- Email: [email protected]
Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: A randomized comparative trial
Levonorgestrel-releasing and copperreleasing (Nova T) IUDs during five years of use: A randomized comparative trial Kerstin Andersson”,
Viveca Odlindf,
G&an Rybo”
‘Department of Obstetrics and Gynecology, Kvinnokliniken, ijstra sjukhuset, Giiteborg, Sweden; and tDepartment of Obstetrics and Gynecology, Kvinnokliniken, Akademiska sjukhuset, Uppsala, Sweden A 20 micrograms124 hours levonorgestrel-releasing intrauterine contraceptive device (LNG-IUD) has, in an open randomized multicenter study, been compared to the copper-releasing device Nova T during 5 years of use; 1821 women had the LNG-IUD and 937 women had the Nova T inserted. The 5-year cumulative gross pregnancy rate was 5.9 % for Nova T and 0.5% for the LNG-IUD. The local effect of levonorgestrel in the uterine cavity causes reduction of menstrual blood loss and development of oligo-amenorrhea, and the termination rates because of heavy and/or prolonged menstrual flow were significantly (P < 0.001) lower among LNG-IUD users. However, thegross termination rate because of amenorrhea was 6.0 in this group. Hb increased during use of the LNG-IUD and decreased during Nova T use, and the difference between the devices was statistically significant. The incidence of pelvic inflammatory disease (PID) was low in LNGIUD users regardless of age, whereas in the Nova T group, the PID rate was increased among the youngest women, which makes the difference between the devices significant (P < 0.01). The gross termination rate for reasons considered to be hormonal was 12.1 in the LNGIUD group compared to 2.0 in the Nova T group (P < 0.001). The LNG-IUD is a long-acting reversible contraceptive method for 5 years with a pregnancy rate comparable to female sterilization. Submitted for publication January 11, 1993; accepted for publication November 24, 1993. Address correspondence to: Kerstin Andersson, Dept of Obstetrics & Gynecology, East Hospital, S-41685 GBteborg, Sweden.
56
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1994:49, January
0 1994 Butterworth-Heinemann
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
The incidence of PID is low even in young women. In addition, the positive health effects such as decreased menstrual blood loss and increased blood haemoglobin concentration make the LNG-IUD a favorable combination of hormonal and intrauterine contraception. Keywords: Levonorgestrel-releasing
IUD; Nova T; contraception
Introduction Progestogen-releasing intrauterine contraceptive devices were initially developed to reduce uterine contractility and, thus, to prevent expulsion. However, it was found that the steroid did not influence the expulsion rate but increased the contraceptive efficacy compared to a plain T device’ and reduced the menstrual blood 10~s.~ The progesterone-releasing IUD (Progestasert) had to be replaced at 12-month intervals and was associated with an increased risk of ectopic pregnancies.” Levonorgestrel is not metabolized by the endometrium as rapidly as progesterone and has a more uniform and profound local effect.4 An intrauterine contraceptive device which releases 20 micrograms levonorgestrel/24 hours (LNG-IUD) has been studied in comparative trials with the copper-releasing IUDs, Nova T, Copper T 200, Copper T 220 and Copper T 380, and with levonorgestrel-releasing subdermal implants (Norplant-2). The 5 years’ experience of LNG-IUD as compared to Nova Ts and with Copper T 380” and the 3 years’ experience of LNG-IUD as compared to Nor-plant-2’ and Copper T 200, Copper T 220 and Copper T 380x have been reported. These studies have demonstrated both high contraceptive efficacy and decreased menstrual bleeding with LNG-IUD, but also discontinuation because of amenorrhea. At that time, when the 5-year studies where LNG-IUD was compared to a copper IUD were started, oligo-amenorrhea was not known to be a frequent concomitant to intrauterine release of levonorgestrel. Therefore, the information about the strong effect of the LNG-IUD on menstrual bleeding and the frequent and expected development of oligo-amenorrhea was not given to the women. The aim of the present investigation was to more extensively, in a randomized comparative way, study LNG-IUD and Nova T during five years of use, and to apply an open design to ensure an efficient and high quality counselling. The results after the first and the third year”,‘0 have earlier been published.
Materials and Methods Nova-T is a copper-releasing device with a silver-cored copper wire wound around the vertical stem. The copper surface area is 200 mm2 and the
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Levonorgestrel-
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effective life span is at least five years. I1 LNG-IUD has the same polyethylene skeleton as Nova T and the steroid is homogeneously dispersed in a polydimethyl-siloxane reservoir covered by a rate-limiting membrane on the vertical arm of the device (Figure 1). The devices used in this study contained 46 mg of levonorgestrel. The initial in vitro release rate of levonorgestrel is 20 micrograms/24 hours and about 15 micrograms/24 hours after five years. The life span of the LNG-IUD is at least five years.s As the steroid reservoir is slightly thicker than the copper wire, the insertion tube of the LNG-IUD is 4.8 mm compared to 3.7 mm for the Nova T insertion tube. Both IUDs are manufactured by Leiras OY, Turku, Finland. The study was carried out in four clinics in Finland, four clinics in Sweden, two clinics in Denmark, one clinic in Hungary and one in Norway. Women, who were visiting the clinics requesting contraception, were asked if they wanted to participate in a clinical trial and informed verbal consent was obtained. The woman had to be healthy, 18-38 years old and should have had at least one previous pregnancy. If she had a history of ectopic pregnancy, was breast-feeding or had used injectable steroid
FIGURE 1. The 20 micrograms/24 hours levonorgestrel-releasing the copper-releasing device (Nova T) to the right.
58
device (LNG-IUD)
Contraception
is shown to the left and
1994149, January
Levonorgestrel- and copper-releasing IUDs:
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hormones for contraception during the preceding 12 months, she was not accepted into the study. The woman had to be willing to accept an induced abortion in case of an accidental pregnancy with the LNG-IUD, as knowledge about teratogenic risks is lacking. Into the treatment groups 2758 women were allocated, 937 had a Nova T and 182 1 had an LNG-IUD inserted. All devices were inserted between November 1982 and December 1984. In the Nova-T group 133 and in the LNG-IUD group 305 women had the IUD inserted in connection with an induced first trimester abortion, but this group is too small for separate evaluation. The mean age was 30.3 years in both groups (SD 4.9 in the Nova T and 5.0 in the LNG-IUD group] and the distribution of age is shown in Table 1. The mean parity were 1.7 (SD 0.9) and 1.8 (SD 0.9) in the Nova T and LNG-IUD groups, respectively. At the completion of the study, life table analysis of pregnancy and discontinuation rates was made using the terminology suggested by Tietze & Lewit.12 Multiple-decrement life table rates (net rates) and singledecrement (gross) rates were calculated. The differences in the cumulative life table rates between the two groups were tested for statistical significance with Mantel-Cox (log-rank) statistics of the BMDP software package.13 The limit of statistical significance was set at I? = 0.05. Approval for the study was obtained from the ethics committees of all universities involved.
Study Design The study was an open randomized comparative multicenter trial of two parallel groups. The IUD was inserted within 3-10 days after the onset of menstruation. If signs of cervicitis were noted, the infection was treated and the IUD insertion was postponed. The device could also be inserted in connection with a first trimester abortion. A specially designed protocol
TABLE
1. Distribution of age in 2758 women receiving Nova T or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD)
Nova T
LNG-IUD
Total
N
%
N
%
5 25 26-30 31-35 236
177 263 358 139
18.9 28.1 38.2 14.8
338 532 645 306
18.6 29.2 35.4 16.8
TOTAL
937
Age (years)
Contraception 1994:49, January
100
1821
100
N
%
515 795 1003 445
18.7 28.8 36.4 16.1
2758
100
59
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and copper-releasing
IUDs:
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et al.
was used in all centers and a standardized interview was performed at admission and at every follow-up visit, which was planned after 3 and 12 months and then yearly up to five years. Furthermore, during the first 12 months, all women were requested to note bleeding patterns continuously on a specially designed chart. In case of any problem, the women were immediately seen by the investigators. Prospective uniform criteria for diagnosis and treatment of side effects have been used, and the women were encouraged to contact the investigator’s clinic in case of problems, and the event was reported to the study center. The diagnosis pelvic inflammatory disease (PID) included acute salpingo-oophoritis, tubo-ovarian abscess and pelvic peritonitis. In the study protocol, the PID diagnosis required at least two of the following symptoms or signs: 1) history of lower abdominal pain and body temperature more than 38” C, 2) increased sedimentation rate over 30 mm/hour, 3) tenderness on pelvic examination, 4) mass on pelvic examination, and 5) laparoscopy or ultrasound examination if other clinical evidence was controversial.
