BASICS
DESCRIPTION
Definition: failure of a couple to conceive after ≥12 months of regular unprotected intercourse or after ≥6 months if the woman is ≥35 years. Primary: Couple has never been pregnant. Secondary: Couple has been pregnant. Fecundability: the probability of achieving pregnancy in one menstrual cycle.
EPIDEMIOLOGY
Incidence
Incidence is the probability of achieving a pregnancy within 1 year. ~85% of couples will conceive within 12 months of unprotected intercourse.
Prevalence
- In the United States, 5-15% of women currently trying to conceive are infertile.
- ~11.5% of married couples between ages 15 and 34 years and 42% between ages 35 and 44 years meet the criteria for being infertile.
- May increase as more women delay childbearing; 20% of women in the United States have their first child >35 years.
ETIOLOGY AND PATHOPHYSIOLOGY
- Most cases multifactorial: Approximately 50% of cases due to female factors (of which 20% are due to ovulatory dysfunction and 30% due to tubal and pelvic pathology), 30% due to male factors and 20% are of unknown etiology.
- Acquired: Most common cause of infertility in the United States is pelvic inflammatory disease (PID) secondary to chlamydia, endometriosis, polycystic ovary syndrome (PCOS), premature ovarian failure, and increased maternal age.
- Diminished ovarian reserve (DOR): low fertility due to low quantity or functional quality of oocytes.
- Congenital: anatomic and genetic abnormalities.
Genetics
- Higher incidence of genetic abnormalities among infertile population, including Klinefelter syndrome (47XXY), Turner syndrome (45X or mosaic), and fragile X syndrome.
- Y chromosomal microdeletions are associated with isolated defects of spermatogenesis ā†’ found in 16% of men with azoo-/severe oligospermia.
- Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation causing congenital bilateral absence of vas deferens (CBAVD).
RISK FACTORS
- Female
- Gynecologic history: irregular/abnormal menses, sexually transmitted infections (STIs), dysmenorrhea, fibroids, prior pregnancy
- Medical history: endocrinopathy, autoimmune disease, undiagnosed celiac disease (1), collagen vascular diseases (2), thrombophilia, obesity, and cancer
- Surgical history: appendicitis, pelvic surgery, intrauterine surgery, tubal ligation.
- Social history: smoking, alcohol/substance abuse, eating disorders, exercise, advanced maternal age
- Male
- Medical history: STI, prostatitis, medication use (i.e., β-blockers, calcium channel blocker, antiulcer medication), endocrinopathy, cancer
- Surgical history: orchiopexy, hernia repair, vasectomy with/without reversal
- Social: smoking, alcohol/substance abuse, anabolic steroids, environmental exposures, occupations leading to increased scrotal temperature
GENERAL PREVENTION
Normal diet and exercise, avoid smoking and other substance abuse, prevention of STIs
COMMONLY ASSOCIATED CONDITIONS
- Sexual behavior increasing risk for STIs
- Pelvic pathology: endometriosis, ovarian cysts, endometrial polyps, and uterine fibroids
- Endocrine dysfunction (thyroid, glucose metabolism, menstrual cycle abnormalities, prolactin)
- Anovulation is commonly associated with hyperandrogenism and PCOS.
DIAGNOSIS
HISTORY
- Complete reproductive history:
- Age at menarche, regularity of menstrual cycle, physical development, previous methods of contraception, history of abnormal Pap smears and treatment
- History of abortion, D&Cs, bilateral tubal ligation, vasectomy, or other pelvic/abdominal surgery
- Frequency of intercourse and sexual dysfunction
- Abdominal pain or other abdominal symptoms
- STI
- History of endocrine abnormalities
- History of malignancy or chronic illness
- Family history: close relatives with congenital abnormalities or mental retardation; infertility or early menopause in close relatives of female partner
- Medications: drug abuse, allergies, occupation, and exposure to environmental hazards
PHYSICAL EXAM
- BMI and distribution of body fat
- Female
- Pubertal development with Tanner staging
- Signs of PCOS: androgen excess, obesity, signs of insulin resistance
- Breast exam: galactorrhea
- Vaginal exam: describe rugation, discharge, anatomic variation
- Uterine size/shape, mobility, tenderness
- Adnexal tenderness infection or mass
- Male
- Abnormalities of the penis or urethral meatus
- Testes: volume, symmetry, masses (varicocele, hydrocele), presence/absence of vas deferens
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
Evaluation is directed by history:
- Assessment of ovulation
- Irregular or infrequent menses, not accompanied by consistent premenstrual or moliminal characteristics, which are inconsistent in flow and duration, are indicative of ovulatory dysfunction.
