345
Int. .I. Gynecol. Obstet., 1990, 33: 345-357 International Federation of Gynecology and Obstetrics
Study of NorplantR implants in Shanghai: three-year experience M.K. Dua, H.M. Zheng”, H.C. Chenb and L.P. Chow’ aGynecology and Obstetrics Hospital, Shanghai Medical University, Shanghai (China), bDepartment of Community Health, Emory Univemity School of Medicine, Atlanta, Georgia and =Department of Population Dynamics, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland (USA) (Received June lZth, 1989) (Revised and accepted September 11th, 1989)
Abstract A clinical follow-up study conducted in Shanghai, China conJitmed earlier reports that the NorplantR implants, NorplantR-I and NorplantR-2, are both highly effective with high continuation rates. The implants, however, tend to cause menstrual disturbance, spotting and bleeding. The mean hemoglobin value, however, did not change and the blood pressure remained stable. The report of 8 cases of thrombocytopenia among 301 NorplantR-2 users is a source of concern. Keywords: Norplant R; Contraceptive effectiveness; Contraceptive implants; Follow-up study. Introduction The development of contraceptive implants and their approval for use in 1983 in Finland appeares to be a milestone event toward *NorplantR is the Population Council’s Trademark for contraceptive subdermal implants; Norplant’and Norplant”-2. Throughout this article, Norplant, Norplant- and Norplantall refer to Norplant”, NorplanP-1 and NorplanP-2, respectively.
omo-7292/90/%03
so
@ 1990 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
developing an “ideal” contraceptive. The implants seems to have the advantage of high efficacy of IUD and orals, yet do not have the disadvantage of irreversibility of sterilization. By January 1988, the contraceptive implants, NorplantR-1 * and NorplantR-2* had been approved for study in some 30 countries, and for general distribution in some 11 countries. More than 200,000 women in the world are estimated to have been using these implants [8]. NorplantR* implants, Norplant-l and Norplant-2, were introduced into China in 1984 by the Population Council for trial use. A multi-hospital clinical trial project was organized to study the acceptability, safety, and effectiveness of these devices. The Family Planning Department of the Shanghai Obstetrics and Gynecology Hospital participated in the study project and this article reports the preliminary results of the first three years of their use. Materials and methods The Norplant implants, Norplant-l and Norplant-2, used in this study were manufactured by Leiras Pharmaceuticals in Finland and provided for the study by the Population Council of New York. Clinical and Clinical Research
346
Du el al.
The recruitment of study subjects was started in October 1984 and by March 1988 a total of 1662 women were registered for the study: 1361 for Norplant-l and 301 for Norplant-2 implantation. Norplant-l comprises six 3.4 cm silastic capsules, each with an outside diameter of 2.4 mm, containing 36 mg of levonorgestrel, totalling 216 mg of levonorgestrel in six capsules. Norplant- is a covered rod system with two silastic rods, each 4.4 cm in length, 2.4 mm in diameter, and containing 70. mg of levonorgestrel, totalling 140 mg in two rods. The devices are designed to continuously release approximately 30 pg of levonorgestrel every day, a dosage similar to a minipill. Recruitment of the study subjects was through a week of advertisement in local newspapers. Women who became aware of this new contraceptive device came to the hospital to inquire about it. Those who volunteered to accept the devices, and who were determined by the clinical investigators in the hospital to be eligible for participating in the study, were enlisted and given the implants. The criteria of eligibility to participate in the study included: women must be under 40 years old; currently married and living with their husbands; have had at least one living child; are not currently pregnant or breastfeeding; voluntarily choose these contraceptive implants for fertility control; and indicated willingness to comply with the requirement for periodic follow-up examinations. During the initial clinic visit, medical history was taken and thorough physical and gynecological examinations were conducted by specialists of obstetrics and gynecology in the hospital. Women with any history, sign, or symptom of cardiovascular diseases, jaundice, diabetes, pelvic inflammatory diseases, depression or other psychological symptoms, severe varicose veins, periodic and rather severe headache, and ectopic pregnancy, were excluded from participation. If a woman was accepted for the study, a Papanicolou smear was taken, her breasts were examined manIn1 J Gynecol
Obstet 33
ually and a blood specimen was drawn for measurement of hemoglobin value. Implanting Norplant-l and Norplant- was not systematic: Norplant-l was first introduced for use followed by the introduction of Norplant-2. After reports of some side effects, the use of Norplant- was suspended. There are fewer cases of Norplant- users in this study. The placement of the implants involved minor outpatient surgery with local anesthesia, as described elsewhere [5]. The devices were usually implanted within the first week following the onset of menstrual cycle. After receiving the implants, women were requested to return for periodic follow-up examinations at 1, 3, 6, and 12 months after implantation then annually thereafter, for a total duration of 5-7 years. During each of these follow-up visits, a thorough physical examination was undertaken. Gynecologial examination was conducted once every 6 months during the first year, then annually. A blood specimen for measurement of hemoglobin was taken annually. A Daily Menstrual Record Card was given to each participant for recording, on a daily basis, the onset, duration and amount of each menstrual episode. Women were also told to record any change or “abnormality” in menstural pattern, such as irregularity, spotting, bleeding, heavy bleeding, or amenorrhea; “spotting” meaning vaginal bleeding in quantity small enough not to require the use of menstrual pads; “bleeding” meaning in quantity large enough, such as regular menstural flow, to require the use of pads; and “heavy bleeding” meaning vaginal bleeding in quantity in excess of women’s “regular” menstrual flows. If the onset of menstruation was delayed for more than 15 days, a pregnancy test was conducted, followed by an ultrasound examination, if necessary, to either confirm or deny pregnancy. If an implant had to be removed for medical, personal, or any other reason, local anesthesia was administered and the device pulled
Study of NorplanP implants in Shanghai
out with a small incision of the skin. The women were asked to return to the clinic for a final follow-up examination 3-12 months after the removal. The study is continuing, but observation was “cut-off” on March 30, 1988 for a preliminary analysis. The data were coded and a set of complete data was brought by the senior author to the Johns Hopkins University School of Hygiene and Public Health and the Centers for Disease Control for analysis. The life table technique was used in most of the data analysis. Results Characteristics of the study subjects More than half (53.0%) of the study subjects were 30-34 years old when the devices were implanted. Most (97.0%) of these women had only one living child. The implants were placed mostly (81 .O%) within 4 -5 days following the onset of menstruation. Prior to accepting the implants, 39.6% of the women used IUDs, 20.3% of their husbands used condoms, and 5.1% of them took oral contraceptives for fertility control. Approximately one-third (3 1.7%) of these women were not using any contraceptive method. There were no significant differences in these characteristics between -the acceptors of Norplant-l and Norplant-2. The mean duration of observation was 25.6 months for the users of Norplant-1, 26.9 months for Norplant-2, and 26.0 months for both combined (Table I). Continuation and effectiveness of the implan Is The continuation rates of Norplant use among the study subjects were high: 99.5% at 3 months; 98.8% at 6 months; 96.5% at 12 months; and 86.2% at 24 months. At 36 months, 77.2% of the acceptors were still using the implants. There were no differences in continuation rates between Norplant-l and Norplant-2, except at 36 months the rate of the former
347
(78.2%) appears to be somewhat better than the rate of the latter (73.6%). The difference, however, is not significant. Nor was there any significant difference in continuation rates by age groups or body weight of women except that the 24 month rate for women of heaviest weight (56-82 kg) was significantly lower than those of lightest weight (35-49 kg): 84.3% for the former compared to 90.0% for the latter group of women (Table II). The termination rates, which are the complements of continuation rates, therefore were low: 0.5%, 1.3070, 3.2%, 12.4%, and 22.8% at 3, 6, 12, 24, and 36 months, respectively. The rather sharp increase in the termination rates from 3.2% at 12 months to 12.4% at 24 months, and again to 22.8% at 36 months, deserves some attention (Table III). Table III also shows that medical reasons, especially menstrual disturbance, was the predominant reason for the implant loss. There were five pregnancies among the study subjects, three of which were confirmed within one month after the placement of the devices. These might have been luteal phase pregnancies, or else the implants might have been less effective during the first month of use. One pregnancy was detected during the 2nd month of use and another during the 13th month of use. The cumulative gross pregnancy rates, including the three presumably luteal phase pregnancies, were 0.2% at 12 months and 0.3% at 24 and 36 months, indicating high efficacy of Norplants. All five pregnancies occurred among the Norplant-l users. There was a total of 262 removals of which 152, or 53.2%, were for menstrual disturbances, including prolonged or heavy bleeding, spotting, irregular cycles, and amenorrhea. Eighty-three [83] removals for “other medical reasons” included headache, myoma of uterus or annexitis, diseases of the liver and gallbladder, weight gain or hypertension, thrombocytopenia and others (Table IV). The occurrence of eight cases of thrombocytopenia, decreased platelet count, all of Clinical and Clinical Research
348
Duet al.
