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 International Journal of Medical Sciences and Pharma Research 

Open Access to Medical Science and Pharma Research

Copyright  © 2024 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Review Article                                                          

Antioxidants and the Prevention of Congenital Heart Defects

Emmanuel Ifeanyi Obeagu ¹* and Getrude Uzoma Obeagu ²

¹ Department of Medical Laboratory Science, Kampala International University, Uganda.

² School of Nursing Science, Kampala International University, Uganda.

 

 

Introduction

Congenital heart defects (CHDs) are structural anomalies of the heart that are present at birth and represent one of the most common types of birth defects, affecting approximately 1 in 100 live births worldwide. These defects can lead to significant morbidity and mortality, with affected infants often requiring surgical interventions or long-term medical care. The etiology of CHDs is complex and multifactorial, involving genetic, environmental, and maternal factors. Among these, oxidative stress has gained attention as a significant contributor to the pathogenesis of CHDs, leading researchers to explore the potential of antioxidants as a preventive strategy. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these harmful compounds. Elevated levels of ROS can result from various factors, including maternal health conditions, lifestyle choices, and environmental exposures. During critical periods of fetal development, the heart is particularly vulnerable to oxidative damage due to high metabolic activity and rapid cell division. Understanding the mechanisms through which oxidative stress influences cardiac development is essential for identifying potential interventions to reduce the risk of CHDs.^1-5 Recent studies have shown that oxidative stress can disrupt normal signaling pathways involved in cardiac morphogenesis, leading to structural abnormalities. Factors such as maternal diabetes, obesity, and exposure to environmental toxins have been associated with increased oxidative stress and a higher incidence of CHDs. This connection underscores the importance of maternal health and environmental factors in fetal heart development and highlights the need for effective strategies to mitigate oxidative damage during pregnancy. Antioxidants are compounds that can neutralize ROS and protect against oxidative damage. The body’s antioxidant defense system consists of enzymatic antioxidants, such as superoxide dismutase, catalase, and glutathione peroxidase, as well as non-enzymatic antioxidants like vitamins C and E, beta-carotene, and various phytochemicals. These antioxidants work synergistically to maintain cellular homeostasis and protect tissues from oxidative injury. Research has indicated that adequate antioxidant levels during pregnancy may support maternal and fetal health, potentially reducing the risk of congenital heart defects.^6-10

The potential benefits of antioxidant supplementation during pregnancy have been supported by emerging evidence suggesting that specific antioxidants can improve maternal health and fetal outcomes. For instance, vitamins C and E have been shown to enhance vascular function and reduce oxidative stress, while other antioxidants, such as selenium and coenzyme Q10, may provide additional protective effects.  Moreover, the significance of dietary intake during pregnancy cannot be overstated. A balanced diet rich in antioxidants can enhance the body’s natural defense mechanisms against oxidative stress. Health professionals should emphasize the importance of consuming antioxidant-rich foods, including fruits, vegetables, nuts, and whole grains, as part of a comprehensive prenatal care plan. Educating expectant mothers about the impact of nutrition on fetal development may empower them to make informed dietary choices that promote their health and that of their infants.^11-15

Mechanisms of Oxidative Stress in Congenital Heart Defects

Oxidative stress plays a crucial role in the pathogenesis of congenital heart defects (CHDs) through various interrelated mechanisms that disrupt normal cardiac development. During critical periods of fetal growth, the heart undergoes complex morphogenetic processes that are highly sensitive to environmental influences, including oxidative stress. The imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms can lead to significant cellular and molecular alterations, contributing to the formation of structural anomalies. One of the primary mechanisms by which oxidative stress contributes to CHDs is through direct damage to cellular components. Elevated ROS levels can induce lipid peroxidation, leading to membrane damage and altered fluidity, which compromises cell integrity and function. Additionally, ROS can modify proteins through oxidation, impairing their function and disrupting signaling pathways essential for cardiac development. For instance, oxidative modification of transcription factors can alter gene expression, resulting in impaired cellular differentiation and growth.^16-20

