A random control study of indomethacin-containing MYCu intrauterine contraceptive device for 60 months
A Random Control Study of Indomethacin-containing MYCu Intrauterine Device Inserted for 60 Months
WANG Li-yan*, LI Shu-zhi, WU Shu-ying, ZHAO Yan-hui, WANG Yu. *Department of Obstetrics & Gynecology,
Corresponding author: WANG Li-yan, Email:wangliyanjdd@163.com
【Abstract】Objective To explore the clinical efficacy and safety of MYCu intrauterine contraceptive device(IUD) containing indomethacin. Methods From October 1 to December 31, 2004, women of child-bearing age requiring IUD for contraception were chosen from the Outpatient Departments of China-Japan Friendship Hospital of Jilin University,
【Key words】Intrauterine devices, medicated; Intrauterine devices, copper; Controlled clinical trial
Since 1959,
with independent intellectual property right has been launched into market. To further observe its safety and efficacy, the study result of random contrast between MYCu IUD and TCu380A IUD inserted for 60 months is reported as follows:
Object and Methods
1. Object: From October 1st 2004 to December 31th 2004, healthy women 20～40 years old, with regular menstruation, cohabit with husband, with history of pregnancy, will to take IUD as the unique contraceptive method and follow-up in time were chosen at China-Japan Friendship Hospital of Jilin University, Peking University First Hospital, Peking University Third Hospital, Jilin University Second Hospital and Affiliated Shengjing Hospital of China Medical University and filled up inform consent. All together 2000 cases without contraindication after check were randomly inserted with MYCu IUD and TCu380A IUD. The study was approved by the Hospital Ethics Committee of the above five hospitals.
2. Methods: objects were strictly divided into 2 groups, each for 1000 cases, after being selected and under the operation of specially trained doctors for random sampling by random envelop according to documentation [1]. Women in the test group were inserted with MYCu IUD(MYCu group) which was researched and produced by Liaoning AiMu Medical Science & Technology Co, Ltd. MYCu IUD has TiNi shape memory alloy support, copper surface area of 225mm2, and indomethacin 25mg. Women in the contrast group were inserted with TCu380A IUD (TCu group) which was produced by CHINA SIPING MEDICAL DEVIUCE FACTORY. They uniformly filled up acceptance form and operation record form. Follow-up visits were carried out 1, 3, 6, 12, 24, 36, 48, and 60 months after insertion and the content includes the occurrence of side effects and its main symptoms after IUD insertion, such as systematic reaction, change in menstruation and other. The occurrence of side effects was determined by follow–up visitors through recording whether objects had chief complaints without any hint. Where there was chief complaint, there was side effects considered. In that case, the symptoms of chief complaint were further found out accordingly. One person may had 1～2 symptoms, calculate by person-time. IUD’s location was confirmed by X ray or B ultrasonic wave or observing tail filament, follow-up forms were filled up. After observing all objects for 60 full months, women who required removing IUD for second pregnancy were followed -up from May 9th 2010 to July 31th 2012(pregnancy state investigation). The research was funded by Liaoning AiMu Medical Science & Technology Co., Ltd.
3. Statistical processing: all data were reviewed and audited, typed by two people, confirmed correct after checking and verification. Life table was adopted to analyze the effect, and the result was statistically analyzed by WHO LTA 2.0 edition life table statistical software. SPSS 13.0 statistical software was adopted, and comparison on difference in statistical significance adopted X2 or t test, P＜0.05 was considered with statistical significance.
Results
1. Comparison on general biological characteristics of two groups of objects: There is no statistical significance between the differences on age, pregnancy/delivery times, outcomes of last pregnancy, insertion time, menstruation parameters, without or without formerly medical history, gynecological disease history, height, weight, and depth of uterine cavity (all P＞0.05). Objects in two groups are comparable (table 1).
2. Application effect: up to January 7th, 2011, observation on all objects had exceeded 60 months. The loss rate of two groups were 4.96/100 women per year and 4.91/100 women per year respectively, loss to follow up cases were objects can not be reached. The cumulative rate of pregnancy with IUD in situ were 2.38/100 women per year and 2.84/100 women per year respectively. All those were operated IUD removal and artificial abortion to terminate pregnancy. The cumulative expulsion rates were 0.87/100 women per year and 2.94/100 women per year, mainly partial expulsion and removal for downward movement. The cumulative rates of termination due to bleeding /pain were 3.57/100 women per year and 4.83/100 women per year (table 2).
