Comparison of pregnancy outcomes between IVF-ET pregnancies and spontaneous pregnancies in women of advanced maternal age

Abstract Aim To explore the impact of IVF on pregnancy complications and birth outcomes in women of advanced maternal age. Methods In this retrospective study, 3325 women were divided into the ART pregnancy group (n = 241) and the natural pregnancy group (n = 3086). The differences in maternal general conditions, pregnancy complications and birth outcomes were compared between the two groups. Results The ART group had higher rates of primiparity (78.4% vs 20.4%), cesarean section (90.5% vs 76.2%) and twin births (28.6% vs 2.1%). The risk of gestational hypertension (5.8% vs 2.9%), preeclampsia (5.0% vs 2.3%) and preterm birth [28 ∼ 31 + 6 weeks (2.9% vs 1.1%), 32 ∼ 33 + 6 weeks (5.0% vs 1.4%), 34 ∼ 36 + 6 weeks (15.8% vs 9.4%)] was significantly higher in the ART group than in the natural pregnancy group. Neonates in the ART group had lower birth weights (2882.61 ± 657.70 vs 3223.05 ± 534.28). However, in the singleton-only comparison, only gestational hypertension still showed a statistically significant difference. Conclusions For women of advanced maternal age, IVF-ET pregnancies may result in higher rates of pregnancy complications and adverse birth outcomes, but this is likely to be due to increased rates of multiple pregnancies.


Introduction
Pregnant women over the age of 35 are generally referred to as advanced maternal age (AMA) in clinical practice. Age is an independent factor in infertility, and as women's fertility declines with age, assisted reproductive technology (ART) has become an attractive option for many older women [1,2]. Older women may be at higher risk for pregnancy complications and adverse pregnancy outcomes, including hyperemesis, gestational diabetes mellitus (GDM), fetal growth restriction (FGR), neonatal death, and so on [3][4][5]. At the same time, despite the long and widespread clinical use of assisted reproductive technology (ART), its effects on pregnancy outcomes are still contentious. Part of the studies suggest that IVF increases the risk of obstetric complications such as twin pregnancies, preterm delivery, placenta praevia, gestational diabetes mellitus, and gestational hypertension [6,7].
Advanced age may put women with ART pregnancies at higher risk of pregnancy complications [8]. Conversely, the increased risk of maternal and neonatal outcomes associated with advanced age is probably exacerbated by ART treatment [9,10]. A retrospective study of very advanced maternal age (>45 years) women reported that those women who conceive on ART are more likely to have a cesarean delivery and retained placenta [11]. In general, current studies of advanced age women conceived with ART are more limited to pregnancy rates and live birth rates in ART cycles, and relatively little research has been done on whether ART further increases the risk of pregnancy complications and adverse birth outcomes in advanced maternal age. Therefore, we designed a retrospective study to examine the impact of ART on pregnancy outcomes (both maternal and fetal) in advanced maternal age greater than or equal to 35 years. divided these women into two groups by pregnancy mode, the natural pregnancy group (3084 cases) and the ART pregnancy group (241 cases). The ART group only included patients who underwent IVF-ET treatment. Neonates in both groups were live births at 28 weeks of gestation. We also excluded women with medical and surgical diseases such as hypertension, diabetes mellitus, heart disease, and immune system disorders before pregnancy, as well as women who had undergone multifetal pregnancy reduction (MFPR) and triplet pregnancies. The two groups were retrospectively analyzed to compare their maternal general conditions, maternal outcomes, and infant outcomes. Because this was a retrospective observational study, no ethical issues were involved.
Our study was statistically analyzed using SPSS 26.0 software. Data for continuous variables were expressed as mean ± SDs, and data for dichotomous variables were expressed as n (%). T-test, Fisher's exact test, and v 2 test were used to test the differences between the two groups, and p .05 was considered statistically significant.
This retrospective study conformed to the provisions of the Declaration of Helsinki, and it was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (number 2022-138).

Results
Maternal general conditions are shown in Table 1. The two groups of pregnant women were all of advanced maternal age, with both reaching an average age of approximately 37 years. Among them, ART pregnancies were significantly lower in gravidity, parity, and gestational week than spontaneous pregnancies. The majority of the ART group was primiparous and had a higher risk of cesarean delivery and twin births. The age and pre-pregnancy body mass index (BMI) of pregnant women in the two groups did not show statistical differences. Table 2 shows the maternal outcomes in both groups. In, the risk of gestational hypertension, preeclampsia, and preterm delivery was significantly higher in the ART group than in the natural pregnancy group. GDM, intrahepatic cholestasis of pregnancy (ICP), placenta praevia, premature rupture of membranes, and placental abruption did not show significant differences. And the differences in perinatal outcomes between the two groups were mainly in terms of weight. The ART group had a higher probability of low birthweight (LBW) and a lower probability of macrosomia compared to the natural pregnancy group.
The results changed after the exclusion of the twin pregnancies. Statistical differences disappeared for both maternal and fetal outcomes, except for hyperemesis (Table 2). When the ART group was compared into two subgroups, singleton and twin, women with twin pregnancies had notably shorter gestational weeks and an increased proportion of preterm births. Also, the birth weight of fetuses in the twin group was lower than in the singleton group, and the risk of low birthweight and very low birth weight (VLBW) was significantly increased, and the incidence of macrosomia is reduced (Table 3).

