Age-Related Fertility Decline

Etiology

As women age, fertility declines. In earlier times, a 35-year-old pregnant woman would be a rarity; however, currently, women aged 35 years and older conceiving their first or second child are common. The decline in fertility is a modern problem seen throughout the world, which is not always easily solved by assisted reproductive technology.[3] The age-related fertility decline stems from several factors. However, the primary underlying cause is the decline in oocyte quantity and quality with advancing age. Other factors include an increased risk of pregnancy complications, miscarriage, changes in the ovulatory cycle, exposure to environmental toxins, and a potential decline in uterine health.[7]

The number of gametes in the ovary decreases through the process of atresia, with an initial decline from the maximum number of approximately 6 to 7 million gametes around 20 weeks of gestation to approximately 1 to 2 million oocytes at birth, to 300,000 to 500,000 at puberty, to 25,000 at age 37, and around 1,000 at age 51. The average age of menopause in the United States is 51.[4] Methods to slow or reverse this decline in gametes during perimenopause have not been identified. While the exact mechanism is unknown, oocyte atresia is believed to be related to changes in circulating hormones, specifically rising levels of follicle-stimulating hormone paired with declining levels of AMH and inhibin B. Additionally, the quality of oocytes declines with age.[4]

A high-quality oocyte is critical for successful fertility. Gamete quality is closely tied to gamete genetics, which is more frequently adversely affected in women with increasing age than in men. In mothers younger than 25 years, the rate of Down syndrome is around 2%. However, in women aged 35 or older, that risk jumps to almost 35%. As a person ages, the risk of chromosomal abnormalities, specifically aneuploidy, increases.[8] Aneuploidy occurs when an incorrect number of chromosomes is present in a germ cell. The presence of such aneuploidy dramatically affects oocyte quality.

This, in turn, affects fertility, as the presence of aneuploidy is a common cause of early miscarriage and one of the most common causes of infertility.[9] Aneuploidy can be attributed to 65% to 75% of early failed pregnancies and approximately 35% of clinically recognized miscarriages. Aneuploidy risk increases 10 times after the maternal age of 40 compared to a maternal age younger than 25. The occurrence of aneuploidy is primarily attributed to meiotic nondisjunction caused by changes in the meiotic spindle, but little is known about how to correct this process. Age is clearly related.[10] 

Epidemiology

While the ability to conceive is not the same across all populations and can vary due to many factors, patterns of predicted infertility have been established. Studies have analyzed the average age of infertility in many countries. In a Japanese study, the highest fertility rates were in women aged 24 or younger. Their fertility decreased with age, a pattern consistent with data from a similar study of European women.[11]

Fertility decreases with age, but other contributing factors are likely present. Sexual activity tends to decline with age. Furthermore, tubal disease, leiomyomas, endometriosis, tubal and ovarian surgeries, and chemotherapy may also play into the decrease in fertility seen with aging.[4] Because fertility can be linked to many factors, determining the exact prevalence of age-related causes is difficult. However, based on data from multiple trials of both insemination and in vitro fertilization, the chances of conception, both naturally and via artificial reproductive technology, decrease with age. As many as 10% to 15% of all couples attempting conception have reported difficulties with fertility.[12][13]

Pathophysiology

The pathophysiology of age-related fertility decline in females is multifactorial. A decrease in the number of gametes and the integrity of those gametes is affected by age due to oocyte atresia over time and changes in the meiotic spindle, which can lead to aneuploidy. Other contributing factors include changes in ovulation patterns with age, aging of the uterus, and increasing risks of complications.[7] The mechanisms underlying decreased fertility are poorly understood but are most likely genetically encoded on the X chromosome and autosomes.[4] Age-related alterations in granulosa cells can impair oocyte quality, reduce follicular support, and ultimately contribute to reduced fertility, especially among women of advanced maternal age.[14] Physiologic factors that can diminish oocyte quantity and quality include the following:

• DNA damage
• Genetic mutations
• Cohesion deterioration and chromosome missegregation
• Meiotic recombination errors
• Spindle assembly checkpoint
• Telomere shortening
• Mitochondrial dysfunction
• Ovarian fibrosis and inflammation [15] 

Endometrial dysfunction also plays a significant role in age-related reproductive decline. Optimizing endometrial health is therefore important, as aging is associated with progressive deterioration in endometrial function and receptivity. Mitochondrial dysfunction appears to be a key contributor to this process, acting as a central driver of cellular aging. Irreversible mitochondrial damage may lead to endometrial senescence, which in turn may contribute to the gradual decline in reproductive potential and implantation receptivity.[16]

History and Physical

No specific history or physical examination findings suggest declining fertility, except for age. Menstrual irregularities (eg, abnormal uterine bleeding and oligomenorrhea) may not necessarily be present in a patient with decreasing fertility but are often associated with perimenopausal and postmenopausal transitions. However, laboratory and ultrasound examinations can be useful in evaluating fertility issues.[3]

