- Email: [email protected]
Performance of the frameless GyneFix and the TCu380A IUDs in a 3-year multicenter, randomized, comparative trial in parous women
ORIGINAL RESEARCH ARTICLE
Performance of the Frameless GyneFix and the TCu380A IUDs in a 3-Year Multicenter, Randomized, Comparative Trial in Parous Women Shangchun Wu,* Jing Hu,* and Dirk Wildemeersch*†
This study was conducted to evaluate a new and improved inserter (GyneFix) for the anchoring of the Frameless IUD in the uterine cavity. Previous studies conducted with a prototype inserter (Flexigard) did not show fully the advantages of the new anchoring concept because of the shortcomings of the Flexigard inserter and the complexity of the insertion technique. The GyneFix IUD was compared with the TCu380A IUD in six centers in China in approximately 300 women in each group. Only parous women were included in the study. The data from this 3-year, ongoing study demonstrate that the shortcomings of the inserter have been corrected, resulting in better performance and a much reduced rate of failed insertion/expulsion of the frameless and anchored device. The cumulative expulsion rate with the GyneFix IUD was 3.0 at 3 years (annual rates 2.67, 0.33, and 0.0, respectively) compared with a cumulative expulsion rate of 7.38 at 3 years with TCu380A (annual rates 4.63, 1.76, and 1.04, respectively). This difference is statistically significant. The majority of the expulsions with the anchored IUD occurred early in the study, indicating improper anchoring technique. The study also shows that both devices are highly efficacious. No pregnancies occurred with the GyneFix IUD (cumulative pregnancy rate 0.0 at 3 years) versus one pregnancy with TCu380A (cumulative pregnancy rate 0.34 at 3 years). The total use-related discontinuation rate at 3 years was significantly lower with the GyneFix IUD (8.34) than with the TCu380A IUD (14.13) and results in a higher rate of continuation with the GyneFix IUD compared to the TCu380A IUD (90.73 vs 85.25). Neither perforations nor pelvic inflammatory disease cases were encountered with either device in this study, demonstrating the safety of the
*National Research Institute for Family Planning, Beijing, People’s Republic of China; and †Contrel Europe nv/sa, Knokke-Heist, Belgium Name and address for correspondence: Dr. Dirk Wildemeersch, Piers de Raveschootlaan 125, 8300 Knokke, Belgium; Tel.: (32)50-600900; Fax: (32)50622429; e-mail: [email protected]. Website: www.gynefix.com Submitted for publication July 8, 1999 Revised December 22, 1999 Accepted for publication December 27, 1999
© 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
anchoring system. CONTRACEPTION 2000;61:91–98 © 2000 Elsevier Science Inc. All rights reserved. WORDS: GyneFix, frameless IUD, new inserter, TCu380A IUD, multicenter randomized comparative trial, pregnancy, failed insertion, expulsion rates
KEY
Introduction
T
he GyneFix anchoring technology was developed to suspend bio-active substances in the uterine cavity (eg, copper for contraception or steroids for menopausal treatment). At the same time, the development of the string-shaped, flexible design of the GyneFix device aimed at a significant enhancement of the acceptability of the method and a reduction to a minimum of side effects commonly seen with conventional intrauterine devices (IUDs), such as pain and bleeding. A prototype version of the frameless copper device, called Flexigard, was compared with the TCu380A IUD during two randomized comparative multicenter clinical trials. The 3-year results of these studies were published in this journal in 1995 (World Health Organization (WHO) study)1 and in 1996 (study reported by Rosenberg et al.),2 respectively. Significant difficulties were encountered with the Flexigard inserter during the studies because of deficiencies in the insertion procedure, resulting in cumulative expulsion rates at 1, 2, and 3 years of 5.7, 6.4, and 7.4, respectively1 and of 9.8 and 11.4 at 1 and 2 years, respectively.2 In addition, the inserter had shortcomings, which were reflected in a high number of insertion failures and expulsions. A substantial number of devices were not properly inserted or pulled out, either partially or totally during withdrawal of the inserter. Because of these shortcomings—the complexity of the insertion technique, the absence of training in the new insertion technique in some centers, and the failure to correct the inserter probISSN 0010-7824/00/$20.00 PII S0010-7824(00)00087-1
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Figure 1. GyneFix (left) and TCu380A (right) IUD.
lems during the studies—the value of the anchoring concept could not be fully appreciated. To circumvent the technical problems with the Flexigard inserter, an international, multicenter, noncomparative study was initiated with an improved (GyneFix) inserter in 1039 women. A 3-year analysis concluded that the inserter was reliable, avoiding the above mentioned insertion problems. The cumulative expulsion rate at 3 years was 0.6.3 The present article summarizes the experience in another study with the new inserter and also reports on a randomized comparison between the GyneFix IUD and the TCu380A IUD. It is noteworthy that investigators were included in this study who had difficulties and insertion failures when using the prototype Flexigard inserter in the World Health Organization study.1
Materials and Methods The main objective of the study was to evaluate the novel insertion technique with the new GyneFix inserter and to determine whether, by correcting the shortcomings of the Flexigard inserter, a better performance and much reduced rates of insertion failure and expulsion of the frameless and anchored device could be demonstrated. In addition, another objective of the study was to compare the pregnancy, expulsion, and discontinuation rates for the GyneFix and the TCu380A IUD. No special training courses were considered necessary because the investigators already had some experience with the anchoring technique. Six centers participated. The study was approved by the IUD Steering Committee, State Family Planning Commission, P.R. China. Description of the Devices and Inserter (Figure 1) The TCu380A IUD (ParaGard) consists of a polyethylene, T-shaped body with a collar of approximately
Figure 2. The GyneFix IUD in situ.
