British Journal of Obstetrics and Gynaecology June 1978. Vol85. pp 437-441
VAGINAL PROSTAGLANDIN Ez IN THE MANAGEMENT OF FETAL INTRAUTERINE DEATH BY
E. M. SOUTHERN G. D. GUTKNECHT
N. R. MOHBERG AND
D. A. EDELMAN Fertility Research Unit, The Upjohn Company, Kalamazoo, Michigan, and the International Fertility Research Program, North Carolina, USA Summary The results of a multicentre clinical trial of prostaglandin E, (PGEJ administered by the vaginal route in the management of intrauterine fetal death and missed abortion showed an overall efficacy of 97 per cent. The mean induction-abortion interval was 10.7 hours with a mean total dose of 6 0 . 4 mg of PGE,. Side effects were tolerated well and there was no evidence of significant alterations in hepatic or renal function. THEideal therapeutic agent for the management of intrauterine fetal death should be effective, easy to administer and free of hazards or seiious side effects. Preliminary clinical trials of prostaglandin E, (PGE,) vaginal pessaries have been encouraging (Bailey et al, 1975; Southern and Gutknecht, 1976; Kent and Goldstein, 1976; Lauersen and Wilson, 1977). We now describe an expanded multicentre trial of PGE, pessaries in the management of intrauterine fetal death. PATIENTS AND METHODS From 1st June, 1972, to 1st February, 1977, 709 unselected in-patients in whom a diagnosis of either missed abortion or intrauterine fetal death had been confirmed by radiological, ultrasonic and laboratory evaluation were treated using a uniform protocol. A group of 486 patients was treated by 22 investigators who all managed at least ten patients. The remaining 223 patients were reported by 437
individual investigators with little or no prior experience of PGE, pessaries. Patients were volunteers from whom written and informed consent had been obtained. Patients with known hypersensitivity to PGE, or in whom attempts had already been made to terminate the present pregnancy were excluded from the study. Specimens of venous blood were drawn before and during treatment as well as after abortion. The samples were used for complete blood counts, platelet counts, serum bilirubin, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphates, serum creatinine, serum electrolytes, blood glucose, blood urea and blood corticol levels. Fibrinogen levels, partial thromboplastin time and fibrin-fibrinogen degradation products were measured before and after abortion in most patients in whom the fetus was thought to have been dead for three weeks or more.
438
SOUTHERN, GUTKNECHT, MOHBERG AND EDELMAN
Blood pressure, temperature, respiratory rate and pulse rate as well as side effects were recorded during therapy. Vaginal pessaries each containing 20 mg of PGE, in a 1 g lipid base were inserted into the posterior fornix at 3- to 5-hour intervals or as deemed necessary by the clinical progress of abortifacient activity or by patient tolerance. The patient remained in the supine position for approximately 20 minutes following insertion of each pessary but otherwise was allowed to remain ambulant. Analgesic drugs were administered when necessary. In some patients drugs to control diarrhoea and vomiting were used. Table I shows the characteristics of the patients treated. Figure 1 shows distribution of gestational age and Figure 2 the time of fetal death. The probable cause of fetal death was identified in 161 patients: 29 per cent were associated with maternal hypertension, renal disease or placental abruption; rhesus incompatibility played a role in 30 per cent, diabetes mellitus in 18 per cent and cord complications in 16 per cent; the other 7 per cent were associated with sickle cell disease, systemic lupus erythematosis, thrombocytopenic purpura, placental anomalies and maternal abdominal trauma. Successful therapy was defined as the expulsion of the uterine contents.
