Effect of letrozole on uterine artery Doppler flow indices prior to first-trimester termination of pregnancy: a randomized controlled trial.

OBJECTIVE: We previously demonstrated that a sequential regimen of letrozole and misoprostol resulted in a marked reduction in the serum estradiol concentration and in a higher efficacy of first-trimester termination of pregnancy than misoprostol alone. The aim of this study was to evaluate the effect of letrozole on uterine artery Doppler flow indices during early pregnancy. METHODS: This was a randomized controlled trial. Thirty women requesting termination of pregnancy up to 63 days' gestation were randomized into two groups: a letrozole group receiving 10 mg of letrozole, daily, for 3 days, and a control group receiving a placebo for 3 days. Serum estradiol, progesterone and human chorionic gonadotropin (hCG) concentrations were measured before drug administration and then daily for 6 days. Ultrasound scanning for fetal viability and measurement of the pulsatility (PI) and resistance (RI) indices of the uterine arteries was performed before drug administration, and then on day 3 and day 7 after starting letrozole or placebo. All pregnancies were terminated by surgical evacuation on day 7 or day 8. RESULTS: Uterine artery PI and RI decreased significantly in the letrozole group, but not in the control group. Serum estradiol concentrations were significantly lower in the letrozole group than in the control group from day 2 onwards. Serum progesterone and hCG concentrations were comparable for the two groups throughout the 7 days. There were significantly more women in the letrozole group with vaginal bleeding. CONCLUSION: We have demonstrated that the use of letrozole in the first trimester of pregnancy suppresses serum estradiol levels but results in an increase in blood flow to the uterus. Further studies should be carried out to elucidate the mechanism of letrozole pretreatment in medical abortion.

A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion.

BACKGROUND: The conventional timing of misoprostol administration after mifepristone for second trimester medical abortion is 36-48 h, but simultaneous administration, which may make the regimen more convenient, has not been studied. The objective of this randomized comparison study is to compare two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester medical abortion. METHODS: Eligible women with gestational age between 12 and 20 weeks were randomized to receive mifepristone 200 mg orally followed by 600 microg misoprostol vaginally either immediately or 36-38 h later, followed by 400 microg vaginal misoprostol every 3 h for a maximum of four doses. The primary outcome measure was the success rate at 24 h after the start of misoprostol treatment and the secondary outcome measures were the induction-to-abortion interval and the frequency of side effects. RESULTS: There was a significant difference in the success rate at 24 h (36-38 h: 100%; immediate: 91.5%). The median induction-to-abortion interval was significantly shorter in the 36-38 h regimen (4.9 h) compared with the immediate regimen (10 h). Side effects in terms of febrile episodes and chills/rigors were significantly higher in the immediate administration group. CONCLUSIONS: Simultaneous use of mifepristone and misoprostol for second trimester medical abortion is not as effective as the regimen using a 36-38 h dosing interval.

Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomised factorial controlled equivalence trial.

OBJECTIVE: To compare the efficacy of 100 mg and 200 mg of mifepristone and 24- and 48-hour intervals to administration of 800 microg vaginal misoprostol for termination of early pregnancy. DESIGN: Placebo-controlled, randomized, equivalence trial, stratified by centre. SETTING: 13 departments of obstetrics and gynecology in nine countries. POPULATION: 2,181 women with 63 days or less gestation requesting medical abortion. METHODS: Two-sided 95% CI for the risk differences of failure to complete abortion were calculated and compared with 5% equivalence margin between two doses of mifepristone and two intervals to misoprostol administration. Proportions of women with adverse effects were compared between the regimens using standard testes for proportions. OUTCOME MEASURES: Rates of complete abortion without surgical intervention and adverse effects associated with the regimens. RESULTS: Efficacy outcome was analysed for 2,126 women (97.5%) excluding 55 lost to follow up. Both mifepristone doses were found to be similar in efficacy. The rate of complete abortion was 92.0% for women assigned 100 mg of mifepristone and 93.2% for women assigned 200 mg of mifepristone (difference 1.2%, 95% CI: -1.0 to 3.5). Equivalence was also evident for the two intervals of administration: the rate of complete abortion was 93.5% for 24-hour interval and 91.7% for the 48-hour interval (difference -1.8%, 95% CI: -4.0 to 0.5). Interaction between doses and interval to misoprostol administration was not significant (P = 0.92). Adverse effects related to treatments did not differ between the groups. CONCLUSIONS: Both the 100 and 200 mg doses of mifepristone and the 24- and 48-hour intervals have a similar efficacy to achieve complete abortion in early pregnancy when mifepristone is followed by 800 micrograms of vaginally administered misoprostol.

