The distribution of age-related aneuploidy (a type of chromosomal abnormality) is significantly higher in women over 40 years and can reach values of approximately 60% in women over 42. Considering that more than 50% of women seeking ART treatments are 35 years or older, and that the proportion of patients older than 40 is steadily increasing, this is cause for concern, the European Society of Human Reproduction and Embryology (ESHRE) heard today (Monday).
A recent study by the SISMER centre in Bologna used biopsies on polar bodies – the waste products produced by oocytes (eggs) during maturation – to show the extent of aneuploidy, caused by an incorrect separation of chromosomes, and that this was far more frequent in older women. “We could also see that some conditions of infertility such as endometriosis or the presence of a diminished ovarian reserve increased the incidence of chromosomal abnormalities and had greatly compromised oocyte viability,” said Dr. Luca Gianaroli, coordinator of the study and ESHRE chairman.
“The patient’s response to hormonal stimulation appears to influence the process of chromosome separation during oocyte maturation with a consequent negative effect on oocyte quality. Specialists in the field of assisted reproduction should be aware of these risk factors, and tailored protocols especially for ovarian stimulation should be available for all patients,” Dr. Gianaroli concluded. The study was based on more than 4,000 oocytes and demonstrated how the natural decrease in oocyte quality along with age is accelerated in women having an abnormal response to hormonal stimulation. In other words, a reduced sensitivity to the hormones regulating oocyte maturation is related to the quantity and quality of the collected oocytes and determines reduced pregnancy and implantation rates in poor responders, especially after the age of 35.
Many young women believe the scientific progress in ART can ensure motherhood at any age, but with the number and quality of eggs decreasing with age, the possibilities reproductive medicine can offer are limited. In the last 25 years fertility rates have been reduced by almost three-fold from 2.7 to 1.2 children per woman in Europe. In Italy a similar trend was observed. This trend is inversely related to the increase in mean age at first pregnancy, which is currently between 30 and 35 in Europe. The delay of the first pregnancy with a resulting increase in maternal age in Italy but also in other European countries is one of the main reasons of the increased difficulties in obtaining a viable pregnancy.
Many women delay the decision to have a child to pursue a career or because they simply have not found Mr. Right. However, after the age of 35 the chances of natural conception decrease substantially. “When the woman is 20-24 years old, 86% of these couples will conceive within a year of regular intercourse, this figure decreases to 42% when the woman is 40 years and older. This decrease in fertility caused by delaying pregnancy until the woman is older leads to many couples seeking ART,” said Dr. Filippo Ubaldi from the GENERA clinic in Rome. Scientific data indicate two crucial factors are responsible for this: a reduction in the number of available oocytes (the so called ovarian reserve) and a decline in the quality of the oocytes.
“Regardless of their age, between 20 and 25% or patients have poor ovarian response (POR) and to induce the growth of multiple follicles is a challenge and sometimes a frustrating problem,” said Dr. Ubaldi. POR is one of the most debated aspects of assisted reproduction and there has been controversies surrounding the variety of methods used to treat POR and the lack of an objective and clear definition of term ‘Poor Ovarian Response’. In fact, poor responders have a reduced chance of getting pregnant. As a consequence ESHRE gathered its 11 Special Interest Groups from all aspects in the field of assisted reproduction to discuss the definition of POR. A consensus was reached during the campus symposium in Bologna in March 2010 and all agreed that maternal age (>40 years) had a relevant impact on POR.
In the UK the number of women delivering after 40 years of age has increased two-fold in ten years and three-folds in the last twenty years. A similar trend was observed in Italy with 6% of babies born to women over 40 in 2008 compared with 2% in 1995. In the same period the age of women seeking ART treatments increased dramatically. The Italian national register reported to the ESHRE European IVF Monitoring Group that 19% of all ART cycles were performed in women aged 40 and older. “At our centre 75% of all female patients are 35 years and older, while 25% are above 40 years old,” said Dr. Gianaroli.
“As a consequence we expect the incidence of POR to increase as well,” said Dr. Ubaldi. “So far, a variety of different stimulation protocols have been suggested for poor responders, but the lack of any large-scale, prospective, randomized, controlled trials of the different management strategies and the fact that there are too many heterogeneous groups of patients, do not allow us to draw any definite conclusions.” Dr. Ubaldi and colleagues are currently looking at natural cycles of IVF as an alternative to the usual stimulation protocols that have often delivered disappointing results. The group hopes that natural cycles may be an easy and cheap alternative in the approach to poor responding patients who usually receive much more complex and demanding stimulation protocols.
Several published papers have reported clinical pregnancy rates per embryo transfer of between 14% and 18%. In this group of patients the pregnancy rate also decreased with increasing age. The most important drawback of natural cycle IVF is the need for counselling since the chances of obtaining an embryo for transfer are estimated to be approximately 50% at each initiated cycle. “Considering the average pregnancy rate per embryo transfer of 14%, the patient needs to be clearly informed about the possibility that 50% of cycles can fail and that a 7% pregnancy rate per embryo transfer is more realistic,” concluded Dr. Ubaldi.
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