Development and evaluation of an inhibitor-releasing matrix for intrauterine devices

Antifibrinolytic agents when released into the uterine cavity decrease menorrhagia associated with IUD use. Our objective was to develop a matrix that could be incorporated onto an IUD and release anti-fibrinolytic agents. The copolymer ethylene-vinyl acetate (EVA) was selected for detailed study because it has the advantage over other materials in that it can release large molecular weight substances for more than 100 days, and allows incorporation of large amounts of anti-fibrinolytic agents with different molecular weights. Two compounds, tranexamic acid (AMCA, MW=157) and Trasylol (Kunitz pancreatic trypsin inhibitor, (MW=6,500) were incorporated into the EVA matrix and their release rates measured. In vitro studies with AMCA showed that after the initial burst, a constant high release rate was obtained over a prolonged period of time. The in utero release rate of AMCA from the EVA matrix in rabbits was similar to that obtained in vitro. By contrast, the release rate of Trasylol decreased to low levels during incubation in vitro. The release rate of Trasylol in utero however, appeared to be higher than that in vitro.     

The new intrauterine contraceptive devices: Safe and effective

Reviews of the safety of intrauterine contraception usually are based on studies that do not reflect changes in clinical practice that have occurred over time, and that include many types of IUDs that are no longer used. Studies of insertions of the Multiload 375 and Copper T 380 performed since 1980, which more accurately reflect current clinical practice, show that these IUDs provide a high level of protection against pregnancy and are associated with low rates of complications. Current clinical opinion regarding the safety of IUDs needs to be reassessed in light of the positive safety record of these IUDs.

---

Resumen Los estudios relativos a la seguridad de la anticoncepción intrauterina suelen basarse en estudios que no reflejan los cambios en las prácticas clínicas ocurridos con el correr del tiempo y que incluyen muchos tipos de DIU que ya no se utilizan. Los estudios relativos a las inserciones del Multiload 375 y Copper T 380 realizados después de 1980, y que reflejan mejor la práctica clínica actual, indican que estos DIU ofrecen un alto nivel de protección contra los embarazos y están asociados con bajos porcentajes de complicationes. En lo que respecta a la seguirdad de los DIU, es necesario evaluar nuevamente la opinión clínica actual a la luz de los resultados positivos obtenidos con estos dispositivos.

---

Resumé Les études portant sur la sáreté de la contraception intra-utérine sont en général fondées sur des études ne reflètant pas les changements dans les pratiques cliniques intervenus au cours des années et se rapportent à de nombreux types de DIU qui ne sont plus utilisés. Les études concernant les insertions de Multiload 375 et Copper T 380 effectuées depuis 1980, qui d'ailleurs reflètent mieux la pratique clinique actuelle, indiquent que ces DIU offrent un haut niveau de protection contre les grossesses et qu'ils sont associés à de faibles pourcentages de complications. S'agissant de la sûreté des DIU, il y a lieu de réévaluer l'opinion clinique actuelle à la lumière des résultats positifs obtenus avec ces dispositifs dans ce domaine.

     

四川省3个县农村育龄妇女宫内节育器使用情况调查

目的:了解四川省农村育龄妇女宫内节育器(IUD)使用情况。方法:采用多阶段分层整群抽样的方法,对四川省3个县农村,共2107例于2004年7月1日～2005年6月30日期间放置IUD妇女进行横断面及前瞻随访研究。结果:3个县育龄妇女普遍使用的3种IUD分别是:母体乐375、TCu380A、宫铜,不同地区使用种类不同(P<0.001)。平均续用率为86.9%,75.3%IUD在乡级服务机构放置。IUD使用失败原因前3类依次为脱落、因症取器和下移取器,分别占4.7%、2.8%、2.7%;带器妊娠率为1.0%。logistic单因素分析显示,防止IUD脱落的保护因素是施术者5年内接受培训(OR=0.817,P=0.007)。结论:建议引入以循证医学为基础的临床路径的管理模式,针对各型IUD特点制定相应的标准操作程序作为技术指南,促进服务质量提高。     

