Definition and Operationalization

Our ability to identify and address the causes and consequences of infertility and improve access to services requires a better understanding of its magnitude and determinants. Definitions of infertility that appropriately reflect both biomedical, clinical, and social perspectives are needed to address these gaps and distinct study aims, including approaches for optimizing diagnosis and treatment, monitoring population health, identifying need for services, and understanding the experiences of infertile individuals. However, owing in part to this diversity of research aims, studying infertility represents unique measurement challenges for researchers. Unlike other types of conditions, infertility is defined by the absence of an event (i.e., not getting pregnant or having a live birth), usually after a defined period of time, and its recognition is often dependent on having tried to become pregnant (Koropatnick et al., 1993). As such, there is considerable variability in measures used to assess infertility across study populations (Gurunath et al., 2011).

Given this variability, standard definitions have been developed to harmonize data collection and enable meaningful comparisons within and across disciplines (Centers for Disease Control and Prevention, 2014; Gurunath et al., 2011; Thoma, 2015; Zegers-Hochschild et al., 2017). Clinical definitions recognize infertility as a medical condition that may be remedied with timely and appropriate diagnosis and treatment. Accordingly, the International Committee for Monitoring Assisted Reproductive Technologies (ICMART), in conjunction with the World Health Organization (WHO), defines infertility as “a disease characterized by the failure to establish a clinical pregnancy [(diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy)] after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person’s capacity to reproduce either as an individual or with his/her partner” (Zegers-Hochschild et al., 2017). Twelve months is consistent with clinical recommendations to initiate further diagnostic tests and begin treatment if appropriate (Olsen et al., 1998). For women over 35 years of age, a shorter time period of six months is often applied to account for potential reductions in fertility with age (Practice Committee of American Society for Reproductive Medicine, 2013). Despite declines in fertility with increasing paternal age (S. L. Johnson et al., 2015), there is no equivalent definition applied to men. Infertility can be further delineated into primary infertility (infertility with no prior clinical pregnancy) or secondary infertility (infertility with a prior clinical pregnancy). The term “subfertility” is synonymous with “infertility,” but in some literature it may refer to diminished fertility more generally without reference to a specific period of time (Jenkins et al., 2004; Zegers-Hochschild et al., 2017).

In contrast, because they are often used to identify population-level phenomena, demographic survey definitions of infertility rely on behavioral indicators—that is, the absence of a live birth among sexually active women (or men) who are not using contraception (Larsen, 2005; Mascarenhas et al., 2012a; Rutstein & Shah, 2004). These definitions often rely on longer periods of time in which couples have not conceived a pregnancy ending in a live birth (e.g., two- or five-year periods). Primary and secondary infertility are categorized as infertility at the time of assessment among individuals who have not had a prior live birth or have had a prior live birth, respectively. The reliance of demographic definitions on live births reflects the limited availability and completeness of population-level data on clinically recognized pregnancies, particularly in LMICs (Larsen, 2005). Where data on pregnancy are available, the absence of a pregnancy, rather than a live birth, may be used (Schmidt & Münster, 1995). Demographers also differentiate between the concept of fertility/infertility and fecundity (i.e., the physiological capacity to reproduce)/infecundity (Smarr et al., 2017; Wood, 1989). In this case, demographers may also use the term “infecundity” to refer to a woman who has not yet had a live birth or “involuntary infecundity” to refer to a woman who wants to have a child but has not yet had a live birth (Schmidt & Münster, 1995).

In an attempt to align measures of infertility across disciplines, several authors have proposed using TTP as a functional measure that can be used in both clinical and population-based studies (Gnoth et al., 2005; Gurunath et al., 2011; Joffe, 2003; Thoma, 2015). TTP provides a relatively efficient approach for assessing infertility or conception delay in surveys and is a common question asked of patients attending infertility clinics. It can be measured in months or menstrual cycles and provides information on the full spectrum of fertility—from normal to the complete inability to conceive (Gurunath et al., 2011). Thus, measures of TTP can be adapted to a range of definitional cutoffs (e.g., greater than 12 or 24 months), facilitating comparisons across studies. Different study designs and approaches for measuring TTP have their strengths and limitations and are discussed in greater depth elsewhere (Joffe et al., 2005; Olsen et al., 1998; Scheike & Keiding, 2006; Rémy Slama et al., 2014; Weinberg & Gladen, 1986). It is important to note that standard definitions and proposed measures do not distinguish the cause of infertility, which could be due to male, female, couple, environmental, or unexplained factors. Information on causes of infertility is limited in population-based data (Centers for Disease Control and Prevention, 2014) and, even if collected, may be missing for over half of individuals who do not seek or receive medical care for their infertility (Boivin et al., 2007) (Box 2).

Data Collection Considerations

Where and how we collect reproductive health data can also impact our understanding of infertility at the population level and at the interpersonal level. Clinical data are an important source of information on populations who access services but are not representative of the general population. This is because access to treatment is highly unequal. Individuals and couples who make use of clinical services must be motivated to seek help, to opt into these services, and then to be able to access treatment. This is demonstrated by the highly critiqued overrepresentation of White, Western, insured, heterosexual, middle-class women in early literature on infertility (Barnes, 2014; Bell, 2009, 2014; Ceballo et al., 2015; Fledderjohann & Barnes, 2018; Inhorn et al., 2009a; 2009b; Inhorn & Fakih, 2006; Nordqvist, 2008). Although such data are helpful for understanding current practice and service use among a subset of the population, drawing broader conclusions based on these data serves to perpetuate the stratification of reproduction by promulgating an exclusionary picture of infertility.

