CoChat
Sign Up
Cited by 34Sexual Differentiation and DisordersBirth, Development, and HealthFetal and Pediatric Neurological Disorders

First trimester prenatal dexamethasone treatment is associated with alterations in brain structure at adult age

Open access
van’t Westeinde, Annelies, Karlsson, Leif, Nordenström, Anna, Padilla, Nelly, Lajic, Svetlana·2020·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa340PMC PMC7304558
Open this paper in CoChat — free account

Abstract

Context: Prenatal treatment of human disease is rare. Dexamethasone (DEX) is used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in an affected female fetus. The safety and long-term consequences of prenatal DEX exposure on the brain are largely unknown. Objective: We investigate whether first-trimester prenatal DEX treatment is associated with alterations in brain structure at adult age, and if these alterations are associated with DNA methylation, mood, and cognitive abilities. Design, Setting, and Participants: T1-weighted and diffusion-weighted imaging scans, from a single research institute, are compared between 19 (9 women) first-trimester DEX-treated individuals, at risk of CAH but not having CAH, and 43 (26 women) controls (age range, 16.0-26.4 years). Results: DEX-treated participants showed bilateral enlargement of the amygdala, increased surface area and volume of the left superior frontal gyrus, and widespread increased radial, mean, and axial diffusivity of white matter, in particular in the superior longitudinal fasciculi and corticospinal tracts. In the DEX-treated group, increased mean and radial diffusivity correlated with increased methylation of the promotor region of the FKBP5 gene. There were no group differences in cognition or in scales assessing depression or anxiety, and the relationship between brain structure and cognition did not differ between DEX-treated and controls. Conclusions: First-trimester prenatal DEX treatment is associated with structural alterations of the brain at adult age, with an accompanying change in gene methylation. The findings add to the safety concerns of prenatal DEX treatment in the context of CAH.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/clinem/dgaa340

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Negative effects on glucose and lipid metabolism in childhood and in young adulthood have been reported in individuals without CAH but exposed to Dex during the first trimester.

    “Negative effects on glucose and lipid metabolism in childhood and in young adulthood have been reported in individuals without CAH but exposed to Dex during the first trimester.”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [487]

    The Discussion reports brain-structure changes in adults without CAH after first-trimester DEX exposure, but does not report glucose or lipid outcomes. Searches for glucose, lipid metabolism, and related metabolic outcomes found no passage addressing the claimed effects in childhood or young adulthood. The indexed passages provide section labels but no page numbers. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 53

