Environmental and Genetic Influences on Placental Morphogenesis: Integrating Maternal Health and Fetal Outcomes

The placenta is a vital, multifunctional organ that serves as the interface between mother and fetus during pregnancy. Often described as the “lifeline” of gestation, it plays critical roles in nutrient and gas exchange, waste elimination, hormonal signaling and immune regulation. Beyond these immediate physiological functions, the placenta profoundly influences both maternal adaptation to pregnancy and long-term health outcomes for the offspring. Abnormalities in placental development and function have been linked to pregnancy complications such as preeclampsia, gestational diabetes, intrauterine growth restriction (IUGR) and preterm birth [1-3].

Placental morphogenesis-the orchestrated formation and maturation of placental tissue-is governed by both genetic and environmental factors. Genetically, key developmental processes such as trophoblast differentiation, vascular remodeling and immune tolerance are regulated by signaling pathways including VEGF, Wnt and Notch [4,5]. Polymorphisms in genes involved in these pathways, such as those in the VEGF gene, have been associated with impaired angiogenesis and abnormal placental architecture, elevating the risk of fetal growth restriction [6,7].

Environmental influences interact with genetic predispositions to further shape placental development. Maternal conditions like obesity, hypertension and diabetes can induce systemic oxidative stress and inflammation, which adversely affect placental vascularization and function. Additionally, exposure to environmental toxins-such as airborne pollutants, pesticides and heavy metals-can cause cellular and epigenetic changes in placental tissues, exacerbating underlying genetic vulnerabilities [8,9]. Nutritional deficiencies in essential micronutrients, including folic acid, iron and vitamin D, impair trophoblast proliferation and vascular remodeling, underlining the significance of maternal health and environment in placental function [10,11].

Recent advances in epigenetics have revealed how environmental exposures and genetic factors converge to influence gene expression during placental development. Mechanisms such as DNA methylation, histone modification and non-coding RNA regulation allow the placenta to respond to environmental stressors. However, maladaptive epigenetic alterations can result in placental pathologies such as villous hypoplasia, fibrin deposition and chronic inflammation, ultimately compromising placental efficiency [14,15] (Figure 1).

Importantly, disruptions in placental development have consequences that extend beyond pregnancy. Placental dysfunction is increasingly recognized as a driver of long-term health risks in offspring, including cardiovascular disease, metabolic syndrome and neurodevelopmental disorders-a phenomenon known as fetal programming [16,17].

Technological advancements have significantly enhanced the study of placental biology. High-throughput tools such as single-cell RNA sequencing, proteomics and metabolomics offer deep insights into the molecular basis of placental development. Imaging modalities, including placental MRI and three-dimensional ultrasound, enable non-invasive, real-time assessments of placental structure and function, facilitating early diagnosis and intervention [18,19].

Despite these scientific advances, few studies have comprehensively examined the interaction of environmental and genetic influences on placental development in real-world clinical settings, particularly within specific regional contexts such as Saudi Arabia. This study addresses this gap by analyzing histological, genetic and clinical data from 85 pregnancies in the northern region, aiming to elucidate the multifactorial nature of placental morphogenesis and its impact on maternal and fetal health.

Aims and Objectives

This study aims to investigate the combined influence of environmental exposures and genetic variations on placental morphogenesis and to evaluate how these factors affect maternal health and fetal outcomes. By integrating histological, molecular and clinical data, the study seeks to:

• Identify structural abnormalities in the placenta associated with maternal conditions such as obesity, hypertension and nutritional deficiencies
• Determine the role of specific genetic polymorphisms-particularly in genes regulating angiogenesis and cell proliferation (e.g., VEGF, MTHFR, NOTCH1)-in placental development

Figure 1: Hot spots of epigenetic action

• Examine the interaction between environmental toxins and genetic susceptibility in contributing to placental dysfunction
• Correlate placental abnormalities with neonatal outcomes, including birth weight, gestational age and APGAR scores

Study Design and Setting

This cross-sectional study was conducted in the northern region of Saudi Arabia. Data were collected from 85 pregnancies, with participants recruited through antenatal clinics affiliated with regional hospitals. Ethical approval was obtained from the institutional review board and informed consent was secured from all participants prior to sample collection.

Participant Recruitment

Participants were selected through a purposive sampling method based on clinical eligibility. Recruitment included in-person and online outreach. A pre-filled consent form and an online questionnaire were used to gather demographic and environmental exposure data.