Therefore, survey data provide an important complementary source of information for monitoring infertility globally (Centers for Disease Control and Prevention, 2019; Greil et al., 2010a; Larsen, 2000; Mascarenhas et al., 2012a; Stephen & Chandra, 2006), but research design choices can still result in an incomplete picture of infertility. These choices are not neutral, but rather they reflect sociocultural notions of who can and should reproduce, and who is deemed responsible for doing so (Daniels, 2008; Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018; Inhorn et al., 2009b; Slauson-Blevins & Johnson, 2016). Survey inclusion criteria together with the design of survey instruments can serve to systematically render invisible some groups and their reproductive needs—that is, to omit the “invisible infertile” (Barnes & Fledderjohann, 2020; Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018).

An example of defining the population at-risk in an exclusionary way can be seen in the Demographic and Health Surveys (DHS) (United States Agency for International Development, n.d.), a large-scale survey of reproductive and general health in ~90 LMICs, widely used to estimate infertility rates (Larsen, 2000; Larsen & Raggers, 2001; Mascarenhas et al., 2012a; Mascarenhas et al., 2012b; Polis et al., 2017). Just under one-fifth of countries with at least one DHS survey available have never collected data for men (Fledderjohann & Roberts, 2018), focusing instead exclusively on women. The availability of men’s data in the DHS has increased over time, but some subgroups have been excluded (e.g., divorced and single men) because the inclusion criteria for men at times include a stipulation that they must be married to a woman in the DHS sample. Men’s historical exclusion as reproductive actors in their own right reflects and perpetuates a broader cultural notion that women are responsible for reproduction and also renders men’s reproductive needs invisible (Barnes, 2014; Dyer et al., 2005; Fledderjohann, 2012; Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018; Goldscheider & Kaufman, 1996; Greene & Biddlecom, 2000; Inhorn, 2003; Inhorn et al., 2009b; Slauson-Blevins & Johnson, 2016).

A second example comes from the Integrated Fertility Survey Series (IFSS) (Fledderjohann & Barnes, 2018). The series started in 1955 to monitor reproduction, including infertility, in the United States. The survey series, which is currently operating as NSFG, is the main data source for tracking infertility to inform public health and family planning policy (Centers for Disease Control and Prevention, 2018, 2019). At its inception, the inclusion criteria for sampling was White married women ages 18–39, explicitly excluding, for example, people of color, men, and single individuals. The IFSS became progressively more inclusive over time, with married women of all races included beginning in 1960; married and single women of all races included since 1970 (though single women had to have been previously married or have children in the household until 1982); and men included beginning in 2002. Yet it still does not capture fully the population at-risk of infertility. For instance, the NSFG still explicitly excludes institutionalized populations, including incarcerated adults (Barnes & Fledderjohann, 2020; Centers for Disease Control and Prevention, 2019). That this sampling decision is a common practice in household surveys is highly problematic, perpetuating race- and class-based structural inequalities in the way the infertility is tracked and, consequently, the way that healthcare is structured.

Even where sampling is inclusive, however, instrument design can foster invisibility of some groups or issues (Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018). Taking another example from the DHS, in the most recent questionnaires, both male and female respondents are asked whether or not they and/or their partner is medically sterilized (Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018; United States Agency for International Development, 2015).¹ Due to the survey’s skip pattern, only respondents who indicate that neither they nor their partner is sterilized are then asked a series of questions where they are able to respond “can’t get pregnant”; this is the only opportunity anywhere in the instrument for respondents to indicate self-identified concerns regarding their ability to conceive. Respondents who have a sterilized partner but also self-identify as infertile would not be captured by this skip pattern (Fledderjohann & Barnes, 2018; Fledderjohann & Roberts, 2018). This is significant not least because of both qualitative (Bledsoe, 2002; Gerrits, 1997; Leonard, 2002) and quantitative (Fledderjohann & Johnson, 2015; K. M. Johnson et al., 2019) evidence that there is a poor alignment between self-identified difficulties conceiving and biomedical or demographic measures. Where the aim is to understand the social causes and consequences of infertility, this is a substantial oversight.

Creating a More Inclusive Definition of Infertility

Taken together, the literature on definitions and survey instruments demonstrates how seemingly simple choices about how to define, measure, and collect data on infertility can dramatically shift our understanding of who experiences infertility, and how. These processes both shape and are shaped by how we diagnose and treat infertility; how we document its prevalence; and how we understand the psychosocial, sociocultural, and biobehavioral causes and consequences of infertility.

While interest remains in understanding the biological ability to conceive, other researchers have begun to advocate for a broader definition of infertility—social infertility—which would capture not only biological aspects of ability to conceive but also the social factors which restrict access to reproduction for some individuals and couples (Lo & Campo-Engelstein, 2018). This movement is based in part on the idea that extant definitions of infertility restrict access to services and treatments for those who struggle to conceive due to not having a partner or being in a same-sex relationship (Maxwell et al., 2018).

Ovulatory Dysfunction and Oocyte Quality

Regular ovulation is dependent on very tight and delicate neuroendocrine mechanisms that operate through an intact hypothalamic–pituitary–ovarian (HPO) axis.² Any factor or set of factors that cause the HPO axis to malfunction has the potential to result in ovulatory dysfunction. The most common endocrine disorder in women that affects ovulation is polycystic ovary syndrome (PCOS) (Teede et al., 2018). PCOS is a neuroendocrine and metabolic disorder that is diagnosed using the Rotterdam criteria, of which any two of the three criteria should be present for a diagnosis: oligo-ovulation/anovulation,³ polycystic ovarian morphology, or clinical or biochemical hyperandrogenism. Despite the large pool of antral (i.e., immature) follicles in the ovaries, the hormonal imbalances disrupt normal follicular recruitment and development, which results in amenorrhoea of varying durations in women with PCOS. Women with PCOS and obesity demonstrate a more severe pattern of reproductive imbalance (Broughton & Moley, 2017).

