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Evaluation and management of infertility in females of advancing age

Evaluation and management of infertility in females of advancing age
Literature review current through: Jan 2024.
This topic last updated: Sep 07, 2023.

INTRODUCTION — In many countries, the mean maternal age at first birth is rising. However, fertility declines with advancing age. Thus, many females in more advanced age groups are presenting for fertility evaluation and treatment.

This topic will discuss the background, evaluation, and treatment of infertility in females of advancing reproductive age (ARA). While the phrase "advanced maternal age," or AMA, has traditionally been used to describe these patients, we prefer the broader phrase "advancing reproductive age" because it applies to all aspects of reproductive biology and not just maternity. Related topics on infertility in female individuals are presented separately.

(See "Overview of infertility".)

(See "Female infertility: Evaluation".)

(See "Female infertility: Treatments".)

In this topic, when discussing study results, we will use the terms "woman/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 diverse individuals.

EPIDEMIOLOGY — In resource-rich countries, the median age of first birth is rising, with many women not starting a family until after their 35th birthday [1]. These trends have been attributed to a number of societal changes, such as increased education for women, higher employment rates, and better access to reliable birth control [2].

The rising mean age of first pregnancy has been further impacted by declining birth rates in younger individuals combined with rising birth rates in individuals of advancing reproductive age. A report on United States birth data from 2017 to 2018 found declining birth rates for individuals ages 20 to 29 years, stable birth rates for those 30 to 34 years, and a 2 percent increased birth rate in those 35 to 44 years [3]. The mean age of females having their first child increased from 21.4 years in 1970 to 26.9 in 2018.

BIOLOGY OF FEMALE FERTILITY — Fertility declines as a female matures, with gradual decline beginning at 32 years of age [4]. Although exceptions exist, there are few spontaneous conceptions that result in live births in females over 43 years of age [5,6]. This decline in fertility is likely multifactorial. Females are born with a fixed number of oocytes, which decreases with age. The quality of oocytes also falls with age because meiotic errors occur more frequently with increasing age [7]. During the menstrual cycle, the process to select a dominant follicle for ovulation does not exclude genetically abnormal oocytes [8]. Thus, as females age, the number of chromosomally anomalous oocytes ovulated increases, which results in lower fertility and increased risk of miscarriage. In addition to the endogenous accumulation of genetic errors in the oocyte pool over time, other factors such as smoking, other environmental exposures, and certain medical and surgical treatments can compromise oocyte quality, ovarian reserve, and chance for a healthy outcome for pregnancy as females age.

This decrease in both oocyte quantity and quality is manifested by a prolongation in the average time for achieving conception [9]. Fecundability (ie, the probability of achieving a pregnancy in one menstrual cycle) begins to drop significantly in the early to middle 30s with a more rapid decline a few years later (approximately age 37) [10]. Several lines of evidence from both natural and assisted cycles support this finding:

In historical cohorts in whom deliberate fertility control was rare and conception did not generally precede marriage, the rate of involuntary childlessness in women who married at age 20 to 24, 25 to 29, 30 to 34, 35 to 39, and 40 to 44 was 6, 9, 15, 30, and 64 percent, respectively [6]. In other similar groups, the average age of last birth ranged from 40.9 to 45.7 years and 87 to 99 percent of women were infertile at age 45 [11,12].

A large well-designed study reported the probability of clinical pregnancy following intercourse on the most fertile cycle day in women of average fertility age 19 to 26 years, 27 to 34 years, and 35 to 39 years was approximately 50, 40, and 30 percent, respectively, if the male partner was the same age [13].

A classic study of women undergoing donor insemination for male factor infertility (azoospermia) found women ≥35 years of age had lower conception rates and required more cycles to achieve conception [14]. Women who were 26 to 30 years of age had similar conception rates to women 25 years of age or younger, while women 31 to 35 had an intermediate success rate. Conception rates for women under age 31 years, age 31 to 35 years, and over age 35 years were 74, 62, and 54 percent, respectively.

Population-based data on outcome of in vitro fertilization using fresh nondonor eggs reported the success rate for females in their late 30s and early 40s was significantly lower than for females under 37 years of age [15,16]. The live birth rates for females <35 years of age, 35 to 37 years, 38 to 40 years, and >40 years were approximately 52, 37, 24, and 8 percent per cycle, respectively. By contrast, in individuals who used eggs obtained from healthy, young donors, 58 (fresh oocyte donation) and 47 (frozen oocyte donation) percent of fresh embryo transfers resulted in a live birth, regardless of the age of the recipient.