Table 1. Percentage distribution of selected variables by types of Norplant implanted. Selected variables
Norplant- 1
Norplant-
Total
1. Age of acceptors 20-29 30-34 35-40
32.6 53.2 14.2
32.2 52.2 15.6
32.6 53.0 14.4
2. Number of live births One Two
97.1 2.9
96.3 3.7
97.0 3.0
3. Contraceptive use before acceptance IUD Condom Oral pill Others Not using any
39.0 19.9 5.4 3.5 32.2
42.5 22.6 3.7 1.7 29.6
39.6 20.3 5.1 3.3 31.7
4. Year of acceptance 1984 1985 1986 1987 1988
6.3 49.6 22.2 21.3 0.6
3.3 32.9 63.8 0.0 0.0
5.8 46.5 29.7 17.5 0.5
5. Days between onset of LMP and implant o-3 4-5 6-7 8-11 Unknown
9.4 81.2 7.4 1.6 0.4
13.6 80.1 6.0 0.3 0.0
10.2 81.0 7.1 1.4 0.3
6. Lengths (months) of Norplant use observed O-11 12-23 24-35 36-41
7.5 30.6 26.6 35.3
2.0 11.9 57.8 28.3
6.5 27.2 32.3 34.0
100.0 (1361)
100.0 (301)
(1662)
7. Total (Vo) (Number of acceptors)
them among 301 Norplantusers, deserves serious attention. No such case has been detected among the total of 1361 users of Norplant-1, which contains the same hormone but in a higher total dose (216 mg vs. 140 mg) and which has a different manufacturing process. Int J Gynecol Obstet 33
100.0
Table V shows the platelet counts of these cases during the use of implants, at their removals, and after the implants were removed. Unfortunately, no platelet count was taken at the time of implantation. When the platelet counts were found to be low for these eight cases, the Norplant-
Study of NorplanP implantsin Shanghai
349
Life table cumulative continuation rates and their standard errors or Norplant use at 3.6, 12.24 and 36 months of use by Table II. type of Norplant, age of women and body weight (rates per 100 women). Variables
Months after acceptance 3
6
12
24
36
Total
99.5 (0.2)’
98.8 (0.3)
96.5 (0.4)
86.2 (0.9)
77.2 (1.3)
Type of Norplant Norplant-l Norplant-
99.4 (0.2) 99.7 (0.3)
98.5 (0.3) 99.3 (0.5)
96.4 (0.5) 98.3 (0.7)
88.0(1.0) 86.7 (2.0)
78.2 (1.5) 73.6 (3.3)
Age of women 24-29 30-31 32-40
99.6 (0.3) 99.3 (0.3) 99.6 (0.4)
99.1(0.4) 98.6 (0.4) 97.9 (0.9)
97.7 (0.6) 96.3 (0.6) 96.2 (1.2)
88.4 (1.6) 87.3 (1.2) 87.0 (2.3)
78.4 (2.3) 75.3 (1.9) 80.2(3.1)
Body weight (kg) 35-49 50-55 56-82
99.6 (0.3) 99.4 (0.3) 99.5 (0.3)
99.1 (0.4) 98.9 (0.4) 98.1 (0.6)
97.1 (0.8) 98.2 (0.5) 94.9 (0.9)
90.0 (1.5) 88.8 (1.4) 84.3 (1.7)
79.3 (2.5) 78.2 (2.1) 74.3 (2.4)
‘Standard error of the rate is given in parentheses.
device was promptly removed. Post-removal follow-up examination indicated generally increased platelet counts to the 100,000120,000 mm3 range, except in two cases, one of which was rather severe with general petechiae and had to be hospitalized for treat-
ment. Her platelet count increased from 12,000/mm3 to 50,000/mm3 in about three months after removal; unfortunately she contracted Hepatitia-A infection and was hospitalked. At her last follow-up examination, her platelet count was still low: 26,000/mm3.
Life table cumulative gross termination rates and their standard errors of Norplant use at 3.6, 12, 24 and 36 months of Table III. use by pregnancy and removal for medical, non-medical, and personal reasons (rates per 100 women). Reasons
Months after acceptance 3
6
12
24
36
Total
0.5 (0.2)
1.3 (0.3)
3.2 (0.4)
12.4 (0.9)
22.8 (1.3)
Pregnancyb
0.2 (0.1)
0.2 (0.1)
0.2 (0.1)
0.3 (0.1)
0.3 (0.1)
Medical reasons Menstrual Non-menstrual
0.0 (0.0) 0.3 (0.2)
0.4 (0.2) 0.6 (0.2)
l.l(O.3) 1.6(0.3)
7.4 (0.7) 4.2 (0.5)
14.3 (1.1) 7.6 (0.9)
Personal reasons
0.0 (0.0)
0.1 (0.1)
0.3 (0.1)
1.0 (0.3)
2.3 (0.5)
‘Standard error of the rate is given in parentheses. bAll five pregnancies occurred among Norplant-l users. Three of these pregnancies occurred within one month after implantation, which presumably were luteal phase pregnancies. One pregnancy occurred during the 2nd and another during the 12th month of use. Clinicaland ClinicalResearch
350
Du et al.
Table IV.
Detailed classification
of reasons
for removing
Reasons for removal
Total number
Norplant.
Number
of removals
Menstrual Disturbances Prolonged or heavy bleeding Too frequent or irregular cycles Amenorrhea
cases
Norplant-l
Norplant-
Total (%)
202
60
262(10&O)
110 15 22 8
42 33 4 2
152 (53.2) 108 26 IO
5
3
Others Other medical reasons Headache
of removal
8
66 13
83 (38.3) 14
Hepatomegaly, hepatitis Myoma of uterus or annexity Thrombocytopenia Weight gain or hypertension
10 10 0 6
I0
Inflammation Others
3 24
Personal
of gallbladder
reasons
Planned pregnancy Divorced, widowed,
or others
10 8 6 3 32
21
I
22 (5.7)
1 20
0
I 21
5
0
Pregnant
1
Table V. Blood platelet counts of eight cases of thymobocytopenia count was made at the time of implantation. Implantation
During use
30
-
60,000 (?)
48b
(2/9/85) -
82
(3/18/85) -
Case No.
(7/l/85) 103 165’
(8/22/85) (3/6/86)
170
during Norplant
-
75,000 (3/3/86)
-
86,000 (g/27/87) 91,000 (5/27/86) -
78,000 (619187) 57,000 (3/87) -
64,000 (4/14/87)
94,000 (10/7/87)
(3/8/86) 244 299“
(415186) (5/2/86)
bPetechiae in extremities which disappared after removal of Norplant. ‘Petechiae on the whole body surface. Contracted Hepatitis-A infection dDiagnosed as chronic nephritis. The data of the event is given in parentheses
Int .I Gynecol Obstet 33
(mm/dd/;y).
5 (2.8)
use, at removal,
and after removal.
