Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: diagnostic criteria

GINEVRA MICANGELI1, MICHELA MENGHI1, ROBERTO PAPARELLA1, MAURO CECCANTI2, GIOVANNA CORIALE3, DANIELA FIORENTINO4, GIAMPIERO FERRAGUTI5, MARCO FIORE6, LUIGI TARANI1; INTERDISCIPLINARY STUDY GROUPS* SAPIENZA, ISS, ISTAT, AIDEFAD, SITAC, SIFASD, FIMMG-LAZIO, SIPPS, SIMPESV, CIPe

1Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Italy; 2SITAC, Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze, Rome, Italy; 3CRARL Lazio, ASL Roma 1, Rome, Italy; 4ASL Rieti, Rieti, Italy; 5Department of Experimental Medicine, Sapienza University of Rome, Italy; 6Institute of Biochemistry and Cell Biology (IBBC-CNR), c/o Department of Sensory Organs, Sapienza University of Rome, Italy.

Summary. Fetal Alcohol Spectrum Disorders (FASD) encompass a spectrum of clinical manifestations resulting from maternal alcohol consumption during pregnancy. This condition presents with diverse anomalies including intrauterine and extrauterine growth retardation, phenotypic abnormalities, cerebral structural anomalies, cognitive delays, and behavioral abnormalities. Regrettably, FASD remains an irreversible and epigenetic condition, with total abstention from alcohol during pregnancy being the sole effective preventive measure due to the absence of a viable therapy. Diagnosis typically occurs postnatally, based on a combination of alcohol exposure history and the presence of aforementioned physical or behavioral abnormalities. The diagnosis is not always easy to make even in the post-natal period due to the different subtypes of existing FASD. Indeed, only some of these subtypes cause behavioral or neurodevelopmental abnormalities in the absence of pathognomic physical anomalies. Although the diagnostic criteria are useful, unfortunately, there is a heterogeneity resulting from the different guidelines that are used in different countries. The aim of our review, based on a literature search of online databases including Medline, Medline Complete, PubMed, and Google Scholar, is therefore to provide an overview of the diagnostic criteria used in Italy.

Key words. Alcohol-related birth defects, fetal alcohol spectrum disorders, fetal alcohol syndrome, pediatrician, prenatal alcohol exposure.

Linee guida italiane per la diagnosi e il trattamento dei disturbi dello spettro feto-alcolico: criteri diagnostici.

Riassunto. I disturbi dello spettro feto-alcolico (FASD) comprendono una serie di manifestazioni cliniche derivanti dal consumo di alcol da parte della madre durante la gravidanza. Questa condizione si presenta con diverse anomalie, tra cui ritardo della crescita intrauterina ed extrauterina, anomalie fenotipiche, anomalie strutturali cerebrali, ritardi cognitivi e anomalie comportamentali. Purtroppo, la FASD rimane una condizione irreversibile ed epigenetica, con l’astensione totale dall’alcol durante la gravidanza come unica misura preventiva efficace a causa dell’assenza di una terapia praticabile. La diagnosi avviene in genere nel periodo postnatale, in base a una combinazione di anamnesi di esposizione all’alcol e alla presenza delle suddette anomalie fisiche o comportamentali. La diagnosi non è sempre facile da fare anche nel periodo postnatale a causa dei diversi sottotipi di FASD esistenti. Infatti, solo alcuni di questi sottotipi causano anomalie comportamentali o neuroevolutive in assenza di anomalie fisiche patognomoniche. Sebbene i criteri diagnostici siano utili, sfortunatamente, esiste un’eterogeneità derivante dalle diverse linee guida utilizzate nei diversi Paesi. Lo scopo della nostra revisione, basata su una ricerca bibliografica di banche dati online tra cui Medline, Medline Complete, PubMed e Google Scholar, è quindi quello di fornire una panoramica dei criteri diagnostici utilizzati in Italia.

Parole chiave. Difetti congeniti correlati all’alcol, disturbi dello spettro feto-alcolico, esposizione prenatale all’alcol, pediatra, sindrome feto-alcolica.

Introduction

Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term1-6 that encompasses a range of conditions caused by prenatal alcohol exposure (PAE) such as:

• Fetal Alcohol Syndrome (FAS): this is the most severe form of FASD and is characterized by a specific set of physical, cognitive, and behavioral features7,8;

• Partial Fetal Alcohol Syndrome (pFAS): some diagnostic systems or clinicians may use the term “partial FAS” to describe individuals who exhibit some, but not all, of the characteristic features of Fetal Alcohol Syndrome9;

• Alcohol-Related Neurodevelopmental Disorder (ARND): this category is used when there are central nervous system abnormalities (CNS) and cognitive or behavioral impairments but without the physical features associated with FAS10;

• Alcohol-Related Birth Defects (ARBD): this category may be used when physical abnormalities are present without the characteristic facial features of FAS11.

