Age and female fertility

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Female fertility is affected by age and is a major fertility factor for women. A woman's fertility is in generally good quality from the late teens to early thirties, although it declines gradually over time. [1] Around 35, fertility is noted to decline at a more rapid rate. [1] At age 45, a woman starting to try to conceive will have no live birth in 50–80 percent of cases. [2] Menopause, or the cessation of menstrual periods, generally occurs in the 40s and 50s and marks the cessation of fertility, although age-related infertility can occur before then. [3] The relationship between age and female fertility is sometimes referred to as a woman's "biological clock." [4]

Contents

Quantification of effect

Cumulative percentage and average age for women reaching subfertility, sterility, irregular menstruation and menopause. Age and female fertility.svg
Cumulative percentage and average age for women reaching subfertility, sterility, irregular menstruation and menopause.

In adolescence

The average age of a girl's first period (menarche) is 12 to 13 (12.5 years in the United States, [6] 12.72 in Canada, [7] 12.9 in the UK [8] ) but, in postmenarchal girls, about 80% of the cycles are anovulatory in the first year after menarche, which declines to 50% in the third year, and to 10% by the sixth. [9] Little is known about fertility in young adolescents, as early teenage pregnancies are uncommon in most societies. [10]

In adulthood

A woman's fertility peaks between her late teens to late-20s after which it starts to decline. [1] However, the exact estimates of the chances of a woman to conceive after a certain age are not clear, and are subject to debate. [11]

According to the National Institute for Health and Clinical Excellence (NICE) over 80 out of every 100 women aged under 40 who have regular unprotected sexual intercourse will get pregnant within 1 year of trying. In the second year the percentage rises to over 90%. [12]

A 2004 study by Henri Leridon, PhD, an epidemiologist with the French Institute of Health and Medical Research, of women trying to get pregnant, without using fertility drugs or in vitro fertilization, had the following results on rates of conception by age:

According to a study done on a sample of 782 healthy European couples ages 19–39, fertility starts declining after age 27 and drops at a somewhat greater rate after age 35. Statistical analysis showed that the women in the 27–29 age group had significantly less chance on average of becoming pregnant than did the 19- to 26-year-olds. Pregnancy rates did not change notably between the 27–29 age group and the 30–34 age group, but dropped significantly for the 35–39 age group. [14]

The age of the male partner had a significant impact on female fertility among the women who had reached their mid-30s, but not among the younger women. However, experts said the new study was too small and there were too many variables which were too difficult to sort out, for a clear conclusion to be drawn. Some experts suggested that the main change in fertility in the older women was the fact that it took them longer to conceive, not necessarily that they were significantly more unlikely to eventually succeed. David Dunson, a biostatistician at the U.S. National Institute of Environmental Health Sciences, said that: "Although we noted a decline in female fertility in the late 20s, what we found was a decrease in the probability of becoming pregnant per menstrual cycle, not in the probability of eventually achieving a pregnancy." [14]

A French study found no difference between the fertility rate of women under 25 and those ages 26–30, after which fertility started to decrease. Estimating the "fertility of a woman" is quite difficult because of the male factor (quality of sperm). This French study looked at 2,193 women who were using artificial insemination because their husbands were azoospermic. The cumulative success rates after 12 cycles of insemination were 73% for women under age 25, 74% in women ages 26–30, 61% for ages 31–35, and 54% in the over 35 age group. [15]

In Hungary, a study by the Központi Statisztikai Hivatal (Central Statistics Office) estimated that 7–12% of Hungarian women younger than 30 were infertile; 13–22% of women age 35 were infertile; and 24–46% of women age 40 were infertile. [16]

The below is a table containing estimates of the percentage of women who, if starting to conceive at a certain age, will fail to obtain a live birth. [2] Note that while for the young ages researchers tend to agree, for older ages there is discrepancy.

