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Phase III clinical trial with NorplantR II (two covered rods): Report on five years of use
Clinical Article Phase III clinical trial with NorplantR II (two covered rods): Report on five years of use Division of Human Resource Development Research, Indian Council of Medical Research Task Force on Hormonal Contraception, Ansari Nagar, New Delhi, India Investigators: Buckshee K1, Chatterjee P2, Dhall G13, Hazra MN4, Kodkany BS5, Lalitha K6, Logambal A’, Manchanda P, Nanda UK9, RaiChoudhury G’O, Rajaram I’ll, Sengupta PC12, Sivaraman R13, Sutaria UD14 Zaveri Kls
Coordinatini
Unit: Datey S, Gaur LN, Gupta NK, Menta S, Roy
M, Saxena NC, Yadav SC, Vishwanath Research, New Delhi
P, Indian Council
of Medical
Project Coordinator: Saxena BN* * All India Institute of Medical Sciences, New Delhi; 2 RG Kar Medical College, Calcutta; 3 Postgraduate Institute of Medical Education and Research, Chandigarh; 4 Medical College, Baroda; 5 Jawaharlal Nehru Medical College, Belgaum; 6 SAT Hospital, Trivandrum; 7 Medical College, Madurai; 8 Kasturba Hospital, New Delhi; 9 SCB Medical College, Cuttack; lo Safdarjung Hospital, New Delhi; l1 Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry; I2 Rama Krishna Mission Seva Pratisthan, Calcutta; l3 Institute of Obstetrics and Gynaecology, Madras; I4 BJ Medical College, Pune; l5 JJ Group of Hospitals, Bombay
The subdermal implant NORPLANT II contraceptive was studied for its safety, efficacy and acceptability over a period of 5 years of use in a phase III multicentre clinical trial. A total of 1,466 women were observed for 52,849 women-months of use. Only four pregnancies *Address correspondence to: Senior Deputy Director General and Chief, Division of Human Resource Development Research, Indian Council of Medical Research, Ansari Nagar, Delhi 110029, India. Submitted for publication March 22, 1993. Accepted for publication June 10, 1993.
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were reported during the study period, giving a method failure rate of 0.8 per 100 users at 5 years of use. The continuation rates were 61.4, 49.0 and 42.1 per 100 users at 3, 4 and 5 years of use, respectively. The majority of the discontinuations were due to bleeding irregularities which accounted for 22.2, 26.3 and 28.5 per 100 users at 3, 4 and 5 years of use, respectively. The next common reason was planning pregnancy which was observed mainly in women having one child. The discontinuations due to infection, expulsion or displacement of device were very low (0.2-0.3 per 100 users). Due to vigorous efforts made by the centers to follow the subjects, the lost-to-follow-up rate was very low (1.6% at 5 yr). Key words: Levonorgestrel subdermal implant NORPLANT II contraceptive, phase III clinical trial, 5 years efficacy/acceptability, continuation rates, discontinuations.
Introduction Contraceptive systems releasing low dose of synthetic progesterone have been studied for nearly two decades. Low doses of progestogens are preferred because of low systemic side effects and lower risks of severe complications. The advantage of a sustained-release system is that a long period of contraceptive efficacy can be provided with a relatively small quantity o steroid due to the avoidance of hepatic first-pass metabolism (1). The first generation implant with sustained release of low dose of levonorgestrel is NORPLANT I contraceptive, which consists of 6 capsules, and is marketed in 23 countries (2). The second generation NORPLANT II contraceptive, which consists of two covered rods, was later developed. NORPLANT implants become effective within a few hours of insertion and provide effective, continued contraceptive protection for 5 years (3) requiring minimal user compliance. Studies comparing NORPLANT I with NORPLANT II contraceptives indicate that both systems are comparable in effectiveness and in the pattern of side effects, menstrual problems being the most common (4-6). The results of an ICMR earlier phase II study in two groups of about 80 women each with NORPLANT I (6 capsules) and NORPLANT II (two covered rods) contraceptives also indicated that 2 rods were as effective and acceptable as 6 capsules up to 24 months of use (7). Since it was felt that two rods are easier to insert and remove, an expanded phase III clinical trial with NORPLANT II implants was initiated. A report on 24 months of use showed that the device is safe, efficacious and acceptable (8). The present paper is a continuation of the already published results on 24 months of NORPLANT II implants use and reports the findings on acceptability, side effects and efficacy of the NORPLANT II system as observed
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Clinical Article during 5 years of use. The data on bleeding pattern are being reported in separate publications.
and return of fertility
Methodology The NORPLANT II system consists of 2 sterile rods containing 70 mg of levonorgestrel (LNG) per rod. The implants release LNG at a rate of approximately 80 ug per 24 hr during the first 6-18 months of use; thereafter, the release rate is maintained at 30 ug per 24 hr (9). The phase III clinical trial with NORPLANT II implants was initiated in April 1983 in 15 Human Reproduction Research Centres (HRRCs) of ICMR situated at medical colleges in different regions of the country, having different cultural and social background. Healthy women volunteers in the age group of 18-38 years with no contraindications to steroidal hormone treatment were enrolled in the study. Detailed methodology has been given in the published paper on 24 months of NORPLANT II contraceptive use (8). The usual site of inserting the implant was on the left forearm about 8 cm from the elbow crease. However, four of the participating centres placed the implants in the medial aspect of the left upper arm. Following NORPLANT II implants insertion, the follow-up visits of the study subjects were scheduled at 7 days, 1, 3 and 6 months and every 6 months subsequently for the period of 5 years. During the course of the study, in 1987, two problems arose. (i) Data gene ra t e d m other countries suggested an increased failure rate after 3 years of use in women weighing more than 70 kg. (ii) The manufacturer announced that it would no longer make Medical Grade Elastomer 382, used in the NORPLANT II implant rods. The investigators were informed about both these developments and were given the choice to remove the device or obtain a fresh consent from the women if they wished to continue using the device. In 489 women, devices were removed for this reason. Net cumulative probabilities were computed by daily life table technique (10). Log rank method was used for test of significance. Paired “t” test was used to study the changes in Hb, Wt, etc. The data on the 489 subjects referred above were included in the analysis until NORPLANT II implants removal. However, these removals were not included while computing the overall net cumulative discontinuation rate for all reasons.
Results NORPLANT II implants were inserted in a total of 1,569 women. The data on 103 women were excluded because they were subsequently found
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not to fulfil the study inclusion criteria. The analysis was carried out on 1,466 women who fulfilled the admission criteria. These women were observed for 52,849 women-months of use. Of these, 876 women have completed 3 years, 392 women have completed 4 years and 207 women have completed 5 years of use.