Notably, the terminology and diagnostic criteria may vary across regions and medical professionals12-15. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes criteria for Neurodevelopmental Disorders associated with PAE, but it doesn’t use the specific term pFAS16-19. Clinicians may use a combination of features and assessments to diagnose individuals within the broader FASD spectrum20. In particular, FAS is considered one of the most severe outcomes of PAE21. The developing fetus is particularly vulnerable to the effects of alcohol because alcohol crosses the placenta and can interfere with the normal development of the baby’s organs and tissues22.

The key features of FAS include:

• facial abnormalities: children with FAS may have distinctive facial features, such as a thin upper lip, a smooth philtrum (the groove between the nose and upper lip), and small eye openings;

• growth deficiencies: FAS can lead to growth problems, both before and after birth. Babies born with FAS may have lower birth weight and length23;

• CNS abnormalities: alcohol exposure can affect the development and function of the central nervous system, leading to cognitive and behavioral issues24-29. Children with FAS may have learning disabilities, developmental delays, poor impulse control, and attention problems7,30;

• organ dysfunction: alcohol exposure can also affect the development and function of various organs, potentially leading to heart defects, kidney problems, and other abnormalities.

Furthermore, the severity of FAS can vary, and not all individuals with prenatal alcohol exposure will exhibit the same set of features10,15,31,32.

Epidemiology

The epidemiology of FASD involves studying the incidence, prevalence, risk factors, and distribution of these disorders in populations33. Accurate epidemiological data can be challenging to obtain because FASD encompasses a spectrum of conditions, and not all affected individuals may be diagnosed30. Additionally, underreporting and misdiagnoses can contribute to the complexity of obtaining precise epidemiological figures34,35.

The prevalence of FASD varies across different populations and regions; estimates suggest that FASD is a global health concern, with prevalence rates ranging from 1% to 5% in certain high-risk populations35,36. However, these figures may not capture the full extent of the problem due to underdiagnoses and varying diagnostic criteria37.

PAE is the primary risk factor for FASD, along with others such as timing, frequency, and quantity of alcohol consumption during pregnancy36,38. Maternal age, socioeconomic status, and access to healthcare may also play a role31. FASD is often underreported and misdiagnosed due to a lack of awareness, limited access to specialized diagnostic services, and the variability of symptoms; many individuals with FASD may not receive a diagnosis until later in life, if at all11,39.

Efforts to improve the understanding and surveillance of FASD include increased awareness among healthcare professionals, enhanced prenatal education and improved access to diagnostic services. Early identification and intervention are crucial for providing support and improving outcomes for individuals with FASD. Ongoing research and public health initiatives aim to address the challenges associated with the epidemiology of FASD and enhance prevention and intervention strategies. According to a 2011 study based on 607 children born in 7 hospitals in different Italian regions, the prevalence of PAE was found to be 7.9%. As highlighted in the ISS press release dated September 1st, 2021, in 2011 the prevalence estimates of FAS and FASD were 1.2 and 63 per 1000 live births, respectively35,40,41.

According to the WHO Global Status Report on Alcohol and Health 2018, countries in the European Region exhibit the highest prevalence of alcohol consumption during pregnancy (of any quantity), averaging at 25%. Even more alarming is the data indicating that in 2.7% of cases alcohol consumption occurs in a “binge drinking” manner, i.e. “drinking to get drunk”, the most harmful form of intake, especially with regards to FASD42,43. The prevalence estimates of alcohol consumption among pregnant women mirror the alcohol intake of the general population in the country under investigation, similarly to the varied prevalence estimates of FAS and FASD across different populations and studies within the same community35,44. According to recent WHO estimates, 65.5% of women of childbearing age in the European Region consume alcohol, and given that almost half of pregnancies are unplanned (42%), the risk of alcohol consumption during the early stages of gestation is very high45.

Given the clinical heterogeneity, our review aims to identify the comprehensive diagnostic criteria for FASD used in Italy. The literature for this review was sourced from online databases including Medline, Medline Complete, PubMed, and Google Scholar, utilizing search terms such as fetal alcohol spectrum disorders, fetal alcohol syndrome, prenatal alcohol exposure, and alcohol-related birth defects. The objective of our work was also to provide healthcare professionals with an overview of the different existing guidelines with particular attention to those currently used in Italy.

