Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study

Abstract

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks’ gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20–25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20–25 weeks’ gestation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Trajectories of head circumference z-scores from prenatal measurements through 2 years of age, stratified by fetal cranial growth trajectories.
Fig. 3: Changes at 2 years of age associated with fetal cranial growth trajectories in the INTERBIO-21st Study.

Similar content being viewed by others

Data availability

Anonymized data will be made available upon reasonable request for academic use and within the limitations of the informed consent. Requests must be made to the corresponding author. Every request will be reviewed by the INTERBIO-21st Consortium Executive Committee. After approval, the researcher will need to sign a data access agreement with the INTERBIO-21st Consortium.

References

  1. Meyer, U., Yee, B. K. & Feldon, J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? Neuroscientist 13, 241–256 (2007).

    Article  CAS  Google Scholar 

  2. Keats, E. C., Haider, B. A., Tam, E. & Bhutta, Z. A. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst. Rev. 3, CD004905 (2019).

    PubMed  Google Scholar 

  3. Bhutta, Z. A. et al. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet 382, 452–477 (2013).

    Article  Google Scholar 

  4. Kennedy, S. et al. Deep clinical and biological phenotyping of the preterm birth and small for gestational age syndromes: the INTERBIO-21st Newborn Case–Control Study protocol. Gates Open Res. 2, 49 (2019).

  5. Papageorghiou, A. T. et al. International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet 384, 869–879 (2014).

    Article  Google Scholar 

  6. Papageorghiou, A. T. et al. International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy. Ultrasound Obstet. Gynecol. 44, 641–648 (2014).

    Article  CAS  Google Scholar 

  7. de Onis, M., Garza, C., Onyango, A. W. & Martorell, R. WHO child growth standards. Acta Paediatr. Suppl. 450, 1–101 (2006).

    Google Scholar 

  8. Fernandes, M. et al. INTERGROWTH-21st Project international INTER-NDA standards for child development at 2 years of age: an international prospective population-based study. BMJ Open 10, e035258 (2020).

    Article  Google Scholar 

  9. Villar, J. et al. The likeness of fetal growth and newborn size across non-isolated populations in the INTERGROWTH-21st Project: the fetal growth longitudinal study and newborn cross-sectional study. Lancet Diabetes Endocrinol. 2, 781–792 (2014).

    Article  Google Scholar 

  10. Lee, A. C. C. et al. National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010. Lancet Glob. Health 1, e26–e36 (2013).

    Article  Google Scholar 

  11. Nagin, D. S. & Odgers, C. L. Group-based trajectory modeling in clinical research. Annu Rev. Clin. Psychol. 6, 109–138 (2010).

    Article  Google Scholar 

  12. Fernandes, M. et al. The INTERGROWTH-21st project neurodevelopment package: a novel method for the multi-dimensional assessment of neurodevelopment in pre-school age children. PLoS ONE 9, e113360 (2014).

    Article  Google Scholar 

  13. Murray, E. et al. Evaluation of the INTERGROWTH-21st neurodevelopment assessment (INTER-NDA) in 2 year-old children. PLoS ONE 13, e0193406 (2018).

    Article  Google Scholar 

  14. Nolan, T. M. et al. Child behaviour checklist classification of behaviour disorder. J. Paediatr. Child Health 32, 405–411 (1996).

    Article  CAS  Google Scholar 

  15. Adoh, T. O., Woodhouse, J. M. & Oduwaiye, K. A. The Cardiff Test: a new visual acuity test for toddlers and children with intellectual impairment. A preliminary report. Optom. Vis. Sci. 69, 427–432 (1992).

    Article  CAS  Google Scholar 

  16. Villar, J. et al. Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations. Nat. Commun. 10, 511 (2019).

    Article  CAS  Google Scholar 

  17. Multicentre Growth Reference Study Group. WHO motor development study: windows of achievement for six gross motor development milestones. Acta Paediatr. Suppl. 450, 86–95 (2006).

    Google Scholar 

  18. Villar, J. et al. The satisfactory growth and development at 2 years of age of the INTERGROWTH-21st Fetal Growth Standards cohort support its appropriateness for constructing international standards. Am. J. Obstet. Gynecol. 218, S841–S854 (2018).

    Article  Google Scholar 

  19. Cheikh Ismail, L. et al. Anthropometric standardisation and quality control protocols for the construction of new, international, fetal and newborn growth standards: the INTERGROWTH-21st Project. BJOG 120, 48–55 (2013).

