Associations of Mitochondrial Function, Stress, and Neurodevelopmental Outcomes in Early Life: A Systematic Review

Neurodevelopmental deficits are characterized by limitations in intellectual functioning and adaptive behavior, e.g., lack of competence in social, conceptual, and practical skills [1]. Increased preterm birth rates and improved survival rates of these infants (<37 weeks’ gestational age [GA]) come with increased complications and risk for neurodevelopmental deficits in these populations [2, 3]. Through the transition from the intrauterine to the extrauterine world, newborn infants are exposed to multiple prenatal stress, e.g., maternal childhood maltreatment (MCM) and intrauterine growth restriction (IUGR), as well as postnatal stress, e.g., prematurity, toxic postnatal environment, and painful/stressful experiences during neonatal intensive care hospitalization. Mitochondrial function/dysfunction has been found to be associated with multiple neurodegenerative diseases such as Parkinson [4], Alzheimer’s disease [5], and neuropathic pain [6]. It may also influence infant neurodevelopmental outcomes, especially in preterm infants who experience excessive pain/stress in early life [7, 8].

Preterm infants may face multiple challenges in both the prenatal and postnatal periods. Mother of infants may experience high rate of MCM, defined as maternal childhood abuse (physical, sexual, emotional) or neglect (physical, emotional) [9, 10]. 18% of preterm infants have IUGR [11], defined as fetal growth repression and failure to reach full growth potential [12]. Both MCM and IUGR were reportedly associated with early-life adversity in infants, although the evidence is still limited and requires further investigation. Infant born preterm lose the protection of the placenta, which modulates homeostasis in the intrauterine environment and epigenetic effects on neurodevelopment in infants [13]. The very preterm infant is at high risk of neurodevelopmental deficits due to impaired myelination of the posterior limb of internal capsule (PLIC) which is normally initiated in the uterus by 23–29 weeks of GA [14‒18]. In addition, during the neonatal intensive care unit (NICU) hospitalization, preterm infants are exposed to multiple stress events associated with adverse neurodevelopmental outcomes [19]. It has been reported that intermittent hypoxic stress during the first 2–3 months after birth was associated with motor impairment, cognitive, or language delay at 18 months in preterm infants [20]. Although the negative impacts of early life pain/stress on physiological and behavioral changes are known after birth [21] and persist in childhood and later life [22, 23], less is known regarding the biological mechanisms of stress and neurodevelopmental deficits in preterm infants.

Accumulating evidence suggests that acute and chronic stressors influence mitochondrial biology and function [24]. Mitochondrial function is the organelle’s ability to generate the chemical energy required to support the cell’s biochemical reactions and regulate communication between cells and tissues to sustain the metabolic homeostasis [25]. Besides being the powerhouse of each cell, generating adenosine triphosphate (ATP), mitochondria play a central role in reactive oxygen species (ROS) generation, calcium buffering, ion homeostasis, biosynthetic pathways, signaling, and programmed cell death [24, 26]. Prolonged and excessive stress exposure may damage mitochondrial structure and function. Mitochondrial dysfunction is defined as the inability to generate the chemical energy required to support the cell’s biochemical reaction and can occur due to mitochondrial structure fragmentation, mitochondrial DNA (mtDNA) damage, decreased ATP production, and increased ROS generation, which all pose a high risk for neuronal loss [13, 27‒30]. Although mitochondrial dysfunction has been found to be related to neurological disorders such as Huntington’s disease [31], multiple sclerosis [32], and amyotrophic lateral sclerosis [33], the mechanism of mitochondrial dysfunction in stress-associated neurodevelopmental deficits in preterm infants is still poorly understood.

