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Induction of term labor with intravenous PGF2α: A review
INDUCTION OF TERM LABOR WITH INTRAVENOUS PGF2a : A REVIEW
Gerald G. Anderson Department of Obstetrics and Gynecology Yale University School of Medicine New Haven, Connecticut
Since the first report by Karim (I) in 1968 indicating that intravenous prostaglandin F2a (PGF2a) was effective in inducing term labor in 10 women, numerous Tnvestigators throughout the world have performed similar studies. This review will seek to summarize 45 significant publications out of approximately 100 which have been published since 1968, with a view to seeking answers to certain basic questions regarding the present status of PGF2a. It is not the intent of this review to examine all the details of each study, but rather to attempt to draw same broad conclusions. The most basic question involves the comparative efficacy and safety of PGF2a as compared to commercially available oxytocln. More specifically: are there any advantages of PGF2a over oxytocin; are uterine contractile responses similar and physiologic; is the dosage regimen similar; is the range of safety in dosage schedules similar; have side effects been noted and if so are they controllable, serious or permanent; and finally, have a sufficient number and type of studies been done of good quality to answer all of these questions? The studies under consideration are unique in at least two aspects: PGF2a so caught the imagination of the reproductive world that in 3 years publications have come from many major universities in most of the developed countries of the world, and the studies, although varying in quality, have been the best ever done in the general area of labor induction with any drug. HISTORICAL DEVELOPMENT BergstrSm (2) has recently reviewed the work which proceeded quietly at the Karolinska Institute in Stockholm for many years before the term "prostaglandins" became generally known. There the early collaborative work with Bygdeman (3) on uterine muscle strips was suggesffve of a myometriat stimulating effect, but the results were also conflicting in many aspects, especially when compared to later in vivo results. It wasn't until Karim reported the first successful term inductions (ibid) that PGF2a became a recognized clinical research drug. The jump From years of bloc~mical Accepted September 14, 1973 PROSTAGLANDINS N O V E M B E R 1973
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studies and in vitrowork was not taken wlthout ample evidence which logically placed PGF2a in t-he physiologic process of normal labor. Using a bloassay, Karlm identified a high concentration of PGF2a in the deeldua of the term pregnant uterus, in umbilical cord jelly, in the amnlotlc fluid, and in maternal plasma during labor (4,5). Thusone of the significant attributes of PGF2a was established, it is present in normal, spontaneous labor and is therefore a natural compound. In 1969, Karim, et al, reported a study (6) in which 29 out of 35 women were successfully induced at term with intravenous PGF2a delivered at a rate of 0.05 pg/kg/min. The recorded pattern of uterine activity was reported to be similar to that of normal labor. There followed reports of several additional and ancillary studies from the same group, (7, 8, 9, & 10). They indicated efficacy and safety of PGF2a but the studies did not include control groups for comparison. The Swedish investigators directed their efforts towards dose response and physiological role studies (11, 12, 13, 14, & 15). They pointed out a great variability in individual patient responsesand also questioned whether the uterine contractions produced by PGF2a or PGE2 were physiologic. At the New York Academy of Science meeting on prostaglandlns in April, 1971, four papers were delivered which dealt with the induction of term human labor. Karim rep&ted results in over 1,000 patients in whom PGF2a and PGE2 were used, and ~h a separate double-blnd study in 300 women found a comparative advantage h~ efficacy of PGE2 over PGF2a and oxytocin (10). Embrey reported the successful use of PGE2 in 30 patients at term and suggested a synergistic action with oxytocin (16). Gillespie reported a double-bllnd study using PGE 2 and oxytocln in which there was no difference in efficacy. He stressed that a step-wlse increase in dose, rathe~tl~h the constant dose suggested by Karim, was desirable in atta|ning'~maxlmal efficacy with prostaglandins (17). Anderson, et al, (18) reported a preliminary study which, in addition to being double-bllnd, also included, for the first time, a semi-objective method of determining the expected ease of induction of individual patients by applying the Bishop scoring index. This refinement increased the slgn|flcance of double-bllnd studies by al!owinga more objective analysis of groups. Fortunately this Facet of protocol design was adopted by others thus making inter-investlgation comparlsons'more meaningful EFFICACY Anderson, et al/reported a study involving a double-blind protocol in which the Bishop score classified patients before induction (19,20). The investigation used PGF2a and oxytocin in 169 women. All patients
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with a high Bishop score delivered regardless of the drug used while patients with a score of 6 or less, difficult inductions, had similar efficacy rates. Efficacy with PGF2a ranged From 93% in patients with a Bishop score of 5 to 6to a rate of 40% in five patients with a score of 0 to 2. Resultswith oxytocln were almost exactly the same. Dosages of PGF2a and oxytocin and duration of infusion in most studies done in the U.S.A. were standardized, while those from other countries often varied in those parameters. This obviously hinders comparison of efficacy studies. Karlm reported a 98% efficacy rate in 86 patients receiving PGF2a at a constant infusion rate. However, the study did not include oxytocin controls and inducibility was not'scored (10). A further study was reported by Karlm in which three groups of 100 patients each received PGF2a, PGE2 and oxytocln in a double-blind trial (7). The success rates were noted to be 67%, 96% and 56%, respectively. Once again, inducibility was not taken into account in weighing the efficacy results, but on the basis of this study, Karim came to favor PGE2 and soon replaced the intravenous infusion with oral tablets. Since that time over three thousand patients have been induced with prostaglandins in Uganda. Csapo recently estimated that over 5,000 patients have received the drugs for term induction world--wlde(21). in a study using tke same protocol design as Anderson's, Spellacy (22) reported efficacy results in 222 women which were similar to those noted by Anderson. Allowing for uncontrollable variables, the studies of Rangarajan, et al, (23) Moghlssl, et al, (24) and Sherman and Vakhariya, (25, 26, 27) also using a standard protocol gave similar efficacy results. Therefore, in terms of efficacy, none of the studies quoted above suggest that PGF2a is more efficacious in inducing term labor than oxytocln. Various foreign studies have been reported using PGF2a, but have been small in number and protocol design was not standard, (28, 29, 30, 31) therefore the claimed efficacy rates cannot be proven to be significant. From the studies available, one can only conclude that PGF2a is as efficacious as ocytocin in the induction of term labor. In special situations, however, some studies suggest an advantage of PGF2a. These investigations are all preliminary and are related to the capability of PGF2a, unlike oxytocin, to trigger uterine contractions at any stage of gestation. Kenoshlta (30) has reported 30 cases, all of which delivered successfully, in which artificial rupture of the membranes was performed as the intravenous infusion was begun. Karim (32) and Pedersen (33) have each reported small series in which PGF2a infusions were succesfully used in cases of missed abortion, intrauterine death, molar gestations, and anencephalic pregnancies. Sherman (27) has detected a trend suggesting an advantage of PGF2a overoxytooin in patients with very low Bishop scores.
