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Auroraivf.caSOGC CLINICAL PRACTICE GUIDELINE
No. 269, November 2011 Advanced Reproductive Age and Fertility
This clinical practice guideline has been prepared by the
Reproductive Endocrinology and Infertility Committee,
Objective: To improve awareness of the natural age-related
reviewed by the Family Physicians Advisory Committee and
decline in female and male fertility with respect to natural the Maternal-Fetal Medicine Committee, and approved by
fertility and assisted reproductive technologies (ART) and the Executive and Council of the Society of Obstetricians
provide recommendations for their management, and to review and Gynaecologists of Canada.
investigations in the assessment of ovarian aging .
Options: This guideline reviews options for the assessment of
Kimberly Liu, MD, Toronto ON ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility .
Allison Case, MD, Saskatoon SK Outcomes: The outcomes measured are the predictive value of
REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY
ovarian reserve testing and pregnancy rates with natural and assisted fertility .
Anthony P . Cheung, MD (Co-Chair), Vancouver BC Evidence: Published literature was retrieved through searches
Sony Sierra, MD (Co-Chair), Toronto ON of PubMed or Medline, CINAHL, and The Cochrane Library in Saleh AlAsiri, MD, Vancouver BC June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART) . Belina Carranza-Mamane, MD, Sherbrooke QC Results were restricted to systematic reviews, randomized Allison Case, MD, Saskatoon SK controlled trials/controlled clinical trials, and observational studies . Cathie Dwyer, RN, Toronto ON There were no date or language restrictions . Searches were updated on a regular basis and incorporated into the guideline to James Graham, MD, Calgary AB December 2010 .
Jon Havelock, MD, Burnaby BC Values: The quality of evidence was rated using the criteria described
Robert Hemmings, MD, Montreal QC in the Report of the Canadian Task Force on Preventive Health Care . Recommendations for practice were ranked according to Francis Lee, MD, Winnipeg MB the method described in that report (Table) .
Kimberly Liu, MD, Toronto ON Benefits, harms, and costs: Primary and specialist health care
Ward Murdock, MD, Fredericton NB providers and women will be better informed about ovarian aging Vyta Senikas, MD, Ottawa ON and the age-related decline in natural fertility and about options for assisted reproductive technology .
Tannys D .R . Vause, MD, Ottawa ONBenjamin Chee-Man Wong, MD, Calgary AB Disclosure statements have been received from all members of the committee .
1 . Women in their 20s and 30s should be counselled about the age- related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care . Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s . (II-2A) 2 . Because of the decline in fertility and the increased time to Key Words: Ovarian aging, advanced reproductive age, assisted
conception that occurs after the age of 35, women > 35 years reproductive technology of age should be referred for infertility work-up after 6 months of trying to conceive . (III-B)
This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate
amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be
reproduced in any form without prior written permission of the SOGC.
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SOGC CLINICAL PRACTICE GUIDELINE
3 . Ovarian reserve testing may be considered for women ≥ 35 first-time mothers who are > 30 years of age increased years of age or for women < 35 years of age with risk factors steadily from 11% in 1987 to 26% in 2005.1 During the for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to follicle-stimulating hormone, same period, there was a significant rise in first-time previous exposure to chemotherapy or radiation, or unexplained mothers > 35 years of age, from 4% in 1987 to 11% in infertility . (III-B) 2005, and a corresponding decrease in the group who are 4 . Ovarian reserve testing prior to assisted reproductive technology < 25 years.1 Similar trends have been seen in other parts treatment may be used for counselling but has a poor predictive value for non-pregnancy and should be used to exclude women from treatment only if levels are significantly abnormal . (II-2A) Ovarian function declines as women approach their later 5 . Pregnancy rates for controlled ovarian hyperstimulation are low for reproductive years until menopause, and increasing age is women > 40 years of age . Women > 40 years should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian associated with lowered fecundity and infertility. Women hyperstimulation . (II-2B) experience a decline in natural fertility that begins in the 6 . The only effective treatment for ovarian aging is oocyte donation . mid-30s, and they will often reach sterility many years A woman with decreased ovarian reserve should be offered before the complete cessation of menses.4 Although ART oocyte donation as an option, as pregnancy rates associated with may aid some couples who present with fertility issues, it this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a will not compensate for the decline in natural fertility that woman's own eggs . (II-2B) occurs with delayed child-bearing.5 ART is also invasive, 7 . Women should be informed that the risk of spontaneous expensive, and not covered by most provincial health pregnancy loss and chromosomal abnormalities increases with plans for this indication. In addition, complications of age . Women should be counselled about and offered appropriate pregnancy increase for both the mother and the offspring prenatal screening once pregnancy is established . (II-2A) with advanced maternal age.6 8 . Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and Women and their health care providers should be aware of weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women the effects of age on reproductive potential.