As mitochondrial function/dysfunction has been shown to be an important mechanism underlying neurodevelopmental outcomes in preterm infants, it is of interest to incorporate this mechanism into a conceptual model for the purpose of research in the field. Therefore, we developed a conceptual model to address mitochondrial function/dysfunction related to stress which impacts the neurodevelopmental outcomes in preterm infants. The model proposes that prenatal and postnatal stress-related high energy demand request increased mitochondrial function to adapt to the external changes. However, prenatal/postnatal stress overload will damage the mitochondrial function due to its limited adaptive capacity and induce the neurodevelopmental deficits (see Fig. 1). By guiding with this conceptual model, a systematic review of the literature was undertaken to provide a synthesis of the current research. In addition, this review provided insights into advances in understanding the association between infants’ early life stress and neurodevelopment and identified specific biomechanism and the significance of mitochondrial function/dysfunction in predicting neurodevelopmental outcomes in preterm infants. The research questions addressed in the review were as follows: (1) Is prenatal/postnatal stress associated with mitochondrial function/dysfunction in mothers and infants? and (2) Is mitochondrial function/dysfunction associated with neurodevelopmental outcomes in full-term and preterm infants?

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [34] statement was used in the development of this systematic review [35] to examine the role of mitochondrial function/dysfunction in the association between prenatal and postnatal stress and neurodevelopmental deficits in full-term and preterm infants. Inclusion criteria were (a) quantitative studies using any quantitative research design and methods; (b) human subject participants born prematurely (less than 37 weeks of gestational age [GA]) or full-term with early life stress, and/or women who experienced stress/adversities during pregnancy and/or the postpartum period; (c) studies focused on neurodevelopmental outcomes and mitochondrial function/dysfunction; and (d) studies published in English between 2010 and 2021. Exclusion criteria were (a) studies focused on topics other than stress, neurodevelopmental outcomes, and mitochondrial function/dysfunction; (b) studies with enrolled infants having congenital neurological deficits; and (c) qualitative research studies.

Articles were searched in PubMed, Scopus, PsycINFO, and Biosis Database. Four key terms were searched: stress, neurodevelopment, mitochondria, and infant. The categories were searched as follows, stress: MCM, oxidative stress, stress, pain, and fetal growth restriction (FGR); infant: preemie, preterm, young gestational age, neonatal, premature babies; genomic/proteomic of mitochondria; neurodevelopment: brain, white matter, brain injury, encephalopathy. Identified studies were imported to EndNote to remove the duplicates. The target outcomes were grouped in three main parts: (a) stress in infants including preterm infants; (b) the impact of stress in mitochondrial function/dysfunction; and (c) mitochondrial function and neurodevelopmental outcomes.

A PRISMA flow diagram was developed (see online suppl. Fig. S1; see www.karger.com/doi/10.1159/000526491 for all online suppl. material) based on inclusion and exclusion criteria for study selection [34]. The quality appraisal was conducted using the Critical Appraisal Skills Programme [36]. The 11 items on the checklist evaluated the research aim, research method, subjects’ recruitment, control selection, and (exposure) measurement, etc. (see online suppl. Table S1). Due to the early level of research in the field, it was of interest to include all research studies, thus no studies were restricted based on the quality appraisal if they failed to match the requirement of one item. However, studies were excluded from the review if they did not match any requirement of 11 items. Data were extracted for study purpose, study design, sample size and characteristics, measurements (stress indicators; mitochondrial related gene, protein, function measurements, neurodevelopmental and behavioral outcomes and assessment), and main findings. The first and corresponding authors validated the literature search and extraction.

A total of 317 papers were identified in the initial phase by searching the databases (see online suppl. Fig. S1). After removing duplications, reviews, mitochondrial disease and mutation publications, and preclinical studies, total 30 studies remained for the final systematic review (N = 30). Of these publications, studies were from 12 countries including the USA, Germany, Italy, Spain, France, the UK, Serbia, India, Belgium, Iran, the Czech Republic, and Japan (see Table 1).

The 28 prospective observational study and two experimental studies were included in the systematic review. The total of 2,812 infants (preterm infants were 980, 34.85%), 1,346 mothers and 391 adults were enrolled in these 30 studies. Sample size was varied in individual studies, ranged from 290 subjects [37] to 12 subjects [38]. All the 30 studies met first three requirements of quality appraisal check list (see online suppl. Table S1), which worth proceeding with the remaining items [36].

