Document Type : Research Article
Authors
1 Department of Obstetrics and Gynecology, Akbar Abadi Teaching Hospital, Iran University of Medical Sciences and Health Services, Tehran, Iran;Department of Endocrinology and Female Infertility at Reproductive Biomedicine
2 Department of Obstetrics and Gynecology, Akbar Abadi Teaching Hospital, Iran University of Medical Sciences and Health Services, Tehran, Iran
3 Department of Endocrinology and Female Infertility at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Abstract
Keywords
The majority of infertile couples seek a less invasive and less costly therapeutic option in assisted reproductive techniques (ART); intrauterine insemination (IUI) is one of these options.
Overall pregnancy rate (PR) that have been reported
in previous studies range from as low as
2.7 to as high as 70% (
This study aims to identify the prognostic factors that affect PRs in IUI treatments within different infertility etiology groups. The results of this study might be useful to assist with making the best individual decision in the treatment of patients with different infertility etiologies.
This study retrospectively considered the consecutive artificial insemination with husband semen cycles carried out at the Infertility Center of Akbarabadi Hospital located at Tehran University of Medical Science, Tehran, Iran, from 2008 to 2010. The Institutional Review Board and Ethical Committee of Tehran University of Medical Science approved this study.
All study couples had at least one year history of infertility and had undergone standard infertility evaluations prior to IUI. The evaluations consisted of monitoring ovulation by ultrasound, serum hormone assays on the third day of the menstrual cycle [follicle-stimulating hormone (FSH), luteinizing hormone (LH), mid luteal progesterone, prolactin and thyroid hormone concentrations] and at least two semen analyses. Tubal patency was evaluated by hysterosalpingography or laparoscopy. The couple was included in the tubal factor subgroup if only one tube was patent.
Male factor infertility was considered in our study when the total motile sperm count was <20×106/ml, normal morphology <30%, or progressive motility (grade A+B) <40% before sperm preparation. We excluded total motile sperm after preparation of less than 1×106/ml from the study.
Ovarian factor infertility group included polycystic ovary syndrome (PCOS; diagnosed by Rotterdam criteria), ovarian insufficiency (serum FSH level >9.5 IU/L on the third day of the menstrual cycle) and age factor (women age ≥ 35 years old). Anovulatory disorder was diagnosed when the menstrual cycle was not regular and/or a mid-luteal serum progesterone concentration <10 nmol/l as luteal phase disorder diagnosis.
Endometriosis diagnosis was based on the combination of findings of laparoscopy, history of dysmenorrhea and dyspareunia, observation of rectovaginal endometriosis during pelvic examination or ovarian endometrioma as seen by ultrasonography.
All cycles in the study underwent stimulation by clomiphene citrate (CC; Clomifen; Leiras, Tampere, Finland), human menopausal gonadotropin (hMG) combined with CC, or human chorionic gonadotropin (HCG, Pregnyl; Organon, Netherlands). Many patients at their first cycles were treated with CC (50-150 mg/day) which administrated between days 3 and 7. If the antiestrogenic effect of CC was unsatisfactory in terms of results and side effects, hMG was given in the same or next cycle combined with CC, or only hMG was used in the next cycle. For CC/hMG cycles, 100 mg CC was administrated between days 3 and 7, followed by 150 IU of hMG by day 9. For cycles that only were given hMG stimulation began on day 3 with 75-150 IU/day hMG, which depended on the woman’s hormonal profile, age and duration of infertility. The dose was adjusted according to ultrasonographic findings. Ovarian and endometrial responses were monitored by serial vaginal ultrasonography on cycle days 9 to 13. In all cycles, HCG (5000-10000 IU) was given when at least one follicle was greater than 18mm in mean diameter. A transvaginal ultrasound measured endometrial thickness on the day of HCG injection. Standard IUI was performed 36-40 hours after administration of HCG.
The husband’s semen was collected by masturbation
into sterile container after 2-4 days
abstinence from coitus. After 10-15 minutes of
liquefaction atroom temperature, each sample
was examined by World Health Organization
(WHO) guidelines (
IUIs were performed 36 hours after the administration of HCG. The procedure was carried out using an intrauterine catheter (Gray color catheter, ORI Medical Products, India) with a one-ml-syringe. The IUI catheter was gently directed into the uterine lumen, and one ml sperm suspension slowly infused. The women were placed supine position for 10-15 minutes after IUI. After insemination, each patient received 400mg vaginal or rectal suppositoryor 100mg intramuscular progesterone daily, which followed as the same dosage after pregnancy for 6-12 weeks. Two weeks after insemination, plasma β-HCG levels were measured routinely. Clinical pregnancy was determined as transvaginal ultrasonographic observation of intrauterine gestational sac.