> age 40 . (III-B) 9 . Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum The loss of oocytes from the ovaries is a continual process disorders, and schizophrenia . Men > age 40 and their partners should be counselled about these potential risks when they are that begins in utero. The ovaries in the female fetus contain seeking pregnancy, although the risks remain small . (II-2C) 6 to 7 million oocytes at approximately 20 weeks' gestation. At birth, 1 to 2 million oocytes remain, and only 300 000 to 500 000 are present at the onset of puberty.7 This process J Obstet Gynaecol Can 2011;33(11):1165–1175 continues until menopause, when only a few hundred oocytes remain.8 During the reproductive years, 400 to 500 oocytes will be ovulated; the majority of oocytes are lost through apoptosis, or programmed cell death. Earlier ocial trends in Canada and around the world have led research suggested that a more accelerated process of to women delaying child-bearing into their 30s and, in decline occurs in the last 10 to 15 years before menopause, some cases, their 40s. The average age of women giving beginning around the age of 38 years.9 However, more birth has increased from 27 to 29.3 over the last 20 years.1 recent data suggest that oocyte loss occurs at the same In 2006, the fertility rate for women aged 30 to 34 was the rate through the reproductive lifetime, with the slope of highest of any age group, surpassing that of the previous decline remaining fairly consistent until menopause.10 highest group, women aged 25 to 29.2 The percentage of As the ovarian fol icular pool decreases, women will experience infertility, sterility, cycle shortening, menstrual irregularity, and final y menopause (Figure 1).10 In Western countries, the mean age of menopause is 51, and antral follicle count 1% wil experience premature ovarian failure before age antimüllerian hormone 40.11 There appears to be a fixed interval through these assisted reproductive technology stages of ovarian function. Women who experience an controlled ovarian hyperstimulation earlier menopause wil have an earlier loss of fertility12; therefore, approximately 10% of women wil have decreased ovarian function in their early to mid-30s.13 1166 l NOVEMBER JOGC NOVEMBRE 2011
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Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on
Preventive Health Care
Quality of evidence assessment*
Classification of recommendations† I: Evidence obtained from at least one properly randomized A . There is good evidence to recommend the clinical preventive action II-1: Evidence from well-designed controlled trials without B . There is fair evidence to recommend the clinical preventive action II-2: Evidence from well–designed cohort (prospective or C . The existing evidence is conflicting and does not allow to make a retrospective) or case–control studies, preferably from recommendation for or against use of the clinical preventive action; more than one centre or research group however, other factors may influence decision-making II-3: Evidence obtained from comparisons between times or D . There is fair evidence to recommend against the clinical preventive action places with or without the intervention . Dramatic results in uncontrolled experiments (such as the results of treatment with E . There is good evidence to recommend against the clinical preventive penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, L . There is insufficient evidence (in quantity or quality) to make descriptive studies, or reports of expert committees a recommendation; however, other factors may influence *The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care .95 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care .95 Child-bearing usual y ends 10 years before menopause, 30.12 Markers of ovarian reserve may be useful to predict and this time period is consistent regardless of the age an earlier menopause or menopause transition for women of menopause.14,15 Cycle irregularity wil usual y occur who do not yet have clinical signs or symptoms of ovarian 6 to 7 years before menopause,14 regardless of the age aging but who may already have decreased fertility.
