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.     

Continuous extraovular administration of prostaglandin F2alpha for midtrimester abortion

Midtrimester abortion was successfully induced in 74 of 76 patients by a continuous extraovular administration of (PGF2alpha) prostaglandin F2alpha via a constant-infusion pump. 2 patients in the 13th-14th weeks of gestation failed to abort despite good uterine activity. The mean abortion time for successful inductions was 16.21 hours. Parous patients aborted somewhat faster than nulliparous patients, but the difference was not statistically significant. All patients were monitored throughout the abortion procedure, and uterine activity was calculated and analyzed. Uterine activity developed within 15 minutes of PGF2alpha instillation and showed the characteristic uterine response to PGs with a sharp rise in intrauterine tonus. The gastrointestinal side effects in this series were much less than those reported for intraamniotic instillation of PG, and there was good patient tolerance of the procedure. The main complication of extraovular administration of PGF2alpha for midtrimester abortion was endometritis, which occurred in 7 patients. The patients who developed endometritis had, as a group, longer abortion times (mean=28 hours). 3 patients with severe preeclampsia and intrauterine death in the third trimester also had successfully induced labor with extraovular administration of PGF2alpha. The method of PGF2alpha administration in the series was found to have a high success rate, good patient tolerance, and fewer side effects than when abortion was induced by intraamniotic instillation of PGF2alpha.     

The induction of midtrimester abortion with intra-amniotic prostaglandin F2alpha. A single-dose technique

30 healthy women between 14-37 and between 14-20 weeks' gestation were administered with a single injection of 40 mg of PGF2 alpha over a 5 minute period to induce abortion. 28 patients aborted within 48 hours; 14 aborted completely and 14 required surgical removal of the placenta; 1 patient required intravenous oxytocin, and 1 failed to abort within 48 hours. The mean instillation to abortion interval for multiparas was 18.6 hours, for nulliparas it was 32.2 hours. Only 1 patient had excessive bleeding, 3 had syncopal episodes, 9 experienced vomiting, 3 diarrhea, and 3 diarrhea, nausea, and vomiting. A single injection of PGF2 alpha seems superior to intraamniotic hypertonic saline solution administration alone, and is effective as administration of hypertonic saline and intravenous oxytocin. The multiple dose technique of PG administration does reduce the mean abortion time, but entails an increased incidence of gastrointestinal side effects and requires repuncture or the use of an indwelling catheter, which may increase the incidence of infection. The mode of administration described can be used in selected patients when hypertonic saline solution is contraindicated.     

Intravenous prostaglandin F2 for therapeutic abortion: the efficacy and tolerance of three dosage schedules

To determine the most optimal procedure for use of prostaglandins (PGs) clinically for abortion, the abortifacient efficacy and complications of 3 types of intravenous PGF2 alpha schedules were compared over 18 hours. 17 healthy women from 7-20 weeks gestation were infused with PGF2 alpha for therapeutic abortion. The subjects were divided into 3 groups: 1 receiving a constant infusion beginning at 25 mcgm/minute increasing to 200 mcgm up to the maximum FDA dose; the second receiving progressive doses at specified times until the patient developed 350 Montevideo units (MU) of uterine activity; and the third receiving 25 mcgm/minute for 1/2 hour followed by maintenance at 50 mcgm/minute until abortion. All patients aborted with the low-dosage schedule and there were fewer complications. No difference in uterine contractility was seen among subjects receiving the 3 dosage schedules or between those patients aborting and those who failed to abort.     

Induction of labor in patients with missed abortion and fetal death in utero with protaglandin E2 suppositories

Labor was successfully induced in 20 patients with a diagnosis of missed abortion or intrauterine fetal death (IUFD) by intravaginal administration of prostaglandin E2 suppositories. Fifteen patients delivered with the prostaglandin alone while a concomitant oxytocin infusion was employed to augment contractions in the other five patients. The mean induction-delivery time was 9.80 hours; nulliparous patients delivered in a mean time if 7.78 hours, parous patients in a mean time of 12.29 hours. The uterus appeared to be sensitive to the PGE2 stimulation in all patients and all were delivered completely without the need for surgical intervention. Fifty per cent of patients were delivered within 8 hours and 80 per cent by 12 hours. The side effects associated with prostaglandin administration--vomiting, diarrhea, and temperature elevation--were well tolerated and therapy did not have to be terminated in any patient. The administration of PGE2 vaginal suppositories offers an effective and safe technique for the induction of labor in patients with IUFD. Labor can be induced with PGE2 suppositories as soon as the diagnosis of IUFD is confirmed, which eliminates the need for waiting until spontaneous labor occurs.     

