe hydrops fetalis and placentae (7.8 cm thick, 1030 g) with pronounced maternal hydrops syndrome

Male fetus with sex-linked genetic disorder (recessive X-linked agammaglobulinemia) Rubella ’ Rubella vaccination at 5-6 wk gestation 2 Rubella Rubella 2 Hydatidiform mole (no fetus)

of preg-

300 400 None Nausea, vomiting Vomiting None Nausea, vomiting None Nausea None None Incomplete Complete Incomplete Complete Incomplete Complete Incomplete Incomplete Complete

21.2 1 40.0 32.3 24.5 1 16.0 t 21.3 35.5 t 36.0 1 4.2

9.5 31.5 30.0 13.0 3.5 15.0 32.5 22.5 1.2

120 350 50 710

100 150 1000


Total blood (ml)


Side effects


Complete or incomplete abortion


Inductionabortion interval (h)




Total dose of

of pregnancy in cases of fetal abnormality

Indication for termination nancy

Fza for termination

t Patients given intravenous oxytocin during the last 1.5-3 h of the induction-abortion interval. 2 Rubella infection confirmed by anatomopathological abnormalities of the conceptus and/or isolation of the virus.




Para/ gravida



Patient No.


3 S. P K 2 E S s 4 3 11 c;’




of fetal abnormality or hydatidiform mole. Relevant details on these cases are shown in Table II. After thorough cleansing of the cervix a No. 16 Foley catheter was inserted and retained in the extraamniotic space by means of the balloon, inflated with IO ml saline. PGFz,-tromethamine salt (Prostin Fzol, Upjohn Nederland) was diluted to an aqueous solution of 0.25 mg PGFa,/ml and administered via the catheter at 1 h intervals. Treatment was started with 0.5 mg (2 ml) and the initial dosage was increased by increments of 0.25 mg to a maximum of 1 mg/h if uterine contractility did not ensue. Temperature, pulse rate and blood pressure were checked regularly. Antibiotherapy (ampicillin) was routinely given at the beginning of this study but later abandoned. Pethidine was used as an analgesic whenever required. Results Abortion or delivery was achieved in all 25 cases studied. The total dose of PGFzo, required in each case and the intervals between induction and abortion or delivery are shown in Tables I and II. In all but 1 of the patients with intrauterine fetal death, delivery occurred within 24 h and the placenta was delivered spontaneously and complete in 11 of the 15 patients (73%). There was no relationship between the duration of fetal death and induction-delivery interval (Table I). In cases with an abnormal but living fetus or hydatidiform mole, abortion was frequently incomplete (Table II) and the mean inductionabortion interval (24.4 h) was 10 h longer than that observed in cases of intrauterine fetal death (14.5 h). Furthermore 5 of the 10 patients required intravenous oxytocin from a cervical dilatation of 3-6 cm onwards and from 14-30 h after the start of PGFaa administration. In these cases abortion always followed within 3 h of starting the oxytocin infusion. Side effects were moderate in both groups of patients (Tables I and II) and pyrexia of 38’C or more was never encountered. None of the patients showed any signs of intrauterine infection despite the fact that half of those with intrauterine fetal death had additional risk factors such as one or more amniocenteses (7 patients) and intrauterine transfusion (3 patients). Blood loss exceeded 500 ml in 4 of the 25 patients studied (16%) but only 1 patient, with a molar pregnancy, lost as much as 1000 ml.

J. Luengo et al.: Extraamniotic

prostaglandin Fza!

Discussion In the past, attitudes toward the management of intrauterine fetal death have been mostly conservative due to the relative inefficiency and dangers of a more active approach. In the meantime little attention has been paid to the mental distress and the sense of revulsion to which the patient is exposed by the knowledge that the fetus is dead. Any such considerations were weighed against the ineffectiveness of oxytocin administration and the risks of a surgical approach. Understandably from the beginning of their clinical application prostaglandins have been advocated in such cases (Karim, 1970; Filshie, 1971; Miller, 1973), but the high incidence of side effects, particularly pyrexia which may be difficult to differentiate from signs of intrauterine infection, has retarded their routine application in clinical practice. Using the extraamniotic route of administration these side effects are minimal and our experience confirms that of Embrey et al. (1974) in that pyrexia was not encountered. Three main conclusions can be reached from the present study. Firstly, there was no relationship between the induction-delivery interval and the duration of fetal death. Hence there appears to be no reason to await events in patients with an intrauterine death whose overwhelming and understandable desire is to be delivered without delay. Secondly, the duration of pregnancy did not bear any relationship to either induction-delivery interval, total dose of PGFa, required or the incidence of side effects, and delivery could be achieved effectively at any gestational age. Thirdly, any initial fears of hemorrhage and infection appear to be greatly exaggerated in view of our present experience with cases of whom half had been exposed to added risks by previous amniocenteses and intrauterine transfusions. Our experience with PGFao, in termination of preg nancy for fetal abnormality beyond 16 wk gestation is limited but results were inferior to those obtained in cases of intrauterine fetal death. It is tempting to relate this difference to the high prostaglandin metabolizing capacity found in viable intrauterine tissues throughout pregnancy (Keirse, Williamson and Turnbull, 1975; Keirse and Turnbull, 1975). Although insufficient evidence is as yet available on the fate of prostaglandin metabolizing enzymes in cases