Independent of PCOS, obesity has also been shown to cause ovulatory malfunction that prolongs the time to conception and lowers chances for a live birth after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to women with normal body mass index (Practice Committee of the American Society for Reproductive Medicine, 2015b). The relationship between reproductive function and body weight involves complex endocrine and metabolic pathways that effect steroid metabolism, insulin, and other hormones, such as leptin and ghrelin, that can result in ovulatory malfunction and impaired implantation (Broughton & Moley, 2017). Additionally, underweight and extreme weight loss may also interfere with the HPO axis resulting in anovulation and delayed conception (Boutari et al., 2020).

In addition to the frequency of ovulation, the quantity and/or quality of oocytes is another important predictor of fertility (i.e., ovarian reserve). Age is the strongest predictor of declining ovarian reserve; however, the exact mechanism by which age contributes to this decline is unclear (Farquhar et al., 2019). This decline is thought to be gradual prior to the mid- to late 30s and to accelerate thereafter. A number of proposed mechanisms have been postulated for this age-related decline and are discussed elsewhere (Farquhar et al., 2019) but generally relate to the accumulation of DNA damage in oocytes over time or changes in hormones that influence related processes, such as oocyte maturation. Some women may also experience decreased ovarian reserve prematurely, which can lead to an earlier age at menopause. This is referred to as premature ovarian insufficiency (POI), which is defined by the premature occurrence of decreased ovarian reserve (Farquhar et al., 2019).

Tubal and Uterine Abnormalities

The site of natural conception is the ampullary portion (i.e., widest section) of the fallopian tubes. Any structural or functional disturbance of the anatomy of the fallopian tubes can lead to reduced fertility. This is because the fluids produced by the tubes and the cilia found along their course play important roles in transportation of oocytes and sperm and in preparing these gametes for fertilization. Ascending infections from the vagina can cause pelvic inflammatory disease (PID). If untreated, PID leads to scarring, adhesions, or complete blockage of the fallopian tubes. The risk of tubal damage increases with increasing number of episodes of PID (Weström et al., 1992). Sexually transmitted infections (STIs), such as Neisseria Gonorrhea and Chlamydia Trachomatis, are the most common risk factors for PID (Weström, 1994). In countries with a high prevalence of tuberculosis, such as India, genital tuberculosis is another common cause of tubal infertility (N. Singh et al., 2008). Pregnancy terminations performed in unsafe and unhygienic conditions and untreated infections following delivery also increase the risk of tubal-factor infertility (Weström et al., 1992). Other noninfectious risk factors for tubal damage include pelvic surgeries and endometriosis (Macer & Taylor, 2012; ten Broek et al., 2013). Endometriosis is endometrial tissue that has escaped from the uterine cavity to other areas of the pelvis, including the fallopian tubes. Tubal endometriosis can cause scarring in the fallopian tubes; however, endometriosis may be related to infertility in other ways that have not been fully understood (Macer & Taylor, 2012).

The uterus is the site of implantation and development of the fetus. Risk factors that compromise the ability of the uterus to optimally perform this role may impair implantation or lead to pregnancy loss. Intrauterine adhesions and endometrial scar tissue can develop from infections of the endometrial tissue (i.e., endometritis) or from uterine surgery (Kodaman & Arici, 2007). For example, Asherman’s syndrome is a rare acquired condition characterized by amenorrhea or hypomenorrhea and cyclic pelvic pain, which may develop as a result of intrauterine adhesions following curettage or surgery (March, 2011). Other uterine abnormalities can also affect implantation and fetal development, the most common of which are uterine fibroids. The prevalence of fibroids increases with age and generally varies between racial groups, with Black women having the highest prevalence (E. A. Stewart et al., 2017). Even though uterine fibroids do not cause fertility problems per se, fibroids that distort the uterine cavity may impair implantation or result in pregnancy loss (Bozdag et al., 2008). A review of studies on the impact of fibroids on the likelihood of achieving or maintaining a pregnancy concluded that there was insufficient evidence to determine the specific role of fibroids on pregnancy outcomes, given variation in size, number, and location (Penzias et al., 2017). A common surgery to remove symptomatic fibroids is myomectomy, which may optimize pregnancy outcomes in some women (Penzias et al., 2017). However, this surgical procedure may lead to adhesions that affect tubal or uterine anatomy causing infertility (Ikechebelu et al., 2018). Myomectomy should, therefore, be performed only when properly indicated, especially in women who have never conceived before or intend to conceive in the future (Carranza-Mamane et al., 2015).

Clinical Treatment Options

The management and treatment of infertility should be determined based on evidence and a thorough diagnostic investigation that identifies the underlying etiology of the individual and couple’s infertility. Extensive guidelines are produced by the European Society of Human Reproduction and Embryology (ESHRE), the U.K.-based National Institute for Health and Care Excellence (NICE) and Royal College of Obstetricians and Gynaecologists (RCOG), and the U.S.-based American College of Obstetricians and Gynaecologists (ACOG) and the American Society for Reproductive Medicine (ASRM). Although this section presents options for managing infertility for both male and female factors, it is important to note that infertility treatment tends to focus more extensively on female bodies, even when the cause is attributed to male factors, and may be invasive in nature.

Over half of all couples who have been unable to conceive in one year and have normal testing results and a female partner under 35 will conceive without assistance by the end of their second year of well-timed intercourse (Brandes et al., 2011; National Collaborating Centre for Women’s and Children’s Health, 2013; te Velde et al., 2000). Thus, expectant fertility management is an appropriate recommendation in these cases (Gunn & Bates, 2016; Lindsay & Vitrikas, 2015). Counseling can also be a first-line approach to managing infertility and/or offered in combination with other treatment options. Both women and men should be counseled to have regular sexual intercourse two to three days per week, attain a normal body mass index (BMI), abstain from smoking and addictive drugs, reduce alcohol intake, and treat any existing psychosexual problems (Kamel, 2010; Lindsay & Vitrikas, 2015; National Collaborating Centre for Women’s and Children’s Health, 2013; Thurston et al., 2019). Men should also be recommended to avoid occupational or social situations that may cause testicular heating and to wear loose-fitting underwear and pants; however, it is unclear whether the latter can improve fertility (National Collaborating Centre for Women’s and Children’s Health, 2013; Thurston et al., 2019).

