• Users Online: 241
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2016  |  Volume : 1  |  Issue : 1  |  Page : 3-8

Demand of pregnancy in advanced age: A challenge to fertility specialists

Department of ART, Calcutta Fertility Mission, Ballygunge, Kolkata, West Bengal, India

Date of Submission27-Apr-2016
Date of Acceptance09-May-2016
Date of Web Publication2-Jun-2016

Correspondence Address:
Siddhartha Chatterjee
21, Bondel Road, Kolkata - 700 019, West Bengal
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2456-1975.183267

Rights and Permissions

The couples of advanced age nowadays are requesting for the promotion of fertility for the first time quite more than what it was before. This is because of career making of men and women, increased divorce, and re-marriage. Physicians dealing with infertility problems are facing a lot of challenges in this regard. The diminished fecundity in advanced age is a routine happening. That is because of diminished ovarian reserve and there may be more aneuploidy in the oocytes or problem with the male gametes, so far as the genetic constitution, fertilizability, and motility are concerned. Research is going on all over the world in this regard, and the present way out is egg donation for elderly women with poor ovarian reserve. Though in a certain percentage of cases, in elderly women, natural conception is possible with or without ovulation induction, in males, usually fertility remain for long, even up to the advanced age, and reproductive assistance in the form of intracytoplasmic sperm injection is required with very poor sperm quality.

Keywords: Advanced age, intracytoplasmic sperm injection, in vitro fertilization, oocyte donation, reproduction

How to cite this article:
Chatterjee S. Demand of pregnancy in advanced age: A challenge to fertility specialists. BLDE Univ J Health Sci 2016;1:3-8

How to cite this URL:
Chatterjee S. Demand of pregnancy in advanced age: A challenge to fertility specialists. BLDE Univ J Health Sci [serial online] 2016 [cited 2021 Dec 2];1:3-8. Available from: https://www.bldeujournalhs.in/text.asp?2016/1/1/3/183267

The social trend in women worldwide shows a tendency for postponement of pregnancy until later years of reproduction. All these may be due to building up of a career in a woman, late marriages, increased divorce, re-marriage, or some allied reasons. Many of the reasons why women are choosing to postpone childbearing reflect the availability of safe, effective, and reversible contraception, which has allowed women the reproductive autonomy to decide if and when they will have children. The advanced reproductive age is associated with a reduction in quality and quantity of follicular pool in the ovary, leading to reduced fertility and fecundity. The usual gradual decline of follicular pool size with aging is accelerated to rapid decline after the age of 35 years, exerting severe negative impacts on the fertility potential. Although reduced fertility potential, either natural or following Assisted Reproductive Techniques (ART), is retained usually for at least 4 years after rapid decline. [1],[2] Biologically, the optimum period for childbearing is between 20 and 35 years of age. After 35 years of age, fecundity decreases and the chance of miscarriage, spontaneous abortion, pregnancy complications, and adverse pregnancy outcomes (including preterm labor or PTL and multiple births) increases. [3] As women age, many opt for fertility treatment to improve their chance of conception. The effectiveness of various reproductive technologies declines steadily after the age of 35, while the risk of pregnancy complications and adverse outcome increases with both maternal age and the use of reproductive assistance. [4],[5] These pregnancy complications include ectopic pregnancy, spontaneous abortion, fetal chromosomal abnormalities, certain congenital anomalies, placenta previa, gestational diabetes, preeclampsia, multiple births, PTL, and cesarean section. These in turn are associated with an increased risk of preterm birth and perinatal and maternal mortality and morbidity. [6],[7],[8],[9],[10] Infants born preterm, especially multiples are at increased risk of morbidity, mortality, and long-term disability. In 2006, the fertility rate for women aged 30-34 was the highest of any age group, surpassing that of the previous highest group, women aged 25-29. [11] The percentage of first-time mothers who are >30 years of age increased steadily from 11% in 1987 to 26% in 2005. During the same period, there was a significant rise in first-time mothers >35 years of age, from 4% in 1987 to 11% in 2005, and a corresponding decrease in the group who are <25 years. Similar trends have been seen in other parts of the world. [12] Ovarian function declines as women approach their later reproductive years until menopause, and increasing age is associated with lowered fecundity and infertility. Women experience a decline in natural fertility that begins in the mid-30s and they will often reach sterility many years before the complete cessation of menses. [13] Although ART may aid some couples who present with fertility issues, it will not compensate for the decline in natural fertility that occurs with delayed childbearing. [3] ART is also invasive, expensive, and mostly not covered by health insurance plans. In addition, complications of pregnancy increase for both the mother and the offspring with advanced maternal age. [14] Women and their health-care providers should be aware of the effects of age on reproductive potential. There is also an age-related decline in sperm function and male fertility. There is also a decline in the testicular function, which includes a decline in testosterone levels in males. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased the frequency of some autosomal dominant conditions like autism spectrum disorders and schizophrenia. Men of more than 40 years of age and their partners should be counseled about these potential risks when they are seeking pregnancy, although the risks remain small.