Moreover, oxidative stress can affect key signaling pathways involved in cardiac morphogenesis. The development of the heart is regulated by various signaling cascades, including the Wnt/β-catenin pathway, transforming growth factor-beta (TGF-β) signaling, and the fibroblast growth factor (FGF) signaling pathway. Oxidative stress can interfere with these pathways, leading to abnormal cell proliferation, apoptosis, and improper cardiac tissue remodeling. Disruption of these signaling mechanisms during critical developmental windows can result in structural heart defects, highlighting the importance of maintaining redox balance for proper cardiac formation. In addition to direct cellular damage, maternal health conditions can exacerbate oxidative stress and increase the risk of CHDs. Conditions such as diabetes and obesity are associated with elevated ROS levels and inflammation, which further contribute to oxidative damage in the developing fetus. For example, maternal hyperglycemia can lead to increased oxidative stress, promoting abnormal cardiac development in the offspring. Similarly, maternal exposure to environmental toxins, such as heavy metals and air pollutants, can also elevate oxidative stress levels, negatively impacting fetal heart development.^21-25 Genetic factors may also play a role in modulating the effects of oxidative stress on congenital heart defects. Variations in genes responsible for antioxidant defense mechanisms can influence an individual's susceptibility to oxidative damage during fetal development. For instance, polymorphisms in genes encoding antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase, may affect the efficacy of the body’s antioxidant defenses, potentially increasing the risk of CHDs in genetically predisposed individuals. Furthermore, the interplay between oxidative stress and inflammation is another critical aspect of CHD development. Oxidative stress can trigger inflammatory responses, leading to the release of pro-inflammatory cytokines and further exacerbating oxidative damage. This chronic low-grade inflammation can disrupt normal developmental processes, contributing to the occurrence of congenital heart defects.^26-30

Antioxidant Defense Systems

The body possesses a sophisticated antioxidant defense system that protects against oxidative stress by neutralizing reactive oxygen species (ROS) and mitigating cellular damage. This system comprises both enzymatic and non-enzymatic components that work synergistically to maintain redox homeostasis. A better understanding of these antioxidant defense systems is essential for comprehending how they can be leveraged to prevent congenital heart defects (CHDs) in pregnancy.^31-32

1. Enzymatic Antioxidants: Enzymatic antioxidants are crucial for detoxifying ROS and include several key enzymes:

• Superoxide Dismutase (SOD): This enzyme catalyzes the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen. There are three isoforms of SOD, with mitochondrial SOD (SOD2) being particularly important in protecting cardiac tissues during fetal development.³³
• Catalase: Catalase breaks down hydrogen peroxide into water and oxygen, preventing its accumulation and potential toxicity. It works in conjunction with SOD to reduce oxidative stress.³⁴
• Glutathione Peroxidase (GPx): GPx uses glutathione to convert hydrogen peroxide into water. It is vital for cellular defense against oxidative damage, especially in the context of cardiac development, where ROS levels can fluctuate significantly.³⁵

These enzymes are often regulated by the availability of essential nutrients, such as selenium (a cofactor for GPx) and copper and zinc (cofactors for SOD), highlighting the importance of adequate maternal nutrition in supporting antioxidant defense mechanisms during pregnancy.

2. Non-Enzymatic Antioxidants: Non-enzymatic antioxidants include a range of vitamins, minerals, and phytochemicals that can directly scavenge ROS and provide cellular protection:

• Vitamin C (Ascorbic Acid): Vitamin C is a potent water-soluble antioxidant that can regenerate other antioxidants, such as vitamin E. It plays a crucial role in protecting tissues from oxidative damage and is particularly important during pregnancy, as it supports placental function and fetal development.³⁶
• Vitamin E (Tocopherol): Vitamin E is a fat-soluble antioxidant that protects cell membranes from lipid peroxidation. It also plays a role in immune function and cellular signaling. Adequate vitamin E levels during pregnancy may help mitigate oxidative stress in the maternal-fetal environment.³⁷
• Glutathione: Glutathione is a tripeptide that acts as a major intracellular antioxidant, playing a critical role in detoxifying ROS and maintaining cellular redox balance. It also contributes to the regeneration of other antioxidants, thereby amplifying the body’s overall antioxidant capacity.³⁸
• Coenzyme Q10 (Ubiquinone): Coenzyme Q10 is a lipid-soluble antioxidant found in the mitochondria, where it plays a critical role in the electron transport chain. It also possesses direct antioxidant properties, helping to protect cardiac tissues from oxidative damage during fetal development.³⁹

