Emilie Derisoud

Juliette Auclair-Ronzaud

Eric Palmer

Morgane Robles

Pascale Chavatte- Palmer

Female age and parity in horses: how and why does it matter?

Although puberty can occur as soon 14-15 months of age, depending on their breed and use, the reproductive career of mares may start up to advanced age. Once mares are used as broodmares, they will usually produce foals once a year until they become unfertile, and their production can be enhanced and/or prolonged through embryo technologies. There is a general consensus that old mares become less fertile, but maternal age and parity are confounding factors as younger mares are usually nulliparous and older mares are multiparous in most studies. This review shows that age essentially affects cyclicity, folliculogenesis, oocyte and embryo quality as well as oviductal masses and uterine tract function. Maternal parity has a non-linear effect. Primiparity has a major influence on placental and foal development, with smaller foals in first gestation that remain smaller postnatally. After the first gestation, endometrial quality and uterine clearance capacities progressively decline with increasing parity, whilst placental and foal birthweight and milk production increase. These combined

effects should be carefully weighed when breeding mares, in particular when choosing and caring for recipients and their foals.

Introduction

Horses and ponies are mainly bred for athletic performance and leisure (mainly ponies and warmblood horses), some being also used for meat production (mainly draft horses). For sport and leisure, the length of a horse's athletic career varies depending on the discipline, but also on performance and health. For instance, Thoroughbreds are usually trained for flat races, being allowed to compete until 4 years of age, while trotters compete from 2 to 7-8 years of age. In show jumping, dressage, however, horses are commonly competing past 15 years of age while for leisure, they may still be ridden after 20. Although puberty can occur as soon 14-15 months of age if this age happens during the breeding season [START_REF] Driancourt | Some interactions of season of foaling, photoperiod and ovarian activity in the equine[END_REF], the reproductive career of mares may start at different ages after completing their performance. In contrast, draft mares, similar to cattle, are usually bred at an early age.

Unlike in other farm animal production schemes, a horse breeder may have several reasons to produce foals from old mares: i) the mare previously produced valuable foals, ii) the mare's performances and/or genetic or sentimental value is important, iii) the mare is fertile. There are many old mares in breeding farms. In Canada and Finland, 37% and 53% of Standardbred mares, respectively, were reported to be older than 10 (Physick-Sheard 1995; [START_REF] Katila | A 15-year survey of reproductive efficiency of Standardbred and Finnhorse trotters in Finland -descriptive results[END_REF]. In a retrospective study of 3373 Thoroughbred broodmares in UK, 54% were older than 8 and 4% older than 18 [START_REF] Allen | Reproductive efficiency of Flatrace and National Hunt Thoroughbred mares and stallions in England[END_REF]. In Spain, a survey on 296 Thoroughbred mares showed that mean age at first foaling in was 6.88, that mares produced a mean of 5.47 foals, with a mean time from last foaling to death of 18 months and a total reproductive career of 10.93 years in average [START_REF] Hevia | Reproductive performance of thoroughbred horses in Spain[END_REF]. Moreover, in Finland, 63% of Finn horse mares are older than 10 at insemination [START_REF] Katila | A 15-year survey of reproductive efficiency of Standardbred and Finnhorse trotters in Finland -descriptive results[END_REF].

Regardless of breed and for a long time, many studies have shown that mares' embryo recovery [START_REF] Pascoe | Effect of endometrial pathology on the success of non-surgical embryo transfer[END_REF][START_REF] Vogelsang | Influence of donor parity and age on the success of commercial equine embryo transfer[END_REF][START_REF] Ball | Survival of Day-4 embryos from young, normal mares and aged, subfertile mares after transfer to normal recipient mares[END_REF][START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF][START_REF] Uliani | Effect of mare breed and age on embryo transfer efficiency[END_REF][START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF][START_REF] Marinone | The effect of mare's age on multiple ovulation rate, embryo recovery, post-transfer pregnancy rate, and interovulatory interval in a commercial embryo transfer program in Argentina[END_REF]Cuervo-Arango et al. 2019b), fertility [START_REF] Ball | Pregnancy rates at Days 2 and 14 and estimated embryonic loss rates prior to day 14 in normal and subfertile mares[END_REF][START_REF] Woods | Early pregnancy loss in brood mares[END_REF][START_REF] Barbacini | Equine frozen semen: results obtained in Italy during the 1994-1997 period[END_REF][START_REF] Morris | Reproductive efficiency of intensively managed Thoroughbred mares in Newmarket[END_REF][START_REF] Samper | Analysis of some factors associated with pregnancy rates of frozen semen: a multi-center study[END_REF][START_REF] Allen | Reproductive efficiency of Flatrace and National Hunt Thoroughbred mares and stallions in England[END_REF][START_REF] Bosh | Impact of reproductive efficiency over time and mare financial value on economic returns among Thoroughbred mares in central Kentucky[END_REF][START_REF] Benhajali | Factors influencing conception rates of Arab mares in Tunisia[END_REF][START_REF] Sharma | Reproductive efficiency of Thoroughbred mares under Indian subtropical conditions: A retrospective survey over 7 years[END_REF][START_REF] Hanlon | Reproductive performance of Thoroughbred mares in the Waikato region of New Zealand: 1. Descriptive analyses[END_REF][START_REF] Haadem | A retrospective cohort study on fertility in the Norwegian Coldblooded trotter after artificial insemination with cooled, shipped versus fresh extended semen[END_REF][START_REF] Lane | Key Factors Affecting Reproductive Success of Thoroughbred Mares and Stallions on a Commercial Stud Farm[END_REF][START_REF] Kareskoski | Analysis of factors affecting the pregnancy rate of mares after inseminations with cooled transported stallion semen[END_REF] or foaling rates [START_REF] Hutton | Reproductive Efficiency on Fourteen Horse Farms[END_REF][START_REF] Jeffcott | An assessment of wastage in Thoroughbred racing from conception to 4 years of age[END_REF][START_REF] Gibbs | A field study on reproductive efficiency of mares maintained predominately on native pasture[END_REF][START_REF] Mcdowell | Effect of book size and age of mare and stallion on foaling rates in thoroughbred horses[END_REF][START_REF] Baker | The live foaling rate per cycle in mares[END_REF][START_REF] Brück | Reproductive performance of Thoroughbred mares on six commercial stud farms[END_REF][START_REF] Morley | A survey of reproductive performance in Thoroughbred mares and morbidity , mortality and athletic potential of their foals[END_REF][START_REF] Vidament | Equine frozen semen: freezability and fertility field results[END_REF][START_REF] Hemberg | Reproductive Performance of Thoroughbred Mares in Sweden[END_REF][START_REF] Allen | Reproductive efficiency of Flatrace and National Hunt Thoroughbred mares and stallions in England[END_REF][START_REF] Katila | A 15-year survey of reproductive efficiency of Standardbred and Finnhorse trotters in Finland -descriptive results[END_REF][START_REF] Sharma | Reproductive efficiency of Thoroughbred mares under Indian subtropical conditions: A retrospective survey over 7 years[END_REF][START_REF] Nath | Reproductive efficiency of Thoroughbred and Standardbred horses in north-east Victoria[END_REF][START_REF] Haadem | A retrospective cohort study on fertility in the Norwegian Coldblooded trotter after artificial insemination with cooled, shipped versus fresh extended semen[END_REF] decrease with maternal age, due to increased embryo and fetal mortality [START_REF] Bain | Foetal losses during pregnancy in the thoroughbred mare: A record of 2,562 pregnancies[END_REF][START_REF] Platt | Aetiological aspects of abortion in the thoroughbred mare[END_REF][START_REF] Pascoe | Effect of endometrial pathology on the success of non-surgical embryo transfer[END_REF][START_REF] Woods | Recent studies relating to early embryonic death in the mare[END_REF][START_REF] Ball | Survival of Day-4 embryos from young, normal mares and aged, subfertile mares after transfer to normal recipient mares[END_REF][START_REF] Chevalier-Clément | Pregnancy loss in the mare[END_REF][START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF][START_REF] Gibbs | A field study on reproductive efficiency of mares maintained predominately on native pasture[END_REF][START_REF] Baker | The live foaling rate per cycle in mares[END_REF][START_REF] Brück | Reproductive performance of Thoroughbred mares on six commercial stud farms[END_REF][START_REF] Morley | A survey of reproductive performance in Thoroughbred mares and morbidity , mortality and athletic potential of their foals[END_REF][START_REF] Morris | Reproductive efficiency of intensively managed Thoroughbred mares in Newmarket[END_REF][START_REF] Hemberg | Reproductive Performance of Thoroughbred Mares in Sweden[END_REF][START_REF] Allen | Reproductive efficiency of Flatrace and National Hunt Thoroughbred mares and stallions in England[END_REF][START_REF] Bosh | Impact of reproductive efficiency over time and mare financial value on economic returns among Thoroughbred mares in central Kentucky[END_REF][START_REF] Uliani | Effect of mare breed and age on embryo transfer efficiency[END_REF][START_REF] Sharma | Reproductive efficiency of Thoroughbred mares under Indian subtropical conditions: A retrospective survey over 7 years[END_REF][START_REF] Panzani | Factors Affecting Recipients' Pregnancy, Pregnancy Loss, and Foaling Rates in a Commercial Equine Embryo Transfer Program[END_REF][START_REF] De Mestre | Multivariable analysis to determine risk factors associated with early pregnancy loss in thoroughbred broodmares[END_REF][START_REF] Malheiros De Souza | Age-dependent effect of foal heat breeding on pregnancy and embryo mortality rates in Thoroughbred mares[END_REF]. The age of oocyte donors, however, does not appear to affect blastocyst production [START_REF] Altermatt | Effects of age and equine folliclestimulating hormone (eFSH) on collection and viability of equine oocytes assessed by morphology and developmental competency after intracytoplasmic sperm injection (ICSI)[END_REF] nor gestation rate after oocyte transfer [START_REF] Carnevale | Factors affecting the success of oocyte transfer in a clinical program for subfertile mares[END_REF]). In addition, several studies did not observe any difference in mare fertility related to maternal age [START_REF] Mccue | 177 Live foal rate: effects of embryo transfer and donor mare age[END_REF][START_REF] Uliani | Effect of mare breed and age on embryo transfer efficiency[END_REF][START_REF] Avci | The influence of insemination time, age and semen dose on fertility of mares inseminated with frozen semen[END_REF][START_REF] Pérez-Marín | Embryo recovery results in Hispano-Arabe horse and Spanish donkey breeds[END_REF][START_REF] Malheiros De Souza | Age-dependent effect of foal heat breeding on pregnancy and embryo mortality rates in Thoroughbred mares[END_REF][START_REF] Carluccio | Effect of age and of reproductive status on reproductive indices in horse mares carrying mule pregnancies[END_REF]. These discrepancies on the effect of mare age on fertility could be due to the difficulty to define at what age a mare will experience reproductive aging. Indeed, there is a great variation in fertility decline depending on individuals, breeds, mare management, farms and thus, according to studies.

The analysis of 35,746 fertility records in mixed breeds in France showed that mares' fertility was the highest from 4 to 6 years of age and then decreased gradually to become almost zero at 25-26 [START_REF] Langlois | Statistical analysis of some factors affecting the number of horse births in France[END_REF]. This study also calculated that if a decline of 10% of her highest fertility was chosen as a cutoff value to stop a broodmare's breeding career, then mares older than 8 should not be bred anymore [START_REF] Langlois | Statistical analysis of some factors affecting the number of horse births in France[END_REF]. Similarly, a progressive decline in fertility with age was described in Thoroughbred mares, starting from 75% fertility at 4 years of age (Figure 1) [START_REF] Jeffcott | An assessment of wastage in Thoroughbred racing from conception to 4 years of age[END_REF]. In a Brazilian study, analysis of 11 years lactating Thoroughbreds' fertility data showed that the threshold for embryo mortality to remain above average was 10 years of age (Malheiros de [START_REF] Malheiros De Souza | Age-dependent effect of foal heat breeding on pregnancy and embryo mortality rates in Thoroughbred mares[END_REF].

Therefore, if fertility was the only criterion for keeping a broodmare, as in other farm animal breeding, mares older than 10 should be culled, which would also increase genetic progress [START_REF] Chavatte-Palmer | Contribution of reproduction management and technologies to genetic progress in horse breeding[END_REF]. Nevertheless, this is not the case as breeders will continue breeding as long as they can produce a foal from their favorite mare(s). Thus, treatments to improve older mares' fertility are part of routine practice for veterinarians.

As sport career is prioritized in Warmbloods, it is common to see nulliparous mares (mares that did not previously foal, also known as maiden mares) bred at old age. Indeed, nulliparous mares older than 10 years of age have been shown to represent 20.5% of Finn horse and 15.5% of Standardbred bred mares in Finland [START_REF] Katila | A 15-year survey of reproductive efficiency of Standardbred and Finnhorse trotters in Finland -descriptive results[END_REF]. In farm animals and draft horses, maternal age is highly correlated with parity, as defined, for an individual mare, as the number of her pregnancies that reached a viable gestational age, stillbirths and live birth included. Indeed, younger animals have given birth to less offspring than older dams. In equine studies, this is mainly also true, especially when animals dedicated to equine research studies are used.

The effects of parity alone on fertility, embryo recovery, embryo/fetal mortality rates and term birth have been studied but results are controversial. Only one study reported a detrimental effect of mares' nulliparity on pregnancy rate and only when using frozen semen (35% pregnancy rate per cycle in 155 maiden mares versus 53% and 54% in 94 barren and 174 foaling mares, respectively) [START_REF] Squires | Retrospective study of factors affecting fertility of fresh, cooled and frozen semen[END_REF]). This detrimental effect seems to be due to older nulliparous mares as an important number of mares were older than 7, whereas in papers showing no effect, maiden mares were between 3 and 5 years old [START_REF] Brück | Reproductive performance of Thoroughbred mares on six commercial stud farms[END_REF]. Similar observations on reduced fertility in maiden mares older than 8 have also been reported by others [START_REF] Samper | Analysis of some factors associated with pregnancy rates of frozen semen: a multi-center study[END_REF]. In terms of embryo development, while some did not find any effect of parity [START_REF] Platt | Aetiological aspects of abortion in the thoroughbred mare[END_REF][START_REF] Chevalier-Clément | Pregnancy loss in the mare[END_REF][START_REF] Gibbs | A field study on reproductive efficiency of mares maintained predominately on native pasture[END_REF][START_REF] Vidament | Equine frozen semen: freezability and fertility field results[END_REF][START_REF] Morris | Reproductive efficiency of intensively managed Thoroughbred mares in Newmarket[END_REF][START_REF] Langlois | Statistical analysis of some factors affecting the number of horse births in France[END_REF][START_REF] Hanlon | Reproductive performance of Thoroughbred mares in the Waikato region of New Zealand: 1. Descriptive analyses[END_REF][START_REF] Panzani | Factors Affecting Recipients' Pregnancy, Pregnancy Loss, and Foaling Rates in a Commercial Equine Embryo Transfer Program[END_REF], others showed that mares that did not previously foal are more productive with lower embryo and fetal mortality compared to multiparous mares [START_REF] Baker | The live foaling rate per cycle in mares[END_REF][START_REF] Brück | Reproductive performance of Thoroughbred mares on six commercial stud farms[END_REF]; [START_REF] Barbacini | Equine frozen semen: results obtained in Italy during the 1994-1997 period[END_REF][START_REF] Hemberg | Reproductive Performance of Thoroughbred Mares in Sweden[END_REF][START_REF] Nath | Reproductive efficiency of Thoroughbred and Standardbred horses in north-east Victoria[END_REF][START_REF] Hanlon | Reproductive performance of Thoroughbred mares in the Waikato region of New Zealand: 1. Descriptive analyses[END_REF][START_REF] Carluccio | Effect of age and of reproductive status on reproductive indices in horse mares carrying mule pregnancies[END_REF].

Moreover, when embryos collected from nulliparous mares were transferred in commercial embryo transfer programs, the pregnancy rate increased and the abortion rate decreased [START_REF] Vogelsang | Influence of donor parity and age on the success of commercial equine embryo transfer[END_REF]) compared to embryos collected from other mares. In most of these latter studies, however, mainly young mares were used. In studies where donors were mostly old and nulliparous at the same time, however, fertility was decreased [START_REF] Samper | Analysis of some factors associated with pregnancy rates of frozen semen: a multi-center study[END_REF][START_REF] Katila | A 15-year survey of reproductive efficiency of Standardbred and Finnhorse trotters in Finland -descriptive results[END_REF]).

