Archives of
Arch. Gynecol. 227, 171-179 (1979)
Gynecology © J. F. Bergmann Verlag 1979
The Use of Prostaglandin Gel in Obstetrics and Gynecology T. H. Lippert Universit/its-Frauenklinik Tfibingen(Geseh~iftsfiihrenderDirektor: Prof. Dr. H. A. Hirseh), SehleiehstraBe 4, D-7400 Tiibingen, Federal Republic of Germany
Die Anwendung von Prostaglandln-Gel in Gyn~ikologie und Geburtshilfe Zusammenfassung. In der vorliegenden Ubersichtsarbeit wird fiber die Anwendung von Prostaglandin-Gel bei den Indikationen: therapeutischer Schwangerschaftsabbruch im 2. Trimenon, Einleitung bei intrauterinem Fruchttod, Reifung der Zervix und Geburtseinleitung bei lebendem Kind berichtet. Mit Prostaglandin-Gel wird bei den genannten Indikationen neben guter Akzeptanz ffir die Patientinnen eine hohe Effektivit~it bei geringer Nebenwirkungs- und Komplikationsrate erzielt. Sehliisselw8rter: Prostaglandin-Gel - Schwangerschaftsabbruch im 2. Trimenon - Intrauteriner Fruchttod - Zervixreifung - Geburtseinleitung Summary. The use of prostaglandin gel for therapeutic termination of second trimester pregnancy, the management of intrauterine fetal death, ripening of the cervix and induction of labour is reviewed. For these indications, prostaglandin gel is acceptable to patients, effective, and has a low incidence of side effects and complications.
Key words: Prostaglandin gel - Termination of second trimester pregnancy Intra-uterine fetal death - Ripening of the cervix - Induction of labour Since 1970, the naturally occurring prostaglandins E 2 and F2a have found widely spread therapeutic uses in obstetrics and gynecology. Various routes of administration have been tried because the systemic route produces side effects and prostaglandin is inactivated in its passage through the maternal lungs so that only a small proportion of the dose given reaches the uterus. Till now, the intra-amniotic and extra-amniotic routes have found most favour, the former being preferred for induction of abortion in advanced second trimester pregnancy and the latter for induction of abortion in the early part of the second trimester (WHO recommendation). With the extra-amniotic route, prostaglandin is instilled between the membranes and the myometrium and so comes into direct contact with uterine muscle. Thus, relatively small amounts of prostaglandin are
0170-9925/79/0227/0171/$ 01.80
172
T.H. Lippert
required to produce effect. However, repeated doses are necessary as prostaglandin is metabolised rapidly. To avoid repeated administration, continuous extra-amniotic instillations were tried [11] but were found to require too much supervision for general use. When high doses of prostaglandin were given, pallor, painful uterine contractions, shivering, and nausea were often observed in the subsequent 30 to 45 min; many think that this is due to rapid, systemic absorption caused by damage to blood vessels when the catheter is introduced. To avoid this, Wiqvist et al. (1974) advised against introducing the catheter too far. This apparently sudden absorption and presumed catabolism of prostaglandins in the lungs seems to be associated with a poor success rate in therapeutic abortion [15-17]. To overcome this problem extra-amniotic prostaglandin has been incorporated in a medium of high viscosity.
