research on fetal alcohol syndrome (fas) indicates that

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• Published: 23 February 2023

Fetal alcohol spectrum disorders

• Svetlana Popova   ORCID: orcid.org/0000-0002-6308-1157 1 ,
• Michael E. Charness 2 , 3 , 4 , 5 ,
• Larry Burd 6 ,
• Andi Crawford 7 ,
• H. Eugene Hoyme 8 ,
• Raja A. S. Mukherjee 9 ,
• Edward P. Riley   ORCID: orcid.org/0000-0001-8747-891X 10 &
• Elizabeth J. Elliott 11 , 12  

Nature Reviews Disease Primers volume  9 , Article number:  11 ( 2023 ) Cite this article

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• Human behaviour
• Neonatal brain damage

Alcohol readily crosses the placenta and may disrupt fetal development. Harm from prenatal alcohol exposure (PAE) is determined by the dose, pattern, timing and duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use, and epigenetic responses. A safe dose of alcohol use during pregnancy has not been established. PAE can cause fetal alcohol spectrum disorders (FASD), which are characterized by neurodevelopmental impairment with or without facial dysmorphology, congenital anomalies and poor growth. FASD are a leading preventable cause of birth defects and developmental disability. The prevalence of FASD in 76 countries is >1% and is high in individuals living in out-of-home care or engaged in justice and mental health systems. The social and economic effects of FASD are profound, but the diagnosis is often missed or delayed and receives little public recognition. Future research should be informed by people living with FASD and be guided by cultural context, seek consensus on diagnostic criteria and evidence-based treatments, and describe the pathophysiology and lifelong effects of FASD. Imperatives include reducing stigma, equitable access to services, improved quality of life for people with FASD and FASD prevention in future generations.

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Introduction.

Alcohol consumption has occurred for centuries, with harms from prenatal alcohol exposure (PAE) being mentioned in Greek and biblical verses and depicted in the art and literature of the eighteenth and nineteenth centuries 1 , 2 . A French-language publication from 1968, which received little attention at the time, described perinatal death, prematurity, growth retardation, facial features and malformations in the offspring of women who consumed alcohol during pregnancy 3 . Unaware of the French publication, Jones et al. described a similar pattern of altered morphogenesis and function in 11 children of mothers with ‘alcoholism’ in the Lancet in 1973 (ref. 4 ). They reported specific facial features (thin upper lip, smooth philtrum (the vertical groove between the base of the nose and the border of the upper lip) and short palpebral fissures) and coined the term fetal alcohol syndrome (FAS) 5 . By 1977, the US government had issued a warning about the health risks of alcohol use during pregnancy, which was endorsed by professional organizations in the USA 6 , 7 . In 1981, the US Surgeon General issued stronger advice that “women who are pregnant (or considering pregnancy) not drink alcoholic beverages” 8 and other countries subsequently issued similar advice. The teratogenic effects of alcohol were subsequently confirmed in animal studies 9 .

Later studies found that, in addition to FAS, PAE could cause behavioural, cognitive and learning problems, such as attention deficit hyperactivity disorder (ADHD) and speech and language delay, in the absence of facial and other physical features 10 . Recognition of the disconnect between the neurodevelopmental and physical effects (which relate to first-trimester exposure) of PAE and the wide range of outcomes caused by PAE led to the introduction of the term fetal alcohol spectrum disorders (FASD) 11 . Subsequent research identified groups at increased risk of FASD 12 and associations between FASD and metabolic, immunological and cardiovascular diseases in adults 13 , 14 .

FASD occur in all socioeconomic and ethnic groups 15 and are complex, chronic conditions that affect health and family functioning 16 . Individuals with FASD usually require lifelong health care as well as social and vocational support. Some require remedial education and others interact with the justice system. Early diagnosis and a strength-based management approach will optimize health outcomes.

FASD are the most common of the potentially preventable conditions associated with birth anomalies and neurodevelopmental problems 13 , and their global effects, including huge social and economic costs, are substantial 17 . For example, in Canada, the annual cost associated with FASD is an estimated ~CAD$ 1.8 billion (CAD$ 1.3 billion to CAD$ 2.3 billion) 17 , which is attributable in part to productivity loss (41%), correction services (29%) and health care (10%). In North America, the lifetime cost of supporting an individual with FASD is estimated at >CAD$ 1 million 18 . Addressing and preventing alcohol use in pregnancy is a public-health imperative.

This Primer presents the epidemiology of FASD and the latest understanding of its pathophysiology as well as approaches to diagnosis, screening and prevention. The Primer also describes outcomes across the lifespan, management and quality of life (QOL) of people living with FASD, and highlights important areas for future research and clinical practice.

Epidemiology

Alcohol use during pregnancy.

No safe level of PAE has been established 19 , and international guidelines advise against any amount or type of alcohol use during pregnancy 20 , 21 , 22 , 23 . Nevertheless, ~10% of pregnant women worldwide consume alcohol 24 , 25 . The highest prevalence of alcohol use during pregnancy is in the WHO European Region (25.2% 24 ; Fig.  1 ), consistent with the prevalence of heavy alcohol use, heavy episodic drinking and alcohol use disorders in this region 26 .

The highest pooled prevalence (%) of alcohol use during pregnancy in the general population is estimated in the WHO European Region (25.2%, 95% CI 21.6–29.6), followed by the Region of the Americas (11.2%, 95% CI 9.4–12.6), the African Region (10.0%, 95% CI 8.5–11.8), the Western Pacific Region (8.6%, 95% CI 4.5–11.6) and the South-East Asia Region (1.8%, 95% CI 0.9–5.1), and the lowest prevalence is estimated in the Eastern Mediterranean Region (0.2%, 95% CI 0.1–0.9), where most of the population is of Muslim faith and the rates of abstinence from alcohol are very high. The pooled global prevalence of alcohol use during pregnancy in the general population is estimated at 9.8% (95% CI 8.9–11.1). Data from ref. 24 .

In 40% of the 162 countries evaluated, >25% of women who consumed any alcohol during pregnancy drank at ‘binge’ levels (defined as ≥4 US standard drinks containing 14 g of pure alcohol per drink on a single occasion). Binge drinking, which increases the risk of FASD, is common in early pregnancy and before pregnancy recognition 25 , 27 . Many fetuses are inadvertently exposed to alcohol because binge drinking is prevalent in young women, millions of women who consume alcohol report having unprotected sex and approximately half of all pregnancies are unplanned 28 , 29 , 30 , 31 . Alcohol use during pregnancy is higher in certain subpopulations, including some Indigenous populations in Australia (55%) 32 , South Africa (37%) 33 and Canada (60%) 34 , often in the context of disadvantage, violence and ongoing traumatic effects of colonization 35 .

Risk factors for maternal alcohol consumption

Various risk factors have been identified for maternal alcohol use in pregnancy, including higher gravidity and parity 36 , delayed pregnancy recognition, inadequate prenatal care or reluctance of health professionals to address alcohol use 37 , 38 , a history of FASD in previous children 38 , alcohol use disorder and other substance use (including tobacco) 39 , mental health disorders (such as depression) 39 , a history of physical or sexual abuse, social isolation (including living in a rural area during pregnancy), intimate partner violence 38 , 40 , alcohol and/or drug use during pregnancy by the mother’s partner 38 , 41 or other family members 38 , 41 , and poverty 42 .

Risk factors for alcohol use during pregnancy vary across countries and throughout the course of pregnancy. For example, in Australia, first-trimester alcohol use was associated with unplanned pregnancy 43 , age <18 years at first intoxication 30 , frequent and binge drinking in adolescence 44 , and current drinking and a tolerant attitude to alcohol use in pregnancy 45 . Women who continued to drink alcohol throughout pregnancy were more likely to be older, have higher socioeconomic status, salary and educational levels, smoke, have a partner who consumes alcohol, and have an unintended pregnancy than those who abstained, and were less likely to agree with guidelines that recommend avoiding alcohol use in pregnancy 30 , 31 , 46 , 47 .

FASD prevalence

The estimated global prevalence of FASD among the general population is 7.7 cases per 1,000 individuals 25 , 48 . Consistent with rates of alcohol use during pregnancy, FASD prevalence (Fig.  2 ) is highest in the WHO European Region (19.8 per 1,000) and lowest in the WHO Eastern Mediterranean Region (0.1 per 1,000) 25 , 48 . In terms of individual countries, South Africa (111.1 per 1,000), Croatia (53.3 per 1,000), Ireland (47.5 per 1,000), Italy (45.0 per 1,000) and Belarus (36.6 per 1,000) have the highest FASD prevalence, whereas Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates have no recorded cases of FASD 25 , 48 . Furthermore, 76 countries have a prevalence of FASD of >1% 25 , 48 , which exceeds the prevalence of neurodevelopmental conditions, including Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), spina bifida and anencephaly in the USA 49 , and is similar to the prevalence of autism spectrum disorders (1.1–2.5%) 50 .

In line with the prevalence of alcohol use during pregnancy, the highest pooled prevalence (per 1,000) of fetal alcohol spectrum disorders (FASD) was in the WHO European Region (19.8 per 1,000 population, 95% CI 14.1–28.0), followed by the Region of the Americas (8.8 per 1,000 population, 95% CI 6.4–13.2), the African Region (7.8 per 1,000 population, 95% CI 5.4–10.7), the Western Pacific Region (6.7 per 1,000 population, 95% CI 4.5–11.7) and the South-East Asia Region (1.4 per 1,000 population, 95% CI 0.6–5.3), and the lowest prevalence was estimated in the Eastern Mediterranean Region (0.1 per 1,000 population, 95% CI 0.1–0.5). The pooled global prevalence of FASD was estimated to be 7.7 (95% CI 4.9–11.7) per 1,000 in the general population. Data from refs. 25 , 48 .

Based on global epidemiological data, an estimated 1 in 13 women who consume alcohol while pregnant will deliver a child with FASD, resulting in the birth of ~630,000 children with FASD globally every year 48 . FASD confers lifelong disability, and an estimated >11 million individuals aged 0–18 years and 25 million aged 0–40 years have FASD 51 .

A systematic review and meta-analysis revealed that FASD prevalence is 10–40 times higher in some subpopulations than in the general population, including in children in out-of-home care and correctional, special education, and specialized clinical settings 12 (Fig.  3 ). The pooled prevalence of FASD among children in out-of-home or foster care is 25.2% in the USA and 31.2% in Chile (32-fold and 40-fold higher than the global prevalence, respectively) 12 . FASD prevalence among adults in the Canadian correctional system (14.7%) is 19-fold higher than in the general population, and the prevalence among special education populations in Chile (8.4%) is over 10-fold higher than in the general population 12 . Moreover, the prevalence of FASD is 62% among children with intellectual disabilities in care in Chile 52 , >50% in adoptees from Eastern Europe 53 , 54 and ~40% among children in Lithuanian orphanages 55 . The prevalence of FASD is 36% in one Australian youth correctional service 56 , >23% in Canadian youth correctional services 57 , >14% among USA populations in psychiatric care 58 and 19% in some remote Australian Indigenous communities 59 . The highest prevalence estimates for FAS (46–68%) are in children with developmental abnormalities in Russian orphanages 60 . The high prevalence of FASD in some subpopulations has prompted calls for targeted screening in these groups.

The pooled prevalence (per 1,000) of fetal alcohol spectrum disorders (FASD) is markedly higher in some subpopulations than in the general global population. Subpopulations with a high prevalence of FASD include children in out-of-home care, individuals involved with correctional services and those receiving special education. FAS, fetal alcohol syndrome.

Mechanisms/pathophysiology

Alcohol rapidly equilibrates between the maternal and fetal compartments and is eliminated primarily through maternal metabolism 61 . As previously mentioned, no safe level of PAE has been established 19 . Several developmentally important molecular targets of alcohol, including the L1 neural cell adhesion molecule and GABA A receptors, are disrupted at blood alcohol concentrations attained after one or two US standard drinks 62 , 63 , 64 , 65 , 66 . Hence, repeated exposure to low levels of alcohol or a single exposure at critical periods in gestation could affect development. Indeed, drinking ≤20 g of alcohol per occasion (≤1.5 US standard drinks) or ≤70 g alcohol per week (≤5 US standard drinks) was associated with mild facial dysmorphology (determined via 3D facial imaging) 67 , microstructural brain abnormalities, and externalizing behaviours such as aggression and violation of social norms 68 . The Adolescent Brain Cognitive Development (ABCD) Study, a large, prospective, longitudinal study of child and adolescent development, reported a dose-dependent association between low-level drinking during pregnancy, increased cerebral volume and regional cortical surface area, and a range of adverse cognitive, psychiatric and behavioural outcomes in children aged 9–10 years 69 . There was no inflexion point in the dose–response curves to suggest a cut-off for PAE effects, and significant effects were observed with as little as 1.1 US standard drinks per week throughout pregnancy. Increased brain volume was attributed to impairment of synaptic pruning in the preadolescent brain, consistent with research demonstrating the effect of PAE on trajectories of brain development 70 , 71 .

Genes associated with PAE

Several gene variants confer heightened risk or resilience to PAE 72 , 73 , 74 , and there is higher concordance for FAS among monozygotic than among dizygotic twins 74 . Genetic effects may be exerted through the mother and/or the fetus 72 . ADH1 (encoding alcohol dehydrogenase 1) polymorphisms, such as ADH1B*2 and ADH1B*3 , which increase alcohol metabolism and decrease blood alcohol levels, are associated with reduced risk of FASD 72 . Moreover, zebrafish with pdgfra (encoding platelet-derived growth factor receptor-α) haploinsufficiency have increased susceptibility to craniofacial malformations caused by PAE, which is mirrored in individuals with PDGFRA polymorphisms 75 . Similarly, haploinsufficiency of either Shh or Gli2 (a downstream effector of Shh ) is clinically silent in mice; however, PAE in these mice results in midline craniofacial malformations 76 . Interestingly, hypermethylation of GLI2 (which decreases GLI2 expression) was identified in genome-wide DNA methylation profiling of children with FASD 77 . Prenatal or postnatal choline supplementation improves cognition in animal models and clinical studies 78 and the effect of choline supplementation is modified by polymorphisms in SLC44A1 (encoding choline transporter-like protein 1) 79 .

Timing and quantity of PAE during gestation

The effects of PAE vary according to the quantity, frequency, duration, pattern and timing of exposure 80 . Periconceptional alcohol exposure can adversely affect fetal development and predispose to disease in later life 81 , 82 . PAE at different stages of organogenesis has distinct developmental consequences. PAE during first-trimester organogenesis may cause brain, craniofacial, skeletal and internal organ dysmorphology 80 . In mice, PAE during gastrulation (equivalent to the third week post-fertilization in humans, when an embryo transforms from a bilaminar disc to a multilayered structure comprising the three primary germ layers: ectoderm, mesoderm and endoderm) reproduces the sentinel craniofacial abnormalities of FAS: thin upper lip, smooth philtrum and short palpebral fissures 9 (Fig.  4 ). By contrast, alcohol exposure during neurulation (starting in gestational week three in humans, resulting in the folding of the neural plate to form the neural tube) produces a facial phenotype that resembles DiGeorge syndrome, a chromosomal disorder (22q11.2 deletion) associated with facial anomalies, immune dysfunction, cardiac defects and neurodevelopmental abnormalities 83 .

a , b , The facial phenotype of fetal alcohol spectrum disorders can be reproduced in a preclinical model. Comparable to the facial features of the child with fetal alcohol syndrome (FAS) (part a ), the mouse fetus exposed prenatally to alcohol shows a thin upper lip with a smooth philtrum, short palpebral fissures and a small midface (part b ). c , The normal features in a control mouse fetus (not prenatally exposed to alcohol). Part a courtesy of Sterling Clarren. Parts b and c adapted with permission from ref. 9 , AAAS.

The brain is vulnerable to PAE throughout pregnancy 84 , 85 . PAE after 8 weeks of gestation affects neurogenesis, differentiation of neural precursor cells, neuronal migration, pathfinding, synaptogenesis and axon myelination 72 , 85 , 86 but does not cause sentinel craniofacial dysmorphology or major organ defects. Thus, PAE after major organogenesis may result in a FASD phenotype with neurodevelopmental disorder but without physical alterations, making diagnosis difficult 80 . Nutritional deficiency during pregnancy may potentiate the effects of PAE on developmental outcomes, and maternal alcohol intake may further reduce the availability of developmentally important nutrients 87 .

Effects of PAE on the embryo and fetus

Brain development.

As previously mentioned, PAE can affect brain development 88 , 89 . Retrospective examination of 149 brains from individuals with PAE who died between birth and adulthood identified gross abnormalities in brain development causing microcephaly (a smaller than normal head for age and sex using population-based normative data, often associated with a smaller than normal brain (micrencephaly)) in 20.8%. This study found isolated hydrocephalus in 4.0% of individuals with PAE, corpus callosum defects in 4.0%, prenatal ischaemic lesions in 3.4%, minor subarachnoid heterotopias (the presence of normal tissue at an abnormal location, such as an ectopic cluster of neurons within the white matter, often due to abnormal neuronal migration during early brain development) in 2.7%, holoprosencephaly (whereby the embryonic forebrain fails to develop into two discrete hemispheres, often affecting midline brain and craniofacial structures) in 0.7% and lissencephaly (smoothness of the brain surface due to impaired development of cerebral gyri) in 0.7% 88 . Hence, because macroscopic neuropathology is not present in most individuals with FASD, microscopic neuropathology likely underlies many of the associated cognitive and behavioural abnormalities of this disorder. Studies in non-human primates show that first-trimester-equivalent alcohol exposure reduces brainstem and cerebellar volume and disrupts various white matter tracts, including one connecting the putamen and primary sensory cortex 90 . Third-trimester-equivalent alcohol exposure reduced hippocampal neuronal numbers in infant and juvenile Vervet monkeys 86 .

Brain structure

Relatively few macroscopic brain lesions have been identified in clinical neuroimaging studies of children with FASD 80 , 91 . Blind evaluation of clinical MRI studies by neuroradiologists identified clinically significant abnormalities in 3% of individuals with PAE or FASD and in 1% of typically developing controls 91 . Four of 61 patients with FAS had heterotopias 92 . By contrast, quantitative research imaging studies in groups of children with PAE and FASD have revealed region-specific increases or decreases in grey matter thickness, microstructural white matter abnormalities, and neuronal and glial migration defects 69 , 93 , 94 . Volume reduction is disproportionate in the cerebrum, cerebellum, caudate, putamen, basal ganglia, thalamus and hippocampus after accounting for overall reductions in brain volume 94 . Age-dependent decreases in cortical gyrification are also observed 94 , 95 , 96 and the corpus callosum can be hypoplastic, posteriorly displaced or, in rare cases, absent 94 , 97 , 98 , 99 , 100 . Moreover, studies using diffusion tensor imaging reveal reduced integrity of large white matter tracts, including in the corpus callosum, cerebellar peduncles, cingulum and longitudinal fasciculi 101 . Hypoplasia of the corpus callosum in children with FASD is associated with impaired interhemispheric transfer of information 102 .

Imaging studies have also demonstrated the effect of PAE on postnatal grey matter development 99 , 103 . Typical brain development is associated with a large increase in cortical grey matter during early childhood followed by loss of cortical grey matter during late childhood and adolescence via synaptic pruning, a process that reflects cortical plasticity 70 . By contrast, children with FASD show region-specific loss of grey matter and decreased gyrification from early childhood through adolescence 70 , 99 , 102 . This change may partly explain contradictory findings of increased or decreased grey matter volume in various studies, which sampled different brain regions during distinct developmental periods or evaluated populations with different levels of PAE 69 . A relatively small sample size is another source of variation in results among brain imaging studies 104 .

One frequently observed effect of PAE is the disruption of brain plasticity 105 . Animal models and human studies have demonstrated enduring deficits in learning and memory following PAE, associated with abnormal plasticity in hippocampal, thalamic, cortical and cerebellar circuits 105 , 106 , 107 . These deficits are associated with changes in alpha oscillations on magnetoencephalography, fractional anisotropy (a measure of white matter integrity) on diffusion tensor imaging, and functional and resting-state MRI in children with PAE 68 , 94 , 108 , 109 .

Craniofacial development

Brain and craniofacial development are mechanistically linked; therefore, brain and craniofacial abnormalities frequently co-occur 98 , 110 . For example, abnormalities of midline brain structures, such as the corpus callosum, diencephalon and septum, are associated with midline craniofacial abnormalities 98 , 103 , 110 . Craniofacial development relies on the highly choreographed migration of cranial neural crest cells and is most sensitive to PAE during the third week of gestation. Alcohol induces apoptosis of neural crest cells through oxidative injury and disruption of Sonic hedgehog (Shh) signalling 111 . Shh regulates embryonic morphogenesis and organogenesis, including the organization of cells of the central nervous system (CNS), limbs and other body parts. In animal models, diverse antioxidants and inhibitors of apoptosis mitigate the effects of alcohol on neural crest cells 112 , 113 .

Mechanisms of alcohol teratogenesis

Multiple mechanisms of alcohol-induced teratogenesis have been elucidated 9 , 80 , 114 , 115 (Fig.  5 ). Alcohol has protean effects on brain and craniofacial development in part because it is a weak drug that requires millimolar concentrations to produce even mild euphoria 116 . For example, in the USA, legal intoxication is defined as 17.4 mM or 0.08 g/dl; at these high concentrations, alcohol interacts with diverse molecules and signalling pathways that regulate development 117 .

Alcohol (ethanol) metabolism to acetaldehyde and acetic acid generates reactive oxygen species (ROS) that induce programmed cell death. During gastrulation, acetaldehyde competes with retinaldehyde for metabolism by retinaldehyde dehydrogenase 2 (RALDH2), reducing the biosynthesis of retinoic acid, a critical morphogen. Acetyl-CoA, a metabolite of acetic acid, acetylates histones and, therefore, modifies gene expression. Alcohol also alters epigenetic gene regulation through changes in DNA methylation. Moreover, alcohol disrupts neuronal–glial interactions, induces inflammatory changes in the developing brain and causes microencephaly partly by depletion of neural stem cells. Other effects of alcohol include the disruption of Shh signalling (an effect that is potentiated by cannabinoids) and disrupted neuronal migration. The effects of alcohol on the placenta contribute to intrauterine growth retardation and adverse neurodevelopmental outcomes. Modification of gut microbiota by alcohol may influence brain development through the action of circulating microbial by-products. Collectively, these actions of alcohol result in altered neural circuits and decreased neuronal plasticity. ADH, alcohol dehydrogenase; ALDH2, aldehyde dehydrogenase.

Epigenetic changes and disrupted development

Epigenetic changes are chemical modifications (methylation or acetylation) to DNA and surrounding histones that influence gene expression and often occur in response to environmental exposures 118 , 119 . Normal development depends on numerous epigenetic changes in embryonic stem cells that facilitate their transition to fully differentiated and functional cell lineages such as neurons, muscle and fat cells 120 . Alcohol can disrupt development by inducing DNA methylation and histone acetylation in gene clusters and altering gene expression 121 . Epigenetic alterations resulting from PAE have been observed in animal models and humans, and these changes may be lifelong and inherited by future generations 118 , 122 , 123 , 124 . A pattern of DNA methylation in buccal epithelial cells was reasonably accurate (positive predictive value 90%; negative predictive value 78.6%) in discriminating children with FASD from typically developing controls or children with autism spectrum disorders 125 . Large replication studies in different populations are required before this approach might be considered for diagnostic purposes.

Brain injury

Exposure of astrocytes to alcohol and metabolism of alcohol by cytochrome P450 2E1 result in the production of damaging reactive oxygen species 84 , 126 . Alcohol is metabolized to acetaldehyde, a toxin that causes DNA damage, epigenetic gene regulation, mitochondrial and proteosome dysfunction, and altered cellular metabolism 127 , 128 , 129 . Metabolism of acetaldehyde to acetate and then to acetyl-CoA modifies gene expression in the brain via increased histone acetylation 121 (Fig.  5 ).

Disruption of morphogens and growth factors

Retinoic acid is a critical morphogen (a signalling molecule that alters cellular responses to modulate patterns of tissue development), and its deficiency causes craniofacial defects similar to those of FASD 127 , 130 . Retinol is oxidized to retinaldehyde, which is subsequently oxidized by retinaldehyde dehydrogenase 2 (RALDH2) to retinoic acid (Fig.  5 ). During gastrulation, RALDH2 is the predominant enzyme for acetaldehyde metabolism. Therefore, acetaldehyde and retinaldehyde compete for RALDH2, reducing the synthesis of retinoic acid and inducing a state of retinoic acid deficiency, thereby promoting craniofacial defects associated with PAE 127 , 130 .