DIMINISHED OVARIAN RESERVE

Definition – Ovarian reserve describes the functional capability of the ovary and includes the number and quality of a woman's remaining oocytes [17,18]. Generally, diminished ovarian reserve (DOR) refers to a woman of reproductive age who has regular menses but reduced fecundity or decreased response to ovarian stimulation compared with age-matched women. However, there are no universally agreed upon criteria for diagnosing DOR. Tests can include assessment of follicle-stimulating hormone (FSH) and estradiol (both drawn on the third day after start of menses), anti-müllerian hormone (AMH), antral follicle count (AFC). In fact, either AMH or AFC can be used alone depending on the experience of the ultrasonographer. Previously a clomiphene challenge test was done but this is no longer endorsed by the American Society for Reproductive Medicine (ASRM) [17-19]. The National Assisted Reproductive Technology Surveillance System (NASS) also includes reduced ovarian volume related to congenital, medical, surgical or other causes and age greater than 40 years in its definition [20].

Limitations – Because of the heterogeneity of definitions, it is difficult to provide a prognosis to those who are suspected to have DOR. While these markers may predict decreased ovarian response to ovarian stimulation, they do not predict conception or live birth [21]. In a prospective cohort study of women age 30 to 44 years without a history of infertility who had been trying to conceive for three months or less, the predicted probability of conception after either 6 or 12 cycles of spontaneous attempts was similar among women with normal and abnormal levels of AMH and FSH [22]. This study, however, does not address conception or birth rates for women with a known diagnosis of infertility. For women in this age group with known infertility who are considering in vitro fertilization (IVF), these tests do have some prognostic value [23]. A discussion of the specific tests used to assess ovarian reserve is presented separately. (See "Female infertility: Evaluation", section on 'Assessment of ovarian reserve'.)

Our approach – In our practice, we define diminished ovarian reserve similarly to the European Society of Human Reproduction and Embryology consensus statement [24]. To be diagnosed with poor ovarian response, two of the three must be present: (1) Advanced age (greater than or equal to 40 years old) or any other risk factor, (2) Previous poor response to ovarian stimulation (three or fewer oocytes with IVF), and (3) Any abnormal ovarian reserve test (AFC <5 or AMH <1.1 ng/mL). Because the definition includes results from ovarian stimulation, patients who are over 40 years with abnormal ovarian reserve testing are also considered poor responders.

Impact of age – Even with very sensitive laboratory testing, age is one of the most reliable single prognostic factors for both spontaneous conception and for successful fertility treatments. As an example, even in the setting of normal laboratory testing, women who are over the age of 40 can struggle to conceive and/or deliver a healthy pregnancy. Conversely, younger women who have abnormal testing may have a limited amount of time to complete reproduction but may have better outcomes depending on the cause of the low ovarian reserve. For example, a woman who has had multiple cystectomies for dermoids may have a better prognosis than a woman with low ovarian reserve of a genetic etiology (eg, Turner's syndrome). Thus, women of any age who have abnormal ovarian reserve testing should be expeditious in building their family.

EVALUATION — Consistent with the American Society for Reproductive Medicine (ASRM), we advise initiating an infertility evaluation after six months of attempting conception for women 35 years and older and immediate consultation for those who are attempting at 40 years and older [9]. Additionally, risk factors such as prior pelvic surgery (particularly involving the ovaries or ovarian vasculature), endometriosis, chemotherapy, pelvic infections, and known male factor infertility should prompt consideration of an earlier evaluation. Thus, we consider any woman with risk factors for infertility as given above as needing a timely evaluation. The general evaluation of female infertility is presented separately. (See "Female infertility: Evaluation", section on 'Assessment of ovarian reserve'.)

In addition to the general infertility evaluation, women ≥40 years usually undergo a clomiphene citrate challenge test (CCCT). While the utility of the CCCT has been debated, CCCT is still widely used [17,18]. However, the ASRM has stated that its use should be stopped and antral follicle count (AFC) or anti-müllerian hormone (AMH) levels be used instead [17,25]. In the presence of an experienced ultrasonographer, AFC should be the primary test used [26]. They also caution that while AMH levels and AFC are predictive of oocyte and embryo yield, they are weakly associated with positive pregnancy test.

TREATMENT OPTIONS

Our approach — Selecting a treatment strategy can be a complex process. In addition to giving thought to test results, there are social and financial considerations. Issues that need to be discussed prior to outlining a treatment plan include the size of family the patient envisions, religious and ethical views on reproduction interventions, and the patient's attitudes about genetic testing of embryos, selective reduction, termination of pregnancy, and the potential for having a child with a chromosomal anomaly such as Down syndrome. As with many treatments that are heavily dependent on the patient's values, there is often more than one option, and the choice is ultimately determined by the patient.

In our practice, if there are no medical, financial, or social limitations, we suggest a more aggressive approach with women age 35 years and older who have undergone an infertility evaluation and offer them treatment as follows (algorithm 1):

For women who do not have adequate ovarian reserve, and thus a poor prognosis for live birth from their own oocytes, we counsel regarding using donor oocytes or alternate family planning options, such as adoption [23,27]. (See 'Donor oocytes' below.)

For women with adequate ovarian reserve but additional abnormal testing on fertility evaluation (eg, male factor, distal or bilateral tubal factor), we recommend they proceed directly with in vitro fertilization (IVF) as IVF has demonstrated efficacy for these women with a fecundability rate higher than that of natural conception or ovarian stimulation (OS) with intrauterine insemination (IUI) [6,28,29]. (See 'In vitro fertilization' below.)

