EVALUATION OF ROLE OF INTRAUTERINE INSEMINATION (IUI) IN INFERTILITY SUJOY DASGUPTA Purvita Dam Jhantu Kr Saha Prof P S Chakravorty

INFERTILITY “Infertility is a disease. The duration of failure to conceive should be ≥12 months before an investigation is undertaken unless medical history and physical findings dictate earlier evaluation and treatment” * Monthly fecundity rate in general population is only 15-20%** *American Society of Reproductive Practice Committee; Hum Reprod 2004;19:1497-501 **Federation CECOS. N Eng J Med 1982;206(7):404-6

EITIOLOGY OF INFERTILITY

OPTIONS FOR THE COUPLES Medical Management Surgical Management Artificial Insemination (AI) IUI Intravaginal Insemination Intracervical Insemination Direct Intraperitoneal Insemination (DIPI) Fallopian Tube Sperm Perfusion (FSF) Direct Intrafollicular Insemination (DIFI) Assisted Reproductive Techniques (ART) IVF-ET GIFT, ZIFT ICSI POST Third Party Reproduction Adoption

Intrauterine Insemination (IUI) Washed sperm (of the male partner or the donor) is introduced in the uterine cavity in proper time First used by John Hunter, 1770 Mechanisms Eliminates toxins, bacteria, free radicals present in seminal plasma Bypasses hostile vaginal acidic pH and cervical mucus Shortens the distance travelled by the sperms to reach the site of fertilization Overcomes faulty coital technique

Aims and Objectives The pregnancy rates per cycle of IUI The pregnancy rates per couple (undergoing IUI) Prognostic factors associated with successful IUI Adverse effects of IUI (if any)

MATERIALS AND METHODS

STUDY AREA STUDY PERIOD STUDY DESIGN STUDY POPULATION Deptt of Obstetrics and Gynaecology, Eden Hospital, Medical College and Hospital, Kolkata STUDY PERIOD 1 year (1st June, 2011- 31st May, 2012) STUDY DESIGN Observational Longitudinal Study STUDY POPULATION Infertile couples attending the Infertility clinic, who conform to the inclusion criteria

STUDY DESIGN Inclusion Criteria Female partner- 20-40 years Regular frequent unprotected intercourse >1 year but unable to conceive Male factors - Anatomic defects of penis Sexual dysfunction Mild & moderate oligozoospermia (sperm concentration 5-20 x 106/ml) Mild asthenozoospermia (<50% sperms showing fast forward and slow progressive motility) Mild teratozoospermia (morphologically normal sperm 4-15% according to Kruger’s strict criteria) Female factors - Anatomic defects of vagina or cervix Minimum to mild endometriosis (AFS score ≤15) PCOS (defined according to Rotterdam Consensus, 2003- ESHRE and ASRM) Other causes of anovulation Unexplained infertility All the above factors not responding to conventional medical/ surgical treatment, wherever possible

Exclusion Criteria Female factors- Male factors- Bilateral tubal blockage Pelvic tuberculosis Severe pelvic endometriosis Male factors- Azoospermia (No sperm in the ejaculate, confirmed in three properly collected samples) Severe oligo-astheno-terato-zoospermia(Sperm density <5 x 106/ml, No motile sperms in the sample, <4% sperm morphologically normal according to Kruger’s strict criteria) Retrograde ejaculation and anejaculation

STUDY TECHNIQUE Female Partner- USG, HSG/Laparoscopy, Informed Consent Both partners- History, Physical Examinations, Routine Blood, Serology Male Partner- Semen Analysis Female Partner- USG, HSG/Laparoscopy, Hormonal assay (as needed) Ovulation Induction – Clomiphene Citrate, HMG/FSH- as indicated

STUDY TECHNIQUE (Contd.) TVS- Follicular size & number, -Endometrial Thickness Ovulation triggering by hCG IUI (H) after 36 hours of hCG Injection (Single Insemination) Husband’s Semen Collection Semen Preparation- Swim-up Technique -Ham’s F-10 medium

