A Public Health Focus on Infertility Prevention, Detection, and Management
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The desire to have children is powerful and widespread, but for a sizeable minority it is not easily fulfilled. Challenges to fertility arise from genetic abnormalities, infectious or environmental agents, delayed childbearing, behavior, and certain diseases. Awareness of the potential risks may lead some people to adopting corrective behaviors and maintain fertility. Many people, however, find themselves coping with infertility. The journey for those people who are infertile may begin with unrecognized health problems; continue with difficulties in obtaining services that often are not covered by health insurance; and even after success with physically demanding and expensive medical procedures, it may lead to unexpected adverse effects on the health and quality of life of the patients and their children. Each step of this journey is characterized by interactions among the physical and social environment, the biological background and behavior of individuals, and the health care system. On the population scale, these interactions create patterns of disease, utilization of services, and outcomes that are increasingly a topic of public debate. The range of issues raised by the debate includes identifying and managing risk factors for infertility, addressing racial and economic disparities in access to care, addressing the ethical and financial implications of medically assisted reproduction, and assessing the risks and benefits of such technologies. The purpose of this article is to outline the reasons why infertility is a public health concern and open a discussion about the role that the public health community can play in addressing the problem. This article is not intended to propose specific solutions but to propose a list of topics that should be discussed in a forum open to scientists in academic institutions, industry, and government agencies; health care professionals and their organizations; individuals and couples who are coping with infertility and their advocacy groups; and the general public. We hope that the article, and the discussion that it sparks, will create the momentum necessary to develop a national plan for infertility prevention, detection, and management. The broad objectives of such a plan include the reduction of the burden of infertility and impaired fecundity and the improvement of the quality of life of Americans who live with infertility, through better diagnosis, safe and effective treatment of infertility, and improved access to these services.
Challenges to human fertility may arise from many conditions caused by genetic abnormalities, infectious or environmental agents, and certain behaviors. Natural aging processes also place a limit to human fertility. For some individuals, the fertility window closes earlier than expected. Recent trends toward postponing age at first pregnancy have highlighted the natural limits of fertility and accelerated the development and use of medical technology to overcome such limits. The proportion of first births to women aged 30 years and older has increased more than fourfold since 1975, from 5% to 24% in 2006. The absolute number of these births increased from more than 69,000 to approximately 405,000 during this period (1) and (2). Although some perceive infertility as a quality-of-life issue, the American Society for Reproductive Medicine (ASRM) regards infertility as a disease (3). A U.S. Supreme Court opinion agreed with a lower court statement that reproduction is a major life activity and confirmed that conditions that interfere with reproduction should be regarded as disabilities, as defined in the Americans with Disabilities Act (4).
According to data from the National Survey of Family Growth (NSFG), in 2002 an estimated 7.3 million American women aged 15–44 years had impaired fecundity (i.e., experienced difficulties conceiving or bringing a pregnancy to term during their lifetime) (5). Two million couples in the United States were infertile (i.e., had not conceived during the previous 12 months despite trying) (5). Although the focus of research and services has traditionally been on women (and, as a consequence, much of this article reflects it), fertility impairments may be just as common among men (6). The statistics cited above distinguish impaired fecundity from infertility. In this article we refer to infertility more broadly, including all fertility impairments. Recurrent pregnancy loss (miscarriage) is a component of impaired fecundity, distinct from infertility (ASRM, unpublished data) and is not included in this presentation.
Societal and behavioral shifts in the last quarter of the 20th century may have affected levels of infertility, although it is unclear whether the prevalence of fertility impairments has changed over time (7). In part because “baby boomers” (i.e., the generation born between 1946 and 1964) have steadily postponed the age at which they choose to conceive their first child, and in part because new technologies have made it possible for some couples to overcome infertility and have made news with spectacular outcomes such as high-order multiple births (8), Americans are increasingly aware of and concerned about infertility. It is unclear whether infertility disproportionately affects less privileged people in the United States. Although data from the NSFG do not show large disparities in infertility (5), social and racial disparities in health status and in the frequency of certain risk factors (e.g., sexually transmitted infections that may lead to infertility if untreated) would suggest that preventable causes of infertility disproportionately affect the less privileged. A recent report from the Coronary Artery Risk Development in Young Adults (CARDIA) study indicates that among non–surgically sterile women, African American women had a twofold increase in odds of reporting a history of infertility (9). Financial barriers limit access to diagnosis, evaluation, and treatment and may lead to selectively underestimating the frequency of infertility in the same population groups (10). Thus, it is difficult to interpret the available data. On the other hand, delaying childbearing may be more common among professionals and other higher-income groups, making these groups more vulnerable to the cumulative effect of causes of infertility, including the effect of aging. Different subgroups may have infertility of different etiology.
