TABLE 2.
Included studies that examine the association between infant immune system biomarkers and neurodevelopmental outcomes (N = 40)
| Author (year), country | Population context | Covariates | Study design | Final N (% male) | Biomarker(s) | Source | Source analytic method | Biosample age | Outcome measure (domains) | Age at outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| Ghassabian et al. (2018), USA | Typically developing (TD) | Gestational age, birth order, maternal age and level of education, maternal smoking during pregnancy, and maternal depressive symptoms | Cohort | 3038 (52%) | bFGF; IL‐8; IL‐1ra; IL‐1α; MCP‐1, MIP‐1α; MIP‐1β; VEGF; CCL21; CCL27; IL‐16; IL‐20; MCP‐2; MIP‐1d; CCL12; CCL‐17; sICAM‐1; sVCAM‐1; Cathepsin D; MPO; PDGF‐AA; PAI‐1; NCAM; CRP | Newborn dried blood spot | Milliplex Panels II and III (Millipore) | 2–3 days | ASQ; (cognitive, motor, communication, social) | 4–36 months |
| Nist, Pickler, et al. (2020), USA | Very preterm | PMA at birth, DOL of blood collection for cytokine analysis, and infant age at the time of neurobehavioral/neurodevelopmental assessment | Cohort | 62 (60%) | IL‐1RA; IL‐6; IL‐10; IL‐8; MCP‐1; GCSF; GMCSF | Infant blood | Bio‐Plex multiplex assay | 0–3 weeks postbirth | BSID‐III; (cognition, language, motor skills); NAPI (irritability, alertness) | 6 months |
| Liu & Feng (2010), China | HIE | Not reported | Cohort | 52 (not specified) | IL‐1β; IL‐8; TNF‐α | Child blood | Human multiplexing bead immunoassays | 0–1 week | DDST‐II (gross motor skills; fine motor skills; language, social skills) | 6 and 12 months |
| Varner et al. (2015), USA | CP or NDD | Gestational age at birth, maternal education level, and exposure to magnesium sulfate (MgSO4) | Case–control | 615 (not specified) | IL‐1β; IL‐8; TNF‐α | Umbilical cord blood | Enzyme‐linked immunosorbent assay | Birth | BSID‐II (cognition; motor skills) | 6, 12, and 24 months |
| Camargos et al. (2017), Brazil | Overweight, obese or normal‐weight infants | Age and gender of child | Cross‐sectional | 50 | sTNFR1; sTNFR2; MCP‐1; IL‐8; IP‐10; RANTES; MIG | Infant blood | Blood plasma, serum erythrocyte lysate | 6–24 months | BSID‐III (cognition; motor skills) | 6–24 months |
| Jensen et al. (2019), Bangladesh | Living in poverty | Gestational age | Cohort | 122 (not specified) | CRP | Infant blood | Enzyme‐linked immunosorbent assays (Immuniidiagnostik) | 4–12 months | MSEL (gross motor skills; fine motor skills); WPPSI (visual reception; receptive language; expressive language; intelligence) |
6, 27, and 36 months (MSEL) 60 months (WPPSI) |
| Xie et al. (2019), Bangladesh | Living in poverty, high risk for chronic systemic inflammation PROVIDE and CRYPTO cohort | Height‐for‐age Z‐scores | Cohort | 260 (not specified) | CRP | Infant blood | Not specified | 18–104 weeks | MSEL (cognition); WPPSI‐III (intelligence); Face‐oddball task (event‐related potential) |
6 and 36 months (ERP) 27 months (MSEL) 48 months (WPPSI‐III) |
| Magalhaes et al. (2017), Brazil | Poor motor development compared to control | Not reported. | Cohort | 40 (55%) | IL‐1β; IL‐6; IL‐8; IL‐10; IL‐12p70; TNF‐α; MCP‐1; RANTES; IP‐10; MIG | Infant urine, infant blood | Cytometric bead assay (BD Biosciences, California) Human Inflammatory Kit (CBA) Human Chemokine Kit (CBA) | 0–3 weeks | TIMP (posture motor coordination) | 48 h, 72 h, and 3 weeks after birth |