of menopause, coinciding with approximately 10 000 fol icles remaining.8 When menopause occurs, there are often a few hundred follicles remaining. There is still ovarian activity and As the total number of remaining follicles decreases, there is estrogen production during the first year after menopause.14 a corresponding decrease in the available follicular cohort. Although the mean age of menopause in Western countries As a consequence of a smaller follicular cohort, there is a is 51, there is a significant range, from 40 to 60 years of decline in inhibin-B, which is produced by the granulosa age. Sibling and twin studies have shown a significant cells in the early follicular phase.16 There is an inverse genetic component to the age of menopause.19 Smoking correlation between FSH and inhibin-B, which is likely due has been associated with a decreased follicular pool and to a loss in negative feedback; the rise in FSH during the earlier menopause.14 early follicular phase is one of the earliest signs of ovarian aging.17 This initial stage may not be clinically apparent, Oocyte quality also appears to be affected by age. Studies on or present only as infertility, because ovarian hormone IVF oocytes have shown that the rate of oocyte aneuploidy production remains constant, and women continue to increases with age.20 The rate is low in women < age 35 ovulate and have regular cycles. The first clinical signs of (10%), but increases to 30% at the age of 40, to 40% at the ovarian aging may be shortening of menstrual cycles, which age of 43, and to 100% in women > age 45.20 These were is due to a shorter follicular phase. More rapid follicular gonadotropin stimulated oocytes, and therefore may not development leads to earlier recruitment of a dominant reflect the rate of aneuploidy in oocytes from a dominant follicle.18 As this transition continues, women will notice fol icle recruited during a non-stimulated or natural cycle; that their cycles lengthen and become more irregular as however, this correlates with the increase in chromosomal y they enter the menopause transition and ovulation is less abnormal pregnancies and spontaneous abortions with age. consistent.8 Once women start to notice clinical signs of The decline in oocyte quality may be in the formation and ovarian aging such as cycle shortening or irregularity, their function of the spindles, which appear to be more diffuse.21 fertility may already be greatly diminished. One review This may result in chromosomes being less tightly arranged article found that women who were sterile after age 35 had and may therefore lead to meiotic errors. Data also suggest already demonstrated lower fecundity before the age of that the selection process may deteriorate with age, al owing NOVEMBER JOGC NOVEMBRE 2011 l 1167
SOGC CLINICAL PRACTICE GUIDELINE
Figure 1. Schematic representation of the number of primordial follicles
present in the ovaries and the chromosomal quality of oocytes in relation to
female age and corresponding reproductive events.
Number of follicles Proportion of poor quality oocytes Number of follicles 103
Proportion of poor quality oocytes (%)
Graph was drawn after Hansen et al . and de Bruin et al . Broekmans FJ, Soules MR, Fauser BC . Ovarian aging: mechanisms and clinical consequences . Endocr Rev 2009;30:465–93 .12 Copyright 2009, The Endocrine Society . Reproduced with permission .
Figure 2. Natural fertility by age
poorer quality oocytes the opportunity to develop into the dominant fol icle, or to be selected during an IVF cycle. The selection of the available fol icular cohort may be less discriminating, al owing fol icles to mature which should have undergone atresia.22 Other proposed mechanisms include cumulative damage to the oocyte with age and decreasing quality of granulosa cel s.23 FEMALE ADVANCED REPRODUCTIVE
AGE AND INFERTILITY
Population studies have consistently noted that the decline Rate per 1000 wives 100
in birth rates begins when women reach the age of 35 (Figure 2).4 On average, women wil deliver their last child at age 41, with a range of 23 to 51.24 Natural population studies Age of wife
may not take into account non-reproductive factors, such as The ten populations (in descending order at age 20 to 24) are desire to prevent pregnancy, coital frequency, aging partners, Hutterites, marriages 1921–30 ( ); Geneva bourgeoisie, husbands and other medical conditions that may affect live birth rates. born 1600–49 ( ); Canada, marriages 1700–30 ( ); Normandy, In addition, conditions such as fibroids and endometriosis marriages 1760–90 ( ); Hutterites, marriages before 1921 ( ); Tunis, marriages of Europeans 1840-59 ( ); Normandy, marriages are more frequent in later reproductive years. These studies 1674–1742 ( ); Norway, marriages 1874–76 ( ); Iran, village therefore may not offer a ful reflection of a woman's marriages, 1940–50 ( ); Geneva bourgeoisie, husbands born maximum fertility potential. Natural fertility studies of before 1600 ( ).