Age of woman when she starts to try to conceive% who will have no live birth according to Vincent (1950)% who will have no live birth according to Henry (1953), England% who will have no live birth according to Henry (1953), Norway% who will have no live birth according to Pittenger (1973)% who will have no live birth according to Leridon (1977)% who will have no live birth according to Trussell-Wilson (1985)% who will have no live birth according to Menken-Larsen (1986)
2043.53.52.23-4
256653.3667
30101186.5101112
3517191316171622
4037332440292446
45755850795058-

Ovarian reserve

"Percentage of ovarian reserve related to increasing age. The curve describes the percentage of ovarian reserve remaining at ages from birth to 55 years, based on the ADC model. 100% is taken to be the maximum ovarian reserve, occurring at 18-22 weeks post-conception. The percentages apply to all women whose ovarian reserve declines in line with a particular model where late and early menopause are associated with high and low peak NGF populations, respectively. It is estimated that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. At birth, women have all their follicles for folliculogenesis, and they steadily decline until menopause." Non-Growing Follicles.png
"Percentage of ovarian reserve related to increasing age. The curve describes the percentage of ovarian reserve remaining at ages from birth to 55 years, based on the ADC model. 100% is taken to be the maximum ovarian reserve, occurring at 18–22 weeks post-conception. The percentages apply to all women whose ovarian reserve declines in line with a particular model where late and early menopause are associated with high and low peak NGF populations, respectively. It is estimated that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. At birth, women have all their follicles for folliculogenesis, and they steadily decline until menopause."

In terms of ovarian reserve, a typical woman has 12% of her reserve at age 30 and has only 3% at age 40. [18] 81% of variation in ovarian reserve is due to age alone, [18] making age the most important factor in female infertility.

The most common methods of checking the status of the ovarian reserve is to perform a blood test on day 3 of the menstrual cycle to measure serum Follicle-Stimulating Hormone (FSH) level, alternatively a blood test to measure the serum Anti-Müllerian Hormone (AMH) level can give similar information. Transvaginal ultrasound can also be used to "count the number of follicles" and this procedure is called Antral Follicle Count.

The American College of Obstetricians and Gynecologists recommends ovarian reserve testing should be performed for women older than 35 years who have not conceived after 6 months of attempting pregnancy and women at higher risk of diminished ovarian reserve, such as those with a history of cancer treated with gonadotoxic therapy, pelvic irradiation, or both; those with medical conditions who were treated with gonadotoxic therapies; or those who had ovarian surgery for endometriomas. [19]

It is important to recognize that a poor result from ovarian reserve testing does not signify an absolute inability to conceive and should not be the sole criterion considered to limit or deny access to infertility treatment. [19]

Historical data

A study of a population of French women from 1670 and 1789 shows that those who married at age 20–24 had 7.0 children on average and 3.7% remained childless. Women who married at age 25–29 years had a mean of 5.7 children and 5.0% remained childless. Women who married at 30–34 years had a mean of 4.0 children and 8.2% remained childless. [20] The average age at last birth in natural fertility populations that have been studied is around 40. [21]

In 1957, a study was done on a large population (American Hutterites) that never used birth control. The investigators measured the relationship between the age of the female partner and fertility. (Infertility rates today are believed to be higher in the general population than for the population in this study from the 1950s.)

This 1957 study found that: [22]

Impact

Family planning

The inverse correlation between age and female fertility in later reproductive life is argued to motivate family planning well before having reached 35 years of age. [23] Mapping of a woman's ovarian reserve, follicular dynamics and associated biomarkers can give an individual prognosis about future chances of pregnancy, facilitating an informed choice of when to have children. [24] Notably, a higher level of anti-Müllerian hormone when tested in women in the general population has been found to have a positive correlation with natural fertility in women aged 30–44 aiming to conceive spontaneously, even after adjusting for age. [25] Thus, AMH measurement is helpful to determine which women may need to conceive at an earlier age, and which women can potentially wait. [26]

Reproductive medicine

It is recommended that women have an infertility evaluation if they are over the age of 40, or if they are over the age of 35 and have not achieved pregnancy after trying for 6 months. [27] In many cases, infertility can be treated with many reproductive technologies, but their success declines with age. The issues of age can be discussed with a qualified fertility specialist such as a reproductive endocrinologist.

In Vitro Fertilization (IVF) is an assisted reproductive technology used to treat infertility and to help families have offspring. While many women in advanced age may opt for IVF treatment in order to have children, patients with higher maternal age (>40 years old) were found to have worse IVF outcomes and a higher miscarriage rate compared to 20–30 year olds. [28] Most IVF centers will attempt IVF using the patient's own eggs until about age 43–45, [22] and clinically reproductive endocrinologists tend to pursue IVF more aggressively in women over 35. [15]