Misoprostol for the termination of pregnancy up to 12 completed weeks of pregnancy.

The aim was to review the current knowledge about the use of misoprostol alone for abortion induction during the first 12 weeks of pregnancy. Publications reporting experiences with misoprostol alone for pregnancy termination within the first 12 weeks of pregnancy were included in the analysis. Vaginal administration of 800 microg repeated up to three times at 6, 12 or 24 h intervals has an 85% to 90% effectiveness, defined as complete abortion, in most studies. Oral administration is less effective, but sublingual administration at 3-hour interval has the same effectiveness, with more frequent side effects. The oral and sublingual routes appear to be better accepted than vaginal administration. Most studies are limited to the first 9 weeks of pregnancy. The experience on pregnancy termination between 10 and 12 weeks is not yet sufficient for a recommendation.

Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects.

Misoprostol, a synthetic prostaglandin E1 analogue, is commonly used for medical abortion, cervical priming, the management of miscarriage, induction of labor and the management of postpartum hemorrhage. It can be given orally, vaginally, sublingually, buccally or rectally. Studies of misoprostol's pharmacokinetics and effects on uterine activity have demonstrated the properties of the drug after various routes of administration. These studies can help to discover the optimal dose and route of administration of misoprostol for individual clinical applications. Misoprostol is a safe drug but serious complications and teratogenicity can occur with unsupervised use.

Cervical priming with misoprostol prior to transcervical procedures.

Cervical priming with misoprostol has shown to facilitate transcervical procedures and to reduce side-effects. Cervical priming is recommended by several evidence-based guidelines prior to surgical abortion, dilatation and curettage, hysteroscopy and intrauterine device insertion. It is effective in pregnant as well as in non-pregnant women while the results in post-menopausal women are conflicting. Misoprostol is the best suited prostaglandin for a number of reasons: it has a short half-life, few side effects, it is stable at room temperature, it is relatively cheap and the dosage can easily be adjusted according to the clinical need. Various doses, routes, and time intervals between misoprostol application and the intervention have been evaluated. A single dose of 400 microg given sublingually or vaginally 3h before the intervention has given the best efficacy with the least side effects. Higher doses or longer intervals do not improve the effect on the cervix. Pain is a frequent side effect, but usually responds well to NSAIDs. Other side effects are rare.

Misoprostol for the termination of pregnancy with a live fetus at 13 to 26 weeks.

A combination of mifepristone and misoprostol is the regimen of choice for termination of pregnancy between 13 to 26 weeks. In many countries, mifepristone is still not available, and misoprostol has to be used alone. Many misoprostol-alone regimens have been reported in the literature with apparently good results. Most of the trials were conducted in pregnancies between 13 and 22 weeks. For this gestational period, we recommend the regimen of 400 microg of vaginal misoprostol every 3 h up to 5 doses, as it appears to be effective without excessive side effects or complications. There is inadequate data to recommend a regimen for the gestational period of 23 to 26 weeks but it is advisable to reduce the dose and frequency of administration of misoprostol. Common side effects of misoprostol-induced termination of pregnancy include gastrointestinal side effects, abdominal cramps, bleeding, fever and chills. Complications may include infection or rarely rupture of uterus.

A prospective, randomized, double-blind study to compare two doses of recombinant human chorionic gonadotropin in inducing final oocyte maturity and the hormonal profile during the luteal phase.