Profile of acceptors The mean age of the acceptors was 25.5 years with average of 2.0 living children. The average weight and height were 44.6 kg and 151.4 cm, respectively. The majority of the acceptors (82%) had completed primary education. Most of the acceptors (85.7%) were housewives. NORPLANT II implants were inserted within the first 7 days of the menstrual cycle in 61.0% of women; in the remaining 39.0%, it was inserted within 5 days of medical termination of pregnancy (MTP).
Contraceptive efficacy A total of four pregnancies was reported during 5 years of the study period. These occurred at 18, 27, 43 and 54 months of use, resulting in a net cumulative discontinuation rate of 0.8 at the end of 5 years (Table 1). One pregnancy occurred when the woman was on Rifampacin treatment. One woman continued with the pregnancy and delivered a full term, normal, healthy baby; the remaining three women (including the one on Rifampacin therapy) had induced abortion.
Continuation rate The overall continuation rates were 61.4, 49.0 and 42.1 per 100 users at 3, 4 and 5 years of use, respectively. Extensive efforts were made to trace the women who had continued with the device and had not come for removal at the end of 5 years. Because of these efforts, the lost to followup at the end of 5 years was only 1.6 % (Table 1).
Discontinuation rates The majority of the discontinuations from the study were due to menstrual irregularities. The next common reason for discontinuation was planning pregnancy. Besides these, there were other reasons like infection at site of implant, expulsion of the rod(s), other medical and personal reasons (Table 2 and 3).
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Clinical Article TABLE 1.
Efficacy and acceptability
of Norplant II implants
Acceptors at the beginning of interval Women-months of use Pregnancy rate per 100 users ?SE Continuation rate per 100 users % Lost to follow-up ‘207 women have completed
TABLE 2.
Net cumulative
1v
2 yr
3 yr
4 yr
5 yr
1,466
1,281
1,074
876
392(207)’
16,560 0.0 2 0.0
30,658 0.1 k. 0.1
42,295 0.2 2 0.1
49,836 0.4 k 0.2
52,849 0.8 k 0.4
88.0 0.6
74.0 0.8
61.4 1.1
49.0 1.5
42.1 1.6
5 years.
discontinuation
rates per 100 users
Rate 2 S.E Reasons
1 yr
Pregnancy Expulsion of device Migration of device Infection at site of implant Menstrual disturbances Other medical reasons Planning pregnancy No need for further contraception Other personel reasons All reasons
TABLE 3.
Net cumulative
0.0 0.2 0.1 0.3 8.2 0.9 0.7 0.6
k
2 2 + + 2 + 5
2 yr 0.0 0.1 0.1 0.2 0.7 0.3 0.2 0.2
1.2 + 0.3 12.0 ?I 0.9
discontinuation
0.1 0.2 0.2 0.3 16.6 2.4 4.2 1.8
3 yr
k 0.1 -?r 0.1 k 0.1 k 0.2 2 1.0 k 0.4 k 0.6 2 0.4
2.5 k 0.4 26.0 2 1.1
0.2 0.2 0.2 0.3 22.2 3.5 11.0 3.3
2 t 2 2 +k k 2
4 yr 0.1 0.1 0.1 0.2 1.1 0.5 0.9 0.5
3.9 k 0.6 38.6 k 1.3
0.4 0.2 0.2 0.3 26.3 4.6 18.7 7.2
‘-’ -r2 2 2 2 k 2
5 yr 0.2 0.1 0.1 0.2 1.2 0.6 1.2 0.9
6.5 + 0.8 51.0 2 1.3
0.8 0.2 0.2 0.3 28.5 6.0 21.5 10.2
-+ +” 2 2 2 + +
0.4 0.1 0.1 0.2 1.3 0.8 1.4 1.1
9.7 + 1.1 57.9 + 1.4
rates per 100 users for menstrual disturbances
Rate k S.E
1 yr
Reasons Prolonged bleeding Irregular bleeding Amenorrhoea All menstrual disturbances
124
6.7 1.3 0.3 8.2
2 0.7 2 0.3 I?I 0.1 2 0.7
2 yr 13.5 2.8 0.8 16.6
2 ? t +
3 yr 0.9 0.5 0.2 1.0
18.3 3.7 1.1 22.2
t 2 k 2
4 yr 1.1 0.5 0.3 1.1
21.4 4.8 1.6 26.3
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+ 1.2 I~I 0.6 t 0.4 t 1.2
21.9 7.0 1.6 28.5
t k 2 2
1.2 0.9 0.6 1.3
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(i) Menstrual disturbances As expected with a low-dose progestogen-only contraceptive, the net cumulative discontinuation rates due to menstrual disturbances were high; 22.2, 26.3 and 28.5 per 100 users at 3, 4 and 5 years of use, respectively. The majority of the discontinuations were due to prolonged or excessive bleeding (Table 3). Discontinuation rate due to amenorrhoea was low, probably because of counselling and the reassurance that medical termination of pregnancy could be done if pregnancy occurred. (ii) Expulsio n / migration/infection
at site of implant
Discontinuation rates due to expulsion, migration and infection were very low (Table 2). In 3 subjects, one of the implants was partially or completely expelled; all within 2 months of insertion. In 2 subjects, the devices had to be removed since the implant had migrated to the elbow crease causing inconvenience to the women. In 5 subjects, there was infection at the site of implant which required removal. Three out of 5 infections occurred after 2 months of insertion. All the infections, expulsions and migrations were observed in the early insertions when experience in insertion and removal of the device was limited. (iii) Other medical reasons A total of 54 subjects discontinued due to different medical reasons, giving a net cumulative discontinuation rate of 3.5, 4.6 and 6.0 per 100 users at 3,4 and 5 years of use, respectively (Table 2). Medical reasons for removal were: NO. OF
REASON Weight gain Weight loss Headache Giddiness/weakness
SUBJECTS 8 3 7 8
Mastalgia
I
Arthritis with dimness of vision Infectious hepatitis Subendocardial infarction
1
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3 1
REASON
Migraine Hypertension Depression Deep vein thrombosis Surgery for rheumatic heart disease Fibroadenoma of breast Cervical spondolysis Galactorrhoea
NO. OF SUBJECTS 1 1
2 1 1 1 1
1
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Clinical
Article REASON
Thyrotoxicosis Fungal dermatitis Generalised urticaria On Rifampacin ther-
NO. OF SUBJECTS 1 1 2
REASON
NO. OF SUBJECTS 2 1 1
Bronchial asthma Diabetes Hysterectomy
5*
apy *Does not include
case of method
failure
Four deaths were reported during the study period, the cause of death being hepatic failure, ventricular fibrillation, ? heart attack and suicide [personal problem).