For women with adequate ovarian reserve, otherwise normal fertility evaluation, and no restrictions to IVF, we suggest they proceed with IVF because of the higher pregnancy rates in fewer treatment cycles for IVF compared with initial treatment with OS and IUI [30]. (See 'In vitro fertilization' below.)

For women who decline IVF but have adequate ovarian reserve and otherwise normal fertility evaluation, we offer OS and IUI. For women of advanced reproductive age, the author prefers OS with gonadotropins because gonadotropin treatment results in a higher probability of live birth compared with clomiphene citrate (CC) [31]. However, gonadotropin treatment also results in more multiple gestations, including triplet and higher gestations. For this reason, other experts prefer CC as the first OS agent and proceed with gonadotropin treatment only if CC/IUI is not successful. This discrepancy reflects the challenge of balancing the desire for live birth with the risk of multiple gestations. Thus, careful counseling is required for women considering OS. We do not use aromatase inhibitors because they have a lower pregnancy rate than either gonadotropin or CC treatment, although some experts will use aromatase inhibitors in women who are unable to proceed with IVF and have not conceived with gonadotropins or CC [31]. We typically treat with up to three cycles of OS/IUI and again offer IVF if the woman has not conceived.

For women ≥35 years of age, we typically proceed with assisted reproductive technology (ART) but also offer clomiphene if ART is not possible (eg, financial restraints). Advancing directly to ART has been shown to shorten the time to pregnancy (median time to pregnancy 8 and 11 months, respectively) [32]. In addition, ART offers the option of cryopreserving excess embryos for future use.

Historically, these women were offered gonadotropin OS and IUI [33-35]. The use of gonadotropin/IUI as a first-line treatment has fallen out of favor because of the increased rate of multiple gestations, including a rate of twin pregnancies of up to 20 percent [33]. During ART, the number of embryos transferred into the uterus is controlled by the clinician and the patient.

For those who do not desire or are unable to proceed with ART, we offer three to six cycles of OS, as clinically indicated, with IUI. (See "Overview of ovulation induction", section on 'Gonadotropin therapy' and "Overview of ovulation induction", section on 'Letrozole'.)

Expectant management — For females who present with idiopathic infertility who are 35 years and younger, the fecundability plateaus at 2 percent per month after one year of attempting. As females age, this continues to decline until the 44th birthday, when the fecundability is negligible. Expectant management is most appropriate for those who do not want to or cannot pursue more aggressive approaches.

Ovarian stimulation — Given that the pool of healthy oocytes is reduced in females with advancing age, pharmacologic ovarian stimulation (OS) is one approach to increase the chances of a successful pregnancy [36]. The principal behind OS in women who are already ovulatory is to medically rescue potentially healthy oocytes that are lost during the ovulatory process to atresia. Although the fraction of chromosomally abnormal oocytes increases with age, OS increases the number of oocytes that are matured and ovulated each month, thus increasing the probability that one of the oocytes released will be healthy and available for fertilization. [31]. (See "Overview of ovulation induction".)

Risks associated with OS include formation of ovarian cysts that can result in hemorrhage and/or torsion and ovarian hyperstimulation syndrome (OHSS), although OHSS is relatively rare in women with limited ovarian reserve. Pregnancy-related risks include ectopic pregnancy and multifetal gestation. Maternal risks of multifetal gestations include hypertension, diabetes, need for cesarean section, and acute fatty liver. Fetal risks include intrauterine growth restriction, congenital anomalies, and preterm delivery. Selective reduction is an option for those with multifetal gestation, but it is associated with a risk of loss of the entire pregnancy. Each of these issues is presented in more detail separately:

(See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)

(See "Prevention of ovarian hyperstimulation syndrome".)

(See "Management of ovarian hyperstimulation syndrome".)

(See "Ectopic pregnancy: Clinical manifestations and diagnosis".)

(See "Gestational hypertension".)

(See "Preeclampsia: Clinical features and diagnosis".)

(See "Neonatal complications of multiple births".)

OS can be monitored by ultrasound to determine the number of follicles developing and by checking estradiol levels. These steps may reduce the risks of multiple pregnancy and possibly lower the risk of OHSS. The goal number of follicles for ovulation is dependent on the clinical situation. In general, the desired number of follicles recruited increases with female reproductive age and is similar to the number of embryos one would suggest being transferred during IVF. After appropriate follicular recruitment, ovulation can be monitored naturally (by monitoring urine luteinizing hormone with commercially available kits) or induced with human chorionic gonadotropin (hCG). Both allow for optimal timing of intercourse. If desired, or if there is evidence of male subfertility, an IUI can be done.

In women with idiopathic infertility age 35 years and younger, OS increases the monthly fecundity from 2 percent per month to a cumulative pregnancy rate of approximately 30 percent over three cycles [37]. For women age 35 and older, the effectiveness declines.