Inclusion Criteria

• Pregnant individuals with complete prenatal and delivery records
• Availability of placental samples for both histological and molecular analysis

Exclusion Criteria

• Pregnancies complicated by congenital anomalies unrelated to placental dysfunction
• Incomplete clinical, environmental or genetic data

Data Collection

Maternal health data-including nutritional status, Body Mass Index (BMI), comorbidities (e.g., hypertension, diabetes) and exposure to environmental toxins (e.g., air pollution, pesticides, heavy metals)-were collected via structured questionnaires and medical records. Online consent procedures were supplemented by follow-up contact for clarification or missing data.

Placental samples were collected post-delivery and preserved using standard protocols. Tissues were processed for histological evaluation using hematoxylin and eosin (H&E) staining. Molecular analysis was conducted using Polymerase Chain Reaction (PCR) and DNA sequencing to detect gene polymorphisms, particularly in VEGF, MTHFR, NOTCH1 and TGF-β1.

Histological and Genetic Analysis

Histopathological examination assessed abnormalities such as villous hypoplasia, fibrin deposition, inflammation and calcification. Genetic analyses focused on identifying single nucleotide polymorphisms (SNPs) related to angiogenesis and trophoblast proliferation.

Statistical Analysis

Data were analyzed using SPSS version [insert version]. Descriptive statistics summarized maternal characteristics and placental findings. Inferential tests, including chi-square and ANOVA, were used to assess associations between maternal factors, genetic polymorphisms and placental abnormalities. Logistic regression was considered but not applied due to sample size limitations. Clinical outcomes (birth weight, gestational age, APGAR scores) were correlated with placental findings to evaluate fetal impact. A p-value <0.05 was considered statistically significant.

This study analyzed placental histology, maternal health conditions, genetic polymorphisms, environmental exposures and their associations with fetal outcomes in a cohort of 85 pregnancies.

Villous hypoplasia was the most frequent abnormality observed, affecting nearly half of all placental samples, followed by fibrin deposition. These findings suggest widespread impairment in vascular development and placental integrity, indicative of chronic stress and compromised function (Table 1, Figure 2).

Obesity was the most common maternal health issue, associated with both structural and inflammatory placental abnormalities. Nutritional deficiencies and toxin exposures also played significant roles, emphasizing the importance of maternal environment in placental development (Table 2, Figure 3).

The VEGF rs699947 polymorphism was the most prevalent and linked with impaired angiogenesis. These findings underscore the contribution of specific gene variants to placental morphogenesis and dysfunction (Table 3, Figure 4).

Table 1: Common histological abnormalities in placental tissues

Figure 2: Common histological abnormalities in placental tissues

Figure 3: Maternal health factors and placental abnormalities

Figure 4: Distribution of genetic polymorphisms in placental samples

Table 2: Maternal health factors and placental abnormalities

Table 3: Distribution of genetic polymorphisms in placental samples

Table 4: Correlation between placental abnormalities and birth outcomes

Table 5: Maternal exposure to environmental toxins and placental function

Villous hypoplasia was associated with the most severe impact on neonatal health, including significantly reduced birth weight and gestational age. Other abnormalities, though less severe, also correlated with suboptimal outcomes (Table 4).

Exposure to air pollutants and pesticides was significantly associated with oxidative stress and inflammation in placental tissues. Heavy metal exposure further contributed to fibrin deposition, indicating toxic injury (Table 5, Figure 5).

Both obesity and hypertension were associated with markedly reduced placental vascular density, suggesting impaired angiogenesis. Nutritional deficiencies had a moderate impact, supporting their role in vascular development but to a lesser extent (Table 6, Figure 6, 7).

Obesity and hypertension were associated with significantly reduced vascular density, indicating compromised angiogenesis and impaired nutrient delivery to the fetus. In contrast, patients with nutritional

Figure 5: Maternal exposure to environmental toxins and placental function

Figure 6: Placental vascular density in different maternal health conditions

Figure 7: Placenta morphogenesis is impaired as early as embryonic day 9.5

Table 6: Placental vascular density in different maternal health conditions

deficiencies showed moderate reductions in vascular density, suggesting a milder impact on placental vascular development.

