4 Discussion

The results of our study showed that advanced age was an independent risk factor for early miscarriage, which is similar to the results of previous relevant research.^3,4 In the fresh embryo transfer cycle, the early miscarriage rates in the <35-year-old group and ≥35-year-old group were 8.4% and 13.9%, respectively. Although there was no statistical difference after multivariate analysis (p ​> ​0.05), it can still be seen that the early miscarriage rate increased significantly with increasing age. However, there was no significant difference because the sample size of the fresh cycle group was small. The high miscarriage rate in the older patients was mainly related to the aneuploidy of the embryos. Pylyp et al.⁵ examined the early miscarriage tissues of ICSI pregnancies using cytogenetic technology and found that the chromosome abnormality rates in the miscarriage tissues of the <35 years-old group, the 36-40 years-old group, and the ≥40 years-old group were 45.32%, 54.7%, and 63.2%, respectively, suggesting that the aneuploidy rate of the embryos was the main cause of ICSI pregnancy miscarriage. Gruhn et al.⁶ discovered that the relationship between human oocyte aneuploidy and age described a u-curve; that is, the aneuploidy rate of oocytes in women <20 years old and >35 years old was significantly higher, because only 1%–8% of male spermatozoa showed aneuploidy, and this did not increase with the ages of the men. However, about 20%–30% of oocytes in women of childbearing age were aneuploid.^7,8 The aneuploidy rate of oocytes in women aged >35 years old is as high as 70%.⁹ Therefore, female age is an independent factor leading to early miscarriage in IVF/ICSI, and the increase in oocyte aneuploidy is the root cause.

A randomized controlled trial showed a significant increase in the live birth rate of frozen-thawed embryo transfer cycle compared with fresh cycle,¹⁰ but there was no significant difference in the miscarriage rate. However, we found that the frozen-thawed embryo transfer cycle was an independent risk factor for early miscarriage in IVF-ET, which may be due to the fact that embryo freezing technology affects the developmental potential of embryos. Although vitrification freezing technology is currently recognized as being economical and safe, embryos still have to undergo the process of freezing and thawing, and are exposed to physical and chemical media such as cryoprotectants, which may affect the structure of cells and the integrity of the genome. In addition, differences in the skills of laboratory operators may have different effects on the embryos.¹¹ Because this paper reports a retrospective study, the general situation of the infertile population is heterogeneous, so the results have some limitations.

The results of this study show that compared with the HRT cycle, the NC cycle is a protective factor for early miscarriage, and studies by Cerrillo¹² and Hatoum¹³ et al. have reached similar conclusions. The use of a large amount of estrogen in the HRT cycle, and the high level of estrogen and the imbalance of estrogen and progesterone, have adverse effects on the receptivity of the endometrium. Morozov et al.,¹⁴ found that the E2 level in the HRT cycle was higher than in the NC cycle. The high serum E2 level affects endometrial receptivity by regulating the expression of endometrial genes. Therefore, high estradiol levels in the HRT cycle may interfere with embryo implantation and thus affect the pregnancy outcome.¹⁵ Also, in the HRT cycle, the dose and timing of progesterone administration will also affect the pregnancy outcome. Generally, the endometrium will have histological changes on the sixth day of progesterone administration. However, Gomaa and Díaz-Gimeno et al.^16,17 found that about 25% of the endometrium had no histological changes and presented a delayed state. The time of progesterone administration and transfer in the HRT cycle were closely related to the synchronicity of the embryo and endometrium, while NC cycle transplantation did not involve this problem. Therefore, endometrial biopsy can be used to determine whether there are histological changes in the endometrium, so as to adjust the number of days after progesterone administration before embryo transfer and to correct the non-synchronization of endometrial and embryonic development, which may reduce the occurrence of miscarriage in the HRT cycle. There is no doubt that endometrial thickness affects the embryo implantation rate. Previous studies in our center have found that when the endometrium is ​< ​6 ​mm thick, the embryo implantation rate, clinical pregnancy rate, and live birth rate significantly decrease.¹⁸ In this study, we found that endometrial thickness is an independent factor that influences early miscarriage (OR ​= ​0.78, p ​< ​0.05), and the rate of early miscarriage was lower when the endometrium was ≥8.5 ​mm thick. Gallos et al.¹⁹ reached a similar conclusion, which have a certain guiding significance for clinical treatment.

In this study, we found that the early miscarriage rate of those women with high-quality embryos in the fresh cycle (7.2%) was significantly lower than that in women without high-quality embryos (13.9%, p ​< ​0.05). Chang et al.²⁰ found that the high-quality embryo rate and miscarriage rate were lower in women with ovarian dysfunction. Therefore, the number of high-quality embryos, to a certain extent, reflects the quality of ovarian reserve function, which thus affects the outcome of the pregnancy.