66.5 mg of copper on each of the transverse arms and 176 mg of copper wire wound on its vertical shaft. A monofilament polyethylene thread is tied through the bulb at the tip of the T, resulting in two threads to aid in the detection and removal of the device. The GyneFix IUD consists of six copper sleeves, each 5 mm in length and approximately 2.2 mm in diameter. The six copper sleeves are threaded, and the uppermost and lowest sleeves are crimped onto the polypropylene suture thread. A single knot is made in the upper portion of the thread, which serves as a small retention body when inserted in the myometrium of the uterine fundus at a controlled depth of 1.0 cm. The weight of the six copper cylinders is 420 mg, and the total surface of copper, including the inner and outer surfaces, is approximately 330 mm2. Notably, the GyneFix lacks a plastic frame and this accounts for its flexibility. The anchoring system is essential for retention of the frameless device. The minimum effective life of the GyneFix IUD is 5 years. The frameless IUD in situ is illustrated in Figure 2. The insertion instrument (Figure 3) to anchor the
Contraception 2000;61:91–98
Figure 3. The GyneFix insertion apparatus used in this study. A, the GyneFix System; B, the plunger (1, stainless steel stylet; 2, plastic rod; 3, middle segment; 4, handle); C, 3.8-mm-wide tube provided with centimeter marks and flange (5); D, uterine sound.
GyneFix IUD in the fundal wall of the uterus consists of two parts. The 3.8 mm-wide tube is semirigid to avoid reduction of the inner diameter of the tube during bending, which could cause the device tail to get caught between the two parts of the inserter during its withdrawal from the uterus, as was the case with the Flexigard inserter. The plunger has a stainless steel stylet, the pointed end of which is specially shaped with a “shoulder” or notch that carries the anchoring knot. The proximal end of the plunger is a handle. The IUD is preloaded into the inserter and packed in a peel-pack. The units are ethylene oxide– sterilized, ready for use. Insertion Technique for TCu380A The conventional insertion technique used for the TCu380A was employed with a tenaculum applied to the anterior lip of the cervix. The TCu380A is loaded by folding the horizontal arms down and inserting the arms into the inserter tube. The loaded inserter is introduced through the cervical canal into the uterine cavity until the tip of the tube comes in contact with the fundus. The device is released from the tube by holding the inserter rod steady and retracting the tube. After the arms are released, the tube is moved gently upward until the resistance of the fundus is encountered. The inserter rod and then the inserter tube are withdrawn, and the threads trimmed. Insertion Technique for GyneFix IUD A tenaculum is put about 1 cm above the external os to allow proper stretching of the uterus. The uterine cavity is then sounded, using the sterile sound en-
GyneFix and TCu380A in a Randomized Trial
93
closed in the GyneFix package. The inserter is then introduced into the uterus until the tip of the inserter makes contact with the uterine fundus. The plunger is then moved forward, gently and slowly, for the full 1 cm, so as to allow the stylet and the anchoring knot to penetrate the myometrium. Penetration by the anchor should be clearly felt by the operator. The thread is then carefully released from the notch, while the operator holds the inserter against the fundal wall. The handle is then slowly withdrawn while the insertion tube is kept pressed against the uterine fundus. Then, the insertion tube is withdrawn. It was recommended to exert gentle traction on the tail of the GyneFix to confirm that the anchor is properly inserted. The thread is then trimmed.
Admission Procedure and Randomization The World Health Organization (WHO) criteria were used. All women volunteering for the study were screened for their clinical suitability for IUD insertion and compliance with the eligibility criteria. The following were excluded: nulliparous women, women with a history of pelvic inflammatory disease (PID) or pelvic abscess since their last pregnancy, an interval of ⬍6 weeks since parturition or abortion, a history of ectopic pregnancy, recent sexually transmitted disease, undiagnosed genital tract bleeding, a congenital genital tract malformation, known or suspected genital malignancy, multiple uterine fibromyomas associated with menstrual disorders, clinical or laboratory evidence of anemia as locally defined, or a history of hydatiform mole in the last pregnancy. After having given fully informed consent for participation in the study, a medical, obstetric, and gynecological history was obtained from each subject. A subject number was assigned to eligible subjects from a register kept in each center. Each center was issued a series of sealed envelopes on which were printed the trial and subject numbers. Once the subject number had been allocated, the envelope was opened and the device to be inserted was read from a slip of paper inside the envelope. The devices were allocated at random from a computer-generated list, and balanced in blocks of 10. Because the devices were different in appearance and required different insertion techniques, it was not possible for the physician to be blinded as to which device was inserted. The number of GyneFix insertions was 302 and the number of TCu380A IUD insertions 305. The number of insertions per center is given in Table 1. The sample size was calculated according to Machin et al.4 The first insertion was done on 24 July 1994 and the last one on 13 November 1995.
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Table 1. Number of insertions per center GyneFix or TCu380A Center
No.
1 2 3 4 5 6 Total
72 100 100 100 113 122 607
Follow-Up Procedures The subjects were requested to return for follow-up after the first menstruation and at 3, 6, and 12 months after insertion and then yearly thereafter. Women were instructed to return to the clinic any time if they experienced any problems with the device, and were free to return to the clinic at any time and to request removal of the device. Data Collection, Monitoring and Analysis Data were recorded on standard precoded forms in duplicate at admission, at each scheduled and unscheduled follow-up visit, and upon discontinuation from the study. All data were sent to the data coordinating center at the National Research Institute for Family Planning in Beijing, where they were managed according to standard procedures. Clarifications were sought from the individual centers as necessary. The rates of discontinuation for individual reasons and groups of reasons were computed following the standard definitions used for WHO contraceptive and IUD clinical trials.7,8 The cut-off date was the date of insertion plus 1125 days (365 ⫻ 3 ⫹ 30) and the date of analysis 18 June 1999. The data were analyzed using the SAS statistical software package (SAS, Cary, NC) and the cumulative discontinuation rates were computed using the daily life table method.7 Comparison between discontinuation rates were made using the 2 test.8
Results Life table analysis of the pregnancy, expulsion, and use-related discontinuations rates at 1, 2, and 3 years revealed significant differences in expulsion and total use-related discontinuations, but not in pregnancy rate. Events at Insertion There were 302 insertions with GyneFix. One GyneFix IUD came out with the inserter (0.3%). There were no insertion failures in the TCu380A group. The
reason for the insertion failure with the GyneFix device was unfamiliarity with the insertion technique. There were neither perforations nor pelvic inflammatory disease (PID) cases reported for either device either during or immediately after insertion. Subject Characteristics The number of insertions and characteristics of IUD users, by device, are shown in Table 2. The age, gravidity, and parity distributions were similar in the two groups. Life Table Rates The events and 3-year cumulative net discontinuation rates for the GyneFix and TCu380A IUDs are presented in Table 3 (all centers combined). No pregnancies occurred with the GyneFix IUD (cumulative pregnancy rate 0.0 at 3 years), versus one pregnancy with TCu380A (cumulative pregnancy rate 0.34 at 3 years). The total use-related discontinuation rate at 3 years was significantly lower with the GyneFix IUD (8.34) than with the TCu380A IUD (14.13) and resulted in a higher rate of continuation with the GyneFix IUD compared to the TCu380A IUD (90.73 vs 85.25). No complications (ie, perforations, PID) were encountered with either device during this 3-year study, demonstrating the safety of the anchoring system.