No platelet
Removal
After removal
69,000 (1 l/4/86)
94,000 (2187)
106,000 (8/88)
56,000 (5123185) 75,000 (l/12/87) 52,000 (10/23/87) 12,000 (4/28/87)
89,000 (8185) 100,000 (8/12/88)
-
72,000 (3/31/87) 96,000 (l/26/88)
58,000 (l/10/88) 26,000 (8/88) 80,000 (6/l/87) 120,000 (7110188)
36,000 (2/5/88)
48,000 (7/10/88)
and was hospitalized
in January
1988
100,000 (8/20/88) 102,000 (8/11/88) --
351
Study of Norplot@ implants in Shanghai
were consistently observed for 36 months (Table VI). Table VII shows the proportion of users complaining of side effects by such variables as type of Norplants, age of women, and body weight of the users. There was no significant difference in the proportion of complaints between the two types of implants. Younger women appeared to have complained more but, except in several categories, the differences were not significant. A total of 541 women kept adequate Daily Menstrual Records, which were analyzed. The observation was divided into twelve 90day periods; first period means the first 90 days after placement of the implants, the second period is from the 91st to 180th day after implementation, and so forth. Table VIII indicates that most women had had two or three menstrual cycles during each of the go-day periods. The average number of cycles experienced ranged between 2.58 during the 3rd period to 2.93 during the 10th period. Amenorrhea seemed to be relatively infrequent; the highest rate was 3.4% amenorrhea during the 3rd period (Table VIII). During the first go-day period, the women,
Another case has been diagnosed as having chronic nephritis, and her platelet count increased only slightly from 36,000 before to 48,000 after removal of Norplant-2. There were 13 removals because of diseases of the liver and gall bladder, all from among the Norplant- 1 users. Side effects
The Norplant users frequently complained about untoward effects. At the first month’s follow-up visit, 54.7% of the users complained of some side effects. This proportion increased to 62.8% at the third monthly visit and then started to decline rather significantly to 37.1% at the 36-month visit. Menstrual disturbance was the predominant type of complaint. The proportion complaining of menstrual disturbance increased from 50.9% at the first month’s visit to 60.5% at the 3-month visit, and then decreased to 33.9% at the 36-month visit. Less frequent complaints of side effects by longer-term users is partly due to selection. This pattern of complaint of side effects was essentially the same for the 629 cases who
Table VI. Percentage of Norplant users complained of side effects at 1-, 3-, 6, 12-, 24- and 36-month follow-up visits for two groups of users.
Months of follow-up visits
Percentage of users having complaints
Sample size (N)
Menstrual disturbance
Other medical problems
Total
50.9 60.5 54.1 40.3 36.0 33.9
3.8 2.3 1.3 1.7 2.1 3.2
54.1 62.8 55.4 42.0 38.1 37.1
1,113 1,184 1,631 1,577 1,139 635
2.2 1.3 1.1 1.0 0.6 3.0
55.9 59.6 57.2 41.9 34.9 36.4
629 629 629 629 629 629
Cases observed at each visit
1 3 6 12 24 36
Cases consistently observed for 3 years I 53.1 3 58.3 6 56.1 12 40.9 24 34.3 36 33.4
Clinical and Clinical Research
352
Du et al.
Table VII. Proportion of Norplant users who complained devices and age and body weight of women. Month of visit
Variables
Proportion
of side effects at l-, 3-, 12-, 24- and 36-month
follow-up
of users having complaints
visit, by type of
Sample size
Menstrual disturbance
Other medical problems
Total
Norplant-
52.5
Norplant-
46.8
3.7 4.0
56.2 50.8
812 301
3
Norplant-l Norplant-
61.6 57.1
2.2 2.7
63.8 39.8
883 301
12
NorplantNorplant-
39.1 43.6
2.2 0.7
41.3 44.3
1279 298
24
Norplant-l Norplant-
34.7 40.1
2.1 2.2
36.8 42.3
870 269
36
NorplantNorplant-
32.4 41.6
3.2 3.0
35.6 44.6
534 101
Type of device 1
1
WI
Age of women 1
24-29 30-34 35-40
60.5** 46.8 45.2
2.0 4.7 4.5
62.5** 51.5 49.7
357 579 177
3
24-29
64.5” 60.4 52.5
1.6 2.4 3.2
66.1*
30-34 35-40
62.8 55.7
380 621 183
24-29 30-34
43.8 38.4
0.4* 2.2
44.2 40.6
516 830
35-40
39.4
3.0
42.4
231
24
24-29 30-34 35-40
39.4 34.2 35.3
1.4 2.6 1.8
40.8 36.8 37.1
360 609 170
36
24-29 30-34 35-40
33.6 36.4 27.1
2.8 3.2 3.7
36.4 39.6 30.8
217 311 107
58.1** 51.5 47.6 44.0
2.7 3.5 5.7 3.7
60.8* 55.0 53.3 41.7
301 346 248 218
62.7 62.3 61.3 53.5
1.5 2.2 2.7 3.1
64.2 64.5 64.0 56.6
332 361 263 228
41.6 43.1 37.6
0.9’ 1.5 1.4
37.5
3.6
42.5 44.6 39.0 41.1
440 469 364 304
12
Body weight at acceptance 1 35-49 50-54 55-59 60-82 3
35-49 50-54 55-59 60-82
12
35-49 50-54 55-59 60-82
Int J Gynecol Obstet33
Study of Norplanp implantsin Shanghai Table VII.
353
(continued)
Menstrual disturbance
Other medical problems
Total
Sample sire WI
35-49 50-54 55-59 60-82
40.6* 38.4 35.5 21.6
1.8 2.0 2.0 3.0
42.4’ 40.4 35.5 30.6
328 354 254 203
35-49 50-54 55-59 60-82
39.6* 36.1 26.4 29.0
3.3 3.5 3.6 1.8
42.9* 40.2 30.0 30.8
182 199 140 114
Month of visit
Variables
24
36
Proportion of users having complaints
*The differences of rates among groups are statistically significant at P < 0.05. **The differences of rates among groups are statistically significant at P< 0.01.
on an average, spotted for 21.5 days, bled for 11.O days, and experienced heavy bleeding for 0.5 days, totalling 33.0 days. In other words, more than one-third of the duration was spent for some bleeding episodes, either spotting, bleeding, or heavy bleeding. This number gradually decreased to an average of 24.5 days during the 12th 90-day period (Table IX). Although Norplants seem to have the propensity of increasing the frequency, amount
and duration of bleeding episodes, the mean value of hemoglobin among the users did not decrease. The mean value was 11.4 mg at acceptance, which increased slightly to 11.7 mg and stayed at about that level thereafter. Neither was there any significant change in body weight and blood pressure, both systolic and diastolic, as indicated in Table X. These findings are the same for the 633 cases who were consistently observed and examined for three years.
Table VIII.
Percentage distribution and mean number of menstrual cycles during 1st to 12th 90-day periods after implantation.
%-Day period
% distribution of menstrual cycles in the period
Mean cycles’
N
0
1
2
3
4
5
6+
Total
1st 2nd 3rd 4th
0.0
3.2 3.4 1.5
11.6 10.6 12.9 10.9
29.0 29.3 29.7 29.4
37.0 33.1 36.1 36.8
16.5 17.0 12.7 14.4
5.2 4.7 4.2 5.8
0.7 1.5 1.0 1.2
100.0 100.0 100.0 100.0
2.77 2.71 2.58 2.74
541 528 526 521
5th 6th 7th 8th
3.1 1.8 3.1 1.6
12.1 11.5 12.9 10.2
28.5 26.2 28.5 25.1
36.4 38.2 38.5 41.8
15.6 16.5 12.2 15.5
3.1 4.6 3.8 4.0
1.2 1.2 0.9 1.8
100.0 loo.0 loo.0 100.0
2.63 2.75 2.59 2.76
519 4% 449 374
9th 10th 11th 12th
1.5 1.3 1.4 0.4
8.8 6.0 6.0 5.7
25.4 24.3 30.9 26.8
40.0 42.5 38.0 47.2
17.0 20.3 19.4 12.8
5.8 4.3 3.9 6.0
1.5 1.3 0.4 1.1
100.0 loo.0 100.0 100.0
2.86 2.93 2.81 2.89
330 301 284 265
‘Average number of menstrual cycles per person in the 90-day period. bThe number of women on which the percentage is based. Clinicaland ClinicalResearch
354
Duet al.
Table IX.
90-day period
Days of spotting, bleeding, and heavy bleeding per
person
during 1st to 12th 90-day periods after Norplant implantation.
Average number of days having Spotting
Bleeding
Heavy bleeding
Total
1st 2nd 3rd 4th
21.5 18.4 15.0 14.2
11.0 12.2 Il.1 12.5
0.5 0.8 0.9 0.9
33.0 31.4 27.0 27.6
541 528 526 521
5th 6th 7th 8th
13.8 13.8 12.8 12.6
11.5 12.4 11.3 12.8
1.0 1.1 0.9 1.1
26.3 21.3 25.0 26.5
519 496 449 374
9th 10th 11th 12th
11.9 11.6 11.6 11.3
13.2 12.3 11.6 12.3
1.1 1.0 0.9 0.9
26.2 24.9 24.4 24.5
330 301 284 265
“Number of women on which the average number of days was based.
users. The implant was removed from one of these cases. In another case, biopsy result indicated lipoma and the implant was left in place for continued use. At la-month follow-up, six women complained about breast engorgement. At 24month follow-up, only three women complained of breast engorgement, but only
Although not shown in the tables, a breast mass of about 1 cm in size was detected in a Norplant-l user at the 6-month follow-up examination. During the la-month examination, three cases with breast masses of 1-2 cm in diameter were detected, including the 1 previously detected: 2 of these cases were from Norplant-l and 1 from Norplant-
Table X. Changes in hemoglobin concentration, bodyweight, and blood pressures at acceptance and 1, 2, and 3 years after implantation. Note: Figures in the parentheses are numbers of women observed on which the averages were based.
