Fetal constraint as a potential risk factor for craniosynostosis
Open accessAbstract
Non‐syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi‐site case–control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post‐term gestational age (≥42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single‐gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint‐related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint‐related factors. © 2010 Wiley‐Liss, Inc.
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Epidemiological studies have identified demographic and environmental associations with sCS, including male sex, advanced maternal age, and specific prenatal exposures such as maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies.
“Epidemiological studies have identified several demographic and environmental associations, such as male sex, advanced maternal age, and specific prenatal exposures including maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies [15, 26–35].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
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Experimental — accuracy not yet measuredThe relative contribution of genetic and environmental factors in the pathogenesis of sagittal synostosis remains unclear, and current evidence is fragmented and often limited by small sample sizes or investigation of isolated risk factors.
“Despite these findings, the relative contribution of genetic and environmental factors in the pathogenesis of sagittal synostosis remains unclear. Current evidence is fragmented and often limited by small sample sizes or the investigation of isolated risk factors [10, 29, 31, 36].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
The Introduction says no population-based study had directly assessed fetal-constraint factors in nonsyndromic craniosynostosis, and the Discussion says the underlying causes need further investigation. This supports uncertainty and investigation of selected risk factors, but the paper does not characterize the evidence on sagittal synostosis generally as fragmented or often limited by small samples; it describes its own study as the largest population-based study to date. (LLM, conf=0.82)
Experimental — accuracy not yet measuredVery low birth weight <2500 g is correlated with sCS, with OR=1.5-2.32.
“At birth, there are some phenotypes that has been seen to correlate with sCS, from high weight at birth ≥ 4000 g (OR 1.61–2.91) [2, 82] to very low birth weight < 2500 g (OR = 1.5–2.32) [29, 102]), also to breech presentation (OR = 2.39) [63, 102].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
The Results (page unavailable) report that low birth weight was associated with increased craniosynostosis risk when all suture types were analyzed together. The passages in our copy do not establish the <2500 g cutoff or the claimed odds-ratio range of 1.5–2.32. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRace and ethnicity have been reported as modifiers of sagittal craniosynostosis (sCS) risk.
“In addition, race and ethnicity have also been reported as modifiers of sCS risk. Several studies consistently report a higher prevalence among individuals of white race [29, 93], whereas lower risks have been observed in black (OR = 0.2), Hispanic (OR = 0.4), and other racial or ethnic groups (OR = 0.6) [56, 96].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
The Results report that mothers of craniosynostosis cases were more likely than control mothers to be non-Hispanic white (74% versus 60%), and the Discussion notes a non-Hispanic white predominance among cases. These findings concern craniosynostosis across suture types; the passages do not establish race or ethnicity as modifiers of sagittal craniosynostosis risk specifically or report the quoted odds ratios for other groups. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFertility treatments correlate with increased presence of only sagittal synostosis if there is a twin gestation, with OR 1.6.
“It has been reported also that fertility treatments correlate to an increased presence of only sagittal synostosis if there is a twin gestation OR 1.6 [29].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
The Discussion (page unavailable) reports an association between plurality and sagittal synostosis when cases involving fertility treatments were included. It does not establish that fertility treatments themselves increase sagittal synostosis risk in twin gestations. The Results (page unavailable) instead give an adjusted OR of 2.1 for sagittal cases among twins or higher-order births after mothers who had fertility treatments were excluded, not the claimed OR of 1.6. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Several studies consistently report a higher prevalence of sCS among individuals of white race.
“Several studies consistently report a higher prevalence among individuals of white race [29, 93]”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [29]
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References 44 · Cited by 106
- Authors
- Sanchez‐Lara, P. A., Carmichael, S. L., Graham, J. M., Lammer, E. J., Shaw, G. M., Ma, C., & Rasmussen, S. A.
- Affiliations
- March of Dimes (US)
- Cedars-Sinai Medical Center (US)
- Centers for Disease Control and Prevention (US)
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2010-01-25
- Volume
- 152A
- Issue
- 2
- Pages
- 394-400
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- PMC
- PMC2815148
- OpenAlex
- W2078555692
- Cited by
- 106
- References
- 44
- Citations by year
- 2026: 10 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 9 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 9 · 2014: 4 · 2013: 1 · 2012: 7
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Robert Wood Johnson Foundation
- National Institutes of Health
- Centers for Disease Control and Prevention (1u01dd000489-01)
- U.S. Public Health Service (U50/CCU925286)
- National Institute of General Medical Sciences (5-T32-GM08243, T32GM008243)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 22657, P01HD022657, K12-HD05954, K12HD052954)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Cleft Lip and Palate Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- craniosynostosis, metopic craniosynostosis, coronal craniosynostosis, twins, macrosomia, nulliparity, preterm birth, low birth weight, nonsyndromic craniosynostosis, risk factors
- MeSH terms
- Congenital Abnormalities, Birth Weight, Craniosynostoses, Female, Fetal Growth Retardation, Gestational Age, Humans, Infant, Newborn, Male, Pregnancy, Pregnancy Complications, Risk, Risk Factors, Odds Ratio, Case-Control Studies
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