Oocyte cryopreservation (egg freezing) is a procedure done to preserve eggs (oocytes) to have the eggs thawed, fertilized, and transferred to the uterus via an IVF procedure. This gives women the ability to delay pregnancy and avoid many of the infertility problems that arise from germ cell deterioration. Studies have shown that the risk of acquiring congenital abnormalities is not increased in the infants born from frozen and thawed eggs, [29] and IVF from thawed eggs have the same successful implantation rate compared to IVF performed with fresh eggs. [30] While chromosomal abnormalities are avoided with egg freezing, pregnancy at older age increases the risk of gestational diabetes, preeclampsia, preterm labor, and cesarean section regardless of conception method. [31]

Elite egg donor agencies that advertise in places such as Ivy League student newspapers offering $20,000–50,000 for donor eggs seek donors under the age of 29.[ citation needed ]

A review in 2012 came to the result that therapeutic interventions to halt or reverse the process of reproductive ageing in women is limited, despite recent reports of the potential existence of stem cells which may be used to restore the ovarian reserve. [24]

Complications

Women who become pregnant after age 35 are at increased risk for complications that affect the mother and fetus.

When it comes to the mother, several research studies have shown that pregnant women over 35 years of age are at increased risk for hypertension during pregnancy, eclampsia (hypertension during pregnancy with seizures), and gestational diabetes. [1] [32] Further, women who become pregnant after age 35 are also at risk for delivery complications. These include stillbirth, miscarriage, and complications leading to delivery via caesarean section. [1] [33] [34] [32]

Fetal complications for pregnant women after age 35 are also high. One well-known risk is the increased risk of having a baby with Down syndrome. According to the Academy of Obstetrics and Gynecology, research has shown that risk for Down syndrome increases proportionally to increasing maternal age. [1]

Probability of conceiving a child with Down syndrome according to maternal age by NDSS: [35]

In addition to Down syndrome, pregnant women over 35 are also at increased risk for other birth defects. A study conducted by Gill et al. found an association of advanced maternal age >40 and birth defects such as cardiac issues, esophageal atresia, hypospadias, and craniosynostosis. [36] Lastly, studies have reported that pregnant women over 35 also have increased risk for premature birth and babies with low birth weight. [1] [33]

Ovarian aging

Substantial evidence indicates that the capability to repair DNA double strand breaks by a repair pathway involving BRCA1 (Breast cancer type 1 susceptibility) protein and ATM (ataxia–telangiectasia mutated) serine/threonine kinase weakens with age in oocytes of numerous species including humans. [37] The specific DNA repair pathway affected by age is the homologous recombination DNA repair pathway. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. [37]

See also

Related Research Articles

<span class="mw-page-title-main">In vitro fertilisation</span> Assisted reproductive technology procedure

In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro. The process involves monitoring and stimulating a patient's ovulatory process, removing an ovum or ova from their ovaries and letting sperm fertilise them in a culture medium in a laboratory. After the fertilised egg (zygote) undergoes embryo culture for 2–6 days, it is transferred by catheter into the uterus, with the intention of establishing a successful pregnancy.

Infertility is the inability of an animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species. It is the normal state of a human child or other young offspring, because they have not undergone puberty, which is the body's start of reproductive capacity.

<span class="mw-page-title-main">Assisted reproductive technology</span> Methods to achieve pregnancy by artificial or partially artificial means

Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes or embryos, and/or the use of fertility medication. When used to address infertility, ART may also be referred to as fertility treatment. ART mainly belongs to the field of reproductive endocrinology and infertility. Some forms of ART may be used with regard to fertile couples for genetic purpose. ART may also be used in surrogacy arrangements, although not all surrogacy arrangements involve ART. The existence of sterility will not always require ART to be the first option to consider, as there are occasions when its cause is a mild disorder that can be solved with more conventional treatments or with behaviors based on promoting health and reproductive habits.

<span class="mw-page-title-main">Embryo transfer</span> Method of assisted reproduction

Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique - which is often used in connection with in vitro fertilization (IVF) - may be used in humans or in other animals, in which situations and goals may vary.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Anti-Müllerian hormone</span> Mammalian protein found in humans

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis. In humans, it is encoded by the AMH gene, on chromosome 19p13.3, while its receptor is encoded by the AMHR2 gene on chromosome 12.

Egg donation is the process by which a woman donates eggs to enable another woman to conceive as part of an assisted reproduction treatment or for biomedical research. For assisted reproduction purposes, egg donation typically involves in vitro fertilization technology, with the eggs being fertilized in the laboratory; more rarely, unfertilized eggs may be frozen and stored for later use. Egg donation is a third-party reproduction as part of assisted reproductive technology.