Acceptance
Intervals of Check-up Visits 1 Year
Cases observed at each visit Hemoglobin (g) Body weight (kg) Blood pressures (mm) Systolic Diastolic
3 Years
11.4 (1657) 53.7 (1662)
11.7(1534) 54.2 (1577)
11.7 (1095) 54.5 (1139)
11.8 (569) 54.8 (635)
107.7 (1662) 69.5 (1662)
104.0 (1577) 66.2 (1577)
105.2(1139) 67.2 (1139)
108.6 (635) 70.1 (635)
11.7 (625) 53.8 (633)
11.6(630) 54.8 (633)
11.8 (568) 54.8 (633)
103.0 (633) 65.5 (633)
102.7 (663) 64.8 (633)
108.5 (663) 70.1 (633)
Cases consistently observed for 3 years Hemoglobin (g) 11.4 (628) Body weight (kg) 53.2 (633) Blood pressures (mm) Systolic 109.3 (663) Diastolic 71.2 (633)
Int J Gynecol Obstet 33
2 years
Study of NorplanP implants in Shanghai
one of them was serious enough to warrant the removal of the device. Ovarian cysts of 4-5 cm diameter were detected in two women at 6-month follow-up, one of whom was diagnosed as cancer of the ovary metastasized from the intestine. At 12month follow-up, pelvic examination indicated that approximately 2.7% of the women were found to show some “abnormality,” including 17 cases of small ovarian cysts, confirmed with ultrasound examination. In one of them, laparoscopic examination was performed and follicule cyst was diagnosed. The fluid was drawn from the cyst and the ovary returned to normal size. At 24-month followup, ovarian cysts disappeared from 14 of the 17 women previously so diagnosed. The implants were removed from two of them, one at 37 and another at 38 months. There were ten women whose uteri had enlarged somewhat, of which seven demonstrated pain at palpation of annexae. They were treated with anti-inflammatory drugs. For three of them, the size of uteri remained somewhat enlarged and because they also complained of menorrhagia, the device was removed. Subsequently, seven removals were made during 13 -24 months, three removals during 25-36 months, and one removal during 37-50 months, all for similar reasons. Discussion This study confirmed earlier reports that Norplant implants are highly effective with high continuation rates [1,2,6,7]. The cumulative pregnancy rate of 0.3 per 100 women at 36 months compares nearly equally with the rate for sterilization. The rate could be lowered by taking appropriate precaution during the first month of implantation, either by minimizing the chance of luteal pregnancy, or by combined use with another contraceptive method. Assuming a constant monthly termination rate, 77% continuation at 36 months implies a monthly termination rate of 0.0073 (0.73%), or the “life expectancy” of 137.7
355
months (or 11.5 years). At the end of five years when the devices are to be replaced, there will still be nearly two-thirds (64.5%) of the original devices still being retained. The greatest disadvantage of Norplant implants are their propensity to cause menstrual disturbance, which has been the major cause of device loss. Sivin, based on their multinational study of Norplants, reported that during the first year of Norplant use, the women, on average, were “spotting” for a total of 92.3 days, and “bleeding” for a total of 54.3 days, totalling 146.6 days out of 365. Women were either “spotting” or “bleeding” for more than 40% (40.2%) of the duration of Norplant use [8]. Under the current study, women were found to be “spotting” or “bleeding” for a total of 119 days out of 360, or 33.1% of the first 360-day period of Norplant use. The number of days of bleeding episodes decreased to 105.1 or 29.2% of the second 360-day period, and to 100 or 27.8% during the third 360-day period. Since couples generally refrain from sexual intercourse during wives’ menstrual bleeding period in many cultures of the developing world, including China, the prolonged period of bleeding episodes with Norplant use may eventually adversely affect their acceptability. It will be a deterrent to popular acceptance of Norplants especially in the Moslem countries. Although medical removals for reasons other than menstrual distrubance were relatively infrequent, the 13 cases of liver and gallbladder diseases reported from 1361 Norplant-l users, and the eight cases of thrombocytopenia reported from 301 Norplant- users are causes for some concern. The prevalence of hepatitis and hepatoma is high among the Chinese population and, therefore, the longterm implication of Norplant use, especially through a mass campaign approach as frequently done in China, deserves caution. Further investigation is needed to determine if the use of Norplant- was in any way related to the thrombocytopenia, which is a serious complication. The distribution and use of Clinical and Clinical Research
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Duet al.
Norplant- have been suspended by the Population Council because of this reported complication. It is interesting to note that women of heavier weight had somewhat lower rates of complaints of menstrual disturbances. A plausible explanation might be that steroid hormone is stored in fatty tissue and heavier women, with more fatty tissues, store more and metabolize more slowly the hormone released by the implants than women of lighter build. However, it must be pointed out that heavier women had somewhat lower continuation rates at 24 and 26 months than lighter women (Table II). In spite of the prolongation of bleeding, and the increase in the amount of bleeding during Norplants use, the hemoglobin value among the users did not decrease. It is also reassuring that the blood pressure of the Norplant users, both systolic and diastolic, did not increase. The possibility of the occurrence of luteal phase pregnancy following the placement of implants raises an issue of the timing of implantation. The feasibility of placing the implants shortly after the onset of menstruation should be explored. Or, if the implants are less effective during the first month, then combined use with another contraceptive method should be considered. Since change of menstrual pattern is the most frequent and significant complaint causing device loss, a more careful analysis of the women’s menstrual records is needed. Future analysis of the data should use seven parameters: cycle regularity, cycle length, menstrual flow duration, amount of flow, dysmennorhea, amennorhea, and intermenstrual bleeding and spotting. The changes, if any, should be compared with the base-line information, for example, the patterns observed during the three cycles before placement of the implants [4]. Methods of prior contraceptive use must be controlled in such analysis [3]. The subjects included in the present study were highly selected. All of them were working women in a large metropolitan area who Int J Gynecol Obstet 33
were in good general health. The results of this study therefore may not be generalized. Introduction of a new contraceptive method into an area or a country needs careful study, not only of its acceptability, use-effectiveness, and under clinical conditions, but also of its impact on the existing contraceptive practice and its eventual net demographic impact. For example, if a new method is able to motivate those hitherto considered “hardto-reach” to accept and use contraceptives, it will have significant positive impact. On the contrary, if the new method introduced simply substitutes the existing methods being practiced, then it will have little or no net fertility impact. The net impact may well be negative if, for example, couples who otherwise would have elected to be sterilized, decide to accept the implants. The issue related to substitution is especially important in China where contraceptive prevalence is extremely high (approx. 80%), especially the use of highly effective and longlasting contraceptive methods, such as IUD and sterilization. Whether the introduction of Norplant implants will improve further the overall use-effectiveness of contraceptives in China, thereby reducing the need for abortion, will be another research question of significant practical implication. References Affandi B, Santos SSI: Five-Year Experience with Norplant. Contraception 36: 417, 1987. Alvarez-Sanchez F et al: The clinical performance of Norplant implants over time: a comparison of two cohorts. Stud Fam Plann 19: 118, 1988. Bhiwandiwala PP, Mumford SD, Feldblum PJ: Menstrual pattern changes following laparoscopic sterilization with different occlusion techniques: a review of 10,004 cases. Am J Obstet Gynecol145: 684, 1983. DeStefano F, Brach V, Faundes A: Long-term risk of menstrual disturbance after tubal sterilization. Am J Obstet Gynecol152: 835, 1985. The Population Council: Investigators Manual for Norplant Subderman Implants, Revised edition, August 1983. Segal SJ: A new delivery system for contraceptive steroids. Am J Obstet Gynecol157: 1090, 1987.
Stidy of NorplantRimplantsin Shanghai 7 8
Sivin 1: Norplant contraceptive implants. Out Look 3: January 1984. Sivin I: International experience with Norplant and Norplant-2 contraceptives. Stud Fam Plann 19: 81, 1988.