STUDY TECHNIQUE (Contd.) Insemination - IUI Catheter -Disposable Speculum Progesterone for Luteal Support Follow up- Menstrual H/O, Urine for Pregnancy Test Couple with Failed IUI- Repeat IUI up to Maximum Six Cycles Successful IUI- Followed up throughout the Pregnancy

RESULTS

TOTAL NUMBER OF IUI CYCLES Number Of COUPLES Total Number Of CYCLES One 10 Two 14 28 Three 18 54 Four 6 24 Five 3 15 Six 2 12 TOTAL 53 143

AGE DISTRIBUTION OF THE COUPLES

AGE DISTRIBUTION OF THE COUPLES

URBAN/ RURAL DISTRIBUTION OF THE COUPLES

SOCIO-ECONOMIC STATUS OF THE COUPLES

DURATION OF INFERTILITY OF THE COUPLES

PAST OBSTETRIC HISTORY OF THE WOMEN

CAUSE OF INFERTILITY OF THE COUPLES

INITIAL SEMINAL PARAMETERS OF MALE PARTNERS Number Of Male Partners (n = 53) Percentage (%) Mean ± SD Sperm density (per ml) ≥20 x 106 36 67.92 38.04 ± 24.34 ≥10 x 106 <20 x 106 10 18.87 ≥5 x 106 <10 x 106 7 13.21 Normal sperm morphology ≥15% 22.19 ± 11.72 ≥10% <15% 9 16.98 ≥4% <10% 8 5.10 Sperm motility ≥50% 32 60.38 53.75 ± 9.98 <50% 21 39.62

INSEMINATING MOTILE SPERM COUNT (IMSC)

OVARIAN RESPONSE TO THE DRUGS USED FOR OVULATION-INDUCTION

ENDOMETRIAL THICKNESS

OUTCOMES OF IUI IN TERMS OF PREGNANCY Total Number of Couples Total Number of IUI Cycles Number Of Pregnancy After IUI Reported Live Birth 53 143 14 8 Pregnancy Rate Per Cycle of IUI Cycle Fecundability 9.79% Pregnancy Rate Per Couple 26.42% Live Birth Rate Per Cycle of IUI (Reported) Cycle Fecundity 5.59%

OUTCOMES OF PREGNANCY AFTER IUI

RELATIONSHIP BETWEEN PREGNANCY AND NUMBER OF IUI CYCLES

RELATIONSHIP BETWEEN PREGNANCY AND AGE OF THE WOMEN

RELATIONSHIP BETWEEN PREGNANCY AND AGE OF THE MEN

RELATIONSHIP BETWEEN PREGNANCY AND DURATION OF INFERTILITY

RELATIONSHIP BETWEEN PREGNANCY AND TYPE OF INFERTILITY

RELATIONSHIP BETWEEN PREGNANCY AND INITIAL SEMINAL PARAMETERS

RELATIONSHIP BETWEEN PREGNANCY AND INITIAL SEMINAL PARAMETERS (Contd.)

RELATIONSHIP BETWEEN PREGNANCY AND INITIAL SEMINAL PARAMETERS (Contd.)

RELATIONSHIP BETWEEN PREGNANCY AND IMSC

RELATIONSHIP BETWEEN PREGNANCY AND OVARIAN RESPONSE

RELATIONSHIP BETWEEN PREGNANCY AND ENDOMETRIAL THICKNESS

POST-IUI COMPLICATIONS

COMPLICATIONS OF POST-IUI PREGNANCIES

DISCUSSION

Why Six Cycles? Studies showed- most women conceive after 4-6 cycles of IUI cycle fecundability declines by ½ to 2/3 thereafter 1,2 The NICE fertility guidelines - up to 6 IUI cycles for patients with unexplained infertility, male subfertility, cervical factor and minimum to mild endometriosis 3 In Our Study- Most women conceived after 3rd cycle No pregnancy was reported after 6th cycle Ragni G et al. Fertil Steril. 1999;72(4):619-22 Khalil MR et al.; Acta Obstet Gynaecol Scand. 2001 Jan, 80(1): 74-81 National Institute of Clinical Excellence. Fertility: Clinical guidelines. No 11. London: Abba Litho Ltd. UK, 2004