3. Nutritional Antioxidants: A variety of dietary components can enhance antioxidant defense mechanisms. Fruits, vegetables, nuts, and whole grains are rich in antioxidants and phytochemicals that can help reduce oxidative stress. For example, flavonoids and carotenoids, found in various plant-based foods, can scavenge ROS and enhance the activity of enzymatic antioxidants. Ensuring an adequate intake of these nutritional antioxidants during pregnancy can support the maternal antioxidant defense system and promote fetal health.^40-41

4. Genetic Regulation of Antioxidant Systems: The effectiveness of antioxidant defense systems can also be influenced by genetic factors. Variations in genes encoding antioxidant enzymes can affect individual capacity to manage oxidative stress. 

Antioxidant Supplementation and Prevention of Congenital Heart Defects

The potential role of antioxidant supplementation in preventing congenital heart defects (CHDs) has garnered increasing attention in recent years. Given the established link between oxidative stress and the etiology of CHDs, there is a growing body of evidence suggesting that enhancing antioxidant defenses during pregnancy could mitigate the risk of these congenital anomalies. This section will discuss various antioxidant supplements, their mechanisms of action, and the implications for preventing CHDs.^42-43

1. Types of Antioxidant Supplements: Several types of antioxidant supplements have been studied for their potential protective effects against oxidative stress during pregnancy. These include vitamins, minerals, and other phytochemicals:

• Vitamins C and E: These fat- and water-soluble vitamins are among the most well-researched antioxidants. Vitamin C acts as a free radical scavenger, while vitamin E protects cell membranes from oxidative damage. Clinical studies have indicated that adequate intake of these vitamins may reduce oxidative stress levels in pregnant women and potentially lower the risk of CHDs in their offspring.⁴⁴
• Folic Acid: Although primarily known for its role in preventing neural tube defects, folic acid has also been shown to exert antioxidant effects. It may help reduce homocysteine levels and improve endothelial function, thereby potentially reducing oxidative stress. Research suggests that folic acid supplementation may be beneficial in reducing the incidence of CHDs, particularly in populations with high rates of these defects.⁴⁵
• Coenzyme Q10 (CoQ10): CoQ10 is a powerful antioxidant that plays a critical role in mitochondrial function and energy production. It has been shown to improve redox status and reduce oxidative damage in various tissues. Supplementation with CoQ10 during pregnancy may help improve maternal and fetal health outcomes, including reducing the risk of CHDs.⁴⁶
• Alpha-Lipoic Acid: Alpha-lipoic acid is a versatile antioxidant that can regenerate other antioxidants and has been shown to reduce oxidative stress in several models. Its potential role in preventing CHDs warrants further investigation, particularly in high-risk populations.⁴⁸

2. Mechanisms of Action: Antioxidant supplementation can help prevent CHDs through several interconnected mechanisms:

• Reduction of Oxidative Stress: Antioxidants neutralize ROS and reduce the oxidative damage to cellular components, including lipids, proteins, and DNA. By mitigating oxidative stress, antioxidants may help maintain proper cellular function and signaling during critical periods of cardiac development.⁴⁹
• Regulation of Inflammatory Responses: Oxidative stress is often associated with inflammation, which can further exacerbate tissue damage during cardiac development. Antioxidants can modulate inflammatory pathways, reducing the production of pro-inflammatory cytokines that may contribute to CHDs.⁵⁰
• Support of Endothelial Function: Antioxidants may improve endothelial function, enhancing blood flow and nutrient delivery to the developing fetus. Proper vascularization is critical for normal cardiac development, and any disruption in this process can lead to structural anomalies.

3. Clinical Evidence: Several clinical studies have investigated the impact of antioxidant supplementation on the incidence of CHDs. While results are still emerging, some studies suggest that women who receive antioxidants, particularly vitamins C and E, during pregnancy may experience a reduced risk of CHDs in their infants. However, the evidence is not uniform, and more large-scale randomized controlled trials are needed to establish definitive conclusions about the effectiveness of antioxidant supplementation in preventing CHDs.⁵¹

4. Maternal Nutrition and Lifestyle Factors: The effectiveness of antioxidant supplementation may also depend on the overall nutritional status and lifestyle of the mother. A balanced diet rich in fruits, vegetables, and whole grains can provide a natural source of antioxidants and enhance the body's overall antioxidant capacity. Additionally, lifestyle factors such as smoking, alcohol consumption, and exposure to environmental toxins can increase oxidative stress and undermine the potential benefits of antioxidant supplementation. Therefore, addressing these factors alongside antioxidant supplementation is crucial for maximizing the protective effects against CHDs.⁵²

5. Personalized Approaches: Given the variability in genetic and environmental factors influencing oxidative stress, a one-size-fits-all approach to antioxidant supplementation may not be optimal. Personalized nutritional strategies based on individual risk factors, genetic predispositions, and specific health conditions could enhance the efficacy of antioxidants in preventing congenital heart defects.

