Available online on 15.07.2024 at ijmspr.com

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

The Impact of Maternal Malaria on Adaptive Immune Responses in Offspring

*Emmanuel Ifeanyi Obeagu ¹ and Getrude Uzoma Obeagu²

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

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

 

 

Introduction

Maternal malaria, primarily caused by Plasmodium falciparum, remains a critical public health issue, particularly in malaria-endemic regions of the world.^1-2 The disease has significant implications for both maternal and fetal health, impacting pregnancy outcomes and contributing to long-term health challenges for offspring. One area of increasing concern is the effect of maternal malaria on the adaptive immune responses of children. Adaptive immunity, which includes the functions of T-cells and B-cells, is vital for protecting the body against infections and diseases. Prenatal exposure to malaria can profoundly influence the development and functionality of the immune system in offspring, potentially shaping their health trajectory throughout life.^3-4 During pregnancy, the immune system undergoes complex changes to balance maternal and fetal needs while defending against infections. Maternal malaria introduces additional challenges, including a heightened inflammatory environment and alterations in immune signaling. These conditions can disrupt normal immune development in the fetus, leading to long-lasting effects on adaptive immune responses.^5-8  T-cells and B-cells are central to adaptive immunity, responsible for recognizing and responding to specific pathogens.⁹ Maternal malaria can alter the development and function of these cells in several ways. For example, prenatal exposure to malaria may lead to changes in T-cell subset distribution, affecting the balance between different types of T-cells (e.g., Th1 and Th2 cells). These changes can influence how offspring respond to infections and their overall immune competence. Similarly, maternal malaria can impact B-cell function, impairing antibody production and affecting the ability to mount effective immune responses against pathogens.^10-11

In addition to direct effects on T-cells and B-cells, maternal malaria can influence cytokine production in offspring. Cytokines are signaling molecules that regulate immune responses and inflammation. Maternal malaria is associated with elevated levels of pro-inflammatory cytokines, which can cross the placenta and affect the developing immune system.¹² Altered cytokine profiles in children exposed to maternal malaria may impact their susceptibility to infections and the severity of inflammatory diseases. The mechanisms by which maternal malaria affects immune responses in offspring include chronic inflammation, placental transfer of malaria-related factors, and potential epigenetic modifications. Chronic inflammation resulting from maternal malaria can create a pro-inflammatory environment that disrupts normal immune development. Additionally, malaria-induced factors, such as cytokines and antigens, can cross the placenta and influence fetal immune system maturation. Epigenetic modifications, which can alter gene expression without changing the DNA sequence, may also play a role in shaping the immune responses of offspring.^13-17 Preventive measures, such as the use of insecticide-treated bed nets, intermittent preventive treatment with antimalarials, and improved antenatal care, are crucial for reducing the incidence of maternal malaria and its impact on offspring immunity. Strengthening these measures can help mitigate the risks associated with maternal malaria and improve overall health outcomes for mothers and their children.^18-20

Maternal Malaria and Immune System Development

Maternal malaria, caused predominantly by Plasmodium falciparum, poses significant risks to both maternal and fetal health.²¹ One of the critical areas of concern is its impact on the developing immune system of the offspring. The immune system is a complex network of cells and molecules responsible for defending the body against infections and diseases. During pregnancy, the immune system undergoes significant changes to accommodate the needs of both the mother and the developing fetus. Maternal malaria introduces additional challenges that can disrupt this delicate balance, potentially leading to long-lasting effects on immune system development in the offspring.^22-24 The fetal immune system begins to develop early in gestation, with the formation of primary lymphoid organs, such as the thymus and bone marrow, and the emergence of immune cells, including T-cells and B-cells. This development is crucial for establishing a functional immune system capable of responding to pathogens after birth. Maternal malaria can interfere with this process, leading to alterations in the maturation and function of immune cells.^25-27 Maternal malaria induces a state of chronic inflammation, characterized by elevated levels of pro-inflammatory cytokines such as TNF-alpha and IL-6.²⁸ This inflammatory environment can affect fetal immune development by altering cytokine signaling pathways and disrupting the normal maturation of immune cells. Chronic inflammation during critical periods of immune system development can lead to imbalances in T-cell and B-cell populations, affecting the overall functionality of the immune system.^29-31

