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From Conception to Prevention: How Metabolic Mastery Before Pregnancy Could Revolutionize Cerebral Palsy Prevention

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dr Leonard Andreas Wiyadharma, BMedSci

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A New Path to Prevention

The understanding of cerebral palsy (CP) is undergoing a significant paradigm shift. Historically, many cases were attributed to perinatal complications or unknown causes. However, robust scientific evidence now demonstrates that parental metabolic health—particularly maternal diabetes, obesity, and metabolic syndrome—plays a critical, preventable role in elevating CP risk in offspring [1–4]. This risk elevation is not random; it occurs through specific and measurable pathophysiological mechanisms, including chronic inflammation, hyperglycemia-induced oxidative stress, and the resultant disruption of fetal neurodevelopment [5, 6].

This realization transforms CP management from a reactive effort—focusing on treatment after diagnosis—to a proactive health strategy. The evidence supports a comprehensive preventive medicine approach centered on preconception metabolic optimization, targeted lifestyle modifications, and specific medical management during gestation [7, 8]. By optimizing the biological environment before conception, healthcare systems and parents can substantially reduce these quantifiable risks, representing a fundamental change in how cerebral palsy incidence can be addressed globally.

Decoding the Connection: Why Metabolic Health Matters to Baby’s Brain

Cerebral Palsy: Defining the Challenge and the Hope

Cerebral palsy is defined as a permanent disorder affecting movement, posture, and coordination, resulting from non-progressive injury to the developing brain [9]. While the condition remains non-curable, the discovery that many cases previously categorized as being of “unknown origin” are directly linked to modifiable parental metabolic disorders offers immense therapeutic hope [10]. This scientific knowledge is the most powerful tool available, moving the field toward effective primary prevention.

The Blueprint: How the Fetus Builds a Brain

Fetal neurodevelopment involves several complex and highly sensitive stages, including neurogenesis (the creation of nerve cells) and synaptogenesis (the formation of connections). Among the most critical processes is myelination, which involves insulating the long “wires” (axons) of the nerve cells, ensuring rapid and efficient signal transmission throughout the central nervous system (CNS). [11, 12]

The installation of this vital insulation is the responsibility of specialized support cells known as Oligodendrocytes. These glial cells are essential components of the CNS, wrapping axons in a protective layer of myelin. Functional oligodendrocytes are crucial for the development of white matter, the brain tissue responsible for connecting different regions. Critically, these cells are among the last types of cells to be generated in the CNS and are particularly vulnerable to external insults during their development. When exposed to metabolic distress, the failure of oligodendrocytes to correctly install this myelin insulation is a signature pathology of the white matter injury that often precedes CP. [12–14]

The central pathological link connecting parental metabolic disorders (like diabetes and obesity) to CP risk is the presence of sustained, high levels of metabolic fuel (excess glucose and fatty acids) within the intrauterine environment. This “fuel excess” fundamentally alters cellular conditions, promoting chronic stress and damage in fetal tissues.

A primary consequence of this fuel imbalance is oxidative stress. Oxidative stress can be conceptualized as “cellular rust” or an uncontrolled chemical fire inside the body’s cells. It describes an imbalance where highly reactive molecules, known as reactive oxygen species (ROS), overwhelm the body’s natural antioxidant defenses [15]. This imbalance causes molecular damage to proteins, lipids, and DNA within cellular structures, potentially leading to cell death (apoptosis or necrosis) and deterioration of function [16].

Maternal hyperglycemia and chronic inflammation—hallmarks of metabolic disease—drive this oxidative stress. This hostile environment preferentially damages the most vulnerable developing tissues [17], including the oligodendrocytes responsible for brain insulation [18–21]. Therefore, the metabolic insult creates a clear molecular “footprint” that causes functional impairment in the developing fetal brain, establishing a direct causal chain between poor metabolic control and subsequent neurodevelopmental injury [22, 23].

The Maternal Metabolic Landscape: Key Risks and Mechanisms

Diabetes: The Most Significant Challenge

Diabetes mellitus present during pregnancy is recognized as the single most significant maternal metabolic risk factor for cerebral palsy. Population-based cohort studies have confirmed that children born to mothers with pregestational diabetes mellitus face an 84% increased risk of cerebral palsy (HR: 1.84, 95% CI: 1.59-2.14) [4].

Analysis of this risk demonstrates a clear dose-response relationship, indicating that the severity of the metabolic disorder, often reflected in the difficulty of maintaining glycemic control, directly correlates with the offspring’s risk. Type 2 diabetes confers the highest risk (RR 3.2, 95% CI: 1.8-5.4), followed by Type 1 diabetes (RR 2.2, 95% CI: 1.4-3.4) [24]. This severity gradient highlights that the underlying issue of insulin resistance and subsequent metabolic instability often seen in Type 2 diabetes makes control more challenging, thereby increasing the pathological exposure [25].

The underlying pathophysiology is clear: sustained maternal hyperglycemia creates a hostile intrauterine environment [17, 18]. Elevated glucose levels initiate specific pathological events, including the promotion of oxidative stress, the activation of chronic inflammatory cascades, and the disruption of fetal cellular metabolism[17, 26]. These disturbances specifically target vulnerable populations of cells, such as the oligodendrocytes, thereby impairing the white matter development necessary for normal motor function [19–21].

