Infertility Evaluation: Who, When and How

SUMMARY

Patients who fail to achieve a successful pregnancy after 12 months of regular, unprotected intercourse should be evaluated with the diagnosis of infertility. Evaluation should be initiated after 6 months for women >35 years. If over 40 years of age, or a condition known to cause infertility is present, evaluation should not be delayed. Evaluation of women for infertility should be timely, cost effective, and initially focused on the most common causes of infertility such as ovulatory dysfunction. If ovulatory function is normal, uterine anatomy and tubal patency should be investigated.  Tests for ovarian reserve can not predict failure to conceive and therefore should not be used to deny fertility treatment. Ovarian reserve testing should not be used to predict the likelihood of spontaneous conception or menopause.

ASRM Definition of Infertility

ASRM defines infertility as a disease, condition, or status with the following characteristics

The inability to achieve a successful pregnancy based on a patient’s medical, sexual, and reproductive history, age, physical findings, diagnostic testing, or any combination of those factors

The need for medical intervention, including, but not limited to, the use of donor gametes or donor embryos in order to achieve a successful pregnancy either as an individual or with a partner

In patients having regular, unprotected intercourse and without any known etiology for either partner suggestive of impaired reproductive ability, evaluation should be initiated at 12 months when the female partner is under 35 years of age and at six months when the female partner is 35 years of age or older

Indications for Immediate Evaluation Include

• History of oligo / amenorrhea | Known/ suspected uterine, tubal,  peritoneal disease | Endometriosis (stage III/IV) | Known/ suspected male factor subfertility | >40 years | Genetic disorder know to affect fertility (e.g., FMR1 premutation or radiation/chemotherapy exposure)

Definition of Unexplained Infertility (30% of infertile couples)

• Above definition of infertility is met
• Infertility evaluation is normal
• Minimum evaluation: Confirm ovulatory function | Tubal patency | Semen analysis

KEY POINTS:

Relevant History

• Infertility related
  • Menstrual history
  • Pregnancy history
  • Previous contraception
  • Frequency of intercourse
  • Previous evaluations and treatments
  • Family history of reproductive problems and birth defects
• Surgical history
• History of endocrine abnormalities such as
  • Hypothyroidism
  • Hyperprolactinemia
• Abnormal cervical cancer screening and treatments
• Medications and allergies including
  • Occupational exposures
  • Tobacco, alcohol, drugs

Physical Exam

• Vital signs including BMI
• Thyroid exam
• Breast exam
• Evaluation of androgen excess
  • Acne
  • Hirsutism
  • Male pattern balding
  • Clitoromegaly
  • Pelvic examination including evaluation of cul de sac masses / nodularity

Ovarian Assessment

Ovulatory Function

• Ovulatory dysfunction accounts for 40% of infertility in women
• Menstrual history of abnormal bleeding / oligo or amenorrhea
  • Cycles typically regular and predictable | Range from 21 to 35 days
  • If regular cycles and menstrual molimina is present, ovulatory function is likely to be normal
  • History of oligo- or amenorrhea is enough to establish anovulation and requires further evaluation
• Serum progesterone approx. 1 week prior to menses
  • >3 ng/mL (15.9 nmol per L) indicates ovulation
  • Does not assess quality of luteal phase
• Urinary LH (ovulation predictor kits)
• Cervical mucous changes (clear, stretchy)
• TSH (thyroid function)
• Prolactin (hyperprolactinemia): indicated only if galactorrhea, oligomenorrhea, or amenorrhea

Ovarian Reserve

• Goal is to identify women who may be poor responders to gonadotropin stimulation during treatment; does not imply inability to conceive or sub fertility
• Ovarian reserve testing may be of help in the following scenarios (higher risk for diminished ovarian reserve)
  • > 35 years
  • Unexplained infertility
  • Planning ART
  • Poor response to GnRH stimulation
  • Have family history of early menopause
  • At higher risk of diminished ovarian reserve (e.g., chemotherapy and/or pelvic irradiation; ovarian surgery for endometriomas)
• Measured by the following
  • Basal FSH and estradiol (E2) levels on days 2-5
    • FSH > 10 IU/L: Lesser response to ovarian stimulation
  • Serum anti-Mullerian hormone (AMH) levels (independent of day): <1 ng/mL
  • Antral follicle count on cycle day 2-5 (early follicular phase)
    • Low count: Fewer than 5 to 7 follicles
• The best surrogate marker for oocyte quality is age
• Note: Unexplained diminished ovarian reserve or elevated FSH <40 years: Offer Fragile X carrier screening for FMR1 premutation (associated with premature ovarian failure)