patients who had recently discontinued contraception have shown that younger women have a higher fecundity rate, Menken J, Trussell J, Larsen U . Age and infertility . Science 1986; 233(4771):1389–1394 .4 Reprinted with permission from AAAS . and therefore conceive sooner than older women.25 1168 l NOVEMBER JOGC NOVEMBRE 2011
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The incidence of infertility and sterility increases as the Age-associated infertility appears to be primarily related age of the female partner increases. Although the true to ovarian aging and the diminishing ovarian fol icle incidence of sterility is difficult to determine because of count. The uterine endometrium has the capacity to non-reproductive factors such as voluntary childlessness, maintain a pregnancy throughout a woman's reproductive population studies can provide some insight. In one study years and, with newer technologies such as egg donation, of 7 populations in which contraception use is rare and in even beyond the natural reproductive years. Age does which there is a low incidence of premarital conceptions, not affect the endometrium's response to hormonal the percentage of women who remained childless was stimulation.34 Pregnancy rates from donor egg cycles higher in those who married later.4 Only 6% of women also confirm that the age of the recipient does not affect who married in their early 20s remained childless, while pregnancy rates.33 64% of women who were not married until their 40s remained childless. Studies in the Hutterite population confirm an increase in infertility with age, escalating from 1. Women in their 20s and 30s should be counselled 11% after age 34 to 33% by age 40 and to 87% by age 45.26 about the age-related risk of infertility when other reproductive health issues, such as sexual health Although social changes have led to women delaying or contraception, are addressed as part of their their reproduction, concomitant advances in reproductive primary well-woman care. Reproductive-age women sciences have led to increased options for fertility treatment should be aware that natural fertility and assisted and ART. Unfortunately, this may give women false optimism reproductive technology success (except with egg that they can delay pregnancy while pursing their education donation) is significantly lower for women in their and careers with the expectation that ART wil help them to late 30s and 40s. (II-2A) conceive if they have difficulty conceiving later. However, 2. Because of the decline in fertility and the increased success rates for ART treatment for women using their own time to conception that occurs after the age of eggs are directly linked to the age of the women,27 and many 35, women > 35 years of age should be referred women may not realize that older women are successful for infertility work-up after 6 months of trying to using ART to achieve pregnancy later in life only with donor conceive. (III-B) eggs. Computer models have demonstrated that the current ART success rates cannot compensate for the loss in natural ASSESSMENT OF OVARIAN AGING
fertility that occurs in a women who has delayed child- bearing from 30 to 35 years of age.5 Ovarian aging will have begun before women notice any clinical changes to their menstrual cycles; therefore, they are Studies on donor insemination confirm an age-related often unaware that they may be at greater risk of infertility. decline in pregnancy rates. Most of the earlier donor Ovarian reserve testing has been explored as a means to insemination studies were performed in couples with severe determine a woman's fertility potential and provide an male factor infertility. These studies are thought to be a assessment of ovarian aging. Although chronological age good reflection of female fertility because non-reproductive alone serves as a good marker of ovarian reserve, some factors such as coital frequency are removed. A negative women will experience a decline in their natural fertility effect on pregnancy rates is seen in women > age 30, and sooner than average, while some older women may is even more pronounced for women > age 35.28–31 One maintain above average ovarian function. Identification of study of almost 3000 cycles showed cumulative pregnancy these two groups, in which ovarian reserve is inconsistent rates of 62% for women < 30 years of age, and 44% for with chronological age, may be useful for counselling and women aged ≥ 30 years after 12 cycles. Younger women planning treatment.35 often conceive quickly, and more cycles of treatment were often needed for women aged ≥ 35 years.29,31 Many tests of ovarian reserve have been tried. However, testing has mainly been performed on infertile populations, Pregnancy rates col ected from ART treatment cycles show with little data on the distribution in the normal fertile the significant impact of female age on success. The 2007 population. Ovarian reserve testing cannot be used to Canadian live birth rate after IVF was 37.4% for women predict infertility or time to infertility; therefore, its < 35 years of age, 26.5% for women aged 35 to 39 years, and application to the general population as a screening tool 11.4% for women aged ≥ 40 years.32 ART reports from the is untested. Most studies have used these tests to try to United States show similar age-related success rates.33 Age is predict a woman's ovarian response and prognosis with the most significant prognostic factor for IVF success.