Results Continuation Rate In the Nova T group 133 women (14% of the acceptors) and in the LNGIUD group 115 women (6.3% of the acceptors) were lost to follow-up during the study. Of the 2758 women enrolled into the study, 315 acceptors of Nova T and 736 acceptors of LNG-IUD completed the 60 months follow-up and the continuation rate at five years was 44.5 for Nova-T and 46.9 for the LNG-IUD (Table 2). The continuation rate was, for both IUDs, higher in the older age groups (Table 3).
Contraceptive Efficacy The 5-year cumulative gross pregnancy rate was 5.9 for Nova-T and 0.5 for LNG-IUD [(P < 0.001) Figure 2, Table 31. During the 60-month observation period, 35 women in the Nova-T and 5 in the LNG-IUD group became pregnant. Among the pregnancies, 7 were ectopic in the Nova-T group and 1 in the LNG-IUD group (Table 4). The pregnancies in the LNG-IUD group and the woman’s age at IUD insertion are described below: 1. Occurred during the 10th month of use after an unnoticed expulsion in a 35.year-old woman. An induced abortion was performed. 2. Occurred 23 months after insertion in a 37-year-old woman. When the
60
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Net cumulative termination rates per 100 each year in 937 women using Nova T and 1821 women using a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD) during 5 years
TABLE 2.
Event Pregnancy Expulsion Bleeding problems Amenorrhea Pain Hormonal PID Other medical Planning pregnancy Other personal Continuation
1
2
Year 3
4
5
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
0.9 3.4 5.7
0.1 3.4 5.8
2.2 4.1 9.0
0.1 4.2 8.3
3.1 4.8 12.0
0.2 4.8 9.6
4.0 5.3 14.3
0.3 4.9 10.3
4.2 5.5 16.2
0.3 4.9 10.9
0.0 1.6 0.1 0.4 2.4 1.9
1.5 1.6 2.3 0.3 2.7 1.9
0.0 2.6 0.1 1.0 3.8 5.5
2.9 2.8 4.8 0.5 3.6 5.7
0.0 3.3 0.6 1.5 5.4 8.1
3.6 3.4 6.4 0.5 4.8 8.2
0.0 3.8 0.7 1.5 6.4 10.6
4.2 3.9 7.6 0.5 5.5 10.1
0.0 4.2 1.1 1.6 7.6 11.8
4.3 4.2 8.4 0.6 5.8 10.8
0.6 83.0
0.6 79.9
1 .o 70.7
1.5 65.6
1.7 59.4
2.0 56.7
2.5 50.8
2.3 50.6
3.3 44.5
2.9 46.9
termination of pregnancy was performed, submucous uterine fibroids were diagnosed. 3. Ectopic pregnancy after 30 months of IUD use in a woman aged 28; the device was found in situ. The right tube was resected. 4. Intrauterine pregnancy in a 35year-old woman 41 months after insertion. The device was found in situ and spontaneous abortion occurred in the sixth week. 5. Occurred after a complete unnoticed expulsion of the device in a 40year-old woman 46 months after insertion. Spontaneous abortion occurred in the sixth week. Seven ectopic pregnancies occurred in the Nova T group after 4-23 months of IUD use and the mean age of these women was 34 (range 27-38) years. Expulsion The 60-month cumulative gross expulsion rate was 6.7 in the Nova T group and 5.8 in the LNG-IUD group (Table 3). Most of the expulsions were noted during the first months after insertion. Bleeding
Problems
The gross cumulative removal rate for bleeding was 20.7 for the Nova T and 13.7 for the LNG-IUD (P c 0.01) at five years (Table 3). Termination
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1994:49, January
61
TABLE
3. Cumulative 60-month age-specific gross rates of use-related terminations and continuation in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD, N = 1821)
Age (years) 5 25 PREGNANCY 14.9 Nova T LNG-IUD P ; Expulsion Nova T 8.2 LNG-IUD 4.9 P NS BLEEDING PROBLEMS 34.7 Nova T LNG-IUD 20.9 P NS AMENORRHEA 0 Nova T LNG-IUD 9.3 * P PAIN Nova T 8.6 LNG-IUD 6.2 P NS HORMONAL 6.6 Nova T LNG-IUD 10.0 P NS PID Nova T 5.6 LNG-IUD 0.3 * P OTHER MEDICAL 11.3 Nova T LNG-IUD 8.2 P NS PLANNING PREGNANCY 40.7 Nova T 42.0 LNG-IUD P NS OTHER PERSONAL 12.6 Nova T LNG-IUD 5.1 P NS CONTINUATION RATE Nova T 18.9 LNG-IUD 29.0 P NS NS = not significant.*
62
26-30
31-35
2 36
Total
6.9 0.4
4.0 0.5
5.9 0.5
t
t
2.8 0.9 NS
6.4 7.7 NS
7.8 5.2 NS
1.6 5.9 NS
6.7 5.8 NS
22.2 17.8 NS
17.2 9.7
21.4 9.0 f
20.9 13.7
0 8.8
0 4.4
0 6.0
t
t
0 2.6 NS
8.7 6.6 NS
3.6 6.3 NS
4.4 3.8 NS
5.8 5.9 NS
1.1 15.0
2.4 12.3
0 9.8
2.0 12.1
t
t
l
t
l
t
t
t
3.0 1.4 NS
1.4 0.7 NS
0 0.3 NS
2.2 0.8 *
9.4 7.1 NS
9.2 7.7 NS
13.0 7.3 NS
10.6 7.7 NS
25.1 19.1 NS
7.8 6.9 NS
2.9 2.2 NS
16.3 15.2 NS
7.3 3.1 NS
4.5 5.3 NS
4.4 3.8 NS
5.9 4.4 NS
37.4 39.3 NS
54.4 54.1 NS
58.1 63.3 NS
53.1 55.5 NS
= P 5 0.01. t = P < 0.001.
Contraception
1994:49,
January
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
6-
et al.
r----r---a
I4 , __’ _-_I-
a
_--a
4r--
I
_I -_a
I
__
I
__
I-
I
2-
__,aI-
--
c--
dI
L
2
3
4
5
Year FIGURE 2. Five-year cumulative gross pregnancy rate per 100 women for 937 women during use of Nova T (- - -) and for 1821 women during use of a 20 micrograms/24 hours levonorgestrel-releasing device (-).
TABLE 4. Number of pregnancies and pregnancy rate per 100 women-years (Pearl rates) during five years’ use of Nova T and a 20 micrograms/24 hours levonorgestrel-releasing device (LNGIUD)
Nova T All pregnancies (N) Ectopic pregnancies (N) Women-years (WY) Pregnancy rate/l 00 WY Ectopic rate/100 WY
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1994:49, January
35 7 2776
1.26 0.25
LNG-IUD 5 1 5615 0.09 0.02
Levonorgestrel-
and copper-releasing
KIDS:
Andersson
et al.
for heavy and prolonged menstrual flow differed significantly between the groups in favour of the LNG-IUD, whereas the removal rate for irregular bleeding or spotting did not differ (Table 5). The bleeding patterns during the first year were studied in detail by analyzing the menstrual records from 739 women in the Nova-T and 1495 in the LNG-IUD group (Figure 3). During the first three months after insertion, there were, on average, more days with menstruation-like bleeding and/or spotting in the LNG-IUD group compared to the Nova-T group (P < 0.001). With passing time, the situation changed, and at 12-month follow-up, the mean number of days with bleeding and/or spotting was significantly lower in the LNG-IUD group [(P < O.OOl), [Figure 3)]. When only days with menstruation-like bleeding were calculated, the mean number of days were initially equal in both groups, and there was a gradual decrease in the LNG-IUD group during the observation period, whereas in the Nova-T group, the number of days with bleeding per month was unchanged after the initial months.
