Acta Obstet Gynecol Scand 1990; 69: 621-625
VAGINAL ADMINISTRATION OF PGE, FOR INDUCTION OF LABOR STIMULATES ENDOGENOUS PGF,, PRODUCTION Ian A. Greer,' Margaret McLaren2 a n d Andrew A. Calder' From the 'Department of Obstetrics and Gynaecology, University of Edinburgh, EH3 9EW and *Department of Medicine, University of Dundee, DDl 9SY. Scotland. Abstract. Prostaglandin E, is effective for induction of labor but many preparations exist using a variety of vehicles from which the active ingredient may not be equally available. Plasma concentrations of bicyclic PGE, metabolite (PGEM) and 13, 16dihydr0, 15-keto PGF, (PGFM) were measured following administration of a 3mg PGE, vaginal tablet or l m g PGE, vaginal gel to twenty-four parous women with favorable induction features, randomly allocated to receive one or other preparation. PGEM increased rapidly following both administration of the 3mg PGE, vaginal tablet and the l m g PGE, vaginal gel, reaching a peak within 40 minutes of PGE, administration. The maximal rise in PGEM in the gel group correlated directly with the change in cervical score and inversely with the need for augmentation with oxytocin and the induction-delivery interval. A secondary rise in PGFM was noted in both groups 3-4 hours following PGE, administration. The magnitude of the increase in PGE, may be important in the clinical response to PGE, administration, while PGE, absorption may switch-on endogenous PGF,, production, similar to what is seen in spontaneous labor. Key words: prostaglandins, metabolites, induction of labor, labor physiology, labor pharmacology, randomised trial
Prostaglandin E2plays a major role in the physiology and pharmacology of parturition where it is an important mediator of both cervical ripening and uterine contractility ( 1 , 2). During spontaneous labor amniotic fluid concentrations of PGE, and PGF,, increase substantially (3). In peripheral plasma, PGF,,, metabolites also increase although no change has been noted with regard to PGE, metabolites (4). Prostaglandin E2 has been exploited as a pharmacological agent for cervical ripening and induction of labor (2). The most commonly employed route of administration for PGE, is vaginally and a variety of vehicles have been employed for the prostaglandin. These range from wax and lactose based preparations (5,6) to sustained release hydrogel polymers (7). Two widely used commercially available prep-
Abbreviations: PGE, (Prostaglandin E,), PGEM (Prostaglandin E, metabolite), PGF," (Prostaglandin F2Jr PGFM (Prostaglandin F, metabolite). 40
arations are 3mg PGE, lactose based vaginal tablets and triacetin gel preparations containing either lmg or 2mg of PGE,. Despite the widespread use of PGE, for induction of labor, there is little information on changes in PGE, and PGF,, metabolites in the circulation following PGE, administration. This has, at least in part, been due to problems associated with measurement of PGE, metabolites in plasma. The primary prostaglandin, PGE,, is unstable and is converted by prostaglandin dehydrogenase to 13, 14 dihydro, 15keto PGE, which is itself unstable and is converted to 13.14-dihydro, 15-keto PGA, by dehydration. This latter metabolite also binds covalently to albumen, compounding difficulties of measurement. The identification of a degradation product of these major metabolites (1 1-deoxy-13,14-dihydro-15-keto1l~,l6s-cyclo-PGE2) (8) has allowed a more reliable assay to be developed (9), which can be utilised to study changes in PGE, metabolites in peripheral plasma. The aim of this study was to measure PGE, and Acta Obstet Gynecol Scand 69 (1990)
622
Ian A . Greer el al.
