Myometrial response to prostaglandins enhanced by progesterone

The effect of estrogen and progesterone on prostaglandin-induced uterine contractions was studied in ovariectomized rats fitted with intrauterine recording balloons. The effects of the three prostaglandins, PGE₁, PGE₂, and PGF_2α, injected intravenously were very similar. Pretreatment with estradiol benzoate (1 μg per rat per day) resulted in a considerable reduction of the contractile response to the prostaglandins and was frequently associated with tachyphylactic reactions. Progesterone pretreatment (5 mg. per rat per day), on the other hand, markedly increased the uterine response to prostaglandins and no tachyphylaxis was observed. Intact pregnant rats were studied at mid-gestation; the uterine response in these rats was similar to the response in progesterone-treated rats.     

Cervical Ripening

The purpose of this study was to evaluate the efficacy of adding laminaria tents to sequential intravaginal prostaglandin E₂ (PGE₂) gel for cervical ripening.

A prospective, randomized study was conducted from October 1994 to May 1995. Pregnant women with maternal or fetal indications for induction of labor at ≥37 weeks gestation and a Bishop score of ≤4 were eligible. Nineteen patients received laminaria tents in addition to 4 mg PGE₂ gel, while 25 patients received PGE₂ gel alone. After 4 hr, the laminaria tents were removed and the gel was continued in both groups at 4-hr intervals. Induction with oxytocin was initiated after a Bishop score of >5 was achieved.

The groups were comparable with respect to maternal age, parity, gestational age, reason for induction, and initial Bishop score. The addition of laminaria tents to sequential PGE₂ gel did not statistically improve the time to a favorable cervix (control group 12.7 ± 8.5 hr (95% CI, 9.1–16.3) and study group 10.9 ± 7.1 hr (95% CI, 7.5–14.3) (P = 0.59). The 6-hr difference from the time of the initial PGE₂ gel placement to delivery was not detected (control group 22.4 ± 11.2 hr, 95% CI 17–27 and study group 23.4 ± 13.1 hr, 95% CI 17–29.6 (P = 0.79). The combination approach of laminaria tents and PGE₂ gel did not have a significant impact on the vaginal delivery rate, with 28.0% of patients in the control group and 26.3% of patients in the study group undergoing cesarean section (P = 0.90). Maternal and neonatal complications were rare in both groups.

We had insufficient evidence to show that the addition of laminaria tents to PGE₂ gel improved cervical ripening, the induction to delivery interval, or the cesarean section rate in patients at term undergoing induction of labor.     

A comparison between vaginal prostaglandin E2 suppositories and intrauterine extra-amniotic prostaglandins in the management of fetal death in utero

This retrospective study was undertaken to compare the efficacy, side effects, and complications of prostaglandin E₂ (PGE₂) given as a vaginal suppository with those of PGE₂ administered via the intrauterine extra-amniotic route to induce labor after fetal death. The induction-to-delivery intervals were comparable, with 9.2 ± 3.94 hours and 8.6 ± 4.49 hours, respectively. However, the mean total amount of PGE₂ administered was much less via the intrauterine extra-amniotic route (1.8 milligrams) than by the vaginal suppository (45.2 mg). There was a 100% success rate in the patients treated by the intrauterine extra-amniotic route, but only a 91.3% success rate in those patients treated via the vaginal route. The side effects (vomiting, diarrhea, fever) and the complications (incomplete abortion, uterine rupture, oxytocin augmentation) occurred more frequently with the use of PGE₂ as a vaginal suppository. The vaginal route of administration of PGE₂ is somewhat more convenient, but the intrauterine extra-amniotic route may offer a higher degree of efficacy and safety with fewer side effects in the management of fetal death in utero.     