Composition of Gel
Prostaglandin gel, introduced by Lippert and Modly in 1973, has the following composition: Tylose MH 300 4%, Glycerin 2%, Chlorhexidine digluconate 1%, Distilled water 83%, Prostaglandin solution 10%. The gel base is Tylose (hydroxyethylmethylcellulose, Hoechst AG). Like other methylcellulose derivatives, this Tylose base has high viscosity and can be used as a vehicle for drugs. The preparation is easily sterilised without chemical degradation by autoclaving at 120° C for 20 min. Addition of glycerin increases the viscosity of the preparation and delays drying out of the gel. Furthermore, glycerin itself has an action on uterine muscle [22] and was once used as an abortifacient. However, the amount of glycerin in prostaglandin gel is almost certainly too small to have any effect. Chlorhexidine gluconate is included in the gel to allow longer storage, the antiseptic action of chlorhexidine being only a secondary but desirable effect. Prostaglandin, in alcoholic solution, is easily incorporated into the aqueous gel base. The complete prostaglandin gel preparation is placed in aluminium tubes, protected from light and can be stored at - 2 0 ° C for up to one year. Others have chosen simpler and more viscous gel preparations and add the prostaglandin only just before use. In most cases, the gel base is also hydroxyethylmethylcellulose but methylcellulose [9], sodiumcarboxymethylcellulose [18, 19] and a strong solution of dextran [28] have also been used. The cellulose concentrations varied from 2 to 6% while the volume instilled varied from 0.5 to i 1.0 ml per injection. In many cases, the cellulose was autoclaved at 112 ° C for 15 min as a dry powder before being mixed with sterile distilled water; sometimes the highly viscous solution was sterilised after preparation. Since storage of such preparations was only intended for short spells at 4 ° C, no stabilising ingredient was necessary.
Administration of the Gel
A preparation of such high viscosity requires considerable pressure to force it through a catheter; polyethylene, Nelaton, or Foley catheters are used. With Foley
The Use of Prostaglandin Gel in Obstetrics and Gynecology
173
catheters, a balloon inflated with 5 to 30 ml of physiological saline prevents escape of the gel from the cervix. To avoid damage to blood vessels, catheters should not be passed very far into the uterus [25, 28]. Accidental rupture of the membranes is fortunately rare [25] and does not preclude successful induction of abortion [21]. Embrey and Mollison (1967) showed that an intracervical balloon could be used to induce labour but most people believe that the balloon itself has little therapeutic effect.
The Absorption of Prostaglandin Given in Aqueous and Viscous Vehicles One of the main advantages of administering prostaglandin in a medium of high viscosity is the greatly delayed prostaglandin release with an increase in the success rate of abortion and a diminution of observed side effects. Mackenzie and coworkers (1977) have examined the release of prostaglandins from aqueous and viscous media. They found a more rapid rise in intrauterine pressure when prostaglandin was given in aqueous solution, the absolute pressure being on average about 30% higher with the aqueous solution than with the gel. This difference was still evident after 2 h when a steady basal tone had developed. In only three of their patients given prostaglandin gel were pressure responses similar to those seen with aqueous solutions and it was assumed that in these patients rapid absorption occurred due to damage of blood vessels. These authors also found higher plasma and amniotic fluid prostaglandin concentrations after extra-amniotic prostaglandin E 2 in aqueous solution. They also examined radiologically the disappearance of a contrast medium added to the prostaglandin base and found that contrast medium disappeared more rapidly with aqueous solution than with gels. The higher incidence of side effects with aqueous solutions can be attributed to the rapid absorption of prostaglandin into the systemic circulation [14, 23]. The exact level at which the aqueous solution is instilled seems to be of no significance. Wiqvist et al. (1974) tested the prostaglandin derivative 15-methyl prostaglandin F2~ in a low viscous medium (aqueous solution) in a highly viscous medium (30% dextran 70) and in a solid medium (suppositories with lipid base) all given by the extra-amniotic route; they showed that the viscous medium was best, being associated with the lowest incidence of side effects due to rapid absorption and the highest success rate.