T-cells, including CD4+ helper T-cells and CD8+ cytotoxic T-cells, play a vital role in adaptive immunity.³² Maternal malaria can influence the development and differentiation of these T-cell subsets in the fetus. For example, prenatal exposure to malaria may result in a skewed Th1/Th2 balance, where Th1 responses are favored over Th2 responses or vice versa. This imbalance can impact the offspring's ability to mount appropriate immune responses to various pathogens. Maternal malaria may also affect T-cell function by altering their activation and proliferation. Infected mothers may have elevated levels of inhibitory cytokines or other factors that can suppress T-cell responses in the fetus. This impairment can result in reduced ability to respond effectively to infections and an increased risk of developing autoimmune conditions later in life.^33-35 B-cells are essential for antibody production and the establishment of humoral immunity. Maternal malaria can disrupt the normal maturation of B-cells in the fetus, leading to alterations in their ability to produce antibodies. Impaired B-cell function can affect the offspring’s ability to mount effective immune responses against pathogens and may influence the efficacy of vaccines. Children born to mothers with malaria may exhibit altered antibody responses due to compromised B-cell function. This impairment can result in reduced production of specific antibodies and affect the ability to establish long-term immunity. The impact on antibody responses can have significant implications for the child’s susceptibility to infections and the effectiveness of vaccination programs.^36-40

During pregnancy, factors such as cytokines and malaria antigens can cross the placenta from the mother to the fetus. These factors can influence the development and function of the fetal immune system. Elevated levels of pro-inflammatory cytokines and malaria antigens can affect immune cell maturation and function, potentially leading to long-term alterations in immune responses. Chronic inflammation in the placenta due to maternal malaria can also impact fetal immune development. Placental inflammation can disrupt the normal transfer of nutrients and immune factors to the fetus, affecting immune system maturation and increasing the risk of immune dysregulation.^41-44 Maternal malaria may induce epigenetic modifications in the offspring, affecting gene expression related to immune responses.⁴⁵ Epigenetic changes can result in long-term alterations in immune function and susceptibility to diseases. Research into epigenetic modifications associated with maternal malaria can provide insights into the mechanisms underlying immune system alterations and potential targets for intervention. Epigenetic modifications induced by maternal malaria may have lasting effects on immune health, influencing the risk of autoimmune diseases, chronic inflammatory conditions, and susceptibility to infections later in life. Understanding these modifications can help in developing strategies to mitigate long-term health risks associated with maternal malaria. Effective prevention of maternal malaria is crucial for protecting fetal immune development. Strategies such as the use of insecticide-treated bed nets, intermittent preventive treatment with antimalarials, and regular antenatal care can help reduce the incidence of maternal malaria and its impact on immune system development.^46-50

Cytokine Profile Changes

Cytokines are key signaling molecules in the immune system, regulating a wide range of immune responses and inflammatory processes. In the context of maternal malaria, characterized predominantly by Plasmodium falciparum, the cytokine milieu is significantly altered.⁵¹ This alteration can have profound effects on both maternal and fetal health, influencing immune system development in offspring. Changes in the cytokine profile during maternal malaria can impact fetal immune development, potentially leading to long-term health consequences for the child. Maternal malaria is associated with elevated levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). These cytokines contribute to a state of chronic inflammation, which can cross the placenta and affect the developing fetus. Elevated levels of these cytokines can disrupt the normal development of the fetal immune system, leading to alterations in immune responses and increased susceptibility to infections.^52-55 In addition to pro-inflammatory cytokines, maternal malaria can also affect the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). These cytokines play a crucial role in regulating immune responses and maintaining immune tolerance. An imbalance between pro-inflammatory and anti-inflammatory cytokines can contribute to immune dysregulation in the offspring, affecting their ability to respond to infections and modulating the risk of autoimmune conditions.

The altered cytokine profile in maternal malaria can impact the maturation and function of immune cells in the fetus.⁵⁶ For example, elevated pro-inflammatory cytokines can affect the differentiation of T-cells and B-cells, leading to imbalances in T-cell subsets (e.g., Th1 vs. Th2) and impaired antibody responses. These disruptions can affect the overall functionality of the immune system and influence the child’s ability to mount effective immune responses after birth. The cytokine environment in maternal malaria can also influence the development of immune tolerance in the fetus. Proper immune tolerance is essential for preventing autoimmune reactions and maintaining immune balance. Disruptions in cytokine signaling can impair the development of tolerance mechanisms, potentially leading to an increased risk of autoimmune diseases and chronic inflammatory conditions in offspring.^57-59 Children born to mothers with malaria may have altered cytokine profiles, which can affect their susceptibility to infections.⁶⁰ An altered balance between pro-inflammatory and anti-inflammatory cytokines can impair the ability of offspring to mount effective immune responses against pathogens. This increased susceptibility can lead to higher rates of infections and greater morbidity in early life. The altered cytokine profile in offspring exposed to maternal malaria can also impact vaccine efficacy. Effective vaccination relies on the ability of the immune system to respond appropriately to vaccine antigens. Disruptions in cytokine signaling and immune cell function can reduce the effectiveness of vaccines, leading to lower levels of protective immunity and an increased risk of vaccine-preventable diseases.^61-63 Maternal malaria-induced cytokines can cross the placenta and influence the developing fetal immune system. The transfer of these cytokines can alter the cytokine environment in the fetus, affecting immune cell maturation and function. Understanding the mechanisms of placental transfer and its effects on fetal cytokine profiles is crucial for elucidating the impact of maternal malaria on offspring immune health. Maternal inflammatory mediators, including cytokines and other immune factors, can influence the cytokine profile of the fetus. Chronic inflammation in the mother can lead to the production of inflammatory mediators that impact fetal immune development. Research into these maternal-inflammatory factors can provide insights into the mechanisms by which maternal malaria affects cytokine profiles in offspring.^64-67

