A retrospective cohort study was conducted on the perinatal outcomes of pregnant women who had undergone ART from 2013 to 2018 in Shanghai, China by means of registry-database linkage, and the matching rate of the target population was 92%. The results showed that ART resulted in a higher rate of multiple birth, PTB, LBW, cesarean section, placenta previa and GDM compared with spontaneous conception, not only in the full cohort, but also in the singletons cohort. As for PIH, the incidence of ART was higher than spontaneous conception in the full cohort, but there was no difference in the singleton cohort. In the singleton cohort, the rates of PTB, LBW, cesarean section, and PIH in frozen embryo transfer women were higher than those in fresh embryo transfer, and there was no difference between IVF and ICSI. Multivariate regression analysis showed that after excluding the influence of other factors, the risk of PIH in patients with FET was still increased. Moreover, FET is also related to the severity of pregnancy induced hypertension in our cohort.
In terms of perinatal outcomes of ART patients, many foreign reproductive researches have been reported in recent years many, most of which are retrospective[4-6]. The consistent results are that the incidence of multiple births and preterm birth after ART is significantly increased, and the corresponding complications are also increased[11, 12]. Our results showed that the rate of multiple birth was 24 times higher in the ART group than in the SC group. In addition, of all the 12,017 patients we collected, only 592 (4.9%) had 1 embryo transferred, 10,525 (87.6%) had 2 embryos transferred, and even 900 (7.5%) had 3 embryos transferred. With foreign experts advocating elective single embryo transfer (eSET) to reduce the incidence of multiple pregnancy and protect the safety of mother and child. In November 2018, Shanghai municipality issued a notice on The Regulations for Human Assisted Reproductive Technology in Shanghai, which clearly suggested the total number of embryos transferred per cycle shall not exceed 2, and no more than one embryo should be transferred during the first cycle. Even if only comparing the pregnancy outcomes of singleton offspring, the results of this study suggest that the incidence of preterm birth and very preterm birth in ART singleton infants is significantly higher than that in natural pregnancy offspring, and the incidence of LBW and VLBW is also significantly higher than that in natural pregnancy offspring. These results are consistent with the results reported in several previous literatures[13, 14].
The most common complications of pregnancy are pregnancy induced hypertension syndrome (PIH) and gestational diabetes mellitus (GDM). A meta-analysis showed that ART are linked to increased risk of GDM[15]. As GDM pregnant women, the patients after ART treatment have a higher risk of adverse pregnancy outcomes[16, 17]. The results of this study are consistent with those reported. As for PIH, prior literatures have reported that ART therapy is correlated with the occurrence of PIH to a certain extent[18, 19]. In the current study, the incidence of PIH in ART patients increased only in the full cohort, and was not significantly different in the singleton cohort compared with natural pregnancy. This may indicate that the high incidence of PIH in ART patients is mainly related to the high incidence of multiple pregnancies[19]. However, other studies have found that there is no statistically significant difference in the risk of PIH between twins treated with ART and normal pregnancy[20]. Therefore, it is still controversial whether the influence of maternal infertility factors or the process of art treatment plays a leading role in the increase of the risk of adverse pregnancy outcomes[21, 22].
In order to analyze the influence of different treatment factors, we compared the pregnancy outcomes of ART patients receiving different treatment protocols, and the results suggested that different in vitro fertilization methods had no effect on pregnancy outcomes. However, frozen embryo transfer was a risk factor for PIH, with an adjusted OR of 1.526 (95%CI: 1.300-1.790). After controlling for maternal age, male infertility factors only, multiple pregnancies and GDM, the risk of PIH in patients using FET treatment was still higher than that in patients using fresh cycles. In addition, the more severe the PIH, the higher the adjusted OR value of FET patients. In fact, with the increasing use of FET in clinical practice, relevant studies have found that the risk of PIH/preeclampsia after FET treatment is higher than that after fresh embryo transfer[23, 24]. A multicenter randomized controlled trial in China found that the risk of preeclampsia after FET was increased in patients with PCOS[25], but there was no difference in the infertile patients with normal ovulation[26].