Beyond expectant management and counseling, there are three main types of infertility treatment: medical treatment, surgical procedures, and assisted conception. Treatment of infertility with oral and injectable medication is primarily used for controlled ovarian stimulation (COS; when an increased number of ovulatory follicles are desired) or ovulation induction (OI; when ovulation is not occurring naturally) in female-factor infertility and can be used with timed intercourse or intrauterine insemination (IUI) when there is a concomitant male factor (Stevenson et al., 2016). Oral medications work through negative feedback to central receptors, encouraging increased production of endogenous gonadotropins (Beall & DeCherney, 2012). Clomiphene citrate is an oral medication that is affordable and effective in inducing ovulation in 50–70% of cases of oligo-ovulation and in achieving pregnancy rates of 15–25% per cycle (Ombelet et al., 2008). Other oral medications such as letrozole (Eskew et al., 2019; National Collaborating Centre for Women’s and Children’s Health, 2013) and tamoxifen (J. Brown & Farquhar, 2016) may be used off-label for oral ovulation induction. Injectable gonadotropins work directly on the ovary to induce ovulation. COS and OI can result in multiple gestation pregnancies or in ovarian hyperstimulation syndrome (OHSS) (more common with gonadotropins), a potentially life-threatening complication (Sharma et al., 2009); thus, patients should be monitored closely for these risks. Medication and other nonsurgical approaches can also be used for the treatment of some causes of male-factor infertility; for example, clomiphene citrate and gonadotropins may be recommended for the management of hypogonadotrophic hypogonadism (Fraietta et al., 2013; National Collaborating Centre for Women’s and Children’s Health, 2013; Wheeler et al., 2019), PDE5 inhibitors for erectile dysfunction (Gong et al., 2017), and electroejaculation for ejaculatory dysfunction (Kamischke & Nieschlag, 1999).

Surgical treatment for infertility may be indicated for some female- and male-factor infertility. For women, for example, tubal surgery may be beneficial for mild cases of tubal disease (Daniilidis et al., 2017). Uterine surgery may be indicated in certain circumstances; for example, amenorrhoeic women with intrauterine adhesions may benefit from the surgical removal of adhesions through hysteroscopic adhesiolysis (Pabuçcu et al., 1997). Surgical removal of uterine fibroids through myomectomy may be indicated in certain circumstances; however, the impact it has on live birth rates needs to be examined with more rigorous research studies (Zepiridis et al., 2016). Endometriosis may be destroyed or removed through laparoscopic surgery, which has been found to improve reproductive outcomes in mild to moderate cases (Duffy et al., 2014). Women who have had a tubal ligation but later wish to conceive may benefit from tubal ligation reversal (tubal reanastamoses) (Godin et al., 2018).

Some men with infertility may also benefit from surgery. For example, men who have obstructive azoospermia or erectile or ejaculatory dysfunction may benefit from surgical extraction of sperm through procedures such as testicular sperm extraction (TESE) (Agarwal et al., 2020). There may be some benefit from surgical repair of varicoceles in men with oligozoospermia though the evidence on whether this improves spontaneous pregnancy rates is inconclusive (Baazeem et al., 2011). However, among couples undergoing assisted reproductive technology (ART), repairing varicoceles among azoospermic or oligospermic men can, according to a meta-analysis, improve pregnancy and live birth rates (Kirby et al., 2016). Men with vasectomies who desire more children can benefit from vasectomy reversals (vasovasostomies) to restore their fertility (Schwarzer & Steinfatt, 2013; Valerie et al., 2018).

IUI is a procedure by which sperm from a partner or donor is inserted into a woman’s uterus prior to ovulation. It is often indicated in cases of male infertility, for unexplained infertility, and in women with minimal or mild endometriosis (ESHRE Capri Workshop Group, 2009). Unstimulated IUI cycles may also be recommended when individuals are unable or find it difficult to have vaginal intercourse, for conditions that require specific consideration in relation to methods of conception such as human immunodeficiency virus (HIV), as part of donor insemination, or when people have social, cultural, or religious objections to IVF (National Collaborating Centre for Women’s and Children’s Health, 2013). IUI can be carried out in a natural cycle without drugs or in combination with ovarian stimulation. Common stimulation agents include clomiphene citrate, Letrozole, and gonadotrophins (R. Wang et al., 2019). Overall, evidence on the effectiveness and safety of IUI is limited. For male-factor infertility, a review by the ESHRE Capri Working Group (2009) as well as a Cochrane Systematic Review, concluded that there is insufficient evidence on the effectiveness of IUI to be able to recommend or advise against its use with or without stimulation above timed intercourse (Bensdorp et al., 2007). Similarly, for unexplained infertility, the authors of another Cochrane Systematic Review concluded that there was insufficient evidence on the effectiveness of IUI with or without stimulation compared to timed intercourse or expectant management with or without stimulation to conclude that it improves live birth rates with acceptable multiple pregnancy rates (Ayeleke et al., 2020). The lack of sufficient high-quality evidence on the effectiveness of IUI in improving live birth rates has resulted in debate over its use in certain circumstances. For example, as of 2013, NICE no longer recommends offering IUI to people with mild male-factor infertility, unexplained infertility, or mild endometriosis (National Collaborating Centre for Women’s and Children’s Health, 2013). Instead, NICE recommends that people with these conditions try to conceive for a total of two years before considering IVF.

