Table 1.

Included studies that examine association of stress, mitochondrial function/dysfunction, and neurodevelopmental outcomes

Author, year, country	Study aim	Study design	Sample (size, gender)	Intervention	Measurement			Main findings	Limitation (L) and recommendation for future study (R)
					stress indicators	MT related gene, protein, function measures	neurodevelopmental and behavioral (outcomes and assessment)
Gumpp et al. [53] 2020, Germany	To explore the intergenerational transmission of maternal MCM exposure induced mt bioenergetic alternation from mother to child	Observational study	N = 209 (mothers, n = 105; newborns, n = 104); maternal PBMC and neonatal umbilical cord blood	N/A	MCM	Mitochondrial respiration and density	CTQ was used to assess MCM	1. Maternal and neonatal citrate synthase activity was positively correlated. 2. Female infants had higher mt respiration than male cohorts which was independent of maternal CM exposure. 3. Maternal CM load is only associated with mt respiration and density in mothers, but not in infants	L: no neurodevelopmental outcomes were evaluated R: Need to be confirmed in larger sample size
Mitra et al. [67] 2019, UK	To explore the role of oxCCO and MABP in HIE associated brain metabolic activity	Observational study	N = 23, stable term infants	N/A	Therapeutic hypothermia following hypoxic ischemic encephalopathy	oxCCO-MA BP semblance at 48 h after birth, and Lac/NAA (day 5–7) to predict the neurodevelopment outcomes	Bayley III at 1 year	oxCCO-MABP semblance at 48 h can be used as a biomarker to (1) predict early and 1 year of age neurodevelopmental outcome after HIE; (2) differentiate between the infants with good or poor neurodevelopmental outcomes after HIE	L: no data within 24 h; no gender difference; small sample size; did not measure mitochondrial function R: Enlarge sample size
Lapp et al. [51] 2019, USA	To explore the association between adverse childhood experience (ACE) and mitochondrial genetic variation	Observational study	N = 90,48.4% female, age = 32.12±15.1; buccal swabs; two groups (ACE = 0, ACE ≥4)	N/A	Adverse childhood experience, lifetime discrimination, daily discrimination, perceived stress, and city stress	Polymorphisms of gene 5-HTTLPR, NR3C1, FKBP5; MT-ND6 methylation and mtDNAcn	Current stress test	(1) mitochondrially encoded NADH dehydrogenase 6 (MT-ND6) methylation level was higher in ACE ≥4 group compared with ACE = 0 group; (2) No mtDNAcn difference between these two groups	L: No gender difference was assessed; small sample size R: Future study should explore the biological mechanisms between early life stress and mitochondrial DNA methylation
Brunst et al. [59] 2018, USA	To assess the combined effect of utero PM2.5 and maternal stress exposure on mtDNAcn	Observational study	N = 167, first time pregnant women, placenta samples, infants’ cord blood samples	N/A	Maternal stress and PM2.5 exposure	mtDNAcn	N/A	Increased PM2.5 and maternal trauma were associated with decreased mtDNAcn; 2. PM2.5 exposure level between 25 and 40 GW was positively associated with placental mtDNAcn in boys with high maternal trauma level, while negatively associated with mtDNAcn in girls with low maternal trauma level	L: No neurodevelopmental outcomes assessed in infants R: Longitudinal study should be conducted to explore the association between mt involved genetic variations and neurobehavioral changes
Yang et al. [39] 2018, USA	To explore the variation of SIRT1 in preterm infants exposed to hyperoxia and the protective effect of resveratrol	1st experimental design (n = 10: ctrl no O2; n = 30 O2) 2nd experimental design (n = 40, no O2, divided in 4 groups)	Total N = 80 (40 control, 40 neonatal respiratory distress syndrome [NRDS]), premature infants, gestational age <32 weeks; PBMC	Resveratrol	Oxidative stress	Protein levels of SIRT1; ROS level; MDA level	N/A	Hyperoxia or ROS injury induced SIRT1 transportation from nuclei of PBMC to cytoplasm and decreased SIRT1 expression and activity can be protected by Resveratrol	L: No neurodevelopmental outcomes assessed; no gender difference analyzed; no mitochondrial function detected R: Future study will focus on SIRTI’s pharmacological regulation