Gestational Diabetes Mellitus (GDM) and Insulin Resistance

Gestational diabetes mellitus (GDM), defined as diabetes diagnosed for the first time during pregnancy, also represents a substantial and independently causal risk factor for CP. Recent Mendelian randomization (MR) studies demonstrate that GDM increases CP risk by 74% (OR: 1.74, 95% CI: 1.27-2.37) [27].

The underlying mechanism in GDM is rooted in insulin resistance, which creates a specific metabolic milieu. This environment is characterized by persistent chronic inflammation, altered and excessive nutrient transport across the placenta, and the disruption of fetal insulin signaling pathways [28]. Since insulin signaling is crucial for normal growth and development, these metabolic disturbances disproportionately affect critical periods of fetal brain development, including neurogenesis, synaptogenesis (connection formation), and myelination [29, 30].

Beyond Sugar: Maternal Obesity and Chronic Inflammation

Maternal obesity is another critical and independent metabolic risk factor. Meta-analyses consistently demonstrate that offspring of obese mothers face increased risk. Specifically, early-pregnancy obesity confers a 35% increased risk (aRR: 1.35), while the presence of broader chronic cardiovascular or metabolic disorders increases the risk by 89% (aRR: 1.89) [1].

Significantly, this association appears strongest for term births, suggesting that the primary mechanism operates through developmental disruption rather than complications solely linked to preterm delivery [1]. The underlying pathway is systemic inflammation. Maternal obesity sustains a chronic, low-grade inflammatory state throughout the body. This inflammation acts as a persistent stressor that can directly damage developing fetal neural tissue, independent of hyperglycemia [31].

It is important to recognize that hyperglycemia, GDM, and obesity are diverse clinical conditions, yet they converge on a common pathological link: the induction of a chronic, low-grade inflammatory state. This sustained inflammation is the primary driver of oxidative stress and subsequent damage to the fetal brain. Understanding that inflammation is the common pathological denominator simplifies the therapeutic target: effective management of inflammation, through diet, weight optimization, and targeted medication, inherently manages a significant portion of the CP risk, irrespective of the primary metabolic diagnosis. [26, 28, 32]

The Paternal Contribution: A Shared Responsibility

While clinical focus traditionally centers on maternal health, emerging scientific evidence confirms that paternal metabolic status profoundly influences offspring neurodevelopmental outcomes. Optimizing health for CP prevention must therefore encompass both parents.

Father’s Age and Health: More Than Just Genetics

A father’s age, often associated with accumulating metabolic dysfunction, is a measurable risk factor. Studies indicate that advanced paternal age, defined as 46 years or older, is associated with increased risk of cerebral palsy in the offspring [33]. While age itself is non-modifiable, the associated metabolic decline, including issues like increasing insulin resistance and weight gain, often are modifiable lifestyle factors.

This familial connection is further reinforced by clustering studies, which show that siblings of an affected child face a robust 3.0- to 9.2-fold increased risk of cerebral palsy [34]. This strong familial aggregation strongly indicates that shared genetic and environmental factors, including both parents’ metabolic phenotypes, are significant drivers of the outcome, affirming that metabolic health optimization is a shared family requirement [35].

Epigenetics Explained: Setting the Gene Switches

A father’s health and lifestyle choices directly impact the quality and programming of his sperm cells. This mechanism operates through epigenetics. Epigenetics dictates how the genetic code is interpreted and expressed—which genes are turned “on” or “off” in specific cells. DNA can be thought of as the musical score for the body, containing all instructions, while epigenetics acts as the conductor of the orchestra, determining which instruments (genes) play, and with what intensity. [36]

Paternal metabolic dysfunction, such as that stemming from obesity or a poor diet, can incorrectly set these epigenetic “switches” within the sperm’s genetic material. These altered patterns can subsequently be inherited by the offspring, potentially programming them for metabolic and neurodevelopmental issues. Research, largely from animal models [37, 38], suggests paternal undernutrition or diet-induced obesity can negatively alter epigenetic profiles in spermatozoa, affecting offspring metabolic health. The implication is clear: optimal paternal metabolic health is essential for ensuring that the sperm carries the correct, healthy instructions for early development. [39, 40]

The Paternal Preconception Checklist

Converting the scientific findings into actionable steps requires a focused preconception checklist for fathers:

  1. Weight Management: Achieving and maintaining a healthy weight range is essential, as paternal obesity can negatively affect sperm quality and subsequent offspring metabolic health programming. [41–43]
  2. Toxic Exposure Avoidance: Quitting smoking is mandatory at least three months prior to conception, as tobacco use damages the DNA within sperm. Similarly, limiting or avoiding alcohol and exposure to known environmental toxins is critical to protect sperm integrity. [44, 45]
  3. Overall Health Screening: Because up to half of infertility cases involve male factors, a general medical check-up is recommended to screen for untreated chronic conditions, including diabetes risk, and infections like STIs. [46]

The robust evidence demonstrating shared familial risk and the epigenetic impact of paternal health underscores that the pursuit of preconception health should not be viewed as a solitary maternal task. Instead, it must be an essential shared family endeavor. This mutual commitment and shared accountability enhance practical and emotional support, dramatically improving compliance with lifestyle changes and maximizing the protective environment for the developing child.