Implications for Susceptibility to Infections

Maternal malaria, particularly due to Plasmodium falciparum, not only affects pregnancy outcomes but also has significant implications for the immune health of the offspring.⁶⁸ One of the key concerns is how prenatal exposure to malaria influences the susceptibility of children to infections later in life. The altered immune environment resulting from maternal malaria can impair the offspring’s ability to effectively combat infections, leading to increased morbidity and mortality.  Children born to mothers with malaria often exhibit altered immune responses due to the impact of maternal malaria on their developing immune system. Changes in T-cell and B-cell function, as well as disruptions in cytokine profiles, can impair the ability of offspring to respond effectively to infections. For example, alterations in T-cell subsets, such as a skewed Th1/Th2 balance, can affect the ability to mount appropriate immune responses against various pathogens. Maternal malaria can affect B-cell function, leading to impaired antibody production in offspring. Reduced production of specific antibodies can diminish the ability of children to neutralize pathogens and respond effectively to infections. This impairment can also influence the effectiveness of vaccines, as a compromised antibody response can result in reduced vaccine efficacy and increased susceptibility to vaccine-preventable diseases.^69-73 The altered immune environment in children exposed to maternal malaria can lead to reduced responses to vaccines.⁷⁴ Effective vaccination relies on the ability of the immune system to recognize and respond to vaccine antigens, generating protective immunity. Disruptions in immune cell function and cytokine signaling can impair the development of vaccine-induced immunity, resulting in lower levels of protective antibodies and increased risk of infections. The reduced vaccine efficacy observed in children exposed to maternal malaria has broader implications for immunization programs, particularly in malaria-endemic regions. Ensuring effective vaccination coverage and achieving high immunization rates are crucial for preventing infectious diseases. Addressing the challenges posed by maternal malaria and improving vaccine responses in affected children are essential for maintaining the effectiveness of vaccination programs and reducing disease burden.

Maternal malaria induces a state of chronic inflammation characterized by elevated levels of pro-inflammatory cytokines. This inflammatory environment can persist in offspring, affecting their immune responses and increasing susceptibility to infections. Chronic inflammation can impair the function of immune cells and disrupt the balance between pro-inflammatory and anti-inflammatory signals, leading to a heightened risk of infections. Malaria-induced factors, such as cytokines and antigens, can cross the placenta and impact fetal immune development. The transfer of these factors can alter the cytokine environment and immune cell function in the fetus, contributing to increased susceptibility to infections.^75-80 The increased susceptibility to infections observed in children exposed to maternal malaria can result in higher rates of morbidity and mortality.⁸¹ These children may experience more frequent and severe infections, leading to greater healthcare needs and potential long-term health consequences. Addressing the increased infection risk and providing appropriate healthcare support are crucial for improving health outcomes for these children. Increased susceptibility to infections can also affect the growth and development of children. Recurrent infections can lead to malnutrition, growth retardation, and developmental delays, further compounding the health challenges faced by children born to mothers with malaria. Ensuring adequate nutrition, healthcare, and early intervention are essential for supporting healthy growth and development in these children. Preventing maternal malaria through measures such as insecticide-treated bed nets, intermittent preventive treatment with antimalarials, and improving antenatal care is crucial for reducing the impact on offspring immunity.⁸² Effective malaria prevention can help reduce the incidence of maternal malaria and mitigate its effects on the health of children. Addressing the challenges posed by maternal malaria requires enhancing immunization strategies to ensure effective vaccine responses in affected children. This may involve optimizing vaccine formulations, adjusting vaccination schedules, and providing additional doses to overcome reduced vaccine efficacy. Public health efforts should focus on improving vaccination coverage and addressing specific needs in malaria-endemic regions.