357
Address for reprints: L.P. Chow Johns Hopkins School of Hygiene and Public He&h 615 North Wolfe Street Baltimore, MD 212QS.USA
Clinicaland ClinicalResearch
Int. .I. Gynecol. Obstet., 1990, 33: 345-357 International Federation of Gynecology and Obstetrics
Study of NorplantR implants in Shanghai: three-year experience M.K. Dua, H.M. Zheng”, H.C. Chenb and L.P. Chow’ aGynecology and Obstetrics Hospital, Shanghai Medical University, Shanghai (China), bDepartment of Community Health, Emory Univemity School of Medicine, Atlanta, Georgia and =Department of Population Dynamics, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland (USA) (Received June lZth, 1989) (Revised and accepted September 11th, 1989)
Abstract A clinical follow-up study conducted in Shanghai, China conJitmed earlier reports that the NorplantR implants, NorplantR-I and NorplantR-2, are both highly effective with high continuation rates. The implants, however, tend to cause menstrual disturbance, spotting and bleeding. The mean hemoglobin value, however, did not change and the blood pressure remained stable. The report of 8 cases of thrombocytopenia among 301 NorplantR-2 users is a source of concern. Keywords: Norplant R; Contraceptive effectiveness; Contraceptive implants; Follow-up study. Introduction The development of contraceptive implants and their approval for use in 1983 in Finland appeares to be a milestone event toward *NorplantR is the Population Council’s Trademark for contraceptive subdermal implants; Norplant’and Norplant”-2. Throughout this article, Norplant, Norplant- and Norplantall refer to Norplant”, NorplanP-1 and NorplanP-2, respectively.
omo-7292/90/%03
so
@ 1990 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
developing an “ideal” contraceptive. The implants seems to have the advantage of high efficacy of IUD and orals, yet do not have the disadvantage of irreversibility of sterilization. By January 1988, the contraceptive implants, NorplantR-1 * and NorplantR-2* had been approved for study in some 30 countries, and for general distribution in some 11 countries. More than 200,000 women in the world are estimated to have been using these implants [8]. NorplantR* implants, Norplant-l and Norplant-2, were introduced into China in 1984 by the Population Council for trial use. A multi-hospital clinical trial project was organized to study the acceptability, safety, and effectiveness of these devices. The Family Planning Department of the Shanghai Obstetrics and Gynecology Hospital participated in the study project and this article reports the preliminary results of the first three years of their use. Materials and methods The Norplant implants, Norplant-l and Norplant-2, used in this study were manufactured by Leiras Pharmaceuticals in Finland and provided for the study by the Population Council of New York. Clinical and Clinical Research
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Du el al.
The recruitment of study subjects was started in October 1984 and by March 1988 a total of 1662 women were registered for the study: 1361 for Norplant-l and 301 for Norplant-2 implantation. Norplant-l comprises six 3.4 cm silastic capsules, each with an outside diameter of 2.4 mm, containing 36 mg of levonorgestrel, totalling 216 mg of levonorgestrel in six capsules. Norplant- is a covered rod system with two silastic rods, each 4.4 cm in length, 2.4 mm in diameter, and containing 70. mg of levonorgestrel, totalling 140 mg in two rods. The devices are designed to continuously release approximately 30 pg of levonorgestrel every day, a dosage similar to a minipill. Recruitment of the study subjects was through a week of advertisement in local newspapers. Women who became aware of this new contraceptive device came to the hospital to inquire about it. Those who volunteered to accept the devices, and who were determined by the clinical investigators in the hospital to be eligible for participating in the study, were enlisted and given the implants. The criteria of eligibility to participate in the study included: women must be under 40 years old; currently married and living with their husbands; have had at least one living child; are not currently pregnant or breastfeeding; voluntarily choose these contraceptive implants for fertility control; and indicated willingness to comply with the requirement for periodic follow-up examinations. During the initial clinic visit, medical history was taken and thorough physical and gynecological examinations were conducted by specialists of obstetrics and gynecology in the hospital. Women with any history, sign, or symptom of cardiovascular diseases, jaundice, diabetes, pelvic inflammatory diseases, depression or other psychological symptoms, severe varicose veins, periodic and rather severe headache, and ectopic pregnancy, were excluded from participation. If a woman was accepted for the study, a Papanicolou smear was taken, her breasts were examined manIn1 J Gynecol
Obstet 33
ually and a blood specimen was drawn for measurement of hemoglobin value. Implanting Norplant-l and Norplant- was not systematic: Norplant-l was first introduced for use followed by the introduction of Norplant-2. After reports of some side effects, the use of Norplant- was suspended. There are fewer cases of Norplant- users in this study. The placement of the implants involved minor outpatient surgery with local anesthesia, as described elsewhere [5]. The devices were usually implanted within the first week following the onset of menstrual cycle. After receiving the implants, women were requested to return for periodic follow-up examinations at 1, 3, 6, and 12 months after implantation then annually thereafter, for a total duration of 5-7 years. During each of these follow-up visits, a thorough physical examination was undertaken. Gynecologial examination was conducted once every 6 months during the first year, then annually. A blood specimen for measurement of hemoglobin was taken annually. A Daily Menstrual Record Card was given to each participant for recording, on a daily basis, the onset, duration and amount of each menstrual episode. Women were also told to record any change or “abnormality” in menstural pattern, such as irregularity, spotting, bleeding, heavy bleeding, or amenorrhea; “spotting” meaning vaginal bleeding in quantity small enough not to require the use of menstrual pads; “bleeding” meaning in quantity large enough, such as regular menstural flow, to require the use of pads; and “heavy bleeding” meaning vaginal bleeding in quantity in excess of women’s “regular” menstrual flows. If the onset of menstruation was delayed for more than 15 days, a pregnancy test was conducted, followed by an ultrasound examination, if necessary, to either confirm or deny pregnancy. If an implant had to be removed for medical, personal, or any other reason, local anesthesia was administered and the device pulled
Study of NorplanP implants in Shanghai
out with a small incision of the skin. The women were asked to return to the clinic for a final follow-up examination 3-12 months after the removal. The study is continuing, but observation was “cut-off” on March 30, 1988 for a preliminary analysis. The data were coded and a set of complete data was brought by the senior author to the Johns Hopkins University School of Hygiene and Public Health and the Centers for Disease Control for analysis. The life table technique was used in most of the data analysis. Results Characteristics of the study subjects More than half (53.0%) of the study subjects were 30-34 years old when the devices were implanted. Most (97.0%) of these women had only one living child. The implants were placed mostly (81 .O%) within 4 -5 days following the onset of menstruation. Prior to accepting the implants, 39.6% of the women used IUDs, 20.3% of their husbands used condoms, and 5.1% of them took oral contraceptives for fertility control. Approximately one-third (3 1.7%) of these women were not using any contraceptive method. There were no significant differences in these characteristics between -the acceptors of Norplant-l and Norplant-2. The mean duration of observation was 25.6 months for the users of Norplant-1, 26.9 months for Norplant-2, and 26.0 months for both combined (Table I). Continuation and effectiveness of the implan Is The continuation rates of Norplant use among the study subjects were high: 99.5% at 3 months; 98.8% at 6 months; 96.5% at 12 months; and 86.2% at 24 months. At 36 months, 77.2% of the acceptors were still using the implants. There were no differences in continuation rates between Norplant-l and Norplant-2, except at 36 months the rate of the former
347
(78.2%) appears to be somewhat better than the rate of the latter (73.6%). The difference, however, is not significant. Nor was there any significant difference in continuation rates by age groups or body weight of women except that the 24 month rate for women of heaviest weight (56-82 kg) was significantly lower than those of lightest weight (35-49 kg): 84.3% for the former compared to 90.0% for the latter group of women (Table II). The termination rates, which are the complements of continuation rates, therefore were low: 0.5%, 1.3070, 3.2%, 12.4%, and 22.8% at 3, 6, 12, 24, and 36 months, respectively. The rather sharp increase in the termination rates from 3.2% at 12 months to 12.4% at 24 months, and again to 22.8% at 36 months, deserves some attention (Table III). Table III also shows that medical reasons, especially menstrual disturbance, was the predominant reason for the implant loss. There were five pregnancies among the study subjects, three of which were confirmed within one month after the placement of the devices. These might have been luteal phase pregnancies, or else the implants might have been less effective during the first month of use. One pregnancy was detected during the 2nd month of use and another during the 13th month of use. The cumulative gross pregnancy rates, including the three presumably luteal phase pregnancies, were 0.2% at 12 months and 0.3% at 24 and 36 months, indicating high efficacy of Norplants. All five pregnancies occurred among the Norplant-l users. There was a total of 262 removals of which 152, or 53.2%, were for menstrual disturbances, including prolonged or heavy bleeding, spotting, irregular cycles, and amenorrhea. Eighty-three [83] removals for “other medical reasons” included headache, myoma of uterus or annexitis, diseases of the liver and gallbladder, weight gain or hypertension, thrombocytopenia and others (Table IV). The occurrence of eight cases of thrombocytopenia, decreased platelet count, all of Clinical and Clinical Research
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Duet al.