Etiology

The primary and well-established cause of FASD is PAE. Alcohol crosses the placenta and can impact the developing fetus at various stages of pregnancy8,46. The risk is present at any time during pregnancy, and the severity of the effects may depend on factors such as the timing, amount, and pattern of alcohol consumption47. The effects of PAE can vary depending on the timing of the pregnancy. Critical periods of vulnerability exist when specific organs and systems undergo crucial development8,48-51. For instance, the CNS is particularly sensitive to alcohol exposure throughout pregnancy21,52-56.

A dose-response relationship exists between the amount of alcohol consumed during pregnancy and the risk and severity of FASD. Higher levels of alcohol consumption are typically linked with an increased risk of adverse outcomes47,57. However, not all individuals exposed to alcohol during pregnancy develop FASD, indicating significant individual variability in susceptibility. Factors such as genetic predisposition, maternal health, nutritional status, and other environmental influences may contribute to this variability13,57.

The mechanisms through which alcohol inflicts damage on the developing fetus are complex and multifaceted. Alcohol can interfere with cell proliferation, migration, and differentiation, thereby resulting in structural abnormalities in organs and tissues58,59. Additionally, it can disrupt neurotransmitter systems in the developing brain, affecting cognitive and behavioral functions60. FASD should be considered a preventable condition, with abstention from alcohol during pregnancy being the most effective preventive measure61. Early and accurate diagnosis of FASD is paramount for offering appropriate interventions and support for affected individuals and their families62-64.

Diagnostic criteria

The diagnostic criteria for FAS typically encompass a combination of physical, developmental, and behavioral features23,37. These criteria may exhibit slight variations depending on the diagnostic system or guidelines employed by healthcare professionals33,37,39,62,65-73.

Over the years, different guidelines for diagnosis have been developed by different research groups including:

• the Institute of Medicine Guidelines (IOM)74;

• the 4-Digit Diagnostic Code75;

• the Hoyme Updated Clinical Guidelines37;

• the Canadian FASD Guidelines76;

• the Centers for Disease Control and Prevention (CDC) Guidelines77;

• the British Medical Association Guidelines (BMA Board of Science)78;

• the Australian Guide to the diagnosis of FASD79.

The absence of universally accepted diagnostic criteria on an international scale renders the diagnosis of FAS/FASD a complex, continuously evolving, and ongoing challenge8,31,37. In Italy, the diagnosis is based on the Hoyme criteria, with the latest updated criteria from 2016 presented in tables 1-437.













In Italy these criteria have always been preferred to other guidelines for greater completeness in making the clinical diagnosis. This is probably also due to the fact that they are very rigid and precise criteria and therefore the risk of underestimating the pathology is reduced compared to other guidelines.

The presence of these features aids clinicians in making a diagnosis of FAS; nevertheless, not all individuals with PAE will exhibit all of these characteristics, and the severity can vary61,80. Consequently, healthcare professionals may use terms such as “pFAS” or “ARND” to describe a range of outcomes associated with PAE31,34,64.

Hence, diagnosis involves both clinical examination and subsequent laboratory testing, also including exploratory diagnostic techniques such as brain magnetic resonance imaging and ultrasound scans of the brain, heart, or kidneys64,81,82. Among genetic tests, comparative genomic hybridization on microarrays, or Array-CGH, is recommended to identify DNA anomalies that may underlie various pathologies30,58,60,83. In general, the guidelines mentioned above share four common diagnostic criteria: the presence of dysmorphological signs, growth defects, documented exposure to alcohol, and the presence of cognitive/behavioral disorders21. What distinguishes the various guidelines is the starting point for data collection. The IOM and Canadian guidelines consider data collection related to dysmorphological signs and alcohol exposure, while the Australian ones are based on information regarding the individual’s cognitive and behavioral functioning, supplemented by collecting information on documented exposure to alcohol39,72,84,85. Table 5 shows the criteria for defining the alcohol consumption during pregnancy35,86.




In addition to the international guidelines, the DSM criteria can also be used, which in its fifth edition87 included FAS within the diagnostic category: Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE)47,67. Individuals who meet the criteria for a diagnosis of FASD according to the IOM guidelines may also meet the criteria for ND-PAE42,88. Unlike international guidelines, the DSM-5 employs two criteria to establish a diagnosis: disorders of CNS functioning (cognitive and behavioral) and data concerning fetal exposure to alcohol21,89,90.