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Tchillngulrlan (34) has found PGF2a to be an effective and safe drug in the induction af labor in a small group of "high risk" obstetrical patients. Finally, Barden (35) has used a PGF2a infusion in 10 patients with premature rupture of the membranes and unfavorable cervices and found the regimen to be efficacious in comparison to 10 patients induced at term. Much work needs to be done to clarify efficacy results in these special situations. SAFETY The safety of both the mother and fetus have to be taken into account during labor induction with a new drug. Two studies have directly applied themselves to the effect on the fetus and neonate of PGF2a infusions. Their/, et ai, (36) studied the following parameters in 82 normal term inductions: continuous labor monitoring of uterine contractions and fetal heart rate, amnlotic fluid meconlum staining, biochemical determinations of fetal and neonatal acid-bose status, and clinical status at time of delivery. They concluded that, provided uterine hyperstimulation was avoided, PGF2a had no deleterious effect on the fetus. Blackburn, et ai, (37) studied twenty-three neonates born to mothers undergoing a double-blind induction with either intravenous PGF2a or oxytocln. The double-blind aspect of the investigation was maintained throughout the pediatric evaluation during the first 6 hours of life, and during re-evaluation at 48 to 72 hours. Parameters included: time to first breath, general physical examination, tlme to cessation of arterial pulsations of the umbilical stump, ! and 5 minute Apgar scores, chest x-rays, continuous measurement of body temperature and blood pressure, EKG, blood gases, CBC, periodic sampi|ng of blood glucose, electrolytes, and determinations of sleep-awake and voiding patterns. None of these parameters was any different in the two groups indicating that PGF2a , when administered to the mother for the induction of labor, appears to have no direct effect on the fetus or neonate that distinguishes it from oxytocin. The first safety consideration in the mother concerns the incidence and severity of excessive uterine response. The end results of uterine hypertonus, or more severe tetany, can be fetal damage secondary to hypoxia and/or traumatic maternal injuries, in their double-bllnd study using PGF2a and Syntoclnon, Anderson, et al, (20) found 9 instances of hypertonus. All occurred with prostaglandins, none with Syntocinon. Karim and Hillier, (38) have recently painted out that comparisons of the incidence of uterine hyperstimulation between various investigators are difficult because different baseline values are used For diagnostic purposes. In Anderson's study, fetal heart rate patterra indicative of fetal hypaxla occurred in 2 of the9 instances of hypertonus and quickly reverted to normal after stopping the infusion. Other investigators utilizing double-blind protocols also found a varying but
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increased incidence of uterine hypertonus with PGF2a (23, 28, & 36) . Only Spellacy (22) thus far, has published a report of a Fetal death thought to be associated with uterine tetany secondary to a PGF2a infusion. The amount of PGF2a each patient was receiving at the onset of the reported uterine hypertonus eposides was not always stated, however, it is generally agreed that the response of individual patients is highly variable, and is in agreement with the earlier work of Roth-Brandel (13). This Finding has necessitated a dosage regimen which begins at a low level and precedes step-wise until an adequate response is received. This type of dosage regimen was used in most recent large studies and is similar to that used in administering oxytocln intravenously. The results suggest that the range of safety between adequate response and hyperstimulation is much narrower for PGF2a than for oxytocln. The safety and efficacy results thus far reported are mainly based upon a step-wise increase in dosage between 2.5 and 40 tJg/min, while using the usual criteria for adjusting the dosage of oxytocin, i.e. progress in labor without excessive uterine response. Exceptions to this regimen include the early studies of Karlm (7) in which a constant infusion of 0.05 ~g/kg/'min. was used and a later study by Witting, et al, (39) which utilized a constant rate of 4 pg/'min. Anderson, et al, (20) in their double-blind PGF2a -oxytocln study, were concerned with the increased incidence of hypertonus found to be associated with PGF2a. Therefore the criteria for advancing dosage levels was changed to give less weight to frequency and intensity of concentractlons as long as the patient was progressing in labor. This had the effect of decreasing the incidence of hypertonus without affecting the efficacy rate. To the experienced clinician, the contractions in the double-bllnd study appeared indistinguishable so that it was not possible to predict whether the patient was receiving PGF2a or oxytocln. Therefore, a statistical analysis was done on over 1000 contractions using the method suggested by Schulman and Romney (40) which occurred in 60 patients during the active phase of spontaneous, oxytocln, or PGF2a induced labor. Frequency curves were drawn of contractile frequency, intensity, and duration. Comparison revealed no significant differences in the three parameters (,~1). This would suggest that dosage regimens, other than those most often employed, may yield better results in terms of efficacy and safety. All results thus far reported must be interpreted in this light. The duration of the infusion must also be considered when assessing efficacy results. Although this interval has varied from study to study, the most often utilized duration has been 10 hours. In that PGF2a will stimulate uterine contractions in even the lowest Bishop score patient (although the