Another critical morphogen, Shh, is a downstream target of retinoic acid 72 , 130 . Genetic abnormalities of the Shh pathway cause holoprosencephaly syndrome, which is associated with abnormal midline craniofacial and brain development similar to that of FASD 72 , 76 . Alcohol exposure in chick embryos decreases Shh expression and induces craniofacial dysmorphology and cranial neural crest cell death; viral vector-mediated expression of Shh rescues these effects 111 . Alcohol exposure during neurulation of the mouse rostroventral neural tube disrupts the function of cilia, which transduce Shh signals by modulating the expression of genes that regulate ciliogenesis, protein trafficking and stabilization of primary cilia 131 , 132 . The associated dysmorphology in zebrafish can be mitigated by activating downstream elements in the Shh signalling pathway 133 . Alcohol also decreases cellular stores of cholesterol, thereby reducing the covalent binding of cholesterol to Shh (which is necessary for Shh secretion and function) 72 , 134 . These findings suggest that alcohol causes a transient ciliopathy, secondarily disrupting Shh signalling within cilia and producing craniofacial and brain dysmorphology 131 .

Disruption of neuronal and glial migration

PAE is associated with macroscopic and microscopic evidence of impaired neuronal and glial migration, including heterotopias (collections of aberrantly migrated neurons). Heterotopias are associated with seizures, and seizures or abnormal EEG results are reported in up to 25% of individuals with FASD 135 . The L1 neural cell adhesion molecule regulates neuronal migration, axon fasciculation and pathfinding in the developing brain 136 . Mutations in L1CAM (which encodes L1) cause neurodevelopmental abnormalities such as those observed in FASD, including hydrocephalus, hypoplasia or agenesis of the corpus callosum, and dysplasia of the anterior cerebellar vermis 64 . Alcohol inhibits L1-mediated cell adhesion by binding to specific amino acids at a functionally important domain in the extracellular portion of L1 (ref. 137 ). The sensitivity of L1 to alcohol is regulated by phosphorylation, which promotes L1 association with the cytoskeleton 62 , 138 . Importantly, molecules that block alcohol inhibition of L1 adhesion prevent the teratogenic effects of alcohol in mouse embryos 62 , 139 .

GABAergic interneurons comprise the principal inhibitory network of the brain. Alcohol enhances GABA A receptor-mediated depolarization of migrating GABAergic interneurons through activation of L-type voltage-gated calcium channels, thereby accelerating tangential migration 63 . Dysfunction of GABAergic interneurons may impair inhibitory control of brain networks. In mice, PAE during corticogenesis also disrupts radial migration and pyramidal cell development in the somatosensory cortex, which could be linked to decreased tactile sensitivity during adolescence 140 .

Effects on neural stem cells

Effects of PAE on neural stem cells (NSCs) may contribute to reduced brain volume in individuals with FASD. Alcohol causes cell death in differentiated neural cells but not in NSCs; rather, PAE depletes NSCs by blocking their self-renewal and accelerating their transition into more mature neural progenitors and differentiation into astroglial lineages 141 . PAE also selectively upregulates gene expression for the calcium-activated potassium channel Kcnn2 in neural progenitor cells from the motor cortex, and Kcnn2 blockers in adult mice reduced motor learning deficits 142 . Alcohol may trigger the maturation of NSCs by increasing the release of selected microRNAs (miRNAs) from extracellular vesicles in NSCs and activating certain pseudogenes that encode non-protein-coding RNAs 141 , 143 . Proteomic analysis revealed selective enrichment of extracellular vesicles for RNA-binding and chaperone proteins in alcohol-exposed NSCs 144 .

Disruption of neuronal–glial interactions

Brain growth and development are dependent on neuronal–glial interactions 84 , 85 . PAE decreases the proliferation of radial glial cells partly by decreasing Notch1 and fibroblast growth factor 2 receptor signalling 145 . This altered signalling reduces the density and fasciculation of radial glial fibres, which serve as a scaffold for migrating neurons 85 , 145 . PAE perturbs the maturation of oligodendroglia in human fetal brains, increasing the expression of markers of early oligodendroglia progenitors (Oct4 and Nanog) and decreasing the expression of markers of mature oligodendroglia (Olig1, Olig2 and myelin basic protein) 146 . Alcohol also increases apoptosis to a greater extent in oligodendroglia than in neurons 146 , 147 . As myelination is mediated by oligodendroglia, apoptosis of these cells might partly account for the effects of PAE on white matter integrity. The associated upregulation of oligodendroglia-derived chemokines (CXCL1/GRO, IL-8, GCP2/CXCL6, ENA78 and MCP1) could also affect neuronal survival 146 . Astroglial apoptosis is mediated by acetaldehyde toxicity, reactive oxygen species, reductions in the antioxidant glutathione and inflammatory signalling 85 .

Neuroinflammation

PAE activates an inflammatory response in the developing nervous system. Alcohol stimulates the production of reactive oxygen species in microglia and astrocytes, leading to neuronal apoptosis 84 . Moreover, alcohol stimulates the production of pro-inflammatory cytokines (such as IL-1β and TNF) and chemokines (such as CCL2 and CXCL1) through enduring epigenetic modifications that sustain a chronic neuroinflammatory response 119 (Fig.  5 ). Unique networks of pro-inflammatory cytokines in serum from women in the second trimester of pregnancy are markers of PAE and adverse neurodevelopmental outcomes 148 . The persistence of pro-inflammatory cytokines in childhood could predispose to autoimmune and inflammatory conditions later in life 149 . Similarly, PAE may hypersensitize microglia to increased inflammatory signalling, leading to an enduring, heightened neuroinflammatory response 84 .

Gut microbiota alterations

PAE may cause enduring changes in the gut microbiota 150 , and there is increasing recognition of the interplay between gut microbes and nervous system development and function. In a mouse model of PAE, gut microbial metabolites were detected in maternal plasma, fetal liver and fetal brain 151 . Further research is required to determine how effects of PAE on the gut microbiota influence development and later health.

Placental effects

Not all developmental effects of PAE result from the direct actions of alcohol on the developing nervous system. A retrospective autopsy study reported placental abnormalities in 68% of individuals with PAE or FASD 88 . PAE in humans decreases placental weight, epigenetic marks, vasculature and metabolism 81 . PAE during the first 60 of 168 days of gestation in rhesus macaques caused diminished placental perfusion and ischaemic placental injury from middle to late gestation 152 . RNA sequencing analysis revealed activation of inflammatory and extracellular matrix responses. Rats with PAE demonstrate reduced nitric oxide-mediated uterine artery relaxation, potentially contributing to dysregulation of uterine blood flow and intrauterine growth retardation 153 . miRNA act by silencing RNA and modifying post-transcriptional regulation of gene expression. A cluster of 11 extracellular miRNA from serum of women in the second trimester of pregnancy was a marker of PAE and predicted adverse neurodevelopmental outcomes in Ukrainian and South African populations 154 , 155 . Injection of the same 11 miRNAs into pregnant mice decreased placental and fetal growth, suggesting that they mediate the adverse outcomes of PAE 156 .

Synergistic effects of alcohol and other substances

PAE is often associated with prenatal exposure to other drugs. Among 174 individuals with PAE, almost all had prenatal nicotine exposure 88 . Nicotine and alcohol synergistically decrease birthweight and increase the risk of sudden infant death syndrome 157 . The legalization of cannabis has led to increases in the combined use of cannabinoids and alcohol during pregnancy 158 . Alcohol and cannabinoids synergistically increase the frequency of ocular defects in mice by disrupting separate elements in the Shh signalling pathway 132 . PAE and opioids each affect neurodevelopment, raising the possibility of additive or synergistic effects 159 . Alcohol also disrupts the developing blood–brain barrier, exposing the developing CNS to drugs and toxins that are normally excluded 160 .

Diagnosis, screening and prevention

Diagnosis of fasd, principles of diagnosis.

Diagnosis of FASD requires assessment of PAE, neurodevelopmental function and physical features, including facial features (Fig.  6 ). Timely, accurate diagnosis of FASD is crucial to enable early intervention and improve outcomes 161 , but there is no diagnostic test, biomarker or specific neurodevelopmental phenotype for FASD. Ideally, assessment and diagnosis should be conducted by a multidisciplinary team (MDT) comprising paediatricians, neuropsychologists, speech pathologists, occupational therapists, physiotherapists and social workers, with access to psychiatrists and geneticists/dysmorphologists. However, this approach is expensive, time consuming and unavailable to many children worldwide. Often, children present first to family physicians, paediatricians and psychologists who lack sufficient expertise to confidently diagnose FASD. Thus, education and training are urgently needed to increase the capacity for recognition of FASD outside specialist FASD assessment services 51 , 162 and to address its underdiagnosis and misdiagnosis 163 , 164 .

Fetal alcohol syndrome has three characteristic (sentinel) facial features: thin upper lip (with absent cupid bow), smooth philtrum (with absence of the normal midline vertical groove and lateral ridges extending from the base of the nose to the vermilion border of the upper lip) and short palpebral fissures (the space between the medial and lateral canthus of the open eye). Image created by Ria Chockalingam using an image from Generated Photos and modified with Adobe Photoshop.

Approaches to the diagnosis of FASD

The most commonly used diagnostic systems for FASD are the Collaboration on FASD Prevalence (CoFASP) Clinical Diagnostic Guidelines 10 , the University of Washington 4-Digit Diagnostic Code 165 , 166 and the Canadian Guidelines 167 (Table  1 ). The Canadian Guidelines have been adapted for use in Australia 168 and the UK 169 and are also used in New Zealand 170 . Guidelines have also been recommended by the US Centers for Disease Control and Prevention 171 , the State Agency for Prevention of Alcohol-Related Problems (PARPA) in Poland 172 , and The German Federal Ministry of Health 173 .

All diagnostic systems recommend evaluating PAE, facial and non-facial dysmorphology, and CNS structure and function using an MDT approach. Although all these systems recommend assessing otherwise unexplained prenatal and postnatal growth restriction, the Canadian and derivative guidelines exclude growth as a diagnostic criterion. The diagnostic systems differ in their definitions of PAE, thresholds for individual diagnostic elements, required combination of elements to confirm an FASD diagnosis and diagnostic classifications.

Diagnosis of FASD can be challenging. Confirmation of PAE by biological mothers during a diagnostic assessment of children with suspected FASD is often difficult: the topic is sensitive and recall bias is possible 174 . Additionally, many children live in foster or adoptive care, and obstetric records often lack details about PAE 80 . In these situations, clinicians should seek firsthand witness reports and child protection, justice and medical records. A standardized tool 175 , 176 , 177 should be used, when possible, to record the pattern of alcohol intake, either at an interview with the biological mother or using witness reports or records. A challenge in evaluating facial dysmorphology is the unavailability of suitable lip-philtrum guides and standards for palpebral fissure length (PFL) for many racial and ethnic groups, including Indigenous Australians 178 . PFL is the distance between the endocanthion and exocanthion of the eye (the inner (nasal) and outer points, respectively, where the upper and lower eyelids meet) and may be shortened following PAE. Because some domains of cognitive function cannot be evaluated in infants and young children, confirmation of brain dysfunction in this population may be based on global developmental delay, established using a validated tool 10 , 167 . FASD are diagnosed with increasing confidence in children aged 6 years and older, who are more cooperative in physical examinations, and in whom facial dysmorphology and neurocognitive function can be assessed with greater reliability using digital photography and standardized psychometric tests.

In the absence of a ‘gold standard’ for diagnosis of FASD, no diagnostic system may be considered superior. Each system has advantages and disadvantages, including its use in clinical and community settings and the sensitivity and specificity of diagnostic criteria. Diagnosis using these systems shows incomplete agreement 179 , 180 , 181 , confirming the need for a unified approach internationally (Table  1 and Supplementary Boxes  1 and 2 ).

A clinical diagnosis of FASD requires recognition of neurodevelopmental disabilities and a reproducible pattern of minor malformations (dysmorphic features), none of which are pathognomonic, and many of which overlap with other teratogenic or genetic disorders (phenocopies). Thus, a diagnosis of FASD is a diagnosis of exclusion that is made after considering and excluding other causes for the phenotype 10 , 167 . For example, prenatal exposure to teratogens, such as toluene, anticonvulsants or phenylalanine (when the mother has phenylketonuria), can result in dysmorphic features also observed in FASD 10 , 182 , 183 . Additionally, postnatal exposures (such as adverse childhood experiences (ACE)) can contribute to neurodevelopmental impairment, comorbidities (Box  1 ) and adverse ‘secondary’ outcomes (Box  2 ). Genetic conditions with dysmorphic features similar to FASD include Aarskog syndrome, blepharophimosis, ptosis, epicanthus inversus syndrome, CHARGE syndrome, de Lange syndrome, 22q11.2 deletion, Dubowitz syndrome, inverted duplication 15q, Noonan syndrome, Smith–Lemli–Opitz syndrome and Williams syndrome. Patients with intellectual disability without a recognizable pattern of anomalies may also share some dysmorphic features with FASD 10 , 182 . Thus, before establishing a diagnosis of FASD, it is important to ask whether the family history suggests a genetic disorder, whether other teratogenic exposures occurred during pregnancy and whether the patient has features not previously described in FASD. If so, referral to a clinical geneticist/dysmorphologist for evaluation is recommended. When indicated, genetic testing should include chromosome microarray analysis 184 , 185 and exclusion of Fragile X syndrome 186 as a minimum, and whole-exome sequencing should be performed if other genetic pathologies due to point mutations are suspected 10 , 187 . When PAE is confirmed and/or the physical and neurodevelopmental examinations are supportive, the diagnosis can be made by a paediatrician or other health professional familiar with FASD.

Neurobehavioural impairment accounts for the major functional disabilities associated with FASD. Although the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) 188 criteria for intellectual disability are not always met in patients with FASD, cognitive impairment is often identified and can affect multiple domains, including executive function, memory, mathematical and other academic skills, attention and visuospatial processing 80 , 189 . Poor social skills, inattention and impaired impulse control can adversely affect school and work performance and independent living.

Although no specific constellation of neurobehavioural deficits have been identified in FASD, some groups have attempted to characterize clusters of impairment associated with PAE 190 , 191 . One set of criteria, Neurodevelopmental Disorder associated with PAE, has been proposed as a condition for further study in the DSM-5 (ref. 188 ); it requires deficits in cognition, behaviour and social adaptation. The ICD-11, published in 2022, lists several ‘toxic or drug-related embryofetopathies’ (code LD2F.0) including ‘fetal alcohol syndrome’ (code LD2F.00) 192 . The confounding or potentiating influence of ACE presents a major challenge in identifying a specific neurobehavioural profile 193 .

Box 1 Common comorbidities in patients with fetal alcohol spectrum disorders

More than 400 comorbid conditions have been identified in individuals with fetal alcohol spectrum disorders, which span 18 of the 22 chapters of the ICD-10 (ref. 13 ), the most prevalent coming from the groups of:

Congenital malformations, deformations and chromosomal abnormalities (Chapter XVII) and Mental and behavioural disorders (Chapter V). Shown below are selected comorbid conditions (with codes) from Chapters V and XVII and diseases of the eye (Chapter VII) and ear (Chapter VIII). For more detailed information, see ref. 13 .

Chapter XVII. Congenital malformations, deformations and chromosomal abnormalities

Q02 Microcephaly

Q03 Congenital hydrocephalus

Q04.0 Congenital malformations of corpus callosum

Q04.3 Other reduction deformities of brain

Q04.6 Congenital cerebral cysts

Q04.8 Other specified congenital malformations of brain

Q04.9 Congenital malformation of brain, unspecified

Q05 Spina bifida

Q06.8 Other specified congenital malformations of spinal cord

Chapter V. Mental and behavioural disorders

F10.2 Mental and behavioural disorders due to use of alcohol, dependence syndrome

F19.2 Mental and behavioural disorders due to the use of multiple drugs and use of other psychoactive substances, dependence syndrome

F41.1/F33.8 Anxiety/depression

F80.1 Expressive language disorder

F80.2 Receptive language disorder

F81.9 Developmental disorder of scholastic skills, unspecified

F89 Unspecified disorder of psychological development

F90.0 Disturbance of activity and attention

F91 Conduct disorder

G40 Epilepsy/seizure disorder

Chapter VII. Diseases of the eye

H47.0 Disorders of optic nerve

H52.6 Refractive errors

H54 Visual impairment

Q10.0 Congenital ptosis

Q10.3 Other congenital malformations of eyelid

Q10.6 Other congenital malformations of lacrimal apparatus

Q11.2 Microphthalmos

Q12.0 Congenital cataract

Chapter VIII. Diseases of the ear

H65.0 Acute serous otitis media

H65.2 Chronic serous otitis media

H90.8 Mixed conductive and sensorineural hearing loss, unspecified

Box 2 Challenges for adolescents and adults with fetal alcohol spectrum disorders

Involvement in child welfare services (75%) 309

Disrupted school experiences due to learning and/or behavioural problems (61%) 267

Interaction with the justice system (30% 309 to 60% 267 )

Confinement (detention, prison, or psychiatric or alcohol/drug inpatient setting; 50%) 267

Substance use disorder: alcohol and other drugs (50%) 309

Inappropriate sexual behaviour (49%) 236 , 310

Increased risk of metabolic abnormalities (includes type 2 diabetes, low high-density lipoprotein, high triglycerides, and female-specific overweight and obesity) 311

Difficulties with independent living and trouble gaining and retaining employment (80%) 267

Mean life expectancy (34 years; 95% CI 31–37 years) is considerably lower than in the general population 275 ; leading causes of death are ‘external causes’ (44%), including suicide (15%), accidents (14%), poisoning by illegal drugs or alcohol (7%) and other external causes (7%)

Screening for alcohol use in pregnancy

Early detection of alcohol use during pregnancy can lead to decreased consumption, abstinence or decreased risk of alcohol use in subsequent pregnancies 22 , 194 . The early identification of alcohol use facilitates education about the harms of PAE, delivery of timely, office-based brief interventions, and referral to substance use treatment services if required. Reducing the high prevalence of FASD requires large-scale, population-based screening programmes to ensure that every pregnant woman is asked about alcohol use, with special attention to populations at high risk 22 , 195 , 196 (Table  2 ).

Screening for alcohol use during pregnancy is underused globally 197 , 198 . Barriers to screening include lack of public-health guidelines 199 or screening mandates, insufficient clinician training 200 , 201 , 202 , 203 , competing demands on clinician time, the cost of completing validated alcohol use screening questionnaires 204 , 205 , 206 , and the unavailability of clinically reliable biological markers for PAE. Even a single, clinician-directed question about alcohol use may reduce PAE 207 , 208 ; however, successful screening requires that practitioners understand the importance of preventing PAE and providing non-judgmental screening and brief interventions 196 . Preliminary evidence suggests that web-based or app-based mobile health interventions may mitigate patient stigma and reluctance to report alcohol use and might circumvent barriers related to clinician time constraints, training and motivation 209 . Similarly, mobile health approaches may reduce alcohol and substance use in the preconception, prenatal, and postnatal periods 209 and improve access to interventions for families in rural and remote settings. Empathic, compassionate support of abstinence during pregnancy may improve opportunities for treatment of substance use disorders 22 , 47 , 196 , 202 . Screening for alcohol and substance use should be repeated throughout pregnancy and equally across populations to avoid stigmatizing marginalized populations with selective screening 22 , 196 , 210 , 211 . People who screen positive should be directed to a well-developed management pathway for clinical care.

Prevention (Fig.  7 ) and treatment of alcohol and substance use disorders in pregnancy are central to the 2015 United Nations Sustainable Development Goals (SDG 3.5) 212 . The WHO recommends universal screening and intervention for alcohol use in pregnancy as a primary prevention strategy for FASD 22 , 213 . Prevention programmes should be evidence based and evaluated following implementation. A wide range of approaches has been deployed, including public awareness strategies, preconception interventions (such as preconception clinics and school-based FASD education), holistic support of women with substance use disorders, and postpartum support for new mothers and babies 214 , 215 . These approaches show promise in increasing awareness of FASD and decreasing alcohol use during pregnancy 216 ; however, the quality of supporting evidence is highly variable. Any primary prevention strategy must be underpinned by evidence-based policy and legislation intended to minimize harms from alcohol, including increased alcohol pricing and taxation, restrictions on advertising and promotion of alcohol, and restricted access to alcohol such as by limiting opening hours and the density of liquor outlets 217 . Public-health authorities agree that the alcohol industry should have no involvement in the development of public-health policies owing to their inherent conflict of interest 218 , 219 . The framework in Fig.  7 illustrates one approach that could be linked to national policy to address diverse aspects of population-based prevention of FASD.

A hierarchy of strategies can be used to prevent fetal alcohol spectrum disorder (FASD), ranging from awareness campaigns for the whole population to health, educational and social support for women and children. The strategies are placed in the context of cultural, political and environmental factors that influence access to, use of and attitudes towards alcohol use in pregnant women. SES, socioeconomic status.

Level 1: raising public awareness through campaigns and other broad strategies

Public-health initiatives that promote and support women’s health, in general, may raise awareness about PAE/FASD. More specific measures include warning signs on alcohol products, pamphlets and public education programmes that encourage healthy, alcohol-free pregnancies 220 , 221 . However, evidence in support of these campaigns is preliminary 216 . Moreover, campaigns that use triggering imagery or blaming/shaming language (such as ‘FASD is 100% preventable’) can stigmatize and isolate pregnant women who use alcohol, particularly when paired with judgmental interventions 196 . Reframing alcohol use in pregnancy as a shared responsibility of women, partners, prenatal health-care providers, treatment programmes for substance use disorder, families, community and government may be helpful 222 .

Level 2: brief counselling with women and girls of reproductive age

Discussing alcohol use and its associated risks with women of childbearing age during preconception conversations about reproductive health is effective in preventing PAE and FASD 215 , primarily by improving contraception use 207 . Screening, Brief Intervention and Referral to Treatment (S-BIRT) for non-pregnant adolescent and adult women reduces the risk of PAE 207 , particularly following multi-session interventions 223 . Preliminary studies suggest that such interventions are also beneficial for Indigenous communities 224 , 225 .

Level 3: specialized prenatal support

Treatment for alcohol use during pregnancy may prevent ongoing PAE and decrease adverse infant outcomes 226 . The combination of case management by a social worker or nurse (including problem identification and preparation, implementation and monitoring of a health-care plan) and motivational interviewing (an evidence-based approach to facilitating behaviour change) reduce drinking by pregnant women at high risk 194 . Moreover, specialized, intensive home-visiting interventions for pregnant women at high risk improve maternal and child outcomes and are cost-effective in preventing new cases of FASD 227 , 228 . Improving maternal nutrition and reducing smoking and family violence may also improve child outcomes in current and future pregnancies 227 , 229 , 230 .

Level 4: specialized postnatal support

In the postpartum period, home-visiting of women at high risk by health professionals or lay supporters improves child outcomes and reduces the risk of PAE in future pregnancies 227 , 231 , 232 . Application of a FASD prevention framework requires consideration of local policy and practices. Best practice programmes support the needs of both the mother and child, recognizing the connections between women’s alcohol use, parenting, family influences and child development. Central to the effective implementation of prevention strategies is the establishment of strong cross-cultural and community partnerships and the embrace of cultural knowledge systems and leadership 233 . Mitigating stigma is vital while addressing the structural and systemic factors that promote prenatal alcohol consumption 35 .

Principles of management of FASD

The complex pathophysiology of FASD (Boxes  1 and  2 ) emphasizes the need for thorough, individualized assessment and treatment. Treatment plans should be culturally appropriate, consider the family and community context, and be developed in partnership with families and individuals with lived experience of FASD 234 , 235 .

Therapeutic approaches must be tailored to individual strengths and needs. For example, an individual who has experienced trauma but has normal intelligence and social and emotional skills requires a trauma-informed, emotion-focused approach. By contrast, an individual with cognitive deficits and poor social and emotional skills may require a more directed, psycho-educational approach or environmental modifications to support and prevent secondary outcomes of FASD such as poor academic performance or inability to obtain/maintain employment 236 .

Management involves multiple service providers and changing interventions across the lifespan. Treatment comprises interventions to anticipate the delivery of a newborn with PAE, prevention of exposure to ACE, home-visiting by a public-health nurse, referral to infant developmental services, vision and hearing screening, preschool speech and language therapy, school-based support for learning disorders, occupational and physical therapy, behavioural and psychological interventions, pharmacotherapy, vocational support, and support for independent living in adolescence and adulthood. Specialized medical or surgical interventions may be required for congenital anomalies and accompanying comorbidities. There remains limited evidence from high-quality trials to support specific interventions for FASD 237 , 238 .