Statement on intrauterine devices

These policy statements and guidelines from the International Planned Parenthood Federation's (IPPF) International Medical Advisory Panel (IMAP) concern IUDs. The following contraindications to IUD use are recognized: 1) pelvic inflaminatory disease, 2) known or suspected pregnancy, 3) history of previous ectopic pregnancy, 4) gynecological bleeding disorders, 5) suspected malignancy of the genital tract, 6) congenital uterine abnormalities or fibroids distorting the cavity, and 7) anemia, blood coagulation, severe cervical stenosis, copper allergy, Wilson's disease, and others. Generalities regarding appropriate IUDs are: 1) non-medicated devices (e.g. Lippes Loop) are studied for women who may not return for regular check-ups, 2) smaller medicated devices usually cause less menstrual blood loss than the non-medicated devices, 3) smaller devices are better for a smaller uterus and larger devices for the larger uterus, and 4) when a smaller device is expelled it is advisable to try a larger one and vice versa. Dalkon Shields should not be used by the IPPF system and all women using them should have the device removed. Correct insertion of IUDs is important and should be done by properly trained personnel. The timing of insertion is best during the menstrual period. Withdrawal of the applicator while leaving the device in place is the recommended insertion technique. Sterilization of IUDs should follow instructions on bulk-packaged IUDs. Complications include perforation, bleeding and pain, infection, and ectopic pregnancy. IUD removal should be done during menstruation. Good clinical management and follow-up care are recommended.     

Long-term use of intrauterine devices

Analysis was performed of data relative to 10,001 IUD insertions (mostly Lippes Loop D and C) in 8091 women in Slovenia between 1965 and 1972. Data were gathered on sociodemographic characteristics of the users; cumulative life-table rates per 100 women for removals due to pregnancy, expulsion, bleeding/pain, other medical reasons, and personal reasons as well as continuation rates and the rate of follow-up; and the proportion of women with bleeding, spotting, vaginitis, and pelvic inflammatory disease (PID) at 1-, 5-, and 10-year follow-up. The most frequent reason for removal was bleeding. Increased duration of IUD use was associated with a smaller number of women with bleeding and PID episodes. Of those with first insertions, 608 were hospitalized for IUD-related complications (49% for bleeding requiring curettage and 20% with PID). IUD use for more than five years carried a relative risk of 3.9 for a severe episode when PID developed. Of the women who terminated use of their first IUD because of expulsions, pregnancy, or bleeding, 28% asked for reinsertion. Over the 15 years of IUD use, 853 pregnancies occurred with an IUD in situ. If the IUD was removed after conception, the pregnancy outcome did not differ from women without IUDs. If the IUD was not removed, there was an increased risk of spontaneous abortion, preterm labor, and intrauterine fetal infection. While the IUD users experienced the same risk of ectopic pregnancy as noncontraceptors, if the IUD user did become pregnant, their risk of ectopic pregnancy was twice as high as that faced by those who did not use IUDs. Duration of IUD use and type of IUD had no effect on time from removal to desired conception. This duration was increased, however, in women with a history of PID and in older women. Women over 40 tolerated the IUD better than younger women but as women approached 50, removals for bleeding became more frequent. In conclusion, the IUD is a very safe contraceptive agent and is well tolerated if users are selected carefully, are motivated, and receive help with side effects.     

A three-year evaluation of TCu 380Ag 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.     

Safety and effectiveness of intrauterine devices

The life-table analysis of about 16,000 first insertions of the Copper T Model 200 (TCu-200) in the United States indicates that about 58.5 percent of these women terminated the use of the TCu-200 by the end of three years following the insertion. This includes about 6.6 percent who became pregnant during this period. The results of the TCu-200 are compared with the Copper 7 and with Dalkon Shields from two double-blind studies of these devices. In the end, the index — The Mortality Benefit Ratio — defined in terms of the number of deaths per 1000 births averted, is used to compare the relative risks and benefits associated with various forms of contraception. Based on the experience in the United States, the values of the Mortality Benefit Ratio indicate that IUDs are at least as safe, if not safer, than other forms of contraception currently available.     

The safety of intrauterine devices.

