Assisted Reproductive Technology and the risk of Fetal Congenital Heart Disease: insights from a Tertiary Care Referral Centre.

Assisted Reproductive Technology and the risk of Fetal Congenital Heart Disease: insights from a Tertiary Care Referral Centre. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assisted Reproductive Technology and the risk of Fetal Congenital Heart Disease: insights from a Tertiary Care Referral Centre. Linda Piemonti, Laura Vettor, Anna Balducci, Antonio Farina, Elena Contro This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4456271/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Aug, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose To investigate whether congenital heart diseases exhibit higher rates in pregnancies achieved through assisted reproductive technology (ART) compared to natural conception. Methods In this retrospective cohort study, multinomial logistic regression was employed to analyze the relationship between categories of congenital heart diseases and three conception groups (IVF, ICSI and natural pregnancies). The main outcome measure are risks of congenital heart disease categories in IVF and ICSI groups using the natural group as reference. We selected fetuses referred for fetal echocardiography to IRCCS Policlinico Sant’Orsola, Bologna, between January 2005 and November 2023, diagnosed with congenital heart diseases. Results We categorized the congenital heart diseases into six groups based on anatomical and embryological criteria. The estimated risk of left ventricular outflow tract, valvular, conotruncal and atrioventricular septal defects was lower in the IVF group compared to natural conception. The estimated risk of valvular and atrioventricular septal defects was lower in the ICSI group vs natural. Conversely, the risk for right heart anomalies was higher both in the IVF and ICSI groups compared to natural conception. Heart rhythm diseases were more frequent in IVF pregnancies. When comparing ART methods, valvular defects, conotruncal defects, and right heart anomalies were more frequently observed in the ICSI group, while atrioventricular septal defects were more common in the IVF group. Conclusion Significant differences were found in the occurrence of congenital heart diseases in pregnancies conceived through IVF and ICSI, versus those conceived naturally, underscoring the importance of further studying the underlying mechanisms of these associations. Congenital heart defects assisted reproductive technology intracytoplasmic sperm injection in vitro fertilization fetal What does this study adds to the clinical work This study reveals significant differences in the occurrence of specific congenital heart disease categories between pregnancies conceived through ART and those conceived naturally. These findings underscore the need for further research to understand the mechanisms linking ART to CHD development. Introduction Congenital heart defects (CHD) stand as the most prevalent birth abnormalities and constitute a leading cause of infant mortality. Variations in definitions, population characteristics, and diagnostic methods result in a wide range of prevalence estimates. In Europe, the average total prevalence of CHD is 8.0 per 1000 births, with a live birth prevalence of 7.2 per 1000 births, varying between countries [ 1 ]. The utilization of Assisted Reproductive Technology (ART) has experienced a significant rise in recent years, particularly with the adoption of oocyte and sperm donation. In the United States, approximately 1.9 percent of all births result from ART [ 2 ] while Italy has experienced a significant increase in the rate of ART-conceived births over the past fifteen years, reaching 3.7 percent of all births in 2022 [ 3 ]. It is well established that conception through ART is associated with obstetric and perinatal complications, including multiple gestations, preterm delivery, low birth weight, and congenital anomalies. Reviews and meta-analyses have consistently shown that the risk of congenital anomalies is potentially increased by approximately one-third compared to pregnancies conceived naturally [ 4 , 5 ]. However, uncertainties persist regarding the risks of birth defects, especially CHD. Particularly, the incidence of CHD differs greatly from study to study. The incidence of moderate and severe forms of CHD is approximately 6 per 1,000 live births. However, the overall incidence increases to 75 per 1,000 live births if minor forms such as tiny muscular Ventricular Septal Defects (VSD) present at birth and other trivial lesions or variants are included [ 6 ]. A recent major meta-analysis showed that the risk of CHD in intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) pregnancies is significantly higher, by approximately 50%, compared to naturally conceived pregnancies [ 7 ]. Despite these findings, consensus regarding the clinical utility of performing fetal echocardiography in ART pregnancies remains elusive with conflicting recommendations provided by different scientific societies [ 8 ]. Furthermore, conflicting data in the literature regarding the specific subtypes of CHD further complicates the matter. Despite advances in prenatal diagnosis, the medical and surgical management of infants with CHD still carries high risks of morbidity and mortality, especially for severe cases. The etiology of CHDs is largely unknown, with only less than 15% of cases linked to known genetic anomalies. Non-syndromic congenital defects have diverse causes, including environmental factors, maternal diabetes, phenylketonuria, maternal obesity, alcohol use, rubella infection, febrile illnesses, certain drugs (e.g., thalidomide), exposure to solvents or herbicides, maternal age over 40, and paternal age over 35 [ 9 ]. The remaining non-syndromic CHD cases have a multifactorial etiology, suggesting interaction between various genetic and environmental factors [ 10 ]. The role of ART remains uncertain and clarifying the link between ART and CHDs is of paramount importance for both clinicians and couples considering fertility treatments. We aim to determine if there is an association between CHD and different ART methods. In this paper, we present original findings from a cohort study and discuss the possible implications for clinical practice and future research. Materials and Methods In this retrospective cohort study, the authors selected all natural and ART pregnancies (IVF and ICSI, homologous and heterologous) referred for fetal echocardiography to IRCCS Policlinico Sant’Orsola, Bologna, between January 2005 and November 2023 diagnosed with CHD. The indications for the exams were: suspected fetal cardiac structural anomaly or abnormality of cardiac function (e.g. cardiomegaly, hydrops fetalis, irregular cardiac rhythm); fetal extracardiac anomaly; first or second-degree relatives with CHD (parents, siblings, half-siblings); first or second-degree relative with Mendelian inheritance disease and a history of childhood cardiac manifestations; patients diagnosed with pregestational diabetes or any type of CHD. Maternal history and characteristics, gestational age, type of ART and CHD were retrospectively extracted from ultrasound reports. Twin pregnancies, fetuses identified with genetic anomalies via invasive diagnostic procedures or having multiple structural anomalies affecting different organs were excluded. Considering the lack of demographic and clinical data, we opted to exclude patients with a Body Mass Index (BMI) over 35, or those with type 1 or type 2 diabetes where known. The study population was composed by two main groups: ART pregnancies diagnosed with CHD and subsequently divided according to the technique (IVF; ICSI); natural pregnancies diagnosed with CHD. In order to study the possible association of types of CHDs with ART techniques, we introduce a classification of CHDs based on the anatomical and embryological origin of the defects, which were classified into six subcategories each containing a set of anomalies: Left Ventricle Outflow Tract disease (LVOT); Conotruncal abnormalities (CNTRA); Valvular Diseases (VD); Right Heart Anomalies (RHA); Atrioventricular Septal Defects (AVSD); Heart Rhythm Diseases (HRD). Further information is shown in Table 1 . Due to the low incidence, we did not evaluate situs anomalies, and anomalous pulmonary venous connection. This classification addresses the challenge of investigating specific CHDs despite limited data availability. All ultrasound cardiac assessments were carried out by a group of experienced senior operators, including fetal cardiologists and subspecialists in fetal medicine with expertise in fetal cardiac scanning. All cardiac ultrasound scans adhered to ISUOG guidelines, encompassing the 4-chamber view, outflow tracts, three vessels and tracheal view, aortic and ductal arches views, and the inferior and superior vena cava view [ 11 , 12 ]. Color Doppler was applied to these views, along with M-mode and spectral Doppler/Color Doppler. The ultrasound machines used during the study period were Voluson E8 or E10 (GE Healthcare, Austria) equipped with multifrequency convex transducers. Demographic data were analyzed using routine tests. For statistical analysis, each subject in the three groups (natural, IVF, ICSI) was assigned a weight proportional to the inverse of the size of its respective group. This weighting strategy aims to allocate an equal "a-priori" risk to each type of CHD across the three groups, thereby ensuring a balanced representation of subjects within each group. Multinomial logistic regression adjusted for maternal age was employed to model the relationship between each CHD category and the three groups of patients, taking into account data weighting. Under this approach, a multivariable patient-specific-risk of belonging to each of the three groups is calculated for