Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets.

To determine the safety of transcervical administration of quinacrine pellets as a method of voluntary female sterilization, three noncomparative Phase I clinical trials of the administration of 250 mg quinacrine were carried out in 21 women who were scheduled to undergo hysterectomy 24 h or one month later. Detailed results are presented for one of the trials using 10-min pellets. Six of 10 women had minor transitory complaints during the postinsertion 24-h follow-up period. Five women reported pelvic/abdominal cramping, one experienced headache, and one experienced dizziness. Blood chemistry values were not adversely influenced by the quinacrine. The average plasma level of quinacrine peaked at 3 h, 36.1 ng/ml, slightly lower than the value observed 4 h after oral administration of 200 mg in a previous study. An average of 27% of the administered dose was recovered in tampons. Quinacrine was detected in the plasma of two women at the four/six-week visit. Selected results are presented from two other trials that were halted because of slow recruitment. The transcervical administration of 250 mg of 10-min quinacrine pellets was well tolerated. However, based on recent mutagenicity testing and meetings with regulatory officials, it appears unlikely that the use of quinacrine for nonsurgical sterilization could be approved in the United States or Europe.

A three-year evaluation of TCu 380 Ag and multiload Cu 375 intrauterine devices.

A randomized, comparative, multicenter clinical trial of TCu 380Ag and Multiload Cu 375 intrauterine devices (IUDs) was conducted. Safety and acceptability were evaluated through three years following insertion in 884 patients. The two IUDs were similar with respect to all event rates. Thirty-six month life table pregnancy rates were 0.6 per 100 TCu 380Ag users and 1.8 per 100 Multiload Cu 375 users. Continuation rates were 67.4 and 61.4 per 100 users of the respective devices at three years after insertion.

Efficacy of two insertions of 100-minute releasing quinacrine hydrochloride pellets for non-surgical female sterilization.

Extensive research has been undertaken to develop a simple method of non-surgical female sterilization. Zipper and associates identified quinacrine hydrochloride as a drug likely to produce tubal occlusion when placed into the uterus. Zipper's early work with a solution of quinacrine led to the development of quinacrine pellets, a delivery system that was designed to bring the quinacrine into prolonged contact with the tubal ostia through extended uterine retention. Three transcervical uterine insertions of 10-minute releasing quinacrine hydrochloride pellets performed at monthly intervals have produced a 12-month pregnancy rate of 3.3 per 100 women. The ultimate goal is to develop an effective, single insertion procedure, but the performance of the quinacrine pellets in occluding tubes has necessitated more than one insertion. FHI developed a 100-minute extended release pellet system with the expectation that more prolonged drug exposure would produce a higher rate of tubal closure. A study of the 100-minute releasing pellet system has been conducted in Santiago, Chile. Two monthly insertions in 112 women has resulted in a 12-month pregnancy rate of 2.0 per 100 women. Postprocedure problems occurring within the first year were reported by 13% of the women; most were minor and transitory.

Evaluation of two applications of methylcyanoacrylate for female sterilization.

Sixty-one women underwent non-surgical female sterilization with two applications of methylcyanoacrylate (MCA) at intervals of two months, three months or four months apart. Bilateral closure (as determined by hysterosalpingogram (HSG) ranged from 86% for women with an interval of four months between applications to 100% for women with an interval of two months between applications. One pregnancy occurred in a women three months after she was declared sterile.

An evaluation of the TCu 380Ag and the Multiload Cu375.

The TCu 380Ag (Outokumpu Oy, Pori, Finland) and the Multiload Cu375 (Multilan, Organon, Oss, The Netherlands) were evaluated in 1477 women in a multicenter clinical trial. The intrauterine devices showed similar, low-event rates. Cumulative life-table pregnancy rates were less than 1.0, and continuation rates were approximately 90 per 100 women at 1 year after insertion. The risk of subsequent hospitalization or pelvic infection was low.

PIP: This study evaluated the effectiveness, safety, and acceptability of the TCu 380Ag and the Multiload Cu375 IUDs in a multicenter international trial involving 1499 acceptors. The 2 devices were randomly assigned to women who entered the trial at 5 centers in Yugoslavis, Panama, Costa Rica, and Egypt between September 1980 and June 1982. The median age of the 737 women in the TCu 380Ag group was 26.7 years, with an average parity of 1.8; the median age of the 740 women in the Multiload Cu375 group was 27.5 years, with an average parity of 1.9. At insertion, 6.8% of women in the TCu 380Ag group and 6.2% of those in the Multiload Cu375 group complained of mild pain, 1.1% of women in both groups reported moderate pain, and there were no reports of severe pain. 1-year bleeding and pain removal rates were 3.8; removal rates for other medical reasons were less than 1.0/100 women. Significantly more women in the TCu 380Ag group reported intermenstrual pelvic pain, but this difference was confined to women under 30 years of age. The continuation rate at 1 year was 90.9% for the TCu 380Ag group and 88.7% for the Multiload Cu375 group. These rates are considerably higher than those reported for other IUDs. Of the 7 pregnancies reported in the 1st year after insertion, 2 occurred in the Tcu 380Ag group and 5 occurred in the Multiload Cu375 group. The results from this trial suggest that both the TCu 380Ag and Multiload Cu375 IUDs provide a highly effective, safe, and acceptable method of contraception. For women who wish to achieve contraceptive effectiveness for long periods, the TCu 380Ag may be the IUD of choice. It remains effective for 10-15 years, while the Multiload Cu375 has a life span of only 3-5 years.

A comparative study of the TCu200B with and without strings.

PIP: The role of the IUD string in the development of pelvic inflammatory disease (PID) was assessed in a multicenter trial. Subjects were 1st time IUD users with no clinical signs of uterine abnormalities or infection. TCu 200B IUDs with strings were inserted in 150 women; the remaining 150 women were fitted with devices without strings. Clinical follow up was scheduled at 1, 3, 6, and 12 months after insertion or at any time complications occurred. 5 cases of PID were reported during the follow up period: 3 involved women with parity 1 and 2 who received IUDs without strings, and 2 occurred in women of parity 3 or over who received IUDs with strings. These differences were not statistically significant. The 1-year PID rate in the current study was 2.2/100. About 75% of women in both study groups reported purulent discharge at least once during the 1-year follow up period. Urinary problems were reported by 5-10% of particpants. There were no significant differences between women with stringless IUDs and those receiving IUDs with strings in terms of dysmenorrhea, intermenstrual pain, spotting, or pain. Continuation rates at 1 year were 80% for women in both groups of parity 1-2 and 91% for those of parity 3 or more. These results fail to provide any evidence of an increased risk of PID in association with IUD strings.^ieng

Postpartum insertion of modified intrauterine devices.

The immediate postpartum insertion of standard intrauterine devices (IUDs) and those specially modified for postpartum use was evaluated in a multicenter clinical trial. The immediate postpartum insertion of IUDs was not associated with any increased risk of perforation or infection, although expulsion rates were higher than with interval insertions. The expulsion rate varied widely between centers using similar devices, suggesting that training in insertion is essential. Postpartum IUD insertions can be a practical contraceptive option for patients and providers of medical services.

PIP: The postpartum insertion of IUDs, especially in the case of institutional deliveries, has a number of advantages, including ease of insertion, availability of skilled personnel, appropriate facilities, and convenience for the mother. Immediate postpartum insertion of IUDs is not associated with increased risk of perforation or pelvic inflammatory disease (PID), although expulsion rates are higher than with interval insertions. In studies by Family Health International (FHI), expulsion rates varied widely between centers using similar devices. Expulsion rates ranged from 6-37/100 women at 6 months after insertion. This finding suggests that insertion may be as important a factor in influencing expulsion as the configuration of the device. FHI has developed modified IUDs with added suture material to project into the endometrium and reduce expulsion. After insertion the suture projections become soft and pliable and biodegrade completely within 6 weeks. Standard IUDs used for modification were the TCu and Lippes Loop. Adequate training and supervision of delivery room staff in insertion of IUDs is necessary. Midwives can betrained to insert the IUD after parturition through demonstrations and followup monitoring. Timing of IUD insertion is very important; FHI data show a significantly higher (p0.05) expulsion rate associated with insertions performed within the period of 10 minutes to 36 hours as compared to the immediate postpartum period (within 10 minutes). The use of postpartum IUDs raises questions of how much overlap there will be with the natural suppression of ovulation, especially in breastfeeding women, and whether the altered physiology of the reproductive tract interacts with the method. The inability to predict for individual women when ovulation will return, particularly among those who are breastfeeding, combined with inconvenience and sometimes impossibility of returning to a medical facility for insertion make the compromise of immediate postpartum insertion demographically effective and reasonable in many circumstances.

Menstrual patterns after female sterilization: variables predicting change.

Previous studies of the changes in menstrual pattern characteristics following sterilization have been flawed by methodologic errors. As a result, contradictory findings have been reported. Appropriate methodologic approaches to the study of poststerilization menstrual patterns are presented, and a new methodologic approach-an index of menstrual pattern change-is offered, which evaluates four menstrual parameters simultaneously. A carefully controlled study using this index indicates that most women report no change in menstrual pattern at 12 months poststerilization, and among those who do experience change, changes in one direction are balanced by changes in the other direction. The changes reported include improvements as well as changes for the worse. The best predictor of whether a woman would experience menstrual pattern change after sterilization is whether her pattern had any abnormal characteristics during the three months prior to the procedure. Surgical variables and special subgroups of women are also evaluated.

PIP: Previous studies of the changes in menstrual pattern characteristics following sterilization have been flawed by methodological errors. As a result, contradictory findings have been reported. Appropriate methodological approaches to the study of poststerilization menstrual patterns are presented, and a new methodologic approach--an index of menstrual pattern change--is offered, which evaluates 4 menstrual parameters simultaneously. A carefully controlled study using this index indicates that most women report no change in menstrual pattern at 12 months poststerilization; among those who do experience change, changes in 1 direction are balanced by changes in the other direction. The changes reported include improvements as well as changes for the worse. The best predictor of whether a woman would experience menstrual pattern change after sterilization is whether her pattern had any abnormal characteristics during the 3 months prior to the procedure. Surgical variables and special subgroups of women are also evaluated. More women reported that dysmenorrhea had decreased than those who reported that it increased; more women became regular than were irregular. These differences were not statistically significant, however. In general, women with extreme menstrual patterns at the time of sterilization were more likely to experience change than women with average menstrual patterns. With the exception of dysmenorrhea and regularity, it would be difficult to define changes as improvements or otherwise. It is not entirely clear whether regular arrival of the menses is important for women who have been sterilized and know they are not pregnant. Particularly interesting is that no single variable emerges as a good predictor of menstrual pattern change. All variables in combination do not produce a very high regression coefficient. Both tubal rings and spring-loaded clips were associated with less change than the other methods of tubal occlusion, and ligation and excision were associated with more change. Although both age and parity were included in the equation, only parity made a statistically significant but small contribution. The data used for this study were collected by Family Health International during 24 clinical trails at 45 hospitals in 23 countries, and consisted of 1555 interval patients who sought sterilization between July 1972 and August 1978 for contraceptive purposes. All were aged 25-34 years, had between 2 and 6 live births and not using hormonal or IUD contraception in the 3 previous months.

A new approach to measuring menstrual pattern change after sterilization.

Methodologic problems with previous research on menstrual changes after sterilization have resulted in conflicting results. This research overcomes these problems by restricting the categories of patients and by minimizing recall difficulties. When the methodologic approach is improved, the result is that the majority of women experience no change, and among those who do, changes in one direction are counterbalanced by changes in the other direction. Three cycles preceding sterilization were compared with three cycles 12 months after the operation for four menstrual parameters. The parameters were examined separately and simultaneously by means of an index of menstrual pattern changes. Rings and spring-loaded clips were associated with less change than other methods of occlusion. The most important variable was the patient's menstrual pattern at the time of admission. Women defined as having abnormal patterns were three times more likely to experience change than women with normal cycles, and many of the former experienced change in the direction of normality.

Effects of breastfeeding on IUD performance.

The effect that lactation might have on intrauterine device (IUD) performance was investigated by using data from a series of multicenter clinical trials. Life-table methods were applied to compare breastfeeding and non-breastfeeding women with respect to IUD expulsion, accidental pregnancy, IUD removal for various reasons, and overall continuation of IUD use. Results indicate that breastfeeding does not increase the risk of expulsion or other events, whether the device is inserted immediately (within ten minutes) or more than 42 days after delivery. (Am J Public Health 1983; 73:384-388.)

Wider opportunities for IUD insertion.

PIP: The timing of IUD insertion has important implications for those who insert the devices as well as the users. In 1978 the US Food and Drug Administration recommended insertion during menstruation but acknowledged that it is also "necessary and proper" to insert IUDs at other times in the cycle. A 1977 study found that 30% of European and North American obstetricians limited insertion to the time of menstruation. Nearly half those in Africa and the Middle East and 13% of those in Asia followed this practice. Consequently, many women are required to make more than 1 visit to a clinic, meaning inconvenience for both the user and provider and some unintended pregnancies. In developing countries women may depend on mobile clinics or infrequent visits by trained personnel and many seek help without an appointment. 1 reason for insertion at or just after menstruation is to ensure that the woman is not pregnant when the IUD is inserted. 2 recent articles attempt to assess the best time for IUD insertion with regard to IUD performance. White et al. found that women whose Copper T IUDs were inserted on days 1-5 of the menstrual cycle had a lower continuation rate in the 1st few months than did those whose IUDs were inserted at a later time in the cycle. Edelman et al. found that Copper T and Copper 7 IUDs could be inserted at any time during the menstrual cycle without any increased risk of subsequent pregnancy, removal for medical reasons or expulsion during the 1st 12 months after insertion. Pooled International Fertility Research Program (IFRP) data indicate that there is no consistent pattern with regard to the time in the cycle that the IUD is inserted and its later performance. In no case is there a distinct advantage for the 1st 5 days of the menstrual cycle. It is much simpler to offer a woman an IUD when she is first seen, provided she is reasonably sure she is not pregnant. New practices are evolving in relation to recently pregnant women. The postabortal use of IUDs has been extensively researched and is a useful option, using a variety of currently available devices. In regard to the postpartum use of IUDs, some programs have reported a high expulsion rate. Provided proper insertion technique is used, IUDs can be inserted immediately postpartum with a high degree of retention. Another use for copper containing IUDs is insertion within 5 days of unprotected sexual intercourse. In sum, women can be provided with IUDs upon request at any time during the menstrual cycle.^ieng

A comparison of the Lippes Loop and two copper-bearing intrauterine devices.

A review of published studies and studies conducted through the International Fertility Research Program on the Lippes Loop D, TCu and Cu-7 shows that none of the three devices evaluated is better with respect to continuation and all types of event rates. There is a trend toward lower expulsion rates for the copper-bearing IUDs, but other factors such as the cost of devices and the need for replacement must be considered in determining the merits of the devices for large-scale programs.

Modification of the CuT 220C for immediate postpartum use.

PIP: Postpartum insertion of IUDs has an unacceptably high expulsion rate. The International Fertility Research Program (IFRP) modified the Lippes Loop D and Copper T 220C with chronic suture extensions (Ethicon, No 2) for postpartum insertion. These biodegradable extensions or projections are added to the IUD to hold them in place during the involution period. Preliminary data shows that such modified devices have an expulsion rate of 5.3 + or - 1.3 per 100 women at 6 months. A clinical trial of 247 hand insertions performed in the immediate postpartum period (within 10 minutes after delivery of placenta) in Chile and in the Philippines revealed an expulsion rate of 4.2 + or - 1.3 at 3 months, and 6.5 + or - 1.6 at 6 months after insertion, rates similar to those of the sutured loop (3.1 + or - 1.0 and 5.3 + or - 1.3, respectively). At 6 months and 1290 women-months of use, continuation rate was 91.7%. Preliminary data also suggest a success rate for the sutured Copper T 22OC similar to that of the sutured Lippes Loop D. These data also imply that modification of any standard device for immediate postpartum insertion for increased effectiveness can be achieved if done in a similar way.^ieng

Laparoscopy and minilaparotomy: two major advances in female sterilization.

PIP: Laparoscopy and minilaparotomy have contributed significantly to the rapidly escalating popularity of female sterilization. This paper reviews these procedures and personnel requirements and compares their safety and efficacy, using data collected by the International Fertility Research Program. It concludes that minilaparotomy with the ligation method of tubal occlusion is the surgical sterilization procedure that can be offered practically, safely, and effectively to the greatest number of women worldwide.^ieng

Nonsurgical female sterilization.

