Oral or vaginal misoprostol for induction of labor.

OBJECTIVE: To compare vaginal versus oral misoprostol for induction of labor. METHOD: Induction of labor was carried out in 40 women near term in two equal and randomized groups (according to a computer generated table) using misoprostol. Group I received vaginal misoprostol (100 micrograms) every 3 h while group II patients were given the same dose via the oral route. The dose was doubled if no response was detected under continuous cardiotocographic (CTG) tracings. RESULT: The vaginal route of administration induced a higher success rate in a shorter time interval using a lower dose but was associated with more abnormal FHR patterns and instances of uterine hyperstimulation. CONCLUSION: It is recommended to use the vaginal approach with cardiotocographic monitoring.

Effect of Norplant implants on the pituitary-adrenal axis function and reserve capacity.

The present work investigated the effects of Norplant implants on the pituitary-adrenal function among 15 users of Norplant implants prior to and 6 months after insertion of the implants. Serum cortisol levels and their diurnal variations, ACTH and 24-h urinary 17-ketosteroids, ketogenic steroids, 17-hydroxy steroids, and creatinine, were measured. Also, a dynamic test (the 5-h Synacthen depot = ACTH stimulation test) was done before and 6 months after implants insertion. The 9 a.m. cortisol levels were blunted (within the normal ranges) while the 6 p.m. values were unaltered. The 24-h urinary ketogenic, hydroxy, and ketosteroids were also unchanged after Norplant implants use. The ACTH stimulation test showed a decreased adrenal response which was also within normal ranges. These data should raise the question related to suprarenal response to acute or prolonged stresses, such as surgical operations or shock in women using Norplant implants.

PIP: To ensure that Norplant contraceptive implants are not associated with a risk of pituitary-adrenal suppression, a series of laboratory tests were conducted in 15 women both before and 6 months after Norplant insertion. Comparisons of hormonal profiles before and after Norplant insertion revealed a significant drop in morning serum cortisol levels (404.33 +or- 84.07 nmol/l vs. 353.67 +or- 56.65 nmol/l, p 0.05), but no significant change in evening readings. The observed changes in morning cortisol values were still within the normal range. Serum ACTH values and 24-hour urinary 17-hydroxy steroids, 17-ketogenic steroids, and 17-ketosteroids were not different after insertion compared to baseline. Before Norplant insertion, injection of synthetic ACTH resulted in a 259.59 +or- 169.53% increase in the mean level of serum cortisol 5 hours later; 6 months after Norplant insertion, the percent rise above baseline was 165.85 +or- 91.64%. The significantly lower adrenal response among Norplant users (although still within normal limits) is presumably due to a local inhibition of the adrenal itself and not of the hypothalamic-pituitary axis. Although these findings suggest a minimal suppressive effect of prolonged microdose release of levonorgestrel from Norplant implants, the suprarenal response to acute or prolonged stresses (e.g., surgical operations or shock) in Norplant users requires investigation.

Human endometrial nuclear estrogen receptors among Norplant implant users.

Twenty-four parous women were included in this study. Sixteen cases were using the Norplant implant contraceptive system for more than 6 months (Group A) while eight cases served as matched controls in the secretory phase (Group B). Norplant implant users belonged to one of two equal subgroups according to whether they experienced regular menstrual bleeding (Subgroup A1) or prolonged episodes of amenorrhoea (Subgroup A2). Endometrial samples were processed for nuclear oestrogen receptor assay and for evaluation of the receptor's binding affinity to oestrogen. The results showed marked reduction in endometrial nuclear oestrogen receptors in Norplant users compared with controls as the majority of users had undetectable receptor levels. This down-regulation effect was significantly more pronounced among women with prolonged episodes of amenorrhoea. The affinity section of the study revealed no significant differences between groups or subgroups probably due to the small number of subjects with detectable receptor concentrations for comparison. These data may help in the understanding of contraceptive mechanisms and menstrual associated problems, and in the development of therapeutic measures.

An evaluation of the copper-T 380A IUD's safety and efficacy at three African centers.