Of the publications identified, 11 studies focused on preterm infants. Some studies focused on identifying the indicators and consequences of mitochondrial dysfunction by assessing: (1) the association between hyperoxia and SIRT1/resveratrol signaling [39], (2) FMRP/mTOR signaling cascade and hypoxic-ischemic brain injury [40], (3) altered glutamate and glutamine and white matter injury (WMI) [41], (4) polymorphisms of antioxidant enzymes and ROS-induced complications [42], and (5) 8-OHdG and neurodevelopment outcomes [43]. Other studies explored the association between ROS and complications of antioxidant capacity, pain, low birth weight, DNA damage, placenta lesion, and preterm prelabor rupture of the membranes (PPROM) in preterm infants [44‒50].

Biological samples collected in the studies included saliva [51], buccal swabs [51], cerebrospinal fluid (CSF) [52], peripheral blood mononuclear cells (PBMC) [39, 53‒55], umbilical cord blood (UBMC) [44‒46, 48‒50, 52‒57], whole blood [37, 42, 47], placenta [38, 58‒66], brain [40], cytotrophoblast cells [65], urine [43], and fibroblast [66]. Placenta samples (9 studies) and umbilical cord blood (9 studies) were the most common sampling sources among the 30 studies (60%). Only four studies of preterm infants applied noninvasive tests (e.g., saliva, buccal swabs, urine, and magnetic resonance spectroscopy [MRS]) [41, 43, 51, 67].

Two of the 30 studies tested an intervention on the biological samples collected. Thomas et al. [38] showed that hydrogen peroxide (H₂O₂) could induce ROS in placenta explants and decrease ATP and placental fatty acid oxidation (FAO). Resveratrol, a plant polyphenolic compound, was used in Yang’s study as a natural agonist of silent mating-type information regulation 2 homolog 1 (SIRT1) to inhibit the hyperoxia toxicity in cultured PBMC [39].

Stress types in these 30 studies were ROS, pain, preterm birth, placental lesion, PPROM, and meconium-stained amniotic fluid, MCM, childhood trauma, maternal stress, IUGR, hypoxic ischemic, glutamate excitotoxicity, and PM_2.5.

Both in vitro and in vivo ROS were examined in Yang’s study: (1) preterm infants received the oxygen supplementation during their hospitalization and (2) the extracted PBMC from preterm infants was treated with different levels of oxygen [39]. In Giusti’s study, although there was no direct ROS assessment in preterm infants, the respiratory distress syndrome (RDS) diagnosis and the history of mechanical ventilation treatment indicating ROS overload [42]. Thomas et al. [38] also reported on ROS induced by H₂O₂ exposure using placenta samples. Bartha et al. [63] assessed the level of FAO in placentas, which was related to ROS-induced preeclampsia. Garrabou et al. [56] considered carbon monoxide, the byproduct of smoking, as a stress factor that could impact the pregnancy. The questionnaire of Fagerstrom test was administered to assess the smoking dependence in smoking [56]. Self-reported tobacco consumption together with cotinine levels in the plasma of pregnant women and infants and urine samples of mothers were evaluated to assess the reliability of the questionnaire [56].

Only one paper in our review focused on the association between procedure pain and ROS [47]. The pain scores were assessed using the Premature Infant Pain Profile (PIPP) which included seven items of GA, behavioral state, heart rate, oxygen saturation, brow bulge, eye squeeze, and nasolabial furrow [47]. Tissue damaging procedures such as tape removal and indwelling central arterial or venous catheter were considered as pain stress which positively associated with ROS production [47].

Díaz et al. [64] focused on the small for GA-associated ROS production in infants. The association between ROS caused by preterm birth, twin birth, maternal stress, meconium-stained amniotic fluid, placenta lesion, PPROM, and infants’ growth were also the focus in our reviewed studies [43‒46, 48‒50, 57].

Hypoxic-ischemic encephalopathy (HIE) as a stress in term and preterm infants was examined in three studies [40, 52, 67]. The perinatal HIE is diagnosed if four signs are present: prenatal distress, immediate depression, metabolic acidosis, and early neonatal encephalopathy [52]. HIE was then categorized into three stages (mild, moderate, and severe) based on the severity of the symptoms [52].