Management of intrauterine fetal death with prostaglandin E2 vaginal suppositories

The recent Food and Drug Administration's approval of prostaglandin E₂ (PGE₂) vaginal suppositories provides the clinician with a technique for the immediate management of missed abortion and intrauterine fetal death (IUFD). During a 4-year period at our institution, 78 of 80 patients with gestations ranging from 13 to 42 weeks had pregnancy successfully terminated with PGE₂ suppositories with a dose schedule of 20 mg every 2 hours. The mean interval from induction to delivery of the fetus was 8.9 hours. Fifty percent of the patients spontaneously expelled the placenta; active intervention to remove the placenta within 2 hours of delivery of the fetus is recommended to avoid excessive vaginal bleeding. The most frequently encountered side effect was a temperature elevation, which was managed by less frequent administration of the prostaglandin. Gastrointestinal side effects were minimized by premedication with antidiarrheal and antiemetic agents, which also were administered during the induction period when indicated by the patient's symptoms. A concomitant oxytocin infusion was utilized in 38 patients. In gestations of less than 24 weeks the oxytocin was administered via intravenous drip at a rate of 10 U/hour. In the case of a patient with IUFD and a gestation of 24 weeks or more, oxytocin should be administered only with a constant-rate infusion pump starting at a dose schedule of 1 mU/minute with careful titration of the dose against the monitored uterine activity. The availability of the vaginal PGE₂ suppositories for missed abortion and IUFD makes it important for the clinician to fully acquaint himself with the drug, its administration, effects, and side effects.     

Laminaria versus extra-amniotic saline solution infusion for cervical ripening in second-trimester labor inductions

OBJECTIVE: The aim of this study was to determine which cervical ripening method, laminaria placement or extra-amniotic saline solution infusion, was associated with the shorter interval from induction to delivery in the second trimester. STUDY DESIGN: Women admitted for indicated second-trimester labor induction with an unfavorable cervix were randomly assigned to receive either intracervical placement of laminaria (n = 25) or extra-amniotic saline solution infusion (n = 25) with concurrent concentrated oxytocin and vaginally administered prostaglandin E2 (10 mg every 6 hours). Treatment success was defined as an interval from induction to delivery of < or =24 hours. RESULTS: Maternal age, race, parity, gestational age, and initial cervical dilatation were similar between the groups. Indications for uterine evacuation were also similar and included fetal death (n = 7), aneuploidy (n = 20), fetal structural anomaly (n = 18), and maternal indications (n = 4). There was no difference in the mean intervals from induction to delivery (laminaria, 16 +/- 8 hours, vs extra-amniotic saline solution infusion, 17 +/- 10 hours) or the number of treatment successes (laminaria, n = 23, vs extra-amniotic saline solution infusion, n = 21). Retained placenta, live birth, and hemorrhage occurred with similar frequencies in the two groups. CONCLUSION: Relative to laminaria, extra-amniotic saline solution infusion did not shorten the induction-to-delivery interval in women undergoing indicated second-trimester labor induction with concentrated oxytocin and low-dose vaginally administered prostaglandin E2.     

Posterior cervical rupture following prostaglandin-induced mid-trimester abortion

Two cases of transverse posterior cervical rupture in association with mid-trimester abortion induced by prostaglandin F_2α (PGF_2α) are reported. The mechanism of rupture is described. It is suggested that the effects of PGF_2α upon cervical dilatation must be further explored.     

Termination of second trimester pregnancy with laminaria and intramuscular 15-methyl PGF2 alpha or 16-phenoxy-omega-17,18,19,20-tetranor PGE2 methyl sulfonylamide. A randomized multicenter study

The present study included 592 second trimester healthy informed patients admitted to the participating hospitals for termination of pregnancy. In each patient one medium size laminaria tent was introduced into the cervical canal. The laminaria was withdrawn 12 h later and the patients were randomly allocated to either intramuscular infections of 15-methyl-PGF2 alpha (Prostin 15M), 0.25 mg every second hour, or 16-phenoxy-omega-17,18,19,20-tetranor PGE2 methyl sulfonylamide (Nalodor), 0.5 mg every fourth hour. Both treatment schedules were equally effective. The success rate was 95.6% and 94.5% for the E and F analogs, respectively, within 24 h of prostaglandin treatment. The mean duration of prostaglandin treatment was for Nalodor 10.8 h and for Prostin 15M 11.3 h. The mean total dose given of the two analogs was 1.85 mg and 1.65 mg, respectively. With the E analog, the frequency of gastrointestinal side effects was significantly lower than with the F analog. With the former compound, 83.2% had no episodes of diarrhea and 58.9% no vomiting. The mean number of episodes of vomiting and diarrhea per patient was for the E analog 1.0 and 0.4, respectively. The corresponding figures for the F analog were 2.3 episodes of vomiting and 2.2 episodes of diarrhea per patient. Only in three patients (0.5%) cervical laceration was found. It may be concluded that intramuscular administration of either analog after pretreatment with laminaria would appear to be more effective than other methods presently in use for termination of second trimester pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Termination of second trimester pregnancy with a long-acting vaginal pessary containing 15-methyl-PGF2α methyl ester