Mechanisms of Immune System Alteration

Maternal malaria, primarily caused by Plasmodium falciparum, induces complex immune alterations that can significantly impact fetal immune system development.⁸³ These alterations can lead to long-term effects on the immune health of offspring, influencing their susceptibility to infections and overall immune function. Maternal malaria triggers a robust inflammatory response characterized by elevated levels of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-1β.⁸⁴ This chronic inflammation can persist throughout pregnancy and may affect the placental environment. Persistent maternal inflammation can disrupt normal immune system development in the fetus by creating an inflammatory milieu that alters cytokine signaling pathways and immune cell maturation. The inflammatory cytokines and mediators produced in response to maternal malaria can cross the placenta and influence fetal immune system development. Chronic exposure to these inflammatory factors can lead to imbalances in immune cell populations and function, affecting the overall immune response of the offspring. Disruptions in immune cell maturation and cytokine signaling can result in long-term immune dysregulation. During maternal malaria, factors such as cytokines and malaria antigens can cross the placenta and affect the developing fetal immune system. Elevated levels of pro-inflammatory cytokines and malaria-specific antigens in the maternal circulation can enter the fetal circulation, altering immune cell function and cytokine profiles in the fetus.⁸⁵ This transfer of factors can disrupt normal immune development and contribute to increased susceptibility to infections. Maternal malaria can induce inflammation in the placenta, which can impact the transfer of nutrients and immune factors to the fetus. Inflammatory processes in the placenta can interfere with the normal exchange of molecules and affect fetal immune system development. Placental inflammation can also create an environment that exacerbates immune dysregulation in the offspring.

Maternal malaria can induce epigenetic modifications that affect gene expression related to immune responses.⁸⁶ Epigenetic changes, such as DNA methylation and histone modification, can alter the expression of genes involved in immune cell development and function. These modifications can have long-lasting effects on immune system development and function in offspring. Epigenetic alterations induced by maternal malaria may lead to persistent changes in immune responses and increased susceptibility to diseases. Understanding these modifications can provide insights into the mechanisms underlying immune dysregulation and inform strategies for mitigating the long-term health effects of maternal malaria. Maternal malaria can affect the development of immune tolerance in the fetus. Immune tolerance is essential for preventing autoimmune reactions and maintaining immune balance. Disruptions in cytokine signaling and immune cell function caused by maternal malaria can impair the development of tolerance mechanisms, leading to an increased risk of autoimmune diseases and chronic inflammatory conditions in offspring. Altered cytokine profiles and immune cell function in offspring exposed to maternal malaria can affect the development of T-cell and B-cell tolerance. This can result in a reduced ability to distinguish between self and non-self-antigens, contributing to autoimmune responses and increased susceptibility to autoimmune diseases.

Maternal malaria can disrupt T-cell function by affecting T-cell activation, proliferation, and differentiation.⁸⁷ Changes in T-cell subsets, such as Th1 and Th2 cells, can influence the overall immune response and impact the ability of offspring to respond to infections. Maternal malaria-induced factors can also alter T-cell receptor signaling, affecting T-cell responses. B-cell function can be impaired in offspring exposed to maternal malaria, leading to reduced antibody production and altered antibody responses. Disruptions in B-cell maturation and activation can affect the ability to produce specific antibodies against pathogens, impacting overall immune competence and vaccine efficacy. Genetic factors can influence the susceptibility of offspring to the effects of maternal malaria on immune system development. Genetic variations in immune-related genes may affect the response to malaria-induced factors and influence the severity of immune alterations. Understanding the role of genetic predisposition can help identify individuals at higher risk of immune dysregulation. The interaction between maternal malaria and host genetics can impact immune system development and function in offspring. Genetic factors may influence the severity of immune alterations and contribute to variability in immune responses among individuals exposed to maternal malaria.

Strategies for Mitigation 

Addressing the impact of maternal malaria on offspring immunity requires a multifaceted approach that includes preventive measures, effective treatment, and targeted interventions. By implementing strategies to reduce maternal malaria incidence and mitigate its effects on the developing immune system, it is possible to improve health outcomes for both mothers and their children.  The use of insecticide-treated bed nets is one of the most effective strategies for preventing malaria transmission.⁸⁸ Insecticide-Treated Bed Nets (ITNs) provide a physical barrier against mosquito bites and reduce the risk of malaria infection. Widespread distribution and use of ITNs can significantly decrease the incidence of maternal malaria and its impact on fetal immune development. Intermittent preventive treatment with antimalarial drugs during pregnancy (IPTp) is a proven strategy to prevent malaria in pregnant women.⁸⁹ Intermittent Preventive Treatment (IPT) involves administering antimalarial medication at scheduled intervals, regardless of whether the woman is symptomatic. This approach reduces the risk of malaria infection and lowers the associated risks for both the mother and the fetus. Comprehensive vector control programs, including indoor residual spraying and larviciding, can help reduce the mosquito population and decrease malaria transmission. Effective vector control measures complement the use of ITNs and IPTp, contributing to a significant reduction in maternal malaria cases and improving overall health outcomes. Regular antenatal care that includes screening for malaria is essential for early detection and management of the disease. Pregnant women should be routinely tested for malaria and provided with appropriate treatment if necessary. Early detection and treatment can prevent complications and reduce the impact of malaria on fetal immune development. Providing comprehensive care packages that include malaria prevention, antenatal care, and maternal health education can help address the multifaceted needs of pregnant women. These packages should include counseling on the importance of using ITNs, adhering to IPTp, and seeking timely medical care for malaria symptoms.

