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High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study

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Abstract

Purpose

We investigated the association between maternal use of folic acid (FA) during pregnancy and child anthropometric measures at birth.

Methods

We included 2302 mother–child pairs from a population-based birth cohort in Spain (INMA Project). FA dosages at first and third trimester of pregnancy were assessed using a specific battery questionnaire and were categorized in non-user, < 1000, 1000–4999, and ≥ 5000 µg/day. Anthropometric measures at birth (weight in grams, length and head circumference in centimetres) were obtained from medical records. Small for gestational age according to weight (SGA-w), length (SGA-l) and head circumference (SGA-hc) were defined using the 10th percentile based on Spanish standardized growth reference charts. Multiple linear and logistic regression analyses were used to explore the association between FA dosages in different stages of pregnancy and child anthropometric measures at birth.

Results

In the multiple linear regression analysis, we found a tendency for a negative association between the use of high dosages of FA (≥ 5000 µg/day) in the periconceptional period of pregnancy and weight at birth compared to mothers who were non-users of FA (β = − 73.83; 95% CI − 151.71, 4.06). In the multiple logistic regression, a greater risk of SGA-w was also evident among children whose mothers took FA dosages of 1000–4999 (OR = 2.21; 95% CI 1.17, 4.19) and of ≥ 5000 µg/day (OR = 2.32; 95% CI 1.06, 5.08) compared to mothers non-users of FA in the periconceptional period of pregnancy.

Conclusion

Our findings suggest that a high dosage of FA (≥ 1000 µg/day) may be associated with an increased risk of SGA-w at birth.

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Acknowledgements

We would like to appreciate the English revision made by Mr. Jonathan Whitehead. The full list of the institutions is: CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Public Health, History of Medicine and Gynecology, Universidad Miguel Hernández, Alicante Institute for Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain; Pediatric Service, Hospital San Agustin, Avilés, Asturias, Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Instituto de Investigación Sanitaria, BIODONOSTIA, San Sebastian; Departamento de Medicina Preventiva y Salud Pública, Universidad del País Vasco UPV-EHU; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona (Spain); Universitat Pompeu Fabra (UPF), Barcelona (Spain); Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, The Netherlands; Department of Medicine, Universidad de Oviedo, Oviedo, Asturias, Spain; Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain; Department of Medicine, Universitat Jaume I, Castellón de la Plana, Spain.

Author information

Author notes

  1. Eva María Navarrete-Muñoz and Desirée Valera-Gran contributed equally.

Authors and Affiliations

  1. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

    Eva María Navarrete-Muñoz, Garcia-de-la-Hera Manuela, Isolina Riaño, Mario Murcia, Aitana Lertxundi, Mònica Guxens, Adonina Tardón, Pilar Amiano, Martine Vrijheid, Marisa Rebagliato & Jesus Vioque

  2. Department of Public Health, History of Medicine and Gynecology, Alicante Institute for Health and Biomedical Research (ISABIAL–FISABIO Foundation), Universidad Miguel Hernández, Ctra. Nacional 332 S/n, Sant Joan D’alacant, 03550, Alicante, Spain

    Eva María Navarrete-Muñoz, Desirée Valera-Gran, Garcia-de-la-Hera Manuela, Sandra Gonzalez-Palacios & Jesus Vioque

  3. Pediatric Service, Hospital San Agustin, Avilés, Asturias, Spain

    Isolina Riaño

  4. Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain

    Mario Murcia & Marisa Rebagliato

  5. Instituto de Investigación Sanitaria, BIODONOSTIA, San Sebastian, Spain

    Aitana Lertxundi

  6. Departamento de Medicina Preventiva y Salud Pública, Universidad del País Vasco UPV-EHU, Leioa, Spain

    Aitana Lertxundi

  7. ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain

    Mònica Guxens & Martine Vrijheid

  8. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Mònica Guxens & Martine Vrijheid

  9. Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Mònica Guxens

  10. Department of Medicine, Universidad de Oviedo, Oviedo, Asturias, Spain

    Adonina Tardón

  11. Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain

    Pilar Amiano

  12. Department of Medicine, Universitat Jaume I, Castellón de la Plana, Spain

    Marisa Rebagliato

Authors
  1. Eva María Navarrete-Muñoz
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  2. Desirée Valera-Gran
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  3. Garcia-de-la-Hera Manuela
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  5. Isolina Riaño
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  6. Mario Murcia
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  7. Aitana Lertxundi
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  8. Mònica Guxens
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  13. Jesus Vioque
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Consortia

On behalf of the INMA Project

Contributions

EMNM and JV conceived the study. EMNM, DVG and JV conducted the data analysis and prepared the manuscript; MGH contributed to the conceptual approach and manuscript preparation; SGP and MGH assisted with the nutritional data and provided feedback; JV designed the FFQ and contributed to manuscript preparation; MG, PA, AT, MR and JV supervised the data collection, obtained funding, helped with data interpretation and manuscript preparation. Critical revision of the manuscript for important intellectual content: EMNM, DVG, MGH, SGP, MG, MV, IR, AT, PA, AL, MR, JV.

Corresponding author

Correspondence to Jesus Vioque.

Ethics declarations

Funding

This study was funded by grants from Instituto de Salud Carlos III and Spanish Ministry of Health (Red INMA G03/176; CB06/02/0041; FIS 97/0588; 00/0021-2, PI061756; PS0901958; FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314; 09/02647; FIS-PI041436, FIS-PI081151, FIS-PI06/0867; FIS-PS09/00090, FIS-PI042018, FIS-PI09 02311, FIS PI11/01007, FISPI13/02429) Universidad de Oviedo, Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya-CIRIT 1999SGR 00241,Department of Health of the Basque Government (2005111093 and 2009111069), the Provincial Government of Guipuzcoa (DFG06/004 and DFG08/001).

Conflict of interest

All authors declared that they have no conflict os interest.

Ethics approval

This study was conducted with the approval of the The Institut Municipal d’Investigació Mèdica (Barcelona), the Asturian Regional Ethics Committee (Asturias), Hospital La Fe (Valencia) and Hospital Donostia (Gipuzkoa).

Additional information

For a complete list of INMA project researchers: http://www.proyectoinma.org/presentacion-inma/listado-investigadores/en_listado-investigadores.html.

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Navarrete-Muñoz, E.M., Valera-Gran, D., Garcia-de-la-Hera, M. et al. High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study. Eur J Nutr 58, 241–251 (2019). https://doi.org/10.1007/s00394-017-1588-7

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