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eventual delivery rate thus Far is no better than that with oxytocin), it is possible that continuing the infusion time for a longer period would show an advantage of PGF2a over oxytocin. Various other side effects have been reported, however their occurrence has been variable, limited, and in no instance were they considered significant in terms of patient safety or comfort. These include nausea, vomiting, diarrhea, ard a local transient infusion vein phlebitis. The latter has been dealt with by slowing the infusion rate or by further diluting the PGF2a; it disappears shortly thereafter without sequelae. The incidence of gastrointestinal side effects has varied between 0% (16) and 10% (22) in various studies while the overall occurrence of the transitory phlebitis is in the range of 5%. Intensive laboratory blood analyses have been carried out in several hundred women before and 12 hours following induction with PGF2a and oxytocin. These include: calcium, phosphorus, triglycerldes, billrubln, alkaline phosphatase, total proteln, SGOT, SGPT, cholesterol, creatlne phosphokinase, creatlne, glucose, BUN, uric acid, and lactic dehydrogenase. No differences (19, 22, 27) were found between patients who had received PGF2 or oxytocln. LeMaire, et al, (42) found no changes in maternal plasma progesterone or estrlol, Anderson, eta I, found a gradual decrease in maternal plasma estriol not noted in oxytocln-lnduced or spontaneous labor (20), and Spellacy, et al, (43) found no changes in blood glucose, insulin, or HCS levels during PGF2a induction. In terms of safety there is a possible advantage of PGF2a over ocytocin in the area of antidiuresis. Roberts (44, 45) has shown that PGF2a, as administered to induce labor, has no antidluretlc effect. Oxytocln is known to have this capabillty and occasional clinical compllcations have been produced. SUMMARY PGF2a emerges as a major new drug to be used for the induction of labor. Its efficacy in normal term induction appears no better than that noted with oxytocin; however, various constraints of protocol design and lack of an adequate number of studies in specific situations (e.g. premature rupture of the membranes) have not as yet fully clarified this point. It is anticipated that dominance of PGF2a will emerge in certain clinical situations with equal efficacy in other areas. Although present information indicates an increased incidence of hypertonus with PGF2a, the evidence suggests that the incidence of this side effect can be substantially decreased by decreasing dosage. The lack of an ADH effect-with PGF2a can be considered an
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additional safety factor. The questions asked in the introduction to this review cannot be fully answered on the basis of the presented studies; however, one can deduce that the use of PGF2a for the induction of labor can be an efficacious and safe practice for the mother, fetus and neonate. Further studies are needed to substantiate that excessive uterine stimulation need not accompany the use of PGF2a, and to demonstrate its unique properties in certain obstetrical situations. REFERENCES . Karim, S . M . M . , Trussell, R.R., Patel, R.C. and Hilller, K.: Response of pregnant human uterus to prostaglandln-F2a- induction of labour. Brit. Med. J. 4:621, 1968. 2. BergstrSm, S., Bygdeman, M . , Samuelsson, B. and Wiqvist, N.: The prostaglandins and human reproduction. Hosp. Pract. 62:51, 1971. . Bygdemgn, M.: The effect of different prostaglandlns on human myometrlum in vitro. Acta. Physiol. Scand. 63:suppl. 242, 1964. 4. Karlm, S.M.M. and Pharm, B.: Appearance of prostaglandin F2a in human blood during labour. Brit. Med. J. 4:618, 1968. 5. Karim, S.M.M.: Physiological role of prostaglandins in the control of parturition and menstruation. J. Reprod. Fert. Suppl. 16:105, 1972. 6. Karlm, S.M.M., Trussell, R.R. and Hilller, K.: Induction of labour with prostaglandin F2a. J. Obstet. Gynaec. Brit. Cwlth. 76:769, 1969. 7. Karim, S.M.M. and Trussell, R.R.: The use of prostaglandins in obstetrics. E. African Med. J. 48:1, January 1971. .
Karlm, S . M . M . , Hilller, K., Trussell, R.R. and Patel, R.C.: Induction of labour with prostaglandln E. J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, March 1970.
9. Kar|m, S.M.M.: Effects of oral administration of prostaglandins E2 and F2a on the human uterus. J. Obstet. Gynaec. Brit. Cwlth. 78:4, April 1971. 10. Karim, S.M.M.: Action of prostaglandln in the pregnant woman. Ann. N.Y. Acad. Sci. 180:483, 1971.