  Ovarian Aging Top

In the last 10-15 years ahead of menopause, there is a rapid decline of ovarian function. However, recent data indicate that this decline of ovarian function is in a constant downward slope. Ovarian oocyte loss which starts in utero is a continuous process. At 20 weeks of pregnancy, approximately 6-7 million oocytes are found in female fetal ovaries, which decreases and comes down to 1-2 million postbirth and with the onset of puberty, only 300,000-500,000 oocytes are found remaining in the ovaries. [15] At menopause, only some hundreds of oocytes remain in the ovary, indicating that the loss of oocytes persists until ovarian functions come to a complete standstill. [16] Maximum numbers of oocytes are destroyed through programmed cell death called apoptosis, and merely 400-500 oocytes undergo ovulation during the reproductive phase of a woman. The process of decrease in oocytes starts around 38 years of age and hastens during the last 10-15 years prior to menopause, as per the early research findings. [17] However, as per more recent data, the rate of oocyte loss is similar throughout female reproductive phase and remains consistent until the onset of menopause. [18]

With the diminution of the ovarian follicular pool, women experience infertility, sterility, cycle shortening, menstrual irregularities, and finally menopause. [18] The mean age of menopause is the end of the 4 th decade, and about 1-2% women experiences premature ovarian failure or menopause before 40 years of age. Women undergoing earlier menopause suffer from earlier loss of fertility. [19] Hence, 10-15% women have decreased in their ovarian functions due to low ovarian reserve by mid-30s. Spontaneous childbearing usually ends 10 years before menopause and this period is consistent regardless of the age of menopause. [20],[21] Cycle irregularity may be the earlier sign of impending menopause and may start 6-7 years before actual menopause sets in.

With the decrease in the total number of follicles, there is corresponding decrease in the available follicular cohort. Subsequently, there is a decrease in inhibin-B production from the granulosa cells (GCs) in early follicular phase. Follicle-stimulating hormone (FSH) rises due to lack of the negative feedback by inhibin-B and this becomes the earliest signs of ovarian aging. [22] The clinical sign of ovarian aging may be shortening of the menstrual cycle, which may be due to shorter follicular phase. Once women start to experience or notice clinical signs of ovarian aging like cycle shortening or menstrual irregularities, their fertility may also be greatly diminished. The ovarian reserve markers usually detect premenopausal women, who do not yet have clinical signs or symptoms of ovarian aging, but who may already have decreased fertility. With menopause, a few hundred follicles remain in the ovaries. The ovarian activity is still there and there is also a production of estrogen by ovary during the 1 st year of menopause. [20] Sibling and twin studies have shown a significant genetic component to the menopausal age. [23] Smoking is also known to decrease the follicular pool, leading to early menopause. [20]

The oocyte quality also gets affected by age. Oocyte aneuploidy increases in elderly women. [24] Below the age of 35, aneuploidy rate is 10%, which increases to 30% and 40% at 40 years and 43 years of age, respectively, and about 100% above 45 years of age. [24] In gonadotropin (Gn)-stimulated cycles, the rate of aneuploidy in dominant follicle may not be apparent in comparison to that in a natural cycle. However, there is a correlation between the increase in chromosomal abnormality and spontaneous abortion in elderly women. Diminution in the quality of oocytes may be in the formation and function of meiotic spindles, which appear to be more diffuse in aging oocytes. [25] The diffuse formation of spindles may result in the formation of chromosomes which are not very tightly arranged, leading to meiotic division errors. In an advanced age with Gn stimulation, poor quality follicles may also become selected and many follicles mature, who otherwise may have undergone atresia, leading to a chromosomal abnormality.