Behaviour support

Several large-scale randomized controlled trials (RCTs) support specific developmental and psychological interventions for FASD in children but few high-quality studies have been conducted in adolescents and adults 237 .

Positive behaviour support 239 is supported by positive results from RCTs and underpins three interventions for FASD: GoFAR 240 , the Math Interactive Learning Experience (MILE) 241 and the Families Moving Forward programme 242 . Positive behaviour support strengthens skills that enhance success and satisfaction in social, academic, work and community settings while proactively preventing problem behaviours; maintaining family involvement is an important element 16 . Where available, these specialized programmes oblige therapists to prioritize treatment for individuals most likely to benefit. The GoFAR intervention (FAR is an acronym for Focus and plan, Act, and Reflect) promotes self-regulation and adaptive function using direct instruction, practice and feedback, and strategies for emotional and behavioural self-regulation 243 . Interventions such as GoFAR, which involve the child and parents in the context of real-life adaptive behavioural problems, improve daily living skills and attention 243 . The MILE intervention provides individualized mathematical instruction through interactive learning and environmental modifications and improves math knowledge and parent report of child behaviour problems 241 , 244 , 245 . Families Moving Forward helps parents reframe their child’s behaviour within a neurodevelopmental paradigm. Adaptation of this approach to an app-based platform may reduce barriers to care 242 .

Self-regulation and executive function

Most children with FASD have significant problems with executive function and self-regulation 189 . The ALERT programme, a 12-week manualized approach using sensory integration and cognitive behavioural strategies, aims to help children regulate their behaviour and address sensory challenges 246 in a home environment 247 , 248 but is less effective when delivered in schools 249 . ALERT programme training is available online but requires adaptation to the family and community context 249 .

Social skills

Interventions to improve social connections in children with FASD include the Children’s Friendship Training (CFT) 250 and the Families on Track programme 251 . CFT involves 12 weeks of social and friendship skill training for children with FASD and their parents; it improves social skills and decreases problem behaviours in children with FASD 250 . Similarly, the Families on Track programme increases emotional regulation and self-esteem and decreases anxiety and disruptive behaviour 251 . However, interventions such as CFT and Families on Track are not widely available, and barriers to their use include the need to adapt to cultural context 252 . International partnerships and sharing of expertise may increase accessibility to these interventions 252 .

Pharmacological interventions

Pharmacological interventions for FASD are widely used and include medications, such as cognitive enhancers, to treat core impairments and medications to treat comorbidities, including ADHD, anxiety, and arousal or sleep disorders 253 . Large RCTs evaluating their effectiveness in FASD are urgently needed.

Children with FASD and ADHD have a different pattern of neurocognitive and behavioural abnormalities than children with ADHD alone 254 , suggesting the need for a tailored therapeutic approach. Expert consensus approaches for the management of ADHD in FASD have been developed. Recommendations in the UK suggest the use of a dexamphetamine-based medication (rather than a methylphenidate-based medicine) for first-line treatment of ADHD in children and adults with FASD; however, research is needed to understand the basis of treatment responses 255 . Guanfacine XL or similar medications can be used in individuals with comorbidities such as autism spectrum disorders 255 . Algorithms have also been developed in Canada for the use of psychotropic medications in FASD 256 . Although based on clinical consensus, these strategies form the basis for future research 256 .

Preclinical trials suggest that choline supplements improve cognitive deficits following PAE but clinical data are limited 257 . A small, placebo-controlled RCT demonstrated that children who received choline supplementation had higher non-verbal intelligence and visual-spatial skills, better working memory and verbal memory, and fewer behavioural symptoms of ADHD at 4-year follow-up than children who received placebo 258 . Despite these positive results, choline supplementation is not routinely recommended for children with FASD due to a lack of strong evidence for its effectiveness.

The role of exposure to adversity

A relationship between PAE and ACE is well established, and both may influence the life course in FASD 193 . Comprehensive neuropsychological assessment and MRI show that PAE accounts for the largest proportion of the variance in regional brain size and brain function in children with both exposures 259 . Furthermore, PAE imparts more risk for adverse outcomes than ACE in individuals with PAE in adoptive care 260 . However, adversity does affect the developmental trajectory and ACE are associated with maladaptive problems in children with FASD 261 . For example, school-age children with FASD and ACE are particularly vulnerable to language and social communication deficits 262 , which are hypothesized to result from the additive effect of prenatal and postnatal environmental exposures. This emphasizes the need for an individualized approach to treatment for individuals with life trauma and FASD.

Attempts have been made to understand the individual and combined effects of PAE and postnatal events on individual behaviours in FASD 263 . One model of complex trauma (Supplementary Fig.  1 ) displays neurodevelopmental variation as a complex interplay between prenatal and postnatal events and improves understanding of their interactions and association with outcomes. Child maltreatment viewed through a neurodevelopmental lens highlights the benefit of a sequential model of therapeutics rather than a focus on specific therapeutic techniques 264 .

Supplementary Fig.  1 highlights how vulnerabilities may present, whereas Supplementary Fig.  2 identifies methods to manage the same vulnerabilities based on understanding the individual and using anticipatory interventions to support development. Box  3 contains some useful resources on FASD for professionals and parents.

Box 3 Resources on alcohol use in pregnancy and fetal alcohol spectrum disorders

Australian guidelines to reduce health risks from drinking alcohol

Canada No. 245 — Alcohol Use and Pregnancy Consensus Clinical Guidelines 312

Centers for Disease Control and Prevention

Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)

Fetal Alcohol Spectrum Disorders (FASD) — American Academy of Pediatrics

FASD Hub Australia

FASD United

FASD — Care Action Network

Learning with FASD

National Organization for FASD Australia (NOFASD)

National Institute for Health and Care Excellence UK. Quality Standard QS204. FASD

National Institute on Alcohol Abuse and Alcoholism. Fetal Alcohol Exposure

Pan American Health Organization. Assessment of Fetal Alcohol Spectrum Disorders (2020) 313

The European FASD Alliance

WHO. Guidelines for identification and management of substance use and substance use disorders in pregnancy (2014) 22

Quality of life

Few published studies address QOL in individuals with FASD. One systematic review and meta-analysis identified more than 400 comorbid conditions among individuals with FASD, spanning 18 of 22 chapters of the ICD-10 (ref. 13 ). The most prevalent conditions were within the chapters of “Congenital malformations, deformations, and chromosomal abnormalities” (Chapters Q00–Q99; 43%) and “Mental and behavioural disorders” (Chapters F00–F99; 18%). Comorbid conditions with the highest pooled prevalence (50–91%) included abnormal functional studies of the peripheral nervous system and special senses, conduct disorder, receptive and expressive language disorders, and chronic serous otitis media 13 . Other studies report a high prevalence of vision and hearing problems among people with FASD 265 , 266 . All of these comorbid conditions affect the function and QOL of individuals with FASD and their families (Box  1 ).

Neurodevelopmental impairments may lead to lifelong ‘secondary’ disabilities, including academic failure, substance abuse, mental health problems, contact with law enforcement and inability to live independently or obtain/maintain employment 267 (Box  2 ). These conditions adversely affect QOL and require health, remedial education and correctional, mental health, social, child protection, developmental, vocational and disability services across the lifespan 17 , 268 , 269 . Lack of societal understanding of FASD is a barrier to addressing these secondary disabilities 16 , 270 .

A shift from a deficit-based to a strength-based management approach emphasizes the need to harness the abilities of individuals with FASD to improve their QOL and well-being. A review of 19 studies exploring the lived experience of people with FASD highlighted their strengths, including self-awareness, receptiveness to support, capacity for human connection, perseverance and hope for the future 271 . The lack of accessible, FASD-informed services perpetuates a deficit-based model.

Longitudinal cohort studies of FASD consistently show that adverse outcomes are more likely where support services are lacking. These studies are limited by selection bias and are based on cohorts with severe deficits rather than population-based cohorts receiving adequate support 267 , 270 . Nevertheless, they suggest the potential to modify developmental trajectories by addressing postnatal environmental exposures and opportunities. To address QOL, future studies should better articulate outcomes of interest for individuals and families living with FASD 272 .

FASD is associated with an increased risk of premature death of affected individuals, their siblings and mothers 273 , 274 . One study reported a mean age at death of 34 years for individuals with FASD 275 . Individuals with FASD have nearly fivefold higher mortality risk than people of the same age and year of death, and nearly half of all deaths occur in young adults 276 . In childhood, the leading causes of death in FASD are congenital malformations of the CNS, heart or kidney, sepsis, cancer, and sudden infant death syndrome, and more than half of deaths (54%) occur in the first year of life 277 . In the USA, >29% of adolescent males with FASD reported a serious suicide attempt, which is >19-fold higher than the national average 236 , 278 .

Among children and adolescents with FASD, the mortality rate of siblings with and without FASD is 114 per 1,000, which is approximately sixfold higher than among age-matched controls 273 . Furthermore, mothers of children with FASD have a 44.8-fold increased mortality risk compared with mothers of children without FASD 274 .

Caregiver burden

The complexity of parenting a child with FASD increases across adolescence and young adulthood. Caregivers of children with FASD experience increased burden, levels of stress and feelings of isolation 279 , 280 . The lifelong challenges and unmet needs of caregivers negatively affect family functioning and QOL 281 .

Early recognition of FASD and early emphasis on the prevention of secondary disabilities may decrease demands on families. Moreover, a diagnosis of FASD may indicate the need for specific interventions and parenting supports such as respite care, peer-support groups, treatment for parental alcohol misuse and education of other professionals who care for people with FASD.

FASD are the most common preventable cause of neurodevelopmental impairment and congenital anomalies 164 . These disorders are the legacy of readily available alcohol and societal tolerance to its widespread use, including during pregnancy. FASD affect all strata of society, with enormous personal, social and economic effects across the lifespan.

Diagnostic challenges

The greatest global challenges in the clinical management of FASD are the paucity of resources for diagnosis and treatment and the large number of affected individuals 163 . A substantial increase in resources is required, both for centres of expertise with MDTs and to build diagnostic capacity among non-specialist health services. However, this alone will not bridge the gap in services for children and adults, and a paradigm shift is needed. This might include recognition of the important role of primary care providers and use of new technologies such as app-based screening, diagnostic and treatment tools. Telehealth services will reduce the need for face-to-face care 282 and tele-education could build clinician awareness and skills, especially in rural and remote areas 283 . However, in many low-income and middle-income countries, this technology is not widely available.

Without a definitive diagnostic test, a clinical diagnosis of FASD must be made. Diagnosis is facilitated by identification of PAE in association with neurodevelopmental impairment, with or without specific craniofacial dysmorphology, and exclusion of alternative diagnoses. Many clinicians fail to document alcohol use in pregnancy or PAE in children, highlighting the need for enhanced training, standardized tools to document PAE and, especially, routine screening for alcohol use before and during pregnancy. Biomarkers for PAE are urgently needed because many children with FASD live in out-of-home care and reliable PAE histories are frequently unavailable. Although biomarkers for PAE (such as fatty acid ethyl esters, ethyl glucuronide and phosphatidylethanol) are identifiable in maternal hair, blood and meconium, their clinical use is limited, and testing may be costly or unavailable 284 . Identification of miRNAs from women in the second trimester and epigenetic signatures in placental and infant tissue hold promise as biomarkers for PAE and hence for risk of abnormal neurodevelopment 154 , 155 , 156 , 187 ; however, further research is required before their use becomes routine in clinical practice 81 , 125 .

Accessible e-health technologies to facilitate the diagnosis of FASD are under development. For example, 3D facial imaging may facilitate diagnosis by automatically quantifying the three sentinel facial features of FASD and identifying more subtle facial dysmorphology that reflects PAE after gastrulation 67 , 285 . The use and availability of 3D imaging will increase as more sophisticated and cheaper 3D cameras evolve and image capture on smartphones combined with cloud-based image analysis become available. Similarly, web-based tools are in development for identification of neurocognitive impairments associated with FASD. BRAIN-online enables screening for cognitive and behavioural features of PAE or FASD 286 . Decision trees simplify neurocognitive testing by including only tests that contribute most to the diagnosis of FASD 287 . Porting this software to tablets or online websites will broaden access to relevant neurocognitive testing. For example, the FASD-Tree 288 provides a dichotomous indication and a risk score for FASD, considering both neurobehaviour and dysmorphology, and successfully discriminates between children with and without PAE with a high predictive value 289 .

The lack of internationally agreed diagnostic criteria for FASD is challenging and hinders the comparison of prevalence and clinical outcomes between studies. In response, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has convened an international consensus committee to analyse data derived from existing diagnostic systems and develop a consensus research classification for FASD 290 . The field would also benefit from improved, population-based, normative data for growth and PFL as well as internationally accepted definitions of a standard drink and of the ‘low, moderate and high’ levels of risk of PAE. Additionally, the range and aetiology of adult outcomes require clarification to inform assessment and prognosis in FASD 291 . A research initiative for elderly people with FASD is urgently needed as there is virtually no information about the diagnostic criteria or neuropsychological outcomes of FASD in this age group.

Understanding pathophysiology

Functional MRI can be used to elucidate brain growth trajectories and disruptions to neuronal pathways after PAE (including low-level PAE), thereby assisting our understanding of CNS dysfunction in FASD 68 . Advances in our understanding of the genetics of rare neurodevelopmental disorders may identify genes that govern susceptibility or resilience to PAE and provide additional insights into the pathogenesis of FASD 187 . Advances in neuroscience research, including novel preclinical studies, may help elucidate the relationship between PAE-induced brain dysfunction and the FASD phenotype and inform therapeutics and prevention 292 .

Prevention and management

Preclinical studies suggest that epigenetic changes induced by PAE underpin metabolic, immunological, renal and cardiac disorders in FASD 13 , but further studies in patients are required to confirm this. The paucity of high-quality evidence to inform the treatment of neurodevelopmental impairments and comorbidities associated with FASD across the lifespan requires urgent redress 237 , 238 . Behavioural, family-based, school-based and pharmacological treatments require evaluation through multicentre RCTs. Moreover, little attention has been paid to preventing and managing the secondary outcomes of FASD in adults: substance use, mental health disorders, contact with the justice system, and issues with sleep, sexuality and violence. These must be prioritized to improve the QOL of individuals and reduce the societal and economic effects of FASD.

The COVID-19 pandemic demonstrated the use of telemedicine for virtual neuropsychiatric assessment and delivery of therapy 282 . Telemedicine approaches may also partly fill the need to increase health professionals’ capacity for FASD-informed care and to help education, child protection and justice professionals to recognize and understand FASD 283 .

Improving the primary prevention of alcohol use in pregnancy and hence FASD is also warranted 237 , 238 . Alcohol consumption and binge drinking are increasing among women of childbearing age in many countries, particularly in the most populous countries such as China and India 26 . This rise reflects increased availability of alcohol, societal acceptance of drinking among women, shifting gender roles, increasing income of women, and targeted marketing of alcohol to women and predicts a future global increase in FASD prevalence. Alcohol use in adolescence predicts subsequent use during pregnancy, and family physicians can play a role in identifying young women at risk 293 .

Another concern is that a large proportion of pregnancies globally are unplanned 29 , which can result in unintentional exposure of the embryo to PAE in the earliest stages of pregnancy. Accordingly, effective and cost-effective population-based preventive strategies should be adapted such as those promoted by the WHO in their Global Action Plan for the Prevention and Control of NCDs 294 and their Global Strategy to Reduce the Harmful Use of Alcohol 295 .

Although the role of national guidelines, community education and family support is important, these efforts must be underpinned by strategies proven to drive behavioural change and reduce alcohol harm, including legislated restrictions on the advertising and promotion of alcohol, appropriate taxation and pricing, and limited access to alcohol through restricted liquor outlets and opening hours and community-initiated alcohol restrictions 26 , 295 .

In pregnant women with ongoing alcohol consumption, food supplementation with folic acid, selenium, DHA, L-glutamine, boric acid or choline may reduce the effects of PAE 87 , 296 . However, research is required to define optimal levels of nutritional supplementation for pregnancy. Women who consume large amounts of alcohol often have iron deficiency, which increases the risk of FASD, and iron supplementation may be valuable 297 . Although novel in utero therapies with potential to prevent harm from PAE have been explored in preclinical models, none have been proven safe or effective in human RCTs 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 . Candidate therapies include agents that reduce ethanol-induced oxidative stress, cerebral neuronal apoptosis, growth deficits and structural anomalies caused by PAE 308 .

Future research should be collaborative and informed by people living with FASD and their families. FASD is a lifelong condition and information must be sought about adult patients, including the elderly. Further understanding of the pathophysiology underpinning the teratogenic and neurotoxic effects of PAE is required to inform prevention and management. Moreover, novel diagnostic tools and treatments must be rigorously tested, and new approaches are needed to reduce stigma, improve the QOL of people with FASD and prevent FASD in future generations.

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Acknowledgements

M.E.C. and E.P.R.: part of the work on mechanisms of alcohol harm was done in conjunction with the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), which is funded by grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Support was provided by U24 AA014811 (E.P.R. and M.E.C.). Additional information about CIFASD, including information on how to request data, can be found at www.cifasd.org . H.E.H.: the section on diagnostic guidelines was partially supported by the National Institute on Alcohol Abuse and Alcoholism grants R01 AA11685, R01/U01 AA01115134, and U01 AA019879-01/NIH-NIAAA (Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP)), and by the Oxnard Foundation, Newport Beach, CA, USA. E.J.E. is supported by an Australian Medical Research Futures Fund Next Generation Fellowship (#MRF1135959) and National Health and Medical Research Council of Australia funding for a Centre of Research Excellence in FASD (#GNT1110341).

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Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

Svetlana Popova

VA Boston Healthcare System, West Roxbury, MA, USA

Michael E. Charness

Department of Neurology, Harvard Medical School, Boston, MA, USA

Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

North Dakota Fetal Alcohol Syndrome Center, Department of Pediatrics, University of North Dakota School of Medicine and Health Sciences, Pediatric Therapy Services, Altru Health System, Grand Forks, ND, USA

Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Andi Crawford

Sanford Children’s Genomic Medicine Consortium, Sanford Health, and University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA

H. Eugene Hoyme

National UK FASD Clinic, Surrey and Borders Partnership NHS Foundation Trust, Redhill, Surrey, UK

Raja A. S. Mukherjee

Center for Behavioral Teratology, San Diego State University, San Diego, CA, USA

Edward P. Riley

Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

Elizabeth J. Elliott

New South Wales FASD Assessment Service, CICADA Centre for Care and Intervention for Children and Adolescents affected by Drugs and Alcohol, Sydney Children’s Hospitals Network, Westmead, Sydney, New South Wales, Australia

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Data & Statistics on FASDs

Prevalence of fasds, cost of fasds, state-level estimates of alcohol use among women, alcohol use among pregnant people in the united states, screening for alcohol use and brief counseling, alcohol use data sets.

• We do not know exactly how many people have fetal alcohol spectrum disorders (FASDs). Several different approaches have been used to estimate how many persons are living with FASDs in the population. FASDs include several diagnoses related to exposure of the baby to alcohol during pregnancy. More specifically, fetal alcohol syndrome (FAS) is the most involved diagnosis, used when several physical and developmental disabilities are present (see Facts about FASDs ).
• Using medical and other records, CDC studies have identified about 1 infant with FAS for every 1,000 live births in certain areas of the United States. 1 The most recent CDC study analyzed medical and other records and found FAS in 0.3 out of 1,000 children from 7 to 9 years of age. 2
• Studies using in-person assessment of school-aged children in several U.S. communities report higher estimates of FAS: 6 to 9 out of 1,000 children. 3,4
• Few estimates for the full range of FASDs are available. Based on the National Institutes of Health-funded community studies using physical examinations, experts estimate that the full range of FASDs in the United States and some Western European countries might number as high as 1 to 5 per 100 school children (or 1% to 5% of the population). 3,4,5
• The lifetime cost of care for one individual with FAS in 2002 was estimated to be $2 million. This is an average for people with FAS and does not include data on people with other FASDs. People with certain disabilities, such as profound intellectual disability, have much higher costs. It is estimated that the cost to the United States for FAS alone is over $4 billion annually. [ Read summary ]

• Estimates of alcohol use among women of childbearing age vary from state to state. View your state’s alcohol consumption rate in 2019
• Data come from the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey that tracks national and state-specific self-reported health risk behaviors of adults, 18 years and older, in the United States.

• In a 2022 Morbidity and Mortality Weekly Report (MMWR) , CDC researchers found that nearly 14% (or 1 in 7) pregnant people reported current drinking* and about 5% (or 1 in 20) reported binge drinking† in the past 30 days. Pregnant people who experienced frequent mental distress (14 or more days of poor mental health in the past 30 days) and those who did not have a usual healthcare provider were more likely to report alcohol use.
• A 2020 report published in the American Journal of Preventive Medicine found that both current alcohol use and binge drinking among pregnant women aged 18–44 years in the United States increased slightly from 2011 to 2018. Current drinking (having at least one drink of any alcoholic beverage in the past 30 days) increased from 9.2% in 2011 to 11.3% in 2018.

• In a 2023 Morbidity and Mortality Weekly Report (MMWR) , CDC researchers found that 80% of people who were pregnant were asked about alcohol use; however, only 16% of those who self-reported drinking within the past 30 days were advised to quit or reduce their use. These findings highlight missed opportunities to integrate alcohol SBI in practice, utilize strategies to address recognized barriers (e.g., improving reimbursement for alcohol SBI), and to help reduce alcohol use during pregnancy.
• Among adults who reported being asked about their alcohol use at a checkup in the past 2 years and reported current binge drinking, 80% (or 4 of 5 persons) were not counseled to reduce their drinking. Routine alcohol screening and brief counseling has been shown to be effective at reducing binge drinking and is recommended for all adults.

This telephone survey tracks national and state-specific health risk behaviors of adults, aged 18 years and older, in the United States. The BRFSS is administered and supported by the Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, CDC.

National Health Interview Survey (NHIS): The NHIS is a multi-purpose nationwide household health survey of the U.S. civilian noninstitutionalized population conducted annually by the National Center for Health Statistics (NCHS), CDC, to produce national estimates for a variety of health indicators.

This survey provides information on the prevalence, patterns, and consequences of alcohol, tobacco, and illegal drug use and abuse in the general U.S. population, 12 years and older. It is conducted by the Substance Abuse and Mental Health Services Administration.

This software, supported by CDC’s National Center for Chronic Disease Prevention and Health Promotion, generates estimates of alcohol-related deaths and Years of Potential Life Lost (YPLL) due to alcohol consumption.

1 CDC. Fetal alcohol syndrome-Alaska, Arizona, Colorado, and New York, 1995-1997. MMWR Morb Mortal Wkly Rep. 2002;51(20):433-5. [ Read article ]

2 CDC. Fetal Alcohol Syndrome Among Children Aged 7-9 Years – Arizona, Colorado, and New York, 2010. MMWR Morb Mortal Wkly Rep. 2015;64(3):54-57. [ Read article ]

3 May PA, Baete A, Russo J, Elliott AJ, Blankenship J, Kalberg WO, Buckley D, Brooks M, Hasken J, Abdul-Rahman O, Adam MP, Robinson LK, Manning M, Hoyme HE. Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics. 2014;134:855-66. [ Read summary ]

4 May PA, Gossage JP, Kalberg WO, Robinson LK, Buckley D, Manning M, Hoyme HE. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev. 2009;15:176-92. [ Read summary ]

5 May PA, Chambers CD, Kalberg WO, Zellner J, Feldman H, Buckley D, Kopald D, Hasken JM, Xu R, Honerkamp-Smith G, Taras H, Manning MA, Robinson LK,  Adam MP, Abdul-Rahman O, Vaux K, Jewett T, Elliott AJ, Kable JA, Akshoomoff N, Falk D, Arroyo JA, Hereld D, Riley EP, Charness ME, Coles CD, Warren KR, Jones KL, Hoyme HE. Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities. Journal of American Medical Association. 2018;319(5):474–482. [ Read article ]

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Fetal Alcohol Syndrome

Children's hospital of philadelphia, what is fetal alcohol syndrome (fas).

An infant born to a mother who drinks alcohol during pregnancy can have problems included in a group of disorders called fetal alcohol spectrum disorders (FASDs).  FASDs include the following:

Fetal alcohol syndrome (FAS). These are the most severe effects that can occur when a woman drinks during pregnancy, and include fetal death. Infants born with FAS have abnormal facial features and growth and central nervous system (CNS) problems, including intellectual disability.