Table I. Patient characteristics of the two groups randomised to receive either PGE, vaginal tablets or gel
n Mean age (years) Parity Para 1 Para 2 Para 3
Indication for Induction Post Term Hypertension
Vaginal Tablet
Vaginal Gel
12 29.8 (SD 3.8)
12 26.5 (SD 7.2)
8 3 1
6 4 2
9 3
11 1
PGF2, metabolites in peripheral plasma following induction of labour with 3mg PGE, vaginal tablets and lmg PGEz in triacetin gel given vaginally. MATERIAL AND METHODS Twenty-four parous women at term with favorable induction features were studied. No patient had received any previous prostaglandin administration, and cervical scores (2) were in the range 4-7. The patients were randomised by random selection of envelopes to receive either a 3mg PGE? lactose based vaginal tablet (Upjohn) or lmg PGE, vaginal triacetin gel (Upjohn). The two groups were comparable in terms of age, parity and indication for induction (Table I). The cervical score was assessed before PGE, administration and four hours later by the same observer. A water based lubricant (K-Yjelly) was used for all examinations. Forewater amniotomy was performed at four hours and patients were augmented with escalating intravenous oxytocin two hours following amniotomy if not in established labor (cervix > 3cm dilated with regular, painful uterine activity). Labor was augmented after six hours if progress was slow (less than l c d h o u r progressive cervical dilatation for two hours or more). Venous blood samples were obtained using a 17 gauge intra-venous cannula placed into a forearm vein. Samples
were obtained prior to and at 20, 40, 60,120, 180 and 240 minutes following prostaglandin administration, the final samples being obtained prior to vaginal examination and amniotomy. The blood was placed immediately into icecold tubes containing 3.8% trisodium citrate and 3 x M indomethacin (nine volumes of blood to one volume anticoagulant). The samples were kept on ice and then centrifuged for 15 minutes at 4°C and 3,000 rpm within 30 minutes of obtaining the sample. Plasma was separated and then stored at -70°C until assayed. PGE, and PGF,,, were measured by radioimmunoassay of 1l-deoxy-13,14-dihydro-15-keto-11~,16~-cyclo PGE, (PGEM) (Amersham U.K.) and 13.14 dihydro 15-keto PGF,, (PGFM) (Sigma U.S.A.). The Wilcoxon signed rank test for paired data was used to assess changes in prostaglandin metabolites and in cervical score within each group. The Student’s r-test was used to compare age, induction-delivery interval, amniotomydelivery interval, birthweight and blood loss and the x2 test to compare parity, indication for induction and number requiring augmentation between the groups. The MannWhitney “U”test was used to assess differences in cervical scores at 0 and 4 hours between the groups. Correlation was assessed using the Spearman rank test.
RESULTS There was no significant difference between the groups in terms of clinical features or clinical outcome (Table 11). The changes in PGEM and PGFM are shown in Fig. 1. In the gel group there was a rapid increase in PGEM within 20 minutes and concentrations remained elevated over the four hour period. There was a small but significant rise in PGFM after 20 minutes and concentrations remained relatively stable until between 3 and 4 hours when a marked secondary increase in PGFM occurred. The vaginal tablet group showed a much smaller increase in PGEM reaching significance at only 40 minutes and at 3 and 4 hours. There was a significant increase in PGFM levels over the first
Table II. Clinical outcome in the two groups randomised to vaginal PGE, tablets or gel
Median (range) initial cervical score Median (range) 4 hour cervical score Median (range) change in cervical score Number augmented with oxytocin Mean induction-delivery interval (hours) Mean amniotomy-delivery interval (hours) Number with spontaneous vaginal delivery Mean blood loss (ml) Mean birthweight (9) Median (range) Apgar scores - 5 min