We do not know what proportion of the infertility burden can be prevented, but it may be substantial. For example, tubal infertility affects 18% of the couples who try to overcome infertility by using assisted reproductive technology (ART) (11) and is typically the consequence of chronic pelvic inflammatory disease (PID), which can lead to tubal scarring. The latter can be prevented by early detection and treatment of sexually transmitted infections and, in particular, chlamydia infection (12). More than 1 million chlamydia cases are reported to the CDC annually (13). In 2006, reported chlamydia rates were eight times higher among African Americans than among whites, highlighting the large disparities in this important risk factor for infertility (13).
Other modifiable factors contribute to the burden of infertility. Although the proportion of male factor infertility due to varicocele is unknown, this common condition is reported in approximately half of the inpatient surgery services and approximately two thirds of office visits for male factor infertility in the United States (14). Varicocele is easily treated, although the impact of treatment on subsequent fertility is unclear (15). Environmental and occupational hazards account for an unknown proportion of infertility but are suspected causes of declining human sperm quality in industrialized countries (16). Although approximately 84,000 chemicals are in the workplace (2,000 new chemicals every year), information on reproductive toxicity is available only for a few thousand. A consensus workshop sponsored by The National Toxicology Program identified 43 chemicals and prioritized the need for field studies on the basis of available toxicology and numbers of workers potentially exposed (17). For example, it was estimated that more than 2 million workers are potentially exposed to the solvent 2-butoxy ethanol (17). The prioritized list was incorporated into the National Occupational Research Agenda (18). There is also increasing evidence that lifestyle factors, such as tobacco smoking and obesity, which cause chronic disease and disability later in life, can cause fertility impairment during the reproductive years (19) and (20). The Surgeon General's Report on the Health Consequences of Smoking highlights numerous adverse reproductive effects of tobacco smoking, including infertility (21) and (22). In women, tobacco smoking is associated with decreased fecundability (probability of conception in a month) in a dose-dependent fashion (23), with ovulatory dysfunction (24), and with early menopause (25) and (26). Although the evidence is less consistent than with female infertility, among men, tobacco smoking is associated with lower volume of the ejaculate, lower sperm density, and worse morphology of the spermatozoa (27). Although the proportion of infertility that is due to tobacco smoking is unknown, infertility specialists are increasingly aware that exposure to tobacco products can cause infertility and interferes with its treatment (28) and that tobacco screening and cessation is an important component of infertility care (29). The metabolic disorder associated with the polycystic ovary syndrome has highlighted the link between overeating, insulin resistance, and the endocrine changes that reduce fertility in women with polycystic ovary syndrome (20). Obesity is associated with ovulatory and menstrual dysfunction and subsequent infertility, increased risk of miscarriage, and decreased effectiveness of ART (30). Obesity in men is associated with erectile dysfunction and decreased androgen production, but its effects on male fertility are not as clear (30).
In addition to infertility due to environmental exposures, specific medical conditions, and behaviors, fertility impairments resulting from the treatment of diseases may also be successfully addressed. For cancer, the negative effects of specific chemotherapy and radiation on fertility are well known. Thus, cancer patients need to be informed about the reproductive consequences of treatment and about options available to address them, such as sperm banking, relocation of the ovary away from the radiation field, or oocyte or embryo cryopreservation before the initiation of treatment (31), (32) and (33). Other therapeutic interventions, including highly active antiretrovirals used for the treatment of individuals infected with HIV, may also interfere with reproduction (34) and (35). Available ART procedures offer the promise of maintaining the ability to procreate among individuals who cope with life-threatening diseases and may experience infertility as a side effect of treatment.
