Introduction
Melanoma remains a significant malignancy among women of reproductive age, with approximately one-third of female melanoma cases diagnosed during the childbearing years. Several series indicate that melanoma is frequently encountered cancer in the context of pregnancy, representing roughly 30% of all cancers identified during gestation [1]. The reported incidences range from approximately 2.8–5.0 per 100,000 pregnancies in European cohorts to about 45 per 100,000 maternities in Australian populations, reflecting regional melanoma prevalence and methodological differences across studies [2]. The designation “pregnancy-associated melanoma” (PAM) is commonly applied to melanomas diagnosed within one year prior to conception through up to one year postpartum, although definitions vary across studies [2].
Historically, concerns have persisted since the mid-20th century that the hormonal, vascular and immunological shifts accompanying pregnancy might adversely affect the onset or course of melanoma [2]. Indeed, physiological changes such as increased melanocytic activity, hyperpigmentation (for example, melasma or genital/areolar darkening) and modifications in benign melanocytic nevi (increased mitotic activity, diameter expansion in sites of skin stretching, augmented vascularity, and enhanced clustering of melanocytes in superficial dermis) are well documented. These alterations raised the plausible hypothesis that pregnancy might facilitate malignant transformation or accelerate progression of melanocytic lesions [3].
However, despite these biologically plausible changes, the preponderance of clinical and histologic evidence suggests that many of the benign nevus changes observed during pregnancy resolve within 12 months postpartum, and do not inevitably signal increased melanoma risk or poorer prognosis. Experimental murine models, for instance, revealed that although pregnancy triggered expression of intrinsic apoptotic pathways (e.g., activation of caspases 7 and 9), the net effect was inhibition of apoptosis in melanoma cells – suggesting a complex, rather than uniformly promotive, effect of pregnancy on melanoma behaviour [4].
Nevertheless, dysplastic nevi specific changes such as increased cellular atypia and enhanced expression of oestrogen-β receptors have been described, raising the possibility of a hormone-mediated acceleration of melanocytic atypia, albeit without conclusive evidence of a direct link to disease progression [4]. Indeed, in the era of immune checkpoint inhibitors and targeted BRAF/MEK therapy – therapeutic modalities scarcely studied in the pregnant population – the question of how pregnancy might impact melanoma characteristics, treatment options and outcomes remains of profound clinical relevance.
Clinically, the question of whether pregnancy negatively affects melanoma prognosis has generated conflicting findings. Some meta-analyses have reported increased recurrence and mortality rates among women with PAM, whereas others suggest that outcomes (in terms of overall survival and disease-free survival) are no worse than in non-pregnant counterparts [2]. Against this backdrop, the absence of formalised guidelines for the management of PAM – particularly in the setting of advanced disease or therapeutic innovation – underscores the urgency of further study.
Methodological approach of the review
This article is conceived as a narrative, clinically oriented review of PAM. A literature search was conducted using PubMed/MEDLINE, supplemented by Embase and reference lists of key articles. The search covered publications from January 2000 through September 2025, reflecting both historical perspectives and contemporary management strategies. Search terms included combinations of “pregnancy-associated melanoma,” “melanoma in pregnancy,” “maternal melanoma,” “placental metastasis,” “foetal metastasis,” “immunotherapy,” “targeted therapy,” and “radiotherapy in pregnancy.”
Eligible publications comprised original observational studies, cohort studies, case series, systematic reviews, meta-analyses, and relevant clinical guidelines published in English. Case reports were included selectively when addressing rare but clinically relevant scenarios. Studies focusing exclusively on non-melanoma skin cancers, animal- only experiments without clinical correlation, or publications lacking sufficient clinical detail were excluded.
Given the rarity of PAM and the heterogeneity of available evidence, no formal quantitative synthesis or meta- analysis was undertaken. Studies were prioritized based on clinical relevance, methodological rigour, sample size, and recency, with particular emphasis on data informing prognosis, diagnostic strategies, and therapeutic decision- making during pregnancy. The review aims to integrate available evidence with contemporary oncologic and obstetric practice to provide a clinically meaningful synthesis rather than an exhaustive systematic appraisal.
Risk factors and mechanisms of pregnancy-associated melanoma
Pregnancy is characterized by profound physiological, hormonal, and immunological adaptations that may influence melanoma biology through multiple, interrelated pathways. One clinically relevant mechanism is delayed recognition of malignant lesions. Gestation is associated with generalized hyperpigmentation and benign nevus changes, which may obscure early malignant transformation and contribute to diagnostic delay. Given that approximately two-thirds of melanomas arise from pre-existing nevi, any evolving pigmented lesion during pregnancy warrants a low threshold for prompt excisional or incisional biopsy, irrespective of gestational age [5].