Vaginal Tablet
Vaginal Gel
(n= 12)
(n=12)
5 (4-7) 7 (4-10)** 2 (0-3) 5 10.4 (SD 3.50) 6.2(SD 3.57) 12 190 (SD 138) 3510 (SD 315) 9 (8-10)
4.5 (4-7) 6.5(4-12)’ 2 (0-5) 5 9.0 (SD 3.0) 4.9 (SD 3.33) 12 219 (SD 267) 3560 (SD 430) 9 (8-10)
* p
VAGINAL ADMINISTRATION OF PGE, FOR INDUCTION OF LABOR STIMULATES ENDOGENOUS PGF,, PRODUCTION Ian A. Greer,' Margaret McLaren2 a n d Andrew A. Calder' From the 'Department of Obstetrics and Gynaecology, University of Edinburgh, EH3 9EW and *Department of Medicine, University of Dundee, DDl 9SY. Scotland. Abstract. Prostaglandin E, is effective for induction of labor but many preparations exist using a variety of vehicles from which the active ingredient may not be equally available. Plasma concentrations of bicyclic PGE, metabolite (PGEM) and 13, 16dihydr0, 15-keto PGF, (PGFM) were measured following administration of a 3mg PGE, vaginal tablet or l m g PGE, vaginal gel to twenty-four parous women with favorable induction features, randomly allocated to receive one or other preparation. PGEM increased rapidly following both administration of the 3mg PGE, vaginal tablet and the l m g PGE, vaginal gel, reaching a peak within 40 minutes of PGE, administration. The maximal rise in PGEM in the gel group correlated directly with the change in cervical score and inversely with the need for augmentation with oxytocin and the induction-delivery interval. A secondary rise in PGFM was noted in both groups 3-4 hours following PGE, administration. The magnitude of the increase in PGE, may be important in the clinical response to PGE, administration, while PGE, absorption may switch-on endogenous PGF,, production, similar to what is seen in spontaneous labor. Key words: prostaglandins, metabolites, induction of labor, labor physiology, labor pharmacology, randomised trial
Prostaglandin E2plays a major role in the physiology and pharmacology of parturition where it is an important mediator of both cervical ripening and uterine contractility ( 1 , 2). During spontaneous labor amniotic fluid concentrations of PGE, and PGF,, increase substantially (3). In peripheral plasma, PGF,,, metabolites also increase although no change has been noted with regard to PGE, metabolites (4). Prostaglandin E2 has been exploited as a pharmacological agent for cervical ripening and induction of labor (2). The most commonly employed route of administration for PGE, is vaginally and a variety of vehicles have been employed for the prostaglandin. These range from wax and lactose based preparations (5,6) to sustained release hydrogel polymers (7). Two widely used commercially available prep-
Abbreviations: PGE, (Prostaglandin E,), PGEM (Prostaglandin E, metabolite), PGF," (Prostaglandin F2Jr PGFM (Prostaglandin F, metabolite). 40
arations are 3mg PGE, lactose based vaginal tablets and triacetin gel preparations containing either lmg or 2mg of PGE,. Despite the widespread use of PGE, for induction of labor, there is little information on changes in PGE, and PGF,, metabolites in the circulation following PGE, administration. This has, at least in part, been due to problems associated with measurement of PGE, metabolites in plasma. The primary prostaglandin, PGE,, is unstable and is converted by prostaglandin dehydrogenase to 13, 14 dihydro, 15keto PGE, which is itself unstable and is converted to 13.14-dihydro, 15-keto PGA, by dehydration. This latter metabolite also binds covalently to albumen, compounding difficulties of measurement. The identification of a degradation product of these major metabolites (1 1-deoxy-13,14-dihydro-15-keto1l~,l6s-cyclo-PGE2) (8) has allowed a more reliable assay to be developed (9), which can be utilised to study changes in PGE, metabolites in peripheral plasma. The aim of this study was to measure PGE, and Acta Obstet Gynecol Scand 69 (1990)
622
Ian A . Greer el al.