<span class="mw-page-title-main">Ovarian reserve</span>

Ovarian reserve is a term that is used to determine the capacity of the ovary to provide egg cells that are capable of fertilization resulting in a healthy and successful pregnancy. With advanced maternal age the number of egg cell that can be successfully recruited for a possible pregnancy declines, constituting a major factor in the inverse correlation between age and female fertility.

<span class="mw-page-title-main">Female infertility</span> Diminished or absent ability of a female to achieve conception

Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Infertility is caused by many sources, including nutrition, diseases, and other malformations of the uterus. Infertility affects women from around the world, and the cultural and social stigma surrounding it varies.

Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction. The variability in definitions is in part explained by the effects of increasing age occurring as a continuum rather than as a threshold effect.

<span class="mw-page-title-main">Hydrosalpinx</span> Medical condition

A hydrosalpinx is a condition that occurs when a fallopian tube is blocked and fills with serous or clear fluid near the ovary. The blocked tube may become substantially distended giving the tube a characteristic sausage-like or retort-like shape. The condition is often bilateral and the affected tubes may reach several centimeters in diameter. The blocked tubes cause infertility. A fallopian tube filled with blood is a hematosalpinx, and with pus a pyosalpinx.

<span class="mw-page-title-main">Oocyte cryopreservation</span> Procedure to preserve a womans eggs (oocytes)

Oocyte cryopreservation is a procedure to preserve a woman's eggs (oocytes). This technique has been used to enable women to postpone pregnancy to a later date – whether for medical or social reasons. Several studies have shown that most infertility problems are due to germ cell deterioration related to aging. The procedure intends that the woman may choose to have the eggs thawed, fertilized, and transferred to the uterus as embryos to facilitate a pregnancy in the future. The procedure's success rate varies depending on the age of the woman, with the odds being higher in younger, adult women.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

Fertility preservation is the effort to help cancer patients retain their fertility, or ability to procreate. Research into how cancer, ageing and other health conditions effect reproductive health and preservation options are growing. Specifically sparked in part by the increase in the survival rate of cancer patients.

Pregnancy rate is the success rate for getting pregnant. It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where insemination or any artificial equivalent is used, which may be simple artificial insemination (AI) or AI with additional in vitro fertilization (IVF).

Unexplained infertility is infertility that is idiopathic in the sense that its cause remains unknown even after an infertility work-up, usually including semen analysis in the man and assessment of ovulation and fallopian tubes in the woman. It is usually an exercise in excluding all possible causes before making a diagnosis, however the age of the female partner as well as the duration of infertility are often the most scrutinized characteristics of any infertility case.

Natural Cycle In Vitro Fertilization (IVF) is an assisted reproductive technique designed to closely mimic a woman's natural menstrual cycle. In traditional IVF, a woman's ovaries are stimulated with fertility medications to produce multiple eggs, which are then retrieved and fertilized outside the body. A natural cycle IVF, on the other hand, works with the woman's natural hormonal fluctuations and ovulation cycle.

Partner-assisted reproduction, reception of oocytes from partner (ROPA), reciprocal IVF,shared motherhood, partner IVF or co-IVF is a method of family building that is used by couples who both possess female reproductive organs. The method uses in vitro fertilization (IVF), a method that means eggs are removed from the ovaries, fertilized in a laboratory, and then one or more of the resulting embryos are placed in the uterus to hopefully create a pregnancy. Reciprocal IVF differs from standard IVF in that two partners are involved: the eggs are taken from one partner, and the other partner carries the pregnancy. In this way, the process is mechanically identical to IVF with egg donation. Reciprocal IVF offers the highest chance for pregnancy and a lower chance of a multiple births.

Endometriosis and its complications are a major cause of female infertility. Endometriosis is a dysfunction characterized by the migration of endometrial tissue to areas outside of the endometrium of the uterus. The most common places to find stray tissue are on ovaries and fallopian tubes, followed by other organs in the lower abdominal cavity such as the bladder and intestines. Typically, the endometrial tissue adheres to the exteriors of the organs, and then creates attachments of scar tissue called adhesions that can join adjacent organs together. The endometrial tissue and the adhesions can block a fallopian tube and prevent the meeting of ovum and sperm cells, or otherwise interfere with fertilization, implantation and, rarely, the carrying of the fetus to term.

References

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    In turn citing:
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  37. 1 2 Turan V, Oktay K. BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging. Hum Reprod Update. 2020 Jan 1;26(1):43-57. doi: 10.1093/humupd/dmz043. PMID 31822904; PMCID: PMC6935693
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