The findings of this study underscore the complex interplay between genetic, environmental and maternal health factors in shaping placental morphogenesis. This interplay not only governs the structural and functional integrity of the placenta but also determines maternal and fetal health outcomes. Genetic predispositions emerged as significant determinants of placental structure and function. Polymorphisms in key genes, such as VEGF, Notch1 and MTHFR, were strongly associated with abnormalities, including villous hypoplasia and fibrin deposition. The VEGF rs699947 polymorphism, observed in 45% of cases, disrupted angiogenic signaling, impairing vascular remodeling and leading to reduced placental vascular density [20,21]. This aligns with existing literature linking VEGF polymorphisms to fetal growth restriction and preeclampsia [22,23].

The impact of MTHFR polymorphisms on folate metabolism highlights the interplay between genetics and maternal nutrition. Folate deficiency, exacerbated by MTHFR mutations, was associated with increased fibrin deposition and placental infarctions, emphasizing the importance of addressing maternal nutritional needs during pregnancy [24,25]. Environmental exposures, including air pollution, pesticides and heavy metals, were significant contributors to placental dysfunction. Elevated levels of oxidative stress markers such as malondialdehyde (MDA) were observed in pregnancies affected by high levels of air pollution, while pesticide exposure was linked to chronic inflammation and villous calcification. These findings corroborate previous studies showing that environmental toxins disrupt trophoblast differentiation and induce epigenetic changes, compounding the effects of genetic susceptibilities [26,27].

The role of maternal health conditions, particularly obesity and hypertension, was also evident. Obesity, observed in 40% of participants, was associated with reduced placental vascular density and chronic inflammation, indicating compromised nutrient and oxygen delivery to the fetus. Hypertension exacerbated these effects, leading to increased fibrin deposition and villous infarctions, both hallmarks of ischemic placental disease [28,29]. Histological analysis revealed distinct abnormalities, including villous hypoplasia, chronic inflammation and calcification, which were strongly correlated with adverse maternal and fetal outcomes. Villous hypoplasia, observed in 48% of cases, was associated with severe fetal growth restriction, while chronic inflammation and fibrin deposition contributed to preterm delivery and low birth weight. These findings align with previous research emphasizing the critical role of placental morphology in determining pregnancy outcomes [30,31].

The integrative approach of combining genetic, environmental and histological analyses provides a comprehensive understanding of placental dysfunction. These findings highlight the need for targeted interventions, including maternal nutritional optimization, particularly addressing deficiencies in folate, iron and vitamin D; minimizing environmental toxin exposures, including air pollution and pesticide contact, through public health initiatives; and management of maternal comorbidities, such as obesity and hypertension, to reduce placental stress and improve vascularization.

Advances in diagnostic technologies, including molecular biomarkers and imaging modalities, hold promise for early detection and intervention in high-risk pregnancies. For instance, placental MRI and three-dimensional ultrasound can provide detailed assessments of placental structure and blood flow, enabling timely therapeutic interventions. Future research should explore the epigenetic mechanisms underlying the interaction between genetic and environmental factors in placental development. Large-scale, longitudinal studies are needed to validate the identified genetic markers and investigate their predictive value for adverse pregnancy outcomes. Additionally, clinical trials targeting maternal nutrition, toxin exposure and comorbidities could further elucidate the modifiable factors influencing placental health.

This study underscores the complex interplay of genetic, environmental and maternal health factors in placental morphogenesis, revealing their critical roles in shaping pregnancy outcomes. Genetic polymorphisms, such as those in VEGF and MTHFR, were linked to structural abnormalities like villous hypoplasia, while environmental exposures, including air pollution and pesticides, exacerbated oxidative stress and inflammation. Maternal conditions, particularly obesity and hypertension, compounded these effects, leading to adverse outcomes such as fetal growth restriction and preterm delivery. These findings highlight the importance of addressing modifiable factors like maternal nutrition and toxin exposure to improve placental health. Advances in diagnostic technologies and targeted interventions offer significant potential for early detection and management of placental dysfunction, paving the way for improved maternal and fetal outcomes.

Acknowledgement

The authors gratefully acknowledge the cooperation of the pregnant individuals who participated in this study. We also thank the laboratory staff and clinical coordinators at the University of Hail and Najran University for their assistance in data collection, sample processing and genetic analysis. Special appreciation is extended to the ethical review committees for their guidance and timely approval of this research.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper. All authors have contributed equally and have no financial or personal relationships that could inappropriately influence or bias the content of the article.

Ethical Approval

This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the institutional review board of the University of Hail. Informed consent was obtained from all participants prior to data and sample collection. Confidentiality of participant information was strictly maintained and genetic data were anonymized and securely stored.

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