each CHD category (whether isolated or in combination). These risks are mutually exclusive, ensuring that the total risk across the three groups always sums to 100%. Comparison of the patient-specific-risk distributions among and between groups was performed using ANOVA and Bonferroni post hoc test. A p-value < 0.05 was considered statistically significant. As for statistical analysis, the SPSS version 27.0 (IBM Corp. Released 2020. IBM SPSS Statistics) was adopted. Table 1 Classification of CHD according to the anatomic and embryological development SUBCATEGORY OF CHD TYPE OF CHD AVSD Atrioventricular septal defect Ventricular septal defects Atrial septal defects Common atrium/cor biventricular Univentricular Heart CNTRA Transposition of great arteries Tetralogy of Fallot Double outlet right ventricle Double outlet left ventricle Truncus arteriosus HRD Persistent supraventricular tachycardia Atrial Extrasystole Ventricular Extrasystole LVOT Hypoplastic left syndrome disease Interruption or anomalies of aortic arch Atresia or Coarctation of aorta RHA Hypoplastic right heart syndrome Idiopatic right heart cardiomegaly Right ventricle hypoplasia Right atrial enlargement VD Defects of pulmonary valves (atresia; dysplasia; stenosis; insufficiency) Ebstein’s anomaly AVSD atrioventricular septal defects; CNTRA conotruncal abnormalities; HRD heart rhythm disease; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases Results Table 2 resumes the demographic data of the study population. As shown, maternal age was significantly higher in ART groups compared to natural pregnancies. Among the 656 cases of CHDs, the majority, 588 (89.6%), were natural pregnancies, 30 (4.6%) were conceived through IVF, and 38 (5.8%) through ICSI. All cases were categorized into six distinct groups based on anatomical and embryological criteria: AVSD (213/656, 32.5%), CNTRA diseases (219/656, 33.4%), LVOT defects (203/656, 30.9%), VD (136/656, 20.7%), RHA (26/656, 4%), and HRD (16/656, 2.4%). The most frequent combinations of CHD’s categories included AVSD + CNTRA (8.5%), AVSD + LVOT (6.3%), and AVSD + VD (5.8%). All categories’ frequencies are shown in Table 3 . To comprehensively evaluate the patient-specific-risk associated with each CHD’s category, we calculated the risk considering both cases where the category was isolated and those where it co-occurred with others. This approach resulted in a single patient-specific-risk estimation encompassing both isolated and combined CHD’s occurrences, leading to more observations than individual cases, thus ensuring a thorough evaluation of the risk associated with each type of CHD. After adjusting for maternal age and CHD patterns, we found that the mean estimated patient-specific-risk of CNTRA, AVSD, LVOT and VD was significantly lower in IVF group compared to the natural one. The estimated mean patient-specific-risk of CNTRA was higher in ICSI group versus natural pregnancies, while it was lower for AVSD and VD, and non-significant for LVOT. Conversely, the mean patient-specific-risk for RHA was significantly higher both in IVF and ICSI groups compared to natural conception. HRDs were significantly more frequent in IVF versus natural pregnancies, and no cases were found in the ICSI group. When comparing ART methods, it emerged that CNTRA, VD, and RHA were more frequently observed in ICSI, while AVSD was more common in IVF. The distributions of the most prevalent association of CHD’s categories revealed that the estimated mean patient-specific-risk quoted for AVSD + CNTRA, AVSD + LVOT, and AVSD + VD were more frequent in natural pregnancies. Notably, a higher mean patient-specific-risk of AVSD + CNTRA was observed in ICSI vs IVF. For a summarized view of the results refer to Table 4 . Table 2 – Demographic data of the study population including natural, IVF, and ICSI pregnancies Variable Natural pregnancies (n = 588) IVF pregnancies (n = 30) ICSI pregnancies (n = 38) p-value Maternal Age (mean ± SD) 32.4 ± 5.52 37.5 ± 5.60 38.4 ± 4.42 < 0.001 (α, β, δ) Gestational Age (mean ± SD) 26.5 ± 5.4 25.1 ± 5.9 24.1 ± 4.5 ns (α, δ) 0.020 (β) Nullipara (%) 48.5 23.3 18,4 < 0.001 (α, β, δ) α Natural pregnancies vs IVF pregnancies; β Natural pregnancies vs ICSI pregnancies; δ IVF pregnancies vs ICSI pregnancies; ns non-significant Table 3 , Frequencies of CHD’s categories among the study population CHD’s categories Natural pregnancies (%) IVF pregnancies (%) ICSI pregnancies (%) Total (%) AVSD 111 (16.9) 7 (1.1) 6 (0.9) 124 (18.9) AVSD HRD 1 (0.2) 0 0 1 (0.2) AVSD LVOT 35 (5.3) 3 (0.5) 3 (0.5) 41 (6.3) AVSD LVOT VD 5 (0.8) 0 0 5 (0.8) AVSD RHA 4 (0.6) 0 0 4 (0.6) AVSD VD 37 (5.6) 1 (0.2) 0 38 (5.8) CNTRA 99 (15.1) 5 (0.8) 12 (1.8) 116 (17.7) CNTRA AVSD 53 (8.1) 1 (0.2) 2 (0.3) 56 (8.5) CNTRA AVSD HRD 1 (0.2) 0 0 1 (0.2) CNTRA AVSD LVOT 6 (0.9) 0 0 6 (0.9) CNTRA AVSD LVOT RHA 1 (0.2) 0 0 1 (0.2) CNTRA AVSD RHA 1 (0.2) 0 0 1 (0.2) CNTRA AVSD VD 6 (0.9) 0 0 6 (0.9) CNTRA LVOT 9 (1.4) 0 0 9 (1.4) CNTRA LVOT VD 4 (0.6) 0 0 4 (0.6) CNTRA VD 19 (2.9) 0 0 19 (2.9) HRD 9 (1.4) 3 (0.5) 0 12 (1.8) LVOT 120 (18.3) 5 (0.8) 8 (1.2) 133 (20.3) LVOT HRD 1 (0.2) 0 0 1 (0.2) LVOT VD 3 (0.5) 0 0 3 (0.5) RHA 8 (1.2) 2 (0.3) 0 10 (1.5) VD 49 (7.5) 3 (0.5) 3 (0.5) 55 (8.4) VD RHA 5 (0.8) 0 4 (0.6) 9 (1.4) VD RHA HRD 1 (0.2) 0 0 1 (0.2) Total 588 (89.6) 30 (4.6) 38 (5.8) 656 (100.0) AVSD atrioventricular septal defects; CHD congenital Heart Disease; CNTRA conotruncal abnormalities; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases; HRD heart rhythm disease Table 4 Mean estimated patient specific risk (%) and interquartile range of each CHD when occurring alone or in combination, calculated using weighted multinomial logistic regression across the three study groups. ANOVA and Bonferroni post hoc tests were conducted, assuming an equal number of observations among the three groups, as available for the natural group. Due to the occurrence of multiple CHDs in the same patient, the number of observations exceeds the number of cases. Quantitative maternal age was used as covariate. Only most frequent combination are reported. CHD (n) Natural pregnancies (n = 588) IVF pregnancies (n = 30) ICSI pregnancies (n = 38) p-value ( α) p-value ( β) p-value ( δ) CNTRA (219) 37.29 (25–49) 22.04 (18–25) 40.67 (29–48) < 0.001 0.011 < 0.001 AVSD (213) 39.15 (18–59) 35.28 (19–51) 25.57 (22–30) 0.036 < 0.001 < 0.001 LVOT (203) 35.99 (22–52) 30.67 (25–36) 33.35 (25–40) 0.001 0.202 0.189 VD (136) 40.08 (25–47) 25.14 (23–29) 34.79 (24–41) < 0.001 0.046 < 0.001 RHA (26) 16.50 (4–23) 32.34 (24–42) 51.16 (50–53) < 0.001 < 0.001 < 0.001 HRD (16) 18.11 (10–20) 81.88 (75–89) - < 0.001 - - AVSD + CNTRA (56) 62.75 (54–69) 14.85 (12–18) 22.39 (12–78) < 0.001 < 0.001 0.002 AVSD + LVOT (41) 58.14 (48–61) 22.03 (19–28) 19.83 (18–24) < 0.001 < 0.001 0.734 AVSD + VD (38) 66.52 (47–75) 17.01 (12–27) 16.47 (13–24) < 0.001 0.99 α Natural pregnancies vs IVF pregnancies; β Natural pregnancies vs ICSI pregnancies; δ IVF pregnancies vs ICSI pregnancies; AVSD atrioventricular septal defects; CHD congenital Heart Disease; CNTRA conotruncal abnormalities; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases; HRD heart rhythm disease Discussion Over the past few decades, the use of ART has substantially increased, providing a chance to conceive to many couples struggling with infertility. However, emerging evidence suggests a potential link between ART and an increased risk of fetal CHDs [ 9 ], although findings are inconclusive, leaving the discussion ongoing. Our study confirms very different rates of CHD categories in ART-conceived pregnancies compared to natural conception. While they highlighted a higher risk of congenital and chromosomal defects in ART pregnancies, particularly male urogenital defects and CHD, the authors concluded that ART procedures are generally safe [ 13 ]. Additionally, Kermani et al. indicated a significant elevation in the risk of major congenital malformations among singleton infants conceived through ART, with CHDs being prominently reported. This underscores the importance of considering the mode of conception when assessing CHD risk [ 14 ]. Similarly, Shechter-Maor et al. conducted an assessment of birth anomalies among all live births in the United States and observed that infants conceived through ART faced a twofold higher risk of experiencing one of the evaluated birth defects, with CHDs being particularly prevalent in the ART group [ 15 ]. Moreover, Talebi et al. revealed a higher occurrence not only of all types of CHDs but also of endothelial dysfunction, morphological changes, and increased vascular stiffness in infants conceived through ART compared to those conceived naturally, which is indicative of a heightened risk for premature cardiovascular issues. Consequently, the authors emphasized the necessity for increased monitoring through fetal echocardiography and postnatal cardiovascular assessment [ 16 ]. Nevertheless, the precise mechanisms linking ART and CHD remain unclear, with proposed hypotheses including the influence of underlying parental factors such as advanced maternal age, maternal comorbidities, and parental subfertility, which are more prevalent among couples undergoing ART procedures [ 7 ]. The pathogenesis of CHD itself remains a highly debated topic, encompassing genetic causes and maternal characteristics including comorbidities (e.g., obesity, diabetes) and behavioral factors (i.e., alcohol, drugs, smoking). Interestingly, women undergoing ART are educated about maintaining proper weight, abstaining from smoking and alcohol, suspending potentially harmful therapies, and early integration of folic acid. Therefore, the ART population is complex to investigate due to its dual nature: exposed to certain major risks (e.g., older age, subfertility, comorbidities like diabetes and hypertension) while protected from others (e.g., obesity, smoking, alcohol, lack