Fetal effects of cervical ripening with extra-amniotic prostaglandin E2 in gel

A gel containing 0.5 mg prostaglandin E2 (PGE2) was extra-amniotically instilled to 90 clinically normal gravidae at term, for ripening of the cervix before elective induction of labor by amniotomy and intravenous PGE2. An acceptable increase in the Bishop score was noted to have occurred in 87/90 women, when assessed eight hours after administration of the gel; 14 of these women were then in established labor, which progressed uneventfully. Four of the 90 subjects required cesarean section for cephalopelvic disproportion. No adverse maternal or fetal effects of the procedure were detected under careful clinical, electronic and biochemical monitoring. However, epidural anesthesia adversely influenced the acid-base equilibrium of the fetus.     

Cervical ripening and plasma prostaglandin levels. Comparison of endocervical and extra-amniotic PGE2

Two modes of cervical application of a gel containing PGE2 have been compared in a total of 30 patients with indication for induction of labor and unripe cervix. Fifteen patients had gel injected endocervically; in 10 patients the gel contained 400 micrograms PGE2, in 5 controls the gel was inactive. Fifteen subjects had a 15 ml Foley catheter passed through the cervix and placed extra-amniotically; in 10 of them 3 ml gel with 400 or 800 micrograms PGE2 was injected, while 5 controls received inactive gel. Plasma levels of 13,14-dihydro-15-keto-PGE2 alpha (PGFM) were measured in blood samples drawn before and 1/2, 1, 2, 4, 6, and 8 hours after gel application. Neither the Foley catheter nor the application of inactive gel caused significant changes in the cervical scores or the PGFM levels. PGE2 in the endocervix increased cervical scores without altering plasma PGFM levels. Extra-amniotic PGE2 caused a more rapid increase of the cervical scores and a progressive rise in PGFM levels. The plasma (PGFM) levels were found to be related to the degree and to the rate of cervical dilatation. The correlation with cervical dilatation was highly significant. Labor began spontaneously or after artificial rupture of the membranes in 80% of the extra-amniotic, and 50% of the endocervical PGE2-group, but in none of the controls. These data indicate that increased uterine PGF2 alpha production is not necessary for the early stages of cervical ripening, whereas dilatation beyond 4 cm does not proceed without such increase.     

Comparative study of oestradiol and prostaglandin E2 vaginal gel for ripening the unfavourable cervix before induction of labour.

Oestradiol 150 mg and prostaglandin E2 (PGE2) 4 mg suspended in viscous gel and applied intravaginally were compared with regard to ripening the unfavourable cervix of patients randomly allocated to two study groups. In primigravidae no significant difference was observed in the efficacy of the two substances. Some multiparous patients, however, had considerably more uterine sensitivity to PGE2 quickly developed decelerative cardiotocographic tracings after insertion of the gel. In the group given oestradiol there was a significant absence of uterine activity after gel application. The findings suggest that oestradiol applied vaginally is a safe, comfortable, cheap, and equally effective alternative to PGE2 for ripening the cervix, without the disadvantages of uterine stimulation frequently encountered with PGE2.     

Cervical ripening prior to induction of labor (intracervical application of a PG E2 viscous gel).

In 38 pregnant patients at term with unfavorable cervices labor induction was initiated with PG-E2 after a preceding intracervical application of 0.1, 0.2 or 0.3 mg PG-E2 in 1 ml viscous gel. The mean Bishop score improved from 3.36 to 7.0 in an average time of 2 h 37 min. The cervical diameter increased from 14 mm to 22.7 mm. 31 patients delivered their babies spontaneously, while 7 patients were delivered by cesarean section due to cervical dystocia and delayed labor. Fetal outcome was normal in all cases, with an average Apgar score of 8.7 and an average pH-value in the umbilical artery of 7.245. The study indicates that local application of PG-E2 induces cervical dilatation, and is of particular use in patients presenting a low Bishop score. A possible local effect of PG E2 is discussed.     

Endocervical prostaglandin E2 gel for preinduction cervical softening

A single, endocervical application of a new commercial preparation of prostaglandin E2 (PGE2) gel, 0.5 mg of PGE2 in 2.5 ml (3 g), was evaluated for preinduction cervical softening. Safety and efficacy were assessed in a comparison with a 2.0 mg PGE2 vaginal tablet and placebo in normal nulliparous women at term, with low Bishop scores. Treatment was administered in randomized, double blind fashion. Overall success, defined as a progression in Bishop score of at least 3 points within 12 hours, was achieved in 22/40 (55%) of the gel group, 15/41 (37%) in the tablet treated women, and 8/40 (20%) in those receiving placebo. Of interest was the observation that of women with very unfavorable induction features (Bishop score 0-2), the cervical gel treatment resulted in a 6/8 (75%) success rate compared with 2/13 (15%) success for the vaginal tablet and 0/17 (0%) for placebo. In as much as a very low incidence of side effects accompanied this treatment scheme, expanded multi-center testing is recommended.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm.

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E2 suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE2 suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE2 suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2 degrees F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last adminstration of PGE2. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE2 suppositories is a very effective abortifacient technque during the midtrimester, however the use of PGE2 in conjunction with a diaphragm did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE2 suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death.

In established intrauterine fetal death, 20 patients were treated with prostaglandin E2 gel administered extraamniotically. The results were compared with those of another group of 20 patients who had received combined treatment. In this group, one or more of the following agents had been administered :- i.v. oxytocin, 20% NaCl solution or Premarin instilled intraamniotically, introduction of a balloon catheter or Rivanol administered extraamniotically. Average induction-abortion interval for the PG group was about 12 hours while for the second group it was about 30 hours. The side effects observed were slight in both groups. The results show that administration of PG-gel can be used with advantage in fetal demise because of the relatively short induction-abortion intervals obtained, the insignificant side effects and the low dose of PG required.     

Cervical ripening and uterine contraction induced by prostaglandin E2-gel in pregnant Japanese monkeys (Macaca fuscata fuscata)

Effects of intracervical administration of PGE₂-gel were studied in pregnant Japanese monkeys (Macaca fuscata fuscata) near term. Administration of PGE₂-gel induced cervical ripening and an increase in maternal plasma PGE₂ but no change in PGF_2α. Ultrastructural observations of the connective tissue of the cervix after PGE₂-gel treatment revealed a decrease in the number of collagenous fibers. These results show that intracervical administration of PGE₂-gel induces cervical ripening without induction of labor in the Japanese monkey.     

Cervical ripening and plasma prostaglandin levels. Comparison of endocervical and extra-amniotic PGE2

Two modes of cervical application of a gel containing PGE₂ have been compared in a total of 30 patients with indication for induction of labor and unripe cervix. Fifteen patients had gel injected endocervically; in 10 patients the gel contained 400μg PGE₂, in 5 controls the gel was inactive. Fifteen subjects had a 15 ml Foley catheter passed through the cervix and placed extra-amniotically; in 10 of them 3 ml gel with 400 or 800μg PGE₂ was injected, while 5 controls received inactive gel. Plasma levels of 13,14-dihydro-15-keto-PGF_2α (PGFM) were measured in blood samples drawn before and , 1, 2, 4, 6, and 8 hours after gel application. Neither the Foley catheter nor the application of inactive gel caused significant changes in the cervical scores or the PGFM levels. PGE₂ in the endocervix increased cervical scores without altering plasma PGFM levels. Extra-amniotic PGE₂ caused a more rapid increase of the cervical scores and a progressive rise in PGFM levels. The plasma (PGFM) levels were found to be related to the degree and to the rate of cervical dilatation. The correlation with cervical dilatation was highly significant. Labor began spontaneously or after artificial rupture of the membranes in 80% of the extra-amniotic, and 50% of the endocervical PGE₂-group, but in none of the controls. These data indicate that the increased uterine PGF_2α production is not necessary for the early stages of cervical ripening, whereas dilatation beyond 4 cm does not proceed without such increase.     

Prostaglandin metabolite levels during cervical ripening with a controlled-release hydrogel polymer prostaglandin E2 pessary

Prostaglandin E and F metabolite (PGEM and PGFM) concentrations in peripheral plasma were assayed following the vaginal administration of a controlled release hydrogel polymer pessary designed to release 0.6 mg PGE2 per hour in vivo. A linear relationship between calculated PGE2 release from the pessary and PGEM levels was observed with a correlation coefficient of 0.78. A significant rise in PGEM levels occurred two hours following pessary administration, with significantly higher PGEM levels in patients delivering within the eight hour observation period compared with those delivering later. PGFM levels increased more slowly. The results suggest that PGE2 released by the pessary crosses the vaginal epithelium and may stimulate endogenous prostaglandin production. The controlled rise of metabolites in association with the polymer pessary suggest that it should provide greater control in labour induction than other vehicles we have studied, but this should be confirmed by clinical trials.     

Single extra-amniotic injection of prostaglandin E2 in viscous gel to induce mid-trimester abortion.

In a preliminary study a single extra-amniotic injection of 1.5 mg of prostaglandin E-2 incorporated into an aqueous viscous gel was given to 24 patients aborted within 24 hours, and the mean induction-abortion interval (plus or minus S.E. of mean) was 13.5 plus or minus 1.5 hours. Vomiting occurred in seven patients, and transient severe uterine cramps, pallor, nausea, and shivering occurred in one patient immediately after injection. Complete abortion occurred in 20patients. A delay in the time taken to abort seemed to be associated with an immediate and rapid rise in uterine tone after the injection which required prompt analgesia; this probably reflected rapid decidual absorption and dissolution of the prostaglandins away from their site of action. The degree of distention of the catheter-retaining balloon did not influence abortion times.     

Inducing labour with vaginally administered prostaglandin E2.

In 50 consecutive pregnant women at a 125-bed community hospital with 1000 deliveries annually, labour was induced with prostaglandin E2 administered intravaginally. There were no stillbirths or neonatal deaths, and complications in the mothers were few. In nine women (18%) oxytocin was subsequently administered because of a failure of labour to progress; in spite of this, cesarean section was required in two (4%) of the patients. The overall cesarean section rate was 6%. Prostaglandins have been used routinely to induce labour in the United Kingdom for several years. This noninvasive method is safe, effective and well received by women in a community hospital setting, including those wanting "natural childbirth".     

Regulation of agonist-induced prostaglandin E1 versus prostaglandin E2 production. A mass analysis.

Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2), derived by enzymatic oxidation of cellular dihomogammalinolenic acid (DHLA) and arachidonic acid (AA), respectively, have diverse and, at times, distinct biological actions. It has been suggested that PGE1 specifically inhibits a variety of inflammatory processes, and, in light of the potential therapeutic benefit of PGE1 and its fatty acid precursor in inflammatory disorders, there is growing interest in the biochemical mechanisms which determine the balance between PGE1 and PGE2 synthesis. Metabolic studies in this area have been hampered by the difficulties in measuring the extremely small masses of these prostaglandins which are generated in cell culture systems. We studied the regulation of PGE1 versus PGE2 synthesis using an essential fatty acid-deficient, PGE-producing, mouse fibrosarcoma cell line, EFD-1. Because EFD-1 cells contain no endogenous AA or DHLA, we were able to replete the cells with AA and DHLA of known specific activities; thus, the mass of both cellular AA and DHLA, and synthesized PGE1 and PGE2, could be accurately determined. The major finding of this study is that production of PGE2 was highly favored over production of PGE1 due to preferential incorporation of AA versus DHLA into, and release from, the total cellular phospholipid pool. Further, we correlated the selective release of AA versus DHLA from total cellular phospholipids with the selective incorporation of AA versus DHLA into specific phospholipid pools. In addition, we showed that conversion of DHLA to AA by delta 5 desaturase was enhanced by increasing the cellular mass of n-6 fatty acids and by increasing the cell proliferative activity. Together, these results indicate that the relative abundance of PGE2 versus PGE1 in vivo is not merely a function of the relative abundance of AA versus DHLA in tissues, but also relates to markedly different cellular metabolism of these two fatty acids.     

Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2

Here we report the molecular identification of membrane-bound glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (mPGES), a terminal enzyme of the cyclooxygenase (COX)-2-mediated PGE(2) biosynthetic pathway. The activity of mPGES was increased markedly in macrophages and osteoblasts following proinflammatory stimuli. cDNA for mouse and rat mPGESs encoded functional proteins that showed high homology with the human ortholog (microsomal glutathione S-transferase-like 1). mPGES expression was markedly induced by proinflammatory stimuli in various tissues and cells and was down-regulated by dexamethasone, accompanied by changes in COX-2 expression and delayed PGE(2) generation. Arg(110), a residue well conserved in the microsomal GSH S-transferase family, was essential for catalytic function. mPGES was functionally coupled with COX-2 in marked preference to COX-1, particularly when the supply of arachidonic acid was limited. Increased supply of arachidonic acid by explosive activation of cytosolic phospholipase A(2) allowed mPGES to be coupled with COX-1. mPGES colocalized with both COX isozymes in the perinuclear envelope. Moreover, cells stably cotransfected with COX-2 and mPGES grew faster, were highly aggregated, and exhibited aberrant morphology. Thus, COX-2 and mPGES are essential components for delayed PGE(2) biosynthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer.     

Induction of labour with a sustained-release prostaglandin E2 vaginal pessary.

A new polymer vaginal pessary providing sustained constant release of prostaglandin E2 was administered to 66 patients before planned induction of labour. Effective ripening of the unfavourable cervix was achieved in each of 18 primigravidas, in eight of whom labour was initiated without further treatment. When the cervix was moderately favourable the need for orthodox induction of labour was obviated in 16 out of 23 primigravidas and 21 out of 23 multigravidas. This method of sustained release of prostaglandin E2 is simple and convenient and readily acceptable to the patient; it is an important step in the development of non-invasive methods of inducing labour.     

Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis

Prostaglandin E₂ (PGE₂) plays an important role in the normal physiology of many organ systems. Increased levels of this lipid mediator are associated with many disease states, and it potently regulates inflammatory responses. Three enzymes capable of in vitro synthesis of PGE₂ from the cyclooxygenase metabolite PGH₂ have been described. Here, we examine the contribution of one of these enzymes to PGE₂ production, mPges-2, which encodes microsomal prostaglandin synthase-2 (mPGES-2), by generating mice homozygous for the null allele of this gene. Loss of mPges-2 expression did not result in a measurable decrease in PGE₂ levels in any tissue or cell type examined from healthy mice. Taken together, analysis of the mPGES-2 deficient mouse lines does not substantiate the contention that mPGES-2 is a PGE₂ synthase.     

Induction of labour using prostaglandin E2 pessaries.

The routine method of induction at Queen Charlotte''s Maternity Hospital is now by the use of prostaglandin E2 pessaries. The first 502 consecutive patients thus induced are presented: the caesarean section rate for a failed induction with an unfavourable cervix has fallen to 2%. The prostaglandin E2 pessary is highly efficient and acceptable for all cases in which a simple amniotomy will not suffice.