|Year : 2016 | Volume
| 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 Submission||27-Apr-2016|
|Date of Acceptance||09-May-2016|
|Date of Web Publication||2-Jun-2016|
21, Bondel Road, Kolkata - 700 019, West Bengal
Source of Support: None, Conflict of Interest: None
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
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. , 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.  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. , 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. ,,,, 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.  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.  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.  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.  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.  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|| |
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.  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.  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.  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. 
With the diminution of the ovarian follicular pool, women experience infertility, sterility, cycle shortening, menstrual irregularities, and finally menopause.  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.  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. , 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.  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.  Sibling and twin studies have shown a significant genetic component to the menopausal age.  Smoking is also known to decrease the follicular pool, leading to early menopause. 
The oocyte quality also gets affected by age. Oocyte aneuploidy increases in elderly women.  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.  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.  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|| |
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. 
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  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.  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.  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. 
| Consequences of Delayed Childbearing|| |
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|| |
Advanced maternal age
Declining birth rate begins when women are of 35 years of age.  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.  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.  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.  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. , 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.  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. 
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. ,
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. 
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. , No difference has been observed in egg donation cycle as well. , The effect of paternal age on the number of cleavage stage embryo is also small.  However, a significant decrease is noted in day 5 blastocyst formation and in the number of cryopreserved embryos. , Recent studies suggest that advanced paternal age either alone or in combination with that of maternal age may increase the risk of Down syndrome.  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. ,,,,,
| Treatment of Age-related Infertility|| |
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%.  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.  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. 
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.  Another study showed that in women more than 42 years age, the live birth rate decreased to below 5%.  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. , Pregnancy and live birth have been reported in women in their 60s,  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. ,,, The arbitrary cutoff point for the age of OD is controversial.  Many clinicians believe that the natural menopausal age is the maximum age for offering OD.
| Maternal Age-related Risk in Conception|| |
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.  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. , 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.  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. ,
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. 
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|| |
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, ,, pregestational diabetes, eclampsia, ,, pregnancy-induced hypertension,  induction of labor, ,, and cesarean section ,, 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.  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. ,,, There is also a risk of increased instrumental delivery and cesarean section with increasing maternal age.
| Conclusion|| |
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.
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