(iv) Planning pregnancy
and other personal reasons
The net cumulative discontinuation rate due to planning pregnancy was 4.2 per 100 users at 24 months of use. There was three-fold increase in the discontinuation rate at 3 years of use (11 .O per 100 users). Discontinuation rate due to no need for further contraception was 10.2 at 5 years; the majority of these subjects opted for tubal sterilization. Discontinuations due to other personal reasons (e.g., transfer, objection from husband, etc.) were 9.7 per 100 users at 5 years of use (Table 2).
Continuation rates in relation to number of living children A positive association was observed between number of living children and continuation rates throughout the study period; the difference increased with time (Table 4). At 5 years, the continuation rate was much
TABLE 4.
Cumulative
continuation
rates per 100 users by number of living children Continuation
No. of living children One child (n = 405) Two children (n = 775) Three or more children (n = 286) P
126
1 yr
2 yr
Rate
3 yr
5 yr
4 yr
85.9
68.5
51 .l
38.4
30.9
87.5
74.6
63.8
51.7
44.4
92.2
79.9
69.3
56.6
51.7
CO.05
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lower in women having one child (30.9 per 100 users] as compared to those who had 2-to-3 children (44-52 per 100 users). The major reason which accounted for this difference was higher discontinuation rates for planning pregnancy in women having one child (about 25 and 47 per 100 users at 3 and 5 years, respectively). On the other hand, substantially lower proportion of women having 2-to-3 children discontinued due to this reason (9 to 13 per 100 users at 5 years).
Status of the implant The site of the implant was observed at every follow-up visit. In 85 women (5.8%), the implant was found to be displaced from its original site of insertion. However, these displacements did not warrant removal of the device except in 2 subjects, as stated earlier. Details are given below: Migration
along the tract (superficial)
58 Subjects
Migration
into deeper layers
20 Subjects 1 Subject
Lying crisscross Migration
Difficulty
along the tract and distorted
6 Subjects
in removal of device
The NORPLANT II implants were removed in a total of 1,442 subjects; the remaining 24 subjects were lost to follow-up. Difficulty in removal of the device was reported in 3.8% of removals (55 subjects). Following are the reasons: Migration along the tract (required 2 incisions)
10 subjects
Migrated to deeper layers (adhesions)
28 subjects
One or both rods broken
17 subjects
Changes in body weight Weight of the acceptors was recorded quently at every 6 months. It was had gained more than 5 kg of weight The average weight change was 1.5,
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at the time of enrollment and subseobserved that 43 percent of women during NORPLANT II implant use. 2.5, 3.3, 3.1 and 4.0 at 1, 2, 3, 4, and
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Clinical Article 5 years of use, respectively. (Table 5).
This
increase
was Statistically
significant
Blood pressure The blood pressure was recorded at registration and at 6-monthly intervals or earlier if required. It was observed that in 10 subjects, the diastolic blood pressure was more than 90mm Hg (92mm Hg - 1OOmm Hg) during various periods of time. In 9 women, there was a transient rise and in one woman who had persistent hypertension, the device was removed.
Other findings There was no appreciable change in haemoglobin, even at 60 months of use. Adnexal cyst was palpable in 10 women which regressed on its own except in 2 subjects where it was palpable until the removal of the NORPLANT II implants.
Discussion Data from the present study indicate that NORPLANT II implants retain contraceptive efficacy for 5 years. Net cumulative pregnancy rate at 5 years was very low (0.8/100 users). Similar findings have been reported from several countries including Singapore and Indonesia ( 1 l- 15). Higher pregnancy rates due to method failure after 3 years have, however, been reported with NORPLANT II implants in countries like Sweden (lb). Analysis of global data suggests that pregnancy rates are low (well below l.O/lOO users) in women who weigh less than 50 kg, but are higher in
TABLE 5.
Change in body weight during Norplant II implants use
Change in body weight Weight gain 5-10 kg Weight gain > 10 kg Weight loss > 5 kg No change in weight (within 5 kg) Total number of subjects Average weight (mean r SD)
lp
1 yr
2v
Enrollment
%
%
3 yr %
4 yr %
5 yr %
-
15.3 0.7 2.9 81 .l
25.2 3.5 3.1 68.2
31.4 5.5 3.4 59.7
34.1 8.6 4.5 52.8
32.3 11.0 3.9 52.8
1027 46.0* 58.5
771 46.7* k8.3
538 47.5* k8.8
177 47.6’ k9.4
55 49.0* k7.0
1466 44.6 c7.9
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heavier women ( 17). Pregnancy rate in Indian NORPLANT II contraceptive users is low, as the majority of the women weigh less than 50 kg. The continuation rates observed in this study were lower as compared to those reported in studies from other countries with NORPLANT I and NORPLANT II implants (12,13,15). However, the continuation rate at 3 years compares favourably with continuation rates reported for IUDs in the HRRC network of ICMR (18), and the continuation rates are comparable with the WHO studies on IUDs (Rowe P, WHO, personal communication). Although insertion of NORPLANT implants involves a minor surgical procedure, complications at site of implant were few. These rates are lower than those reported in studies with NORPLANT I implants (19,20). Three out of 5 subjects developed infection after 2 months; similar observation has been reported in another study (19). The exact reason for the apparent long interval between infection and insertion is not clear. It was observed that during the study period, there was displacement of the devices from their original site in 5.8% of the subjects. Some were superficially along the tract and in some cases it was in the deeper layers. The displacement of the devices was observed more often when the devices were inserted in the forearm. Such displacement of devices has been reported in early studies with NORPLANT I implants (21,22). Difficulty in removal was reported in 3.5 percent of subjects due to displacement/ fibrous sheath/breakage of the device, etc. Most of the women had menstrual irregularities at some time during use of NORPLANT II implants; however, the discontinuation rate for this reason was 28.5 per 100 users at 5 years. This rate is higher than the reported rate of 8/100 users in studies in Egypt and Mexico with NORPLANT I implants and in Singapore with NORPLANT II implants (12,20,15). As expected with a low-dose progestogen-only contraceptive, only 6 women discontinued due to major medical problems. The rest of the discontinuations for medical reasons were due to problems such as weight gain/weight loss, giddiness, etc. It was observed that discontinuation rate due to planning pregnancy increased after 24 months of use. The majority (61%) of the women who discontinued for planning pregnancy had one child. For such women, devices like Capronor biodegradable implant, newer devices like progestin ST 1435 or keto-desogestrel single implant may be more suitable as these devices are effective for 18-24 months. However, these devices are still under clinical evaluation. There was significant change in body weight at 5 years of use. The average weight change was 4.0 kg at the end of 5 years; 43% of women gained more than 5 kg. Studies carried out in Egypt and Nigeria reported a slight, statistically insignificant increase in weight (12,241. There was