Discussion The present study was conducted mainly to evaluate an optimized inserter for the insertion and anchoring of the frameless IUD. Two previously conducted randomized, comparative studies were unable to provide a proper evaluation of the anchoring concept because of shortcomings of the prototype (Flexigard) insertion apparatus.1,2 The clinical trial analyzed by Rosenberg et al.2 incorrectly referred to the “Cu-Fix IUDs,” whereas, in fact, this should have been the “Flexigard” IUD, because the inserter used in this study was different from the one used in the previously conducted “Cu-Fix” studies.9 It is clear from the present study that the anchoring concept is valid, and that the risk of expulsion is virtually nil when the device is properly anchored.3 The challenge with the development of the frameless GyneFix was to enhance the performance and acceptability of the method. With this new concept, a plastic frame to retain the IUD becomes superfluous, thus overcoming possible dimensional problems, which could generate expulsive forces that are responsible for displacement and expulsion as well as the occurrence of side effects (eg, bleeding, pain).
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Table 2. Number of insertions and characteristics of IUD users by device
Age (y), mean
ⱕ19 20–24 25–29 30–34 35–40 Total
30.45
29.84 %
No.
%
15 123 106 58 302
5.0 40.7 35.1 19.2 100.0
1 17 132 108 47 305
0.3 5.6 43.3 35.4 15.4 100.0
2.14
2.09
No.
%
No.
%
87 120 95
28.8 39.7 31.4
99 122 84
32.5 40.0 27.5
302
Parity, mean
1 2 Total
TCu380A
No.
Gravidity, mean
1 2 3 Total
GyneFix
305
1.03
1.02
No.
%
No.
%
292 10
96.7 3.3
300 5
98.4 1.6
302
Compatibility between the foreign body and the endometrial cavity is likely to result in enhanced effectiveness and a high continuation of use. Moreover, because of the anchoring of the device in the uterine fundus, the copper ions are optimally delivered to prevent the occurrence of intrauterine and ectopic pregnancy.10 No pregnancies occurred in this study with the frameless GyneFix, confirming the high effectiveness observed in previous studies conducted with the device.3 The higher rate in the first year in the WHO study1 can be explained by deficiencies in the insertion procedure and the shortcomings of the inserter, resulting in unnoticed expulsion and accidental pregnancy. Only one ectopic pregnancy occurred in ⬎5000 insertions during clinical trials with the frameless IUD.1,3,9,10 This is reassuring, because the prevalence of ectopic pregnancy in Western societies is approximately one ectopic for every 100 pregnancies.11 Greater effectiveness is important because of the potentially increased morbidity when a woman becomes pregnant with an IUD in situ.13 In the present study there were nine expulsions with the GyneFix IUD, compared with 22 expulsions in the TCu380A wearers. Eight GyneFix IUD were expelled within the first year after insertion, of which four occurred during the first 3 months. The majority were clustered in two centers, indicating improper implantation of the anchoring knot in the fundal
305
myometrium because of inexperience with the new technique. These are considered insertion failures. As mentioned previously,1 the term “insertion failure” has a broadened meaning when applied to the GyneFix device, as it includes failure to implant the knot in the fundal myometrium. Failure to implant the knot can mean that the device is removed together with the inserter tube. This is manifested by expulsion of the frameless device within weeks of the insertion attempt. This is borne out by the observation that the majority of the expulsions occur in the first 90 days of use. Inadequate positioning of the inserter against the fundal wall before anchoring is probably the reason for the improper anchoring. Only one expulsion occurred after the first year with the GyneFix IUD in this study. The reason for this late expulsion is unclear. Late expulsions have been very rare in all studies conducted with the GyneFix inserter so far.13 The expulsion rate with TCu380A is similar to that of previous studies conducted with the device.14 The removal rate for medical reasons in this study is lower with the frameless device than with the TCu380A IUD. As this study was conducted in parous women only, the advantages of the frameless device could not be fully appreciated because dimensional incompatibility is more likely to occur in nulligravid/nulliparous women. IUDs are rarely used in young nulliparous women in China. This may
*Patient moved to another city.
Pregnancy 0 Expulsion 8 Perforation 0 Total medical removals 3 Total pain and/or bleeding 2 Pain 0 Bleeding 2 Pain and bleeding 0 PID 0 Other medical removals 1 Total use-related discontinuations 11 Pregnancy wish 0 Other personal reasons 2 Other discontinuations (IUD not removed) 0 Lost to follow-up 0 Continuation rate 95.36 No. recruited 302 No. women completing the interval 289 Women-months of experience 3580
No.
0.68
0.34 3.66
1.02 0.68 0.00 0.68 0.00
0.00 2.67
Rate
GyneFix
281 3494
0 0 91.80 305
1 14 0 9 9 1 6 1 0 1 24 0 0
No.
Year 1
0.34 7.88 (0.0253)
3.08 3.08 (0.0320) 0.36 2.05 0.34
0.34 4.63
Rate (p value)
TCu380A
0.34 4.66 0.34 0.34
1.71 1.38 0.00 1.38 0.00
0.00 3.0
Rate
285 7049
0 1 0.35 94.37 302
0 9 0 5 4 0 4 0 0 1 14 1 1
No.