Amenorrhea During the first year after IUD insertion, 2.7% of the Nova-T users and 16.8% of the LNG-IUD users experienced a period of at least 90 days’ amenorrhea. The cumulative net rate of removal because of amenorrhea was 4.3 for LNG-IUD and 0 for Nova T ((P < O.OOl), (Table 2)]. The corresponding gross rates in different age groups appear in Table 3. Amenorrhea led to higher termination rate in younger women compared to older.
Pain No difference (Table 2).
between
the groups in termination
rates for pain was seen
TABLE
5. Cumulative 60-month gross termination rate because of bleeding problems in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device [(LNGIUD), (N = 1621)]
Nova T
LNG-IUD
Frequent irregular bleeding Heavy menstrual flow Prolonged menstrual flow
3.9 9.7 6.5
5.3 1.3 2.3
NS
Spotting Other bleeding problems
2.2 0.4
1.6 3.9
NS *
NS = not significant.
64
P
l
*
* = P < 0.001.
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1994:49, January
Levonorges trek- and copper-releasing
Andersson
I UDs:
et al.
14 12 10 -
642-
0'
0
I
1
I
I
I
2
3
4
I
I
1
I
I
1
I
I
5
6
7
8
9
10
11
12
Period
8-
6-
4-
2-
0’
I
0
1
1
I
I
I
I
I
I
2
3
4
5
6
7
8
I
9
I
10
I
17
1
12
Period
FIGURE 3. Mean number of days with bleeding and/or spotting or only bleeding each month during the first year of use of Nova T (open circles) or a 20 micrograms/24 hours levonorgestrel-releasing device (solid circles).
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1994149, January
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Levonorgestrel-
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Pelvic Infections There was in neither the Nova T nor in the LNG-IUD group an increased incidence of PID in relation to the IUD insertion (Figure 4). The 60-month gross removal rates for PID were 2.2 in the Nova T and 0.8 in the LNGIUD group [(P < O.OS), (Table 3)]. In the LNG-IUD users, the incidence of PID was low regardless of age whereas in the Nova T group, there was a significantly (P < 0.01) increased PID rate compared to LNG-IUD among the youngest women (Table 3).
Hormonal Side Effects A number of side effects shown in Table 6, were considered to be related to the levonorgestrel administration and the discontinuation rate because of such hormonal side effects was higher in the LNG-IUD group than in the Nova T group [(P < O.OOl), (Table 3)].
O/O
8
6-
4-
2-
*_py-;;-,I,
0
-_ _--a 1
,-I-,
I-’
_,-__I’ (
1 1
-_-__--
__-------_-------
f
I ,
,
(
1
,
,
3
2
,
I
,
4
,
I
5
Year FIGURE 4. Five-year cumulative gross rate of pelvic inflammatory disease per 100 women, for 937 women during use of Nova T (- - -) and for 1821 women during use of a 20 micrograms/24 hours levonorgestrelreleasing IUD ().
66
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IUDs:
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et al.
TABLE
6. The cumulative 60-month gross termination rate for hormonal reasons in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device [(LNGIUD) N = 18211
Nova T 0 0.4 0.2 0 0 0.4 0 0 0.7
Depression Acne Headache Weight change Breast tenderness Nausea Hirsutism Other skin problems Other mood changes NS = not significant.
* = P < 0.05. T = P < 0.01.
LNG-IUD 2.9 2.3 1 .Q 1.5 0.8 0.8 0.7 0.5 1.5
P
*
: f NS NS NS NS
* = P < 0.001.
Other Medical Reasons The 60-month gross removal rate for other medical reasons than reported above are shown in Table 3. The termination rates per 100 women-years for enlarged follicles were almost similar in the two groups-O.07 for Nova T and 0.09 for LNG IUD. Four women in the LNG-IUD group discontinued the study due to hypertension and none in the Nova-T group discontinued for this reason. During the observation period, there were no changes in mean systolic or mean diastolic blood pressure in any women using LNG-IUD or copperreleasing IUD.
Personal Reasons Planning pregnancy and other personal reasons for termination were similarly age-related in users of both IUDs and more common among young women (Table 3).
Effect on Weight and Haemoglobin The mean weight at admission was 61.9 (SD 10.6) kg in the Nova T group and 62.0 (SD 10.0) in the LNG-IUD group. After five years the mean weight had increased to 64.4 kg in both groups. The changes in haemoglobin concentration during the observation period are shown in Table 7. After 5 years, the mean haemoglobin concentration showed an increase of 1.6 g/l during use of LNG-IUD and a decrease of 2.6 g/l during use of Nova T. The differences between the two device
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1994:49, January
67
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Andersson
IUDs:
et al.
TABLE 7. Mean values (SD) of Hb during five years’ use of Nova-T or a 20 micrograms/24 hours levonorgestrelreleasing device (LNG-IUD). Only women where values are available at admission as well as at the control visit are included. The percentage of women completing each observation period and in whom Hb values are available is presented (%). P values indicate the differences in change of Hb between the device groups.
Nova T Time
Hb
N
LNG-IUD (“A)
Hb 135.7 137.6 135.6 136.4 133.9 134.9 133.4
N 10.7) 10.4) 10.7) 9.3) 10.0) 9.3) 9.8)
1227 1227 1043 1043 706 706 571
W)
P
(86)
t
(91)
*
(73)
l
Adm 1 year Adm 2 years Adm 3 years Adm
135.8 134.9 135.9 132.4 134.3 132.0 132.9
(10.3) (11.1) (10.9) (10.5) (10.6) (11.2) ( 9.8)
618 618 509 509 343 343 253
4 years Adm
132.3 ( 9.9) 135.4 (10.0)
253 254
(65)
134.5 ( 9.9) 134.6 (10.7)
571 622
(67)
’
5 years
132.8 (10.1)
254
(80)
136.2 ( 9.5)
622
(85)
*
(84) (84) (72)
* = P< 0.05. t = P< 0.01. * = P < 0.001
groups, in change of haemoglobin concentration, cant during the entire follow-up period.
are statistically
signifi-
Reported Subjective Side Effects Main categories of side effects elicited by asking the woman the question “How have you been feeling?” are described in Table 8. The rate of reported side effects decreased over time but at three months there were significant differences between the devices concerning back pain, headache, nausea, depression, menstrual problems, acne and mastalgia which were all more often reported in the LNG-IUD group. At five years, 25.9% of the NovaT users and 15.1% of the LNG-IUD users mentioned problems. Menstrual problems were pointed out by 18.8% and 6.3%, respectively (P < O.OOl), and other complaint categories were reported at a rate of less than 5%.
