Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study
Abstract
:1. Introduction
2. Results
2.1. Study Participants
2.2. Maternal Inflammatory Biomarkers and ASQ Scores
2.3. Change in Biomarker Levels across Pregnancy and ASQ Scores
2.4. Interactions between Maternal Inflammatory Biomarkers with Offspring Sex, Breastfeeding and Vitamin D Supplementation
2.5. Sensitivity Analyses
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Maternal Measures of IL-8 and CRP
4.3. The Ages and Stages Questionnaire
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Girchenko, P.; Lahti-Pulkkinen, M.; Heinonen, K.; Reynolds, R.M.; Laivuori, H.; Lipsanen, J.; Villa, P.M.; Hamalainen, E.; Kajantie, E.; Lahti, J.; et al. Persistently High Levels of Maternal Antenatal Inflammation Are Associated With and Mediate the Effect of Prenatal Environmental Adversities on Neurodevelopmental Delay in the Offspring. Biol. Psychiatry 2020, 87, 898–907. [Google Scholar] [CrossRef] [PubMed]
- Darras-Hostens, M.; Achour, D.; Muntaner, M.; Grare, C.; Zarcone, G.; Garcon, G.; Amouyel, P.; Zerimech, F.; Matran, R.; Guidice, J.L.; et al. Short-term and residential exposure to air pollution: Associations with inflammatory biomarker levels in adults living in northern France. Sci. Total Environ. 2022, 833, 154985. [Google Scholar] [CrossRef] [PubMed]
- Kruger, K.; Dischereit, G.; Seimetz, M.; Wilhelm, J.; Weissmann, N.; Mooren, F.C. Time course of cigarette smoke-induced changes of systemic inflammation and muscle structure. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 309, L119–L128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gilman, S.E.; Hornig, M.; Ghassabian, A.; Hahn, J.; Cherkerzian, S.; Albert, P.S.; Buka, S.L.; Goldstein, J.M. Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood. Proc. Natl. Acad. Sci. USA 2017, 114, 6728–6733. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huizink, A.C.; Robles de Medina, P.G.; Mulder, E.J.; Visser, G.H.; Buitelaar, J.K. Stress during pregnancy is associated with developmental outcome in infancy. J. Child Psychol. Psychiatry 2003, 44, 810–818. [Google Scholar] [CrossRef]
- Brown, A.S.; Hooton, J.; Schaefer, C.A.; Zhang, H.; Petkova, E.; Babulas, V.; Perrin, M.; Gorman, J.M.; Susser, E.S. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am. J. Psychiatry 2004, 161, 889–895. [Google Scholar] [CrossRef]
- Nist, M.D.; Pickler, R.H. An Integrative Review of Cytokine/Chemokine Predictors of Neurodevelopment in Preterm Infants. Biol. Res. Nurs. 2019, 21, 366–376. [Google Scholar] [CrossRef]
- Sproston, N.R.; Ashworth, J.J. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol. 2018, 9, 754. [Google Scholar] [CrossRef] [Green Version]
- Camerota, M.; Wylie, A.C.; Goldblum, J.; Wideman, L.; Cheatham, C.L.; Propper, C.B. Testing a cascade model linking prenatal inflammation to child executive function. Behav. Brain Res. 2022, 431, 113959. [Google Scholar] [CrossRef]
- Irwin, J.L.; McSorley, E.M.; Yeates, A.J.; Mulhern, M.S.; Strain, J.J.; Watson, G.E.; Grzesik, K.; Thurston, S.W.; Love, T.M.; Smith, T.H.; et al. Maternal immune markers during pregnancy and child neurodevelopmental outcomes at age 20 months in the Seychelles Child Development Study. J. Neuroimmunol. 2019, 335, 577023. [Google Scholar] [CrossRef]