The variables considered for multiple regression analysis were female age, male age, duration of infertility, infertility etiology, number of cycles, stimulation protocol, number of preovulatory follicles, the diameter of the dominant follicle, endometrial thickness and inseminated motile sperm count (IMC). Categorical variables were compared using the chi-square test. All statistical analyses were performed using SPSS for Windows software, version 16.0 (SPSS Inc., Chicago, IL, USA). The significance value for all analyses was p<0.05.
Totally, 1348 insemination cycles of 632 couples were included. For each couple, one to six insemination cycles were performed. Table 1 shows PRs per cycle and different variables frequencies according to different etiology groups. Women in unexplained group had the highest clinical PR per cycle (19.9%), while the lowest rate among women belonged to multiple factors group (10.6%) with existence of a significant difference (p=0.04).
In the male factor group, the PR per cycle was 18.1%. Older women and long infertility duration negatively affected PR, but the relationship was not statistically significant (p=0.09, p=0.1). Ovulation induction with sequential CC/hMG had a significantly better result. We found similar result in terms of PR per cycle in cases with over 5 million IMC versus those with 1- 5 million (20.1 vs. 15.2%; p<0.05).
In cases of unexplained infertility, the PR per cycle was 19.9%. However, PR decreased with increasing infertility duration, particularly if the duration was greater than 5 years in primary infertility cases. The highest PRs were seen after CC/hMG stimulation (26.3%) in women with secondary type of infertility (26.8%) and men with IMC>30×106 (22%), but the tendency didn’t reach statistical significance (p=0.08, p=0.2 and p=0.06, respectively).
In the ovarian factor group, the PR per cycle was 13.8%. The best PRs were observed in women aged between 30 and 34 years (20.8%), with 2-3 preovulatory Follicles (37.8%) and infertility duration between 1 and 3 years (20.8%). Only infertility duration (p=0.03) and number of preovulatory follicles (p=0.01) were statistically significant.
In couples with multiple factors for infertility, the PR per cycle was 10.6%. With the exception of infertility duration and IMC (p=0.005 and p=0.01), other variables had no significant effect on PR.
In women with tuboperitoneal infertility, the PR per cycle was 17.3%. The best PRs were seen after CC/hMG stimulation (23.3%), IMC >30×106 (23.5%) and infertility duration between 1 and 3 years (33.3%). In this group, only infertility duration was statistically significant (p=0.008).
Pregnancy rates per cycle according to etiology
Parameters٭ | Male factor | Ovarian factor | Unexplained | Tuboperitoneal | Multiple factors |
---|---|---|---|---|---|
<30 | 21.3 (13/61) | 12.1 (5/ 41) | 30.7( 20/65) | 20 (2/10) | 9.4 (5/53) |
30-34 | 22.5 (25/111) | 20.8 (20/96) | 27.2 (30/110) | 24.1 (7/29) | 14.7 (10/68) |
35-39 | 16.1 (19/118) | 14.5 (14/96) | 12.9 (20/ 155) | 20 (6/30) | 8.7(5/57) |
≥40 | 5.7 (2/35) | 5.8 (5/85) | 14 (10/71) | 6.8 (2/29) | 7.1(2/28) |
