Comparison of intrauterine insemination done 36 and 42 hours after human chorionic gonadotropin injection in unexplained infertility: a randomized clinical trial

Rationale:

Unexplained infertility is diagnosed in around 1/3rd of total cases of infertility. Ovulation induction with Intrauterine insemination (IUI) is the first-line treatment for unexplained infertility. Studies comparing single IUI (36 hours) to double IUI (24 hours and 48 hours) have shown similar results, hence single IUI is recommended in stimulation cycles. While some studies have conflicting findings, it is generally recommended to perform a single IUI after 36 hours. The success rate of IUI with ovulation induction in unexplained infertility is around 10%. One of the factors affecting the success rate of IUI is the timing of IUI after Human Chorionic Gonadotropin (HCG) injection for ovulation trigger. Researchers have attempted various ways to increase IUI success rates by doing different timing of IUI (12, 18, 36-40 hours) after HCG injection with conflicting results. Interestingly, a few studies have suggested that IUI at 42 hours after Human chorionic gonadotropin (HCG) injection may result in better pregnancy rates compared to IUI at 36 hours.

AIM: Comparison of the effectiveness of intrauterine insemination done 36 and 42 hours after human chorionic gonadotropin injection on pregnancy rates in unexplained infertility.

OBJECTIVES:

Primary objectives: To compare the biochemical and clinical pregnancy rates after IUI between two groups having IUI done 36 and 42 hours after HCG injection in ovarian stimulation cycles in unexplained infertility.

Secondary objectives:

- To compare the documented ovulation rates before the IUI procedure between two groups.

- To compare the pregnancy rates in IUI done with or without ovulation.

PLACE OF STUDY: The study will be carried out in the Department of Obstetrics and Gynaecology at UCMS and GTBH, Delhi.

STUDY DESIGN: Randomized Clinical Trial

Time Frame: 1stApril 2024 – 31st August 2025

Sample size: As per the study by Firouz M. et al1 (JFRH 2020) in Iran in cases of unexplained infertility undergoing Ovarian stimulation with IUI, considering the biochemical pregnancy rates as 32% in group A (IUI done at 42 hours after HCG) and 14% in group B (IUI done at 36 hrs after HCG) ) and clinical pregnancy rates as 28% in group A and 14% in group B, to estimate this difference at alpha 5% and power of 80%, a sample of 85 subjects (as per biochemical pregnancy rates) and 132 subjects (as per clinical pregnancy rates) is required in each group respectively. As per available hospital data and limited time for the study, a convenient sample size of 100 cases (50 in each group) of unexplained infertility will be taken.

RECRUITMENT CRITERIA

Diagnosed cases of unexplained infertility attending the infertility clinic of the Department of Obstetrics and Gynaecology who will be requiring IUI as a treatment modality will be recruited in the present study.

INCLUSION CRITERIA

1.      Diagnosed cases of unexplained infertility

- Documented ovulation

- At least one patent tube

- Normal uterine cavity

- Normal semen analysis

2.      Age: 20-38 years

3.      Normal ovarian reserve

EXCLUSION CRITERIA

1. Any medical condition contraindicating pregnancy.

2. Endocrine disorders such as uncontrolled hypothyroidism or diabetes mellitus.

3. Active infections such as pelvic inflammatory disease, vaginal or cervical infection.

4. The presence of four or more dominant follicles in the ultrasound imaging before HCG injection.

5. No dominant follicles in the stimulated cycle.

METHODOLOGY

Ethical clearance will be obtained from the Institutional Ethics Committee for Human Research. The study will be registered with the Clinical Trials Registry-India (CTRI) after ethical approval. Eligible infertile couples having female partners between 20-38 years of age with unexplained infertility will be enrolled in the study after written and informed consent. Complete subject information will be recorded in the Case Record Form. Female partners will be given ovulation stimulation with Tab letrozole 5 mg from day 2/3 for 5 days of the cycle. Serial follicular monitoring will be done from day 9 onwards of the menstrual cycle till the leading follicle is 18-20mm. If required Injection of human menopausal gonadotropins (HMG) 75 IU I/M will be given from day 9 as per routine practice.  Once a dominant follicle is formed patient will be randomized into group A (42 hours) and group (B) to do IUI after HCG injection based on computer-generated randomization tables (www.randomization.com will be used for randomization). Then HCG trigger (10,000 IU I/M) will be given. Group A will be called for IUI after 42 hours and Group B will be called for IUI after 36 hours of the HCG trigger. On the day of IUI, an ultrasound will be done to document signs of ovulation (follicle size regression, irregular margins, intrafollicular echoes, free fluid in the pouch of Douglas). Semen sample will be provided by the male partner. The semen will be prepared by double density gradient method. Total motile sperm count will be measured in prepared semen before IUI. IUI will be done as per standard practice.  Luteal support will be given with micronized progesterone (400mg intravaginal per day) from the next day of IUI. All the females will be followed up till the next cycle. In case of missed periods, a urine pregnancy test (UPT) will be done. If UPT is positive, it is considered a biochemical pregnancy. After 2 weeks of missed period, a transvaginal ultrasound will be done. If a gestational sac is seen Clinical Pregnancy will be diagnosed.

OUTCOME MEASURES:

PRIMARY OUTCOME:

1. Comparison of Biochemical pregnancy rates in percentage in both groups (based on the period between HCG injection and IUI) of unexplained infertility.

2. Comparison of Clinical pregnancy rates in percentage in both groups (based on the period between HCG injection and IUI) of unexplained infertility.

SECONDARY OUTCOME:

1. Comparison of Documented Ovulation in percentage (signs of ovulation on USG) on the day of IUI in both the groups.

2. Comparison of Biochemical and clinical pregnancy rates in percentage in IUI done with and without documented ovulation.

STATISTICAL ANALYSIS:

• All the data will be analyzed under SPSS v 20.0 statistical software.

• All the qualitative parameters will be compared between both the groups by Chi-square/ Fischer exact test.

• Quantitative parameters will be compared between both groups by unpaired t-test. p<0.05 level of significance.