The use of intrauterine devices in Africa is low compared with other contraceptive methods such as oral contraceptives. This study, coordinated by Family Health International, evaluated the clinical performance (safety and efficacy) of the TCu 380A IUD in three African centers, respectively, in Cameroon, Egypt, and Nigeria from 1986-1989. The 12-month unintended pregnancy rates were low for all three centers, ranging from none to 1.6 per 100 women. The 12-month discontinuation rates for all reasons ranged from 8.8 to 26.9 per 100 women. Statistically significant differences were observed among clinics for discontinuation rates for bleeding and/or pain and for planned pregnancy. The overall performance of the TCu 380A IUDs was considered satisfactory. Thus, the limited use of IUD in Africa could be due to the lack of accessibility, lack of information about, and confidence in the method rather than to documented clinical performance.

Termination of pregnancy with fetal death in the second and third trimesters--the double balloon versus extra-amniotic prostaglandin.

OBJECTIVES: To evaluate the use of a double balloon catheter in the termination of pregnancy with fetal death in the second and third trimesters, in comparison with the administration of extra-amniotic PGF2-alpha. METHODS: Twenty cases with IUFD at > 20 weeks of gestation were divided into two groups. Group I was subjected to the double balloon alone, while in Group II extra-amniotic instillation of PGF2-alpha via a Foley's catheter was used. RESULTS: There were no significant differences between the two groups with regard to induction-expulsion time, induction-delivery time and failure rate. CONCLUSIONS: The double balloon catheter proved to be an effective non-pharmacological method. The technique was simple and well tolerated by the patients. The side-effects of the prostaglandin and the cost of the medication were avoided.

Existing once-a-month combined injectable contraceptives.

Long-acting contraception by monthly intramuscular injection is an attractive method for family planning which fills a gap in birth control technology. The main advantage of this approach over long-acting (2-6 months) progestin injectables is much better cycle control. To achieve this goal, an estrogen had to be included in the formulation with significant reduction in the progestin dose. Until 1976, there were only three monthly injectables available (Injectable No. 1, Cycloprovera and Deladroxate), but they were faced with logistic, toxicological or clinical problems. It took over 15 years to resolve many of these problems and add a new product (Mesigyna = 50 mg norethisterone enantate plus 5 mg estradiol valerate in an oily solution). Cycloprovera, at a lower dose, received the new name of Cyclofem and Deladroxate was manufactured under the trade names of Perlutal or Topasel. The latter requires in-depth re-evaluation of its toxicological hazards. There are many other formulations currently being developed with incomplete data so far on safety and efficacy.

PIP: The major advantage of once-a-month combined injectable contraceptives over long-acting progestin injectables is a considerably improved cycle control. Researchers added an estrogen while greatly reducing the progestin dose to achieve better cycle control. The only 3 monthly injectables available up to 1976 (Cycloprovera, Deladroxate, and Injectable No. 1) had logistical, toxicological, or clinical problems. Some of the toxicological problems for Deladroxate, for instance, included pituitary hyperplasia development in rats, a carry-over effect, and estradiol accumulation. Researchers resolved many of these problems over more than 15 years. Pharmacologists reduced the dose of Cycloprovera, which was then remarketed under the new name of Cyclofem. Since the original manufacturer withdrew Deladroxate from the market, other manufacturers now market it as Perlutal and Topasel. Researchers need to conduct a detailed reevaluation of the toxicological hazards of Deladroxate before it is approved for general use or is banned for its toxicity in humans. A new once-a-month combined injectable contraceptive has also been added, Mesigyna (50 mg norethisterone enanthate + 5 mg estradiol valerate in an oily solution consisting of castor oil and benzyl benzoate at a ratio of 6:4). Mesigyna performance is similar to that of Cyclofem. Monthly combined injectables with limited clinical experience include the trade names of Unimens and Lutofollin and 4 with various new combinations (e.g., 50 mg NET-EN and 5 mg estradiol unducelate). Four other products are at an early development stage.

Serum nickel, copper and zinc in Norplant users.