The Preconception Protocol: Maximizing Your Health Foundation

The Golden Window: Why Preconception Matters Most

The foundation of cerebral palsy prevention must be established well before conception. The earliest weeks of fetal development represent a critical window where metabolic interventions yield maximum impact. Preconception health optimization ensures that the fetal environment is established optimally during the crucial periods of neurogenesis and myelination. [47, 48]

Successful preconception care involves a comprehensive, multi-component package encompassing screening, management of chronic diseases, mental health support, nutritional counseling, and weight management. This proactive approach targets modifiable risk factors at a time when they can be reversed or controlled before pregnancy complications arise.

Mastering Glycemic Control (For Pre-Existing Diabetes)

For women with pre-existing Type 1 or Type 2 diabetes, the single most impactful intervention to reduce CP risk is achieving and maintaining optimal glycemic control prior to conception. The clinical target is to sustain a hemoglobin A1c (HbA1c) level below 6.5%, and ideally 6.0% once pregnancy is established, for at least three months before attempting to conceive. [47, 49–51]

Achieving this rigorous target requires proactive, sophisticated management:

  • Technology Implementation: The use of Continuous Glucose Monitoring (CGM) is crucial. CGM provides real-time data on blood glucose levels and patterns, allowing for dynamic, immediate adjustments to insulin regimens and lifestyle choices. [49, 50]
  • Specialized Teamwork: Collaboration with a dedicated, high-risk Obstetrician-Gynecologist (OB-GYN) and an endocrinologist is necessary to develop and adjust medication protocols and plan for potential pregnancy complications. [49, 50]
  • Proactive Screening: A thorough dilated eye exam is required before conception, as the metabolic and hormonal changes of pregnancy can rapidly exacerbate pre-existing diabetic retinopathy. [49, 52]
  • The devastating outcomes, such as severe neonatal encephalopathy resulting from maternal diabetic ketoacidosis, vividly illustrate the absolute necessity of preventing severe hyperglycemic episodes through meticulous, sustained preconception management. [47, 49, 52]

Achieving a Healthy Weight Together

Weight optimization before conception is vital, especially for individuals diagnosed with metabolic syndrome (a cluster of conditions including hypertension, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels). Preconception weight optimization significantly reduces the associated cerebral palsy risk. [1]

Evidence-based interventions must be structured and sustainable:

  1. Lifestyle Modification Programs: These programs combine targeted dietary counseling, increased physical activity, and behavioral strategies focused on establishing lasting healthy habits. [53]
  2. Medical Management: Components of metabolic syndrome, including hypertension, dyslipidemia (abnormal cholesterol), and insulin resistance, must be aggressively managed and treated prior to pregnancy. [54, 55]
  3. Systemic Success: Real-world examples confirm the effectiveness of this approach. A nurse practitioner-led cardiovascular prevention program demonstrated significant improvements in metabolic syndrome components among high-risk women, achieving a reduction in prevalence from 34.4% to 29.7% over 12 months, proving the success of sustained, interdisciplinary clinical efforts. [53, 55, 56]

Nutritional Optimization for Neurodevelopment

Nutrition plays a paramount role in supporting the future pregnancy and mitigating inflammatory risks. The nutritional strategy for CP prevention focuses on adopting a diet that is inherently anti-inflammatory and supports optimal fetal brain development. [57, 58]

The most effective framework involves adopting a Mediterranean dietary pattern, which emphasizes healthy fats, lean proteins, complex carbohydrates, and high amounts of anti-inflammatory foods. [57, 58]

Key neuroprotective nutrients include:

  • Omega-3 Fatty Acids (EPA/DHA): These are essential for strong anti-inflammatory effects and directly support fetal brain and eye development. Aiming for 2 to 3 grams daily, either through dietary sources (fatty fish like salmon, walnuts, flaxseeds) or targeted supplementation, is recommended. [59]
  • Antioxidants: Found abundantly in colorful berries and vegetables, antioxidants are compounds that directly combat oxidative stress, protecting developing cells from cellular “rust”. [60, 61]
  • Vitamin D: Optimization of Vitamin D levels (25-hydroxyvitamin D concentrations maintained above 30 ng/mL) is essential for supporting a healthy immune system and modulating inflammation. [42, 62]
  • Traditional Anti-Inflammatories: Incorporating spices such as turmeric and ginger into the diet can provide additional potent anti-inflammatory properties. [60, 63, 64]
  • Micronutrients: Adequate levels of folate, Vitamin D, and B-vitamins must be secured before and throughout pregnancy. [42]
Action AreaMother’s Goal/ActionFather’s Goal/ActionWhy It Matters (The Risk)
Weight/BMIAchieve a healthy BMI range before conception; seek professional support for metabolic syndrome.Be in a healthy weight range; obesity affects sperm quality and DNA integrity.Obesity contributes to chronic inflammation, a key CP risk pathway.
Diabetes ControlMaintain HbA1c below 6.5% for at least 3 months pre-conception; use CGM.Maintain healthy blood sugar and screen for Type 2 diabetes risk.High glucose creates oxidative stress, damaging vulnerable fetal brain cells.
Toxic ExposureQuit smoking (ages ovaries, lowers fertility); limit alcohol/caffeine; review all medications.Quit smoking (DNA damage risk); cut back on alcohol; avoid chemical exposures.Toxic exposure damages genetic material in sperm and egg, increasing health risks for the baby.
Anti-Inflammatory DietFocus on Omega-3s, Vitamin D, and antioxidants (Mediterranean pattern).Optimize diet for sperm quality and overall metabolic health.Reduces the systemic inflammation that drives fetal neurodevelopmental disruption.
Table 1. The Two-Parent Preconception Metabolic Checklist