3. Side effects: the number of women had side effect (chief complaint) after IUD insertion in MYCu group was less than those in TCu group, comparative difference between two groups in the previous 48 months had statistical significance, P＜0.05, comparative difference between two groups in full 60 months had no statistical significance, P＞0.05. Main side effects were abnormal menstruation, pain in waist and abdomen, and leucorrhea increasing, the comparison between two groups had statistical significance, P＜
4. Other related circumstances after IUD insertion: at the time of IUD insertion, objects didn’t have such complications as infection and perforation. During 8 times of follow-up visits, no side effect was reported, no anemia was recorded, and all women were safe.
5. Post-IUD-removal pregnancy situation contrast on women willing to have second pregnancy: in this study, after observation on all objects for 60 full months, the operated women willing to have second pregnancy were followed up after IUD removal. In MYCu IUD group and TCu group, 39 cases and 32 cases had IUD removed respectively. Their IUD retaining time varied from 15 to 52 months, and the time had IUD removed varied from 9～67 months. Total pregnancy rates in two groups were 84.6% (33/39) and 87.5% (28/32) respectively. The rates of not getting pregnant were 2.6% (1/39) and 3.1% (1/32) in sequential. Continuous contraception rates were 7.7% (3/39) and 6.3% (2/32) respectively. Lose follow-up rates were 5.1% (2/39) and 3.1% (1/32) respectively.
Table 1 General situation of two groups of objects
|
|
|
General circumstances (X±s) |
Insertion time |
|||||||||||
|
group |
cases |
Age (years old) |
Preg pregnancy time times(times) |
delivery times (times) |
height(cm) |
weight(kg) |
history of cesarean section |
menstruation intervals |
immediately after induced abortion |
lactation period and other time |
||||
|
|
|
|
|
|
|
|
cases |
rate (%) |
cases |
rate(%) |
cases |
rate(%) |
cases |
rate (%) |
|
MYCu |
1000 |
30±3 |
1.9±1.0 |
1.1±0.4 |
160±4 |
57±8 |
153 |
15.3 |
835 |
83.5 |
84 |
8.4 |
81 |
8.1 |
|
Tcu |
1000 |
30±4 |
1.8±1.0 |
1.1±0.4 |
160±4 |
56±7 |
141 |
14.1 |
844 |
84.4 |
93 |
9.3 |
63 |
6.3 |
|
P value |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
＞0.05 |
|||||
Table 2 60-months application effect contrast between objects in two groups (case/100 women per year)
|
terminate reason |
12 months |
24 months |
36 months |
60 months |
||||
|
MYCu group |
TCu group |
MYCu group |
TCu group |
MYCu group |
TCu group |
MYCu group |
TCu group |
|
|
pregnant |
1(0.1) |
3(0.31) |
9(0.93) |
12(1.27) |
14(1.47) |
22(2.38) |
22(2.38) |
26(2.84) |
|
pregnant with IUD in situ |
1(0.1) |
3(0.31) |
9(0.93) |
12(1.27) |
14(1.47) |
22(2.38) |
21(2.27) |
26(2.84) |
|
ectopic pregnancy |
0(0) |
0(0) |
0(0) |
0(0) |
0(0) |
0(0) |
1(0.11) |
0(0) |
|
expulsion |
1(0.1) |
17(1.73)a |
3(0.31) |
20(2.05)a |
4(0.42) |
25(2.59)a |
8(0.87) |
28(2.94)a |
|
complete expulsion |
0(0) |
0(0) |
0(0) |
1(0.11) |
0(0) |
1(0.11) |
0(0) |
1(0.11) |
|
partial expulsion |
1(0.1) |
17(1.73)a |
1(0.1) |
17(1.73)a |
1(0.1) |
17(1.73)a |
2(0.21) |
17(1.73) |
|
removal for downward movement |
0(0) |
0(0) |
2(0.21) |
2(0.21) |
3(0.32) |
7(0.77) |
6(0.66) |
10(1.13) |
|
remove for medical reason |
15(1.51) |
29(2.94)a |
21(2.13) |
33(3.36) |
27(2.77) |
37(3.79) |
37(3.88) |
49(5.15) |
|
bleeding/pain |
15(1.51) |
29(2.94)a |
21(2.13) |
33(3.36) |
24(2.45) |
35(3.58) |
34(3.57) |
46(4.83) |
|
pain |