Boecket al. [54] 2017, Germany	To explore the association between MCM and cortisol, oxytocin, and mitochondrial oxygen consumption	Cohort (baseline, 3 months postpartum follow up)	N = 49 (mothers, 22–44 years old); PBMC blood sample	N/A	MCM: maltreatment load using CTQ	Mitochondrial oxygen consumption; Gene expression of PGC-1 α (qPCR)	N/A	(1) Mother with higher CTQ had higher level of anxiety; (2) The maximum respiratory capacity was only modestly increased, and no change was found in PGC-1α expression in mothers with MCM	L: small sample size and no gender difference was assessed R: Future study should focus on larger sample size
Brunst et al. [58] 2017, USA	To examine the associations among maternal stress, psychological functioning, and placental mt function	Prospective cohort study	N = 147, first time pregnant women, placenta samples	N/A	Maternal stress (prenatal stress, postnatal depression, PTSD, and cumulative lifetime stress)	Mitochondrial DNA copy number (mtDNAcn)	N/A	Higher level of prenatal stress and psychological symptom scores and lower mtDNAcn were found in non-white compared with white women; prenatal stress was negatively associated with mtDNAcn (marker of mt dysfunction)	L: no gender difference; no infants’ neurodevelopmental outcomes R: Future study should focus on the stress intervention in pregnant women which will benefit maternal-infant health
Tyrka et al. [37] 2016, USA	To explore the association between the variation of mtDNAcn and the early life adversity and psychiatric disorder	Observational study	N = 290 adults, blood sample; 4 groups by combining adverse (+/−) and diagnose (+/−)	N/A	Parental loss (death and separation) and childhood trauma	mtDNAcn	Psychiatric diagnosis using SCID, IDS-SR, STAI, PSS, CD-RISC, CTQ scales and/or inventory	The early life adversity was associated with mtDNAcn while (−/−) group had lower mtDNAcn compared with other three groups; participants who had anxiety and past substance, lifetime depressive disorder had higher mtDNAcn	L: Not preterm infants; no gender difference was assessed R: Future study should further analyze larger sample size and mitochondrial genetic variations
Lechpammer et al. [40] 2016, USA	To explore the role of FMRP/mTOR signaling cascade in the pathology of encephalopathy in premature infants	Pilot study	N = 30 (newborns’ normal brain, n = 15; premature hypoxic-ischemic injured brain, n = 11; adult normal control brain, n = 4)	N/A	Hypoxic-ischemic brain injury	Proteins of mTOR, total FMRP, phospho-FMRP(Ser499)	Encephalopathy of prematurity	(1) During 36–39 GW, overexpression of FMRP was confirmed in the cortical of normal brain, although down regulated total FMRP, phospho-FMRP, and overexpressed mTOR was found in cortical in preterm infants with encephalopathy; (2) During 23–37 GW, FMRP level was predominantly increased in premature white matter compared with normal brain; (3) Co-expression of mGluR5 with FMRP has been observed in infants with encephalopathy at 36–39 GW.	L: Did not consider gender; did not measure mitochondrial function; no history of neurodevelopmental outcomes R: Future study needs to focus on gender difference, and larger sample size
Boeck et al. [55] 2016, Germany	To explore whether mitochondrial activity and ROS are involved in the CM-induced inflammation	Cross-sectional design of the exploratory study	N = 67, women 6 days following parturition (>18 years); PBMC blood sample	N/A	CM; maltreatment load using chCTQ	Mitochondrial oxygen consumption (cellular oxygen consumption [ATP]; maximal capacity of the respiratory chain; residual oxygen consumption; flux control ratios)	Stress, anxiety and depressive symptoms	Dose-response relationship of increasing CM load with higher level of pro-inflammatory cytokines and ROS in PBMC	L: small sample size; no gender difference; no neurodevelopmental assessment; no infants assessment; not longitudinal design; no genetic evaluation R: Should have a lifespan study from childhood until adulthood to explore the association between the mitochondrial function and CM induced inflammation
Lambertini et al. [60] 2015, USA	To explore whether there is an association between the MT gene expression, MPSP and fetal temperament development	Cohort	Placenta samples, N = 108, mot her-infant dyads (274.26±17.16 days of gestational age)	N/A	MPSP	All 13 protein-coding mitochondrial-encoded genes were analyzed, gene MT-ND2	Infant temperament at 6 months of age is assessed by the Infant Behavior Questionnaire Revised (IBQ-R) administered to mothers	Mitochondrial function mediated negatively impact of MPSP on infants’ tempera ment development	L: No gender difference assessed; no mitochondrial function detected R: Increased sample size of the cohort in the future