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Clinical Article no clinically appreciable change in the haemoglobin level even at 5 years of use. Similar findings have been reported in Nigeria and Singapore with NORPLANT I implants (23,24). At present, NORPLANT II implants are not available for wide-spread use as the manufacturer has announced that it would no longer make Medical Grade Elastomer 382, used in the NORPLANT II contraceptive rods. The reason for this decision was a request by the U.S. Environmental Protection Agency for additional testing in animals, based on laboratory studies showing that compounds related to a minor ingredient in this elastomer caused liver tumors in rats and mice when given to them in extremely high doses. Rather than spend additional years and funds to test the product further, the manufacturer decided to stop production. The Population Council consulted scientists, clinical investigators, independent experts in medicine, biochemists, toxicologists and with women’s health groups, and it was concluded that the small amount of this ingredient used in NORPLANT II contraceptive rods did not present a risk to women; that preintroductory trials of NORPLANT II implants could continue, and that the rods did not have to be removed, but no new users were to be enrolled. A WHO Toxicological Group Consultation concluded that exposure of women to the maximal amount of the compound in NORPLANT II implants presents no human toxicological risk. A review by the U.S. FDA concluded that it had no objection to the continuation of studies currently under way with NORPLANT II implants. The Population Council has reformulated the NORPLANT II contraceptive rods using a different elastomer and phase III clinical studies are currently underway to compare equivalency and other data with the original rod and with NORPLANT I implants (6 capsules). To sum up, NORPLANT II implants were observed to be efficacious and acceptable to the women. NORPLANT implants are a provider-dependent method; it is a contraceptive that depends on the service delivery system to provide women with access to personnel who can insert and remove it. Women’s satisfaction with NORPLANT implants, therefore, depends not only on the features of the method (its high level of effectiveness, long-acting duration and convenience) but also on the quality of the family planning services.
Acknowledgement The authors are grateful to the Population Council, New York, for the gift of the NORPLANT II devices as well as providing partial travel support for monitoring the present study. NORPLANT@ is a registered trademark of the Population Council, Inc.
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References 1. Davies GC, Newton JR. Subdermal contraceptive implants: review with special reference to Norplant. Brit J Fam Plan 1991; 17:4-g. 2. Population Reports (suppl). Decision for Norplant Programmes. 1992 K-4,20. 3. The Population Council, New York. NORPLANT (Levonorgestrel implants). A summary of Scientific Data, 1990. 4. Sujuan G, Mingun D, Yuan YD et al. A two-year study on acceptability, side effects and effectiveness of Norplant and Norplantimplants in the People’s Republic of China. Contraception 1988;38:641-57. 5. Pasquale SA, Branders V, Cruz RL et al. Norplant contraceptive implants: rods verses capsules. Contraception 1987;36:305-15. 6. Singh K, Viegas OAC, Ratnam SS. A three-year evaluation of metabolic changes in Singaporean Norplantrod acceptors. Adv Contraception 199Oj6:71-80. 7. ICMR National Programme of Research in Human Reproduction: Task Force on Hormonal Contraception. Phase II randomized comparative clinical trial of NorplantR six capsules with Norplan+ [two covered rods) subdermal implants for long-term contraception: Report of a 24 month study. Contraception 1986;33:233-44. 8. ICMR Task Force on Hormonal Contraception. Phase III- clinical trial with Norplan+ covered rods: report of a 24-month study. Contraception 1988;38:659-73. 9. WHO, Geneva. Facts about an implantable contraceptive: Memorandum from a WHO Meeting. Bull WHO 1985;63:485-94. 10. Azen SP, Roy S, Pike MC, Casagrande J, Mishell DR Jr. A new procedure for statistical evaluation of intrauterine contraception. Am J Obstet Gynaecol 1977j128:329. 11. Shoupe D, Mishell DR Jr. Norplant: Subdermal implant system for long-term contraception. Am J Obstet Gynecol 1989; 160: 1286-92. 12. Sahah M, Ahmed AG, Abo-Eloyoun M, Shaaban MM. Five-year experience with Norplant implants in Assiut, Egypt. Contraception 1987;35:543-50. 13. Affandi B, Santoso SSI, Djajadilaga et al. Five-year experience with Norplant. Contraception 1987:36:417-28. 14. Singh K, Viegas OAC, Fong VF, Ratnam SS. Acceptability of NorplantR implants for fertility regulation in Singapore. Contraception 1992; 45:39-47. 15. Singh K, Viegas OAC, Ratnam SS. Acceptability of Norplan+ rods as a method of family planning. Contraception 1992;45:453-61. 16. Olsson SE, Odlind V, Johansson ED, Sivin I. Contraception with Norplant implants and Norplant II implants (two covered rods). Results from a comparative clinical study in Sweden. Contraception 1988;37:61-73. 17. Sivin I. International experience with Norplant and Norplant II contraceptives. Stud Fam Plann 1988;19:81-94. 18. ICMR Task Force on IUD. Randomised clinical trial with intrauterine devices (levonorgestrel intrauterine device (LNG), CUT 380Ag, CUT 220C and CUT 200B). A 36-month study. Contraception 1989;39:37-52. 19. Klavon SL, Grubb GS. Insertion site complications during the first year of Norplant use. Contraception 1990;41:27-37.
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Clinical Article 20. Aznar RR, Lara RR, Lozano BM, Reynoso RL. Levonorgestrel-releasing subcutaneous implants, first year experience. Ginecol Obstet Mex 1991;59: 138. 21. Sivin I, Alvarez-Sanchez F, Diaz S et al. Three-year experience with NORPLANTR subdermal contraception. Fertil Steril 1983;39:799-808. 22. Shaaban MM, Maher Shalah M, Zarzqur A, Abdullah SA. A prospective study of Norplant implants and TCu 380 Ag IUD in Assiut, Egypt. Stud Fam Plann 1983;14:6-7. 23. Fakeye 0, Balogh S. Effect of Nor-plant contraceptive use on haemoglobin, packed cell volume and menstrual bleeding patterns. Contraception 1989;39:265-74. 24. Iegas AC, Singh K, Koh S, Singh I?, Ratnam SS. The effects of Nor-plant on clinical chemistry in Singaporean acceptors after one year of use. I. Haemostatic changes. Contraception 1988;38:313-23.
