**3.2. Ageing uterus**

In addition to changes observed in the ovarian reserve and quality of the oocytes, the uterus is an essential organ to achieve pregnancy. As in any other human organ, ageing also has an effect on the uterus of fertile women. Even though it is difficult to evaluate these changes in humans, animal studies indicate that older mice show an impaired artificially induced decidual response, probably due to reduced progesterone secretion [17–19]. Microscopic changes have also been confirmed, with more hyperaemia and higher vascular development and growth of the myometrium and stroma of young hamsters in comparison with the older ones [20]. Older mothers are also more likely to experience intrapartum complications and the rate of caesarean delivery is higher, suggesting that myometrial function is impaired by advanced maternal age [21]. The risk of stillbirth in mothers over the age of 40 is twice as high as younger mothers due to foetal chromosomal abnormalities, multiple pregnancy, obesity, pre-eclampsia, insulin-dependent diabetes, and multiple pregnancy [21, 22]. These evidences suggest that changes in the uterus in older women may have a reflection on fertility and the ability of maintaining a pregnancy.

## **3.3. Chromosomal abnormalities**

Women who delay childbearing are at an increased risk of foetal chromosomal abnormalities. This occurs as a consequence of an error in chromosomal disjunction during maternal meiosis I or II, which has been reported as more frequent in advanced age women [23–25]. Among them, numeric chromosomal abnormalities seem to be more frequent than structural chromosomal abnormalities. Chromosomal aneuploidies related to maternal age include trisomy 21, trisomy 18, trisomy 13, triple X syndrome, and Klinefelter syndrome [26]. A recent study highlights that trisomy 21 showed an incidence rate of 11.34 out of 1000 cases at the age of 35 years, 15.41 cases at the age of 40, and 37.04 cases at the age of 45. In addition, trisomy 18 showed an incidence rate of 1.89 out of 1000 cases at the age of 35 years, 5.14 cases at the age of 40, and 37.04 cases at the age of 45. Nowadays, prenatal diagnostic techniques such as ultrasound and cell-free foetal DNA test allow professionals to make an early screening for foetal aneuploidy. However, invasive techniques remain the gold standard for definitive diagnosis, with a risk of miscarriage *per se* of 0.35% (CI 95%: 0.07 to 0.63) following amniocentesis and 0.35% (95% CI: -0.31 to 1.00) following chorionic villus sampling [27].