GyneFix
0.34 9.85 (0.0145)
3.43 3.43 0.35 2.40 0.71
0.34 6.34
Rate (p value)
274 6850
0 1 0.34 89.84 305
1 19 0 10 10 1 7 2 0 1 30 0 0
No.
Year 2
TCu380A
1.06 8.34 0.34 0.34
5.50 4.50 0.00 4.50 0.00
0.00 3.0
Rate
274 10455
0 1 0.35 90.73 302
0 9 0 16 13 0 13 0 0 3 25 1 1
No.
GyneFix
261 10107
1* 1 85.25 305
1 22 0 20 18 3 12 3 0 2 43 0 0
No.
Year 3
0.38 0.34
0.75 14.13 (0.0223)
6.98 6.27 1.08 4.21 1.08
0.34 7.38 (0.0179)
Rate (p value)
TCu380A
Table 3. Randomized comparative trial of TCu380A versus the Frameless GyneFix IUD: events and net cumulative discontinuation rates by device (all centers).
96 Wu et al. Contraception 2000;61:91–98
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Figure 4. Ultrasound of the GyneFix IUD in a small, nulliparous uterus.
change, as teenage pregnancies are steeply rising. Earlier reports have indicated the seriousness of this problem.15 It is therefore important that new contraceptive options be made available for interval, emergency, and postabortion contraception in young women. Experience in Europe has shown that young women tolerate GyneFix and are no more susceptible to pregnancy than are older women.3,16 Randomized comparative studies in nulligravid/ nulliparous women comparing GyneFix with conventional IUD have not yet been conducted. The usefulness of these studies could be questioned, as a lower performance and a significantly higher rate of side effects with “framed” IUD are a likely consequence of
dimensional problems. Moreover, randomized comparative studies with T-shaped devices in parous and nulliparous women have concluded that the failure rates, removal rates for bleeding or pain, and expulsion rates of the T-shaped device (including TCu380A) in nulliparous women are significantly higher when compared to those in parous women.13 The ultrasound pictures in Figures 4 and 5, showing the marked difference in size between a nulligravid uterus (Figure 4) and a normal parous uterus (Figure 5), illustrate the importance of harmony between the IUD and the uterine cavity to minimize side effects and to obtain optimal patient satisfaction and, hence, continuation of the method.
Figure 5. Ultrasound of the GyneFix IUD in a relatively large, parous uterus.
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Conclusions The development of the frameless IUD is a response to the growing need to develop high-performing, longacting, reversible, and acceptable contraceptives with a high continuation of use. The present study shows that GyneFix has a very low failure rate. Its performance is further optimized by the atraumatic frameless design, which minimizes the side effects and discomforts experienced with conventional IUDs. The safety of the anchoring concept is beyond doubt, as was demonstrated again in this study. However, the advantages of the new concept will only be fully appreciated when young, nulliparous/nulligravid women also start to use the frameless IUD. Its design and performance characteristics suggest that the GyneFix IUD could become a first choice contraceptive in this group of women, and could help reduce the rapidly increasing number of unintended pregnancies and induced abortions in China and elsewhere.15,17
Contraception 2000;61:91–98
2.
3.
4. 5. 6. 7. 8.
9.
Acknowledgments The authors thank Dr. Patrick Rowe, World Health Organization, for providing the 5-year data of the randomized comparative trial between the TCu380A and the frameless “Flexigard” IUD. The present study was sponsored by Contrel Europe nv/sa.
10.
11.
Appendix The following principal investigators, coinvestigators, and institutes participated in the conduct of this multicenter trial: Dr. S. Wu, Dr. J. Hu, Dr. J. Dong, National Research Institute for Family Planning, Beijing; Dr. M. Wu, Dr. X. Zhu, Beijing Obstetrical and Gynecological Hospital, Beijing; Dr. L. Wong, Dr. X. Jing, Beijing Red Cross Chaoyang Hospital, Beijing; Dr. X. Wu, Dr. W. Wang, Shanghai No. 1 Maternity and Infant Hospital, Shanghai; Dr. L. Zhang, Dr. X. Yang, Shanghai International Peace Maternity and Infant Hospital, Shanghai; Dr. X. Cao, Dr. Y. Gao, Tianjing Municipal Research Institute for Family Planning; and Dr. Z. Feng, Shanghai Institute for Planned Parenthood Research, Shanghai. The Study Coordinator was Dr. S. Wu, National Research Institute for Family Planning, Beijing.
References 1. UNDP, UNFPA and WHO Special Programme for Research, Development and Research Training in Human Reproduction, World Bank: IUD Research Group. The TCu380A IUD and the Frameless “FlexiGard”, Interim
12. 13.
14. 15. 16. 17.