Table 1. Percentage distribution of selected variables by types of Norplant implanted. Selected variables
Norplant- 1
Norplant-
Total
1. Age of acceptors 20-29 30-34 35-40
32.6 53.2 14.2
32.2 52.2 15.6
32.6 53.0 14.4
2. Number of live births One Two
97.1 2.9
96.3 3.7
97.0 3.0
3. Contraceptive use before acceptance IUD Condom Oral pill Others Not using any
39.0 19.9 5.4 3.5 32.2
42.5 22.6 3.7 1.7 29.6
39.6 20.3 5.1 3.3 31.7
4. Year of acceptance 1984 1985 1986 1987 1988
6.3 49.6 22.2 21.3 0.6
3.3 32.9 63.8 0.0 0.0
5.8 46.5 29.7 17.5 0.5
5. Days between onset of LMP and implant o-3 4-5 6-7 8-11 Unknown
9.4 81.2 7.4 1.6 0.4
13.6 80.1 6.0 0.3 0.0
10.2 81.0 7.1 1.4 0.3
6. Lengths (months) of Norplant use observed O-11 12-23 24-35 36-41
7.5 30.6 26.6 35.3
2.0 11.9 57.8 28.3
6.5 27.2 32.3 34.0
100.0 (1361)
100.0 (301)
(1662)
7. Total (Vo) (Number of acceptors)
them among 301 Norplantusers, deserves serious attention. No such case has been detected among the total of 1361 users of Norplant-1, which contains the same hormone but in a higher total dose (216 mg vs. 140 mg) and which has a different manufacturing process. Int J Gynecol Obstet 33
100.0
Table V shows the platelet counts of these cases during the use of implants, at their removals, and after the implants were removed. Unfortunately, no platelet count was taken at the time of implantation. When the platelet counts were found to be low for these eight cases, the Norplant-
Study of NorplanP implantsin Shanghai
349
Life table cumulative continuation rates and their standard errors or Norplant use at 3.6, 12.24 and 36 months of use by Table II. type of Norplant, age of women and body weight (rates per 100 women). Variables
Months after acceptance 3
6
12
24
36
Total
99.5 (0.2)’
98.8 (0.3)
96.5 (0.4)
86.2 (0.9)
77.2 (1.3)
Type of Norplant Norplant-l Norplant-
99.4 (0.2) 99.7 (0.3)
98.5 (0.3) 99.3 (0.5)
96.4 (0.5) 98.3 (0.7)
88.0(1.0) 86.7 (2.0)
78.2 (1.5) 73.6 (3.3)
Age of women 24-29 30-31 32-40
99.6 (0.3) 99.3 (0.3) 99.6 (0.4)
99.1(0.4) 98.6 (0.4) 97.9 (0.9)
97.7 (0.6) 96.3 (0.6) 96.2 (1.2)
88.4 (1.6) 87.3 (1.2) 87.0 (2.3)
78.4 (2.3) 75.3 (1.9) 80.2(3.1)
Body weight (kg) 35-49 50-55 56-82
99.6 (0.3) 99.4 (0.3) 99.5 (0.3)
99.1 (0.4) 98.9 (0.4) 98.1 (0.6)
97.1 (0.8) 98.2 (0.5) 94.9 (0.9)
90.0 (1.5) 88.8 (1.4) 84.3 (1.7)
79.3 (2.5) 78.2 (2.1) 74.3 (2.4)
‘Standard error of the rate is given in parentheses.
device was promptly removed. Post-removal follow-up examination indicated generally increased platelet counts to the 100,000120,000 mm3 range, except in two cases, one of which was rather severe with general petechiae and had to be hospitalized for treat-
ment. Her platelet count increased from 12,000/mm3 to 50,000/mm3 in about three months after removal; unfortunately she contracted Hepatitia-A infection and was hospitalked. At her last follow-up examination, her platelet count was still low: 26,000/mm3.
Life table cumulative gross termination rates and their standard errors of Norplant use at 3.6, 12, 24 and 36 months of Table III. use by pregnancy and removal for medical, non-medical, and personal reasons (rates per 100 women). Reasons
Months after acceptance 3
6
12
24
36
Total
0.5 (0.2)
1.3 (0.3)
3.2 (0.4)
12.4 (0.9)
22.8 (1.3)
Pregnancyb
0.2 (0.1)
0.2 (0.1)
0.2 (0.1)
0.3 (0.1)
0.3 (0.1)
Medical reasons Menstrual Non-menstrual
0.0 (0.0) 0.3 (0.2)
0.4 (0.2) 0.6 (0.2)
l.l(O.3) 1.6(0.3)
7.4 (0.7) 4.2 (0.5)
14.3 (1.1) 7.6 (0.9)
Personal reasons
0.0 (0.0)
0.1 (0.1)
0.3 (0.1)
1.0 (0.3)
2.3 (0.5)
‘Standard error of the rate is given in parentheses. bAll five pregnancies occurred among Norplant-l users. Three of these pregnancies occurred within one month after implantation, which presumably were luteal phase pregnancies. One pregnancy occurred during the 2nd and another during the 12th month of use. Clinicaland ClinicalResearch
350
Du et al.
Table IV.
Detailed classification
of reasons
for removing
Reasons for removal
Total number
Norplant.
Number
of removals
Menstrual Disturbances Prolonged or heavy bleeding Too frequent or irregular cycles Amenorrhea
cases
Norplant-l
Norplant-
Total (%)
202
60
262(10&O)
110 15 22 8
42 33 4 2
152 (53.2) 108 26 IO
5
3
Others Other medical reasons Headache
of removal
8
66 13
83 (38.3) 14
Hepatomegaly, hepatitis Myoma of uterus or annexity Thrombocytopenia Weight gain or hypertension
10 10 0 6
I0
Inflammation Others
3 24
Personal
of gallbladder
reasons
Planned pregnancy Divorced, widowed,
or others
10 8 6 3 32
21
I
22 (5.7)
1 20
0
I 21
5
0
Pregnant
1
Table V. Blood platelet counts of eight cases of thymobocytopenia count was made at the time of implantation. Implantation
During use
30
-
60,000 (?)
48b
(2/9/85) -
82
(3/18/85) -
Case No.
(7/l/85) 103 165’
(8/22/85) (3/6/86)
170
during Norplant
-
75,000 (3/3/86)
-
86,000 (g/27/87) 91,000 (5/27/86) -
78,000 (619187) 57,000 (3/87) -
64,000 (4/14/87)
94,000 (10/7/87)
(3/8/86) 244 299“
(415186) (5/2/86)
bPetechiae in extremities which disappared after removal of Norplant. ‘Petechiae on the whole body surface. Contracted Hepatitis-A infection dDiagnosed as chronic nephritis. The data of the event is given in parentheses
Int .I Gynecol Obstet 33
(mm/dd/;y).
5 (2.8)
use, at removal,
and after removal.