Discussion

Diagnosing FAS requires a comprehensive assessment by healthcare professionals, which includes physical examinations, developmental and behavioral evaluations, and obtaining a detailed history of PAE. Early diagnosis and intervention are crucial in providing appropriate support and services for individuals affected by FAS91,92. Given the absence of a genetic test, as FASD is of epigenetic origin, and the lack of specific and standardized biomarkers for detecting patients with FASD, diagnosis remains challenging for physicians. Furthermore, the lack of a unique diagnostic guideline also presents challenges in diagnosing FASD. In Italy, the Hoyme guidelines are preferred due to their comprehensiveness, which enhances diagnostic accuracy while minimizing underestimation of the pathology46,77.

Conclusions

Implementing a uniform global guideline would be highly beneficial in ensuring an adequate and consistent number of diagnoses. This study aimed to provide a comprehensive overview of some of the most commonly used guidelines, with a particular focus on those frequently applied in Italy, such as the guidelines proposed by Hoyme and his collaborators.

While these guidelines currently appear to be the most comprehensive and effective in minimizing diagnostic underestimation, we acknowledge the challenges in establishing global guidelines. Therefore, we recommend that further studies and collaborative efforts are essential to develop at least homogeneous guidelines.

*Interdisciplinary Study Groups: Sapienza Università di Roma, ISTAT - Istituto nazionale di statistica, AIDEFAD - Associazione Italiana Disordini da Esposizione Fetale ad Alcol e/o Droghe, SITAC - Società italiana per il trattamento dell’alcolismo e delle sue complicanze. SIFASD - Società Italiana Sindrome Feto-Alcolica, ISS - Istituto Superiore di Sanità, SIPPS - Società Italiana di Pediatria Preventiva e Sociale, FIMMG-Lazio - Federazione Italiana dei Medici di Medicina Generale Lazio, SIMPeSV - Società Italiana di Medicina di Prevenzione e degli Stili di Vita, CIPe - Confederazione Italiana Pediatri. Adele Minutillo, Alba Crognale, Alberto Chiriatti, Alberto Spalice, Andrea Liberati, Angelo Selicorni, Antonella Polimeni, Antonio Greco, Arianna Barzacchi, Camilla Di Dio, Duccio Cordelli, Francesca Fanfarillo, Francesca Tarani, Giovanni Corsello, Lina Corbi, Luca Cavalcanti, Lucia Leonardi, Camilla Perna, Lucia Ruggieri, Luigi Meucci, Marco Lucarelli, Maria Grazia Piccioni, Maria Pia Graziani, Mario Vitali, Marisa Patrizia Messina, Martina Derme, Nunzia La Maida, Patrizia Riscica, Sabrina Venditti, Sergio Terracina, Serafino Zangaro, Pier Luigi Bartoletti, Silvia Francati, Simona Pichini, Stefania Bazzo, Stefania Pipitone.

Conflict of interests: the authors have no conflict of interests to declare.

References

1. Terracina S, Tarani L, Ceccanti M, et al. The impact of oxidative stress on the epigenetics of Fetal Alcohol Spectrum Disorders. Antioxidants 2024; 13: 410.

2. Coriale G, Ceccanti M, Fiore M, et al. Delay in the fine-tuning of locomotion in infants with meconium positive to biomarkers of alcohol exposure: a pilot study. Riv Psichiatr 2024; 59: 52-9.

3. Weinberg J, Sliwowska JH, Lan N, Hellemans KGC. Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome. J Neuroendocrinol 2008; 20: 470-88.

4. Rasmussen C, Bisanz J. Executive functioning in children with Fetal Alcohol Spectrum Disorders: profiles and age-related differences. Child Neuropsychol 2009; 15: 201-15.

5. Walker D, Fisher C, Sherman A, Wybrecht B, Kyndely K. Fetal alcohol spectrum disorders prevention: an exploratory study of women’s use of, attitudes toward, and knowledge about alcohol. J Am Acad Nurse Pract 2005; 17: 187-93.

6. Popova S, Lange S, Shield K, Burd L, Rehm J. Prevalence of fetal alcohol spectrum disorder among special subpopulations: a systematic review and meta-analysis. Addiction 2019; 114: 1150-72.

7. Memo L, Gnoato E, Caminiti S, Pichini S, Tarani L. Fetal alcohol spectrum disorders and fetal alcohol syndrome: the state of the art and new diagnostic tools. Early Hum Dev 2013; 89 (Suppl.1): S40-43.