| Nist, Shoben, et al. (2020), USA | Very preterm | Length of stay in NICU | Cohort | 68 (66.2%) | IL‐1β; IL‐4; IL‐6; IL‐8; IL‐10; IL‐17A; TNF‐α; MCP‐1 | Infant blood | Bio‐plex multiplex assay | 0–35 weeks | NAPI (motor development and vigor alertness and orientation) | 35 weeks |
| Jiang et al. (2014), Bangladesh | Living in poverty | Sex, monthly family income, maternal education, febrile illness, and LAZ at 12 months | Cohort | 127 (58.3%) | IL‐1β; IL‐6; TNF‐α; IL‐4; IL‐10 | Infant blood | Human Bio‐Plex Pro Assays (Bio‐Plex 200 Platform) | 6 months | BSID‐III (cognition; language; motor skills) | 12 months |
| Benavides et al. (2022), USA | Very preterm, ELBW | Sex, birth weight, GA at birth, day of age, and pretransfusion hemoglobin within 24 h of assessment | Cohort | 71 (data on BSID‐II for 26) (39.4%) | IL‐1β; IL‐2; IL‐4; IL‐6; IL‐8; IL‐10; IL‐12; IL‐13; IL‐17; IL‐18; IFN‐γ; IP‐10; MCP‐1; IFN‐γ; TNF‐α; TNF‐β; sICAM‐1; sVCAM‐1; VEGF; TPO | Infant blood | V‐PLEX Plus Pro‐inflammatory Panel 1 Human Kit (Multiplex); V‐PLEX Plus Vascular Injury Panel 2 Human Kit (Multiplex); U‐PLEX Biomarker Group 1 (hu) Assays (Multiplex) | 22–29 weeks | BSID‐III (cognition; language; motor skills) | 12 months |
| Etheredge et al. (2018), Tanzania | Non‐stunted from low‐income country | Assessor, study baseline, length‐for‐age, weight‐for‐age, exclusive breastfeeding at 6 weeks and 6 months, any respiratory infection or diagnosis, anemia, iron deficiency, and inflammation | RCT | 107 (49.5%) | CRP | Infant blood | Immunoturbidimetric assay (Roche Diagnostics) | 6 weeks, 6 months, 12 months | BSID‐III (cognition; language; motor skills) | 15 months |
| Chalak et al. (2014), USA | HIE | Not reported | Cohort | 27 (57%−70%) | Il‐1; Il‐6; IL‐8; VEGF; TNF‐α; INF‐γ | Umbilical blood | Enzyme‐linked immunosorbent assay | 6–24, 48, 72, and 78 h | BSID‐III (cognitive; language motor) | 15–18 months |
| Dietrick et al. (2020), Ireland | NE compared to control | Gestational age and sex | Cohort | 185 (40%−57%) | IL‐6; IL‐8; IL‐10; VEGF | Infant blood and cerebrospinal fluid | Custom multiplex enzyme‐linked immunosorbent assay | 0–1 week postbirth | BSID‐III (cognition; language; motor skills) | 15–30 months |
| Lee et al. (2021), South Korea | Very preterm and/or VLBW | Postmenstrual age and gestational age | Cohort | 94 (41%–62%) | IL‐1β; IL‐6; IL‐8; TNF‐α; CRP | Infant blood and cerebrospinal fluid | Enzyme‐linked immunosorbent assay (Cloud‐Clone Corp, Texas) Quantikine (R&D systems, Minnesota) | <35 weeks gestational age | BSID‐III (cognition; language; motor skills social–emotional development; adaptive behavior) | 18 months |
| Rose et al. (2016), USA | Very preterm, VLBW | Not reported | Cohort | 92 (not specified) | CRP | Infant blood | Not specified | Within 14 days postbirth | BSID‐III (cognition; language; motor skills) | 18–22 months |
| Carlo et al. (2011), USA | ELBW | Race and gestational age | Cohort | 755 (41.6%) | IL‐1β; IL‐8; TNF‐α; RANTES; IL‐2 | Umbilical cord blood and infant whole blood spots | Multiplex Luminex assay | 0–3 weeks | BSID‐II (cognition; motor skills) | 18–22 months |
