Aging and Fertility
As women age, their fertility declines due to normal, age-related changes that occur in their ovaries. A female fetus will have the highest number of eggs around 16-20 weeks of pregnancy (6-7 million); at birth this number decreases to about 2 million, and by puberty to approximately 300,000. This constant and dynamic process of decline continues until menopause, and is not interrupted by birth control pills, pregnancy, or ovulation. From this reservoir of eggs, fewer than 500 eggs will ovulate during a woman's reproductive years, and the rest will undergo a degenerative process entitled "atresia". Smoking appears to accelerate atresia, and is linked to earlier menopause.
As a woman approaches menopause, the ovaries commence a poorer response to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). As a result, the production of these hormones is increased by the pituitary gland, in an attempt to augment ovarian response. For this reason, measurements of FSH and estradiol (E2), the biological ovarian reaction, serve as biomarkers for ovarian reserve and fertility capability.
This blood test is performed on the second or third day of the menstrual cycle (conventionally, the first day of flow is cycle day 1). For most laboratories currently using chemiluminescent assays, FSH and E2 values of >10 mIU/ml and >70 pg/ml, respectively, are elevated.
It is customary to inform the patient that if, during the early phase of a natural cycle, the FSH is >19 mIU/ml, the possibility of pregnancy occurring is almost nonexistent. By the time the woman reaches menopause at about age 48-53, the ovaries will contain few or no eggs.
Female age is extremely important when considering the probability of pregnancy. The real issue is egg quantity and quality, which then converts to embryo quality after fertilization. Increased infertility with age is a well-documented problem and most apparent in modern society.
Successful pregnancy outcome with treatment is largely related to female age, particularly when using the woman's own eggs. Most clinics have a certain upper age limit after which they will not perform in vitro fertilization (IVF) with the woman's own eggs. In the United States, the age limit is somewhere between 42 and 45 in most programs. Most IVF clinics allow the patient to be a recipient of donor eggs through to about age 50. When donor eggs are being used, the age of the egg donor is the important issue. With egg donation, the age of the recipient does not seem to affect the chances of success.
The age of the male partner is not quite as important. This is due to the fact that all the female eggs are present at birth, whereas sperm are generated constantly after puberty. Eggs age over time, while new sperm continue to appear from the production line.
Age related fertility: from How old are your eggs? D.Nikolaou, Current Opinion in Obstetrics and Gynecology
Pregnancy rates and infertility course over the years (Both of the above line graphs are for women with normal reproductive function).
This chart illustrates the decline in live birth success rates by female age beginning at approximately age 31. Infertility increases with age. This curve becomes steeper starting at about age 37. At age 44 and above births resulting from IVF using the female’s own eggs are almost nonexistent. The live birth success rate using eggs over age 43 is 2% per attempt. Most IVF centers are willing to attempt IVF using the female partner's eggs until about age 43-45, after which the couple would be offered egg donation as the only realistic and appropriate fertility approach.
It is also of the utmost importance to bear in mind that every couple is unique, and could be more fertile, or less, compared to the average success rate for their age.
A study published in 1957 by Tietze in Fertility and Sterility examined the relationship between the age of the female partner and fertility. This study found that the percentages of infertile couples were:
• By age 30 = 7%
• By age 35 = 11%
• By age 40 = 33%
• At age 45 = 87%
In a review of data from the various IVF centers in the USA, the Central for Disease Control reported that the live birth rate was 16% per cycle at age 40, and only 3% per cycle at age 44.
The above graph illustrates live birth rates according to age if the fertilization involved patients' own eggs, or using donor eggs. It can be clearly seen that the most important factor is the age of the eggs, and not the age of the recipient.
Although this data specifically relates to IVF and age, a similar loss in fertility potential also occurs with age in the general, "normal" population.
Tests to determine whether age is a significant fertility factor in an individual couple
Although age (as a number) is important, the actual fertility issue is egg quality, which differs in various individuals. At present satisfactory screening for measuring ovarian reserve is not available. Most infertility specialists use the measurements of day 3 FSH, and some also use follicular count, which is a most inadequate form of measurement. These tests, and mainly the FSH test, predict quantity, rather than the quality, of the remaining eggs.
Miscarriage and female age
Numerous studies have documented the increased risk for miscarriage as the age of women advances. The following graph (modified from: Heffner L., Advanced, maternal age – how old is too old? New England Journal of Medicine 2004; 351(19):1927–29 depicts fertility and miscarriage rates as a function of maternal age. Miscarriage is defined as spontaneous pregnancy loss before the 20th week of gestation.
Miscarriage rates for women with a history of infertility tend to be higher than for those who are fertile. Most of the increased risk for miscarriage in "older" women is due to the rise in chromosomal abnormalities (karyotype) in their eggs. However, this is still a controversial issue, as not all published data are in agreement.
Miscarriage rates begin to increase among women in their mid-to-late thirties, and continue with advancing age, reaching 43% at age 42 years. The miscarriage rates observed among women undergoing assisted reproductive technology (ART, [i.e. IVF]) procedures appear to be no higher than those pregnancies conceived through intercourse.
The miscarriage rate after fetal heart activity seen on ultrasound was 11%, 20% and 41% at ages 30, 38, and 42 years of age, respectively.
Chromosomal problems in aging eggs
We are not fully aware of why, as women age, chromosomal abnormalities are higher in eggs. However, research studies have clarified some of the issues involved.
The meiotic spindle is a critical component of eggs, with involvement in organizing the chromosomal pairs so that proper division of the pairs can occur as the egg develops. It was found (Battaglia DE, et al: Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reproduction 1996; 11: 2217-2222) that studies of eggs from women 20-25 years of age showed that 17% had an abnormal spindle appearance, while 79% of eggs from women 40-45 years of age had an abnormal spindle appearance, resulting in an unbalanced chromosomal situation in the egg.
Ultimately, it appears that as women mature, the incidence of chromosomally-abnormal eggs increases dramatically. This results in lower chances for conception, as well as increased risk for miscarriage.
For some patients, we may recommend a Clomid Challenge Test (CCT), which is more sensitive for assessing ovarian reserve. For this test we assess FSH and E2 values on cycle day 3, then administer Clomid (clomiphene citrate, 100 mg/day) from cycle days 5-9, and then reassess the FSH value on day 10. All three blood test results should be within a normal range for the overall test result to be standard. Any other value indicates an abnormal CCT. The FSH value on cycle day 10 should be <10 mIU/ml, and if elevated indicates diminished ovarian reserve.
If fertility treatment is unsuccessful based on a diagnosis of diminished ovarian reserve, options include egg donation, adoption, or choosing to live childless. While these decisions may be difficult, it is comforting to know that options are available, as well as support for assisting the patient in achieving her goal of building a family.
Risk of Chromosomal Abnormality in Newborns by Maternal Age
The probability of multiple pregnancies in women above the age 40 who undergo fertility treatment
Infertile patients over the age of 40 are generally considered to have a low chance of success with ART cycles despite high numbers of embryos transferred. The risk of multiple pregnancies in this group of patients is not well established. The rate of embryo wastage for women over age 40 is approximately 95%, and these women have a correspondingly low rate of multiple pregnancy per cycle start (2.5% and 1.6% for women aged 41-42 and 43-44), respectively. These data underscore the low reproductive efficiency of oocytes in women over the age of 40 and the very low probability of a multiple gestation live birth despite the high number of embryos transferred. This information is an important additional counseling tool at the time of embryo transfer in this group of patients.