Prompt and effective treatment of maternal malaria is crucial for minimizing its impact on both maternal and fetal health. Antimalarial treatment should be tailored to the specific type of malaria and the stage of pregnancy, with consideration for safety and efficacy. Ensuring access to quality healthcare services and appropriate treatment is essential for managing maternal malaria. Management of complications related to maternal malaria, such as anemia and placental malaria, is important for improving health outcomes. Providing supportive care, including blood transfusions and iron supplementation, can help address these complications and reduce their impact on fetal development.⁸⁹ Research into optimizing vaccine formulations to enhance efficacy in children exposed to maternal malaria is essential. This may involve developing vaccines that account for potential immune alterations induced by maternal malaria or adjusting vaccine schedules to improve immune responses. Monitoring vaccine responses in children born to mothers with malaria can help identify potential issues with vaccine efficacy and guide adjustments in vaccination strategies. Evaluating immune responses and ensuring effective vaccination coverage are important for preventing infectious diseases. Public health campaigns to raise awareness about the importance of malaria prevention during pregnancy can help increase the use of ITNs, adherence to IPTp, and overall health-seeking behavior. Educating communities about the impact of maternal malaria on offspring health and the available preventive measures can drive behavior change and improve health outcomes. Integrating health education programs into antenatal care services can provide pregnant women with information about malaria prevention, symptoms, and treatment. Empowering women with knowledge and resources can support better health practices and reduce the incidence of maternal malaria.

Conclusion

Maternal malaria presents a significant public health challenge with far-reaching implications for both maternal and offspring health. The complex interplay between malaria infection, immune system alteration, and subsequent risks to child health underscores the need for comprehensive strategies to address and mitigate these impacts. Maternal malaria alters immune system development in offspring through mechanisms such as chronic inflammation, placental transfer of malaria-induced factors, and epigenetic modifications. These alterations can lead to increased susceptibility to infections, reduced vaccine efficacy, and long-term health complications. Children born to mothers with malaria may face heightened risks of infections, impaired immune responses, and developmental issues, necessitating targeted interventions to address these challenges.

To mitigate the impact of maternal malaria, it is essential to implement a multifaceted approach that includes preventive measures such as insecticide-treated bed nets, intermittent preventive treatment, and vector control programs. Improving antenatal care with regular monitoring and comprehensive care packages can help detect and manage malaria effectively. Therapeutic interventions should focus on prompt treatment of maternal malaria and management of associated complications. Enhancing immunization strategies to ensure effective vaccine responses in affected children is also crucial. Supporting research into immune system alterations and developing targeted interventions based on these findings can provide valuable insights and lead to improved health outcomes. Additionally, public health campaigns and health education programs are vital for raising awareness and promoting preventive practices.

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37. 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.

38. Anyiam AF, Arinze-Anyiam OC, Omosigho PO, Ibrahim M, Irondi EA, Obeagu EI, Obi E. Blood Group, Genotype, Malaria, Blood Pressure and Blood Glucose Screening Among Selected Adults of a Community in Kwara State: Implications to Public Health. Asian Hematology Research Journal. 2022;6(3):9-17.

39. Madekwe CC, Madekwe CC, Obeagu EI. Inequality of monitoring in Human Immunodeficiency Virus, Tuberculosis and Malaria: A Review. Madonna University journal of Medicine and Health Sciences. 2022;2(3):6-15.

40. Offie DC, Ibekwe AM, Agu CC, Esimai BN, Okpala PU, Obeagu EI, Ufelle SA, Ogbonna LN. Fibrinogen and C-Reactive Protein Significance in Children Infected by Plasmodium falciparum Species in Enugu, Enugu State, Nigeria. Journal of Pharmaceutical Research International. 2021;33(15):1-8. https://doi.org/10.9734/jpri/2021/v33i1531280

41. Obeagu EI, Ogunnaya FU. PREGNANCYINDUCED HAEMATOLOGICAL CHANGES: A KEY TO MARTERNAL AND CHILD HEALTH. European Journal of Biomedical. 2023;10(8):42-43. 