As described above, maternal age and parity in horses have been shown to affect reproductive efficiency. Reproductive efficiency is dependent of oocyte, embryo and uterine quality as well as maternal ability to carry out gestation. Those factors are known in other species to possibly also affect long term offspring health [START_REF] Watkins | Impact of the periconceptional environment on the programming of adult disease[END_REF][START_REF] Duranthon | Long term effects of ART: What do animals tell us?[END_REF].

In a first approach, it would seem logical that age would affect ovary and oocyte quality primarily, while parity could affect the reproductive tract and feto-placental development. Nevertheless, these effects need to be studied thoroughly. Thus, the aim of this review is first to focus on the known effects of mares' age and parity on ovarian environment, oocyte and embryo development and to summarize effects of maternal age and parity on gestation, placental and fetal development, as well as long-term effects on the offspring. Since almost no studies on the effects of maternal age used the same comparison groups, the authors decided to use the words "old" and "young" to represent the oldest or youngest groups in a study, respectively. The precise age categories for each study cited below are represented in the various summary tables.

Ovary and the estrus cycle (Table 1)

Follicular reserve

As for other mammals, mares are born with a set number of primordial follicles, that varies between individuals [START_REF] Driancourt | Seasonal effects on ovarian follicular development in pony mares[END_REF][START_REF] Monniaux | The Ovarian Reserve of Primordial Follicles and the Dynamic Reserve of Antral Growing Follicles: What Is the Link?1[END_REF]. Starting around 1 year of age, mares' oocytes are released from the follicle during ovulation or degraded by atresia [START_REF] Ginther | Reproductive biology of the mare : basic and applied aspects[END_REF]. Therefore, the number of available follicles declines with aging (Carnevale, Bergfelt et al. 1993;[START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF][START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF][START_REF] Claes | The interrelationship between anti-Müllerian hormone, ovarian follicular populations and age in mares: Anti-Müllerian hormone and ovarian follicular populations[END_REF][START_REF] Claes | The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares[END_REF][START_REF] Alves | Preantral follicle density in ovarian biopsy fragments and effects of mare age[END_REF]Cuervo-Arango et al. 2019b;[START_REF] Goncalves | Influence of age and ovarian antral follicle count on the reproductive characteristics of embryo donor mares[END_REF]. Even if "menopause" per se does not apply to horses, because mares do not menstruate, ovarian activity is reduced after 15 years of age [START_REF] Wesson | Influence of Season and Age on Reproductive Activity in Pony Mares on the Basis of a Slaughterhouse Survey[END_REF] and is not observed anymore in an average 17% pony and Saddlebred mares over 20 [START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF][START_REF] Carnevale | Aging effects on follicular activity and concentrations of FSH, LH, and progesterone in mares[END_REF]. It has been suggested that at 25 years of age, mares have consumed all their available oocyte stock [START_REF] Ginther | Reproductive biology of the mare : basic and applied aspects[END_REF]. For several mammals, antral follicle counts (AFC), related to ovarian reserve, are predicted by anti-Müllerian hormone (AMH) serum concentrations, a granulosa-cell-derived hormone (for review, [START_REF] Visser | Anti-Müllerian hormone and folliculogenesis[END_REF]. For horses, the measurement of AMH serum concentration has been shown to predict mare fertility [START_REF] Ball | Relationship between anti-Müllerian hormone and fertility in the mare[END_REF]. While in old mares the correlation between AFC and AMH is strong, it appears weaker in young mares [START_REF] Claes | The interrelationship between anti-Müllerian hormone, ovarian follicular populations and age in mares: Anti-Müllerian hormone and ovarian follicular populations[END_REF][START_REF] Uliani | Anti-Müllerian hormone and ovarian aging in mares[END_REF][START_REF] Korkmaz | The Correlation Between Anti-Müllerian Hormone Concentrations and Reproductive Parameters in Different Age Groups in Purebred Arabian Mares[END_REF].

Estrus cycle and follicular waves

Mares are seasonal breeders with a long day breeding season [START_REF] Burkhardt | Transition from anoestrus in the mare and the effects of artificial lighting[END_REF][START_REF] Nishikawa | Studies on reproduction in horses. Singularity and artificial control in reproductive phenomena[END_REF]. The breeding period is shorter in pony mares younger than 5 [START_REF] Wesson | Influence of Season and Age on Reproductive Activity in Pony Mares on the Basis of a Slaughterhouse Survey[END_REF] and delayed in ponies over 15 years old [START_REF] Wesson | Influence of Season and Age on Reproductive Activity in Pony Mares on the Basis of a Slaughterhouse Survey[END_REF] and in mares at 20 years of age [START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF][START_REF] Carnevale | Age and pasture effects on vernal transition in mares[END_REF]. During the reproductive season, mares' reproductive cycle lasts in average 21 days [START_REF] Nishikawa | Studies on reproduction in horses. Singularity and artificial control in reproductive phenomena[END_REF]. Mares older than 20-year-old have been shown to have a longer interovulatory interval due to prolonged follicular growth but without changes in luteal phase length [START_REF] Ginther | DELAY IN EMERGENCE OF THE OVULATORY FOLLICULAR WAVE IN OLD MARES[END_REF][START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF][START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF]Carnevale, Bergfelt et al. 1993;[START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF][START_REF] Carnevale | Aging effects on follicular activity and concentrations of FSH, LH, and progesterone in mares[END_REF][START_REF] Marinone | The effect of mare's age on multiple ovulation rate, embryo recovery, post-transfer pregnancy rate, and interovulatory interval in a commercial embryo transfer program in Argentina[END_REF][START_REF] Claes | The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares[END_REF]). One explanation for this prolonged follicular growth is that, at the time of luteolysis, older mares have smaller follicles [START_REF] Wesson | Influence of Season and Age on Reproductive Activity in Pony Mares on the Basis of a Slaughterhouse Survey[END_REF][START_REF] Ginther | DELAY IN EMERGENCE OF THE OVULATORY FOLLICULAR WAVE IN OLD MARES[END_REF][START_REF] Carnevale | Age and pasture effects on vernal transition in mares[END_REF]). In addition, the follicular wave emerges later [START_REF] Ginther | DELAY IN EMERGENCE OF THE OVULATORY FOLLICULAR WAVE IN OLD MARES[END_REF] and with less follicles in old mares than in younger [START_REF] Ginther | DELAY IN EMERGENCE OF THE OVULATORY FOLLICULAR WAVE IN OLD MARES[END_REF][START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF]. This is associated with a reduction in the ovulatory follicle growth in oldest mares (Carnevale, Bergfelt et al. 1993;Ginther et al. 2008;[START_REF] Altermatt | Effects of FSH and LH on ovarian and follicular blood flow, follicular growth and oocyte developmental competence in young and old mares[END_REF].

Hormonal profiles prior to ovulation

As demonstrated in other species, such as cows or women, age-related differences are associated with a higher follicle stimulating hormone (FSH) plasma concentration in older mares (Carnevale, Bergfelt et al. 1993;[START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF][START_REF] Claes | The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares[END_REF]. Two studies have also shown that maximal luteinizing hormone (LH) plasma concentration is reduced in mares older than 10 years of age [START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF][START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF] while another one only finds a difference when mares were older than 20 compared to younger mares (Carnevale, Bergfelt et al. 1993). In humans, the increased FSH plasma concentration and the less pronounced peak of LH plasma concentration, that is also observed in mares, is thought to be an early sign of reproductive aging [START_REF] Carnevale | The mare model for follicular maturation and reproductive aging in the woman[END_REF]. Furthermore, FSH upregulation is responsible for the recruitment of more follicles per wave than required, which is accelerating the reduction of follicle number [START_REF] Davis | Menopause[END_REF]. Subsequently, the reduction in follicle number induces a decreased ovarian production of hormones such as estradiol or inhibin, leading to a reduced hypothalamic pituitary axis inhibitory feedback. The effect of mares' aging on estradiol plasma concentrations is controversial: one study reported that mares younger than 10 years have a higher maximum concentration of estradiol [START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF]) while others did not find any difference according to age [START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF]). In any case, improper feedback leads to a gradual dysregulation of circulating gonadotropins concentration.

Ovulation

Hormonal perturbations are expected to alter the ovulation process, although studies show contradictory results. Mare's age was reported to be negatively correlated with follicular size prior to ovulation [START_REF] Carnevale | Age and pasture effects on vernal transition in mares[END_REF][START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF][START_REF] Morel | Factors affecting pre-ovulatory follicle diameter in the mare: the effect of mare age, season and presence of other ovulatory follicles (multiple ovulation)[END_REF][START_REF] Mata | Investigating follicle growth, uterine oedema and other factors affecting reproductive success in the Lusitano[END_REF]) but other studies did not demonstrate any association (Carnevale, Bergfelt et al. 1993;[START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF][START_REF] Claes | The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares[END_REF]. In terms of ovulation, an almost 40 years old study based on veterinarian responses to a survey indicated that maternal age does not seem to influence multiple ovulation rate [START_REF] Ginther | Twinning in mares: a survey of veterinarians and analyses of theriogenology records[END_REF]). Nevertheless, more recent studies showed that multiple ovulation rates continuously increase until mares reach around 20 years of age (Davies [START_REF] Morel | Ovulation rate and distribution in the thoroughbred mare, as determined by ultrasonic scanning: the effect of age[END_REF][START_REF] Morel | The effect of age on multiple ovulation rates, multiple pregnancy rates and embryonic vesicle diameter in the mare[END_REF][START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF][START_REF] Marinone | The effect of mare's age on multiple ovulation rate, embryo recovery, post-transfer pregnancy rate, and interovulatory interval in a commercial embryo transfer program in Argentina[END_REF] and subsequently decrease [START_REF] Morel | The effect of age on multiple ovulation rates, multiple pregnancy rates and embryonic vesicle diameter in the mare[END_REF][START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF]. Follicular vascularization, as measured by Doppler ultrasonography, has been shown to be greater in old compared to younger mares. This may be partly due to the altered LH secretion or follicular sensitivity and could therefore be the result of differences in the timing of follicular maturation between ages [START_REF] Altermatt | Effects of FSH and LH on ovarian and follicular blood flow, follicular growth and oocyte developmental competence in young and old mares[END_REF].

Induction of ovulation

Reproductive cycle alterations in old mares also interfere with the response to induction of ovulation. Indeed, more mares over 16 years of age were shown to fail to ovulate 48 hours after human Chorionic Gonadotropin (hCG) injection compared to younger mares [START_REF] Barbacini | Retrospective study on the efficacy of hCG in an equine artificial insemination programme using frozen semen[END_REF]. This could actually be due to immunization against hCG in older mares. The ovulatory response to deslorelin acetate implant was shown to be reduced in mares older than 20 [START_REF] Farquhar | Efficacy of the gnrh agonist deslorelin acetate for inducing ovulation in mares relative to age of mare and season[END_REF], but the data are moderately convincing because ovulation rates were very similar to the other groups, with a limited number of mares.

Luteal phase

After ovulation, the ruptured follicle develops as corpus luteum (CL) and starts producing progesterone [START_REF] Stabenfeldt | Ovarian Activity During the Estrous Cycle of the Mare[END_REF]. Luteal phase plasma progesterone concentrations are increased in reproductively active old mares although the threshold age to observe this increase varies from one study to another (Carnevale, Bergfelt et al. 1993;[START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF][START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF][START_REF] Claes | The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares[END_REF]. Old mares' CL were shown to undergo structural remodeling (increased luteal volume that compensates a reduced luteal vascularization) enabling the maintenance of progesterone production [START_REF] Ferreira | Luteal vascularity and embryo dynamics in mares during early gestation: Effect of age and endometrial degeneration[END_REF].

In summary, mare's age affects the ovarian cycle of the mare with altered cycle regularity and reduced number of ovulatory cycles in very old mares (>18-20), accompanied with reduced AMH concentrations, indicating a declining follicular reserve. Nevertheless, signs of reduced ovarian activity may appear as early as 15 years of age. Together with increasing FSH concentrations, age induces a higher incidence of multiple ovulations.

To the authors' knowledge, the effects of mare parity have not been studied.

Follicular organization, oocytes and embryos (Table 2)

Follicular organization

In addition to the reduced number of follicles observed in old mares described above, these follicles are less likely to be morphologically regular in terms of shape and number of granulosa cell layers surrounding the oocyte [START_REF] Alves | Preantral follicle density in ovarian biopsy fragments and effects of mare age[END_REF]. Mares' age has also been shown to affect the expression of genes involved in mitochondrial function, receptors of metabolic hormones, inflammatory processes, steroids and tissue remodeling in granulosa cells, all of which could impair fertility (Sessions-Bresnahan and Carnevale 2015).

Changes in gene expression in the granulosa cells may also impair follicular fluid composition. Although plasma concentrations of ovarian steroids are not affected by mares' age, insulin-like growth factor 1 (IGF-1) concentrations in follicular fluid are higher in old compared to young mares [START_REF] Ginther | Effects of age on follicle and hormone dynamics during the oestrous cycle in mares[END_REF]. The analysis of follicular fluid's exosomes and microvesicles reveals an effect of maternal age on miRNAs, suggesting an altered communication between granulosa cells and oocyte in old mares [START_REF] Da Silveira | Cell-Secreted Vesicles in Equine Ovarian Follicular Fluid Contain miRNAs and Proteins: A Possible New Form of Cell Communication Within the Ovarian Follicle[END_REF][START_REF] Da Silveira | Effects of age on follicular fluid exosomal microRNAs and granulosa cell transforming growth factor-β signalling during follicle development in the mare[END_REF]. Interestingly, the addition of follicular fluid from old mares in in vitro oocyte maturation medium tended to improve horse blastocyst development compared to follicular fluid of young mares [START_REF] Spacek | Impact of Equine and Bovine Oocyte Maturation in Follicular Fluid From Young and Old Mares on Embryo Production in Vitro[END_REF].

Oocyte morphology

The effect of maternal age on general morphology of immature and mature oocytes is controversial: some studies failed to observe any differences [START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF][START_REF] Carnevale | Comparison of oocytes from young and old mares with light and electron microscopy[END_REF][START_REF] Frank | Association of equine oocyte and cleavage stage embryo morphology with maternal age and pregnancy after intracytoplasmic sperm injection[END_REF] while others observed different characteristics (irregular shape, irregularities in organelle distribution in the cytoplasm) in oocytes from old mares associated with development failure [START_REF] Carnevale | Factors affecting the success of oocyte transfer in a clinical program for subfertile mares[END_REF][START_REF] Altermatt | Effects of age and equine folliclestimulating hormone (eFSH) on collection and viability of equine oocytes assessed by morphology and developmental competency after intracytoplasmic sperm injection (ICSI)[END_REF]). Moreover, using light microscopy, a larger incidence of oocyte abnormalities such as large cytoplasmic vesicles was described in old mares compared to young mares, which is also a sign of cell development defect [START_REF] Carnevale | Comparison of oocytes from young and old mares with light and electron microscopy[END_REF].

Oocyte quality

If effects of age on oocyte morphology do not seem obvious, oocyte developmental potential is clearly affected by maternal age. Indeed, old mares' oocytes have been shown to have four times less chance to reach metaphase II after in vitro maturation compared to oocytes from young mares [START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF], suggesting that maternal age affects oocyte quality. During in vivo development, the quantitative and temporal expression of several genes essential for oocyte maturation differs according to maternal age, suggesting an age-related desynchronization during oocyte maturation [START_REF] Campos-Chillon | Effects of aging on gene expression and mitochondrial DNA in the equine oocyte and follicle cells[END_REF]. In cumulus-oocytes complexes, moreover, maternal age alters the expression of 48 genes identified in humans to be related to maternal aging and aneuploidy, which may be associated to the reduced developmental competence observed in old mares' oocytes [START_REF] Cox | Expression profiles of select genes in cumulus-oocyte complexes from young and aged mares[END_REF]. After in vitro maturation (IVM), predisposition to chromosome misalignment on the metaphase II spindle have been observed in oocytes from old mares [START_REF] Rizzo | Advanced mare age impairs the ability of in vitro-matured oocytes to correctly align chromosomes on the metaphase plate[END_REF], possibly linked to a weakened centromeric cohesion of spindle [START_REF] Rizzo | The horse as a natural model to study reproductive aging-induced aneuploidy and weakened centromeric cohesion in oocytes[END_REF], as confirmed by the reduced expression of Mono Polar Spindle 1 kinase (MPS1) in IVM oocytes from old mares leading to meiotic spindle instability, which could in return predispose to poorer chromosome segregation [START_REF] Rizzo | Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability[END_REF]. Loss of cohesion and poor spindle stability induce premature and poor separation of sister chromatids during the end of the first meiotic division, conducive to embryonic aneuploidy (Rizzo et al. 2019[START_REF] Rizzo | The horse as a natural model to study reproductive aging-induced aneuploidy and weakened centromeric cohesion in oocytes[END_REF][START_REF] Rizzo | Compromised MPS1 Activity Induces Multipolar Spindle Formation in Oocytes From Aged Mares: Establishing the Horse as a Natural Animal Model to Study Age-Induced Oocyte Meiotic Spindle Instability[END_REF]. Surprisingly, the vitrification of oocytes is more deleterious for young mares' compared to old mares' oocytes [START_REF] Ducheyne | Vitrifying immature equine oocytes impairs their ability to correctly align the chromosomes on the MII spindle[END_REF]. Authors hypothesize that, in old mares, mechanisms related to spindle are already compromised before vitrification, limiting impacts of vitrification on oocyte quality in old mares [START_REF] Ducheyne | Vitrifying immature equine oocytes impairs their ability to correctly align the chromosomes on the MII spindle[END_REF].

