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


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.

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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.

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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.


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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

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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.

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Correspondence to José Villar.

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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.

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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).

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