42. Obeagu EI, Ofodile AC, Okwuanaso CB. A review of urinary tract infections in pregnant women: Risks factors. J Pub Health Nutri. 2023; 6 (1).2023;137:26-35

43. Obeagu EI, Obeagu GU, Musiimenta E. Post partum haemorrhage among pregnant women: Update on risks factors. Int. J. Curr. Res. Med. Sci. 2023;9(2): 14-17.DOI: https://doi.org/10.22192/ijcrms.2023.09.02.003 

44. Obeagu EI, Obeagu GU, Ogunnaya FU. Deep vein thrombosis in pregnancy: A review of prevalence and risk factors. Int. J. Curr. Res. Chem. Pharm. Sci. 2023;10(8): 14-21.DOI: 10.22192/ijcrcps.2023.10.08.002

45. Arama C, Quin JE, Kouriba B, Östlund Farrants AK, Troye-Blomberg M, Doumbo OK. Epigenetics and malaria susceptibility/protection: A missing piece of the puzzle. Frontiers in Immunology. 2018; 9:1733. https://doi.org/10.3389/fimmu.2018.01733 PMid:30158923 PMCid:PMC6104485

46. 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.DOI: https://doi.org/10.22192/ijcrbm.2018.03.09.001 

47. Onyenweaku FC, Amah HC, Obeagu EI, Nwandikor UU, Onwuasoanya UF. Prevalence of asymptomatic bacteriuria and its antibiotic susceptibility pattern in pregnant women attending private ante natal clinics in Umuahia Metropolitan. Int J Curr Res Biol Med. 2017;2(2): 13-23.DOI: https://doi.org/10.22192/ijcrbm.2017.02.02.003 

48. Okoroiwu IL, Chinedu-Madu JU, Obeagu EI, Vincent CC, Ochiabuto OM, Ibekwe AM, Amaechi CO, Agu CC, Anoh NV, Amadi NM. Evaluation of Iron Status, Haemoglobin and Protein Levels of Pregnant Women in Owerri Metropolis. Journal of Pharmaceutical Research International. 2021;33(27A):36-43. https://doi.org/10.9734/jpri/2021/v33i27A31491

49. Obeagu EI, Njar VE, Obeagu GU. Infertility: Prevalence and Consequences. Int. J. Curr. Res. Chem. Pharm. Sci. 2023;10(7):43-50.

50. Emeka-Obi OR, Ibeh NC, Obeagu EI, Okorie HM. Evaluation of levels of some inflammatory cytokines in preeclamptic women in owerri. Journal of Pharmaceutical Research International. 2021;33(42A):53-65. https://doi.org/10.9734/jpri/2021/v33i42A32384

51. Broen K, Brustoski K, Engelmann I, Luty AJ. Placental Plasmodium falciparum infection: causes and consequences of in utero sensitization to parasite antigens. Molecular and biochemical parasitology. 2007;151(1):1-8. https://doi.org/10.1016/j.molbiopara.2006.10.001 PMid:17081634

52. 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):41-49.

53. Ogbonna LN, Ezeoru VC, Ofodile AC, Ochiabuto OM, Obi-Ezeani CN, Okpala PU, Okafor CJ, Obeagu GU, Busari AI, Obeagu EI. Gender Based Variations of Haematological Parameters of Patients with Asymptomatic Malaria in Akure, Ondo State, Nigeria. Journal of Pharmaceutical Research International. 2021;33(8):75-80. https://doi.org/10.9734/jpri/2021/v33i831216

54. Eberendu IF, Ozims SJ, Agu GC, Amah HC, Obasi CC, Obioma-Elemba JE, Ihekaire DE, Ibanga IE, Amah CC, Obeagu EI, Nwosu DC. Impact of human activities on the breeding of mosquitoes of human disease in Owerri metropolis, Imo state. Int J Adv Res Biol Sci IJARBS. 2017;4(12):98-106. https://doi.org/10.22192/ijarbs.2017.04.12.010

55. Obeagu EI, Ofodile AC, Okwuanaso CB. A review on socio economic and behavioral aspects of malaria and its control among children under 5 years of age in Africa. J Pub Health Nutri. 2023; 6 (1): 136.

56. Djontu JC, Siewe Siewe S, Mpeke Edene YD, Nana BC, Chomga Foko EV, Bigoga JD, Leke RF, Megnekou R. Impact of placental Plasmodium falciparum malaria infection on the Cameroonian maternal and neonate's plasma levels of some cytokines known to regulate T cells differentiation and function. Malaria journal. 2016; 15:1-1. https://doi.org/10.1186/s12936-016-1611-0 PMid:27871325 PMCid:PMC5117507

57. Obeagu EI, Faduma MH, Uzoma G. Ectopic Pregnancy: A Review. Int. J. Curr. Res. Chem. Pharm. Sci. 2023;10(4): 40-4.DOI: https://doi.org/10.22192/ijcrcps.2023.10.04.004 

58. Obeagu EI, Gamade SM, Obeagu GU. The roles of Neutrophils in pregnancy. Int. J. Curr. Res. Med. Sci. 2023;9(5): 31-35.DOI: https://doi.org/10.22192/ijcrms.2023.09.05.005 

59. Obeagu EI, Obeagu GU. Molar Pregnancy: Update of prevalence and risk factors. Int. J. Curr. Res. Med. Sci. 2023;9(7): 25-28.DOI: https://doi.org/10.19080/JGWH.2023.25.556169

