The outcome of Assisted Reproductive Technologies (ART) is profoundly influenced by patient age.
The ART Surveillance-United States (2000) published by the Centers for Disease Control (1) provided data on 99,629 procedures performed that year. The delivery rate for <35 years was 38%, 35-37 years was 33.0 %, 38-40 years was 24%, 41-42 years was 14.3 %, and >42 years was 6.0 %. Dew et al (2) reported on 779 patients and found that those over forty years of age had lower ovarian responses, fertilization rates, pregnancy rates and worse pregnancy outcomes. This general trend has been seen for the past 2-3 decades in ART. This, in general, is related to factors in the oocyte (egg) and how age affects them. In general, the miscarriage rate increases with age just as the risk of Down's Syndrome increases. Down's Syndrome is trisomy 21, where an extra chromosome 21 is present and is responsible for the condition. Recently pre-implantation genetic testing has been attempted to help improve outcome in the older patients undergoing ART.
The decline in pregnancy rates appears to correlate with increasing aneuploidy (abnormal chromosome number) rates in older patients. Munne et al (3) found that aneuploidy increased with maternal age in non-arrested embryos analyzed by FISH (fluorescent in situ hybridization) and that this may contribute to the lower pregnancy rates in older patients. Kuliev et al (4) analyzed 6733 human oocytes with FISH for pre-implantation diagnosis of age related aneuploidy by assessing the 1st and 2nd polar bodies for chromosomes 13, 16, 18, 21, and 22. They found 52.1 % of the oocytes were aneuploid. Overall 41.8 % of oocytes had meiosis I errors, 30.7 % had meiosis II errors, and 27.6 % had both meiotic division errors. Aneuploidy rates in cleavage stage embryos increased with age.
Marquez et al (5) found that 3.1 % of embryos in patients 20-34 years of age were aneuploidic compared to 17 % of embryos in patients 40 years of age or greater. Pellestor et al (6) examined 1397 unfertilized oocytes in IVF and found two mechanisms of non-disjunction in female meiosis. Whole chromosome non-disjunction and chromatid predivision contributed to anueploid oocytes. Groups E and G chromosomes had more non-disjunction than others, though non-disjunction was present in all groups. Munne et al (7) uses PGD to assess numerical abnormalities in older patients using single blastomere biopsy and FISH for several chromosomes (X,Y, 13, 15, 16, 18, 21,22, plus a ninth probe -1,7,14, or 17). When they replaced presumptively normal embryos on day 4 they had 19.2 % pregnancy rate compared to 8.8 % in the controls. PGD may therefore help with age related aneuploidy. Clearly, age affects the outcome of IVF through the increased incidence of chromosomally abnormal offspring.
The decreased ovarian response to stimulation is related to diminished ovarian reserve, essentially the depletion of follicles that normally occurs with age. A precipitous decline occurs after the age of 38. This may explain the increased requirement for gonadotropins (medicines typically used in IVF to produce multiple eggs) in this age group. While older patients have decreased implantation and pregnancy rates, oocyte donation has essentially normal pregnancy rates characteristic of younger women. This tells us that it is ovarian/oocyte factors more than endometrial factors that are paramount in the decreased outcome seen in older patients.
In summary, age is a major factor and the 'biological clock' is real.
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