Changes in serum nickel, copper and zinc were evaluated in 45 Norplant users. Two groups were selected for this study. Group I included 15 regularly menstruating females as controls and as short-term users (90 days after Norplant insertion). Group II included 30 Norplant users for one year or more as long-term users. These elements were determined by atomic absorption spectrophotometry. Serum nickel showed no significant change in short-term nor in long-term users when compared to the control group or to each other. Serum copper and zinc revealed a significant increase in short-term users for a short period of time, which returned to normal levels in long-term users. There was disappearance of the cyclic changes in serum copper and zinc concentrations on comparing their levels in ovulatory to non-ovulatory Norplant users. The use of Norplant has no deleterious effects on serum levels of nickel, copper and zinc.

PIP: Serum nickel, copper, and zinc levels were monitored by atomic absorption spectrophotometry in 15 women in the proliferative and luteal phases of their cycles before beginning Norplant contraception and 3 months later, and in 30 users of Norplant for 1 year or more. Serum nickel did not change significantly in short or longterm Norplant users in comparison with before Norplant self-controls or between groups, ranging from 0.221 to 0.28 mcg.dl. Serum copper rose from 100.07 mcg.dl in new users on Cycle Day 5 to 110.86 in ovulating women and 123.5 in nonovulating women in the control cycle. Copper was 118.7 before Norplant and not significantly different at 120.87 after 3 months. Copper levels were 104.26 in the 1st sample in longterm users, rising to 129.14 and 126.5 in ovulating and non-ovulating longterm users 3 months later. Zinc averaged 121.1 mcg/dl before Norplant on Day 5, falling to 94.86 and 97.38 in ovulating and nonovulating women in the luteal phase. Zinc rose slightly from 118.9 to 125.27 before and after 3 months on Norplant. Zinc fell from 107.9 to 91.86 and 94.61 in ovulating and nonovulating longterm users. The similarities and differences of these results with prior reports of trace element in oral and injectable contraceptive users are discussed.

Effect of prostaglandin E2 or prostaglandin synthesis inhibitors on human gonadotrophins and prolactin.

A role for prostaglandins (PGs) in the release of pituitary hormones in humans is controversial. The effect of PGE2 or PG synthesis inhibitors on gonadotrophin and prolactin (PRL) levels was evaluated in 50 volunteers (25 males and 25 females). Forty cases in four equal groups (Group I & II were males and group III & IV were females) received iv infusion of PGE2 in one cycle and non-steroidal anti-inflammatory drugs (NSAID) [Indomethacin or Naproxen] in the subsequent cycle. Control groups A & B (5 males and 5 females) received saline infusions in one cycle and placebo capsules in the next cycle. Neither PGE2 nor any of the two NSAID altered the basal levels of FSH or LH significantly. PGE2 infusions in males depressed PRL levels significantly two hours after the onset of infusions. Indomethacin raised PRL levels while Naproxen did not. In women, a similar response was also observed but prolactin levels decreased earlier (30 min from the PGE2 infusion). These data indicate a probable role for PGE2 or other prostanoids as well in the regulation of human PRL release but not in gonadotrophin secretion.

Improving placental blood flow in pre-eclampsia with prostaglandin A1.

Prostaglandin A1 is a potent hypotensive, peripheral vasodilator, a weak oxytocic, antiplatelet aggregator. It improves the renal hemodynamics. Its effect on placental circulation was evaluated (expressed as systolic/diastolic ratio and umbilical artery resistance index) in 20 women with severe pre-eclampsia and 10 normotensive pregnant women, by using the Doppler technique. Moreover, another 10 women with severe pre-eclampsia received dextrose 5% as a placebo for comparative purposes. Significant improvements in both parameters studied were observed in the women with severe pre-eclampsia. The beneficial changes differed significantly from the recorded values when using dextrose in pre-eclampsia or prostaglandin A1 in normotensive subjects. Such promising data add another important perspective to prostaglandin A1 in severe pre-eclampsia and may open up new avenues for its use in other situations with compromised placental flow.

Low dose acetyl salicylic acid in severe preeclampsia.