- Goines, P.E.; Croen, L.A.; Braunschweig, D.; Yoshida, C.K.; Grether, J.; Hansen, R.; Kharrazi, M.; Ashwood, P.; Van de Water, J. Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Mol. Autism 2011, 2, 13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, A.S.; Sourander, A.; Hinkka-Yli-Salomaki, S.; McKeague, I.W.; Sundvall, J.; Surcel, H.M. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol. Psychiatry 2014, 19, 259–264. [Google Scholar] [CrossRef]
- Jones, K.L.; Croen, L.A.; Yoshida, C.K.; Heuer, L.; Hansen, R.; Zerbo, O.; DeLorenze, G.N.; Kharrazi, M.; Yolken, R.; Ashwood, P.; et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol. Psychiatry 2017, 22, 273–279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zerbo, O.; Traglia, M.; Yoshida, C.; Heuer, L.S.; Ashwood, P.; Delorenze, G.N.; Hansen, R.L.; Kharrazi, M.; Van de Water, J.; Yolken, R.H.; et al. Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: The early markers for autism study. Transl. Psychiatry 2016, 6, e783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abdallah, M.W.; Larsen, N.; Grove, J.; Norgaard-Pedersen, B.; Thorsen, P.; Mortensen, E.L.; Hougaard, D.M. Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders. World J. Biol. Psychiatry 2013, 14, 528–538. [Google Scholar] [CrossRef] [PubMed]
- Gilman, S.E.; Cherkerzian, S.; Buka, S.L.; Hahn, J.; Hornig, M.; Goldstein, J.M. Prenatal immune programming of the sex-dependent risk for major depression. Transl. Psychiatry 2016, 6, e822. [Google Scholar] [CrossRef] [Green Version]
- Goldstein, J.M.; Cherkerzian, S.; Seidman, L.J.; Donatelli, J.A.; Remington, A.G.; Tsuang, M.T.; Hornig, M.; Buka, S.L. Prenatal maternal immune disruption and sex-dependent risk for psychoses. Psychol. Med. 2014, 44, 3249–3261. [Google Scholar] [CrossRef] [Green Version]
- Mehler, M.F.; Kessler, J.A. Cytokines in brain development and function. Adv. Protein Chem. 1998, 52, 223–251. [Google Scholar] [CrossRef]
- Umemura, A.; Oeda, T.; Yamamoto, K.; Tomita, S.; Kohsaka, M.; Park, K.; Sugiyama, H.; Sawada, H. Baseline Plasma C-Reactive Protein Concentrations and Motor Prognosis in Parkinson Disease. PLoS ONE 2015, 10, e0136722. [Google Scholar] [CrossRef]
- Luan, Y.Y.; Yao, Y.M. The Clinical Significance and Potential Role of C-Reactive Protein in Chronic Inflammatory and Neurodegenerative Diseases. Front. Immunol. 2018, 9, 1302. [Google Scholar] [CrossRef] [PubMed]
- Litonjua, A.A.; Carey, V.J.; Laranjo, N.; Harshfield, B.J.; McElrath, T.F.; O’Connor, G.T.; Sandel, M.; Iverson, R.E., Jr.; Lee-Paritz, A.; Strunk, R.C.; et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial. JAMA 2016, 315, 362–370. [Google Scholar] [CrossRef] [PubMed]
- Squires, J.; Bricker, D.D. Ages & Stages Questionnaires, 3rd ed.; Paul H. Brookes Publishing Co.: Baltimore, MD, USA, 2009. [Google Scholar]
- Pinares-Garcia, P.; Stratikopoulos, M.; Zagato, A.; Loke, H.; Lee, J. Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders. Brain Sci. 2018, 8, 154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- May, T.; Adesina, I.; McGillivray, J.; Rinehart, N.J. Sex differences in neurodevelopmental disorders. Curr. Opin. Neurol. 2019, 32, 622–626. [Google Scholar] [CrossRef] [PubMed]