| Sweetman et al. (2021), Ireland | NE compared to control | Not reported | Cohort | 94 (not specified) | GM‐CSF; IL‐8 | Infant blood and cerebrospinal fluid | Human Ultra‐Sensitive IL‐8; Human Ultra‐Sensitive GM‐CSF | 1, 3, and 7 days | BSID‐III; MRI (cognition; language; motor skills) | 18–24 months |
| Dilli et al. (2013) | VLBW, with or without sepsis | Not reported | Cohort | 40 (50%) | IL‐6; CRP; CD64 | Infant blood | Tinaquant CRP (Latex) high sensitive immunoturbidimetric assay for CRP; chemiluminescent sequential immunometric assay for IL‐6 Flow cytometry for CD64 | First 7 days after birth | BSID‐II (cognition; language; motor skills) | 18–24 months |
| Jiang et al. (2017), Bangladesh | Living in poverty PROVIDE | Sex, family income, education, length‐for‐age | Cohort | 422 (51.7%) | TNF‐α; IL‐1β; IL‐6; IL‐10; CRP | Infant blood | Human Bio‐Plex Pro Assays Enzyme‐linked immunosorbent assay | 18 weeks postbirth for all biomarkers beside CRP. CRP assessed at 6, 18, 40, 53, and 104 weeks | BSID‐III (cognition; language; social–emotional development) | 78 and 104 weeks |
| Silveira & Procianoy (2011), Brazil | Very preterm, VLBW, high risk for sepsis | Not reported | Cohort | 62 (not specified) | IL‐1β; IL‐6; IL‐8; IL‐10; TNF‐α | Infant blood | Human cytokine lincoplex kit (Linco Research) | 24–32 weeks gestational age | BSID‐II (cognition; motor skils) | 22–24 months |
| Rodríguez‐Trujillo et al. (2019), Spain | Preterm | Not reported | Cohort | 98 (59.5%) | IL‐6 | Amniotic fluid | Enzyme‐linked immunosorbent assay | Birth | ASQ‐III (communication; fine motor skills; gross motor skills; problem solving; personal–social development) | 23.5 months |
| Leviton et al. (2013), USA | Extremely preterm ELGAN | Gestational age, sex | Cohort | 805 (51.7%) | CRP; SAA; MPO; IL‐1β; IL‐6; IL‐6R; TNF‐α; TNF‐R1; TNF‐R2; IL‐8; MCP‐1; MCP‐4; MIP‐1β; RANTES; I‐TAC; ICAM‐1; ICAM‐3; VCAM‐1; E‐SEL; MMP‐1; MMP‐9; VEGF; VEGF‐R1; VEGF‐R2; IGFBP‐1 | Infant blood spots | Meso Scale Discovery electrochemiluminescence multiplex platform Sector Imager 2400 | 0–1 week | BSID‐II (cognition) | 24 months |
| Leviton et al. (2016), USA | Extremely preterm ELGAN | Birthweight Z‐score | Cohort | 750 (not specified) | CRP; SAA; MPO; IL‐1β; IL‐6; IL‐6R; TNF‐α; TNF‐R2; IL‐8; RANTES; ICAM‐1; MMP‐9; VEGF; VEGF‐R2; TSH; EPO | Infant blood spots | Meso Scale Discovery electrochemiluminescence | 3–4 weeks | BSID‐II (cognition; motor skills) | 24 months |
| O'Shea et al. (2012), USA | Extremely preterm ELGAN | Gestational age | Cohort | 939 (53%) | CRP; SAA; MPO; IL‐1β; IL‐6; IL‐6R; TNF‐α; TNF‐R1; TNF‐R2; IL‐8; MCP‐1; MCP‐4; MIP‐1β; RANTES; I‐TAC; ICAM‐1; ICAM‐3; VCAM‐1; E‐SEL; MMP‐1; MMP‐9; VEGF; VEGF‐R1; VEGF‐R2; IGFBP‐1 | Infant blood | Meso Scale Discovery multiplex platform and Sector Imager 2400 (MSD, Maryland) | 0–2 weeks | BSID‐II (cognition; language; motor skills) | 24 months |
| O'Shea et al. (2013), USA | Extremely preterm ELGAN | Gestational age | Cohort | 800 (not specified) | CRP; SAA; MPO; IL‐1β; IL‐6; IL‐6R; TNF‐α; TNF‐R1; TNF‐R2; IL‐8; MCP‐1; MCP‐4; MIP‐1β; RANTES; I‐TAC; ICAM‐1; ICAM‐3; VCAM‐1; E‐SEL; MMP‐1; MMP‐9; VEGF; VEGF‐R1; VEGF‐R2; IGFBP‐1 | Infant blood | Multiplex assays (electrochemiluminescence multiplex detection system) | 0–2 weeks | BSID‐II, VABS (cognition; motor skills) | 24 months |