Twenty pregnant patients in the third trimester with severe preeclampsia were allocated at random into two equal groups. The first group was treated for 10 days with a low dose (75 mg/day) of acetyl salicylic acid (ASA) then with conventional therapy for another 10 days. The second group received the same regimen but conventional therapy in the first 10 days and ASA in the second 10 days. Changes in systolic and diastolic blood pressure, albuminuria, lower limb edema and urinary output were closely monitored and recorded. This comparative crossover study indicated that both the low dose ASA and conventional therapy significantly reduced systolic and diastolic blood pressure which was more pronounced with ASA and in group I. Crossover from one treatment to the other maintained the response but was more beneficial when ASA was given first.

Management of severe preeclampsia detected in early labor by prostaglandin A1 or dihydralazine infusions.

The presence of severe pregnancy-induced hypertension at the onset of labor requires therapy with a potent hypotensive agent. Prostaglandin A1 is a powerful vasodepressor that augments renal blood flow and glomerular filtration and possesses antiplatelet aggregator and oxytocic properties. A continuous intravenous infusion of prostaglandin A1 (40 to 50 micrograms/min) or dihydralazine (35 to 50 micrograms/min) was administered to 20 women with severe preeclampsia (10 in each group). The induced hypotensive response was similar with both drugs but the maximum reduction in blood pressure was achieved sooner with dihydralazine (4 hours) compared with prostaglandin A1 (7.5 hours). The more gradual hypotensive response is probably less dangerous on placental perfusion than a sudden change. Moreover, the oxytocic property of prostaglandin A1 shortened the time to delivery, which constitutes another potential advantage.

Treatment of severe pre-eclampsia by acetyl salicylic acid.

Low-dose Aspirin inhibits thromboxane A2 with minimal effects on prostacyclin and induces clinical improvements in pre-eclampsia. Two groups of pre-eclamptic women (10 in each) were treated either by low-dose acetyl salicylic acid (group I) or by conventional therapy (group II). Both groups showed a significant drop in systolic and diastolic blood pressure, a decrease in temperature, edema and albuminuria and an increase in urine volume. These effects were more significant in group I than in group II, except for the diastolic blood pressure. The obstetric progress and perinatal outcome were rather similar in both groups. These data offer a new potential therapeutic measure for the management of severe pre-eclampsia and call for further evaluation in a larger group of cases.

The use of prostaglandins in post-partum haemorrhage.

PIP: The low postpartum levels of PGI2 interacting with oxytocin vis-a-vis myometrial contractility may prevent postpartum hemorrhage. Predisposing factors for atonic postpartum bleeding are uterine overdistension, grand multiparity, prolonged labor, anemia, toxemia, and heavy narcosis. Routine administration of oxytocic agents reduce uterine atony. In 1 group of 40 patients .2 mg methyl ergometrine given iv postplacentally produced less bleeding than in the other group of 40 getting placebo. 1 mg of iv PGE1, .2 mg ergometrine, 3 IU oxytocin or a combination of PGE1 and ergometrine was compared in 180 women. PGE1 did not reduce blood loss. PGF2alpha was used successfully to induce labor in 21 women reducing blood loss compared to oxytocin. Another 10 women received in syntometrine and 5 got im .25 mg sulprostone at the moment of crowning, and the latter reduced postpartum blood loss. 90 women in 3 groups of 30 each at high risk of hemorrhage were injected im .2 mg methyl ergometrine maleate, .25 mg 15-methyl-PGF2alpha, and .5 mg sulprostone, respectively, resulting in prevention of severe hemorrhage. Intramyometrial injection of .5-1 mg of PGF2alpha induced uterine contractions and controlled bleeding in atonic hemorrhage when oxytocin failed. 20 mg PGE2 vaginal suppositories controlled postpartum atony after cesarean section, although fever and hypotension did occur. Im 15-methyl-PGF2alpha proved superior in producing hemostasis to intramyometrial PGF2alpha injection. In 2 studies .25 mg of 15-methyl-PGF2alpha was injected at 1.5 hour intervals arresting hemorrhage in 15 out of 16 and 18 out of 20 cases, respectively. Intrauterine infection caused all 3 failures. Sulprostone by infusion of 1.7-30 mcg/min or by 500 mcg im injection also controls postpartum hemorrhage.^ieng

Intrauterine administration of drugs for termination of pregnancy in the second trimester.