- Luteal-phase progesterone ≥3 ng/mL confirms ovulation has recently occurred but does not indicate when it occurred.
- Luteinizing hormone (LH) testing kit: identifies mid-cycle LH surge, which occurs approximately 14 to 26 hours prior to ovulation. Greatest fertility on day of LH surge until 2 days after. Predicts time of ovulation in advance so couples can time intercourse.
- Basal body temperature (BBT): ~1 degree increase in BBT taken upon wakening indicates ovulation has occurred: Greatest fertility spans 7 days PRIOR to rise in BBT. Not preferred
- Assessment of ovarian reserve
- Follicle-stimulating hormone (FSH)/estradiol (E2): FSH and E2 levels on cycle days (CD) 2 to 5 are used to predict response to ovulation induction and pregnancy. High FSH levels >10 mIU/mL and high estradiol (>80 pg/mL) indicate a low chance of pregnancy with in vitro fertilization (IVF).
- Anti-m ¼llerian hormone (AMH) and antral follicle counts (AFCs): The number of antral follicles measured by transvaginal ultrasound (US) at any one time in the ovary is termed the "antral follicle count."¯ AMH is secreted by the granulosa cells of the antral follicles and decreases as a woman approaches menopause. AMH <0.7 Ī¼/dL and total AFC <10 between both ovaries during the follicular phase indicate DOR.
- Clomiphene challenge test: Measure FSH on CD 3, administer 100 mg clomiphene CDs 5 to 9, recheck FSH on CD 10. FSH ≥10 mIU/mL on CDs 3 or 10 indicates DOR; may increase the sensitivity of the standard day 3 FSH test
- Semen analysis
- Warranted in all infertile couples. Semen analysis alone is not used to predict male fertility potential: normal results in 6-27% of infertile males, abnormal results in fertile males
- Semen collection: collected after 2 to 5 days of abstinence. Repeat test 2 to 3 times due to inherent variability within the same individual.
- Parameters for male subfertility: sperm concentration <13.5 mill/mL, sperm motility <32%, sperm morphology <9% normal
- Additional labs
- Prolactin, thyroid-stimulating hormone, 17-hydroxyprogesterone, androgen levels
- HIV, HSV 1 and 2, chlamydia gonorrhea antibody, RPR, hepatitis B and C, CMV
- Genetic testing based on family history
- Transvaginal US for anatomic abnormality
- Hysterosalpingogram (HSG) to evaluate patency of tubes and contour of the cavity; may be both diagnostic and therapeutic.
- Sonohysterography (SHG) may provide a more detailed evaluation of the uterine cavity, if indicated.
Follow-Up Tests & Special Considerations
- Abnormal lab values warrant reevaluation/referral.
- Abnormal imaging may require surgical evaluation.
Diagnostic Procedures/Other
- Hysteroscopy: gold standard, used to directly visualize the endometrial cavity; may be indicated to evaluate filling defects on HSG or SHG
- Laparoscopy: used to directly visualize the peritoneal cavity and may be indicated to evaluate abnormal findings on HSG. It is the only way to definitively diagnose endometriosis.
TREATMENT
GENERAL MEASURES
- Be aware of insurance coverage for each patient. Be minduful of the couple's emotional state: depression, anger, anxiety, and marital discord are common. Many patients benefit from counseling and support measures.
- All female fertility patients should be taking folate supplementation.
- New evidence is suggesting beneficial effects of antioxidants in decreasing time to pregnancy. Additionally, dietary carotenoids in males may improve sperm quality (3,4).
- IVF is the most effective infertility treatment available:
- Eggs are removed from the female and fertilized outside the body. The embryo is monitored for 3 to 5 days and then implanted into the uterus on day 3 or day 5.
- Anatomic causes should be referred immediately for IVF, although surgical consult may be required.
- Fewer complications have been reported for individuals undergoing IVF for anatomic causes rather than ovulatory dysfunction (low APGAR scores, DM) (5)[A].
