Pregnancy outcome after endometrial scratching in intrauterine insemination: A randomized controlled trial

INTRODUCTION

Endometrium is a complex tissue consisting of distinct cellular compartment including epithelial cells, endothelial cells, stromal cells, and leukocytes. It is also a dynamic tissue which undergoes a series of morphological, biochemical, and molecular changes during the menstrual cycle. It provides an optimum environment for opposition, attachment, and invasion of embryo during a defined implantation window period for establishing pregnancy.^[1]

Implantation is the rate limiting step in natural pregnancies as well as in artificial reproductive techniques. About 75% of pregnancies are lost soon after conception, implicating either the implantation failure or early embryopathy.^[2] The causes for repeated implantation failure may be reduced endometrial receptivity, embryonic defects, or multifactorial. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules, and immunological factors may decrease endometrial receptivity, whereas genetic abnormalities of male and female, sperm defects, embryonic aneuploidy, or zona hardening are among the embryonic reasons for failure of implantation.^[3]

The opposition and attachment process of embryo to the endometrium are the primary stages of implantation. Following which, there is subsequent invasion into the stroma of uterine wall. It is a complex and multistage process involving several cytokines and growth factors as well as synchronization between the embryonic tissue and endometrium.^[4] Implantation is affected by receptivity of endometrium and interaction between endometrium and embryo. Receptivity of endometrium depends on estrogen and progesterone.^[5] Endometrial receptivity is a time period in which the endometrium becomes capable of receiving and adhering the human embryo.^[3,4] This endometrial receptivity is usually limited to 19 to 24 days of menstrual cycle.^[6]. Uterine receptivity is enhanced by local endometrial injury which facilitates the embryo implantation. Endometrial injury before in vitro fertilization (IVF) among women with previous repeated IVF failures is associated with increased rates of implantation, clinical pregnancy, and live birth.^[7]

The present study was planned to see the effect of local endometrial injury on pregnancy rate in intrauterine insemination.

MATERIALS AND METHODS

This is a randomized controlled trial conducted in the outpatient department (OPD) and fertility clinic of Department of Obstetrics and Gynecology of Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University (AMU) Aligarh from November 2015 to November 2017. Approval was taken from the ethical committee of the institution (document attached). It has also been registered under Clinical Trial Registry India.

Inclusion criteria:

1. Below 40 years of age

2. Body mass index (BMI) less than 35 kg/m²

3. Bilateral/unilateral tubal patency

4. Mild male factor subfertility: sperm count >5×10⁶/ml motility >10%

Exclusion criteria:

1. Women above 40 years of age

2. BMI more than 35 kg/m²

3. Bilateral tubal blockage

4. Severe medical disorder

5. Severe male factor subfertility: sperm count <5×10⁶/ml and motility <10%

Patients were recruited from gynecology OPD and fertility clinic. Initial infertility evaluation including complete detailed history, examination, and relevant investigations was carried out in all patients. Consent was taken from all the patients who were fulfilling the inclusion criteria, and the patients were divided into two groups through computer-based randomization.

Group A: Patients who underwent endometrial scratching on day 8 of menstrual cycle of intrauterine uterine insemination (IUI).

Group B: Patients who did not undergo endometrial scratching in IUI cycle.

Day 2 antral follicle count was carried out and dose of Clomiphene was decided according to ovarian reserve. Controlled ovarian hyperstimulation was started with tablet Clomiphene citrate, administered orally from day 2 to day 6 of the cycle. On day 8/9, transvaginal sonography was performed to monitor the follicular response to therapy and according to the response gonadotropin was added. On the same day, in group A, endometrial scratching was carried out with pipelle. The procedure was carried out with all aseptic precautions. Folliculometry was carried out from day 8/9 on alternate day. When the dominant follicle reached 18 mm and triple line preovulatory endometrial maturation with thickness >7 mm was present, then trigger was given with injection human chorionic gonadotropin (HCG) and IUI was carried out 34 to 36 h after HCG trigger.