Medical methods have been used for many years to terminate mid-trimester pregnancy, ranging from irritant chemicals and traditional plants to ecbolic agents and solutions instilled locally into the uterus. These methods had serious limitations, with relatively high rates of maternal mortality and morbidity. Surgical evacuation requires special skills not available to all practitioners and many doctors consider second trimester dilatation and evacuation as a surgical taboo. In recent years several approaches evolved and reached the clinics, presenting safer and more effective options. Intra-amniotic instillation of hypertonic solutions, particularly saline or urea, proved in many hands to be a good method for pregnancies beyond 15 weeks of gestation. Due to a long latency period after instillation, these agents are often supplemented by an intravenous oxytocin infusion. Extraovular hypertonic saline or ethacridine (Rivanol) have their advocates, particularly in the grey-zone of pregnancy range from 13-15 weeks. In the last two decades, intrauterine prostaglandins were added to the methods in current use. Extra-amniotic prostaglandins (E2, F2 alpha or 15-methyl F2 alpha) were originally given in repeated doses or as a continuous local drip, but later a single instillation was used, usually mixing the drug with a viscous solution or gel. Intra-amniotic prostaglandins, in much higher doses, particularly the 15-methyl analogue, proved highly effective and relatively safe, especially when combined with laminaria tent insertion in the cervix. Various combinations of methods have provided a wide spectrum of data which is difficult to evaluate at present. Studies comparing different methods were mainly attempted in the mid-seventies. The outcome raised many pertinent questions and left many major issues unresolved. Most of the comparisons were not randomized or well-controlled and only referred to the natural prostaglandin compounds. The analogues, however, seem to offer several advantages and the role of additional methods such as laminaria or antiprogestins remains to be further evaluated.

PIP: There are several medical methods of inducing 2nd trimester abortion, each with merits and drawbacks, difficult to compare, especially when supplemental techniques are used. Drugs used are hypertonic saline, urea, natural and synthetic prostaglandins (PGs), mannitol, formalin, ethacridine lactate (Rivanol) and others for intraamniotic route; saline, PGs, Rivanol, utus paste and other extraamniotically; and the above methods combined with oral antiprogestins, iv oxytocics, in or intravaginal PGs, or mechanical cervical dilators. Few double-blind studies exist comparing drugs. About 50,000 mid-trimester abortions are done in the US yearly, about 10% of all terminations, but these cause 2/3 of all complications and half of the deaths. Saline can be used after 15 weeks, can cause hypernatremia or coagulopathy, and takes up to 72 hours unless augmented with ocytocin and/or laminaria. Urea may have less risk of coagulopathy. Rivanol is considered safer than both in some countries, e.g., Scandinavia, Eastern Europe, Israel, India and Japan. It can be instilled transcervically. Various intrauterine PGs have been compared in several doses and routes by WHO Task Force research groups and others. Extraamniotic PGs require a lower dose, cause fewer cervical lacerations, and can be used when membranes are ruptured, in molar pregnancy, at Weeks 13-15, and in cases of fibroids. This route is somewhat less effective than intraamniotic PGs, and may require multiple doses. Intraamniotic PGs act slower but are more effective, after only 1 dose. Laminaria speed up the process, but adding oxytocin increases risk of injury. PGs may be safer than saline, especially if intramuscular route is used, because there is no danger of coagulation, cardiovascular, renal or hypernatremic complications or inadvertent injection. It is possible that some of the higher complications attributed to PGs are related to selection of patients with more severe medical conditions. PGs are more expensive, and require medication for side effects.

Changes in menstrual blood loss after four methods of female tubal sterilization.

One-hundred females requesting tubal sterilization were included in this study. They were enrolled into 4 groups, each n = 25. They were allocated to a particular method of sterilization on a randomized basis. The four modalities used were: laparoscopic Falope ring application, bipolar electrocoagulation, Hulka clip application and Pomeroy tubal ligation via minilaparotomy. The menstrual blood loss (MBL) was quantitatively estimated, using the alkaline hematin method, prior to sterilization and after 3, 6 and 12 months. No significant changes in MBL were observed after the four sterilization techniques. Moreover, they did not differ significantly in this context.