Clinical Implications and Recommendations

The relationship between oxidative stress and congenital heart defects (CHDs) underscores the importance of clinical strategies that incorporate antioxidant supplementation as a preventive measure. As emerging evidence suggests that antioxidants may help mitigate the risk of CHDs, healthcare providers can play a pivotal role in guiding pregnant women toward optimal antioxidant intake. This section outlines the clinical implications of antioxidant supplementation and provides recommendations for practitioners.

1. Risk Assessment and Screening: Healthcare providers should routinely assess pregnant women for risk factors associated with oxidative stress and CHDs. This includes evaluating maternal health history, nutritional status, lifestyle factors, and any known genetic predispositions. Women with a higher risk of CHDs, such as those with a family history of congenital anomalies or preexisting conditions like diabetes, hypertension, or obesity, may benefit from a tailored antioxidant supplementation plan.⁵³

2. Nutritional Guidance: Providing comprehensive nutritional counseling is essential. Clinicians should educate patients about the importance of a well-balanced diet rich in natural antioxidants, including fruits, vegetables, whole grains, nuts, and seeds. Foods high in vitamins C and E, folate, and other micronutrients should be emphasized, as these can help enhance the body's natural antioxidant defenses. Additionally, recommendations should include reducing processed foods and limiting exposure to environmental toxins, which can exacerbate oxidative stress.⁵¹

3. Antioxidant Supplementation Protocols: Based on individual risk assessments, clinicians may consider recommending specific antioxidant supplements. The following guidelines can be proposed:

• Vitamin C and E: Supplementation with vitamin C (500-1000 mg/day) and vitamin E (400 IU/day) may be beneficial for high-risk pregnant women, but the optimal dosages should be determined through further research.
• Folic Acid: Pregnant women should receive adequate folic acid supplementation (at least 400-800 mcg/day) to support fetal development and reduce oxidative stress.
• Coenzyme Q10 and Alpha-Lipoic Acid: Consider recommending CoQ10 (100-200 mg/day) and alpha-lipoic acid (300-600 mg/day) for women at increased risk of oxidative stress. However, clinical trials are needed to establish safety and efficacy.

4. Monitoring and Evaluation: Regular monitoring of maternal and fetal health outcomes is crucial when implementing antioxidant supplementation. Clinicians should assess for any potential adverse effects of supplementation and track improvements in maternal oxidative stress markers through appropriate laboratory tests. This ongoing evaluation can help tailor supplementation strategies and provide feedback on the effectiveness of the intervention.⁵²

5. Collaborative Care: Interdisciplinary collaboration among healthcare providers is essential for optimizing maternal-fetal health. Obstetricians, dietitians, and maternal-fetal medicine specialists should work together to develop comprehensive care plans that include dietary, lifestyle, and supplementation recommendations. This team-based approach ensures that all aspects of a pregnant woman's health are addressed, enhancing the overall effectiveness of antioxidant interventions.⁵³

6. Patient Education and Empowerment: Educating patients about the role of antioxidants in pregnancy and their potential benefits for preventing CHDs is vital. Patients should be encouraged to actively participate in their health management by making informed dietary choices and adhering to supplementation recommendations. Providing clear and accessible resources can empower women to take control of their nutritional intake and overall health during pregnancy.

Conclusion

The role of antioxidants in the prevention of congenital heart defects (CHDs) presents a promising avenue for enhancing maternal and fetal health. Given the established link between oxidative stress and the etiology of CHDs, antioxidant supplementation offers a potential strategy to mitigate this risk during critical periods of pregnancy. The evidence supporting the benefits of antioxidants—such as vitamins C and E, folic acid, coenzyme Q10, and alpha-lipoic acid—highlights their capability to reduce oxidative damage, improve endothelial function, and modulate inflammatory responses, all of which are essential for proper cardiac development.