Assisted reproductive technology — ART includes IVF, intracytoplasmic sperm injection (ICSI), and assisted reproductive hatching. As ICSI and hatching are more advanced IVF technologies that have not demonstrated superiority to IVF in this population, this discussion will focus on IVF [38,39]. Details of IVF and ICSI are presented separately. (See "In vitro fertilization: Overview of clinical issues and questions" and "Intracytoplasmic sperm injection".)

In vitro fertilization — The basic steps of IVF include hormonally stimulating the ovaries, harvesting oocytes, fertilizing the oocytes, and transferring one or more embryos back into the woman's uterus to implant and develop. As with spontaneous conception, increasing maternal age negatively impacts the live birth rate after embryo transfer when the patient's own eggs are used (figure 1 and figure 2). This effect is particularly pronounced for women age 40 and greater (figure 3).

The goal is to harvest a larger number of oocytes than would normally be ovulated; these oocytes would otherwise be lost to atresia. Because a larger number of oocytes are available, there are more resultant embryos than during a natural ovulatory cycle. During IVF, these embryos are observed for the first few days of development. There is evidence that the pattern of an embryo's development is correlated with its genetic health and therefore with the probability of implantation and further development [37]. Thus, IVF results in higher fecundity compared with natural cycles. The risks, benefits, and techniques available for IVF are presented in detail separately. (See "In vitro fertilization: Overview of clinical issues and questions".)

For women who desire fertility treatment, at least one trial has reported that pursuing IVF instead of OS results in higher pregnancy rates with fewer treatment cycles [30]. However, women with extremely low ovarian reserve are not good candidates for IVF because the potential power of IVF is based on obtaining more oocytes than would normally be ovulated. For women of advanced reproductive age with low anti-müllerian hormone, and low antral follicle count, there can be a failure of multi-follicular recruitment simply because of the low number of antral follicles present. If it is suspected that fewer than four to five oocytes will be obtained, IVF may present a challenge. As an example, a 43-year-old woman would need to generate six to eight oocytes during an IVF cycle in order to have four to five embryos to transfer (anticipated fertilization rate of 60 to 70 percent), providing a 10 percent chance of live birth. In one retrospective cohort study, the live birth rate among all women with poor ovarian response during IVF was only 4 percent [27]. Thus, in our practice, for women ages 40 and older undergoing an IVF cycle, we convert from IVF to IUI if fewer than three dominant follicles develop, unless there is evidence of severe tubal disease or male factor infertility. Women who are unlikely to have an adequate ovarian response should be counseled about other fertility treatments (eg, donor oocytes) and other family planning options (eg, adoption, foster parenting).

The American Society for Reproductive Medicine (ASRM) has published guidelines for age-appropriate numbers of embryos for transfer based on the age of the woman at the time the oocytes were retrieved (table 1) [40]. These guidelines are based on predicted attrition of the embryo cohort and thus do not predict the outcome for any one woman. While transfer of more embryos increases the probability of pregnancy, the likelihood of multiple gestation also rises with increasing number of embryos transferred. Multifetal gestations can be effectively avoided in women of advanced reproductive age either through preimplantation genetic testing (PGT; resulting in transfer of only genetically euploid embryos) or selective reduction after implantation has occurred. As selective reduction is not acceptable to all women, these options are discussed prior to initiating IVF treatment. (See "Strategies to control the rate of high order multiple gestation" and "Twin pregnancy: Overview" and "Triplet pregnancy" and "Neonatal complications of multiple births".)

Expected outcomes for IVF, stratified by the age of the patient, are reported by both the Society of Assisted Reproductive Technologies and the Centers for Disease Control and Prevention. Results are stratified by patient age because age is one of the single most important prognostic factors. For example, women <35 years old who undergo IVF with their own eggs can expect an approximately 42 percent chance of singleton live birth from an IVF cycle (including all transfers) [41]. This percentage of live birth with IVF drops with advancing reproductive age: 31 percent for women ages 35 to 37 years, 19 percent for women ages 38 to 40 years, and 9 percent for women ages 41 to 42 years. After age 42, the probability of live birth decreases to less than 3 percent; thus, many clinics will not provide IVF to women using autologous oocytes after the 44th birthday. Of note, the decreasing live birth rate by age occurs despite more embryos being transferred during IVF cycles in older women. In 2020 in the United States, for women undergoing transfer of fresh embryos from their own eggs, an average of 1.1 embryos were transferred in women under age 35, 1.2 embryos for women ages 35 to 37 years, 1.3 embryos for women ages 38 to 40 years, and 1.6 embryos for women ages 41 to 42 years [41].

Minimum stimulation IVF — For individuals with diminished ovarian reserve for whom OS is not an option, attempt can be made at a minimum stimulation IVF. Protocols vary but they typically use clomid, letrozole, or low-dose gonadotropins to recruit multiple follicles. One randomized controlled trial including 394 participants with age ≥35 years and/or poor ovarian reserve reported similar ongoing pregnancy rates after once cycle using high-dose or minimum stimulation protocols (13.6 versus 12.8 percent, risk ratio 0.95, 95% CI 0.57-1.57) [42].