Wisnowski et al. [41] 2013, USA	To explore whether the altered glutamate and glutamine are associated with WMI	Observational study	N = 218, born <37 GA, not older than 60 weeks post concept ion a 1 age at the time of MRI, WMI diagnosed	N/A	Glutamate induced excitotoxicity	Glutamate and N-acetyl aspartate (NAA) (both released from MT of neurons)	WMI	(1) MRI/MRS can be used to as biomarker to identify WMI in preterm infants; (2) Increased Glutamine and decreased NAA were found in parietal WM in infants with WMI	L: No demographic data were presented; no neurobehavioral outcomes reported R: Future study should focus on mitochondrial function and gender difference
Giusti et al. [42] 2012, Italy	To identify the association between SNPs of SOD 1,SOD2, SOD3, and CAT and the severity of RDS (MV, BPD, IVH, and ROP) in preterm infants	Retrospective study	N = 152, preterm infants, ≤28 GW, blood DNA, polymorphisms	N/A	ROS of preterm birth	SNPs of SOD 1,SOD2, SOD3, and CAT	N/A	(1) rs8192287 SOD3 was found associated with decreased risk of developing IVH; (2) The association between homozygous infants for rs4880, rs5746136 for SOD2 polymorphism and lower gestational age; (3) haplotypes of SOD1, SOD3 and CAT genes were risk predictors of RDS complications	L: No gender difference was evaluated; 2. No neurodevelopment assessed; 3. No longitudinal genetic variation was evaluated R: Larger sample size need to be assessed in the future
Vasiljevic et al. [52] 2011, Serbia	To examine the role of neuroinflammation, ROS, and deficient or overproduced growth factors in hypoxic-ischemic brain damage	Prospective study	N = 90; neonates gestational age >32 weeks with hypoxic-ischemic encephalopathy	N/A	Hypoxic-ischemic brain damage	IL-6, GPX, NSF, VEGF	Cerebrospinal fluid (CSF) and Denver Developmental Screening Test at 12 months	(1) NSE in CSF could be used as a biomarker of severity of HIE; (2) Remarkably increased GPX activity in CSF (indicate overproduced ROS) was associated with the severity of HIE; (3) Decreased VEGF and increased IL-6 in CSF were associated with the severity of H IE and brain damage	L: Did not clarify the number of preterm and term infants; no gender difference was discussed; no mitochondrial function was measured R: Future study focus on the diagnostic and prognostic value of these markers
Thomas et al. [38] 2019, USA	To testify whether the placenta mitochondria dysfunction mediates the impact of acute ROS on decreased FAO and increased esterification	Experimental study	N = 12, women age 21–41 years, term maternal face of the placenta were extracted	H2O2 incubation for 4 h (200, 400, and 800 µm); incubated for 18 h with [3H]-pa Imitate	H202	Genes and protein expression: CPT-1b and PPAR-α ATP production; FAO	N/A	ROS decreased placental FAO and ATP production can explain damaged placenta effectiveness which cause fetal growth restriction (FGR); However, acute ROS did not change the gene and protein expression	L: no gender difference, small sample size, no neurodevelopmental outcomes were assessed R: Future study focus on the larger sample size, mitochondrial function, and neurodevelopmental outcomes
Jones et al. [61] 2020, USA	To determine the association between the placental expression of all 13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis- regulatory genes with IUGR	Case-control study	50 IUGR and 100 control pregnancies, placenta samples	N/A	IUGR	13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis-regulatory genes, PDK1, 2, 3, 4, PKLR, PKM, OGT	N/A	MT-ND5, MT-ND6, and MT-ATP6 were negatively associated with IUGR, while one glycolysis-regulatory gene, PDK1 was positively associated with IUGR. mtDNA abundance and OS were positively associated with IUGR.	L: no direct mt function assessed; no gender difference R: Future study should focus on the gender difference and mitochondrial function assessment
Naha et al. [62] 2020, India	To examine the association between the placental mtDNA and IUGR condition	Case-control study	N = 67 pregnant women, n = 29 control, n = 18 IUGR, n = 20 SGA, Placenta samples	N/A	IUGR	mtDNAcn, Whole mt genome sequencing, proteins of NRF1 and SIRT3. Succinate dehydrogenase (SDH) staining	N/A	The increased mtDNAcn, decreased SIRT3 expression, decreased SDH activity were found in IUGR placenta tissue, which indicate the association between mt dysfunction and the fetal growth restriction	L: No gender, no neurodevelopmental outcomes were assessed R: Future study will focus on the intervention strategy based on the findings