- Donor eggs may be obtained.
- Male factor
- Consider lifestyle changes.
- Intrauterine insemination (IUI): Sperms are placed via a catheter directly in the uterus. IUI effectively increases the sperm count.
- Intracytoplasmic sperm injection (ICSI) is performed in conjunction with IVF for males with severe abnormalities (i.e., <5 million sperm) or those who have failed to conceive with IUI. A single sperm is injected directly into the cytoplasm of the egg. Fertilization occurs ~70% of the time.
- Donor sperm may be obtained.
MEDICATION
First Line
- Treatment of infertility depends on the etiology.
- Anovulation: must determine if HYPOgonadotrophic or NORMOgonadotrophic.
- Hypogonadotrophic patients: Standard treatment to induce ovulation consists of daily injections of both FSH and LH, which need to be carefully monitored to avoid overstimulation, resulting in ovarian hyperstimulation syndrome (OHSS).
- Normogonadotrophic patients: most commonly due to PCOS. Ovulation induction with clomiphene citrate (Clomid). Regimen: 50 mg/day for 5 days beginning typically on CD 5 after spontaneous or progestin-induced withdrawal bleed. If no ovulation, increase dose to 100 mg/day in subsequent cycles; maximum, 150 mg/day. Some will increase dose with ovulation but no pregnancy. Most effective with ~10% body weight loss if obese.
- Unexplained infertility: IVF most effective; IUI, clomiphene, or LH/FSH yield minor improvements; better outcomes in combination
- Coital or cervical problems: IUI
- Endometriosis: either IVF or surgery; medical therapy does not increase pregnancy rates.
Second Line
- If clomiphene fails to induce ovulation:
- Aromatase inhibitors (i.e., letrozole) may produce a better response.
- Metformin beneficial in anovulatory women with PCOS; initiate with 500 mg daily and increase to ~1,500 mg/day; monitor renal function. Metformin may take up to 3 months to be effective. Consider also oral contraceptive pills (OCPs) for ≥2 cycles, and then retry the clomiphene immediately after stopping the OCPs.
- Generally in subspecialty care: Gonadotropin therapies (injectable FSH or FSH + LH) are effective, but riskier, treatments for infertility. They are effective for hypothalamic dysfunction for which clomiphene generally is not.
ISSUES FOR REFERRAL
Reproductive endocrinology and/or urology: Specialized lab prep is needed for IUI. FSH + LH therapies and IVF warrant referral in most cases.
ADDITIONAL THERAPIES
Consider using surrogate pregnancy if couple is amenable and female cannot conceive.
SURGERY/OTHER PROCEDURES
Reproductive surgery may be necessary in those with anatomic causes of infertility. Polypectomy could be beneficial for large polyps obstructing the lumen of the uterus. Myomectomy may increase pregnancy success rates for intramural fibroids that obstruct or distort the uterine cavity. Salpingectomy is recommended and increases fertility in those with hydrosalpinx.
COMPLEMENTARY & ALTERNATIVE MEDICINE
Acupuncture may increase live birth rates with IVF.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Rarely needed; however, may be needed occasionally for problems in early pregnancy and OHSS
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patients should be referred to a specialist and consider more aggressive options if not successful after 3 to 6 cycles of oral ovulation induction.
Patient Monitoring
Cycle monitoring may decrease risks. US can show the number of developing follicles per cycle, which may help to predict OHSS and risk of multiple gestations.
DIET
A diet with sufficient calories to maintain a BMI permissive for ovulation. If obese, weight loss is recommended.
PATIENT EDUCATION
- Knowledge of women of reproductive age is lacking regarding the adverse effects of STI, irregular menses, and obesity on reproduction. Infertility treatment should focus on patient education (6)[A].
- American Society for Reproductive Medicine (http://www.asrm.org)
- Resolve: Patient advocacy group (http://www.resolve.org)
PROGNOSIS
Excellent; most couples will achieve a pregnancy. Without therapy, ~50% of couples not yet pregnant will conceive during the second and third years of trying.
COMPLICATIONS
Anxiety (stress levels are high during treatment), multiple pregnancy (rates increase with all medical ovulation induction therapies), OHSS (very rare with oral medications but more common with FSH treatments). Couples with infertility may have a slightly increased risk of congenital abnormalities in offspring.