| O'Shea et al. (2014), USA | Extremely preterm ELGAN | Gestational age, birth weight Z‐score, first pregnancy, and multifetal pregnancy | Cohort | 600 (not specified) | CRP; SAA; MPO; IL‐1β; IL‐6; IL‐6R; TNF‐α; TNF‐R1; TNF‐R2; IL‐8; MCP‐1; MCP‐4; MIP‐1β; RANTES; I‐TAC; ICAM‐1; ICAM‐3; VCAM‐1; E‐SEL; MMP‐1; MMP‐9; VEGF; VEGF‐R1; VEGF‐R2; IGFBP‐1 | Infant blood | Multiplex assays (electrochemiluminescence multiplex detection system) | 0–2 weeks | BSID‐II (cognition); CBCL (Behavior emotional reactivity) | 24 months |
| van den Berg et al. (2016), Netherlands | Very preterm | Gestational age, birth weight, sex, and one or more serious neonatal infections | Case–control | 79 (59.21%) | IL‐1β; Il‐2; IL‐4; IL‐6; IL‐8; IL‐10; IL‐17; IFN‐ γ; TNF‐α | Blood samples | Fluorescent bead‐based multiplex immunoassay (Luminex xMAP technology), and cytokine assay kits were purchased from Bio‐rad (Hercules, California) | 48 h postbirth; preintervention 7 days; 14 days postnatal | BSID‐II/III (mental developmental index, psychomotor index) | 2 years |
| Sevenoaks et al. (2021), South Africa | Maternal HIV compared to control | Maternal sociodemographic and lifestyle factors (adjusted for clinic, maternal smoking during pregnancy, maternal alcohol use during pregnancy, maternal socioeconomic status, maternal BMI at 6 weeks postpartum), infant health (adjusted for birth weight, prematurity, infant sex and exclusive breastfeeding [yes/no]), maternal HIV disease parameters (adjusted for maternal CD4+ during pregnancy, maternal viral load during pregnancy, maternal ART regimen during pregnancy and initiation of ART [before or during pregnancy]) | Cohort | 267 (28.8%–39%) | IFN‐γ; IL‐1β; IL‐2; IL‐4; IL‐5; IL‐6; IL‐7; IL‐8; IL‐10; IL‐12p70; IL‐13; TNF‐α; GM‐CSF; NGAL; MMP‐9 | Infant blood | Multiplex bead assay; Enzyme‐linked immunosorbent assay | 6–10 weeks; 24–28 months | BSID‐III (cognition; language; motor skills) | 24–28 months |
| Lodha et al. (2010), Canada | NEC | Not reported | Cohort | 40 (57.5%) | TNF‐α; IL‐6; IL‐8 | Infant blood | DPC Immulite system | 2–3 weeks | BSID‐II (cognition; motor skills) | 24–28 months |
| Krakowiak et al. (2017), USA | ASD compared to control | Age at bloodspot collection, years between sample collection and elution, birth month, gestational age | Case–control | 303 (59%–88%) | IL‐1β; IL‐2; IL‐4; IL‐5; IL‐6; IL‐10; IL‐12; IL‐13; IFN‐γ; TNF‐α; IL‐8; MCP‐1; MIP‐1α; MIP‐1β; IP‐10; RANTES | Infant blood | Luminex multiplex Bio‐Plex Precision Pro Human Cytokine Assays MILLIPLEX human cytokine kits | Birth | MSEL (cognitive development); VABS (personal‐social skills); ABC (maladaptive behavior) | 24–60 months |
| Ashwood et al. (2011), USA | ASD compared to control | Child's age at blood draw and gender, diagnostic group | Case–control | 223 (80%–86.6%) | GM‐CSF; IFN‐γ; IL‐1β; IL‐2; IL‐4; IL‐5; IL‐6; IL‐8; IL‐10; IL‐12(p40); IL‐13; TNF‐α | Child blood | Human multiplexing bead immunoassays | 24–60 months (not specified) | SCQ (ASD symptoms); VABS (adaptive behavior); MSEL (cognition); ABC (maladaptive behavior) | 24–60 months (not specified) |
| Voltas et al. (2017), Spain | TD | Socioeconomic status, breastfeeding, gestational age, mother's age (score), GHQ mother, exposure to tobacco during pregnancy, bottle fed iron fortified, BMI at 30 months | Cohort | 51 (49.02%) | Il‐1β; IL‐4; IL‐6 | Infant blood | Multiplex assay (FlowCytomix) | 6–12 months | BSID‐II (cognition; motor skills); CBCL (behavior; emotional reactivity) | 30 months |
| Kinjo et al. (2011), Japan | VLBW | APGAR scores | Cohort | 29 (55%) | IL‐1β; IL‐6; IL‐8; IL‐10; TNF‐α; IL‐12p70; CXCL9; CXCL10; MCP‐1 | Infant blood | Cytometric bead array (Becton Dickinson) | Birth 4 weeks | KSPD (Postural motor; cognition; adaptive behavior; language; social skills) | 36 months |
| Ahearne et al. (2017), Ireland | HIE | Not reported | Cohort | 33 (66.6%) | IL‐6; IL‐16 | Umbilical cord blood | Luminex assays | Birth | BSID‐III (cognition; language; motor skills) | 36–42 months |
| Abraham et al. (2021), (Israel) | RD | SES, parents and children age and gender | Cohort | 47 (55.3%) | s‐IgA | Child saliva | Enzyme‐linked immunosorbent assay | 36–55 months | Behavior observation (regulation; negative emotionality) | 40.41 months (4.82) |
| Blok et al. (2011), Netherlands | Very preterm | Not reported | Cohort | 105 (46%) | IL‐6; IL‐8; TNF‐α | Infant blood | Enzyme‐linked immunosorbent assay | 0–5 days | GMDS (personal–social; hearing and speech; locomotor; eye‐hand coordination; performance; practical reasoning) | 3.5 years |
| Sorokin et al. (2014), USA | Mothers at risk for preterm birth | Gestational age at delivery, treatment group | Cohort | 465 (not specified) | IL‐6; CRP; MPO | Umbilical cord blood | Enzyme‐linked immunosorbent assay | Birth | BSID‐II (mental development; psychomotor development) | 36–42 months |
| Kyriklaki et al. (2019), Greece | Typically developing | Prepregnancy BMI, smoking early in pregnancy, parity, birth weight, preterm birth, BMI at the age of 4 and passive smoking of the child at 4 years of age | Cross‐sectional (nested) | 642 (52%) | IL‐1β; IL‐6; IL‐8; IL‐10; IL‐17; TNF‐α; MIP‐1α; IFN‐γ | Child blood | Milliplex Map human high sensitivity T cell magnetic bead panel (Millipore, MA) | 4 years | MSCA (cognition; memory; verbal; motor skills; quantitative; perceptual) | 4 years |
| von Ehrenstein et al. (2012), USA | Typically developing | Birth weight, gender, race/ethnicity, and smoking during pregnancy | Cohort | 369 (51.5%) | IL‐4; IL‐10; IL‐12p70; TNF‐α; IFN‐γ | Umbilical cord blood | Linco Immunoassay; Luminex 100 IS (Millipore) | Birth | WPPSI‐R (verbal intelligence; performance intelligence) | 5 years |
Abbreviations: ABC, Aberrant Behavior Checklist; ASQ, Ages & Stages Questionnaire; BSID‐II, Bayley Scales of Infant Development—Second Edition; BSID‐III, Bayley Scales of Infant Development—Third Edition; CBCL, Child Behavior Checklist; DDST, Denver Developmental Screening Test; GMDS, Griffiths Mental Developmental Scales; KSPD, Kyoto Scale of Psychological Development; MRI, magnetic resonance imaging; MSCA, McCarthy Scales of Children's Abilities; MSEL, Mullen Scales of Early Learning; NAPI, Neurobehavioral Assessment of the Preterm Infant, Revised Second Edition; TIMP, Test of Infant Motor Performance; VABS, Vineland Adaptive Behavior Scale; WPPSI, Wechsler Preschool and Primary Scale of Intelligence.