Preimplantation genetic testing — Women who undergo IVF can have their embryos tested for aneuploidy prior to transfer (preimplantation genetic testing for aneuploidy [PGT-A], formerly called preimplantation genetic screening [PGS]) or tested for specific genetic diseases (preimplantation genetic testing for monogenic disorders [PGT-M]) or structural rearrangements (PGT-SR). PGT is generally performed at the blastocyst stage. A few cells are removed from the trophectoderm, and the embryo is cryopreserved until a result is available. (See "Preimplantation genetic testing".)

As the number of aneuploid oocytes increases with advancing maternal age, the opportunity for screening can be considered in females undergoing IVF. However, evolving data have provided conflicting results, and a patient-centric approach is thus required.

Benefit – In a trial of over 200 women ages 38 to 41 years undergoing IVF comparing PGT-A without genetic evaluation prior to blastocyst transfer, the women in the PGT-A group required fewer embryo transfers (68 versus 91 percent), had lower miscarriage rates (3 versus 39 percent), and had higher live birth rates after the first transfer, both per transfer (53 versus 24 percent) and per patient (36 versus 22 percent), compared with the no PGT-A group [43]. Although there were no differences in the cumulative delivery rates per patient by six months after study closure, the women in the PGT-A group had a lower mean number of embryo transfers per live birth (1.8 versus 3.7) and a shorter time to pregnancy (7.7 versus 14.9 weeks) compared with the no PGT-A women. Of note, the use of PGT-A improved outcomes despite resulting in a lower number of cycles that reached embryo transfer (69 versus 91 percent for PGT-A and no PGT-A, respectively), mainly because of the large reduction in miscarriage rate for the women in the PGT-A group.

Lack of benefit – A 2020 meta-analysis including 13 trials with over 2700 females did not show an increase in live birth rate after first transfer, increased cumulative live birth rate, or decreased miscarriage rate in women undergoing IVF with PGT-A over women undergoing IVF [44].

Our approach – In view of the above data, we offer PGT-A to women of all ages who are proceeding with IVF. However, based on age-related risk of aneuploidy, PGT-A is primarily utilized by women of advancing reproductive age who desire single embryo transfer [45] or by those who wish to avoid an aneuploid pregnancy. We counsel patients that, due to limitations of the technique and potential mosaicism, false-positive and false-negative results are possible. (See "Preimplantation genetic testing", section on 'Potential candidates for PGT-A' and "Preimplantation genetic testing", section on 'Unproven indications'.)

Women who undergo PGT-A still have the option of performing traditional prenatal aneuploidy testing (eg, early risk assessment, cell-free fetal DNA, chronic villus sampling, or amniocentesis), if desired. (See "Preimplantation genetic testing".)

Donor oocytes — For women with decreased ovarian reserve, multiple failed cycles, or clinical findings associated with low probability of success, treatment using donor oocytes (either fresh or frozen) results in a live birth rate of approximately 50 percent, which is higher than the live birth rate of women undergoing IVF with fresh nondonor eggs [46,47]. Cumulative success rates up to 80 percent can be expected since multiple frozen embryos are often available after a donor oocyte cycle [48]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)

As the incidence of diminished ovarian reserve rises with increasing age, the use of donor oocytes to achieve pregnancy also rises as women age. In a study of United States births resulting from ART during 2012 to 2014, 36 percent of live births to women ages 45 to 49 years resulted from donor oocytes, which increased to 74 percent for women ≥50 years [49]. For comparison, 0.4 percent of births to women age 35 to 39 involved donor oocytes.

PREGNANCY — The management of pregnant patients of advanced maternal age [50] and the outcomes of pregnancies conceived with assisted reproductive technology are presented separately.

(See "Effects of advanced maternal age on pregnancy".)

(See "Management of pregnancy in patients of advanced age".)

(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

FUTURE DIRECTIONS — Future options for fertility preservation include improved education to help patients (female and male) understand the impact of age on fertility and plan their families and preservation of embryos or oocytes.

Raising awareness — Providing public education regarding reproduction and family planning is as important as education on appropriate use of birth control. Studies including both men and women have reported a limited understanding of age-related fertility decline [51-53]. Unfortunately, because social and financial issues are important in family building, discussing timely family building can create a great deal of discomfort for patients as they may feel that they are unable to control many of the factors that influence the time frame in which they can build a family. In a study of reproductive age Japanese men and women comparing fertility education with control interventions, the group who received fertility education reported greater knowledge but also more anxiety. A study of female clinicians revealed that almost half would have made other reproductive choices if they had known more about fertility and infertility earlier in their careers [54].

An additional challenge is that clinicians often do not have an accurate understanding of age-related fertility changes. As an example, a survey of general gynecologists reported that half of those interviewed thought that the reproductive life span extended up to 50 years of age, that oral contraceptive pill use prolonged the fertility age window, and that assisted reproductive technology was more effective in women of advanced reproductive age than it actually is [55].