References

1. Okamgba OC, Nwosu DC, Nwobodo EI, Agu GC, Ozims SJ, Obeagu EI, Ibanga IE, Obioma-Elemba IE, Ihekaire DE, Obasi CC, Amah HC. Iron Status of Pregnant and Post-Partum Women with Malaria Parasitaemia in Aba Abia State, Nigeria. Annals of Clinical and Laboratory Research. 2017;5(4):206.

2. Agreen FC, Obeagu EI. Anaemia among pregnant women: A review of African pregnant teenagers. Journal of Public Health and Nutrition. 2023;6(1):138.

3. Obeagu EI, Obeagu GU. Eosinophil Dynamics in Pregnancy among Women Living with HIV: A Comprehensive Review. Int. J. Curr. Res. Med. Sci. 2024;10(1):11-24. https://doi.org/10.22270/ijmspr.v10i2.95

4. Obeagu EI, Obeagu GU, Chukwueze CM, Ikpenwa JN, Ramos GF. Evaluation of protein C, protein S and fibrinogen of pregnant women with malaria in Owerri metropolis. Madonna University journal of Medicine and Health Sciences ISSN: 2814-3035. 2022 Apr 19;2(2):1-9.

5. Obeagu EI, Obeagu GU. Eosinophilic Changes in Placental Tissues of HIV-Positive Pregnant Women: A Review. Elite Journal of Laboratory Medicine, 2024; 2(1): 14-32

6. Joo EH, Kim YR, Kim N, Jung JE, Han SH, Cho HY. Effect of endogenic and exogenic oxidative stress triggers on adverse pregnancy outcomes: preeclampsia, fetal growth restriction, gestational diabetes mellitus and preterm birth. International journal of molecular sciences. 2021;22(18):10122. https://doi.org/10.3390/ijms221810122

7. Juan CA, Pérez de la Lastra JM, Plou FJ, Pérez-Lebeña E. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. International journal of molecular sciences. 2021;22(9):4642. https://doi.org/10.3390/ijms22094642

8. Feng Y, Feng Q, Qu H, Song X, Hu J, Xu X, Zhang L, Yin S. Stress adaptation is associated with insulin resistance in women with gestational diabetes mellitus. Nutrition & diabetes. 2020;10(1):4. https://doi.org/10.1038/s41387-020-0107-8

9. Obeagu EI, Abdirahman BF, Bunu UO, Obeagu GU. Obsterics characteristics that effect the newborn outcomes. Int. J. Adv. Res. Biol. Sci. 2023;10(3):134-43.

10. Anyiam AF, Obeagu EI, Obi E, Omosigho PO, Irondi EA, Arinze-Anyiam OC, Asiyah MK. ABO blood groups and gestational diabetes among pregnant women attending University of Ilorin Teaching Hospital, Kwara State, Nigeria. International Journal of Research and Reports in Hematology. 2022;5(2):113-121.

11. Okorie HM, Obeagu EI, Eze EN, Jeremiah ZA. Assessment of some haematological parameters in malaria infected pregnant women in Imo state Nigeria. Int. J. Curr. Res. Biol. Med. 2018;3(9):1-4.

12. Okorie HM, Obeagu EI, Eze EN, Jeremiah ZA. Assessment of coagulation parameters in malaria infected pregnant women in Imo state, Nigeria. International Journal of Current Research in Medical Sciences. 2018;4(9):41-9.

13. Obeagu EI, Obeagu GU. Neonatal Outcomes in Children Born to Mothers with Severe Malaria, HIV, and Transfusion History: A Review. Elite Journal of Nursing and Health Science, 2024; 2(3): 38-58

14. Obeagu EI, Obeagu GU. The Vital Role of Antioxidants in Enhancing Fertility and Pregnancy Success: A Review. Elite Journal of Nursing and Health Science. 2023;1(1):1-2.

15. Obeagu EI, Ubosi NI, Uzoma G. Antioxidant Supplementation in Pregnancy: Effects on Maternal and Infant Health. Int. J. Adv. Multidiscip. Res. 2023;10(11):60-70.