fertility treatment and IVF. Overall, markers of ovarian NOVEMBER JOGC NOVEMBRE 2011 l 1169
SOGC CLINICAL PRACTICE GUIDELINE
reserve have been shown to correlate with egg quantity and The clomiphene challenge test is performed by response to ovarian stimulation, but not with egg quality.
administering 100 mg of clomiphene daily from day 5 to day 9 of the cycle. FSH is measured on day 3 and on day 10. If The most commonly used test of ovarian reserve is the an adequate response to clomiphene is generated, the rise cycle day 3 or basal FSH level. An elevated basal FSH level in FSH will be suppressed by the release of estradiol and (> 14 IU/L) is the first sign of ovarian aging that can be inhibin-B by developing follicles. Systematic reviews have detected in women, and usually occurs in women aged not shown a benefit to the clomiphene challenge test over 35 to 40.36 Physiologically, the follicular pool is reduced basal FSH or AFC.35 Inhibin-B and basal estradiol have not to approximately 10% of the levels present at puberty.9 been shown to be more useful predictors of poor response The rise in basal FSH is due to a loss in ovarian feedback or pregnancy than basal FSH.35 However, basal estradiol (inhibin-A and B) as the available follicular cohort levels are often screened in conjunction with FSH and can diminishes. Basal FSH levels are easy to obtain, and no confirm correct timing in the menstrual cycle. An elevated special skills are required to perform the test or interpret estradiol level may also falsely suppress FSH levels.
the results; therefore, it is easily accessible. However, basal FSH levels have been shown to be predictive for poor Ovarian reserve tests performed before ART treatment is response to ovarian stimulation and for non-pregnancy begun may be useful for counsel ing, but they have a poor only when the levels are extremely elevated.35 Although predictive power for pregnancy.12 AFC and AMH have been a high threshold may improve the usefulness of the test shown to be useful for prediction of poor ovarian response in predicting a poorer prognosis, only a small number with IVF.12 Although significantly abnormal results are of women will have abnormal tests at this threshold. In associated with lower pregnancy rates (< 5%), only about addition, it has been associated with a false positive rate of 3% of women wil have results in this category.35 In general, 5%.35 Elevated basal FSH levels are also less predictive of ovarian reserve testing is useful for predicting egg quantity pregnancy for women < age 35.37,38 and ovarian response to stimulation but has little value for the prediction of egg quality. Therefore, although these tests An ovarian antral follicle count can be performed early may be useful for counsel ing before ART treatment, testing in the menstrual cycle. Antral follicles between 2 mm and should not be used to exclude women from ART treatment, 10 mm can be identified by transvaginal ultrasound and abnormal tests do not preclude the possibility of performed by an experienced sonographer using a vaginal pregnancy. These test results can be used to obtain individual transducer with a minimum frequency of 7 MHz.39 Antral prognostic information to help to guide the choice of follicles are sensitive to FSH and are considered to be treatment and best use of resources.
representative of the available follicle pool. The number of antral follicles seems to correlate with the number Ovarian reserve testing may be considered in women > age of primordial follicles in the ovary, with a decline in 35 to screen for age-related infertility, although its results primordial follicles being reflected in a lower number of may be useful only for counselling and to aid women in antral follicles.24 In later reproductive years, the proportion their decision-making process. Testing in women < 35 of antral follicles to total follicles may increase as the years may be considered if they have risk factors for ovary allows a higher proportion of follicles to be selected. decreased ovarian reserve, such as a single ovary, previous This may reflect a loosening of the selection process.14 ovarian surgery, poor response to FSH, previous exposure The decline in AFC may not be as steep as the decline to chemotherapy or radiation, or unexplained infertility.42 in fertility. Although decline in AFC is correlated with Although markers of ovarian reserve are not good both the menopause transition and ovarian response to predictors of pregnancy rate with ART for women < 35,38 stimulation, it is not a good predictor of pregnancy.35 identification of these women may prompt shorter delay to infertility investigations and treatment.