    Article  Google Scholar 

  20. Hochberg, Y. & Benjamini, Y. More powerful procedures for multiple significance testing. Stat. Med. 9, 811–818 (1990).

    Article  CAS  Google Scholar 

  21. Murray, E. et al. Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review. BJOG 122, 1062–1072 (2015).

    Article  CAS  Google Scholar 

  22. Dupont, C. et al. The predictive value of head circumference growth during the first year of life on early child traits. Sci. Rep. 8, 9828 (2018).

    Article  Google Scholar 

  23. Tanner, J. C., Candland, T. & Odden, W. S. Later Impacts of Early Childhood Interventions: A Systematic Review (World Bank Group, 2015).

  24. Armstrong, B. G. Effect of measurement error on epidemiological studies of environmental and occupational exposures. Occup. Environ. Med. 55, 651–656 (1998).

    Article  CAS  Google Scholar 

  25. Kjaer, M., Fabricius, K., Sigaard, R. K. & Pakkenberg, B. Neocortical development in brain of young children—a stereological study. Cereb. Cortex 27, 5477–5484 (2017).

    PubMed  Google Scholar 

  26. Cheikh Ismail, L. et al. Preterm feeding recommendations are achievable in large-scale research studies. BMC Nutr. 2 (2016).

  27. Dewey, K. G., Cohen, R. J., Arimond, M. & Ruel, M. T. Developing and Validating Simple Indicators of Complementary Food Intake and Nutrient Density for Breastfed Children in Developing Countries: Final Report (Academy for Educational Development, 2005).

  28. WHO Multicentre Growth Reference Study Group. Complementary feeding in the WHO Multicentre Growth Reference Study. Acta Paediatr. Suppl. 450, 27–37 (2006).

    Google Scholar 

  29. de Onis, M., Onyango, A. W., Van den Broeck, J., Chumlea, W. C. & Martorell, R. Measurement and standardization protocols for anthropometry used in the construction of a new international growth reference. Food Nutr. Bull. 25, S27–S36 (2004).

    Article  Google Scholar 

  30. Perumal, N., Gaffey, M. F., Bassani, D. G. & Roth, D. E. WHO child growth standards are often incorrectly applied to children born preterm in epidemiologic research. J. Nutr. 145, 2429–2439 (2015).

    Article  CAS  Google Scholar 

  31. Garza, C., Borghi, E., Onyango, A. W., de Onis, M. & WHO Multicentre Growth Reference Study Group. Parental height and child growth from birth to 2 years in the WHO Multicentre Growth Reference Study. Matern. Child Nutr. 9, 58–68 (2013).

  32. Tanner, J. M. Fetus into Man: Physical Growth from Conception to Maturity (Harvard University Press, 1990).

  33. Victora, C. G. et al. Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340–357 (2008).

    Article  CAS  Google Scholar 

  34. WHO. An evaluation of infant growth: the use and interpretation of anthropometry in infants. WHO Working Group on Infant Growth. Bull. World Health Organ. 73, 165–174 (1995).

    Google Scholar 

  35. Achenbach, T. M. & Rescorla, L. A. Manual for the ASEBA Preschool Forms & Profiles: An Integrated System Of Multi-informant Assessment (University of Vermont, Research Center for Children, Youth, and Families, 2000).

  36. McLachlan, D. & Peel, D. Finite Mixture Models (Wiley, 2000).

  37. Heggeseth, B., Harley, K., Warner, M., Jewell, N. & Eskenazi, B. Detecting associations between early-life DDT exposures and childhood growth patterns: a novel statistical approach. PLoS ONE 10, e0131443 (2015).

    Article  Google Scholar 

  38. Ziyab, A. H., Karmaus, W., Kurukulaaratchy, R. J., Zhang, H. & Arshad, S. H. Developmental trajectories of body mass index from infancy to 18 years of age: prenatal determinants and health consequences. J. Epidemiol. Community Health 68, 934–941 (2014).

    Article  Google Scholar 

  39. Magee, C. A., Caputi, P. & Iverson, D. C. The longitudinal relationship between sleep duration and body mass index in children: a growth mixture modeling approach. J. Dev. Behav. Pediatr. 34, 165–173 (2013).