A public health strategy focusing on primary prevention (e.g., through removal of risk factors for infertility such as those described above) would reduce the prevalence of infertility, improve health and quality of life, and avert the costs of infertility treatment, including the downstream costs produced by adverse outcomes of such treatment on mothers and children. For some causes of infertility, primary prevention is feasible. Chlamydia screening in women, preventing initiation of cigarette smoking in adolescents, facilitating smoking cessation among adults, and promoting physical activity and a healthy diet are all clinical services with proven efficacy and cost-effectiveness (37) and (38), although their possible impact on infertility is yet to be determined. The public health community can play an important role by disseminating information, by advocating for the adoption of effective interventions by public health program and health care services, and by monitoring effectiveness through surveillance.
Whereas primary prevention is important, infertility diagnosis and treatment are relevant to public health in their own merit. First, infertility is an area where health care costs are borne most often by the individual, creating significant economic and racial disparities. Second, early diagnosis and treatment of underlying medical conditions (secondary prevention) may lead to effective restoration of fertility. Third, infertility treatment, although generally safe, is associated with adverse health outcomes for the mother and the child; epidemiologic surveillance efforts are increasingly necessary to design and implement tertiary prevention programs (i.e., the prevention of adverse outcomes of infertility treatment). Finally, the treatment of infertility, as well as some of its outcomes, contributes to increasing the cost of health care for all.
According to the NSFG, in 2002 7.3 million, or 12% of women of childbearing age in the United States had ever received infertility services (including counseling and diagnosis) in their lifetime. More than 1.1 million women sought medical help to get pregnant in the previous year (5). Of these, approximately 74% received counseling, 59% underwent some testing, 46% received drug treatment, 13% underwent IUI, and 8% underwent surgery for blocked tubes, whereas 3% used ART (39).
Assisted reproductive technology has been used in the United States since 1981 to help women become pregnant, most commonly through IVF of human eggs followed by transfer of the embryos into the woman's uterus (11). Data from the National ART Surveillance System (NASS) indicate that in 2005 134,242 ART cycles were performed at 422 reporting clinics in the United States, resulting in 38,910 deliveries of one or more living infants and 52,041 infants (40). Although use of ART is still relatively rare as compared with the potential demand, use has doubled over the past decade, and ART-born infants now account for more than 1% of all U.S.-born infants and 18% of all multiple births (41). This proportion is larger in states where statutes mandate insurance coverage of infertility treatment (42).
The NSFG data reported above indicate that infertility treatment other than ART, such as ovarian stimulation followed by natural conception or IUI, is much more common than ART. Although the scientific literature indicates that the efficacy of these treatments is lower than that of ART (pregnancy rates generally below 15%; for a review of trials of ovarian stimulation and IUI, see reference 43), their higher frequency makes it likely that just as many or more children are conceived through these forms of infertility treatment. There is no population-based information on the success rates or on the adverse health outcomes that are associated with non-ART approaches to infertility treatment (39).
Fertility assistance may be necessary not only for couples who live with infertility but also for fertile couples for whom natural conception may pose health risks, such as HIV-discordant couples or those affected by cancer. Whereas there is recognition that denying fertility services to such persons would be unethical (36), there is not yet a broad consensus as to which assisted reproduction procedures should be offered.
Although infertility treatment, including ART, is generally safe, adverse outcomes have been described both in women undergoing ART and in infants born from these procedures (44). Ovarian hyperstimulation syndrome is a rare but very serious adverse effect of ART and ovarian stimulation (45). Multiple-gestation pregnancies are much more common after infertility treatment than after natural conception and increase the risk for maternal complications (46) and (47). Multiple-birth infants are at increased risk for low birth weight, preterm delivery, infant death, and disability among survivors (46), (47), (48), (49), (50) and (51). Recent systematic reviews of the literature (52) and (53) indicate that ART-conceived singletons also face increased risks for low birth weight, very low birth weight, preterm delivery, and fetal growth restriction. These findings have been confirmed in population-based studies in the United States (8) and (54). For infertile women who have a good prognostic profile (i.e., a high expected probability of success with ART), perhaps the simplest and most effective strategy for reducing the risk of adverse ART outcomes is elective single embryo transfer (SET). Clinical trials have shown that a protocol consisting of a SET cycle, followed by a second SET cycle if the first fails, is associated with a cumulative probability of success that is similar to that of a single conventional ART cycle in which two embryos are transferred simultaneously (55), (56), (57) and (58). The SET protocol, however, carries a much lower risk of multiple delivery, with consequently lower risk of adverse maternal and child health outcomes (59). The cost-effectiveness of SET is not as clear for patients with less-than-optimal prognosis (60). More research is needed to understand the causes of adverse consequences unrelated to multiple ET, and the long-term effects of infertility treatment on infertile women and their children (44). As the number of young women who donate oocytes for use in ART is increasing, the potential health consequences of participation in these programs need to be evaluated. Economic and racial disparities may be present not only in the frequency of infertility impairment or access to treatment but also in treatment outcomes (61).