Three studies focused on MCM. The participants from these studies were mothers within 1 week after parturition [53‒55]. They were all assessed retrospectively using the German short version of the Childhood Trauma Questionnaire (CTQ) during the mothers’ psychodiagnostics interview. CTQ includes emotional, physical, and sexual abuse, as well as emotional and physical neglect subscales. Each subscale has 5 items and a total of 25 items with scores from 25 to 125. The CTQ score was documented as MCM load. Four groups from “none” to “severe” MCM experience were classified based on CTQ sum scores.

The pregnant mothers’ lifetime stress (previous 12 months) was assessed using Life Stressor Checklist-Revised (LSC-R) [58, 59], LSC-R included 30 traumatic events (e.g., sexual assault, abortion, interpersonal violence). Mothers’ prenatal negative life events (previous 6 months) were assessed using the Crisis in Family Systems-Revised survey which has 11 domains (e.g., income, job, relationships, safety, and housing). Further, the Diagnostic and Statistical Manual of Mental Disorder-posttraumatic stress disorder (PTSD) were used to assess the PTSD symptomatology.

In another study, self-administered questionnaires were administered at the 2nd and 3rd trimesters to assess maternal psychosocial stress in pregnancy (MPSP) [60]. MPSP questionnaires included the Perceived Stress Scale (PSS-14), the Pregnancy Related Anxieties Questionnaire (PRAQ)-Revised, the Perinatal PTSD Questionnaire (PPQ), and the State-Trait Anxiety Inventory for Adults (STAI).

Three studies introduced IUGR as a stress indicator. IUGR was identified if the fetal growth was under 5th percentile using longitudinal sonographic measurements [65]. IUGR was also identified once the ultrasound estimation of fetal weight was <10th percentile for its gestational age [61, 62].

One study reported maternal PM_2.5 exposure as a stress indicator. Brunst et al. [59] used an exposure model assessing temporally and spatially resolved PM_2.5 to estimate PM_2.5 level of the pregnant women. The daily PM_2.5 was estimated based on subjects’ location and time at each address. Wisnowski’s team assessed the glutamate-induced excitotoxicity in neonatal WMI, grade I or II intraventricular hemorrhage, and cerebellar hemorrhage using magnetic resonance spectroscopy [41].

The genetic variations assessed in the reviewed 30 studies included polymorphisms of genes 5-HTTLPR, NR3C1, FKBP5, SOD1, SOD2, SOD3, and CAT, MT-ND6 methylation, and mtDNA copy number (mtDNAcn); protein levels of SIRT1, mTOR, total FMRP, phosphor FMRP, NRF1, SIRT3, COX, VDAC, respiratory chain complexes (RCC); gene expression of PGC-1 α; and all 13 protein-coding genes encoded by mitochondria, seven key nuclear glycolysis regulatory genes (PDK1, PDK2, PDK3, PDK4, PKLR, PKM, OGT), CPT-1b, PPAR-α, LCHAD, MCAD, NRF1, RCC. The major findings are shown below.

Findings from the reviewed studies showed that ROS overexposure-induced mitochondrial dysfunction may occur via the nitric oxide mediated injury pathway by inhibiting oxidation state of cytochrome-c-oxidase (oxCCO) activity in infants with HIE injury [67]. Decreased citrate synthase activity [68], mitochondrial intracellular density and respiration [51], FAO [38], and increased 8-Hydroxy-2-deoxy guanosine (8-OH-dG) [43, 45, 46, 57], Malondialdehyde (MDA) [47], and 15-F_2t-isoprostane [44], were associated with ROS induced mitochondrial dysfunction. Increased Glutamine and decreased N-acetylaspartate (NAA) were found in parietal white matter in infants with WMI [41], Negative relationship between the activity of glutathione peroxidase (GPX) in CSF and the adverse neurological outcomes was found in preterm infants with severe HIE injuries [52]. Dose-response relationship increased the childhood maltreatment load with higher level of pro-inflammatory cytokines and ROS in mother’s PBMC [55].