REFERENCES
11 Tersigni C, Castellani R, de Waure C, et al. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update. 2014;20(4):582-593.22 Hurst BS, Lange SS, Kullstam SM, et al. Obstetric and gynecologic challenges in women with Ehlers-Danlos syndrome. Obstet Gynecol. 2014;123(3):506-513.33 Ruder EH, Hartman TJ, Reindollar RH, et al. Female dietary antioxidant intake and time to pregnancy among couples treated for unexplained infertility. Fertil Steril. 2014;101(3):759-766.44 Zareba P, Colaci DS, Afeiche M, et al. Semen quality in relation to antioxidant intake in a healthy male population. Fertil Steril. 2013;100(6):1572-1579.55 Grigorescu V, Zhang Y, Kissin DM, et al. Maternal characteristics and pregnancy outcomes after assisted reproductive technology by infertility diagnosis: ovulatory dysfunction versus tubal obstruction. Fertil Steril. 2014;101(4):1019-1025.66 Lundsberg LS, Pal L, Gariepy AM, et al. Knowledge, attitudes, and practices regarding conception and fertility: a population-based survey among reproductive-age United States women. Fertil Steril. 2014;101(3):767-774.
ADDITIONAL READING
- Fritz MA. The modern infertility evaluation. Clin Obstet Gynecol. 2012;55(3):692-705.
- Pavone ME, Hirshfeld-Cytron JE, Kazer RR. The progressive simplification of the infertility evaluation. Obstet Gynecol Surv. 2011;66(1):31-41.
- Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2012;98(2):302-307.
- Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2012;98(2):294-301.
SEE ALSO
- Endometriosis; Amenorrhea; Infertility; Metabolic Syndrome; Polycystic Ovarian Syndrome (PCOS)
- Algorithm: Infertility
CODES
ICD10
- N97.9 Female infertility, unspecified
- N46.9 Male infertility, unspecified
- N97.1 Female infertility of tubal origin
- N46.8 Other male infertility
- N46.023 Azoospermia due to obstruction of efferent ducts
- N46.125 Oligospermia due to systemic disease
- N46.01 Organic azoospermia
- N97.8 Female infertility of other origin
- N46.022 Azoospermia due to infection
- N97.0 Female infertility associated with anovulation
- N46.122 Oligospermia due to infection
- N46.029 Azoospermia due to other extratesticular causes
- N46.024 Azoospermia due to radiation
- N97.2 Female infertility of uterine origin
- N46.129 Oligospermia due to other extratesticular causes
- N46.123 Oligospermia due to obstruction of efferent ducts
- N46.124 Oligospermia due to radiation
- N46.121 Oligospermia due to drug therapy
- N46.025 Azoospermia due to systemic disease
- N46.11 Organic oligospermia
- N46.021 Azoospermia due to drug therapy
ICD9
- 628.9 Infertility, female, of unspecified origin
- 606.9 Male infertility, unspecified
- 628.2 Infertility, female, of tubal origin
- 606.8 Infertility due to extratesticular causes
- 628.4 Infertility, female, of cervical or vaginal origin
- 606.0 Azoospermia
- 628.3 Infertility, female, of uterine origin
- 606.1 Oligospermia
- 628.1 Infertility, female, of pituitary-hypothalamic origin
- 628.8 Infertility, female, of other specified origin
- 628.0 Infertility, female, associated with anovulation
SNOMED
- 6738008 female infertility (disorder)
- 2904007 male infertility (disorder)
- 39446004 Female infertility of tubal origin
- 84245004 Infertility due to extratesticular cause
- 198448006 Female infertility of pituitary - hypothalamic origin
- 227561004 female infertility associated with anovulation (disorder)
- 3160009 Female infertility of cervical origin
- 359559003 Infertility due to azoospermia
- 26899006 Female infertility of uterine origin
- 71349004 Infertility due to oligospermia
CLINICAL PEARLS
- Women <35 years of age should be evaluated for infertility after failing to conceive after 1 year of unprotected intercourse; those ≥35 years should receive evaluation after 6 months, and those ≥40 years should receive assistance immediately.
- Medical therapy for endometriosis does not increase pregnancy rates, but surgical treatment does.