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11. Roth-Brandel, U., Bygdeman, M. and Wiqvlst, N.: Effect of intravenous administration of prostaglandln EI and F2a on the contractillty of the nonpregnant human uterus in vlvo. Acta. Obs. Gyn. Scand. 49:!9, 1970. 12. Roth-Brandel, U., Bygdeman, M. and Wiqvlst, N . : A comparative study on the influence of prostaglandin El, oxytocln and ergometrin on the pregnant human uterus. Acta. Obst. Gyn. Scand. 49:1, 1970. 13. Roth-Brandel, U.: Responseof the pregnant human uterus to low and high doses of prostaglandln E1 and E2. Acta. Obst. Gyn. Scand. 50:159, 1971. 14. Roth-Brandel, U. and Adams, M.: An evaluation of the possible use of prostaglandln El, E2 and F2a for induction of labour. Acta. Obst. Gyn. Stand. 5:9, 1970. 15. Bygdeman, M., Kwon, S.U., Mukherjee, T., Roth-Brandel, U. and W|qvlst, N.: The effect of the prostaglandin F compounds on the contractillty of the pregnant human uterus. Am. J. Obstet. Gynec. 106: 567, 1970. 16. Embrey, M.: PGE compounds for induction of labour and abortion. Ann. N.Y. Acad. Sci. 180:518, 1971. 17. Gillespie, A.: Use of prostaglandlns for induction of abortion and labor. Ann. N.Y. Acad. Sci. 180:524, 1971. 18. Anderson, G . G . , Hobblns, J.C., Cordero, L. and Speroff, L.: Clinical use of prostaglandlns as ocytocln substances. Ann. N.Y. Acad. Scl. 180:499, 1971. t9. Anderson, G . G . , Hobbins, J.C. and Speroff, L.: Intravenous prostaglandlns E2 and F2a for the induction of term labor. Am. J. Obstet. Gynec. 112:382, 1972. 20. Anderson, G I G . , Hobblns, J.C., Speroff, L. and Caldwell, B.V.: Intravenous prostaglandins E2 and F2a and syntocinon for the induction of term labor. J. Reprod. Med. 9:287, 1972. 21. Csapo, A.: Discussant: Brooklodge Symposium, June 12-14, 1972. 22. Spellacy, W . N . and Gall, S.A.: Prostaglandln F2a and oxytocin for term labor induction. J. Reprod. Med. 9:300, 1972. 23. Rangarajan, N.S., LaCrols, G.E. and Moghlssl, K.S.: Induction of labor with prostaglandin. Obstet. and Gynec. 38:546, 1971. 24. /Vk~ghissi, K.W., Rangarajan, N.S. and LaCrols, G.E.: Induction of labor with prostaglandin F2a and oxytocin. J. Reprod. Med. 9:304, 1972.
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25. Vakharlya, V.R. and Sherman, A . I . : Prostaglandln 1:2a For induction of labor. Am. J. Obstet. Gynec. 113:212, 1972. 26. Sherman, A . I . : 7 Jan., t972.
Inducing tough deliveries Faster. Med. WId. News:
27. Sherman, A.I. and Vakharlya, V.R.: An evaluation of prostaglandin F2a For the induction of labor at term. J. Reprod. Med. 9:292, 1972. 28. Caballero, A., Corredera, J., Garcla-Albertos, F., et al.: Prostaglandln PGF2a in induction of labor. Toko-Ginecologia Practlca 31:3, 1972. 29. Embrey, M.P.: Prostaglandlns. Proc. Roy. Soc. Med. 64:1018, 1971. 30. Kinoshita, K., Wagatsuma, T., Hogaki, M and Sakamoto, S.: The induction of labor with prostagland~n F2a. Acta. Obstet. Gynecol. Jap. 18:87, 1971. 31. Roberts, G. and Turnbull, A.C.: Uterine hypertonus during labour induced by prostaglandlns. Brit. Med. J. 1:702, 1971. 32. Karlm n S.M.M.: Use of prostaglandin E2 in the management of missed abortion, missed labour, and hydatldiForm mole. Brit. Med. J. 1:196, 1970. 33. Pedersen, P.H., Larsen, J.F. and Sorensen, B.: Induction of labour with prostaglandin F2a in missed abortion, Fetus mortuus, and anencephalia. Prostagl. 2:135, 1972. 34. Tchilinguirlan, N . G . O . : Comparison of prostaglandin F2a and pitocin in the induction of labor in high risk pregnant women. J. Reprod. Med. 9:331, 1972. 35. Barden, T.P.: Induction of preterm labor with prostaglandin F2a in patients with premature rupture of membranes. J. Reprod. Med. 9:339, 1972° 36. Thlery, M . , Vroman, B., Vanderheyden, K., deHemptlme, D., Derom, R., Van Kets, H. and Martens, G.: The fetal effect of prostaglandln F2a applied in the elective induction of labor at term. J. Reprod. Med. 9:314, 1972. 37. Blackburn, M . G . , Mancusi-Ungaro, H.R., Jr., Orzalesi, M . M . , Hobbins, J.C. and Anderson, G . G . : EFFectson the neonate of the induction of labor with prostaglandln F2a and oxytocln. Am. J. Obstet. Gynec. 116:847, 1973. 38. Karim, S.M.M. and Hillier, K.: Prostaglandlns and the induction of labor. Res. in Prostagl. 2:1, 1973. 39. Witting, W.C., Work, B.A. and karos, R.K.: Uterine activity response to constant infusion of prostaglandin F2a in term human pregnancy. J. Reprod. Med. 9:283, 1972. NOVEMBER 1973 VOL. 4 NO. 5
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40. Schulman, H. and Romney, S. k .: Variability of uterine contractions in normal human parturition. Obstet. and Gynec. 36:215, 1970. 41. Anderson, G.G.: Unpublished data. 42. LeMaire, W.J., Spe!lacy, W.N., Shevach, A.B. and Gall, S.A.: Changes in plasma estrlol and progesterone during labor induced with prostaglandln F2a or oxytocln. Prostagl. 2:93, 1972. 43. Spellacy, W . N . , Buhi, W.C. and Holslnger, K.K.: The effect of prostagland|n F2a and E2 on blood glucose and plasma insulin levels during pregnancy. Am. J. Obstet. Gynec. 111:239, 1971. 44. Roberts, G.: Induction of labour using prostaglandins. J. Reprod. Fert. 23:370, 1970. ,$5. Roberts, G., Anderson, A., McGarry, J. and Turnbull, A.C.: Absence of antldluresis during administration of prostaglandln F2a. Brit. Med. J. 2:152, 1970.