High numbers of mitochondria are present in the oocyte, and their number and activity have been described to decline with age in women (for review [START_REF] Van Der Reest | Mitochondria: Their relevance during oocyte ageing[END_REF]. In equine, oocyte mtDNA copy numbers were shown to be decreased in old mare oocytes, while in young mares, they remains stable during in vitro [START_REF] Rambags | Advancing maternal age predisposes to mitochondrial damage and loss during maturation of equine oocytes in vitro[END_REF] or in vivo maturation [START_REF] Campos-Chillon | Effects of aging on gene expression and mitochondrial DNA in the equine oocyte and follicle cells[END_REF]. One study, however, did not observe any difference according to maternal age but reduced metabolic function and capacity in oocytes and day-2 embryos originating from oocytes of old when compared to young mares. In mature oocytes, however, mtDNA was quantified by real-time PCR and was not different between the age groups [START_REF] Catandi | Equine maternal aging affects oocyte lipid content, metabolic function and developmental potential[END_REF]. Nevertheless, in this study, the abundance of free fatty acids was reduced in old mares' oocytes and developmental capacity was impaired, suggesting that mitochondrial copy numbers may not be indicative of mitochondrial function [START_REF] Catandi | Equine maternal aging affects oocyte lipid content, metabolic function and developmental potential[END_REF]. After in vitro maturation but not before, old mares' oocytes mitochondria display more swelling and less cristae compared to controls, suggesting a predisposition to mitochondrial degeneration with aging [START_REF] Rambags | Advancing maternal age predisposes to mitochondrial damage and loss during maturation of equine oocytes in vitro[END_REF]. In contrast, others reported that maternal aging does not affect ATP content nor the expression of selected genes involved in mitochondria replication and function in oocytes [START_REF] Hendriks | Maternal age and in vitro culture affect mitochondrial number and function in equine oocytes and embryos[END_REF].

Fertilisation

Fertilization does not seem to be impaired by maternal age as the number of embryos collected via oviductal flushing at Day 2 post ovulation is similar between young, fertile mares and old, subfertile mares [START_REF] Ball | Pregnancy rates at Days 2 and 14 and estimated embryonic loss rates prior to day 14 in normal and subfertile mares[END_REF]. Cytoskeleton differences at fertilization between oocytes from young and old mares, however, are observed. On one hand, in vitro sperm-injected oocytes from younger mares present more microtubule multiasters related to oocyte activation [START_REF] Ruggeri | Cytoskeletal alterations associated with donor age and culture interval for equine oocytes and potential zygotes that failed to cleave after intracytoplasmic sperm injection[END_REF]. On the other hand, oocytes from older mares present more actine vesicles, indicating an age-related cytoskeletal remodeling [START_REF] Ruggeri | Cytoskeletal alterations associated with donor age and culture interval for equine oocytes and potential zygotes that failed to cleave after intracytoplasmic sperm injection[END_REF]. How these differences affect embryo development remains unknown. Using either artificial insemination, oocyte or Day 4 embryo transfer into young recipient mares, less pregnancies are obtained when donor mares are old [START_REF] Ball | Pregnancy rates at Days 2 and 14 and estimated embryonic loss rates prior to day 14 in normal and subfertile mares[END_REF][START_REF] Ball | Survival of Day-4 embryos from young, normal mares and aged, subfertile mares after transfer to normal recipient mares[END_REF][START_REF] Carnevale | Defective Oocytes as a Cause of Subfertility in Old Mares[END_REF][START_REF] Carnevale | Factors affecting the success of oocyte transfer in a clinical program for subfertile mares[END_REF]. Conversely, in most studies, maternal age is not shown to affect the number of in vitro blastocysts produced from oocytes [START_REF] Altermatt | Effects of age and equine folliclestimulating hormone (eFSH) on collection and viability of equine oocytes assessed by morphology and developmental competency after intracytoplasmic sperm injection (ICSI)[END_REF]Cuervo-Arango et al. 2019a;b) although some authors find different results [START_REF] Catandi | Equine maternal aging affects oocyte lipid content, metabolic function and developmental potential[END_REF]). It appears, therefore, that age of the mare leads to oocyte deficiency by altering its developmental competency but that oocyte environmental manipulation, such as in vitro maturation, may partly reduce the deleterious effects of mare age.

Embryo development

Effects of maternal age on embryo morphology are not clear. At various developmental stages after in vivo or in vitro development, some studies showed that embryos from old mares are smaller [START_REF] Woods | Recent studies relating to early embryonic death in the mare[END_REF][START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF][START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF][START_REF] Willmann | Effects of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early-pregnant mares[END_REF][START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF][START_REF] Ferreira | Luteal vascularity and embryo dynamics in mares during early gestation: Effect of age and endometrial degeneration[END_REF], while others do not observed any difference in size [START_REF] Carnevale | The mare model for follicular maturation and reproductive aging in the woman[END_REF]Ginther 1992, 1995;[START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF][START_REF] Morel | The effect of age on multiple ovulation rates, multiple pregnancy rates and embryonic vesicle diameter in the mare[END_REF][START_REF] Frank | Association of equine oocyte and cleavage stage embryo morphology with maternal age and pregnancy after intracytoplasmic sperm injection[END_REF][START_REF] Derisoud | Maternal age affects equine Day 8 embryo gene expression both in trophoblast and inner cell mass[END_REF]. At Day 1.5 post ovulation, in vivo oviductal embryos have the same number of cells regardless of the mare's age although, when embryos are recovered from old mares, cells are less uniform (size and texture) and present more imperfections and abnormalities [START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF]. At Day 3 post ovulation, in addition to the poorer morphology, embryo cell number is reduced in old mares [START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF]. Conversely, at Day 2 and 4 post ovulation, other studies did not find any difference related to maternal age for diameter, number, size or texture of blastomeres in in vivo oviductal embryos [START_REF] Ball | Pregnancy rates at Days 2 and 14 and estimated embryonic loss rates prior to day 14 in normal and subfertile mares[END_REF][START_REF] Ball | Survival of Day-4 embryos from young, normal mares and aged, subfertile mares after transfer to normal recipient mares[END_REF]. In in vitro produced embryos, the number of blastomeres was reduced on Day 1 post intra-cytoplasmic sperm injection (ICSI) but not any more on Day 2 [START_REF] Altermatt | Effects of age and equine folliclestimulating hormone (eFSH) on collection and viability of equine oocytes assessed by morphology and developmental competency after intracytoplasmic sperm injection (ICSI)[END_REF]). On Day 7 to day 10 post ovulation, uterine in vivo embryos collected during commercial embryo transfer program are smaller [START_REF] Woods | Recent studies relating to early embryonic death in the mare[END_REF][START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF]. Poorer embryo quality was also reported in one study [START_REF] Woods | Recent studies relating to early embryonic death in the mare[END_REF] but not the other [START_REF] Panzani | Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program[END_REF]. In vitro, ICSI produced embryos from young and old mare oocytes had comparable blastomere size, ooplasm fragments and membrane extrudates at 24h post-ICSI [START_REF] Frank | Association of equine oocyte and cleavage stage embryo morphology with maternal age and pregnancy after intracytoplasmic sperm injection[END_REF]. At the time of transfer, however, embryos from mares older than 20 years old had a higher cell count [START_REF] Frank | Association of equine oocyte and cleavage stage embryo morphology with maternal age and pregnancy after intracytoplasmic sperm injection[END_REF]. In another study, after 7 days of culture, blastocysts derived from Day 2 in vivo embryos collected in old mares were smaller with less cells and had a poorer quality score than the ones collected in young mares [START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF]. As for oocytes, these data suggest that in vitro production of embryos may at least partially erase deleterious effects of maternal aging, maybe due to the low efficiency of the technique.

In terms of gene expression, differences observed in oocytes are also found in embryos. Indeed, in Day 2 in vitro produced embryos derived from oocytes of old mares, metabolic function and capacity were also reduced, as observed directly in oocytes [START_REF] Catandi | Equine maternal aging affects oocyte lipid content, metabolic function and developmental potential[END_REF]. In Day 7 embryos recovered from old mares, a reduced quantity of mitochondrial DNA copy number, representing the number of mitochondria, is observed, while genomic DNA, representing the number of cells, remains stable, indicating that embryos from old mares have fewer mitochondria per cell [START_REF] Hendriks | Maternal age and in vitro culture affect mitochondrial number and function in equine oocytes and embryos[END_REF], which can compromise preimplantation development. A recent study from our laboratory showed that in Day 8 blastocysts, maternal age affects the expression of genes related to mitosis, translation and transcription, cell signaling and adhesion, mitochondrial function and cell commitment, which may affect further embryo development [START_REF] Derisoud | Maternal age affects equine Day 8 embryo gene expression both in trophoblast and inner cell mass[END_REF].

Subsequently, maternal age appears to impact embryo mobility and day of fixation although studies are controversial. One recent study showed that embryo mobility is prematurely reduced in old mares without affecting the day of fixation [START_REF] Ferreira | Luteal vascularity and embryo dynamics in mares during early gestation: Effect of age and endometrial degeneration[END_REF]. Conversely, an older study shows that embryo mobility is not affected by maternal age although fixation of embryos from old mares occurs one day later compared to embryos from young mares [START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF].

Finally, in a study looking exclusively at embryo recipients of different ages, the age of the recipient did not affect initial pregnancy rates up to 15-18 years of age but embryo loss between first pregnancy diagnosis and D50 was 20.5% in mares aged from 10 to 18 versus 13.3% in younger mares [START_REF] Carnevale | Factors affecting pregnancy rates and early embryonic death after equine embryo transfer[END_REF]. This latter observation may be due to endometrial ageing, as discussed in the following section.

In summary, despite some discrepancies in the literature, there are clear effects of mare age on follicle, oocyte and embryo quality. Disturbed gene expression was observed in old mares' granulosa cells, among which genes involved in immunity and inflammation. Both oocyte morphology and quality are disturbed in older mares, including alterations of oocyte spindle stability that could lead to embryo aneuploidy, altered gene expression, reduced mitochondrial DNA copy numbers, all leading to reduced oocyte developmental potential and altered cell numbers and metabolism in the embryo. Indeed, although fertilization rates appear to be globally similar between young and older mares, development to the blastocyst stage is in general reduced in mares older that 16, together with reduced embryo diameter and an increased incidence of morphological abnormalities.

The little data available for effects of parity do not indicate any effect.

The reproductive tract: oviducts, uterus and cervix (Table 3) Oviduct Fertilization and early embryo development take place in the oviducts and the oviductal environment may be affected by maternal age. Old mares' oviducts have a higher risk of developing fibrosis compared to young mares [START_REF] Pinto-Bravo | Is mare endometrosis linked to oviduct fibrosis?[END_REF]. Collagen type 3 gene, related to endometrial fibrosis, is less expressed in oviducts of mares older than 10-year-old [START_REF] Pinto-Bravo | Is mare endometrosis linked to oviduct fibrosis?[END_REF].

Moreover, macroscopic structures now known as fibroblast masses have been reported in horse oviducts [START_REF] Niekerk | Persistence and parthenogenetic cleavage of tubal ova in the mare[END_REF][START_REF] Onuma | Retention of tubal eggs in mares[END_REF][START_REF] Liu | Clinical observations of oviductal masses in the mare[END_REF]). Cells from ovaries initiate masses formation, most likely due to degenerated unfertilized oocytes and cumulus cells. These masses are not identified in oviducts from prepubertal mares and maternal age is positively correlated with the number of masses observed on oviduct [START_REF] Aguilar | Living fibroblast cells in the oviductal masses of mares[END_REF]. They could interfere with fertilization and/or migration of the ova, spermatozoids or the embryo and be a potential cause of infertility (Zent et al. 1993).

Using electrophoresis, a 25 year old study identified a relatively comparable protein composition in in vitro secretions from cultured oviductal epithelial cells collected from old and subfertile or young and fertile mares, although 9 non-identified proteins were less abundant in old mares' oviductal secretions, suggesting that oviductal environment may be partly responsible for failure to sustain embryo development in older animals [START_REF] Brinsko | Characterization of polypeptides synthesized and secreted by oviductal epithelial cell explants obtained from young, fertile and aged, subfertile mares[END_REF]. When embryos are co-cultured with oviductal epithelial cells from young fertile versus old and subfertile mares, however, no difference in blastocyst development rate was observed, although young mares' Day 7 blastocysts were bigger and with a higher quality score when co-cultured with oviductal cells from young and fertile mares [START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF].

Uterus -uterine cysts and vascularization

After 5-6 days in the oviduct, the embryo induces its own passage in the uterus at the late morula/early blastocyst stage [START_REF] Weber | Prostaglandin E2 secretion by oviductal transport-stage equine embryos[END_REF][START_REF] Weber | Prostaglandin E2-specific binding to the equine oviduct[END_REF][START_REF] Weber | Relaxatory Effect of Prostaglandin E2 on Circular Smooth Muscle Isolated from the Equine Oviductal Isthmus1[END_REF]. Maternal age and parity have been shown to induce degenerative changes in the uterus. Indeed, uterine cysts covering a large uterine surface are commonly observed in old and multiparous mares [START_REF] Adams | Effect of uterine inflammation and ultrasonically-detected uterine pathology on fertility in the mare[END_REF][START_REF] Chevalier-Clément | Pregnancy loss in the mare[END_REF][START_REF] Bracher | Videoendoscopic evaluation of the mare's uterus: II. Findings in subfertile mares[END_REF][START_REF] Eilts | Prevalence of Endometrial Cysts and Their Effect on Fertility[END_REF][START_REF] Tannus | Influence of Endometrial Cysts on Conception Rate of Mares[END_REF][START_REF] Ferreira | Uterine blood flow and perfusion in mares with uterine cysts: effect of the size of the cystic area and age[END_REF]. The effect of cysts on pregnancy rates are controversial before and after implantation [START_REF] Adams | Effect of uterine inflammation and ultrasonically-detected uterine pathology on fertility in the mare[END_REF][START_REF] Eilts | Prevalence of Endometrial Cysts and Their Effect on Fertility[END_REF][START_REF] Tannus | Influence of Endometrial Cysts on Conception Rate of Mares[END_REF]. It has been demonstrated that cysts could prevent embryo movements in the uterus while this movement is mandatory for maternal recognition of pregnancy in horses [START_REF] Mcdowell | Restricted conceptus mobility results in failure of pregnancy maintenance in mares[END_REF]. Cysts might also interfere with embryo fixation and implantation. Furthermore, a larger cystic area is positively correlated with reduced vascular perfusion in the uterus [START_REF] Ferreira | Uterine blood flow and perfusion in mares with uterine cysts: effect of the size of the cystic area and age[END_REF].

In old and multiparous mares with uterine cysts, gravid uterine perfusion is reduced [START_REF] Ousey | Uterine haemodynamics in young and aged pregnant mares measured using Doppler ultrasonography: Uterine haemodynamics in mares[END_REF]. When cysts are not present, however, the perfusion of old or young multiparous uteri is similar [START_REF] Ferreira | Uterine blood flow and perfusion in mares with uterine cysts: effect of the size of the cystic area and age[END_REF] although uterine artery resistance is increased [START_REF] Bollwein | Transrectal color Doppler sonography of the arteria uterina in cyclic mares[END_REF]. Regardless of cysts, vascular alterations are observed in early gestation in old compared to young mares [START_REF] Ferreira | Effect of age and endometrial degenerative changes on uterine blood flow during early gestation in mares[END_REF]. Decreased uterine perfusion has been associated with elastosis, characterized as increased presence of elastic fibers [START_REF] Esteller-Vico | Effects of vascular elastosis on uterine blood flow and perfusion in anesthetized mares[END_REF]. Frequent angiosclerotic lesions, such as mild to moderate perivascular and intimal sclerosis, are observed in old multiparous mares [START_REF] Grüninger | Incidence and morphology of endometrial angiopathies in mares in relationship to age and parity[END_REF]. Furthermore, both an hyperplasia of intimal elastic fibers, related to elastosis, and a thinning of the medial smooth musculature, have been observed in uterine arteries as mares become older [START_REF] Oikawa | Microscopical characteristics of uterine wall arteries in barren aged mares[END_REF][START_REF] Nambo | Age-related Morphometrical Changes of Arteries of Uterine Wall in Mares[END_REF] or parity increases [START_REF] Esteller-Vico | Uterine vascular degeneration is present throughout the uterine wall of multiparous mares. Colinearity between elastosis, endometrial grade, age and parity[END_REF]. One study showed that vascular degeneration is clearly related to the number of previous foaling and not to the mares' age [START_REF] Esteller-Vico | Uterine vascular degeneration is present throughout the uterine wall of multiparous mares. Colinearity between elastosis, endometrial grade, age and parity[END_REF].