CONTEXT: Different doses of human chorionic gonadotropin (hCG) have been used in various in vitro fertilization (IVF) treatment protocols to achieve final oocyte maturation. There is as yet no agreement on the optimum dose required. OBJECTIVES: The objective of this study was to compare the effectiveness of 250 and 500 microg recombinant hCG (r-hCG), which represented the lower and upper limits of the dose range, in inducing final oocyte maturation during IVF and intracytoplasmic sperm injection cycles. DESIGN: This was a prospective, randomized, double-blind study. SETTING: This study was performed at an IVF clinic in a teaching hospital. PATIENTS: Sixty patients with an indication for intracytoplasmic sperm injection were studied. INTERVENTION: The treatment dose used was 250 or 500 microg r-hCG. MAIN OUTCOME MEASURES: The percentage of metaphase II oocytes retrieved per patient, as an indicator of oocyte maturation, and the hormone profiles of the treatment cycle starting from the day of hCG up to hCG+10 d were the main outcome measures. RESULTS: The percentage of metaphase II oocytes was similar in the two groups (89.3% vs. 86.0%; P = 0.326) despite higher serum and follicular fluid hCG levels on hCG+2 and hCG+4 d, as was the follicular fluid to serum hCG ratio in the 500-microg r-hCG group. Serum estradiol and progesterone levels were comparable initially, but became significantly higher in the 500-microg r-hCG group on hCG+10 d. CONCLUSION: The two doses of r-hCG were equally effective in inducing final oocyte maturation. It remains unclear whether the higher midluteal estradiol and progesterone levels in the 500-microg r-hCG group confer any benefit.

Paracervical block with and without conscious sedation: a comparison of the pain levels during egg collection and the postoperative side effects.

OBJECTIVE: To compare the pain levels during egg collection and the subsequent postoperative side effects in patients receiving a paracervical block (PCB) with and without conscious sedation. DESIGN: A prospective, randomized, double-blind, and placebo-controlled study. SETTING: A tertiary assisted reproduction unit. PATIENT(S): 150 patients undergoing egg collection. INTERVENTION(S): Randomized to receive PCB only (control group) and PCB in conjunction with conscious sedation (sedation group). MAIN OUTCOME MEASURE(S): Vaginal and abdominal pain levels; severity of postoperative side effects. RESULT(S): The median pain levels during vaginal punctures were 12.0 (2.5th--97.5th centiles: 0--84.3) and 30.0 (2.5th--97.5th centiles: 0--100) in the sedation and placebo groups, respectively. The corresponding median abdominal pain levels were 16.5 (2.5th--97.5th centiles: 0--100) and 43.0 (2.5th--97.5th centiles: 0--100). The pain levels were significantly higher in the placebo group than the sedation group. There were no significant differences between the two groups in the severity of nausea, vomiting, dizziness, and drowsiness. CONCLUSION(S): Patients who received only a PCB during the egg collection experienced 2.5 times higher levels of vaginal and abdominal pain as compared to those who received both PCB and conscious sedation. The use of PCB along is not recommended for all patients but it may be considered with selected patients after they have been given extensive counseling.

Pilot study on the use of sublingual misoprostol for medical abortion.

A new route of sublingual administration of misoprostol was used by 25 women with first trimester, non-viable intrauterine gestation and by 18 women requesting mid-trimester termination of pregnancy. Twenty-three women (92%, 95% CI 75, 98) with first trimester, non-viable gestation had complete abortion after sublingual misoprostol. All women (100%, 95% CI 82, 100) requesting second trimester abortion aborted, and the median induction-to-abortion interval was 11.6 h. Our preliminary results on sublingual misoprostol show that it is a promising method for medical abortion. Prospective randomized studies are required to compare its efficacy and side effects with vaginal misoprostol and to work out the dosage and dosing interval.

Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study.