However, the specific mechanism is still unclear, which may be related to the fact that FET is more prone to abnormal placental anatomy and vascular pathological changes[27]. In addition, a prospective cohort study found that pregnant women using the programmed FET cycle had a higher risk of PIH than those using natural cycle[28]. Because ovulation is inhibited in patients with programmed FET cycle, these pregnant women lack endogenous corpus luteum (CL), and need progesterone support after transplantation. It was found that the number of corpus luteum in early pregnancy of IVF pregnant women may be related to the risk of PIH / preeclampsia[29-31]. This hypothesis is biologically plausible because CL produces hormones such as estrogen, progesterone, relaxin, and vascular endothelial growth factor (VEGF)[32-34]. As relaxin and VEGF cannot be supplemented by drugs, the lack of these vasoactive substances in the programmed FET cycle may lead to the initial placental formation disorders or the decreased maternal circulation adaptation[30, 35, 36]. However, clinical observational studies cannot exclude the influence of other confounding factors, so its specific mechanism needs further research. In this study, FET patients could not distinguish between the programmed cycle and the natural cycle, because relevant information was not collected during the first part of data collection, so no further subgroup analysis was performed.
In addition, the difference of the pregnancy outcomes between different fertilization methods (IVF and ICSI) in this study was not significant. In reviewing the literature, the effect of ICSI on maternal pregnancy outcome remains controversial. The current consensus is that ICSI offspring have a higher risk of birth defects than normal pregnancy offspring and IVF offspring[37]. The results of this study also revealed that ART was associated with significantly higher odds of PTB, LBW, cesarean section, and placenta previa. These results are in line with those of previous studies[38-40].
The main advantage of this study is that it uses the high-quality registry data of the government health department to search and match the pregnancy outcomes and newborns of the subjects. The reliability and accuracy are significantly higher than the pregnancy outcomes obtained by telephone follow-up of reproductive centers. According to a report on 70 years of women’s reproductive, maternal, newborn, child, and adolescent health in China, by the end of 2019, there were 517 medical institutions approved to carry out human assisted reproductive technology in China[10]. However, in the follow-up of ART patients, patients are reluctant to cooperate due to the privacy of patients involved, and there is still no national ART reporting system with integrated information, leading to a high rate of lost follow-up of ART patients after childbirth in mainland China. Several high-quality multicenter prospective cohort studies are still in their infancy, the number of cases is still small[26]. Therefore, there are few studies and reports on maternal pregnancy outcomes after ART treatment in China in the past 20 years. The pregnancy outcomes involved in some studies are obtained from patients by the staff of the reproductive center through telephone follow-up. They are not professional in disease name and severity classification, and the data on birth weight and gestational week are not accurate enough, resulting in the results obtained by this survey method having a certain subjective impact and inaccurate. The research method of this paper can avoid this problem, make the results more accurate and have more reference value. At the same time, because it is a group survey, the result report does not involve the patient's personal privacy.
This study has some limitations. First, the data on ART treatment are from 10 different reproductive centers in Shanghai. We can't assess whether the specific operation processes are completely consistent. We can only consider that they are all qualified reproductive centers, which should be operated according to the specified operation specifications, and the sample size is sufficient, which can reduce this part of bias. Secondly, the patients in this study delivered in 111 hospitals in different districts and counties of Shanghai, and the standard of disease diagnosis and the control of medical history quality cannot be monitored. Therefore, we did not use the name of disease diagnosis for screening, but chose to use the ICD-10 code of disease to unify the standard, but we still cannot completely avoid the inaccurate clinical diagnosis. Third, our study is retrospective. When collecting the basic information of patients, we lack some possible interfering factors, such as the patient's race, occupation, pre-pregnancy BMI, smoking, alcohol abuse, etc. Most medical histories do not contain relevant information and are therefore excluded from the statistics. All the cases included in our study were female with household registration in Shanghai, so the influence of different races, different family backgrounds and dietary habits was relatively reduced, but the influence of pre-pregnancy BMI on the results could not be avoided. Finally, the cases in the natural pregnancy group came from the affiliated obstetrics and Gynecology Hospital of Fudan University, which is a AAA specialized hospital in Shanghai. District hospitals will choose to refer to the hospital when they encounter unmanageable twins, pregnancy complications and other high-risk pregnant women. Therefore, the proportion of natural pregnancy twins and pregnancy complications in this hospital will be higher than the average level in Shanghai. However, the incidence of ART group was still significantly higher than that of the control group. Considering that compared with the average level of the city, it is expected that the OR value will be higher.
Our study and literature strongly suggest that FET increase the risk of PIH/preeclampsia, but the specific influencing factors are not clear so far. Although some studies have reported that the use of hormone in programmed FET cycles leads to endogenous luteal deficiency, the specific mechanism remains to be further studied. As the influence of China's three-child policy, the utilization of FET is more and more widely, increasing number of elderly women with low fertility will be affected. This is of great significance for conducting relevant basic research to explore its mechanism, and standardizing the ART treatment process to avoid possible pathogenic risks and improve the safety of ART.