Gender differences in congenital heart defects: a narrative review

Introduction

Background

Congenital heart defects (CHD) represent the most frequent human birth defects, occurring in almost 1% of all live newborns and up to 10% of stillbirths globally (1). Moreover, if mild cardiac structural anomalies are included [i.e., bicuspid aortic valve (BAV) and septal defects] the cumulative prevalence of CHD in liveborn infants may be as high as ~5% (2).

In the last decades, the outstanding progress in the diagnostic tools and surgical strategies for CHD determined a substantial improvement of short-term and long-term survival, allowing a growing proportion of newborns with critical CHD reaching adulthood.

Moreover, the global improvement of personalized care and clinical research on CHD diagnosis and management has changed the landscape of adult patients with CHD.

Despite that, the morbidity burden of CHD is still high since the presence of these defects often leads to altered quality of life in terms of health-related complications, reduced exercise tolerance, higher risk of arrhythmias and endocarditis, neurodevelopmental impairment, pulmonary arterial hypertension and suboptimal kidney function (3).

The concept of “gender medicine” has first emerged in the late 1990s (4) and it refers to the study of how gender influences the complex interaction among biological, genetic, epigenetic, cultural, and environmental factors in defining several pathological entities (5).

Biological gender, also known as sex, refers to the classification of individuals as male or female based on their reproductive anatomy and physiology. It is determined by a combination of genetic, hormonal, and anatomical factors. The term “gender” in the following text refers to biological gender.

Currently, gender medicine has to be considered as a crucial step to achieve a personalized medicine and patient-centered care (6).

Understanding the effects of gender in pathophysiological processes has a key role in defining personalized prevention, disease identification, prognosis definition and individualized therapeutic strategies and, nowadays, the attempt to achieve a holistic approach to patients and diseases cannot be separated from applying gender difference.

Rationale and knowledge gap

Despite the growing evidence regarding gender differences for acquired heart diseases (coronary artery diseases and arrhythmias), the contribution of gender to pathophysiology and epidemiology of CHD to our knowledge has been poorly investigated.

Objective

The main objective of this narrative review is to provide the reader with an overview of gender differences in the epidemiology of CHD in order to improve the entire management of people born with CHD. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-23-260/rc).

Methods

This narrative review was performed through a standardized search of three electronic databases (Medline via PubMed; Scopus and Embase via Elsevier) using the following Medical Subject Headings (MeSH) terms: gender, difference(s), male, female, congenital heart defects, epidemiology, prevalence and their variable combinations.

Two researchers (Pugnaloni F, Felici A) in consensus assessed each investigation.

We decided to include observational, prospective, population based and retrospective studies reporting gender differences in the prevalence of isolated or syndromic CHD. We screened all available articles with at least an abstract.

Exclusion criteria were the following: no English language, conference abstracts or study setting different from included studies, non-human studies, no full text available.

Further relevant papers were later selected by hand-searching of the references list of chosen articles.

Two reviewers (Pugnaloni F, Felici A) independently analyzed the search results and developed a dedicated online data extraction sheet (Excel 16: Microsoft Corporation, Redmond, WA, USA).

Studies included in data extraction sheet were marked for inclusion or exclusion with exclusion reason based on the predefined criteria. Any disagreement about data extraction was resolved by discussion with a third review author (Putotto C) in order to resolve any disputes. The last update was performed on March 15^th, 2023. The search strategies are available in Table 1.

Results

The initial search identified 1,904 potentially relevant papers: 945 papers were found via PubMed, 594 studies via Embase and 365 studies via Scopus. After removing duplicates, 1,885 papers were screened by title or abstract. Excluding papers not written in English, wrong study design/conference abstracts and irrelevant papers for the topic, 17 full-text studies were considered potentially eligible for inclusion.

After exclusion of seven studies, additional 11 papers were included by hand-searching review of references lists. The final number of articles included is 21.

The flow diagram of the study selection process is provided in Figure 1.

Figure 1 Flow diagram of study selection process.

Changing incidence and prevalence of CHD

The incidence of CHD has been demonstrated to progressively rise over years, reaching current values of 10–14/1,000 live births (7-12).