The development of a safe, effective nonsurgical method of female sterilization that can be performed by paramedical personnel remains a high priority. The method should have a blind delivery system and require only one application. Methyl cyanoacrylate and quinacrine hydrochloride are the two most promising chemical agents. Quinacrine has evolved from instillations of a solution to the development of pellets to the use of an IUD vector. By using an IUD vector to deliver the quinacrine, tubal occlusion can be achieved with a reduction in total dosage and with one insertion instead of the three necessary with the solution and pellet methods.

Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilization.

The efficacy of transcervical insertions of quinacrine hydrochloride pellets to produce tubal occlusion has been evaluated in a study of 139 women in Santiago, Chile. At one year, the pregnancy rate was 3.1%, an acceptable rate for a nonsurgical method of female sterilization.

PIP: 139 volunteers seeking permanent sterilization were treated with 3 transcervical insertions of quinacrine hydrochloride pellets to produce tubal occlusion. The procedure is essentially the same as inserting an IUD. Pregnancy rate at 1 year was 3.1%, and results showed this method to be more effective than the quinacrine solution method, which entails a higher risk of transient toxic psychosis.

Tubal occlusion via laparoscopy in Latin America: an evaluation of 8186 cases.

Ease of performance, safety and effectiveness of laparoscopic sterilization techniques are evaluated for 8186 procedures (6995 interval, 680 postabortion and 511 postpartum) performed in Latin America from June 1972 through February 1978. The tubes were occluded via electrocoagulation or application of the spring-loaded clip or the tubal ring. Less than 1% of the procedures were declared technical failures (ie, those which were not completed as planned). For all the tubal occlusion techniques, interval patients had the lowest rate of surgical complications. Pregnancy rates were low for the electrocoagulation and for the tubal ring techniques; patients sterilized by the spring-loaded clip, however, had a significantly higher pregnancy rate.

Incidence of pain among women undergoing laparoscopic sterilization by electrocoagulation, the spring-loaded clip, and the tubal ring.

Data analyzed from five comparative studies show a relationship between the technique of tubal occlusion and pain experienced by patients both at the time of the procedure and during the recovery period. During the procedure, the spring-loaded clip is the technique least likely and the tubal ring the technique most likely to be associated with pain. During the recovery period, both the spring-loaded clip and the tubal ring are associated with higher rates of abdominal or pelvic pain than is electrocoagulation. Differences in pain that occurred during the recovery period did not persist to the early follow-up visit.

A comparison of the clip and ring techniques for laparoscopic sterilization of postabortion and postpartum patients.

The spring-loaded clip and the tubal ring techniques of laparoscopic female sterilization are compared for ease of performance, safety and effectiveness at the Kandang Kerbau Hospital in Singapore. The two techniques were randomly assigned to 299 postpartum patients and 300 postabortion patients. The assigned procedure could not be performed for two of the ring cases and three of the clip cases. Bleeding and equipment problems made laparotomy necessary in two clip cases and equipment problems caused a change in technique in the other clip case. Hydrosalpinx and adhesions were responsible for a change to laparotomy in the two ring cases. Surgical difficulties, chiefly the result of equipment problems, were significantly higher for both postpartum and postabortion clip procedures. Complications and complaints reported immediately after surgery and at the 7- to 21-day follow-up visit were low for all four groups. For both postabortion and postpartum patients, six- and 12-month data show that pregnancy rates are significantly higher for patients sterilized with the clip than with tubal rings.

Risks and benefits of culdoscopic female sterilization.

This paper reviews the risks and benefits of the culdoscopic approach to female sterilization in an alnalysis of 2153 culdoscopic sterilization procedures performed at 11 centers in nine countries. Inability to occlude the tubes as planned was reported for approximately 6.0% of the cases including 1.4% in which one or both tubes could not be occluded by any technique. Surgical difficulties were reported for about 13.0% of the procedures, and surgical complications, of which the most frequent was torn or bleeding tubes, occurred in 2.0% of the cases. Pregnancy rates were significantly higher for patients whose tubes were occluded by tantalum clips (7.7 per 100 women at 12 months), indicating that this is not the preferred technique of tubal occlusion; the 12-month life table pregnancy rates were 0.1 per 100 women for tubal ring and 0.0 for Pomeroy and fimbriectomy. Comparison of these data with similar pooled data on laparoscopy and minilaparotomy indicates that culdoscopy is associated with greater technical difficulty and morbidity. Thus, abdominal procedures will continue to be preferred for use in most large-scale programs.