Discussion The intrauterine release of levonorgestrel makes the endometrial glands atrophic, the epithelial cells inactive and the stroma decidua1ized.1~ The endometrium is converted to be insensitive to ovarian estradiol. These changes are probably the most important for the clinical performance of the LNG-IUD. There are only limited effects on ovulation and on the pituitary.‘“,‘” The contraceptive efficacy of the LNG-IUD was, in this study, comparaand so far, the LNG-IUD is one of the most ble to female sterilization,”
68
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TABLE 8. Subjective side effects (%) reported at 3 and 60 months in women using Nova T copper IUD or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD)
3 Months
No problems Back pain Low abdominal pain Headache Nausea Depression Menstrual problems Acne Mastalgia Other NS = not significant.
l
60 Months
Nova T
LNG-IUD
P
Nova T
LNG-IUD
64.5
49.8
t
74.1
84.9
1.9 1.8
3.1 10.5
0.3 2.7
1 .o 2.0
NS NS
0.8 0.2 0.4 22.2
2.8 2.4 2.5 32.1
f *
1 .o 0 0.3 18.8
1.6 0.3 0.6 6.3
NS NS NS
0.4 0.2 6.1
3.5 3.1 8.7
f
0.3 0.7 4.8
1.8 1 .o 3.6
NS NS NS
= P < 0.001.
l
NS
l l
l
t
P *
l
t = P c 0.05.
effective long-term reversible contraceptive methods requiring single application. The rate of ectopic pregnancy in our study (0.02 per 100 women-years in the LNG-IUD group and 0.25 per 100 women-years with Nova T) could be compared to the ectopic pregnancy rate of 1.2-1.6 per 100 womenyears in sexually active Swedish women age 15-44 seeking pregnancy.lX The estimated ectopic pregnancy rate in women using TCu 380 or MLCu 375 is similar to LNG-IUD; 0.02 per 100 women-years indicating that these devices are highly effective in preventing ectopic pregnancies as well.3 The ectopic pregnancy rate in the Nova T group (0.25 per 100 women-years) was higher in our study compared to other investigations3 This may be explained by an increased incidence in the population studied and in Sweden the ectopic rate has been increasing the last decade.lR Bleeding problems were the most common reason for discontinuing the use of both IUDs, but termination for this reason was more common in the Nova-T group. These results concerning the copper IUD are similar to those presented by other investigators.” The termination rate for heavy and prolonged menstrual flow was lower with LNG-IUD compared to Nova T. However, the removal rate for irregular bleeding and spotting was similar in both groups. Frequent irregular bleeding is more common during the first months after LNG-IUD insertion, and during prolonged use of the LNG-IUD, a reduction of the number of days with bleeding and/or spotting will occur. It is crucial that the woman has been carefully
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1994149,
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69
Levonorgestrel-
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Andersson
et al.
informed about what to expect concerning the bleeding pattern after LNGIUD insertion, to avoid an unnecessary removal. The local effect on the endometrium by levonorgestrel leads to reduction of the menstrual blood loss and to oligo-amenorrhea.19,zo The nature of this endometrial amenorrhea should be included into the information which is given to the woman before insertion of the LNG-IUD, to prevent uncertainties about pregnancy or later return to fertility. The 5-year gross cumulative termination rate because of amenorrhea was 6.0, but this is not an estimate of the incidence of amenorrhea, the menstrual diaries have to be analyzed for calculation. In Sivin’s blind study,” the gross removal rate because of amenorrhea was 19.7 after 5 years. When women are well informed about the reduction of bleeding and development of oligo-amenorrhea, they may learn to like the freedom of the non-bleeding situation. It is important to inform the women that amenorrhea does not reduce the ability to conceive after removal of the LNG-IUD. Return to fertility is as rapid after removal of LNG-IUD as after Nova-T.*’ Moreover, excessive menstrual blood loss is the most common cause of anemia in fertile women, and nonmedicated IUDs increase the blood loss about 50-75 % .22 The LNG-IUD reduces the blood loss and increases the hemoglobin concentration during use. This may be especially important for women in developing countries where poor nutrition and/or diseases may contribute to an iron-deficient situation. The strong progestogen dominance of the endometrium has also been used as therapeutic principle to treat excessive menstrual bleeding. It seems that the LNGIUD can replace hysterectomy and endometrial ablation in most women suffering from idiopathic menorrhagia.2” The reduced risk of PID in the LNG-IUD group compared to Nova T use, has earlier been demonstrated. lo In other studies where LNG-IUD has been compared to copper IUD, similar PID rates have been demonstrated in both groups.i,6,X The incidence of PID, in the present study, is low in both IUD groups; nevertheless, there was a decreased risk of PID during LNG-IUD use, and the difference between the device groups is statistically significant in women less than 25 years of age. This is the age group where PID is most common and an increased risk of PID following use of conventional IUDs makes intrauterine contraception unsuitable for young women. Use of LNG-IUD may change this opinion. It is important to notice that no increase in PID was seen in relation to the insertions. The reason for this may be that cervicitis was excluded before and aseptic technique used at insertion. Removal rate for reasons which were classified as “hormonal” was higher in the LNG-IUD group compared to Nova-T. Most of the reported side effects after three months of use were hormonal, but these side effects decreased during the study period. However, it is obvious that the dosage of 20 micrograms levonorgestrel/24 hours exerts certain systemic hormonal
70
Contraception
1994~49, fanuary
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
effects. Therefore, it is important that counselling also includes information that the LNG-IUD is a hormonal contraceptive method, even if the daily dose of levonorgestrel is only a fraction of the dose which is given in oral contraceptives.
Acknowledgments This multicenter study was conducted by the following investigators: Maija Haukkamaa and Tapani Luukkainen (City Maternity Hospital, Helsinki, Finland), Juhani Toivonen (Planned Parenthood Association, Helsinki, Finland), Pentti Holma and Tapani Pyorala (Central Hospital, Jyvaskyla, Finland), J u h ani Terho (Health Center, Tampere, Finland), Hannu Allonen (Leiras Oy, Turku, Finland), Elof Johansson, Viveca Odlind, and Sven-Eric Olsson (University Hospital, Uppsala, Sweden), Staffan Nilsson (Falu Hospital, Falun, Sweden), Bo Sikstrom and Ann-Charlotte Smeds (Central Hospital, Eskilstuna Sweden), Kerstin Andersson and Goran Rybo (East Hospital, Goteborg, Sweden), Paula Atterfeldt, (Sociala Huset, Goteborg, Sweden), Arnt Steier and Magnar Ulstein (Haukeland Hospital, Bergen, Norway), Istvan Batar (University Medical School, Debrecen, Hungary), Niels Christian Nielsen (Bispebjerg Hospital, Copenhagen, Denmark), Mogens Osler (University Hospital, Copenhagen, Denmark). Financial support was obtained from Leiras Oy, Turku, Finland, and from the Hjalmar Svensson Foundation (University of Goteborg), Sweden.
References 1. 2. 3. 4.
5.
6.
7.
Contraception
Pharriss BB, Ericksson R, Bashow J, Hoff S, Place VA, Zaffaroni A. ProgestasertR: A uterine therapeutic system for long-term contraception: Philosophy and clinical efficacy. Fertil Steril 1974;25:915-21. Bergkvist A, Rybo G. Treatment of menorrhagia with intrauterine release of progesterone. Br J Obstet Gynaecol 1983;90:255-8. Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol 1991;78:291-8. Nilsson CG, Luukkainen T, Arko H. Endometrial morphology of women using a d-norgestrel-releasing intrauterine device. Fertil Steril 1978;29: 397-401. Luukkainen T, Allonen H, Haukkamaa M, Lahteenmaki P, Nilsson CG, Toivonen J. Five years’ experience with levonorgestrel-releasing IUDs. Contraception 1986;33:139-48. Sivin I, El Mahgoub S, McCarthy T, et al. Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the Copper T 380 Ag intrauterine devices: A five-year randomized study. Contraception 1990;42:361-78. Wang SL, Wu SC, Xin XM, Chen JH, Gao J. Three years’ experience with levonorgestrel-releasing intrauterine device and Norplantimplants: a randomized comparative study. Adv Contracep 1992;8:105-14.
1994:49, January
71
Levonorgestrel8.
9.
10.
11.
12. 13. 14.
15.
16. 17. 18. 19.
20.
21.
22.
23.
72
and copper-releasing
IUDs:
Andersson
et al.