  1. [1]White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000; 21(3): 245- 291. 10857554
  2. [4]Gidlöf S, Wedell A, Guthenberg C, von Döbeln U, Nordenström A. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr. 2014; 168(6): 567- 574. 24733564
  3. [5]Nordenström A, Servin A, Bohlin G, Larsson A, Wedell A. Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2002; 87(11): 5119- 5124. 12414881
  4. [6]Forest MG, Bétuel H, David M. Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: up-date 88 of the French Multicentric Study. Endocr Res. 1989; 15(1-2): 277- 301. 2667968
  5. [7]Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043- 4088. 30272171 PMC6456929
  6. [8]Miller WL. Fetal endocrine therapy for congenital adrenal hyperplasia should not be done. Best Pract Res Clin Endocrinol Metab. 2015; 29(3): 469- 483. 26051303
  7. [9]McCann-Crosby B, Placencia FX, Adeyemi-Fowode O, et al. Challenges in prenatal treatment with dexamethasone. Pediatr Endocrinol Rev. 2018; 16(1): 186- 193. 30371037 PMC6786883
  8. [10]Lajic S, Karlsson L, Nordenström A. Prenatal treatment of congenital adrenal hyperplasia: long-term effects of excess glucocorticoid exposure. Horm Res Paediatr. 2018; 89(5): 362- 371. 29742490
  9. [11]Hirvikoski T, Nordenström A, Lindholm T, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab. 2007; 92(2): 542- 548. 17148562
  10. [13]Karlsson L, Nordenström A, Hirvikoski T, Lajic S. Prenatal dexamethasone treatment in the context of at risk CAH pregnancies: long-term behavioral and cognitive outcome. Psychoneuroendocrinology. 2018; 91: 68- 74. 29529521
  11. [14]Sidman RL, Rakic P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. 1973; 62(1): 1- 35. 4203033
  12. [15]Karlsson L, Barbaro M, Ewing E, Gomez-Cabrero D, Lajic S. Epigenetic alterations associated with early prenatal dexamethasone treatment. J Endocr Soc. 2019; 3(1): 250- 263. 30623163 PMC6320242
  13. [17]Stonawski V, Frey S, Golub Y, et al. Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children. Dev Psychopathol. 2019; 31(2): 419- 431. 29606180
  14. [18]Wrigglesworth J, Ryan J, Vijayakumar N, Whittle S. Brain-derived neurotrophic factor DNA methylation mediates the association between neighborhood disadvantage and adolescent brain structure. Psychiatry Res Neuroimaging. 2019; 285: 51- 57. 30771753
  15. [19]Chen D, Meng L, Pei F, Zheng Y, Leng J. A review of DNA methylation in depression. J Clin Neurosci. 2017; 43: 39- 46. 28645747
  16. [21]Joëls M. Corticosteroids and the brain. J Endocrinol. 2018; 238(3): R121- R130. 29875162
  17. [22]Davis EP, Sandman CA, Buss C, Wing DA, Head K. Fetal glucocorticoid exposure is associated with preadolescent brain development. Biol Psychiatry. 2013; 74(9): 647- 655. 23611262 PMC3985475
  18. [23]Li J, Wang ZN, Chen YP, et al. Late gestational maternal serum cortisol is inversely associated with fetal brain growth. Neurosci Biobehav Rev. 2012; 36(3): 1085- 1092. 22206902
  19. [24]Buss C, Poggi Davis E, Shahbaba B, Pruessner JC, Head K, Sandman CA. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proc Nat Acad Sci. 2012; 109(20): E1312- E1319. 22529357 PMC3356611
  20. [25]Buss C, Davis EP, Muftuler LT, Head K, Sandman CA. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6-9-year-old children. Psychoneuroendocrinology. 2010; 35(1): 141- 153. 19674845 PMC2795128
  21. [26]Kim DJ, Davis EP, Sandman CA, et al. Prenatal maternal cortisol has sex-specific associations with child brain network properties. Cereb Cortex. 2016; 27(11): 5230- 5241. PMC6084613 27664961
  22. [29]Nikolić I, Kostović I. Development of the lateral amygdaloid nucleus in the human fetus: transient presence of discrete cytoarchitectonic units. Anat Embryol. 1986; 174(3): 355- 360. 3766991
  23. [30]Karlsson L, Gezelius A, Nordenström A, Hirvikoski T, Lajic S. Cognitive impairment in adolescents and adults with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2017; 87(6): 651- 659. 28771762
  24. [34]Barkley RA. Barkley Deficits in Executive Functioning Scale (BDEFS for Adults). New York, NY: Guilford Press; 2011.
  25. [35]Pallant JF, Bailey CM. Assessment of the structure of the Hospital Anxiety and Depression Scale in musculoskeletal patients. Health Qual Life Outcomes. 2005; 3: 82. 16364179 PMC1343593
  26. [36]Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983; 67(6): 361- 370. 6880820
  27. [38]Smith SM, Jenkinson M, Johansen-Berg H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006; 31(4): 1487- 1505. 16624579
  28. [39]Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999; 9(2): 195- 207. 9931269
  29. [40]Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999; 9(2): 179- 194. 9931268
  30. [41]Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage. 2001; 14(1 Pt 1): 21- 36. 11525331
  31. [42]Douaud G, Smith S, Jenkinson M, et al. Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain. 2007; 130(Pt 9): 2375- 2386. 17698497
  32. [43]Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004; 23(Suppl 1): S208- S219. 15501092
  33. [48]Andersson JLR, Graham MS, Zsoldos E, Sotiropoulos SN. Incorporating outlier detection and replacement into a non-parametric framework for movement and distortion correction of diffusion MR images. Neuroimage. 2016; 141: 556- 572. 27393418
  34. [49]Smith SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002; 17(3): 143- 155. 12391568 PMC6871816
  35. [50]Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ. Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging. 1999; 18(8): 712- 721. 10534053
  36. [51]van’t Westeinde A, Karlsson L, Nordenström A, Paddila N, Lajic S. Data from: first trimester prenatal dexamethasone treatment is associated with alterations in brain structure at adult age. figshare. Deposited April 28, 2020. https://figshare.com/articles/vantWesteinde_DEXBrain_SupplementaryMaterials_docx/12205373 PMC7304558 32497228
  37. [52]Kang HJ, Kawasawa YI, Cheng F, et al. Spatio-temporal transcriptome of the human brain. Nature. 2011; 478(7370): 483- 489. 22031440 PMC3566780
  38. [53]Tsiarli MA, Rudine A, Kendall N, et al. Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in murine cerebral architecture and behavior. Transl Psychiatry. 2017; 7(6): e1153. 28608856 PMC5537650
  39. [54]Frahm KA, Peffer ME, Zhang JY, et al. Research resource: the dexamethasone transcriptome in hypothalamic embryonic neural stem cells. Mol Endocrinol. 2016; 30(1): 144- 154. 26606517 PMC4695633
  40. [55]Anacker C, Cattaneo A, Luoni A, et al. Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacology. 2013; 38(5): 872- 883. 23303060 PMC3672002
  41. [56]Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology. 1985; 117(6): 2505- 2511. 2998738
  42. [57]Wang Q, Verweij EW, Krugers HJ, Joels M, Swaab DF, Lucassen PJ. Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients. Brain Struct Funct. 2014; 219(5): 1615- 1626. 23748930
  43. [58]Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN. Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab. 2003; 88(4): 1760- 1765. 12679470
  44. [59]Teffer K, Semendeferi K. Human prefrontal cortex: evolution, development, and pathology. Prog Brain Res. 2012; 195: 191- 218. 22230628
  45. [60]Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev. 2010; 20(4): 327- 348. 21042938 PMC2989000
  46. [61]Constantinof A, Moisiadis VG, Kostaki A, Szyf M, Matthews SG. Antenatal glucocorticoid exposure results in sex-specific and transgenerational changes in prefrontal cortex gene transcription that relate to behavioural outcomes. Sci Rep. 2019; 9(1): 764. 30679753 PMC6346022
  47. [62]Symonds CS, McKie S, Elliott R, William Deakin JF, Anderson IM. Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI. Eur Neuropsychopharmacol. 2012; 22(12): 867- 874. 22521875
  48. [63]Matsusue Y, Horii-Hayashi N, Kirita T, Nishi M. Distribution of corticosteroid receptors in mature oligodendrocytes and oligodendrocyte progenitors of the adult mouse brain. J Histochem Cytochem. 2014; 62(3): 211- 226. 24309510 PMC3935446
  49. [64]Barres BA, Lazar MA, Raff MC. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development. 1994; 120(5): 1097- 1108. 8026323
  50. [65]Davis EP, Townsend EL, Gunnar MR, et al. Antenatal betamethasone treatment has a persisting influence on infant HPA axis regulation. J Perinatol. 2006; 26(3): 147- 153. 16467857
  51. [66]Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013; 16(1): 33- 41. 23201972 PMC4136922
  52. [68]Davies MN, Volta M, Pidsley R, et al. Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol. 2012; 13(6): R43. 22703893 PMC3446315
  53. [69]Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016; 41(1): 261- 274. 26250598 PMC4677131