Embryo or oocyte cryopreservation — For women who desire pregnancy at some time in the future and are concerned about age-related fertility decline, options for fertility preservation include embryo and oocyte cryopreservation. The risks and benefits of these two therapies are discussed separately. (See "Fertility preservation for deferred childbearing for nonmedical indications".)

With both embryo and oocyte cryopreservation, though, patients must understand the medical and social ramifications of delaying family building. As described elsewhere, pregnancy complications rise as women age. Additionally, as medical issues arise as parents age, certain aspects of child care may become more challenging. (See "Effects of advanced maternal age on pregnancy".)

Oocyte cryopreservation to preserve future fertility in women without a medical indication is growing in popularity. Data are accumulating about the expected success rates and safety from frozen oocytes from donor oocyte banks. Because this is still a relatively new technology, the long-term health of offspring conceived with cryopreserved oocytes is not known. For this reason, the American Society for Reproductive Medicine (ASRM) advises careful counseling of women who inquire about this technology about risks, expected success rates, and costs [56]. In addition to upfront costs for procedures and medications, one should be made aware of costs of long-term storage and eventual use.

RESOURCES FOR PATIENTS AND CLINICIANS

The American College of Obstetricians and Gynecologists offers a Frequently Asked Questions infographic "Having a Baby After Age 35: How Aging Affects Fertility and Pregnancy."

The National Infertility Association – A nonprofit organization dedicated to improving the lives of individuals living with infertility.

Centers for Disease Control and Prevention – A branch of the United States Department of Health and Human Services that provides health-related information for clinicians and patients.

American Society for Reproductive Medicine (ASRM) – A nonprofit organization that provides "information, education, advocacy, and standards in the field of reproductive medicine."

Society for Assisted Reproductive Technology – The "primary organization of professionals dedicated to the practice of assisted reproductive technologies in the United States."

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".)

SUMMARY AND RECOMMENDATIONS

Fecundability and decline – Fecundability (ie, the probability of achieving a pregnancy in one menstrual cycle) begins to decline significantly in the early 30s (approximately age 32 years), with a more rapid decline a few years later (approximately age 37). This decline in fertility is likely multifactorial. Women are born with a fixed number of oocytes, which declines with age, and the quality of oocytes also declines with age because meiotic errors occur more frequently as age rises. (See 'Biology of female fertility' above.)

Diminished ovarian reserve – Diminished ovarian reserve (DOR) refers to a woman of reproductive age who has regular menses but reduced fecundity or decreased response to ovarian stimulation compared with age-matched women. However, there are no universally agreed upon criteria for defining DOR. Tests can include assessment of follicle stimulating-hormone, anti-müllerian hormone, antral follicle count, Inhibin B, and a clomiphene citrate challenge test. (See 'Diminished ovarian reserve' above.)

Timing of infertility evaluation – Consistent with society guidelines, we advise initiating an infertility evaluation after six months of attempting conception for women 35 years and older and immediate consultation for those who are attempting at 40 years and older. In addition, risk factors such as prior pelvic surgery (particularly involving the ovaries or ovarian vasculature), endometriosis, chemotherapy, pelvic infections, and known male factor infertility should prompt consideration of an earlier evaluation. (See 'Evaluation' above.)

Selecting treatment – Selection of a treatment strategy can be a complex process. In addition to giving thought to test results, there are social and financial considerations. In our practice, if there are no medical, financial, or social limitations, we suggest a more aggressive approach with women age 35 years and older with infertility and offer them treatment as follows (see 'Our approach' above):

For women who do not have adequate ovarian reserve, we recommend using donor oocytes or alternate family planning options, such as adoption or surrogacy (Grade 1B). These women have a poor prognosis for live birth from either spontaneous conception or with assisted reproductive technologies using their own oocytes. (See 'Our approach' above.)

For women with adequate ovarian reserve but additional abnormal testing on fertility evaluation (eg, male factor, distal or bilateral tubal factor), we recommend they proceed directly with in vitro fertilization (IVF) (Grade 1B). IVF has demonstrated efficacy for these women with a fecundability rate higher than that of natural conception or superovulation (OS) with intrauterine insemination (IUI). (See 'Our approach' above.)

For women with adequate ovarian reserve, otherwise normal fertility evaluation, and no social or financial restrictions, we suggest they proceed with IVF (Grade 2B). Women undergoing IVF achieve higher pregnancy rates in fewer treatment cycles compared with OS and IUI. (See 'Our approach' above.)

For women with adequate ovarian reserve and otherwise normal fertility evaluation but who are unable to proceed with or do not desire IVF, an alternate approach is OS and IUI. We prefer OS with gonadotropins because gonadotropin treatment results in a higher probability of success compared with clomiphene citrate OS, albeit with a rate of multiple gestation of approximately 30 percent. Other experts offer only clomiphene citrate OS to limit the rate of multiple gestation. We do not use aromatase inhibitors because they result in a lower pregnancy rate. (See 'Our approach' above.)

