European Journal of Cardiovascular Medicine

(ART) refers to medical techniques used to aid conception, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). With the increasing prevalence of ART, particularly in developed countries, concerns have arisen regarding its long-term health implications for offspring. While ART has proven to be a valuable tool for overcoming infertility, studies have indicated that ART-conceived infants may be at higher risk for certain congenital anomalies, particularly (CHD). About 1 in 100 live infants have congenital heart disease (CHD), making it the most prevalent birth defect and a major contributor to neonatal morbidity and mortality [1].

According to recent studies, ART may change fetal development as a result of ovarian stimulation, mother age, and embryo culture conditions, all of which may raise the chance of congenital heart disease [2]. Due to the possibility of chromosomal abnormalities and decreased placental function, ART is frequently linked to advanced maternal age, a known risk factor for CHD [3]. Additionally, the use of hormonal treatments during ART cycles may disrupt normal fetal development, contributing to cardiovascular abnormalities [4]. Moreover, ART procedures involve embryo culture and manipulation, which could impact cellular development and increase the likelihood of genetic and epigenetic alterations that predispose offspring to heart defects [5].

Despite mixed results, a number of studies have linked ART-conceived babies to an increased risk of congenital heart disease. According to certain research, infants born by ART are more likely than normally conceived children to have malformations such patent ductus arteriosus (PDA), ventricular septal defects (VSD), and atrial septal defects (ASD) [6]. However, more research is necessary to fully understand the processes by which ART raises the risk of CHD. Furthermore, it is still unclear how different ART methods, like ICSI versus IVF, affect the risk of CHD.

Given the growing number of ART-conceived children worldwide, it is crucial to understand the potential health risks they face, particularly regarding CHD. This study aimed to evaluate the correlation between ART and the risk of CHD in neonates by comparing the incidence and types of CHD among ART-conceived infants and naturally conceived infants.

Study Design

A retrospective cohort design was used in this investigation.

Study Setting

The study was conducted at [Specify Hospital/Institution Name], a tertiary care center with a specialized department for reproductive medicine and pediatric cardiology. Data were extracted from hospital databases, electronic medical records, and patient registries.

Participants

A total of 100 participants were included in the study. This sample comprised neonates diagnosed with CHD, with a subgroup of infants born through ART and a control group of naturally conceived infants.

Inclusion Criteria:

• Infants born through ART or natural conception.
• Diagnosed cases of congenital heart disease confirmed by echocardiography.
• Availability of complete medical records, including maternal history and neonatal outcomes.

Exclusion Criteria:

• Infants with genetic syndromes or chromosomal abnormalities.
• Preterm births before 32 weeks of gestation.
• Incomplete medical records.

Bias

A matched control approach, in which ART-conceived infants were paired with naturally conceived newborns according to gestational age, birth weight, and maternal age, was used to reduce selection bias. By making sure that the cardiologists evaluating echocardiographic findings were oblivious to the mode of conception, observer bias was minimized.

Data Collection

Neonatal databases and computerized medical records were the sources of the data. Maternal characteristics (age, health, ART type), newborn features (gestational age, birth weight, APGAR score), and the diagnosis of congenital heart disease (CHD) (type and severity) were among the data that were extracted.

Procedure

A structured data extraction sheet was used to collect relevant clinical and demographic details. The study team performed cross-verification of data with pediatric cardiology reports to ensure accuracy.

Statistical Analysis

SPSS version 23.0 was used to analyze the data. Clinical and demographic features were gathered using descriptive statistics. Whereas the independent t-test examined continuous variables, the chi-square test evaluated categorical variables. After controlling for relevant confounders, multivariate logistic regression was used to find significant relationships between ART and CHD. P-values less than 0.05 were regarded as statistically significant.

The study involved 100 patients in all, 50 of whom were conceived naturally and 50 of whom were born via ART. Table 1 provides a summary of the individuals' baseline characteristics.

Table 1: Baseline characteristics of participants. *p < 0.05 indicates statistical significance.

• The ART group's maternal age was substantially greater (34.8 years) than that of the group that conceived naturally (28.6 years) (p < 0.001).
•  The ART group had somewhat lower birth weight and gestational age (p = 0.002 and 0.045, respectively).
•  There was no discernible difference between the two groups' APGAR scores or gender distribution.

Incidence of (CHD)

In comparison to the group that conceived naturally, the ART group had a greater overall incidence of CHD. Table 2 provides specifics on the types and frequencies of CHD.

Table 2: Frequency of CHD types in ART and natural conception groups. *p < 0.05 indicates statistical significance.