three-year data from an international multicenter trial. Contraception 1995;52:77– 83. Rosenberg MJ, Foldesy R, Mishell DR Jr, Speroff L, Waugh MS, Burkman R. Performance of the TCu380A and Cu-Fix IUDs in an international randomized trial. Contraception 1996;53:197–203. Van Kets H, Vrijens M, Van Trappen Y, et al. The frameless GyneFix威 intrauterine implant: a major improvement in efficacy, expulsion and tolerance. Adv Contracept 1995;11:131– 42. Machin D, Campbell M, Sayers P, Pinol A. Sample size tables for clinical studies, 2nd ed. Oxford: Blackwell Science, 1997. Farley TMM. Life table methods for contraceptive research. Stat Med 1986;5:475– 89. Tietze C, Lewit S. Recommended procedures for the statistical evaluation of intrauterine contraception. Stud Fam Plann 1972;4:35– 42. SAS Institute Inc. SAS User’s Guide: Basics, Version 5 Edition. Cary, NC: SAS Institute, 1985. Azen SP, Roy S, Pike MC, Casarande J, Mishell DR Jr. A new procedure for the statistical evaluation of intrauterine contraception. Am J Obstet Gynecol 1977;128: 329 –35. Wildemeersch D, Van Der Pas H, Thiery M, Van Kets H, Parewijck W, Delbarge W. The Copper-Fix (Cu-Fix): a new concept in IUD technology. Adv Contracept 1988;4:197–205. Wildemeersch D, Batar I, Webb A, et al. GyneFIX威. The frameless intrauterine contraceptive implant for interval, emergency and postabortal contraception—an update. Br J Fam Plann 1999;24:149 –59. Sivin I. Extrauterine pregnancies and intrauterine devices reassessed. In: CWB Bardin, DR Mishell Jr, eds. A New Look at IUDs—Advancing Contraceptive Choices. Fourth Conference on IUDs. Boston: Butterworth-Heinemann, 1992:195–209. Van Kets H, Wildemeersch D, Van der Pas H et al. IUD expulsion solved with implant technology. Contraception, 1995;51:87–92. Atrash HK, Frye A, Hogue CJR. Incidence of morbidity and mortality with IUD in the 1980s and 1990s. In: CWB Bardin, DR Mishell Jr, eds. A New Look at IUDs—Advancing Contraceptive Choices. Fourth Conference on IUDs. Boston, Butterworth-Heinemann, 1992:76 – 87. Sivin I. The TCu380A intrauterine device: a summary of scientific data. New York: The Population Council, 1992. Wu ZC, Gao ES, Ku XY et al. Induced abortion among unmarried women in Shanghai, China. Int Fam Plann Perspect 1992;18:51– 6. Kishen M. Gynefix. IPPF Medical Bulletin, Vol. 23, No. 1, February 1998. Wildemeersch D, Van Kets H, Vrijens M, et al. Intrauterine contraception in adolescent women: the GyneFix威 intrauterine implant. In: Creatsas G, Mastorakos G, Chrousos G, eds. Annals of the New York Academy of Sciences, Vol 816: Adolescent Gynecology and Endocrinology: Basic and Clinical Aspects. New York Academy of Sciences, 1997:440 –50.
Performance of the Frameless GyneFix and the TCu380A IUDs in a 3-Year Multicenter, Randomized, Comparative Trial in Parous Women Shangchun Wu,* Jing Hu,* and Dirk Wildemeersch*†
This study was conducted to evaluate a new and improved inserter (GyneFix) for the anchoring of the Frameless IUD in the uterine cavity. Previous studies conducted with a prototype inserter (Flexigard) did not show fully the advantages of the new anchoring concept because of the shortcomings of the Flexigard inserter and the complexity of the insertion technique. The GyneFix IUD was compared with the TCu380A IUD in six centers in China in approximately 300 women in each group. Only parous women were included in the study. The data from this 3-year, ongoing study demonstrate that the shortcomings of the inserter have been corrected, resulting in better performance and a much reduced rate of failed insertion/expulsion of the frameless and anchored device. The cumulative expulsion rate with the GyneFix IUD was 3.0 at 3 years (annual rates 2.67, 0.33, and 0.0, respectively) compared with a cumulative expulsion rate of 7.38 at 3 years with TCu380A (annual rates 4.63, 1.76, and 1.04, respectively). This difference is statistically significant. The majority of the expulsions with the anchored IUD occurred early in the study, indicating improper anchoring technique. The study also shows that both devices are highly efficacious. No pregnancies occurred with the GyneFix IUD (cumulative pregnancy rate 0.0 at 3 years) versus one pregnancy with TCu380A (cumulative pregnancy rate 0.34 at 3 years). The total use-related discontinuation rate at 3 years was significantly lower with the GyneFix IUD (8.34) than with the TCu380A IUD (14.13) and results in a higher rate of continuation with the GyneFix IUD compared to the TCu380A IUD (90.73 vs 85.25). Neither perforations nor pelvic inflammatory disease cases were encountered with either device in this study, demonstrating the safety of the
*National Research Institute for Family Planning, Beijing, People’s Republic of China; and †Contrel Europe nv/sa, Knokke-Heist, Belgium Name and address for correspondence: Dr. Dirk Wildemeersch, Piers de Raveschootlaan 125, 8300 Knokke, Belgium; Tel.: (32)50-600900; Fax: (32)50622429; e-mail: [email protected]. Website: www.gynefix.com Submitted for publication July 8, 1999 Revised December 22, 1999 Accepted for publication December 27, 1999
© 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
anchoring system. CONTRACEPTION 2000;61:91–98 © 2000 Elsevier Science Inc. All rights reserved. WORDS: GyneFix, frameless IUD, new inserter, TCu380A IUD, multicenter randomized comparative trial, pregnancy, failed insertion, expulsion rates
KEY
Introduction
T
he GyneFix anchoring technology was developed to suspend bio-active substances in the uterine cavity (eg, copper for contraception or steroids for menopausal treatment). At the same time, the development of the string-shaped, flexible design of the GyneFix device aimed at a significant enhancement of the acceptability of the method and a reduction to a minimum of side effects commonly seen with conventional intrauterine devices (IUDs), such as pain and bleeding. A prototype version of the frameless copper device, called Flexigard, was compared with the TCu380A IUD during two randomized comparative multicenter clinical trials. The 3-year results of these studies were published in this journal in 1995 (World Health Organization (WHO) study)1 and in 1996 (study reported by Rosenberg et al.),2 respectively. Significant difficulties were encountered with the Flexigard inserter during the studies because of deficiencies in the insertion procedure, resulting in cumulative expulsion rates at 1, 2, and 3 years of 5.7, 6.4, and 7.4, respectively1 and of 9.8 and 11.4 at 1 and 2 years, respectively.2 In addition, the inserter had shortcomings, which were reflected in a high number of insertion failures and expulsions. A substantial number of devices were not properly inserted or pulled out, either partially or totally during withdrawal of the inserter. Because of these shortcomings—the complexity of the insertion technique, the absence of training in the new insertion technique in some centers, and the failure to correct the inserter probISSN 0010-7824/00/$20.00 PII S0010-7824(00)00087-1
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Figure 1. GyneFix (left) and TCu380A (right) IUD.