  Assessment of Ovarian Aging Top

The onset of ovarian aging takes place long before women notice clinical changes in their menstrual cycles. Hence, ovarian reserve test (ORT) has become very important in assessing ovarian aging. The chronological age alone though serves as a good marker of ovarian reserve, some women face a decline in their natural fertility even at younger ages, though in some women the reverse is true. If the ovarian reserve is inconsistent with chronological age, identifying ovarian reserve may be of immense help in counseling and planning treatments. [26]

ORT, which nowadays has become a routine fertility workup, is considered to be a good predictor of ovarian response to stimulation. Among so many parameters of ORT, a woman's chronological age is one of the most significant determinants of both quality and quantity of follicular pool that reflects the ovarian reserve and her subsequent reproductive potential. A woman's ovarian response to stimulation is measured in terms of antral follicle counts (AFCs) and the total numbers of retrieved oocytes and these are considered to be the most standardized and fairly constant parameters of ORT compared to others. Anti-mullerian hormone (AMH), a glycoprotein, belonging to transforming growth factor family [27] is produced by the GCs of primary, preantral, and small antral follicles in the ovary and then secreted in blood, exerting inhibitory effects on the recruitment of primordial follicles, and response of growing follicles to FSH. [28] There are other parameters of assessing ovarian function, such as estimation of inhibin level, ovarian volume, and clomiphene challenge test. With more and more use of the former three tests, these parameters have become less useful.

The assessment of ovarian reserve, as per most studies, can predict a woman's ovarian response to fertility treatment, particularly in in vitro fertilization (IVF) program. This co-relates with the responses of ovarian stimulation and the oocyte quantity obtained and not oocyte quality. ORT performed before ART treatment has a poor predictive power for pregnancy. The AFCs and AMH are useful in predicting poor ovarian response with IVF. [19] Therefore, although these tests are useful for counseling women before ART treatment, poor results should not prevent women from receiving ART treatment and should not preclude the possibility of pregnancy. ORT is offered to women more than 35 years of age and below that provided there are risk factors such as single ovary, previous ovarian surgery, poor ovarian response to ovarian stimulation, and poor response to FSH, exposure to chemotherapy or radiation previously, or unexplained infertility. [29]

  Consequences of Delayed Childbearing Top

An increased risk of infertility, maternal comorbidity, pregnancy, birth complications, and rise in maternal and fetal morbidity and mortality all these factors are closely associated with delayed childbearing. All these risks are comparatively less in women who start family planning early, at 20 years of age and complete family by 35 years.

  Infertility Due to Advance Reproductive Age Top

Advanced maternal age

Declining birth rate begins when women are of 35 years of age. [13] In addition, conditions such as endometriosis and fibroids are found to be more frequent in women in later reproductive years, resulting in a reduction of their fertility potentials. Natural fertility studies indicate that fecundity rate in women after discontinuation of contraception is more in younger than elderly women. [30] Only 6% of women, who marry in the early 20s, remain childless, so as 64% of women remaining unmarried till 40 years of age. It has been shown that the percentage of women remaining childless is higher in those marrying later. [31] As social changes make women delay their reproduction, advances in fertility science opened increased options for fertility treatments and ART. Unfortunately, women of advanced age suffer from false optimism that they can delay pregnancy while pursuing education and career, with the expectation that newer methods will help them to conceive, if they face difficulties. However, the success rate of ART in women using their own eggs directly linked with the age of the women. [32] Many women do not realize that older women are successful in achieving pregnancy later in life only with donor eggs. It has been observed in donor insemination that younger women conceive quickly and more frequently than their older counterparts. A study of 3,000 cycles showed that women below 30 years of age had a cumulative pregnancy rate of 62% compared to 44% in women in their 30s or more than 30 years. In women of 35 years, pregnancy is achieved quickly following more cycles of treatment. [33],[34] Similarly, the pregnancy rate in ART treatment cycle shows a significant impact of female age on success. Age is the most important prognostic factor for the success of IVF.