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Coordinatini
Unit: Datey S, Gaur LN, Gupta NK, Menta S, Roy
M, Saxena NC, Yadav SC, Vishwanath Research, New Delhi
P, Indian Council
of Medical
Project Coordinator: Saxena BN* * All India Institute of Medical Sciences, New Delhi; 2 RG Kar Medical College, Calcutta; 3 Postgraduate Institute of Medical Education and Research, Chandigarh; 4 Medical College, Baroda; 5 Jawaharlal Nehru Medical College, Belgaum; 6 SAT Hospital, Trivandrum; 7 Medical College, Madurai; 8 Kasturba Hospital, New Delhi; 9 SCB Medical College, Cuttack; lo Safdarjung Hospital, New Delhi; l1 Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry; I2 Rama Krishna Mission Seva Pratisthan, Calcutta; l3 Institute of Obstetrics and Gynaecology, Madras; I4 BJ Medical College, Pune; l5 JJ Group of Hospitals, Bombay
The subdermal implant NORPLANT II contraceptive was studied for its safety, efficacy and acceptability over a period of 5 years of use in a phase III multicentre clinical trial. A total of 1,466 women were observed for 52,849 women-months of use. Only four pregnancies *Address correspondence to: Senior Deputy Director General and Chief, Division of Human Resource Development Research, Indian Council of Medical Research, Ansari Nagar, Delhi 110029, India. Submitted for publication March 22, 1993. Accepted for publication June 10, 1993.
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0 1993 Butterworth-Heinemann
NORPLANT
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years
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III trial:
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et al.
were reported during the study period, giving a method failure rate of 0.8 per 100 users at 5 years of use. The continuation rates were 61.4, 49.0 and 42.1 per 100 users at 3, 4 and 5 years of use, respectively. The majority of the discontinuations were due to bleeding irregularities which accounted for 22.2, 26.3 and 28.5 per 100 users at 3, 4 and 5 years of use, respectively. The next common reason was planning pregnancy which was observed mainly in women having one child. The discontinuations due to infection, expulsion or displacement of device were very low (0.2-0.3 per 100 users). Due to vigorous efforts made by the centers to follow the subjects, the lost-to-follow-up rate was very low (1.6% at 5 yr). Key words: Levonorgestrel subdermal implant NORPLANT II contraceptive, phase III clinical trial, 5 years efficacy/acceptability, continuation rates, discontinuations.
Introduction Contraceptive systems releasing low dose of synthetic progesterone have been studied for nearly two decades. Low doses of progestogens are preferred because of low systemic side effects and lower risks of severe complications. The advantage of a sustained-release system is that a long period of contraceptive efficacy can be provided with a relatively small quantity o steroid due to the avoidance of hepatic first-pass metabolism (1). The first generation implant with sustained release of low dose of levonorgestrel is NORPLANT I contraceptive, which consists of 6 capsules, and is marketed in 23 countries (2). The second generation NORPLANT II contraceptive, which consists of two covered rods, was later developed. NORPLANT implants become effective within a few hours of insertion and provide effective, continued contraceptive protection for 5 years (3) requiring minimal user compliance. Studies comparing NORPLANT I with NORPLANT II contraceptives indicate that both systems are comparable in effectiveness and in the pattern of side effects, menstrual problems being the most common (4-6). The results of an ICMR earlier phase II study in two groups of about 80 women each with NORPLANT I (6 capsules) and NORPLANT II (two covered rods) contraceptives also indicated that 2 rods were as effective and acceptable as 6 capsules up to 24 months of use (7). Since it was felt that two rods are easier to insert and remove, an expanded phase III clinical trial with NORPLANT II implants was initiated. A report on 24 months of use showed that the device is safe, efficacious and acceptable (8). The present paper is a continuation of the already published results on 24 months of NORPLANT II implants use and reports the findings on acceptability, side effects and efficacy of the NORPLANT II system as observed
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Clinical Article during 5 years of use. The data on bleeding pattern are being reported in separate publications.
and return of fertility
Methodology The NORPLANT II system consists of 2 sterile rods containing 70 mg of levonorgestrel (LNG) per rod. The implants release LNG at a rate of approximately 80 ug per 24 hr during the first 6-18 months of use; thereafter, the release rate is maintained at 30 ug per 24 hr (9). The phase III clinical trial with NORPLANT II implants was initiated in April 1983 in 15 Human Reproduction Research Centres (HRRCs) of ICMR situated at medical colleges in different regions of the country, having different cultural and social background. Healthy women volunteers in the age group of 18-38 years with no contraindications to steroidal hormone treatment were enrolled in the study. Detailed methodology has been given in the published paper on 24 months of NORPLANT II contraceptive use (8). The usual site of inserting the implant was on the left forearm about 8 cm from the elbow crease. However, four of the participating centres placed the implants in the medial aspect of the left upper arm. Following NORPLANT II implants insertion, the follow-up visits of the study subjects were scheduled at 7 days, 1, 3 and 6 months and every 6 months subsequently for the period of 5 years. During the course of the study, in 1987, two problems arose. (i) Data gene ra t e d m other countries suggested an increased failure rate after 3 years of use in women weighing more than 70 kg. (ii) The manufacturer announced that it would no longer make Medical Grade Elastomer 382, used in the NORPLANT II implant rods. The investigators were informed about both these developments and were given the choice to remove the device or obtain a fresh consent from the women if they wished to continue using the device. In 489 women, devices were removed for this reason. Net cumulative probabilities were computed by daily life table technique (10). Log rank method was used for test of significance. Paired “t” test was used to study the changes in Hb, Wt, etc. The data on the 489 subjects referred above were included in the analysis until NORPLANT II implants removal. However, these removals were not included while computing the overall net cumulative discontinuation rate for all reasons.
Results NORPLANT II implants were inserted in a total of 1,569 women. The data on 103 women were excluded because they were subsequently found
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not to fulfil the study inclusion criteria. The analysis was carried out on 1,466 women who fulfilled the admission criteria. These women were observed for 52,849 women-months of use. Of these, 876 women have completed 3 years, 392 women have completed 4 years and 207 women have completed 5 years of use.