Interruption of pregnancy by prostaglandin 15-methyl F2alpha.

The current study was formulated to investigate the abortifacient activity of prostaglandin 15-methyl F2alpha (15-methyl PGF2alpha) administered intramuscularly to 80 healthy women with gestations between 8 and 22 weeks. Goals were the establishment of an effective dosage schedule and assessment of the incidence and severity of side effects. All 80 gravidas were aborted, with a mean time to abortion of 15.70 hours (SD, 6.52). Gastrointestinal side effects occurred in 89% of the patients; temperature elevations greater than or equal to 100.6 degrees F were noted in 14 cases. No other significant complications were encountered. Transabdominal intra-amniotic pressure monitoring indicated the need to administer the drug at 2-hour intervals. The 15-methyl PGF2alpha patients were matched for parity and gestational length with 80 gravidas aborted with PGE2 20-mg vaginal suppositories. The difference in interval to abortion in the two groups was not statistically significant. While gastrointestinal side effects were more common with 15-methyl PGF2alpha, the frequency of drug-induced temperature elevations was reduced.     

Mid-second-trimester labor induction: concentrated oxytocin compared with prostaglandin E2 vaginal suppositories

A concentrated oxytocin infusion and prostaglandin E2 (PGE2) vaginal suppositories were compared in a retrospective analysis for indicated abortion in the mid-second trimester (17-24 weeks' gestation). Eighty-one women underwent second-trimester pregnancy termination, 59 by PGE2 suppositories and 22 by concentrated oxytocin infusion. Success was achieved by PGE2 in 93% (55 of 59) and oxytocin in 91% (20 of 22). The mean duration of labor was 13.1 hours with PGE2 and 8.2 hours with oxytocin. The mean dose of PGE2 was 65.2 mg; of oxytocin, 200 units. Women who received PGE2 experienced nausea (46%), vomiting (37%), fever (64%), and diarrhea (20%) despite appropriate premedication. Few side effects occurred in the women who were treated with oxytocin. We conclude that concentrated oxytocin infusion seems to be a reasonable alternative to PGE2 vaginal suppositories for induction of labor in the mid-second trimester.     

Uterine motility and cervical ripening in second trimester elective abortion by two different PGE analogues.

The clinical effects were studied of two different PGE analogues on the uterine motility and cervical ripening of eighty pregnant women asking for a second trimester elective abortion for fetal abnormalities. Forty women received vaginal suppositories each containing 1 milligram of 16, 16-dimethyl-trans-s2-PGE1 (Gemeprost) every 3 hours (5 mg max). Intramuscular injections of 500 micrograms of 16-phenoxy-w 17, 18, 19, 20 tetranor PGE2 methyl-sulphonylamide (Sulprostone) were administered every four hours (2000 mcg max.) to the remaining forty patients. Thirty-three Gemeprost treated patients (82.5%) and 34 Sulprostone treated patients (85%) experienced a complete abortion in the mean of 12.92 +/- 6.95 hours and 11.88 +/- 6.8 hours respectively. The histological and ultrastructural findings of cervical ripening were similar in both groups, while the tocographic patterns showed different characteristics. Side effects occurred in 16 Sulprostone (40%), but only in 9 (22.5%) Gemeprost treated patients, demonstrating that Gemeprost, although equally effective, is better tolerated.     

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.     

