Key words
insemination - infertility - reproductive medicine - pregnancy
Schlüsselwörter
Insemination - Infertilität - Reproduktionsmedizin - Schwangerschaft
Introduction
The term “intrauterine insemination” (IUI) is used to describe the transfer of sperm
into the uterus. It is one of the oldest techniques of reproductive medicine, first
performed in 1790 by the English physician Dr. John Hunter and described by Home in
1799 [1]. The current practice of intrauterine
insemination comprises sorting and washing the sperm, determining the optimal time
of conception and introducing the sperm into the uterine cavity. In many cases,
women additionally undergo controlled ovarian stimulation to trigger ovulation. The
prerequisite for successful insemination is an intact tubular and uterine transport
system, sufficient numbers of healthy sperm, and guaranteed ovulation. Intrauterine
insemination should not lead to any delay in attempting more effective
procedures.
Intrauterine insemination is less widely used than other, more effective but much
more invasive procedures in reproductive medicine such as in vitro fertilisation
(IVF) and intracytoplasmic sperm injection (ICSI). In 2008, 21 000 IUI cycles were
carried out in Germany in addition to 42 958 IVF and ICSI cycles [2]. Intrauterine insemination can be a successful procedure
in selected patients. Acceptance of IUI by patients is high as it is similar to
natural insemination and is perceived to be a less invasive intervention in the
coupleʼs reproductive life.
Since 2004, § 27 a of the SGB V (German Code of Social Law) requires statutory heath
insurance companies in the Federal Republic of Germany to contribute to the costs
of
3 insemination cycles after previous stimulation with follicle-stimulating hormone
FSH in married couples where the woman is below the age of 40 and the man is below
the age of 50. Using the data from a large number of insemination cycles this study
aimed to evaluate the impact of maternal age and number of insemination cycles on
the success rates for insemination.
Method
Between 1998 and 2010, the Wiesbaden Fertility Clinic carried out a total of 6053
homologous intrauterine inseminations in 2262 patients. Insemination was only done
after previous examination found no indications of tubular damage. All patients were
ovulating, either as part of their natural cycle, or following low-dose FSH
stimulation or stimulation with clomifene. Ovulation was triggered by the
administration of human chorionic gonadotropin (hCG).
Inclusion criteria for this retrospective analysis were a maximum patient age of 45
years, limited sperm motility of the patientʼs partner and stimulation with FSH. A
total sperm count of at least 10 million/ml and a motility of at least 35 % were
required for insemination. A total of 4246 insemination cycles in 1612 women were
included in the analysis. The average number of IUI cycles per patient was 2.24
(1–14). In this patient cohort, 158 patients became pregnant more than once through
insemination. A second insemination after a previous pregnancy was classified as a
first cycle, so that 1770 “treated cases” were evaluated overall. Previous
treatments in other fertility clinics were not included in this analysis.
Preparation of the ejaculate consists of washing and the swim-up technique. Washing
of the ejaculate is done to separate sperm cells from seminal plasma. Washing is
done by mixing and centrifuging the ejaculate with a culture medium. After the
heavier spermatozoa collect at the bottom, the remaining liquid are siphoned off and
the spermatozoa are mixed and diluted with another culture medium for direct use.
In
a further preparation step termed “swim-up”, the washed semen is centrifuged again
and the supernatant siphoned off. The remaining sperm are mixed with a culture
medium. The motile sperm swim upwards and can be directly aspirated with a catheter
[3].
The insemination cycles were analysed retrospectively. Patient age, number of
insemination cycles carried out till pregnancy or until this form of treatment was
abandoned and pregnancy rates were included in the analysis. The study was approved
by the Ethics Commission of the Johannes-Gutenberg University. All patients gave
their informed consent to the study.
Aim of the study was to identify the benefit of repeated insemination cycles for
women in different age groups. Statistical analysis was done using the statistical
software programme SPSS 18. Logistic regression analysis was used to calculate the
impact of maternal age on becoming pregnant. The odds ratio was calculated. The
level of significance α was set at 5 %.
Results
Average patient age was 33.9 years at the start of therapy. Age range of patients
was
from 19 to 45 years. Patients were grouped into age groups to show age distribution.
Both the pregnancy rates per cycle and the pregnancy rates per patient decreased
significantly with increased age ([Table 1]).
Table 1 Pregnancy rate as a function of age.
|
Age (years)
|
< 24
|
25–29
|
30–34
|
35–39
|
40, 41
|
42, 43
|
> 43
|
|
Patients
|
32
|
260
|
687
|
658
|
94
|
27
|
12
|
|
Total number of cycles
|
61
|
564
|
1 650
|
1 652
|
222
|
64
|
29
|
|
Mean number of cycles
|
1.91
|
2.17
|
2.40
|
2.52
|
2.36
|
2.37
|
2.42
|
|
IUI without pregnancy
|
49
|
491
|
1 470
|
1 506
|
202
|
60
|
28
|
|
IUI with pregnancy
|
12
|
73
|
180
|
146
|
20
|
4
|
1
|
|
Pregnancy rate/cycle(%)
|
19.67
|
12.94
|
10.91
|
8.84
|
9.01
|
6.25
|
3.45
|
|
Pregnancy rate/patient (%)
|
37.5
|
28.02
|
26.20
|
22.19
|
21.28
|
14.81
|
8.33
|
Patient age had a statistically measurable impact on pregnancy rates. Logistic
regression analysis showed a drop in pregnancy rates with increasing age (p = 0.000,
CI: 0.905–0.962). The likelihood of becoming pregnant after insemination dropped by
6.7 % in the analysed age groups, with an odds ratio of 0.933 per additional year
of
life.