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Gerald G. Anderson Department of Obstetrics and Gynecology Yale University School of Medicine New Haven, Connecticut
Since the first report by Karim (I) in 1968 indicating that intravenous prostaglandin F2a (PGF2a) was effective in inducing term labor in 10 women, numerous Tnvestigators throughout the world have performed similar studies. This review will seek to summarize 45 significant publications out of approximately 100 which have been published since 1968, with a view to seeking answers to certain basic questions regarding the present status of PGF2a. It is not the intent of this review to examine all the details of each study, but rather to attempt to draw same broad conclusions. The most basic question involves the comparative efficacy and safety of PGF2a as compared to commercially available oxytocln. More specifically: are there any advantages of PGF2a over oxytocin; are uterine contractile responses similar and physiologic; is the dosage regimen similar; is the range of safety in dosage schedules similar; have side effects been noted and if so are they controllable, serious or permanent; and finally, have a sufficient number and type of studies been done of good quality to answer all of these questions? The studies under consideration are unique in at least two aspects: PGF2a so caught the imagination of the reproductive world that in 3 years publications have come from many major universities in most of the developed countries of the world, and the studies, although varying in quality, have been the best ever done in the general area of labor induction with any drug. HISTORICAL DEVELOPMENT BergstrSm (2) has recently reviewed the work which proceeded quietly at the Karolinska Institute in Stockholm for many years before the term "prostaglandins" became generally known. There the early collaborative work with Bygdeman (3) on uterine muscle strips was suggesffve of a myometriat stimulating effect, but the results were also conflicting in many aspects, especially when compared to later in vivo results. It wasn't until Karim reported the first successful term inductions (ibid) that PGF2a became a recognized clinical research drug. The jump From years of bloc~mical Accepted September 14, 1973 PROSTAGLANDINS N O V E M B E R 1973
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studies and in vitrowork was not taken wlthout ample evidence which logically placed PGF2a in t-he physiologic process of normal labor. Using a bloassay, Karlm identified a high concentration of PGF2a in the deeldua of the term pregnant uterus, in umbilical cord jelly, in the amnlotlc fluid, and in maternal plasma during labor (4,5). Thusone of the significant attributes of PGF2a was established, it is present in normal, spontaneous labor and is therefore a natural compound. In 1969, Karim, et al, reported a study (6) in which 29 out of 35 women were successfully induced at term with intravenous PGF2a delivered at a rate of 0.05 pg/kg/min. The recorded pattern of uterine activity was reported to be similar to that of normal labor. There followed reports of several additional and ancillary studies from the same group, (7, 8, 9, & 10). They indicated efficacy and safety of PGF2a but the studies did not include control groups for comparison. The Swedish investigators directed their efforts towards dose response and physiological role studies (11, 12, 13, 14, & 15). They pointed out a great variability in individual patient responsesand also questioned whether the uterine contractions produced by PGF2a or PGE2 were physiologic. At the New York Academy of Science meeting on prostaglandlns in April, 1971, four papers were delivered which dealt with the induction of term human labor. Karim rep&ted results in over 1,000 patients in whom PGF2a and PGE2 were used, and ~h a separate double-blnd study in 300 women found a comparative advantage h~ efficacy of PGE2 over PGF2a and oxytocin (10). Embrey reported the successful use of PGE2 in 30 patients at term and suggested a synergistic action with oxytocin (16). Gillespie reported a double-bllnd study using PGE 2 and oxytocln in which there was no difference in efficacy. He stressed that a step-wlse increase in dose, rathe~tl~h the constant dose suggested by Karim, was desirable in atta|ning'~maxlmal efficacy with prostaglandins (17). Anderson, et al, (18) reported a preliminary study which, in addition to being double-bllnd, also included, for the first time, a semi-objective method of determining the expected ease of induction of individual patients by applying the Bishop scoring index. This refinement increased the slgn|flcance of double-bllnd studies by al!owinga more objective analysis of groups. Fortunately this Facet of protocol design was adopted by others thus making inter-investlgation comparlsons'more meaningful EFFICACY Anderson, et al/reported a study involving a double-blind protocol in which the Bishop score classified patients before induction (19,20). The investigation used PGF2a and oxytocin in 169 women. All patients
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with a high Bishop score delivered regardless of the drug used while patients with a score of 6 or less, difficult inductions, had similar efficacy rates. Efficacy with PGF2a ranged From 93% in patients with a Bishop score of 5 to 6to a rate of 40% in five patients with a score of 0 to 2. Resultswith oxytocln were almost exactly the same. Dosages of PGF2a and oxytocin and duration of infusion in most studies done in the U.S.A. were standardized, while those from other countries often varied in those parameters. This obviously hinders comparison of efficacy studies. Karlm reported a 98% efficacy rate in 86 patients receiving PGF2a at a constant infusion rate. However, the study did not include oxytocin controls and inducibility was not'scored (10). A further study was reported by Karlm in which three groups of 100 patients each received PGF2a, PGE2 and oxytocln in a double-blind trial (7). The success rates were noted to be 67%, 96% and 56%, respectively. Once again, inducibility was not taken into account in weighing the efficacy results, but on the basis of this study, Karim came to favor PGE2 and soon replaced the intravenous infusion with oral tablets. Since that time over three thousand patients have been induced with prostaglandins in Uganda. Csapo recently estimated that over 5,000 patients have received the drugs for term induction world--wlde(21). in a study using tke same protocol design as Anderson's, Spellacy (22) reported efficacy results in 222 women which were similar to those noted by Anderson. Allowing for uncontrollable variables, the studies of Rangarajan, et al, (23) Moghlssl, et al, (24) and Sherman and Vakhariya, (25, 26, 27) also using a standard protocol gave similar efficacy results. Therefore, in terms of efficacy, none of the studies quoted above suggest that PGF2a is more efficacious in inducing term labor than oxytocln. Various foreign studies have been reported using PGF2a, but have been small in number and protocol design was not standard, (28, 29, 30, 31) therefore the claimed efficacy rates cannot be proven to be significant. From the studies available, one can only conclude that PGF2a is as efficacious as ocytocin in the induction of term labor. In special situations, however, some studies suggest an advantage of PGF2a. These investigations are all preliminary and are related to the capability of PGF2a, unlike oxytocin, to trigger uterine contractions at any stage of gestation. Kenoshlta (30) has reported 30 cases, all of which delivered successfully, in which artificial rupture of the membranes was performed as the intravenous infusion was begun. Karim (32) and Pedersen (33) have each reported small series in which PGF2a infusions were succesfully used in cases of missed abortion, intrauterine death, molar gestations, and anencephalic pregnancies. Sherman (27) has detected a trend suggesting an advantage of PGF2a overoxytooin in patients with very low Bishop scores.