ART is defined as “all interventions that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of reproduction. This includes, but is not limited to, in vitro fertilization (IVF) and embryo transfer (ET), intracytoplasmic sperm injection (ICSI), embryo biopsy, preimplantation genetic testing (PGT), assisted hatching, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), gamete and embryo cryopreservation, semen, oocyte and embryo donation, and gestational carrier cycles” (Zegers-Hochschild et al., 2017, p. 1790). Considerable advances have been made in ART procedures since their inception (see box 4 and Figure 1). These procedures continue to change and update as new advancements are made in the optimization of its delivery to improve pregnancy rates and maximize patient safety (Brezina et al., 2012). The most common type of ART is IVF, a procedure in which mature oocytes are extracted from a woman’s ovary/ovaries and then combined with sperm in a laboratory for fertilization. Fertilized oocytes (pre-embryos) are then typically monitored for three to five days before being transferred to the woman’s uterus for implantation (Alexander et al., 2016).

ICSI is a common micromanipulation procedure done in combination with in vitro fertilization in which a single sperm is injected directly into an oocyte to assist with fertilization (Zegers-Hochschild et al., 2017). In fact, ICSI has become widely used with an estimated 66.5% of all nondonor ART cycles using the technique worldwide; however, significant variation in use across regions exists ranging from 55% of cycles in Asia to nearly 97% of cycles in the Middle East (Adamson et al., 2018). ICSI was developed in the early 1990s as a technique to address male-factor infertility (Stevenson et al., 2016) and can be used in combination with surgical sperm retrieval (Agarwal et al., 2020). Since its inception, ICSI has been extended for use in a variety of non-male-factor etiologies such as unexplained infertility, advanced maternal age, failed prior ART cycles, low oocyte yield, and use of preimplementation genetic testing (Boulet et al., 2015). The use of ICSI in couples with non-male-factor infertility has increased despite little to no evidence that ICSI improves reproductive outcomes in these cases relative to IVF (Abbas et al., 2020). For example, a study that assessed national trends and reproductive outcomes in the use of ICSI in the United States found that the use of ICSI in fresh IVF cycles increased from 36.4% in 1996 to 76.2% in 2012 despite a lack of improved postfertilization reproductive outcomes relative to conventional IVF (Boulet et al., 2015).

Because one of the greatest risks associated with ART is fetal and maternal complications due to multiple pregnancies (Fauser et al., 2005; Pinborg, 2005), the International Federation of Fertility Societies surveillance found that 48 of 85 responding countries have established guidelines and or regulations on the number of embryos to transfer to a women’s uterus in a given treatment cycle (International Federation of Fertility Societies, 2019). Advances in ART have resulted in higher-quality embryos and improved rates of implantation, which has led to a reduction in the number of embryos being transferred per cycle. In 2011, single-embryo transfer (SET) represented an estimated 31.4% of fresh nondonor IVF/ICSI cycles globally (Adamson et al., 2018), up from 23.4% in 2007 (Ishihara et al., 2015).

Cryopreservation is the process of freezing gametes or embryos for future use and has provided individuals and couples undergoing infertility treatment with safer and more effective options for achieving pregnancy. For example, it allows a woman experiencing OHSS from fertility medications to delay the transfer of embryos to a later and safer time (International Federation of Fertility Societies, 2019) and allows people facing gonadotoxic treatment of cancer, hormonal treatment for gender affirmation, or surgical removal of gonads to preserve their reproductive abilities. Common techniques used in cryopreservation include slow freezing and vitrification. Advances in freezing techniques for cryopreservation of embryos, including the introduction of vitrification, has resulted in equivalent and sometimes superior success in pregnancy and live birth rates for transfers using frozen embryos relative to those using fresh embryos (Z.-J. Chen et al., 2016; Kemper et al., 2019; Shi et al., 2018; Vuong et al., 2018). These promising results have led some experts to question whether a “freeze-all” approach should be used in all ART cycles (Sciorio & Esteves, 2020). This approach would involve the cryopreservation of all viable embryos from controlled ovarian stimulation to then be transferred to the uterus in a subsequent cycle. However, a mini-review of a “freeze-all” approach did not find evidence of additional benefit of this approach for all patients undergoing ART treatment at this time but did find evidence of its utility for certain clinical scenarios, such as for women at risk of OHSS or undergoing PGT at the blastocyst stage (Sciorio & Esteves, 2020).

Third-party reproduction includes the use of donor semen, ooctyes, or embryos as well as gestational carriers.⁸ Use of gestational carriers has spurred ethical debate primarily due to the potential for exploitation, commodification, and/or coercion of the carrier when she is compensated for her services (Deonandan et al., 2012; Pande, 2014; Patel et al., 2018), and raising broad questions about autonomy and choice in reproduction (H. D. Singh, 2017). Transnational use of gestational carriers and its impact on how reproductive work is viewed and defined can also compound already complex local systems of inequality (H. D. Singh, 2014). As a result, legality of gestational carrier agreements varies by country and has contributed to cross-border use of these services (Crockin, 2013; Patel et al., 2018). In separate articles, Crockin (2013) and Deonandan (2015) outline multiple ethical; legal; financial; emotional; and physical risks to gestational carriers, intended parents, and or offspring involved in the use of cross-border gestational carriers, highlighting the urgent need for an internationally accepted framework or basic principles that can help minimize risk while respecting the different values and policies across countries.

Preimplantation genetic testing (PGT) can be performed in vitro to test for abnormal chromosomes in a developing embryo prior to being transferred to the uterus for implantation (American Society for Reproductive Medicine, 2014). PGT can assist in selecting and transferring embryos unaffected by certain genetic disorders and or chromosomal abnormalities (American Society for Reproductive Medicine, 2014). This technique is also becoming more common. For example, in the United States, 22% of ART procedures in 2017 included PGT (Centers for Disease Control and Prevention, 2018).