Table I. Patient characteristics of the two groups randomised to receive either PGE, vaginal tablets or gel
n Mean age (years) Parity Para 1 Para 2 Para 3
Indication for Induction Post Term Hypertension
Vaginal Tablet
Vaginal Gel
12 29.8 (SD 3.8)
12 26.5 (SD 7.2)
8 3 1
6 4 2
9 3
11 1
PGF2, metabolites in peripheral plasma following induction of labour with 3mg PGE, vaginal tablets and lmg PGEz in triacetin gel given vaginally. MATERIAL AND METHODS Twenty-four parous women at term with favorable induction features were studied. No patient had received any previous prostaglandin administration, and cervical scores (2) were in the range 4-7. The patients were randomised by random selection of envelopes to receive either a 3mg PGE? lactose based vaginal tablet (Upjohn) or lmg PGE, vaginal triacetin gel (Upjohn). The two groups were comparable in terms of age, parity and indication for induction (Table I). The cervical score was assessed before PGE, administration and four hours later by the same observer. A water based lubricant (K-Yjelly) was used for all examinations. Forewater amniotomy was performed at four hours and patients were augmented with escalating intravenous oxytocin two hours following amniotomy if not in established labor (cervix > 3cm dilated with regular, painful uterine activity). Labor was augmented after six hours if progress was slow (less than l c d h o u r progressive cervical dilatation for two hours or more). Venous blood samples were obtained using a 17 gauge intra-venous cannula placed into a forearm vein. Samples
were obtained prior to and at 20, 40, 60,120, 180 and 240 minutes following prostaglandin administration, the final samples being obtained prior to vaginal examination and amniotomy. The blood was placed immediately into icecold tubes containing 3.8% trisodium citrate and 3 x M indomethacin (nine volumes of blood to one volume anticoagulant). The samples were kept on ice and then centrifuged for 15 minutes at 4°C and 3,000 rpm within 30 minutes of obtaining the sample. Plasma was separated and then stored at -70°C until assayed. PGE, and PGF,,, were measured by radioimmunoassay of 1l-deoxy-13,14-dihydro-15-keto-11~,16~-cyclo PGE, (PGEM) (Amersham U.K.) and 13.14 dihydro 15-keto PGF,, (PGFM) (Sigma U.S.A.). The Wilcoxon signed rank test for paired data was used to assess changes in prostaglandin metabolites and in cervical score within each group. The Student’s r-test was used to compare age, induction-delivery interval, amniotomydelivery interval, birthweight and blood loss and the x2 test to compare parity, indication for induction and number requiring augmentation between the groups. The MannWhitney “U”test was used to assess differences in cervical scores at 0 and 4 hours between the groups. Correlation was assessed using the Spearman rank test.
RESULTS There was no significant difference between the groups in terms of clinical features or clinical outcome (Table 11). The changes in PGEM and PGFM are shown in Fig. 1. In the gel group there was a rapid increase in PGEM within 20 minutes and concentrations remained elevated over the four hour period. There was a small but significant rise in PGFM after 20 minutes and concentrations remained relatively stable until between 3 and 4 hours when a marked secondary increase in PGFM occurred. The vaginal tablet group showed a much smaller increase in PGEM reaching significance at only 40 minutes and at 3 and 4 hours. There was a significant increase in PGFM levels over the first
Table II. Clinical outcome in the two groups randomised to vaginal PGE, tablets or gel
Median (range) initial cervical score Median (range) 4 hour cervical score Median (range) change in cervical score Number augmented with oxytocin Mean induction-delivery interval (hours) Mean amniotomy-delivery interval (hours) Number with spontaneous vaginal delivery Mean blood loss (ml) Mean birthweight (9) Median (range) Apgar scores - 5 min
Vaginal Tablet
Vaginal Gel
(n= 12)
(n=12)
5 (4-7) 7 (4-10)** 2 (0-3) 5 10.4 (SD 3.50) 6.2(SD 3.57) 12 190 (SD 138) 3510 (SD 315) 9 (8-10)
4.5 (4-7) 6.5(4-12)’ 2 (0-5) 5 9.0 (SD 3.0) 4.9 (SD 3.33) 12 219 (SD 267) 3560 (SD 430) 9 (8-10)
* p
