Breast cancer (BC) is the most common malignancy among women worldwide, with an estimated 2.3 million new cases diagnosed annually, accounting for one in four cancer cases among women. Despite advances in diagnosis and treatment, it remains a leading cause of cancer-related mortality and a major global public health challenge (1-3). Various reproductive and obstetric factors have been investigated to understand their association with BC risk (4), among which mode of delivery has recently garnered significant attention (5).

Cesarean section (CS) has become one of the most frequently performed surgical procedures worldwide, with rates rising far above the World Health Organization's recommended threshold of 10-15% in numerous regions. In 2021, global estimates indicated that >21% of all deliveries occurred by CS, a figure projected to reach nearly one-third of all births by 2030(6). The convergence of these two major health concerns-rising CS prevalence and persistent BC burden- underscores the importance of investigating whether delivery mode may influence long-term maternal cancer risk.

The potential link between cesarean delivery and BC risk is grounded in several biological and epidemiological hypotheses. One proposed mechanism is the difference in hormonal milieu between vaginal delivery (VD) and CS. Studies have indicated that levels of oxytocin, known to have antiproliferative effects on BC cells, are significantly lower during CS compared with VD (7,8). Additionally, fetal microchimeric cells (FMc)-fetal-derived cells that can persist in maternal tissues and circulation for decades after pregnancy-are transferred at higher levels during CS. These cells have been implicated in both protective and adverse outcomes regarding maternal malignancies (5).

Despite accumulating evidence on the association between CS and increased risk of malignancies, particularly uterine cancer (5), the link between CS and BC remains inconclusive. Some studies have reported a higher incidence of BC in women with a history of CS, while others have not found significant associations. For example, a study analyzing a large cohort found an increased risk of BC in women with CS, particularly in those diagnosed within one year postpartum (9). By contrast, another study failed to demonstrate a significant difference in BC risk between women who delivered vaginally and those who had a CS (5).

Moreover, CS has been associated with adverse prognostic factors in BC, such as increased rates of lymphovascular invasion and extracapsular extension, which are markers of more aggressive disease (7). CS association with adverse prognostic factors in BC is particularly evident in estrogen receptor-positive (ER⁺) cases, where patients with a history of CS were found to have a poorer prognosis compared with those without (10).

Given the rising prevalence of CS worldwide and the potential implications for long-term maternal health, it is crucial to comprehensively assess its relationship with BC. Accordingly, the present systematic review had two distinct aims: i) to evaluate whether a history of CS is associated with an increased incidence of BC, and ii) to investigate whether CS correlates with specific tumor characteristics or features of biological aggressiveness in affected women.

The present systematic review included 4 studies that investigated the association between CS and BC risk and prognosis. These studies were conducted in three countries: Israel, Turkey and Korea. The study designs comprised cohort studies, including one population-based cohort conducted in Israel, one nationwide cohort conducted in Korea, and two retrospective cohort studies conducted in Turkey.

The total sample size across the four studies was 1,492,962 women, with individual study populations ranging from 434 to 1,384,551 women. All studies compared the outcomes between women who underwent CS and those who had VD or no CS. Characteristics of the included studies are displayed in Table II. The systematic review evaluated the association between CS and BC risk by synthesizing data from various studies. The findings regarding the relationship between CS and BC were inconsistent across the studies.

Some studies reported a slight increase in the risk of BC following CS. A nationwide cohort study conducted in Korea by Kang et al (9) observed a higher risk of postpartum BC among women who had undergone CS compared with those who had vaginal deliveries. The ORs reported were 1.237 [95% CI: 0.986-1.553] and 1.211 (95% CI :1.034-1.418) for different population groups. The study also highlighted that older maternal age (≥35 years) significantly increased the risk of postpartum BC, with an OR of 2.003 (95% CI 1.567-2.560). By contrast, a large population-based cohort study from Israel, conducted by Schwarzman et al (5), found no statistically significant association between CS and BC incidence, reporting similar rates between CS and VD groups (0.64 vs. 0.54 per 1,000 patient-years, P=0.072).