Evaluation

Testing women for decreased ovarian reserve with antral follicle count, AMH levels, ultrasound, and hysterosalpingogram may be recommended in women aged 35 and older attempting conception without success after 6 months.[8] This age parameter may be lowered for women with diminished ovarian reserve risk factors (eg, having only 1 ovary, a history of ovarian surgery, exposure to chemotherapy or radiation, and unexplained infertility). In any patient aged 40 and older seeking infertility care, recommending evaluation by a reproductive endocrinologist is appropriate.[17]

Clinicians should be aware that while tests for ovarian reserve may indicate the number of gametes a woman has left, these values do not reflect oocyte quality.[17] Testing for ovarian reserve can predict a patient’s potential response to gonadotropin stimulation. Patients with decreased ovarian reserve have been shown to have less likelihood of pregnancy success with assisted reproductive technology. Currently, the preferred biomarker for evaluating patients is AMH, which has been shown to correlate with the number of available oocytes.[18]

AMH is secreted from the ovary, specifically from the granulosa cells. Currently, no direct measure of the remaining ovarian primordial follicles is available, but AMH is a marker of functional ovarian reserve. Beginning at age 25, AMH levels start to decrease with increasing age. However, significant variation in AMH levels has been noted between similarly aged women due to ethnicity and other contributing factors. Furthermore, AMH levels can vary by 20.7% depending on the timing within the menstrual cycle. This, plus the lack of an international standard and inter-assay variations, are limitations that may hamper the clinical utility of AMH levels in an individual patient.[19]

Treatment / Management

Obstetric and gynecology clinicians are essential as patient educators and links to reproductive endocrinology specialists. Patient counseling should include general ways to optimize fertility, including maintaining a healthy weight and upholding a healthy lifestyle, including smoking cessation and reduction of alcohol intake.[5] Obstetric and gynecology clinicians should educate patients regarding fertility concerns and family planning, regardless of the patient's current desire to actively achieve pregnancy. Clinicians should discuss the decreasing pregnancy rates for patients in their 30s and 40s, both naturally and using assisted reproductive technology, as part of routine counseling about family planning.[20] (B3)

Various techniques for fertility preservation with cryopreservation of oocytes or embryos are now available worldwide. "Age-banking" is now used for oocyte preservation to avoid age-related infertility. With ovarian stimulation followed by the vitrification of 15 oocytes, a woman younger than 35 has an 85.2% probability of a live birth. Banking of ovarian tissue is another option, although more invasive. Oocyte cryopreservation remains the best option currently for women who want to preserve fertility due to concerns about age-related decline in fertility. Embryo cryopreservation is a less ideal option because, if the couple subsequently separates, ownership disputes can arise.[21] 

Although most couples prefer to have a child with genetic material from both parents if possible, oocyte donation may be the best option for some couples. Because aneuploidy rates increase with increasing age, in vitro fertilization with a woman older than 42 has an 85% risk of aneuploidy. Similarly, a woman aged 35 needs about 5 oocytes to get a euploid embryo, whereas a woman older than 42 would need 200 oocytes. Decreased responsiveness to ovarian stimulation is also seen in older women. With donor oocyte use, in vitro fertilization success depends on the donor's age. Reproductive endocrinologists discuss this option with patients who have not previously undergone oocyte cryopreservation, as donor oocytes have a high likelihood of a good clinical outcome.[22]

Differential Diagnosis

The differential diagnosis of age-related infertility includes many other causes of infertility. Although infertility can be attributed to a myriad of causes, the 3 main components include ovulatory factor, tubal factor, and male factor.[23] Environmental factors, sexual dysfunction, genetic abnormalities, premature ovarian insufficiency, and unexplained infertility are all included in the differential diagnosis of age-related decline in fertility. 

The following factors have the potential to decrease fertility:

• Autoimmune diseases
  • Thyroid disease
  • Addisons disease
  • Diabetes
  • Rheumatoid arthritis
  • Crohns disease
  • Myasthenia gravis
  • Systemic lupus erythematosus
  • Multiple sclerosis
• Sickle cell anemia
• Endometriosis 
• Testosterone for gender-affirming care 
• Alcohol consumption
• Endocrine Disruptors
  • Perfluoroalkyl substances
  • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
  • Bisphenol-A (BPA)
  • Phthalates
  • Parabens [1]

Prognosis

While age-related fertility decline has no actual cure, patients who are promptly evaluated and referred to a reproductive endocrinologist have multiple options available to them for treatment. This is important, as patients with infertility can be emotionally affected by their diagnosis. Prompt evaluation and referral to a specialist is the best thing that an obstetric and gynecologic clinician can do for patients of advancing age who are seeking fertility.

Furthermore, another factor to consider is that assisted reproductive technology can be prohibitively expensive for patients, as insurance often does not cover the cost.[24] By talking over family planning and options for fertility preservation at routine well-woman examinations when women are younger, an opportunity to delay childbearing without as much concern about age-related infertility decline may be discussed and implemented based on shared decision-making.

Complications

Potential complications of age-related fertility decline include a true inability to conceive. The cost of utilizing assisted reproductive technology, as well as the low success rates for older women, are additional complications to keep in mind. Women who give birth at age 34 or older have increased rates of miscarriage, preterm birth, and congenital malformations, especially after the age of 40. Once pregnancy is achieved, complications, eg, gestational hypertension, preeclampsia, and gestational diabetes, are risks that are increased during pregnancy.