Cited by

Sorted by citations

Authors
van’t Westeinde, A., Karlsson, L., Nordenström, A., Padilla, N., & Lajic, S.
Affiliations
  • Department of Women’s and Children’s Health, Karolinska Institutet, Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden
  • Karolinska University Hospital (SE)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-06-04
Volume
105
Issue
8
Pages
2575-2586
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa340
PMC
PMC7304558
OpenAlex
W3033020676
Cited by
34
References
11
Citations by year
2026: 3 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 9 · 2020: 2
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Marianne and Marcus Wallenberg Foundation
  • International Fund raising for Congenital Adrenal Hyperplasia
  • European Society for Pediatric Endocrinology
  • Stockholm County Council
  • Foundations of Lisa and Johan Grönberg
  • Stiftelsen Frimurare Barnhuset i Stockholm
  • Samariten, Jerringfonden, Sällskapet Barnavård
  • Wera Ekströms stiftelse för Pediatrikforskning
  • Erik and Edith Fernströms Stiftelse
  • Foundation for Research and Education in Pediatric Endocrinology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
dexamethasone, prenatal glucocorticoid exposure, congenital adrenal hyperplasia, first trimester, brain structure, amygdala enlargement, white matter diffusivity, superior longitudinal fasciculus, corticospinal tract, mood, cognitive function, neurodevelopmental effects
MeSH terms
Tacrolimus Binding Protein 5, Adolescent, Adrenal Hyperplasia, Congenital, Adult, Brain, Dexamethasone, Female, Humans, Male, Pregnancy, Pregnancy Trimester, First, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Virilism, Case-Control Studies, DNA Methylation, Tacrolimus Binding Proteins, Diffusion Magnetic Resonance Imaging, Fetal Therapies, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review