T allele in FKBP5 was significantly associated with higher cortisol level, while methylation levels of MT-ND6 was positively associated with adverse childhood experiences (ACE) [51]. rs8192287 SOD3 polymorphism is a protective factor for intraventricular hemorrhage (IVH) in preterm infants [42].

mtDNAcn was found to be negatively associated with the Edinburgh Postnatal Depression Scale (EPDS) and PM_2.5 exposure [58, 59]. In contrast, mtDNAcn was found positively associated with early life adversity [37]. mtDNAcn, ROS and mitochondrial gene expression were all associated with pathology of IUGR [59]. The increased mtDNAcn, decreased SIRT3 protein expression, and decreased succinate dehydrogenase (SDH) activity indicated mitochondrial dysfunction and were associated with IUGR [62]. Decreased mtDNAcn and SOD activity were associated with FGR in the placenta for the small for GA pregnancy [64].

Hyperoxia or ROS could activate SIRT1 expression and activity and induce SIRT1 transportation from the nuclei of PBMC to the cytoplasm [39]. The maximum respiratory capacity was only modestly increased and no change was found in PGC-1α expression in mothers with MCM, which may not explain the intergenerational transmission of MCM [54]. FMRP/mTOR signal pathway was associated with hypoxic-ischemic encephalopathy [40]. Increased mitochondrial content and NRF1 gene expression level in IUGR placenta could explain fetal growth restriction caused by increased oxygen consumption in placenta and limited oxygen delivered to the fetus [65].

Five studies identified differential stress levels and mitochondrial function by biological sex and ethnicity in their findings. Female infants were found to have a higher mitochondrial respiration rate than male cohorts, which was independent of MCM [53]. At 25–40 gestational weeks, PM_2.5 exposure level was positively associated with placenta mtDNAcn in boys with high maternal trauma level, while negative associations were observed in girls with the low maternal trauma level [59]. Mandò also studied gender difference although no significant findings were reported [65]. High level of prenatal stress and psychological symptom scores and lower mtDNAcn as a marker of mitochondrial dysfunction, were found in non-white mothers, which may impact infants’ health outcomes [58]. Higher levels of 15-F_2t-isoprostane were found in male preterm infants compared with female cohorts, which dependent of maternal stress exposure [44].

Among 30 studies, 10 studies discussed the neurodevelopment outcomes in infants and adults with early life adversity. Measurements of Bayley scores, stress tests, anxiety tests, neurological symptoms, psychiatric diagnosis, encephalopathy diagnosis, temperament assessment were applied in these 10 studies.

Mitra et al. [67] assessed infants’ neurodevelopmental outcomes following HIE and found that the ratio of thalamic lactate/N-acetylasperate higher than 0.3 using the NICHD neonatal MRS brain injury scoring system between days 5 and 7 after birth was associated with poor neurodevelopmental outcomes. They also used the Bayley Scales of Infant Development-III to evaluate the neurodevelopmental outcomes in infants at 1 year of age [67]. Infants who scored less than 85 of Bayley were considered to have adverse outcomes [67]. Another study conducted neurodevelopmental assessment using the Mental Developmental Index (MDI) and the Psychomotor Development Index (PDI) of Bayley scale at 18 months’ corrected age in preterm infants with very low birth weight (<1,500 g) [43]. MDI lower than 80 was considered as subnormal outcomes [43].

Trier Social Stress Test was conducted in adult participants to assess the acute stress response to psychosocial stimulators [51]. Lifetime psychopathology was evaluated using the Structured Clinical Interview for DSM-IV (SCID), the Inventory for Depressive Symptoms-Self Report, the State-Trait Anxiety Inventory, and the Perceived Stress Scale [37]. Psychiatric symptom load was also measured using a HADS depression sum score and HADS anxiety sum score [55]. In one study, Infant Behavior Questionnaire Revised (IBQ-R) was given to mothers to rate infants’ temperament-related behaviors at 6 months of age [60]. Six constructs of activity level, smile and laughter, fear, distress to limitations, duration of orientation, and soothability were covered by IBQ-R. Denver Developmental Screening Test was used to assess the neurodevelopmental outcomes in term infants at 1-year corrected GA [52]. The infants were categorized into three groups (normal, motor developmental delay, and severe adverse outcome) based on the Denver Developmental Screening Test score [52].