Precision Prevention During Pregnancy

Even when conception is unplanned or if metabolic issues emerge during gestation, targeted interventions can significantly reduce risk. This requires precision management and acute neuroprotective measures.

Primary Prevention and Management of Gestational Diabetes (GDM)

For women with identified risk factors, primary prevention of GDM is paramount. Evidence-based strategies show promise: Myo-inositol supplementation (4000 mg daily) starting in early pregnancy has been demonstrated in randomized controlled trials to reduce insulin resistance and lower the overall incidence of GDM [65]. This intervention supports better metabolic function throughout gestation.

For women who develop GDM, intensive secondary management prevents adverse outcomes. This includes early screening in high-risk populations, often using first-trimester risk assessment, followed by continuous glucose monitoring for precise glycemic control [66]. Lifestyle modification programs tailored to pregnancy needs are the first line of defense, supplemented by pharmacological intervention when metabolic targets cannot be met through diet and exercise alone [65].

Fighting Systemic Inflammation and Modulating Immunity

Chronic inflammation serves as the crucial pathway linking parental metabolic disorders to CP risk. Therefore, continuous strategies targeting inflammation must be employed throughout pregnancy.

This includes maintaining an anti-inflammatory regimen focused on continued high intake of Omega-3 fatty acids and antioxidants [59–61]. Optimization of Vitamin D status (target 25-hydroxyvitamin D levels above 30 ng/mL) is also essential, as Vitamin D is known to support immune function and modulate inflammatory pathways [42, 62]. Furthermore, emerging research highlights the importance of the gut microbiome, which mediates both metabolic health and inflammation. Dietary fiber supplementation and utilization of probiotics or fermented foods can support beneficial bacterial populations, potentially influencing offspring metabolic programming [42].

Immune Defense: Preventing Infections

Maternal infections are a separate, yet critically important, pathway to increased CP risk, operating by triggering systemic immune activation and subsequent inflammation [67]. A comprehensive strategy for infection prevention is a non-negotiable component of metabolic risk management. Key actionable steps include: routine screening and treatment of genitourinary infections; ensuring vaccination status is optimized (including influenza and pertussis immunization); hygiene education; and the prompt, aggressive treatment of any identified infections to prevent the progression to systemic inflammation and fetal distress [68, 69].

Advanced Intervention: The Power of Magnesium Sulfate (The Brain Shield)

For women with metabolic disorders facing the risk of preterm delivery (typically before 32 weeks gestation), antenatal administration of magnesium sulfate (MgSO4) is a powerful and highly effective neuroprotective intervention.

Magnesium sulfate provides dual benefits: it can suppress premature labor, thereby delaying preterm birth, and, crucially, it provides direct neuroprotective effects to the fetal brain. Magnesium sulfate functions as a “brain shield” by multiple mechanisms: stabilizing neuronal membranes, blocking damaging excitatory neurotransmitters, normalizing cerebral blood flow, and directly protecting against the very oxidative and inflammatory injuries that metabolic disorders initiate [70, 71].

Clinical evidence demonstrates the substantial impact of this intervention. Research suggest that antenatal MgSO4 reduces the risk of any type of cerebral palsy by 32% [72] and the risk of handicapping CP by 45% [73].

The efficacy of MgSO4 in protecting against oxidative and inflammatory damage means it is profoundly synergistic when used in women with underlying metabolic disorders. A patient with poorly controlled GDM who faces threatened preterm delivery is simultaneously receiving targeted metabolic management (diet, insulin) and acute pharmacological protection (MgSO4) against the same core cellular insults that the metabolic disorder initiated. [70, 71]

Systems, Support, and Future Hope

Integrating Preconception Care into Routine Health

Successful implementation of metabolic prevention strategies requires a transformation in healthcare delivery, shifting from managing complications reactively to integrating proactive optimization into routine preconception and prenatal care.

Preconception Care Programs

Systematic programs must be established to identify women with metabolic risk factors, using formalized risk assessment tools. These programs should utilize interdisciplinary teams that include endocrinologists, nutritionists, exercise physiologists, and behavioral therapists. Establishing patient education programs emphasizing the direct link between metabolic health and offspring outcomes, alongside rigorous follow-up protocols, is necessary to ensure sustained behavior change and measurable metabolic improvement.