Profile of acceptors The mean age of the acceptors was 25.5 years with average of 2.0 living children. The average weight and height were 44.6 kg and 151.4 cm, respectively. The majority of the acceptors (82%) had completed primary education. Most of the acceptors (85.7%) were housewives. NORPLANT II implants were inserted within the first 7 days of the menstrual cycle in 61.0% of women; in the remaining 39.0%, it was inserted within 5 days of medical termination of pregnancy (MTP).
Contraceptive efficacy A total of four pregnancies was reported during 5 years of the study period. These occurred at 18, 27, 43 and 54 months of use, resulting in a net cumulative discontinuation rate of 0.8 at the end of 5 years (Table 1). One pregnancy occurred when the woman was on Rifampacin treatment. One woman continued with the pregnancy and delivered a full term, normal, healthy baby; the remaining three women (including the one on Rifampacin therapy) had induced abortion.
Continuation rate The overall continuation rates were 61.4, 49.0 and 42.1 per 100 users at 3, 4 and 5 years of use, respectively. Extensive efforts were made to trace the women who had continued with the device and had not come for removal at the end of 5 years. Because of these efforts, the lost to followup at the end of 5 years was only 1.6 % (Table 1).
Discontinuation rates The majority of the discontinuations from the study were due to menstrual irregularities. The next common reason for discontinuation was planning pregnancy. Besides these, there were other reasons like infection at site of implant, expulsion of the rod(s), other medical and personal reasons (Table 2 and 3).
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123
Clinical Article TABLE 1.
Efficacy and acceptability
of Norplant II implants
Acceptors at the beginning of interval Women-months of use Pregnancy rate per 100 users ?SE Continuation rate per 100 users % Lost to follow-up ‘207 women have completed
TABLE 2.
Net cumulative
1v
2 yr
3 yr
4 yr
5 yr
1,466
1,281
1,074
876
392(207)’
16,560 0.0 2 0.0
30,658 0.1 k. 0.1
42,295 0.2 2 0.1
49,836 0.4 k 0.2
52,849 0.8 k 0.4
88.0 0.6
74.0 0.8
61.4 1.1
49.0 1.5
42.1 1.6
5 years.
discontinuation
rates per 100 users
Rate 2 S.E Reasons
1 yr
Pregnancy Expulsion of device Migration of device Infection at site of implant Menstrual disturbances Other medical reasons Planning pregnancy No need for further contraception Other personel reasons All reasons
TABLE 3.
Net cumulative
0.0 0.2 0.1 0.3 8.2 0.9 0.7 0.6
k
2 2 + + 2 + 5
2 yr 0.0 0.1 0.1 0.2 0.7 0.3 0.2 0.2
1.2 + 0.3 12.0 ?I 0.9
discontinuation
0.1 0.2 0.2 0.3 16.6 2.4 4.2 1.8
3 yr
k 0.1 -?r 0.1 k 0.1 k 0.2 2 1.0 k 0.4 k 0.6 2 0.4
2.5 k 0.4 26.0 2 1.1
0.2 0.2 0.2 0.3 22.2 3.5 11.0 3.3
2 t 2 2 +k k 2
4 yr 0.1 0.1 0.1 0.2 1.1 0.5 0.9 0.5
3.9 k 0.6 38.6 k 1.3
0.4 0.2 0.2 0.3 26.3 4.6 18.7 7.2
‘-’ -r2 2 2 2 k 2
5 yr 0.2 0.1 0.1 0.2 1.2 0.6 1.2 0.9
6.5 + 0.8 51.0 2 1.3
0.8 0.2 0.2 0.3 28.5 6.0 21.5 10.2
-+ +” 2 2 2 + +
0.4 0.1 0.1 0.2 1.3 0.8 1.4 1.1
9.7 + 1.1 57.9 + 1.4
rates per 100 users for menstrual disturbances
Rate k S.E
1 yr
Reasons Prolonged bleeding Irregular bleeding Amenorrhoea All menstrual disturbances
124
6.7 1.3 0.3 8.2
2 0.7 2 0.3 I?I 0.1 2 0.7
2 yr 13.5 2.8 0.8 16.6
2 ? t +
3 yr 0.9 0.5 0.2 1.0
18.3 3.7 1.1 22.2
t 2 k 2
4 yr 1.1 0.5 0.3 1.1
21.4 4.8 1.6 26.3
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5 yr
+ 1.2 I~I 0.6 t 0.4 t 1.2
21.9 7.0 1.6 28.5
t k 2 2
1.2 0.9 0.6 1.3
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(i) Menstrual disturbances As expected with a low-dose progestogen-only contraceptive, the net cumulative discontinuation rates due to menstrual disturbances were high; 22.2, 26.3 and 28.5 per 100 users at 3, 4 and 5 years of use, respectively. The majority of the discontinuations were due to prolonged or excessive bleeding (Table 3). Discontinuation rate due to amenorrhoea was low, probably because of counselling and the reassurance that medical termination of pregnancy could be done if pregnancy occurred. (ii) Expulsio n / migration/infection
at site of implant
Discontinuation rates due to expulsion, migration and infection were very low (Table 2). In 3 subjects, one of the implants was partially or completely expelled; all within 2 months of insertion. In 2 subjects, the devices had to be removed since the implant had migrated to the elbow crease causing inconvenience to the women. In 5 subjects, there was infection at the site of implant which required removal. Three out of 5 infections occurred after 2 months of insertion. All the infections, expulsions and migrations were observed in the early insertions when experience in insertion and removal of the device was limited. (iii) Other medical reasons A total of 54 subjects discontinued due to different medical reasons, giving a net cumulative discontinuation rate of 3.5, 4.6 and 6.0 per 100 users at 3,4 and 5 years of use, respectively (Table 2). Medical reasons for removal were: NO. OF
REASON Weight gain Weight loss Headache Giddiness/weakness
SUBJECTS 8 3 7 8
Mastalgia
I
Arthritis with dimness of vision Infectious hepatitis Subendocardial infarction
1
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3 1
REASON
Migraine Hypertension Depression Deep vein thrombosis Surgery for rheumatic heart disease Fibroadenoma of breast Cervical spondolysis Galactorrhoea
NO. OF SUBJECTS 1 1
2 1 1 1 1
1
125
Clinical
Article REASON
Thyrotoxicosis Fungal dermatitis Generalised urticaria On Rifampacin ther-
NO. OF SUBJECTS 1 1 2
REASON
NO. OF SUBJECTS 2 1 1
Bronchial asthma Diabetes Hysterectomy
5*
apy *Does not include
case of method
failure
Four deaths were reported during the study period, the cause of death being hepatic failure, ventricular fibrillation, ? heart attack and suicide [personal problem).
