Normal Reproduction

Normal spontaneous reproduction is a complex process that involves a series of steps.¹ For women, these include:

• Coordination between the hypothalamus, pituitary, and ovary to allow development of (usually) a single dominant egg (oocyte);
• Preparation of the lining of the uterus (the endometrium) to receive an embryo;
• Release of the egg (ovulation) from the ovary;
• “Capture” of the egg by the fallopian tube;
• Interaction with sperm within the tube resulting in fertilization;
• Transport of the fertilized egg (zygote) through the tube and into the uterine cavity, as the zygote divides and becomes a multi-cell embryo; and
• Implantation of the embryo into the endometrium, and development of the placenta.

For men, the steps include:

• Production of sperm in sufficient number and of sufficient motility to allow enough travel from the vagina through the cervix and uterus into the fallopian tube; and
• Fertilization itself, which involves a complex chemical interaction between sperm and egg.

Conditions that affect any of these processes reduce the chances of conception in a given cycle; if the condition is chronic, it can lead to the clinical condition of infertility.

Infertility

The most commonly used definition of infertility is at least 12 months of unprotected intercourse without conception, used in everything from population-based surveys² to clinical practice recommendations.³ Approximately 10 to 15 percent of couples will meet this definition, based on observational studies.^4,5 Up to half of those couples reaching the 12-month threshold may conceive within the next 36 months,⁴ a finding borne out in clinical trials, where four to five percent of subjects may conceive spontaneously between enrollment and the beginning of treatment.^6,7 Because a large number of couples meeting the definition of infertility are actually capable of conceiving and simply represent one end of the distribution of fecundity, many, particularly in Europe, prefer the term “subfertility.”^5,8 This is the term preferred, for example, by the Cochrane Collaboration, where the relevant review group is the Cochrane Menstrual Disorders and Subfertility Group. The use of “subfertility” has, however, not been widely accepted in the United States; therefore, this report will use the more common U.S. term “infertility” throughout the text.

Assisted Reproductive Technologies

The 1992 Fertility Clinic Success Rate and Certification Act mandates that all clinics providing assisted reproductive services report results annually to the Centers for Disease Control and Prevention (CDC).^9,10 The Act defines “assisted reproduction technologies” as those that involve the handling of both sperm and eggs. The vast majority of these involve in vitro fertilization (IVF), a process that involves direct removal of oocytes from the mother's body, combining sperm and oocytes in the laboratory, and returning the embryo to the woman's body. Fertilization of the oocyte occurs either through co-incubation of sperm and oocytes (classic IVF) or through direct injection of a single sperm into the oocyte under microscopic visualization (intracytoplasmic sperm injection, or ICSI); ICSI is particularly effective for couples where there are problems with number and/or function of sperm.¹¹ This report covers these techniques, as well as those that involve stimulation of the ovary, either to induce ovulation in women who do not ovulate at all, or only very irregularly, or to stimulate production of extra oocytes (superovulation) to increase the chances of conception. We do not address other treatments for specific conditions that cause infertility, such as surgical procedures for tubal infertility or endometriosis. Although specific interventions used in men also fall into this framework, there were only a few relevant studies; this report thus focuses on interventions in the female patient and the embryo and identifies further studies in men as a research priority. We also focus on treatments using the couple's own sperm and oocytes, and in which the embryos are returned to the female patient's body. While the use of donor gametes and gestational surrogates provides another set of options for infertile couples, the scientific, ethical, and policy issues are complex enough to warrant a separate report.

Prevalence and Burden of Disease

World-wide, an estimated nine percent of couples meet the definition of infertility, with 50 to 60 percent of them seeking care.¹² In the United States, approximately seven percent of married couples reported at least 12 months of unprotected intercourse without conception, while two percent of women reported an infertility-related clinic visit within the past year, based on estimates from the National Survey of Family Growth.²

Although there is some controversy about whether the proportion of the population with self-reported infertility is increasing, stable, or decreasing,^10,13 there has clearly been increasing utilization of assisted reproductive technology (ART; Figure 1).