Indian Council of Medical Research. Task force on IUD. Randomized clinical trial with intrauterine devices, (levonorgestrel intrauterine device (LNG), CUT 380Ag, CUT 220C and CUT 200B. A 36-month study. Contraception 1989;39:37-52. Luukkainen T, Allonen H, Haukkamaa M et al. Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study. Contraception 1987;36:169-79. Toivonen J, Luukkainen T, Allonen H. Protective effect of intrauterine release of levonorgestrel on pelvic infection: Three years comparative experience of levonorgestreland copper-releasing intrauterine devices. Obstet Gynecol 1991;77:261-4. Luukkainen T, Allonen H, Nielsen NC, Nygren KG, Pyorala T. Five years experience of intrauterine contraception with the Nova-T and the CopperT-200. Am J Obstet Gynecol 1983;147:885-92. Tietze C, Lewit S. Recommended procedures for the statistical evaluation of intrauterine contraception. Stud Fam Plan 1973;4:35-42. BMDP Statistical Software, Inc; Version 1988, Version X90. Los Angeles, CA, USA. Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Path01 1986;5:235-41. Nilsson CG, Lahteenmaki P, Luukkainen T. Ovarian function in amenorrhoeic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steril 1984;41:52-5. Barbosa I, Bakos 0, Olsson SE, Odlind V, Johansson EDB. Ovarian function during use of a levonorgestrel-releasing IUD. Contraception 1990;42:5 l-66. Chick PM, Frances M, Paterson PJ. A comprehensive review of female sterilization-tubal occlusion methods. Clin Reprod Fertil 1985;3:81-97. Lindblom B, Thorburn J. Spiralgraviditet. Lakartidningen 1988;11:923-4. Nilsson CG. Comparative quantitation of menstrual blood loss with a dnorgestrel-releasing IUD and a Nova-T copper device. Contraception 1977;15:379-87. Scholten PC, van Eykeren MA, Christiaens GCML, Haspels A. Menstrual blood loss with levonorgestrel, Nova-T and Multiload Cu250 intrauterine devices. Dissertation, 1989, University of Utrecht, Holland. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrel-releasing intrauterine device and Nova-T. Contraception 1992;46: 575-84. Milsom I, Rybo G, Lindstedt G. The influence of copper surface area on menstrual blood loss and iron status in women fitted with an IUD. Contraception 1989;41:271-81. Andersson K, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97:690-4.
Contraception
1994:49, January
Viveca Odlindf,
G&an Rybo”
‘Department of Obstetrics and Gynecology, Kvinnokliniken, ijstra sjukhuset, Giiteborg, Sweden; and tDepartment of Obstetrics and Gynecology, Kvinnokliniken, Akademiska sjukhuset, Uppsala, Sweden A 20 micrograms124 hours levonorgestrel-releasing intrauterine contraceptive device (LNG-IUD) has, in an open randomized multicenter study, been compared to the copper-releasing device Nova T during 5 years of use; 1821 women had the LNG-IUD and 937 women had the Nova T inserted. The 5-year cumulative gross pregnancy rate was 5.9 % for Nova T and 0.5% for the LNG-IUD. The local effect of levonorgestrel in the uterine cavity causes reduction of menstrual blood loss and development of oligo-amenorrhea, and the termination rates because of heavy and/or prolonged menstrual flow were significantly (P < 0.001) lower among LNG-IUD users. However, thegross termination rate because of amenorrhea was 6.0 in this group. Hb increased during use of the LNG-IUD and decreased during Nova T use, and the difference between the devices was statistically significant. The incidence of pelvic inflammatory disease (PID) was low in LNGIUD users regardless of age, whereas in the Nova T group, the PID rate was increased among the youngest women, which makes the difference between the devices significant (P < 0.01). The gross termination rate for reasons considered to be hormonal was 12.1 in the LNGIUD group compared to 2.0 in the Nova T group (P < 0.001). The LNG-IUD is a long-acting reversible contraceptive method for 5 years with a pregnancy rate comparable to female sterilization. Submitted for publication January 11, 1993; accepted for publication November 24, 1993. Address correspondence to: Kerstin Andersson, Dept of Obstetrics & Gynecology, East Hospital, S-41685 GBteborg, Sweden.
56
Contraception
1994:49, January
0 1994 Butterworth-Heinemann
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
The incidence of PID is low even in young women. In addition, the positive health effects such as decreased menstrual blood loss and increased blood haemoglobin concentration make the LNG-IUD a favorable combination of hormonal and intrauterine contraception. Keywords: Levonorgestrel-releasing
IUD; Nova T; contraception
Introduction Progestogen-releasing intrauterine contraceptive devices were initially developed to reduce uterine contractility and, thus, to prevent expulsion. However, it was found that the steroid did not influence the expulsion rate but increased the contraceptive efficacy compared to a plain T device’ and reduced the menstrual blood 10~s.~ The progesterone-releasing IUD (Progestasert) had to be replaced at 12-month intervals and was associated with an increased risk of ectopic pregnancies.” Levonorgestrel is not metabolized by the endometrium as rapidly as progesterone and has a more uniform and profound local effect.4 An intrauterine contraceptive device which releases 20 micrograms levonorgestrel/24 hours (LNG-IUD) has been studied in comparative trials with the copper-releasing IUDs, Nova T, Copper T 200, Copper T 220 and Copper T 380, and with levonorgestrel-releasing subdermal implants (Norplant-2). The 5 years’ experience of LNG-IUD as compared to Nova Ts and with Copper T 380” and the 3 years’ experience of LNG-IUD as compared to Nor-plant-2’ and Copper T 200, Copper T 220 and Copper T 380x have been reported. These studies have demonstrated both high contraceptive efficacy and decreased menstrual bleeding with LNG-IUD, but also discontinuation because of amenorrhea. At that time, when the 5-year studies where LNG-IUD was compared to a copper IUD were started, oligo-amenorrhea was not known to be a frequent concomitant to intrauterine release of levonorgestrel. Therefore, the information about the strong effect of the LNG-IUD on menstrual bleeding and the frequent and expected development of oligo-amenorrhea was not given to the women. The aim of the present investigation was to more extensively, in a randomized comparative way, study LNG-IUD and Nova T during five years of use, and to apply an open design to ensure an efficient and high quality counselling. The results after the first and the third year”,‘0 have earlier been published.
Materials and Methods Nova-T is a copper-releasing device with a silver-cored copper wire wound around the vertical stem. The copper surface area is 200 mm2 and the
Contraception
1994:49, January
57
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
effective life span is at least five years. I1 LNG-IUD has the same polyethylene skeleton as Nova T and the steroid is homogeneously dispersed in a polydimethyl-siloxane reservoir covered by a rate-limiting membrane on the vertical arm of the device (Figure 1). The devices used in this study contained 46 mg of levonorgestrel. The initial in vitro release rate of levonorgestrel is 20 micrograms/24 hours and about 15 micrograms/24 hours after five years. The life span of the LNG-IUD is at least five years.s As the steroid reservoir is slightly thicker than the copper wire, the insertion tube of the LNG-IUD is 4.8 mm compared to 3.7 mm for the Nova T insertion tube. Both IUDs are manufactured by Leiras OY, Turku, Finland. The study was carried out in four clinics in Finland, four clinics in Sweden, two clinics in Denmark, one clinic in Hungary and one in Norway. Women, who were visiting the clinics requesting contraception, were asked if they wanted to participate in a clinical trial and informed verbal consent was obtained. The woman had to be healthy, 18-38 years old and should have had at least one previous pregnancy. If she had a history of ectopic pregnancy, was breast-feeding or had used injectable steroid
FIGURE 1. The 20 micrograms/24 hours levonorgestrel-releasing the copper-releasing device (Nova T) to the right.
58
device (LNG-IUD)
Contraception
is shown to the left and
1994149, January
Levonorgestrel- and copper-releasing IUDs:
Andersson et al.
hormones for contraception during the preceding 12 months, she was not accepted into the study. The woman had to be willing to accept an induced abortion in case of an accidental pregnancy with the LNG-IUD, as knowledge about teratogenic risks is lacking. Into the treatment groups 2758 women were allocated, 937 had a Nova T and 182 1 had an LNG-IUD inserted. All devices were inserted between November 1982 and December 1984. In the Nova-T group 133 and in the LNG-IUD group 305 women had the IUD inserted in connection with an induced first trimester abortion, but this group is too small for separate evaluation. The mean age was 30.3 years in both groups (SD 4.9 in the Nova T and 5.0 in the LNG-IUD group] and the distribution of age is shown in Table 1. The mean parity were 1.7 (SD 0.9) and 1.8 (SD 0.9) in the Nova T and LNG-IUD groups, respectively. At the completion of the study, life table analysis of pregnancy and discontinuation rates was made using the terminology suggested by Tietze & Lewit.12 Multiple-decrement life table rates (net rates) and singledecrement (gross) rates were calculated. The differences in the cumulative life table rates between the two groups were tested for statistical significance with Mantel-Cox (log-rank) statistics of the BMDP software package.13 The limit of statistical significance was set at I? = 0.05. Approval for the study was obtained from the ethics committees of all universities involved.