(iv) Planning pregnancy
and other personal reasons
The net cumulative discontinuation rate due to planning pregnancy was 4.2 per 100 users at 24 months of use. There was three-fold increase in the discontinuation rate at 3 years of use (11 .O per 100 users). Discontinuation rate due to no need for further contraception was 10.2 at 5 years; the majority of these subjects opted for tubal sterilization. Discontinuations due to other personal reasons (e.g., transfer, objection from husband, etc.) were 9.7 per 100 users at 5 years of use (Table 2).
Continuation rates in relation to number of living children A positive association was observed between number of living children and continuation rates throughout the study period; the difference increased with time (Table 4). At 5 years, the continuation rate was much
TABLE 4.
Cumulative
continuation
rates per 100 users by number of living children Continuation
No. of living children One child (n = 405) Two children (n = 775) Three or more children (n = 286) P
126
1 yr
2 yr
Rate
3 yr
5 yr
4 yr
85.9
68.5
51 .l
38.4
30.9
87.5
74.6
63.8
51.7
44.4
92.2
79.9
69.3
56.6
51.7
CO.05
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lower in women having one child (30.9 per 100 users] as compared to those who had 2-to-3 children (44-52 per 100 users). The major reason which accounted for this difference was higher discontinuation rates for planning pregnancy in women having one child (about 25 and 47 per 100 users at 3 and 5 years, respectively). On the other hand, substantially lower proportion of women having 2-to-3 children discontinued due to this reason (9 to 13 per 100 users at 5 years).
Status of the implant The site of the implant was observed at every follow-up visit. In 85 women (5.8%), the implant was found to be displaced from its original site of insertion. However, these displacements did not warrant removal of the device except in 2 subjects, as stated earlier. Details are given below: Migration
along the tract (superficial)
58 Subjects
Migration
into deeper layers
20 Subjects 1 Subject
Lying crisscross Migration
Difficulty
along the tract and distorted
6 Subjects
in removal of device
The NORPLANT II implants were removed in a total of 1,442 subjects; the remaining 24 subjects were lost to follow-up. Difficulty in removal of the device was reported in 3.8% of removals (55 subjects). Following are the reasons: Migration along the tract (required 2 incisions)
10 subjects
Migrated to deeper layers (adhesions)
28 subjects
One or both rods broken
17 subjects
Changes in body weight Weight of the acceptors was recorded quently at every 6 months. It was had gained more than 5 kg of weight The average weight change was 1.5,
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1993148,
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at the time of enrollment and subseobserved that 43 percent of women during NORPLANT II implant use. 2.5, 3.3, 3.1 and 4.0 at 1, 2, 3, 4, and
127
Clinical Article 5 years of use, respectively. (Table 5).
This
increase
was Statistically
significant
Blood pressure The blood pressure was recorded at registration and at 6-monthly intervals or earlier if required. It was observed that in 10 subjects, the diastolic blood pressure was more than 90mm Hg (92mm Hg - 1OOmm Hg) during various periods of time. In 9 women, there was a transient rise and in one woman who had persistent hypertension, the device was removed.
Other findings There was no appreciable change in haemoglobin, even at 60 months of use. Adnexal cyst was palpable in 10 women which regressed on its own except in 2 subjects where it was palpable until the removal of the NORPLANT II implants.
Discussion Data from the present study indicate that NORPLANT II implants retain contraceptive efficacy for 5 years. Net cumulative pregnancy rate at 5 years was very low (0.8/100 users). Similar findings have been reported from several countries including Singapore and Indonesia ( 1 l- 15). Higher pregnancy rates due to method failure after 3 years have, however, been reported with NORPLANT II implants in countries like Sweden (lb). Analysis of global data suggests that pregnancy rates are low (well below l.O/lOO users) in women who weigh less than 50 kg, but are higher in
TABLE 5.
Change in body weight during Norplant II implants use
Change in body weight Weight gain 5-10 kg Weight gain > 10 kg Weight loss > 5 kg No change in weight (within 5 kg) Total number of subjects Average weight (mean r SD)
lp
1 yr
2v
Enrollment
%
%
3 yr %
4 yr %
5 yr %
-
15.3 0.7 2.9 81 .l
25.2 3.5 3.1 68.2
31.4 5.5 3.4 59.7
34.1 8.6 4.5 52.8
32.3 11.0 3.9 52.8
1027 46.0* 58.5
771 46.7* k8.3
538 47.5* k8.8
177 47.6’ k9.4
55 49.0* k7.0
1466 44.6 c7.9
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et al.
heavier women ( 17). Pregnancy rate in Indian NORPLANT II contraceptive users is low, as the majority of the women weigh less than 50 kg. The continuation rates observed in this study were lower as compared to those reported in studies from other countries with NORPLANT I and NORPLANT II implants (12,13,15). However, the continuation rate at 3 years compares favourably with continuation rates reported for IUDs in the HRRC network of ICMR (18), and the continuation rates are comparable with the WHO studies on IUDs (Rowe P, WHO, personal communication). Although insertion of NORPLANT implants involves a minor surgical procedure, complications at site of implant were few. These rates are lower than those reported in studies with NORPLANT I implants (19,20). Three out of 5 subjects developed infection after 2 months; similar observation has been reported in another study (19). The exact reason for the apparent long interval between infection and insertion is not clear. It was observed that during the study period, there was displacement of the devices from their original site in 5.8% of the subjects. Some were superficially along the tract and in some cases it was in the deeper layers. The displacement of the devices was observed more often when the devices were inserted in the forearm. Such displacement of devices has been reported in early studies with NORPLANT I implants (21,22). Difficulty in removal was reported in 3.5 percent of subjects due to displacement/ fibrous sheath/breakage of the device, etc. Most of the women had menstrual irregularities at some time during use of NORPLANT II implants; however, the discontinuation rate for this reason was 28.5 per 100 users at 5 years. This rate is higher than the reported rate of 8/100 users in studies in Egypt and Mexico with NORPLANT I implants and in Singapore with NORPLANT II implants (12,20,15). As expected with a low-dose progestogen-only contraceptive, only 6 women discontinued due to major medical problems. The rest of the discontinuations for medical reasons were due to problems such as weight gain/weight loss, giddiness, etc. It was observed that discontinuation rate due to planning pregnancy increased after 24 months of use. The majority (61%) of the women who discontinued for planning pregnancy had one child. For such women, devices like Capronor biodegradable implant, newer devices like progestin ST 1435 or keto-desogestrel single implant may be more suitable as these devices are effective for 18-24 months. However, these devices are still under clinical evaluation. There was significant change in body weight at 5 years of use. The average weight change was 4.0 kg at the end of 5 years; 43% of women gained more than 5 kg. Studies carried out in Egypt and Nigeria reported a slight, statistically insignificant increase in weight (12,241. There was
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1993:48, Aug.