Findings from ten studies reported a significant association between prenatal and postnatal stress and neurodevelopmental outcomes, and found this relationship was mediated by mitochondrial function/dysfunction. MPSP-induced mitochondrial dysfunction was associated with infant temperament changes at 6 months of age [60]. oxCCO-MABP semblance at 48 after birth could be used to predict HIE-associated neurodevelopmental deficits at 1 year of age [67]. Neonatal hypoxic-ischemic brain damage and mitochondrial ROS overproduction were associated with neurodevelopmental outcomes at 12 months after birth [52]. Abnormal lipid peroxidation was associated with developmental deficits in preterm infants at 18 months [43]. Further, stress-induced mitochondrial genetic variations lead to WMI and encephalopathy of prematurity in preterm infants [40, 41]. In adults, mitochondrial dysfunction played a role in (1) MCM-associated stress and anxiety, (2) parental loss and childhood trauma-associated psychiatric symptoms, and (3) stress-associated adult females with ACE [37, 51, 55].

To the best of our knowledge, this is the first systematic review to explore the relationship between prenatal/postnatal stress, mitochondrial function/dysfunction, and neurodevelopmental outcomes in infants. Findings from the review support our proposed conceptual framework which explains the association between early life stress-associated mitochondrial function/dysfunction and neurodevelopmental outcomes in term and preterm infants. The findings suggest that mitochondrial function/dysfunction and relative genetic variations might interface between the association of early life stress and neurodevelopmental outcomes in infants. This result warrants early stress intervention at birth, as this stress experience during their early life might have life-long consequences for neurodevelopmental and behavioral health.

Accumulative evidence has shown the association between stress and mitochondrial function/structure changes. Stress at a moderate level will initiate the prosurvival process: increased energy demand, promote mitochondrial biogenesis, stabilize cellular response, and improve immune function [68]. However, stress overload will produce more ROS, damage the mitochondrial function, and decrease ATP production [69]. The imbalance between ROS and antioxidant ability caused by stress overload are more common in preterm infants due to their developmental vulnerability and unmature antioxidant system compared with term infants [70].

In this review, evidence was found to support the notion that both prenatal and postnatal stress influence infants’ mitochondrial function/dysfunction. Prenatal stress such as MCM as a stress indicator is associated with increased ROS production, and decreased mitochondrial function in mothers [55], and was intergenerationally transmitted to their infants [53, 60, 71]. These intergenerational transmission effects of MCM were also found to play a role in infants’ physical and mental health [72, 73]. Although mitochondrial bioenergetic cross-generational transmission mechanisms are still underdeveloped, MCM-related epigenetic alternations have been documented during the embryo period through genetic maternally inherit (DNA, RNA, and protein regulation) [71]. IUGR is another example of prenatal stress which induces maternal phenotype and genotype intergenerational transmission [74]. IUGR is associated with increased ROS production, mtDNA abundance, and antioxidants consumption in the placenta, which leads to the decreased oxygen and antioxidants deliver to the fetus [61], resulting in infants’ low birth weight, complications of metabolic syndrome, and pulmonary arterial hypertension.

During the postnatal period, the preterm infant is exposed to pain stimulation, hypoxic ischemic, and hyperoxia, which all lead to ROS overproduction and mitochondrial dysfunction because of an immature antioxidant system [43]. Although procedure pain is very common in preterm infants during their NICU stay, only one study reported the association between procedure pain and mitochondrial function. Mitochondrial function such as ATP production, ROS production, mitochondrial permeability transition pore (MPTP), apoptotic pathways, and intracellular calcium mobilization play a role in the pathology of procedure pain [47, 75, 76]. Normal mitochondria produce a small but stable amount of ROS leak along the electron transport chain sustaining the redox state [77]. Alan and Isha stated that the mismatch of oxygen supply and demand will damage cellular function and mitochondrial function [78]. Long episode of hypoxic ischemia increases electron leakage, increases mitochondrial ROS production, and impairs efficacy of the antioxidant system causing the mitochondrial dysfunction [79]. Hyperoxia exposure such as oxygen therapy is standard procedure in preterm infants to sustain normal heart rate and blood oxygen level [80]. However, an excess supply of oxygen to infants will cause excessive ROS and lead to multiple organs (lung, central nervous system, and retina) injury [81].