No platelet
Removal
After removal
69,000 (1 l/4/86)
94,000 (2187)
106,000 (8/88)
56,000 (5123185) 75,000 (l/12/87) 52,000 (10/23/87) 12,000 (4/28/87)
89,000 (8185) 100,000 (8/12/88)
-
72,000 (3/31/87) 96,000 (l/26/88)
58,000 (l/10/88) 26,000 (8/88) 80,000 (6/l/87) 120,000 (7110188)
36,000 (2/5/88)
48,000 (7/10/88)
and was hospitalized
in January
1988
100,000 (8/20/88) 102,000 (8/11/88) --
351
Study of Norplot@ implants in Shanghai
were consistently observed for 36 months (Table VI). Table VII shows the proportion of users complaining of side effects by such variables as type of Norplants, age of women, and body weight of the users. There was no significant difference in the proportion of complaints between the two types of implants. Younger women appeared to have complained more but, except in several categories, the differences were not significant. A total of 541 women kept adequate Daily Menstrual Records, which were analyzed. The observation was divided into twelve 90day periods; first period means the first 90 days after placement of the implants, the second period is from the 91st to 180th day after implementation, and so forth. Table VIII indicates that most women had had two or three menstrual cycles during each of the go-day periods. The average number of cycles experienced ranged between 2.58 during the 3rd period to 2.93 during the 10th period. Amenorrhea seemed to be relatively infrequent; the highest rate was 3.4% amenorrhea during the 3rd period (Table VIII). During the first go-day period, the women,
Another case has been diagnosed as having chronic nephritis, and her platelet count increased only slightly from 36,000 before to 48,000 after removal of Norplant-2. There were 13 removals because of diseases of the liver and gall bladder, all from among the Norplant- 1 users. Side effects
The Norplant users frequently complained about untoward effects. At the first month’s follow-up visit, 54.7% of the users complained of some side effects. This proportion increased to 62.8% at the third monthly visit and then started to decline rather significantly to 37.1% at the 36-month visit. Menstrual disturbance was the predominant type of complaint. The proportion complaining of menstrual disturbance increased from 50.9% at the first month’s visit to 60.5% at the 3-month visit, and then decreased to 33.9% at the 36-month visit. Less frequent complaints of side effects by longer-term users is partly due to selection. This pattern of complaint of side effects was essentially the same for the 629 cases who
Table VI. Percentage of Norplant users complained of side effects at 1-, 3-, 6, 12-, 24- and 36-month follow-up visits for two groups of users.
Months of follow-up visits
Percentage of users having complaints
Sample size (N)
Menstrual disturbance
Other medical problems
Total
50.9 60.5 54.1 40.3 36.0 33.9
3.8 2.3 1.3 1.7 2.1 3.2
54.1 62.8 55.4 42.0 38.1 37.1
1,113 1,184 1,631 1,577 1,139 635
2.2 1.3 1.1 1.0 0.6 3.0
55.9 59.6 57.2 41.9 34.9 36.4
629 629 629 629 629 629
Cases observed at each visit
1 3 6 12 24 36
Cases consistently observed for 3 years I 53.1 3 58.3 6 56.1 12 40.9 24 34.3 36 33.4
Clinical and Clinical Research
352
Du et al.
Table VII. Proportion of Norplant users who complained devices and age and body weight of women. Month of visit
Variables
Proportion
of side effects at l-, 3-, 12-, 24- and 36-month
follow-up
of users having complaints
visit, by type of
Sample size
Menstrual disturbance
Other medical problems
Total
Norplant-
52.5
Norplant-
46.8
3.7 4.0
56.2 50.8
812 301
3
Norplant-l Norplant-
61.6 57.1
2.2 2.7
63.8 39.8
883 301
12
NorplantNorplant-
39.1 43.6
2.2 0.7
41.3 44.3
1279 298
24
Norplant-l Norplant-
34.7 40.1
2.1 2.2
36.8 42.3
870 269
36
NorplantNorplant-
32.4 41.6
3.2 3.0
35.6 44.6
534 101
Type of device 1
1
WI
Age of women 1
24-29 30-34 35-40
60.5** 46.8 45.2
2.0 4.7 4.5
62.5** 51.5 49.7
357 579 177
3
24-29
64.5” 60.4 52.5
1.6 2.4 3.2
66.1*
30-34 35-40
62.8 55.7
380 621 183
24-29 30-34
43.8 38.4
0.4* 2.2
44.2 40.6
516 830
35-40
39.4
3.0
42.4
231
24
24-29 30-34 35-40
39.4 34.2 35.3
1.4 2.6 1.8
40.8 36.8 37.1
360 609 170
36
24-29 30-34 35-40
33.6 36.4 27.1
2.8 3.2 3.7
36.4 39.6 30.8
217 311 107
58.1** 51.5 47.6 44.0
2.7 3.5 5.7 3.7
60.8* 55.0 53.3 41.7
301 346 248 218
62.7 62.3 61.3 53.5
1.5 2.2 2.7 3.1
64.2 64.5 64.0 56.6
332 361 263 228
41.6 43.1 37.6
0.9’ 1.5 1.4
37.5
3.6
42.5 44.6 39.0 41.1
440 469 364 304
12
Body weight at acceptance 1 35-49 50-54 55-59 60-82 3
35-49 50-54 55-59 60-82
12
35-49 50-54 55-59 60-82
Int J Gynecol Obstet33
Study of Norplanp implantsin Shanghai Table VII.
353
(continued)
Menstrual disturbance
Other medical problems
Total
Sample sire WI
35-49 50-54 55-59 60-82
40.6* 38.4 35.5 21.6
1.8 2.0 2.0 3.0
42.4’ 40.4 35.5 30.6
328 354 254 203
35-49 50-54 55-59 60-82
39.6* 36.1 26.4 29.0
3.3 3.5 3.6 1.8
42.9* 40.2 30.0 30.8
182 199 140 114
Month of visit
Variables
24
36
Proportion of users having complaints
*The differences of rates among groups are statistically significant at P < 0.05. **The differences of rates among groups are statistically significant at P< 0.01.
on an average, spotted for 21.5 days, bled for 11.O days, and experienced heavy bleeding for 0.5 days, totalling 33.0 days. In other words, more than one-third of the duration was spent for some bleeding episodes, either spotting, bleeding, or heavy bleeding. This number gradually decreased to an average of 24.5 days during the 12th 90-day period (Table IX). Although Norplants seem to have the propensity of increasing the frequency, amount
and duration of bleeding episodes, the mean value of hemoglobin among the users did not decrease. The mean value was 11.4 mg at acceptance, which increased slightly to 11.7 mg and stayed at about that level thereafter. Neither was there any significant change in body weight and blood pressure, both systolic and diastolic, as indicated in Table X. These findings are the same for the 633 cases who were consistently observed and examined for three years.
Table VIII.
Percentage distribution and mean number of menstrual cycles during 1st to 12th 90-day periods after implantation.
%-Day period
% distribution of menstrual cycles in the period
Mean cycles’
N
0
1
2
3
4
5
6+
Total
1st 2nd 3rd 4th
0.0
3.2 3.4 1.5
11.6 10.6 12.9 10.9
29.0 29.3 29.7 29.4
37.0 33.1 36.1 36.8
16.5 17.0 12.7 14.4
5.2 4.7 4.2 5.8
0.7 1.5 1.0 1.2
100.0 100.0 100.0 100.0
2.77 2.71 2.58 2.74
541 528 526 521
5th 6th 7th 8th
3.1 1.8 3.1 1.6
12.1 11.5 12.9 10.2
28.5 26.2 28.5 25.1
36.4 38.2 38.5 41.8
15.6 16.5 12.2 15.5
3.1 4.6 3.8 4.0
1.2 1.2 0.9 1.8
100.0 loo.0 loo.0 100.0
2.63 2.75 2.59 2.76
519 4% 449 374
9th 10th 11th 12th
1.5 1.3 1.4 0.4
8.8 6.0 6.0 5.7
25.4 24.3 30.9 26.8
40.0 42.5 38.0 47.2
17.0 20.3 19.4 12.8
5.8 4.3 3.9 6.0
1.5 1.3 0.4 1.1
100.0 loo.0 100.0 100.0
2.86 2.93 2.81 2.89
330 301 284 265
‘Average number of menstrual cycles per person in the 90-day period. bThe number of women on which the percentage is based. Clinicaland ClinicalResearch
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Duet al.
Table IX.
90-day period
Days of spotting, bleeding, and heavy bleeding per
person
during 1st to 12th 90-day periods after Norplant implantation.
Average number of days having Spotting
Bleeding
Heavy bleeding
Total
1st 2nd 3rd 4th
21.5 18.4 15.0 14.2
11.0 12.2 Il.1 12.5
0.5 0.8 0.9 0.9
33.0 31.4 27.0 27.6
541 528 526 521
5th 6th 7th 8th
13.8 13.8 12.8 12.6
11.5 12.4 11.3 12.8
1.0 1.1 0.9 1.1
26.3 21.3 25.0 26.5
519 496 449 374
9th 10th 11th 12th
11.9 11.6 11.6 11.3
13.2 12.3 11.6 12.3
1.1 1.0 0.9 0.9
26.2 24.9 24.4 24.5
330 301 284 265
“Number of women on which the average number of days was based.
users. The implant was removed from one of these cases. In another case, biopsy result indicated lipoma and the implant was left in place for continued use. At la-month follow-up, six women complained about breast engorgement. At 24month follow-up, only three women complained of breast engorgement, but only
Although not shown in the tables, a breast mass of about 1 cm in size was detected in a Norplant-l user at the 6-month follow-up examination. During the la-month examination, three cases with breast masses of 1-2 cm in diameter were detected, including the 1 previously detected: 2 of these cases were from Norplant-l and 1 from Norplant-
Table X. Changes in hemoglobin concentration, bodyweight, and blood pressures at acceptance and 1, 2, and 3 years after implantation. Note: Figures in the parentheses are numbers of women observed on which the averages were based.