≤30 | 14 (10/71) | 9.7 (8/82) | 21.9 (20/91) | 16.6 (3/ 18) | 8.6 (5/58) |
30-34 | 20.4 (20/98) | 17.9 (12/67) | 25 (20/80) | 20 (4/20) | 9.3 (7/75) |
35-39 | 21.2 (21/99) | 15.3 (15/98) | 18.2 (30/164) | 19.5 (8/41) | 16.6 (8/48) |
>40 | 14 (8/57) | 14.7 (9/61) | 15.1 (10/66) | 11.7 (2/17) | 8 (2/25) |
1-3 | 22.4 (24/107) | 20.8 (20/96) | 26.5 (39/147) | 33.3 (8/24) | 22.5 (9/40) |
3-5 | 20 (21/105) | 17.8 (12/66) | 23.9 (23/96) | 26 (6/23) | 9.5 (8/84) |
≥5 | 12.3 (14/113) | 7.6 (12/156) | 11.4 (18/158) | 5.8 (3/51) | 6 (5/82) |
Primary | 21.1 (44/208) | 14.1 (30/212) | 17.8 (55/308) | 18.7 (6/32) | 10.5 (15/142) |
Secondary | 12.8 (15/117) | 14.5 (14/96) | 26.8 (25/93) | 16.6 (11/66) | 10.9 (7/64) |
1 | 10.8 (10/ 92) | 12.8 (10/78) | 21.7 (25/115) | 36 (9/25) | 17.2 (5/29) |
2 | 18.2 (27/148) | 15.1 (23/152) | 20.5 (30/146) | 11.1 (4/36) | 12.5 (13/104) |
3 | 28.9 (20/69) | 11.9 (10/84) | 17.5 (20/114) | 9 (3/33) | 5 (3/60) |
≥4 | 12.5 (2/16) | 25 (1/4) | 19.2 (5/26) | 25 (1/4) | 7.7 (1/13) |
Clomiphene citrate | 14.5 (23/159) | 13.2 (20/152) | 16.2 (25/154) | 17.5 (10/57) | 9.7 (11/113) |
hMG | 9 (1/11) | 7.6 (2/23) | 13.1 (10/76) | 0 (0/11) | 6.2 (1/16) |
Combination | 22.6 (35/155) | 15.4 (22/143) | 26.3 (45/171) | 23.3 (7/30) | 12.9 (10/77) |
1 | 8 (5/ 62) | 3.7 (3/80) | 9.8 (12/122) | 0 (0/ 38) | 6.4 (5/78) |
2 | 23.9 (27/113) | 18.2 (25/137) | 24.8 (33/ 133) | 18.7 (3/16) | 12.1 (10/82) |
3 | 19.6 (10/51) | 19.6 (12/61) | 28.7 (23/80) | 25 (7/28) | 16.6 (5/30) |
≥4 | 17.1 (17/99) | 10 (4/40) | 18.1 (12/66) | 43.7 (7/16) | 12.5 (2/16) |
1- 5 | 15.2 (20/131) | 0 (0/7) | |||
5.1–10 | 20.1 (39/194) | 4 (2/ 50) | 8.9 (2/23) | 10 (1/10) | 6.8 (6/86) |
10.1–20 | 12.5(9/72) | 17.9 (14/78) | 11.1 (3/26) | 10.3 (6/58) | |
20.1–30 | 15.8 (10/63) | 20 (20/100) | 17.8 (5/28) | 19 (4/21) | |
≥30 | 17.2 (23/133) | 22 (44/200) | 23.5 (8/34) | 17.6 (6/34) | |
18.1 (59/ 325) | 13.8 (44/318) | 19.9 (80/401) | 17.3 (17/98) | 10.6 (22/206) | |
*; Values were presented as % (number of pregnancy /number f cycles).
The overall PR was 16% and 35.1% per cycle and per couple, respectively. Pregnancy outcomes per couple are shown in table 2. There was no significant relationship between pregnancy occurrence per couple and cause of infertility (p=0.1). Women in male factor group had the highest miscarriage rate (15.4%), while the lowest rate among women belonged to multiple factors group (4.5%) with existence of a significant difference (p=0.03). Multiple pregnancies were observed only in patients with ovulatory dysfunction (0.7%) and those with unexplained infertility (0.9%).
Logistic regression analysis revealed the following
five predictive variables regarding pregnancy
in stimulating IUI cycles: i. number of preovulatory
follicles (p=0.02), ii. duration of infertility
(p=0.015), iii. age (p=0.019), iv. infertility etiology
(p=0.05) and v. stimulation regimen (p=0.01)
(
Table 4 shows that the pregnancy outcome per cycle and couple in each subgroup of ovarian factor group, while the patients in PCOS subgroup had higher PR in comparison with other subgroups.