A recent meta-analysis reported that worldwide birth prevalence in children <5 years of age increased from 0.6/1,000 live births in 1930 to 9.1/1,000 live births after 1995 (13) and that mild CHD, such as not hemodynamically significant atrial septal defects (ASDs) and patent ductus arteriosus (PDA), have substantially increased, while severe and critical CHD have shown a trend of decreasing incidence in recent decades.

This effect is the result of two parallel phenomena. On one hand, the great improvement in diagnostic and screening tools (i.e., color-Doppler echocardiography) enabled a significant increase in case detection, on the other hand the greater availability of prenatal diagnosis tests and voluntary abortion determined a significant reduction in the incidence of complex and critical CHD (8,13).

In the changing background of epidemiology of CHD, gender differences in worldwide prevalence have been previously recognized. From the literature reports, the cumulative prevalence of CHD is considerably higher in females both in adulthood and childhood (7,14,15).

This observation may be related to the fact that the relevant proportions of mild forms of CHD, which are growing over the years, are more preponderant in females (16).

Prevalence of specific CHD among genders

Biological differences between females and males include genetic and hormonal status differences that may contribute to different anatomical subtypes of CHD.

Gender differences in specific CHD have been documented since 1970s, and these observations have been consistent over time. The first description of a gender-specific distribution of different CHD dates back to the late 1970s when national registries of congenital diseases, including CHD, became widespread. We included in our review epidemiologic studies based on data extracted from international, national, and regional registries. Those large healthcare databases provide precise CHD prevalence information, that can be generalizable to the entire population under analysis. The additional studies incorporated within the review primarily investigate the epidemiology of CHD with a specific emphasis on factors such as gender distribution and demographics of cohorts. Despite the limitations in sample size, these studies yield valuable data that contribute to our understanding of gender-related distribution of CHD and a summary of all the studies is shown in Table 2.

Left ventricular outflow tract obstruction (LVOTO)

A consistent association is observed between the presence of LVOTO and male sex. In a multicenter study by García et al. (22) involving 5,000 Colombian children with CHD, it was found that only 33.5% of patients with LVOTO were female. Similar findings were reported by Hoang et al. (26) in their analysis of data from the Pediatric Cardiac Genomics Consortium (PCGC) cohort, which included 8,693 patients. Among cases with LVOTO, approximately 65.8% were male. McBride et al. (29) conducted a study specifically focused on patients with non-complex LVOTO and demonstrated a male sex predisposition with respect to aortic valvular stenosis (AVS), coarctation of the aorta (CoAo), and hypoplastic left heart syndrome (HLHS).

Additionally, all included studies consistently establish a correlation between aortic stenosis (AS) and male sex. Egbe et al. (8) utilized data from the National Institutes of Health (NIH) (USA) national registry in 2008, focusing on live birth hospitalizations, and reported a fourfold higher prevalence of AS in males compared to females. Pradat et al. (27) conducted a study using a substantial case series derived from medical records in three countries (Sweden, France, and the USA) between 1981 and 1992, revealing an M:F ratio of 2.41 among AS patients. Similarly, Sokal et al. (24) observed nearly double the prevalence in males based on a sample of 794,169 infants, while Tennant et al. (20), analyzing healthcare records from the Northern Congenital Abnormality Survey (NorCAS) registry between 1985 and 2003 encompassing fetuses, stillbirths, and live births, reported a male to female relative risk of 2.50 for AS/aortic atresia. Other studies also support a higher prevalence of AS in males, albeit with less pronounced results (15,19,21,26). Among studies focused on cohorts of cardiac patients, Rothman’s study (18), drawing from CHD infants data in the New England Regional Infant Cardiac Program (NERICP) registry, and Ferencz et al. (17), examining the Baltimore-Washington infants study, disclosed a male percentage of 78% and 71.6%, respectively, among infants with AS.

In the context of aortic coarctation (CoAo), numerous studies have indicated a correlation with male sex, although the association is not as pronounced as that observed for AS. Egbe et al. (8) reported a male-to-female (M:F) ratio of 2.3:1, which aligns with the M:F ratio of 1.72 reported by Pradat et al. (27). Other population-based studies have found a slightly higher prevalence of males compared to females, with male-to-female prevalence ratios ranging from 1.3 to 1.68 (7,20,22,24).