Gene editing of embryos has generated a number of scientific and ethical questions on its use in clinical practice, particularly in relation to its use in ART. Genetic editing is a new technology that employs CRISPR-Cas 9 proteins to knock out harmful genes from DNA molecules in embryos (Yang & Huang, 2019). The ability to edit the genes of embryos by removing disease-causing genes prior to implantation could prevent the development of genetic disorders, such as Duchenne muscular dystrophy and congenital deafness, in susceptible children.⁹

Current research in gene editing can best be described as experimental and the safety and precision of gene editing has not yet been established. In November 2018, a Chinese scientist, Jiankui He, reported the birth of twins in China in whom he had edited the C-C chemokine receptor type 5 (CCR5) genes (Ma et al., 2019). The rationale for this genetic modification was to render the babies, whose parents were discordant for HIV infection, immune from HIV infection. Jiankui He’s announcement received widespread condemnation in China and international outcry given that the scientific and ethical basis of gene editing had not yet been established to permit its use in clinical practice. Recently, He and colleagues were found guilty of conducting an illegal medical practice in Chinese courts in December 2019 (Joseph, 2019). More research is needed in this emerging field of ART to establish the safety, precision, and ethical principles of gene editing before clinical application can be approved.

Open in new tab

Figure 1. Major milestones in assisted reproductive technologies, 1970–2020.

Nonbiomedical Practices

In both low- to middle-income countries and high-income countries, nonbiomedical practices are often used in combination or succession with clinical management of infertility (Cox & Johnson, 2020; Dierickx et al., 2019; Perry & Hirshfeld-Cytron, 2013; Rayner et al., 2011; Van Balen & Gerrits, 2001). In fact, a systematic scoping review on the use of nonbiomedical practices for fertility enhancement found that most studies reported between 30 and 70% of their participants, most of whom were recruited from fertility clinics, had used at least one nonbiomedical practice to enhance their fertility (Cox & Johnson, 2020). Other studies have documented that, for some individuals experiencing infertility, nonbiomedical treatment is the sole treatment sought, often due to cultural beliefs about the causes of infertility and or the lack of accessible biomedical care (Dierickx et al., 2019; Nahar, 2010; Perry & Hirshfeld-Cytron, 2013; Sarkar & Gupta, 2016; Van Balen & Gerrits, 2001). For example, an ethnographic study conducted in Bangladesh found that many rural women attributed childlessness to an indigenous creature called joha-juhi, which is believed to reside in the wombs of infertile women, eating their embryos when they become pregnant. Herbalists are believed to be able to rid the creature from women’s wombs, resulting in little to no perceived need for biomedical treatment for infertility (Nahar, 2010).

Biologically based treatments, particularly herbal medicines, are the most commonly used nonbiomedical practices globally followed by religious and spiritual interventions (Cox & Johnson, 2020). However, individuals engage in a wide variety of nonbiomedical practices to enhance their fertility, including, but not limited to, lifestyle modifications such as diet, exercise, and sexual practices; acupuncture and other energy therapies; manipulative and body-based methods including chiropractic treatment, heat and hydrotherapy, and massage; and mind–body interventions such as meditation (Cox & Johnson, 2020; Rayner et al., 2011). Use of these practices varies by country and context. For example, use of heat and hydrotherapy, such as visits to thermal spas and baths, is commonly asked about and reportedly used for fertility enhancement in studies conducted in Turkey (Ayaz & Efe, 2010; Edirne et al., 2010; Günay et al., 2005; Nazik et al., 2015; Özkan et al., 2018). In a study of infertility in The Gambia, Bledsoe (2002) contextualizes the surprising finding that women who have struggled to conceive or carry a pregnancy to term take oral contraceptives in order to help themselves conceive. She finds that women identify repeated physical strain on their bodies as an underlying cause of infertility, and so seek to rest their bodies by using contraceptives. This practice fits within a broader construction of time as nonlinear; women see the use of contraceptives as a means of reversing aging caused by physical strain on the body, thereby enabling them to conceive in the future.

Despite widespread use of nonbiomedical practices to enhance fertility, there is a dearth of research on the safety and effectiveness of these practices (Miner et al., 2018; Weiss et al., 2011). A scoping review conducted by Miner et al. (2018) examined the evidence on the effectiveness of 12 complementary and alternative medicine methods on improving fertility outcomes. Overall, the authors found a lack of quality evidence due to study design as well as contradictory results, making it challenging to draw conclusions about the effectiveness of these methods. Even acupuncture, which has been the most widely studied nonbiomedical practice and has the highest level of evidence, shows inconclusive results for improving fertility (Miner et al., 2018; Weiss et al., 2011). More research is needed to gain a comprehensive understanding of the use of nonbiomedical practices for managing infertility and the effectiveness and safety of these practices.