16. Obeagu EI, Obeagu GU. Enhancing Maternal and Fetal Well-being: The Role of Antioxidants in Pregnancy. Elite Journal of Medical Sciences. 2024;2(4):76-87.

17. Obeagu EI, Obeagu GU. Harnessing the Power of Antioxidant-Rich Diet for Preconception Health: A Review. Elite Journal of Health Science. 2023;1(1):1-3.

18. Nowak D, Gośliński M, Wojtowicz E, Przygoński K. Antioxidant properties and phenolic compounds of vitamin C‐rich juices. Journal of Food Science. 2018;83(8):2237-2246. https://doi.org/10.1111/1750-3841.14284

19. Obeagu EI, Adias TC, Obeagu GU. Influence of Antioxidants on Maternal and Fetal Immune Response: A Review. Elite Journal of Nursing and Health Science. 2024;2(6):1-3.

20. Obeagu EI, Batisani K, Obeagu GU. Antioxidants and Neurodevelopmental Outcomes in Offspring: A Review of Maternal Interventions. Elite Journal of Health Science. 2023;2(5):1-9.

21. Obeagu EI, Batisani K, Obeagu GU. Antioxidants and Postpartum Complications: Preventions. Elite Journal of Nursing and Health Science. 2024;2(5):30-40.

22. Obeagu EI, Obeagu GU. Antioxidants and Gestational Diabetes Mellitus: A Comprehensive Review of Preventive Strategies. Elite Journal of Health Science. 2024;2(5):19-29.

23. Obeagu EI, Obeagu GU. Harnessing the Power of Antioxidants: Enhancing Gamete Quality and Fostering Successful Pregnancy. Elite Journal of Nursing and Health Science. 2024;2(3):73-83.

24. Obeagu EI, Muhimbura E, Obeagu GU. Hypoxia-Induced Oxidative Stress: Maternal and Fetal Implications. Elite Journal of Haematology, 2024; 2 (8).:57-72.

25. Obeagu EI, Obeagu GU. Managing Hypoxia in Pregnancy: Current Strategies and Future Directions. Elite Journal of Medical Sciences. 2024;2(8):53-63.

26. Obeagu EI, Obeagu GU. Hypoxia-induced Metabolic Changes in Pregnancy: Clinical Perspectives. Elite Journal of Medicine. 2024;2(8):50-9.

27. Obeagu EI, Chukwu PH. Maternal Well-being in the Face of Hypoxia during Pregnancy: A Review. Int. J. Curr. Res. Chem. Pharm. Sci. 2024;11(7):25-38.

28. Dhakar RC, Prajapati SK, Maurya SD, Tilak VK, Das MK, Das S, Verma KK, Jain N, Antioxidant Potential of Cordia dichotoma: A Review, Asian Journal of Dental and Health Sciences. 2021;1(1):19-23https://doi.org/10.22270/ajdhs.v1i1.6

29. Obeagu EI, Obeagu GU. Oxygen Deprivation in Pregnancy: Understanding Hypoxia's Impact on Maternal Health. Journal home page: http://www. journalijiar. com.;12(01).

30. Obeagu EI, Obeagu GU. Hypoxia-Induced Inflammation: Implications for Maternal Health. Elite Journal of Scientific Research and Review. 2024;2(6):8-25.

31. Obeagu EI, Obeagu GU. Hypoxia in Pregnancy: Implications for Fetal Development. Int. J. Curr. Res. Chem. Pharm. Sci. 2024;11(7):39-50.

32. Obeagu EI, Obeagu GU. Hypoxia and Pregnancy: The Role of Genetics and Epigenetics. Elite Journal of Medical Sciences. 2024;2(8):24-36.

33. Carter AM. Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses. Physiological reviews. 2012;92(4):1543-1576. https://doi.org/10.1152/physrev.00040.2011

34. Obeagu EI, Obeagu GU. Maternal Hypoxia: Impact on Immune System Development in Offspring. Elite Journal of Health Science. 2024;2(8):45-57.

35. Obeagu EI, Obeagu GU. Maternal Hypoxia and Placental Dysfunction: Insights from Molecular Biology. Elite Journal of Health Science. 2024;2(8):58-69.