Beyond diagnostic considerations, pregnancy constitutes a pro-angiogenic and pro-lymphangiogenic state. Pregnancy-associated upregulation of lymphatic vessel formation may facilitate tumour cell dissemination, and increased intratumoral lymphangiogenesis has been correlated with sentinel lymph node involvement in melanoma [6]. Concurrently, maternal immune adaptation aimed at maintaining foetal tolerance – including trophoblast-mediated attenuation of maternal T-cell activation, modulation of indoleamine 2,3-dioxygenase activity, and increased expression of immune checkpoint molecules such as programmed death-ligand 1 – may inadvertently create an immunologic milieu permissive to tumour immune evasion. Melanoma cells are known to exploit the same pathways, suggesting a biologically plausible mechanism by which pregnancy could modulate tumour progression [6].
Hormonal influences represent an additional, though incompletely defined, factor. Elevated oestrogen and progesterone levels during pregnancy promote melanocyte activation and melanin synthesis. Emerging evidence suggests that reduced expression of oestrogen receptor α in melanoma correlates with increasing Breslow thickness and adverse prognosis, raising the hypothesis that pregnancy-related hormonal shifts may influence tumour behaviour. Furthermore, pregnancy-associated plasma protein-A (PAPP-A), through activation of insulin-like growth factor-1 (IGF-1) signalling, has been implicated in enhanced melanoma cell motility and metastatic potential. Elevated PAPP-A expression in metastatic melanoma has been associated with poorer outcomes, highlighting a potential mechanistic and biomarker role that warrants further investigation in pregnancy-associated disease [7].
Despite these biologically plausible mechanisms, clinical outcome data remain inconsistent. While some studies report no adverse prognostic impact of pregnancy on localized melanoma, others suggest increased recurrence or melanoma-specific mortality. A nationwide Norwegian cohort study demonstrated a modest but statistically significant increase in melanoma-specific mortality among pregnant women compared with non-pregnant controls (HR 1.52; 95% CI: 1.01–2.31) [8], whereas a contemporary Swedish cohort found no such association [9]. Meta-analyses spanning several decades similarly yield discordant results [10], likely reflecting methodological heterogeneity, retrospective designs, limited cohort sizes, and inadequate control for confounding variables. Collectively, these findings underscore the ongoing uncertainty regarding the true prognostic influence of pregnancy itself, while reinforcing the importance of timely diagnosis and stage- appropriate management.
Importantly, the persistent inconsistencies across studies examining the prognostic impact of pregnancy on melanoma are likely multifactorial rather than purely biological. Many earlier series were limited by retrospective design, small sample sizes, and heterogeneous definitions of PAM, with variable inclusion of cases diagnosed during gestation vs. the postpartum period. Inadequate adjustment for critical prognostic variables – such as Breslow thickness, ulceration status, mitotic rate, stage at diagnosis, and access to contemporary treatments – has further confounded interpretation. Additionally, delays in diagnosis attributable to pregnancy-related nevus changes or reduced healthcare utilization may falsely attribute poorer outcomes to pregnancy itself rather than to more advanced disease at presentation [9]. Temporal bias also plays a role, as older cohorts predate the widespread adoption of sentinel lymph node biopsy, modern imaging, and effective systemic therapies, limiting comparability with contemporary populations. Collectively, these methodological limitations suggest that pregnancy per se is unlikely to be an independent adverse prognostic factor; rather, observed outcome differences are more plausibly driven by stage migration, diagnostic delay, and treatment-era effects.
Diagnosis, staging, and management of pregnancy-associated melanoma
In light of the biological considerations outlined above and the persistent uncertainty regarding prognosis, early diagnosis and standardized oncologic management remain paramount in PAM. Pregnancy-associated melanoma presents a unique clinical challenge due to gestational physiological changes and the absence of dedicated evidence-based guidelines; consequently, management is largely extrapola- ted from non-pregnant melanoma protocols and principles established for other malignancies during pregnancy [11]. Optimal care requires a multidisciplinary approach, integrating dermatology, surgical and medical oncology, maternal-foetal medicine, radiology, and pharmacology to balance maternal benefit with foetal safety.
Pregnant patients should undergo close surveillance of melanocytic lesions, and any lesion demonstrating suspicious features – such as asymmetry, border irregularity, colour variation, diameter enlargement, or evolution – should prompt immediate biopsy without delay. Excisional biopsy under local anaesthesia is considered safe throughout pregnancy [11]. Standard dermatologic practice, including excision with narrow (1–2 mm) margins for diagnostic purposes, should be adhered to in order to ensure histopathological accuracy and potential complete lesion removal.