Uterus -endometrial degenerative changes

Most studies showed that severe endometrial changes are more frequent in endometrial biopsies from old and/or multiparous mares in comparison to biopsies from young and/or nulliparous mares [START_REF] Ricketts | Endometrial biopsy as a guide to diagnosis of endometrial pathology in the mare[END_REF][START_REF] Doig | The Use of Endometrial Biopsy in the Infertile Mare[END_REF][START_REF] Waelchli | Endometrial biopsy in mares under nonuniform breeding management conditions: Prognostic value and relationship with age[END_REF][START_REF] Ricketts | The effect of age and parity on the development of equine chronic endometrial disease[END_REF][START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF][START_REF] Grüninger | Incidence and morphology of endometrial angiopathies in mares in relationship to age and parity[END_REF][START_REF] Woodward | Susceptibility to persistent breeding-induced endometritis in the mare: Relationship to[END_REF][START_REF] Esteller-Vico | Uterine vascular degeneration is present throughout the uterine wall of multiparous mares. Colinearity between elastosis, endometrial grade, age and parity[END_REF], 2015;[START_REF] Ferreira | Effect of age and endometrial degenerative changes on uterine blood flow during early gestation in mares[END_REF]. Only one study did not find any differences according to age [START_REF] Annandale | Influence of cycle stage, age and endometrial biopsy score on oxytocin receptor distribution and gene expression in the cervix and uterus of non-pregnant mares[END_REF]. Observed changes were related to inflammatory and fibrotic modifications [START_REF] Kenney | Cyclic and pathologic changes of the mare endometrium as detected by biopsy, with a note on early embryonic death[END_REF] with severity of uterine fibrosis being positively correlated with mares' age [START_REF] Doig | The Use of Endometrial Biopsy in the Infertile Mare[END_REF][START_REF] Siemieniuch | Advanced age in mares affects endometrial secretion of arachidonic acid metabolites during equine subclinical endometritis[END_REF]. Moreover, the height of the lining and glandular endometrium epithelium's stratum compactum is less variable between estrus and diestrus [START_REF] Dubrovskaya | Comparative histomorphological characteristics of the endometrium of young and aged mares in estrus and diestrus[END_REF] in old compared to younger mares. In addition, fewer and larger uterine glands are present in old mares' endometrium, both in estrus and diestrus [START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF][START_REF] Dubrovskaya | Comparative histomorphological characteristics of the endometrium of young and aged mares in estrus and diestrus[END_REF], with more extensive inflammatory cell infiltrations and fibrotic changes [START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF].

Parity in young mares does not seem to influence the ultrastructure of the endometrium [START_REF] Tunón | Ultrastructure of the secretory endometrium during oestrus in young maiden and foaled mares[END_REF]. In contrast, old maiden mares also develop endometrial degenerative changes [START_REF] Ricketts | The effect of age and parity on the development of equine chronic endometrial disease[END_REF], suggesting that maternal aging is mostly responsible for these degenerative changes, over semen challenge, infection, pregnancy, parturition and post-partum involution [START_REF] Ricketts | The effect of age and parity on the development of equine chronic endometrial disease[END_REF][START_REF] Esteller-Vico | Uterine vascular degeneration is present throughout the uterine wall of multiparous mares. Colinearity between elastosis, endometrial grade, age and parity[END_REF].

Endometritis

For old mares, a higher incidence of endometritis has been demonstrated in old compared to young mares [START_REF] Adams | Effect of uterine inflammation and ultrasonically-detected uterine pathology on fertility in the mare[END_REF][START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF][START_REF] Barbacini | Equine frozen semen: results obtained in Italy during the 1994-1997 period[END_REF][START_REF] Woodward | Susceptibility to persistent breeding-induced endometritis in the mare: Relationship to[END_REF] whereas mare primiparity does not affect the prevalence of endometritis [START_REF] Barbacini | Equine frozen semen: results obtained in Italy during the 1994-1997 period[END_REF].

Delayed uterine clearance [START_REF] Leblanc | Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis[END_REF]) and endometrial degeneration [START_REF] Troedsson | Correlations between histologic endometrial lesions in mares and clinical response to intrauterine exposure with Streptococcus zooepidemicus[END_REF] are identified factors in mares with endometritis. In old mares, uterine clearance is reduced [START_REF] Evans | Factors affecting uterine clearance of inoculated materials in mares[END_REF], resulting in an increased incidence of intrauterine fluid retention [START_REF] Woodward | Susceptibility to persistent breeding-induced endometritis in the mare: Relationship to[END_REF].

Uterine clearance is facilitated by uterine contractility, which is also reduced and inconsistent in old mares [START_REF] Carnevale | Relationships of age to uterine function and reproductive efficiency in mares[END_REF][START_REF] Ferreira | Luteal vascularity and embryo dynamics in mares during early gestation: Effect of age and endometrial degeneration[END_REF]. Moreover, uterine clearance is facilitated by a good uterine position [START_REF] Leblanc | Differences in uterine position of reproductively normal mares and those with delayed uterine clearance detected by scintigraphy[END_REF]. Increased parity contributes to a more ventral position of the uterus that could impair uterine clearance [START_REF] Leblanc | Differences in uterine position of reproductively normal mares and those with delayed uterine clearance detected by scintigraphy[END_REF]. Cervical dilation is a key factor for a good uterine clearance [START_REF] Leblanc | Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis[END_REF]. Nulliparous mares have poorer cervical dilation, and it was suggested that old nulliparous are more likely to develop endometriosis as a result of the combination of altered cervical dilation and uterine conformation and as well as increased incidence of pneumovagina [START_REF] Leblanc | Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis[END_REF]. The only study comparing uterine fluids according to mare age and parity showed that although mare age does not affect uterine fluid total protein concentration in healthy mares, the concentration of one protein (not precisely identified but with a molecular weight ranging from 60 to 71kDa, possibly albumin) is higher in the uterine fluid of young compared to old mares [START_REF] Tunón | Concentrations of total protein, albumin and immunoglobulins in undiluted uterine fluid of gynecologically healthy mares[END_REF]. Mare parity, however, did not affect the composition of uterine fluids [START_REF] Tunón | Concentrations of total protein, albumin and immunoglobulins in undiluted uterine fluid of gynecologically healthy mares[END_REF]).

In addition to the impaired uterine clearance, old mares have also a longer vulva [START_REF] Pascoe | Observations on the length and angle of declination of the vulva and its relation to fertility in the mare[END_REF], which represents a larger entrance for bacteria and could explain why bacteria counts are increased in old compared to younger mare uteri [START_REF] Evans | Factors affecting uterine clearance of inoculated materials in mares[END_REF]. A recent study showed an impairment of the expression of genes involved in local uterine immune response in old mares (Crociati et al. 2019 p. 201). Studying endometrial tissue cultures from mares affected by subclinical endometritis, an increased production of prostaglandin E2 (PGE2), 6-oxoprostaglandin F1alpha (6-keto-PGF1a) and leukotriene C4 (LTC4) is observed in old mares in comparison to younger mares [START_REF] Siemieniuch | Advanced age in mares affects endometrial secretion of arachidonic acid metabolites during equine subclinical endometritis[END_REF]. This dysregulation of selected arachidonic acid metabolites, known to be endocrine modulators of reproductive processes and immunological mediators, may be responsible for the reduced fertility of aged mares affected with endometritis [START_REF] Siemieniuch | Advanced age in mares affects endometrial secretion of arachidonic acid metabolites during equine subclinical endometritis[END_REF].

Effects of age and parity of recipient for embryo transfer

For embryo transfer recipient mares, neither mare age nor parity were shown to affect the likelihood of pregnancy after blastocyst transfer [START_REF] Carnevale | Factors affecting pregnancy rates and early embryonic death after equine embryo transfer[END_REF][START_REF] Panzani | Factors Affecting Recipients' Pregnancy, Pregnancy Loss, and Foaling Rates in a Commercial Equine Embryo Transfer Program[END_REF][START_REF] Claes | Factors affecting the likelihood of pregnancy and embryonic loss after transfer of cryopreserved in vitro produced equine embryos[END_REF].

The number of cells and morphology grade of Day 2 post ovulation embryos transferred for 2 days in oviduct of recipients mares were not affected by recipient age [START_REF] Carnevale | Age-associated subfertility before entry of embryos into the uterus in mares[END_REF]). However, embryo death was increased older mares [START_REF] Carnevale | Factors affecting pregnancy rates and early embryonic death after equine embryo transfer[END_REF] but no difference was observed according to mare parity [START_REF] Panzani | Factors Affecting Recipients' Pregnancy, Pregnancy Loss, and Foaling Rates in a Commercial Equine Embryo Transfer Program[END_REF][START_REF] Claes | Factors affecting the likelihood of pregnancy and embryonic loss after transfer of cryopreserved in vitro produced equine embryos[END_REF].

In summary, fertility may be impaired in old mares due to the increased presence of oviductal masses that may disturb the migration of the fertilized embryo to the uterus. The old mare uterus as well as that from mares with high parity undergoes morphological changes including the presence of uterine cysts and fibrosis, regardless of parity. In addition, endometritis is more common in old mares, partly due to poorer conformation and delayed uterine clearance. Since chronic degenerative endometrial disease has been reported also in aged maiden mares, a direct effect of age is suspected.

Gestation, placenta, fetal and foal development (Tables 4567)

Increasing age and/or parity appear to affect the reproductive tract with structural and functional degeneration. These alterations, along with a decreased embryo quality could affect placental, fetal intrauterine and offspring post-natal growth and long-term health, in the context of the Developmental Origins of Health and Diseases (DOHaD).

Gestational length (Table 4)

Gestational length is know to vary according to season of birth, foals' age and breed among other factors [START_REF] Valera | Genetic study of gestation length in andalusian and arabian mares[END_REF]. Strict control of all these factors is difficult and may explain the variability of the reported data.

In terms of age, studies with large animal samples mostly observed that old mares have longer gestations [START_REF] Satué | Gestational length in Carthusian broodmares: effects of breeding season, foal gender, age of mare, year of parturition, parity and sire[END_REF][START_REF] Langlois | Genetic parameters for gestation length in French horse breeds[END_REF][START_REF] Reilas | Gestation lengths of Finnhorse and Standardbred mares in Finland: effects of breeding season and reproductive status[END_REF][START_REF] Ewert | Determinants of gestation length in Thoroughbred mares on German stud farms[END_REF][START_REF] Rodrigues | Genetic and Environmental Factors Influencing Gestation Length in Lusitano Horses[END_REF]. The studies that indicate a similar gestation length have usually smaller sample numbers [START_REF] Winter | Drosophila Rho-Associated Kinase (Drok) Links Frizzled-Mediated Planar Cell Polarity Signaling to the Actin Cytoskeleton[END_REF][START_REF] Winter | Gestational Length and First Postpartum Ovulation of Criollo Mares on a Stud Farm in Southern Brazil[END_REF][START_REF] Morel | Factors affecting gestation length in the Thoroughbred mare[END_REF][START_REF] Sevinga | Retained placenta in friesian mares: incidence, and potential risk factors with special emphasis on gestational length[END_REF][START_REF] Heidler | Body weight of mares and foals, estrous cycles and plasma glucose concentration in lactating and non-lactating Lipizzaner mares[END_REF][START_REF] Aoki | Factors Affecting Gestation Length in Heavy Draft Mares[END_REF][START_REF] Bene | SOME EFFECTS ON GESTATION LENGTH OF TRADITIONAL HORSE BREEDS IN HUNGARY[END_REF][START_REF] Reilas | Gestation lengths of Finnhorse and Standardbred mares in Finland: effects of breeding season and reproductive status[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Malinska | Animal and environmental factors associated with gestation length in the endangered Old Kladruber horse[END_REF][START_REF] Popova | BREEDING AGE OF MARES FROM THE HAFLINGER BREED[END_REF][START_REF] Carluccio | Effect of age and of reproductive status on reproductive indices in horse mares carrying mule pregnancies[END_REF][START_REF] Milojevic | Effects of Age and Sex of The Foal on The Gestation Length of Thoroughbred Mares[END_REF]. Only three studies reported a shortening of gestation length with increasing maternal age [START_REF] Bos | Length of gestation periods of horses and ponies belonging to different breeds[END_REF][START_REF] Valera | Genetic study of gestation length in andalusian and arabian mares[END_REF][START_REF] Kuhl | Maternal Lineage of Warmblood Mares Contributes to Variation of Gestation Length and Bias of Foal Sex Ratio (EZ Cameron[END_REF], but these study did not consider any very old mare nor had very high sample size of the same breed.

In terms of parity, on one hand, primiparous mares have been shown to have a shorter gestation in only one study [START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF] while most studies showed that primiparous mares have a longer gestation, with increases varying from a few days up to 15 days [START_REF] Pool-Anderson | Maternal influences on growth and development of full-sibling foals2[END_REF][START_REF] Valera | Genetic study of gestation length in andalusian and arabian mares[END_REF][START_REF] Satué | Gestational length in Carthusian broodmares: effects of breeding season, foal gender, age of mare, year of parturition, parity and sire[END_REF][START_REF] Reilas | Gestation lengths of Finnhorse and Standardbred mares in Finland: effects of breeding season and reproductive status[END_REF][START_REF] Talluri | Factors affecting length of gestation in artificially inseminated Marwari mares of India[END_REF]. On the other hand, no differences according to maternal parity have been observed in some studies [START_REF] Aoki | Factors Affecting Gestation Length in Heavy Draft Mares[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Ewert | Determinants of gestation length in Thoroughbred mares on German stud farms[END_REF].

Gestation (Table 5)

Early feto-placental development Although during the preimplantation period, effects of maternal age on embryo morphology differ between studies, at the time of implantation, fetal size is reduced in mares older than 8 compared to younger dams [START_REF] Willmann | Effects of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early-pregnant mares[END_REF], probably due to prior delayed development that did not lead to pregnancy loss.

Effects of maternal age and parity on equine Chorionic Gonadotropin (eCG) production are controversial. A 75-year-old study on ponies did not report any correlation between maternal eCG serum concentration and mares' age or parity although it might be due to the lack of accuracy in age and parity estimation. Nevertheless, they highlighted decreased maternal eCG serum concentrations in successive pregnancies [START_REF] Day | SERUM GONADOTROPHIN IN WELSH AND SHETLAND PONIES[END_REF]. In a more recent study, old mares have been shown to produce more eCG throughout the endometrial cups' lifespan compared to younger mares but no association with fetal development has been observed [START_REF] Willmann | Effects of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early-pregnant mares[END_REF]. Finally, fetal eCG production was shown to start and stop earlier, beginning from the 3 rd pregnancy, compared to the first two in young mares, leading to a non-significantly reduced eCG production over time [START_REF] Wilsher | Factors influencing equine chorionic gonadotrophin production in the mare: Equine chorionic gonadotrophin production[END_REF]).

Blood flow and metabolism

Uterine blood flow during gestation has been demonstrated to be reduced during pregnancy in older compared to younger mares [START_REF] Ousey | Uterine haemodynamics in young and aged pregnant mares measured using Doppler ultrasonography: Uterine haemodynamics in mares[END_REF]. Another study showed that maternal parity had a more important effect on blood flow than age (for mares younger than 16) with larger uterine arteries' diameter correlated to an increased blood flow volume in multiparous compared to primiparous [START_REF] Klewitz | Effects of age, parity, and pregnancy abnormalities on foal birth weight and uterine blood flow in the mare[END_REF]. From 100 to 250 days of gestation, in primiparous mares, the combined thickness of uterus and placenta increases, associated, with larger fetal eye cross-sectional and biparietal crosssectional surface area after 220 days of gestation compared to mares with a higher parity [START_REF] Hendriks | Maternal age and parity influence ultrasonographic measurements of fetal growth in Dutch Warmblood mares[END_REF]. In contrast, maternal age negatively affects fetal aorta diameter when mares are 15 years old or older [START_REF] Hendriks | Maternal age and parity influence ultrasonographic measurements of fetal growth in Dutch Warmblood mares[END_REF].