129
Clinical Article no clinically appreciable change in the haemoglobin level even at 5 years of use. Similar findings have been reported in Nigeria and Singapore with NORPLANT I implants (23,24). At present, NORPLANT II implants are not available for wide-spread use as the manufacturer has announced that it would no longer make Medical Grade Elastomer 382, used in the NORPLANT II contraceptive rods. The reason for this decision was a request by the U.S. Environmental Protection Agency for additional testing in animals, based on laboratory studies showing that compounds related to a minor ingredient in this elastomer caused liver tumors in rats and mice when given to them in extremely high doses. Rather than spend additional years and funds to test the product further, the manufacturer decided to stop production. The Population Council consulted scientists, clinical investigators, independent experts in medicine, biochemists, toxicologists and with women’s health groups, and it was concluded that the small amount of this ingredient used in NORPLANT II contraceptive rods did not present a risk to women; that preintroductory trials of NORPLANT II implants could continue, and that the rods did not have to be removed, but no new users were to be enrolled. A WHO Toxicological Group Consultation concluded that exposure of women to the maximal amount of the compound in NORPLANT II implants presents no human toxicological risk. A review by the U.S. FDA concluded that it had no objection to the continuation of studies currently under way with NORPLANT II implants. The Population Council has reformulated the NORPLANT II contraceptive rods using a different elastomer and phase III clinical studies are currently underway to compare equivalency and other data with the original rod and with NORPLANT I implants (6 capsules). To sum up, NORPLANT II implants were observed to be efficacious and acceptable to the women. NORPLANT implants are a provider-dependent method; it is a contraceptive that depends on the service delivery system to provide women with access to personnel who can insert and remove it. Women’s satisfaction with NORPLANT implants, therefore, depends not only on the features of the method (its high level of effectiveness, long-acting duration and convenience) but also on the quality of the family planning services.
Acknowledgement The authors are grateful to the Population Council, New York, for the gift of the NORPLANT II devices as well as providing partial travel support for monitoring the present study. NORPLANT@ is a registered trademark of the Population Council, Inc.
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References 1. Davies GC, Newton JR. Subdermal contraceptive implants: review with special reference to Norplant. Brit J Fam Plan 1991; 17:4-g. 2. Population Reports (suppl). Decision for Norplant Programmes. 1992 K-4,20. 3. The Population Council, New York. NORPLANT (Levonorgestrel implants). A summary of Scientific Data, 1990. 4. Sujuan G, Mingun D, Yuan YD et al. A two-year study on acceptability, side effects and effectiveness of Norplant and Norplantimplants in the People’s Republic of China. Contraception 1988;38:641-57. 5. Pasquale SA, Branders V, Cruz RL et al. Norplant contraceptive implants: rods verses capsules. Contraception 1987;36:305-15. 6. Singh K, Viegas OAC, Ratnam SS. A three-year evaluation of metabolic changes in Singaporean Norplantrod acceptors. Adv Contraception 199Oj6:71-80. 7. ICMR National Programme of Research in Human Reproduction: Task Force on Hormonal Contraception. Phase II randomized comparative clinical trial of NorplantR six capsules with Norplan+ [two covered rods) subdermal implants for long-term contraception: Report of a 24 month study. Contraception 1986;33:233-44. 8. ICMR Task Force on Hormonal Contraception. Phase III- clinical trial with Norplan+ covered rods: report of a 24-month study. Contraception 1988;38:659-73. 9. WHO, Geneva. Facts about an implantable contraceptive: Memorandum from a WHO Meeting. Bull WHO 1985;63:485-94. 10. Azen SP, Roy S, Pike MC, Casagrande J, Mishell DR Jr. A new procedure for statistical evaluation of intrauterine contraception. Am J Obstet Gynaecol 1977j128:329. 11. Shoupe D, Mishell DR Jr. Norplant: Subdermal implant system for long-term contraception. Am J Obstet Gynecol 1989; 160: 1286-92. 12. Sahah M, Ahmed AG, Abo-Eloyoun M, Shaaban MM. Five-year experience with Norplant implants in Assiut, Egypt. Contraception 1987;35:543-50. 13. Affandi B, Santoso SSI, Djajadilaga et al. Five-year experience with Norplant. Contraception 1987:36:417-28. 14. Singh K, Viegas OAC, Fong VF, Ratnam SS. Acceptability of NorplantR implants for fertility regulation in Singapore. Contraception 1992; 45:39-47. 15. Singh K, Viegas OAC, Ratnam SS. Acceptability of Norplan+ rods as a method of family planning. Contraception 1992;45:453-61. 16. Olsson SE, Odlind V, Johansson ED, Sivin I. Contraception with Norplant implants and Norplant II implants (two covered rods). Results from a comparative clinical study in Sweden. Contraception 1988;37:61-73. 17. Sivin I. International experience with Norplant and Norplant II contraceptives. Stud Fam Plann 1988;19:81-94. 18. ICMR Task Force on IUD. Randomised clinical trial with intrauterine devices (levonorgestrel intrauterine device (LNG), CUT 380Ag, CUT 220C and CUT 200B). A 36-month study. Contraception 1989;39:37-52. 19. Klavon SL, Grubb GS. Insertion site complications during the first year of Norplant use. Contraception 1990;41:27-37.
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Clinical Article 20. Aznar RR, Lara RR, Lozano BM, Reynoso RL. Levonorgestrel-releasing subcutaneous implants, first year experience. Ginecol Obstet Mex 1991;59: 138. 21. Sivin I, Alvarez-Sanchez F, Diaz S et al. Three-year experience with NORPLANTR subdermal contraception. Fertil Steril 1983;39:799-808. 22. Shaaban MM, Maher Shalah M, Zarzqur A, Abdullah SA. A prospective study of Norplant implants and TCu 380 Ag IUD in Assiut, Egypt. Stud Fam Plann 1983;14:6-7. 23. Fakeye 0, Balogh S. Effect of Nor-plant contraceptive use on haemoglobin, packed cell volume and menstrual bleeding patterns. Contraception 1989;39:265-74. 24. Iegas AC, Singh K, Koh S, Singh I?, Ratnam SS. The effects of Nor-plant on clinical chemistry in Singaporean acceptors after one year of use. I. Haemostatic changes. Contraception 1988;38:313-23.
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