1. Infertility: Definition, diagnosis and treatment options Emalee Danforth, CNM University Reproductive Care University of Washington

2. Infertility Definition “Infertility is a disease defined by the failure to achieve a successful pregnancy after 12 months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination. Earlier evaluation and treatment may be justified based on medical history and physical findings and is warranted after 6 months for women over age 35 years.” ASRM Practice Committee Opinion, 2013

3. Infertility Incidence Infertility is experienced by 15% of couples. This rate is likely higher in developing countries given the higher burden of infectious and chronic disease.

4. Infertility Evaluation 85-90% of infertility can be explained through the evaluation of 3 primary factors 1) Sperm – semen analysis 2) Tubal patency – hysterosalpingogram (HSG) 3) Ovarian reserve and ovulatory function Also evaluate thyroid, prolactin, vitamin D

5. Ovary on cycle day 2-4

6. Ovarian Reserve evaluation Follicle Stimulating Hormone (FSH) Cycle day 2-4, <10 is considered WNL Anti-Mullerian Hormone (AMH) Between 1-3 is considered normal, but not a definite range of normal Antral Follicle Count (AFC) Range 7-15 is WNL but not absolute There is no one perfect test for ovarian reserve, look at the whole picture Age of female partner is the biggest independent prognosticator for the likelihood of achieving pregnancy

7. Age & Fertility Relationship

8. Cycle day 2-4 follicular monitoring

9. Polycystic ovary

10. Ovulatory Function Taking a thorough menstrual history is key to determining if a patient is ovulatory Obtain details such as cycle length range, number of days of bleeding, occurrence of cramps, amount of bleeding, spotting preceding cycle Regular monthly menstrual cycles with consistent moliminal symptoms are strongly correlated with ovulatory cycles Irregular or absent cycles or cycles >35 days indicate likely anovulation or oligo-ovulation. Luteal phase progesterone level >3 confirms ovulation. Check 7 days after ovulation/7 days before the expected onset of next menses

11. Semen Analysis 4 primary factors Volume >1.45ml Concentration >14 million/ml Motility >39% Progressive >31% Rapid & linear >11% Morphology >4% by strict Krueger criteria Progressive motile sperm per ejaculate >12.4 million

12. Semen Analysis example Component Results ComponentValueRange & UnitsStatus Testing Location:Male Fertility Laboratory, Department of Urology. 206 543 4671 Abstinence From Ejaculation6 (H)2 - 5 days Collect To Analysis Time3420 - 60 min Semen Volume4.3>1.45 mL Semen VolumeWHO 2010 Sperm Concentration63>14 mil sperm/mL Sperm ConcentrationWHO 2010 Sperm Motility30 (L)>39 % Sperm Motility(WHO category a+b+c) Sperm MotilityWHO 2010 Progressive Motility, %22 (L)>31 % Progressive Motility, %WHO Categories a+b: Rapid and slow progressive sperm Progressive Motility, %WHO 2010 Rapid & Linear Motility, Comp2 (L)>11 % Strict Normal Morphology1 (L)>3.9 % Strict Normal MorphologyTYGSC using WHO 2010. Note: Guzick et al 2001 (NEJM 345:1388) consider <9% infertile, 9-12% indeterminate. Round Cells (WBC & Immature Germ)3300 (H)0 - 1000 CELLS/microL Round Cells (WBC & Immature Germ)Reflexive Differential performed to calculate WBC concentration Progr Mot Sperm Per Ejac, Mill60>12.4 mil/ejaculate Progr Mot Sperm Per Ejac, MillWHO 2010 Semen Other Abnormal FindingsMuch debris, pH 8.7. Semen Other Abnormal FindingsNormal pH 7.8 to 8.6 Semen Other Abnormal FindingsIncomplete liquefaction Notes:ASTHENOTERATOZOOSPERMIA Notes:Reference: World Health Organization, WHO laboratory manual for the examination and processing of human semen (5th ed.) Cambridge, U.K., Cambridge University Press, 2010. This sample demonstrates low motility and low morphology = asthenoteratozoospermia