- Bar, S.; Milanaik, R.; Adesman, A. Long-term neurodevelopmental benefits of breastfeeding. Curr. Opin. Pediatr. 2016, 28, 559–566. [Google Scholar] [CrossRef] [PubMed]
- Luu, T.M.; Rehman Mian, M.O.; Nuyt, A.M. Long-Term Impact of Preterm Birth: Neurodevelopmental and Physical Health Outcomes. Clin. Perinatol. 2017, 44, 305–314. [Google Scholar] [CrossRef] [PubMed]
- Morales, E.; Guxens, M.; Llop, S.; Rodriguez-Bernal, C.L.; Tardon, A.; Riano, I.; Ibarluzea, J.; Lertxundi, N.; Espada, M.; Rodriguez, A.; et al. Circulating 25-hydroxyvitamin D3 in pregnancy and infant neuropsychological development. Pediatrics 2012, 130, e913–e920. [Google Scholar] [CrossRef] [Green Version]
- Edlow, A.G. Maternal obesity and neurodevelopmental and psychiatric disorders in offspring. Prenat. Diagn. 2017, 37, 95–110. [Google Scholar] [CrossRef] [Green Version]
- Girchenko, P.; Lahti-Pulkkinen, M.; Lipsanen, J.; Heinonen, K.; Lahti, J.; Rantalainen, V.; Hamalainen, E.; Laivuori, H.; Villa, P.M.; Kajantie, E.; et al. Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children. Mol. Psychiatry 2022. [Google Scholar] [CrossRef]
- Mirzakhani, H.; Kelly, R.S.; Yadama, A.P.; Chu, S.H.; Lasky-Su, J.A.; Litonjua, A.A.; Weiss, S.T. Stability of developmental status and risk of impairment at 24 and 36 months in late preterm infants. Infant Behav. Dev. 2020, 60, 101462. [Google Scholar] [CrossRef]
- Chen, Y.S.; Mirzakhani, H.; Knihtila, H.; Fichorova, R.; Luu, N.; Laranjo, N.; Kelly, R.; Weiss, S.T.; Litonjua, A.A.; Lee-Sarwar, K. The association of prenatal C-reactive protein and interleukin-8 levels with maternal characteristics and preterm birth. Am. J. Perinatol. 2022. [Google Scholar] [CrossRef]
- Case, A.; Fertig, A.; Paxson, C. The lasting impact of childhood health and circumstance. J. Health Econ. 2005, 24, 365–389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Szabo, Y.Z.; Slavish, D.C.; Graham-Engeland, J.E. The effect of acute stress on salivary markers of inflammation: A systematic review and meta-analysis. Brain Behav. Immun. 2020, 88, 887–900. [Google Scholar] [CrossRef] [PubMed]
- Ellman, L.M.; Deicken, R.F.; Vinogradov, S.; Kremen, W.S.; Poole, J.H.; Kern, D.M.; Tsai, W.Y.; Schaefer, C.A.; Brown, A.S. Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr. Res 2010, 121, 46–54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meyer, U.; Yee, B.K.; Feldon, J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: The earlier the worse? Neuroscientist 2007, 13, 241–256. [Google Scholar] [CrossRef] [PubMed]
- Ghassabian, A.; Sundaram, R.; Chahal, N.; McLain, A.C.; Bell, E.M.; Lawrence, D.A.; Gilman, S.E.; Yeung, E.H. Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study. Paediatr. Perinat. Epidemiol. 2018, 32, 337–345. [Google Scholar] [CrossRef]
- Vecchie, A.; Bonaventura, A.; Carbone, F.; Maggi, D.; Ferraiolo, A.; Carloni, B.; Andraghetti, G.; Affinito Bonabello, L.; Liberale, L.; Dallegri, F.; et al. C-Reactive Protein Levels at the Midpregnancy Can Predict Gestational Complications. Biomed. Res. Int. 2018, 2018, 1070151. [Google Scholar] [CrossRef]
- Monthe-Dreze, C.; Rifas-Shiman, S.L.; Gold, D.R.; Oken, E.; Sen, S. Maternal obesity and offspring cognition: The role of inflammation. Pediatr. Res. 2019, 85, 799–806. [Google Scholar] [CrossRef]
- Chen, J.; Dueker, G.; Cowling, C. Profiles and predictors of risk for developmental delay: Insights gained from a community-based universal screening program. Early Hum. Dev. 2018, 127, 21–27. [Google Scholar] [CrossRef]
- Dammann, O.; Leviton, A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr. Res. 1997, 42, 1–8. [Google Scholar] [CrossRef] [Green Version]
- Fink, N.R.; Chawes, B.; Bonnelykke, K.; Thorsen, J.; Stokholm, J.; Rasmussen, M.A.; Brix, S.; Bisgaard, H. Levels of Systemic Low-grade Inflammation in Pregnant Mothers and Their Offspring are Correlated. Sci. Rep. 2019, 9, 3043. [Google Scholar] [CrossRef]
- Djuardi, Y.; Wibowo, H.; Supali, T.; Ariawan, I.; Bredius, R.G.; Yazdanbakhsh, M.; Rodrigues, L.C.; Sartono, E. Determinants of the relationship between cytokine production in pregnant women and their infants. PLoS ONE 2009, 4, e7711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Piek, J.P.; Dawson, L.; Smith, L.M.; Gasson, N. The role of early fine and gross motor development on later motor and cognitive ability. Hum. Mov. Sci. 2008, 27, 668–681. [Google Scholar] [CrossRef] [PubMed]
- Singh, A.; Squires, J.; Yeh, C.J.; Heo, K.H.; Bian, H. Validity and reliability of the developmental assessment screening scale. J. Fam. Med. Prim. Care 2016, 5, 124–128. [Google Scholar] [CrossRef] [PubMed]
- Litonjua, A.A.; Lange, N.E.; Carey, V.J.; Brown, S.; Laranjo, N.; Harshfield, B.J.; O’Connor, G.T.; Sandel, M.; Strunk, R.C.; Bacharier, L.B.; et al. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): Rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemp. Clin. Trials 2014, 38, 37–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tamayo, J.M.; Rose, D.; Church, J.S.; Schwartzer, J.J.; Ashwood, P. Maternal Allergic Asthma Induces Prenatal Neuroinflammation. Brain Sci. 2022, 12, 1041. [Google Scholar] [CrossRef]
- Hermann, C.; von Aulock, S.; Dehus, O.; Keller, M.; Okigami, H.; Gantner, F.; Wendel, A.; Hartung, T. Endogenous cortisol determines the circadian rhythm of lipopolysaccharide-but not lipoteichoic acid-inducible cytokine release. Eur. J. Immunol. 2006, 36, 371–379. [Google Scholar] [CrossRef]
- Ruskovska, T.; Beekhof, P.; Velickova, N.; Kamcev, N.; Jansen, E. Circadian rhythm and time-of-day-effects of (anti)oxidant biomarkers for epidemiological studies. Free Radic. Res. 2021, 55, 792–798. [Google Scholar] [CrossRef]
- Balieiro, L.C.T.; Gontijo, C.A.; Marot, L.P.; Teixeira, G.P.; Fahmy, W.M.; Moreno, C.R.C.; Maia, Y.C.P.; Crispim, C.A. Circadian misalignment measured by social jetlag from early to late pregnancy and its association with nutritional status: A longitudinal study. Sci. Rep. 2021, 11, 18678. [Google Scholar] [CrossRef]
- Wright, K.P., Jr.; Drake, A.L.; Frey, D.J.; Fleshner, M.; Desouza, C.A.; Gronfier, C.; Czeisler, C.A. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav. Immun. 2015, 47, 24–34. [Google Scholar] [CrossRef] [Green Version]
- Piek, J.P.; Dyck, M.J.; Nieman, A.; Anderson, M.; Hay, D.; Smith, L.M.; McCoy, M.; Hallmayer, J. The relationship between motor coordination, executive functioning and attention in school aged children. Arch. Clin. Neuropsychol. 2004, 19, 1063–1076. [Google Scholar] [CrossRef]
- Stene-Larsen, K.; Brandlistuen, R.E.; Lang, A.M.; Landolt, M.A.; Latal, B.; Vollrath, M.E. Communication impairments in early term and late preterm children: A prospective cohort study following children to age 36 months. J. Pediatr. 2014, 165, 1123–1128. [Google Scholar] [CrossRef] [PubMed]
Variable | Mean/n | SD/% | ||
---|---|---|---|---|
Maternal Inflammatory Biomarkers | Early Pregnancy CRP | (mg/L) | 2.09 | 1.12 |
Late Pregnancy CRP | (mg/L) | 2.02 | 1.04 | |
Early Pregnancy Trimester IL8 | (pg/mL) | 1.38 | 1.36 | |
Late Pregnancy Trimester IL8 | (pg/mL) | 1.25 | 1.10 | |
Maternal Characteristics | Age at recruitment | (yrs) | 27.7 | 5.4 |
Race/Ethnicity | Black-Hispanic | 21 | 4.3% | |
Black-Non-Hispanic | 187 | 38.1% | ||
Other-Hispanic | 42 | 8.6% | ||
Other-Non-Hispanic | 38 | 7.7% | ||
White-Hispanic | 65 | 13.2% | ||
White-Non-Hispanic | 138 | 28.1% | ||
Study Site | Boston | 143 | 29.1% | |
San Diego | 169 | 34.4% | ||
St Louis | 179 | 36.5% | ||
Education | Less than college grad | 307 | 62.5% | |
College grad or higher | 184 | 37.5% | ||
Marital Status | Not living with Father | 126 | 25.7% | |
Married/Cohabiting | 365 | 74.3% | ||
N. previous pregnancies at reruitment | 0 | 173 | 35.2% | |
1 | 125 | 25.5% | ||
2 | 91 | 18.5% | ||
3 | 50 | 10.2% | ||
4 | 27 | 5.5% | ||
>5 | 25 | 5.1% | ||
N. living children at recruitment | 0 | 227 | 46.2% | |
1 | 152 | 31.0% | ||
2 | 78 | 15.9% | ||
3 | 20 | 4.1% | ||
4 | 13 | 2.7% | ||
5 | 1 | 0.2% | ||
Treatment Arm | Placebo | 254 | 51.7% | |
Vitamin D | 237 | 48.3% | ||
Offspring Characteristics | Gestational age at delivery | (weeks) | 39.2 | 1.59 |
Gestational Age < 37 weeks | Yes | 34 | 6.9% | |
Sex | Female | 242 | 49.3% | |
Male | 249 | 50.7% | ||
Race/Ethnicity a | Black-Hispanic | 40 | 8.1% | |
Black-Non-Hispanic | 193 | 39.3% | ||
White- Hispanic | 62 | 12.6% | ||
White-Non-Hispanic | 104 | 21.2% | ||
Other- Hispanic | 54 | 11.0% | ||
Other-Non-Hispanic | 38 | 7.7% | ||
Weight at birth | (grams) | 3311.2 | 504.0 | |
Length at birth | (cm) | 50.8 | 2.9 | |
Head circumference at birth | (cm) | 34.1 | 1.9 | |
Exclusive breast feeding for first 4 months of life | Yes | 157 | 32.0% | |
No | 300 | 61.1% | ||
Missing | 34 | 6.9% |
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Kelly, R.S.; Lee-Sarwar, K.; Chen, Y.-C.; Laranjo, N.; Fichorova, R.; Chu, S.H.; Prince, N.; Lasky-Su, J.; Weiss, S.T.; Litonjua, A.A. Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study. Int. J. Mol. Sci. 2022, 23, 15249. https://doi.org/10.3390/ijms232315249
Kelly RS, Lee-Sarwar K, Chen Y-C, Laranjo N, Fichorova R, Chu SH, Prince N, Lasky-Su J, Weiss ST, Litonjua AA. Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study. International Journal of Molecular Sciences. 2022; 23(23):15249. https://doi.org/10.3390/ijms232315249
Chicago/Turabian StyleKelly, Rachel S., Kathleen Lee-Sarwar, Yih-Chieh Chen, Nancy Laranjo, Raina Fichorova, Su H. Chu, Nicole Prince, Jessica Lasky-Su, Scott T. Weiss, and Augusto A. Litonjua. 2022. "Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study" International Journal of Molecular Sciences 23, no. 23: 15249. https://doi.org/10.3390/ijms232315249