Mortality and morbidity associated with the IUD -- already relatively low -- can probably be reduced to a minimum with greater awareness of the risks of IUD use. This assessment focusses on 4 main areas of concern: 1) Consequences of contraceptive failure. A unique feature of intrauterine contraception is that the morbidity of pregnancies due to failure of the method is increased by the method itself. When pregnancy occurs with the IUD in place, incidence of extrauterine pregnancy, spontaneous abortion, bleeding, and prmature and still births are increased, with the miscarriage rate up to 50% (compared to 10 to 20% in the general population). This latter incidence is steeply reduced if the IUD can be removed. 2) Pelvic infection. Many studies have shown increased incidence among IUD users, the consistency of reports indicating a causal relationship, especially worrying in that the highest risk is among young nulliparas. A variety of causes has been suggested. While infection cannot be completely eliminated, strict attention to antisepsis at insertion, recognition of early warning signals, and avoidance of use by high risk groups, should minimize the dangers. 3) Problems associated with insertion. A major concern is avoidance of perforation. Special care is needed when inserting a device up to 8 weeks after pregnancy. A perforated IUD should be removed -- copper-bearing devices may be especially risky. Laparotomy or minilap may be preferable to laparoscopy for removal of bioactive devices. Risks at insertion should be considered when prescribing medicated devices which require more frequent replacement. 4) Anemia. All IUDs have some effect on bleeding, most causing increased bleeding during menstruation and some intermenstrual bleeding and spotting. This has primarily been seen as a cause for discontinuation, but may have medical consequences in developing countries where iron loss cannot be easily made up nutritionally. A small but real risk from therapeutic practices (use of drugs and antibiotics to reduce side effects, and surgical procedures for removal of perforated IUDs) is also noted.     

Copper release from copper-T intrauterine devices

In this investigation of the copper loss in utero from the Copper-T, the release rate was estimated by iodometric titration and the corrosion was microscopically examined in ground plastic casts. The release rate was determined in 28 preweighed Copper-Ts with a surface area of 100–400 mm² during the first month, and in 60 Copper-T-200s (TCu-200) which had been used for 5.3 to 40.3 months. The depth of corrosion was measured in 68 TCu-200s used for 3.2 to 52.0 months.During the first month the copper release from preweighed Copper-Ts with a surface area of 100,200,300 or 400 mm² was 26.3, 44.4, 75.2 and 73.6 μg/day, respectively. The release rate increased with increasing surface area up to 300 mm², but not thereafter. The average release rate of the TCu-200s was 43.8 μg/day from the 21st up to the 41st months of use. However, the release rate was significantly higher in devices removed because of bleeding. In these, it was twice or even four times as high as in the devices removed from symptom-free patients. Metallurgic micrographs revealed both inter- and intraindividual variations in corrosion of the wire. Wire breakage occurred as early as in the 12th month of use, and the risk of breakage was about 30 per cent during the fourth year.Owing to the corrosion, a replacement of TCu-200 seems indicated in symptom-free patients every three years, in patients with abnormal bleeding even more often. The life time of copper IUDs could be prolonged by increasing the thickness of the wire and by supplementing it with a non-corrodable (e.g. silver) core, which would eliminate the fragmentation due to corrosion. Moreover, an increase of the wire surface to 300 mm² would probably reduce the pregnancy rate.     

Long-term experience with Multiload intrauterine devices

This paper reports the joint experience of three investigators who used three types of the Multiload (ML) IUD (MLCu250 Short, MLCu250 Standard, and MLCu375) in 1987 consecutive insertions during which an experience of 56005 woman-months of use was accumulated. The material was analyzed using the life-table method and complemented with a case by case investigation, the main purpose of the study being the specific analysis of IUD-related complications. The authors also evaluated return of fertility whenever a device was removed because of wish of pregnancy.Results indicate that serious IUD-related complications were rare, continuation rate high, and reversibility of fertility unaffected by the device.

---

Resumen En este trabajo se informa sobre la experiencia conjunta de tres investigadores que emplearon tres tipos de dispositivo intrauterino Multiload (ML) (MLCu250 Short, MLCu250 Standard y MLCu375) en 1.987 inserciones consecutivas, durante las cuales se registró una experiencia de 56.005 meses-mujer de uso. El material se analizó utilizando el método de tabla de vida y se complementó con un estudio de cada caso individual; el objetivo principal del estudio fue el análisis específico de complicaciones relacionadas con el empleo del DIU. Los autores evaluaron asimismo el retorno de la fecundidad cuandoquiera que se retirase un dispositivo debido al deseo de la mujer de quedar ambarazada.Los resultados indican que rara vez hubo complicaciones graves relacionadas con el empleo del dispositivo, que la tasa de continuación fue alta y que la reversibilidad de la fecundidad no se vio afectada por el dispositivo.

---

Resumé Cet article rapporte l'expérience de trois investigateurs avec trois types de DIU Multiload (MLCu250 court, standard et MLCu375) dans une série consécutive de 1987 insertions et un total de 56.005 cycles. Le matériel a été analysé en faisant usage des tables-vie, complété par une investigation de chaque cas, le but principal étant cependant l'évaluation de complications relatives au port du DIU. Les auteurs ont également analysé la réversibilité de la fertilité après retraît pour désir d'une nouvelle grossesse. Les résultats indiquent que les complications sérieuses dues au DIU étaient rares et le taux de continuation élevé. Apparemment le retour de la fertilité n'était pas influencé par le port d'un DIU.

     

Endometrial morphology with copper-bearing intrauterine devices

Copper-containing intrauterine devices such as the endouterine Copper T (CuT) first developed by Zipper and Tatum appear to offer great promise. The clinical effectiveness of these devices and their low rate of associated side effects such as expulsion, bleeding, and cramping compare favorably with other devices.The antifertility effect of the CuT is believed to be related to the metallic copper covering. Experimental data suggest that a local, rather than a systemic, contraceptive mechanism is operative due either to direct spermatocidal action, the inhibition of implantation, or a combination of these.The present study was undertaken to extend the electron microscopic studies of CuT-IUCD-bearing endometria using both scanning and transmission electron microscopy and to examine copper distribution utilizing an energy dispersive X-ray analyzer.     

The corrosion chemistry of copper intrauterine devices

A combination of chemical and spectroscopic investigations have proven that the corrosion layer on Copper-7 intrauterine devices (IUDs) consists primarily of copper(I) and copper(II) species with lesser amounts of calcium, iron, and nonmetallic components. Photoacoustic spectroscopy of the intact layer as well as wet chemical analysis combined with atomic absorption spectroscopy has allowed evaluation of both metal composition and copper oxidation state percentages, which vary appreciably from sample to sample. Results indicate that the copper oxidation is caused by oxygen and not by oxidized glutathione as suggested earlier by others.     

Surgical management of intra-abdominal mislocated intrauterine devices

OBJECTIVE: We report on our experience in surgical treatment of patients with intra-abdominal intrauterine devices (IUDs). MATERIAL AND METHODS: A total of 10 patients were retrospectively analyzed. Diagnosis was based on gynecologic examination, transvaginal sonography, and abdominal X-ray. RESULTS: All of the IUDs were inserted by trained midwives, either in the puerperal period (n=3) or within 1 year after puerperium (n=7). Five women were asymptomatic at the time of diagnosis, three were pregnant and two complained of pelvic pain. Eight patients were managed by laparoscopy, whereas laparotomy was required in two. Abscess formation was present in two cases. The postoperative course was uneventful in all patients. CONCLUSION: A missing string during gynecologic examination is the first sign of an intra-abdominal IUD in all cases. Transvaginal sonography should be combined with abdominal X-ray to reach a definitive diagnosis. Laparoscopic treatment may be appropriate in most of the cases.     

Post-cesarean section insertion of intrauterine devices.

Among 52 women who delivered by cesarean section in a medical center in Beijing, China and had either a Delta Loop or Delta T intrauterine device (IUD) inserted manually through the incision wound, the expulsion rates were significantly lower than among a comparable group of 147 women who both delivered and had the IUD inserted vaginally (4.1 versus 20.5 per 100 women at six months post-insertion). Since the cesarean delivery rate is increasing worldwide, we deem this preliminary finding important for postpartum contraception programs and urge further studies.     

Use of intrauterine devices in nulliparous women

Five intrauterine devices (IUDs) are available in the United States: four levonorgestrel-releasing intrauterine systems (two containing 52 mg, one containing 19.5 mg and one containing 13.5 mg) and one copper-bearing device (Copper T 380A). All IUDs have very low typical-use failure rates and high acceptability ratings, yet they are used by a minority of women, with nulliparous women less likely to do so than parous women. The objective of this clinical review is to give evidence-based recommendations for the use of IUDs in nulliparous women. Intrauterine devices are safe and effective for the majority of women including those who are nulliparous, and should be routinely included in the contraception options offered to them.     

Fertility after discontinuation of levonorgestrel-releasing intrauterine devices

The conception rate and outcome of pregnancy of twenty-one women who had been using a levonorgestrel-releasing intrauterine contraceptive device and who had had the device removed because of planned pregnancy were studied. Eighteen women (85.7 per cent) conceived during the follow-up period. All but one of the pregnancies ended in the birth of a full-term healthy child.