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Overview of infertility

Overview of infertility
Literature review current through: Jan 2024.
This topic last updated: Oct 18, 2023.

INTRODUCTION — Infertility is a common condition with important psychologic, economic, demographic, and medical implications. Demand for infertility services has grown substantially even though the prevalence of infertility has been stable. This phenomenon likely reflects greater awareness of infertility in the general population, increased access to fertility services (eg, mandated insurance coverage, increase in specialty-trained physicians), and the improving success rates of assisted reproductive technologies.

This topic review will provide an overview of infertility issues. More detailed discussions of both male and female infertility are found elsewhere.

Female-specific content

(See "Female infertility: Causes".)

(See "Female infertility: Evaluation".)

(See "Female infertility: Treatments".)

Male-specific content

(See "Causes of male infertility".)

(See "Approach to the male with infertility".)

(See "Treatments for male infertility".)

In this topic, when discussing study results, we will use the terms "woman/en", "man/en", or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

DESCRIPTION AND RELATED TERMS — The American Society for Reproductive Medicine (ASRM) defines infertility as "a disease, condition, or status characterized by any of the following" [1]:

"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 6 months when the female partner is 35 years of age or older."

Other terms used when discussing fertility include [2]:

Fecundity is clinically defined as the capacity to have a live birth.

Fecundability is the probability of achieving a pregnancy in a single menstrual cycle with adequate sperm exposure and no contraception that results in a live birth.

Fertility is the ability to have a clinical pregnancy.

Sterility is a permanent state of infertility.

Time to pregnancy refers to the length of time, usually measured in months, that it takes a couple to conceive. This parameter is often used in epidemiological studies as a measure of subfecundity [3,4].

NORMAL FERTILITY — Most pregnancies occur during the first six menstrual cycles of attempted conception [4-8]. Additional details of normal fertility are presented in related content. (See "Natural fertility and impact of lifestyle factors", section on 'What is normal natural fertility?'.)

PREVALENCE AND INFLUENCING FACTORS — Based on global data collected between 1990 and 2021, the World Health Organization (WHO) estimates that approximately 1 in 6 adults has experienced infertility at least once in their life [9]. Prevalence estimates were 17.8 percent for adults in high-income countries and 16.5 percent for adults in low- and middle-income countries. Challenges to obtaining representative data include that infertility prevalence varies based on the definition used and study variables included, such as time/period, geographic region, and patient demographic factors.

Impact of increasing female age – Infertility prevalence generally rises with increasing female age. Analysis of data from the 2016 Global Burden of Disease Study reported females aged 20 to 24 years had the lowest rates of infertility (approximately 3 percent) while those aged 35 to 39 years had the highest rates (approximately 5.5 percent) [10]. Age-specific contributors include declining ovarian reserve and accrued impact of gynecologic disease, medical comorbidities, and infection, among others. (See "Evaluation and management of infertility in females of advancing age".)

Impact of race/ethnicity While race/ethnicity may impact the prevalence of infertility [11], this association likely reflects underlying confounders, such as socioeconomic disadvantage, rather than a true relationship [12].

Impact of nulliparity For females, nulliparous individuals are more likely to experience infertility than those with a prior pregnancy, across all age groups. In the analysis of data from the US National Survey of Family Growth, nulliparous individuals as a group had more than twice the prevalence of infertility compared with parous individuals (13 versus 6 percent) [11]. Nulliparous individuals aged 35 to 39 years had a nearly fourfold increased prevalence of infertility compared with their parous counterparts (27.2 versus 7 percent).

Access to reproductive health services – The ability to access reproductive health services is associated with reduced prevalence of infertility, likely through improved screening and treating of gynecologic disease and infection [11]. This finding has significant implications for public policy.

CAUSES OF INFERTILITY — The World Health Organization (WHO) task force on Diagnosis and Treatment of Infertility performed a study of 8500 infertile couples and utilized standard diagnostic criteria to determine the medical conditions contributing to infertility [13]. In developed countries, female factor infertility was reported in 37 percent of infertile couples, male factor infertility in 8 percent, and both male and female factor infertility in 35 percent. Five percent of couples had unexplained infertility and 15 percent became pregnant during the study. This study illustrates that infertility should not be assumed to result primarily from disorders in the female partner.

Some causes of infertility are easily identifiable, such as azoospermia (no sperm cells in the ejaculate), longstanding amenorrhea, or bilateral tubal obstruction. However, the situation is less clear in most couples: the sperm may be reduced in number, but are not absent; there may be oligomenorrhea with some ovulatory cycles; the woman may have partial tubal obstruction; or a menstrual history may suggest intermittent ovulation. It is often difficult to weigh or prioritize these findings when counseling infertile couples or planning treatment programs.

Adding to the complexity of the situation, there are few data regarding the predictive validity of these tests despite their widespread use. Thus, short of the absolute infertility factors mentioned (eg, azoospermia or bilateral tubal obstruction), an abnormal test result cannot be said to be the cause of infertility in a particular couple.