Bart ha et al. [63] 2012, Spain	To investigate the role of fatty acid oxidation (FAO) in women with preeclampsia	Observational study	N = 28 (ctrl = 14 and preeclapsia = 14), pregnant women, placenta samples	N/A	FAO	Gene expression of LCHAD and MC AD; mt fatty acid oxidation rate; mitochondrial citrate synthase activity	N/A	Decreased LCHAD expression but not mitochondrial content related to the FAO deficits in women with preeclampsia, which support the role of FAO in the pathology of preeclampsia	L: No gender, small sample size, no neurodevelopmental outcomes measures R: Large sample size should be considered in the future
Garrabou et al. [56] 2016, Spain	To explore the role of CO-induced mt dysfunction in reduced birth weight in newborns tobacco exposure	Observational study	N = 51, mother-infant dyads (non-smoking Ctrl = 21, smoking subjects = 30), pregnant women, PBMCs and CBMCs	N/A	Carbon monoxide (CO)	Protein expression of COX; citrate synthase activity (mt content); VDAC protein expression (mt apoptotic analysis); TUN EL (apoptosis in placenta)	N/A	The correlation was found between the decreased birth weight, COX activity, increased mtDNA, ROS, apoptosis and the hx of smoking in pregnant women. Which suggests mitochondrial dysfunction and apoptosis may be the key in the reduced birth weight in smoking pregnant women	L: small sample size, no gender difference, no neurodevelopment outcomes was assessed R: Explore the relationship between mt mass and citrate synthase activity; enlarge the sample size to confirm the findings
Díaz et al. [64] 2014, Belgium	To assess the association between fetal growth restriction (FGR) and mt dysfunction	Observational study	N = 48 (n = 24 AGA and n = 24 SGA); mother-infant dyads, placenta samples	N/A	ROS	mtDNA content, SOD activity, citrate synthase activity	N/A	Decreased mtDNAcn and increased SOD activity were associated with FGR in placenta in SGA pregnancy	L: No genetic analysis, small sample size, no gender difference, no neurodevelopment outcomes assessment R: Larger sample size should be considered in the future
Mandò et al. [65] 2014, Italy	To compare the different mt content, function and respiration between IUGR and preeclampsia pregnancy	Observational study	N = 22 (8 IUGR, 6 preeclampsia, 8 Ctrl); pregnant women; placenta; cytotrop ho blast cells	N/A	ROS	mtDNA content; NRF1 and respiratory chain complexes (RCC) gene expression; RCC protein expression; RCC efficiency; O2 consump-tion	N/A	Mt content and NRF1 gene expression level were higher in placenta but reversed in the isolated cytotrophoblast cells in IUGR group compared with control group. Which suggested the placental cell linage dependent mt features. Increased placental O2 consumption may explain the limitation of O2 delivery to fetus. No gender difference was found in the findings	L: No gender difference, small sample size, no neurodevelopmental outcomes R: Larger sample size should be considered in the future
Minghetti, et al. [44] 2013, Italy	To evaluate ROS, antioxidant capacity in newborn twins	Observational study	80 twin preterm infant (38 F, 42 M), >28 GW, umbilical cord blood sample	N/A	Premature and twins birth caused ROS	ROS bio marker 15-F2t-isoprostane and antioxidant capacity (tAOC)	N/A	Males was higher than female cohorts in 15-F2t-isoprostane but not in tAOC. Gender difference in vulnerability of ROS injury will explain the developmental gender disparity in later life	No neurodevelopmental outcomes, which should be considered in the future study
Negi et al. [45] 2012, India	To analyze the association between ROS and low birth weight (LBW) and prematurity	Observational study	55 preterm infants (<37 GW, birth-weight <2,500g) and 24 full term controls (≥37 GW, birth-weight >2,500g), umbilical cord blood	N/A	ROS caused during pregnancy stress exposure	Oxidative DNA damage marker: 8-Hyd roxy-2-deoxy guanosine (8-OHdG) and antioxidant status marker: Malondialdehyde (MDA)	N/A	Increased level of 8-OHdG, MDA, and negative association between 8-OHdG, birthweight and GA were found in preterm infants	No neurodevelopmental outcomes, which should be considered in the future study