Discussion
Advanced age is a common risk factor for high-risk pregnancies. According to previous studies, although still controversial, advanced age has been widely associated with the risk of adverse pregnancy outcomes [1,12]. In addition to the increased risk of developing chronic diseases before pregnancy with age, advanced age may also raise the probability of late obstetric complications such as hyperemesis gravidarum and GDM [13]. If ART is a factor contributing to the enhanced risk of pregnancy, then women of advanced maternal age who have opted for ART due to reduced fertility may be at higher risk. If ART is a factor contributing to the increased risk of pregnancy, women of advanced age who have chosen to conceive with ART due to reduced fertility may be at higher risk.
In our study, the maternal general conditions of the two groups showed significant differences, except for BMI and age (probably because the inclusion condition of advanced age was already screened for maternal age). Mothers in the ART group had a higher risk of cesarean delivery and twin pregnancies, which is consistent with previous studies [6,14]. Overall, in this study, women who conceived with ART had a higher risk of pregnancy relative to those who conceived spontaneously, including higher rates of gestational hypertension, pre-eclampsia, preterm birth, and LBW. This finding is consistent with many previous studies. But comparing the results for singleton pregnancies alone resulted in a statistical disappearance of the difference, suggesting that the difference in risk for adverse pregnancy outcomes between the two groups is likely due to women in the ART group having a higher rate of twin pregnancies. When excluding the effect of twin pregnancies, the risk of developing hyperemesis remained markedly different. However, although the incidence of preeclampsia was slightly higher in the ART group than in the spontaneous pregnancy group at this time (4.1% vs 2.3%), it did not show a statistical difference, which may be related to the small sample size. The relationship between gestational hypertension and ART has been investigated by many scholars in the past, which is contradictory and controversial. Some studies have reported that ART increases the incidence of hypertensive disorders during pregnancy, and this is consistent with our results. [15][16][17]. However, several other studies have suggested that the association is confounded by multiple pregnancies (our study ruled out this confusion by examining singleton pregnancies) [18,19]. The occurrence of gestational hypertension and preeclampsia may be related to the protocol of the transfer. One study investigated the relationship between hypertensive disorders of pregnancy and corpus luteum and found that frozen embryo transfer in artificial cycles led to an increased incidence of preeclampsia because of the lack of corpus luteum compared to fresh embryo transfer [20]. However, two Japanese studies came to the opposite conclusion, arguing that  ART could instead reduce the incidence of hyperemesis, although the effect of a small sample size cannot be ruled out [21,22]. Our study itself has excluded women with a history of hypertension before pregnancy, but in actual clinical practice, the older the woman, the greater the likelihood of comorbid hypertension. Age 35 years or older is a moderate risk factor for pre-eclampsia [23]. Combining the results of this study and some other studies, for women with advanced maternal age on ART, special attention should be paid to the possibility of hypertension and the management of blood pressure. Low-dose aspirin may be used to prevent pre-eclampsia in the presence of a combination of other intermediate or high-risk factors [24].
IVF-ET could result in multiple pregnancies, with twin pregnancies being the most common. Twin pregnancies may adversely affect multiple systems of the fetus as well as the mother, causing various complications such as preterm delivery, miscarriage, fetal growth restriction, gestational hyperemesis, GDM, and increased perinatal mortality of the mother [25,26]. In this study, the comparison between the two subgroups of the ART group also showed that twin pregnancies may be associated with a higher risk of low birth weight and preterm infants, suggesting that twin pregnancies remain an independent risk factor in women of advanced age who conceived with ART. In general, multiple pregnancies may be an important source of risk caused by ART. Transferring a single embryo may reduce the incidence of multiple pregnancies and improve the perinatal safety of women. Studies have reported that transferring a single blastocyst is effective in reducing the risk of pregnancy, including twin pregnancies, with no significant difference in live birth rates compared to double cleavage embryos [27]. The ultimate goal of IVF is to meet the fertility needs of couples. However, the safety of the mother and fetus is a long-term and significant indicator of IVF. We should promote age-appropriate fertility to circumvent the effects of advancing age. When advanced age is inevitable, the dual difficulties of reduced ART success and increased pregnancy risk should be traded off on a case-by-case basis between improving pregnancy rates and reducing pregnancy risk. Although the pregnancy and live birth rates are not as high as those of double blastocyst transfer [27,28], single blastocyst transfer is a better compromise for women of advanced age. Additionally, these women should be encouraged to perform pre-pregnancy counseling. Active pre-pregnancy preparation, including weight control, smoking and alcohol cessation and other healthier lifestyles can also help reduce the incidence of pregnancy complications.
Our center is higher level (provincial) hospitals located in Southwest China. The maternal population delivered here is complex and includes more difficult patients, so the overall rate of obstetric complications and cesarean deliveries is likely to be above the average for mainland China [6]. This may lead to an underestimation of the obstetric risks associated with ART. In addition, only live births after 28 weeks were selected for our study; late miscarriages and intrauterine fetal deaths were not included, and we lacked an assessment of these partial risks. For women undergoing IVF-ET, we did not classify them in terms of ovarian stimulation protocol, embryo transfer protocol, and number of embryos transferred. Therefore, we could not further clarify the source of risk. In addition, we did not distinguish the cause of maternal infertility, so the possible impact of the primary condition causing infertility on pregnancy outcome confounded the results.

Conclusion
In advanced maternal age greater than or equal to 35 years, women who conceive with ART may be at higher risk for cesarean delivery, obstetric complications, and adverse fetal outcomes. But most of the increased risk, with the exception of gestational hyperemesis, may be related to the increased rate of twin pregnancies. Therefore, we need to pay attention to the control of blood pressure in advanced maternal age and to minimize the occurrence of multiple pregnancies in ART treatment.