Maternal alcohol consumption during pregnancy associates with bone fractures in early childhood. A birth-cohort study of 6718 participants

Parviainen, Roope; Auvinen, Juha; Serlo, Willy; Järvelin, Marjo‐Riitta; Sinikumpu, Juha‐Jaakko

doi:10.1016/j.bone.2020.115462

Cited by 10 publications

(6 citation statements)

References 32 publications

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“…In a sheep model of PAE, similar reductions in tibial and femoral strength have also been observed, yet sex differences have not been reported [ 32 , 33 ]. A study in FASD children has shown that they are more prone to fracture during early childhood, yet skeletal investigations in adults have not been performed [ 24 ]. Given these observations in preclinical models, further studies are warranted in human cohorts and to ensure that sex-stratification is included to delineate any potential sexual dimorphism.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Biol Sex Differ

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Background Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. Methods Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology. Results Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. Conclusions Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

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Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Biol Sex Differ

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“…A comparison with the facial phenotype of the birth parents is not possible because there is no contact with them. There is an increased risk of fractures for children with FASD up to about eight years of age (174). The patient's pelvic fracture occurred a few years later than the calculated risk age (173).…”

Section: Importance Of Cgcg In the Diagnosis Of Jcs In Nf1mentioning

confidence: 92%

Neurofibromatosis Type 1 With Cherubism-like Phenotype, Multiple Osteolytic Bone Lesions of Lower Extremities, and Alagille-syndrome: Case Report With Literature Survey

Friedrich

Zustin

Luebke

et al. 2021

In Vivo

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Background/Aim: Neurofibromatosis type 1 (NF) is an autosomal dominant hereditary disease. The cardinal clinical findings include characteristic skeletal alterations. Difficulties in diagnosis and therapy can arise if an individual has further illnesses. Case Report: This is a case report of a 16-year-old patient affected by NF1. She also suffered from Alagille syndrome and the consequences of fetal alcohol exposure. The patient's facial phenotype showed findings that could be assigned to one or more of the known diseases. The patient was referred for treating a cherubismlike recurrent central giant cell granuloma (CGCG) of the jaw. The patient developed bilateral, multilocular nonossifying fibromas (NOF) of the long bones of the lower extremity. Treatment of the skeletal lesions consisted of local curettage. While NOF regressed after surgery, the CGCG of the jaw remained largely unchanged. Extensive genetic tests confirmed a previously unknown germline mutation in the JAG1 gene, the germline mutation of the NF1 gene, and the somatic mutation in the NF1 gene in the diffuse plexiform neurofibroma, but not in the CGCG. Conclusion: Assigning facial findings to a defined syndrome is ambiguous in many cases and especially difficult in patients who have multiple diseases that can affect the facial phenotype. Surgical therapy should be adapted to the individual findings.Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder (1). The disease has a high penetrance (about 100%). However, the phenotype is extremely variable (2). The NF1 gene is located on chromosome 17q11.2 (3, 4). NF1 is a tumor suppressor gene syndrome (5) and the most common monogenetic disease predisposing to cancer (1). NF1 is primarily characterized by multiple skin tumors. The tumors are of neurogenic origin termed neurofibroma. Somatic mutations of NF1 gene in neurofibroma arise in Schwann cells or precursors of Schwann cells. Since Schwann cells originate from the neural crest, NF1 is rated among the diseases that are characterized by mutations in neural crest cells (6). The frequent and numerous neoplasms of NF1 patients arise primarily from the connective soft tissues. Genetic studies show that many of the different neoplasms arising in NF1 patients meet the criteria of somatic allelic loss of NF1 gene according to Knudson's two-hit hypothesis of tumor development (7). However, the unusual variety of symptoms and findings in NF1 patients go far beyond the spectrum of neoplastic lesions (1). Most cases are diagnosed by clinical examination (Table I). Diagnosis and treatment of NF1 patients can be made more difficult if other diseases develop in the same individual and 1711 This article is freely accessible online.

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“…However, animal studies have suggested that even low levels of alcohol exposure are deleterious to bone development independent of the effect on foetal growth [46]. In a large prospective birth cohort study in Finland, moderate maternal alcohol consumption was associated with a more than two-fold increased risk of fracture before 8 years of age [47], but to our knowledge, there are no studies assessing pregnancy alcohol use and offspring BMD.…”

Section: Maternal Lifestyle In Pregnancy and Offspring Bone Healthmentioning

confidence: 94%

Early Life Programming of Skeletal Health

Moon,

Citeroni,

Aihie

et al. 2023

Curr Osteoporos Rep

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Purpose of Review Increasing bone mineral accrual during childhood might delay the onset of osteoporosis. We discuss the scientific evidence for early life approaches to optimising skeletal health. Recent Findings There is an ever-growing body of evidence from observational studies suggesting associations between early life exposures, particularly during foetal development, and bone mineral density (BMD). The findings of such studies are often heterogeneous, and for some exposures, for example, maternal smoking and alcohol intake in pregnancy or age at conception, intervention studies are not feasible. The most frequently studied exposures in intervention studies are calcium or vitamin D supplementation in pregnancy, which overall suggest positive effects on offspring childhood BMD. Summary Maternal calcium and/or vitamin D supplementation during pregnancy appear to have positive effects on offspring BMD during early childhood, but further long-term follow-up is required to demonstrate persistence of the effect into later life.

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Maternal alcohol consumption during pregnancy associates with bone fractures in early childhood. A birth-cohort study of 6718 participants

Cited by 10 publications

References 32 publications

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Neurofibromatosis Type 1 With Cherubism-like Phenotype, Multiple Osteolytic Bone Lesions of Lower Extremities, and Alagille-syndrome: Case Report With Literature Survey

Early Life Programming of Skeletal Health

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