Effect of infused prostaglandin F 2 on hormonal levels during early pregnancy

In light of the theory of prostaglandin (PG) mechanism of action as removal of a progesterone block mediating myometrial stimulation, the effect of PGF2alpha on hormonal patterns was analyzed in 8 patients between 11.5 and 18.5 weeks of gestation. PGF2 alpha was administered intravenously by pump and blood samples were drawn hourly during the first 12 hours and every 2 hours thereafter until abortion occurred. Serum estradiol (2) and estriol (E3) were assayed by radioimmunassay, as was plasma progesteronep. 2 patients had missed abortions; 5 of the 6 remaining patients aborted successfully. The remaining patient of 12 weeks gestation failed to abort. Missed abortion patients had absence of detectible E3 in serum, and E2 and P values were decreased 50%. 3 of 5 successful terminations showed decreases in E3 within first 4 infusion hours and aborted in 17 hours. A 4th patient showed a precipitous E3 drop at 16 infusion hours and aborted at 26 hours. 1 patient showed little E3 change until after abortion, and then it was a 50% decrease. Serum P declined in all 5 successful terminations. E2 values reduced within 4-8 hours before abortion and after infusion. The authors suggest that these findins show a direct effect of PGF2 alpha on steroidogenesis.     

The effects of intramuscular injections of 15(S)-15-methyl prostaglandin F2alpha in failed abortions

Intramuscular injections of 15(S)-15-methyl prostaglandin F2alpha (15-Me-PGF2alpha) induced abortion in 38 patients who had failed to abort with other techniques, such as intra-amniotic instillation of saline or PGF2alpha and intravaginal insertion of prostaglandin-impragnated Silastic devices. The intramuscular injections of 15-Me-PGF2alpha were initiated when the original abortion techniques, even when augmented by intravenous oxytocin, failed to produce expulsion of the fetus. The dose schedule was 250 microgram or 500 microgram every 2 to 4 hours, and the concomitant intravenous oxytocin was continued at a rate of 167 mU/minute. Of the 38 patients, 26 aborted with two or fewer injections of 15-Me-PGF2alpha, and 30 patients required only 1 mg of the drug to expel the fetus successfully. The mean time from the first injection of 15-Me-PGF2alpha to the expulsion of the fetus was 5.25 hours; one-half of the patients aborted in less than 4 hours. The placenta was expelled spontaneously in 15 patients, removed manually from the vagina in 18, and removed by sponge forceps in 3. Two abortions were incomplete and surgical intervention was required. Twenty-eight patients (74%) experienced gastrointestinal disturbances, chiefly vomiting and diarrhea. Intramuscular administration of 15-Me-PGF2alpha eliminates the need for repeated amniocentesis, and the dose may be adjusted to meet the precise requirements of the clinical situation.     

Management of intrauterine fetal demise and missed abortion using prostaglandin E2 vaginal suppositories.

Two hundred and twelve patients diagnosed as having a missed abortion or intrauterine fetal death were managed by the use of prostaglandin E2 vaginal suppositories. The method had a high efficacy rate with 98% of the patients experiencing successful evacuation of the uterine contents. The mean time to abortion was 10.9 hours with a mean dose of 60 mg (3 suppositories). Side effects were well tolerated. Transient pyrexia was present in 36% of the patients during therapy, but returned to pretreatment levels after abortion. No intrauterine infection was observed. The risks associated with active treatment can be avoided. The ease of administration permits initiation of therapy as soon as the diagnosis is confirmed.     

The prognostic value in threatened abortion of plasma progesterone values and the cornification index of vaginal smears

The predictive values of plasma progesterone levels in 70 patients threatening to abort was investigated. It was found that no patient aborted whosed plasma progesterone level remanined above 35 nmol/l between 7 and 16 weeks of pregnancy, whereas if the plasma progesterone level was less than this, subsequent abortion always occurred. The predictive value of cornification index in vaginal smears was also examined: many smears were unsatisfactory for assessment and in patients with threatened abortion there was a 14 per cent incidence of falsely optimistic and 29 per cent of falsely pessimistic predictions.     