Ovarian aging is a primary cause of age-related infertility due to diminishing ovarian follicular count. On the other hand, uterine endometrium retains normal capacity of implantation throughout a woman's reproductive years and even beyond that as proved by pregnancy with egg donation in postmenopausal women, indicating that endometrial response to hormones is not affected by age. [35] Pregnancy rates from donor egg cycle confirm that the recipient's age does not influence pregnancy rate in donor IVF cycle, even in postmenopausal women.

Advanced paternal age

Testicular hypofunction is one of the expressions in advanced paternal age. There may be a reduction in testicular volume and reduction in basal testosterone secretion gradually with advancing age. Sperm parameters including semen volume, motility, and morphology diminish with age. However, a decrease in sperm concentration has not been shown. [36]

Studies trying to describe the effects of male age on natural fertility often have not accounted for female age. One study suggested that the odds of conception diminish 3% per year. Other studies indicated that the effect of maternal age on natural monthly conception alone is small. [37],[38]

Many agents have been tried for improving sperm parameters for elderly men. These may be micronutrients, L-arginine, co-enzyme Q10, astaxanthin, keratinoid, etc. All these agents work probably as placebo. Antioxidants may be helpful in improving sperm functions but not count. If there is endocrinopathy like hypothyroidism, targeted therapy may be helpful. [39]

Most studies indicate that male age does not affect IVF or intracytoplasmic sperm injection (ICSI) pregnancy rates, despite lower motility and fertilization rates of male gametes. [40],[41] No difference has been observed in egg donation cycle as well. [42],[43] The effect of paternal age on the number of cleavage stage embryo is also small. [44] However, a significant decrease is noted in day 5 blastocyst formation and in the number of cryopreserved embryos. [45],[46] Recent studies suggest that advanced paternal age either alone or in combination with that of maternal age may increase the risk of Down syndrome. [47] Advanced paternal age does not influence spontaneous abortion or chromosomal abnormality rate when the effect of maternal age is excluded. Advanced paternal age has been associated with autosomal dominant disorders, such as Alport syndrome, achondroplasia, and neurofibromatosis. [48],[49],[50],[51],[52],[53]

  Treatment of Age-related Infertility Top

The aim of treatment in advanced age is to increase monthly fecundity and decrease the time to conception. If the duration of infertility is short, a small period of attempt of natural conception may be undertaken. On many occasions, it is found that in advanced age, men and women retain their fertilities more than what is expected. Otherwise, women may be offered ovarian stimulation with clomiphene citrate (CC) and ± Gn, or controlled ovarian hyperstimulation (COH) with the addition of LhRh-analog, followed by intrauterine insemination (IUI) in some cases, or IVF and embryo transfer mostly. These treatments are intended to increase the number of mature oocytes to balance the decrease in oocyte quality. Some adjuvants can be used, like addition of some forms of androgen and to improve oocyte quality with various effects as well. It is to be understood that age-related infertility due to declining egg quality is oocyte donation (OD), where IVF technology is to be undertaken to achieve pregnancy. Ovulation stimulation with CC followed by IUI in women between 38 and 40 years of age leads to a pregnancy rate of 7% and that of 41-42 years is 4%. However, women above 42 years have a pregnancy rate of merely 2%. [54] A small study of 130 cycles, where Gn was used, followed by IUI, showed a 6% live birth rate for women of 38-39 years of age and 2% for women above 40 years. [55] All live births occurred between the first or second cycle. Older women may consider one or two COH cycles if they want to try with IU as the first line of treatment. However, they should quickly shift to IVF, if unsuccessful within the first couple of cycles. [56]