RESULTS A total of 709 patients with intrauterine fetal death was treated by 158 investigators ; treatment met with success in 687 patients (96.9 per cent). Ninety-two patients (13 per cent) required suction aspiration or curettage for retained products of conception. The mean inductionabortion interval for successful treatment was TABLE I Characteristics of 709 patients with intrauterine fetal death
Maternal age (years) Body weight (kg) Parity Gestational age (weeks)
Mean rt SD
Range
2 6 . 8 h 6.12 66.1113.9 1.4* 1.72 27 f 6.86
14 to 51 35 to 139.1 0 to 12
160
140
r
n
t
lh
GESTATIONAL AGE ( W E E K S )
FIG.1 Distribution of gestational age (weeks) of 699 patients with intrauterine fetal death treated with PGE. pessaries. (Mean 26.8 weeks, SE 0.26 weeks.) 160 -
140
-
-
-
120 -
+ f 100 = + I v)
-
g u =
{
80
-
60-
z 40 -
I t
20 -
0
rn 5-6
I 0
ESTIMATED RETENTION T I M E I N WEEKS S I N C E L M P
FIG.2 Distribution of estimated duration of retention of the fetus in utero in 699 patients with intrauterine fetal death treated with PGE, pessaries. (Mean 4 . 0 weeks,)
10.7 hours, and the cumulative percentages at varying intervals from first medication are shown in Table 11.Thirteen patients (1 - 9per cent) failed to abort within 30 hours. In 11, cervical effacement and dilatation had progressed
439
VAGINAL PGE2 FOR FETAL DEATH
TABLE I1 Timefrom first medication to abortion Hours
Successful abortion (cumulative percentage)
0.0- 1.0 4.1- 5 . 0 8.1- 9 . 0 11.1-12.0 18.1-20.0 24' 1-30.0
0.4 16.5 54.0 74.3 88.9 98.1
TABLE 111 Distribution of successfuI abortion by dose of PGE, administered
-
dose of PGE* (mg)
Mean time 10.7 hours.
sufficiently to allow for uterine evacuation by either suction aspiration or curettage without additional cervical dilatation and two patients had a laparotomy. One of these patients had severe rhesus incompatability and she had a hysterectomy as a method of sterilization after only one pessary. Thus PGE, treatment in this patient was not given an adequate trial. The second patient had a 25-week gestation which was terminated by hysterotomy because of intrauterine infection 14 hours after starting PGE,; she had ruptured her membranes several hours before the first PGE, pessary. Inadequate total dosage of PGE, (40 mg or less) or failure to adhere to the trial protocol was responsible for failure in the majority of the patients who required evacuation of the uterus. There were no recorded cases of uterine rupture or injury to the cervix. The mean time between the onset of PGE, therapy and abortion was 9 . 4 hours for those who had retained a dead fetus for less than 3 weeks and 11.1 hours whose fetus had been dead for 3 weeks or more. This difference is statistically significant (P
VAGINAL PROSTAGLANDIN Ez IN THE MANAGEMENT OF FETAL INTRAUTERINE DEATH BY
E. M. SOUTHERN G. D. GUTKNECHT
N. R. MOHBERG AND
D. A. EDELMAN Fertility Research Unit, The Upjohn Company, Kalamazoo, Michigan, and the International Fertility Research Program, North Carolina, USA Summary The results of a multicentre clinical trial of prostaglandin E, (PGEJ administered by the vaginal route in the management of intrauterine fetal death and missed abortion showed an overall efficacy of 97 per cent. The mean induction-abortion interval was 10.7 hours with a mean total dose of 6 0 . 4 mg of PGE,. Side effects were tolerated well and there was no evidence of significant alterations in hepatic or renal function. THEideal therapeutic agent for the management of intrauterine fetal death should be effective, easy to administer and free of hazards or seiious side effects. Preliminary clinical trials of prostaglandin E, (PGE,) vaginal pessaries have been encouraging (Bailey et al, 1975; Southern and Gutknecht, 1976; Kent and Goldstein, 1976; Lauersen and Wilson, 1977). We now describe an expanded multicentre trial of PGE, pessaries in the management of intrauterine fetal death. PATIENTS AND METHODS From 1st June, 1972, to 1st February, 1977, 709 unselected in-patients in whom a diagnosis of either missed abortion or intrauterine fetal death had been confirmed by radiological, ultrasonic and laboratory evaluation were treated using a uniform protocol. A group of 486 patients was treated by 22 investigators who all managed at least ten patients. The remaining 223 patients were reported by 437
individual investigators with little or no prior experience of PGE, pessaries. Patients were volunteers from whom written and informed consent had been obtained. Patients with known hypersensitivity to PGE, or in whom attempts had already been made to terminate the present pregnancy were excluded from the study. Specimens of venous blood were drawn before and during treatment as well as after abortion. The samples were used for complete blood counts, platelet counts, serum bilirubin, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphates, serum creatinine, serum electrolytes, blood glucose, blood urea and blood corticol levels. Fibrinogen levels, partial thromboplastin time and fibrin-fibrinogen degradation products were measured before and after abortion in most patients in whom the fetus was thought to have been dead for three weeks or more.