Cross-sectional studies on the effects of depot-medroxyprogesterone acetate (DMPA) on bone mineral density (BMD) have been controversial. The present longitudinal cohort study on 59 Chinese women over a period of 3 years has shown that their annual rate of bone loss at 3 sites (0.44% in lumbar spine, 0.40% in neck of femur, 1.05% in Ward's triangle) was substantially less than the projected values (1.1% in lumbar spine, 2.3% in neck of femur, 3.5% in Ward's triangle) in a cross-sectional study that had demonstrated a significant reduction in BMD in DMPA users than the non-user population. The trochanter BMD measurement did not show the projected annual bone loss of 2.4%. The rate of bone loss is probably non-linear, with a rapid loss in the first 5 years and a leveling off afterwards. The duration of DMPA use was not significantly correlated with the rate of bone loss. Multiple linear regression analysis demonstrated that age and body mass index were significant variables in modeling the rate of bone loss in the lumbar spine and neck of femur, but not in the trochanter and Ward's triangle areas. The Z scores also suggested a retardation in bone loss with time and potentially due to the effect of progesterone in decreasing bone turnover that is similar to the situation in postmenopausal women. The present data provide another aspect of reassurance to the long-term use of DMPA.

Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases.

The treatment outcomes of 956 women undergoing second trimester termination of pregnancy with mifepristone and gemeprost were studied. The median gestational age was 16 weeks (range: 12-24 weeks). All women were treated with 200 mg mifepristone orally, followed 36 h later with 1 mg vaginal gemeprost administered every 6 h to a maximum of 4 doses in the first 24 h. A second course of 1 mg vaginal gemeprost was given 3-hourly in the next 12 h, if abortion had not occurred. Overall, 96.4% and 98.8% of the women aborted within 24 and 36 h, respectively. The median induction-to-abortion interval was 7.8 h (range: 0.5-109.9 h). The induction-abortion interval was longer in nulliparous women and women with a gestation age 17 weeks or above. Surgical evacuation of the uterus was performed in 11.5% of women for incomplete abortion or retained placenta. More multiparous women (16.7%) required surgical evacuation of uterus than did nulliparous women (7.3%; p <0.001). Ten (0.1%) women failed to abort with gemeprost and required other methods for abortion. In conclusion, a combination of mifepristone and gemeprost is a safe, effective, and noninvasive method of medical abortion for second trimester pregnancy.

Long-term depot-medroxyprogesterone acetate and bone mineral density.

The association between long-term use of depot-medroxyprogesterone acetate (DMPA) and bone mineral density (BMD) has been controversial, as seen in three case-control studies in New Zealand, Thailand, and the United Kingdom. In the present case-controlled study of BMD, a group of 67 Chinese women who had used DMPA from 5-15 years was compared with 218 women of the same age range who had not used any steroidal hormones. DMPA users were found to have a significantly lower BMD at lumbar vertebra (L2-4) (0.93 g/cm2), neck of femur (0.69 g/cm2), trochanter (0.59 g/cm2), and Ward's triangle (0.58 g/cm2), as compared with the control group, whose corresponding BMD values were 1.03 g/cm2, 0.83 g/cm2, 0.71 g/cm2, and 0.78 g/cm2, respectively (p < 0.001). The average percentage of bone loss per year was estimated to be 1.1% in L2-4, 2.3% in neck of femur, 2.4% in trochanter, and 3.5% in Ward's triangle. The percentage of bone loss in L2-4 was found to be more pronounced with age. This study provided information that the use of DMPA in a Chinese group for > 5 years in associated with bone loss, and a prospective study is needed to confirm these data, which are different from two case-control studies.

PIP: The effect of long-term use of depot medroxyprogesterone acetate (DMPA) on bone mineral density remains controversial. The present study compared bone mineral densities in 67 long-term (5 years or more) DMPA users recruited consecutively from the Hong Kong (China) Family Planning Association with those in 218 age-matched controls recruited from 8 family health service clinics in Hong Kong. Mean age was 42.8 years (range, 34-46 years) in the DMPA group and 40.0 years (range, 34-46 years) among controls. Body mass index, calcium intake, and smoking were similar in both groups. The median duration of DMPA use was 6 years (range, 5-15 years). Long-term DMPA users had significantly lower bone mineral densities than controls at the lumbar vertebra (0.93 vs. 1.03 g/sq. cm), neck of femur (0.69 vs. 0.83 g/sq. cm), trochanter (0.59 vs. 0.71 g/sq. cm), and Ward's triangle (0.58 vs. 0.78 g/sq. cm). The percentage of bone loss in L2-4 was more pronounced with increasing age. For each year of DMPA use, the decrease in bone mineral density was estimated to be 0.011 g/sq. cm (1.1%) in L2-4, 0.0193 g/sq. cm (2.3%) in the neck of femur, 0.0169 g/sq. cm (2.4%) in the trochanter, and 0.0277 g/sq. cm (3.5%) in Ward's triangle.