IVF with controlled ovarian stimulation (COS) still offers higher pregnancy and live birth rates than COS with IUI, although the rate is significantly lower with OD. In 2007, one Canadian study indicated a live birth rate of 11.4% per cycle in women aged more than 40 years. [57] Another study showed that in women more than 42 years age, the live birth rate decreased to below 5%. [58] The miscarriage rate is also quite high in advanced age group of 47 years. IVF with OD offers a significant pregnancy rate in menopausal women or women with declining ovarian functions. The pregnancy rate in OD is related to the age of the donor and not of the recipient. [26],[59] Pregnancy and live birth have been reported in women in their 60s, [60] though the use of donor oocyte post-50 years of age is controversial. It is to be kept in mind that there is an increase in obstetric and maternal complications in advanced age, such as hypertension, prematurity, maternal death, fetal and neonatal death, and operative delivery. [8],[61],[62],[63] The arbitrary cutoff point for the age of OD is controversial. [64] Many clinicians believe that the natural menopausal age is the maximum age for offering OD.

  Maternal Age-related Risk in Conception Top

Chromosomal aneuploidy

The age-related errors largely due to dysfunction of meiotic spindles are associated with increased risk of nondisjunction, leading to unequal chromosomal products at the end of division. As a result, higher rate of aneuploid embryos is formed, which in turn raises spontaneous abortion rates and decreases the chances of successful pregnancy outcome. The estimate is that most oocytes may be aneuploid after 45 years of age. [6] With the exception of pregnancy achieved through ICSI, the incidence of chromosomal abnormality in pregnancy following ART treatment is similar to the rate of spontaneously conceived pregnancy. ICSI utilizes the sperms from subfertile men and this procedure itself is thought to raise the risk of chromosomal abnormalities in children conceived by this method. [65],[66] Hence, couples undergoing ICSI for male factor infertility should receive information and genetic counseling regarding the increased risk of chromosomal abnormalities. Prenatal diagnosis should also be offered to these couples if conceives. [66] Preimplantation genetic diagnosis with the transfer of chromosomally normal embryos is advocated to reduced risk of spontaneous abortion in elderly women and to avoid chromosomally abnormal births. It has been observed in contrary that if the aneuploid embryos selected out of this procedure, preimplantation genetic diagnosis for aneuploidy screening selection is proved ineffective in improving pregnancy outcomes in women aged 35-41 years. At present, this is not recommended for advanced maternal age only. [67],[68]

Gene abnormalities

The effect of advanced maternal age on genetic abnormalities, other than clinical areas of ART, is not well known. Epidemiologic studies suggested that there is a correlation between autism and advanced paternal and maternal ages. However, far more studies are required to understand this association. [69]

Congenital malformations

The risk of certain nonchromosomal birth defects increases with maternal age. Advanced maternal age between 25 and 40 years is associated with an increased risk of congenital heart defects, tricuspid atresia, club food, diaphragmatic hernia, hypospadias, and craniosynostosis. The incidence of structurally malformed infants increases progressively with maternal age. The OR for cardiac defects was 3.95 in infants of women above 40 years of age to those aged between 20 and 24 years. Overall, the additional age-related risk of nonchromosomal malformations was approximately 1% in women more than 35 years of age.

  Impact of Maternal Age on Pregnancy Outcome Top

The extensive literary survey is available despite the impact of advanced maternal age on pregnancy outcome. The increased risk of spontaneous abortions, ectopic pregnancy, placenta previa, [8],[63],[70] pregestational diabetes, eclampsia, [8],[61],[71] pregnancy-induced hypertension, [8] induction of labor, [8],[66],[72] and cesarean section [8],[70],[72] are prevalent in women more than 35 years of age, compared to their younger counterparts. Perinatal and neonatal death and stillbirth also increase with advancing maternal age. [72] The aging process also influences some of the obstetric complications, while others are related to coexisting factors such as multiple gestations, higher parity, hypertension, diabetes mellitus, and renal diseases that become more prevalent with advanced age. [8],[66],[70],[72] There is also a risk of increased instrumental delivery and cesarean section with increasing maternal age.

