Contraception
45:22 l-227,
1992
Cervical softening with mifepristone (RU 486) after pretreatment with naproxen A double-blind
Department
randomized
study
Arne Radestad and Marc Bygdeman, of Obstetrics and Gynecology, Karolinska S-104 01 Stockholm, Sweden
Hospital,
ABSTRACT Pretreatment with the progesterone antagonist mifepristone reduces the stiffness and facilitates mechanical dilatation of the uterine cervix. We studied the influence of the cycle-oxygenase inhibitor naproxen on the softening effect of mifepristone on the cervix in thirty nulliparae.The patients were randomly allocated to receive 500 mg naproxen (group A) or placebo (group B) orally 60,48,36,24 and 12 hours prior to vacuum aspiration. All patients received 100 mg mifepristone 48 and 36 hours before surgery. We found that the cervical softening effect of mifepristone was not antagonized by naproxen. The study indicates that the effect of mifepristone on the early pregnant cervix is not mediated through an increased production of prostaglandins. INTRODUCI’ION Softening and dilatation of pregnant uterine cervix is an important concept to the gynecologist. It has a bearing on clinical problems as abortion and preterm labour. Mechanical dilatation of the cervical canal at vacuum aspiration can cause damage to the cervix, especially in nulliparae where the cervix is stiff and firm. Hemorrhage and incomplete evacuation of the products of conception (1) may arise as well as cervical incompetence in subsequent pregnancies (2). Several methods such as treatment with prostaglandins or different tents have been used to achieve a more gentle cervical dilatation (7). Although these methods are effective, the drawbacks for prostaglandins are gastrointestinal side-effects and uterine pain, and for the tents, difficulties in inserting and withdrawing the device. Mifepristone (RU 486; Roussel Uclaf, Paris, France) is a progesterone antagonist which binds to the progesterone receptor, thus inhibiting the effect of the hormone. Treatment with mifepristone during early pregnancy will result in an increased uterine contractility and a significantly increased sensitivity of the myometrium to prostaglandin (3). In spite of the fact that progesterone is considered essential for the maintenance of pregnancy, administration of mifepristone alone is not always sufficient to induce abortion (3-5). However, the combination of mifepristone and a low dose of a Submitted for publication November 4, 1991 Accepted for publication January 24, 1992
Copyright
@ 1992 Butterworth-Heinemann
222
Contraception
prostaglandin analogue has been shown to be a highly effective terminate early pregnancy (3, 6).
method
to
Oral, single- or multiple-dose administration of 25-600 mg mifepristone dilates the cervical canal, reduces the cervical stiffness and facilitates mechanical dilatation of the cervix during pregnancy (8-14). The exact mechanism of this effect is not clear. In vitro experiments have shown that mifepristone stimulates prostanoid synthesis (15, 16). This has led to the frequently postulated hypothesis that mifepristone in vivo changes the local balance between estrogen and progesterone causing an increased prostanoid synthesis. The aim of the present study was to test this hypothesis by evaluating the softening effect of mifepristone on the cervix in pregnant women who received the cyclooxygenase inhibitor naproxen. MATERIAL
AND METHODS
Thirty healthy nulliparae from 7 to 11 weeks’ gestation requesting an abortion were included in the study. None of the patients had a history of previous cervical surgery. Ultrasonography was used to estimate the gestational age when the uterine size disagreed with the clinical data. The patients were randomly allocated to receive 500 mg naproxen (group A) or placebo (group B) orally 60,48,36,24 and 12 hours prior to cervical dilatation and vacuum aspiration. All subjects in group A and B received 100 mg mifepristone orally 48 and 36 hours before surgery. All patients received premeditation with morphine-scopolamine (10 mg + 0.4 mg) (AC0 L;ikemedel AB, Solna, Sweden) subcutaneously and obtained a paracervical nerve block with 20 ml Xylocaine (10 mg/ml) (Astra LBkemedel, SGderWje, Sweden). The cervical canal was then step-wise dilated from 4 to 11 mm and the stiffness of the uterine cervix for each dilatation step was measured using an instrument described previously (8). The same procedure was used for all patients and only one investigator performed all dilatations and measurements. All the assessments of load and dilatation were made without knowledge of whether the patient had received naproxen or placebo. The blood loss was measured after sieving the products evacuated from the uterus. At surgery, a blood sample was taken for measurement of the mifepristone and naproxen plasma concentrations. Two patients did not comply with the prescribed medication and were excluded before the randomization protocol was exposed. Both were thereafter found to belong to treatment group A. The material thus comprises 13 patients in group A and 15 in group B.
223
Contraception
The study had been approved by the local ethical committee of the Karolinska Hospital and an informed consent was obtained from each woman. Conventional statistical methods as well as the Mann-Whitney U-test have been used in the present study. Prior to the investigation, p>O.O5 was fixed as non-significant.
RESULTS
There were no differences between the two treatment age, weight and duration of pregnancy (Table I 1.