Use of Prostaglandin Gel in Gynecology Prostaglandin gel was first introduced in 1973 for induction of abortion in the 2nd trimester [12]. Since then, it has been used successfully in a highly viscous medium in various centres. Table 1 summarises the data available from published work. This includes not only results of induction of abortion but also results of inducing labour in cases of intrauterine fetal death. The gestational age was relatively uniform, the majority of patients being in the 2nd trimester. Prostaglandin E2, F2~ and 15-methylprostaglandin F2~ in highly viscous media have all been employed. The criteria for
174
T.H. Lippert
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Arch. Gynecol. 227, 171-179 (1979)
Gynecology © J. F. Bergmann Verlag 1979
The Use of Prostaglandin Gel in Obstetrics and Gynecology T. H. Lippert Universit/its-Frauenklinik Tfibingen(Geseh~iftsfiihrenderDirektor: Prof. Dr. H. A. Hirseh), SehleiehstraBe 4, D-7400 Tiibingen, Federal Republic of Germany
Die Anwendung von Prostaglandln-Gel in Gyn~ikologie und Geburtshilfe Zusammenfassung. In der vorliegenden Ubersichtsarbeit wird fiber die Anwendung von Prostaglandin-Gel bei den Indikationen: therapeutischer Schwangerschaftsabbruch im 2. Trimenon, Einleitung bei intrauterinem Fruchttod, Reifung der Zervix und Geburtseinleitung bei lebendem Kind berichtet. Mit Prostaglandin-Gel wird bei den genannten Indikationen neben guter Akzeptanz ffir die Patientinnen eine hohe Effektivit~it bei geringer Nebenwirkungs- und Komplikationsrate erzielt. Sehliisselw8rter: Prostaglandin-Gel - Schwangerschaftsabbruch im 2. Trimenon - Intrauteriner Fruchttod - Zervixreifung - Geburtseinleitung Summary. The use of prostaglandin gel for therapeutic termination of second trimester pregnancy, the management of intrauterine fetal death, ripening of the cervix and induction of labour is reviewed. For these indications, prostaglandin gel is acceptable to patients, effective, and has a low incidence of side effects and complications.
Key words: Prostaglandin gel - Termination of second trimester pregnancy Intra-uterine fetal death - Ripening of the cervix - Induction of labour Since 1970, the naturally occurring prostaglandins E 2 and F2a have found widely spread therapeutic uses in obstetrics and gynecology. Various routes of administration have been tried because the systemic route produces side effects and prostaglandin is inactivated in its passage through the maternal lungs so that only a small proportion of the dose given reaches the uterus. Till now, the intra-amniotic and extra-amniotic routes have found most favour, the former being preferred for induction of abortion in advanced second trimester pregnancy and the latter for induction of abortion in the early part of the second trimester (WHO recommendation). With the extra-amniotic route, prostaglandin is instilled between the membranes and the myometrium and so comes into direct contact with uterine muscle. Thus, relatively small amounts of prostaglandin are
0170-9925/79/0227/0171/$ 01.80
172
T.H. Lippert
required to produce effect. However, repeated doses are necessary as prostaglandin is metabolised rapidly. To avoid repeated administration, continuous extra-amniotic instillations were tried [11] but were found to require too much supervision for general use. When high doses of prostaglandin were given, pallor, painful uterine contractions, shivering, and nausea were often observed in the subsequent 30 to 45 min; many think that this is due to rapid, systemic absorption caused by damage to blood vessels when the catheter is introduced. To avoid this, Wiqvist et al. (1974) advised against introducing the catheter too far. This apparently sudden absorption and presumed catabolism of prostaglandins in the lungs seems to be associated with a poor success rate in therapeutic abortion [15-17]. To overcome this problem extra-amniotic prostaglandin has been incorporated in a medium of high viscosity.
