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doi:10.1111/jog.12315

J. Obstet. Gynaecol. Res. Vol. 40, No. 5: 1324–1330, May 2014

Hysteroscopy in patients with repeated implantation failure improves the outcome of assisted reproductive technology in fresh and frozen cycles Marzieh Agha Hosseini, Nasim Ebrahimi, Atossa Mahdavi, Ashraf Aleyasin, Leili Safdarian, Parvin Fallahi and Fatemeh Esfahani Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Abstract Aim: Repeated implantation failure (RIF) is still a problem for many patients and their physicians. Some interventions have been practiced to overcome the problem; one is uterine cavity assessment before assisted reproductive technology (ART) cycles. This study aimed to evaluate the effect of hysteroscopy in women experiencing recurrent implantation failure with apparently normal uterine cavity before assisted reproductive techniques. Material and Methods: This was a cohort study with historical controls conducted in a university hospital. A total of 353 women with RIF undergoing ART with normal hysterosalpingography and transvaginal ultrasound were evaluated. The intervention group underwent hysteroscopy with a rigid, 30°, 4-mm hysteroscope in the menstrual cycle just before ART; in the control group hysteroscopy was not performed. Basal characteristics, stimulation parameters and pregnancy rates were compared between the two groups. Results: Chemical pregnancy occurred in 58.5% of women in the hysteroscopy group versus 34.1% of control women (odds ratio [OR]: 2.7; 95% confidence interval [CI]: 1.7–4.2; P < 0.001). Clinical pregnancy occurred in 50.7% and 30.3% of women in the hysteroscopy and control groups, respectively (OR: 2.4; 95%CI: 1.5–3.7; P < 0.001). Delivery rate was 35.5% in hysteroscopy women and 21.1% in control women (OR: 1.9; 95%CI: 1.2–3.1; P = 0.008). The results of hysteroscopy were normal in 103 women (72.5%), and they revealed inflammation in 22 (15.5%), polyp in 16 (11.3%) and Asherman syndrome in one patient (0.7%). Conclusions: Hysteroscopy in the menstrual cycle before ovarian stimulation in fresh cycles and before endometrial preparation in frozen thawed cycles in women experiencing recurrent implantation failure with apparently normal uterine cavity significantly increases the pregnancy rates in fresh and frozen cycles, respectively. Key words: assisted reproductive technology, fresh, hysteroscopy, implantation failure, pregnancy.

Introduction Repeated implantation failure (RIF) is still a problem for many patients and their physicians. It is diagnosed when embryos with good quality and quantity repeatedly fail to implant after several assisted reproductive

technology (ART) cycles. Accordingly, different ART centers may use different criteria for RIF definition.1 Some interventions have been practiced to overcome the problem, but many variations exist in the management of RIF.2,3 On the other hand, anatomic and/or functional endometrial factors contribute a major role

Received: February 13 2013. Accepted: September 30 2013. Reprint request to: Dr Atossa Mahdavi, Department of Infertility, Shariati Hospital, North Karegar Street, Tehran 1411713135, Iran. Email: [email protected], [email protected]

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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology

Hysteroscopy and implantation failure

in some patients, so uterine cavity assessment before ART, especially RIF, have been proposed.4 Among different approaches, such as hysterosalpingography (HSG), transvaginal ultrasound scan (TVS), saline hysterosonography, 3-D ultrasound scan, magnetic resonance imaging (MRI) and hysteroscopy, the last one is considered the gold standard for the investigation of the uterine cavity.4 It has the benefits of direct visualization of uterine cavity plus direct intervention and removal of the observed pathologies. Due to its safety and benefits it is a routine tool for evaluation work-up of a couple with RIF in many ART centers. Considering positive impacts, this prospective study aimed to evaluate the effect of hysteroscopy in women experiencing recurrent implantation failure with apparently normal uterine cavity before ART.

Methods This prospective trial was conducted at the Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences during the 2-year period of 2010– 2011. The proposal was in accordance with the Helsinki Declaration and was approved by the Ethics Committee of the university. In total, 353 women with RIF undergoing ART were enrolled. RIF was defined as ≥ two ART cycles with fresh and good quality (according to previous ART history of the patient) and quantity (at least eight) embryos transferred. A total of 282 women entered the fresh cycle and 71 women entered the frozen thawed embryo transfer. Women > 38 years of age, body mass index ≥ 35 kg/ m2, with apparent uterine and tubal pathology, with hypothalamic amenorrhea and patients with history of hysteroscopy during the last 3 months were excluded from the study. Also, couples requiring testicular sperm extraction and aspiration for sperm recovery and gamete or embryo donations, couples with abnormal karyotype and women with positive thrombophilia were excluded. For all the women, history was taken, gynecological examination was carried out and semen analysis, hormonal profile, HSG and TVS were performed. Women with abnormal HSG and/or TVS were excluded from the study. The consecutive 142 patients (120 fresh cycles and 22 frozen cycles) were invited to enter the hysteroscopy (intervention) group, which was compared with a no hysteroscopy (control) group. The control group was 211 previous comparable RIF patients with similar basal characteristics and ART stimulation parameters. Although RIF was defined as history

of ≥ two ART cycles with fresh and good quality and quantity embryos, we used a historical control group, including 211 patients with fresh (162 participants) and frozen (49 participants) embryos for this cycle (Fig. 1). Hysteroscopy in the dorsolithotomy position and under general anesthesia was performed in the menstrual cycle just before ovarian stimulation or endometrial preparation by the attending physicians of the department. Rigid hysteroscope (continuous flow; 30° forward oblique view) with outer diameter of 4 mm using 0.9% normal saline via a pressure pump was applied. The uterine cavity was adequately distended with the preset pressure between 80 and 100 mmHg. Entry into the uterine cavity was under direct vision and a systematic inspection for the whole cavity (including cervical canal, uterine isthmus and cavity, and cornua) was performed. Observed appearance and any probable abnormal pathology were reported. If any polyps, fibroids or adhesions were detected, they were removed by mechanical instruments, such as forceps and scissors. We considered any focal or diffuse hyperemia or stromal edema and endometrial micropolyps (less than 1 mm in size) as inflammation. In all patients, after complete desensitization with long protocol using buserelin, ovarian stimulation with recombinant gonadotrophin, Gonal F and human menopausal gonadotrophin on the basis of age, weight and ovarian reserve was started. Transvaginal ultrasound was performed every 3–5 days to monitor follicular development and final oocyte maturation was triggered with 10 000 IU human chorionic gonadotrophin (hCG). Then, oocytes were collected transvaginally 36–38 h later. After fertilization through intracytoplasmic sperm injection (ICSI), up to four good-quality embryos were transferred transcervically 3 days later. Luteal phase support was by progesterone suppository Cyclogest. Serum β-hCG was checked 14 days after embryo transfer, and a transvaginal ultrasound scan was performed 2 weeks later to detect gestational sac. Each pregnant woman was followed up with ultrasound scan until the fetal heart was documented (clinical pregnancy) and until delivery. Frozen cycle was used in 22 women (15.5%) in the hysteroscopy group and 49 women (23.2%) in the control group. After complete desensitization with a long protocol as said before, estradiol valerate was started from 2 mg per day till 6 mg daily to achieve an adequate endometrial pattern (triple line) and thickness (8–12 mm). Then, up to four good-quality embryos were transferred transcervically by attending physicians in the cleavage stage (eight embryonic cells).

© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology

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Recurrent implantaƟon failure n = 353

Hysteroscopy group

Control or No hysteroscopy group

n = 142 n = 211

Fresh cycle

Frozen cycle

Fresh cycle

Frozen cycle

n = 120

n = 22

n = 162

n = 49

Chemical pregnancy

Chemical pregnancy

n = 71

n = 17 No chemical pregnancy

No chemical pregnancy

n = 49

n = 32 Chemical pregnancy

Chemical pregnancy

n = 55

n = 12 No chemical pregnancy

No chemical pregnancy

n = 10

n = 107

Figure 1 Patient enrollment.

Our definition of good-quality embryos was according to the standard embryologic definition.5,6 Luteal phase support and pregnancy detection and follow-up were the same as fresh cycles. Due to the historical control nature of the study, it should be mentioned that our center had similar pregnancy rates in the 2 years mentioned.

Statistical analysis The sample size was calculated to be 328 participants with power of 80% and a level of significance of 0.05.

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spss 12 was used for data analysis. The normality of continuous variables was checked by histogram. Gravidity, number of previous abortions, number of previous ART attempts, duration of stimulation, number of frozen embryos and sacs were non-parametric variables, and Mann–Whitney U-test was used to assess differences between groups. The other variables displayed a normal distribution, and were compared with the independent t-test. Categorical variables were compared by χ2-test or Fisher’s exact test where appropriate. The odds ratio and corresponding 95% confidence

© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology

Hysteroscopy and implantation failure

intervals were calculated. Binary logistic regression analysis was done to detect independent predictor of pregnancy outcome. The significance level was set at α = 0.05.