This report summarizes the results of three studies comprising 1147 second trimester patients admitted to 11 different centres for termination of pregnancy. In the first study, mainly early second trimester patients received one long-acting vaginal pessary containing 3.0 mg 15-methyl-PGF_2α methyl ester, in the second study the pessary was randomly compared with intraamniotic administration of 2.5 mg 15-methyl-PGF_2α in late second trimester patients (after the 15th week of gestation), and in the third study the same type of patients received the long-acting pessary complemented, if necessary at 24 h, with intramuscular injections of 15-methyl-PGF_2α (0.2–0.4 mg every third hour) for up to 12 h. The efficacy of the long-acting pessary was related to the duration of pregnancy. In patients 15 weeks or less pregnant, the frequency of abortion was 81.2% within 30 h; in pregnancies greater than 15 weeks duration the success was 73.3% (P < 0.05). Both vaginal administration of the long-acting pessary containing 15-methyl-PGF_2α methyl ester and intraamniotic administration of 15-methyl-PGF_2α were equally effective during the first 24 h following start of therapy. However, within the next 6 h, the intraamniotic administration was found to be significantly superior, especially in patients with a more advanced pregnancy. To achieve an efficacy comparable to the intrauterine treatment, it was necessary to add intramuscular injections of 15-methyl-PGF_2α. This combined treatment resulted, however, in an increased frequency of cervical laceration. The results of the present study indicate that a treatment with a long-acting pessary is useful in second trimester pregnancy up to the 15th week of gestation, when puncture of the amniotic sac is difficult. After the 15th week of pregnancy, intraamniotic administration of 15-methyl-PGF_2α appears to be a more effective method with less side effects despite the invasive route of administration. The long-acting pessary in conjunction with intramuscular supplement is equally effective if appropriately given.     

Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial

Objective To determine whether nitric oxide donors can induce cervical ripening before surgical termination of pregnancy in the first trimester.
Design Prospective, randomised controlled trial.
Setting Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow.
Participants Forty-eight primigravid women undergoing surgical termination of pregnancy before 12 weeks of gestation.
Methods The women were randomised to receive per vaginam before surgery either the nitric oxide donor isosorbide mononitrate, the nitric oxide donor glyceryl trinitrate, the prostaglandin analogue gemeprost, or no treatment.
Main outcome measures The cumulative force required to dilate the cervix to 8 mm was measured objectively and the cervical diameter before surgical dilatation was recorded.
Results Following isosorbide mononitrate or gemeprost, a lower cumulative force was required to dilate the cervix to 8 mm and a higher cervical diameter before dilatation was recorded. Pretreatment with glyceryl trinitrate reduced the cumulative force required to dilate the cervix but had no effect on cervical diameter.
Conclusions Like the prostaglandin analogue gemeprost, the nitric oxide donors isosorbide mononitrate and glyceryl trinitrate can effect cervical ripening. Nitric oxide donors may provide an alternative to prostaglandins for cervical ripening before surgical procedures in the first trimester.     

Gemeprost for first trimester missed abortion

In 87 patients with a missed abortion prior to 13 weeks, the application of a prostaglandin (PG) E₁ derivative (1 mg gemeprost, Cergem®) was compared to conventional surgical termination of pregnancy by cervical dilatation and curettage. In 33 patients with PGE₁ application, complete expulsion of the abnormal pregnancy occurred after an average of 2.8 ± 1.5 vaginal suppositories. PGE₁ treatment was effective in 76.7%, and surgical management was effective in 90.9% of patients. Sixty percent of the patients in the PGE₁ group required analgesia because of uterine pain in comparison to 4.5% in the surgical group. The possibility of medical termination with synthetic PG derivatives should be further investigated.     