Quality Improvement Initiatives

Systematic quality improvement initiatives are vital for translating evidence into widespread practice. The PReCePT program in England [74] provides a successful model, demonstrating that standardizing protocols—such as the systematic administration of magnesium sulfate for neuroprotection—significantly increases the uptake of evidence-based interventions. This systematic approach has been shown to prevent an estimated seven cases of cerebral palsy, resulting in lifetime cost savings of £5.6 million. Implementation strategies require standardized protocols for metabolic assessment, robust staff education, and audit mechanisms that track intervention effectiveness and guide necessary resource allocation.

The Economic Case for Prevention

The evidence unequivocally supports the significant economic benefits of prevention strategies when compared to the enormous lifetime costs associated with managing cerebral palsy.

While investments are necessary in high-quality preconception care programs, integrating technology like continuous glucose monitoring, and comprehensive staff training, these costs are rapidly offset by the long-term savings. The prevention of even a small number of CP cases, which require lifelong care, generates massive fiscal returns. When prevention is shown to save millions, the argument for establishing supportive healthcare policy—including mandatory insurance coverage for high-cost preventive services like preconception consultation and specialized technology—becomes a fiscal imperative, not just an ethical one. Quality metrics must be introduced to incentivize this shift toward preventive, evidence-based care.

Cutting-Edge Research: Personalized Prevention

Future research is moving toward highly personalized, precision medicine approaches, leveraging genetic and epigenetic factors to optimize prevention strategies.

Pharmacogenomics and Risk Stratification

Understanding how an individual’s unique genetic profile dictates their response to metabolic interventions enables highly personalized treatment. Developments in pharmacogenomics will allow for genetic testing to predict responses to diabetes medications, while nutrigenomics will inform tailored dietary recommendations. Furthermore, genetic susceptibility profiles can be utilized for precise risk stratification, ensuring that the most intensive and costly interventions are delivered to those who stand to benefit the most.

Epigenetic Mechanisms and Biomarkers

Maternal metabolic status is known to influence offspring outcomes through epigenetic modifications that alter gene expression [75]. Research is focused on identifying epigenetic biomarkers that can accurately predict offspring risk, offering the potential for intervention timing to be optimized during critical windows of epigenetic modification. This research area also seeks to understand the transgenerational effects of metabolic interventions, studying the long-term consequences of parental health decisions on future generations.

Microbiome and Metabolic Health

The gut microbiome is increasingly recognized as a crucial mediator of metabolic health and neurodevelopmental outcomes [76–78]. Future research aims to modulate the maternal microbiome through targeted dietary fiber and probiotic interventions to support optimal metabolic programming in the offspring.

Clinical Recommendations and Guidelines

Primary Care Integration

Primary care providers must lead the front line in implementing metabolic prevention strategies. This requires routine metabolic screening for all women of reproductive age, identifying high-risk individuals who need specialized referral. Core components include comprehensive lifestyle counseling emphasizing diet, exercise, and weight management, integrated with clear referral protocols to ensure immediate access to specialists (endocrinology, nutrition) when indicated.

Specialist Care Coordination

Coordination between specialists is essential for high-risk populations. Maternal-fetal medicine teams must manage high-risk pregnancies, utilizing advanced fetal monitoring to enable early detection of complications and developing delivery plans that optimize timing and method based on both maternal and fetal status. Collaboration with endocrinology is necessary for meticulous diabetes management optimization and appropriate insulin regimen adjustments throughout the dynamic changes of pregnancy. Crucially, postpartum care planning must include strategies to prevent future metabolic complications and maintain the long-term health gains achieved during the preconception period.

Conclusion

The prevention of cerebral palsy through parental metabolic health optimization represents a potentially transformative approach to reducing the incidence of this permanent disability. Strong scientific evidence conclusively links maternal diabetes, obesity, and metabolic syndrome to increased cerebral palsy risk through specific, well-defined pathological mechanisms involving hyperglycemia, chronic inflammation, and subsequent disruption of fetal neurodevelopment.

Comprehensive prevention requires synergistic strategies: rigorous preconception metabolic optimization, effective management or prevention of gestational diabetes, active reduction of inflammation, and the utilization of acute, evidence-based neuroprotective interventions like magnesium sulfate. These approaches demand systematic integration within healthcare, patient-centered behavioral modification, and policy frameworks that support universal access to high-quality metabolic care.

Given the profound economic benefits of prevention, coupled with the devastating personal and societal costs associated with lifelong cerebral palsy management, there is a compelling justification for widespread implementation of metabolic health optimization programs. The collective prioritization of parental metabolic health as a fundamental strategy for cerebral palsy prevention offers a path to achieving substantial reductions in incidence globally, securing improved neurodevelopmental outcomes for future generations.