Pregnancy outcome of intrauterine insemination cycles per couple according to infertility etiology
Male factor n=146 | Anovulatory n=133 | Unexplained n=214 | Tuboperitoneal n=46 | Multiple factors n=93 | P value | |
---|---|---|---|---|---|---|
59 (40.4) | 44 (33) | 80 (37.3) | 17 (36.9) | 22 (30.9) | 0.1 | |
7 (11.8) | 1 (2.2) | 1 (1.2) | - | 2 (9) | 0.005 | |
9 (15.4) | 5 (11.3) | 11 (13.8) | 2 (11.7) | 1 (4.5) | 0.03 | |
43 (29.4) | 38 (28.5) | 68 (31.7) | 15 (32.6) | 19 (20.4) | 0.1 | |
- | 1 (0.7) | 2 (0.9) | - | - | 0.9 | |
Logistic regression analysis for predicting the success of intrauterine insemination
Variable | ORa | CIb | P value |
---|---|---|---|
2.1 | (1.0-4.5) | 0.019 | |
2.3 | (1.1-4.7) | 0.015 | |
1.9 | (0.9-3.5) | 0.045 | |
1.7 | (0.8-3.2) | 0.05 | |
3.1 | (1.3-6.4) | ||
3.4 | (1.6-6.9) | ||
2.7 | (1.2-5.6) | ||
2 | (1.03-4.1) | 0.01 | |
a; Odds ratio, b; Confidence interval and c; Odds ratio in contrast to the poorest category.
Pregnancy rates per couple and per cycle in different diagnosis in ovulatory factor group
Anovulatory with out specified diagnosis | Anovulatory with PCOS diagnosis | Age factor | Hypothalamic amenorrhea | |
---|---|---|---|---|
8/34 (23.5) | 36/81 (44.4) | 0/16 (0) | 0/2 (0) | |
8/68 (11.8) | 36 /218 (16.5) | 0/28 (0) | 0/4 (0) | |
Our findings show that infertility etiology has
an important role in the prognosis of IUI cycles.
Additionally, differences in factors affect the PR,
which is in agreement with a study by to Ahinko-
Hakamaa et al. (
Our results confirm that IUI is the best firstline
treatment in cases of mild and moderate
male factor infertility. We observed the best
results in cases with IMC ≥5×106 (not significant)
and infertility duration less than 5 years.
In contrast to the recent studies (
In cases of unexplained infertility, the cost/efficacy
balance between IUI and
In our study, the PR per cycle in the ovarian
factor infertility group was lower than the
results obtainedin a study by Ahinko-Hakamaa
et al. (
It shows that we can recommend IUI treatment as first-line treatment in women with PCOS diagnoses and infertility duration less than 5 years , but in the patients with an ovulatory without specific diagnosis subgroup, the PR per couple (23.5%) and per cycle (11.8%) were lower than patients with PCOS subgroup. It seems that women in an ovulatory factor group with PCOS diagnosis need to more cycles to become pregnant.
In the tuboperitoneal infertility group, the PR per cycle was high (17.3%). We had 30 cases with one patent tube, 9 cases with uterine factor and 7 cases with mild endometriosis in this subgroup. Because of the low number of endometriosis cases and low number of cycles in this subgroup (n=98), a conclusion cannot be drawn. Nevertheless, it seems that IUI in cases with one patent tube can be of great benefit when female age and duration of infertility are appropriate.
The PR per cycle in the multiple factors infertility
subgroup was low in comparison with the study
by Ahinko-Hakamaa et al. (
In our study, stimulation with sequential CC/
hMG resulted in the highest PR in all infertility
subgroups, which was significant in comparison
with hMG alone, but not CC alone. Several
studies have reported the superiority of FSH or
hMG over CC alone (
The age-related decline in female fecundity has
been well documented (
We found that the PR decreased with increased
infertility duration, which confirmed some studies
(
In our study, the highest PR (22.5%) was observed
in cycles with three pre-ovulatory follicles,
being statistically higher than in cycles with only
one follicle (6.5%). In agreement with previous
studies (
Some studies (
In decision making for choosing the best treatment options for infertile couples should be considered the numerous variables in different etiologies of infertility. It must be remembered that within different etiologies of infertility, the number of preovulatory follicles; motile sperm count; stimulation protocol; and demographic characteristics of couples do not have the same effect. The simple and relatively noninvasive nature of IUI allows physicians to choose IUI as a cost-effective first-line treatment in most cases of infertility. Favorable patient characteristics for treatment success are age <40, duration of infertility ≤5 years and a cause of infertility except of multiple factors. Additional information on the predictors of IUI success to provide a more exact basis for counseling patients on expectations and treatment options is needed.