Definitive surgical management should likewise not be postponed solely due to pregnancy. Wide local excision of the primary tumour should follow established margin recommendations based on Breslow thickness and tumour characteristics, consistent with non-pregnant melanoma guidelines [11].
Sentinel lymph node biopsy (SLNB) may be performed safely during pregnancy when clinically indicated and undertaken by experienced multidisciplinary teams. The procedure should utilize technetium-99m radiocolloid alone, avoiding teratogenic or anaphylaxis-associated dyes such as methylene blue or isosulfan blue. Foetal radiation exposure from technetium-99m mapping remains minimal (< 5 mGy), well below established teratogenic thresholds [12]. The timing of SLNB should be individualized, taking into account gestational age, disease stage, and whether results would meaningfully alter immediate management; in selected cases, postponement until the postpartum period may be appropriate [12].
The anaesthetic management of pregnant patients undergoing melanoma surgery requires careful balancing of maternal safety, foetal well-being, and the physiological changes of gestation. Local anaesthesia with lidocaine, with or without epinephrine at dilute concentrations, is widely considered safe throughout pregnancy and is the preferred modality for cutaneous procedures, minimizing systemic exposure and reducing foetal risk [13]. In contrast, agents such as mepivacaine and bupivacaine are generally reserved for specific indications due to potential associations with adverse foetal effects and maternal hemodynamic changes [14]. For more extensive surgical intervention requiring sedation or general anaesthesia, multidisciplinary consultation is essential, and regional anaesthetic techniques should be preferred when feasible to reduce foetal exposure to systemic drugs [15]. Perioperative strategies, including maternal positioning to avoid aortocaval compression and intraoperative monitoring, are integral to optimizing both maternal and foetal outcomes [15].
Staging in PAM must balance maternal oncologic needs with foetal safety [16]. Imaging modalities that avoid ionizing radiation, such as ultrasonography and magnetic resonance imaging (MRI) without gadolinium, are preferred, with MRI considered safe from the second trimester onward and permissible in the first trimester if clinically necessary. Positron emission tomography (PET)/MRI can be considered in advanced disease to reduce foetal radiation exposure compared with PET/computed tomography (CT), while high-dose modalities such as single photon emission computed tomography/CT should be avoided whenever possible. All imaging should be optimized to minimize foetal exposure, including patient hydration and bladder voiding protocols [16].
Systemic therapy options during pregnancy are extremely limited. BRAF/MEK inhibitors are teratogenic and generally avoided [17]. Immune checkpoint inhibitors – including anti-programmed death 1 (PD-1) (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and LAG-3 inhibitors (e.g., relatlimab) – are largely contraindicated outside exceptional circumstances due to the potential for disruption of maternal-foetal immune tolerance [18]. Theoretical risks include impaired maternal tolerance of the foetus and immune-mediated complications. Consequently, systemic therapy should be deferred until postpartum whenever feasible, and any use during gestation requires multidisciplinary consultation, individualized risk-benefit assessment, and thorough patient counselling.
These challenges are increasingly relevant in the contemporary melanoma treatment landscape, where adjuvant systemic therapy has become standard of care for resected stage II and III melanoma, and neoadjuvant immunotherapy is being progressively adopted worldwide for high-risk, resectable disease. As a result, a growing number of women of reproductive age may be exposed to immune checkpoint inhibitors either prior to conception or in the adjuvant setting. This raises complex clinical scenarios when pregnancy occurs during or shortly after systemic treatment, for which prospective safety data are lacking [19].
Of particular concern are immune-related endocrine toxicities induced by checkpoint inhibition, including thyroiditis, hypophysitis, adrenal insufficiency, and insulin-dependent diabetes mellitus. These endocrinopathies may overlap with or exacerbate physiological hormonal adaptations of pregnancy, complicate obstetric management, and pose potential risks to both maternal and foetal health [20]. Accor- dingly, patients who become pregnant while receiving or shortly after completing adjuvant anti-PD-1 therapy require close endocrine monitoring and coordinated care involving oncology, maternal-foetal medicine, and endocrinology specialists. In most reported cases and expert recommendations, interruption of immunotherapy upon recognition of pregnancy is advised, followed by careful surveillance and consideration of postpartum treatment resumption.
Conventional cytotoxic chemotherapy is rarely employed in PAM owing to limited efficacy and teratogenic potential, whereas modern localized radiotherapy techniques – including stereotactic radiotherapy and intensity- modulated radiation therapy – may be considered for isolated disease when the uterus can be reliably excluded from the radiation field [4]. The systemic treatment options for PAM are summarised in Table 1.