    Article  Google Scholar 

  40. Pryor, L. E. et al. Developmental trajectories of body mass index in early childhood and their risk factors: an 8-year longitudinal study. Arch. Pediatr. Adolesc. Med. 165, 906–912 (2011).

    Article  Google Scholar 

  41. Carter, M. A., Dubois, L., Tremblay, M. S., Taljaard, M. & Jones, B. L. Trajectories of childhood weight gain: the relative importance of local environment versus individual social and early life factors. PLoS ONE 7, e47065 (2012).

    Article  CAS  Google Scholar 

  42. Ventura, A. K., Loken, E. & Birch, L. L. Developmental trajectories of girls’ BMI across childhood and adolescence. Obesity (Silver Spring) 17, 2067–2074 (2009).

    Article  Google Scholar 

  43. de Boor, C. A Practical Guide to Splines (Springer, 2001).

  44. Proust-Lima, C., Sene, M., Taylor, J. M. & Jacqmin-Gadda, H. Joint latent class models for longitudinal and time-to-event data: a review. Stat. Methods Med. Res. 23, 74–90 (2014).

    Article  Google Scholar 

  45. Dempster, A. P., Laird, N. M. & Rubin, D. B. Maximum likelihood with incomplete data via the E–M algorithm. J. R. Stat. Soc. Ser. B Stat. Methodol. 39, 1–38 (1977).

    Google Scholar 

Download references

Acknowledgements

This project was supported by a generous grant (OPP49038) from the Bill & Melinda Gates Foundation to the University of Oxford, for which we are very grateful (J.V., R.B.G., S.A.R., M.C.R.M., M.F., R.C., L.C.I., E.O.O., A.L., A.W., B.E. and A.T.P.). A.T.P. is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the NIHR Biomedical Research Centre funding scheme. The views expressed herein are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or any of the other funders. We would like to thank the health authorities in Pelotas, Brazil; Karachi, Pakistan; Kilifi, Kenya; Nairobi, Kenya; Johannesburg, South Africa; and Oxford, UK who facilitated the project by allowing participation of these study sites as collaborating centres. The participating hospitals included: Brazil, Pelotas (Hospital Miguel Piltcher, Hospital São Francisco de Paula, Santa Casa de Misericórdia de Pelotas and Hospital Escola da Universidade Federal de Pelotas); Pakistan, Karachi (Aga Khan Hospital); Kenya, Kilifi, (The Kilifi District Hospital); Nairobi, Kenya (Aga Khan University Hospital); South Africa, Johannesburg (Chris Hani Baragwanath Academic Hospital); Thailand, Mae Sot (Maela Wang Pha and Mawker Thai Clinics); and UK, Oxford (John Radcliffe Hospital). We are extremely grateful to Philips Medical Systems which provided the ultrasound equipment and technical assistance throughout the project. We also thank MedSciNet for setting up the INTERBIO-21st website and for the development, maintenance and support of the online data management system. We thank the parents and infants who participated in the studies and the more than 200 members of the research teams who made the implementation of this project possible. Finally, we acknowledge the contributions of all the members of the INTERBIO-21st Committees and the local investigators listed below. Scientific Advisory Committee: M. Katz (Chair), M. K. Bhan, C. Garza, A. Langer, P. M. Rothwell, S. Zaidi. Steering Committee: R. Uauy (Chair), S. H. Kennedy (Co-Principal Investigator), J. Villar (Co-Principal Investigator), D. G. Altman, F. C. Barros, J. A. Berkley, F. Burton, M. Carvalho, L. Cheikh Ismail, W. C. Chumlea, A. Lambert, S. Munim, S. Norris, F. Nosten, A. T. Papageorghiou, C. Victora. Executive Committee: J. Villar (Chair), D. G. Altman (died in 2018), L. Cheikh Ismail, R. Craik, S. H. Kennedy, A. Lambert, A. T. Papageorghiou, R. Uauy. Study Coordinating Unit: J. Villar (Head), S. Ash, R. Craik, L. Cheikh Ismail, S. H. Kennedy, A. Lambert, A. T. Papageorghiou, M. Shorten. Data Analysis Group: D. G. Altman (Head), E. O. Ohuma, A. T. Papageorghiou, E. Staines Urias, J. Villar. Data Management Group: D. G. Altman (Head), I. Ahmed, S. Ash, C. Condon, M. Mainwaring, D. Muninzwa, M. F. da Silveira, E. Staines Urias, L. Walusuna, S. Wiladphaingern. Ultrasound Group: A. T. Papageorghiou (Head), L. Salomon (Senior External Advisor), M. Buckle, N. Jackson, A. Mitidieri, S. Munim, H. Mwangudzah, R. Napolitano, T. Norris, J. Sande, J. Shah, G. Zainab. Anthropometry Group: L. Cheikh Ismail (Head), W. C. Chumlea (Senior External Advisor), J. Kizidio, B. Monyepote, F. Puglia, M. Salim, R. Salam, V. I. Carrara. Laboratory Group: R. Craik (Head), D. Alam, Y. Guman, J. Kilonzo, A. Min, V. Ngami, I. Olivera, G. Deutsch. Neonatal Group: Z. A. Bhutta (Head), E. Bertino, F. Giuliani, R. Uauy. Environmental Health Group: B. Eskenazi (Head), J. Villar. Neurodevelopment Group: A. Stein (Head), M. Fernandes (Coordinator), A. Abubakar, J. Acedo, L. Aranzeta, L. Cheikh Ismail, F. Giuliani, D. Ibanez, S. H. Kennedy, M. Kihara, E. de Leon, C. R. Newton, S. Savini, A. Soria-Frisch, J. Villar, K. Wulff. INTERBIO-21st participating countries and local investigators: Brazil: F.C. Barros (Principal Investigator), M. Domingues, S. Fonseca, A. Leston, A. Mitidieri, D. Mota, I. K. Sclowitz, M. F. da Silveira. Kenya (Kilifi): J. A. Berkley (Principal Investigator), B. Kemp, H. Barsosio, S. Mwakio, H. Mwangudzah, V. Ngami, M. Salim, A. Seale, L. Walusuna. Kenya (Nairobi): M. Carvalho and W. Stones (Co-Principal Investigators), D. Muninzwa, J. Kilonzo, J. Kizidio, R. Ochieng, J. Sande, J. Shah. Pakistan: Z. Bhutta and S. Munim (Co-Principal Investigators), I. Ahmed, D. Alam, A. Raza, R. Salam, G. Zainab. South Africa: S. Norris (Principal Investigator), Y. Guman, T. Lephoto, S. Macauley, L. Malgas. Thailand: F. Nosten (Principal Investigator), N. Jackson, R. McGready, A. Min, V. I. Cararra, S. Wiladphaingern. UK: S. H. Kennedy (Principal Investigator), S. Ash, M. Baricco, A. Capp, L. Cheikh Ismail, R. Craik, S. Hussein, A. Laister, A. Lambert, T. Lewis, E. Maggiora, R. Napolitano, T. Norris, A. T. Papageorghiou, B. Patel, F. Puglia, F. Roseman, S. Roseman, M. Sharps, A. Varalda, R. Carew. Full acknowledgement of all those who contributed to the development of the project protocol appears at www.interbio21.org.uk.