Results Two groups were well matched in terms of maternal age, gravidity, history of abortion duration, type of infertility and number of previous ART. The cause of infertility was similar in both groups (Table 1). Frozen cycle was used in 22 women (15.5%) in the hysteroscopy group and 49 women (23.2%) in the control group (P = 0.079). As shown in Table 2, the two groups were comparable with respect to treatment characteristics. Table 3 shows pregnancy outcomes. Chemical pregnancy occurred in 58.5% of women in the hysteroscopy group versus 34.1% of women in the control group (OR: 2.7; 95%CI: 1.7–4.2; P < 0.001). Nine (10.8%) of 83 chemical pregnancies in the hysteroscopy group were missed before detecting fetal heart rate (FHR) and two (2.4%) were EP. These figures were four (5.5%) and four

(5.5%) of 72 chemical pregnancies in the control group, respectively (P = 0.689). The clinical pregnancy rate was 50.7% and 30.3% in the hysteroscopy and control group, respectively (OR: 2.4; 95%CI: 1.5–3.7; P < 0.001). Delivery rate was 35.5% in the hysteroscopy group and 21.1% in the control group (OR: 1.9; 95%CI: 1.2–3.1; P = 0.008). Using binary logistic regression analysis the odds ratios of chemical or clinical pregnancy or delivery rates did not change after adjusting for kind of cycle. There were only five sets of twins in the hysteroscopy group and four sets of twins in the control group. The results of hysteroscopy were normal in 103 women (72.5%) and they revealed inflammation in 22 (15.5%), polyp in 16 (11.3%) and Asherman syndrome in one (0.7%). Pregnancy outcomes were closed in the normal and abnormal hysteroscopy subgroups and were still higher than in the control group. Table 4 outlines these results. The procedure was well tolerated by almost all women and no complications were reported. No technical failure was encountered.

Table 1 Demographic and obstetric characteristics of patient groups

Age (years) Gravidity Previous abortion Infertility duration (years) Previous ART Primary infertility Cause of infertility: Male factor Female factor Unexplained

Hysteroscopy (n = 142)

Control (n = 211)

P

32.6 (±4.2) 0 (0–2) 0 (0–2) 9.2 (±5.1) 2.5 (2–9) 126 (88.7)

32.7 (±4.3) 0 (0–5) 0 (0–5) 8.8 (±4.4) 3 (2–8) 183 (86.7)

0.836 0.635 0.427 0.429 0. 818 0.576 0.695

26 (18.3) 33 (23.2) 83 (58.5)

39 (18.5) 55 (26.1) 111 (52.6)

Data presented as Mean (±SD) or Median (range) or frequency (%). ART, assisted reproductive technology.

Table 2 Comparison of treatment characteristics of patient groups (only fresh cycles)

Stimulation days Total gonadotrophins† Total HMG† Total rec FSH† Oocytes retrieved Metaphase 2 oocytes Transferred embryo

Hysteroscopy (n = 120)

Control (n = 162)

P

8 (4–16) 57.5 (±18.5) 30.5 (±10.7) 27.6 (±8.5) 11.0 (±5.1) 7.6 (±4.3) 3 (1–4)

9 (4–22) 57.5 (±18.6) 30.9 (±10.8) 26.5 (±9.2) 11.6 (±6.4) 8.5 (±5.5) 3 (1–4)

0.956 0.996 0.764 0.328 0.402 0.164 0.255

†Number of ampoules. Data presented as mean (±SD) or median (range). FSH, folliclestimulating hormone; HMG, human menopausal gonadotrophin.

© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology

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Table 3 Comparison of treatment outcomes of patient groups

Chemical pregnancy Clinical pregnancy Delivery rate Pregnancy outcome†: Abortion Ectopic pregnancy Preterm delivery Term delivery Ongoing pregnancy

Hysteroscopy (n = 142)

Control (n = 211)

P

83 (58.5) 72 (50.7) 46 (35.4)

72 (34.1) 64 (30.3) 45 (21.1)

Hysteroscopy in patients with repeated implantation failure improves the outcome of assisted reproductive technology in fresh and frozen cycles.

Repeated implantation failure (RIF) is still a problem for many patients and their physicians. Some interventions have been practiced to overcome the ...
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