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Tchillngulrlan (34) has found PGF2a to be an effective and safe drug in the induction af labor in a small group of "high risk" obstetrical patients. Finally, Barden (35) has used a PGF2a infusion in 10 patients with premature rupture of the membranes and unfavorable cervices and found the regimen to be efficacious in comparison to 10 patients induced at term. Much work needs to be done to clarify efficacy results in these special situations. SAFETY The safety of both the mother and fetus have to be taken into account during labor induction with a new drug. Two studies have directly applied themselves to the effect on the fetus and neonate of PGF2a infusions. Their/, et ai, (36) studied the following parameters in 82 normal term inductions: continuous labor monitoring of uterine contractions and fetal heart rate, amnlotic fluid meconlum staining, biochemical determinations of fetal and neonatal acid-bose status, and clinical status at time of delivery. They concluded that, provided uterine hyperstimulation was avoided, PGF2a had no deleterious effect on the fetus. Blackburn, et ai, (37) studied twenty-three neonates born to mothers undergoing a double-blind induction with either intravenous PGF2a or oxytocln. The double-blind aspect of the investigation was maintained throughout the pediatric evaluation during the first 6 hours of life, and during re-evaluation at 48 to 72 hours. Parameters included: time to first breath, general physical examination, tlme to cessation of arterial pulsations of the umbilical stump, ! and 5 minute Apgar scores, chest x-rays, continuous measurement of body temperature and blood pressure, EKG, blood gases, CBC, periodic sampi|ng of blood glucose, electrolytes, and determinations of sleep-awake and voiding patterns. None of these parameters was any different in the two groups indicating that PGF2a , when administered to the mother for the induction of labor, appears to have no direct effect on the fetus or neonate that distinguishes it from oxytocin. The first safety consideration in the mother concerns the incidence and severity of excessive uterine response. The end results of uterine hypertonus, or more severe tetany, can be fetal damage secondary to hypoxia and/or traumatic maternal injuries, in their double-bllnd study using PGF2a and Syntoclnon, Anderson, et al, (20) found 9 instances of hypertonus. All occurred with prostaglandins, none with Syntocinon. Karim and Hillier, (38) have recently painted out that comparisons of the incidence of uterine hyperstimulation between various investigators are difficult because different baseline values are used For diagnostic purposes. In Anderson's study, fetal heart rate patterra indicative of fetal hypaxla occurred in 2 of the9 instances of hypertonus and quickly reverted to normal after stopping the infusion. Other investigators utilizing double-blind protocols also found a varying but
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increased incidence of uterine hypertonus with PGF2a (23, 28, & 36) . Only Spellacy (22) thus far, has published a report of a Fetal death thought to be associated with uterine tetany secondary to a PGF2a infusion. The amount of PGF2a each patient was receiving at the onset of the reported uterine hypertonus eposides was not always stated, however, it is generally agreed that the response of individual patients is highly variable, and is in agreement with the earlier work of Roth-Brandel (13). This Finding has necessitated a dosage regimen which begins at a low level and precedes step-wise until an adequate response is received. This type of dosage regimen was used in most recent large studies and is similar to that used in administering oxytocln intravenously. The results suggest that the range of safety between adequate response and hyperstimulation is much narrower for PGF2a than for oxytocln. The safety and efficacy results thus far reported are mainly based upon a step-wise increase in dosage between 2.5 and 40 tJg/min, while using the usual criteria for adjusting the dosage of oxytocin, i.e. progress in labor without excessive uterine response. Exceptions to this regimen include the early studies of Karlm (7) in which a constant infusion of 0.05 ~g/kg/'min. was used and a later study by Witting, et al, (39) which utilized a constant rate of 4 pg/'min. Anderson, et al, (20) in their double-blind PGF2a -oxytocln study, were concerned with the increased incidence of hypertonus found to be associated with PGF2a. Therefore the criteria for advancing dosage levels was changed to give less weight to frequency and intensity of concentractlons as long as the patient was progressing in labor. This had the effect of decreasing the incidence of hypertonus without affecting the efficacy rate. To the experienced clinician, the contractions in the double-bllnd study appeared indistinguishable so that it was not possible to predict whether the patient was receiving PGF2a or oxytocln. Therefore, a statistical analysis was done on over 1000 contractions using the method suggested by Schulman and Romney (40) which occurred in 60 patients during the active phase of spontaneous, oxytocln, or PGF2a induced labor. Frequency curves were drawn of contractile frequency, intensity, and duration. Comparison revealed no significant differences in the three parameters (,~1). This would suggest that dosage regimens, other than those most often employed, may yield better results in terms of efficacy and safety. All results thus far reported must be interpreted in this light. The duration of the infusion must also be considered when assessing efficacy results. Although this interval has varied from study to study, the most often utilized duration has been 10 hours. In that PGF2a will stimulate uterine contractions in even the lowest Bishop score patient (although the