Study Design The study was an open randomized comparative multicenter trial of two parallel groups. The IUD was inserted within 3-10 days after the onset of menstruation. If signs of cervicitis were noted, the infection was treated and the IUD insertion was postponed. The device could also be inserted in connection with a first trimester abortion. A specially designed protocol
TABLE
1. Distribution of age in 2758 women receiving Nova T or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD)
Nova T
LNG-IUD
Total
N
%
N
%
5 25 26-30 31-35 236
177 263 358 139
18.9 28.1 38.2 14.8
338 532 645 306
18.6 29.2 35.4 16.8
TOTAL
937
Age (years)
Contraception 1994:49, January
100
1821
100
N
%
515 795 1003 445
18.7 28.8 36.4 16.1
2758
100
59
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
was used in all centers and a standardized interview was performed at admission and at every follow-up visit, which was planned after 3 and 12 months and then yearly up to five years. Furthermore, during the first 12 months, all women were requested to note bleeding patterns continuously on a specially designed chart. In case of any problem, the women were immediately seen by the investigators. Prospective uniform criteria for diagnosis and treatment of side effects have been used, and the women were encouraged to contact the investigator’s clinic in case of problems, and the event was reported to the study center. The diagnosis pelvic inflammatory disease (PID) included acute salpingo-oophoritis, tubo-ovarian abscess and pelvic peritonitis. In the study protocol, the PID diagnosis required at least two of the following symptoms or signs: 1) history of lower abdominal pain and body temperature more than 38” C, 2) increased sedimentation rate over 30 mm/hour, 3) tenderness on pelvic examination, 4) mass on pelvic examination, and 5) laparoscopy or ultrasound examination if other clinical evidence was controversial.
Results Continuation Rate In the Nova T group 133 women (14% of the acceptors) and in the LNGIUD group 115 women (6.3% of the acceptors) were lost to follow-up during the study. Of the 2758 women enrolled into the study, 315 acceptors of Nova T and 736 acceptors of LNG-IUD completed the 60 months follow-up and the continuation rate at five years was 44.5 for Nova-T and 46.9 for the LNG-IUD (Table 2). The continuation rate was, for both IUDs, higher in the older age groups (Table 3).
Contraceptive Efficacy The 5-year cumulative gross pregnancy rate was 5.9 for Nova-T and 0.5 for LNG-IUD [(P < 0.001) Figure 2, Table 31. During the 60-month observation period, 35 women in the Nova-T and 5 in the LNG-IUD group became pregnant. Among the pregnancies, 7 were ectopic in the Nova-T group and 1 in the LNG-IUD group (Table 4). The pregnancies in the LNG-IUD group and the woman’s age at IUD insertion are described below: 1. Occurred during the 10th month of use after an unnoticed expulsion in a 35.year-old woman. An induced abortion was performed. 2. Occurred 23 months after insertion in a 37-year-old woman. When the
60
Contraception
1994:49, January
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
Net cumulative termination rates per 100 each year in 937 women using Nova T and 1821 women using a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD) during 5 years
TABLE 2.
Event Pregnancy Expulsion Bleeding problems Amenorrhea Pain Hormonal PID Other medical Planning pregnancy Other personal Continuation
1
2
Year 3
4
5
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
Nova T LNG-IUD
0.9 3.4 5.7
0.1 3.4 5.8
2.2 4.1 9.0
0.1 4.2 8.3
3.1 4.8 12.0
0.2 4.8 9.6
4.0 5.3 14.3
0.3 4.9 10.3
4.2 5.5 16.2
0.3 4.9 10.9
0.0 1.6 0.1 0.4 2.4 1.9
1.5 1.6 2.3 0.3 2.7 1.9
0.0 2.6 0.1 1.0 3.8 5.5
2.9 2.8 4.8 0.5 3.6 5.7
0.0 3.3 0.6 1.5 5.4 8.1
3.6 3.4 6.4 0.5 4.8 8.2
0.0 3.8 0.7 1.5 6.4 10.6
4.2 3.9 7.6 0.5 5.5 10.1
0.0 4.2 1.1 1.6 7.6 11.8
4.3 4.2 8.4 0.6 5.8 10.8
0.6 83.0
0.6 79.9
1 .o 70.7
1.5 65.6
1.7 59.4
2.0 56.7
2.5 50.8
2.3 50.6
3.3 44.5
2.9 46.9
termination of pregnancy was performed, submucous uterine fibroids were diagnosed. 3. Ectopic pregnancy after 30 months of IUD use in a woman aged 28; the device was found in situ. The right tube was resected. 4. Intrauterine pregnancy in a 35year-old woman 41 months after insertion. The device was found in situ and spontaneous abortion occurred in the sixth week. 5. Occurred after a complete unnoticed expulsion of the device in a 40year-old woman 46 months after insertion. Spontaneous abortion occurred in the sixth week. Seven ectopic pregnancies occurred in the Nova T group after 4-23 months of IUD use and the mean age of these women was 34 (range 27-38) years. Expulsion The 60-month cumulative gross expulsion rate was 6.7 in the Nova T group and 5.8 in the LNG-IUD group (Table 3). Most of the expulsions were noted during the first months after insertion. Bleeding
Problems
The gross cumulative removal rate for bleeding was 20.7 for the Nova T and 13.7 for the LNG-IUD (P c 0.01) at five years (Table 3). Termination
Contraception
1994:49, January
61
TABLE
3. Cumulative 60-month age-specific gross rates of use-related terminations and continuation in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD, N = 1821)
Age (years) 5 25 PREGNANCY 14.9 Nova T LNG-IUD P ; Expulsion Nova T 8.2 LNG-IUD 4.9 P NS BLEEDING PROBLEMS 34.7 Nova T LNG-IUD 20.9 P NS AMENORRHEA 0 Nova T LNG-IUD 9.3 * P PAIN Nova T 8.6 LNG-IUD 6.2 P NS HORMONAL 6.6 Nova T LNG-IUD 10.0 P NS PID Nova T 5.6 LNG-IUD 0.3 * P OTHER MEDICAL 11.3 Nova T LNG-IUD 8.2 P NS PLANNING PREGNANCY 40.7 Nova T 42.0 LNG-IUD P NS OTHER PERSONAL 12.6 Nova T LNG-IUD 5.1 P NS CONTINUATION RATE Nova T 18.9 LNG-IUD 29.0 P NS NS = not significant.*
62
26-30
31-35
2 36
Total
6.9 0.4
4.0 0.5
5.9 0.5
t
t
2.8 0.9 NS
6.4 7.7 NS
7.8 5.2 NS
1.6 5.9 NS
6.7 5.8 NS
22.2 17.8 NS
17.2 9.7
21.4 9.0 f
20.9 13.7
0 8.8
0 4.4
0 6.0
t
t
0 2.6 NS
8.7 6.6 NS
3.6 6.3 NS
4.4 3.8 NS
5.8 5.9 NS
1.1 15.0
2.4 12.3
0 9.8
2.0 12.1
t
t
l
t
l
t
t
t
3.0 1.4 NS
1.4 0.7 NS
0 0.3 NS
2.2 0.8 *
9.4 7.1 NS
9.2 7.7 NS
13.0 7.3 NS
10.6 7.7 NS
25.1 19.1 NS
7.8 6.9 NS
2.9 2.2 NS
16.3 15.2 NS
7.3 3.1 NS
4.5 5.3 NS
4.4 3.8 NS
5.9 4.4 NS
37.4 39.3 NS
54.4 54.1 NS
58.1 63.3 NS
53.1 55.5 NS
= P 5 0.01. t = P < 0.001.