8. 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: 502-12.

9. Varadinova M, Boyadjieva N. Epigenetic mechanisms: a possible link between autism spectrum disorders and fetal alcohol spectrum disorders. Pharmacol Res 2015; 102: 71-80.

10. Guerri C, Bazinet A, Riley EP. Foetal Alcohol Spectrum Disorders and alterations in brain and behaviour. Alcohol Alcohol 2009; 44: 108-14.

11. Ceccanti M, Alessandra Spagnolo P, et al. Clinical delineation of fetal alcohol spectrum disorders (FASD) in Italian children: comparison and contrast with other racial/ethnic groups and implications for diagnosis and prevention. Neurosci Biobehav Rev 2007; 31: 270-7.

12. Marquardt K, Brigman JL. The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: insights from rodent models. Alcohol 2016; 51: 1-15.

13. Stade B, Ali A, Bennett D, et al. The burden of prenatal exposure to alcohol: revised measurement of cost. Can J Clin Pharmacol 2009; 16: e91-102.

14. Heimdahl Vepsä K. Is it FASD? And does it matter? Swedish perspectives on diagnosing fetal alcohol spectrum disorders. Drugs Educ Prev Policy 2021; 28: 547-57.

15. Ferraguti G, Merlino L, Battagliese G, et al. Fetus morphology changes by second-trimester ultrasound in pregnant women drinking alcohol. Addict Biol 2020; 25: e12724.

16. Famy C, Streissguth AP, Unis AS. Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. Am J Psychiatry 1998; 155: 552-4.

17. American Psychiatric Association. Cautionary statement for forensic use of DSM-5. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. 2014.

18. De Vries ALC, Beek TF, Dhondt K, et al. Reliability and clinical utility of gender identity-related diagnoses: comparisons between the ICD-11, ICD-10, DSM-IV, and DSM-5. LGBT Heal 2021; 8: 133-42.

19. American Psychiatric Association. DSM-5 Diagnostic Classification. In: Diagnostic and Statistical Manual of Mental Disorders. 2013.

20. Cranston ME, Mhanni AA, Marles SL, Chudley AE. Concordance of three methods for palpebral fissure length measurement in the assessment of fetal alcohol spectrum disorder. Can J Clin Pharmacol 2009; 16: e234-41.

21. Dunbar Winsor K. An invisible problem: stigma and FASD diagnosis in the health and justice professions. Adv Dual Diagn 2021; 14: 8-19.

22. Olson HC. The effects of prenatal alcohol exposure on child development. Infants Young Child 1994; 6: 10-25.

23. Banakar MK, Kudlur NS, George S. Fetal alcohol spectrum disorder (FASD). Indian J Pediatr 2009; 76: 1173-5.

24. Amos-Kroohs RM, Nelson DW, Hacker TA, Yen CE, Smith SM. Does prenatal alcohol exposure cause a metabolic syndrome? (Non-)evidence from a mouse model of fetal alcohol spectrum disorder. PLoS One 2018; 13: e0199213.

25. Glass L, Ware AL, Mattson SN. Neurobehavioral, neurologic, and neuroimaging characteristics of fetal alcohol spectrum disorders. Handb Clin Neurol 2014; 125: 435-62.

26. Ceci FM, Francati S, Ferraguti G, et al. Behavioral dysregulations by chronic alcohol abuse. Motivational enhancement therapy and cognitive behavioral therapy outcomes. Riv Psichiatr 2022; 57: 1-9.

27. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 302: 999-1001.

28. Hamułka J, Zielin´ska MA, Cha˛dzyn´ska K. The combined effects of alcohol and tobacco use during pregnancy on birth outcomes. Rocz Panstw Zakl Hig 2018; 69: 45-54.

29. Lange S, Shield K, Koren G, Rehm J, Popova S. A comparison of the prevalence of prenatal alcohol exposure obtained via maternal self-reports versus meconium testing: a systematic literature review and meta-analysis. BMC Pregnancy Childbirth 2014; 14: 127.

30. Popova S, Dozet D, Shield K, Rehm J, Burd L. Alcohol’s impact on the fetus. Nutrients 2021; 13: 34-52.

31. May PA, Baete A, Russo J, et al. Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics 2014; 134: 855-66.

32. Zhang Y, Wang H, Li Y, Peng Y. A review of interventions against fetal alcohol spectrum disorder targeting oxidative stress. Int J Dev Neurosci 2018; 71: 140-5.