60. Kabyemela E, Gonçalves BP, Prevots DR, Morrison R, Harrington W, Gwamaka M, Kurtis JD, Fried M, Duffy PE. Cytokine profiles at birth predict malaria severity during infancy. PloS one. 2013;8(10):e77214. https://doi.org/10.1371/journal.pone.0077214 PMid:24130857 PMCid:PMC3795067

61. Ibebuike JE, Ojie CA, Nwokike GI, Obeagu EI, Nwosu DC, Nwanjo HU, Agu GC, Ezenwuba CO, Nwagu SA, Akujuobi AU. Barriers to utilization of maternal health services in southern senatorial district of Cross Rivers state, Nigeria. International Journal of Advanced Multidisciplinary Research. 2017;4(8): 1-9.DOI: https://doi.org/10.22192/ijamr.2017.04.08.001 

62. Emannuel G, Martin O, Peter OS, Obeagu EI, Daniel K. Factors Influencing Early Neonatal Adverse Outcomes among Women with HIV with Post Dated Pregnancies Delivering at Kampala International University Teaching Hospital, Uganda. Asian Journal of Pregnancy and Childbirth. 2023;6(1):203-211. http://research.sdpublishers.net/id/eprint/2819/ .

63. 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.DOI: https://doi.org/10.22192/ijcrms.2018.04.09.006 

64. Obeagu EI, Obeagu GU. Postpartum haemorrhage among women delivering through spontaneous vaginal delivery: Prevalence and risk factors. Int. J. Curr. Res. Chem. Pharm. Sci. 2023;10(8): 22-6.DOI: https://doi.org/10.22192/ijcrcps.2023.10.08.003 

65. Obeagu E, Eze RI, Obeagu EI, Nnatuanya IN, Dara EC. ZINC LEVEL IN APPARENTLY PREGNANT WOMEN IN URBAN AREA. Madonna University journal of Medicine and Health Sciences. 2022;2(1):134-48. https://www.journal.madonnauniversity.edu.ng/index.php/medicine/article/view/40 .

66. Ogomaka IA, Obeagu EI. Malaria in Pregnancy Amidst Possession of Insecticide Treated Bed Nets (ITNs) in Orlu LGA of Imo State, Nigeria. Journal of Pharmaceutical Research International. 2021;33(41B):380-386. https://doi.org/10.9734/jpri/2021/v33i41B32377

67. Obeagu EI, Ogunnaya FU, Obeagu GU, Ndidi AC. SICKLE CELL ANAEMIA: A GESTATIONAL ENIGMA. migration. 2023; 17:18.

68. Harrington WE, Kakuru A, Jagannathan P. Malaria in pregnancy shapes the development of foetal and infant immunity. Parasite immunology. 2019;41(3):e12573. https://doi.org/10.1111/pim.12573 PMid:30019470

69. Ifeanyi OE, Uzoma OG. A review on erythropietin in pregnancy. J. Gynecol. Womens Health. 2018;8(3):1-4. https://www.academia.edu/download/56538560/A_Review_on_Erythropietin_in_Pregnancy.pdf . https://doi.org/10.19080/JGWH.2018.08.555740

70. Ifeanyi OE. A review on pregnancy and haematology. Int. J. Curr. Res. Biol. Med. 2018;3(5): 26-8.DOI: 10.22192/ijcrbm.2018.03.05.006

71. Nwosu DC, Nwanjo HU, Obeagu EI, Ibebuike JE, Ezeama MC. Ihekireh. Changes in liver enzymes and lipid profile of pregnant women with malaria in Owerri, Nigeria. International Journal of Current Research and Academic Review. 2015;3(5):376-383.

72. Ibebuike JE, Ojie CA, Nwokike GI, Obeagu EI, Nwosu DC, Nwanjo HU, Agu GC, Ezenwuba CO, Nwagu SA, Akujuobi AU. Factors that influence women's utilization of primary health care services in Calabar Cros river state, Nigeria. Int. J. Curr. Res. Chem. Pharm. Sci. 2017;4(7):28-33. https://doi.org/10.22192/ijcrcps.2017.04.07.006

73. Elemchukwu Q, Obeagu EI, Ochei KC. Prevalence of Anaemia among Pregnant Women in Braithwaite Memorial Specialist Hospital (BMSH) Port Harcourt. IOSR Journal of Pharmacy and Biological Sciences. 2014;9(5):59-64. https://doi.org/10.9790/3008-09525964

74. Natama HM, Moncunill G, Rovira-Vallbona E, Sanz H, Sorgho H, Aguilar R, Coulibaly-Traoré M, Somé MA, Scott S, Valéa I, Mens PF. Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life. BMC medicine. 2018; 16:1-5. https://doi.org/10.1186/s12916-018-1187-3 PMid:30384846 PMCid:PMC6214168

75. Akandinda M, Obeagu EI, Katonera MT. Non Governmental Organizations and Women's Health Empowerment in Uganda: A Review. Asian Research Journal of Gynaecology and Obstetrics. 2022;8(3):12-26.