3(0.3) |
6(0.61) |
6(0.62) |
7(0.72) |
6(0.62) |
8(0.83) |
8(0.85) |
11(1.19) |
|
bleeding |
7(0.71) |
11(1.13) |
10(1.02) |
12(1.23) |
12(1.24) |
13(1.35) |
19(2.03) |
19(2.03) |
|
pain and bleeding |
5(0.5) |
12(1.22) |
5(0.5) |
13(1.33) |
6(0.61) |
14(1.44) |
7(0.73) |
16(1.68) |
|
remove for pelvic inflammation |
0(0) |
0(0) |
0(0) |
1(0.11) |
0(0) |
2(0.22) |
0(0) |
3(0.33) |
|
other medical reasons |
0(0) |
0(0) |
0(0) |
0(0) |
3(0.33) |
0(0) |
3(0.33) |
0(0) |
|
terminate for reasons related to IUD |
17(1.71) |
49(4.92)a |
33(3.34) |
65(6.54)a |
45(4.59) |
84(8.51)a |
67(6.99) |
103(10.55)a |
|
pregnancy will |
1(0.1) |
0(0) |
13(1.34) |
9(0.97) |
28(2.94) |
21(2.29) |
39(4.17) |
32(3.57) |
|
remove for no contraception need |
0(0) |
0(0) |
1(0.1) |
1(0.11) |
6(0.65) |
4(0.44) |
8(0.88) |
6(0.68) |
|
other personal reasons |
0(0) |
0(0) |
2(0.21) |
2(0.21) |
4(0.43) |
3(0.33) |
5(0.55) |
6(0.68) |
|
loss to follow up |
4(0.4) |
4(0.4) |
9(0.91) |
9(0.93) |
18(1.86) |
17(1.81) |
46(4.96) |
44(4.91) |
|
total terminate circumstances |
22(2.2) |
53(5.30)a |
58(5.8) |
86(8.60)a |
101(10.1) |
129(12.90)a |
165(16.5) |
191(19.1) |
|
continuous application circumstances |
97.8 |
94.7 |
94.2 |
91.4 |
89.9 |
87.1 |
83.5 |
80.9 |
Note: a P＜0.05;removal for medical reasons are the sum of bleeding/pain, pelvic inflammation and so on medical reasons. Other medical reasons are other chief-complaint reasons possibly related to IUD except bleeding/pain and pelvic inflammation.
IUD partial expulsion means part of the IUD has expulsed out the orifice of uterus. IUD downward movement means IUD has moved downward but not expulsed out the orifice of uterus.
Table 3 Side effects occurrence circumstances in two groups of objects (cases)
|
time(month) |
group |
total followed-up cases |
had chief complaint |
abnormal menstruation |
irregular bleeding |
pain in waist and abdomen |
leucorrhea increasing |
|
1 |
MYCu |
994 |
309(31.1) |
202(20.3) |
42(4.2) |
77(7.7) |
102(10.3) |
|
|
TCu |
993 |
447(45.0)a |
326(32.8)a |
133(13.4)a |
172(17.3)a |
126(12.7) |
|
3 |
MYCu |
991 |
142(14.3) |
124(12.5) |
17(1.7) |
30(3.0) |
44(4.4) |
|
|
TCu |
983 |
323(32.9)a |
281(28.6)a |
85(8.6)a |
128(13.0)a |
63(6.4) |
|
6 |
MYCu |
982 |
71(7.2) |
43(4.4) |
9(0.9) |
22(2.2) |
23(2.3) |
|
|
TCu |
956 |
243(25.4)a |
169(17.7)a |
52(5.4)a |
92(9.6)a |
39(4.1)a |
|
12 |
MYCu |
978 |
31(3.2) |
15(1.5) |
5(0.5) |
12(1.2) |
17(1.7) |
|
|
TCu |
947 |
70(7.4)a |
42(4.4)a |
37(3.9)a |
56(5.9)a |
45(4.8)a |
|
24 |
MYCu |
942 |
38(4.0) |
19(2.0) |
7(0.7) |
12(1.3) |
19(2.0) |
|
|
TCu |
914 |
74(8.1)a |
30(3.3) |
31（3.4)a |
37(4.0)a |
39(4.3)a |
|
36 |
MYCu |
899 |
30(3.3) |
13(1.4) |
6(0.7) |
11(1.2) |
16(1.8) |
|
|
TCu |
871 |
54(6.2）a |
23(2.6) |
18(2.1)a |
30(3.4)a |
26(3.0) |
|
48 |
MYCu |
876 |
22(2.5) |
8(0.9) |
4(0.5) |
11(1.3) |
12(1.4) |
|
|
TCu |
844 |
37(4.4)a |
18(2.1)a |
12(1.4)a |
17(2.0) |
17(2.0) |
|
60 |
MYCu |
835 |
16(1.9) |
5(0.6) |
3(0.4) |
5(0.6) |
10(1.2) |
|
|
TCu |
809 |
26(3.2) |
11(1.4) |
6(0.7) |
8(1.0) |
13(1.6) |
Note: a P＜0.05;included in the parentheses is percentage (%0,followed up number of people =［1000-(number of loss to follow up people +number of terminated people］; rate of abnormal menstruation, irregular bleeding, pain in waist and abdomen and
leucorrhea increasing(%) is the occurrence rate of total followed-up. Abnormal menstruation mainly includes prolonged menstruation, increased menstruation volume and reduced menstruation period.
Discussion
The anti-fertility effect of copper ions has fully affirmed, but the function of copper has something to do with its location in uterine cavity and the exposed surface area. IUD is more effective when located in a higher position in uterine cavity rather than a lower position. The larger the copper surface area is, the more effective the contraception effect is. However, as the copper surface area increases, corresponding side effects occurrence rates also increases［2］. For MYCu IUD has a copper surface area of 225mm2, the end of its arms are fixed with copper grains, its side arms are allocated with copper sleeves, and fill the uterine cavity with contraceptive active substance copper ions, thus the contraceptive effect is strengthened［3］. TCu380A IUD with a copper surface area of 380mm2 is recommended by WHO［4］. In this study, 2 kinds of IUDs with different copper surface area were randomly inserted and observed for 60 full months. The rates of pregnancy with IUD in situation of MYCu group and TCu group were 2.38/100 women per year and 2.84/100 women per year respectively. The difference had no statistical significance (P＞0.05). MYCu IUD is confirmed with the same high anti-fertility effect as other IUDs with large copper surface area.
MYCu IUD is the up-grade product of MCu IUD. It combines medicine with medical device on the basis of MCu IUD［3］. Systematical evaluation applying evidence-based medicine by Zhang Lei［5］ and so on people thought the expulsion rate of MCu IUD was lower than that of TCu 380A IUD. Xin Limei ［6］and so on people reported that in random prospective observation on MCuIUD for 550 cases in 48 months, the expulsion rates was 0.38%, lower than that of TCu 380A. In observation on two groups for 60 months, the expulsion rates were 0.87/100 women per year and 2.94/100 women per year in sequential, the difference had statistical significance, P＜0.05. The difference mainly lies in partial expulsion and removal for downward movement, which was the same with that reported by Li Shuzhi［7］ and Ma Lan［8］. The support of MYCu IUD is made of shape memory alloy, which can retain the designed shape within the range of human body temperature, not easy to deform, has fatigue resistance and tissue compatibility. MYCu IUD is designed according to uterus form and dynamic mechanism. Its two arms assume special angle and completely open “V” form, which is compatible with uterus form. Its support has subtle elasticity, can expand and contract as the womb does, not easy to move downward and expulse, thus this IUD has low expulsion rate in clinical.
Indomethacin was affirmed to have the function of inhibiting the synthesis of prostaglandin and reduce side effects caused by IUD long ago in China［9］. Tong Baoguang［10］ reported that MYCu IUD released indomethacin in a non-constant manner and the dose gradually decreased by time. Through this observation, we can see that in the first 6 months after insertion, the side effects of abnormal menstruation, pain, and leucorrhea increasing in MYCu IUD group were obviously lower than that in TCu 380A IUD group. The difference in most inter-group comparison had statistical significance. MYCu IUD was confirmed to release indomethacin during early insertion to decrease the synthesis of prostaglandin, thus had decreased the side effects of uterus bleeding and pain［11-12］.
In this study, objects had IUD removed for secondary pregnancy reason were followed up, and the follow up results showed that both IUDs had good reversibility.
As an IUD combining medicine and medical device together, MYCu IUD has good anti-fertility effect, low expulsion rate, low occurrence rate of side effects, good reversibility, especially low occurrence rate of bleeding and pain during early insertion. Therefore, it is a comparatively ideal IUD. The life time of MYCu IUD is 15 years. Its efficacy and safety after 5 years look forward to continuous follow up study.
References
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