Given that one IVF cycle costs, on average, more than $12,000 (62), IVF continues to generate controversy and debate, including questions about its cost-effectiveness, about the impact of maternal age and multiple births on cost, and about the extent of disparities in access to infertility services (63). On the other hand, the financial impact of involuntary childlessness, including the cost of treating depression and decreased work productivity, has not been fully evaluated (64). In addition to uncertainties about the financial impact of infertility and its consequences, there are inadequate data on the total direct costs of infertility treatment. These include not only the expenses associated with diagnosis and treatment but also those associated with maternal and infant outcomes, including some longer-term disability costs associated with multiple gestation, preterm delivery, and low birth weight. Lack of insurance coverage in many states makes the couple directly responsible for paying for the initial assessment and subsequent treatment, and out-of-pocket expenses for care that is not covered by insurance are more difficult to track than expenses that lead to insurance claims. By contrast, the cost associated with pregnancy and maternal and child health outcomes is covered by most health insurance policies and can be documented more accurately. According to preliminary calculations, which are likely to underestimate the true value, the cost of diagnosing and treating infertility and its sequelae exceeds $5 billion per year.* Clearly, the cost would be higher if all couples affected by infertility sought care and treatment (65). Research into the cost-effectiveness of interventions for the primary prevention of infertility is developing rapidly (66), (67), (68), (69) and (70). Any increase in the utilization and cost of infertility diagnosis and treatment services that may occur in the future will likely increase the cost-effectiveness of primary prevention interventions.
Whereas infertility treatment most often provides couples with the means to have their biological children, surrogacy, adoption, and child-free living are important alternatives. The risks, benefits, and costs of these alternatives are not immediately clear, and decision-making involves serious emotional responses. Consumers cannot easily find objective information on these topics, and the same racial and social disparities that affect access to treatment also affect access to information on alternatives to treatment. A public health approach to managing infertility should promote integration of counseling services on adoption and child-free living with the medical counseling of infertile couples.
Although the focus of this article is on infertility in the United States, the problem of infertility is global (71). Because the global focus of public health policies and programs has justifiably been on containing population growth and providing affordable, safe, and effective family planning services, the inability to procreate has not traditionally made it to the top of the priority list in many developing nations. The Demographic and Health Surveys program estimates that 167 million ever-married women aged 15–49 years in developing countries (excluding China) were infertile in 2002 (72). Infertility rates exceed 30% in sub-Saharan Africa (72). In many countries the demand for infertility treatment and assisted reproduction is increasing with economic development.
Infertility, like reproductive health in general, has multiple dimensions, ranging from the biomedical to the social. Associated legal aspects encompass reporting of outcomes, program management, insurance coverage, government funding of services, clinic and laboratory operation, and public health research (73). The President's Council on Bioethics recently concluded a thorough evaluation of technologies that affect the beginning of life and found that, although the fields of assisted reproduction, human genetics, and embryo research increasingly are converging, no comprehensive systems exist for ascertaining the impact of these technologies, and their practice is largely unregulated (74). On the other hand, some physicians in this field already feel under excessive scrutiny because special laws and regulations mandate embryology laboratory registration and accreditation and the reporting of procedures performed, in addition to the usual certification and licensing requirements common to other medical specialties. Laws and regulations addressing infertility will inevitably change at both federal and state levels to respond to new challenges. It is important for the public health community to engage stakeholders in examining the scientific evidence about the prevention, diagnosis, and management of infertility and work toward addressing significant gaps.