Alcohol-related neurodevelopmental disorder (ARND). Children with ARND may not have full FAS but have learning and behavioral problems due to prenatal exposure to alcohol. These problems may include mathematical difficulties, impaired memory or attention, impulse control and/or judgment problems, and poor school performance.

Alcohol-related birth defects (ARBD). Birth defects related to prenatal alcohol exposure can include abnormalities in the heart, kidneys, bones, and/or hearing.

There is no cure for FASDs, but children who are diagnosed early and receive appropriate physical and educational interventions, especially those in a stable and nurturing home, are more likely to have better outcomes than those who are not.

What causes fetal alcohol syndrome and other fetal alcohol spectrum disorders?

Many drugs can pass from the mother's blood stream through the placenta to the fetus. Alcohol is no exception. Alcohol is broken down more slowly in the immature body of the fetus than in an adult's body. This can cause the alcohol levels to remain high and stay in the baby's body longer.

The full picture of FAS usually occurs in babies born to alcoholic mothers, or to those who drink regularly or binge-drink. However, no amount of alcohol is safe. Even light or moderate drinking can affect the developing fetus.

Why are fetal alcohol spectrum disorders a concern?

Alcohol use in pregnancy has significant effects on the fetus and the baby. Dependence and addiction to alcohol in the mother also cause the fetus to become addicted. At birth, the baby's dependence on alcohol continues. But since the alcohol is no longer available, the baby's central nervous system becomes over stimulated, causing symptoms of withdrawal. Alcohol withdrawal may begin within a few hours after birth, and symptoms may last up to 18 months.

In addition to the acute effects of withdrawal, babies often suffer the teratogenic (causing physical abnormalities) effects of alcohol. Specific deformities of the head and face, heart defects, and intellectual disability are seen with fetal alcohol syndrome (FAS).

What are the symptoms of fetal alcohol spectrum disorders?

According to the CDC, the following characteristics or behaviors may occur in children with FASDs:

Small for gestational age at birth or small stature compared with their peers

Facial abnormalities such as small eyes and thin mouth 

Poor physical coordination

Hyperactive behaviors

Learning disabilities

Developmental disabilities (for example, speech or language delays)

Intellectual disability or low IQ

Problems with daily living

Poor reasoning and judgment skills

Sleep and sucking problems in infancy

Long-term problems in children with FASDs may include psychiatric problems, gang and criminal behavior, poor socialization, unemployment, and incomplete education.

The symptoms of FASDs may resemble other medical conditions or problems. Consult a doctor for a diagnosis.

How are fetal alcohol spectrum disorders diagnosed?

Most often, FASDs are diagnosed based on the mother's history and the appearance of the baby, based on a physical examination by a doctor.

Treatment for fetal alcohol spectrum disorders

The FDA has designated specific drugs for treating the symptoms of withdrawal from alcohol in babies. However, there is no treatment for lifelong birth defects and intellectual disability. Babies and children with alcohol-related damage often need developmental follow-up and, possibly, long-term treatment and care.

Preventing fetal alcohol syndrome

Fetal alcohol spectrum disorders are 100 percent preventable. However, this requires that a mother stop using alcohol before becoming pregnant. Because no amount of alcohol is proven safe, women should stop drinking immediately if pregnancy is suspected.

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Volume 37 Issue 1 January 1, 2015

Advances in Diagnosis and Treatment of Fetal Alcohol Spectrum Disorders: From Animal Models to Human Studies

Part of the Topic Series: Improving Health Through Translational Alcohol Research

Nathen J. Murawski, Ph.D.; Eileen M. Moore, Ph.D.; Jennifer D. Thomas, Ph.D.; and Edward P. Riley, Ph.D.

Nathen J. Murawski, Ph.D., is a postdoctoral fellow at the Center for Behavioral Teratology; Eileen M. Moore, Ph.D., is a research assistant professor in the Department of Psychology; Jennifer D. Thomas, Ph.D., is associate director at the Center for Behavioral Teratology and a professor in the Department of Psychology; and Edward P. Riley, Ph.D., is direc­tor of the Center for Behavioral Teratology and a distinguished professor in the Department of Psychology, all at San Diego State University, San Diego, California.

Prenatal alcohol exposure can cause a number of physical, behavioral, cognitive, and neural impairments, collectively known as fetal alcohol spectrum disorders (FASD). This article examines basic research that has been or could be translated into practical applications for the diagnosis or treatment of FASD. Diagnosing FASD continues to be a challenge, but advances are being made at both basic science and clinical levels. These include identification of biomarkers, recognition of subtle facial characteristics of exposure, and examination of the relation between face, brain, and behavior. Basic research also is pointing toward potential new interventions for FASD involving pharmacotherapies, nutritional therapies, and exercise interventions. Although researchers have assessed the majority of these treatments in animal models of FASD, a limited number of recent clinical studies exist. An assessment of this literature suggests that targeted interventions can improve some impairments resulting from developmental alcohol exposure. However, combining interventions may prove more efficacious. Ultimately, advances in basic and clinical sciences may translate to clinical care, improving both diagnosis and treatment.

Alcohol consumption during preg nancy can interfere with both embryonic and fetal development, producing a wide range of outcomes that fall under the rubric of fetal alcohol spectrum disorders (FASD). FASD is the nondiagnostic umbrella term used to refer to the full range of effects that can occur following prenatal alcohol exposure. Such exposure can produce a variety of effects, including physical birth defects, growth retardation, and facial dysmorphism, but the most profound effects are on the developing brain and accompanying cognition and behavior. The disabilities associated with prenatal alcohol are variable, influenced by numerous factors, and can have a lifelong impact. Therefore, early diagnosis and intervention are essential for improved clinical outcomes (Streissguth et al. 2004).

Animal models have played a critical role in research on FASD, including studies confirming that alcohol is indeed a teratogen and those providing insights into the mechanisms by which alcohol exerts its teratogenic effect. Researchers have used a wide variety of organisms to model the effects of prenatal alcohol exposure, which mimic both the physical and the behavioral alterations seen in human FASD (Wilson and Cudd 2011). These models allow researchers to experimentally control factors, including alcohol dose, pattern and timing of exposure, nutritional status, maternal factors, and genetics, that are known to influence and contribute to variability in clinical outcomes. Animal models also can help identify better strategies for diagnosing and treating FASD. This review will not directly compare the animal and human data because previous reviews have done this (Schneider et al. 2011). Rather, it will highlight and integrate translational research that might lead to advancements in the diagnosis and treatment of FASD. Furthermore, several psychosocial, academic, and behavioral interventions for FASD that recently have been discussed elsewhere (Paley and O’Connor 2011) are difficult to model in animals and thus will not be reviewed here. Instead, this review focuses on recent pharmacological, nutritional, and exercise interventions that have shown promise in preclinical studies and are progressing toward translation to the clinic.

Identification and Diagnosis

To obtain an accurate estimate of FASD prevalence and provide early intervention for affected individuals, it is critical to identify infants prenatally exposed to alcohol. Identification is less problematic on the severe end of the spectrum—where fetal alcohol syndrome (FAS) lies—because it is characterized by obvious growth retardation, central nervous system (CNS) dysfunction, and a specific pattern of craniofacial anomalies (see figure 1A). However, many, if not the majority, of individuals affected by prenatal alcohol exposure do not meet criteria for FAS (Bertrand et al. 2005), yet have significant neurobehavioral impairments (Mattson et al. 2013). These cases are referred to as alcohol-related neurodevelopmental disorders (ARND) and are often difficult to identify because they lack the characteristic facial features and growth retardation seen in FAS. In fact, an ARND diagnosis requires confirmation of prenatal alcohol exposure, which often is unavailable or unreliable (see Riley et al. 2011 for a comparison of various diagnostic schemas for FAS and ARND). Finding novel ways to identify at-risk individuals for disabilities along the spectrum is critical, as is identifying effective interventions to mitigate these cognitive and behavioral effects.

The routine use of objective, validated, and highly specific markers of prenatal alcohol exposure would help improve FASD identification, which currently is hampered by a lack of good information. For example, a recent study (May et al. 2014 a ) found that only 33 percent of the mothers of children given a diagnosis of FAS provided information about their alcohol consumption. In addition, a large number of children with FASD are in adoptive situations or foster care, and there may be little knowledge of their alcohol exposure. Several indirect and direct markers of alcohol exposure (see figure 2A) exist and have been described at length elsewhere (Bakhireva and Savage 2011). Fatty acid ethyl esters, ethyl glucuronide, ethyl sulphate, and the alcohol-derived phospholipid phosphatidylethanol are among several promising metabolic biomarkers. All of these are byproducts of alcohol metabolism, and each is limited by how long after alcohol exposure they are detectable. Another newly identified marker may persist longer than these metabolic markers. As shown in a sheep model, unique circulating microRNAs (miRNA) may help identify individuals consuming alcohol and, importantly, those exposed to alcohol in utero. An initial study suggests that several microRNAs (miRNAs), including miR-9, -15b, -19b, and -20a, are potentially sensitive indices of alcohol exposure in both the pregnant ewe and newborn lamb (Balaraman et al. 2014) (see figure 2B). Researchers are conducting miRNA studies in humans to confirm the sheep findings. If they succeed, miRNAs may provide a new tool to identify alcohol-exposed pregnancies/infants, similar to their use as diagnostic biomarkers in a variety of other disease states (Weiland et al. 2012).

Other novel FASD diagnostic techniques include ways to identify potential at-risk individuals based upon subtle, subclinical facial features. In particular, researchers have developed a computerized method for detecting facial features using three-dimensional facial imaging and computer-based dense-surface modeling (see figure 3). Hammond and colleagues (Suttie et al. 2013) compared this approach with a standard dysmorphology exam for diagnosing FAS and found a high degree of agreement. The researchers used sophisticated mathematical tech niques to characterize the facial features of heavily exposed individuals who did not have facial features that would have led to a diagnosis of FAS using traditional measures. They categorized participants as having facial features that were either “more similar to those with FAS” or “more similar to unex posed controls.” Importantly, the heavily exposed children with FAS-like faces performed at a level similar to the FAS group on neurobehavioral tests, whereas those with more control-like faces exhibited behavioral profiles similar to control subjects. These data were collected on a homogenous ethnic group in South Africa and therefore need to be replicated in other populations. Still, they provide preliminary evidence that this approach may constitute a means to identify at-risk individuals based upon subtle, sub-clinical facial features.

Developing truly accurate and specific methods for identifying individuals with FASD requires an understanding of the full spectrum of alcohol-related consequences and clarification of the various factors, both protective and permissive, that influence outcome variability. Animal models have provided information on the mechanisms by which alcohol affects facial development and the factors that may make a fetus more susceptible to these facial changes (see figure 1B and C for examples of craniofacial defects in the mouse and zebrafish). In the mouse, for example, alcohol administration on gestational day (GD) 7, equivalent to approximately week 3 postfertilization in a human pregnancy, produces a constellation of facial malformations similar to those seen in FAS. Defects include severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum (Godin et al. 2010). However, alcohol exposure delayed a day and a half to GD 8.5 produces a distinctly different pattern of malformations, with mild hypoplasia and shortening of the palpebral fissures and upper lip but a preserved philtrum (Lipinski et al. 2012) (see figure 4A and B). These data suggest that maternal alcohol consumption, even before many women are aware that they are pregnant, can cause significant and selective facial alterations in their offspring. The distinctive facial phenotype of FAS depends on the timing of exposure, and other facial characteristics resulting from alcohol exposure during different critical periods are possible.

As with facial dysmorphology, basic science models illustrate that the timing of alcohol administration also produces differing patterns of brain malformations, which again may account for the variability in outcomes. O’Leary-Moore and colleagues (2011) recently reviewed the different brain changes following a single day of alcohol exposure during early fetal development in the mouse using magnetic resonance imaging (MRI). Alcohol exposure on GD 7 was particularly damaging to medial forebrain regions, with relative sparing of mesencephalic and rhomb encephalic regions (Godin et al. 2010). The morphological changes induced by alcohol exposure on GD 8 included disproportionate volume reductions in the olfactory bulbs, hippocampus, and cerebellum and relative sparring of the pituitary and septal regions (Parnell et al. 2009). GD 9 exposure produced reductions in cerebellar volume, ventricle enlargement, and shape deviations in the cerebral cortex, hippocampus, and right striatum (Parnell et al. 2013). In contrast, offspring exposed to alcohol on GD 10 displayed enlarged ventricles and disproportionate reductions in cortical volume (O’Leary-Moore et al. 2010). Brain-imaging studies in humans with FASD also find morpho logical alterations in many of these brain structures (see Moore et al. 2014 for review), which may vary depending on the specific timing of alcohol exposure. These exposure timing– dependent brain changes likely produce different behavioral outcomes, contributing to the variability in impairment seen clinically. Ultimately, understanding the relationship between alcohol exposure parameters and variability in outcome, including different behavioral phenotypes, may improve detection of individuals with FASD.

Recent studies also suggest that the interaction of alcohol with specific genes involved in brain development and the development of facial features may affect the FASD phenotype. A study in zebrafish, for example, examined the interaction of alcohol with the gene for platelet-derived growth factor receptor alpha (Pdgfra) (McCarthy et al. 2013). This gene is involved in cellular migration and proliferation and is necessary for proper migration of neural crest cells, which contribute to the formation of diverse structures, including the face. The researchers found that pdgfra interacts with alcohol to protect against severe craniofacial defects. Specifically, more than 60 percent of zebrafish heterozygous for the pdgfra gene showed cranial facial defects after alcohol exposure compared with only about 10 percent of the alcohol-treated wild-type embryos (figure 4C). A genome-wide genetic scan, using single nucleotide polymor phisms (SNPs), in humans with FASD supports these findings, showing that craniofacial phenotypes seen in FASD are linked to the PDGFRA gene (McCarthy et al. 2013). A more recent study in zebrafish found that a gene involved in the development of the embryonic axis, vangl2, interacts strongly with alcohol (Swartz et al. 2014). This finding provides another potential gene target to help identify significant sources of variance in terms of susceptibility to the facial characteristics and perhaps changes in brain seen in FASD (see McCarthy and Eberhart 2014 for a recent review of genetic factors involved in FASD).

Basic research in people with FASD also is providing new methods for assessing alcohol’s clinical effects. Studies have identified several relationships between facial measurements and brain structure in FASD (reviewed in Moore et al. 2014). For example, shorter palpebral fissures predict volume reductions in the bilateral ventral diencephalon, a thinner anterior corpus callosum, and a thicker right inferior frontal cortex. The smoothness of the philtrum predicts volumetric reductions in the thalamus and the left pallidum. Facial measures also predict brain maturation patterns: Children with greater facial dysmorphia displayed a linear pattern of cerebral cortex growth, at least from childhood through adolescence, rather than the developmentally appropriate inverted U-shaped trajectory. Continued research examining the relationship between face, brain, and behavioral outcomes resulting from prenatal alcohol eventually may lead to the identification of specific patterns of anomalies that can be used to better identify FASD and improve diagnosis. Moreover, patterns of outcomes may illuminate mechanisms by which alcohol disrupts developmental processes, which can inform treatment strategies. It must be cautioned, however, that the utility of these findings will largely depend on their sensitivity and specificity to alcohol .

Treatment Strategies

Although no specific treatments exist that are unique for FASD, the similarity between the cognitive and behavioral characteristics of FASD and other disorders provides a framework for treatment development. For example, estimates indicate that anywhere from around 50 percent to over 90 percent of individuals with FASD who have been clinically referred meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD) (Bhatara et al. 2006; Fryer et al. 2007). One approach would be to treat individuals with FASD with medications, such as stimulants, that have been successful in treating ADHD. However, mixed results have been found with stimulant treatment in clinical studies on FASD. For example, treatment with stimulant medications may reduce hyperactivity, with little evidence for beneficial effects on attention (e.g., Doig et al. 2008). Other studies have noted variable and unpredictable effects (O’Malley and Nanson 2002) or even poorer outcomes (Frankel et al. 2006) in FASD. Animal studies find that perinatal alcohol exposure leads to hyperactivity and that treatment with stimulants later in life increases, rather than attenuates, animals’ spontaneous locomotor behaviors (Hannigan and Berman 2000). Atomoxetine (Strattera), a nonstimulant medication for ADHD, also is often used in the treatment of attention problems in FASD and a clinical trial of its effectiveness in FASD is under way.

Researchers are using their knowledge of the mechanisms underlying alcohol’s toxic effect on the fetus to design preclinical models that test the efficacy of a number of pharmaceutical agents to mitigate alcohol-related impair ments (Idrus and Thomas 2011). For example, prenatal alcohol exposure results in deficient activation of cyclic-AMP response element–binding protein (CREB), which can impair brain plasticity, a process of neural change important for brain development, learning, and memory. The pharmaceutical vinpocetine, a vasodilator and anti-inflammatory agent, inhibits the enzyme phosphodiesterase type 1, an action that prolongs CREB activation and thereby strengthens synaptic connections. Studies in animal models find that vinpocetine attenuates alcohol-related impairments in cortical plasticity and reduces learning and memory deficits associated with developmental alcohol exposure (Medina 2011). Clinical trials in humans with dementia have shown some promise and no serious adverse consequences, although results with other disorders, such as ischemic stroke remain incon clusive (Medina 2011). Clinical studies to evaluate this drug in humans with FASD are an important next step.

Preclinical models of FASD also have used neuroprotective peptides to mitigate neuropathologies and behavioral impairments resulting from developmental alcohol exposure. Originally, researchers administered the neuroactive peptides NAP and SAL concurrently with alcohol to pregnant rodents in an attempt to prevent alcohol-induced damage in the offspring. Subsequently, researchers have administered the peptides to adolescent rodents exposed to alcohol prenatally and found that they can reduce deficits in behavioral tasks, such as a T-maze and a Morris water maze (Incerti et al. 2010). The peptides also reversed alcohol-related changes in NMDA receptors in the hippocampus and cortex. These peptides are being developed to treat a number of neurodegenerative diseases and may prove useful in the treatment of FASD.

Nutritional Interventions

Research clearly shows that nutritional factors influence alcohol’s damaging effects on the fetus. Moreover, it is possible that postnatal nutrition also might influence physical and behavioral outcomes in individuals with FASD.

Prenatal Nutritional Interventions

Some studies suggest that women who drink during pregnancy have nutritional deficits relative to control subjects. In one study, for example, May and colleagues (2014 b ) examined the nutritional status of a group of South African mothers who gave birth to children with FASD compared with a group of mothers who gave birth to children without FASD. The mothers of children with FASD were more likely to be deficient in several vitamins, including vitamins A, B6, choline, C, D, and E; minerals, including calcium, iron, and zinc; and omega-3 fatty acids. Deficiencies in these micronutrients during pregnancy can contribute to abnormal fetal development (Nyaradi et al. 2013) and may further exacerbate the damaging effects of alcohol on the developing embryo and fetus. In animal models, maternal nutritional deficiencies (e.g., zinc or iron) during pregnancy increase the detrimental effects of prenatal ethanol on brain development and subsequent behavior in offspring. For example, the combined insults of prenatal alcohol exposure and iron deficiency resulted in increased cerebellar apoptosis (cell death), reduced myelin content, and greater impairments in cerebellar-dependent classical eyeblink conditioning compared with either insult alone (Rufer et al. 2012).

Research also finds that nutritional supplementation during pregnancy may attenuate ethanol’s teratogenic effects. In one relatively small study (Avalos et al. 2011), low to moderate alcohol consumption during pregnancy resulted in a twofold increase in small-for-gestational-age infants relative to mothers who abstained. However, the offspring of women who consumed alcohol and reported taking nutritional supplements during pregnancy were no different on these measures than the offspring of abstainers ( Avalos et al. 2011). The study reported similar results for preterm births. In a study of pregnant women currently being conducted in the Ukraine, r esearchers compared the birth outcomes of women given vitamin supplements with those not given supplements. Both groups included women who were consuming alcohol. Although the researchers still are analyzing the results, preliminary reports indicate that the women consuming alcohol and taking micronutrient supplements have a lower rate of babies with FASD than women in the nonsupplement group (Chambers et al. 2013).

Other nutritional interventions target oxidative stress. Alcohol increases oxidative stress, which in turn can initiate a cascade of events that eventually lead to widespread CNS cell loss during development (Brocardo et al. 2011). In rodent models of FASD, pregnant females given nutrients high in antioxidant properties (e.g., vitamin C, vitamin E, omega-3 fatty acids) during the time they also are given alcohol, give birth to offspring with reduced oxidative stress and cell loss, and fewer behavioral impairments (Brocardo et al. 2011; Patten et al. 2013 a ). Although antioxidant treatments in animal models are encouraging, researchers prematurely terminated a clinical trial utilizing high doses of vitamins C and E in women with alcohol-exposed pregnancies because of safety concerns (Goh et al. 2007).

Other studies are examining the role of nutritional supplements on gene transcription. Animal models of FASD demonstrate that prenatal alcohol exposure significantly affects gene transcription through epigenetic modifications (Ungerer et al. 2013). Specifically, alcohol-induced changes in DNA methylation, histone modification, and noncoding RNAs may alter the expression patterns of numerous genes important for neurodevelopment and behavior. Nutrients such as choline, betaine, folic acid, methionine, and zinc can influence these epigenetic profiles and can potentially attenuate alcohol-induced changes to the epigenome. For example, supplemental choline in rats exposed to alcohol during development alters alcohol-related changes in global DNA methylation in the hippocampus and prefrontal cortex (Otero et al. 2012) and significantly attenuates ethanol-induced hypermethylation of genes in the hypothalamus (Bekdash et al. 2013). Additionally, access to a diet supple mented with nutrients that act as methyl donors normalized changes to DNA methylation patterns in embryonic tissue following a single binge exposure to alcohol in early gestation (Downing et al. 2011). These nutrient- induced changes to the epigenome may contribute to the behavioral and cognitive improve- ments seen in alcohol-exposed rodents following supplementation (see below).

Additional preclinical research indicates that supplementation with beta- carotene (provitamin A), nicotinamide (the amide of vitamin B3), and zinc all may reduce alcohol’s effects on fetal development, including cell loss, fetal dysmorphology, and cognitive impairments (reviewed in Idrus and Thomas 2011). These animal studies highlight the protective effects that nutrient supplementation can have on development during alcohol exposure. Improving the nutritional status of pregnant women, especially those who consume alcohol, will likely result in improved outcomes in offspring.

Postnatal Nutrient Interventions

Nutritional status also can affect cognitive development throughout childhood (Bryan et al. 2004). Recent studies have examined the nutritional intake of children with FASD. Based on their dietary habits, many children with FASD are not consuming adequate or daily-recommended amounts of omega-3 fatty acids, vitamin D, and choline (figure 5A) (Fuglestad et al 2013; Werts et al. 2014). Although these studies have some limitations—including low sample sizes, comparison with national data rather than a local control group, and relying on self-reports—they do indicate that individuals with FASD ingest inadequate levels of certain nutrients and therefore may benefit from nutrient supplementation. In rodent models, administering these micronutrients during or shortly following developmental alcohol exposure significantly mitigated ethanol-induced impairments on brain and behavior (figure 5B) (Idrus and Thomas 2011; Patten et al. 2013 b ). For example, animal models have shown that choline can attenuate ethanol’s adverse effects on both brain and behavioral development when administered postnatally, long after alcohol exposure has ceased (Ryan et al. 2008).

Clinical studies currently are under- way to examine the effectiveness of choline supplementation in children with FASD. Preliminary results from a study examining choline supplementation in children with FASD aged 2.5–4.9 years suggest that supplemental choline is both feasible and tolerable, with few side effects being reported (Wozniak et al. 2013). The results on behavioral measures should be available soon. In addition to nutrient supplementation, at-risk populations may benefit from better access to food naturally high in nutrients found to improve outcomes in animal studies.

Exercise Interventions

Exercise has many beneficial effects on brain and behavior outcomes. Reports in both human and rodents indicate that exercise improves learning and memory; increases circulating proteins that support brain function, such as brain-derived neurotrophic factor (BDNF); and, in rodents, increases generation of new neurons in the adult hippocampus (Voss et al. 2013). In addition, clinical studies show beneficial cognitive effects following exercise in normal aging, Alzheimer’s disease, and Parkinson’s disease (reviewed in Yau et al. 2014). No published studies to date have implemented an exercise intervention to improve cognitive and behavioral outcomes in individuals with FASD, but preliminary data and preclinical results are promising, as described below.