of folates) [ 15 ]. Despite potential confounding factors, the manipulation of gametes and embryos during ART procedures, alongside hormonal stimulation protocols, may impact embryonic development and contribute to the higher risk of CHDs [ 9 ]. Contrasting evidence exists; Anzola et al. found no differences in congenital anomalies prevalence between babies conceived by fresh versus frozen embryo transfer after IVF [ 17 ]. Moreover, recent studies have attempted to synthesize data from available literature. Gullo et al. indicated an increased risk of minor CHDs among ART-conceived pregnancies compared to natural ones [ 9 ]. Conversely, Shamshirsaz et al. discovered a significantly higher risk for cyanotic congenital heart diseases (cCHDs) among infants conceived through ART (adjusted relative risk (aRR) 2.4, 95% CI 2.1 to 2.7) and non-ART fertility treatments (aRR 1.9, 95% CI 1.6 to 2.2) compared to naturally conceived infants [ 18 ]. In addition, contrasting data come from a cohort population study conducted by Iwashima et al., in which no significant differences were detected through echocardiography screening in the prevalence of CHD and severe CHD between women who conceived naturally and those who underwent ART [ 19 ]. A recent meta-analysis by Giorgione et al., indicates that the likelihood of CHDs is elevated in ART pregnancies compared to those conceived naturally (odds ratio (OR) = 1.45). However, when analyzing the qualitative distribution of CHD types, the heightened risk was statistically significant only for smaller CHDs like VSD [ 7 ]. This was also confirmed by Aderibigbe et al. in their study, where a prevalence of minor cardiac disorders, particularly VSD, is reported among pregnancies conceived through ART [ 20 ]. At the current state, the association with major CHDs remains a point of contention, with inconsistent findings reported across various studies. Given the heterogeneous nature of these conditions, it's crucial to consider how different subtypes of CHDs are associated with ART in order to better understand the potential implications of ART procedures on fetal cardiac development. Tararbit et al., drawing from the Paris registry of congenital malformations, identified a heightened risk for certain CHDs among fetuses conceived through IVF and ICSI, independently of chromosomal abnormalities [ 21 ]. The study suggests a stronger association of CHDs with ICSI compared to IVF and emphasizes that the choice of CHD classification can influence study outcomes, prompting the suggestion to utilize an embryological classification for analyzing the etiopathological role of ART in CHD development. They also examined increased risk in major CHD, signaling a specific rise in Tetralogy of Fallot (TOF) cases. ART was associated with a 2.4-fold higher risk of TOF after adjustment for maternal age, occupation, geographic origin, paternal age and year of birth; ICSI was specifically associated with a 3-fold higher risk of TOF. This has led to an etiopathogenetic hypothesis implicating an altered neural crest cell development in conotruncal heart defects in ART pregnancies, particularly ICSI-conceived [ 22 ]. A subsequent retrospective cohort study conducted by Galdini et al. highlighted an increased prevalence of major CHD in fetuses conceived through ART compared to natural pregnancies, notably TOF and Hypoplastic Left Heart Syndrome. However, when considering specific techniques, it presents conflicting data showing a stronger association with IVF rather than ICSI [ 23 ]. Along with the literature, our study identifies ART as a risk factor for CHD. We found that isolated RHA prevails both in IVF and ICSI pregnancies when compared to natural conception. HRD are more frequent in IVF pregnancies versus natural conception, though none data was available for ICSI pregnancies. Lastly, isolated CNTRA are more prevalent in ICSI pregnancies compared to natural conception. When comparing ART methods, it emerges a higher rate of isolated AVSD in IVF-conceived pregnancies, though we must precise that AVSD category also included minor septal defects. Whereas, CNTRA defects isolated and in combination with AVSD, VD and RHA appear to be more frequent in ICSI-conceived pregnancies. According to our results, taking into account that ART implies a major risk of cardiac anomalies, the type of ART technique plays a fundamental role in defining the severity and type of CHD. Overall, while the existing literature provides valuable insights into the association between ART and CHDs, discrepancies and uncertainties remain because strong levels of evidence are missing, and more prospective and case-control studies are needed. Indeed, guidelines are divergent regarding the indication to refer all ART-conceived pregnancies for an echocardiography. The American Heart Association (AHA) guidelines recognize IVF/ICSI conception as a maternal indication for fetal echocardiography with a recommendation class/level of evidence IIa/A estimating an absolute risk of 1.1–3.3% among live births.[ 24 ] Evenly, the International Society of Ultrasound in Obstetrics & Gynecology (ISUOG) [ 11 ] recognize ART conception, both IVF and ICSI, as a possible indication for fetal echocardiogram, whereas the American Society of Echocardiography (ASE) considers only IVF as a possible indication [ 25 ]. The National Guidelines for Ultrasound in Obstetrics and Gynecology published by Società Italiana di Ecografia Ostetrica e Ginecologica (SIEOG) states that considered the still unclear association between major CHD and ICSI, ICSI is not to be considered an indication for carrying out fetal echocardiography [ 26 ]. In addition, according to the analysis of Chung et al., the cost-effective method of screening for CHDs in IVF or ICSI conceived pregnancies, is to perform a fetal echocardiogram only when a cardiac anomaly is noted during a detailed anatomy ultrasound [ 27 ]. We report the experience of one of the largest tertiary care centers in northern Italy. The main limitation of our study is the retrospective design, anyway, considering the rarity of these conditions a prospective study would result very difficult. Further research, including large-scale multicentric prospective studies, is essential to elucidate the underlying factors contributing to CHD development in ART-conceived offspring and to guide clinical decision-making and counseling for couples undergoing ART procedures. Our study is therefore situated within this line of research. Conclusion Our research findings indicate noteworthy differences in the occurrence of CHDs between pregnancies conceived through ART and those conceived naturally. Additionally, we demonstrated distinct prevalence of specific CHD categories among different ART methods, highlighting a stronger association of CHD with ICSI compared to IVF, particularly with a higher prevalence of severe CHDs like conotruncal anomalies in ICSI-conceived pregnancies. In conclusion, further research is essential to understand the impact of ART procedures on fetal cardiac development, considering the diverse range of CHD subtypes associated with ART, and to clarify the clinical implications of these associations. Declarations Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Author Contributions: Piemonti Linda: Project development; Data collection and management; Data analysis; Manuscript writing Vettor Laura: Project development; Data collection; Manuscript writing Balducci Anna: Project development; Manuscript editing Farina Antonio: Data management; Data analysis; Manuscript editing Contro Elena: Project development; Manuscript editing Ethical approval: This is an observational retrospective cohort study. The Research Ethics Committee has confirmed that no ethical approval is required. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: Informed consent was obtained from all individual participants included in the study. Data sharing statement: The data that support the findings of this study are available from the corresponding author, [LP, AF], upon reasonable request. References Dolk H, Loane M, Garne E, a European Surveillance of Congenital Anomalies (EUROCAT) Working Group (2011) Congenital Heart Defects in Europe: Prevalence and Perinatal Mortality, 2000 to 2005. Circulation 123(8):841–849 Sunderam S, Assisted Reproductive Technology Surveillance United States (2017), US Dep Health Hum Serv Cent Dis Control Prev - Morb Mortal Wkly Rep. 2020;69(9). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755269/pdf/ss6909a1.pdf Certificato di assistenza al parto (CeDAP) Analisi dell’evento nascita Anno (2022) Minist Della Salute Direzione Gen Della Digit Sist Inf Sanit E Della Stat – Uff Stat. 2023 Oct https://www.salute.gov.it/portale/documentazione/p6_2_2_1.jsp?lingua=italiano&id=3346 Cavoretto P, Candiani M, Giorgione V, Inversetti A, Abu-Saba MM, Tiberio F et al (2018) Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta‐analysis of cohort studies. Ultrasound Obstet Gynecol 51(1):43–53 Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A (2012) Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 18(5):485–503 Hoffman JIE, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900 Giorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A et al (2018) Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 51(1):33–42 Quaresima P, Fesslova V, Farina A, Kagan KO, Candiani M, Morelli M et al (2023) How to do a fetal cardiac scan. Arch Gynecol Obstet 307(4):1269–1276 Gullo G, Scaglione M, Laganà AS, Perino A, Andrisani A, Chiantera V et al (2023) Assisted Reproductive Techniques and Risk of Congenital Heart Diseases in Children: a Systematic Review and Meta-analysis. Reprod Sci 30(10):2896–2906 Van Der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJM (2011) The changing epidemiology of congenital heart disease. Nat Rev Cardiol 8(1):50–60 Carvalho JS, Axt-Fliedner R, Chaoui R, Copel JA, Cuneo BF, Goff D et al (2023) ISUOG Practice Guidelines (updated): fetal cardiac screening. Ultrasound Obstet Gynecol 61(6):788–803 Lee W, Allan L, Carvalho JS, Chaoui R, Copel J, Devore G et al (2008) ISUOG consensus statement: what constitutes a fetal echocardiogram? Ultrasound Obstet Gynecol 32(2):239–242 Potiris A, Perros P, Drakaki E, Mavrogianni D, Machairiotis N, Sfakianakis A et al (2024) Investigating the Association of Assisted Reproduction Techniques and Adverse Perinatal Outcomes. J Clin Med 13(2):328 Kermani RM, Bagheri P, Ashrafi M Congenital Malformations in Singleton Infants Conceived by Assisted Reproductive Technologies and Singleton Infants by Natural Conception in Tehran, Iran Shechter-Maor G, Czuzoj-Shulman N, Spence AR, Abenhaim HA (2018) The effect of assisted reproductive technology on the incidence of birth defects among livebirths. Arch Gynecol Obstet 297(6):1397–1403 Talebi T, Mohsen-Pour N, Hesami M, Maleki M, Kalayinia S (2022) The association between in vitro fertilization and intracytoplasmic sperm injection treatment and the risk of congenital heart defects. J Matern Fetal Neonatal Med 35(25):7471–7485 Beltran Anzola A, Pauly V, Montjean D, Meddeb L, Geoffroy-Siraudin C, Sambuc R et al (2017) No difference in congenital anomalies prevalence irrespective of insemination methods and freezing procedure: cohort study over fourteen years of an ART population in the south of France. J Assist Reprod Genet 34(7):867–876 Shamshirsaz AA, Bateni ZH, Sangi-haghpeykar H, Arian SE, Erfani H, Shamshirsaz AA et al (2018) Cyanotic congenital heart disease following fertility treatments in the United States from 2011 to 2014. Heart 104(11):945–948 Iwashima S, Ishikawa T, Itoh H (2017) Reproductive technologies and the risk of congenital heart defects. Hum Fertil 20(1):14–21 Aderibigbe OA, Ranzini AC (2020) Is a Fetal Echocardiography Necessary in IVF-ICSI Pregnancies After Anatomic Survey? J Clin Ultrasound 48(6):307–311 Tararbit K, Houyel L, Bonnet D, De Vigan C, Lelong N, Goffinet F et al (2011) Risk of congenital heart defects associated with assisted reproductive technologies: a population-based evaluation. Eur Heart J 32(4):500–508 Tararbit K, Lelong N, Thieulin A-C, Houyel L, Bonnet D, Goffinet F et al (2013) The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation. Hum Reprod 28(2):367–374 Galdini A, Fesslova VME, Gaeta G, Candiani M, Pozzoni M, Chiarello C et al (2021) Prevalence of Congenital Heart Defects in Pregnancies Conceived by Assisted Reproductive Technology: A Cohort Study. J Clin Med 10(22):5363 Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A et al (2014) Diagnosis and Treatment of Fetal Cardiac Disease: A Scientific Statement From the American Heart Association. Circulation 129(21):2183–2242 Moon-Grady AJ, Donofrio MT, Gelehrter S, Hornberger L, Kreeger J, Lee W et al (2023) Guidelines and Recommendations for Performance of the Fetal Echocardiogram: An Update from the American Society of Echocardiography. J Am Soc Echocardiogr 36(7):679–723 SIEOG. National Guidelines for Ultrasound in Obstetrics and Gynaecology (2021) Nov https://snlg.iss.it/wp-content/uploads/2021/11/LG-SIEOG-2021_def.pdf Chung EH, Lim SL, Havrilesky LJ, Steiner AZ, Dotters-Katz SK (2021) Cost‐effectiveness of prenatal screening methods for congenital heart defects in pregnancies conceived by in‐vitro fertilization. Ultrasound Obstet Gynecol 57(6):979–986 Cite Share Download PDF Status: Published Journal Publication published 01 Aug, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Reviewers agreed at journal 22 May, 2024 Reviewers invited by journal 22 May, 2024 Editor invited by journal 22 May, 2024 Editor assigned by journal 22 May, 2024 First submitted to journal 21 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4456271","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":305651995,"identity":"6f09a87c-8b7e-40d4-8908-e95de2afa0fe","order_by":0,"name":"Linda Piemonti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYBACPmYGBgkgzQPhGtgACcbGA/i0sKFoOWCQBtLSgF8LA0QLBBxgOAyl8Wlh5z144wfDHRl+scPHHn8oOG+3tv0w0JYam2jcDuNLtuxheMYjOTst3eCAwe3kbWcSgVqOpeU24NTCYybBw3CYx+B2jpkESIvZAaAWxobDeLVI/gFqsYdoOZdsdv4hYS3SYFukwVoO2JndIGyLsbWMwTMeidtpaRJnDJITzG4AbUnA4xd+/jOGN99U3LHnn518TKLij5292fn0hw8+1Njg1AIBBgfgzESwygS8ysEAocWesOJRMApGwSgYaQAAuwpaCCoZ7coAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0004-9379-3675","institution":"IRCCS Azienda Ospedaliero-Universitaria di Bologna","correspondingAuthor":true,"prefix":"","firstName":"Linda","middleName":"","lastName":"Piemonti","suffix":""},{"id":305651996,"identity":"1f5b3234-2059-468f-b866-7fcb2e6854bb","order_by":1,"name":"Laura Vettor","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Vettor","suffix":""},{"id":305651997,"identity":"f59ea7db-ba40-4a56-a854-af02473bcda0","order_by":2,"name":"Anna Balducci","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Balducci","suffix":""},{"id":305651998,"identity":"d959a6f4-805c-4468-9deb-968bddea9f02","order_by":3,"name":"Antonio Farina","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Farina","suffix":""},{"id":305651999,"identity":"76271f5a-104b-41b4-b859-7ca4c5a452ee","order_by":4,"name":"Elena Contro","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Contro","suffix":""}],"badges":[],"createdAt":"2024-05-21 16:52:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4456271/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4456271/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-024-07669-x","type":"published","date":"2024-08-01T15:57:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61794432,"identity":"6de5abfb-a25c-4fce-b5a1-6e98742b90be","added_by":"auto","created_at":"2024-08-05 16:18:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":625164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4456271/v1/1339df28-9eeb-4256-8239-9962709723e1.pdf"}],"financialInterests":"","formattedTitle":"Assisted Reproductive Technology and the risk of Fetal Congenital Heart Disease: insights from a Tertiary Care Referral Centre.","fulltext":[{"header":"What does this study adds to the clinical work","content":"\u003cp\u003eThis study reveals significant differences in the occurrence of specific congenital heart disease categories between pregnancies conceived through ART and those conceived naturally. These findings underscore the need for further research to understand the mechanisms linking ART to CHD development.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCongenital heart defects (CHD) stand as the most prevalent birth abnormalities and constitute a leading cause of infant mortality. Variations in definitions, population characteristics, and diagnostic methods result in a wide range of prevalence estimates. In Europe, the average total prevalence of CHD is 8.0 per 1000 births, with a live birth prevalence of 7.2 per 1000 births, varying between countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The utilization of Assisted Reproductive Technology (ART) has experienced a significant rise in recent years, particularly with the adoption of oocyte and sperm donation. In the United States, approximately 1.9 percent of all births result from ART [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] while Italy has experienced a significant increase in the rate of ART-conceived births over the past fifteen years, reaching 3.7 percent of all births in 2022 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is well established that conception through ART is associated with obstetric and perinatal complications, including multiple gestations, preterm delivery, low birth weight, and congenital anomalies. Reviews and meta-analyses have consistently shown that the risk of congenital anomalies is potentially increased by approximately one-third compared to pregnancies conceived naturally [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, uncertainties persist regarding the risks of birth defects, especially CHD. Particularly, the incidence of CHD differs greatly from study to study. The incidence of moderate and severe forms of CHD is approximately 6 per 1,000 live births. However, the overall incidence increases to 75 per 1,000 live births if minor forms such as tiny muscular Ventricular Septal Defects (VSD) present at birth and other trivial lesions or variants are included [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A recent major meta-analysis showed that the risk of CHD in intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) pregnancies is significantly higher, by approximately 50%, compared to naturally conceived pregnancies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Despite these findings, consensus regarding the clinical utility of performing fetal echocardiography in ART pregnancies remains elusive with conflicting recommendations provided by different scientific societies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Furthermore, conflicting data in the literature regarding the specific subtypes of CHD further complicates the matter. Despite advances in prenatal diagnosis, the medical and surgical management of infants with CHD still carries high risks of morbidity and mortality, especially for severe cases. The etiology of CHDs is largely unknown, with only less than 15% of cases linked to known genetic anomalies. Non-syndromic congenital defects have diverse causes, including environmental factors, maternal diabetes, phenylketonuria, maternal obesity, alcohol use, rubella infection, febrile illnesses, certain drugs (e.g., thalidomide), exposure to solvents or herbicides, maternal age over 40, and paternal age over 35 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The remaining non-syndromic CHD cases have a multifactorial etiology, suggesting interaction between various genetic and environmental factors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The role of ART remains uncertain and clarifying the link between ART and CHDs is of paramount importance for both clinicians and couples considering fertility treatments. We aim to determine if there is an association between CHD and different ART methods. In this paper, we present original findings from a cohort study and discuss the possible implications for clinical practice and future research.