Studies performed on maternal age and parity related to modifications of mares' metabolism during pregnancy are scarce. Mares older than 8 have been shown to have increased plasma concentrations of parathyroid hormone, decreased osteocalcin and no change in IGF-1 during the last 2 months of gestation compared to mares aged 3-4, suggesting a different bone metabolism adaptation to pregnancy as mares age increases [START_REF] Filipović | The influence of age on bone metabolism in mares during late pregnancy and lactation[END_REF]. Furthermore, during gestation, basal glucose whole blood concentration is reduced in young primiparous mares compared to older multiparous mares, although parity does not alter urea plasmatic concentrations [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]). In addition, at 280 days of gestation, late-gestation adaptions of the carbohydrate metabolism (i.e., increased insulin resistance) are less pronounced in primiparous mares compared to multiparous mares, which could possibly affect glucose transfer to the fetus [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. At foaling, moreover, increased plasma amino acid concentrations are observed in primiparous mares, in association with decreased plasma amino acid concentrations in their newborns, suggesting impaired placental amino acid transfer to the fetus in primiparous pregnancies [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF].

Placenta (Table 6)

Term placental weight has been studied by different authors, however, its relationship with mare age remains controversial [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Elliott | Factors affecting foal birth weight in Thoroughbred horses[END_REF][START_REF] Ousey | Uterine haemodynamics in young and aged pregnant mares measured using Doppler ultrasonography: Uterine haemodynamics in mares[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. Young multiparous mares produce placentas with a larger microcotyledonary surface than older multiparous mares [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Ousey | Uterine haemodynamics in young and aged pregnant mares measured using Doppler ultrasonography: Uterine haemodynamics in mares[END_REF]. Furthermore, old mares have an increased total volume of microcotyledons, allantoic vessels and height of microtyledons in the placental body compared to mares younger than 8 [START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF].

Reduced placental microcotyledonary development is observed in older and subfertile compared to younger and fertile mares [START_REF] Bracher | Influence of chronic degenerative endometritis (endometrosis) on placental development in the mare[END_REF]. Furthermore, one study showed that endometrial degenerative changes induced by age affect placental development throughout gestation and lead to reduced microplacentome development and fetal growth [START_REF] Abd-Elnaeim | Structural and Haemovascular Aspects of Placental Growth Throughout Gestation in Young and Aged Mares[END_REF]. In old mares, altered feto-placental development could be explained by the presence of uterine cysts and degenerative changes in uterus (see section above). Moreover, age and parity are generally positively correlated and their respective impact is still to be determined.

Placentas at term are lighter and less voluminous in primiparous compared to multiparous mares [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Elliott | Factors affecting foal birth weight in Thoroughbred horses[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF] except in one study [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. Moreover, placentas from primiparous mares were shown to present a reduced microcotyledonary surface compared to placentas from multiparous dams [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Elliott | Factors affecting foal birth weight in Thoroughbred horses[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF]. Another study, however, showed that only the microcotyledonary conjunctive tissue is reduced in placentas from young primiparous mares [START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF]) and another did not show difference in microcotyledonary area according to mares' parity [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. The only study performed on three different placental sites (pregnant horn, nonpregnant horn and placental body) showed that the haemotrophic trophoblast surface density is reduced in the placental body of primiparous compared to multiparous mares [START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF].

The authors also observed a decreased microcotyledonary length in the three zones of primiparous compared to multiparous placentas [START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF]. The reduced capacity of placentas from primiparous mares might be explained by a lack of elasticity in the uterus which need to be "primed" by a first pregnancy to reach its maximum productivity and development [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF].

Effects of maternal parity on placental efficiency (as calculated as foal weight/m² of placenta) differ according to studies: efficiency is either reduced [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF] or increased [START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF]) in primiparous mares.

At term, the expression of several genes is affected by maternal parity and age, suggesting placental nutrient transfer alterations [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. Moreover, the global DNA methylation in term placentas is decreased in young primiparous compared to older multiparous mares, suggesting different placental epigenetic regulations that may impact fetal intra-uterine growth [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF].

Fetal and foal development (Table 7)

Maternal age has been demonstrated to affect foal morphology: both youngest and oldest dams produce lighter and smaller foals at birth and until 510 days of age [START_REF] Hintz | Growth rate of Thoroughbreds. Effect of age of dam, year and month of birth, and sex of foal[END_REF]. Without considering extreme age ranges, the birth foal weight appears to increase with maternal age although this association is mainly due to mare parity [START_REF] Elliott | Factors affecting foal birth weight in Thoroughbred horses[END_REF][START_REF] Fernandes | Which paternal, maternal and placental parameters influence foal size and vitality[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Malinska | Animal and environmental factors associated with gestation length in the endangered Old Kladruber horse[END_REF]. In almost all previously cited studies, younger mares are primiparous while older are multiparous. Only one study compared young and old multiparous dams and showed that foal birthweight is higher when mares are between 10 and 15 years old [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF].

Nevertheless, to the authors knowledge, no study compared birthweight of foals born to young and old primiparous, while in breeding farms it is common to see old primiparous broodmares.

Foals from primiparous mares remain smaller until at least one year of age and lighter until 4 months of age in most studies [START_REF] Pool-Anderson | Maternal influences on growth and development of full-sibling foals2[END_REF][START_REF] Cymbaluk | The ontogeny of serum insulin-like growth factor-I concentration in foals: Effects of dam parity, diet, and age at weaning[END_REF][START_REF] Fernandes | Which paternal, maternal and placental parameters influence foal size and vitality[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF], except in one study [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF].

Depending on breeds, increased maternal age reduces the size of foals until at least 6 months of age [START_REF] Hintz | Growth rate of Thoroughbreds. Effect of age of dam, year and month of birth, and sex of foal[END_REF][START_REF] Klewitz | Effects of age, parity, and pregnancy abnormalities on foal birth weight and uterine blood flow in the mare[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF]). One study on flat racehorses, however, showed that mare age and parity do not influence morphology of the competing adult [START_REF] Paksoy | Multivariate analysis of morphometry effect on race performance in Thoroughbred horses[END_REF]. These differences in growth have been related to reduced plasma IGF-1 concentration in foals from primiparous dams until 4 months of age [START_REF] Cymbaluk | The ontogeny of serum insulin-like growth factor-I concentration in foals: Effects of dam parity, diet, and age at weaning[END_REF].

Furthermore, foals from young and primiparous mares have a more immature regulation of glucose homeostasis and testicular development [START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF]). It has also been shown by epidemiological analysis that maternal age does not influence the risk of morbidity between 15 days and 1 year after birth although, with increasing mare age, foal mortality risk after 15 days of age is also increased [START_REF] Morley | A survey of reproductive performance in Thoroughbred mares and morbidity , mortality and athletic potential of their foals[END_REF].

In contrast to effects of age, the effects of parity are very clear with many studies showing that primiparous dams produce smaller and lighter foals at birth than multiparous mares, regardless of breeds or whether they are the result of embryo transfer [START_REF] Doreau | Effect of parity and physiological state on intake, milk production and blood parameters in lactating mares differing in body size[END_REF][START_REF] Lawrence | Changes in body weight and condition of gestating mares[END_REF][START_REF] Pool-Anderson | Maternal influences on growth and development of full-sibling foals2[END_REF][START_REF] Cymbaluk | The ontogeny of serum insulin-like growth factor-I concentration in foals: Effects of dam parity, diet, and age at weaning[END_REF][START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF][START_REF] Elliott | Factors affecting foal birth weight in Thoroughbred horses[END_REF][START_REF] Hendriks | Maternal age and parity influence ultrasonographic measurements of fetal growth in Dutch Warmblood mares[END_REF][START_REF] Fernandes | Which paternal, maternal and placental parameters influence foal size and vitality[END_REF][START_REF] Klewitz | Effects of age, parity, and pregnancy abnormalities on foal birth weight and uterine blood flow in the mare[END_REF][START_REF] Affonso | Influence of mare parity on weight, height, thoracic circumference and vitality of neonatal foals[END_REF][START_REF] Talluri | Factors affecting length of gestation in artificially inseminated Marwari mares of India[END_REF][START_REF] Meirelles | Influence of Maternal Age and Parity on Placental Structure and Foal Characteristics From Birth up to 2 Years of Age[END_REF][START_REF] Robles | Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half[END_REF][START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF]. The comparison of the same mares over their first and second gestation gave the same result with the first foal being lighter [START_REF] Wilsher | The effects of maternal age and parity on placental and fetal development in the mare[END_REF].

Epidemiological studies give different conclusions regarding effects of maternal age and parity on foals' performance. Indeed, in flat race, the third and fourth foals of a mare perform better while the first, the ninth foal and over are less successful [START_REF] Barron | The effect of maternal age and parity on the racing performance of Thoroughbred horses[END_REF]. In a more recent study, however, neither maternal age nor parity significantly affected the racing performance of a total of 431 horses trained at 2 and 3 years old [START_REF] Wilsher | Factors associated with failure of Thoroughbred horses to train and race[END_REF]. In French show jumping horses, primiparous mares were shown to produce less performant horses, especially when mares were older than 10 years old [START_REF] Palmer | Maternal Effects on Offspring Performance in Show Jumping[END_REF]. Maternal age also significantly reduces [START_REF] Barron | The effect of maternal age and parity on the racing performance of Thoroughbred horses[END_REF] or tends to reduce [START_REF] Morley | A survey of reproductive performance in Thoroughbred mares and morbidity , mortality and athletic potential of their foals[END_REF] performance of foals in flat races while in French show jumping, maternal age, without considering parity, does not affect foals' performances [START_REF] Palmer | Maternal Effects on Offspring Performance in Show Jumping[END_REF]. Two other studies, however, did not show any effect of mares' age and parity on foals' flat race performances (Wilsher et al. 2006). Maternal age does not seem to influence racing time but affects the earnings of the flat race foals [START_REF] Köseman | Some phenotypic and genetic parameters of racing performance in Arabian horses[END_REF]. In flat races, the first foal is also less likely to suffer from a fracture than the following ones and this risk also decreases with maternal age [START_REF] Verheyen | Fracture rate in Thoroughbred racehorses is affected by dam age and parity[END_REF]. Post-partum complications, maternal behavior, lactation quality and quantity (Tables 8 and9)

Altogether

Post-partum complications

One of the most common problem encountered after foaling is the retention of fetal membrane (RFM) occurring in 2 to 10% of foalings [START_REF] Frazer | Post partum complications in the mare. Part 2: Fetal membrane retention and conditions of the gastrointestinal tract, bladder and vagina[END_REF]. Few studies assessed the impact of age and/or parity on this subject. An increase of RFM in young (4 years old) and old mares (above 17 years old) was observed, compared to middle-aged mares (between 5 and 17 years old) [START_REF] Sevinga | Retained placenta in friesian mares: incidence, and potential risk factors with special emphasis on gestational length[END_REF]. In a more recent study [START_REF] Schürmann | Retained placenta in mares-an analysis of 121 cases[END_REF], however, no effect of neither age nor parity was highlighted. In terms of age, those results are in accordance with earlier results [START_REF] Provencher | Retained fetal membranes in the mare: a retrospective study[END_REF]. Regarding post-partum fever [START_REF] Aoki | Factors affecting the incidence of postpartum fever in heavy draft mares[END_REF], another post-partum complication, no impact of age or parity was found.

Dystocia is the main cause of neonatal foal mortality and is generally the result of foal malpresentation [START_REF] Ginther | On-the-farm incidence and nature of equine dystocias[END_REF]. No interaction between dystocia and mare age was identified in Quarter horses [START_REF] Mccue | Parturition, dystocia and foal survival: a retrospective study of 1047 births[END_REF][START_REF] Rioja | Perioperative risk factors for mortality and length of hospitalization in mares with dystocia undergoing general anesthesia: a retrospective study[END_REF]. In contrast, in draft horses, mares aged 3 were shown to have more difficult foalings and increased neonatal foal mortality than older mares [START_REF] Sabbagh | Genetic and environmental analysis of dystocia and stillbirths in draft horses[END_REF]. From 4 years of age to more than 10, no apparent effect was highlighted although a trend for more difficulties occurring in mares aged 4 than in mares ages 5 to 9 years of age was identified [START_REF] Sabbagh | Genetic and environmental analysis of dystocia and stillbirths in draft horses[END_REF]). In the same study, authors also highlighted the effect of parity with more dystocia and stillbirth associated with the first foaling compared to the second and the third. Thus, they conclude that the most disadvantageous combination was a mare aged 3 having her first foal although a mare aged 10 years or more in her first parity encountered almost the same risks. In terms of foal mortality, an effect of age for mare under 3 years of age was also identified although it was correlated with poor maternal behavior toward the foal: when maternal behavior was taken into account, the effect of age was no more significant [START_REF] Haas | Risk factors associated with the incidence of foal mortality in an extensively managed mare herd[END_REF].

Maternal behavior

Pony foals born to young (3 years old) mares compared to older mares (5 years old) were shown to be more frequently harassed by other mares from the same herd due to their lower hierarchical position [START_REF] Rho | Age of the Jeju pony (Equus caballus) at first reproduction: potential costs for foals and mothers that first reproduce early in life[END_REF]. Possibly as a result of these aggressions, these young mares are more protective of their foal.

Several studies have reported that primiparous mares are more likely to reject their foal than multiparous mares, demonstrating the importance of previous experience for maternal behavior [START_REF] Chavatte | Maternal behaviour in the horse; theory and practical applications to foal rejection and fostering[END_REF][START_REF] Houpt | A survey of foal rejecting mares[END_REF][START_REF] Juarbe-Díaz | Prevalence and characteristics of foal rejection in Arabian mares[END_REF]). After foals have been adopted, however, there is no difference in maternal behavior in terms of proximity index and reactivity to foal handling [START_REF] Søndergaard | The effect of early handling of foals on their reaction to handling, humans and novelty, and the foal-mare relationship[END_REF]. Nevertheless, increased maternal parity was associated with lower foal heart rates at 6 weeks of age when foals were introduced to a new object [START_REF] Søndergaard | The effect of early handling of foals on their reaction to handling, humans and novelty, and the foal-mare relationship[END_REF]. In addition, maternal parity did not affect the onset of conflicts over suckling during the socialization period nor did it affect maternal protectiveness [START_REF] Heitor | Maternal care and foal social relationships in a herd of Sorraia horses: Influence of maternal rank and experience[END_REF]. Foals born to higher parity mares were also more socially active in the herd [START_REF] Heitor | Maternal care and foal social relationships in a herd of Sorraia horses: Influence of maternal rank and experience[END_REF].

Colostrum

Colostrum is produced by the mare during the first 24 hours after foaling and is essential for the passive transfer of immunity to the foal. Thus, efficiency of this transfer was assessed regarding both age and/or parity and, in most studies, no effect was identified in terms of immunoglobulin G (IgG) concentrations in foal plasma [START_REF] Morris | Passive transfer failure in horses: incidence and causative factors on a breeding farm[END_REF][START_REF] Leblanc | Factors that influence passive transfer of immunoglobulins in foals[END_REF][START_REF] Raidal | The incidence and consequences of failure of passive transfer of immunity on a Thoroughbred breeding farm[END_REF][START_REF] Erhard | Assessment of colostral transfer and systemic availability of immunoglobulin G in new-born foals using a newly developed enzyme-linked immunosorbent assay (ELISA) system[END_REF], mare plasma [START_REF] Morris | Passive transfer failure in horses: incidence and causative factors on a breeding farm[END_REF][START_REF] Kenzig | Colostral, Milk and Serum Immunoglobulin G Concentrations in Quarter Horse Mares and Their Foals[END_REF] or mare colostrum [START_REF] Erhard | Assessment of colostral transfer and systemic availability of immunoglobulin G in new-born foals using a newly developed enzyme-linked immunosorbent assay (ELISA) system[END_REF][START_REF] Kenzig | Colostral, Milk and Serum Immunoglobulin G Concentrations in Quarter Horse Mares and Their Foals[END_REF]. A study, however, mentioned an effect of mare age on colostral IgG [START_REF] Leblanc | Factors that influence passive transfer of immunoglobulins in foals[END_REF] with mare younger than 10 showing higher concentrations. The increased foal morbidity and mortality risks observed in mares aged above 15 [START_REF] Morley | A survey of reproductive performance in Thoroughbred mares and morbidity , mortality and athletic potential of their foals[END_REF]) may be related to the poorer passive transfer of immunity observed in these older mares [START_REF] Leblanc | Factors that influence passive transfer of immunoglobulins in foals[END_REF]). Moreover, while not finding an effect of mare age, a study showed that foals from multiparous mares were less likely to present failure of passive transfer (Franco Ayala and Oliver-Espinosa 2016).

