Pregnancy after in vitro fertilization: obstetric and perinatal risks

According to current statistics, the prevalence of infertility in marriages in the Russian Federation is up to 20% [1]. In Altai Krai, the prevalence is 15% and 19.3% in urban and rural populations, respectively [2]. Moreover, its prevalence is steadily increasing [1, 3]. Assisted reproductive technologies (ART) have become a popular method of treating infertility in the 21st century [1, 3]. This is evidenced by the annual increase in the number of reproductive centers and ART protocols [4]. However, despite more than 40 years of history in medical practice, ART still raises concerns regarding the risks to both the mother and fetus, which remain topics of scientific research and debate.

Some researchers believe that obstetric and perinatal risks depend primarily on the age and initial physical health of expectant parents [5]. On the other hand, other experts claim that pregnancy after ART is an independent risk factor for adverse maternal and perinatal outcomes [5, 6]. We conducted our study because of conflicting data on obstetric and perinatal complications, and neonatal risks in pregnant women following different ART techniques.

This study aimed to evaluate the incidence and structure of obstetric and perinatal complications in pregnant women of the Altai Krai, whose pregnancies resulted from in vitro fertilization (IVF).

Materials and methods

A retrospective analysis of the course of pregnancy and childbirth was initially performed in 127 patients whose pregnancies resulted from ART from 2020 to 2022. In 115/127 (90.6) pregnancies occurred after the standard IVF procedure, in 9/127 (7.1%) after cryopreserved transfer, and in 3/127 (2.4%) after intracytoplasmic sperm injection (ICSI). Pregnancy with one fetus occurred in 96/127 (75.6%) patients, and multiple pregnancies (twins) occurred in 31/127 (24.4%) patients. Considering that the most common ART method in Altai Krai is IVF, in the second stage, a retrospective comparative analysis of the course of pregnancy, childbirth, and perinatal outcomes was performed in 96 patients with a singleton pregnancy resulting from IVF (study group) and 96 patients with a spontaneous singleton pregnancy (control group).

This study was conducted at the Altai Center for Maternal and Child Health (Barnaul), which is the clinical affiliation of the Department of Obstetrics and Gynecology, Altay State Medical University (Chief Physician – Smirnov K.V., PhD).

Inclusion criteria were singleton pregnancy resulting from IVF and informed consent from patients for the use and publication of their personal data.

The exclusion criteria were multiple pregnancies, pregnancy after ICSI or cryopreserved transfer.

During the study, an analysis was carried out on the data presented in the main medical documentation (delivery notes and developmental histories of newborns and individual records of pregnant and postpartum women), including an assessment of the full set of general clinical data and the results of laboratory and functional research methods carried out in accordance with current regulatory documents [7].

Statistical analysis

Statistical analysis was performed using Statistica 11.0 and Microsoft Excel 2010. The distribution of continuous variables was tested for normality using the Shapiro–Wilk test. Continuous variables are presented as median (Me) with interquartile range (Q1; Q3); frequencies and percentages were reported for categorical variables. The Mann–Whitney U test was used to compare continuous variables between the groups. The Pearson's χ² test was used to compare categorical variables. Yates' correction was used when the expected frequencies were >5 or Fisher's two-tailed exact test (when expected frequencies were ≤5). The critical level of statistical significance for the differences (p) was defined as p<0.05 [8].

The study was reviewed and approved by the Research Ethics Committee of Altay State Medical University.

Results and discussion

Pregnant and postpartum women in the study groups were comparable in terms of age, parity, and other matching characteristics (Table 1). The median age was 34 years in the study group [(Q1; Q3)=(32; 36)] and 33 years in the control group [(Q1; Q3)=(31; 33)] (p=0.221). Most patients in the study group, 71/96 (74.0%), had secondary infertility. Peritoneal factor was the main cause of infertility and the need for ART. The median duration of infertility was four years [(Q1; Q3)=(2; 6)].

The frequency and structure of somatic pathology in patients of the study groups did not differ significantly, including chronic arterial hypertension (11/96 (11.5%) and 6/96 (6.3%); p=0.310), chronic diseases of the urinary system (16/96 (16.7%) and 14/96 (14.6%); p=0.099), varicose veins of the lower extremities (17/96 (17.7%) and 9/96 (9.4%); p=0.140), pathology of the thyroid gland, and subclinical hypothyroidism (20/96 (20.8%) and 10/96 (10.4%); p=0.074). It is believed that the presence of an increased body mass index in patients undergoing ART protocols not only reduces their effectiveness but also increases the risk of developing hypertension during pregnancy compared with patients with spontaneous pregnancy [3, 9]. The number of patients who were obese before pregnancy was almost identical between the study groups (16/96 (16.7%) and 15/96 (15.6%); p=1.000).

However, there are conflicting data in the scientific literature regarding the incidence of obstetric complications in pregnant women after ART. Lang M. et al. (2023) reported a 2-fold increase in the incidence of gestational hypertension and pre-eclampsia in pregnant women after ART compared to pregnant women with spontaneous pregnancy [10]. Wei D. et al. (2019) found an increased risk of gestational complications associated with arterial hypertension only after the use of cryopreserved transfer [6]. A study conducted by researchers from Turkey (2021), which included an analysis of the course of pregnancy in 10,929 patients, showed that the frequency of cholestasis during pregnancy in pregnant women after IVF was several times higher than that in the group of patients with spontaneous pregnancy [11]. Several authors have reported a higher incidence of preterm delivery and low birth weight in patients after ART [12].