On the day of IUI, the husband was instructed to give semen that was prepared by swim up technique or double density gradient method according to the semen parameters. After centrifugation of a semen sample in a discontinuous density gradient column, the total motile sperm count was obtained by multiplying the total sperm count by the prewash percentage of motility. The postwash sample parameters were assessed according to World Health Organization criteria.

All the women were provided with luteal phase support with natural micronized progesterone tablet Susten (manufactured by Sun Pharmaceutical Industries Limited, Chennai, Tamil Nadu, India) 200 mg per vaginum daily for 2 weeks. If the menstrual cycles were delayed, urine pregnancy test was carried out. When positive, a transvaginal ultrasound was performed 6 weeks later to confirm clinical pregnancy. The primary end point of this study was a positive urine pregnancy test.

Data were analyzed using the t test, Chi-squared test, and analysis of variance test. A P-value of <0.05 was considered statistically significant.

RESULTS

The basic demographic profile was comparable in both the groups. The prevalence of primary infertility was more than secondary infertility in both the groups. Maximum number of patients (61.29%, n = 38) were in the age group of 26 to 30 years and maximum number of them (74.19%, n = 46) presented within first 5 years of infertility.

Endometrial flow

Maximum number of patients (67.74%, n = 42) have zone 2 endometrial flow in both the groups. In group A, greater number of patients had zone 3 endometrial flow than group B. The difference between the groups was not statistically significant (χ² = 4.436, P > 0.05) [Figure 1].

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Figure 1

Consort flow diagram.

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DISCUSSION

Endometrial scratching has been suggested as one of the interventions to improve pregnancy outcome. In our study, mean ET was 9.32 ± 0.98 in group A, whereas in group B, it was 7.35 ± 0.512 mm. The difference between the two groups was highly significant. Similarly, in randomized control trial (RCT) conducted by Wadhwa et al.^[8] Mean ET was 8.4 ± 1.84 mm and 7.4 ± 1.8 mm in endometrial biopsy group and control group, respectively. ET obtained on day of HCG trigger was significantly high in endometrial biopsy group (P = 0.002) [Tables 1 and 2].

Table 1 Distribution of infertility cases according to demographic profile

Table 2 Effect of endometrial scratching on pregnancy outcome and endometrial indices

Parsanezhad et al.^[9] found mean ET to be 8.94 ± 1.21 mm in endometrial injury group and 9.18 ± 1.3 mm in control group which was also in agreement with our study.

Esmailzadeh and Faramarzi^[10] found mean ET to be 10.1 ± 3.0 mm in women who achieved clinical pregnancy after IUI. In women who did not achieve clinical pregnancy mean ET was 7.7 ± 3.5 mm. They concluded that ET can be considered as a main predictor of pregnancy rate in IUI cycle.

In studies conducted by Inal et al.^[11] and Soliman and Harira^[12] the mean ET was higher in endometrial biopsy group than control group. This was in coherence with our study.

Possible explanation of this increase in pregnancy outcome may be endometrial decidualization, angiogenesis, and inflammatory mechanism induced by endometrial injury or scratching making the endometrium more receptive for implantation.

CONCLUSION

Endometrial scratching is a simple, low cost, and minimally invasive procedure that may enhance biochemical and clinical pregnancy rates. Endometrial tissue repair process following endometrial injury is mediated by expression of immunological factors by endometrial epithelial cells including adhesion molecules, cytokines, growth factors, and other immune mediators which are involved in implantation process. It also promotes decidualization of endometrium making it more receptive for implantation. Endometrial gene modulation following endometrial injury has also been hypothesized to increase endometrial receptivity.

In our study, there was significant increase in ET and blood flow following endometrial scratching which in turn resulted in improved pregnancy rates. In developing countries like India, endometrial scratching can prove itself beneficial as an affordable low-cost intervention. It can be carried out as an OPD procedure before ovulation induction and IUI, thereby improving pregnancy rates before proceeding for other high-cost alternative ART procedures.