Factors influencing colostrum quality in the mare, however, are not well documented, especially when looking at age and parity. A study highlighted that colostrum calcium concentrations are higher in mares older than 7 compared to younger animals [START_REF] Ramin | Relationships among urea, protein and macromineral concentrations in colostrums and whole milk in lactating mares[END_REF]. Age also affects colostrum fatty acid profiles with mares older than 10 producing a colostrum richer in palmitic acid (C16:0) and in polyunsaturated fatty acids compared to mares up to 10 years of age [START_REF] Pikul | Fat content and fatty acids profile of colostrum and milk of primitive Konik horses (Equus caballus gmelini Ant.) during six months of lactation[END_REF]). In the same study, an effect of parity was also identified with mares having foaled less than 5 times showing a decreased colostrum saturated fatty acid:polyunsaturated fatty acid ratio compared to mares with a parity over 5. More specifically, decreased colostrum fatty acid proportions of caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0) acids and increased oleic (C18:1cis9), palmitoleic (C16:1cis7) and arachidonic (C20:4) acids are observed [START_REF] Pikul | Fat content and fatty acids profile of colostrum and milk of primitive Konik horses (Equus caballus gmelini Ant.) during six months of lactation[END_REF]. The significance of those changes remains to be elucidated.

Milk

Different factors have an impact on mares' lactation and, although lactation stage appears to be the strongest, age and parity also affect both milk quantity and quality. Concerning milk quantity, the effect of age appears non-linear during the mare's life and depends on the mare's breed, with greater milk production in multiparous mares in the first two thirds of lactation [START_REF] Pool-Anderson | Maternal influences on growth and development of full-sibling foals2[END_REF]. For nursing mares, maximum milk production is reached around 7, while, for dairy mares, milk production reaches a peak between 11 and 15 years of age [START_REF] Doreau | Milk yield of nursing and dairy mares[END_REF].

A very limited number of studies assessed the question of how mares' age and parity affect milk quality. Two cited studies examined milk quality without highlighting any effect of parity on milk solid content (Gibbs et al. 1982 p. 198;[START_REF] Doreau | Effect of parity and physiological state on intake, milk production and blood parameters in lactating mares differing in body size[END_REF]. Mares' parity, however, did not affect fat contents while an impact on milk protein contents was observed with mares of parity 1 and 2 producing milk richer in protein than mares at or above a parity of 3 [START_REF] Gibbs | Milk Production of Quarter Horse Mares during 150 Days of Lactation[END_REF]. More recently, a study focused on macro-mineral, protein and urea contents without detecting any effect of age [START_REF] Ramin | Relationships among urea, protein and macromineral concentrations in colostrums and whole milk in lactating mares[END_REF]. A decrease in milk lactose concentrations, however, was reported in multiparous mares, leading to the same trend for defatted dry extract [START_REF] Barreto | Chemical composition and lipid profile of mare colostrum and milk of the quarter horse breed[END_REF]. This study also considered mares' age but no effect was detected. Nevertheless, authors mentioned the correlation between age and parity in their study and thus, effects of parity previously mentioned could be partially due to age. When focusing on milk fatty acid profiles, both age appears to have an impact.

When mares up to 10 years of age were compared to older mares, the younger mares were shown to produce milk richer in myristoleic (C14:1), palmitic (C16:0) and palmitoleic (C16:1cis9) fatty acids and poorer in arachidonic acid (C20:4) [START_REF] Pikul | Fat content and fatty acids profile of colostrum and milk of primitive Konik horses (Equus caballus gmelini Ant.) during six months of lactation[END_REF]. The significance of those variations, in animals receiving a similar diet, remains to be understood.

In terms of parity, little is known as results between studies are contradictory. Two studies demonstrated an increase in milk production in multiparous mares compared to primiparous [START_REF] Gibbs | Milk Production of Quarter Horse Mares during 150 Days of Lactation[END_REF][START_REF] Pool-Anderson | Maternal influences on growth and development of full-sibling foals2[END_REF]. In other studies, however, no effect of parity was detected [START_REF] Doreau | Effect of parity and physiological state on intake, milk production and blood parameters in lactating mares differing in body size[END_REF][START_REF] Trottier | A weigh-suckle-weigh approach for estimating milk yield in the Arabian mare[END_REF]). In the last two above-mentioned studies, however, the number of mares studied (4 vs 4 in [START_REF] Doreau | Effect of parity and physiological state on intake, milk production and blood parameters in lactating mares differing in body size[END_REF]) and 3 vs 3 in [START_REF] Trottier | A weigh-suckle-weigh approach for estimating milk yield in the Arabian mare[END_REF])) might explain the lack of results.

Foal suckling

As for milk quality and quantity few studies assessed the effect of age and parity on foal suckling bouts duration and frequency with only two studies assessing the effect of parity and none concerning the effect of mare age. Number and duration of suckling bouts per day does not seem to be influenced by mare parity [START_REF] Trottier | A weigh-suckle-weigh approach for estimating milk yield in the Arabian mare[END_REF]. Another study, however, indicates an increase of bout duration in foals from primiparous [START_REF] Duncan | On lactation and associated behaviour in a natural herd of horses[END_REF]. In summary, so far, little attention has been paid to effects of age or parity on lactation and so far, apart from a greater production after the first lactation, and a peak lactation yield for middle aged mares (between 7 and 15).

Conclusion

In conclusion, both maternal age and parity affect horse reproduction, as summarized in Figure 2.

Mares' age affects cyclicity, folliculogenesis, oocyte and embryo quality as well as oviductal masses and uterine tract function. If effects of ovarian function and gamete/embryo quality and the accumulation of unfertilized eggs in the oviduct were to be expected, it was interesting to observe that age alone affects uterine quality in terms of fibrosis and the presence of endometrial cysts. The threshold for observable deleterious effects on these different factors needs to be better determined, as an epidemiological study demonstrates that ageing actually induces a reduction in fertility as soon as 8 years of age.

Maternal parity appears to have a non-linear effect. Primiparity has a major influence on placental and concomitant foal development, with smaller foals in first gestation that remain smaller postnatally.

Moreover, dystocia is more frequent in primiparous mares, at least in draft mares and the prevalence of foal rejection is increased. Although colostrum quality does not seem affected, milk yield is reduced compared to subsequent lactations. After the first gestation, that one could consider as a "priming", endometrial quality and uterine clearance capacities progressively decline with increasing parity, whilst placental and foal birthweight and milk production increase.

In most studies, however, maternal age and parity are confounding factors as younger mares are usually nulliparous and older mares are multiparous. Interaction between parity and age is essentially observed in very young or very old primiparous mares.

Practically, since first pregnancies and compulsory, the choice of a pony as stallion should be considered so as to produce a small foal that would fit into the pony's morphological standards. In terms of recipient mares, recipients having already had a foal should be preferred. If this is not possible, large mares should be chosen, so as to reduce the effects of primiparity of foal size. In addition, for the management of aging mares with progressive fertility decline, caution should be increased at the time of foaling as placental retention was shown to be more frequent. Embryo transfer is recommended when the uterine tract is not able to sustain pregnancy any more, and ICSI if the quality of collected embryos is too low.

Figure 1: Decline in fertility in mares in relation to age (adapted from Langlois and[START_REF] Langlois | Statistical analysis of some factors affecting the number of horse births in France[END_REF][START_REF] Jeffcott | An assessment of wastage in Thoroughbred racing from conception to 4 years of age[END_REF] Figure 2: Summary of effects of maternal age and parity on maternal factors affecting foal production. biopsy score and age, and variations between seasons. Theriogenology 78, 495-501. doi:10.1016Theriogenology 78, 495-501. doi:10. /j.theriogenology.2012.02.028 .02.028 Zent W. W., Liu I. K. M., and Spirito M. A. (1993). Oviduct flushing as a treatment for infertility in the mare. Equine Veterinary Journal 15, 47-48. doi:10.1111Journal 15, 47-48. doi:10. /j.2042Journal 15, 47-48. doi:10. -3306.1993.tb04824.tb04824

Mare age

Fertility in % [START_REF] Langlois | Statistical analysis of some factors affecting the number of horse births in France[END_REF][START_REF] Jeffcott | An assessment of wastage in Thoroughbred racing from conception to 4 years of age[END_REF] Pre-implantation until blastocyst stage Polo Argentino Interovulatory interval = for 3-4 and 5-10yo groups & Interovulatory interval in 13-25yo group [START_REF] Marinone | The effect of mare's age on multiple ovulation rate, embryo recovery, post-transfer pregnancy rate, and interovulatory interval in a commercial embryo transfer program in Argentina[END_REF] 3-12yo 20-30yo 25 21

Arabian, Quarter Horse, Thoroughbred Delayed in 25-33yo Prolonged follicular growth ≥20yo [START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF]

Hormonal control of follicular growth

Group 1 (5-7yo & LH concentration in 5-6yo group Estradiol concentrations = in all groups [START_REF] Ginther | Age-related dynamics of follicles and hormones during an induced ovulatory follicular wave in mares[END_REF] 3-12yo 20-30yo 25 21

Arabian, Quarter Horse, Thoroughbred & Progesterone concentration in 25-33yo group [START_REF] Vanderwall | Ovarian follicles, ovulations and progesterone concentrations in aged versus young mares[END_REF] Ovulation 3-9yo 10-16yo >16yo 220 251 145

Warmblood

Ovulation induction using hCG have more chance to fail in >16yo mares [START_REF] Barbacini | Retrospective study on the efficacy of hCG in an equine artificial insemination programme using frozen semen[END_REF] Group 1 (5-7yo

Light horse

No difference in oocyte and inner zona pellucida volume & oocyte and ooplasm diameter in 14-19 yo compared to 3-13 yo & inner zona pellucida diameter in 14-19 yo compared to 3-13 yo In 14-19 and 20-23 yo groups, & ooplasm volume compared to 3-13 and 24-27 yo groups. No difference in embryonic development to blastocyst stage rates related to the age of the oviductal cells donor No difference in embryo quality from young and old mares when co-cultured with oviductal cells from old mares while using oviductal cells from young mares, embryos from young donors with & quality Tendency to ( the number of cells in embryos from young donors when co-cultured with old mare oviductal cells while no difference observed in embryos from old mares [START_REF] Brinsko | In vitro development of day 2 embryos obtained from young, fertile mares and aged, subfertile mares[END_REF]

Uterine cysts and vascularization

Age considered as a continuous variable (from 1.5 to ≥ 20 yo) A total of 93 mares One ultrasound examination/mare Mixed breeds

Mares with uterine cysts older (mean of 13.4 yo) than mares without uterine cysts (mean of 6.9 yo) No difference in pregnancy rates at Day 11/12 post ovulation according to the presence, number and size of uterine cysts [START_REF] Leblanc | Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis[END_REF] Yo: years old α : age determined based on dental characteristics Exp: experience Nulliparous: mares that did not previously foal, also known as maiden mares

Multiparous: mares that already foaled at least once (included lactating mares at the time of the study) * number of foalings indicated when knew

  , the studies described above show that effects of age and parity on pregnancy, fetal development and post-natal growth and health are highly dependent on studies, suggesting effects of genetics and/or breeding conditions but maybe also due to different age criteria and statistical power in the different studies. Robles et al. even showed different results in two successive studies in the same experimental farm, demonstrating the difficulty to obtain repeatable results. Nevertheless, analysis of the data indicate that primiparous mares tend to have increased pregnancy length by up to 15 days. Then, gestational length seems to generally increase with advancing mare's age, especially in older mares. Gestational changes in terms of endocrinology, maternal metabolism and uterine artery blood flow don't evidence major differences although blood flow to the uterus appears to be increased in older and multiparous mares. The placenta is in general smaller and appears less efficient in terms of microtyledonary structure in primiparous dams. As a consequence, primiparity has a clear negative effect on feto-placental growth, with post-natal carry-over of the small size and weight, possibly leading to altered glucose metabolism in yearlings and poorer sports performance in older animals. Foal birthweight increases with maternal age and parity together with performance. Apart from one study where genetic value was taken into consideration as a cofactor (Palmer et al. 2018), data on post-natal offspring sport performance are hindered by the lack of information on parental genetics and post-natal environmental constraints.

  uterine cysts with parity ↗ frequency and severity of angiosis, ↗ vascular degenera;ons (elastosis in larger vessels of myometrium) with ↗ parity ↗ slope of uterine-cervical junc;on in mul;parous, ↘ uterine clearance ↗ number of oviductal masses and uterine cysts with age ↗ frequency and severity of angiosis with mare age ↗ frequency of moderate to severe sclero;and earlier eCG peak with ↗ parity ↗ diameter of uterine artery with ↗ parity ↘ fetal size and placental development at implanta;on ↗ combined thickness of uterus and placenta ↗ diameter of both uterine arteries in >7 years old ↗ uterine artery pulsa;lity index in >7 years with ↗ parity ↗ foal mortality with maternal age before and after 15 days of age ↗ foal morbidity with maternal age before 15 days of age ↗ foal birthweight when excluded youngest and oldest mares

.x 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Table 1 :

 1 Summary of literature reports showing effects of mare's age on ovarian activity, follicular growth, cycle length, endocrine function and ovulation rates. To our knowledge, no report on effects of parity on these parameters are available.

		Age categories	Sample size	Breed	Results	Source
					Effect of age
		5-7yo	9
		15-19yo	10	Pony	( Ovulation regularity ≥20yo	(Carnevale et al., 1994)
		≥20yo	16
	Ovarian activity	3-12yo 20-30yo	25 21	Arabian, Quarter Horse, Thoroughbred	Latest first ovulation for old mares ( Number of ovulatory cycles after 20yo	(Vanderwall et al., 1993)
		<5yo >15yo	1,003	Pony	( Ovarian activity after 15yo	(Wesson and Ginther, 1981)
	Anti-Müllerian hormone concentration	Young (3-8yo) Middle-aged (9-18yo) Old (19-27yo) Young (4-8yo) Old (19-25yo) Middle-aged (9-18yo)	10 16 19 12 12 12	Light horse Arabian	( Number of antral follicules in 19-27yo (compared to 3-8yo and 9-18yo) ( AMH concentrations in 19-27yo (compared to 9-18yo) Weak AFC AMH correlation in 3-8yo &AMH concentration in 9-18yo	(Claes et al., 2017) (Korkmaz et al., 2020)
		4-8yo 9-18yo 19-25yo	1,101	Quarter Horse	( AMH concentration ≥20yo & AMH concentration 5-10yo and 10-15yo	(Uliani et al., 2019)
		Young (4-9yo) Old (≥20yo)	22 15	Not defined	( Dominant follicule's growth ≥20yo	(Altermatt et al., 2012)
		Group 1 (5-7yo) Group 2 (15-19yo) Group 3 (≥20yo)	9 11 11	Pony	Prolonged interovulatory interval for ≥20yo group & Follicular activity in 15-19yo compared to ≥20yo	(Carnevale et al., 1993)
		5-7yo 15-19yo ≥20yo	9 10 16	Pony	Delayed follicular activity in ≥20yo Prolonged follicular growth ≥20yo	(Carnevale et al., 1994)
	Breeding period and follicular activity	Exp 1: Young (5-7yo) Old (≥14yo) Exp 2: Young (3-7yo)	12 16 16	Pony	Exp 1: & Follicular activity in 5-7yo Exp 2: Number of follicules highest in 3-7yo group and lowest	(Carnevale et al., 1997)
		Intermediate (17-19yo)	10		in ≥20yo group
		Old (≥20yo)	9
		Young (3-8yo) Middle-aged (9-18yo) Old (19-27yo)	10 16 19	Light horse	( Number of follicules with age Prolonged interovulatory interval for 19-27yo group	(Claes et al., 2017)
		5-7yo	9
		15-19yo	10	Pony	Later primary wave for ≥20yo group	(Ginther et al., 1993)
		≥20yo	11

Table 2 :