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eventual delivery rate thus Far is no better than that with oxytocin), it is possible that continuing the infusion time for a longer period would show an advantage of PGF2a over oxytocin. Various other side effects have been reported, however their occurrence has been variable, limited, and in no instance were they considered significant in terms of patient safety or comfort. These include nausea, vomiting, diarrhea, ard a local transient infusion vein phlebitis. The latter has been dealt with by slowing the infusion rate or by further diluting the PGF2a; it disappears shortly thereafter without sequelae. The incidence of gastrointestinal side effects has varied between 0% (16) and 10% (22) in various studies while the overall occurrence of the transitory phlebitis is in the range of 5%. Intensive laboratory blood analyses have been carried out in several hundred women before and 12 hours following induction with PGF2a and oxytocin. These include: calcium, phosphorus, triglycerldes, billrubln, alkaline phosphatase, total proteln, SGOT, SGPT, cholesterol, creatlne phosphokinase, creatlne, glucose, BUN, uric acid, and lactic dehydrogenase. No differences (19, 22, 27) were found between patients who had received PGF2 or oxytocln. LeMaire, et al, (42) found no changes in maternal plasma progesterone or estrlol, Anderson, eta I, found a gradual decrease in maternal plasma estriol not noted in oxytocln-lnduced or spontaneous labor (20), and Spellacy, et al, (43) found no changes in blood glucose, insulin, or HCS levels during PGF2a induction. In terms of safety there is a possible advantage of PGF2a over ocytocin in the area of antidiuresis. Roberts (44, 45) has shown that PGF2a, as administered to induce labor, has no antidluretlc effect. Oxytocln is known to have this capabillty and occasional clinical compllcations have been produced. SUMMARY PGF2a emerges as a major new drug to be used for the induction of labor. Its efficacy in normal term induction appears no better than that noted with oxytocin; however, various constraints of protocol design and lack of an adequate number of studies in specific situations (e.g. premature rupture of the membranes) have not as yet fully clarified this point. It is anticipated that dominance of PGF2a will emerge in certain clinical situations with equal efficacy in other areas. Although present information indicates an increased incidence of hypertonus with PGF2a, the evidence suggests that the incidence of this side effect can be substantially decreased by decreasing dosage. The lack of an ADH effect-with PGF2a can be considered an
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additional safety factor. The questions asked in the introduction to this review cannot be fully answered on the basis of the presented studies; however, one can deduce that the use of PGF2a for the induction of labor can be an efficacious and safe practice for the mother, fetus and neonate. Further studies are needed to substantiate that excessive uterine stimulation need not accompany the use of PGF2a, and to demonstrate its unique properties in certain obstetrical situations. REFERENCES . Karim, S . M . M . , Trussell, R.R., Patel, R.C. and Hilller, K.: Response of pregnant human uterus to prostaglandln-F2a- induction of labour. Brit. Med. J. 4:621, 1968. 2. BergstrSm, S., Bygdeman, M . , Samuelsson, B. and Wiqvist, N.: The prostaglandins and human reproduction. Hosp. Pract. 62:51, 1971. . Bygdemgn, M.: The effect of different prostaglandlns on human myometrlum in vitro. Acta. Physiol. Scand. 63:suppl. 242, 1964. 4. Karlm, S.M.M. and Pharm, B.: Appearance of prostaglandin F2a in human blood during labour. Brit. Med. J. 4:618, 1968. 5. Karim, S.M.M.: Physiological role of prostaglandins in the control of parturition and menstruation. J. Reprod. Fert. Suppl. 16:105, 1972. 6. Karlm, S.M.M., Trussell, R.R. and Hilller, K.: Induction of labour with prostaglandin F2a. J. Obstet. Gynaec. Brit. Cwlth. 76:769, 1969. 7. Karim, S.M.M. and Trussell, R.R.: The use of prostaglandins in obstetrics. E. African Med. J. 48:1, January 1971. .
Karlm, S . M . M . , Hilller, K., Trussell, R.R. and Patel, R.C.: Induction of labour with prostaglandln E. J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, March 1970.
9. Kar|m, S.M.M.: Effects of oral administration of prostaglandins E2 and F2a on the human uterus. J. Obstet. Gynaec. Brit. Cwlth. 78:4, April 1971. 10. Karim, S.M.M.: Action of prostaglandln in the pregnant woman. Ann. N.Y. Acad. Sci. 180:483, 1971.