Composition of Gel
Prostaglandin gel, introduced by Lippert and Modly in 1973, has the following composition: Tylose MH 300 4%, Glycerin 2%, Chlorhexidine digluconate 1%, Distilled water 83%, Prostaglandin solution 10%. The gel base is Tylose (hydroxyethylmethylcellulose, Hoechst AG). Like other methylcellulose derivatives, this Tylose base has high viscosity and can be used as a vehicle for drugs. The preparation is easily sterilised without chemical degradation by autoclaving at 120° C for 20 min. Addition of glycerin increases the viscosity of the preparation and delays drying out of the gel. Furthermore, glycerin itself has an action on uterine muscle [22] and was once used as an abortifacient. However, the amount of glycerin in prostaglandin gel is almost certainly too small to have any effect. Chlorhexidine gluconate is included in the gel to allow longer storage, the antiseptic action of chlorhexidine being only a secondary but desirable effect. Prostaglandin, in alcoholic solution, is easily incorporated into the aqueous gel base. The complete prostaglandin gel preparation is placed in aluminium tubes, protected from light and can be stored at - 2 0 ° C for up to one year. Others have chosen simpler and more viscous gel preparations and add the prostaglandin only just before use. In most cases, the gel base is also hydroxyethylmethylcellulose but methylcellulose [9], sodiumcarboxymethylcellulose [18, 19] and a strong solution of dextran [28] have also been used. The cellulose concentrations varied from 2 to 6% while the volume instilled varied from 0.5 to i 1.0 ml per injection. In many cases, the cellulose was autoclaved at 112 ° C for 15 min as a dry powder before being mixed with sterile distilled water; sometimes the highly viscous solution was sterilised after preparation. Since storage of such preparations was only intended for short spells at 4 ° C, no stabilising ingredient was necessary.
Administration of the Gel
A preparation of such high viscosity requires considerable pressure to force it through a catheter; polyethylene, Nelaton, or Foley catheters are used. With Foley
The Use of Prostaglandin Gel in Obstetrics and Gynecology
173
catheters, a balloon inflated with 5 to 30 ml of physiological saline prevents escape of the gel from the cervix. To avoid damage to blood vessels, catheters should not be passed very far into the uterus [25, 28]. Accidental rupture of the membranes is fortunately rare [25] and does not preclude successful induction of abortion [21]. Embrey and Mollison (1967) showed that an intracervical balloon could be used to induce labour but most people believe that the balloon itself has little therapeutic effect.
The Absorption of Prostaglandin Given in Aqueous and Viscous Vehicles One of the main advantages of administering prostaglandin in a medium of high viscosity is the greatly delayed prostaglandin release with an increase in the success rate of abortion and a diminution of observed side effects. Mackenzie and coworkers (1977) have examined the release of prostaglandins from aqueous and viscous media. They found a more rapid rise in intrauterine pressure when prostaglandin was given in aqueous solution, the absolute pressure being on average about 30% higher with the aqueous solution than with the gel. This difference was still evident after 2 h when a steady basal tone had developed. In only three of their patients given prostaglandin gel were pressure responses similar to those seen with aqueous solutions and it was assumed that in these patients rapid absorption occurred due to damage of blood vessels. These authors also found higher plasma and amniotic fluid prostaglandin concentrations after extra-amniotic prostaglandin E 2 in aqueous solution. They also examined radiologically the disappearance of a contrast medium added to the prostaglandin base and found that contrast medium disappeared more rapidly with aqueous solution than with gels. The higher incidence of side effects with aqueous solutions can be attributed to the rapid absorption of prostaglandin into the systemic circulation [14, 23]. The exact level at which the aqueous solution is instilled seems to be of no significance. Wiqvist et al. (1974) tested the prostaglandin derivative 15-methyl prostaglandin F2~ in a low viscous medium (aqueous solution) in a highly viscous medium (30% dextran 70) and in a solid medium (suppositories with lipid base) all given by the extra-amniotic route; they showed that the viscous medium was best, being associated with the lowest incidence of side effects due to rapid absorption and the highest success rate.
Use of Prostaglandin Gel in Gynecology Prostaglandin gel was first introduced in 1973 for induction of abortion in the 2nd trimester [12]. Since then, it has been used successfully in a highly viscous medium in various centres. Table 1 summarises the data available from published work. This includes not only results of induction of abortion but also results of inducing labour in cases of intrauterine fetal death. The gestational age was relatively uniform, the majority of patients being in the 2nd trimester. Prostaglandin E2, F2~ and 15-methylprostaglandin F2~ in highly viscous media have all been employed. The criteria for
174
T.H. Lippert
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