PIP: 100 women seeking surgical sterilization were allocated to 1 of 4 groups--laparoscopic Fallope ring application, bipolar electrocoagulation, Hulka clip application, and Pomeroy tubal ligation through minilaparotomy--and changes in menstrual blood loss prior to sterilization and after 3, 6, and 12 months were compared. The 4 groups were comparable in terms of age, parity, and duration of marriage. All were at least 6 months postpartum or postabortion, had not used hormonal contraception or the IUD for at least 6 months before sterilization, had regular menstrual periods with moderate blood loss, and no gross pelvic pathology. The mean poststerilization increase in menstrual blood loss was greater in terms of volume after electrocoagulation (7.93 ml), lower after Fallope ring and Pomeroy (4.43 and 6.53 ml, respectively), and lowest after clip application (1.97 ml). However, when the 4 sterilization techniques were compared with each other, there were no significant differences in this variable. The percentage of women who developed menorrhagia (menstrual blood loss greater than 80 ml) decreased from 12% at 3 months poststerilization to 8% at 12 months after the procedure. By 12 months, majority (61%) were showing menstrual blood loss levels equal to or less than those recorded before sterilization. These findings lend credence to the assumption that female sterilization is an effective, safe, and feasible method of fertility control with few longterm effects on the menstrual cycle.

Clinical chemistry and pituitary response changes in Egyptian acceptors of L. Norgestrel six rods implants during the first year of use.

PIP: 71 Egyptian women using Norplant contraceptive implants for 1 year were followed with laboratory testing of carbohydrate, lipid and protein metabolism, liver and kidney function tests, serum iron and iron binding capacity and pituitary response to GnRH. The subjects were normal, healthy fertile, non-pregnant, non-lactating women who had not used hormone for 6 months. There were no pregnancies. Most women complained of altered menstrual patterns. Some reported headache, dizziness, increased vaginal discharge, nausea, and pain at the insertion site. There was no significant change in fasting or post-prandial glucose, or kidney function. Cholesterol decreased significantly at 3 months, triglycerides fell at 3 and 12 months, and HDL rose significantly at 3 and 12 months. SGPT fell significantly at 3 and 12 months. Total protein and albumin was significantly lower at 12 months. Serum iron and total iron binding capacity were significantly elevated at 3 and 12 months. Secretion of LH and FSH fluctuated around normal limits. The lipoprotein findings are discrepant from those reported from other developing countries in Norplant trials.^ieng

Treatment of preeclampsia with prostaglandin A1.

The vasodepressor prostaglandin A1 appeared to offer a major clinical potential solution in cases of severe pregnancy-induced hypertension. Thirty pregnant women with severe pregnancy-induced hypertension and a low Bishop score were studied in three equal groups. Group 1 received prostaglandin A1 infusions alone (0.5 microgram/kg/min for a maximum of 24 hours). Group 2 had received initial priming by prostaglandin E2 vaginal gel 6 hours before the onset of the prostaglandin A1 infusion, and group 3 was treated by conventional therapy and oxytocin induction. In the first two groups blood pressure was reduced to normotensive values, and labor was induced satisfactorily in 15 of the 20 cases, but four patients in group 1 were delivered within 24 hours after infusion. Group 2 offered the most favorable results because 80% were delivered during the infusion; thus the postinfusion rebound rise in blood pressure was avoided. Group 3 presented the least acceptable results, with the highest failure rate and an increased number of operative deliveries.

Effect of human menopausal gonadotrophin on the non-pregnant uterine response to intrauterine administration of prostaglandin E2.

The effect of intrauterine instillation of 50 micrograms of prostaglandin E2 (PGE2) on the non-pregnant human uterus was evaluated in 10 volunteers, before and after systemic administration of human menopausal gonadotrophin (HMG). The cases were either in the early proliferative (n = 5) or late secretory (n = 5) phases of the cycle. Before HMG administration, the uterus responded to local PGE2 by stimulation in all the cases. After HMG treatment, no response to PGE2 was detected in eight cases and a decrease in uterine tonus was observed in two cases. The implications of these findings in certain physiological and pathological conditions relating to reproduction are discussed.