In the case of HLHS, a distinct preference for male sex is evident. Sokal et al. (24), supported by a large sample, revealed an even stronger correlation with male sex compared to AS. Other studies included in the review consistently associate HLHS with a higher incidence in males, although the results may vary (8,18,19,21,23,27).

Right ventricular outflow tract obstruction

In contrast to the findings discussed earlier regarding LVOTO, there is evidence suggesting a preference for the female sex in cases of right outflow tract obstruction caused by pulmonary stenosis (PS). Tennant et al. (20), in a population-based study, report a slightly higher prevalence of this condition in females. Egbe et al. (8) describe a higher representation of females with PS and among infants in the Baltimore-Washington study, Ferencz (17) reports a significant female majority (77.8%).

Notably, the study by Pradat et al. (27) highlights a statistically significant association between pulmonary atresia and male sex, a finding supported by Šamánek’s study (19). Additionally, in the pediatric patient cohort presented by Egbe (8), there appears to be a statistically significant correlation between pulmonary atresia and male sex when associated with ventricular septal defects (VSDs), but not in cases of isolated pulmonary atresia.

Some studies also report a slight male predominance among patients with right-sided obstructions due to tricuspid valve stenosis and tricuspid valve atresia (19).

The findings from various studies suggest a slight association with male sex for the tetralogy of Fallot (ToF) as shown by population studies by Shu-Jen Yeh (15), Tennant (20), and Pradat (27). A predilection for male sex in ToF is also observed in the study by Pfitzter et al. (16), based on hospital records. Conversely, Šamánek (19) reports a slightly higher proportion of females in patients with ToF, although the study’s impact is limited due to a relatively small sample size.

Cardiac septation defects

In relation to cardiac septation defects, the studies analyzed reveal notable sex-related differences. Population-based studies demonstrate an association between female sex and the presence of these defects, although the strength of the association varies depending on the specific defect examined. These studies consistently indicate a higher prevalence of ASDs among females, with male-to-female prevalence ratios ranging from 0.61 to 0.73 (8,15,17,20,21,24,27,30).

The results of Ferencz’s study (17) on infants and Verheugt’s study (25) on CHD patients older than 16 exhibit similar patterns in terms of the sex-specific distribution of ASD, suggesting that the sex distribution of this condition is independent of patient age. Moreover, in the study by Pfitzter et al. (16), based on medical records of CHD patients who received hospital care, the prevalence of ASD was almost twice as high in females as in males.

In regard to VSDs, few studies observe statistically significant differences and report a slight association with female sex. Yeh et al. (15), using data from Taiwanese health-care registries, report a male-to-female prevalence ratio of 0.9. Similarly, among Italian patients presented by Calzolari et al. (30), a slight male predominance was observed among VSD patients. The study conducted by Ferencz (17) also reports a higher proportion of females in patients with muscular VSD.

Similarly, atrioventricular septal defects (AVSD) also appear to have a higher prevalence in the female sex, as evidenced by several population-based studies or large cohorts (7,16,18,19,21,26).

Patent ductus arteriosus

Marelli et al. (7), through their analysis of population health records in Quebec, observed a higher frequency of shunt lesions (including ASD, VSD, AVSD, and PDA) among female individuals in both childhood and the adult population (8). Additionally, apart from the aforementioned cardiac shunt lesions, a predisposition of the female sex for PDA has been observed across different age groups, including the first year of life (18), childhood (15,22), and in patients older than 16 years (25).

Conotruncal defects

Collectively, conotruncal heart defects demonstrate a subtle yet statistically significant association with male sex, as observed by Hoang et al. (26) among pediatric patients enrolled in the PCGC program.

In the case of transposition of the great arteries (TGA), Egbe et al. (8) report a fourfold higher representation of males compared to females. Similarly, Ferencz (17), Rothman (18), Šamánek (19), and Pradat (27) report that more than two-thirds of TGA cases were males. Similar findings are reported by additional population-based studies (15,19-21,23,24). The gender-specific disparities in prevalence of TGA do not exhibit significant differences between pediatric and adult populations, as reported by Marelli et al. (7). Verheugt’s study (25) of CHD patients older than 16 years aligns with other pediatric patient cohorts, highlighting a higher representation of males among patients with TGA. Conversely, data on functionally corrected TGA are limited, with only the results of Šamánek (19) indicating a male predilection.