Acceptance
Intervals of Check-up Visits 1 Year
Cases observed at each visit Hemoglobin (g) Body weight (kg) Blood pressures (mm) Systolic Diastolic
3 Years
11.4 (1657) 53.7 (1662)
11.7(1534) 54.2 (1577)
11.7 (1095) 54.5 (1139)
11.8 (569) 54.8 (635)
107.7 (1662) 69.5 (1662)
104.0 (1577) 66.2 (1577)
105.2(1139) 67.2 (1139)
108.6 (635) 70.1 (635)
11.7 (625) 53.8 (633)
11.6(630) 54.8 (633)
11.8 (568) 54.8 (633)
103.0 (633) 65.5 (633)
102.7 (663) 64.8 (633)
108.5 (663) 70.1 (633)
Cases consistently observed for 3 years Hemoglobin (g) 11.4 (628) Body weight (kg) 53.2 (633) Blood pressures (mm) Systolic 109.3 (663) Diastolic 71.2 (633)
Int J Gynecol Obstet 33
2 years
Study of NorplanP implants in Shanghai
one of them was serious enough to warrant the removal of the device. Ovarian cysts of 4-5 cm diameter were detected in two women at 6-month follow-up, one of whom was diagnosed as cancer of the ovary metastasized from the intestine. At 12month follow-up, pelvic examination indicated that approximately 2.7% of the women were found to show some “abnormality,” including 17 cases of small ovarian cysts, confirmed with ultrasound examination. In one of them, laparoscopic examination was performed and follicule cyst was diagnosed. The fluid was drawn from the cyst and the ovary returned to normal size. At 24-month followup, ovarian cysts disappeared from 14 of the 17 women previously so diagnosed. The implants were removed from two of them, one at 37 and another at 38 months. There were ten women whose uteri had enlarged somewhat, of which seven demonstrated pain at palpation of annexae. They were treated with anti-inflammatory drugs. For three of them, the size of uteri remained somewhat enlarged and because they also complained of menorrhagia, the device was removed. Subsequently, seven removals were made during 13 -24 months, three removals during 25-36 months, and one removal during 37-50 months, all for similar reasons. Discussion This study confirmed earlier reports that Norplant implants are highly effective with high continuation rates [1,2,6,7]. The cumulative pregnancy rate of 0.3 per 100 women at 36 months compares nearly equally with the rate for sterilization. The rate could be lowered by taking appropriate precaution during the first month of implantation, either by minimizing the chance of luteal pregnancy, or by combined use with another contraceptive method. Assuming a constant monthly termination rate, 77% continuation at 36 months implies a monthly termination rate of 0.0073 (0.73%), or the “life expectancy” of 137.7
355
months (or 11.5 years). At the end of five years when the devices are to be replaced, there will still be nearly two-thirds (64.5%) of the original devices still being retained. The greatest disadvantage of Norplant implants are their propensity to cause menstrual disturbance, which has been the major cause of device loss. Sivin, based on their multinational study of Norplants, reported that during the first year of Norplant use, the women, on average, were “spotting” for a total of 92.3 days, and “bleeding” for a total of 54.3 days, totalling 146.6 days out of 365. Women were either “spotting” or “bleeding” for more than 40% (40.2%) of the duration of Norplant use [8]. Under the current study, women were found to be “spotting” or “bleeding” for a total of 119 days out of 360, or 33.1% of the first 360-day period of Norplant use. The number of days of bleeding episodes decreased to 105.1 or 29.2% of the second 360-day period, and to 100 or 27.8% during the third 360-day period. Since couples generally refrain from sexual intercourse during wives’ menstrual bleeding period in many cultures of the developing world, including China, the prolonged period of bleeding episodes with Norplant use may eventually adversely affect their acceptability. It will be a deterrent to popular acceptance of Norplants especially in the Moslem countries. Although medical removals for reasons other than menstrual distrubance were relatively infrequent, the 13 cases of liver and gallbladder diseases reported from 1361 Norplant-l users, and the eight cases of thrombocytopenia reported from 301 Norplant- users are causes for some concern. The prevalence of hepatitis and hepatoma is high among the Chinese population and, therefore, the longterm implication of Norplant use, especially through a mass campaign approach as frequently done in China, deserves caution. Further investigation is needed to determine if the use of Norplant- was in any way related to the thrombocytopenia, which is a serious complication. The distribution and use of Clinical and Clinical Research
356
Duet al.
Norplant- have been suspended by the Population Council because of this reported complication. It is interesting to note that women of heavier weight had somewhat lower rates of complaints of menstrual disturbances. A plausible explanation might be that steroid hormone is stored in fatty tissue and heavier women, with more fatty tissues, store more and metabolize more slowly the hormone released by the implants than women of lighter build. However, it must be pointed out that heavier women had somewhat lower continuation rates at 24 and 26 months than lighter women (Table II). In spite of the prolongation of bleeding, and the increase in the amount of bleeding during Norplants use, the hemoglobin value among the users did not decrease. It is also reassuring that the blood pressure of the Norplant users, both systolic and diastolic, did not increase. The possibility of the occurrence of luteal phase pregnancy following the placement of implants raises an issue of the timing of implantation. The feasibility of placing the implants shortly after the onset of menstruation should be explored. Or, if the implants are less effective during the first month, then combined use with another contraceptive method should be considered. Since change of menstrual pattern is the most frequent and significant complaint causing device loss, a more careful analysis of the women’s menstrual records is needed. Future analysis of the data should use seven parameters: cycle regularity, cycle length, menstrual flow duration, amount of flow, dysmennorhea, amennorhea, and intermenstrual bleeding and spotting. The changes, if any, should be compared with the base-line information, for example, the patterns observed during the three cycles before placement of the implants [4]. Methods of prior contraceptive use must be controlled in such analysis [3]. The subjects included in the present study were highly selected. All of them were working women in a large metropolitan area who Int J Gynecol Obstet 33
were in good general health. The results of this study therefore may not be generalized. Introduction of a new contraceptive method into an area or a country needs careful study, not only of its acceptability, use-effectiveness, and under clinical conditions, but also of its impact on the existing contraceptive practice and its eventual net demographic impact. For example, if a new method is able to motivate those hitherto considered “hardto-reach” to accept and use contraceptives, it will have significant positive impact. On the contrary, if the new method introduced simply substitutes the existing methods being practiced, then it will have little or no net fertility impact. The net impact may well be negative if, for example, couples who otherwise would have elected to be sterilized, decide to accept the implants. The issue related to substitution is especially important in China where contraceptive prevalence is extremely high (approx. 80%), especially the use of highly effective and longlasting contraceptive methods, such as IUD and sterilization. Whether the introduction of Norplant implants will improve further the overall use-effectiveness of contraceptives in China, thereby reducing the need for abortion, will be another research question of significant practical implication. References Affandi B, Santos SSI: Five-Year Experience with Norplant. Contraception 36: 417, 1987. Alvarez-Sanchez F et al: The clinical performance of Norplant implants over time: a comparison of two cohorts. Stud Fam Plann 19: 118, 1988. Bhiwandiwala PP, Mumford SD, Feldblum PJ: Menstrual pattern changes following laparoscopic sterilization with different occlusion techniques: a review of 10,004 cases. Am J Obstet Gynecol145: 684, 1983. DeStefano F, Brach V, Faundes A: Long-term risk of menstrual disturbance after tubal sterilization. Am J Obstet Gynecol152: 835, 1985. The Population Council: Investigators Manual for Norplant Subderman Implants, Revised edition, August 1983. Segal SJ: A new delivery system for contraceptive steroids. Am J Obstet Gynecol157: 1090, 1987.
Stidy of NorplantRimplantsin Shanghai 7 8
Sivin 1: Norplant contraceptive implants. Out Look 3: January 1984. Sivin I: International experience with Norplant and Norplant-2 contraceptives. Stud Fam Plann 19: 81, 1988.
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Address for reprints: L.P. Chow Johns Hopkins School of Hygiene and Public He&h 615 North Wolfe Street Baltimore, MD 212QS.USA
Clinicaland ClinicalResearch