Younger women had fewer insemination cycles than older women. Patients below the age
of 25 years underwent an average of 1.91 cycles while women aged more than 43 years
had an average of 2.42 cycles ([Table 1]). Pregnancy
rates remained stable even after several insemination cycles. Up until cycle 7,
pregnancy rates were between 7.5 and 10 %. The number of patients who underwent more
than 3 cycles had already dropped significantly by the 4th cycle ([Table 2]).
Table 2 Pregnancy rates per insemination cycle, 4 262
cycles.
|
Number of IUI cycles
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
> 7
|
|
Total number of women
|
1 770
|
1 298
|
811
|
218
|
90
|
39
|
13
|
7
|
|
IUI without pregnancy
|
1 575
|
1 158
|
747
|
196
|
81
|
35
|
12
|
7
|
|
IUI with pregnancy
|
198
|
140
|
64
|
22
|
9
|
4
|
1
|
0
|
|
Pregnancy rate
|
11.16
|
10.74
|
7.82
|
10.0
|
10.0
|
10.26
|
7.69
|
0
|
[Table 3] shows the pregnancy rates per insemination cycle
depending on maternal age. It is notable that the pregnancy rates of patients aged
40 and 41 did not differ from those of patients aged between 35 and 39. The success
rates were similar for both groups up until the 3rd cycle. This is also shown in
[Fig. 1] which depicts the cumulative pregnancy rates
for each age group.
Fig. 1 Cumulative pregnancy rates after each insemination cycle for the
different age groups.
Table 3 Pregnancy rates per insemination cycle for the
different age groups.
|
Number of IUI cycles
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
> 7
|
|
< 25 years
|
25
|
21.05
|
0
|
0
|
|
|
|
|
|
25–29
|
14.62
|
10.86
|
11.54
|
15.79
|
25.00
|
0
|
|
|
|
30–34
|
12.08
|
11.18
|
9.55
|
6.58
|
6.90
|
15.38
|
0
|
0
|
|
35–39
|
8.66
|
10.16
|
5.38
|
11.96
|
13.04
|
11.11
|
14.29
|
0
|
|
40 + 41
|
9.57
|
12.70
|
6.06
|
5.56
|
0
|
0
|
0
|
|
|
42 + 43
|
3.70
|
4.17
|
0
|
28.57
|
0
|
0
|
|
|
|
> 43
|
0
|
0
|
9.09
|
0
|
0
|
0
|
0
|
0
|
Discussion
Age has an important impact on the success rates after insemination. The pregnancy
rate per patient was significantly higher for women below the age of 25 compared to
women aged 35 to 39. Pregnancy rates gradually decrease over the course of a
patientʼs life. The difference between the youngest group of patients aged less than
25 years and the next group aged between 25 and 29 was very noticeable. There was
a
similar drop in pregnancy rates in the group aged more than 41 years compared to the
group of patients aged 40 or 41. In the group of patients aged 40 and 41 there was
still a concrete likelihood of becoming pregnant comparable to that for the group
aged 35 to 39. Up until the 3rd cycle, the pregnancy rates of patients aged 40 or
41
did not differ from those of patients between 35 and 39 years of age. These data
show that insemination therapy is still justified in patients aged 40 and 41. The
data presented here confirm the results of many other studies [4], [5], [6], [7], which have all described the impact of increasing age
on the success of insemination.
Among the group of patients below the age of 25, no further pregnancies occurred
after 2 insemination cycles. This could be an indication that their unfulfilled wish
to have a child could have another cause, for example, that male subfertility was
more pronounced than originally supposed. Our data suggest that it may not be useful
to carry out more than 2 insemination cycles in these young patients. In all other
patient groups below the age of 40, pregnancy rates per cycle averaged between 5 and
15 % up until the 6th insemination. In women aged more than 40, only a few
pregnancies were achieved after 3 insemination cycles. Custers et al. [8] have also shown that even after several insemination
cycles the pregnancy rates can be quite good. Other studies, however, have reported
a strong decrease in pregnancy rates after only a few cycles [4], [9], [10], [11]. The data used in this study suggested that 6
insemination cycles can be recommended for patients aged between 30 and 40, while
in
patients aged more than 40 only isolated pregnancies occur after the 3rd attempt.
Other working groups have recommended between 3–9 insemination cycles per couple
[8], [9], [10].
The interpretation of the data in this study is complicated by the fact that out of
a
total of 1770 patients, only 218 underwent more than three attempts at insemination.
This is most probably due to the fact that since 2004 statutory health insurance
companies in Germany are not obliged to fund more than 3 cycles. The 4th to 6th
insemination cycles continued to result in good pregnancy rates in women below the
age of 40; however, the patient cohort undergoing these insemination cycles was
significantly smaller than that in the first 3 cycles.
Currently, statutory health insurance companies in Germany contribute to the costs
of
3 insemination cycles after stimulation with FSH in women up to the age of 40. Our
data shows that pregnancies in these patients can still result after additional
insemination cycles. The chances of success for these later cycles correspond to
those for the first 3 insemination cycles. In patients aged 40 and 41, a successful
pregnancy is most likely with 3 insemination cycles. After more than 3 insemination
cycles, pregnancies only occurred in isolated cases.
Conclusion
Intrauterine insemination can be a promising therapy in selected patients. Pregnancy
rates for patients aged 40 years remained stable even after more than 3 cycles, up
until 6 cycles. For the first 3 insemination cycles, the success rates for women
aged 40 and 41 did not differ from those of women under 40. However, no more than
3
insemination cycles should be attempted in these women.
The overall pregnancy rates after insemination were 5–15 % and thus clearly lower
than those obtained with more invasive reproductive methods such as IVF or ICSI, as
demonstrated by data from the German IVF Registry [2].
Patients seeking to become pregnant should be given detailed information about this
point. It could play an important role in the choice of method by older couples.
