Recent years, much attention has been paid to the impact of maternal age on ART success rates, and several studies have revealed that a high maternal age (over 40 years old) has a negative effect on pregnancy outcomes [11, 13]. However, our study showed that no significant association existed between maternal age and singleton birthweight in FET cycles with considering related confounders. Furthermore, linear regression indicated that maternal age was not an independent predictor of singleton birthweight in FET cycles.
Four studies, as we know, have been interested in the potential relationship between maternal age and neonatal birthweight. Wennberg et al. investigated maternal age influencing adverse maternal and neonatal outcomes following ART treatment, suggesting that the risk of LBW and very LBW was significantly higher in ART than in spontaneous conception (SC) singletons in all ages up to maternal age 40 years (LBW: aORs 1.44-2.35; VLBW: aORs 1.67-3.44). Additionally, when the analysis was restricted to maternal age >35 years, an increased risk of LBW existed for SC pregnancies, but not for ART pregnancies [11]. Due to medical, educational and socioeconomic reasons, women who conceive through ART with >35 years old may pay more attention to their state of health and seek medical assistance more often than SC women, which could result in increased detection of complications and decreased risk of LBW. Secondly, Moaddab et al. found that maternal age did not predict newborns’ birthweight in pregnancies with maternal age grouping as <40, 40-44, 45-49, ≥50 years old [12]. However, maternal age group with <40 years old per se have an inadequate analysis on birthweight and miss important information. There may be some interesting findings among groups at ages <25, 26-30, 31-34, 35-40 years old and the increased risk of LBW may appear at age of 35 years old, but this study seemed to miss these potential information. Many studies have set up more detailed groups with maternal age under 40 years old to assess the influence of maternal age on neonatal outcomes and gained the more credible results [13, 14]. Another study reported that the risk of LBW was increased only at maternal ages over 40 years old (6 percentage points, 95% CI: 0.2, 12) with medically assisted reproduction (MAR) compared to the risk of LBW at ages 30–34 years old [13]. However, a limited number of confounders were included in the study, and the effect of different kinds of MAR treatments could not be reliably distinguished, which included less invasive treatments such as ovulation induction only that were less strongly associated with adverse birth outcomes [25]. A recent study based on 4,958 infertile women using a freeze-all strategy observed that maternal age grouping was not related with increased risks of LBW, very LBW, preterm LBW and macrosomia [14]. Yet only 1450 singleton live birth was involved for the analysis of LBW, and the 44–50 year old group of singleton live births was very small (n=9), which may limit the power of statistical analyses between groups.
Our study aimed to improve on the flaws of abovementioned studies, and focused on the exact role of maternal age in the singleton birthweight after FET cycles. The current study based on 12565 singleton newborns born after FET cycles, demonstrated that maternal age itself had no impact on singleton birthweight and neonatal outcomes including PTB, LBW and SGA were similar between the different maternal age groups. Due to so many confounding factors, direct comparability across different age group has very limited clinical significance in table 2. Because of strict exclusion criteria, generality of this finding may be, to some extent, restricted. The reason why no significant correlation existed between maternal age and birthweight in our study is likely complex. It is generally known that with aging comes a reduction in ovarian function, resulting in the decrease of ovarian response to ovulation promoting drugs and the low number of oocytes retrieved [26]. Additionally, the decreased quality of oocytes [27, 28], abnormal endometrial function and degeneration of multiple organs function will appear in women with advanced maternal age [22, 29]. All the above mentioned factors would affect the development of embryo and cause adverse effects on the newborn, leading to LBW. However, with the popularization of education, many women tend to choose late marriage and late childbearing and enjoy a simple single life before marriage. In this kind of life, they are less stressed and have more opportunities to get in touch with life freedom than the women who are married and have children. Meanwhile, these knowledge women tend to choose a healthy and regular life, and possess good habits, physical quality and economic conditions, thus having a better choice on ART treatment [11]. Aging leads to an irreversible decline in fertility, forcing older women to pay more attention on pregnancy and to seek medical help more actively than the young. In addition, the spouse's income also increase with age to guarantee maternity. Most importantly, the development of ART has well fulfilled the reproductive needs of women with different ages to improve the quality of newborns.
In this study, results from multiple linear regression analysis indicated that maternal BMI, embryo developmental stage at transfer, parity, number of embryos transferred, endometrial thickness, year of treatment, gestational age and newborn gender, were the independent predictors for neonatal birthweight, which was consistent with previous results [22, 30, 31]. Z-scores were calculated and compared across the four groups in order to reduce bias caused by newborn gender and gestational age, and no significant difference on Z-scores was found among different maternal age groups. In addition, there were significant differences between the maternal age groups in baseline and cycle characteristics including infertility duration, infertility cause and fertilization method. However, these confounders had no impact on neonatal birthweight based on the linear regression model.
There are limitations in our study. The biggest one is its retrospective design, so we strictly checked the database with strict criteria. Secondly, due to personal privacy restrictions, we were unable to obtain the education and economic background of patients. Thirdly, there are many confounding factors strongly associated with birthweight in linear regression analysis, data bias during the experimental design cannot be all corrected by regression equations. Further, embryo quality and paternal BMI were important factor that may affect neonatal outcomes, yet these data were missed in this manuscript. However, The large number of singleton live births from a single centre can assure the practice consistency, which is the main strength of the current study. Additionally, aside from the change of culture medium types, all other laboratory conditions and protocols remained invariant throughout the study period. Further, maternal age was recorded according to the identification card, and endometrial thickness was measured by the same trained sonographers, reducing the recorder variability. Importantly, a number of potential confounders were included in our study, which may minimize their impact on the findings.