36. Kalagiri RR, Carder T, Choudhury S, Vora N, Ballard AR, Govande V, Drever N, Beeram MR, Uddin MN. Inflammation in complicated pregnancy and its outcome. American journal of perinatology. 2016;33(14):1337-1356. https://doi.org/10.1055/s-0036-1582397

37. Al-Gubory KH. Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development. Reproductive biomedicine online. 2014;29(1):17-31. https://doi.org/10.1016/j.rbmo.2014.03.002

38. Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. The Journal of endocrinology. 2017;232(1):R27. https://doi.org/10.1530/JOE-16-0340

39. Burton GJ, Cindrova-Davies T, wa Yung H, Jauniaux E. Hypoxia and reproductive health: Oxygen and development of the human placenta. Reproduction. 2021;161(1):F53-65. https://doi.org/10.1530/REP-20-0153

40. He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cellular Physiology and Biochemistry. 2017;44(2):532-553. https://doi.org/10.1159/000485089

41. Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria journal of medicine. 2018;54(4):287-293. https://doi.org/10.1016/j.ajme.2017.09.001

42. Roy Z, Bansal R, Siddiqui L, Chaudhary N. Understanding the role of free radicals and antioxidant enzymes in human diseases. Current Pharmaceutical Biotechnology. 2023;24(10):1265-1276. https://doi.org/10.2174/1389201024666221121160822

43. Mirończuk-Chodakowska I, Witkowska AM, Zujko ME. Endogenous non-enzymatic antioxidants in the human body. Advances in medical sciences. 2018;63(1):68-78. https://doi.org/10.1016/j.advms.2017.05.005

44. Sebastiani G, Navarro-Tapia E, Almeida-Toledano L, Serra-Delgado M, Paltrinieri AL, García-Algar Ó, Andreu-Fernández V. Effects of antioxidant intake on fetal development and maternal/neonatal health during pregnancy. Antioxidants. 2022;11(4):648. https://doi.org/10.3390/antiox11040648

45. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS. Vitamins C and E and the risks of preeclampsia and perinatal complications. New England Journal of Medicine. 2006;354(17):1796-1806. https://doi.org/10.1056/NEJMoa054186

46. Cederberg J, Simán CM, Eriksson UJ. Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatric research. 2001;49(6):755-762. https://doi.org/10.1203/00006450-200106000-00007

47. Perkins AV. Placental oxidative stress, selenium and preeclampsia. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2011;1(1):95-99. https://doi.org/10.1016/j.preghy.2010.10.008

48. Rayman MP, Searle E, Kelly L, Johnsen S, Bodman-Smith K, Bath SC, Mao J, Redman CW. Effect of selenium on markers of risk of pre-eclampsia in UK pregnant women: a randomised, controlled pilot trial. British Journal of Nutrition. 2014;112(1):99-111. https://doi.org/10.1017/S0007114514000531

49. Luo J, Wu W, Zhang P, Chen X, Feng Y, Ma N, Yang H, Wang Y, Li M, Xie B, Guo P. Zinc levels and birth weight in pregnant women with gestational diabetes mellitus: a matched cohort study in China. The Journal of Clinical Endocrinology & Metabolism. 2020;105(7): e2337-2345. https://doi.org/10.1210/clinem/dgaa171

50. Sley EG, Rosen EM, van 't Erve TJ, Sathyanarayana S, Barrett ES, Nguyen RH, Bush NR, Milne GL, Swan SH, Ferguson KK. Omega-3 fatty acid supplement use and oxidative stress levels in pregnancy. PloS one. 2020;15(10): e0240244. https://doi.org/10.1371/journal.pone.0240244

51. Orhan H, Önderoglu L, Yücel A, Sahin G. Circulating biomarkers of oxidative stress in complicated pregnancies. Archives of gynecology and obstetrics. 2003; 267:189-195. https://doi.org/10.1007/s00404-002-0319-2

52. Barbosa ML, de Meneses AA, de Aguiar RP, e Sousa JM, Cavalcante AA, Maluf SW. Oxidative stress, antioxidant defense and depressive disorders: a systematic review of biochemical and molecular markers. Neurology, Psychiatry and Brain Research. 2020; 36:65-72. https://doi.org/10.1016/j.npbr.2020.02.006

53. Di Fabrizio C, Giorgione V, Khalil A, Murdoch CE. Antioxidants in pregnancy: do we really need more trials? Antioxidants. 2022 Apr 22;11(5):812. https://doi.org/10.3390/antiox11050812