Induction of abortion by intrauterine bougie

On the initial visit, general and pelvic examinations were made, and hemoglobin and urine tests were given to 100 patients in the second trimester who came for abortion. On the 2nd visit, laminaria tents were inserted and systemic broad spectrum antibiotics given. 24 hours later, in the lithotomy position, the laminaria tents were removed and a sterile rubber bougie introduced extraovularly. When the patient aborted, vaginal examination was performed to assure completeness. In doubtful cases, curettage was performed. When there was an undue delay in abortion, evacuation or abdominal hysterotomy was performed. 86 patients were successfully aborted, 8 required abdominal hysterotomy, dilatation and evacuation was performed in 6 patients. The induction abortion interval varied from 5 hours, 20 minutes to 174 hours, with an average of 51 hours. In primigravidae (48), the interval was found to be 57 hours. Complications were minimal; 7 patients developed pyrexia and responded to systemic antibotics; 1 patient expelled the products through a tear in the posterior lip of the cervix. The average hospital stay was 5.6 days.     

Clinical comparison of abortifacient activity of vaginally administered prostaglandin E2 in two dosage forms.

The effect of prostaglandin E2 (PGE2) release rate from an intravaginal suppository on induced abortion was investigated in a randomized, double-blind study of 71 women who were 7-22 weeks pregnant. 2 dosage forms were compared. Base A was selected to provide a more hydrophilic character than base B. 6 vaginal suppositories, inserted at 4-8 hour intervals as deemed necessary for the clinical progress of abortion, were available for each patient. If abortion did not occur within 48 hours, the trial was discontinued. When time for 50% dissolution of PGE2 (t50%) was plotted as a function of pH for the 2 suppository formulations, the curve for base A was sigmoidal in shape, showing a more rapid release of PGE2 and pH increase. In contrast, base B demonstrated a t50% value of 30 hours which was independent of pH. This independence suggested the hypothesis that the clinical performance of base B would be more uniform than a base A formulation and would exhibit a longer duration of biologic action. Use of base A was found to produce a slight increase in the frequency of successful abortions (79% with base A versus 70.3% with base B). There were no significant differences in the mean times from treatment initiation to complete abortion, the number of incomplete abortions, or failure to abort between the 2 study groups. There was a nonsignificant trend toward reduced total drug use in the base A group. Examination of side effects indicated that women receiving PGE2 in base B had a greater but nonsignificant tendency to experience nausea (62.2% in group B, 58.8% in group A) and vomiting (83.8% group B, 76.5% group A); however, there was a significantly greater amount of diarrhea in the base B group (70.3%) than in the base A group (41.2%). It was concluded that there are no major differences in abortifacient efficiency or the general incidence of side effects when PGE2 therapy in 2 dosage forms is compared. However, a more hydrophilic base, which exhibits a more rapid release of PGE2, appears to slightly reduce side effects and efficacy.     

Complications following prostaglandin F2alpha-induced midtrimester abortion.

Prostaglandin F2alpha (PGF2alpha) was injected intraamniotically in 122 patients between 14 and 20 weeks' gestation in the dosage schedule recommended by the drug manufacturer to induce abortion. Significantly more multiparous (47.5%) than primagravida patients (21.5%) aborted within 16 hours, but the mean duration between PGF2alpha injection and abortion was not significantly different. Complications occurred in 52 (42.6%) patients and included: fall in hematocrit of more than 5 percentage points, failure to abort within 48 hours after injection, infection requiring antibiotic therapy, cervical laceration or fistula, and uterine rupture. The atypical dilatation and effacement of the cervix occurring with PGF2alpha-induced contractions may possibly lead to cervical incompetence with later pregnancies. Although the efficacy of PGF2alpha as an abortifacient is confirmed, the large complication rate with the procedure cannot be ignored.     