Antimüllerian hormone is produced by the granulosa cells of pre-antral and small antral follicles but not dominant 12 AMH levels decrease with decreasing AFC, which in turn is a marker of the primordial follicle count. 3. Ovarian reserve testing may be considered for Levels remain consistent throughout the menstrual cycle40 women ≥ 35 years of age or for women < 35 years and become undetectable in women after menopause.41 of age with risk factors for decreased ovarian reserve, Although AMH provides moderate value in prediction such as a single ovary, previous ovarian surgery, of ovarian response in IVF, it is a poor predictor of poor response to fol icle-stimulating hormone, pregnancy.35 Currently, AMH testing is not widely available previous exposure to chemotherapy or radiation, across Canada.
or unexplained infertility. (III-B) 1170 l NOVEMBER JOGC NOVEMBRE 2011
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4. Ovarian reserve testing prior to assisted Assisted Human Reproduction Act regulates al reproductive reproductive technology treatment may be used for technologies, including the use of donor gametes. counselling but has a poor predictive value for non- Specifical y, the Act prohibits the sale of eggs, sperm, pregnancy and should be used to exclude women or surrogacy services.48 Compensation to donors for from treatment only if levels are significantly receiptable expenses such as medications and parking are abnormal. (II-2A) al owed,49 although the specific regulations are not yet available. Many countries, including the United States, TREATMENT OF AGE-RELATED INFERTILITY
rely on paid, often anonymous, egg donors to ensure an adequate supply to meet the significant demand for this Fertility treatment for age-related infertility is aimed at treatment option. However, as this practice is prohibited increasing monthly fecundity and decreasing the time to in Canada, Canadian women must rely on altruistic conception. Women may be offered controlled ovarian egg donors, usual y family members, close friends, or hyperstimulation with clomiphene citrate or gonadotropins, col eagues. Unfortunately, many women wil not know an or IVF to improve their chances of pregnancy and appropriate donor, so egg donation may not be an option decrease time to pregnancy. Both treatments are intended for them. Other women turn to reproductive tourism and to increase the number of mature oocytes each month to seek treatment in the United States or Europe.
balance decreasing oocyte quality, but they do not address the underlying issue of oocyte quantity or quality. The only Pregnancy rates with oocyte donation are based on the effective treatment for age-related infertility and declining age of the donor, not the recipient.33,50 Pregnancies and oocyte quality is oocyte donation.
live births have been reported in women into their 60s51; however, the use of donor eggs for women after the age of In reality, pregnancy and live birth rates with COH in 50 is controversial. There are increased rates of obstetrical older women are low. In one retrospective review of more and maternal complications with increasing maternal age, than 4000 treatment cycles using clomiphene citrate and including maternal death, hypertension, prematurity, fetal intrauterine insemination, pregnancy rates were 7% for and neonatal death, and operative delivery.52–55 At least one women aged 38 to 40, 4% for women 41 to 42, and 1% for death immediately after delivery has been reported in a women > 42.43 A small study of 130 cycles of COH with 50-year-old woman who conceived with oocyte donation.56 gonadotropins and IUI found a live birth rate of 6% for However, many of these studies show these risks are women aged 38 to 39, and 2% for women > 40.44 All live already increased in women > age 40, and treatment is births happened within the first or second cycles. Older offered to women between the ages of 40 and 50 without women may consider 1 to 2 cycles of COH if they do not significant debate. Many clinicians feel the natural age of want to try IVF as a first-line treatment, but they should menopause is an appropriate maximum age for offering move on to IVF quickly if they are unsuccessful within the oocyte donation, although others argue this is an arbitrary first couple of cycles.45 cut-off point.57 In Canada, there are no regulations that set an age limit for oocyte donation, although many clinics Although chance of success diminishes with age, IVF have set the age of menopause as the maximum age for stil offers higher pregnancy and live birth rates than this treatment.
