Age-Related Fertility Decline

Etiology

As female humans age, fertility is affected. In earlier times, a 35-year-old pregnant woman would be a rarity; however, currently, women aged ≥35 years 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.[1] The age-related fertility decline stems from several factors. However, decreasing oocyte quantity and quality with advancing age is the primary underlying cause. 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.[5]

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 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.[2] 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 the changes in circulating hormones, specifically the rising level of follicle-stimulating hormone paired with declining levels of anti-müllerian and inhibin B hormones. Additionally, the caliber or quality of oocytes decreases with age.[2]

A high-quality oocyte is critical for successful fertility. Gamete quality is tied closely to the genetics of the gametes, which is more frequently negatively affected in women of 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 chances for chromosomal abnormalities, specifically aneuploidy, increase. Aneuploidy occurs when an incorrect number of chromosomes are present in a germ cell. The presence of such aneuploidy dramatically affects the quality of an oocyte. 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.[6] 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 due to meiotic spindle changes, but little information is known regarding how to correct that process. Age is clearly related.[7] 

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, which correlated to data from a similar study on European women.[8]

Fertility decreases with age, but there are likely other contributing factors. 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.[2] Because fertility can be linked to many different factors, defining the exact prevalence of age-related reasons is difficult. However, based on data from multiple trials of both insemination and invitro 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.[9][10]

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.[5] The mechanisms of decreasing fertility are poorly understood but are most likely genetically coded within the X-chromosome and the autosomes.[2] 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 [11] 

History and Physical

No specific history and physical examination findings allude to declining fertility, except 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.[1]

Evaluation

Testing women for decreased ovarian reserve may be recommended in women aged ≥35 years attempting conception without success after 6 months. 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 years seeking infertility care, recommending evaluation by a reproductive endocrinologist is appropriate.[12]

Clinicians should be aware that while the tests for ovarian reserve may provide information regarding the number of gametes a woman has left, these values provide no information regarding oocyte quality.[12] 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 to evaluate patients is the anti-müllerian hormone (AMH) level, which has been shown to correlate to the available oocyte number.[13]

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 that reflects the 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 differ by 20.7% based on timing during 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.[14]

Treatment / Management

Obstetric and gynecology (OBGYN) 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.[3] OBGYN 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 a part of routine counseling about family planning.[15] (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 in cases where the couple subsequently separates, embryo ownership problems can occur.[16] 

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, success with in vitro fertilization is based on the donor's age. Reproductive endocrinologists discuss this option with patients who have not previously done cryopreservation of oocytes, as donor oocytes have a high probability of a good clinical outcome.[17]

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.[18] 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. 

Prognosis

While there is no actual cure for age-related fertility decline, 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 OBGYN clinician can do for patients of advancing age who are seeking fertility. Another factor to consider is that assisted reproductive technology can be prohibitively expensive for patients, as insurance often does not cover the cost.[19] 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 such as gestational hypertension, preeclampsia, and gestational diabetes are risks that are increased during pregnancy.