76. Gamde MS, Obeagu EI. IRON DEFICIENCY ANAEMIA: ENEMICAL TO PREGNANCY. European Journal of Biomedical. 2023;10(9):272-275. 

77. Emeka-Obi OR, Ibeh NC, Obeagu EI, Okorie HM. Evaluation of levels of some inflammatory cytokines in preeclamptic women in owerri. Journal of Pharmaceutical Research International. 2021;33(42A):53-65. https://doi.org/10.9734/jpri/2021/v33i42A32384

78. Emeka-Obi OR, Ibeh NC, Obeagu EI, Okorie HM. Studies of Some Haemostatic Variables in Preeclamptic Women in Owerri, Imo State, Nigeria. Journal of Pharmaceutical Research International. 2021;33(42B):39-48. https://doi.org/10.9734/jpri/2021/v33i42B32402

79. Obeagu EI, Obeagu GU. Postpartum haemorrhage among women delivering through spontaneous vaginal delivery: Prevalence and risk factors. Int. J. Curr. Res. Chem. Pharm. Sci. 2023;10(8):22-26.

80. Obeagu EI, Obeagu GU. Sickle Cell Anaemia in Pregnancy: A Review. International Research in Medical and Health Sciences. 2023;6(2):10-13.

81. Mutabingwa TK, Bolla MC, Li JL, Domingo GJ, Li X, Fried M, Duffy PE. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS medicine. 2005;2(12):e407. https://doi.org/10.1371/journal.pmed.0020407 PMid:16259531 PMCid:PMC1277932

82. Gamble C, Ekwaru PJ, Garner P, Ter Kuile FO. Insecticide-treated nets for the prevention of malaria in pregnancy: a systematic review of randomised controlled trials. PLoS medicine. 2007;4(3):e107. https://doi.org/10.1371/journal.pmed.0040107 PMid:17388668 PMCid:PMC1831739

83. Okoko BJ, Enwere G, Ota MO. The epidemiology and consequences of maternal malaria: a review of immunological basis. Acta tropica. 2003;87(2):193-205. https://doi.org/10.1016/S0001-706X(03)00097-4 PMid:12826295

84. Dobaño C, Berthoud T, Manaca MN, Nhabomba A, Guinovart C, Aguilar R, Barbosa A, Groves P, Rodríguez MH, Jimenez A, Quimice LM. High production of pro-inflammatory cytokines by maternal blood mononuclear cells is associated with reduced maternal malaria but increased cord blood infection. Malaria Journal. 2018; 17:1-3. https://doi.org/10.1186/s12936-018-2317-2 PMid:29743113 PMCid:PMC5944101

85. Umbers AJ, Stanisic DI, Ome M, Wangnapi R, Hanieh S, Unger HW, Robinson LJ, Lufele E, Baiwog F, Siba PM, King CL. Does malaria affect placental development? Evidence from in vitro models. PLoS One. 2013;8(1):e55269. https://doi.org/10.1371/journal.pone.0055269 PMid:23383132 PMCid:PMC3561386

86. Arama C, Quin JE, Kouriba B, Östlund Farrants AK, Troye-Blomberg M, Doumbo OK. Epigenetics and malaria susceptibility/protection: A missing piece of the puzzle. Frontiers in Immunology. 2018; 9:1733. https://doi.org/10.3389/fimmu.2018.01733 PMid:30158923 PMCid:PMC6104485

87. Gbedande K, Carpio VH, Stephens R. Using two phases of the CD 4 T cell response to blood‐stage murine malaria to understand regulation of systemic immunity and placental pathology in Plasmodium falciparum infection. Immunological reviews. 2020;293(1):88-114. https://doi.org/10.1111/imr.12835 PMid:31903675 PMCid:PMC7540220

88. Lindsay SW, Thomas MB, Kleinschmidt I. Threats to the effectiveness of insecticide-treated bednets for malaria control: thinking beyond insecticide resistance. The Lancet Global Health. 2021;9(9):e1325-1331. https://doi.org/10.1016/S2214-109X(21)00216-3 PMid:34216565

89. Akinleye SO, Falade CO, Ajayi IO. Knowledge and utilization of intermittent preventive treatment for malaria among pregnant women attending antenatal clinics in primary health care centers in rural southwest, Nigeria: a cross-sectional study. BMC pregnancy and childbirth. 2009; 9:1-9. https://doi.org/10.1186/1471-2393-9-28 PMid:19589164 PMCid:PMC2719593