Pilot study on the use of a two-week course of oral misoprostol in patients after termination of pregnancy with mifepristone and misoprostol.

Twenty women who requested early first trimester termination of pregnancy were recruited to study the tolerability of a 2-week course of oral misoprostol after termination of pregnancy by mifepristone and vaginal misoprostol. Ten patients (50%) complained of mild diarrhea during the 2-week course of misoprostol. Otherwise, there were no other significant side effects. The 2-week course of misoprostol was well tolerated by women who underwent early first trimester termination of pregnancy with mifepristone and misoprostol.

PIP: A pilot study was conducted to assess whether prolonged use of misoprostol is well tolerated by women who have undergone termination of an early pregnancy with mifepristone and misoprostol and if this regimen increases the complete abortion rate and decreases the duration of bleeding. Enrolled were 20 women from Hong Kong and Shanghai with a menstrual delay of 21 days or less; the mean duration of pregnancy was 40.8 +or- 4.7 days. Women were given 200 mg of oral mifepristone, followed 48 hours later by 400 mcg of vaginal misoprostol. Oral misoprostol (400 mcg) was continued twice daily for 2 weeks. 11 women (55%) aborted during the initial 4-hour observation period and all had complete abortion. The mean duration of bleeding was 25.2 +or- 4.3 days. Nausea, diarrhea, and lower abdominal pain were the most common side effects of misoprostol, but all women were able to complete the 2-week course of treatment. On the basis of the findings of this pilot study, a prospective, randomized study with a larger number of patients is recommended to confirm whether a 2-week course of misoprostol can increase the abortion rate and decrease the duration of postabortal bleeding.

In vitro fertilization and embryo transfer during natural cycles.

OBJECTIVE: To report the results of in vitro fertilization and embryo transfer (IVF/ET) performed during natural cycles. STUDY DESIGN: A prospective clinical study. RESULTS: Thirty-two cycles were started in 19 patients who had regular ovulatory cycles and tubal factors or unexplained infertility only as the cause of infertility. Egg collection was performed in 12 cycles, and four pregnancies resulted from ET in eight cycles. The pregnancy rates were 12.5% per cycle initiated, 33.3% per retrieval cycle and 50% per transfer. CONCLUSION: Natural cycle IVF/ET offers a low-cost alternative to patients with infertility.

Intracervical sodium nitroprusside versus vaginal misoprostol in first trimester surgical termination of pregnancy: a randomized double-blinded controlled trial.

BACKGROUND: Results from small-scale randomized studies on the effectiveness of different preparations of nitric oxide donors in cervical priming before first trimester termination of pregnancies are not consistent. We compared sodium nitroprusside gel to misoprostol, the standard agent for cervical priming in this randomized double-blinded controlled trial. METHODS: Two hundred pregnant patients between 8 to 12 weeks admitted for surgical termination of pregnancy were recruited. They were randomized into either 400 microg vaginal misoprostol and intracervical placebo gel, or 10 mg intracervical sodium nitroprusside gel and placebo tablets 3 h before the procedure. The baseline cervical dilatation and cumulative force required to dilate the cervix from 4 to 9 mm were measured with a tonometer. Blood pressure was measured and side effects were assessed. RESULTS: The cumulative force to dilate the cervix from 4 to 9 mm was significantly higher in the sodium nitroprusside group, and the difference remained when a sub-group analysis was performed according to parity. Baseline cervical dilatation, duration of operation and operative blood loss were all in favour of misoprostol. Transient drop in blood pressure was observed after sodium nitroprusside treatment. CONCLUSIONS: Intracervical sodium nitroprusside is not as effective as misoprostol in cervical priming.