Studies suggest that running may enhance learning and memory in rodents prenatally exposed to alcohol. Rodents will run multiple kilometers per day when they have access to a running wheel, making it ideal for an exercise intervention. Indeed, access to a running wheel significantly attenuates spatial learning and memory impairments in adult rats exposed to alcohol during development (Christie et al. 2005; Thomas et al. 2008). In addition, these improvements in cognitive function following exercise are associated with exercise-induced enhancements in BDNF and adult hippocampal neurogenesis, both of which are influenced by developmental alcohol exposure (Gil-Mohapel et al. 2010).

However, the long-term effects of short periods of exercise may be limited. For example, increases in BDNF return to normal levels within 2 weeks following exercise (Gil-Mohapel et al. 2010). That said, the benefits of exercise may be prolonged through additional environmental experiences, such as those provided by raising animals in an enriched, stimulating environment. In fact, Hamilton and colleagues (2014) have found that the combination of wheel running followed by enrichment significantly increases adult neurogenesis relative to wheel running alone in alcohol-exposed rats. Similarly, exercise plus enrichment mitigates alcohol-induced impairments on behavioral tasks, such as trace eyeblink condi tioning and contextual fear conditioning. Behavioral improvement was associated with increases in adult neurogenesis (Hamilton et al. 2014). In addition, specific motor training can have beneficial effects on the structure and function of the cerebellum among rodents exposed to alcohol prenatally (Klintsova et al. 2000).

In translating these preclinical findings to human studies, researchers may need to tailor their exercise interventions to accommodate some of the motor impairments evident in FASD. A recent meta-analysis of motor skills in children and adolescents with FASD reported impairments in balance, motor coordination, and ball skills (Lucas et al. 2014).

A number of clinical research programs are using these findings to develop motor training and/or exercise interventions and investigate their efficacy in individuals with FASD. None have published results yet, except in abstract form. The following are two promising examples:

• Researchers at the University of Washington are using sensorimotor training via a virtual-reality system to try to improve motor deficits. Participants stand on a moveable surface, wearing virtual-reality goggles as the program attempts to train them to use sensory information for balance (Jirkowic et al. 2014) .
• Researchers at the University of the Fraser Valley are using strength-based interventions in an attempt to improve motor skills and cognitive function in FASD. In this intervention, clinicians create a physical activity and motor skills program based on an individual child’s strengths, with the hope that such training may generalize to some aspects of executive functioning, attention, and visuospatial processing in children with FASD (Keiver et al. 2014).

FASD can be difficult to treat for a number of reasons. First, identifying individuals with prenatal alcohol exposure can be a challenge. Although the characteristics of FAS are well defined, alcohol-affected children who do not meet the criteria for FAS or for whom exposure histories are unknown are more difficult to ascertain. Children who are diagnosed earlier have improved clinical outcomes (Streissguth et al. 2004), highlighting the need for early identification. Although there are methodological and ethical concerns that must be addressed, sensitive and specific biomarkers of exposure or effect would improve identification. Continued research examining the interrelations among alcohol-induced face and brain malformations and neurocognitive outcomes using both human and animal models may yield novel means for identification and/or novel specific targets for interventions.

Overall, studies with animal models of FASD demonstrate a wide array of benefits of pharmacological, nutritional, and environmental interventions to both brain structure/function and behavior. However, relatively few clinical studies have evaluated such treatments in FASD. There are some important potential limitations to these treatments. First, many of the treatments have very specific targets and consequences, whereas the range of deficits in FASD is quite varied. For example, in animal models of FASD, nutritional supplementation with choline has a greater positive effect on hippocampal function compared with cerebellar function; in contrast, motor training may be better able to target cerebellar effects in this population. Interventions that use multiple intervention strategies (e.g., nutrition and exercise) as well as more traditional interventions (educational, speech, occupational and/or physical therapies) may mitigate a wider range of cognitive impairments when translated to clinical cases of FASD. Given the numerous successes in identifying potential interventions in preclinical research, the upcoming years should increase translation of these findings to clinical research and eventually to health care settings.

Apoptosis : A process of programmed cell death.

Brain-derived neurotrophic factor (BDNF) : A protein secreted in the brain to support the survival of neurons; it plays a role in the growth, differentiation, and maintenance of these cells.

Cerebellum : An area of the brain important for coordinating motor function, as well as playing a role in simple learning and attention.

Corpus callosum : A wide bundle of fibers that connects the left and right hemispheres of the brain.

Cortex : The outer layer of the brain that is composed of folded gray matter and associated with perception, voluntary movement, and integration of information to support cognitive functions such as memory, language, and abstract thinking, among others.

cAMP response element–binding protein (CREB) : A protein that binds to certain stretches of DNA and influences activation of genes.

Epigenetics : The study of factors that affect gene expression without directly changing the DNA.

Epigenome : Chemical changes to the DNA and histone proteins that affect gene expression.

Ethyl glucuronide : A byproduct of alcohol metabolism formed in the body after alcohol consumption.

Ethyl sulphate : A byproduct of alcohol metabolism formed in the body after alcohol consumption.

Fatty acid ethyl esters : The products of a reaction between ethanol and fatty acid cells.

NMDA receptors : A receptor in the brain activated by the neurotrans-mitter glutamate. Among its many roles, NMDA receptors help control synaptic plasticity (the ability of the brain to change and evolve), learning and memory.

Oxidative stress : When there is an imbalance between the body’s production of reactive oxygen species (free radicals), and antioxidants, which defend against reactive oxygen species.

Pallidum : Refers to the globus pallidus, a subcortical brain structure involved in the regulation of voluntary movement.

Palpebral fissures : The opening between the upper and lower eyelids; length is measured as the distance between the inner to outer eye corners.

Peptide : Chains of 10 to 50 amino acids.

Philtrum : The typically vertical groove between the upper lip and nose.

Phosphatidylethanol : A metabolite of alcohol, created when phospholipase D interacts with alcohol.

Teratogen : A substance that interferes with development and causes birth defects.

Thalamus : A part of the vertebrate brain made up of two symmetrical halves deep in the middle of the brain. Among other roles, it is involved in relaying sensory and motor signals to the cerebral cortex, and regulating consciousness, sleep, and alertness. 

Disclosures

The authors declare that they have no competing financial interests.

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LEEANNE DENNY, MD, SARAH COLES, MD, AND ROBIN BLITZ, MD

This is a corrected version of the article that appeared in print. Figure 2 has been updated.

Am Fam Physician. 2017;96(8):515-522A

AAFP Resource: See related resources from the American Academy of Family Physicians on alcohol misuse.

Patient information: A handout on this topic is available at https://familydoctor.org/condition/fetal-alcohol-syndrome .

Author disclosure: No relevant financial affiliations.

Fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) result from intrauterine exposure to alcohol and are the most common nonheritable causes of intellectual disability. The percentage of women who drink or binge drink during pregnancy has increased since 2012. FAS is commonly missed or misdiagnosed, preventing affected children from receiving needed services in a timely fashion. Diagnosis is based on the presence of the following clinical features, all of which must be present: prenatal and/or postnatal growth retardation, facial dysmorphology, central nervous system dysfunction, and neurobehavioral disabilities. FASD is a broader diagnosis that encompasses patients with FAS and others who are affected by prenatal alcohol exposure but do not meet the full criteria for FAS. Management is multidisciplinary and includes managing comorbid conditions, providing nutritional support, managing behavioral problems and educational difficulties, referring patients for habilitative therapies, and educating parents. The Centers for Disease Control and Prevention and other organizations recognize no safe amount of alcohol consumption during pregnancy and recommend complete abstinence from alcohol. All women should be screened for alcohol use during preconception counseling and prenatal care, and alcohol use should be addressed with brief interventions.

Fetal alcohol spectrum disorders (FASD) result from prenatal exposure to alcohol and include fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (PFAS), alcohol-related neurodevelopmental disorder, and alcohol-related birth defects. 1 FAS is the most severe form of FASD. 2

WHAT IS NEW ON THIS TOPIC: FETAL ALCOHOL SPECTRUM DISORDERS

According to the Centers for Disease Control and Prevention, the percentage of pregnant women who consume alcohol increased from 7.6% in 2012 to 10.2% in 2015, and the number of pregnant women reporting binge drinking (at least four alcoholic beverages at once) increased from 1.4% to 3.1%.

A study demonstrated that more than one-half of children with fetal alcohol spectrum disorders do not consume the recommended dietary allowance of fiber, calcium, or vitamins D, E, and K.

According to the Centers for Disease Control and Prevention, the percentage of pregnant women who consume alcohol increased from 7.6% in 2012 to 10.2% in 2015, and the number of pregnant women reporting binge drinking (four or more alcoholic beverages at once) increased from 1.4% to 3.1%. 3 , 4 These trends are concerning because alcohol is the most common teratogen, and FASD is the most common cause of nonheritable intellectual disability. 5 Binge drinking is associated with the development of behavioral problems and physical deformities. 6

Although there is wide variation in the estimated prevalence of FAS/FASD, FAS is thought to occur in 0.3 to 0.8 per 1,000 children in the United States and in 2.9 per 1,000 globally. 7 , 8 The prevalence of FASD is estimated at 33.5 per 1,000 children in the United States and 22.8 per 1,000 globally. 8 In the United States, FASD is least prevalent in Hispanic children and most prevalent in Native Americans and Alaska Natives. 4 FAS is diagnosed at an average age of 48.3 months 9 ; however, it is commonly missed or misdiagnosed, preventing affected children from receiving needed services in a timely fashion.

FASD carries a significant economic burden. Children with FAS who are enrolled in Medicaid have annual mean medical expenses nine times higher than those for children without FAS, equating to a median annual expenditure of $6,670 per child (vs. $518 for those without FAS). 10

Any child who was exposed to alcohol pre-natally or presents with growth retardation, facial dysmorphology, central nervous system dysfunction, or neurobehavioral disabilities—the key manifestations of FASD—should prompt consideration of FASD. 11 The assessment and diagnosis require a multidisciplinary team ( Table 1 1 , 12 ) and should include neuropsychological assessment. 1

Diagnosis begins with assessment of prenatal alcohol exposure, including quantity of alcohol consumed per occasion, frequency of use, and timing of consumption during pregnancy. Prenatal alcohol exposure is defined as at least one of the following documented findings: (1) six or more drinks per week for two or more weeks during pregnancy; (2) three or more drinks per occasion on two or more occasions during pregnancy; (3) alcohol-related social or legal problems around the time of pregnancy; (4) intoxication during pregnancy documented by blood, breath, or urinary alcohol testing; (5) positive test for alcohol exposure biomarkers during pregnancy (fatty acid ethyl esters, phosphatidylethanol, and ethyl glucuronide in maternal hair, fingernails, urine, or blood, or in placenta or meconium); (6) increased prenatal risk associated with alcohol use during pregnancy as assessed by a validated screening tool. Documentation includes drinking levels reported by the mother three months before pregnancy recognition or at the time of a positive pregnancy test. Information must be obtained by the mother or a reliable source, such as family member, social service agency, or medical record. 1

Exposure to other teratogens should also be assessed, because women who consume alcohol during pregnancy are more likely to use other drugs. 1 The diagnostic criteria for FAS or PFAS do not require confirmed alcohol use if characteristic findings are present. 1 , 11 However, a confirmed absence of alcohol exposure rules out the diagnoses. Confirmation of alcohol exposure is required for diagnosis of alcohol-related neurodevelopmental disorder and alcohol-related birth defects. 1

KEY DIAGNOSTIC CRITERIA

As previously noted, FASD comprises four distinct categories: FAS, PFAS, alcohol-related neurodevelopmental disorder, and alcohol-related birth defects. Each category is distinguished by the presence or absence of characteristic facial dysmorphology, growth retardation, central nervous system dysfunction, and neurobehavioral disabilities ( Table 2 ) . 1

Characteristic facial dysmorphology associated with FASD includes short palpebral fissures (10th percentile or less for age and racial norms), a thin vermilion border of the upper lip, and a smooth philtrum 1 ( Figure 1 13 ) . Two of the three characteristic features are required for the diagnosis of FAS or PFAS. Palpebral fissures can be measured using a small plastic ruler, noting the distance between the endocanthion (where the eyelids meet medially) and exocanthion (where they meet laterally). The ruler should be angled to follow the curve of the zygoma. 1 The presence of a thin vermilion border and smooth philtrum is scored objectively using the lip-philtrum scoring guide ( Figure 2 ) . 14 Scores of 4 or 5 are consistent with FAS or PFAS.

Growth retardation is defined as the 10th percentile or less using height and weight measurements on standard growth curves. 1 For central nervous system dysfunction to qualify as consistent with FASD, it must include deficient brain growth, abnormal structure, or abnormal neurophysiology. This can be documented as a head circumference in the 10th percentile or less on appropriate growth curves, structural brain abnormalities, or recurrent nonfebrile seizures with no other identifiable cause. 1 Magnetic resonance imaging has identified structural brain abnormalities in children with FASD (e.g., temporal lobe asymmetry, change in size or shape of corpus callosum, cerebellum, or basal ganglia), and it may be used in the evaluation of suspected FASD; it can also be helpful if there is a question about the differential diagnosis. 1 , 15 – 17

Neurobehavioral disabilities in FASD include deficient global intellectual ability and cognition, and poor behavior, self-regulation, and adaptive skills. These domains should be measured using standardized testing, which often cannot be administered until after three years of age. A deficiency on these tests is characterized by scores of at least 1.5 standard deviations below the mean. 1 Alcohol-related neurodevelopmental disorder is diagnosed with documented prenatal alcohol exposure and neurobehavioral impairment in at least two domains in the absence of other defining characteristics for FAS.

Although they are not included in the diagnostic criteria for FAS or PFAS, multiple congenital abnormalities associated with prenatal alcohol exposure have been described for nearly every organ system ( Table 3 ) . 15 , 18 – 21 In the absence of defining criteria for FAS or PFAS, documented prenatal alcohol exposure and the presence of one or more major malformations known to result from prenatal alcohol exposure are diagnostic for alcohol-related birth defects 1 ( eTable A , Figure 3 13 ).

Differential Diagnosis

The differential diagnosis for FASD includes a variety of chromosomal abnormalities, exposure to other teratogens, and behavioral and psychiatric diagnoses ( Table 4 ) . 2 , 22 – 28 If the diagnosis is uncertain, the workup should include referral to a developmental pediatrician or geneticist for further evaluation, which may involve a chromosomal microarray, cranial neuroimaging, and cardiac/abdominal ultrasonography. 2

There is no cure for FASD. 5 There is a lack of evidence on which to base recommendations for optimal management; therefore, much of the management is based on expert opinion. Treatment consists of providing a medical home for the patient and family, managing comorbid conditions, providing nutritional support, addressing behavioral and emotional problems, arranging referrals for habilitative therapies (therapeutic intervention for those who have never developed a specific skill), coordinating care with a multidisciplinary team, and educating parents ( Table 5 ) . Early intervention is necessary to optimize health outcomes. 11 , 29

MANAGING COMORBID CONDITIONS

Children with FASD can have a range of comorbid conditions ( Table 3 ) 15 , 18 – 21 ; referrals to members of the multidisciplinary team are based on the specific needs identified. Because hearing and vision impairments are correlated with prenatal alcohol exposure, all children with suspected FASD should have hearing and vision screening. 30 , 31

NUTRITIONAL SUPPORT

Children with FASD are nutritionally and socially vulnerable and may benefit from nutritional education and support. By midchildhood, most of these children have spent, on average, one-fourth of their life with unmet basic needs and one-third of their life with someone who abuses alcohol or drugs. 29 One study showed that more than 50% of children with FASD do not consume the recommended dietary allowance of fiber, calcium, or vitamins D, E, and K. 32 It is important to regularly assess the child's height, weight, and body mass index and refer for support (e.g., nutritionist, social worker) when nutritional problems are identified. 33 Some children will require high-calorie foods and supplements.

MANAGING BEHAVIORAL PROBLEMS

Children with FASD should be monitored and screened for behavioral problems. They have an increased risk of attention-deficit/hyperactivity disorder (40% to 95%), 34 , 35 mood disorders (50%), 36 and oppositional defiant disorder (38%). 35 Medications can improve hyperactivity and impulsivity, but not symptoms of inattention. 37 , 38 Children with FASD and attention-deficit/hyperactivity disorder or other disruptive behaviors should be referred to a developmental pediatrician, psychologist, and/or psychiatrist. Behavioral interventions such as play therapy, children's friendship training, and specially trained case managers have reasonable evidence of effectiveness, but these resources have variable availability. 37

FAMILY SUPPORT

Children with FASD are at increased risk of physical and sexual violence, with 61% experiencing physical or sexual abuse or witnessing domestic violence by 12 years of age. 29 , 39 Sexual abuse should be considered in children who present with inappropriate sexual behaviors. Children with FASD who remain in the care of their biologic mother are more likely to experience family dysfunction and instability (e.g., divorce, unemployment, drug and alcohol use). 25 , 29 Those who are raised in stable homes have improved outcomes and are less likely to be expelled from or drop out of school, be arrested, or develop substance use problems. 29 Interventions should be aimed at stabilizing the home environment and improving parent-child interactions. 11 Such interventions include parental substance abuse referrals, child discipline courses, parent support groups, and child protective services.

Prognosis varies with the degree of impairment. Persons with FASD are more likely to require special education, receive disability pensions, and be unemployed. 40 Those who receive early diagnosis and intervention (before 12 years of age) have significantly better outcomes, including a two- to fourfold reduction in rates of imprisonment and substance abuse. 29

The Centers for Disease Control and Prevention, the American Academy of Family Physicians, the American Academy of Pediatrics, and the American Congress of Obstetricians and Gynecologists recognize no safe amount of alcohol consumption during pregnancy and recommend complete abstinence. 26 , 41 – 43 Although many women abstain from alcohol when they learn they are pregnant, some consume alcohol before they find out. Contraception should be offered to women of child-bearing age who drink; if they desire pregnancy, abstinence from alcohol should be recommended. 44 The American Congress of Obstetricians and Gynecologists recommends screening women in the first trimester for alcohol use, and Canadian guidelines recommend screening all pregnant women for alcohol use. 42 , 45 A useful screening tool is the TACER-3, which identifies women whose drinking may put their fetus at risk of FASD ( Table 6 ) . 46

If alcohol use in pregnancy is identified, physicians should recommend cessation and offer group-based interventions such as Alcoholics Anonymous and alcohol rehabilitation centers. 47 Brief interventions that include the patient's partner improve FASD-related birth outcomes and should include assessing maternal understanding of healthy pregnancy behaviors, assisting the mother in setting the goal of abstinence from alcohol, planning alternative behaviors for when the temptation to drink arises, and inviting the partner to find methods to support the mother's abstinence from alcohol. 48 , 49

This article updates a previous article on this topic by Wattendorf and Muenke . 13

Data Sources: Sources searched include PubMed (OVID), Evidence Summary from the AFP 's editors, Essential Evidence Plus, Cochrane database, and the Agency for Healthcare Research and Quality. Search terms included: fetal alcohol syndrome, fetal alcohol spectrum disorder, alcohol-related birth defects, maternal alcohol consumption, prenatal alcohol exposure. Search dates: February 2016, April 2016, May 2016, June 2016, July 2016, November 2016, and December 2016.

Figures 1 and 3 courtesy of Darryl Leja, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.

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FAS Diagnostic & Prevention Network. Lip-philtrum guides. http://depts.washington.edu/fasdpn/htmls/lip-philtrum-guides.htm . Accessed January 30, 2017.

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Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorders

Affiliation.

• 1 University of Arizona College of Medicine, Phoenix, AZ, USA.
• PMID: 29094891

Fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) result from intrauterine exposure to alcohol and are the most common nonheritable causes of intellectual disability. The percentage of women who drink or binge drink during pregnancy has increased since 2012. FAS is commonly missed or misdiagnosed, preventing affected children from receiving needed services in a timely fashion. Diagnosis is based on the presence of the following clinical features, all of which must be present: prenatal and/or postnatal growth retardation, facial dysmorphology, central nervous system dysfunction, and neurobehavioral disabilities. FASD is a broader diagnosis that encompasses patients with FAS and others who are affected by prenatal alcohol exposure but do not meet the full criteria for FAS. Management is multidisciplinary and includes managing comorbid conditions, providing nutritional support, managing behavioral problems and educational difficulties, referring patients for habilitative therapies, and educating parents. The Centers for Disease Control and Prevention and other organizations recognize no safe amount of alcohol consumption during pregnancy and recommend complete abstinence from alcohol. All women should be screened for alcohol use during preconception counseling and prenatal care, and alcohol use should be addressed with brief interventions.

• Alcohol Drinking / epidemiology*
• Alcohol Drinking / prevention & control
• Fetal Alcohol Spectrum Disorders / diagnosis*
• Fetal Alcohol Spectrum Disorders / prevention & control*
• Fetal Growth Retardation / chemically induced
• Health Education / organization & administration
• Heart Defects, Congenital / chemically induced
• Prenatal Care / organization & administration*
• Prenatal Exposure Delayed Effects / prevention & control*
• Risk Factors

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Sampling of first grade children: oversampling small children and random selection, study procedures: screening in tiers i and ii, study procedures: tier iii — child testing and maternal risk factor questionnaires, final diagnoses made in case conferences, data analysis, estimating fasd prevalence using 3 techniques, child demographic and physical variables, minor dysmorphic features, child cognitive and behavioral test performance, maternal risk factors, prevalence of fasd estimated by 3 techniques, making sense of the prevalence findings, physical characteristics of the children, cognitive and behavioral characteristics, maternal risk measurements, limitations, conclusions, acknowledgments, prevalence and characteristics of fetal alcohol spectrum disorders.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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Philip A. May , Amy Baete , Jaymi Russo , Amy J. Elliott , Jason Blankenship , Wendy O. Kalberg , David Buckley , Marita Brooks , Julie Hasken , Omar Abdul-Rahman , Margaret P. Adam , Luther K. Robinson , Melanie Manning , H. Eugene Hoyme; Prevalence and Characteristics of Fetal Alcohol Spectrum Disorders. Pediatrics November 2014; 134 (5): 855–866. 10.1542/peds.2013-3319

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To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community.

From a consented sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children’s mothers were interviewed for maternal risk.

Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child’s father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%).

Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.

Most studies of fetal alcohol syndrome and fetal alcohol spectrum disorders (FASD) prevalence in the general population of the United States have been carried out using passive methods (surveillance or clinic-based studies), which underestimate rates of FASD.

Using active case ascertainment methods among children in a representative middle class community, rates of fetal alcohol syndrome and total FASD are found to be substantially higher than most often cited estimates for the general US population.

Determining the prevalence of fetal alcohol spectrum disorders (FASD) in a general population has proved to be an elusive task. Since the diagnosis of fetal alcohol syndrome (FAS) was first described in 1973, 1 surveillance systems, prenatal clinic-based studies, and special referral clinics have proven inadequate for determining the prevalence of FAS or FASD. The often cited estimates for general populations are believed to be underestimates; yet very high rates have been found in certain substrate populations. 2 , 3 Rates from high-risk subgroups cannot be extrapolated accurately to general populations. 4 , 5  

The Centers for Disease Control and Prevention (CDC) has estimated that FAS occurs at a rate of 0.2 to 1.5 per 1000 children, 6 , 7 and the Institute of Medicine (IOM) estimates are 0.5 to 3.0 per 1000 children. 8 More current estimates of the prevalence of FAS in the US general population range from 0.2 to 7 per 1000 children, 5 and 2% to 5% for the entire continuum of FASD. 5 , 9  

One approach used successfully to determine the minimal prevalence of FASD in communities in South Africa, 10 , – 14 Italy, 15 , 16 and Croatia 17 , 18 uses active case ascertainment in schools. Providing targeted physical examinations and cognitive/behavioral testing to primary school children 19 , – 22 and interviewing their mothers 23 , – 25 can be effective for studying FASD prevalence and characteristics.

This study examined the prevalence and characteristics of FASD among first grade children in a representative Midwestern US city. Maternal risk factors for FASD were also explored. A total of 160 000 persons reside in the study community, among whom 87% are white. The residents are predominately middle class, with a per capita income of $28 000 and median household income of $51 800; 11% are below the poverty level. These indicators and others are virtually identical to US averages, except that US norms indicate that 14% of the general population is below the poverty level and reflect more racial diversity than the study community. 26 Per capita alcohol consumption in this state was 9.9 L of ethanol per year in 2009, 14% higher than the US average of 8.7 L, 27 but this county had an alcohol-related mortality index 27% less than the state as a whole. 28 The United Health Foundation 29 overall health ranking of this state is between 20 and 25 of 50 states. Data from the CDC Behavioral Risk Factor Surveillance System ranks the general health status of this county at 3.6 (above average) of a possible 5, and cites smoking at the US average. 30 In 2011, CDC data reported that 54% of females there consumed alcohol in the past 30 days, slightly higher than the US average. 31  

Protocols and consent forms were approved by The University of New Mexico School of Medicine, Human Research Review Committee, and the University of North Carolina. Active consents for children and mothers to participate were obtained.