Contraception
1994:49,
January
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
6-
et al.
r----r---a
I4 , __’ _-_I-
a
_--a
4r--
I
_I -_a
I
__
I
__
I-
I
2-
__,aI-
--
c--
dI
L
2
3
4
5
Year FIGURE 2. Five-year cumulative gross pregnancy rate per 100 women for 937 women during use of Nova T (- - -) and for 1821 women during use of a 20 micrograms/24 hours levonorgestrel-releasing device (-).
TABLE 4. Number of pregnancies and pregnancy rate per 100 women-years (Pearl rates) during five years’ use of Nova T and a 20 micrograms/24 hours levonorgestrel-releasing device (LNGIUD)
Nova T All pregnancies (N) Ectopic pregnancies (N) Women-years (WY) Pregnancy rate/l 00 WY Ectopic rate/100 WY
Contraception
1994:49, January
35 7 2776
1.26 0.25
LNG-IUD 5 1 5615 0.09 0.02
Levonorgestrel-
and copper-releasing
KIDS:
Andersson
et al.
for heavy and prolonged menstrual flow differed significantly between the groups in favour of the LNG-IUD, whereas the removal rate for irregular bleeding or spotting did not differ (Table 5). The bleeding patterns during the first year were studied in detail by analyzing the menstrual records from 739 women in the Nova-T and 1495 in the LNG-IUD group (Figure 3). During the first three months after insertion, there were, on average, more days with menstruation-like bleeding and/or spotting in the LNG-IUD group compared to the Nova-T group (P < 0.001). With passing time, the situation changed, and at 12-month follow-up, the mean number of days with bleeding and/or spotting was significantly lower in the LNG-IUD group [(P < O.OOl), [Figure 3)]. When only days with menstruation-like bleeding were calculated, the mean number of days were initially equal in both groups, and there was a gradual decrease in the LNG-IUD group during the observation period, whereas in the Nova-T group, the number of days with bleeding per month was unchanged after the initial months.
Amenorrhea During the first year after IUD insertion, 2.7% of the Nova-T users and 16.8% of the LNG-IUD users experienced a period of at least 90 days’ amenorrhea. The cumulative net rate of removal because of amenorrhea was 4.3 for LNG-IUD and 0 for Nova T ((P < O.OOl), (Table 2)]. The corresponding gross rates in different age groups appear in Table 3. Amenorrhea led to higher termination rate in younger women compared to older.
Pain No difference (Table 2).
between
the groups in termination
rates for pain was seen
TABLE
5. Cumulative 60-month gross termination rate because of bleeding problems in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device [(LNGIUD), (N = 1621)]
Nova T
LNG-IUD
Frequent irregular bleeding Heavy menstrual flow Prolonged menstrual flow
3.9 9.7 6.5
5.3 1.3 2.3
NS
Spotting Other bleeding problems
2.2 0.4
1.6 3.9
NS *
NS = not significant.
64
P
l
*
* = P < 0.001.
Contraception
1994:49, January
Levonorges trek- and copper-releasing
Andersson
I UDs:
et al.
14 12 10 -
642-
0'
0
I
1
I
I
I
2
3
4
I
I
1
I
I
1
I
I
5
6
7
8
9
10
11
12
Period
8-
6-
4-
2-
0’
I
0
1
1
I
I
I
I
I
I
2
3
4
5
6
7
8
I
9
I
10
I
17
1
12
Period
FIGURE 3. Mean number of days with bleeding and/or spotting or only bleeding each month during the first year of use of Nova T (open circles) or a 20 micrograms/24 hours levonorgestrel-releasing device (solid circles).
Contraception
1994149, January
65
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
Pelvic Infections There was in neither the Nova T nor in the LNG-IUD group an increased incidence of PID in relation to the IUD insertion (Figure 4). The 60-month gross removal rates for PID were 2.2 in the Nova T and 0.8 in the LNGIUD group [(P < O.OS), (Table 3)]. In the LNG-IUD users, the incidence of PID was low regardless of age whereas in the Nova T group, there was a significantly (P < 0.01) increased PID rate compared to LNG-IUD among the youngest women (Table 3).
Hormonal Side Effects A number of side effects shown in Table 6, were considered to be related to the levonorgestrel administration and the discontinuation rate because of such hormonal side effects was higher in the LNG-IUD group than in the Nova T group [(P < O.OOl), (Table 3)].
O/O
8
6-
4-
2-
*_py-;;-,I,
0
-_ _--a 1
,-I-,
I-’
_,-__I’ (
1 1
-_-__--
__-------_-------
f
I ,
,
(
1
,
,
3
2
,
I
,
4
,
I
5
Year FIGURE 4. Five-year cumulative gross rate of pelvic inflammatory disease per 100 women, for 937 women during use of Nova T (- - -) and for 1821 women during use of a 20 micrograms/24 hours levonorgestrelreleasing IUD ().
66
Contraception
1994:49,
January
Levonorgestrel-
and copper-releasing
IUDs:
Andersson
et al.
TABLE
6. The cumulative 60-month gross termination rate for hormonal reasons in women using Nova T (N = 937) or a 20 micrograms/24 hours levonorgestrel-releasing device [(LNGIUD) N = 18211
Nova T 0 0.4 0.2 0 0 0.4 0 0 0.7
Depression Acne Headache Weight change Breast tenderness Nausea Hirsutism Other skin problems Other mood changes NS = not significant.
* = P < 0.05. T = P < 0.01.
LNG-IUD 2.9 2.3 1 .Q 1.5 0.8 0.8 0.7 0.5 1.5
P
*
: f NS NS NS NS
* = P < 0.001.
Other Medical Reasons The 60-month gross removal rate for other medical reasons than reported above are shown in Table 3. The termination rates per 100 women-years for enlarged follicles were almost similar in the two groups-O.07 for Nova T and 0.09 for LNG IUD. Four women in the LNG-IUD group discontinued the study due to hypertension and none in the Nova-T group discontinued for this reason. During the observation period, there were no changes in mean systolic or mean diastolic blood pressure in any women using LNG-IUD or copperreleasing IUD.
Personal Reasons Planning pregnancy and other personal reasons for termination were similarly age-related in users of both IUDs and more common among young women (Table 3).
Effect on Weight and Haemoglobin The mean weight at admission was 61.9 (SD 10.6) kg in the Nova T group and 62.0 (SD 10.0) in the LNG-IUD group. After five years the mean weight had increased to 64.4 kg in both groups. The changes in haemoglobin concentration during the observation period are shown in Table 7. After 5 years, the mean haemoglobin concentration showed an increase of 1.6 g/l during use of LNG-IUD and a decrease of 2.6 g/l during use of Nova T. The differences between the two device
Contraception
1994:49, January
67
Levonorgestrel-
and copper-releasing
Andersson
IUDs:
et al.
TABLE 7. Mean values (SD) of Hb during five years’ use of Nova-T or a 20 micrograms/24 hours levonorgestrelreleasing device (LNG-IUD). Only women where values are available at admission as well as at the control visit are included. The percentage of women completing each observation period and in whom Hb values are available is presented (%). P values indicate the differences in change of Hb between the device groups.