lems during the studies—the value of the anchoring concept could not be fully appreciated. To circumvent the technical problems with the Flexigard inserter, an international, multicenter, noncomparative study was initiated with an improved (GyneFix) inserter in 1039 women. A 3-year analysis concluded that the inserter was reliable, avoiding the above mentioned insertion problems. The cumulative expulsion rate at 3 years was 0.6.3 The present article summarizes the experience in another study with the new inserter and also reports on a randomized comparison between the GyneFix IUD and the TCu380A IUD. It is noteworthy that investigators were included in this study who had difficulties and insertion failures when using the prototype Flexigard inserter in the World Health Organization study.1
Materials and Methods The main objective of the study was to evaluate the novel insertion technique with the new GyneFix inserter and to determine whether, by correcting the shortcomings of the Flexigard inserter, a better performance and much reduced rates of insertion failure and expulsion of the frameless and anchored device could be demonstrated. In addition, another objective of the study was to compare the pregnancy, expulsion, and discontinuation rates for the GyneFix and the TCu380A IUD. No special training courses were considered necessary because the investigators already had some experience with the anchoring technique. Six centers participated. The study was approved by the IUD Steering Committee, State Family Planning Commission, P.R. China. Description of the Devices and Inserter (Figure 1) The TCu380A IUD (ParaGard) consists of a polyethylene, T-shaped body with a collar of approximately
Figure 2. The GyneFix IUD in situ.
66.5 mg of copper on each of the transverse arms and 176 mg of copper wire wound on its vertical shaft. A monofilament polyethylene thread is tied through the bulb at the tip of the T, resulting in two threads to aid in the detection and removal of the device. The GyneFix IUD consists of six copper sleeves, each 5 mm in length and approximately 2.2 mm in diameter. The six copper sleeves are threaded, and the uppermost and lowest sleeves are crimped onto the polypropylene suture thread. A single knot is made in the upper portion of the thread, which serves as a small retention body when inserted in the myometrium of the uterine fundus at a controlled depth of 1.0 cm. The weight of the six copper cylinders is 420 mg, and the total surface of copper, including the inner and outer surfaces, is approximately 330 mm2. Notably, the GyneFix lacks a plastic frame and this accounts for its flexibility. The anchoring system is essential for retention of the frameless device. The minimum effective life of the GyneFix IUD is 5 years. The frameless IUD in situ is illustrated in Figure 2. The insertion instrument (Figure 3) to anchor the
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Figure 3. The GyneFix insertion apparatus used in this study. A, the GyneFix System; B, the plunger (1, stainless steel stylet; 2, plastic rod; 3, middle segment; 4, handle); C, 3.8-mm-wide tube provided with centimeter marks and flange (5); D, uterine sound.
GyneFix IUD in the fundal wall of the uterus consists of two parts. The 3.8 mm-wide tube is semirigid to avoid reduction of the inner diameter of the tube during bending, which could cause the device tail to get caught between the two parts of the inserter during its withdrawal from the uterus, as was the case with the Flexigard inserter. The plunger has a stainless steel stylet, the pointed end of which is specially shaped with a “shoulder” or notch that carries the anchoring knot. The proximal end of the plunger is a handle. The IUD is preloaded into the inserter and packed in a peel-pack. The units are ethylene oxide– sterilized, ready for use. Insertion Technique for TCu380A The conventional insertion technique used for the TCu380A was employed with a tenaculum applied to the anterior lip of the cervix. The TCu380A is loaded by folding the horizontal arms down and inserting the arms into the inserter tube. The loaded inserter is introduced through the cervical canal into the uterine cavity until the tip of the tube comes in contact with the fundus. The device is released from the tube by holding the inserter rod steady and retracting the tube. After the arms are released, the tube is moved gently upward until the resistance of the fundus is encountered. The inserter rod and then the inserter tube are withdrawn, and the threads trimmed. Insertion Technique for GyneFix IUD A tenaculum is put about 1 cm above the external os to allow proper stretching of the uterus. The uterine cavity is then sounded, using the sterile sound en-
GyneFix and TCu380A in a Randomized Trial
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closed in the GyneFix package. The inserter is then introduced into the uterus until the tip of the inserter makes contact with the uterine fundus. The plunger is then moved forward, gently and slowly, for the full 1 cm, so as to allow the stylet and the anchoring knot to penetrate the myometrium. Penetration by the anchor should be clearly felt by the operator. The thread is then carefully released from the notch, while the operator holds the inserter against the fundal wall. The handle is then slowly withdrawn while the insertion tube is kept pressed against the uterine fundus. Then, the insertion tube is withdrawn. It was recommended to exert gentle traction on the tail of the GyneFix to confirm that the anchor is properly inserted. The thread is then trimmed.
Admission Procedure and Randomization The World Health Organization (WHO) criteria were used. All women volunteering for the study were screened for their clinical suitability for IUD insertion and compliance with the eligibility criteria. The following were excluded: nulliparous women, women with a history of pelvic inflammatory disease (PID) or pelvic abscess since their last pregnancy, an interval of ⬍6 weeks since parturition or abortion, a history of ectopic pregnancy, recent sexually transmitted disease, undiagnosed genital tract bleeding, a congenital genital tract malformation, known or suspected genital malignancy, multiple uterine fibromyomas associated with menstrual disorders, clinical or laboratory evidence of anemia as locally defined, or a history of hydatiform mole in the last pregnancy. After having given fully informed consent for participation in the study, a medical, obstetric, and gynecological history was obtained from each subject. A subject number was assigned to eligible subjects from a register kept in each center. Each center was issued a series of sealed envelopes on which were printed the trial and subject numbers. Once the subject number had been allocated, the envelope was opened and the device to be inserted was read from a slip of paper inside the envelope. The devices were allocated at random from a computer-generated list, and balanced in blocks of 10. Because the devices were different in appearance and required different insertion techniques, it was not possible for the physician to be blinded as to which device was inserted. The number of GyneFix insertions was 302 and the number of TCu380A IUD insertions 305. The number of insertions per center is given in Table 1. The sample size was calculated according to Machin et al.4 The first insertion was done on 24 July 1994 and the last one on 13 November 1995.
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Table 1. Number of insertions per center GyneFix or TCu380A Center
No.