Among other truncal congenital heart diseases, the limited available data suggest a greater distribution in the male sex regarding double outlet right ventricle (DORV) (19,27) and a predilection for the female sex regarding truncus arteriosus (19).

Other congenital heart defects

Among various subtypes of CHD that exhibit gender-specific distribution differences, there is evidence indicating a male predilection for total anomalous pulmonary venous return (TAPVR). Pradat et al. (27) report a clear majority of males among individuals with TAPVR, while Tennant et al. (20) describe a more than twofold higher prevalence of this defect among male fetuses, stillbirths, and infants in northern England. Additionally, the latter study (20) highlights a significant difference in the prevalence of univentricular heart disease between genders, with nearly three times higher prevalence in males compared to females. This association between male sex and univentricular heart is also described in Pfitzer et al. (16). Lastly, in the studies conducted by Šamánek et al. (19) and Pfitzer et al. (16), Ebstein’s anomaly is observed more frequently in female patients.

BAV is more prevalent in males, with a three to fourfold higher prevalence compared to females (28). Sievers and Schmidtke proposed a surgical classification system for BAV based on the number of cusps, location of raphe, and commissure orientation (32) and a study by Roman et al. (33) found that men more frequently presented with type 1 BAV, characterized by fusion between the left and right coronary cusps, while women more frequently had type 2 BAV, which involved fusion between the right and non-coronary cusps. However, other studies did not find a significant association between BAV phenotypes and gender (28).

In summary, BAV is more common in males, and there are different BAV phenotypes based on cuspal fusion patterns, which may exhibit some gender-specific differences. However, the association between BAV phenotypes and gender is not consistently observed in all studies.

In patients with BAV, Li et al. (28) observed different distribution in BAV related complications; In particular, aortic valve regurgitation and aortic dilatation are more common in men, while moderate to severe AS are more commonly observed in women.

Taken together, these studies support the evidence that heart defects involving the outflow tract predominate in males, while inflow tract defects and shunt lesions prevail in females.

Moreover, severe CHD, defined as all cyanotic CHD or hemodynamically significant not cyanotic lesions requiring surgical and/or percutaneous correction, seem to be significantly associated with male sex in addition to younger age, higher New York Heart Association (NYHA) class, absence of systemic hypertension and hematocrit >50% (31).

Discussion

Despite the consistency of findings among studies on CHD gender prevalence ratio, there is still little evidence on the explanation of these differences.

However, the variation in CHD prevalence by gender may provide valuable clues to their etiology, and a complex interplay between hormonal, genetic, epigenetic and environmental factors affecting heart development may be involved.

The interaction between different sex hormones and system development has been hypothesized as a possible cause of gender differences in some congenital anomalies for example cleft palate and cleft lip (34) as well as in utero exposure to environmental toxins or exogenous exposures (i.e., maternal smoking) (34).

The theory proposed by James in 1999 (35) is that some congenital gender anomalies may be associated with different concentrations of parental sex hormones near conception.

Specifically, James argued that a male preponderance of TGA may be secondary to a hormonal balance favoring androgen in pregnant women. However, there is still no validated evidence for this hypothesis.

Furthermore, there have been studies assessing differences in how males and females respond to stressors during fetal life.

Some authors have suggested that fetal stress factors (maternal illness, drugs during pregnancy, exposure to environmental toxins) may increase the risk of CHD and that the different response of males and females to these stressors may contribute to gender differences in CHD prevalence (36-38).

The differences in CHD prevalence observed between males and females at birth may be suggestive of the theory that one gender is more susceptible to certain endogenous or exogenous factors during the critical early stages of embryonic development.

Consistent with the previous hypothesis, X- and Y-linked genes might contribute differently to the normal development of structures during early stages of development.

For example, the male preponderance of aortopathies (i.e., AS, CoAo) and BAV are thought to be related to genes located on chromosome X.

A significantly high prevalence of aortic defects is also found in one of the most common sex aneuploidies, Turner syndrome, which is caused by the complete or partial absence of X chromosome.