References

  1. Razaz N, Cnattingius S, Lisonkova S, et al. Pre-pregnancy and pregnancy disorders, pre-term birth and the risk of cerebral palsy: a population-based study. Int J Epidemiol 2023; 52: 1766–1773.
  2. Myers-Morrison C. Parental Obesity: The Pandemic of Intergenerational Physical and Mental Health Carnage. Int J Integr Pediatr Environ Med 2023; 8: 1–18.
  3. Zhang J, Peng L, Chang Q, et al. Maternal obesity and risk of cerebral palsy in children: a systematic review and meta‐analysis. Dev Med Child Neurol 2019; 61: 31–38.
  4. Ahmed A, Rosella LC, Oskoui M, et al. In utero Exposure to Maternal Diabetes and the Risk of Cerebral Palsy: A Population-based Cohort Study. Epidemiology 2023; 34: 247–258.
  5. Ayoub G. Neurodevelopment of Autism: Critical Periods, Stress and Nutrition. Cells 2024; 13: 1968.
  6. Al-Ramahi O. Gestational hyperglycemia: a comprehensive overview of multiple defects and neurological disorders. Journal of Neurology & Stroke 2024; 14: 186–189.
  7. Shepherd E, Middleton P, Makrides M, et al. Antenatal and intrapartum interventions for preventing cerebral palsy: an overview of Cochrane systematic reviews. In: Shepherd E (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd, 2016. Epub ahead of print 8 February 2016. DOI: 10.1002/14651858.CD012077.
  8. McLennan N-M, Hazlehurst J, Thangaratinam S, et al. Targeting metabolic health promotion to optimise maternal and offspring health. Eur J Endocrinol 2022; 186: R113–R126.
  9. MacLennan AH, Lewis S, Moreno-De-Luca A, et al. Genetic or Other Causation Should Not Change the Clinical Diagnosis of Cerebral Palsy. J Child Neurol 2019; 34: 472–476.
  10. Cooper MS, Fahey MC, Mackay MT. Making waves: The changing tide of cerebral palsy. J Paediatr Child Health 2022; 58: 1929–1934.
  11. Radlowski EC, Johnson RW. Perinatal iron deficiency and neurocognitive development. Front Hum Neurosci; 7. Epub ahead of print 2013. DOI: 10.3389/fnhum.2013.00585.
  12. Jiang X, Nardelli J. Cellular and molecular introduction to brain development. Neurobiol Dis 2016; 92: 3–17.
  13. Islam M, Behura SK. Role of caveolin-1 in metabolic programming of fetal brain. iScience 2023; 26: 107710.
  14. Yuan S, Liu M, Kim S, et al. Cyto/myeloarchitecture of cortical gray matter and superficial white matter in early neurodevelopment: multimodal MRI study in preterm neonates. Cereb Cortex 2022; 33: 357–373.
  15. Hong Y, Boiti A, Vallone D, et al. Reactive Oxygen Species Signaling and Oxidative Stress: Transcriptional Regulation and Evolution. Antioxidants 2024; 13: 312.
  16. Afzal S, Abdul Manap AS, Attiq A, et al. From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration. Front Pharmacol; 14. Epub ahead of print 18 October 2023. DOI: 10.3389/fphar.2023.1269581.
  17. Yan Y-S, Feng C, Yu D-Q, et al. Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia. Front Nutr; 10. Epub ahead of print 15 May 2023. DOI: 10.3389/fnut.2023.1067282.
  18. Huerta-Cervantes M, Peña-Montes DJ, Montoya-Pérez R, et al. Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects. Nutrients; 12. Epub ahead of print 31 January 2020. DOI: 10.3390/nu12020376.
  19. Márquez-Valadez B, Valle-Bautista R, García-López G, et al. Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects. Front Endocrinol (Lausanne); 9. Epub ahead of print 13 November 2018. DOI: 10.3389/fendo.2018.00664.
  20. Piazza FV, Segabinazi E, de Meireles ALF, et al. Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus. Cell Mol Neurobiol 2019; 39: 401–414.
  21. Rodolaki K, Pergialiotis V, Iakovidou N, et al. The impact of maternal diabetes on the future health and neurodevelopment of the offspring: a review of the evidence. Front Endocrinol (Lausanne); 14. Epub ahead of print 3 July 2023. DOI: 10.3389/fendo.2023.1125628.
  22. Duhig K, Chappell LC, Shennan AH. Oxidative stress in pregnancy and reproduction. Obstet Med 2016; 9: 113–116.
  23. Divvela SSK, Gallorini M, Gellisch M, et al. Navigating redox imbalance: the role of oxidative stress in embryonic development and long-term health outcomes. Front Cell Dev Biol 2025; 13: 1521336.
  24. Strøm MS, Tollånes MC, Wilcox AJ, et al. Maternal Chronic Conditions and Risk of Cerebral Palsy in Offspring: A National Cohort Study. Pediatrics; 147. Epub ahead of print March 2021. DOI: 10.1542/peds.2020-1137.
  25. Ornoy A, Becker M, Weinstein-Fudim L, et al. Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review. Int J Mol Sci 2021; 22: 2965.
  26. Jiménez-Escutia R, Vargas-Alcantar D, Flores-Espinosa P, et al. High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin. Int J Mol Sci 2023; 24: 5243.