Table 1
Systemic therapy options for pregnancy-associated melanoma, including known safety data, teratogenic potential, and recommendations based on current evidence
Women diagnosed with stage IV melanoma during pregnancy should be informed of the small but clinically significant risk of placental and potential foetal involvement. Comprehensive macroscopic and histopathological examination of the placenta is recommended in all such cases, and if placental metastasis is identified, meticulous neonatal evaluation and long-term follow-up are warranted [2]. Placental involvement typically reflects advanced maternal hematogenous dissemination, as placental metastases have not been reported in the absence of additional visceral metastatic disease. The absence of both macroscopic and microscopic placental abnormalities is generally considered sufficient to exclude foetal metastasis. Nevertheless, when foetal dissemination occurs, outcomes are poor, with reported mortality exceeding 80%, although rare cases of spontaneous postpartum regression have been described [21]. Overall, approximately one quarter of infants born to mothers with placental melanoma metastases are reported to die from metastatic disease [22]. Maternal prognosis in such cases mirrors that of stage IV melanoma in the corresponding treatment era [22].
Infants should undergo close clinical surveillance for at least two years, and breastfeeding is generally contraindicated during adjuvant systemic therapy [18].
In pregnant patients with melanoma where local therapy is indicated, brachytherapy represents a feasible conservative radiotherapeutic approach that can achieve effective local tumour control while minimizing systemic exposure. Although data specific to cutaneous melanoma are limited, evidence from intraocular melanoma treated with plaque brachytherapy suggests that localized radiotherapy during gestation does not necessarily compromise maternal oncologic outcomes nor demonstrably harm foetal development when appropriately planned and executed [23]. In a retrospective series of women of reproductive age with uveal melanoma treated with iodine-125 plaque brachytherapy, pregnancy did not negatively impact metastasis-free or overall survival compared to matched non-pregnant controls, and all pregnancies resulted in term deliveries of healthy infants without reported teratogenic effects, although continued long-term follow-up is needed to fully define late sequelae [24]. Pregnancy-adapted radiotherapeutic planning, shielding techniques (e.g., customized lead shields), and multidisciplinary decision-making are critical to optimize maternal treatment while respecting gestational safety.
Psychological support plays a pivotal role in the multidisciplinary management of melanoma diagnosed during pregnancy, as patients face complex decisions that implicate both maternal health and foetal well-being. Pregnant women with melanoma often experience heightened anxiety, decisional conflict, and existential distress due to the dual responsibility for their own prognosis and that of the unborn child, making structured psychosocial counselling an essential component of care [25]. Shared decision-making models that integrate empathetic communication, comprehensive risk-benefit counselling, and involvement of psycho-oncology specialists can help navigate therapeutic options – from timing of surgical interventions to the appropriateness and sequencing of systemic therapies – while respecting patient autonomy and values. Ethical considerations are particularly salient in this context, as clinicians must balance the principle of beneficence for the mother with non-maleficence toward the foetus, reco-gnizing that delaying optimal maternal treatment may adversely impact maternal outcomes, whereas aggressive therapy may pose potential risks to foetal development. Transparent discussion of uncertainties, patient preferen-ces, and gestational age-dependent risks underpins ethically sound care, with a multidisciplinary team providing support to reconcile the medical imperatives with psychosocial needs throughout pregnancy and the postnatal period [26].
Conclusions
Pregnancy-associated melanoma represents a complex clinical scenario at the intersection of maternal oncology and foetal safety. Contemporary evidence increasingly indicates that, when matched for stage and established prognostic factors, maternal outcomes in PAM are comparable to those of non-pregnant women, underscoring that disease stage at diagnosis remains the principal determinant of prognosis. This highlights the critical importance of timely lesion recognition, prompt biopsy, and guideline- concordant surgical management during pregnancy.
While diagnostic, surgical, and local treatment strategies can often be safely adapted to pregnancy, systemic therapies remain restricted and require individualized, multidisciplinary risk-benefit evaluation. Although placental and foetal metastases are rare, their potential severity mandates placental histopathological evaluation and structured neonatal follow-up in advanced disease.
Overall, PAM underscores the necessity of individualized, evidence-informed, multidisciplinary decision-making. Continued accumulation of prospective data and the deve- lopment of pregnancy-specific guidelines will be essential to ensure optimal oncologic care without compromising maternal or foetal safety.
In summary, pregnancy itself does not appear to worsen melanoma prognosis when standard-of-care management is maintained, and outcomes in specialised centres are increasingly comparable to those observed in non-pregnant patients.