We found no significant differences between the study groups in the incidence of arterial hypertension (6/96 (6.3%) and 7/96 (7.3%); p=1.000) and preeclampsia (late, moderate) (3/96 (3.1%) and 5/96 (5.2%); p>0.05), in terms of the incidence of pregnancy complications, such as isthmic cervical insufficiency requiring cerclage (12/96 (12.5%) and 7/96 (7.3%); p=0.334) and preterm delivery (8/96 (8.3%) and 7/96 (7.3%); p=1.000). According to Cavoretto P. et al. (2018), the risk of preterm birth is twice as high in patients who become pregnant after ART as in women who become pregnant spontaneously, including up to 34 weeks [13, 14]. At the same time, in our study, pregnant women after IVF (study group) had two times more gestational complications, such as anemia (54/96 (56.3%) vs. 24/96 (25.0%); p<0.001) and gestational diabetes mellitus (26/96 (27.1%) vs. 11/96 (11.5%); p=0.011).

The use of ART is considered an independent factor in the development of placental abnormalities and dysfunction [15]. As early as 2006, Romundstad L.B. reported a threefold increased risk of placenta accreta in patients whose pregnancy occurred as a result of ART [16], which was later confirmed by other researchers [17, 18]. Johnson K.M. et al (2020) reported that in patients using ART, ischemic disease of the placenta occurs 4 times more often in preterm and 1.7 times more often in term pregnancies [19]. The same data were obtained when the oocyte donation protocols were used [20].

In the present study, there were no cases of abnormal placentation in the group of pregnant women after IVF, but markers of placental dysfunction, such as uteroplacental blood flow disturbance according to Doppler measurements at the end of the third trimester and before delivery, were recorded 1.6 times more frequently than in the control group (40/96 (41.7%) and 25/96 (26.0%), respectively; p=0.033).

Pregnancy resulting from ART is not an indication for cesarean delivery. Previous studies have shown that the relative risk of cesarean delivery in primiparas over 35 years of age with a singleton pregnancy is 1.44–2.27 [5]. However, the cesarean section rate in pregnant women receiving infertility treatment with ART is quite high worldwide [21], which was also the case in our study. The high rate of cesarean sections in patients after IVF is due to the sum of the relative indications. Cesarean section is usually performed routinely (84.5%) in the interest of the fetus because of increased fear of adverse outcomes by both pregnant women and medical staff. Patients in the study group underwent cesarean delivery 2.8 times more often than those in the control group (71/96 (74.0%) and 25/96 (26.0%), respectively; p<0.001). In the group of patients who underwent operative delivery, planned operations predominated in the study group (60/71 (84.5%) and 9/25 (36.0%), respectively; p<0.001), whereas emergency operations were more frequent in the control group (11/71 (15.5%) and 16/25 (64.0%), respectively; p<0.001). The most common indication for emergency cesarean delivery in both groups was intrapartum fetal distress.

According to global statistics, perinatal outcomes in newborns of mothers whose pregnancies resulted from ART have a higher incidence of complications than those in the general population. For example, in an analysis of 425,732 singleton pregnancies, of which 10,235 were the result of ART, antenatal fetal death and stillbirth were significantly more common in women receiving ART [22, 23], as was the incidence of neonatal asphyxia and perinatal mortality [24, 25]. Ombelet W. et al. found a greater frequency of low birth weight for gestational age in women after ART [26], which indirectly indicates the presence of placental dysfunction during pregnancy.

In the present study, despite the higher incidence of placental dysfunction, anemia, and gestational diabetes mellitus in pregnant women after ART, the incidence of low-birth-weight newborns or, conversely, large fetuses in the study groups did not differ significantly and corresponded to the general population data. However, septal heart defects in newborns from mothers in the study group were detected eight times more often than in the control group (Table 2). Our results are consistent with those of the studies by Parizot E. et al. (2019) [27] and other researchers [28], who showed that during pregnancy achieved with the help of ART, the incidence of congenital malformations of the fetus, including heart defects, is higher than that in the general population of pregnant and postpartum women. According to Sung et al. (2021), women with a history of repeated implantation failure should be considered a high-risk group for congenital malformations in the fetus [29].

Perinatal central nervous system damage was observed 2 times more frequently in neonates born to mothers in the study group than in neonates born to mothers in the control group. In addition, perinatal central nervous system damage was classified as severe (p>0.05) in 3/96 (3.1%) infants born vaginally to mothers in the study group. In addition, despite the absence of significant differences in the frequency of most pathological conditions during the neonatal adaptation period, transient hypoglycemia was recorded six times more frequently in neonates of mothers in the study group than in those of the control group, which is directly proportional to the frequency of gestational diabetes in pregnant women after IVF.

Due to various complications of the adaptation period, newborns from mothers in the study group were transferred to the second stage of nursing twice as often as newborns from mothers in the control group.

Conclusion

The study results revealed that patients with singleton pregnancies resulting from IVF are at an increased risk of developing anemia, gestational diabetes mellitus, and placental dysfunction. This dysfunction is characterized by disturbances in uteroplacental blood flow, as indicated by Doppler measurements throughout gestation and before delivery. Additionally, newborns of these patients are susceptible to septal heart defects and transient hypoglycemia. These findings suggest the importance of close clinical observation by a highly skilled obstetrician-gynecologist for pregnant women after ART (IVF), who should collaborate with specialists from various fields, such as therapists, endocrinologists, and hematologists. Furthermore, delivery should be planned at a tertiary care center, as this allows for a targeted and comprehensive approach to address delivery methods, early detection of congenital malformations that may have been missed during pregnancy, and the provision of advanced neonatal care in the postnatal period.