Figure

Figure 1. Growth in numbers of ART cycles, deliveries, and infants in the United States, 1996-2005. From Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2005 Assisted (more...)

Over this time, the proportion of deliveries in the United States resulting from ART has increased from 0.37 percent in 1996 to 0.94 percent in 2005.¹⁴ There is no similar registry for ovulation induction/superovulation.

Measuring the “burden of disease” of infertility is difficult. Some conditions associated with infertility, such as endometriosis, uterine leiomyomata, or polycystic ovary syndrome (PCOS), have other symptoms such as painful or unusually heavy menstrual periods, lack of periods altogether (amenorrhea), or hirsutism which lead to interactions with the health system. These symptoms have a significant impact on health-related quality of life (HRQOL) as measured by standard instruments.^15,16

In the absence of symptoms, however, quantifying the “health” burden of infertility is difficult. In the National Survey of Family Growth, 40 percent of women aged 25–29 and 24 percent of women aged 30–44 who were childless would be bothered “a great deal” if they would never be able to have children; the corresponding numbers for men were 32 percent of men 25–29 and 18 percent of men 30–44.¹⁷ Infertility clearly has an emotional impact on couples,¹⁸ some of which is measurable using generic instruments,^19–21 but there are no population-based data in the United States

What is clear, however, is that there is a substantial economic burden associated with infertility. The diagnostic and treatment modalities used, especially for assisted reproduction, are expensive, with one estimate for total U.S. costs of almost $3 billion.²² Many ART treatments result in multiple pregnancies, and complications of multiple pregnancy, including preterm delivery, contribute significantly to the overall costs^23–25 It is these costs, with the measurable morbidity associated with preterm delivery, that drive the search for ART interventions that maximize pregnancy rates while minimizing multiple birth rates.^10,26

Evidence and Practice

In many ways, infertility practice in the United States is highly regulated. Professional societies require certain credentials for membership, states require licensure for professionals, and there is a Federal requirement for central reporting of outcomes (albeit without penalty for failure to report), which is highly unusual for medical procedures. Laboratories used in assisted reproductive techniques, which handle human tissues, are subject to inspection by the U.S. Food and Drug Administration (FDA). However, as in other areas of medicine where much of the practice involves procedures, such as surgery, there is no explicit regulatory mechanism requiring evidence of safety and efficacy as there is for new drugs.^27,28 Medical devices, such as embryo transfer catheters, while subject to approval by the FDA, have much less stringent approval requirements.²⁹ Variations in regimens for the use of drugs already approved for one indication do not require FDA approval under most circumstances and so do not undergo formal regulatory review. Many insurance companies do not cover infertility services,^30,31 so there is no third-party payer demand for rigorous evidence. Infertility treatment may be one of the closest approximations of a true market between providers and patients; although lack of insurance coverage means that infertility patients tend to be wealthier and better educated,³² there is no evidence that this translates into an ability to judge the evidence on the comparative safety and efficacy of different options for treatment.³³ In this setting, practice patterns may change rapidly without a clear rationale; for example, although ICSI is highly effective for treatment of male infertility, the proportion of ART procedures performed using ICSI increased from 11 to 57 percent between 1995 and 2004, despite no change in the prevalence of male factor infertility or evidence that ICSI was superior to traditional IVF in couples with other causes³⁴ (although this change has also been observed in Europe, where there are stricter regulatory controls³⁵). There has been consistent criticism of the methodological quality of much of the clinical literature, for both immediate outcomes of treatment (such as pregnancy, live birth, and complication rates) and especially for longer term outcomes (such as neonatal and childhood outcomes in children conceived after infertility treatment.^36,37

Uses of This Report

This report summarizes the results of our review of the evidence regarding the outcomes of interventions for ovulation induction, superovulation, and assisted reproduction on pregancy, live birth, and short- and long-term complications of treatment for both mothers and children - the lack of data on men is a clear research need. The report may be used by professional societies, patient advocacy groups, payers, and policymakers to help with practice guidelines, identifying areas for promising research, and setting research priorities. The report may also be used by clinicians as a guide to the available evidence, and, although not primarily intended for patients, may assist some couples in making decisions about available treatment options.