Bandyopadhyay et al. [57] 2017, India	To analyze the relationship between MSAF and ROS, birth weight (BW), gestational age and prematurity	Observational study	N = 109 [59 meconium- stained amniotic fluid (MSAF) and 50 without MSAF]	N/A	MSAF induced ROS	8-OHdG, MDA	N/A	Infants with MSAF had higher level of ROS (increased 8-OHdG, MDA), which was significantly correlated with birth weight	No neurodevelopmental outcomes, gender difference, which should be considered in the future study
Negi et al. [45] 2012, India	To investigate the association between ROS	Observational study	N = 240 124 preterm infants (<37 weeks, birth weight <2,500 g), 116 full term infants, umbilical cord blood	N/A	Premature caused ROS	MDA, carbonyl proteins, total antioxidant capacity and vit A, E, and C	N/A	Increased ROS and decreased antioxidant capacity were observed in the low birth weight preterm infants	No neurodevelopmental outcomes, gender difference, which should be considered in the future study
Shoji et al. [43] 2014, Japan	To assess the association between ROS and neurodevelopment in preterm infants	Observational study	N = 35 preterm infants (F 19, M 16), birth weight <1,500 g, urine	N/A	Premature caused ROS	8-OHdG, and 8-isoprostaglandin F2a (8-isoPGF) marker of lipid peroxidation (ELISA)	At 18 months’ corrected age, (1) Mental and psychomotor: Bayley Scale of Infant Development (BSID)-II; (2) Mental Developmental Index (MDI); (3) Psychomotor Development Index (PDI)	Significant association had been observed between urinary 8-OHdG and mental development rather than psycho motor development at 18 months’ corrected age in preterm infants	Larger sample size and gender difference should be considered in the future study
Slater et al. [47] 2012, USA	To examine the relationship between pain score and behavioral and ROS changes	Observational study	N = 80 preterm infants (<37 GW) (42 with tissue damage procedures [TDP], 38 without TDP), 0.8 mL blood from central catheter 30 min before and after TDP	N/A	Pain score measured using premature infant pain profile (PIPP)	ROS marker of MDA and uric acid (UA)	N/A	Positive association between pain scores and MDA, which indicate the relationship between pain and ROS in preterm infants	Gender difference should be considered in the future study
Norishadkam et al. [48] 2017, Iran	To test the level of ROS and DNA damage between preterm infants and term infants	Observational study	N = 50,25 preterm infant (Ml 3, FI 2) (<34 GW, birth weight <2,000 g), 25 term infant (>37 GW, birth weight >2,500 g), umbilical cord blood	N/A	ROS	Comet assay to measure tailed DNA percent, MDA, antioxidant capacity using 1,1-diphenyl-2picrylhydrazyl (DPPH), SOD activity, plasma catalase activity	N/A	Significantly increased primary DNA damage, plasma ROS, tail DNA percent and tail moment were found in preterm infants	Gender difference and neurodevelopmental outcomes should be considered in the future study
Perrone et al. [49] 2016, Italy	To test the association between placental lesion (chorioamnionitis [CA] or vascular underperfusion [VU]) and ROS	Observational study (prospective cohort study)	N = 120, mother infant dyads, preterm infants (<29 GW), placenta (HCA, VU, Ctrl) and umbilical cord blood	N/A	Placental lesion caused ROS	Isoprostanes (IsoPs), non-protein bound iron (NPBI), and advanced oxidative protein products (AOPP)	N/A	IsoPs, NPBI and AOPP were increased in CA and VU groups compared with Ctrl group. Which indicated that inflammation or impaired perfusion are associated with increased ROS.	Gender difference and neurodevelopmental outcomes should be considered in the future study
Musilova et al. [50] 2016, Czech Republic	To evaluate the association between ROS and preterm prelabor rupture of membranes (PPROM)	Observational study (prospective cohort study)	N = 165, singleton pregnancy women with PPROM, umbilical cord vein blood	N/A	PPROM with microbial invasion of the amniotic cavity (MlAC) and/or histological chorioamnionitis (HCA) caused ROS	Total antioxidant capacity (TAC), ferric reducing antioxidant power (FRAP), thiobarbituric acidreacting substances (TBARS), advanced glycation end products (AGEs) were measured	N/A	TAC, FRAP, TBARS, and AGEs were all found in PPROM sample (MlAC and HCA); The association between ROS markers and short-term neonatal morbidity, e.g., intra ventricular hemorrhage (TBARS)	Gender difference and neurodevelopmental outcomes should be considered in the future study