438
SOUTHERN, GUTKNECHT, MOHBERG AND EDELMAN
Blood pressure, temperature, respiratory rate and pulse rate as well as side effects were recorded during therapy. Vaginal pessaries each containing 20 mg of PGE, in a 1 g lipid base were inserted into the posterior fornix at 3- to 5-hour intervals or as deemed necessary by the clinical progress of abortifacient activity or by patient tolerance. The patient remained in the supine position for approximately 20 minutes following insertion of each pessary but otherwise was allowed to remain ambulant. Analgesic drugs were administered when necessary. In some patients drugs to control diarrhoea and vomiting were used. Table I shows the characteristics of the patients treated. Figure 1 shows distribution of gestational age and Figure 2 the time of fetal death. The probable cause of fetal death was identified in 161 patients: 29 per cent were associated with maternal hypertension, renal disease or placental abruption; rhesus incompatibility played a role in 30 per cent, diabetes mellitus in 18 per cent and cord complications in 16 per cent; the other 7 per cent were associated with sickle cell disease, systemic lupus erythematosis, thrombocytopenic purpura, placental anomalies and maternal abdominal trauma. Successful therapy was defined as the expulsion of the uterine contents.
RESULTS A total of 709 patients with intrauterine fetal death was treated by 158 investigators ; treatment met with success in 687 patients (96.9 per cent). Ninety-two patients (13 per cent) required suction aspiration or curettage for retained products of conception. The mean inductionabortion interval for successful treatment was TABLE I Characteristics of 709 patients with intrauterine fetal death
Maternal age (years) Body weight (kg) Parity Gestational age (weeks)
Mean rt SD
Range
2 6 . 8 h 6.12 66.1113.9 1.4* 1.72 27 f 6.86
14 to 51 35 to 139.1 0 to 12
160
140
r
n
t
lh
GESTATIONAL AGE ( W E E K S )
FIG.1 Distribution of gestational age (weeks) of 699 patients with intrauterine fetal death treated with PGE. pessaries. (Mean 26.8 weeks, SE 0.26 weeks.) 160 -
140
-
-
-
120 -
+ f 100 = + I v)
-
g u =
{
80
-
60-
z 40 -
I t
20 -
0
rn 5-6
I 0
ESTIMATED RETENTION T I M E I N WEEKS S I N C E L M P
FIG.2 Distribution of estimated duration of retention of the fetus in utero in 699 patients with intrauterine fetal death treated with PGE, pessaries. (Mean 4 . 0 weeks,)
10.7 hours, and the cumulative percentages at varying intervals from first medication are shown in Table 11.Thirteen patients (1 - 9per cent) failed to abort within 30 hours. In 11, cervical effacement and dilatation had progressed
439
VAGINAL PGE2 FOR FETAL DEATH
TABLE I1 Timefrom first medication to abortion Hours
Successful abortion (cumulative percentage)
0.0- 1.0 4.1- 5 . 0 8.1- 9 . 0 11.1-12.0 18.1-20.0 24' 1-30.0
0.4 16.5 54.0 74.3 88.9 98.1
TABLE 111 Distribution of successfuI abortion by dose of PGE, administered
-
dose of PGE* (mg)
Mean time 10.7 hours.
sufficiently to allow for uterine evacuation by either suction aspiration or curettage without additional cervical dilatation and two patients had a laparotomy. One of these patients had severe rhesus incompatability and she had a hysterectomy as a method of sterilization after only one pessary. Thus PGE, treatment in this patient was not given an adequate trial. The second patient had a 25-week gestation which was terminated by hysterotomy because of intrauterine infection 14 hours after starting PGE,; she had ruptured her membranes several hours before the first PGE, pessary. Inadequate total dosage of PGE, (40 mg or less) or failure to adhere to the trial protocol was responsible for failure in the majority of the patients who required evacuation of the uterus. There were no recorded cases of uterine rupture or injury to the cervix. The mean time between the onset of PGE, therapy and abortion was 9 . 4 hours for those who had retained a dead fetus for less than 3 weeks and 11.1 hours whose fetus had been dead for 3 weeks or more. This difference is statistically significant (P