13. Normal HSG Image Optimal view of the uterus, no filling defects, normal uterine shape Fallopian tubes demonstrate clear bilateral “fill & spill”

14. Suboptimal image of HSG Uterus is dextrorotated, sub-optimal view of the uterus Able to see bilateral “fill & spill”

15. HSG with filling defect Irregular pattern upon filling within the uterus- suggests polyps This image is taken prior to the fallopian tubes filling

16. HSG demonstrating tubal obstruction Right proximal tubal obstruction. Fill & spill of left tube only. In addition, left LUS filling defect c/w polyp vs. fibroid

17. Treatment options Correct or improve underlying etiology if possible Hyperprolactinemia Thyroid disorder Weight loss PCOS management Surgical treatment of endometriosis or structural anomalies Treatment for reversible causes of male factor

18. Treatment options “Low-Tech” Oral ovulation induction agents Clomiphene Citrate (Clomid), a selective estrogen receptor modulator (SERM) Letrozole (Femara), an aromatase inhibitor Controlled ovarian hyperstimulation/Gonadotropin Follicle stimulating hormone (Gonal-F) FSH & LH (Menopur) Intra-uterine insemination

19. Indications for low-tech No absolute indication for IVF Treatment of oligo- or anovulation Treatment for unexplained infertility, mild male factor, diminished ovarian reserve Used for women that are not good candidates for IVF and decline use of donor egg To increase per cycle chance of conception with use of donor sperm

20. Ovulation Induction Agents

21. Gonadotropins

22. Mature Follicle

23. Midcycle follicular monitoring

24. Midcycle Trilaminar lining

25. Treatment options Assisted Reproductive Technology (ART) In Vitro Fertilization (IVF) Use of patient’s own egg or donor egg Use of patient’s own uterus or a gestational carrier Intra-cytoplasmic sperm insemination (ICSI)

26. Indications for ART Severe male factor Tubal factor Failure to achieve pregnancy with low-tech options Desire to create embryos for future use Oncofertility Social reasons Egg freezing Genetic indications Prenatal genetic screening or diagnosis

27. ART steps ART is a general term for any reproductive assistance that involved removing the egg from the body. In IVF the female patient uses hyperphysiologic levels of gonadotropins to hyperstimulate the ovary and bring as many eggs to maturity simultaneously as possible. The eggs are then surgically removed and fertilized with sperm in the lab setting. This is done either by ICSI or conventional insemination The embryos are grown in culture in the lab setting for a fresh transfer back to the uterus either on day 3 or 5, or for freezing on day 5 or 6.

28. Embryos are transferred back to the uterus at either Day 3 or Day 5. Day 5 has higher success rates – thought to be because the best embryos have “selected out.”

29. SART National Data Summary 2012 Age of the female patient<3535-3738-4041-42>42 Number of cycles386621959918410101676224 Percentage of cycles resulting in pregnancies46.737.829.719.88.6 Percentage of cycles resulting in live births40.731.322.211.83.9 Reliability Range(40.2 - 41.1)(30.7 - 32.0)(21.6 - 22.8)(11.2 - 12.4)(3.5 - 4.4) Percentage of retrievals resulting in live births43.434.525.4145 Percentage of transfers resulting in live births47.137.928.516.36.1 Percentage of cycles with elective single embryo transfer14.88.931.20.6 Percentage of cancellations6.39.212.715.821.5 Implantation Rate37.527.618.49.83.8 Average number of embryos transferred1.922.42.9 Percentage of live births with twins29.52520.313.49 Percentage of live births with triplets or more1.10.7 0.4

30. Resources ASRM.org SART.org My contact information is emalee@uw.edu and you are welcome to email me with questions about infertility and fertility treatments.emalee@uw.edu