33. May PA, Fiorentino D, Phillip Gossage J, et al. Epidemiology of FASD in a province in Italy: prevalence and characteristics of children in a random sample of schools. Alcohol Clin Exp Res 2006; 30: 1562-75.

34. May PA, Gossage JP, Marais AS, et al. Maternal risk factors for fetal alcohol syndrome and partial fetal alcohol syndrome in South Africa: a third study. Alcohol Clin Exp Res 2008; 32: 738-53.

35. Lange S, Probst C, Gmel G, Rehm J, Burd L, Popova S. Global prevalence of fetal alcohol spectrum disorder among children and youth: A systematic review and meta-analysis. JAMA Pediatr 2017; 171: 948-56.

36. May PA, Fiorentino D, Coriale G, et al. Prevalence of children with severe fetal alcohol spectrum disorders in communities near Rome, Italy: new estimated rates are higher than previous estimates. Int J Environ Res Public Health 2011; 8: 2331-51.

37. Hoyme HE, Kalberg WO, Elliott AJ, et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics 2016; 138: e20154256-e20154256.

38. Temple VK, Cook JL, Unsworth K, Rajani H, Mela M. Mental health and affect regulation impairment in Fetal Alcohol Spectrum Disorder (FASD): results from the Canadian National FASD database. Alcohol Alcohol 2019; 54: 545-50.

39. Cordero JF. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: Clarification of the 1996 Institute of Medicine Criteria. Pediatrics 2005; 115: 1787.

40. Olivier L, Curfs LMG, Viljoen DL. Fetal alcohol spectrum disorders: prevalence rates in South Africa. South African Med J 2016; 106: S103-6.

41. Pichini S, Marchei E, Vagnarelli F, et al. Assessment of prenatal exposure to ethanol by meconium analysis: results of an Italian multicenter study. Alcohol Clin Exp Res 2012; 36: 417-24.

42. Grimm J, Stemmler M, Golub Y, et al. The association between prenatal alcohol consumption and preschool child stress system disturbance. Dev Psychobiol 2021; 63: 687-97.

43. Ostrea EM, Hernandez JD, Bielawski DM, et al. Fatty acid ethyl esters in meconium: are they biomarkers of fetal alcohol exposure and effect? Alcohol Clin Exp Res 2006; 30: 1152-9.

44. Garcia-Algar O, Kulaga V, Gareri J, et al. Alarming prevalence of fetal alcohol exposure in a Mediterranean city. Ther Drug Monit 2008; 30: 249-54.

45. Mattson SN, Crocker N, Nguyen TT. Fetal alcohol spectrum disorders: neuropsychological and behavioral features. Neuropsychol Rev 2011; 21: 81-101.

46. Hur YM, Choi J, Park S, Oh SS, Kim YJ. Prenatal maternal alcohol exposure: diagnosis and prevention of fetal alcohol syndrome. Obstet Gynecol Sci 2022; 65: 385-94.

47. Kambeitz C, Klug MG, Greenmyer J, Popova S, Burd L. Association of adverse childhood experiences and neurodevelopmental disorders in people with fetal alcohol spectrum disorders (FASD) and non-FASD controls. BMC Pediatr 2019; 19: 498.

48. D’Angelo A, Petrella C, Greco A, et al. Acute alcohol intoxication: a clinical overview. Clin Ter 2022; 173: 280-91.

49. Ceci FM, Ferraguti G, Petrella C, et al. Nerve Growth Factor in alcohol use disorders. Curr Neuropharmacol 2020; 19: 45-60.

50. Ciafrè S, Ferraguti G, Greco A, et al. Alcohol as an early life stressor: epigenetics, metabolic, neuroendocrine and neurobehavioral implications. Neurosci Biobehav Rev 2020; 118: 654-68.

51. May PA, Hasken JM, Hooper SR, et al. Estimating the community prevalence, child traits, and maternal risk factors of fetal alcohol spectrum disorders (FASD) from a random sample of school children. Drug Alcohol Depend 2021; 227: 108918.

52. Petrella C, Carito V, Carere C, et al. Oxidative stress inhibition by resveratrol in alcohol-dependent mice. Nutrition 2020; 79-80: 110783.

53. Carito V, Ceccanti M, Ferraguti G, et al. NGF and BDNF alterations by prenatal alcohol exposure. Curr Neuropharmacol 2019; 17: 308-17.

54. Ciafrè S, Carito V, Ferraguti G, et al. How alcohol drinking affects our genes: an epigenetic point of view. Biochem Cell Biol 2019; 97: 345-56.