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11. Roth-Brandel, U., Bygdeman, M. and Wiqvlst, N.: Effect of intravenous administration of prostaglandln EI and F2a on the contractillty of the nonpregnant human uterus in vlvo. Acta. Obs. Gyn. Scand. 49:!9, 1970. 12. Roth-Brandel, U., Bygdeman, M. and Wiqvlst, N . : A comparative study on the influence of prostaglandin El, oxytocln and ergometrin on the pregnant human uterus. Acta. Obst. Gyn. Scand. 49:1, 1970. 13. Roth-Brandel, U.: Responseof the pregnant human uterus to low and high doses of prostaglandln E1 and E2. Acta. Obst. Gyn. Scand. 50:159, 1971. 14. Roth-Brandel, U. and Adams, M.: An evaluation of the possible use of prostaglandln El, E2 and F2a for induction of labour. Acta. Obst. Gyn. Stand. 5:9, 1970. 15. Bygdeman, M., Kwon, S.U., Mukherjee, T., Roth-Brandel, U. and W|qvlst, N.: The effect of the prostaglandin F compounds on the contractillty of the pregnant human uterus. Am. J. Obstet. Gynec. 106: 567, 1970. 16. Embrey, M.: PGE compounds for induction of labour and abortion. Ann. N.Y. Acad. Sci. 180:518, 1971. 17. Gillespie, A.: Use of prostaglandlns for induction of abortion and labor. Ann. N.Y. Acad. Sci. 180:524, 1971. 18. Anderson, G . G . , Hobblns, J.C., Cordero, L. and Speroff, L.: Clinical use of prostaglandlns as ocytocln substances. Ann. N.Y. Acad. Scl. 180:499, 1971. t9. Anderson, G . G . , Hobbins, J.C. and Speroff, L.: Intravenous prostaglandlns E2 and F2a for the induction of term labor. Am. J. Obstet. Gynec. 112:382, 1972. 20. Anderson, G I G . , Hobblns, J.C., Speroff, L. and Caldwell, B.V.: Intravenous prostaglandins E2 and F2a and syntocinon for the induction of term labor. J. Reprod. Med. 9:287, 1972. 21. Csapo, A.: Discussant: Brooklodge Symposium, June 12-14, 1972. 22. Spellacy, W . N . and Gall, S.A.: Prostaglandln F2a and oxytocin for term labor induction. J. Reprod. Med. 9:300, 1972. 23. Rangarajan, N.S., LaCrols, G.E. and Moghlssl, K.S.: Induction of labor with prostaglandin. Obstet. and Gynec. 38:546, 1971. 24. /Vk~ghissi, K.W., Rangarajan, N.S. and LaCrols, G.E.: Induction of labor with prostaglandin F2a and oxytocin. J. Reprod. Med. 9:304, 1972.
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25. Vakharlya, V.R. and Sherman, A . I . : Prostaglandln 1:2a For induction of labor. Am. J. Obstet. Gynec. 113:212, 1972. 26. Sherman, A . I . : 7 Jan., t972.
Inducing tough deliveries Faster. Med. WId. News:
27. Sherman, A.I. and Vakharlya, V.R.: An evaluation of prostaglandin F2a For the induction of labor at term. J. Reprod. Med. 9:292, 1972. 28. Caballero, A., Corredera, J., Garcla-Albertos, F., et al.: Prostaglandln PGF2a in induction of labor. Toko-Ginecologia Practlca 31:3, 1972. 29. Embrey, M.P.: Prostaglandlns. Proc. Roy. Soc. Med. 64:1018, 1971. 30. Kinoshita, K., Wagatsuma, T., Hogaki, M and Sakamoto, S.: The induction of labor with prostagland~n F2a. Acta. Obstet. Gynecol. Jap. 18:87, 1971. 31. Roberts, G. and Turnbull, A.C.: Uterine hypertonus during labour induced by prostaglandlns. Brit. Med. J. 1:702, 1971. 32. Karlm n S.M.M.: Use of prostaglandin E2 in the management of missed abortion, missed labour, and hydatldiForm mole. Brit. Med. J. 1:196, 1970. 33. Pedersen, P.H., Larsen, J.F. and Sorensen, B.: Induction of labour with prostaglandin F2a in missed abortion, Fetus mortuus, and anencephalia. Prostagl. 2:135, 1972. 34. Tchilinguirlan, N . G . O . : Comparison of prostaglandin F2a and pitocin in the induction of labor in high risk pregnant women. J. Reprod. Med. 9:331, 1972. 35. Barden, T.P.: Induction of preterm labor with prostaglandin F2a in patients with premature rupture of membranes. J. Reprod. Med. 9:339, 1972° 36. Thlery, M . , Vroman, B., Vanderheyden, K., deHemptlme, D., Derom, R., Van Kets, H. and Martens, G.: The fetal effect of prostaglandln F2a applied in the elective induction of labor at term. J. Reprod. Med. 9:314, 1972. 37. Blackburn, M . G . , Mancusi-Ungaro, H.R., Jr., Orzalesi, M . M . , Hobbins, J.C. and Anderson, G . G . : EFFectson the neonate of the induction of labor with prostaglandln F2a and oxytocln. Am. J. Obstet. Gynec. 116:847, 1973. 38. Karim, S.M.M. and Hillier, K.: Prostaglandlns and the induction of labor. Res. in Prostagl. 2:1, 1973. 39. Witting, W.C., Work, B.A. and karos, R.K.: Uterine activity response to constant infusion of prostaglandin F2a in term human pregnancy. J. Reprod. Med. 9:283, 1972. NOVEMBER 1973 VOL. 4 NO. 5
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40. Schulman, H. and Romney, S. k .: Variability of uterine contractions in normal human parturition. Obstet. and Gynec. 36:215, 1970. 41. Anderson, G.G.: Unpublished data. 42. LeMaire, W.J., Spe!lacy, W.N., Shevach, A.B. and Gall, S.A.: Changes in plasma estrlol and progesterone during labor induced with prostaglandln F2a or oxytocln. Prostagl. 2:93, 1972. 43. Spellacy, W . N . , Buhi, W.C. and Holslnger, K.K.: The effect of prostagland|n F2a and E2 on blood glucose and plasma insulin levels during pregnancy. Am. J. Obstet. Gynec. 111:239, 1971. 44. Roberts, G.: Induction of labour using prostaglandins. J. Reprod. Fert. 23:370, 1970. ,$5. Roberts, G., Anderson, A., McGarry, J. and Turnbull, A.C.: Absence of antldluresis during administration of prostaglandln F2a. Brit. Med. J. 2:152, 1970.
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