IOM diagnostic guidelines for FASD 8 were used. Classification of children is based on (1) physical growth and dysmorphology; (2) cognitive assessments administered by school psychologists and behavioral assessments by teachers; and (3) interviews on maternal risk factors. Other malformation syndromes were ruled out, and final diagnoses made for each child in a data-driven case conference. 32  

The continuum of FASD comprises 4 diagnoses: FAS, partial fetal alcohol syndrome (PFAS), alcohol-related neurodevelopmental disorder (ARND), and alcohol-related birth defects. 8 Each of the diagnostic categories ( Fig 1 ) was considered in this study. The diagnosis of FAS without a confirmed history of alcohol exposure is permitted by the original IOM criteria, 8 and revised criteria 32 permit diagnosis of PFAS with other evidence of prenatal drinking. Many women underreport drinking during pregnancy, 24 , 33 , – 35 yet the diagnosis is rarely made without direct maternal reports of alcohol use before pregnancy recognition and/or in the first trimester, or collateral reports. An ARND diagnosis requires direct confirmation of prenatal alcohol use in the index pregnancy.

Diagnostic guidelines for specific FASDs, according to the Institute of Medicine, as clarified by Hoyme et al 2005.

Because particular dysmorphic features have proven to most clearly identify children exposed to alcohol prenatally, 1 , 32 , 34 , 36 oversampling of small children was undertaken to identify as many of the most dysmorphic children in the population as possible; additionally a random sample of children was drawn to provide candidates for representative, normal controls. All children enrolled in first grade ( n = 2033) in all 32 public and private schools were measured for height, weight, and head circumference (OFC) at the beginning of the school year. Consent forms were then sent to the parents/guardians of all first grade students; 70.5% provided consent to participate. Consented children entered the study simultaneously via oversampling for growth deficiency and/or small OFC and/or random selection as a potential normal control. A few teacher referrals of children who had suspected developmental issues were also accepted in the study ( Fig 2 ). Candidates for the comparison/control group were 250 students whose numbers were randomly selected from school roles; 196 consented to participate. The final control sample was 168 (see Fig 2 ), as 19 of the randomly selected children ultimately received a diagnosis of a FASD or another disorder, and 9 had incomplete data. Identical examinations and testing were performed on all potential subjects and controls ( Fig 2 ).

Sampling methodology for prevalence of FASD in a Midwestern city.

In Tier I, the schools released the consented children’s identified height, weight, and OFC measurements to study personnel along with school rolls. Any consented child ≤25th percentile on OFC or height or weight and all children randomly selected as control candidates were included in Tier II physical examinations ( Fig 2 ). Seventy-six of the randomly selected children also qualified on 1 or more of the growth measures. In-school examinations were then scheduled.

Four teams, each headed by a pediatric dysmorphologist, provided brief, structured examinations including assessment of growth, anthropometric measurements, and minor anomalies of the craniofacies and hands. Each child was assessed for the qualifying cardinal features of FASD and other minor anomalies and then assigned a “dysmorphology score,” an objective quantification of growth deficiency and minor anomalies. (Although not used in the final assignment of FASD diagnoses, the score is a useful research tool, correlating well with maternal drinking and learning/behavior difficulties in affected children.) 12 , 34 Examiners were blinded from previous knowledge of children and mothers. Inter-rater reliability in previous studies has been good. 10 , 13 , 32  

After reviewing dysmorphology findings for each child, a preliminary diagnosis was assigned by the dysmorphologist: (1) not-FASD, (2) diagnosis deferred, rule out a specific FASD or a related disorder, or (3) probable FAS or PFAS.

Development and behavior were assessed by blinded school psychologists with the Beery-Buktenica Developmental Test of Visual-Motor Integration 37 ; the Differential Ability Scales, Second Edition 38 ; and Vineland Adaptive Behavior Scales – Parent/Caregiver Rating Form and Teacher Rating Form. 39  

All consenting mothers of children in Tier III were administered interviews by project staff. Sequencing of questions was to maximize accurate reporting of general health, reproduction, nutrition, alcohol use, socioeconomic status (SES), and maternal height, weight, and OFC. Drinking questions used a timeline, follow-back sequence, 40 , 41 and Vessels alcohol product methodology for accurate calibration of standard alcohol units. 42 , – 44 Current alcohol consumption for the week preceding the interview was embedded into the nutrition questions 45 to aid accurate calibration of drinking quantity, frequency, and timing of alcohol use before and during the index pregnancies. 10 , 11 , 23 , – 25 , 33 Retrospective reports of alcohol use have been found to be superior to concurrent reports, but alcohol use has still been found to be frequently underreported in studies such as this. 33 , 46 , – 48  

Maternal risk data were gathered for 153 women ( Fig 2 ). Data presented focus on confirmation of maternal drinking for diagnosis and general risk factors in the study community. Drinking during pregnancy was confirmed with direct reports of a minimum of 7 drinks or more per week, or a binge of 3 or more drinks during any trimester or before pregnancy recognition in the third week of gestation or later. Collateral reports were also used for confirmation in 7 cases, 5 of which were from the child’s father. Detailed maternal risk factor information for FASD in other populations has been reported elsewhere. 12 , 24 , 25 , 34 , 46  

After completion of data collection, final diagnoses for each child were made in a confidential, structured, multidisciplinary case conference. The examiners, testers, and maternal interviewers each provided an oral and written summary of data and assessments for their domain for each child, and 2-dimensional photographs of the children were reviewed. After discussion of specific findings, final diagnoses were made by the examining dysmorphologist(s) after the team applied the IOM diagnostic criteria ( Fig 1 ).

Data analyses were performed with Excel 49 and SPSS (IBM SPSS Statistics, IBM Corporation). 50 Child physical, cognitive/behavioral, and maternal risk findings were compared across diagnostic groups using χ 2 for categorical variables and 1-way analysis of variance for interval level variables. 51 With statistically significant ANOVAs, post hoc analyses were performed using Dunnett’s correction pairwise comparisons (α = 0.05).

Prevalence rates were calculated from the total number of children in the consented population receiving each diagnosis within the FASD continuum and 2 different denominators: (a) total students enrolled in the first grade classes ( n = 2033), and (b) total children consented into the study ( n = 1433). Because of alcohol-induced growth deficiency, oversampling of small 6- and 7-year-old children who had dysmorphology examinations should capture a majority of all FAS and PFAS cases. 32 And with random selection for potential controls, many ARND cases are likely identified.

The second estimation of prevalence rates used the number and proportion of cases found among the children who were randomly selected as potential control/comparison children. The proportion of each FASD diagnostic category to the total selected was calculated and then projected to rates per 1000 as explained in detail in the results section for Table 5 .

The third technique used the proportion of randomly selected children with each FASD diagnosis projected to the un-consented population ( n = 600) to determine estimated cases of FASD in the un-examined group. These estimated cases were then added to the cases identified by technique 1 methods and rates computed as in Table 5 .

Neither age nor gender distinction by gender ratio was found across diagnostic categories or controls (see Table 1 ). In addition to the demographic variables in Table 1 , racial composition was examined. The overall sample is white (76%), black (7.0%), Asian (4.3%), Native American (3.7%), mixed race (0.8%), and Hispanic (8.2%). The overall racial make-up of all children diagnosed with an FASD does not differ significantly, and when similar individual comparisons are made for each diagnosis (FAS, PFAS, ARND, and not FASD), there are no significant differences by race or ethnicity.

Child Demographic, Growth, and Cardinal FASD Dysmorphology Variables in the Midwestern City by Diagnosis

PFL, palpebral fissure length; —, data not collected for the whole sample on these variables.

Statistical tests compare only individual diagnostic groups and controls and not the whole sample values.

Two controls were reported as alcohol-exposed prenatally.

Post hoc analysis indicates significant difference between FAS and PFAS, FAS and ANRD, FAS and controls, and PFAS and controls.

Post hoc analysis indicates significant difference between FAS and PFAS.

Post hoc analysis indicates significant difference between FAS and PFAS, PFAS and ARND, and PFAS and controls.

Post hoc analysis indicates significant difference between FAS and PFAS, FAS and ARND, FAS and controls, PFAS and ARND, and PFAS and controls.

Virtually all key physical variables (see Table 1 ) differed significantly across diagnostic categories. Child height, weight, and OFC centiles were significantly different among diagnostic groups, with post hoc analyses indicating significant pairwise differences between each of the groups except ARND versus controls. Children who had a FAS diagnosis were shorter, lighter, and had smaller heads than all others. BMI centile differed significantly by diagnosis, with the FAS group having the lowest BMI, and in ascending order PFAS, ARND, and controls. Palpebral fissure length centile differed significantly by child diagnosis, with post hoc analyses indicating significant differences among the PFAS, ARND, and controls. A significantly higher frequency of smooth philtrum exists among children who have FAS than those who have PFAS, ARND, and controls. A narrow vermilion border of the upper lip was significantly different between all children who had a FASD and controls. Finally, all groups differed significantly by mean total dysmorphology score ( Fig 3 ). The FAS group had the highest average, followed by PFAS, ARND, and controls, and the total dysmorphology score significantly discriminated the FAS and PFAS groups from every other group.

Total dysmorphology scores by diagnostic category for a Midwestern city study.

The frequency of minor anomalies not specifically included in the IOM diagnostic criteria, but in the total dysmorphology score, are presented in Table 2 . Short inner canthal distance, inter-pupillary distance, clinodactyly and camptodactyly all differed significantly by diagnosis (see Table 2 ). Children who had a FASD are more likely to have a hypoplastic midface as measured by clinical observation, and they are also likely to have lower measurements on maxillary and mandibular arcs. More clinodactyly and camptodactyly exist among children who had FASD than controls (see Table 2 ). Epicanthal folds were more frequent among children who had FASD, but not significantly different.

Other Minor Anomalies of Study Children in the Midwestern City by Diagnosis

ICD, inner canthal distance; IPD, inter-pupillary distance.

Two controls reported as alcohol-exposed during pregnancy.

Dunnett’s C post hoc analysis shows differences between FAS and controls.

Dunnett’s C post hoc analysis shows differences between FAS and controls; PFAS and controls.

Performance centiles on all cognitive and behavioral tests were significantly lower for children who had FASD than the controls (see Table 3 and Fig 4 ). The FASD group performed most poorly compared with the control group on verbal IQ, working memory, general and conceptual ability, and parent and teacher rating of adaptive behavior.

Child Cognitive and Behavioral Test Performance Centile by Diagnosis in the Midwestern City

DAS, Differential Ability Scales.

Child cognitive/behavioral test performance centiles by diagnosis in a Midwestern city.

Mothers of children who had FASD reported first recognition of pregnancy (measured from the first day of last menstruation) further into gestation than did controls, and fewer health care provider visits during pregnancy, although the latter difference only approached significance. Mothers of children who had FASD reported consuming significantly more drinks per drinking day 3 months before pregnancy than did controls. Approaching significance in the data were that the FASD maternal group reported more first trimester alcohol consumption, were more likely to binge with 5 or more drinks, and reported more drinking days in the past 30 days than controls. Mothers of children who had FASD reported that their husbands/partners consumed significantly more drinks per drinking day during pregnancy, and more paternal binge drinking, although the latter variable only approached significance. Non-significant differences in common maternal risk variables are reported in Table 4 , so that comparisons can be made for this US population with other populations where the traits are more commonly found.

Maternal Characteristics in the Midwestern City by Child Diagnostic Category

Alcohol use during the index pregnancy was confirmed directly by the birth mother or through collateral sources in 100% of the ARND cases, 33% of the FAS cases, and 61% of the PFAS cases. When the diagnosis was made without direct reports from the mothers, confidential collateral reports from relatives and evidence from medical or social service records supported the dysmorphology evidence.

The final diagnoses of the individual children in the entire consented sample are presented in Table 5 , section 1. Twelve children had FAS, 23 were diagnosed with PFAS, 13 had ARND, and none had alcohol-related birth defects. With the first prevalence estimation technique, 2 different denominators were used: the number of children enrolled in first grade classes at all schools ( n = 2033), and the total number with consent to participate in this study ( n = 1433). The assumption is that oversampling small children provided the highest probability of including most of the children who had FAS or PFAS. The rate of FAS with this technique is between 6 and 8 per 1000, the rate of combined FAS and PFAS is 17 to 24 per 1000, and total FASD is 24 to 34 per 1000 (see Table 5 ). For a single rate from this method, the midpoint is useful: FAS = 7.1, PFAS = 13.7, and total FASD = 28.6.

Prevalence Rates (per 1000) of Individual Diagnoses Within the FASD and Total FASD for First Grade Children in the Midwestern City: Prevalence Using 3 Techniques

Rate per 1000 children based on the enrolled sample, denominator = 2033.

Rate per 1000 children based on the sample screened, denominator = 1433.

Rate per 1000 children based on the randomly selected children only, denominator = 196.

Rate per 1000 children calculated from FASD cases diagnosed in consented sample added to the estimated cases in the non-consented sample using the proportional diagnostic distribution of FASD cases from the randomly selected children.

Alternatively, a second rate was calculated from the 16 cases of FASD found within the n = 196 who entered the study via random selection. The rates of FAS and total FASD from this technique are the highest of the 3 produced: 10 FAS cases per 1000 (95% confidence interval [CI], 0–24), the combined FAS and PFAS rate is 31 per 1000 (95% CI, 7–55), and the total FASD rate from this technique is 82 per 1000 (95% CI, 43–119).

The third rate was calculated from the number of total cases that would likely have been found in the 600 unconsented children. Projecting the proportions of FAS, PFAS, and ARND children found among the random sample (technique 2) to estimate the number of cases among the unconsented children and adding them to the cases diagnosed in the consented population, technique 3 estimates the rate of FAS to be 9, PFAS = 17, and a total FASD rate of 48 per 1000, or 4.8% ( Table 5 , section 3). Ninety-five percent confidence intervals make the range of FAS with this technique 39 to 57 per 1000. The final composite estimates of specific diagnoses of FASD and total FASD are found in Fig 5 , section 3.

Final estimate of prevalence of FASD in a Midwestern city.

A variety of FASD cases, from FAS to ARND, was found in this general school population. And on most variables and physical and behavioral averages between FASD diagnostic categories and controls, the FASD traits form a linear continuum in which children who have FAS have the most deficits, followed by PFAS, ARND, and the normal controls. Both dysmorphology and maternal data link the teratogenic agent, alcohol, to the cases. We suspect substantial underreporting of alcohol during pregnancy; nevertheless, several reported drinking measures were significantly different between mothers of children who had FASD and controls 3 months before pregnancy, and the mothers of children who had a FASD recognized that they were pregnant later than others. Also, mothers of children who had a FASD indicated a non-statistically significant trend of more binge drinking, and their partners drank significantly more heavily than fathers of comparison children.

The prevalence of FAS cases in this study of first grade children in this general population is likely 6 to 9 per 1000 (see Fig 5 ). It is significantly higher than older, previously accepted estimates of FAS (0.2 to 3 per 1000) that were generated from less representative samples that did not use active case ascertainment. 8 , 9 , 52 But these findings are similar to recent rates published for the United States, Italy, and Croatia, 2 to 7 per 1000, 5 , 15 , – 18 which used similar, active methods of case identification and as certainment. For FAS and PFAS combined, the likely maximum range of rates is 17 to 26 per 1000, and for total FASD, the rates range from 24 to 48 per 1000. Therefore, rates from this study are all well above the old estimate of 1% for total FASD. 9 It is clear from this study that FAS, PFAS, and total FASD are far more common in this representative general population of first grade students than older estimates would predict.

The large ratio of PFAS and ARND cases to the FAS cases in the present sample is important for several reasons. First, the ability of our clinical team to diagnose less dysmorphic cases has improved with many years of experience, and the criteria for diagnosing the full spectrum are evolving. 12 Second, the proportion of less dysmorphic to more dysmorphic cases seems indicative of a middle SES community with relatively favorable and stable environmental health conditions in which adequate dietary intake and fine universal educational institutions exist. Even with the oversampling of small children in this study, FAS cases identified here are only one-fourth of the children who had FASD, a pattern similar to findings in Italy. On the other hand, in recent studies of lower SES communities in South Africa, FAS cases are 45% or more of FASD cases. 12 We believe this study is an accurate representation of a mainstream, middle SES population.

By definition, all children diagnosed with FAS and PFAS met the facial criteria for at least 2 of the 3 cardinal features of FASD (palpebral fissure ≤10th percentile, smooth philtrum, and/or thin vermilion border of the upper lip), and had significantly smaller heads and BMIs than normal, randomly selected controls. The physical growth of children who had ARND was similar to the growth of other first graders. Not only the cardinal facial features, but other facial measurements and minor anomalies are also important discriminators of FASD. Based on this study and other population-based studies, 10 , – 13 , 15 , 16 other minor anomalies, such as those shown in Table 2 , are reflected in the total dysmorphology score, which differentiates well the FASD diagnostic groups. Minor anomalies play an important role in identifying affected children. 53  

In the cognitive/behavioral testing for this study and studies elsewhere, 11 , 12 those who perform worse generally have more dysmorphology as well. Children who have a FASD performed poorly compared with controls on all cognitive tests and behavior rating instruments. Possibly because fewer of the children who had FAS remained in the study for testing (58% vs 70% with PFAS and 100% with ARND), the PFAS and ARND children performed most poorly compared with controls, especially on verbal IQ, working memory, general conceptual ability, and behavioral problems. Although total dysmorphology and poor cognitive/behavioral traits are correlated, 11 , 12 , 34 , 54 there is also individual variation among the children on most every variable, each category of dysmorphology and performance.

In other study populations, maternal risk for FASD is more clearly defined by childbearing, SES variables, and binge-drinking measures than in this sample. Those populations that are characterized by lower SES generally have high fertility, poorer nutrition, more frequent and heavy binge drinking, and higher gravidity and parity, which more clearly differentiate mothers of children who had FASD from controls. 10 , – 12 , 55 In this middle SES Midwestern American sample, the only significant self-reported measures of maternal risk are longer duration before the mothers of children who had a FASD recognized pregnancy, fewer prenatal visits, more drinking reported 3 months before pregnancy, and heavy drinking by the father of children who had FASD. Drinking 3 months before pregnancy, a proxy for before-pregnancy recognition, has been a frequently recognized risk factor in many US and European studies. 56 , – 61 Recruitment of mothers to obtain maternal risk data posed significant challenges for the interviewers. Therefore, variables that differentiate maternal risk in this population were not as evident or readily obtained in this US population or in our Italian studies 15 , 16 as elsewhere. 23 , – 25 Individualized risk for FASD via genetic and epigenetic factors may be more important to explore in this and similar middle and upper SES populations than the more generalized lower SES and childbearing risk factors of higher prevalence populations. 12 , 16 , 52  

The consent rate for this study was high overall (70.5%). But there was some reluctance among particular individuals and families to continue throughout all parts of the study, as the consent process required signing several consent forms at various stages, which encouraged dropouts. Although 316 children were sought for psychological testing, only 65% of these children were tested, and 53% of the mothers sought were interviewed despite adequate incentives and up to 5 attempts to schedule an interview. Scheduling issues for 2-income families and a reluctance to continue in the study were problems in this population. Therefore, representativeness and completeness of the final sample is difficult to evaluate; to compensate, 3 sets of prevalence rates were calculated to produce a likely range of prevalence. A second limitation is the reluctance among mothers to report prenatal drinking. Only 33% of the mothers of children who had FAS and 61% of the mothers of children who had PFAS were interviewed. Studies elsewhere in the United States and Europe have reported similar problems 62 , – 64 and many have confirmed substantial underreporting by the use of biomarkers. 65 , – 68 Therefore, how underreporting affected the various maternal risk sample values is unknown. For example, the experienced interviewers estimated that at least 14% of the mothers of a child who had PFAS interviewed were clearly not fully forthcoming and truthful. Third, by initiating this study with assessment of child physical growth, development, and dysmorphology, the number of children with ARND and few dysmorphic features may have been under-identified, especially given the reluctance of mothers to report prenatal alcohol use. Therefore, the rate of ARND may be higher than reported here in the oversample estimate, but may be more accurately estimated from the 2 techniques based on random selection.

Children who have FASD, especially those who have FAS and PFAS, can be readily identified in mainstream school populations in the United States. The rate of FAS and overall FASD appear to be substantially higher in this community than most estimates for the general population of the United States, Canada, or Europe. In this community the rate of FASD is likely 6 to 9 per 1000 (midpoint, 7.5), 11 to 17 per 1000 (midpoint, 14) for PFAS, and 24 to 48 per 1000 (2.4% to 4.8%) for total FASD.

alcohol-related neurodevelopmental disorder

Centers for Disease Control and Prevention

95% confidence interval

fetal alcohol spectrum disorders

fetal alcohol syndrome

Institute of Medicine

occipitofrontal (head) circumference

partial fetal alcohol syndrome

socioeconomic status

Dr May is the Principal Investigator who designed the study, received the NIH funding, and wrote the majority of the first and last drafts of the manuscript; Ms Baete, Mr Russo, and Dr Elliott were respectively the program manager, project officer, and co-investigator who organized, implemented, and administered much of the data collection in the Midwestern city, and each contributed written text and edited various drafts of the manuscript; Dr Blankenship performed much of the data and statistical analyses, contributed written text and interpretation, constructed some tables, and edited various drafts of the manuscript before his sudden death on October 29, 2013; Ms Kalberg, Mr Buckley, and Ms Brooks were the designers and supervisors of the field data collection, data management, data entry, and Institutional Review Board activities, and each read drafts and edited the manuscript; Ms Hasken contributed to and edited each draft of the manuscript and produced original figures and the final tables and figures; Drs Abdul-Rahman, Adam, Robinson, and Manning were project dysmorphologists who diagnosed and generated clinical dysmorphology data in field clinics and made final diagnoses; Dr Hoyme was co-Principal Investigator for the site and the chief dysmorphologist supervising the clinical team members, administering clinical examinations, and generating data, he was chief medical officer assuming responsibility for medical liaison with the schools, families, and local administration, and he contributed written material and edited various drafts of the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: This project was funded by the National Institutes of Health (NIH), the National Institute on Alcohol Abuse, and Alcoholism (NIAAA), grants R01 AA11685, and RO1/UO1 AA01115134. Funded by the National Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

The project was started with supplemental stimulus funding to the first referenced grant and was later included in the NIAAA-funded initiative, Collaborative on Fetal Alcohol Syndrome Prevalence (CoFASP) via the second referenced grant. Marcia Scott, PhD, Kenneth Warren, PhD, Faye Calhoun, DPA, and T-K Li, MD of NIAAA have provided intellectual guidance and support for prevalence studies of FASD for many years. Our deepest thanks are extended to the superintendent of schools, administrators, principals, psychologists, and teachers of the school system in the study community who have hosted and assisted in the research process over the years. Their professional support, guidance, and facilitation have been vital to the success of this study. We dedicate this paper to them and also to our deceased colleague, Dr Jason Blankenship, who invested much effort into this project before his untimely death.

Competing Interests

Re:non-specific fasd diagnostic criteria lead to over-diagnosis.

Fetal alcohol spectrum disorders (FASD) are best diagnosed by a medical team headed by a geneticist/dysmorphologist with multidisciplinary input. Malformation syndromes with features similar to FASD must first be ruled out before a FASD diagnosis is assigned. As with any medical condition, no alcohol-related diagnosis is made solely on explicit criteria without the sound clinical judgment of an experienced clinician.

Astley has stated that the presence of all three "sentinel" facial features of FAS is 99.8% specific for FASD. Further, she has stated that "without a specific facial phenotype, a valid diagnosis of fetal alcohol syndrome cannot be rendered."(1) Instead of debating the number of requisite facial features needed for a FASD diagnosis, these findings should be considered in terms of their embryopathogenesis, that is as forme fruste signs of holoprosencephaly. Animal and human models confirm that these features can be genetically determined in addition to being the result of teratogenic exposures.(2,3,4,5) Even with documented teratogenic exposure, the facial phenotype may vary depending on timing.(4) This has been documented in at least two previous human studies,(2,3) and will be borne out in unpublished genetic testing data from our recent study. Thus, FASD cannot be diagnosed on the facial dysmorphology alone.