Comparing Turner syndrome patients with the general population, aortic valve anomalies occur 146 times more commonly and women with pure 45, X monosomy show a significantly higher prevalence of aortic diseases than women with Xq isochromosome (39,40).

In light of the above, it is reasonable to hypothesize that a genetic factor located on the X chromosome modulates the development of the aorta itself and the aortic valve.

There are several putative genes expressed from sex chromosomes that play a role in cardiovascular development. Among the X-linked genes, genes encoding vascular endothelial growth factor (VEGF)-D and the angiotensin type 2 receptor have been extensively studied for their implication in cardiogenesis (41).

As well as for other aortopathies, BAV is thought to be related to a reduced dosage of X-linked genes that escape X inactivation (42).

Gender differences in CHD may also extend to clinical presentation, short- and long-term outcomes and comorbidities, and several efforts have been made over time to summarize these aspects (25,43,44).

It is important to acknowledge that biological gender is a complex concept with a degree of variability. While most individuals can be classified as male or female based on typical biological characteristics, there are instances where intersex variations or other medical conditions can result in atypical presentations.

It is also crucial to recognize that biological gender is distinct from gender identity, which is a deeply-held sense of being male, female, or non-binary, and may not necessarily align with an individual’s biological characteristics. Gender identity is a personal and subjective experience that goes beyond biological factors.

Societal understanding and recognition of gender have evolved, and it is important to respect and acknowledge individuals’ self-identified gender identities and experiences.

Strengths and limitations

Although there is still little information to date, our review has the potential to focus on the importance of gender differences in the prevalence of CHD.

One of the strengths of our study is to summarize the current evidence on gender differences in CHD epidemiology in order to guide gender-specific management and therapy based on the individual characteristics of CHD.

The main limitation of this narrative review derives from the lack of a large sample of population-based data from well-defined geographical areas and well-structured national or international registries. Additionally, epidemiological differences in CHD should also account for the differences in race and ethnicity. Our narrative review also highlights the need for standardized reporting from multiple and uniform sources and a consistent approach to data collection and recording.

Most of the studies presented are, indeed, limited to specific geographic areas and therefore may not be representative of the general population.

Furthermore, most of the reviewed studies showed data not adjusted for socio-economic factors or maternal information that may play a role in the association between gender and the risk for CHD.

An additional issue to consider is that most reports are unable to include CHD diagnosed in pregnancies ending in voluntary termination or spontaneous abortion and the exclusion of these cases may result in a different gender distribution of CHD.

Moreover, to date knowledge of epidemiological data on prevalence does not result in changes in management or therapy. This is evident from the fact that existing guidelines still recommend treatments primarily derived from data obtained from men, which are then extrapolated to women. Unfortunately, women remain underrepresented in clinical trials involving cardiovascular issues and thus, further studies are needed to deeply examine these differences and translate them in gender-specific clinical approaches.

Conclusions

The present review article summarizes the differences between males and females in terms of prevalence of CHD. Our review confirms that there is a greater risk for males to be born with severe CHD mostly involving the outflow tract and for females with milder CHD subtypes occurring in the inflow tract of the heart.

The causative mechanisms of CHD gender distribution are still under investigation, but the widespread use of large population-based resources, such as national or international registries, offers great potential to examine gender differences across the whole spectrum of CHD, as isolated or in the context of genetic syndromes.

Furthermore, healthcare providers should receive education and training on the importance of considering sex and gender in the diagnosis, treatment, and management of CHD.

Developing updated guidelines and clinical protocols that explicitly incorporate gender-specific considerations is crucial. These guidelines should adapt diagnostic criteria, treatment algorithms, and follow-up strategies tailored to the unique needs of both males and females based on collaboration among multidisciplinary teams (cardiologists, geneticists, psychologists, and other specialists) for a holistic approach to care.

Consequently, personalized healthcare should be based on evidence from research studies aimed at understanding how gender influences the risk for CHD and gender medicine should become an established medical approach.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics for the column “Pediatric Heart”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-23-260/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-23-260/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-260/coif). The column “Pediatric Heart” was commissioned by the editorial office without any funding or sponsorship. AFC serves as the Editor-in-Chief of Translational Pediatrics from June 2023 to May 2025, and served as the unpaid Guest Editor of the column. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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