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eIn this retrospective cohort study, the authors selected all natural and ART pregnancies (IVF and ICSI, homologous and heterologous) referred for fetal echocardiography to IRCCS Policlinico Sant\u0026rsquo;Orsola, Bologna, between January 2005 and November 2023 diagnosed with CHD. The indications for the exams were: suspected fetal cardiac structural anomaly or abnormality of cardiac function (e.g. cardiomegaly, hydrops fetalis, irregular cardiac rhythm); fetal extracardiac anomaly; first or second-degree relatives with CHD (parents, siblings, half-siblings); first or second-degree relative with Mendelian inheritance disease and a history of childhood cardiac manifestations; patients diagnosed with pregestational diabetes or any type of CHD. Maternal history and characteristics, gestational age, type of ART and CHD were retrospectively extracted from ultrasound reports. Twin pregnancies, fetuses identified with genetic anomalies via invasive diagnostic procedures or having multiple structural anomalies affecting different organs were excluded. Considering the lack of demographic and clinical data, we opted to exclude patients with a Body Mass Index (BMI) over 35, or those with type 1 or type 2 diabetes where known. The study population was composed by two main groups: ART pregnancies diagnosed with CHD and subsequently divided according to the technique (IVF; ICSI); natural pregnancies diagnosed with CHD. In order to study the possible association of types of CHDs with ART techniques, we introduce a classification of CHDs based on the anatomical and embryological origin of the defects, which were classified into six subcategories each containing a set of anomalies: Left Ventricle Outflow Tract disease (LVOT); Conotruncal abnormalities (CNTRA); Valvular Diseases (VD); Right Heart Anomalies (RHA); Atrioventricular Septal Defects (AVSD); Heart Rhythm Diseases (HRD). Further information is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Due to the low incidence, we did not evaluate situs anomalies, and anomalous pulmonary venous connection. This classification addresses the challenge of investigating specific CHDs despite limited data availability. All ultrasound cardiac assessments were carried out by a group of experienced senior operators, including fetal cardiologists and subspecialists in fetal medicine with expertise in fetal cardiac scanning. All cardiac ultrasound scans adhered to ISUOG guidelines, encompassing the 4-chamber view, outflow tracts, three vessels and tracheal view, aortic and ductal arches views, and the inferior and superior vena cava view [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Color Doppler was applied to these views, along with M-mode and spectral Doppler/Color Doppler. The ultrasound machines used during the study period were Voluson E8 or E10 (GE Healthcare, Austria) equipped with multifrequency convex transducers. Demographic data were analyzed using routine tests. For statistical analysis, each subject in the three groups (natural, IVF, ICSI) was assigned a weight proportional to the inverse of the size of its respective group. This weighting strategy aims to allocate an equal \"a-priori\" risk to each type of CHD across the three groups, thereby ensuring a balanced representation of subjects within each group. Multinomial logistic regression adjusted for maternal age was employed to model the relationship between each CHD category and the three groups of patients, taking into account data weighting. Under this approach, a multivariable patient-specific-risk of belonging to each of the three groups is calculated for each CHD category (whether isolated or in combination). These risks are mutually exclusive, ensuring that the total risk across the three groups always sums to 100%. Comparison of the patient-specific-risk distributions among and between groups was performed using ANOVA and Bonferroni post hoc test. A \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. As for statistical analysis, the SPSS version 27.0 (IBM Corp. Released 2020. IBM SPSS Statistics) was adopted.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClassification of CHD according to the anatomic and embryological development\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSUBCATEGORY OF CHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTYPE OF CHD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtrioventricular septal defect\u003c/p\u003e \u003cp\u003eVentricular septal defects\u003c/p\u003e \u003cp\u003eAtrial septal defects\u003c/p\u003e \u003cp\u003eCommon atrium/cor biventricular\u003c/p\u003e \u003cp\u003eUniventricular Heart\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransposition of great arteries\u003c/p\u003e \u003cp\u003eTetralogy of Fallot\u003c/p\u003e \u003cp\u003eDouble outlet right ventricle\u003c/p\u003e \u003cp\u003eDouble outlet left ventricle\u003c/p\u003e \u003cp\u003eTruncus arteriosus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePersistent supraventricular tachycardia\u003c/p\u003e \u003cp\u003eAtrial Extrasystole\u003c/p\u003e \u003cp\u003eVentricular Extrasystole\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVOT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypoplastic left syndrome disease\u003c/p\u003e \u003cp\u003eInterruption or anomalies of aortic arch\u003c/p\u003e \u003cp\u003eAtresia or Coarctation of aorta\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypoplastic right heart syndrome\u003c/p\u003e \u003cp\u003eIdiopatic right heart cardiomegaly\u003c/p\u003e \u003cp\u003eRight ventricle hypoplasia\u003c/p\u003e \u003cp\u003eRight atrial enlargement\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDefects of pulmonary valves (atresia; dysplasia; stenosis; insufficiency)\u003c/p\u003e \u003cp\u003eEbstein\u0026rsquo;s anomaly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAVSD atrioventricular septal defects; CNTRA conotruncal abnormalities; HRD heart rhythm disease; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e resumes the demographic data of the study population. As shown, maternal age was significantly higher in ART groups compared to natural pregnancies. Among the 656 cases of CHDs, the majority, 588 (89.6%), were natural pregnancies, 30 (4.6%) were conceived through IVF, and 38 (5.8%) through ICSI. All cases were categorized into six distinct groups based on anatomical and embryological criteria: AVSD (213/656, 32.5%), CNTRA diseases (219/656, 33.4%), LVOT defects (203/656, 30.9%), VD (136/656, 20.7%), RHA (26/656, 4%), and HRD (16/656, 2.4%). The most frequent combinations of CHD\u0026rsquo;s categories included AVSD\u0026thinsp;+\u0026thinsp;CNTRA (8.5%), AVSD\u0026thinsp;+\u0026thinsp;LVOT (6.3%), and AVSD\u0026thinsp;+\u0026thinsp;VD (5.8%). All categories\u0026rsquo; frequencies are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. To comprehensively evaluate the patient-specific-risk associated with each CHD\u0026rsquo;s category, we calculated the risk considering both cases where the category was isolated and those where it co-occurred with others. This approach resulted in a single patient-specific-risk estimation encompassing both isolated and combined CHD\u0026rsquo;s occurrences, leading to more observations than individual cases, thus ensuring a thorough evaluation of the risk associated with each type of CHD. After adjusting for maternal age and CHD patterns, we found that the mean estimated patient-specific-risk of CNTRA, AVSD, LVOT and VD was significantly lower in IVF group compared to the natural one. The estimated mean patient-specific-risk of CNTRA was higher in ICSI group versus natural pregnancies, while it was lower for AVSD and VD, and non-significant for LVOT. Conversely, the mean patient-specific-risk for RHA was significantly higher both in IVF and ICSI groups compared to natural conception. HRDs were significantly more frequent in IVF versus natural pregnancies, and no cases were found in the ICSI group. When comparing ART methods, it emerged that CNTRA, VD, and RHA were more frequently observed in ICSI, while AVSD was more common in IVF. The distributions of the most prevalent association of CHD\u0026rsquo;s categories revealed that the estimated mean patient-specific-risk quoted for AVSD\u0026thinsp;+\u0026thinsp;CNTRA, AVSD\u0026thinsp;+\u0026thinsp;LVOT, and AVSD\u0026thinsp;+\u0026thinsp;VD were more frequent in natural pregnancies. Notably, a higher mean patient-specific-risk of AVSD\u0026thinsp;+\u0026thinsp;CNTRA was observed in ICSI vs IVF. For a summarized view of the results refer to Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Demographic data of the study population including natural, IVF, and ICSI pregnancies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNatural pregnancies (n\u0026thinsp;=\u0026thinsp;588)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVF pregnancies (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eICSI pregnancies (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal Age (mean\u003c/b\u003e \u0026plusmn; \u003cb\u003eSD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.4 \u0026plusmn; 5.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.5 \u0026plusmn; 5.