Until now, there has been more concern about a decline in sperm conventional parameters with advanced paternal age[19]. Some results have suggested that increased paternal age has a detrimental effect on blastocyst formation rate[4, 5, 20, 21] and ART outcomes[8, 11, 12, 22–24]. Summarized findings mainly included selective ICSI cycles in which most of the patients had male infertility with oligozoospermic[2, 18] and the sperm parameters are abnormal. Also most studies have limitations that they did not separate IVF cycles and ICSI cycles, and the confounding effects of sperm parameters on embryo quality could not be ruled out. The results cannot clearly explain whether semen sperm parameters or male age affects reproductive outcome, as controversial results have been reported about the effect of male aging on sperm parameters[9, 25, 26] .
Data for IVF cycles in which the sperm parameters are normal are rare. Jolien Van Opstal showed that advanced male age negatively affects the probability of obtaining an eight-cell stage at Day 3 in couples undergoing IVF treatment (OR = 0.960; 95% CI: 0.930–0.991; P = 0.011)[27]. We did not find an effect of male age on the transferable embryos or high-quality embryos due to advanced paternal age in couples undergoing IVF cycles. A retrospective study of 1938 conventional in IVF cycles showed that male age had a detrimental effect on pregnancy rates in cases of paternal ages > 40 y but only in women aged > 35 y[28]. Our study revealed that the pregnancy and implantation rate were significantly lower for couples with male partners aged ≥ 40 years in women aged 30–34 years. We did not study women older than 35 years. Our result is in line with findings from the literature [21]. Due to the small number of cases currently analyzed, more data and larger numbers are required for analysis. In 2016, a study[29] using the large, anonymized HFEA national database collected over two decades demonstrated that there is no evidence to show that live birth and miscarriage occurrence are affected by sperm donor age (aged 41–45 years, (P < 0.05), in which they selected the older sperm donor population based on their optimum sperm quality with normal sperm parameters. In a cohort study based on 71,937 couples, no association was found between paternal age and the risk of birth defects. Although there was a declining trend in the live birth rate but no significant difference in our study, it may be related to the small number of cases in the elderly group. Studies from a prospective study of 5121 couples and a cohort of 17,000 (IUI) cycles both found that the miscarriage rates in male partners older than 35 years were significantly increased compared with partners of men younger than 35 years after controlling for maternal age[30, 31] .Our study showed taht miscarriage rate in the 35–39 y paternal age group was significantly higher (P < 0.05) compared with that in the < 35 y paternal age group and no abnormalities in the birth weight of newborns among the different male age groups. As very few birth defects were recorded (the number was nil in the three subgroups), an evocative analysis in this regard was not possible. Because of the small number of participants in the oldest group of paternal age ≥ 40 y, more neonatal data need to be analyzed.
Most of the previous studies controlled female age by using the oocyte donation model. Despite using young donor eggs in those studies, the results of the studies are also inconclusive[4, 6, 7, 10, 12, 28, 32]. Some suggested that increased paternal age was associated with poor pregnancy outcomes in an oocyte donation model[5], and others suggested that there was no association[14]. Because there were confounding uncontrolled variables, the age of the maternal recipients has not been addressed in analyses of many oocyte donating cycles [9, 28]. In oocyte donation cycles, although the age of the oocyte can be controlled, the age of recipients cannot; thus, the effects of oocyte age and recipient age may be separated. The factor of the recipients’ uterine receptivity usually cannot be controlled. In addition, the interaction between paternal age and maternal age could not be evaluated, but only recipients’ male partner age and donor age were evaluated. A study reported that live birth rates declined with increasing paternal age, but this association was greatly attenuated when adjusted for recipient age[22]. The results demonstrated a decline in live birth rates (LBs) with increasing paternal age and an increased incidence of pregnancy loss when controlling for recipient endometrial preparation[7].
The mechanism for the decline in the pregnancy rate and implantation rate and increase in the abortion rate as a consequence of advanced paternal age remains to be explained. Male genetic alterations in germ cells of older fathers could be a factor[33, 34]. The effect of paternal age on aneuploidy remains debatable. The analyzed result from 11,535 pregnancies obtained by IUI cycles using donor spermatozoa showed that the risk of trisomy 21 for the fetus increased when the donor was 38 years old[35]. Previous studies also reported that an older male may contribute to a higher prevalence of aneuploid embryos[36] which may also explain the increased spontaneous abortion rate in advanced paternal age. Moreover, increased DNA fragmentation in sperm has also been linked to a lower clinical pregnancy rate[37], lower embryo quality[38] and higher risk of pregnancy loss[39]. Sperm DNA damage has already been shown to be elevated in advanced male age[40]. Genetic changes in sperm of older men, including mutations or alterations in genetic imprinting, can be induced by environmental or biological factors in sperm cells[41]. A higher frequency of sperm chromosome numerical and structural aberrations has been described in advancing paternal age [42–44]. Cytogenetic analysis of semen samples from donors has demonstrated an increased risk of numerical and structural aberrations in males 59–74 years old compared with males 23–39 years old[43]. Changes to sperm epigenetic modifications such as methylation have also been shown to be related to male infertility[45–47]. These findings might point to a possible influence of sperm DNA on ART outcomes, even when sperm parameters are normal (as in this study).
This study has limitations due to its retrospective design and monocentric nature. the sample sizes were small. Moreover, the sperm morphology was not evaluated. Our preliminary results remain indicative and worth verifying in larger cohorts. Additional prospective studies are needed to further investigate male age and its potential effects on reproductive outcome.