1 2 3 4 5 6 Total
72 100 100 100 113 122 607
Follow-Up Procedures The subjects were requested to return for follow-up after the first menstruation and at 3, 6, and 12 months after insertion and then yearly thereafter. Women were instructed to return to the clinic any time if they experienced any problems with the device, and were free to return to the clinic at any time and to request removal of the device. Data Collection, Monitoring and Analysis Data were recorded on standard precoded forms in duplicate at admission, at each scheduled and unscheduled follow-up visit, and upon discontinuation from the study. All data were sent to the data coordinating center at the National Research Institute for Family Planning in Beijing, where they were managed according to standard procedures. Clarifications were sought from the individual centers as necessary. The rates of discontinuation for individual reasons and groups of reasons were computed following the standard definitions used for WHO contraceptive and IUD clinical trials.7,8 The cut-off date was the date of insertion plus 1125 days (365 ⫻ 3 ⫹ 30) and the date of analysis 18 June 1999. The data were analyzed using the SAS statistical software package (SAS, Cary, NC) and the cumulative discontinuation rates were computed using the daily life table method.7 Comparison between discontinuation rates were made using the 2 test.8
Results Life table analysis of the pregnancy, expulsion, and use-related discontinuations rates at 1, 2, and 3 years revealed significant differences in expulsion and total use-related discontinuations, but not in pregnancy rate. Events at Insertion There were 302 insertions with GyneFix. One GyneFix IUD came out with the inserter (0.3%). There were no insertion failures in the TCu380A group. The
reason for the insertion failure with the GyneFix device was unfamiliarity with the insertion technique. There were neither perforations nor pelvic inflammatory disease (PID) cases reported for either device either during or immediately after insertion. Subject Characteristics The number of insertions and characteristics of IUD users, by device, are shown in Table 2. The age, gravidity, and parity distributions were similar in the two groups. Life Table Rates The events and 3-year cumulative net discontinuation rates for the GyneFix and TCu380A IUDs are presented in Table 3 (all centers combined). No pregnancies occurred with the GyneFix IUD (cumulative pregnancy rate 0.0 at 3 years), versus one pregnancy with TCu380A (cumulative pregnancy rate 0.34 at 3 years). The total use-related discontinuation rate at 3 years was significantly lower with the GyneFix IUD (8.34) than with the TCu380A IUD (14.13) and resulted in a higher rate of continuation with the GyneFix IUD compared to the TCu380A IUD (90.73 vs 85.25). No complications (ie, perforations, PID) were encountered with either device during this 3-year study, demonstrating the safety of the anchoring system.
Discussion The present study was conducted mainly to evaluate an optimized inserter for the insertion and anchoring of the frameless IUD. Two previously conducted randomized, comparative studies were unable to provide a proper evaluation of the anchoring concept because of shortcomings of the prototype (Flexigard) insertion apparatus.1,2 The clinical trial analyzed by Rosenberg et al.2 incorrectly referred to the “Cu-Fix IUDs,” whereas, in fact, this should have been the “Flexigard” IUD, because the inserter used in this study was different from the one used in the previously conducted “Cu-Fix” studies.9 It is clear from the present study that the anchoring concept is valid, and that the risk of expulsion is virtually nil when the device is properly anchored.3 The challenge with the development of the frameless GyneFix was to enhance the performance and acceptability of the method. With this new concept, a plastic frame to retain the IUD becomes superfluous, thus overcoming possible dimensional problems, which could generate expulsive forces that are responsible for displacement and expulsion as well as the occurrence of side effects (eg, bleeding, pain).
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Table 2. Number of insertions and characteristics of IUD users by device
Age (y), mean
ⱕ19 20–24 25–29 30–34 35–40 Total
30.45
29.84 %
No.
%
15 123 106 58 302
5.0 40.7 35.1 19.2 100.0
1 17 132 108 47 305
0.3 5.6 43.3 35.4 15.4 100.0
2.14
2.09
No.
%
No.
%
87 120 95
28.8 39.7 31.4
99 122 84
32.5 40.0 27.5
302
Parity, mean
1 2 Total
TCu380A
No.
Gravidity, mean
1 2 3 Total
GyneFix
305
1.03
1.02
No.
%
No.
%
292 10
96.7 3.3
300 5
98.4 1.6
302
Compatibility between the foreign body and the endometrial cavity is likely to result in enhanced effectiveness and a high continuation of use. Moreover, because of the anchoring of the device in the uterine fundus, the copper ions are optimally delivered to prevent the occurrence of intrauterine and ectopic pregnancy.10 No pregnancies occurred in this study with the frameless GyneFix, confirming the high effectiveness observed in previous studies conducted with the device.3 The higher rate in the first year in the WHO study1 can be explained by deficiencies in the insertion procedure and the shortcomings of the inserter, resulting in unnoticed expulsion and accidental pregnancy. Only one ectopic pregnancy occurred in ⬎5000 insertions during clinical trials with the frameless IUD.1,3,9,10 This is reassuring, because the prevalence of ectopic pregnancy in Western societies is approximately one ectopic for every 100 pregnancies.11 Greater effectiveness is important because of the potentially increased morbidity when a woman becomes pregnant with an IUD in situ.13 In the present study there were nine expulsions with the GyneFix IUD, compared with 22 expulsions in the TCu380A wearers. Eight GyneFix IUD were expelled within the first year after insertion, of which four occurred during the first 3 months. The majority were clustered in two centers, indicating improper implantation of the anchoring knot in the fundal
305
myometrium because of inexperience with the new technique. These are considered insertion failures. As mentioned previously,1 the term “insertion failure” has a broadened meaning when applied to the GyneFix device, as it includes failure to implant the knot in the fundal myometrium. Failure to implant the knot can mean that the device is removed together with the inserter tube. This is manifested by expulsion of the frameless device within weeks of the insertion attempt. This is borne out by the observation that the majority of the expulsions occur in the first 90 days of use. Inadequate positioning of the inserter against the fundal wall before anchoring is probably the reason for the improper anchoring. Only one expulsion occurred after the first year with the GyneFix IUD in this study. The reason for this late expulsion is unclear. Late expulsions have been very rare in all studies conducted with the GyneFix inserter so far.13 The expulsion rate with TCu380A is similar to that of previous studies conducted with the device.14 The removal rate for medical reasons in this study is lower with the frameless device than with the TCu380A IUD. As this study was conducted in parous women only, the advantages of the frameless device could not be fully appreciated because dimensional incompatibility is more likely to occur in nulligravid/nulliparous women. IUDs are rarely used in young nulliparous women in China. This may
*Patient moved to another city.