Uterine Assessment

• Common causes include polyps, submucosal fibroids, adhesions
• Transvaginal ultrasound is best initial imaging
• Hysteroscopy: Definitive diagnosis under direct visualization, although more invasive
• Sonohysterography: Can detect abnormal intrauterine pathology (polyps, submucosal myomas, synechiae)
• HSG: Best for detecting developmental anomalies; also can show polyps and myomas, although less sensitive
• 3D ultrasound & pelvic MRI: Confirmation and diagnosis of Müllerian anomalies

Fallopian Tube Assessment:

• Tubal disease is a major contributor to infertility and should be excluded
  • HSG (hysterosalpingography): evaluates tubal patency and architecture | presence of salpingitis isthmica nodosa | shows presence of fimbrial phimosis or adhesions
  • SHG (sonohysterography): also shows tubal patency, but does not differentiate between unilateral/bilateral; operator dependent
  • Chromopertubation: performed during laparoscopy with dilute methylene blue or indigo carmine
    • Laparoscopy not recommended for tubal evaluation, although if already being performed, it is reasonable to include chromopertubation

Cervical Assessment

• Cervical factors are rarely the primary cause of infertility
  • Treat cervicitis if noted
  • Post coital tests are no longer recommended

Peritoneal Assessment

• Causes include endometriosis and pelvic adhesions
• Requires laparoscopy for diagnosis
  • Not recommended for routine evaluation of infertile women unless there is suspected pathology or another indication

Male Assessment

• Evaluate both partners at the same time due to high percentage of infertility caused by male factor (40 to 50%)
• Minimal evaluation: Reproductive history and semen analysis

Learn More – Primary Sources:

ASRM: Fertility evaluation of infertile women: a committee opinion (2021) | American Society for Reproductive Medicine

ACOG Committee Opinion 773: The Use of Antimüllerian Hormone in Women Not Seeking Fertility Care

ASRM: Definition Of Infertility 

AHRQ Report: Comparative Effectiveness and Safety of Treatments for Common Causes of Infertility

SUMMARY:

The AHRQ released a systematic review with the goal of evaluating the comparative effectiveness and safety of treatments for common causes of infertility. Previous studies often did not separate outcomes based on diagnoses. This systematic review focuses on the following clinical scenarios

• Women ages 18–44, with infertility due to
  • PCOS
  • Endometriosis
  • Unknown reasons
  • Tubal or peritoneal factors
• Couples with male factor infertility

Findings

• 151 studies
  • 56 for PCOS | 7 for endometriosis | 50 for infertility secondary to unknown causes | 8 for tubal/peritoneal factor | 23 for male factor | 5 for outcomes in male and female gamete donors
  • 21 studies where findings were relevant across all infertility diagnose

PCOS

• Letrozole vs clomiphene results in (moderate strength evidence)
  • Higher live birth rates
  • Reduced multiple births
  • No difference in ectopic pregnancies
• Metformin vs clomiphene (moderate strength evidence)
  • No differences in outcomes when used as primary therapies
• Laparoscopic ovarian drilling vs oral agents (moderate strength evidence)
  • No difference in live birth rates

Couples with unexplained infertility

• Immediate IVF vs starting clomiphene and IUI or gonadotropins and IUI, followed by IVF as necessary (moderate strength evidence)
  • Shorter time to pregnancy
  • Likely no differences for other outcomes including
    • Live birth | Multiple births | Ectopic pregnancy | Miscarriage | Low birthweight | Ovarian hyperstimulation syndrome

Couples with Male factor infertility

• ICSI vs and intracytoplasmic morphological sperm injection (not used in the US)
  • No difference in live birth rate (moderate strength evidence)
  • No difference in miscarriage rate (low strength evidence)

Oocyte donors

• GnRH agonist trigger vs hCG trigger (low strength evidence)
  • Lower incidence of ovarian hyperstimulation syndrome

KEY POINTS:

Additional Findings

• Limited evidence regarding specific comparisons for tubal factor or endometriosis-related infertility
• Lower live birth rates for African-Americans compared with other racial/ethnic groups (low strength evidence)
• Single embryo transfer (low strength evidence)
  • Lower live birth rates 
  • Significant reductions in multiple birth rates
• Maternal cancers and ART (low strength evidence)
  • No increase in most maternal cancers after ART treatment after adjustment for infertility in general or specific causes
• Children born after ART (low strength evidence)
  • Possible increased risk of neurodevelopmental disorders after ICSI compared with IVF alone
  • No difference in overall cancer incidence
• The Evidence Summary states

In general, our current review’s findings are consistent with the NICE and ASRM guidelines— there is a general consensus that the overall body of evidence for many aspects of infertility treatment across all patient groups is limited. One consistent limitation is the relative paucity of studies utilizing live birth per couple as the primary outcome

Learn More – Primary Sources:

Management of Infertility