Cycle fecundability- the probability that a cycle will result in pregnancy Cycle fecundity- the probability that a cycle will result in a live birth Various studies- IUI cycle fecundity- 3-10% 1-3 In Our Study- at least 5.59% Miller D et al. Urology 2002;60:497 Van der W LA et al. J Asst Reprod Gen 1998;15:359-64 Ford WC et al. Baillieres Clin Obstet Gynaecol 1997;11:691 Studies Fecundability Per CYCLE Fecundability Per COUPLE Steven R B et al (2008) 4-18% Haebe J et al (2002) 4-15% Guzick et al (1999) 18% Nulsen et al (1993) 19.3% Martinez AR (1990) 11.9% 20% Our Study 9.79% 26.42%

DETERMINANTS OF IUI OUTCOME Age of the Women Steven R B et al (2008) - Maximum success, if <25 years Marviel et al (2010) – Maximum conception, if <30 years Badawy et al (2009)- Little success, if >35 years In our study- Maximum success- 20-25 years (22.22%) Declines progressively with increased age Age of the Men Mathieu C et al (1995)- Increased age adversely affects outcome In our study- Maximum success 26-30 years (33.33%)

DETERMINANTS OF IUI OUTCOME (Contd.) Duration of Infertility Mathieu C et al (1995)- Highest rate when <3 years Nuojua-H S et al (1999)- Duration <6 years- conception rate 20% Duration >6 years- conception rate 10% In our study- Highest success rate if ≤3 years Then declines rapidly

DETERMINANTS OF IUI OUTCOME (Contd.) Type of Infertility Dickey et al (2002)- maximum success for ovulatory dysfunction, followed by male subfertility Khalil MR et al (2001)- Best results in anovulation and unexplained infertility In our study- The best result in PCOS (25%) Followed by unexplained infertility (20%) And male subfertility (10.81%)

DETERMINANTS OF IUI OUTCOME (Contd.) Initial Seminal Parameters Haebe J et al (2002)- Higher success with total motile sperm count >2 million post wash motility >40% normal sperm morphology >4% Montanaro GM et al (2001)- Pregnancy rates 18.2% when normal sperm morphology >10% Pregnancy rates 4.3% when normal morphology <10% Lee RK et al (2002)- Best results with normal morphology >14% Poor when fewer than 4% sperms were normal. Shulman et al (1998)- Higher success with motility>30% In our study- The best results were obtained when sperm density- 10-20 x 106/ml 10-15% sperms had normal morphology >50% sperms had normal motility

DETERMINANTS OF IUI OUTCOME (Contd.) Ovarian Response Endometrial Thickness Various Studies- Contradictory results 1-3 In our Study- Best results when thickness is 7-9 mm Abdalla HI et al. Hum Reprod 1994;9:363-5 Basil S. Ultrasound Obstet Gynecol 2001;18:258-6 Seddigheh E et al. Fertil Steril 2006;88:432-37 Number of Follicles Pregnancy rates Iberico et al (2004) Our Study One 6.2% 5.55-8.70% Two 12.9% 8.00-12.50% Three 30.0% 10.53-33.33%

COMPLICATIONS OF IUI Important complications- Mild OHSS and multiple pregnancy were observed in 22.30% and 0.70% of total cycles respectively Wang JX et al (2002)- higher incidence of preterm birth associated with IUI pregnancies In our study- preterm birth rate at least 21.43% Nuoja HS et al (1999)- No increased congenital anomaly of the offspring In our study- no congenital anomaly was reported

CONCLUSION

IUI can make many infertile couples feel the taste of parenthood Proper case selection is important before useless wastage of money, time, energy and resources If there is no conception after 6 cycles, the investigations should be reviewed and alternatives should be considered The prognostic factors should be kept in mind before IUI and should be discussed with the couples Can safely be conducted in hospitals with relatively low resources

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