Prevention of Preeclampsia by Linoleic Acid and Calcium Supplementation: A Randomized Controlled Trial

Objective: To determine the effect of low doses of linoleic acid and calcium on prostaglandin (PG) levels and the efficacy of this treatment in the prevention of preeclampsia.Methods: In a randomized, double-blind, placebo-controlled study we treated 86 primigravidas with risk factors for preeclampsia (high biopsychosocial risk [above 3 points], positive roll-over test, and high mean blood pressure [above 85 mmHg)] with daily doses of either 450 mg linoleic acid and 600 mg calcium (n = 43) or 450 mg starch and 600 mg lactose placebo (n = 43) during the third trimester of pregnancy.Results: Four women in the experimental group (9.3%) developed preeclampsia compared with 16 (37.2%) controls (relative risk 0.25, 95% confidence interval 0.09, 0.69, P < .001). The median serum levels of PGE₂ after 4 weeks of treatment increased by 106% in the experimental group (P = .03) and decreased by 33% in the control group (P = .02). The median ratio between thromboxane B₂ and PGE₂ decreased by 40% in the experimental group (P = .02) and increased by 18% in the control group (P = .14). No significant differences were observed in the median ratio between thromboxane B₂ and 6-keto PGF_1α in either group. No serious maternal or neonatal side effects of treatment occurred in either group.Conclusion: The administration of low daily doses of linoleic acid and calcium during the third trimester of pregnancy reduced the incidence of preeclampsia significantly in women at high risk, possibly by correcting the PGE₂ levels.     

Midtrimester abortion by dilatation and evacuation versus intra-amniotic instillation of prostaglandin F2α: A randomized clinical trial

To compare the safety and feasibility of midtrimester abortion by outpatient dilatation and evacuation (D-E) versus inpatient intra-amniotic instillation of prostaglandin F_2α (PGF_2α), we performed a randomized clinical trial with 100 subjects estimated to be 13 to 18 menstrual weeks' pregnant. Subjects undergoing D-E abortion had significantly better compliance with the assigned treatment (100% vs. 88%, p < 0.05) and less delay prior to abortion (mean 3.7 vs. 10.1 days, p < 0.001). Subjects receiving PGF_2α had a relative risk of sustaining a complication 5.7 times that of subjects undergoing D-E (95% confidence interval 2.1–15.3, p < 0.001). Subjects receiving PGF_2α also had significantly higher rates of vomiting and diarrhea (p < 0.01). Midtrimester abortion by outpatient D-E appears to be more acceptable to women, faster, and safer than by instillation of PGF_2α.     

ENDOTHELIN AND BLOOD PRESSURE REGULATION IN THE FEMALE RAT: STUDIES IN NORMAL PREGNANCY AND WITH NITRIC OXIDE SYNTHASE INHIBITION-INDUCED HYPERTENSION

We have measured evoked changes in plasma renin concentration (PRO, plasma renin substrate (PRS) and plasm aldosterone concentration (ALD) during the infusion of angiotensin II (AII) with and without the simultaneous administration of rostaglandin E2, 5 μg min^?1 i.v. (PGE₂) or prostaglandin E₁, 15 ng kg^?1 min^?1 (PGE₁). Expriments have been carried out using PGE₂ in 20 patients, and in 5 patients to date with PGE₁. AII alone (16 ng kg-¹ min¹ i.v.) significantly reduced PRC in both groups of ptients without altering PRS, while ALD concentrations more than doubled. The infusion of PGE₂ stimlated basal PRC; PGE₁ at the dose used did not alter PFC. Neither prostaglandin altered basal Rs. or ALD concentrations. When AII was infused simultaneously, PRC was again suppressed, in the presence of PGE₂. However, only minimal feedback suppression occurred when PGE₁ was being used. Furthermore, AII was still associated with a more than two-fold rise in ALD concentration when given together with PGE₂, but the rise was considerably smaller and not significant in the presence of PGE₁.