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.4 \u0026plusmn; 4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001 (α, β, δ)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational Age (mean\u003c/b\u003e \u0026plusmn; \u003cb\u003eSD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.5 \u0026plusmn; 5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.1 \u0026plusmn; 5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.1 \u0026plusmn; 4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens (α, δ)\u003c/p\u003e \u003cp\u003e0.020 (β)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNullipara (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001 (α, β, δ)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eα Natural pregnancies vs IVF pregnancies; β Natural pregnancies vs ICSI pregnancies; δ IVF pregnancies vs ICSI pregnancies; ns non-significant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e, Frequencies of CHD\u0026rsquo;s categories among the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHD\u0026rsquo;s categories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNatural pregnancies (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVF pregnancies (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eICSI pregnancies (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e124 (18.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD HRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD LVOT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e41 (6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD LVOT VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5 (0.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD RHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38 (5.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e116 (17.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e56 (8.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD HRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD LVOT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD LVOT RHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD RHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA AVSD VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA LVOT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA LVOT VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVOT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e120 (18.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e133 (20.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVOT HRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVOT VD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e55 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVD RHA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVD RHA HRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e588 (89.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e656 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAVSD atrioventricular septal defects; CHD congenital Heart Disease; CNTRA conotruncal abnormalities; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases; HRD heart rhythm disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean estimated patient specific risk (%) and interquartile range of each CHD when occurring alone or in combination, calculated using weighted multinomial logistic regression across the three study groups. ANOVA and Bonferroni post hoc tests were conducted, assuming an equal number of observations among the three groups, as available for the natural group. Due to the occurrence of multiple CHDs in the same patient, the number of observations exceeds the number of cases. Quantitative maternal age was used as covariate. Only most frequent combination are reported.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHD (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNatural pregnancies (n\u0026thinsp;=\u0026thinsp;588)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVF pregnancies (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eICSI pregnancies (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep-value (\u003c/em\u003eα)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep-value (\u003c/em\u003eβ)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep-value (\u003c/em\u003eδ)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNTRA (219)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37.29 (25\u0026ndash;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.04 (18\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40.67 (29\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD (213)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39.15 (18\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35.28 (19\u0026ndash;51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.57 (22\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVOT (203)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.99 (22\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30.67 (25\u0026ndash;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.35 (25\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.189\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVD (136)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40.08 (25\u0026ndash;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.14 (23\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.79 (24\u0026ndash;41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRHA (26)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.50 (4\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32.34 (24\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.16 (50\u0026ndash;53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHRD (16)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.11 (10\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81.88 (75\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD\u0026thinsp;+\u0026thinsp;CNTRA (56)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e62.75 (54\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.85 (12\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.39 (12\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD\u0026thinsp;+\u0026thinsp;LVOT (41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58.14 (48\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.03 (19\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.83 (18\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.734\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAVSD\u0026thinsp;+\u0026thinsp;VD (38)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66.52 (47\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.01 (12\u0026ndash;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.47 (13\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eα Natural pregnancies vs IVF pregnancies; β Natural pregnancies vs ICSI pregnancies; δ IVF pregnancies vs ICSI pregnancies; AVSD atrioventricular septal defects; CHD congenital Heart Disease; CNTRA conotruncal abnormalities; LVOT left ventricular outflow tract abnormalities; RHA right heart anomalies; VD valvular diseases; HRD heart rhythm disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOver the past few decades, the use of ART has substantially increased, providing a chance to conceive to many couples struggling with infertility. However, emerging evidence suggests a potential link between ART and an increased risk of fetal CHDs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], although findings are inconclusive, leaving the discussion ongoing. Our study confirms very different rates of CHD categories in ART-conceived pregnancies compared to natural conception.\u003c/p\u003e \u003cp\u003eWhile they highlighted a higher risk of congenital and chromosomal defects in ART pregnancies, particularly male urogenital defects and CHD, the authors concluded that ART procedures are generally safe [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, Kermani et al. indicated a significant elevation in the risk of major congenital malformations among singleton infants conceived through ART, with CHDs being prominently reported. This underscores the importance of considering the mode of conception when assessing CHD risk [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Similarly, Shechter-Maor et al. conducted an assessment of birth anomalies among all live births in the United States and observed that infants conceived through ART faced a twofold higher risk of experiencing one of the evaluated birth defects, with CHDs being particularly prevalent in the ART group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Moreover, Talebi et al. revealed a higher occurrence not only of all types of CHDs but also of endothelial dysfunction, morphological changes, and increased vascular stiffness in infants conceived through ART compared to those conceived naturally, which is indicative of a heightened risk for premature cardiovascular issues. Consequently, the authors emphasized the necessity for increased monitoring through fetal echocardiography and postnatal cardiovascular assessment [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, the precise mechanisms linking ART and CHD remain unclear, with proposed hypotheses including the influence of underlying parental factors such as advanced maternal age, maternal comorbidities, and parental subfertility, which are more prevalent among couples undergoing ART procedures [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The pathogenesis of CHD itself remains a highly debated topic, encompassing genetic causes and maternal characteristics including comorbidities (e.g., obesity, diabetes) and behavioral factors (i.e., alcohol, drugs, smoking). Interestingly, women undergoing ART are educated about maintaining proper weight, abstaining from smoking and alcohol, suspending potentially harmful therapies, and early integration of folic acid. Therefore, the ART population is complex to investigate due to its dual nature: exposed to certain major risks (e.g., older age, subfertility, comorbidities like diabetes