The uncertain causal relationship between an abnormality on infertility testing and the actual cause of infertility makes it difficult to estimate the relative frequency of the causes of infertility. Nevertheless, it is instructive to estimate the frequency with which various factors are found in association with infertility as a rough proxy for their relative importance. One population-based study reported the following results [14]:

Male factor (hypogonadism, post-testicular defects, seminiferous tubule dysfunction) – 26 percent

Ovulatory dysfunction – 21 percent

Tubal damage – 14 percent

Endometriosis – 6 percent

Coital problems – 6 percent

Cervical factor – 3 percent

Unexplained – 28 percent

Of note, the total in the above study for all causes of infertility is greater than 100 percent because some couples had more than one problem. The frequency of these factors in infertility is similar whether infertility is primary or secondary, and has not changed significantly over the past 25 years in developed countries [15].

These causes are discussed in detail separately:

(See "Female infertility: Causes".)

(See "Causes of male infertility".)

WHO SHOULD PERFORM THE INFERTILITY EVALUATION? — Infertility evaluations should be directed by fertility specialists or physicians with experience in the evaluation and treatment of infertility, where available. In many cases, it is appropriate for primary care physicians to initiate portions of the infertility evaluation. In general, obstetricians-gynecologists should be able to perform the basics of the fertility work-up. In observational studies, however, providers with expertise in diagnosis and treatment of infertility tended to provide more cost-effective care than less experienced primary care providers, and were generally more able to fulfill the emotional, informational, and diagnostic needs of their patients [16-21]. Although a less experienced provider may initiate the infertility evaluation, couples with abnormal test results should be referred to a specialist.

Specific guidelines for practices offering assisted reproductive technologies have been developed by the American Society for Reproductive Medicine [22].

TIMING OF INFERTILITY EVALUATION — The general consensus among infertility experts is that infertility evaluation should be undertaken for couples who have not been able to conceive after 12 months of unprotected and frequent intercourse, but earlier evaluation should be undertaken based on medical history and physical findings, and in women over 35 years of age (table 1) [23]. Some authorities have proposed initiating an infertility work-up after six months of fertility-oriented intercourse without conception since prospective cohort studies have shown that a significant decline in fecundity occurs by this time [4,7,24].

The timing of initial evaluation of infertility depends upon the age of the female partner, as well as the couple's historical risk factors (table 2). Women experience a decline in fecundity as the ovary ages, especially after age 30 [25]. Significantly delaying the evaluation and treatment of an infertile woman in her mid-thirties may diminish the success rate once therapy is initiated. For these reasons, in women between 35 and 40 years of age, we initiate the infertility evaluation after six months of frequent unprotected intercourse without conception and we initiate the evaluation after less than six months in women over 40 years of age. The American College of Obstetricians and Gynecologists (ACOG) and the American Society for Reproductive Medicine (ASRM) recommend that women older than 35 years receive an expedited infertility evaluation and undergo treatment after 6 months of failed attempts to conceive or earlier, if clinically indicated [23].

Evaluation is also initiated promptly if the female partner has a history of risk factors for premature ovarian failure (previous extensive ovarian surgery, exposure to cytotoxic drugs or pelvic radiation therapy, autoimmune disease, smoking, strong family history of early menopause/premature ovarian failure), advanced stage endometriosis, or known or suspected uterine/tubal disease [26]. Male factors can also be indications for initiating early evaluation of the male partner. These factors include a history of testicular trauma requiring treatment, adult mumps, impotence or other sexual dysfunction, chemotherapy and/or radiation, or a history of subfertility with another partner.

For younger couples without risk factors who present with fewer than 12 months of attempted conception, we suggest focusing the initial intervention on teaching timed intercourse, often with the aid of a urinary ovulation predictor kit, and advising that they wait at least 12 months before initiating the infertility evaluation. This recommendation may be modified to fit the specific circumstances of the couple.

In addition, we recommend changes in lifestyle factors that may improve fertility, including achieving an ideal body mass index, cessation of smoking, and limiting exposure to alcohol. As discussed above, evaluation is initiated sooner if the female partner has a history of oligomenorrhea/amenorrhea, chemotherapy and/or radiation, or endometriosis, known or suspected tubal disease, or if male risk factors are present. (See "Natural fertility and impact of lifestyle factors".)

INFERTILITY EVALUATION — The recognition, evaluation, and treatment of infertility are stressful for most couples. The clinician should not ignore the couple's emotional state, which may include depression, anger, anxiety, and marital discord. (See "Psychological stress and infertility".)

It is important to remember that the couple may have multiple factors contributing to their infertility; therefore, a complete initial diagnostic evaluation, including a complete history and physical examination, should be performed. This will detect the most common causes of infertility, if present. Evaluation of both partners is performed concurrently [26]. The same approach is used for both primary and secondary infertility.

The following tests are useful in most couples with infertility:

Semen analysis to assess male factors.

Menstrual history, assessment of luteinizing hormone surge in urine prior to ovulation, and/or luteal phase progesterone level to assess ovulatory function.

Hysterosalpingogram or sonohysterogram with a test of tubal patency such as hysterosalpingo-contrast-sonography to assess tubal patency and the uterine cavity.

