Prenatal alcohol exposure and associations with physical size, dysmorphology and neurodevelopment: a systematic review and meta-analysis

Abstract

Background: Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria.

Methods: Six databases were searched (inception-February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size < 10, PAE determined via biological markers only, or no suitable comparison group. Summary data were extracted and associations between outcomes and standardised levels of PAE or FASD diagnosis determined using random-effects meta-analyses. Certainty of the evidence was assessed using GRADE.

Results: Of the 306 included studies, 106 reported physical size, 43 dysmorphology, 195 functional neurodevelopment and 110 structural/neurological outcomes, with 292 different outcomes examined. There was a dose-response relationship between PAE and head circumference, as well as measures of physical size, particularly at birth. There was also an association between higher PAE levels and characteristic sentinel facial dysmorphology, as well as many of the current functional neurodevelopmental outcomes considered during diagnosis. However, data were often lacking across the full range of exposures. There was a lack of evidence from studies examining PAE to support inclusion of non-sentinel dysmorphic features, social cognition, speech-sound impairments, neurological conditions, seizures, sensory processing or structural brain abnormalities (via clinical MRI) in diagnostic criteria. GRADE ratings ranged from very low to moderate certainty of evidence.

Conclusions: This comprehensive review provides guidance on which components are most useful to consider in the diagnostic criteria for FASD. It also highlights numerous gaps in the available evidence. Future well-designed pregnancy cohort studies should specifically focus on dose-response relationships between PAE and dysmorphology, neurodevelopment and brain structure/neurological outcomes.

Systematic review registration: PROSPERO: CRD42021230522.

Keywords: Birth weight; Diagnostic criteria; Dysmorphology; FASD; Facial features; Fetal alcohol spectrum disorder; Functional neurodevelopment; Head circumference; Prenatal alcohol exposure.

Fig. 1

PRISMA flow chart. # studies where exclusion reasons differed across outcomes. *Studies included in both exposure and diagnosed groups (n = 3). Note: Some studies reported on more than one diagnostic domain. ti = title, ab = abstract, and kw = keyword

Fig. 2

Association between prenatal alcohol exposure (PAE) and size at birth. A Small for gestational age. B Low birth weight. C Birth weight. D Birth length. GRADE Ratings: ⨁◯◯◯=very low certainty; ⨁⨁◯◯=low certainty; ⨁⨁⨁◯=moderate certainty. s=number of studies included in each meta-analysis. n=overall number of participants included in each meta-analysis. OR=odds ratio [95% confidence interval (CI)]. MD=mean difference [95% CI]. I²=indicator of heterogeneity

Fig. 3

Association between prenatal alcohol exposure (PAE) and neurodevelopmental measures related to behaviour and executive function. A Externalising attention. B Measures of executive function. C Caregiver-reported measures of behaviour. D Measures of working memory. Test details provided in Additional file 1: p 90. Lower scores indicate better performance for (A) and (C); higher scores indicate better performance for (B) and (D). GRADE Ratings: ⨁◯◯◯=very low certainty; ⨁⨁◯◯=low certainty; ⨁⨁⨁◯=moderate certainty; ⨁⨁⨁⨁=high certainty. s=number of studies included in each meta-analysis. n=overall number of participants included in each meta-analysis. OR=odds ratio [95% confidence interval (CI)]. MD=mean difference [95% CI]. I²=indicator of heterogeneity. NEPSY=NEuroPSYchological. WCST=Wisconsin Card Sorting Test. D-KEFS=Delis-Kaplan Executive Function System. WISC-III=Wechsler Intelligence Scale for Children

Fig. 4

Association between prenatal alcohol exposure (PAE) and neurodevelopmental measures of motor function and academic performance. A Language abilities. B Overall academic achievement. C Motor function. D General intellectual abilities. Test details are provided in Additional file 1: (p 90). Higher scores indicate better performance for all measures. GRADE Ratings: ⨁◯◯◯=very low certainty; ⨁⨁◯◯=low certainty; ⨁⨁⨁◯=moderate certainty; ⨁⨁⨁⨁=high certainty. s=number of studies included in each meta-analysis. n=overall number of participants included in each meta-analysis. OR=odds ratio [95% confidence interval (CI)]. MD=mean difference [95% CI]. I²=indicator of heterogeneity. BSID-III=Bayley’s Scales of Infant Development. CELF-P=Clinical Fundamentals of Language Preschool. PPVT-R=Peabody Picture Vocabulary Test-Revised. NEPSY=NEuroPSYchological. VMI=Visual Motor Integration

Fig. 5

Association between prenatal alcohol exposure (PAE) and head circumference. A Head circumference (cm) at birth and post-natally. B Head circumference at birth as a percentile. C Odds ratio of small post-natal head circumference (<10th percentile).GRADE Ratings: ⨁◯◯◯=very low certainty; ⨁⨁◯◯=low certainty; ⨁⨁⨁◯=moderate certainty; ⨁⨁⨁⨁=high certainty. s=number of studies included in each meta-analysis. n=overall number of participants included in each meta-analysis. OR=odds ratio [95% confidence interval (CI)]. MD=mean difference [95% CI]. I²=indicator of heterogeneity