 2 Summary of literature reports showing effects of mare's age on follicular organization, oocytes and embryos in Old versus Young mare & interleukin-6 signal transducer (IL6ST) in old than in younger groups & tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in mid-aged than young mares Tended to ( tumor necrosis factor-inducible gene 6 (TNFAIP6) in mid-aged vs old and young mares tended to & LH receptor (LHR) and steroidogenic acute regulatory protein (STAR) in old vs Mid-aged and young, respectively & tissue-type plasminogen activator (PLAU) in young and old compared to mid-aged No difference in follicle diameter, meiotic stage, spindle quality and orientation, thickness of the Factin band and the percentage of the oocyte image with foci of microfilaments No difference in concentrations of estradiol, progesterone and testosterone in the follicular fluid & Insulin like growth factor 1 concentrations in follicular fluid of old mares No difference in oocyte diameter, quantification of organelles Tendency to ( area per section of oocyte occupied by cortical granules & number of oocytes with large vesicles and number of large vesicles/oocyte from old mares & morphological abnormalities (i.e. irregular shapes, areas of ooplasm without organelles)

	) Group 2 (15-19yo) Group 3 (≥20yo)	9 11 11	Pony	Larger follicule in 15-19yo group Smaller follicles for >20yo group compared to 15-19yo group	(Carnevale et al., 1993)
	Young (3-7yo)	16
	Intermediate (17-19yo)	10	Pony	( Follicule size in >20yo group	(Carnevale et al., 1997)
	Old (≥20yo)	9
	Young (3-8yo)	10
	Middle-aged (9-18yo)	16	Light horse	Number of ovulations = in all groups	(Claes et al., 2017)
	Old (19-27yo)	19

  No difference in the oocyte nor the ooplasm volume and diameter ( thickness of the zona pellucida and zona pellucida + matrix in old mare oocytes but not matrix thickness alone & inner zona pellucida and perivitelline space volume in old mare oocytes Different gene expression profile of luteinizing hormone receptor (LHR) à asynchrony of the initiation of oocyte and follicle maturation Different gene expression profile of amphiregulin (AREG) and epiregulin (EREG) in granulosa cells, phosphodiesterase 4D (PDE4D) in cumulus cells and phosphodiesterase 3A (PDE3A) and G-proteincoupled receptor 3 (GPR3) in oocytes ( total gene expression levels of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in old follicles Temporal ( mtDNA copy numbers (meiosis regulators) in old mare oocytes & instability of spindle assembly when MPS1 is inhibited in old mare oocytes à Compromised MPS1 activity = predisposition to meiotic spindle instability in old mare oocyte Tendancy to and ( oocyte-donor mean age for a positive pregnancy diagnosis by, respectively Day 17 and 50 post ovulation No difference in blastomere size, number of cells, presence of fragments of ooplasm nor extruded membrane through zona pellucida after ICSI No difference in the number of hours from ICSI until cleavage At transfer, & number of cells for 20-23 yo compared to 3-13 and 14-19 yo groups ( time to transfer for 20-23 yo compared to 3-13 and 14-19 yo groups Earlier detection of embryonic vesicle in 14-19 yo compared to 20-23 yo group No difference in the diameter of vesicles at detection nor the embryonic vesicle diameter per day of detection

	Frank et al., 2019 Carnevale et al., 2005 Altermatt et al., 2009 Campos-Chillon et al., 2015 Cox et al., 2015 Rizzo et al., 2019 Rizzo et al., 2020 C (AURKC) Rizzo et al., & oocyte grade with mares' age ( gene expression of mitochondrial translational initiation factor 3 (IF3), heat shock transcription factor 5 (HSF5) and Y box binding protein 2 (YBX2) in old oocytes & ADP-ribosylation factor-like 6 interacting protein 6 (ARL6IP6), BCL2-associated X protein (BAX) and hypoxia upregulated 1 (HYOU1) in old mare cumulus cells & chromosome misalignment in ole mare oocytes & thickness of metaphase plate in old mare oocytes No difference in spindle morphometry ( gene expression of the centromere cohesion stabilizing protein, Shugoshin 1 (SGOL1) in old mare oocytes & aneuploidy, premature sister chromatid separation and weakness of centromeric cohesion in old mare oocytes ( gene expression of mono polar spindle 1 (MPS1), SPC25 and Aurora kinase 2021 ( of severity of vitrification-related degenerations in spindle morphology and capacity to reach MII à Reflection of pre-existing compromise spindle assembly checkpoints Ducheyne et al., 2019 ( mtDNA copy number in old mare oocyte after IVM only & swelling and ( number of cristae in mithochondria from old mare oocytes after IVM only Rambags et al., 2014 No difference in relative abundance of glucose, pyruvate, lactate and triglycerides in oocytes and cumulus cells & and ( free fatty acids relative abundance in cumulus cells and oocytes, respectively, from old mares ( Basal and maximum oxygen consumption rate and extracellular acidification rate in oocytes from old mares No difference in mtDNA copy number Catandi et al., 2021 No difference in gene expression nor ATP content in oocytes Hendriks et al., 2015 No difference in Day 2 embryo recovery rates ( number of positive diagnosis in subfertile mares Ball et al., 1986 ( tubulin multiasters in sperm-injected old mare oocytes & actin vesicles in sperm-injected old mare oocytes = different cytoskeletal remodeling in sperm-injected oocytes according to maternal age ( embryo diameter measured by ultrasonography from Day 15 to 19 post ovulation High embryo mobility for both groups from Day 10 to 12 ( embryo movements earlier in old mares Similar day of fixation in the cornual-body junction for both groups Camargo Ferreira et al., 2019 No difference in embryonic vesicle diameter measured by ultrasonography on day 12 and the day of fixation Similar embryo mobility between groups Carnevale and Ginther 1992 No difference in embryonic vesicle diameter measured by ultrasonography on days 13 to 14 Morel et al., 2005 Frank et al., 2019 No difference in embryo diameter Alteration of gene expression in trophoblast and inner cell mass according to maternal age related to mitochondria, translation, transcription, chromatin modification In inner cell mass, disturbance on mitosis, signaling, adhesion and embryo development pathways In trophoblast, disturbance of ion movement related genes Derisoud et al., 2021 No difference in diameter nor number of blastomeres in Day 2 post ovulation embryos Ball et al., 1986 No difference in the morphology nor in diameter of embryos at Day 4 post ovulation Ball et al., 1989 ( number of cells in embryos from old mares at Day 1 post ICSI No difference in the number of cells at Day 2 post ICSI Altermatt et al., 2009 ( Basal oxygen consumption rate in Day 2 embryos from old mares No difference in basal extracellular acidification rate in Day 2 embryos No difference in cell numbers of the Day 2 embryos Catandi et al., 2021 ( mtDNA copy number in old mares Day 8 old mare blastocysts No difference in the expression of 5 genes related to mitochondria Hendriks et al., 2015 Ruggeri et al., 21-24 yo < 20 yo ≥ 20 yo 70 mare-year 67 mare -year 180 162 Light horse Young (4-9 yo) Old (≥ 20 yo) 22 15 40 37 Light horse Young (2-7 yo) α Middle aged (8-14 yo) Young (3-12 yo) Old (≥ 20 yo) One oocyte, granulosa and cumulus cells/mare at 0, 6, 9 and 12 hours after LH administration Light horse 3-12 yo ≥ 18 yo 5 14 COCs 10 COCs Quarter horse-type Young (2-14 Yo) Old (16-27 yo) 169 COCs/75 MII oocytes 134 COCs/ 54 MII oocytes (25 MII oocytes/analysis) Slaughtered mares Breed not defined Young (2-14 Yo) Old (16-27 yo) 106 115 641 COCs/319 MII oocytes 530 COCs/ 241 MII oocytes (4 pool of 10 oocytes/group à gene expression analysis + 394 à chromosome spreads) Slaughtered mares Breed not defined Young (2-14 Yo) Old (16-28 yo) A total of 640 COCs (4 pool of 10 oocytes/group à gene expression analysis + 320 à analysis of inhibitors and immunofluorescence) Slaughtered mares Breed not defined Young (2-14 Yo) Old (16-31 yo) 311 COCs 169 control à 75 MII oocytes 142 vitrified oocytes à 38 MII oocytes 294 COCs 150 control à 64 MII oocytes 144 vitrified oocytes à 48 MII oocytes (19 to 34/group for each analysis) Slaughtered mares Breed not defined < 12 yo α ≥ 12 yo α 268 114 IVM COCs/127 not IVM oocytes 154 IVM COCs/106 not IVM oocytes (mtDNA quantity analysis à all + mitochondrial morphology à 5/group) Slaughtered mares Breed not defined Exp 1 Young (7-11 yo) Old (20-26 yo) Exp 2 Young (6-13 yo) Old (20-27 yo) 8 7 8 One follicle/mare à cumulus cells and oocytes from the same mare 9/10 oocytes 14/13 oocytes Light horse < 12 yo ≥ 12 yo 101 165 oocytes (77 not IVM/88 IVM) 170 oocytes (92 not IVM/78 IVM) Slaughtered mares Breed not defined Normal (average of 4.9 yo + nulliparous) Subfertile (average of 17.4 yo + history of reproductive failure) One embryo collection at day 2 post ovulation and one pregnancy diagnosis at 14 days post ovulation/mare Standardbred Standardbred + Thoroughbred Young (9-13 yo) Old (20-25 yo) Not defined 11 32 Not defined α : age determined based on dental characteristics Oocyte quality Fertilisation breeding seasons 40 embryos Quarter Horse and Standardbred) Young (5-6 yo) α Old (15-20 yo) α 7 6 One beginning of gestation/mare Mixed breed Young (5-7 yo) α Old (≥ 15 yo) α 9 22 One beginning of gestation/mare Pony mares 2-5 yo 6-8 yo 9-11 yo 12-15 yo ≥16 A total of 1213 mares 90 embryos at day 13/ 74 at day 14 201 embryos at day 13/ 124 at day 14 195 embryos at day 13/ 144 at day 14 217 embryos at day 13/ 160 at day 14 128 embryos at day 13/ 104 at day 14 Thoroughbred and Thoroughbred-Warmblood 3-13 yo 14-19 yo 20-23 yo 24-27 yo A total of 86 mares 178 ICSI-produced embryos Light horse Young (6 yo) Old (10-16 yo) 11 20 5 in vivo produced embryos 6 in vivo produced embryos Saddlebred Normal (average of 4.9 yo + nulliparous) Subfertile (average of 17.4 yo + history of reproductive failure) 15 15 One embryo collection at day 2 post ovulation and one pregnancy diagnosis at 14 days post ovulation/mare Standardbred Standardbred + Thoroughbred Normal (average of 5.7 yo + primiparous or multiparous) Subfertile (average of 19.4 yo + history of reproductive failure) 38 22 One embryo collection at day 4 post ovulation and transfer + pregnancy check at 16 days post ovulation/donor mare Standardbred Standardbred + Thoroughbred Young (4-9 yo) Old (≥ 20 yo) 22 15 40 37 Light horse Young (6-13 yo) Old (20-27 yo) 7 8 8 embryos 10 embryos Light horse 4 -11 yo 17-22 yo A total of 10 mares 8 8 Slaughtered mares Breed not defined Yo: years old mtDNA: mitochondrial DNA COCs: cumulus oocyte complexes MII : Metaphase II IVM : in vitro maturation OPU : Ovum Pick-up ICSI : Intra-Cytoplasmic Sperm Injection Fixation on 1.5 days later in old mares Young (6-10 yo) α Old (20-26 yo) α Not defined 12 transferred oocytes 26 transferred oocytes Pony mares Ginther 1995 No difference in embryonic vesicle diameter measured by ultrasonography on days 11 to 14 Carnevale and Exp: experience

α Aged (≥ 15 yo) α Not defined 38 ovaries/432 follicles/288 COCs 17 ovaries/209 follicles/125 COCs 26 ovaries/270 follicles/176 COCs Slaughtered mares Breed not defined x 3 and x 4 ( chances to reach MI and MII, respectively, for oocytes from aged mares Brinsko et al.,

Table 3 :

 3 Summary of literature reports showing effects of mare's age on the reproductive tract

		Categories	Number of animals	Sample size	Breed	Results	Source
					Effect of age
		4-8 yo 10-12 yo ≥17 yo	Not defined	Not defined	Not defined	( expression of collagen type III (COL3) gene in the entire oviduct from mares older than 10 yo	Pinto-Bravo et al., 2018
		Age considered as a continuous variable α (from 2 to 20 yo)	A total of 250 mares	Oviducts and ovaries of each mare	Slaughtered mares Quarter Horse type	& number of masses with mare age	Aguilar et al., 1997
		Young, normal (2-7 yo)	5
	Oviducts	Old, subfertile (17-24 yo, multiparous, no foaling in the 2	5	One oviductal cell explant/mare	Standardbred and Thoroughbred	Age-related differences in the synthesis and secretion of proteins from oviductal cell explants 9 and 7 non identified proteins, respectively, less and more abundant in old mare oviductal cell secretions	Brinsko et al., 1996
		previous years)
		Young & Normal	19	16 co-cultures of oviductal cells with
		(2-7 yo)		8 in vitro embryos from young donors
				8 in vitro embryos from old donors
		Old & Subfertile (17-24	16	16 co-cultures of oviductal cells with	Light horse
		yo + multiparous, no		8 in vitro embryos from young donors
		foaling in the 2		8 in vitro embryos from old donors
		previous years)

  No difference in the mean arterial pressure and blood flow in uterus ( uterine blood perfusion (total volume of blood/min/100 g of uterus) with mare age and elastosis Similar perfusion of both uterine horns in old mares while in young and adult groups, more often ( perfusion in the uterine horn without compared to the one with the embryo No difference in the height of the lining nor the gladular epithelium & diameter of endometrial glands in the stratum spongiosum in estrus and diestrus in old mares ( density of endometrial glands in the stratum compactum in estrus and diestrus in old mares ( density of endometrial glands in the stratum spongiosum in diestrus only in old mares PGF1α in supernatants when biopsy from group 2-5 yo with endometritis compared to groups with endometritis compared to 6-10 yo group with endometritis ( leukotriene B4 in supernatants when biopsy from group 6-10 yo with endometritis compared to groups with endometritis compared to 16-23 yo group with endometritis & leukotriene C4 in supernatants when biopsy from group 16-23 yo with endometritis compared to groups with endometritis compared to 6-10 and 16-23 yo groups with endometritis Parity = best predictor of vascular grade & vascular degenerations (mostly elastosis in larger vessels of myometrium) with & number of No endometritis in studied mares No difference in the morphology (i.e. epithelial status, presence of foreign cells, secretory status of the glands, fibrosis of cystic glands) of the endometrium No difference in the ultrastructure of the endometrium No difference in pregnancy on 14 and 40 days, foal born, the overall pregnancy loss, before 40 days after or 40 days rates Markedly thickened walls of arteries in the uterine wall Marked elastosis in the uterine wall arteries due to concentric multiplication of the layers of the internal elastic lamina Elastic fibers completely digested by elastase Atrophy and reduction in the number of medial smooth muscle cells Chronic infiltrative endometritis and degenerative endometrial diseases with mare age and parity Histopathologic degree of chronic degenerative endometrial disease more correlated with age than mare parity Aged maiden mares with signs of advanced chronic degenerative endometrial diseases