Table
I. Patient
characteristics;
groups with regard
mean (range)
Mifepristone + naproxen (group A; n=13)
Mifepristone + placebo (group B; n=15)
Age (years)
23.1 08-33)
23.3 (19-29)
Weight
61.9 (45-80)
60.4 (45-75)
9.3 (8-10)
9.3 (7-11)
(kg)
Gestational
age (weeks)
to
----------------------------------------------------.-
The plasma levels of mifepristone and of naproxen indicated that all patients except the two excluded had taken the prescribed treatment. In the latter two patients,the plasma levels of naproxen was found to be below average. Both these patients had an increased cervical resistance to dilatation. The softening effect of mifepristone on the cervix was not blocked or reduced by naproxen (Table II). The force necessary for the step-wise dilatation from 8 to 9 mm was even lower (p
45:22 l-227,
1992
Cervical softening with mifepristone (RU 486) after pretreatment with naproxen A double-blind
Department
randomized
study
Arne Radestad and Marc Bygdeman, of Obstetrics and Gynecology, Karolinska S-104 01 Stockholm, Sweden
Hospital,
ABSTRACT Pretreatment with the progesterone antagonist mifepristone reduces the stiffness and facilitates mechanical dilatation of the uterine cervix. We studied the influence of the cycle-oxygenase inhibitor naproxen on the softening effect of mifepristone on the cervix in thirty nulliparae.The patients were randomly allocated to receive 500 mg naproxen (group A) or placebo (group B) orally 60,48,36,24 and 12 hours prior to vacuum aspiration. All patients received 100 mg mifepristone 48 and 36 hours before surgery. We found that the cervical softening effect of mifepristone was not antagonized by naproxen. The study indicates that the effect of mifepristone on the early pregnant cervix is not mediated through an increased production of prostaglandins. INTRODUCI’ION Softening and dilatation of pregnant uterine cervix is an important concept to the gynecologist. It has a bearing on clinical problems as abortion and preterm labour. Mechanical dilatation of the cervical canal at vacuum aspiration can cause damage to the cervix, especially in nulliparae where the cervix is stiff and firm. Hemorrhage and incomplete evacuation of the products of conception (1) may arise as well as cervical incompetence in subsequent pregnancies (2). Several methods such as treatment with prostaglandins or different tents have been used to achieve a more gentle cervical dilatation (7). Although these methods are effective, the drawbacks for prostaglandins are gastrointestinal side-effects and uterine pain, and for the tents, difficulties in inserting and withdrawing the device. Mifepristone (RU 486; Roussel Uclaf, Paris, France) is a progesterone antagonist which binds to the progesterone receptor, thus inhibiting the effect of the hormone. Treatment with mifepristone during early pregnancy will result in an increased uterine contractility and a significantly increased sensitivity of the myometrium to prostaglandin (3). In spite of the fact that progesterone is considered essential for the maintenance of pregnancy, administration of mifepristone alone is not always sufficient to induce abortion (3-5). However, the combination of mifepristone and a low dose of a Submitted for publication November 4, 1991 Accepted for publication January 24, 1992
Copyright
@ 1992 Butterworth-Heinemann
222
Contraception
prostaglandin analogue has been shown to be a highly effective terminate early pregnancy (3, 6).
method
to
Oral, single- or multiple-dose administration of 25-600 mg mifepristone dilates the cervical canal, reduces the cervical stiffness and facilitates mechanical dilatation of the cervix during pregnancy (8-14). The exact mechanism of this effect is not clear. In vitro experiments have shown that mifepristone stimulates prostanoid synthesis (15, 16). This has led to the frequently postulated hypothesis that mifepristone in vivo changes the local balance between estrogen and progesterone causing an increased prostanoid synthesis. The aim of the present study was to test this hypothesis by evaluating the softening effect of mifepristone on the cervix in pregnant women who received the cyclooxygenase inhibitor naproxen. MATERIAL
AND METHODS
Thirty healthy nulliparae from 7 to 11 weeks’ gestation requesting an abortion were included in the study. None of the patients had a history of previous cervical surgery. Ultrasonography was used to estimate the gestational age when the uterine size disagreed with the clinical data. The patients were randomly allocated to receive 500 mg naproxen (group A) or placebo (group B) orally 60,48,36,24 and 12 hours prior to cervical dilatation and vacuum aspiration. All subjects in group A and B received 100 mg mifepristone orally 48 and 36 hours before surgery. All patients received premeditation with morphine-scopolamine (10 mg + 0.4 mg) (AC0 L;ikemedel AB, Solna, Sweden) subcutaneously and obtained a paracervical nerve block with 20 ml Xylocaine (10 mg/ml) (Astra LBkemedel, SGderWje, Sweden). The cervical canal was then step-wise dilated from 4 to 11 mm and the stiffness of the uterine cervix for each dilatation step was measured using an instrument described previously (8). The same procedure was used for all patients and only one investigator performed all dilatations and measurements. All the assessments of load and dilatation were made without knowledge of whether the patient had received naproxen or placebo. The blood loss was measured after sieving the products evacuated from the uterus. At surgery, a blood sample was taken for measurement of the mifepristone and naproxen plasma concentrations. Two patients did not comply with the prescribed medication and were excluded before the randomization protocol was exposed. Both were thereafter found to belong to treatment group A. The material thus comprises 13 patients in group A and 15 in group B.
223
Contraception
The study had been approved by the local ethical committee of the Karolinska Hospital and an informed consent was obtained from each woman. Conventional statistical methods as well as the Mann-Whitney U-test have been used in the present study. Prior to the investigation, p>O.O5 was fixed as non-significant.
RESULTS
There were no differences between the two treatment age, weight and duration of pregnancy (Table I 1.
Table
I. Patient
characteristics;
groups with regard
mean (range)
Mifepristone + naproxen (group A; n=13)
Mifepristone + placebo (group B; n=15)
Age (years)
23.1 08-33)
23.3 (19-29)
Weight
61.9 (45-80)
60.4 (45-75)
9.3 (8-10)
9.3 (7-11)
(kg)
Gestational
age (weeks)
to
----------------------------------------------------.-
The plasma levels of mifepristone and of naproxen indicated that all patients except the two excluded had taken the prescribed treatment. In the latter two patients,the plasma levels of naproxen was found to be below average. Both these patients had an increased cervical resistance to dilatation. The softening effect of mifepristone on the cervix was not blocked or reduced by naproxen (Table II). The force necessary for the step-wise dilatation from 8 to 9 mm was even lower (p