55. Carito V, Ceccanti M, Cestari V, et al. Olive polyphenol effects in a mouse model of chronic ethanol addiction. Nutrition 2017; 33: 65-9.

56. Ceccanti M, Coriale G, Hamilton DA, et al. Virtual Morris task responses in individuals in an abstinence phase from alcohol. Can J Physiol Pharmacol 2018; 96: 128-36.

57. Brzezinski MR, Boutelet-Bochan H, Person RE, Fantel AG, Juchau MR. Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J Pharmacol Exp Ther 1999; 289: 1648-53.

58. De La Monte SM, Kril JJ. Human alcohol-related neuropathology. Acta Neuropathol 2014; 127: 71-90.

59. Jacobson JL, Jacobson SW, Sokol RJ, Martier SS, Ager JW, Kaplan‐Estrin MG. Teratogenic effects of alcohol on infant development. Alcohol Clin Exp Res 1993; 17: 174-83.

60. Anna Dyla˛g K, Sikora-Sporek A, Ban´do B, et al. Magnetic resonance imaging (MRI) findings among children with fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS) and alcohol related neurodevelopmental disorders (ARND). Przegl Lek 2016; 73: 605-9.

61. Fiore M, Petrella C, Coriale G, et al. Markers of neuroinflammation in the serum of prepubertal children with Fetal Alcohol Spectrum Disorders. CNS Neurol Disord Drug Targets 2022; 21: 854-68.

62. Micangeli G, Menghi M, Profeta G, et al. The impact of oxidative stress on pediatrics syndromes. Antioxidants 2022; 11: 1983.

63. Sebastiani G, Borrás-Novell C, Casanova MA, et al. The effects of alcohol and drugs of abuse on maternal nutritional profile during pregnancy. Nutrients 2018; 10: 1008.

64. Jawaid S, Strainic JP, Kim J, et al. Glutathione protects the developing heart from defects and global DNA hypomethylation induced by prenatal alcohol exposure. Alcohol Clin Exp Res 2021; 45: 69-78.

65. Lee E, Bristow J, Arkell R, Murphy C. Beyond ‘the choice to drink’ in a UK guideline on FASD: the precautionary principle, pregnancy surveillance, and the managed woman. Heal Risk Soc 2022; 24: 17-35.

66. De Nicoló S, Tarani L, Ceccanti M, et al. Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain. Nutrition 2013; 29: 681-7.

67. American Psychiatric Association, Association AP. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association, 2013.

68. Ceccanti M, Iannitelli A, Fiore M. Italian Guidelines for the treatment of alcohol dependence. Riv Psichiatr 2018; 53: 105-6.

69. Terracina S, Ferraguti G, Tarani L, et al. Transgenerational abnormalities induced by paternal preconceptual alcohol drinking. Findings from humans and animal models. Curr Neuropharmacol 2021; 19: 1158-73.

70. Tarani L, Rasio D, Tarani F, et al. Pediatrics for disability: a comprehensive approach to children with syndromic psychomotor delay. Curr Pediatr Rev 2021; 18: 110-20.

71. Ferraguti G, Terracina S, Micangeli G, et al. NGF and BDNF in pediatrics syndromes. Neurosci Biobehav Rev 2023; 145: 105015.

72. Cook J, Unsworth K, Flannigan K. Characterising fetal alcohol spectrum disorder in Canada: a national database protocol study. BMJ Open 2021; 11: e046071.

73. Dugas EN, Poirier M, Basque D, Bouhamdani N, Lebreton L, Leblanc N. Canadian clinical capacity for fetal alcohol spectrum disorder assessment, diagnosis, disclosure and support to children and adolescents: a cross-sectional study. BMJ Open 2022; 12: e065005.

74. Stratton K, Howe C, Battaglia FC. Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. Washington, DC: National Academies Press, 1996.

75. Astley SJ, Clarren SK. Diagnosing the full spectrum of fetal alcohol-exposed individuals: Introducing the 4-digit diagnostic code. Alcohol Alcohol 2000; 35: 400-10.

76. Cook JL, Green CR, Lilley CM, et al.; CFASD Research Network. Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan. CMAJ 2016; 188: 191-7.

77. Bertrand J, Floyd LR, Weber MK. Guidelines for identifying and referring persons with fetal alcohol syndrome. MMWR Recomm Rep 2005; 54 (RR-11): 1-14.

78. BMA Board of Science. Alcohol and pregnancy preventing and managing fetal alcohol spectrum disorders, june 2007, updated february 2016. Br Med Assoc 2016.