COH, although significantly lower rates than oocyte donation. In 2007, live birth rates were 11.4% per cycle for women aged > 40 in Canada.32 One study of women aged > 40 undergoing IVF, showed that for women aged 5. Pregnancy rates for controlled ovarian ≥ 42, live birth rates drop to below 5%.46 In this study, hyperstimulation are low for women > 40 years no live births were reported in 54 cycles for women of age. Women > 40 should consider IVF if they aged ≥ 45. A separate study found a significant drop in do not conceive within 1 to 2 cycles of controlled IVF live birth rates in women aged ≥ 43 and over. Live ovarian hyperstimulation. (II-2B) birth rates were 7.4% for women 40 to 42 years of age, 6. The only effective treatment for ovarian aging and only 1.1% for women ≥ 43 years. Miscarriage rates is oocyte donation. A woman with decreased were 43.1% in the younger age group and 65.2% in the ovarian reserve should be offered oocyte donation older age group.47 as an option, as pregnancy rates associated with this treatment are significantly higher Oocyte donation offers women with an intact uterus than those associated with control ed ovarian the opportunity to carry a pregnancy despite declining hyperstimulation or in vitro fertilization with a ovarian function or menopause. In Canada, the 2004 woman's own eggs. (II-2B) NOVEMBER JOGC NOVEMBRE 2011 l 1171
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EARLY PREGNANCY AND
ADVANCED PATERNAL AGE
Although significant focus has been placed on female Advanced reproductive age is associated with early and later reproductive aging, there is also an age-related decline in pregnancy complications in addition to infertility. Age is a sperm function and male fertility. Although "andropause" recognized risk factor for spontaneous abortion. Although is not a clearly defined event for men as menopause the risk of clinical pregnancy loss is low in women < 30 is for women, there is a decline in testicular function, years of age (7% to 15%), it begins to rise for women aged which includes declining testosterone levels each year.59 30 to 34 (8% to 21%) and women aged 35 to 39 (17% to Sperm parameters including semen volume, motility, and 28%), and it increases dramatically for women aged ≥ 40 morphology decrease with age, although a decline in sperm (34% to 52%).15 Data from the Canadian ART clinics also concentration has not been shown.60 show an increase in spontaneous pregnancy loss after ART treatment. Pregnancy loss rates after clinical intrauterine Studies trying to delineate the effects of male age on pregnancy ranged from 10.4% for women aged < 35 to natural fertility often have not accounted for female age. 16.4% for women aged 35 to 39, and increased to 33% for One study has suggested that the odds of conception women aged ≥ 40.27 decrease 3% per year, while other studies have shown that the effect of male age alone on natural monthly conception An increased risk of chromosomal abnormalities also occurs is small.61,62 Similarly, studies in ART treatment have often with age. Much of the increased risk of early pregnancy not controlled adequately for maternal age.63,64 One study loss may be due to the increased rate of chromosomal y suggested that male age > 35 years may have an effect on abnormal conceptions. The previously discussed underlying IUI, but most studies suggest that male age does not affect mechanisms for ovarian aging and declining egg quality IVF/ intracytoplasmic sperm injection pregnancy rates leading to increased oocyte aneuploidy may lead to an despite lower motility and fertilization rates.65,66 There increased rate of chromosomal abnormalities in resultant was also no difference seen in egg donation cycles.67,68 In embryos and pregnancies. The age-related risks for Down couples undergoing ART treatment, it appears that the syndrome increase from 1 in 1477 for women at age 20 to effect of paternal age on the number of cleavage-stage embryos is small.69 However, a significant decrease in the 1 in 39 at age 44. The age-related risk for al chromosomal rate of blastocyst embryo formation on day 5 and in the abnormalities rises from 1 in 526 for women at age 20 to number of cryopreservable embryos has been noted.70,71 1 in 2 at age 45.58 Paternal age > 40 years does appear to be associated with risk of spontaneous abortion, even when maternal Pregnancy in women > 40 years of age is also associated age is controlled for.72,73 For chromosomal abnormalities, with a higher risk of obstetrical complications, including the effect of maternal age is such a significant factor, the operative delivery, gestational diabetes, preeclampsia, paternal age effect is small in comparison and is not found IUGR, and low birth weight.6 Pre-conception screening at all in many studies after maternal age is controlled for.74–77 for significant medical conditions such as hypertension However, recent studies suggest that, either alone or in or diabetes should be considered for women at high risk combination with a maternal effect, paternal effect may before fertility treatment is begun.