  Conclusion Top

With the advancement of the science and technology of fertility treatment, the hope of conceiving in advanced age is increasing. Physicians dealing with infertility problems are facing real challenges in improving conception rates, particularly after 40 years of female age. ART is one of the way-outs, but the success of homologous pregnancy is still far from satisfactory. Till today, a bypass technology like OD or surrogacy is the cornerstone of treatment of elderly couples.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Subrat P, Santa SA, Vandana J. The concepts and consequences of early ovarian ageing: A caveat to women′s health. J Reprod Infertil 2013;14:3-7.  Back to cited text no. 1
Jirge PR. Ovarian reserve tests. J Hum Reprod Sci 2011;4:108-13.  Back to cited text no. 2
[PUBMED]  Medknow Journal  
Leridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 2004;19:1548-53.  Back to cited text no. 3
Human Fertilisation and Embryology Authority. Facts and figures 2006: Fertility problems and treatment, October 2008. London: HEFA; 2010.  Back to cited text no. 4
Arthur. Pregnancy and motherhood: The biological clock. Sex Reprod Menopause 2006;4:3-6.  Back to cited text no. 5
Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet 1985;70:11-7.  Back to cited text no. 6
Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: Population based register linkage study. BMJ 2000;320:1708-12.  Back to cited text no. 7
Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol 2005;105(5 Pt 1):983-90.  Back to cited text no. 8
Storeide O, Veholmen M, Eide M, Bergsjø P, Sandvei R. The incidence of ectopic pregnancy in Hordaland County, Norway 1976-1993. Acta Obstet Gynecol Scand 1997;76:345-9.  Back to cited text no. 9
Luke B, Brown MB. Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. Fertil Steril 2007;88:283-93.  Back to cited text no. 10
Statistics Canada. The Daily. Ottawa: Statistics Canada; 26 September, 2008. Available from: http://www.statcan.gc.ca/daily-quotidien/080926/dq080926a-eng.htm. [Last accessed on 2011 Aug 31].  Back to cited text no. 11
Maher J, Macfarlane A. Trends in live births and birthweight by social class, marital status and mother′s age, 1976-2000. Health Stat Q 2004;23:34-42.  Back to cited text no. 12
Menken J, Trussell J, Larsen U. Age and infertility. Science 1986;233:1389-94.  Back to cited text no. 13
Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: Pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93:9-14.  Back to cited text no. 14
Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Biol Sci 1963;158:417-33.  Back to cited text no. 15
Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: Evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231-7.  Back to cited text no. 16
Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: Implications for forecasting menopause. Hum Reprod 1992;7:1342-6.  Back to cited text no. 17
Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: The decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 2008;23:699-708.  Back to cited text no. 18
Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: Mechanisms and clinical consequences. Endocr Rev 2009;30:465-93.  Back to cited text no. 19
te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002;8:141-54.  Back to cited text no. 20
Stein ZA. A woman′s age: Childbearing and child rearing. Am J Epidemiol 1985;121:327-42.  Back to cited text no. 21
Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ, Soules MR. Reproductive aging: Accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab 1996;81:1038-45.  Back to cited text no. 22
de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA, te Velde ER, et al. The role of genetic factors in age at natural menopause. Hum Reprod 2001;16:2014-8.  Back to cited text no. 23
Pellestor F, Andréo B, Arnal F, Humeau C, Demaille J. Maternal aging and chromosomal abnormalities: New data drawn from in vitro unfertilized human oocytes. Hum Genet 2003;112:195-203.  Back to cited text no. 24
Volarcik K, Sheean L, Goldfarb J, Woods L, Abdul-Karim FW, Hunt P. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: Evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 1998;13:154-60.  Back to cited text no. 25
Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685-718.  Back to cited text no. 26
Lukaszuk K, Ludwikowska B, Liss J, Kunicki M, Sawczak M, Lukaszuk A, et al. Decreasing quality of the new generations of anti-Müllerian hormone assays. Biomed Res Int 2014;2014:165352.  Back to cited text no. 27
Themmen AP. Anti-Müllerian hormone: Its role in follicular growth initiation and survival and as an ovarian reserve marker. J Natl Cancer Inst Monogr 2005;34:18-21.  Back to cited text no. 28
Practice Committee of the American Society for Reproductive Medicine. Aging and infertility in women. Fertil Steril 2006;86 5 Suppl 1:S248-52.  Back to cited text no. 29
Tietze C. Fertility after discontinuation of intrauterine and oral contraception. Int J Fertil 1968;13:385-9.  Back to cited text no. 30
Tietze C. Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957;8:89-97.  Back to cited text no. 31
Gunby J, Bissonnette F, Librach C, Cowan L; IVF Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (ART) in Canada: 2006 results from the Canadian ART register. Fertil Steril 2010;93:2189-201.  Back to cited text no. 32
Shenfield F, Doyle P, Valentine A, Steele SJ, Tan SL. Effects of age, gravidity and male infertility status on cumulative conception rates following artificial insemination with cryopreserved donor semen: Analysis of 2998 cycles of treatment in one centre over 10 years. Hum Reprod 1993;8:60-4.  Back to cited text no. 33
Virro MR, Shewchuk AB. Pregnancy outcome in 242 conceptions after artificial insemination with donor sperm and effects of maternal age on the prognosis for successful pregnancy. Am J Obstet Gynecol 1984;148:518-24.  Back to cited text no. 34
Noci I, Borri P, Chieffi O, Scarselli G, Biagiotti R, Moncini D, et al. I. Aging of the human endometrium: A basic morphological and immunohistochemical study. Eur J Obstet Gynecol Reprod Biol 1995;63:181-5.  Back to cited text no. 35
Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: A review of the literature. Fertil Steril 2001;75:237-48.  Back to cited text no. 36
Goldman N, Montgomery M. Fecundability and husband′s age. Soc Biol 1989;36:146-66.  Back to cited text no. 37
Ford WC, North K, Taylor H, Farrow A, Hull MG, Golding J. Increasing paternal age is associated with delayed conception in a large population of fertile couples: Evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum Reprod 2000;15:1703-8.  Back to cited text no. 38
Chatterjee S, Chowdhury RG, Khan B. Medical management of male infertility. J Indian Med Assoc 2006;104:74, 76-7.  Back to cited text no. 39
Spandorfer SD, Avrech OM, Colombero LT, Palermo GD, Rosenwaks Z. Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection. Hum Reprod 1998;13:334-8.  Back to cited text no. 40
Aboulghar M, Mansour R, Al-Inany H, Abou-Setta AM, Aboulghar M, Mourad L, et al. Paternal age and outcome of intracytoplasmic sperm injection. Reprod Biomed Online 2007;14:588-92.  Back to cited text no. 41
Gallardo E, Simón C, Levy M, Guanes PP, Remohí J, Pellicer A. Effect of age on sperm fertility potential: Oocyte donation as a model. Fertil Steril 1996;66:260-4.  Back to cited text no. 42
Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol 2001;184:818-22.  Back to cited text no. 43
Dain L, Auslander R, Dirnfeld M. The effect of paternal age on assisted reproduction outcome. Fertil Steril 2011;95:1-8.  Back to cited text no. 44
Luna M, Finkler E, Barritt J, Bar-Chama N, Sandler B, Copperman AB, et al. Paternal age and assisted reproductive technology outcome in ovum recipients. Fertil Steril 2009;92:1772-5.  Back to cited text no. 45
Frattarelli JL, Miller KA, Miller BT, Elkind-Hirsch K, Scott RT Jr. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil Steril 2008;90:97-103.  Back to cited text no. 46
Toriello HV, Meck JM; Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008;10:457-60.  Back to cited text no. 47
Orioli IM, Castilla EE, Scarano G, Mastroiacovo P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am J Med Genet 1995;59:209-17.  Back to cited text no. 48
North K. Neurofibromatosis type 1: Review of the first 200 patients in an Australian clinic. J Child Neurol 1993;8:395-402.  Back to cited text no. 49
Bunin GR, Needle M, Riccardi VM. Paternal age and sporadic neurofibromatosis 1: A case-control study and consideration of the methodologic issues. Genet Epidemiol 1997;14:507-16.  Back to cited text no. 50
Jadayel D, Fain P, Upadhyaya M, Ponder MA, Huson SM, Carey J, et al. Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 1990;343:558-9.  Back to cited text no. 51
Riccardi VM, Dobson CE 2 nd , Chakraborty R, Bontke C. The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations. Am J Med Genet 1984;18:169-76.  Back to cited text no. 52
Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: Evidence from osteogenesis imperfecta. J Med Genet 1986;23:227-30.  Back to cited text no. 53
Dovey S, Sneeringer RM, Penzias AS. Clomiphene citrate and intrauterine insemination: Analysis of more than 4100 cycles. Fertil Steril 2008;90:2281-6.  Back to cited text no. 54
Harris ID, Missmer SA, Hornstein MD. Poor success of gonadotropin-induced controlled ovarian hyperstimulation and intrauterine insemination for older women. Fertil Steril 2010;94:144-8.  Back to cited text no. 55
Tsafrir A, Simon A, Margalioth EJ, Laufer N. What should be the first-line treatment for unexplained infertility in women over 40 years of age - Ovulation induction and IUI, or IVF? Reprod Biomed Online 2009;19 Suppl 4:4334.  Back to cited text no. 56
Gunby J, Bissonnette F, Librach C, Cowan L; IVF Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (ART) in Canada: 2007 results from the Canadian ART register. Fertil Steril 2011;95:542-7.e1-10.  Back to cited text no. 57
Hourvitz A, Machtinger R, Maman E, Baum M, Dor J, Levron J. Assisted reproduction in women over 40 years of age: How old is too old? Reprod Biomed Online 2009;19:599-603.  Back to cited text no. 58
United States Centers for Disease Control and Prevention. 2005 Assisted Reproductive Technology Report; 2005. Available from: http://www.cdc.gov/ART/ART2005/section4.htm. [Last accessed on 2010 Apr 23].  Back to cited text no. 59
Paulson RJ, Thornton MH, Francis MM, Salvador HS. Successful pregnancy in a 63-year-old woman. Fertil Steril 1997;67:949-51.  Back to cited text no. 60
Jacobsson B, Ladfors L, Milsom I. Advanced maternal age and adverse perinatal outcome. Obstet Gynecol 2004;104:727-33.  Back to cited text no. 61
Simchen MJ, Yinon Y, Moran O, Schiff E, Sivan E. Pregnancy outcome after age 50. Obstet Gynecol 2006;108:1084-8.  Back to cited text no. 62
Joseph KS, Allen AC, Dodds L, Turner LA, Scott H, Liston R. The perinatal effects of delayed childbearing. Obstet Gynecol 2005;105:1410-8.  Back to cited text no. 63
Smajdor A. The ethics of egg donation in the over fifties. Menopause Int 2008;14:173-7.  Back to cited text no. 64
Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000;15:944-8.  Back to cited text no. 65
Allen VM, Wilson RD, Cheung A. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can 2006;28:220-50.  Back to cited text no. 66
Gianaroli L, Magli MC, Munné S, Fiorentino A, Montanaro N, Ferraretti AP. Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? Hum Reprod 1997;12:1762-7.  Back to cited text no. 67
Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007;357:9-17.  Back to cited text no. 68
Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: A review and integration of findings. Arch Pediatr Adolesc Med 2007;161:326-33.  Back to cited text no. 69
Hollier LM, Leveno KJ, Kelly MA, MCIntire DD, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol 2000;96(5 Pt 1):701-6.  Back to cited text no. 70
Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 2000;15:2433-7.  Back to cited text no. 71
Ozalp S, Tanir HM, Sener T, Yazan S, Keskin AE. Health risks for early (< or=19) and late (> or=35) childbearing. Arch Gynecol Obstet 2003;268:172-4.  Back to cited text no. 72


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Ovarian Aging
Assessment of Ov...
Consequences of ...
Infertility Due ...
Treatment of Age...
Maternal Age-rel...
Impact of Matern...

 Article Access Statistics
    PDF Downloaded324    
    Comments [Add]    

Recommend this journal