Abortifacient efficacy of intravaginal prostaglandin F2

This study determines the efficacy and incidence of side effects associated with intravaginal prostaglandin F2alpha (PGF2alpha). 20 healthy patients (16 to 30 years of age; 9-16 weeks gestational age) with no history of threatened abortion in the current pregnancy were studied. Baseline hematologic, metabolic, urinary, and hormonal studies were conducted. Transabdominal amniocentesis was performed in 7 patients. The uterus was observed for spontaneous contractility. Lactose tablets with 50 mg PGF2alpha (THAM salt) were administered vaginally. The intensity and frequency of uterine contractions in the 7 monitored patients determined the treatment regimen. Prostaglandin tablets were inserted at hourly intervals to maintain frequency of contractions at 5 per 10 minute time interval and/or intensity of contractions greater than an average of 40 mm Hg over a 10 minute-period. 13 patients whose uterine activity during the abortion process was assessed by clinical observation were given a similar time schedule. Blood studies were peformed 6 hours after the onset of therapy and immediately following abortion. Analgesia were used intramuscularly as antiemetic agents where necessary. Prepared questionnaires and personal interviews were completed at the 4-week clinic visit to determine patient acceptability of the method. 19 of 20 patients aborted, with 7 classified as complete and the remaining 12 requiring a uterine exploration and curettage for removal of retained placental fragments. Average induction-complete abortion interval was 17 hours and 50 minutes. There was no difference between multiparous and primiparous patients. In 1 patient who failed to abort with the prostaglandin tablet, administration of 900 mg PGF2alpha and hypertonic saline were used to facilitate abortion which occurred 24 hours later. Emesis occurred in 18 patients, diarrhea in 13, and fever in 11. Of 15 patients who agreed to an interview during the clinic visit, 14 stated they would choose the method again. Vaginal administration of PGs appears to exert effects by systemic, rather than by local mechanism. Although this method is effective, it has a high incidence of side effects and is associated with increased utilization of professional time.     

Second trimester termination of pregnancy with gemeprost: a review of 306 cases

AIM: Prostaglandin analogues provide an effective method for induction of abortion in the second trimester of pregnancy. The clinical outcome and the risk of complications were evaluated in a group of women having a medical termination of pregnancy with gemeprost. METHODS: Three-hundred and six women undergoing second trimester termination of pregnancy, between January 1998 and July 2002 in our center, were studied. All women were given 1 mg vaginal gemeprost every 3 h up to a maximum of 3 doses in the first 24 hours. If the abortion did not occur within the first 24 hours after initiation of treatment, they were given a 2(nd) course of gemeprost. Outcome measures included failure of the 1st course of gemeprost, length of hospital stay after expulsion of conceptus, heavy blood loss with or without necessity of uterine packing or blood transfusion, and failure of induction. RESULTS: There was a significant difference, with better results in women with previous deliveries (vaginal or abdominal), as to the failure to abort after the 1(st) course of PG (P<0.01). Length of hospital stay, complications and failure of induction were independent from parity. Twelve (3.9%) women failed to abort with gemeprost and required other methods for abortion. CONCLUSIONS: The study confirms the efficacy of gemeprost for mid-trimester termination of pregnancy, although it is a risky and costly procedure, requiring hospitalisation and is associated with higher complication rate than the first trimester surgical abortion.     

Intrauterine incarcerated bowel following uterine perforation during an abortion: a case report

The case of small bowel incarcerated within the uterine cavity following a legal abortion is presented. The case, a 26-year old woman, gravida 5, para 4, was aborted with a rigid-type plastic suction cannula at 13 weeks after her last menstrual period. During the 1st hour after the procedure, the patient developed severe abdominal pain and vomiting. The uterus was felt to be 18 weeks in size, firm, and tender. Sonographic examination revealed multiple well-defined round cystic structures within the uterine cavity. At laparotomy, incarcerated and partially gangrenous small intestine was found in an intrauterine location. The perforation had occurred in the anterior fundal region, distant from the uterine scars from the case's 4 previous cesarian sections. This case illustrates a rare and serious complication of abortion and demonstrates the utility of sonography in postprocedure symptomatic patients. No other such cases have been reported in the literature.     

Induction of labor. A double-blind randomized controlled study of prostaglandin E2 vaginal suppositories compared with intranasal oxytocin and with sequential treatment

In a double-blind randomized controlled study of 300 women, 150 primiparas and 150 multiparas, induction of labor by means of vaginal suppositories containing 3 mg prostaglandin E2 (PGE2) was compared with the conventional method of intranasal oxytocin and with a combined method of 3 mg PGE2 vaginal suppositories alternating with intranasal oxytocin. In the PGE2 group the intensity of delivery was significantly greater than in the oxytocin group, among both primiparas and multiparas and among the patients with ripe and unripe cervix. The efficiency of the combined treatment could no be evaluated because of the high intensity of delivery during the first 24 hours. There were no maternal side effects, and no significant difference in the frequencies of failed induction and cesarean section.