79. Bower C, Elliott EJ, Zimmet M, et al. Australian guide to the diagnosis of foetal alcohol spectrum disorder: a summary. J Paediatr Child Health 2017; 53: 1021-3.

80. Berrigan P, Andrew G, Reynolds JN, Zwicker JD. The cost-effectiveness of screening tools used in the diagnosis of fetal alcohol spectrum disorder: a modelled analysis. BMC Public Health 2019; 19: 1746.

81. Benson AA, Mughal R, Dimitriou D, Halstead EJ. Towards a distinct sleep and behavioural profile of Fetal Alcohol Spectrum Disorder (FASD): a comparison between FASD, autism and typically developing children. J Integr Neurosci 2023; 22: 77.

82. Davis K, Desrocher M, Moore T. Fetal Alcohol Spectrum Disorder: a review of neurodevelopmental findings and interventions. J Dev Phys Disabil 2011; 23: 143-67.

83. Sessa F, Salerno M, Esposito M, et al. Understanding the relationship between Fetal Alcohol Spectrum Disorder (FASD) and criminal justice: a systematic review. Healthcare 2022; 10: 84.

84. Economic costs of Fetal Alcohol Specturm Disorder (FASD). J Paediatr Child Health 2018; 54: 7-7.

85. Denny LA, Coles S, Blitz R. Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorders. Am Fam Physician 2017; 96: 515-22.

86. Yelin R, Schyr RB, Kot H, et al. Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels. Dev Biol 2005; 279: 193-204.

87. Fisher G, Roget N. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Encyclopedia of Substance Abuse Prevention, Treatment, & Recovery. Amer Psychiatric Pub, 2014.

88. Chabenne A, Moon C, Ojo C, Khogali A, Nepal B, Sharma S. Biomarkers in fetal alcohol syndrome. Biomarkers and Genomic Medicine 2014; 6: 12-22.

89. Wagner JC, Tergeist M, Kruse B, Sappok T. [Fetal alcohol spectrum disorders in adults]. Nervenarzt 2020; 91: 1069-79.

90. Chater-Diehl EJ, Laufer BI, Castellani CA, Alberry BL, Singh SM. Alteration of gene expression, DNA methylation, and histone methylation in free radical scavenging networks in adult mouse hippocampus following fetal alcohol exposure. PLoS One 2016; 11: e0154836.

91. Morrello R, Cook PA, Coffey M. “Now, with a bit more knowledge, I understand why I’m asking those questions.” Midwives’ perspectives on their role in the Greater Manchester health and social care partnership’s programme to reduce alcohol exposed pregnancies. Midwifery 2022; 110: 103335.

92. Balaraman S, Schafer JJ, Tseng AM, et al. Plasma miRNA profiles in pregnant women predict infant outcomes following prenatal alcohol exposure. PLoS One 2016; 11: e0165081.

93. Morini L, Marchei E, Tarani L, et al. Testing ethylglucuronide in maternal hair and nails for the assessment of fetal exposure to alcohol: comparison with meconium testing. Ther Drug Monit 2013; 35: 402-7.

94. Ceci FM, Fiore M, Agostinelli E, et al. Urinary ethyl glucuronide for the assessment of alcohol consumption during pregnancy: comparison between biochemical data and screening questionnaires. Curr Med Chem 2021; 29: 3125-41.

95. Ferraguti G, Ciolli P, Carito V, et al. Ethylglucuronide in the urine as a marker of alcohol consumption during pregnancy: Comparison with four alcohol screening questionnaires. Toxicol Lett 2017; 275: 49-56.

96. Mattia A, Moschella C, David MC, et al. Development and validation of a GC-EI-MS/MS method for ethyl glucuronide quantification in human hair. Front Chem 2022; 10: 858205.

97. Derme M, Piccioni MG, Brunelli R, et al. Oxidative stress in a mother consuming alcohol during pregnancy and in her newborn: a case report. Antioxidants 2023; 12: 1216.

98. Kulaga V, Pragst F, Fulga N, Koren G. Hair analysis of fatty acid ethyl esters in the detection of excessive drinking in the context of fetal alcohol spectrum disorders. Ther Drug Monit 2009; 31: 261-6.

99. Chiodo LM, Delaney-Black V, Sokol RJ, Janisse J, Pardo Y, Hannigan JH. Increased cut-point of the TACER-3 screen reduces false positives without losing sensitivity in predicting risk alcohol drinking in pregnancy. Alcohol Clin Exp Res 2014; 38: 1401-8.