Assessment of ovarian reserve with day 3 serum follicle-stimulating hormone and estradiol levels, anti-müllerian hormone, and/or antral follicle count.

Thyroid-stimulating hormone.

Prolactin

In select couples, the following additional tests may be warranted:

Pelvic ultrasound to assess for uterine myomas and ovarian cysts.

Laparoscopy to identify endometriosis or other pelvic pathology.

A detailed description of the approach to evaluation of the male and female partners can be found separately:

(See "Female infertility: Evaluation".)

(See "Approach to the male with infertility".)

TREATMENT — Once the cause of infertility is identified, therapy aimed at correcting reversible etiologies and overcoming irreversible factors can be implemented. The couple is also counseled on lifestyle modifications to improve fertility, such as smoking cessation, reducing excessive caffeine and alcohol consumption, and appropriate timing and frequency of coitus (every one to two days around the expected time of ovulation or according to an ovulation predictor kit). (See "Natural fertility and impact of lifestyle factors".)

Therapeutic interventions for treatment of male and female infertility may involve drug therapy, surgery, and/or procedures such as intrauterine insemination or in vitro fertilization. Further research on causes of infertility and therapeutic modalities is needed to improve the overall success of infertility treatment. Reducing the cost of therapy, the risk of multiple gestation, and complications such as ovarian hyperstimulation will improve patient acceptance of, and the safety of, infertility therapy.

The only absolute contraindications to infertility therapy are contraindication to pregnancy and contraindication to use of the drugs or surgery used to enhance fertility. The ethics of restricting infertility therapy for other reasons, such as parental child-rearing ability, severe obesity, lifestyle issues (tobacco smoking, alcohol consumption), are controversial and beyond the scope of this review [27-29]. The parent's marital status, sexual orientation, and HIV status should not be used to deny infertility treatment [30,31].

Approaches to treatment of the male and female partners are described in detail separately:

(See "Female infertility: Treatments".)

(See "Treatments for male infertility".)

(See "Unexplained infertility".)

PREGNANCY OUTCOME — Women who use infertility therapies (in vitro fertilization [IVF] or non-IVF) appear to have a small but statistically significant increase in risk of some pregnancy complications, such as low birth weight, preterm birth, and severe maternal morbidity [32-37]. Compared with the general population, however, an increased risk of preterm birth and low birth weight has also been observed among untreated subfertile women who conceived naturally [35,38]. The relationship between the various causes of infertility, types of infertility treatment, and pregnancy outcomes requires further study to determine the specific risks and the mechanisms involved. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Infertility in couples (The Basics)")

Beyond the Basics topics (see "Patient education: Evaluation of infertility in couples (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and timing of evaluation – Infertility is classically defined as the failure of a couple to conceive; the time frame varies with the age of the female partner (table 1). Fecundability is the probability of achieving a pregnancy in one menstrual cycle. (See 'Description and related terms' above.)

For persons under age 35 years, infertility is the lack of conception after 12 months of regular and appropriately timed intercourse without use of contraception. (See 'Timing of infertility evaluation' above.)

For persons age 35 years and older, infertility is the lack of conception after six months of regular and appropriately timed intercourse without use of contraception. (See 'Timing of infertility evaluation' above.)

Earlier evaluation may be justified based on medical history (eg, history of chemotherapy or pelvic radiation) and physical findings (eg, pelvic mass).

Fecundability – While 80 to 90 percent of couples (combined data, all age groups) will conceive within 12 months of attempting pregnancy, fecundability progressively decreases over time. (See 'Normal fertility' above.)

Common identifiable causes – Infertility can be due to female factors, male factors, or factors contributed by both partners. (See 'Causes of infertility' above.)

Female-specific factors include ovulatory dysfunction, tubal damage, endometriosis, and cervical factor.

Male-specific factors include hypogonadism, post-testicular defects, and seminiferous tubule dysfunction.

Other causes – In some cases, infertility is due to coital problems or is unexplained. (See "Unexplained infertility".)

Evaluation – Components of the basic infertility evaluation include history (table 2) and physical examination, semen analysis, menstrual history, laboratory tests, and assessment of the fallopian tubes and uterus using hysterosalpingography, hysteroscopy, ultrasonography, and/or laparoscopy. Common laboratory tests include assessment of ovarian reserve (may include day 3 serum follicle-stimulating hormone and estradiol levels, anti-müllerian hormone, and/or antral follicle count) and thyroid-stimulating hormone level. (See 'Infertility evaluation' above.)

Treatment – If a cause of infertility is identified, therapy aimed at correcting reversible etiologies and overcoming irreversible factors can be implemented. Therapeutic interventions for treatment of male and female infertility may involve drug therapy, surgery, and/or procedures such as intrauterine insemination or in vitro fertilization. (See 'Treatment' above.)

Discussion of targeted treatments, as well as discussion of unexplained infertility, are described in detail separately.

(See "Female infertility: Treatments".)

(See "Treatments for male infertility".)

(See "Unexplained infertility".)

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References

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