The case of "Johnny" in Dr. Davies' letter over-simplifies our diagnostic process. We gather data and apply diagnostic criteria only after other conditions have been ruled out. Not only are dysmorphic features considered, but also testing results, functional abilities of the child, evidence of prenatal alcohol exposure and other maternal risk factors.

All families receive useful feedback. Families of children for whom there is not an alcohol-related concern receive a report of the testing results detailing their child's performance on an extensive battery of tests. This provides useful information about strengths/deficits and is often, at the request of the families, included in the child's school records.

For children who have a FASD or another condition needing further attention, meetings conducted by a dysmorphologist and psychologist/diagnostician are held with each family. Feedback is provided about the preliminary diagnostic decision of the physician and the child's testing results. None of the results are shared until the families' concerns are discussed openly and a final diagnosis assigned. Therefore, the hypothetical "Johnny" outlined in the letter does not exist.

References:

1. Astley SJ. Comparison of the 4-digit diagnostic code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders. Pediatrics 2006;118;1532.

2. Douzgou S, Breen C, Crow YJ, et al. Diagnosing fetal alcohol syndrome: new insights from newer genetic technologies. Arch Dis Child 2012 Sep;97(9):812-7.

3. Abdelmalik N, van Haelst M, Mancini G, et al. Diagnostic outcomes of 27 children referred by pediatricians to a genetics clinic in the Netherlands with suspicion of fetal alcohol spectrum disorders. Am J Med Genet A 2013 Feb;161A(2):254-60.

4. Lipinski RJ, Hammond P, O'Leary-Moore SK, et al. Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent. PLoS One. 2012;7(8):e43067.

5. Leibson T, Neuman G, Chudley AE, Koren G.J. The differential diagnosis of fetal alcohol spectrum disorder. Popul Ther Clin Pharmacol. 2014;21(1):e1-e30.

Conflict of Interest:

None declared

Re:FAS/PFAS Prevalence Over Estimated

Using active case ascertainment methods to provide medical geneticists/dysmorphologists the opportunity to perform in-person examinations of children in representative schools provides access to more cases, and therefore uncovers high rates of fetal alcohol syndrome (FAS) and also other fetal alcohol spectrum disorders (FASD). About the same time that we reported such findings in South African studies, Dr. Astley's own colleagues from the University of Washington reported that only one of six of the FAS cases (17%) they found in elementary schools had been previously diagnosed.(1) Conversely, prevalence rates generated in clinic- based, surveillance, or referral studies will always be under estimates.

There are several facial phenotypes of FAS, let alone other FASD. Sensitivity and specificity of a diagnosis of complex syndromes like FAS and partial fetal alcohol syndrome (PFAS) must be carefully balanced in any diagnosis and diagnostic system. The final diagnosis must be made by expert dysmorphologists using sound empirical evidence and medical judgment on a multitude of alcohol-linked physical traits and from the best evidence possible from: a targeted battery of cognitive and behavioral tests and sophisticated, multivariate maternal risk factor interviews. Using only three specific facial features to rule in or rule out FAS is neither as sensitive nor as predictive as it could be. The three cardinal facial features of FAS may represent what we now know is only one of the facial phenotypes of FAS.(2) As presented previously, our research in multiple populations indicates that using only the three cardinal features to rule in or rule out a case of FAS is insufficient, for these three features alone are 72% sensitive, 92% specific, have a positive predictive value for only 53% of the cases, and accuracy of 90%. Ruling out a diagnosis of FAS if all three features are not present results in many false negatives. As with other anomalies, individual phenotypic variation dictates that critical evidence must include multiple additional traits that may indicate other influences on child outcomes: specific patterns of alcohol use; maternal health variables and childbearing history; postnatal environment; and genetic and epigenetic factors.(3)

Finally, alcohol has been meticulously linked to all child traits utilized in our studies of FASD in several populations. Studies in South African populations, where mothers have freely provided detailed information on specific prenatal drinking practices, have linked each of the dysmorphic features we employ to alcohol by: quantity, frequency, duration, and timing during gestation.(4) Sophisticated statistical models that control for many other prenatal influences confirm this strong link to the diagnostic variables employed.(5) Furthermore recent publications of imaging and 3-D photographic studies that were carried out by other scholars using children diagnosed by members of our team have confirmed the link to prenatal alcohol exposure.

The range of estimates for FASD published in our paper from the Midwestern City are accurate. The prevalence lies somewhere therein: between 6 and 9 per 1,000 children for FAS and 2.4 to 4.8% for FASD.

1. Clarren SK, Randels SP, Sanderson M, et al. Screening for fetal alcohol syndrome in primary schools: a feasibility study. Teratology. 2001;63:3-10.

2. Lipinski RJ, Hammond P, O'Leary-Moore SK, et al. Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent. PLoS One. 2012;7(8):43067.

3. Sulik KK. Fetal alcohol spectrum disorders: pathogenesis and mechanisms. Handbook of Clinical Neurology. 2014;125:463-475.

4. May PA, Blankenship J, Marais AS, et al. Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking. Drug Alcohol Depend. 2013;133(2):502- 5012.

5. May PA, Tabachnick BG, Gossage JP et al. Maternal risk factors predicting child physical characteristics dysmorphology in fetal alcohol syndrome and partial fetal alcohol syndrome. Drug Alcohol Depeden. 2011;119(1-2):18-27.

Non-specific FASD diagnostic criteria lead to over-diagnosis

We need to talk about Johnny.

He's a representative first-grader in a representative Midwestern city. His mother did not drink alcohol during pregnancy. Johnny's doing great in school and has an IQ of 120, with no evidence of developmental or behavioral problems.

Johnny's palpebral fissure lengths are at the 10th percentile, and he has a somewhat thinner upper lip (rank 4), but a deep philtrum (rank 1). This is not the face of FAS, by any reasonable definition.

In fact, my colleague Dr. Astley empirically confirmed that the FAS face as defined by Hoyme et al. is NOT specific to fetal alcohol exposure. In fact, 25% percent of a control group with above-average intellectual functioning and no prenatal alcohol exposure met the overly relaxed Hoyme FAS facial criteria. [Astley SJ. Comparison of the 4- Digit Diagnostic Code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders. Pediatrics. 2006;118(4):1532-1545 doi:10.1542/peds.2006-0577] Just like Johnny.

Johnny's weight (or height) is at the 10th percentile. His pediatrician has reassured his family that his growth is normal, since he's growing steadily and comes from smaller parents.

According to these authors, Johnny has Partial FAS Without Confirmed Maternal Alcohol Exposure.

What if Johnny's head circumference is also tracking at the 10th percentile? This is also in the normal range, according to his pediatrician. After all, Johnny has no evidence of neurobehavioral impairments.

Now Johnny has FAS Without Confirmed Maternal Alcohol Exposure.

Johnny is a hypothetical, but hardly an edge case. Subjects like him are likely to have contributed to the high estimated prevalence of PFAS in this study. Note that 39% of the PFAS diagnoses in this study were "without confirmed exposure." The estimates of FAS are similarly suspect (2/3 of the FAS diagnoses in this study lacked confirmed exposure).

Overestimating FASD prevalence rates is one problem, that requires more critical peer review. Using non-specific diagnostic criteria in clinical practice is an even greater concern.

Would you feel comfortable sharing Johnny's "diagnosis" with his mother? If not, why have diagnostic criteria that require clinical judgment to prevent misdiagnosis in a child without medical or developmental issues, and no history of prenatal alcohol exposure?

It would be arguably worse if Johnny did have developmental problems of some sort.

When the facial criteria are not specific to FAS, and the growth and neurobehavioral features are not uniquely caused by prenatal alcohol exposure, is it valid to effectively blame the mother for Johnny's impairments with a diagnosis of Fetal Alcohol Syndrome Without Confirmed Maternal Alcohol Exposure?

The authors have stated that they "validated" these proposed revisions to the IOM criteria. It is impossible to know, as they have not published sufficient measures of reliability, validity, or accuracy. Both common pediatric sense and the empiric evaluation in this journal [Astley 2006] show that these criteria are far too relaxed to be used in FASD diagnosis and research.

FAS/PFAS Prevalence Over Estimated

The authors report FAS prevalence in this population is 6-9/1,000 children (3-fold higher than the FAS prevalence estimated by CDC/IOM (0.2- 3.0/1,000)). The authors also report both dysmorphology and maternal data link the teratogenic agent, alcohol, to the cases. The study methodology does not support these conclusions.

The Hoyme(1) diagnostic guidelines used in this study, unlike all other current FASD diagnostic guidelines (CDC, 4-Digit, Canadian, and Australian), relax the diagnostic criteria for the FAS facial phenotype from 3 features (PFL <=2%tile, smooth philtrum and thin upper lip (Rank 4 or 5 on UW Lip-Philtrum Guide) to any two of these three, with the PFL relaxed to <=10%tile.

The relaxation of the FAS facial criteria results in a facial phenotype that is no longer specific to (caused only by) prenatal alcohol exposure. The 3 facial features defined by the 4-Digit Code have a specificity of > 95%(2). The 2 facial features defined by Hoyme(1) have a specificity of only 71.5% (reported by Hoyme at the 5th International FASD Conference,2013). What happens when the specificity is this low? In a 2006 study(3), 25% of a group of high-functioning children (mean IQ 120) with confirmed absence of prenatal alcohol exposure met the Hoyme(1) criteria for the FAS facial phenotype.

When the specificity of the FAS facial phenotype falls below 95%, two problems arise. First, the diagnostic label FAS is rendered medically invalid. If one labels the patient's outcome FAS, one is declaring the patient has a syndrome caused by their mother's consumption of alcohol during pregnancy. But if the face, growth, and CNS abnormalities are not specific to (caused only by) prenatal alcohol exposure, one has no medical or scientific evidence to support this declaration of causation in an individual patient. Second, a diagnosis of FAS can no longer be made in the absence of a confirmed prenatal alcohol exposure. Note, this is why the Hoyme(1) ARND diagnosis cannot be made when alcohol exposure is unknown.

Since the FAS (and PFAS) facial phenotype in the Hoyme(1) guidelines is not specific to prenatal alcohol exposure, a diagnosis of FAS (or PFAS) cannot be rendered when prenatal alcohol exposure is unknown. Only 33% (n=4) of the 12 FAS diagnoses in this study had confirmed alcohol exposure. Thus the prevalence of FAS in this study is at most 1.9- 2.7/1,000 (4/2,033 to 4/1,433); comparable to the CDC/IOM FAS estimates (0.2-3.0/1,000).

The dysmorphology and maternal data do not link the teratogenic agent, alcohol, to the cases in this study. The facial dysmorphology are not specific to prenatal alcohol exposure. Half the FAS/PFAS cases had no confirmed alcohol exposure. No significant link between the "dysmorphology -score" and any alcohol measure was reported. Only 1 of 7 maternal alcohol measures differentiated FASD from Controls in Table 4, but this too fails to establish a causal link between a case's alcohol exposure and their outcomes. None of the children's outcomes reported in this study are specific to (caused only by) prenatal alcohol exposure. The mothers may well have been forthcoming and truthful. 1. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. Pediatrics. 2005;115(1):39-47. 2. Astley SJ. Validation of the fetal alcohol spectrum disorder (FASD) 4- Digit Diagnostic Code. J Popul Ther Clin Pharmacol Vol 20(3):e416-467; November 15, 2013. 3. Astley SJ. Comparison of the 4-Digit Diagnostic Code and the Hoyme Diagnostic Guidelines for Fetal Alcohol Spectrum Disorders. Pediatrics 2006;118(4):1532-1545.

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ORIGINAL RESEARCH article

Development and psychometric evaluation of a questionnaire to measure university students’ knowledge on the effects of alcohol use during pregnancy.

• 1 Departamento de Medicina, Universidade Federal de São Carlos (UFSCar), São Paulo, Brazil
• 2 National Institute on Population Medical Genetics (INAGEMP), Porto Alegre, Brazil
• 3 Departamento de Morfologia e Genética, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

Introduction: Alcohol consumption during pregnancy can lead to fetal alcohol spectrum disorders. This study developed and validated a questionnaire to assess university students’ knowledge regarding the effects of alcohol during pregnancy.

Methods: We designed an instrument with true-false-I do not know statements. Initially, 45 true statements were formulated and subjected to content validation by 19 experts. Based on the Content Validity Index (CVI), 17 items were selected. The instrument, called the Fetal Alcohol Consequences Test (FACT), was first assessed by 31 university students for the level of understanding. Then, the questionnaire was administered to a national Brazilian sample of university students, and an Exploratory Factor Analysis (EFA) was conducted. Each correct FACT answer was worth 1 point, and the knowledge was categorized as high (total score ≥ 80%), moderate (score between 60 and 79%), and low (score ≤ 59%).

Results: When the questionnaire was being designed, the CVI values ranged from 0.779 to 1.0, and all statements were considered suitable by the target audience. For psychometric evaluation, 768 students from 24 Brazilian states participated. In the EFA, five statements were removed, revealing a tool with 12 items and two latent factors: “fetal alcohol spectrum disorders” and “conceptions and guidance on alcohol consumption during pregnancy.” The KMO index (0.76426) and Bartlett’s sphericity test (6362.6, df = 66, p  < 0.00001) both supported the final EFA model. The goodness-of-fit indices for the factor structure were adequate: χ 2  = 119.609, df = 43, p  < 0.00001; RMSEA = 0.048; CFI = 0.977; TLI = 0.965. The mean total FACT score among participants was 7.71 ± 2.98, with a median of 8; 32.03% of the students had high (10–12 points), 24.09% moderate (8–9 points), and 43.88% low knowledge (<8 points). The questionnaire proved reliable, with a floor effect of 1.17%, a ceiling effect of 9.25%, and a Cronbach’s alpha index of 0.798.

Conclusion: The FACT can be utilized in university students’ health education processes, contributing to greater knowledge and information dissemination about the effects of alcohol during pregnancy, in addition to the formulation of policies on the subject directed to this group of young adults.

1 Introduction

Alcohol consumption during pregnancy can cause various types of embryo-fetal damage, which is why it is classified as a chemical teratogen ( 1 ). The mechanisms by which alcohol exerts its teratogenic role include epigenetic changes and disrupted development, brain injury, disruption of morphogens and growth factors, disruption of neuronal and glial migration, effects on neural stem cells, disruption of neuronal–glial interactions, neuroinflammation, gut microbiota alterations, and placental effects ( 2 ).

A distinct phenotype in children whose mothers consumed alcohol during pregnancy was defined in the 1970s and named “fetal alcohol syndrome” (FAS) ( 3 ). FAS is an irreversible condition characterized by craniofacial dysmorphia, intra-and extrauterine growth deficiencies, neurodevelopmental disorders, and various birth defects, most notably cardiac, renal, vertebral, and hearing disorders. The term “fetal alcohol spectrum disorders” (FASD) was coined later and is considered an umbrella term that encompasses all negative outcomes resulting from prenatal alcohol exposure ( 1 , 2 ). Individuals with FASD can have a wide range of clinical phenotypes, ranging from FAS to congenital malformations and neurobehavioral disorders ( 4 ). The global prevalence of FASD is estimated at 19.0 per 1,000 individuals in the European region and 0.1 per 1,000 individuals in the Eastern Mediterranean region ( 2 ).

In line with the prevalence of FASD, the frequency of any amount of alcohol use during pregnancy among the general population is estimated at around 10%, varying from 25.2% in the European region to 0.2% in the Eastern Mediterranean region ( 2 ). In the Brazilian context, studies suggest that approximately 7–40% of women consume alcoholic beverages during pregnancy ( 5 – 11 ). This range has been attributed to the different instruments used to measure consumption and also to the period of pregnancy analyzed ( 5 ).

Greater consumption appears to be related to low education, inadequate housing conditions, low income, smoking, and the use of illicit drugs ( 5 , 9 – 13 ). The literature discusses the risk associated with the marital situation, whereby studies show greater consumption among women who live without partners ( 5 , 11 , 13 , 14 ) and others pointing to a greater risk among women with partners ( 9 ). There is also no consensus regarding the age risk. Although some studies indicate teenage pregnancy as being related to greater consumption ( 13 ), this association may not be due to maternal age but rather to the fact that the pregnancy was unplanned ( 12 , 15 ).

The World Health Organization recommends total abstinence from alcohol consumption throughout pregnancy ( 16 ). In Brazil, the Ministry of Health reiterates that there is no safe amount of alcohol to consume during pregnancy and alerts the population of its deleterious fetal effects, therefore suggesting abstinence ( 17 ). Despite these recommendations, in practice, alcohol abuse during pregnancy is related to women’s individual reasons, as well as their knowledge and previous experiences with the subject. A permissive environment seems to favor consumption, emphasizing the importance of health education on the subject directed not only at women but also to the general population ( 18 – 20 ).

International studies, as well as a few studies conducted in Brazil, have investigated the general population’s knowledge and, particularly, women, whether pregnant or not, of the effects of alcohol consumption during pregnancy. The methodologies used in these studies vary widely, making comparisons difficult. In a study involving 221 postpartum women in South Korea, 86.9% of the participants reported that they had not received information on alcohol consumption during pregnancy and 12.7% continued drinking during their gestation ( 21 ). A Danish study conducted with 1,418 pregnant women showed that women under 25 years of age had a higher risk of not knowing health recommendations related to alcohol use during pregnancy ( 22 ). Among 1,237 pregnant women in Ethiopia, only 15.26% were informed about the risks of drinking alcohol by health care providers, and women who had lower knowledge levels on the harmful effects of alcohol consumption during pregnancy were 3.2 times more likely to drink alcohol compared to women who had a high level of knowledge ( 23 ). An Israeli study conducted with 802 pregnant women showed that the women who consumed alcohol in the 2 months before pregnancy knew less about the risks of such consumption than did the women who had not consumed alcohol ( 24 ). In Australia, a survey of 1,103 non-pregnant women showed that older women, with more children and less education, had less knowledge on the subject ( 25 ). In Russia, research carried out with 648 women showed that only 8% of women had accurate knowledge regarding fetal alcohol exposure ( 26 ). In Ghana, a study involving 294 women of reproductive age revealed that knowledge was directly proportional to the level of education, and participants who lived in rural areas had less knowledge ( 27 ). In general, research conducted with pregnant and postpartum women revealed that many participants did not receive guidance related to the subject during pregnancy from health professionals ( 20 – 24 ), and women with a lower level of education tend to have less knowledge on the theme ( 23 , 25 – 27 ).

The topic is particularly relevant among students as young people are often heavy drinkers of alcohol and may have unprotected sex, leading to unplanned pregnancies ( 28 ). The understanding of high school pupils and university students on the topic has been explored in previous studies, indicating a general awareness regarding the harmful effects of alcohol during pregnancy ( 29 – 32 ). However, a smaller proportion of high school pupils and university students were familiar with the terms FASD, FAS, and their respective meanings ( 30 – 32 ). Among 1,035 American college students, 15% did not recognize the need for absolute abstinence throughout pregnancy ( 29 ). A Brazilian study with 331 university students enrolled in the first year of several health courses showed that 64.6% of participants were unaware of the harmful effects of alcohol on the fetus ( 30 ). In Italy, a survey carried out with 246 secondary school students noted that 30.1% of them believed that alcohol use was possible without damaging the fetus ( 31 ). Another Italian study with 9,921 secondary students showed that female and older students from Central and Northern Italy were better informed about gestational alcohol drinking risks ( 32 ).

In this context, we hypothesize that Brazilian university students have limited knowledge of the effects of alcohol consumption during pregnancy, which is a scientifically important public health issue. However, we did not identify valid instruments to investigate the subject in a systematic way. The purpose of this study was to develop and validate an instrument to measure university students’ knowledge about the effects of alcohol consumption during pregnancy that is user-friendly and can be answered quickly. A better understanding of students’ awareness of the subject can facilitate the development of more effective and culturally sensitive educational programs for this young population.

2 Materials and methods

2.1 study design and ethical considerations.

This is a descriptive and cross-sectional study that was conducted in two phases during August 2022 and January 2024. The questionnaire was developed in the first phase of the study, and the validity and reliability of the instrument were tested in the second phase using an exploratory factor analysis.

Ethical approval was obtained from the Human Research Ethics Committee at the Federal University of São Carlos (process CAAE 58094422.5.0000.5504) and all participants signed an informed consent. A data management plan for this research is available at https://doi.org/10.48321/D1QW4Z .

2.2 Phase 1: Development of the questionnaire

This research phase was conducted between August 2022 and March 2023. The questionnaire was developed in accordance with literature recommendations ( 33 – 38 ). The development phases followed the methodology proposed by Kishore et al. ( 38 ) and Azevedo and Scarpa ( 39 ). An advisory committee consisting of three of the authors (DGM, GPRL, and CMRG) was established. We chose to design an instrument with true-false-I do not know statements ( 40 , 41 ) and a dichotomous score (each correct answer is equivalent to one point; wrong answers or “I do not know” do not score). The knowledge about the effects of alcohol use during pregnancy corresponds to the total score in the questionnaire.

Previously, a relevant literature review was conducted. For this purpose, the PubMed and SciELO databases were consulted. The literature review yielded information on the pathogenesis and clinical findings of FASD, the main beliefs and myths concerning alcohol consumption during pregnancy, the types of questions from existing questionnaires, and recommendations provided by various institutions regarding the topic. Thus, the researchers learned about the major themes in the different subject aspects.

Initially, 45 true statements were produced, and the content was validated by experts. The Content Validity Index (CVI), as proposed by Hernández-Nieto ( 42 ), was calculated for each item of the instrument. To do this, expert judges used a 5-point Likert scale to assess the level of language clarity and practical relevance of the 45 statements. The cutoff point adopted to determine satisfactory levels for language clarity and practical relevance was CVI ≥ 0.80. Additionally, the theoretical adequacy of each of the 45 questionnaire items was assessed using a dichotomous question of yes/no ( 42 , 43 ). The experts also provided suggestions on how to better write the statements. These items were then analyzed and selected by the researchers. After this stage, 17 statements remained, six of which were transformed into false statements.

Following that, the instrument, entitled the Fetal Alcohol Consequences Test (FACT), was evaluated in relation to the level of understanding by the target audience. To achieve this, the questionnaire was administered to university students in the first and second years to check for difficulties and obtain suggestions on how to further clarify the statements. The students answered the following question: “Did you understand what was asked?” A 5-point Likert scale ranging from 0 to 4 was used; answers 3 and 4 were considered satisfactory, as suggested by Conti et al. ( 44 , 45 ). The level of understanding of each item was calculated based on the arithmetic mean of the values given by the students. Changes to the wording of the statements were made based on student feedback. Additionally, the order of the 17 items was randomized following this stage to mitigate any potential bias among pretest respondents.

Since the targeted population for which the FACT was developed was Brazilian students, the original version of the instrument was in Portuguese. For the purpose of reporting, it was translated into English and reviewed by a native English language expert. Therefore, the English version of the instrument, which is also presented in this paper, was not culturally adapted.

2.3 Phase 2: Psychometric evaluation of the FACT questionnaire

A pretest was conducted to evaluate the psychometric properties of the semifinal version of the FACT. The invitation to participate in this study was sent to all Brazilian federal universities and was also heavily publicized on social networks (Facebook and Instagram). The inclusion criteria were Brazilian individuals, aged 18 years or older, who attended a university course at an institution in Brazil. The investigation was therefore carried out on a non-probability convenience sample ( 46 ).

The data were anonymously collected from April 2023 to August 2023 using a self-reported online form. In addition to the FACT, sociodemographic information was obtained using a form prepared for this study ( Appendix S1 ), and the Brazilian version of the Sexual Transmitted Disease-Knowledge Questionnaire (STD-KQ) was applied ( 47 – 49 ), which was used for the FACT external construct validity assessment. The STD-KQ is a true-false-I do not know, comprehensive sexual transmitted infection knowledge questionnaire developed by American researchers in 2007 ( 47 ) and adapted and validated in Brazilian Portuguese ( 48 , 49 ). The Brazilian questionnaire has 23 items; each correct item is worth one point, and the overall knowledge about sexually transmitted infections corresponds to the total score in the questionnaire.

To calculate the sample size, a proportion of at least 25 participants was considered for each item in the FACT, higher than the general recommendation of 10:1 found in the literature ( 50 ), which allows for more accurate exploratory factor analysis.

2.3.1 Data analyses

The data analysis and the discussion of the results were conducted between August 2023 and January 2024. Descriptive analyses were performed for the characteristics of the pretest participants. Results were presented as the percentage, mean ± standard deviation (SD), and median (Mdn), depending on the variable.

