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The state of the art in 5 key areas, with recommendations from ASRM and other experts

February 2007 · Vol. 19, No. 02


The treatment of infertility has advanced rapidly over the past 25 years, thanks to technological developments and improved application of evidence-based clinical algorithms. Many tests and treatments that once were common no longer are, while rising in vitro fertilization (IVF) success rates and other laboratory procedures have transformed many aspects of management.

Changes are occurring so quickly it is often difficult for the general ObGyn to know the most advanced and appropriate treatment for a given patient. The American Society for Reproductive Medicine (ASRM) Practice Committee establishes guidelines based upon well-designed studies to help physicians keep abreast of the best clinical practices. In this article, I focus on recent ASRM guidelines in 5 topical areas associated with substantial misinformation in both the professional and public sectors:

  • when and how gynecologists should initiate infertility testing and treatment
  • how to evaluate and manage recurrent pregnancy loss
  • the need to reduce the rate of multiple gestation from IVF and ART
  • the expanded applications for preimplantation genetic diagnosis
  • the truth about fertility-sparing efforts in young women planning to undergo cancer therapy and other treatments.

When and how to evaluate patients complaining of infertility

Infertility is a disease, but there are different opinions about when a woman reporting this condition should be assessed (TABLE 1). According to the ASRM, a couple should not be considered infertile until they have tried to conceive spontaneously for at least 12 months, unless the medical history and physical findings dictate earlier evaluation and treatment.1

For example, approximately 25% of couples experience infertility when the woman is age 35, and about 50% experience it when the woman is age 40. Therefore, it is reasonable to investigate infertility after 6 months of attempted conception when the woman is over 35 and after 3 months if she is over age 40.2 The primary reason for this age-related reduction in fertility is the diminishing number and quality of oocytes over time.

Other risk factors for infertility include smoking, family history of premature ovarian failure, significant ovarian pathology, previous ovarian surgery, history of oligomenorrhea or amenorrhea, known or suspected disease of the uterus or fallopian tubes, endometriosis, or a partner known to be subfertile.3,4


When to investigate infertility, treat, and refer


After 12 months of unprotected intercourse if age <35

After 6 months of unprotected intercourse if age 35–39

After 3 months of unprotected intercourse if age ≥40

After 0–6 months if patient has history of or risk factors for infertility


Treat identifiable causes of infertility

Optimize factors influencing fertility:

  • Diet, weight, exercise
  • Timed intercourse

Treat empirically (eg, clomiphene, insemination) for 3–6 months in patients <40


History of infertility or significant risk factors

Significant fertility problems identified during investigation

Age ≥40

After 3–6 months of failed treatment for identifiable causes

After 3–6 months of failed empiric treatment

How to evaluate ovarian function

A careful history and physical examination are key components of systematic, expeditious, and cost-effective identification of the cause of infertility (TABLE 2). A menstrual history and basal body temperature recordings are useful in the diagnosis of ovulatory dysfunction and are easy to obtain. Measurements of urinary luteinizing hormone (LH) using ovulation-prediction kits and mid-luteal-phase serum progesterone are also helpful.

Endometrial biopsy is rarely indicated because of its lack of clinical relevance.

Serial vaginal ultrasonography of the size and number of ovarian follicles may be indicated when simpler methods are inconclusive.

Other tests to evaluate ovarian function may include thyroid-stimulating hormone (TSH), serum prolactin, cycle day 3 follicle-stimulating hormone (FSH) and estradiol, and the clomiphene citrate challenge test in selected patients at higher risk of ovarian dysfunction.


Current status of tests and treatments


Postcoital test

Endometrial biopsy

Antisperm antibodies testing

Intracervical insemination

Clomiphene for more than 3–6 cycles

Routine hCG injection to stimulate ovulation in clomiphene cycles


Clomiphene citrate challenge test in selected patients

Serial vaginal ultrasounds to evaluate response to ovarian stimulation

Saline sonohysterography

Preimplantation genetic diagnosis for single-gene defects

Embryo cryopreservation

Single-embryo transfer to reduce multiple pregnancy rates


Preimplantation genetic screening for aneuploidy in older patients

Human lymphocyte antigen typing for recurrent pregnancy loss

Intravenous immunoglobulin for recurrent pregnancy loss

Ovarian tissue or oocyte cryopreservation for fertility preservation

* Should be performed only in clinical trials

Clomiphene citrate is preferred

Ovarian dysfunction can be treated with clomiphene for 3 to 6 cycles5 starting at 50 mg per day from cycle day 5 to 9 and increasing to 100 and then 150 mg per day if ovulation does not occur. The drug may also be effective empiric treatment for unexplained infertility using 100 mg per day from cycle days 3 through 7 for a maximum of 3 to 4 cycles.

Only gynecologists experienced with ovarian stimulation drugs and with access to daily ultrasonographic monitoring and estradiol levels should use them, because of the risk of multiple pregnancy and ovarian hyperstimulation.

For women with polycystic ovary syndrome (PCOS), clomiphene alone is more effective than metformin alone. Ovarian drilling may be an effective surgical treatment for PCOS if clomiphene fails, but the cost and risk of adhesions must be considered.

Human chorionic gonadotropin (hCG) injections during clomiphene treatment to stimulate ovulation should be given only if the patient’s own urinary LH surge cannot be detected.

A single intrauterine insemination (IUI) improves the pregnancy rate slightly in conjunction with clomiphene, and by an odds ratio of approximately 2 in conjunction with gonadotropins. The gonadotropin dosage ranges from about 75 to 600 IU per day for 8 to 12 days, based on patient need and careful monitoring.

When to give up on ovarian stimulation. Failure to achieve pregnancy after 3 to 6 cycles signals the need to expand diagnostic evaluation or change treatment strategies.