  27. Peng H, Shu Y, Lu S, et al. Associations between maternal gestational diabetes mellitus and offspring cerebral palsy: a two-sample Mendelian randomization study. Transl Pediatr 2024; 13: 1923–1932.
  28. Huang S, Chen J, Cui Z, et al. Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus. Sci Adv; 9. Epub ahead of print 3 November 2023. DOI: 10.1126/sciadv.adi7337.
  29. Calvo MJ, Parra H, Santeliz R, et al. The Placental Role in Gestational Diabetes Mellitus: A Molecular Perspective. touchREVIEWS in Endocrinology; 20. Epub ahead of print 2024. DOI: 10.17925/EE.2024.20.1.5.
  30. Mittal R, Prasad K, Lemos JRN, et al. Unveiling Gestational Diabetes: An Overview of Pathophysiology and Management. Int J Mol Sci; 26. Epub ahead of print 5 March 2025. DOI: 10.3390/ijms26052320.
  31. Musa E, Salazar‐Petres E, Arowolo A, et al. Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women. J Physiol 2023; 601: 1287–1306.
  32. Zhou L, Zhang R, Yang S, et al. Astragaloside IV alleviates placental oxidative stress and inflammation in GDM mice. Endocr Connect 2020; 9: 939–945.
  33. Zhou L, Meng Q, von Ehrenstein OS, et al. Parental Age and Childhood Risk for Cerebral Palsy in California. J Pediatr 2023; 255: 147-153.e6.
  34. Tollånes MC, Wilcox AJ, Lie RT, et al. Familial risk of cerebral palsy: population based cohort study. BMJ 2014; 349: g4294.
  35. Richer LP, Dower NA, Leonard N, et al. Familial Recurrence of Cerebral Palsy with Multiple Risk Factors. Case Rep Pediatr 2011; 2011: 1–5.
  36. Garrido N, Boitrelle F, Saleh R, et al. Sperm epigenetics landscape: correlation with embryo quality, reproductive outcomes and offspring’s health. Panminerva Med; 65. Epub ahead of print July 2023. DOI: 10.23736/S0031-0808.23.04871-1.
  37. Wei S, Luo S, Zhang H, et al. Paternal high-fat diet altered SETD2 gene methylation in sperm of F0 and F1 mice. Genes Nutr 2023; 18: 12.
  38. Raad G, Serra F, Martin L, et al. Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice. Elife; 10. Epub ahead of print 30 March 2021. DOI: 10.7554/eLife.61736.
  39. Tomar A, Gomez-Velazquez M, Gerlini R, et al. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature 2024; 630: 720–727.
  40. Pascoal G de FL, Geraldi MV, Maróstica MR, et al. Effect of Paternal Diet on Spermatogenesis and Offspring Health: Focus on Epigenetics and Interventions with Food Bioactive Compounds. Nutrients 2022; 14: 2150.
  41. Venigalla G, Ila V, Dornbush J, et al. Male obesity: Associated effects on fertility and the outcomes of offspring. Andrology 2025; 13: 64–71.
  42. Jahan-Mihan A, Leftwich J, Berg K, et al. The Impact of Parental Preconception Nutrition, Body Weight, and Exercise Habits on Offspring Health Outcomes: A Narrative Review. Nutrients 2024; 16: 4276.
  43. Haberman M, Menashe T, Cohen N, et al. Paternal high-fat diet affects weight and DNA methylation of their offspring. Sci Rep 2024; 14: 19874.
  44. He Y, Zhang Z, Zheng Q, et al. Paternal alcohol exposure affected offspring mesenteric artery via ROS-Cacna1c and DNA hypomethylation. J Hypertens 2025; 43: 631–641.
  45. Prentki Santos E, López-Costa S, Chenlo P, et al. Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia 2011; 43: 431–435.
  46. Li X, Zhang B, Yang H, et al. The emergence of natural products as potential therapeutics for male infertility. Andrology 2024; 12: 1191–1208.
  47. Wahabi HA, Alzeidan RA, Bawazeer GA, et al. Preconception care for diabetic women for improving maternal and fetal outcomes: a systematic review and meta-analysis. BMC Pregnancy Childbirth 2010; 10: 63.
  48. Scher MS. ‘The First Thousand Days’ Define a Fetal/Neonatal Neurology Program. Front Pediatr 2021; 9: 683138.
  49. Feldman AZ, Brown FM. Management of Type 1 Diabetes in Pregnancy. Curr Diab Rep 2016; 16: 76.
  50. Callaway LK, Britten F. Managing pre-existing diabetes prior to and during pregnancy. Aust Prescr 2024; 47: 2–6.
  51. Management of diabetes from preconception to the postnatal period: summary of NICE guidance. BMJ 2008; 336: 714–717.
  52. Alexopoulos A-S, Blair R, Peters AL. Management of Preexisting Diabetes in Pregnancy. JAMA 2019; 321: 1811.
  53. Lim S, Harrison C, Callander E, et al. Addressing Obesity in Preconception, Pregnancy, and Postpartum: A Review of the Literature. Curr Obes Rep 2022; 11: 405–414.
  54. Dutton H, Borengasser SJ, Gaudet LM, et al. Obesity in Pregnancy: Optimizing Outcomes for Mom and Baby. Medical Clinics of North America 2018; 102: 87–106.
  55. Kitzmiller JL, Block JM, Brown FM, et al. Managing Preexisting Diabetes for Pregnancy. Diabetes Care 2008; 31: 1060–1079.