PGE₂ is a known stimulus to renin secretion, apparently acting directly at the juxtaglanerular apparatus. These preliminary results suggest that while a similar mechanism exists in second trimester human pregnancy, PGE₁ may have a different effect. The apparent blockade of the normal feedback suppression of PRC in the presence of increased PGE₁ concentrations by raised concentrations of All is especially interesting.     

Prostaglandin production by guinea-pig placenta and other uterine tissues during mid-pregnancy

Prostaglandin (PG) output from cultured placenta, sub-placenta, endometrium and fetal membranes of guinea-pigs was measured on days 22, 29 and 36 of pregnancy to establish the source of increased PGF_2α production during mid-pregnancy. PGF_2α and 6-keto-PGF_1α were produced in larger quantities than PGE₂ by the placenta, sub-placenta and endometrium; 6-keto-PGF_1α was in the major prostaglandin produced by the fetal membranes. The initial outputs of PGF_2α, PGE₂ and 6-keto-PGF_1α from the sub-placenta, fetal membranes and endometrium either decreased or remained fairly constant between days 22 and 36. In contrast, the initial outputs of PGF_2α, PGE₂ and 6-keto-PGF_1α from the placenta increased 14.7-, 2.5- and 2.0-fold, respectively, between days 22 and 36, indicating that the placenta is the tissue responsible for the increase in PGF_2α output from the mid-pregnant guinea-pig uterus. Aristolochic acid (a phospholipase A₂ inhibitor) inhibited prostaglandin output from the endometrium, but had a more variable effect in prostaglandin output from the other tissues. Thimerosal (an arachidonic acid uptake inhibitor) inhibited PGF_2α and PGE₂ outputs from the endometrium, but generally potentiated 6-keto-PGF_1α output and prostaglandin output from the other tissues. Arachidonic acid release for prostaglandin synthesis in the endometrium, but not the placenta, sub-placental or fetal membranes, is apparently dependent upon a constant level of phospholipase A₂ activity.     

Efficacy and Patient Satisfaction with Outpatient Prostaglandin E2 versus Foley Catheter for Cervical Ripening—A Randomized Trial

Introduction: an important factor in the success of labour induction is the presence of a ripe cervix. The safety and efficacy of outpatient prostaglandin E₂ (PGE₂) administered intracervically compared to extra-amniotic cervical Foley catheter placement to ripen the cervix were studied. Patient satisfaction and overall cost with both methods were reported for the first time.Methods: pregnant women with uncomplicated term pregnancies having an indication for induction of labour were enrolled. Singleton pregnancies with intact membranes and cervical Bishop scores < 5 were randomized blindly to receive .5 mg intracervical PGE2 (n=67) every six to eight hours or intracervical Foley catheter (extra-amniotic) (n=62) insertion overnight. Cervical assessments were carried out prior to treatment and again before induction of labour. Patients filled out a post-treatment Likert questionnaire.Results: overall change in Bishop score did not differ between the two groups. The Foley treatment group were more likely to have Mated to three to four cm (χ²=5.48 DF=1 p=.02). Intrapartum variables, mode of delivery and post-partum complications were similar. For patients completing the questionnaire, pain experienced during insertion was similar, however, fewer patients would recommend the Foley catheter treatment to a pregnant friend (F[1,64]=5.53 p=.02). The price of the Foley catheter is much less than the PGE₂.Conclusion: both methods lead to similar changes in overall Bishop score although the intracervical Foley catheter was more likely to lead to cervical dilatation of three centimetres or more—a dilatation which facilitates amniotomy. There were no differences in the mode of delivery, maternal or neonatal outcomes. Patients reported the same amount of pain with both treatments but patients seem to prefer the more expensive PGE₂.     

Cervical dilatation before first trimester elective abortion: a comparison between laminaria and a newly developed hydrogel tent, the A rod.

The effect of cervical dilatation prior to first trimester abortion by laminaria tent and a newly developed hydrogel tent, the A rod, was studied on 50 patients undergoing first trimester legal abortion. The effect was measured both clinically and by the use of an objective measure of cervical resistance. No significant difference in cervical dilatation was found after 5 h of treatment.     