Author information

Authors and Affiliations

Authors

Contributions

J.V., S.H.K., Z.A.B., A.T.P., C.G.V., F.C.B., J.A.B., F.N. and R.U. designed the study with input from M.F., L.C.I. and A.S. C.O.O.T.M., F.N., R.O., R.M., F.C.B., M.F., V.I.C., S.M., H.C.B., M.C., J.A.B., S.A.N., L.C.I. and R.C. oversaw data collection. The data were curated by M.C.R.M., E.O.O., L.C.I. and S.R. R.C., L.C.I., A.L. and A.W. coordinated the study. R.G., S.R., B.E., M.C.R.M., E.O.O., A.T.P., J.V. and F.C.B. analyzed the data. J.V., S.H.K., A.T.P., A.W., Z.A.B., R.M. and B.E. wrote the first draft of the paper, and all other authors contributed and revised it critically for important intellectual content. All authors approved the final version for publication. Funding was acquired by J.V. and S.H.K.

Corresponding author

Correspondence to José Villar.

Ethics declarations

Competing interests

The authors have no competing interests as defined by Nature Research or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Additional information

Peer review information Nature Medicine thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2 and Supplementary Tables 1–7.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Villar, J., Gunier, R.B., Tshivuila-Matala, C.O.O. et al. Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study. Nat Med 27, 647–652 (2021). https://doi.org/10.1038/s41591-021-01280-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-021-01280-2

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing