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, China-Japan Friendship Hospital, Jilin University, Changchun 130031, China

Corresponding author: WANG Li-yan, Email:wangliyanjdd@163.com

AbstractObjective  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, Peking University First Hospital, Peking University Third Hospital, Jilin University Second Hospital and Affiliated Shengjing Hospital of China Medical University.  They were randomly inserted with MYCu IUD and control TCu 380A IUD each for 1000 cases and followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months post-insertion.   Results When MYCu IUD group and TCu 380A group 60 months post-insertion were compared, the cumulative pregnancy rates with IUD in situ were 2.38/100 women per year and 2.84/100 women per year respectively.  And the difference had no statistical significance (p0.05); the cumulative expulsion rates, mostly of partial expulsion and downward movement, were 0.87/100  women per year and 2.94/100 women per year respectively.  And the difference had statistical significance (p0.05; the cumulative termination rates due to bleeding/pain were  3.57/100 women per year and 4.83/100 women per year respectively.  And the difference had no statistical significance(p0.05);Side effects in MYCu group were less pronounced than those in TCu group.  And the inter-group differences had statistical significance (p0.05.  Conclusion As a comparatively ideal medicated medical device, MYCu IUD has an excellent contraceptive efficacy, a low rate of expulsion and side effects and good reversibility.  Particularly a low occurrence rate of bleeding and pain during early insertion is recommended.  Its life expectancy is 15 years.  And its contraceptive effectiveness and safety after 5 years should be examined during further follow-ups. 

Key wordsIntrauterine devices, medicated; Intrauterine devices, copper; Controlled clinical trial

   

   Since 1959, China has begun the promotion of intrauterine device (IUD), and deepened the research on IUD to enhance its contraceptive effect, reduce side effects occurrence and increase the acceptability of IUD. MYCu IUD containing indomethacin and

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 2040 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 12 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, P0.05 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 P0.05).  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, P0.05, comparative difference between two groups in full 60 months had no statistical significance, P0.05.  Main side effects were abnormal menstruation, pain in waist and abdomen, and leucorrhea increasing, the comparison between two groups had statistical significance, P0.05.  6 months after insertion, the side effects of abnormal menstruation, pain and leucorrhea increasing in MYCu IUD group was obviously lower than that in TCu 380A IUD group.  The difference of most inter-group comparison had statistical significance, P0.05 (Table 3).  As time went on, post-insertion side effects in both two groups gradually decreased.  Most women could tolerate side effects occurred.  The rate of removal due to side effect (for medical reason) in both MYCu IUD group and TCu group were 3.88/100 women per year and 5.15/100 women per year respectively.  

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 967 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 P0.05;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)

313.4)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(6.2a

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 P0.05;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 increases2.  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 strengthened3.  TCu380A IUD with a copper surface area of 380mm2 is recommended by WHO4.  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 (P0.05).  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 IUD3.  Systematical evaluation applying evidence-based medicine by Zhang Lei5 and so on people thought the expulsion rate of MCu IUD was lower than that of TCu 380A IUD.  Xin Limei 6and 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, P0.05.  The difference mainly lies in partial expulsion and removal for downward movement, which was the same with that reported by Li Shuzhi7 and Ma Lan8.  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 China9.  Tong Baoguang10 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 pain11-12.   

  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

1Chinese Medical Association.  Clinical Technical Standard·Family Planning Branch Volume.  Beijing: People’s Military Medical Press, 2004:1-10. 

2Han Xiangyang.  Practical Family Planning.  Harbin: Heilongjiang Science and Technology Press, 1999:371-378. 

3The R & D Department of Liaoning AiMu Medical Science & Technology Co., Ltd.  The Characteristics and Clinical Application of AiMu IUD series. Chinese Journal of Family Planning, 2012, 20:63-64. 

4Li Ying, Zhang Sumin, Chen Feng and so on.  Multi-center Random Contrast Study on IUD Application in Chinese Women.  Chinese Medical Journal, 2011, 91:3172-3175. 

5Zhang Lei, He Yang, Mao Yanyan and so on people.  Systematical Evaluation on the Comparison of MCu110, TCu220, and TCu 380A IUD. Chinese Journal of Family Planning, 2009, 17:262-266.  

6Xin Limei, Zhong Chunli, Sun Liren and so on people.  Multi-center Clinical Contrast Study on MCu IUD Inserted for 8 years.  Chinese Journal of Family Planning, 2010, 18:293-295. 

7Li Shuzhi, Zuo Wenli, Wu Shuying and so on people.  Random Contrast Study on the Application of MYCu IUD Containing 25mg Indomethacin, Chinese Journal of General Practitioners,2010,9:760-764. 

8Ma Lan. Clinical Observation on 150 Cases of MYCu IUD.  Chinese Journal of Practical Medicine, 2012,7:132-133. 

9Liu Changguan, Li Shuxiang, Liu Xiaoai and so on people.  Main Pharmacodynamics Study on Indomethacin-containing IUD.  Reproduction and Contraception, 2000, 20:165-171. 

10Tong Baoguang.  Determination of HPLC in Indomethacin-containing Silicon Rubber Bars on MYCu IUD.  Northwest Pharmaceutical Journal, 2007,22:293-294. 

11Liu Weinan, Liu Zhong.  Observation on the Clinical Effect of MCuII Functional IUD and MYCu IUD.  Contemporary Medicine, 2012, 18:144-145. 

12Xu Hong and Wang Huiying. Contrast on the Clinical Application of MYCu IUD and TCu220C IUD.  Chinese Journal of Family Planning & Gynecotokology, 2012, 4:42-45. 

2013年04月15日

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

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