Role of expectant management – Expectant management is most appropriate for those who do not want to or cannot pursue more aggressive approaches. For women who present with idiopathic infertility who are 35 years and younger, the fecundability plateaus at two percent per month after one year of attempting conception. As women mature, this continues to decline until the 44th birthday, when the fecundability is negligible. (See 'Expectant management' above.)

Superovulation – Given that the pool of healthy oocytes is reduced in women with advancing age, one approach to increase the chances of a successful pregnancy is OS. The principal behind OS in women who are already ovulatory is to medically rescue potentially healthy oocytes that are lost during the ovulatory process to atresia.

In vitro fertilization – The basic steps of IVF include hormonally stimulating the ovaries, harvesting oocytes, fertilizing the oocytes, and transferring one or more embryos back into the woman's uterus to implant and develop. As there are a larger number of oocytes are available, there are more resultant embryos than during a natural ovulatory cycle. (See 'In vitro fertilization' above.)

Fertility preservation – Future options for fertility preservation include improved education to help individuals understand the impact of age on fertility and plan their families and preservation of embryos or oocytes. (See 'Future directions' above.)

  1. Finer LB, Philbin JM. Trends in ages at key reproductive transitions in the United States, 1951-2010. Womens Health Issues 2014; 24:e271.
  2. Mathews TJ, Hamilton BE. Mean age of mother, 1970-2000. Natl Vital Stat Rep 2002; 51:1.
  3. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: Final Data for 2018. Natl Vital Stat Rep 2019; 68:1.
  4. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice, Practice Committee of the American Society for Reproductive Medicine. Female age-related fertility decline. Committee Opinion No. 589. Obstet Gynecol 2014; 123:719. Reaffirmed 2022.
  5. Larsen U, Yan S. The age pattern of fecundability: an analysis of French Canadian and Hutterite birth histories. Soc Biol 2000; 47:34.
  6. Menken J, Trussell J, Larsen U. Age and infertility. Science 1986; 233:1389.
  7. Jones KT. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Hum Reprod Update 2008; 14:143.
  8. Liu XJ. Targeting oocyte maturation to improve fertility in older women. Cell Tissue Res 2016; 363:57.
  9. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril 2014; 101:633. Reaffirmed 2022.
  10. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7:1342.
  11. TIETZE C. Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957; 8:89.
  12. Laufer N, Simon A, Samueloff A, et al. Successful spontaneous pregnancies in women older than 45 years. Fertil Steril 2004; 81:1328.
  13. Dunson DB, Colombo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002; 17:1399.
  14. Schwartz D, Mayaux MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J Med 1982; 306:404.
  15. Centers for Disease Control and Prevention (CDC). Assisted Reproductive Technology (ART) Data. 2020. Available at: https://nccd.cdc.gov/drh_art/rdPage.aspx?rdReport=DRH_ART.ClinicInfo&rdRequestForward=True&ClinicId=9999&ShowNational=1 (Accessed on July 16, 2023).
  16. Centers for Disease Control and Prevention (CDC). Assisted Reproductive Technology (ART) Data. https://nccd.cdc.gov/drh_art/rdPage.aspx?rdReport=DRH_ART.ClinicInfo&rdRequestForward=True&ClinicId=9999&ShowNational=1 (Accessed on February 12, 2021).
  17. Testing And Interpreting Measures Of Ovarian Reserve: A Committee Opinion (2020). American Society for Reproductive Medicine. Available at: https://www.asrm.org/practice-guidance/practice-committee-documents/testing-and-interpreting-measures-of-ovarian-reserve-a-committee-opinion-2020/?_t_tags=siteid:01216f06-3dc9-4ac9-96da-555740dd020c,language:en&_t_hit.id=ASRM_Models_Pages_ContentPage/_c2 (Accessed on August 01, 2023).
  18. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2015; 103:e9.
  19. Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responder--a plea for universal definitions. J Assist Reprod Genet 2015; 32:1709.
  20. Centers for Disease Control and Prevention (CDC). 2014 Assisted Reproductive Technology Fertility Clinic Success Rates Report. www.cdc.gov/art/reports/2014/fertility-clinic.html (Accessed on March 28, 2017).
  21. Iliodromiti S, Kelsey TW, Wu O, et al. The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature. Hum Reprod Update 2014; 20:560.
  22. Steiner AZ, Pritchard D, Stanczyk FZ, et al. Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age. JAMA 2017; 318:1367.
  23. Reijnders IF, Nelen WL, IntHout J, et al. The value of Anti-Müllerian hormone in low and extremely low ovarian reserve in relation to live birth after in vitro fertilization. Eur J Obstet Gynecol Reprod Biol 2016; 200:45.
  24. Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011; 26:1616.
  25. Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Practice Committee of the American Society for Reproductive Medicine. Fertility evaluation of infertile women: a committee opinion. Fertil Steril 2021; 116:1255.