		Young (7-8 yo) Aged (16-21 yo) 3-9 yo 10-16 yo >16 yo Nulliparous Multiparous	6 6 111 126 56 29 49	Ultrasound examination throughout gestation Monitoring of mares in a commercial artificial insemination center Uterine examination after death	Thoroughbred Warmblood Thoroughbred, Quarter Horse, and Arabian horses	( uterine artery blood flow throughout the gestation in old mares ( uterine contractility at 13 days post ovulation in old mares & endometritis with mare age & vascular grade with parity foals	Ousey et al., 2012 Barbacini et al., 1999 Esteller-Vico et al., 2012
	Uterine endometrial degenerative changes Endometritis	2-7 8-12 13-17 18-31 2-31 yo Age group 1 (2-8 yo) Age group 2 (9-16 yo) Age group 3 (17-27 yo) 2-5 yo 11-16 yo 18-29 yo Maiden Multiparous (1-2) Nulliparous Multiparous Age considered as a continuous variable Young (5-6 yo) α Old (15-20 yo) α Maiden Multiparous Not defined Age considered as a continuous variable (from 3 to 21 yo) Nulliparous Multiparous	32 33 28 19 A total of mares 9 22 26 A total of 12 mares 7 7 29 49 A total of mares 7 167 409 6 A total of 700 mares 14 30 14 30	One endometrial biopsy/mare Uterine examination after death One diestrus endometrial biopsy/mare One uterine infusion and collection/mare Over a 3-year period, videoendoscopy and endometrial biopsy/mare Uterine examination after death Uterine examination after death One beginning of gestation/mare Monitoring of mares in a commercial artificial insemination center One endometrial biopsy/mare Scintigraphy during estrous prior ovulation/mare Scintigraphy during estrous prior ovulation/mare	European warmblood, Thoroughbred, Standardbred, Ponies and Draught horses Mixed breeds Not defined Swedish Warmblood and Standardbred Thoroughbred, Quarter Horse, and Arabian horses Thoroughbred Thoroughbred, Quarter Horse, and Arabian horses Mixed breed Warmblood Thoroughbred, Standardbred, Thoroughbreds and Pleasure breeds Thoroughbred, Quarter Horse, Arabian and Saddlebred Standardbred, Quarter Horse, Standardbred, Arabian and	& frequency and severity of angiosis with mare age & frequency of moderate to severe sclerotic vascular lesions & degree of internal elastic lamina thickening with mare age & incidence of uterine fluid at 48 and 96h post insemination in mares older than 9 yo ( speed of uterine clearance in older mares Positive correlation between mare age and bacterial concentration or total number of bacteria Positive correlation between mare age and white blood cell concentration and total number & endometrial grade with parity ( physical clearance in older mares Atrophy and reduction in the number of medial smooth muscle cells in old mares & vascular grade with age No difference in vascular degenerations with & mare age More often ( uterine contractility in old group during the first 20 days of gestation No difference in endometritis prevalence & endometrial fibrosis with age yo & incidence of delayed uterine clearance of intrauterine fluids after mating in mares older than 14 & incidence of delayed uterine clearance of intrauterine fluids after mating in mares older than 14 yo & slope of uterine-cervical junction in multiparous	Grüninger et al., 1998 Nambo et a., Woodward et al., 2012 Tunón et al., 1995 Evans et al., 1987 Esteller-Vico et al., 2012 1995 Esteller-Vico Camargo Barbacini et al., 1999 Ferreira et al., 2019 et al., 2012 Doig et al., 1981 1998 Leblanc et al., Leblanc et al., 1998
		Maiden	10	One uterine fluid collection on Day 2, 3 or 4	European Saddlebred Warmblood and	No difference in the concentration of total protein concentrations and albumin	Tunón et al.,
	Recipients for embryo transfer	4-11 yo 12-24 yo Young (5-8 yo) Old (9-14 yo) Multiparous Nulliparous Multiparous Young (5-7 yo) α Old (≥ 15 yo) α Age considered as a continuous variable (from 3 to >20 yo) Maiden Multiparous	104 88 9 11 10 A total of 164 mares 9 22 A total of 9020 mares A total of 261 mares	One endometrial biopsy/mare One uterine fluid collection on Day 2, 3 or 4 during estrus/mare during estrus/mare 175 embryo transfers 176 embryo transfers One endometrial biopsy/mare One vulva measurement during 62 embryo transfers 199 embryo transfers estrus/mare	warmblood, Thoroughbred, light draft, Standardbred Warmblood and Standardbred Standardbred Standardbred and Haflinger and Arabian Pony mares Thoroughbred, Standardbred and Not defined Arabian Effect of age and parity & fibrotic nests, fibrosis of individual gland branches, cystic glandular degeneration and mononuclear cell infiltration of stratum compactum in older than 12 yo No difference of any of the uterine proteins recorded No difference in the concentration of total protein concentrations and albumin ( concentration of not identified proteins (molecular weight from 60-71 kDa) in old mare uterine fluid & endometrial biopsy fibrotic changes for old mares ( score for gland density for old mares & length of the vulva with age No difference in the likelihood of pregnancy nor embryonic loss	Waelchli 1990 1998 Tunón et al., 1998 Panzani et al., 2016 Carnevale and Ginther 1992 Pascoe 1979 Claes et al., 2019
		Young & Normal Young (6-10 yo)	19			( gene expression of Defensin Beta 4B (DEFB4B), Matrix Metallopeptidase 9 (MMP9) and Tumor	Adams et al.,
	Uterine endometrial Uterine cysts and degenerative changes vascularization	Age considered as a continuous variable (from 2 to 26 yo) (2-7 yo) Old & Subfertile (17-24 <10 yo >10 yo nulliparous Old (12-13 yo) multiparous yo + multiparous, no foaling in the 2 previous years) Young (2-12 yo) maiden Old (13-19 yo) maiden Age considered as a continuous variable (from 5 to 23 years old) Age group 1 (2-8 yo) Age group 2 (9-16 yo) Age group 3 (17-27 yo) 2-5yo 6-10 yo 11-15 yo < 11 yo ≥11 yo Age considered as a continuous variable 16-23 yo 26-31 yo multiparous	A total of 3740 mares on 5 breeding 16 15 10 4 2 29 6 seasons A total of 87 mares 9 22 26 17 23 22 A total of 215 mares A total of mares 20 3	One ultrasound examination around Day 22 of pregnancy/mare One endometrial biopsy/mare One endometrial biopsy/mare One ultrasound examination/mare One endometrial biopsy/mare One videoendoscopic measurement/mare One diestrus endometrial biopsy/mare One in vitro culture of endometrial biopsy/mare Several ultrasound examinations/mare Uterine examination after death	Thoroughbred Standardbred Saddlebred Pony Light horse Standardbred Standardbred Thoroughbred Standardbred Ponies Draught Thoroughbred Mixed breeds Draught Warmblood Thoroughbred Thoroughbred, Arabian horses Quarter Horse, and Thoroughbred	1987 Crociati et al., 2019 Bollwein et al., 1998 Brinsko et al., 1994 Chevalier-Clément 1989 Grüninger et al., 1998 Bracher et al., Woodward et al., 2012 & 6-keto-Siemieniuch Mares with uterine cysts older (mean of 14.7 yo) than mares without uterine cysts (mean of 9.3 yo) & severity of endometrial histologic changes in old and subfertile mares Necrosis Factor (TNFA) in old mare uterine biopsy & Interleukin-6 (IL6) and Collagen Type III Alpha 1 Chain (COL3A1) in old mare uterine biopsy & vascular resistance in the 2 old multiparous mares No difference in fibrosis and inflammation distribution in uterine biopsy Without endometritis no difference of PGE2 and 6-keto-PGF1α in supernatants Without endometritis, ( leukotriene B4 and C4 concentration in supernatant with mare age & concentration of PGE2 in supernatants when biopsy from group 16-23 yo with endometritis & frequency of mild degeneration of the membrana elastica interna, perifibrosis or perifibroelastosis in older maiden mares Only 4 of the 48 mares with cysts < 10 yo Relation between mare age and cysts formation & Age related to a poorer biopsy score compared to 2-5 and 11-15 yo groups with endometritis et al., 2017 1992 X 4.2 times more risk to present endometrial cysts in ≥ 11 yo Eilts et al., 1995 Age = best predictor of endometrial grade et al., 2012 & endometrial grade with age Esteller-Vico Oikawa et al., 1993
	Uterine cysts Recipients for embryo Uterine endometrial degenerative changes transfer Endometritis	<7 yo 7-14 yo > 14 yo Exp 1: <7 yo 7-14 yo 15-25 yo Exp2: young (3-10 yo) Old (15-21 yo) 3-8 yo 12-19 yo bred from 4 yo (from 5 to 23 years old) Mares continuously 15-20 yo Young (4-6 yo) Adult (8-12 yo) Old (15-18 yo) Young (2-9 yo) included 6 mares of 2 yo Old (10-20 yo) 2-9 yo α 10-18 yo α Not defined Age considered as a continuous variable (from 2 to 25 years old) And parity not defined Young (2-9 yo) α Old (≥ 15 yo) α Group 1, Nulliparous 3-8 yo Group 2, Multiparous	116 117 26 A total of 76 mares 11 11 4 7 A total of 87 mares 7 7 7 17 10 412 120 A total of 261 mares A total of 3,804 mares 10 10 4 4	One ultrasound examination/mare One ultrasound examination/mare One endometrial biopsy/mare in etrus and diestrus One videoendoscopic measurement/mare One ultrasound examination/day/mare from Day 12 to Day 20 of gestation One endometrial biopsy/mare A total of 638 embryos transferred into recipients Not defined One endometrial biopsy/mare 10 embryos transferred 10 embryos transferred Scintigraphy during several time point in further estrus cycle/mare	Thoroughbred Large ponies and pony-horse crosses Draft and riding breeds Thoroughbred Mixed breed Light horse Not defined Not defined Thoroughbred, part bred, Arabian, pony, heavy horse and Standardbred Pony Effect of parity Exp 1: Mares with uterine cysts older (mean of 14.0 yo) than mares without uterine cysts (mean of & number of uterine cysts in ≥ 7yo mares & uterine cyst size in >14 yo mares 10.0 yo) & frequency of mares with uterine cysts with age while the frequency of mares without uterine cyst & for 7-14 yo group & number and size of uterine cysts with age No age-related difference in uterine vascular perfusion in mares without cysts Mares with elastosis (in average 18.6 and 20.0 yo) older than mares without elastosis (in average & number of cysts with parity Exp 2: & mesometrial blood flow velocities in old mares without cysts More important uterine vascular changes throughout the study period in young and old compared to adult group Similar perfusion of both uterine horns in old mares while in young and adult groups, more often ( perfusion in the uterine horn without compared to the one with the embryo No difference in biopsy score, distribution and gene expression of oxytocin receptors No difference in pregnancy rates at 12-and 50-days post ovulation & Embryo death in older recipients No difference in the likelihood of pregnancy nor embryonic loss & Ricketts and Tannus and Thun 1995 Dubrovskaya et al., 2019 1992 Bracher et al., Ferreira et al., 2008 Ferreira et al., 2015 Annandale et al., 2018 Carnevale et al., 2000 Alonso, 1991 Claes et al., 2019 Carnevale et No difference in the mean morphology grade and no. of cells for embryos al., 1993 & speed of clearance in multiparous Not defined Poorer cervical dilation in nulliparous
	Endometritis and vascularization	Age considered as a continuous variable Age considered as a continuous variable (from 1.5 to ≥ 20 yo) Maiden 1-2 3-5	20 A total of mares 32 33 28	Blood-flow measurements and postmortem uterine biopsy/mare One ultrasound examination/mare One endometrial biopsy/mare	Thoroughbred Mixed breeds Thoroughbred Standardbred Ponies	9.0 and 10.0 yo) Mares with uterine fluid collection older (mean of 12.2 yo) than mares without (mean of 7.5 yo)	Esteller-Vico et al., 2015 Adams et al., 1987 Grüninger et al., 1998
		Young (4-6 yo) Adult (8-12 yo) Young (5-7 yo) α Old (≥ 15 yo) α >5	7 7 9 22 19	One endometrial biopsy and ultrasound estrus monitoring/mare	Pony mares Draught	& ultrasonically detected intrauterine fluid collections for old mares & endometrial biopsy score for cellular infiltration for old mares	Ginther 1992 Carnevale and
		Old (15-18 yo)	7

One ultrasound examination/day/mare from Day 12 to Day 20 of gestation Mixed breed More important uterine vascular changes throughout the study period in young and old compared to adult group Ferreira et al., & frequency and severity of angiosis with mare parity Unaltered vessels only and no severe vascular changes in maiden mares ( number of clearly defined membrana elastica interna with parity

Table 4 :

 4 Summary of literature reports showing effects of mare's age and parity on gestational length. The age and parity are calculated at foaling (parity 1 = first foal for the mare)

		Categories	Number of animals	Breed	Results	Source
				Effect of age
		4-7 years old	36
		8-12 years old	198	Carthusian Spanish bred	13-17 years old longer than 8-12 years old	Satué et al., (2011)
		13-17 years old	105
		Age considered as a continuous variable (from 2 to >20 years old)	Total = 355 150	Thoroughbred, Arabian, Anglo-Arabian, French Saddle, French Trotter, French draft horses	↗ with age	Langlois and Blouin, (2012)
	Gestation longer in older mares	2-9 years old 10-13 years old 14-16 years old ≥17 years old 2-years groups from 2 to >19 years of age	Total = 13 531 Detail not specified for groups Total = 10 294	American Standardbred, Finnhorse Hanoverian	≥ 17 years old longer than 2-9 years old ↗ with age	Reilas et al., (2014) Christmann et al., (2017)
		≤6 years old	4606
		7-9 years old	4843
		10-12 years old	3455	Thoroughbred	↗ with age	Ewert et al., (2018)
		13-15 years old	1992
		≥16 years old	1330
		Age considered as a continuous variable (from 2 to >20 years old)	Total = 1 027	Lusitano	↗ with age	Rodrigues et al., (2020)
		3-7 years old	16
		8-14 years old	35	Criollo	No difference	Winter et al., (2007)
		≥15 years old	19
		Age considered as a continuous variable (from 3 to >24 years old)	Total = 433	Thoroughbred	No difference	Davies Morel et al., (2002)
		4 years old
		5-17 years old	Total = 502	Freisian	No difference	Sevinga et al., (2004)
		>17 years old
		6-9 years old	15
		10-13 years old	15	Lipizzaner	No difference	Heidler et al., (2004)
		14-23 years old	16
		Age considered as a continuous variable (from 3 to 19 years old)	Total = 209	Draft horses (crossbreds)	No difference	Aoki et al., (2013)
	No difference	Each age is considered as a group (from 3 to 17 years old) 4-8 years old	Total = 680 15	Furioso -north star, Hungarian cold-blood and sport horse, Kisberi, Lipizzaner, Nonius, Shagya	No difference	Bene et al., (2014)
		9-12 years old	15	Brazilian sport horse, Mangalarga paulista	No difference	Meirelles et al., (2017)
		≥ 13 years old	10
		4-6 years old
		7-12 years old	Total = 649	Old kladruber	No difference	Malinska et al., (2019)
		13-23 years old
		2-years groups from 4 to 23 years of age	Total = 49	Haflinger	No difference	Popova (2020)
		<10 years old	68
		10-16 years old	18	Draft mares inseminated with Martina Franca donkey	No difference	Caluccio et al., (2020)
		>16 years old	10
		Age considered as a continuous variable	Total = 138	Thoroughbred	No difference	Milojevic et al., (2020)
		7-8 years old 16-21 years old	6 6	Thoroughbred	No difference	Ousey et al., (2012)
		3 years old	116
	Gestation shorter in older mares	4-8 years old 9-12 years old >12 years old 3 years old (Shetland) ≥4 years old (all breeds)	337 124 63 286 2041	Brandenburg Fjord, Haflinger, Draft horse, Shetland, Freisian	4-8 years old shorter than 3 years old >3 years old shorter	Kuhl et al., (2015) Bos and Van der Mey, (1980)
		<4 years old 4-14 years old (each as a group)	Total = 8439	Andalousian, Arabian	↘ with age	Valera et al., (2006)

Normal (average of 5.7 yo + primiparous or multiparous) Subfertile (average of 19.4 yo + history of reproductive failure)

One embryo collection at day 4 post ovulation and transfer + pregnancy check at 16 days post ovulation/donor mare

Standardbred

Standardbred + Thoroughbred

No difference in Day 4 embryo recovery rates After transfer, ( embryo survival rates for subfertile donors Ball et al., 1989 < 20 No difference in the number of embryos produced by OPU-ICSI session, the blastocyst/injected oocyte nor the likehood of success Cuervo-Arango et al., 2019a Age considered as a continuous variable (from 1 to 29 years old)

A total of 473 mares

In median, mares selected for OPU-ICSI were older No difference in the post-ICSI cleavage rate, the blastocyst/injected or recovered oocyte nor the likehood of pregnancy at Day 12 and 45 and the embryonic loss incidence Cuervo-Arango et al., 2019b Young (6-14 yo) Old (20-28 yo) No difference in embryonic development to blastocyst stage rates ( development for embryos from aged and subfertile mares ( quality score of embryos from old mares at the day of blastulation and after 7 days of culture Tendency to ( blastocyst diameter on day 7 of culture for embryos from old and subfertile mares Tendency to ( number of cells in blastocyst from old and subfertile mares French Anglo-Arabian ↘ whole blood basal glucose concentration at 150 dpo in primiparous ↗ FSIVGTT** disposition index + ↗ glycaemia and insulinemia after meals in primiparous = ↘ ability to metabolically adapt to gestation ↗ amino acid maternal plasma concentration in primiparous at foaling [START_REF] Robles | Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth[END_REF] [START_REF] Pikul | Fat content and fatty acids profile of colostrum and milk of primitive Konik horses (Equus caballus gmelini Ant.) during six months of lactation[END_REF] Foal suckling

Uterine vascularization

Primiparous

Camargue & Duration of suckling bout for parity 1 [START_REF] Duncan | On lactation and associated behaviour in a natural herd of horses[END_REF] 1 ≥2 3 3

Arabian

No difference [START_REF] Trottier | A weigh-suckle-weigh approach for estimating milk yield in the Arabian mare[END_REF]