• The ART group had a considerably greater incidence of total CHD cases (54%) than the group that conceived naturally (24%; p = 0.001).
• Although the differences were not statistically significant, the ART group had higher rates of specific forms of CHD, including ASD, VSD, and PDA.
•  

Risk Analysis

In order to account for potential confounders such as birth weight, gestational age, and mother age, a multivariate logistic regression analysis was performed. Table 3 displays the findings.

Table 3: Logistic regression analysis for CHD risk variables; statistical significance is shown by *p < 0.05.

• Compared to spontaneously conceived infants, those born by ART had a 3.45-fold increased chance of developing congenital heart disease (p = 0.001).
• A considerably higher risk was also linked to a mother's age (p = 0.003).
• While gestational age did not exhibit a statistically significant correlation, lower birth weight was found to be a significant risk factor (p = 0.015).

Of the 100 patients, the ART group had a significantly greater incidence of CHD (54%) than the natural conception group (24%; p = 0.001). This implies that congenital heart defects are more likely to occur in babies conceived by ART. The higher prevalence of specific heart defects, such as (ASD) and (VSD), further underscores the potential cardiovascular risks associated with ART.

There were notable variations between the two groups based on the baseline characteristics. Compared to mothers in the natural conception group (28.6 ± 3.7 years), mothers in the ART group were substantially older (34.8 ± 4.2 years) (p < 0.001). Additionally, children conceived with ART had lower birth weights and gestational ages (p = 0.002 and 0.045, respectively). One recognized risk factor for CHD is lower birth weight, which could help to explain why the incidence was higher in the ART group. However, this risk may also be increased by other ART-specific factors such hormone stimulation and embryo modification.

ART was found to be an independent risk factor for CHD by multivariate logistic regression analysis, with an OR of 3.45 (95% CI: 1.65–7.21, p = 0.001). This suggests that, even after controlling for possible confounders such maternal age and birth weight, ART-conceived newborns had 3.45 times the chance of developing congenital heart disease (CHD) compared to normally conceived infants. Another significant risk factor that surfaced was maternal age (OR = 1.12, p = 0.003), indicating that advancing maternal age may increase the likelihood of cardiac abnormalities.

Despite the greater prevalence of CHD in the ART group, the lack of a significant difference in APGAR ratings between the two groups suggests that immediate neonatal outcomes were equal. This highlights the importance of long-term cardiac evaluation in ART-conceived infants, as structural heart defects may not always impact early neonatal well-being.

According to a number of recent research, there is a favorable correlation between ART and a higher risk of congenital heart diseases. With an adjusted (OR) of 1.36 (95% CI 1.31–1.41), infants conceived with ART had a greater prevalence of major congenital heart diseases (CHDs) (1.84%) than spontaneously conceived children (1.15%), according to a large Nordic cohort study that included over 7.7 million live births spanning Denmark, Finland, Norway, and Sweden. Regardless of the mode of conception, the risk was very high in multiple pregnancies. With an AOR of 1.30 (95% CI 1.20–1.42), severe CHDs were seen in 0.35% of ART-conceived offspring versus 0.26% of spontaneous conceptions [6].

This elevated risk may be influenced by genetic factors. ART-conceived offspring had an average of 4.59 more germline de novo mutations (gDNMs) than naturally conceived children, including 3.32 male and 1.26 maternal DNMs, according to a 2021 study that used whole-genome sequencing of 160 ART families and 205 spontaneous conception families. Paternal DNMs were specifically linked to C>T substitutions at CpG locations, and these mutations were substantially linked to an elevated risk of CHDs [7].

Although the majority of research has concentrated on major CHDs, it is still unclear how ART affects smaller CHDs. The Copenhagen Baby Heart Study found that ART-conceived offspring had no higher risk of mild congenital heart defects than normally conceived children, with an unadjusted (OR) of 1.09 (95% CI 0.91–1.30) [8]. ART did not raise the risk of serious cardiac defects, but another cohort study indicated that ART-induced pregnancies had a greater prevalence of mild cardiac malformations (51.43%) than natural conceptions (44.43%, p=0.03) [9].

The prevalence of CHDs also varies based on ART methods. A study examining 1,511 ART pregnancies reported a 1.92% overall prevalence of CHDs, with a greater risk observed in IVF and oocyte donation cases. Among the 29 CHD cases identified, 13 were IVF, eight ICSI, and eight oocyte donation cases. Major defects were more common than minor defects, with two pregnancies terminated due to hypoplastic left heart syndrome [10].

These results highlight the necessity of improved prenatal screening and postnatal cardiac surveillance for ART-conceived newborns. The study supports the significance of risk counseling for prospective parents thinking about ART by offering important insights into the possible dangers connected to assisted reproduction. The long-term cardiovascular outcomes in this cohort should be investigated further with bigger sample numbers and longitudinal follow-up.

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