  26. Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2020; 114:1151.
  27. Devine K, Mumford SL, Wu M, et al. Diminished ovarian reserve in the United States assisted reproductive technology population: diagnostic trends among 181,536 cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Fertil Steril 2015; 104:612.
  28. Farhi J, Ben-Haroush A, Lande Y, Fisch B. Role of treatment with ovarian stimulation and intrauterine insemination in women with unilateral tubal occlusion diagnosed by hysterosalpingography. Fertil Steril 2007; 88:396.
  29. Society for Assisted Reproductive Technology. National summary report, 2014. www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0 (Accessed on March 29, 2017).
  30. Goldman MB, Thornton KL, Ryley D, et al. A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T). Fertil Steril 2014; 101:1574.
  31. Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med 2015; 373:1230.
  32. Reindollar RH, Regan MM, Neumann PJ, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010; 94:888.
  33. Guzick DS, Carson SA, Coutifaris C, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340:177.
  34. Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006; :CD004635.
  35. Peeraer K, Debrock S, De Loecker P, et al. Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. Hum Reprod 2015; 30:1079.
  36. Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril 2020; 113:305.
  37. Strauss J, Barbieri R. Yen & Jaffe's Reproductive Endocrinology, 6th ed, Elsevier, 2009.
  38. Tannus S, Son WY, Gilman A, et al. The role of intracytoplasmic sperm injection in non-male factor infertility in advanced maternal age. Hum Reprod 2017; 32:119.
  39. Kutlu P, Atvar O, Vanlioglu OF. Laser assisted zona thinning technique has no beneficial effect on the ART outcomes of two different maternal age groups. J Assist Reprod Genet 2010; 27:457.
  40. Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Practice Committee of the Society for Assisted Reproductive Technology. Guidance on the limits to the number of embryos to transfer: a committee opinion. Fertil Steril 2017; 107:901.
  41. Live Births Per Intended Egg Retrieval (All Embryo Transfers). Society for Assisted Reproductive Technology (SART) National Summary Report 2021. Available at: https://sartcorsonline.com/Csr/Public?ClinicPKID=0&reportingYear=2021&newReport=True#patient-cumulative (Accessed on August 01, 2023).
  42. Youssef MA, van Wely M, Al-Inany H, et al. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial. Hum Reprod 2017; 32:112.
  43. Rubio C, Bellver J, Rodrigo L, et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril 2017; 107:1122.
  44. Cornelisse S, Zagers M, Kostova E, et al. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev 2020; 9:CD005291.
  45. Ubaldi FM, Capalbo A, Colamaria S, et al. Reduction of multiple pregnancies in the advanced maternal age population after implementation of an elective single embryo transfer policy coupled with enhanced embryo selection: pre- and post-intervention study. Hum Reprod 2015; 30:2097.
  46. Ethics Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Ethics Committee of the American Society for Reproductive Medicine. Oocyte or embryo donation to women of advanced reproductive age: an Ethics Committee opinion. Fertil Steril 2016; 106:e3.
  47. Yeh JS, Steward RG, Dude AM, et al. Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology. Fertil Steril 2014; 102:399.
  48. Luke B, Brown MB, Wantman E, et al. Cumulative birth rates with linked assisted reproductive technology cycles. N Engl J Med 2012; 366:2483.
  49. Levine AD, Boulet SL, Kissin DM. Contribution of Assisted Reproductive Technology to Overall Births by Maternal Age in the United States, 2012-2014. JAMA 2017; 317:1272.
  50. American College of Obstetricians and Gynecologists’ Committee on Clinical Consensus-Obstetrics, Gantt A, Society for Maternal-Fetal Medicine, et al. Obstetric Care Consensus #11, Pregnancy at age 35 years or older. Am J Obstet Gynecol 2023; 228:B25.
  51. Sørensen NO, Marcussen S, Backhausen MG, et al. Fertility awareness and attitudes towards parenthood among Danish university college students. Reprod Health 2016; 13:146.
  52. Deatsman S, Vasilopoulos T, Rhoton-Vlasak A. Age and Fertility: A Study on Patient Awareness. JBRA Assist Reprod 2016; 20:99.
  53. Gossett DR, Nayak S, Bhatt S, Bailey SC. What do healthy women know about the consequences of delayed childbearing? J Health Commun 2013; 18 Suppl 1:118.
  54. Stentz NC, Griffith KA, Perkins E, et al. Fertility and Childbearing Among American Female Physicians. J Womens Health (Larchmt) 2016; 25:1059.
  55. Revelli A, Razzano A, Delle Piane L, et al. Awareness of the effects of postponing motherhood among hospital gynecologists: is their knowledge sufficient to offer appropriate help to patients? J Assist Reprod Genet 2016; 33:215.
  56. Practice Committee of American Society for Reproductive Medicine. Ovarian tissue cryopreservation: a committee opinion. Fertil Steril 2014; 101:1237.
Topic 111561 Version 21.0

References

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