Evaluate the uterus and tubes

Uterine factors rarely cause infertility but warrant thorough investigation all the same, including assessment of uterine cavity size and shape. A number of methods are available:

  • hysterosalpingography (HSG)
  • ultrasonography
  • saline sonohysterography

Tubal factors can be evaluated using HSG or laparoscopy with “chromotubation.” Fluoroscopic or hysteroscopic selective tubal cannulation confirms or excludes any proximal tubal occlusion suggested by HSG or laparoscopy and may help correct it via recanalization using specialized catheter systems.

Peritoneal factors such as endometriosis or pelvic or adnexal adhesions may occasionally be identified by ultrasonography if there is a mass, but are more likely to require laparoscopy.

When laparoscopy is indicated

If there is evidence or a strong suspicion of endometriosis, pelvic or adnexal adhesions, or significant tubal disease, laparoscopy is warranted. It also may be helpful in younger patients (eg, <35 years) and women with a shorter duration of infertility (eg, <3–4 years), and when there is a reasonably normal male factor.

Because they reduce pregnancy rates by 50%, hydrosalpinges should be removed or the fallopian tube should be ligated proximally before IVF. It also is important to consider the number of patients needed to treat by laparoscopy to obtain 1 additional pregnancy.

Only gynecologists with expertise should perform laparoscopy, because it is important to make the correct diagnosis and be capable of surgically treating conditions found during the surgery.

Skip the postcoital test, but keep the semen analysis

Abnormalities of the cervical mucus or sperm–mucus interaction rarely cause infertility. Therefore, the postcoital test has questionable predictive value and is probably only useful to confirm that the couple can have properly timed intercourse during the cycle.3

A male factor is solely responsible in about 20% of infertile couples and contributory in another 30% to 40%. For this reason, semen analysis is always warranted when the female is being evaluated for infertility.

Examination of the male partner should be performed by the gynecologist, or the male should be referred to a urologist interested in infertility.6

For recurrent pregnancy loss, best treatment is TLC

Recurrent pregnancy loss is challenging because it is so emotionally charged for the patient, the cause is often unclear, and we lack specific treatments. A methodical and empathetic approach is therefore recommended.

What the history can reveal

Many women with recurrent pregnancy loss will eventually have a live birth, but increasing numbers of miscarriages do predict a poorer overall chance of success, as does increasing age.

Lifestyle factors rarely, if ever, cause recurrent pregnancy loss, but the following factors may increase the risk of miscarriage: obesity, high daily caffeine intake, alcohol consumption, use of nonsteroidal anti-inflammatory drugs, and social class and occupation. A previous diagnosis of or treatment for infertility also increases the risk of recurrent loss.

Smoking should be discouraged and healthy lifestyles should be promoted.7

Causes of recurrent pregnancy loss

Definite causal factors include chromosomal abnormalities, such as translocations, in approximately 5% of couples with 2 or more losses.

Probable factors include uterine abnormalities (both congenital abnormalities such as septate, and acquired defects such as adhesions and intrauterine or submucous myomas), uncontrolled thyroid disease or diabetes, PCOS, and antiphospholipid antibody syndrome.

Other thrombophilias, such as those associated with factor V Leiden mutation, activated protein C resistance, and possibly prothrombin G20210A and protein S deficiency, have been found by some investigators to be associated with recurrent pregnancy loss. It is doubtful that antithyroid antibodies and sharing of parental human lymphocyte antigen (HLA) cause recurrent miscarriage.7

Genetic component likely. The risk of recurrent pregnancy loss in first-degree relatives of women with unexplained repeated pregnancy loss who have normal chromosomes is approximately 6 times higher than the risk in the background population, suggesting a polygenic mode of inheritance.7,8

Other possible causes include low plasma folate levels, which have been associated with an increased risk of first-trimester pregnancy loss. Environmental toxins such as ionizing radiation, organic solvents, alcohol, mercury, and lead are confirmed causes of recurrent pregnancy loss; hyperthermia is a suspected cause.8

Recommended evaluation

Investigations that have been proven in many studies include:

  • HSG, hysteroscopy, and sonohysterography
  • karyotyping of the couple
  • measurement of thyroid hormone
  • hemoglobin A1C and serum glucose assessment
  • activated partial thromboplastin time, dilute Russell viper venom time, and lupus anticoagulant assessment
  • measurement of immunoglobulin G and immunoglobulin M anticardiolipin antibodies
  • test for factor V Leiden mutation

Tests that are possibly useful include assessment of androgens and FSH in women with irregular periods.7

Examine products of conception?

Although it is routine practice to send products of conception for histologic examination, mainly to exclude a gestational trophoblastic disorder, the usefulness of this practice is unclear.8 In couples with recurrent pregnancy loss, chromosomal analysis of the products of conception indicates that a normal conceptus karyotype in a previous pregnancy is a predictor of a higher rate of miscarriage in a subsequent pregnancy.8 When stratified by maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with recurrent pregnancy loss, compared with controls.8 The cost-effectiveness of karyotyping is therefore unclear.

High levels of homocysteine (ie, hyperhomocysteinemia) can be associated with recurrent pregnancy loss. Among genetic causes is polymorphism at position 677 in the methylene tetrahydrofolate reductase (MTHFR) gene, which is often evaluated to rule out this condition.

Infections with bacteria, viruses, or parasites can all interfere with early pregnancy development, but none seem to be a significant cause of recurrent pregnancy loss.8 Testing is most useful in the context of an acute infectious episode.

Can recurrent loss be treated?

The hallmark of treatment is empathetic care, along with counseling emphasizing the complexity of this condition. Any endocrinologic, anatomic, or other abnormality that is identified during evaluation should be treated, if possible.

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