Comparison of the Foley catheter and dinoprostone pessary for cervical preparation before second trimester abortion

The Foley catheter and a 3 mg dinoprostone pessary (Prostin E2) were compared as methods for cervical preparation before second trimester dilatation and evacuation. The catheter was well tolerated and provided significantly greater change in cervical dilatation and improved cervical compliance. The Foley catheter would seem to provide a readily available and efficacious means of cervical preparation.     

Effect of prostaglandin E2 and its metabolites on lower segment myometrium in vitro

The spontaneous activity of pregnant human lower segment myometrium has been studied in vitro using strips removed at cesarean section. Contractions were measured isometrically. During the 4-h experiments there was an increase in amplitude and decrease in frequency of contractions in control preparations. Prostaglandin F_2α (PGF_2α), its metabolites and prostaglandin E₂ (PGE₂) have been shown to be oxytocic in vivo, but there are no published data on the oxytocic effect of PGE₂ metabolites. The effect on contractile activity of adding either PGE₂ or one of its initial metabolites (15-keto-PGE₂, 13,14-dihydro-15-keto-PGE₂ or 13,14-dihydro-PGE₂) or prostaglandin A₂ (PGA₂) to the tissue baths has been tested.No significant or consistent change in contractility was observed after the addition of any of the compounds tested. This probably indicates an inherent difference in the response of different portions of the uterine muscle, and cannot be taken to exclude activity in the intact uterus, particularly since PGE₂ is a well-known oxytocic agent in vivo. The difficulty of working with this type of preparation is stressed, since there is wide variation in contractility as well as a constantly changing pattern.     

Vacuum aspiration for termination of early second trimester pregnancy after treatment with vaginal prostaglandin.

Vaginal and intramuscular administration of prostaglandin analogues are routinely used for dilatation of the cervical canal prior to vacuum aspiration in first trimester abortion. Whether the same procedure is also useful during the first weeks of the second trimester has been much less investigated. In the present study, 127 women in the 13th and 14th week of pregnancy were pretreated with 3 mg 9-deoxo-16,16-dimethyl-9-methylene PGE2 administered vaginally 12 hours before surgery. At surgery the cervical canal was dilated to 9.8 mm +/- 2.5 mm (mean +/- SD) and the evacuation of the uterus was uneventful. In 21% of the patients vaginal bleeding occurred prior to the operation. The mean blood loss at surgery was 49 ml and exceeded 100 ml in only 6 patients. Gastrointestinal side effects were rare but analgesic injections were demanded by 29% of the patients during the pretreatment period. No subsequent curettage was performed during the follow-up period but 2 patients (1.6%) were readmitted because of post-abortion endometritis. It can be concluded that after pretreatment with PG, vacuum aspiration can be safely performed during the first weeks of the second trimester.     

The effects of sulprostone in induced abortion performed prior to 12 weeks of amenorrhoea

The effect of the prostaglandin E2 analog sulprostone on cervical dilatation and blood loss during aspiration and curettage was assessed in 44 patients undergoing 1st trimester abortions in 1987. The controls were 113 patients in a 1983 study conducted in the same center by the same 2 practitioners. The 113 abortion patients were randomly assigned to receive or not receive oxytocics during the aspiration. The technical conditions of the abortion were identical except that cervical dilatation was achieved in 1983 by laminaria tents and in 1987 by the effect of sulprostone. The sulprostone was administered in a single dose of .500 mg administered intramuscularly 2-3 hours before the abortion. The 2 series was identical in gestational age. The average dilatation obtained with sulprostone was 8.4 +or- 1.5 mm. Dilatation was correlated to gestational age but not parity. Blood loss was correlated to gestational age in both series. The dose of sulprostone used did not cause uterine contractions strong enough to require analgesia beyond the usual anesthetic premedication. The methodology of the study was controversial because it involved a comparison of 2 different series separated by 4 years. But the consistency of results in the 2 series and the literature support the conclusion that blood loss is minimized with preliminary use of sulprostone and that cervical dilatation is adequate for aspiration and curettage.