and hypertension) while protected from others (e.g., obesity, smoking, alcohol, lack of folates) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Despite potential confounding factors, the manipulation of gametes and embryos during ART procedures, alongside hormonal stimulation protocols, may impact embryonic development and contribute to the higher risk of CHDs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Contrasting evidence exists; Anzola et al. found no differences in congenital anomalies prevalence between babies conceived by fresh versus frozen embryo transfer after IVF [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Moreover, recent studies have attempted to synthesize data from available literature. Gullo et al. indicated an increased risk of minor CHDs among ART-conceived pregnancies compared to natural ones [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Conversely, Shamshirsaz et al. discovered a significantly higher risk for cyanotic congenital heart diseases (cCHDs) among infants conceived through ART (adjusted relative risk (aRR) 2.4, 95% CI 2.1 to 2.7) and non-ART fertility treatments (aRR 1.9, 95% CI 1.6 to 2.2) compared to naturally conceived infants [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, contrasting data come from a cohort population study conducted by Iwashima et al., in which no significant differences were detected through echocardiography screening in the prevalence of CHD and severe CHD between women who conceived naturally and those who underwent ART [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A recent meta-analysis by Giorgione et al., indicates that the likelihood of CHDs is elevated in ART pregnancies compared to those conceived naturally (odds ratio (OR)\u0026thinsp;=\u0026thinsp;1.45). However, when analyzing the qualitative distribution of CHD types, the heightened risk was statistically significant only for smaller CHDs like VSD [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This was also confirmed by Aderibigbe et al. in their study, where a prevalence of minor cardiac disorders, particularly VSD, is reported among pregnancies conceived through ART [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. At the current state, the association with major CHDs remains a point of contention, with inconsistent findings reported across various studies. Given the heterogeneous nature of these conditions, it's crucial to consider how different subtypes of CHDs are associated with ART in order to better understand the potential implications of ART procedures on fetal cardiac development. Tararbit et al., drawing from the Paris registry of congenital malformations, identified a heightened risk for certain CHDs among fetuses conceived through IVF and ICSI, independently of chromosomal abnormalities [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The study suggests a stronger association of CHDs with ICSI compared to IVF and emphasizes that the choice of CHD classification can influence study outcomes, prompting the suggestion to utilize an embryological classification for analyzing the etiopathological role of ART in CHD development. They also examined increased risk in major CHD, signaling a specific rise in Tetralogy of Fallot (TOF) cases. ART was associated with a 2.4-fold higher risk of TOF after adjustment for maternal age, occupation, geographic origin, paternal age and year of birth; ICSI was specifically associated with a 3-fold higher risk of TOF. This has led to an etiopathogenetic hypothesis implicating an altered neural crest cell development in conotruncal heart defects in ART pregnancies, particularly ICSI-conceived [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A subsequent retrospective cohort study conducted by Galdini et al. highlighted an increased prevalence of major CHD in fetuses conceived through ART compared to natural pregnancies, notably TOF and Hypoplastic Left Heart Syndrome. However, when considering specific techniques, it presents conflicting data showing a stronger association with IVF rather than ICSI [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Along with the literature, our study identifies ART as a risk factor for CHD. We found that isolated RHA prevails both in IVF and ICSI pregnancies when compared to natural conception. HRD are more frequent in IVF pregnancies versus natural conception, though none data was available for ICSI pregnancies. Lastly, isolated CNTRA are more prevalent in ICSI pregnancies compared to natural conception. When comparing ART methods, it emerges a higher rate of isolated AVSD in IVF-conceived pregnancies, though we must precise that AVSD category also included minor septal defects. Whereas, CNTRA defects isolated and in combination with AVSD, VD and RHA appear to be more frequent in ICSI-conceived pregnancies. According to our results, taking into account that ART implies a major risk of cardiac anomalies, the type of ART technique plays a fundamental role in defining the severity and type of CHD. Overall, while the existing literature provides valuable insights into the association between ART and CHDs, discrepancies and uncertainties remain because strong levels of evidence are missing, and more prospective and case-control studies are needed. Indeed, guidelines are divergent regarding the indication to refer all ART-conceived pregnancies for an echocardiography. The American Heart Association (AHA) guidelines recognize IVF/ICSI conception as a maternal indication for fetal echocardiography with a recommendation class/level of evidence IIa/A estimating an absolute risk of 1.1\u0026ndash;3.3% among live births.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Evenly, the International Society of Ultrasound in Obstetrics \u0026amp; Gynecology (ISUOG) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] recognize ART conception, both IVF and ICSI, as a possible indication for fetal echocardiogram, whereas the American Society of Echocardiography (ASE) considers only IVF as a possible indication [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The National Guidelines for Ultrasound in Obstetrics and Gynecology published by Societ\u0026agrave; Italiana di Ecografia Ostetrica e Ginecologica (SIEOG) states that considered the still unclear association between major CHD and ICSI, ICSI is not to be considered an indication for carrying out fetal echocardiography [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In addition, according to the analysis of Chung et al., the cost-effective method of screening for CHDs in IVF or ICSI conceived pregnancies, is to perform a fetal echocardiogram only when a cardiac anomaly is noted during a detailed anatomy ultrasound [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We report the experience of one of the largest tertiary care centers in northern Italy. The main limitation of our study is the retrospective design, anyway, considering the rarity of these conditions a prospective study would result very difficult. Further research, including large-scale multicentric prospective studies, is essential to elucidate the underlying factors contributing to CHD development in ART-conceived offspring and to guide clinical decision-making and counseling for couples undergoing ART procedures. Our study is therefore situated within this line of research.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur research findings indicate noteworthy differences in the occurrence of CHDs between pregnancies conceived through ART and those conceived naturally. Additionally, we demonstrated distinct prevalence of specific CHD categories among different ART methods, highlighting a stronger association of CHD with ICSI compared to IVF, particularly with a higher prevalence of severe CHDs like conotruncal anomalies in ICSI-conceived pregnancies. In conclusion, further research is essential to understand the impact of ART procedures on fetal cardiac development, considering the diverse range of CHD subtypes associated with ART, and to clarify the clinical implications of these associations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePiemonti Linda: Project development; Data collection and management; Data analysis; Manuscript writing\u003c/li\u003e\n \u003cli\u003eVettor Laura: Project development; Data collection; Manuscript writing\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBalducci Anna: Project development; Manuscript editing\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFarina Antonio: Data management; Data analysis; Manuscript editing\u003c/li\u003e\n \u003cli\u003eContro Elena: Project development; Manuscript editing\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e This is an observational retrospective cohort study. The Research Ethics Committee has confirmed that no ethical approval is required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement:\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author, [LP, AF], upon reasonable request.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDolk H, Loane M, Garne E, a European Surveillance of Congenital Anomalies (EUROCAT) Working Group (2011) Congenital Heart Defects in Europe: Prevalence and Perinatal Mortality, 2000 to 2005. Circulation 123(8):841\u0026ndash;849\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSunderam S, Assisted Reproductive Technology Surveillance United States (2017), US Dep Health Hum Serv Cent Dis Control Prev - Morb Mortal Wkly Rep. 2020;69(9). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755269/pdf/ss6909a1.pdf\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755269/pdf/ss6909a1.