  56. Aldridge E, Pathirana M, Wittwer M, et al. Effectiveness of a nurse practitioner-led cardiovascular prevention clinic at reduction of metabolic syndrome following maternal complications of pregnancy: a preliminary analysis. Diabetol Metab Syndr 2022; 14: 144.
  57. Fu J, Tan L-J, Lee JE, et al. Association between the mediterranean diet and cognitive health among healthy adults: A systematic review and meta-analysis. Front Nutr; 9. Epub ahead of print 28 July 2022. DOI: 10.3389/fnut.2022.946361.
  58. Picone P, Girgenti A, Buttacavoli M, et al. Enriching the Mediterranean diet could nourish the brain more effectively. Front Nutr; 11. Epub ahead of print 27 November 2024. DOI: 10.3389/fnut.2024.1489489.
  59. Torres-Vanegas J, Rodríguez-Echevarría R, Campos-Pérez W, et al. Effect of a Diet Supplemented with Marine Omega-3 Fatty Acids on Inflammatory Markers in Subjects with Obesity: A Randomized Active Placebo-Controlled Trial. Healthcare 2025; 13: 103.
  60. Milano W, Pizza V, Capasso A. Benefical effects of mediterranean diet in neuroinflammation and related diseases. Integr Food Nutr Metab; 5. Epub ahead of print 2017. DOI: 10.15761/IFNM.1000207.
  61. Franco GA, Interdonato L, Cordaro M, et al. Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease. Int J Mol Sci; 24. Epub ahead of print 15 April 2023. DOI: 10.3390/ijms24087318.
  62. Kvashnina LV, Ignatova TB, Matviyenko IN, et al. Anti-inflammatory properties of omega-3 long-chain polyunsaturated fatty acids. UKRAINIAN JOURNAL OF PERINATOLOGY AND PEDIATRICS 2024; 7–15.
  63. Poggioli R, Hirani K, Jogani VG, et al. Modulation of inflammation and immunity by omega-3 fatty acids: a possible role for prevention and to halt disease progression in autoimmune, viral, and age-related disorders. Eur Rev Med Pharmacol Sci 2023; 27: 7380–7400.
  64. Hornedo-Ortega R, Cerezo AB, de Pablos RM, et al. Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation. Front Cell Neurosci 2018; 12: 373.
  65. Guarnotta V, Cuva G, Imbergamo MP, et al. Myoinositol supplementation in the treatment of gestational diabetes mellitus: effects on glycaemic control and maternal-foetal outcomes. BMC Pregnancy Childbirth 2022; 22: 516.
  66. Asimakopoulos G, Pergialiotis V, Anastasiou E, et al. Effect of dietary myo-inositol supplementation on the insulin resistance and the prevention of gestational diabetes mellitus: study protocol for a randomized controlled trial. Trials 2020; 21: 633.
  67. Ayubi E, Sarhadi S, Mansori K. Maternal Infection During Pregnancy and Risk of Cerebral Palsy in Children: A Systematic Review and Meta-analysis. J Child Neurol 2021; 36: 385–402.
  68. Potcovaru CG, Salmen T, Chitu MC, et al. Cerebral palsy: review of epidemiology, etiology, clinical features, classification and prevention. Romanian Journal of Pediatrics 2022; 71: 18–22.
  69. Wu CS, Pedersen LH, Miller JE, et al. Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy. PLoS One 2013; 8: e57552.
  70. Chollat C, Sentilhes L, Marret S. Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application. Front Neurol; 9. Epub ahead of print 16 April 2018. DOI: 10.3389/fneur.2018.00247.
  71. Chollat C, Marret S. Magnesium sulfate and fetal neuroprotection: overview of clinical evidence. Neural Regen Res 2018; 13: 2044–2049.
  72. Crowther CA, Middleton PF, Voysey M, et al. Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis. PLoS Med 2017; 14: e1002398.
  73. Rouse DJ, Hirtz DG, Thom E, et al. A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy. New England Journal of Medicine 2008; 359: 895–905.
  74. Edwards HB, Sillero-Rejon C, McLeod H, et al. Implementation of national guidelines on antenatal magnesium sulfate for neonatal neuroprotection: extended evaluation of the effectiveness and cost-effectiveness of the National PReCePT Programme in England. BMJ Qual Saf 2025; bmjqs-2024-017763.
  75. Godfrey KM, Sheppard A, Gluckman PD, et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 2011; 60: 1528–34.
  76. Daliry A, Pereira ENG da S. Role of Maternal Microbiota and Nutrition in Early-Life Neurodevelopmental Disorders. Nutrients; 13. Epub ahead of print 9 October 2021. DOI: 10.3390/nu13103533.
  77. Orchanian SB, Hsiao EY. The microbiome as a modulator of neurological health across the maternal-offspring interface. Journal of Clinical Investigation; 135. Epub ahead of print 17 February 2025. DOI: 10.1172/JCI184314.
  78. Biagioli V, Matera M, Ramenghi LA, et al. Microbiome and Pregnancy Dysbiosis: A Narrative Review on Offspring Health. Nutrients 2025; 17: 1033.