High energy demand of brain (20% of the body energy demand) requests high concentration of mitochondria [82]. In response to stress, mitochondria adjust their activity to meet the energetic demand. In our review, mitochondrial dysfunction and associated ROS have been increasingly recognized as the causes of WMI and hypoxic ischemic brain injury or abnormality although the pathological mechanisms are still unknown [41, 67]. Preclinical study showed that hypoxic ischemia induced mitochondrial fission, fragmentation, and loss of motility in myelinated axons [83]. This was consistent with our findings that mTOR signal pathway was inhibited in infants with encephalopathy which attenuate the normal mitochondrial energy production [40, 84]. Additional, mitochondrial respiration and density were increased in neonates and their mothers with MCM [53]. Mitochondrial function mediated impact of MCM in pregnancy on infant temperament development [60].

Our study found many genes, proteins, and metabolites were associated with mitochondrial function/dysfunction and could be used as biomarkers to predict neurodevelopmental outcomes in infants’ later life. However, there is a lack of longitudinal data to support these findings. Further, the signal pathways related to mitochondrial dysfunction, such as p38 MAPK, AKT/mTOR, SIRT1/Nrf2, SIRT1/p53, SIRT1/PGC-1a, AKT/SIRT3/SOD2 signaling, were not found in our reviews but were reported in the preclinical studies, which needs to be addressed in the future study design. No study in our review examined the posttranslational protein modification, such as phosphorylation, acetylation, and O-GlcNAcylation of proteins related to mitochondrial function/dysfunction in different stress levels in term and preterm infants.

Most studies in our review conducted invasive sampling using placenta, PBMC, UBMC, brain, CSF, etc. However, a few publications applied noninvasive sampling of saliva, buccal swabs, urine, and the MRS to assess the infants’ and adults’ mitochondrial function and brain development. It is urgent to verify the highly sensitive and accurate noninvasive sampling to assess mitochondrial function and predict neurodevelopmental outcomes in infants’ early and later life, avoiding any additional stress [85‒87]. These findings point out the new directions for future clinical study focused on the association between stress-induced mitochondrial dysfunction and neurodevelopmental deficits in infants.

The lack of standardized infant developmental scales makes it more difficult to identify and compare neurodevelopmental deficits and behavioral changes in different age groups [88]. The time to initiate Bayley scale is another concern. In our review, two studies conducted the Bayley test; however, they applied this scale at different time points: one was at 1 year and another was at 18 months’ corrected age [43, 67]. Although the two time points described above are both within the scale range, the author should assess the infants’ stability, not just the age. Low correlation between Bayley scores and other scores were reported [89]. To confirm the validity and reliability, future study should consider choosing one standard scale at specified time range or using more than one scale to measure the neurodevelopmental outcomes [88].

CTQ was commonly used to measure childhood trauma and satisfactory validity [90]. The validity of IBQ-R was still the concern when it was applied in diverse samples [91]. For questionnaires, bias may exist in maternal recall behavior (e.g., childhood trauma) or parents-reported child temperament (e.g., IBQ-R) because of maternal psychopathology [92].

Mitochondria play a central role at the interface between prenatal and postnatal stress and the neurodevelopmental deficits in infants’ early and later life. In our review, the stress indicators varied from prenatal stress, such as maternal stress, childhood maltreatment, IUGR to postnatal stress, to infant exposure to pain, hypo-, or hyperoxia stressors. Besides prenatal mitochondrial energetic transgenerational transmission we discussed above, during the postnatal period, impaired maternal caregiving capacity [93], poor bonding, and MCM associated depression [94] may be the major causes of developmental deficit in infants. Animal experiments showed that maternal separation in early life caused cognitive dysfunction that could persist in adolescence [95]. IUGR associated blood flow and nutrients delivery shortages further damaged fetal growth. In human IUGR and animal models, WMI is the most common neurodevelopmental deficit caused by placental insufficiency [96‒98]. IUGR induced fetal hypoxia is another common clinical issue that increases the risk of neurodevelopmental deficit in the infant. Animal models pointed out that early chronic intermittent hypoxia exposure plays a role in infant WMI [99]. Although preterm infants have immature lung and antioxidant systems, they often require high oxygen concentrations (90–100%) during their NICU stay [99]. Both human and animal studies showed that hyperoxia exposure at the 2nd to 14th postnatal days put premature infants at high risk of neurodevelopmental deficit and other comorbidities such as retinopathy of prematurity and bronchopulmonary dysplasia [100‒102].