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCertificato di assistenza al parto (CeDAP) Analisi dell\u0026rsquo;evento nascita Anno (2022) Minist Della Salute Direzione Gen Della Digit Sist Inf Sanit E Della Stat \u0026ndash; Uff Stat. 2023 Oct \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.salute.gov.it/portale/documentazione/p6_2_2_1.jsp?lingua=italiano\u0026amp;id=3346\u003c/span\u003e\u003cspan address=\"https://www.salute.gov.it/portale/documentazione/p6_2_2_1.jsp?lingua=italiano\u0026amp;id=3346\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCavoretto P, Candiani M, Giorgione V, Inversetti A, Abu-Saba MM, Tiberio F et al (2018) Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta‐analysis of cohort studies. Ultrasound Obstet Gynecol 51(1):43\u0026ndash;53\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A (2012) Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 18(5):485\u0026ndash;503\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffman JIE, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890\u0026ndash;1900\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A et al (2018) Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol 51(1):33\u0026ndash;42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuaresima P, Fesslova V, Farina A, Kagan KO, Candiani M, Morelli M et al (2023) How to do a fetal cardiac scan. Arch Gynecol Obstet 307(4):1269\u0026ndash;1276\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGullo G, Scaglione M, Lagan\u0026agrave; AS, Perino A, Andrisani A, Chiantera V et al (2023) Assisted Reproductive Techniques and Risk of Congenital Heart Diseases in Children: a Systematic Review and Meta-analysis. Reprod Sci 30(10):2896\u0026ndash;2906\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJM (2011) The changing epidemiology of congenital heart disease. Nat Rev Cardiol 8(1):50\u0026ndash;60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarvalho JS, Axt-Fliedner R, Chaoui R, Copel JA, Cuneo BF, Goff D et al (2023) ISUOG Practice Guidelines (updated): fetal cardiac screening. Ultrasound Obstet Gynecol 61(6):788\u0026ndash;803\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee W, Allan L, Carvalho JS, Chaoui R, Copel J, Devore G et al (2008) ISUOG consensus statement: what constitutes a fetal echocardiogram? Ultrasound Obstet Gynecol 32(2):239\u0026ndash;242\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePotiris A, Perros P, Drakaki E, Mavrogianni D, Machairiotis N, Sfakianakis A et al (2024) Investigating the Association of Assisted Reproduction Techniques and Adverse Perinatal Outcomes. J Clin Med 13(2):328\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKermani RM, Bagheri P, Ashrafi M Congenital Malformations in Singleton Infants Conceived by Assisted Reproductive Technologies and Singleton Infants by Natural Conception in Tehran, Iran\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShechter-Maor G, Czuzoj-Shulman N, Spence AR, Abenhaim HA (2018) The effect of assisted reproductive technology on the incidence of birth defects among livebirths. Arch Gynecol Obstet 297(6):1397\u0026ndash;1403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTalebi T, Mohsen-Pour N, Hesami M, Maleki M, Kalayinia S (2022) The association between in vitro fertilization and intracytoplasmic sperm injection treatment and the risk of congenital heart defects. J Matern Fetal Neonatal Med 35(25):7471\u0026ndash;7485\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeltran Anzola A, Pauly V, Montjean D, Meddeb L, Geoffroy-Siraudin C, Sambuc R et al (2017) No difference in congenital anomalies prevalence irrespective of insemination methods and freezing procedure: cohort study over fourteen years of an ART population in the south of France. J Assist Reprod Genet 34(7):867\u0026ndash;876\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShamshirsaz AA, Bateni ZH, Sangi-haghpeykar H, Arian SE, Erfani H, Shamshirsaz AA et al (2018) Cyanotic congenital heart disease following fertility treatments in the United States from 2011 to 2014. Heart 104(11):945\u0026ndash;948\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIwashima S, Ishikawa T, Itoh H (2017) Reproductive technologies and the risk of congenital heart defects. Hum Fertil 20(1):14\u0026ndash;21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAderibigbe OA, Ranzini AC (2020) Is a Fetal Echocardiography Necessary in IVF-ICSI Pregnancies After Anatomic Survey? J Clin Ultrasound 48(6):307\u0026ndash;311\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTararbit K, Houyel L, Bonnet D, De Vigan C, Lelong N, Goffinet F et al (2011) Risk of congenital heart defects associated with assisted reproductive technologies: a population-based evaluation. Eur Heart J 32(4):500\u0026ndash;508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTararbit K, Lelong N, Thieulin A-C, Houyel L, Bonnet D, Goffinet F et al (2013) The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation. Hum Reprod 28(2):367\u0026ndash;374\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaldini A, Fesslova VME, Gaeta G, Candiani M, Pozzoni M, Chiarello C et al (2021) Prevalence of Congenital Heart Defects in Pregnancies Conceived by Assisted Reproductive Technology: A Cohort Study. J Clin Med 10(22):5363\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A et al (2014) Diagnosis and Treatment of Fetal Cardiac Disease: A Scientific Statement From the American Heart Association. Circulation 129(21):2183\u0026ndash;2242\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoon-Grady AJ, Donofrio MT, Gelehrter S, Hornberger L, Kreeger J, Lee W et al (2023) Guidelines and Recommendations for Performance of the Fetal Echocardiogram: An Update from the American Society of Echocardiography. J Am Soc Echocardiogr 36(7):679\u0026ndash;723\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSIEOG. National Guidelines for Ultrasound in Obstetrics and Gynaecology (2021) Nov \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://snlg.iss.it/wp-content/uploads/2021/11/LG-SIEOG-2021_def.pdf\u003c/span\u003e\u003cspan address=\"https://snlg.iss.it/wp-content/uploads/2021/11/LG-SIEOG-2021_def.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung EH, Lim SL, Havrilesky LJ, Steiner AZ, Dotters-Katz SK (2021) Cost‐effectiveness of prenatal screening methods for congenital heart defects in pregnancies conceived by \u003cem\u003ein‐vitro\u003c/em\u003e fertilization. Ultrasound Obstet Gynecol 57(6):979\u0026ndash;986\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Congenital heart defects, assisted reproductive technology, intracytoplasmic sperm injection, in vitro fertilization, fetal","lastPublishedDoi":"10.21203/rs.3.rs-4456271/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4456271/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo investigate whether congenital heart diseases exhibit higher rates in pregnancies achieved through assisted reproductive technology (ART) compared to natural conception.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort study, multinomial logistic regression was employed to analyze the relationship between categories of congenital heart diseases and three conception groups (IVF, ICSI and natural pregnancies). The main outcome measure are risks of congenital heart disease categories in IVF and ICSI groups using the natural group as reference. We selected fetuses referred for fetal echocardiography to IRCCS Policlinico Sant\u0026rsquo;Orsola, Bologna, between January 2005 and November 2023, diagnosed with congenital heart diseases.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe categorized the congenital heart diseases into six groups based on anatomical and embryological criteria. The estimated risk of left ventricular outflow tract, valvular, conotruncal and atrioventricular septal defects was lower in the IVF group compared to natural conception. The estimated risk of valvular and atrioventricular septal defects was lower in the ICSI group vs natural. Conversely, the risk for right heart anomalies was higher both in the IVF and ICSI groups compared to natural conception. Heart rhythm diseases were more frequent in IVF pregnancies. When comparing ART methods, valvular defects, conotruncal defects, and right heart anomalies were more frequently observed in the ICSI group, while atrioventricular septal defects were more common in the IVF group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSignificant differences were found in the occurrence of congenital heart diseases in pregnancies conceived through IVF and ICSI, versus those conceived naturally, underscoring the importance of further studying the underlying mechanisms of these associations.\u003c/p\u003e","manuscriptTitle":"Assisted Reproductive Technology and the risk of Fetal Congenital Heart Disease: insights from a Tertiary Care Referral Centre.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 11:58:31","doi":"10.21203/rs.3.rs-4456271/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-05-22T20:08:03+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-22T20:06:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2024-05-22T06:34:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-22T04:55:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2024-05-21T12:52:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"44bd49bf-839f-4992-bd45-1b884f65f79d","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:14:21+00:00","versionOfRecord":{"articleIdentity":"rs-4456271","link":"https://doi.org/10.1007/s00404-024-07669-x","journal":{"identity":"archives-of-gynecology-and-obstetrics","isVorOnly":false,"title":"Archives of Gynecology and Obstetrics"},"publishedOn":"2024-08-01 15:57:58","publishedOnDateReadable":"August 1st, 2024"},"versionCreatedAt":"2024-06-04 11:58:31","video":"","vorDoi":"10.1007/s00404-024-07669-x","vorDoiUrl":"https://doi.org/10.1007/s00404-024-07669-x","workflowStages":[]},"version":"v1","identity":"rs-4456271","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4456271","identity":"rs-4456271","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}