An exploratory factor analysis (EFA) was conducted to evaluate the validity of the FACT internal construct. The FACTOR software ( 51 ), which we used to perform the EFA, offers several goodness-of-fit indices that are usually only seen in the confirmatory factor analysis (CFA). By supplementing the EFA with these indices, we reproduced a partial confirmatory factor analysis (PCFA). The primary utility of a PCFA is that, even when conducting a conventional EFA, we are able to obtain more convincing information as to whether considering a CFA of the model in the future is justifiable. Thus, these goodness-of-fit indices help to justify the recommendation of testing an EFA-derived model via CFA ( 52 , 53 ). The validity and reliability of the FACT were measured in its original language, that is, in Portuguese.

The Kaiser–Meyer–Olkin index (KMO) > 0.5 and Bartlett’s sphericity test with a p -value <0.05 were considered prerequisites for determining whether the matrix was factorable ( 50 ). The number of retained factors was determined using the parallel analysis technique with a random permutation of the raw data ( 54 ). To complement the testing of the number of factors of the total instrument, unidimensionality/multidimensionality techniques were applied: Unidimensional Congruence (UniCo), Explained Common Variance (ECV) and Mean of Item REsidual Absolute Loadings (MIREAL) ( 55 ). The EFA was performed using a polychoric matrix and the Robust Diagonally Weighted Least Squares (RDWLS) as the method for factor extraction ( 56 ). As a rotation technique, we used the Robust Promin ( 57 ).

The adequacy of the model was evaluated using the following goodness-of-fit indices: Root Mean Square Error of Approximation (RMSEA <0.08), Comparative Fit Index (CFI > 0.90), and Tucker–Lewis Index (TLI > 0.90) ( 58 ). The psychometric robustness of the model was assessed through bootstrap validation (500 resamples) that was used to generate a confidence interval (CI) for goodness-of-fit indices. Searching for the best factorial model, the following criteria were used to remove items: low Measure of Sampling Adequacy (MSA) value (<0.25), low factor loading (<0.3), presence of cross-loading (difference between factor loadings <0.15), and low communality (<0.25) ( 59 – 61 ).

Regarding the quality and effectiveness of factor score estimates, accuracy (Overall Reliability of fully Informative prior Oblique N-EAP scores – ORION >0.80), representativeness of the latent trait and effectiveness of factor estimation (Factor Determinacy Index – FDI > 0.90), sensitivity (Sensitivity Ratio – SR > 2.0), and the expected percentage of the factor (Expected Percentage of true Differences – EPTD >90%) were assessed. Composite reliability, calculated by the Composite Reliability Calculator, was based on standardized factor loadings and error variances ( 62 , 63 ); the reference values adopted for these measures were <0.6 low, between 0.6 and 0.7 moderate, and between 0.7 and 0.9 high reliability ( 64 ). The stability of the factors was evaluated using Generalized H indices; values of G-H > 0.80 suggest a well-defined latent variable, which is more likely to be stable in different studies, that is, replicable ( 55 ).

After carrying out the EFA and considering the results of the FACT best model, the questionnaire’s reliability was evaluated in terms of internal consistency using Cronbach’s alpha index, and values ≥0.70 were considered adequate ( 65 ). Descriptive analyses of FACT results were carried out. A response frequency diagram was constructed for each question, and the percentage of correct answers for each item and the general questionnaire was calculated. Floor and ceiling effects were evaluated by calculating the percentages of the responses with the lowest or highest possible scores; rates greater than 15% for the highest and lowest scores indicated ceiling and floor effects, respectively ( 66 ). Knowledge about the effects of alcohol use during pregnancy was categorized into three levels using the original Bloom’s cut-off points: high knowledge if the total score was between 80 and 100%; moderate knowledge if the total score was between 60 and 79%; and low knowledge if the total score was ≤59% ( 67 ).

The normality of the FACT total score was verified using the Kolmogorov–Smirnov test with Lilliefors correction. Since the normality of the FACT total score was rejected ( D  = 0.1119; p  < 0.0001), non-parametric statistical methods were used. The convergent validity of the FACT was determined through the correlation with the STD-KQ using the Spearman correlation coefficient (rho), interpreted as: 0.00 to 0.10—negligible correlation; 0.10 to 0.39—weak correlation; 0.40 to 0.69—moderate correlation; 0.70 to 0.89—strong correlation; and 0.90 to 1.0—very strong correlation analysis ( 68 ). The difference of the FACT scores according to the sociodemographic characteristics of the participants was analyzed using the Mann–Whitney or Kruskal–Wallis tests with Dunn’s post-test, depending on the number of groups in each variable.

Statistical analyses were performed using JASP 0.18.1 ( 69 ), MedCalc 22.014 ( 70 ) and FACTOR 12.04.01 ( 51 ). A p -value of <0.05 was considered statistically significant.

3.1 Development of the FACT questionnaire

After a bibliographical review, the 45 true statements were prepared by the authors ( Supplementary Table S1 ) with approximately the same size, seeking to avoid the tendency of respondents to consider a larger text as correct. The language was adapted to the target audience. All statements addressed topics related to the research themes: three epistemological topics and one topic related to myths and misconceptions, presented, respectively, in Supplementary Tables S2, S3 .

Content validation was performed on these statements by 10 geneticists, 3 pediatricians, 3 obstetrician-gynecologists, and both 3 geneticists and pediatricians. Regarding language clarity, the statements achieved CVI values ranging between 0.779 and 0.979. Regarding practical relevance, CVI values varied between 0.842 and 1.0. The CVI results are detailed in Supplementary Table S4 . In terms of theoretical adequacy, 13 of the 45 statements achieved adequacy lower than 90% (items 5, 6, 10, 12, 13, 21, 23, 26, 27, 28, 29, 35, and 43). Additionally, the judges provided some suggestions about the text writing of the statements.

During this process, the statements were ranked based on the content validation indexes ( Supplementary Tables S5–S7 ), and those with low CVI values were changed or removed from the questionnaire. The statements that received negative criticism from the expert judges and those that, after a new evaluation by the advisory committee, were considered to be of low relevance or similar in meaning to other items already present in the instrument were also removed. The instrument was then reduced by the research advisory committee to 17 statements, with 6 statements transformed into false statements. Supplementary Table S8 presents FACT after expert content validation.

This instrument with 17 items was subjected to an evaluation of the level of understanding, in which 31 university students participated. At this stage, the assertions reached a level of understanding ranging between 3.77 and 4, while FACT as a whole achieved a level of understanding of 3.92 ( Supplementary Table S9 ). The students made some suggestions about the writing of the statements, which were considered by the advisory committee. A semi-final version of the FACT was developed ( Supplementary Table S10 ), consisting of 17 closed-ended items.

3.2 Psychometric evaluation of the FACT questionnaire

3.2.1 pretest participants.

Initially, 785 students had joined the research. From the initial pool, 5 were removed as they were foreign students, 10 because they were under 18, and 2 due to providing incomplete responses. In total, 768 undergraduate students participated in the research, of whom 72.14% ( n  = 554) were female and 27.86% ( n  = 214) were male. These participants came from 24 states, with a significant predominance in São Paulo, representing 64.6% ( n  = 496). The mean age of the respondents was 24.03 ± 6.62 years. Regarding skin color/ethnicity, the majority (67.06%, n  = 515) identified as white, followed by 21.62% ( n  = 166) as mixed-race, 6.51% ( n  = 50) as black, 4.04% ( n  = 31) as Asian, and 0.78% ( n  = 6) as indigenous.

Concerning marital status, the majority of students (78.39%, n  = 602) declared themselves as single. With respect to sexual orientation, 66.41% ( n  = 510) identified as heterosexual, 6.64% ( n  = 51) as homosexual, 19.66% ( n  = 151) as bisexual, 2.34% ( n  = 18) as pansexual, 2.47% ( n  = 19) as asexual, and 2.47% ( n  = 19) did not want to share information. The majority, 88.80% ( n  = 682), did not have children. Among the female participants, 87.36% ( n  = 484) had never been pregnant, 8.12% ( n  = 45) had one pregnancy, 3.07% ( n  = 17) had two pregnancies, and 1.44% ( n  = 8) had three or more pregnancies. Regarding religion, 45.44% ( n  = 349) declared themselves as non-religious, while 28.78% ( n  = 221) identified themselves as Catholics.

The majority of respondents (90.23%; n  = 693) attended public universities. As for the field of study, 28.78% ( n  = 221) were in math and science careers, 20.96% ( n  = 161) in humanities, 17.32% ( n  = 133) in biological sciences, and 32.94% ( n  = 253) in health sciences. Regarding the type of high school attended, 44.92% ( n  = 345) went to public school, 51.04% ( n  = 392) attended private school, and 4.04% ( n  = 31) attended both public and private schools. In terms of monthly income, most college students (37.89%, n  = 291) earned 1–3 minimum wages (MW), 28.52% ( n  = 219) earned 4–6 MW, and 15.63% ( n  = 120) earned 7–10 MW. Supplementary Table S11 presents the sociodemographic information of the participants.

3.2.2 Exploratory factor analysis

The sample size was appropriate for the EFA execution as it allowed 45 respondents per FACT item. Firstly, an EFA was conducted with all 17 FACT items. The KMO index was unacceptable (0.35755) and items 1 and 14 presented normed MSA values below 0.25 (0.15740 and 0.22011, respectively). In a second EFA model, after removing these two items with lower MSA values, the KMO value improved (0.80527). However, this new model showed item 5 with cross-loading and item 17 with factor loading below 0.30. Both items were removed and a new EFA was performed. In this third EFA model, item 13 displayed low communality (0.198) and also needed to be removed. Lastly, the final EFA model was carried out with 12 items, excluding items 1, 5, 13, 14, and 17, and was considered appropriate. Table 1 presents the FACT’s final version with 12 items.

Table 1 . FACT’s final version, after exploratory factor analysis.

The KMO index (0.76426) and Bartlett’s sphericity test (6362.6, df = 66, p  < 0.00001) both supported this final EFA model. The parallel analysis identified that two factors represented the data because two factors of the real-data presented a percentage of explained variance higher than the variance mean of the random data ( Table 2 ). The total explained that the variance of these two FACT factors was 67.35%. The values of UniCo (0.936, <0.95), ECV (0.751, <0.85), and MIREAL (0.365, >0.300) confirmed that the pretesting data did not allow the FACT to be considered unidimensional.

Table 2 . Results of the parallel analysis.

Each factor comprised six items: the first factor contained items 1, 2, 3, 4, 8, and 12, and was named “fetal alcohol spectrum disorders” while the second factor contained items 5, 6, 7, 9, 10, and 11, and was named “conceptions and guidance on alcohol consumption during pregnancy.” The 12 items of the FACT presented adequate factor loadings in their respective factors ( Table 3 ).

Table 3 . Factor loadings and communalities for the 12 items of the FACT, as well as quality and effectiveness of factor score estimates, composite reliability indices, and estimates of replicability of the two factors.

Quality and effectiveness of factor score estimates, composite reliability indices, and estimates of the replicability of factorial scores (G-H indices) were also provided in Table 3 . Both the generated factor scores were considered reliable because ORION values were above 0.80, FDI values were above 0.90, SR values were above 2, and EPTD indices were above 90%. The composite reliability of both factors was high (Factor 1 = 0.859 and Factor 2 = 0.878). As expected, the GH-latent values are higher than GH-observed values for both factors, reflecting the result that the factors are better defined by the underlying responses than by the observed item scores ( 55 ). Finally, the goodness-of-fit indices for the factor structure were adequate: χ 2  = 119.609, df = 43, p  < 0.00001; RMSEA = 0.048 (95% CI 0.0340–0.0535); CFI = 0.977 (95% CI 0.972–0.987); TLI = 0.965 (95% CI 0.956–0.980).

3.2.3 Descriptive results of the FACT, ceiling and floor effects, and reliability statistics

Cronbach’s alpha index for the total FACT was 0.7976, with values ranging from 0.7473 to 0.7827 for each questionnaire item ( Supplementary Table S12 ).

The mean total FACT score was 7.71 (± 2.98, 95% CI 7.50–7.92), with a median of 8, a minimum of 0, and a maximum of 12 points. The floor effect was 1.17% and the ceiling effect was 9.25%. Figure 1 depicts the results of the FACT total score among the pretest participants, while Figure 2 presents the frequency diagram of responses to the 12 items of the FACT.

Figure 1 . The FACT total score distribution in pretest participants ( n  = 768).

Figure 2 . Frequency diagram of responses to the 12 items of the FACT among pretest participants ( n  = 768).

Statements 5 (misconception about alcohol and past pregnancies), 7 (any type of beverage is dangerous), 2 (fetal alcohol syndrome), 10 (scientific studies and alcohol intake), and 11 (alcohol in the first trimester) exhibited, in descending order, the highest percentage of correct responses. They achieved success rates of 95.83, 79.30, 78.00, 76.56, and 71.22%, respectively. On the other hand, statements 8 (alcohol and neurological problems), 4 (alcohol and behavioral problems), 1 (alcohol and heart defects), 3 (alcohol and lower intelligence), and 12 (alcohol and microcephaly) showed, in descending order, the lowest accuracy rates, with success percentages of 62.89, 52.08, 50.39, 47.14, and 26.17%, respectively.

Using the three-level categorization as proposed by Bloom ( 67 ), 32.03% ( n  = 246) of the students had a high knowledge (10 to 12 points), 24.09% ( n  = 185) had a moderate knowledge (8–9 points), and 43.88% ( n  = 337) had a low knowledge (<8 points).

3.2.4 External construct validity with the STD-KQ

Cronbach’s alpha index for the total STD-KQ was 0.8653, with values ranging from 0.8372 to 0.8489 for each questionnaire item ( Supplementary Table S13 ). The mean total STD-KQ score was 15.14 (±5.29, 95% CI 14.76–15.51), with a median of 16, a minimum of 0, and a maximum of 23 points. The floor effect was 1.17% and the ceiling effect was 3.0%.

The FACT scores were positively and moderately correlated with the STD-KQ scores (rho = 0.427, p  < 0.001), indicating that the more knowledge about alcohol consumption during pregnancy the students had, the more knowledge about sexually transmitted infections they also had.

3.3 Comparison of FACT scores among sociodemographic groups

Comparison of FACT scores among sociodemographic groups can be seen in Table 4 . A Mann–Whitney test indicated that the FACT score was greater for female participants (Mdn = 8) than for male participants (Mdn = 7) ( U  = 66,703; p  = 0.007).

Table 4 . The FACT score distribution according to the sociodemographic ( n  = 768).

There was a statistically significant difference between the FACT score by age [ H (3) = 12.240; p  = 0.007], marital status [ H (3) = 13.618; p  = 0.003], previous pregnancy [ H (3) = 27.543; p  < 0.001], alive children [ H (3) = 14.003; p  = 0.003], type of high school [ H (2) = 7.012; p  = 0.030], and field of study [ H (3) = 40.971; p  < 0.001].

Concerning age, the post-test showed a difference between the “18 to 30 years” group compared to the “31 to 40 years” ( p  = 0.048), “41 to 50 years” ( p  = 0.039), and “above 50 years” ( p  = 0.045) groups. There was also a difference between the “31 to 40 years” and “41 to 50 years” groups in relation to the “above 50 years” group ( p  = 0.009 and p  = 0.004, respectively). In terms of marital status, there was a difference between the “single” and “married” groups ( p  = 0.002), the “married” and “divorced” groups ( p  = 0.004), and the “common-law marriage” and “divorced” groups ( p  = 0.039). Regarding previous pregnancy, differences were observed between the group of people who have never been pregnant compared to the groups who have been pregnant once ( p  < 0.001), twice ( p  = 0.006), or three or more times ( p  = 0.012). Concerning the number of alive children, differences were noted between the group of those who do not have alive children compared to those who have one alive child ( p  = 0.004) and those who have three or more alive children ( p  = 0.015). Regarding the type of high school, differences were found between the “public” and “private” groups ( p  = 0.035) and between the “private” and “both, public and private” groups ( p  = 0.05). In terms of the field of study, differences existed between the “health sciences” and “math and science” groups ( p  < 0.001), “health sciences” and “humanities” groups ( p  < 0.001), and “health sciences” and “biological sciences” groups ( p  = 0.004).

4 Discussion

This study developed and validated an instrument to assess university students’ knowledge about the effects of alcohol during pregnancy. In this regard, the FACT is the first tool created in Brazil specifically for this purpose.

During the process of creating the first 45 statements, we reviewed articles on the subject from America, Africa, Europe, Oceania, and Asia, and we noted that several issues were addressed similarly across each study. These issues were categorized into epistemological topics and myths and misconceptions that permeate the use of alcohol during pregnancy. Subsequently, we adapted this categorization to the Brazilian sociocultural context and used it to construct the statements.

Three of the 45 statements (items 16, 33, and 43) achieved language clarity levels below acceptable in the FACT content validation process. We believe that the expressions “placental barrier” (statement 16) and “genetic profile” (statement 33) have been considered hermetic and, therefore, of low clarity. In statement 43, the double negation in “it has none” (in Portuguese: “não tem nenhuma”), although often used in colloquial Brazilian Portuguese, may have affected its clarity. All assertions reached the minimum desired CVI value in relation to practical relevance, which demonstrates the importance of all epistemological themes and myths/misconceptions listed in the research. The expert judges considered 13 of the 45 statements as covering knowledge not appropriate to be evaluated by the target audience, therefore achieving levels of theoretical adequacy below what is desirable. The results of the CVI and the suggestions received by the expert judges supported the changes to the FACT statements made by the advisory committee. As a consequence of that, in the stage of evaluating the level of understanding of FACT among the target population, all 17 items were considered adequate.

Although four distinct theoretical issues (three epistemological topics and one topic related to myths and misconceptions) guided the construction of the 45 initial FACT statements, the EFA indicated a factorial solution with two latent factors (“fetal alcohol spectrum disorders” and “conceptions and guidance on alcohol consumption during pregnancy”). The topic “fetal alcohol spectrum disorders” emerged as a factor, while the other topics converged in a second factor entitled “conceptions and guidance on alcohol consumption during pregnancy.” This factorial solution presented excellent explained variance ( 71 ), which indicates that the proposed model elucidated a significant part of the variance in the data set.

In psychometric terms, the factorial solution found was considered robust, with an adequate sample size and with extraction, retention, and factor rotation methods recommended by current literature ( 72 ). Regarding reliability, the FACT presented adequate internal consistency both in the general instrument and in each of the statements separately ( 65 ). The other goodness-of-fit indices were also within reference values, which strengthens the factorial model developed.

In spite of the factorial model’s good adequacy, it is noteworthy that future studies must apply the FACT to broader samples and populations other than university students in order to properly investigate and corroborate the proposed factorial structure.

Regarding the participants’ performance in each factor, four of the five statements that presented higher rates of “incorrect” or “I do not know” responses (statements 1, 3, 4, and 12) belong to the “fetal alcohol spectrum disorders” factor, while four of the five statements that presented the highest percentage of correct answers (statements 5, 7, 10, and 11) belong to the factor “conceptions and guidance on alcohol consumption during pregnancy.” These findings suggest that although students receive general information about the effects of alcohol during pregnancy, there is a lack of knowledge about fetal alcohol spectrum disorders.

In terms of external construct validity, the convergent analysis was conducted using the STD-KQ ( 47 ) because there was no other previously validated instrument on the same subject that could be utilized as a gold standard and allow concurrent validation. The positive and moderate correlation with the STD-KQ supports the validation of FACT and indicates that the greater the knowledge about sexually transmitted infections, the greater the knowledge about the effects of alcohol consumption during pregnancy.

The sample of university students showed higher knowledge on the subject when compared to other samples of non-pregnant women ( 26 ) and pregnant women ( 23 , 73 ) from the general population. It can be hypothesized that the academic environment to which university students are exposed can help them acquire more knowledge on the subject. However, in relation to North American university students ( 29 ), the Brazilian sample seems to have a lower level of knowledge. When compared to professionals in the areas of health, education, and social services, Brazilian university students also showed less knowledge ( 74 ). These differences may have occurred because the samples were different, but also due to the lack of a unique, standardized instrument for assessment.

The greater knowledge among female participants coincides with the literature ( 32 ). The Brazilian sample also demonstrated results similar to those of other studies by pointing out that younger individuals (under 30 years of age) and older individuals (over 50 years of age) had less knowledge about the effects of alcohol use during pregnancy ( 22 , 25 ). In relation to the number of living children and previous pregnancies, the present study differs from others by pointing out that women who have not had children or previous pregnancies have less knowledge on the subject when compared to those who have had living children and previous pregnancies ( 24 , 25 ). There were statistically significant differences between FACT scores by type of high school, marital status, and field of study. Having attended a private school during high school, being married, and pursuing higher education in the area of health sciences were factors associated with a higher FACT score. Since the topics covered by FACT and those taught to students in this area are thematically related, it was already anticipated that students in the health field would score higher.

4.1 Limitations

This study has some limitations. The sample is of convenience and, therefore, does not necessarily represent the general population of Brazilian university students. There is also a bias concerning data collection, as only university students with internet access were able to respond to the questionnaire. There was an irregular distribution in the origin of the participants, with a predominance of respondents from the state of São Paulo and an absence of participants from three of the 27 Brazilian states (Amapá, Amazonas, and Rondônia). The absence of an analogous instrument, which can be considered a gold standard, prevented us from conducting concurrent validation, forcing us to carry out convergent validation with the STD-KQ, whose issue is different. Furthermore, FACT was developed and validated for the Brazilian sociocultural context, which restricts its application in other scenarios without prior cross-cultural adaptation.

5 Conclusion

This study developed and validated an easy-to-apply questionnaire to assess the knowledge of Brazilian university students about the effects of alcohol consumption during pregnancy. Based on the results of this study, the low level of knowledge among university students regarding alcohol consumption during pregnancy indicates the need for a better dialog between this population and healthcare professionals. In this regard, continuing healthcare education should be implemented, aiming to enhance the technical and communication skills of these professionals so that they can provide updated information in an accessible manner to young people. Implementing public health campaigns can also be a useful strategy for increasing the public’s knowledge of the potential harms associated with alcohol consumption on the fetus and, in turn, contributing to reducing population-level alcohol use during pregnancy.

The lack of awareness among the students and the general population regarding the consequences of alcohol consumption during pregnancy, the absence of an entirely safe level of alcohol consumption, and the misconceptions in the dissemination of knowledge on the subject make it an important area for further research. Therefore, we expect that new studies apply and validate the FACT in different sociocultural contexts to investigate more deeply the variables that can influence knowledge on the subject and identify new factors that may affect drinking behavior. Thus, the FACT can become a more robust tool and assist further investigation of this topic. In summary, using this tool, we expect to facilitate the development of more effective and culturally sensitive educational programs that may contribute to the primary prevention of fetal alcohol spectrum disorders and support the formulation and establishment of public policies in the area.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Human Research Ethics Committee at the Federal University of São Carlos (process CAAE 58094422.5.0000.5504). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

GL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing. LA: Investigation, Validation, Writing – review & editing, Conceptualization. CG: Formal analysis, Investigation, Methodology, Validation, Writing – review & editing, Conceptualization, Supervision. DM: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the São Paulo Research Foundation (FAPESP grant 2022/05564–9), Coordination for the Improvement of Higher Education Personnel (CAPES, grant number 88887.136366/2017–00), and the National Council for Scientific and Technological Development (CNPq grant number 465549/2014–4).

Acknowledgments

We would like to thank the research participants who voluntarily provided the data for this investigation. We are grateful to the São Paulo Research Foundation (FAPESP) for the financial support through grant 2022/05564-9. We are also grateful to the Coordination for the Improvement of Higher Education Personnel - CAPES (grant 88887.136366/2017-00) and to the National Council for Scientific and Technological Development - CNPq (grant 465549/2014-4) for the support provided to the National Institute of Population Medical Genetics – INAGEMP.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2024.1399333/full#supplementary-material

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Keywords: alcohol consumption, pregnancy, fetal alcohol spectrum disorders, fetal alcohol syndrome, health knowledge, students, questionnaire design, Brazil

Citation: Leite GPR, de Avó LRdS, Germano CMR and Melo DG (2024) Development and psychometric evaluation of a questionnaire to measure university students’ knowledge on the effects of alcohol use during pregnancy. Front. Public Health . 12:1399333. doi: 10.3389/fpubh.2024.1399333

Received: 11 March 2024; Accepted: 24 April 2024; Published: 10 May 2024.

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*Correspondence: Débora Gusmão Melo, [email protected]

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