Nova T Time
Hb
N
LNG-IUD (“A)
Hb 135.7 137.6 135.6 136.4 133.9 134.9 133.4
N 10.7) 10.4) 10.7) 9.3) 10.0) 9.3) 9.8)
1227 1227 1043 1043 706 706 571
W)
P
(86)
t
(91)
*
(73)
l
Adm 1 year Adm 2 years Adm 3 years Adm
135.8 134.9 135.9 132.4 134.3 132.0 132.9
(10.3) (11.1) (10.9) (10.5) (10.6) (11.2) ( 9.8)
618 618 509 509 343 343 253
4 years Adm
132.3 ( 9.9) 135.4 (10.0)
253 254
(65)
134.5 ( 9.9) 134.6 (10.7)
571 622
(67)
’
5 years
132.8 (10.1)
254
(80)
136.2 ( 9.5)
622
(85)
*
(84) (84) (72)
* = P< 0.05. t = P< 0.01. * = P < 0.001
groups, in change of haemoglobin concentration, cant during the entire follow-up period.
are statistically
signifi-
Reported Subjective Side Effects Main categories of side effects elicited by asking the woman the question “How have you been feeling?” are described in Table 8. The rate of reported side effects decreased over time but at three months there were significant differences between the devices concerning back pain, headache, nausea, depression, menstrual problems, acne and mastalgia which were all more often reported in the LNG-IUD group. At five years, 25.9% of the NovaT users and 15.1% of the LNG-IUD users mentioned problems. Menstrual problems were pointed out by 18.8% and 6.3%, respectively (P < O.OOl), and other complaint categories were reported at a rate of less than 5%.
Discussion The intrauterine release of levonorgestrel makes the endometrial glands atrophic, the epithelial cells inactive and the stroma decidua1ized.1~ The endometrium is converted to be insensitive to ovarian estradiol. These changes are probably the most important for the clinical performance of the LNG-IUD. There are only limited effects on ovulation and on the pituitary.‘“,‘” The contraceptive efficacy of the LNG-IUD was, in this study, comparaand so far, the LNG-IUD is one of the most ble to female sterilization,”
68
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Levonorgestrel-
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Andersson
et al.
TABLE 8. Subjective side effects (%) reported at 3 and 60 months in women using Nova T copper IUD or a 20 micrograms/24 hours levonorgestrel-releasing device (LNG-IUD)
3 Months
No problems Back pain Low abdominal pain Headache Nausea Depression Menstrual problems Acne Mastalgia Other NS = not significant.
l
60 Months
Nova T
LNG-IUD
P
Nova T
LNG-IUD
64.5
49.8
t
74.1
84.9
1.9 1.8
3.1 10.5
0.3 2.7
1 .o 2.0
NS NS
0.8 0.2 0.4 22.2
2.8 2.4 2.5 32.1
f *
1 .o 0 0.3 18.8
1.6 0.3 0.6 6.3
NS NS NS
0.4 0.2 6.1
3.5 3.1 8.7
f
0.3 0.7 4.8
1.8 1 .o 3.6
NS NS NS
= P < 0.001.
l
NS
l l
l
t
P *
l
t = P c 0.05.
effective long-term reversible contraceptive methods requiring single application. The rate of ectopic pregnancy in our study (0.02 per 100 women-years in the LNG-IUD group and 0.25 per 100 women-years with Nova T) could be compared to the ectopic pregnancy rate of 1.2-1.6 per 100 womenyears in sexually active Swedish women age 15-44 seeking pregnancy.lX The estimated ectopic pregnancy rate in women using TCu 380 or MLCu 375 is similar to LNG-IUD; 0.02 per 100 women-years indicating that these devices are highly effective in preventing ectopic pregnancies as well.3 The ectopic pregnancy rate in the Nova T group (0.25 per 100 women-years) was higher in our study compared to other investigations3 This may be explained by an increased incidence in the population studied and in Sweden the ectopic rate has been increasing the last decade.lR Bleeding problems were the most common reason for discontinuing the use of both IUDs, but termination for this reason was more common in the Nova-T group. These results concerning the copper IUD are similar to those presented by other investigators.” The termination rate for heavy and prolonged menstrual flow was lower with LNG-IUD compared to Nova T. However, the removal rate for irregular bleeding and spotting was similar in both groups. Frequent irregular bleeding is more common during the first months after LNG-IUD insertion, and during prolonged use of the LNG-IUD, a reduction of the number of days with bleeding and/or spotting will occur. It is crucial that the woman has been carefully
Contraception
1994149,
January
69
Levonorgestrel-
and copper-releasing
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et al.
informed about what to expect concerning the bleeding pattern after LNGIUD insertion, to avoid an unnecessary removal. The local effect on the endometrium by levonorgestrel leads to reduction of the menstrual blood loss and to oligo-amenorrhea.19,zo The nature of this endometrial amenorrhea should be included into the information which is given to the woman before insertion of the LNG-IUD, to prevent uncertainties about pregnancy or later return to fertility. The 5-year gross cumulative termination rate because of amenorrhea was 6.0, but this is not an estimate of the incidence of amenorrhea, the menstrual diaries have to be analyzed for calculation. In Sivin’s blind study,” the gross removal rate because of amenorrhea was 19.7 after 5 years. When women are well informed about the reduction of bleeding and development of oligo-amenorrhea, they may learn to like the freedom of the non-bleeding situation. It is important to inform the women that amenorrhea does not reduce the ability to conceive after removal of the LNG-IUD. Return to fertility is as rapid after removal of LNG-IUD as after Nova-T.*’ Moreover, excessive menstrual blood loss is the most common cause of anemia in fertile women, and nonmedicated IUDs increase the blood loss about 50-75 % .22 The LNG-IUD reduces the blood loss and increases the hemoglobin concentration during use. This may be especially important for women in developing countries where poor nutrition and/or diseases may contribute to an iron-deficient situation. The strong progestogen dominance of the endometrium has also been used as therapeutic principle to treat excessive menstrual bleeding. It seems that the LNGIUD can replace hysterectomy and endometrial ablation in most women suffering from idiopathic menorrhagia.2” The reduced risk of PID in the LNG-IUD group compared to Nova T use, has earlier been demonstrated. lo In other studies where LNG-IUD has been compared to copper IUD, similar PID rates have been demonstrated in both groups.i,6,X The incidence of PID, in the present study, is low in both IUD groups; nevertheless, there was a decreased risk of PID during LNG-IUD use, and the difference between the device groups is statistically significant in women less than 25 years of age. This is the age group where PID is most common and an increased risk of PID following use of conventional IUDs makes intrauterine contraception unsuitable for young women. Use of LNG-IUD may change this opinion. It is important to notice that no increase in PID was seen in relation to the insertions. The reason for this may be that cervicitis was excluded before and aseptic technique used at insertion. Removal rate for reasons which were classified as “hormonal” was higher in the LNG-IUD group compared to Nova-T. Most of the reported side effects after three months of use were hormonal, but these side effects decreased during the study period. However, it is obvious that the dosage of 20 micrograms levonorgestrel/24 hours exerts certain systemic hormonal
70
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Levonorgestrel-
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IUDs:
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et al.
effects. Therefore, it is important that counselling also includes information that the LNG-IUD is a hormonal contraceptive method, even if the daily dose of levonorgestrel is only a fraction of the dose which is given in oral contraceptives.
Acknowledgments This multicenter study was conducted by the following investigators: Maija Haukkamaa and Tapani Luukkainen (City Maternity Hospital, Helsinki, Finland), Juhani Toivonen (Planned Parenthood Association, Helsinki, Finland), Pentti Holma and Tapani Pyorala (Central Hospital, Jyvaskyla, Finland), J u h ani Terho (Health Center, Tampere, Finland), Hannu Allonen (Leiras Oy, Turku, Finland), Elof Johansson, Viveca Odlind, and Sven-Eric Olsson (University Hospital, Uppsala, Sweden), Staffan Nilsson (Falu Hospital, Falun, Sweden), Bo Sikstrom and Ann-Charlotte Smeds (Central Hospital, Eskilstuna Sweden), Kerstin Andersson and Goran Rybo (East Hospital, Goteborg, Sweden), Paula Atterfeldt, (Sociala Huset, Goteborg, Sweden), Arnt Steier and Magnar Ulstein (Haukeland Hospital, Bergen, Norway), Istvan Batar (University Medical School, Debrecen, Hungary), Niels Christian Nielsen (Bispebjerg Hospital, Copenhagen, Denmark), Mogens Osler (University Hospital, Copenhagen, Denmark). Financial support was obtained from Leiras Oy, Turku, Finland, and from the Hjalmar Svensson Foundation (University of Goteborg), Sweden.
References 1. 2. 3. 4.
5.
6.
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