J. Luengo et al.: Extraamniotic prostaglandin Fza

of intrauterine fetal death, it is known that these enzymes are rather unstable in intrauterine tissues in vitro (Keirse, 1975), and animal evidence suggests that 15-hydroxy-prostaglandin dehydrogenase may also be short-lived in vivo (Blackwell, Flower and Vane, 1975). Limited as it may be, our experience indicates that there is ample room for improvement in the technique of mid-trimester termination of pregnancy. Supplementing prostaglandin therapy with intravenous oxytocin toward the end of the induction period may, as confirmed by our study, be beneficial in view of the widely acclaimed potentiating effect or synergistic action of prostaglandins and oxytocin both in man (Brummer, 1971; Gillespie, 1972; Embrey , 1973) and in experimental animals (Liggins, 1973). MacKenzie and Embrey (1976) recently reemphasized the known superiority of extraamniotic PGEz over PGFzo, for mid-trimester termination of pregnancy (Embrey, 1973). They advocated extraamniotic injection in a viscous gel, but benefits derived from this technique relate mainly to its simplicity and to a reduction in individual patient care. It should be emphasized, however, that individual care ought to be optimized rather than reduced in patients requiring termination of pregnancy for fetal abnormality. More substantial benefits may perhaps be derived from the development of prostaglandin analogs with a more specific uterine or cervical action than those hitherto available.

References Blackwell, G.J., Flower, R.J. and Vane, J.R. (1975): Rapid reduction of prostaglandin 15-hydroxydehydrogenase activity in rat tissues after treatment with protein synthesis inhibitors. Brit. J. Pharmacol., 55, 233-238. Brummer, H.C. (1971): Interaction of E prostaglandins and Syntocinon on the pregnant human myometrium. J. Obstet. Gynaec. Brit. Cwlth, 78, 305-309. Embrey, M.P. (1973): The use of prostaglandins for thera-

329 peutic termination of pregnancy. In: The Use ofProstaglandins E2 and Fza in Obstetrics and Gynaecology, pp. 69-79. Editors: R.G. Jacomb and R.E. Hardy. Symposia Specialists, Miami, Fla. Embrey, M.P., Hillier, K. and Mahendran, P. (1972): Induction of abortion by extra-amniotic administration of prostaglandins E2 and Fzo. Brit. med. J., 3, 146- 149. Embrey, M.P., Calder, A.A. and Hillier, K. (1974): Extra amniotic prostaglandins in the management of intrauterine fetal death, anencephaly and hydatidiform mole. J. Obstet. Gynaec. Brit. Cwlth, 81, 47-51. Filshie, GM. (1971): The use of prostaglandin E2 in the management of i&a-uterine death, missed abortion and hydatidiform mole. J. Obstet. Gynaec. Brit. Cwlth, 78, 87-91. Gillespie, A. (1972): Prostaglandin-oxytocin enhancement and potentiation and their clinical applications. Brit. med. J., I, 150-152. Karhn, S.M.M. (1970): Use of prostaglandin E2 in the management of missed abortion, missed labour, and hydatidiform mole. Brit. med. J., 3, 196-197. Karim, S.M.M. and Amy, J.J. (1975): Interruption of pregnancy with prostaglandins. In: Prostaglandinsand Reproduction, pp. 77-148. Editor: S.M.M. Karim. MTP, Lancaster. Keirse, M.J.N.C. (1975): Studies on prostaglandins in relation to human parturition. D.Phil. thesis, University of Oxford. Keirse, M.J.N.C. and Turnbull, A.C. (1975): Metabolism of prostaglandins within the pregnant uterus. Brit. J. Obstet. Gynaec., 82, 887-893. Keirse, M.J.N.C., Williamson, J.G. and Turnbull, A.C. (1975): Metabolism of prostaglandin F2o within the human uterus in early pregnancy. Brit. J. Obstet. Gynaec., 82, 142-145. Liggins, G.C. (1973): Hormonal interactions in the mechanism of parturition. Mem. Sot. Endocrinol., 20, 119139. MacKenzie, I.Z. and Embrey, M.P. (1976): Single extraamniotic injection of prostaglandlns in viscous gel to induce abortion. Brit. J. Obstet. Gynaec., 83, 505-507. Miller, A.W.F. (1973): The use of prostaglandins for missed abortion, fetal death in utero and hydatidiform mole. In: The Use of ProstaglandinsE2 and Fza in Obstetrics and Gynaecology, pp. 63-67. Editors: R.G. Jacomb and R.E. Hardy. Symposia Specialists, Miami, Fla. Thiery, M. and Amy, J.J. (1975): Induction of labour with prostaglandins. In: Prostaglandins and Reproduction, pp. 149-228. Editor: S.M.M. Karim. MTP, Lancaster.

Extraamniotic prostaglandin F2 alpha for intrauterine death and fetal abnormality.

Prostaglandin F2alpha (PGF2alpha) was administered extraamniotically for pregnancy termination in 15 cases of intrauterine fetal death between 18-39 w...
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