Randomized comparison of vaginal (200 microg every 3 h) and oral (400 microg every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy.

It is known that when misoprostol is given at 200 microg every 3 h after mifepristone pretreatment, the vaginal route is more effective than the oral route. However, women prefer the oral route. This randomized study was to test our hypothesis that oral misoprostol 400 microg is as effective as vaginal misoprostol 200 microg when given every 3 h in termination of second trimester pregnancy after priming with mifepristone. A total of 142 patients was randomly assigned to group 1 (200 mg mifepristone + 400 microg oral misoprostol every 3 h up to five doses) or group 2 (200 mg mifepristone + 200 microg vaginal misoprostol every 3 h up to five doses). The incidence of side-effects and the preference study were assessed through a standardized questionnaire during and after the abortion. For the oral group, both the incidence of diarrhoea (40.0 versus 23.2%, P = 0.03) and the amount of drug used (1734 compared with 812 microg, P < 0.0001) were significantly higher than that of the vaginal group but the incidence of fever appeared to be lower (not significant). There was no significant difference in complete abortion rate: 81.4% in the oral group and 75.4% in the vaginal group. The median induction-abortion interval was similar in the two groups (10.4 versus 10.0 h). The percentage of women who aborted in 24 h was also similar: 57/70 (81.4%) in the oral group and 58/69 (87.0%) in the vaginal group. Overall, 82.0% of women preferred the oral route. Oral misoprostol (400 microg) given every 3 h up to five doses, when combined with mifepristone, was as effective as the vaginal (200 microg) route in second trimester termination of pregnancy. This regimen could also be offered to those women who found repeated vaginal administration unacceptable.

Measurement of serum CA-125 concentrations does not improve the value of Chlamydia trachomatis antibody in predicting tubal pathology at laparoscopy.

Chlamydia antibody testing (CAT) has been used to predict tubal pathology associated with Chlamydia infection, the leading cause of pelvic inflammatory disease (PID). Tubal pathology not related to C. trachomatis is unlikely to be identified by CAT alone. A correlation between serum CA-125 concentrations and the severity of adnexal inflammation during acute PID was demonstrated. The objectives of this study were to determine the prevalence of C. trachomatis infection in an Asian infertile population and to assess the role of a combination of serum CA-125 and CAT in the prediction of tubal pathology as shown by laparoscopy. A total of 110 consecutive women attending an infertility clinic for work-up were recruited. Blood was taken for CAT and CA-125 on the day of hospital admission and an endocervical swab was taken for culture of C. trachomatis prior to laparoscopy. Two (1.8%) women had C. trachomatis found in the endocervix and 28 (25.5%) women had CAT of > or = 1:32. Serum CA-125 concentrations were > 35 IU/ml in 11 (10%) women. The discriminative capacity of CAT in the diagnosis of tubal pathology including both proximal and distal obstruction was not improved by measuring serum CA-125, regardless of the threshold values of serum CA-125 concentration.

The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme.

Multiple follicular development plays a major role in the successful outcome of IVF and embryo transfer treatment. Prediction of ovarian responses prior to stimulation is useful in counselling patients and helpful in tailoring the dosage of gonadotrophin to individual patients. The objective of this study was to compare age of women, body mass index (BMI), basal FSH concentration, volume of both ovaries and the number of antral follicles of both ovaries in predicting the number of oocytes obtained. A total of 128 consecutive women, who had no history of ovarian surgery, were non-smokers and undergoing the first cycle using a standard regimen of ovarian stimulation were examined. The total number of antral follicles achieved the best predictive value, followed by basal FSH, BMI and age of women. In those women with fewer antral follicles, a longer duration and higher dosage of human menopausal gonadotrophin were required but the number of eggs obtained was significantly less than for those with more antral follicles. Significantly more cycles were cancelled before egg collection in women with < or =6 antral follicles while more cycles of embryo transfer were postponed in order to reduce the risk of ovarian hyperstimulation syndrome in women with >9 antral follicles.