In addition to the variable risk association, some studies identified a link between CS and more aggressive BC features. A retrospective cohort study from Turkey by Oğuz et al (7) reported that women with a history of CS were diagnosed with BC at a younger age and had a higher risk of extracapsular invasion, particularly among patients with estrogen receptor-positive BC. Furthermore, they observed a shorter time interval between the last childbirth and the diagnosis of BC in women with a CS history. Another retrospective cohort study by Kalan et al (10) also demonstrated that CS was associated with a higher risk of lymphovascular invasion and extracapsular extension, identifying CS history as an independent risk factor for both conditions.

The present systematic review and meta-analysis provides the first pooled evidence on the potential association between CS and BC. Our results indicate a modest but statistically significant increased risk of BC incidence among women with a history of CS (OR=1.26, 95% CI: 1.07-1.47). In addition, the pooled analysis demonstrated more than a twofold increased risk of extracapsular extension (OR=2.11, 95% CI: 1.42-3.15), suggesting that CS may be linked not only to incidence but also to more aggressive tumor phenotypes. By contrast, no statistically significant association was observed between CS and lymphovascular invasion (OR=1.63, 95% CI: 0.69-3.89), and this analysis showed substantial heterogeneity.

The biological mechanisms linking CS with BC remain largely theoretical, as none of the four included studies directly evaluated mechanistic pathways. The retrospective cohorts from Turkey reported that women with a history of CS were diagnosed at a younger age and had more aggressive tumor characteristics, such as extracapsular extension and lymphovascular invasion (7,10). These findings suggest that CS could be associated with unfavorable tumor biology, although causality cannot be established. By contrast, the large population-based cohorts from Israel and Korea primarily assessed incidence rather than biological correlates, providing no mechanistic insight (5,9).

Several mechanisms could explain the potential link between CS and an increased risk of BC, as well as the association with more aggressive tumor characteristics. One of the most extensively discussed hypotheses is the role of fetal microchimerism, which refers to the persistence of fetal cells in the maternal bloodstream and tissues long after delivery. It has been observed that the concentration of FMc is significantly higher following CS than VD. These cells can persist in maternal tissues for decades, potentially exerting both protective and harmful effects. While FMc has been shown to participate in tissue repair and immune modulation, it may also promote carcinogenesis through immune evasion and aberrant cellular proliferation. Some studies have linked higher concentrations of FMc with breast and uterine cancers, although the evidence remains inconsistent (5,13-16).

Another potential mechanism is the alteration of hormonal profiles induced by CS. Unlike VD, which triggers a surge of oxytocin and stress hormones, elective CS may result in lower oxytocin levels. Oxytocin has been shown to exhibit antiproliferative effects on BC cells, reducing cell viability and inhibiting tumor growth. The absence of this hormonal boost during CS might reduce the protective effect against BC development (89). Furthermore, higher rates of postpartum lactation failure in women who undergo CS may reduce the long-term protective effects of breastfeeding against BC (17,18).

CS is associated with increased inflammatory responses, which may predispose women to carcinogenesis. The surgical trauma involved in CS triggers a cascade of pro-inflammatory cytokines, such as interleukins and tumor necrosis factors, which could contribute to tumor initiation or progression. Chronic low-grade inflammation has been linked to increased cancer risk and may play a role in BC development among women who undergo CS (19,20).

CS has been associated with a higher prevalence of obesity and metabolic syndrome in later life. Obesity itself is an established risk factor for BC, particularly in postmenopausal women. Increased adipose tissue contributes to elevated estrogen levels and chronic inflammation, creating a favorable environment for tumorigenesis. It is plausible that women who undergo CS are more likely to develop metabolic abnormalities, indirectly increasing their BC risk (21-23).

Women who undergo CS are often of advanced maternal age, have higher parity, or have pregnancy complications, all of which may indirectly influence cancer risk (24,25). Socioeconomic factors and healthcare access may also play a role in the association, as women opting for elective CS may differ systematically from those delivering vaginally (26).

However, these hypotheses remain speculative in the context of the present review. None of the included studies provided molecular or biomarker data to substantiate these pathways. Thus, while biological plausibility exists, the current evidence base does not allow definitive conclusions about causal mechanisms. Future prospective studies integrating epidemiological, clinical and molecular data are essential to clarify whether the observed associations reflect true biological effects or residual confounding. The mechanistic hypotheses linking CS to BC risk are demonstrated in Fig. 5.