Geographic Accessibility

Despite a global increase in the number of facilities offering ART services, many infertile couples remain without access to such facilities. Based on an international surveillance project implemented by the International Federation of Fertility Societies (IFFS), an estimated 132 nations have existing ART programs (International Federation of Fertility Societies, 2019)—a dramatic increase since 2000 when only 45 countries reported ART programs (Inhorn & Patrizio, 2015). Unfortunately, regional disparities in access to ART facilities continue to persist with a large proportion of existing facilities clustered in a handful of countries with only two countries reporting more than 500 clinics—Japan and India (International Federation of Fertility Societies, 2019). Notable increases in the availability of IVF services have been observed throughout Asia, the Middle East, and Latin America; however, within-region disparities exist. For example, in Latin America, the majority of clinics reporting to the Latin America Registry are located in just three countries—Brazil, Argentina, and Mexico (Zegers-Hochschild et al., 2019). Progress in increasing access to IVF services in Central Asia and sub-Saharan Africa remains limited (Inhorn & Patrizio, 2015) as well as in many island nations (International Federation of Fertility Societies, 2019). A systematic review published in 2018 reported that ART services are available in only 10 sub-Saharan African countries primarily through the private sector (Botha et al., 2018). The lack of ART services in sub-Saharan Africa is particularly concerning given high rates of tubal and male factor infertility for which treatment with IVF is often indicated (Nachtigall, 2006). Significant barriers to increasing the availability of ART facilities, especially in LMICs, exist given the high-tech nature of ART as well as the necessary training needed for fertility specialists, which is often only available outside the host country (Horbst, 2012). Limited access to male infertility specialists has also been documented in places such as the United States where, in 2010, there were only 197 male infertility specialists and 13 of 50 states had no male infertility provider (Nangia et al., 2010) and in the United Kingdom where only 3.6% of urology trainees reported exposure to training in the management and investigation of male-factor infertility (Grey et al., 2012).

Within both LMICs and HICs there are huge disparities in rural–urban access to ART services. ART facilities are largely concentrated in urban, metropolitan cities. For example, a 2016 report from the CDC includes a map titled, Locations of ART Clinics in the United States and Puerto Rico, 2016, which visually highlights the unequal geographical access to ART facilities with entire states showing only one to two facilities, whereas states with multiple facilities show clustering around major metropolitan cities (see figure 2) (Centers for Disease Control and Prevention, 2018).

Open in new tab

Figure 2. Locations of ART clinics in the United States and Puerto Rico, 2016.

Source: Centers for Disease Control and Prevention, American Society for Reproductive Medicine, & Society for Assisted Reproductive Technology (2018).

Similarly, a systematic review of ART facilities in sub-Saharan Africa noted that most facilities were largely unavailable to rural communities (Botha et al., 2018). For example, a study in Sudan found that all ART services are located in Khartoum and only offered through private facilities. Even diagnostic services can often only be accessed in private facilities and secondary- and tertiary-level public facilities (Khalifa & Ahmed, 2012). These geographic disparities are seen in countries throughout the world, forcing individuals and couples with infertility in rural communities to travel long distances to receive ART services or to forego these services altogether.

Financial Costs

Even when ART services are geographically accessible, high costs often prohibit individuals and couples from utilizing these services. The cost of a single ART cycle varies significantly between countries with most countries, HIC as well as LMIC, falling within the range of $1,000–$6,000 (Chambers et al., 2013; Giwa-Osagie, 2010; Inhorn & Gurtin, 2012). The United States is a notable exception, with an average cost of $13,000 for a single cycle of IVF (Chambers et al., 2013). In countries without ART financial assistance, related costs are unattainable for most couples. For example, minimum wage in Nigeria is $52–$60 per month yet one cycle of IVF, which is largely paid for out of pocket, costs an average of $2,000–$2,700 (Giwa-Osagie, 2010). Collins (2002) estimates that a 10% decrease in costs would result in a 30% increase in the utilization of ICV/ICSI, highlighting the impact of cost on access to ART services. It is also important to note that not all cases of infertility require ART, in which case lower-cost options that require staff with less training are often sufficient for managing infertility (Ombelet et al., 2008) (see box 5).

The 2019 IFFS surveillance survey found that 47% of the 85 participating countries reported either insurance coverage or government funding for infertility treatment; however, less than 20% reported complete coverage, which would include diagnostic evaluation, fertility medications, IUI, and/or ART (International Federation of Fertility Societies, 2019). When coverage is unavailable, the use of ART services can place individuals at risk for overwhelming expenditures, as was found in a study conducted in South Africa (Dyer et al., 2013). Progress for infertility treatment coverage is being observed in both HICs and LMICs. Most HICs countries provide some level of coverage for infertility treatment within their national health policies (Nachtigall, 2006), though restrictions may apply. In the United States, where fertility-related expenses are paid for either out of pocket or through private insurance, some states have passed legislation mandating full or partial coverage for infertility services to be covered by private insurers (Hornstein, 2016). Recently, the CDC and Office of Population Affairs have established recommendations for the provision of quality family planning services in publicly funded family planning clinics, which include services to support pregnancy achieving and basic fertility care (Gavin et al., 2014). In Turkey, the government provides its citizens two cycles of IVF treatment through state and social insurance (Inhorn & Gurtin, 2012). Even in sub-Saharan Africa, where the expansion of infertility services has been slower than in other regions, progress in providing coverage has been reported. For example, Burkina Faso is beginning to fund insurance for ART services (Inhorn & Gurtin, 2012), the National Health Insurance in Sudan covers doctor’s fees, fees for diagnostic tests at public and private facilities and, in some cases, one cycle of ovulation induction drugs for ART (Khalifa & Ahmed, 2012), and some clinics in Mali are providing “package solutions” that allow patients to purchase multiple cycles up front at a discounted rate (Horbst, 2012).

In addition to explicit, codified barriers to accessing treatment, structural social inequalities may also impair access more indirectly. For example, in the United States, publicly funded reproductive healthcare through family planning programs focuses on pregnancy prevention, preconception care, sexually transmitted infection (STI) prevention and treatment, and cancer screening, with less of a focus on helping individuals achieve a desired pregnancy (Barnes & Fledderjohann, 2020). Although some of these efforts may prevent infertility or help couples achieve pregnancy, fewer services are offered related to basic fertility care and treatment within publicly funded clinics (Loyola Briceno et al., 2019), but recent guidelines emphasize that services to achieve pregnancy in publicly funded clinics should be offered within the broader spectrum of family planning (Gavin et al., 2014). Accordingly, infertility services are more likely to be covered by private insurance (though this coverage is not universal), which is inaccessible for many less privileged people. Taken together, the gradient in private health insurance access and lack of provision for fertility care through the public system in the United States means that these services are less accessible for older, non-White, working-class, geographically remote, less educated, HIV-positive, and disabled people (Barnes & Fledderjohann, 2020; Ceballo et al., 2015; Chandra & Stephen, 2010; Fledderjohann & Barnes, 2018; Greil et al., 2011; Inhorn, et al., 2009a; Inhorn & Fakih, 2006; Kessler et al., 2013; Kissil & Davey, 2012; Mehta et al., 2016).