Although the physiological or psychosociological difference exists between prenatal and postnatal stress factors, the mechanisms and genetic variations associated with mitochondrial function were all connected with shaping the brain structure and function. Gluckman and Hanson called this process “developmental programming” [103]. Although the mechanisms of association among stress, mitochondrial function/dysfunction, and neurodevelopmental outcomes were still unclear. The younger the GA and the smaller the birth weight are, the more sensitive the infants’ brain response to environmental changes is [87], and the more adverse consequence of neurodevelopment it is throughout the entire lifespan.

The present review included studies suggesting that mitochondrial function/dysfunction mediates the impact of prenatal and postnatal stress on neurodevelopmental outcomes in infants. Evidence from animal studies strongly demonstrates that stress impaired neurodevelopment through mitochondrial dysfunction and changed gene expression [92]. However, it remains challenging to identify the association among stress, mitochondrial dysfunction, and neurodevelopmental deficits in clinical studies due to translational failure from preclinical results to the current clinical settings [92].

There has been a growing interest in studying the role played by sex difference in brain programming through regulating mitochondrial function. However, sex disparity in stress load, mitochondrial function/dysfunction, and neurodevelopmental outcomes in early life has received limited attention (5 out of 30 studies). The ethical and practical difficulties hinder the researchers from conducting the clinical trial in preterm infants. A limited number of studies were conducted on preterm infants (11 of the 30 studies). It is urgent to be aware of the challenges and the clinical needs of infants. The lack of standardized developmental scales of infants and longitudinal studies need to be addressed in future studies. Future studies are needed to identify the longitudinal impact of stress-induced mitochondrial dysfunction on neurodevelopmental outcomes in infants. Another major concern was that only five out of 30 studies conducted noninvasive sampling, which avoids extra stress. Limited early stress intervention during NICU stay and noninvasive sampling warrants more attention to prevent stress-influenced brain impairment.

Mitochondrial function/dysfunction was at the interface between stress and neurodevelopmental deficits in infants and understanding this association might provide alternative strategies to manage the stress-induced neurodevelopmental deficit. Prenatal intrauterine and postnatal NICU hospitalizations are critical periods for the brain development of preterm infants. Early GA and low birth weight increase the risk of neonatal neurodevelopmental deficits upon exposure to prenatal and postnatal stress. To prevent mitochondrial bioenergetic intergenerational transmission in infants, psychological assessment and social support should be provided to mothers with MCM and further research on effective interventions is warranted. Additionally, individualized care should be applied to diminish biological sex disparities in infants.

There are not conflicts of interest of funding for each author. There are no declared conflicts of other interests for any of this study’s authors.

This study was supported by the following grant. A grant from the NIH/NINR NR016928 (PI: Xiaomei Cong). Tingting Zhao received grant from: NIH/NINR F31NR019940 (PI); Eastern Nursing Research Society (ENRS)/Council for the Advancement of Nursing Science Dissertation Award (PI); Sigma Theta Tau International (STTI) Mu Chapter Research Grant (PI); and UConn CT Institute for the Brain and Cognitive Sciences (IBACS) Graduate Fellowship (PI).

All the authors met the authorship requirements. Substantial contributions to conception and design, publication review and summarizing the key findings: all authors. Funding acquisition: Xiaomei Cong and Tingting Zhao. Drafting and revising the manuscript: Tingting Zhao, Nathan N. Alder, Angela R. Starkweather, and Xiaomei Cong. Thoroughly reviewed and critiqued the manuscript for revision: Ming-Hui Chen, Adam P. Matson, Wanli Xu, and Jeremy L. Balsbaugh. Final approval of the version to be published: Tingting Zhao, Nathan N. Alder, Angela R. Starkweather, Ming-Hui Chen, Adam P. Matson, Wanli Xu, Jeremy L. Balsbaugh, and Xiaomei Cong.