increase the risk of Down syndrome.78 Although there has been conflicting evidence for an association with pre-term birth and low birth weight, a study conducted in the United 7. Women should be informed that the risk of States and a population study undertaken in Alberta did not spontaneous pregnancy loss and chromosomal find this association after multiple and logistic regression abnormalities increases with age. Women should be analysis.79–81 Advanced paternal age has been associated with counselled about and offered appropriate prenatal autosomal dominant disorders such as Alport syndrome, screening once pregnancy is established. (II-2A) achondroplasia, and neurofibromatosis.82–87 The estimated 8. Pre-conception counselling regarding the risks of risk for autosomal dominant disorders in offspring of pregnancy with advanced maternal age, promotion fathers ≥ 40 years of age is thought to be < 0.5%.78 of optimal health and weight, and screening for concurrent medical conditions such as hypertension Autism spectrum disorders and schizophrenia have been and diabetes should be considered for women associated with advanced paternal age through larger > age 40. (III-B) cohort and population database studies. A large Danish prospective study on autism with one million children 1172 l NOVEMBER JOGC NOVEMBRE 2011
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found a relative risk 1.6 for fathers > 40 to 44 years of age, 5. Leridon H. Can assisted reproduction technology compensate for the and an Israeli cohort study found an OR 5.75 for fathers natural decline in fertility with age? A model assessment. Hum Reprod aged 40 to 49.
88,89 A large US study found an association between autism and both maternal and paternal age, with 6. Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93(1):9–14.
a relative risk of 1.3 for every 10-year increase in paternal 7. Baker TG. A quantitative and cytological study of germ cells in human 90 The link between paternal age and schizophrenia was ovaries. Proc R Soc Lond B Biol Sci 1963;158:417–33.
initially felt to be constitutional: people with this condition 8. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the tend to marry and reproduce later in life. A cohort of menopausal transition: evidence for accelerated loss and ultimate almost 90 000 children in Jerusalem was linked to the exhaustion. J Clin Endocrinol Metab 1987; 65:1231–7.
Israeli Psychiatric Registry. The relative risk for offspring 9. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. with schizophrenia was 2.0 for fathers aged 45 to 49, and Accelerated disappearance of ovarian follicles in mid-life: implications for 3.0 for fathers > age 50.91 This finding has been seen forecasting menopause. Hum Reprod 1992;7:1342–6.
across other studies in other ethnic populations, including 10. Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian populations in Denmark, Sweden, and Japan.92–94 non-growing follicle number from birth to menopause. Hum Reprod The American College of Medical Genetics does not 11. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. Detection recommend additional prenatal testing solely on the basis and clinical relevance. Hum Reprod 2003;18:1137–9.
of advanced paternal age (defined as ≥ 40), although 12. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and prenatal counselling about the potential risks of advanced clinical consequences. Endocr Rev 2009;30:465–93.
paternal age should be undertaken.78 13. Johnson NP, Bagrie EM, Coomarasamy A, Bhattacharya S, Shelling AN, Jessop S, et al. Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic 9. Advanced paternal age appears to be associated review of ovarian reserve test accuracy. BJOG 2006;113:1472–80.
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Measuring cosmology with Supernovae Saul Perlmutter1 and Brian P. Schmidt2 Physics Division, Lawrence Berkeley National Laboratory, University of California,Berkeley, CA 94720, USA Research School of Astronomy and Astrophysics, The Australian NationalUniversity, via Cotter Rd, Weston Creek, ACT 2611, Australia Abstract. Over the past decade, supernovae have emerged as some of the most power-ful tools for measuring extragalactic distances. A well developed physical understandingof type II supernovae allow them to be used to measure distances independent of theextragalactic distance scale. Type Ia supernovae are empirical tools whose precision andintrinsic brightness make them sensitive probes of the cosmological expansion. Bothtypes of supernovae are consistent with a Hubble Constant within ∼10% of H0 = 70