Restrictive Policies and Regulations

Some policies and regulations exist in certain countries that restrict access to and/or reimbursement of ART services, often based on individual attributes (Nachtigall, 2006). Restrictions may occur through various avenues including federal laws; statutes; ordinances; oversight by professional organizations or government agencies with jurisdiction; or mandates by professional organizations, cultural practice, or religious degree (International Federation of Fertility Societies, 2019). The 2019 IFFS surveillance survey identified 40 countries with female age restrictions for reimbursement of ART service costs ranging from 38 years in Latvia and Lithuania to 50 years in Australia (International Federation of Fertility Societies, 2019). Only two countries—Austria and Germany–—reported imposing male age restrictions on reimbursement. In England, guidance is provided from the National Institute for Health and Care Excellence (NICE) on reimbursement of ART services through the National Health Service (NHS) based on the age of women (National Health Service, 2018); however, further constraints on eligibility and treatment through the NHS are decided by local Clinical Commissioning Groups (CCGs), and so can vary quite substantially between different areas of the country. The imposition of additional restrictions beyond those recommended by NICE and the geographic variation in eligibility requirements and treatment access options have led the CCG system to be heavily criticized as a “postcode lottery” system, responsible for stark inequalities in access across the country (National Institute for Health Care and Excellence, 2014). This example underscores the importance of examining the implementation of restrictions and regulations within a country to identify, and subsequently ameliorate, inequities in access to ART services at more local levels.

Marital status and sexual orientation are other attributes by which a number of countries restrict access to ART services and/or reimbursement (International Federation of Fertility Societies, 2019). For example, in the Asia-Oceania region, Australia and New Zealand are the only two countries to report access to ART for both unmarried individuals and same-sex couples (Li et al., 2018). In sub-Saharan Africa, ART is restricted to heterosexual, married couples in some countries such as Cameroon, Mali, and Senegal (Botha et al., 2018). In the United Kingdom, fertility tests are not universally available; rather, same-sex couples and single women are generally required to attempt several rounds of IUI at their own expense through private means before they are able to seek fertility testing through the NHS (Human Fertilisation & Embryology Authority, n.d.). Likewise, in the United States, some states have adopted laws requiring insurance coverage of either infertility diagnoses or treatment; however, these laws often include heteronormative language that the “patient’s oocytes” be fertilized by the “spouse’s sperm” (Stabile, 2016) and/or they require a medical diagnosis of infertility (National Conference of State Legislatures, 2019), thereby limiting access for unmarried and same-sex couples. Furthermore, only 8 of 15 U.S. states with mandates for infertility coverage mention coverage for men with infertility, which restricts the type of care provided and increases the burden on women (Dupree, 2018). Other factors that have been used to restrict or deny access to or reimbursement of ART services include duration of infertility, personal income, number of embryos transferred, concern for the welfare of a future child (International Federation of Fertility Societies, 2019), body weight (R. C. H. Brown, 2019), and HIV status (Khalifa & Ahmed, 2012).

Religion has also played a role in determining access to ART services in certain countries in both direct and indirect ways. In a review article on religious aspects of assisted reproduction, Sallam and Sallam (2016) report variation in acceptance of ART practices across and within religions with Judaism, Hinduism, and Buddhism accepting nearly all forms of ART practices and Roman Catholicism rejecting all forms (Sallam & Sallam, 2016). One of the most contentious types of ART is third-party reproductive assistance. For example, Islam has widely endorsed the use of ART among heterosexual married couples; however, research from the Middle East reveals variation in Islam’s response to and regulation of specific aspects of ART, particularly third-party reproductive assistance (Gürtin et al., 2015; Inhorn & Tremayne, 2016). For example, in a book chapter on Islam and assisted reproduction in the Middle East, Gürtin, Inhorn, and Tremayne describe that third-party reproductive assistance is banned in Sunni Muslim countries as it is considered an act of adultery; has the potential for incest among offspring of unknown donors; and introduces implications for kinship, descent, and inheritance (Gürtin et al., 2015). In contrast, Shia Muslim countries have been more accepting of third-party reproductive assistance though religious leaders remain divided. In Iran, the Shia extended the definition of marriage to include a form of temporary marriage that allowed for third-party reproductive assistance if the donor became a legitimate spouse, even if only temporarily.

The Roman Catholic Church’s prohibition of the use of ART is rooted in a 1956 proclamation defining artificial fecundation as immoral and illegal, because it separates procreation and sexual normal function and due to the church’s belief that the embryo is an individual with rights that should be protected (Sallam & Sallam, 2016). Given the Roman Catholic Church’s complete opposition to assisted reproduction, country-level restrictions and regulations of ART have been influenced by the Catholic Church in countries with a high presence of Catholicism. For example, across Latin America, the Catholic Church has placed moral pressure on governments and the public at large to prevent access to and utilization of ART services (Nachtigall, 2006; Torres et al., 2019). Italy, another example, instated strict restrictions on numerous ART practices through the Medically Assisted Reproduction Law in 2004, a law believed to be inspired and supported by the Catholic Church (Inhorn et al., 2010). Since 2004, much of the law has been dismantled by the Italian Constitutional Court; however, in 2016, Riezzo and colleagues contend that some groups continue to be excluded from access to ARTs in Italy including same-sex couples, single women, and women of a certain age (Riezzo et al., 2016).