Pregnancy 0 Expulsion 8 Perforation 0 Total medical removals 3 Total pain and/or bleeding 2 Pain 0 Bleeding 2 Pain and bleeding 0 PID 0 Other medical removals 1 Total use-related discontinuations 11 Pregnancy wish 0 Other personal reasons 2 Other discontinuations (IUD not removed) 0 Lost to follow-up 0 Continuation rate 95.36 No. recruited 302 No. women completing the interval 289 Women-months of experience 3580
No.
0.68
0.34 3.66
1.02 0.68 0.00 0.68 0.00
0.00 2.67
Rate
GyneFix
281 3494
0 0 91.80 305
1 14 0 9 9 1 6 1 0 1 24 0 0
No.
Year 1
0.34 7.88 (0.0253)
3.08 3.08 (0.0320) 0.36 2.05 0.34
0.34 4.63
Rate (p value)
TCu380A
0.34 4.66 0.34 0.34
1.71 1.38 0.00 1.38 0.00
0.00 3.0
Rate
285 7049
0 1 0.35 94.37 302
0 9 0 5 4 0 4 0 0 1 14 1 1
No.
GyneFix
0.34 9.85 (0.0145)
3.43 3.43 0.35 2.40 0.71
0.34 6.34
Rate (p value)
274 6850
0 1 0.34 89.84 305
1 19 0 10 10 1 7 2 0 1 30 0 0
No.
Year 2
TCu380A
1.06 8.34 0.34 0.34
5.50 4.50 0.00 4.50 0.00
0.00 3.0
Rate
274 10455
0 1 0.35 90.73 302
0 9 0 16 13 0 13 0 0 3 25 1 1
No.
GyneFix
261 10107
1* 1 85.25 305
1 22 0 20 18 3 12 3 0 2 43 0 0
No.
Year 3
0.38 0.34
0.75 14.13 (0.0223)
6.98 6.27 1.08 4.21 1.08
0.34 7.38 (0.0179)
Rate (p value)
TCu380A
Table 3. Randomized comparative trial of TCu380A versus the Frameless GyneFix IUD: events and net cumulative discontinuation rates by device (all centers).
96 Wu et al. Contraception 2000;61:91–98
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Figure 4. Ultrasound of the GyneFix IUD in a small, nulliparous uterus.
change, as teenage pregnancies are steeply rising. Earlier reports have indicated the seriousness of this problem.15 It is therefore important that new contraceptive options be made available for interval, emergency, and postabortion contraception in young women. Experience in Europe has shown that young women tolerate GyneFix and are no more susceptible to pregnancy than are older women.3,16 Randomized comparative studies in nulligravid/ nulliparous women comparing GyneFix with conventional IUD have not yet been conducted. The usefulness of these studies could be questioned, as a lower performance and a significantly higher rate of side effects with “framed” IUD are a likely consequence of
dimensional problems. Moreover, randomized comparative studies with T-shaped devices in parous and nulliparous women have concluded that the failure rates, removal rates for bleeding or pain, and expulsion rates of the T-shaped device (including TCu380A) in nulliparous women are significantly higher when compared to those in parous women.13 The ultrasound pictures in Figures 4 and 5, showing the marked difference in size between a nulligravid uterus (Figure 4) and a normal parous uterus (Figure 5), illustrate the importance of harmony between the IUD and the uterine cavity to minimize side effects and to obtain optimal patient satisfaction and, hence, continuation of the method.
Figure 5. Ultrasound of the GyneFix IUD in a relatively large, parous uterus.
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Conclusions The development of the frameless IUD is a response to the growing need to develop high-performing, longacting, reversible, and acceptable contraceptives with a high continuation of use. The present study shows that GyneFix has a very low failure rate. Its performance is further optimized by the atraumatic frameless design, which minimizes the side effects and discomforts experienced with conventional IUDs. The safety of the anchoring concept is beyond doubt, as was demonstrated again in this study. However, the advantages of the new concept will only be fully appreciated when young, nulliparous/nulligravid women also start to use the frameless IUD. Its design and performance characteristics suggest that the GyneFix IUD could become a first choice contraceptive in this group of women, and could help reduce the rapidly increasing number of unintended pregnancies and induced abortions in China and elsewhere.15,17
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2.
3.
4. 5. 6. 7. 8.
9.
Acknowledgments The authors thank Dr. Patrick Rowe, World Health Organization, for providing the 5-year data of the randomized comparative trial between the TCu380A and the frameless “Flexigard” IUD. The present study was sponsored by Contrel Europe nv/sa.
10.
11.
Appendix The following principal investigators, coinvestigators, and institutes participated in the conduct of this multicenter trial: Dr. S. Wu, Dr. J. Hu, Dr. J. Dong, National Research Institute for Family Planning, Beijing; Dr. M. Wu, Dr. X. Zhu, Beijing Obstetrical and Gynecological Hospital, Beijing; Dr. L. Wong, Dr. X. Jing, Beijing Red Cross Chaoyang Hospital, Beijing; Dr. X. Wu, Dr. W. Wang, Shanghai No. 1 Maternity and Infant Hospital, Shanghai; Dr. L. Zhang, Dr. X. Yang, Shanghai International Peace Maternity and Infant Hospital, Shanghai; Dr. X. Cao, Dr. Y. Gao, Tianjing Municipal Research Institute for Family Planning; and Dr. Z. Feng, Shanghai Institute for Planned Parenthood Research, Shanghai. The Study Coordinator was Dr. S. Wu, National Research Institute for Family Planning, Beijing.
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