Clinical Practice Guideline
The Diagnosis of Fetal Alcohol Syndrome
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Background: The estimated prevalence of fetal alcohol syndrome (FAS) is 8 for every 1000 live births. FAS has serious, lifelong consequences for the affected children and their families. A variety of professionals deal with persons who have FAS, including pediatricians, general practitioners, neurologists, gynecologists, psychiatrists, and psychotherapists. Early diagnosis is important so that the affected children can receive the support they need in a protective environment.
Methods: A multidisciplinary guideline group has issued recommendations for the diagnosis of FAS after assessment of the available scientific evidence. This information was derived from pertinent literature (2001–2011) retrieved by a systematic search in PubMed and the Cochrane Library, along with the US-American and Canadian guidelines and additional literature retrieved by a manual search.
Results: Of the 1383 publications retrieved by the searches, 178 were analyzed for the evidence they contained. It was concluded that the fully-developed clinical syndrome of FAS should be diagnosed on the basis of the following criteria: Patients must have at least one growth abnormality, e.g., short stature, as well as all three characteristic facial abnormalities—short palpebral fissure length, a thin upper lip, and a smooth philtrum. They must also have at least one diagnosed structural or functional abnormality of the central nervous system, e.g., microcephaly or impaired executive function. Confirmation of intrauterine exposure to alcohol is not obligatory for the diagnosis.
Conclusion: Practical, evidence-based criteria have now been established for the diagnosis of the fully-developed FAS syndrome. More research is needed in order to enable uniform, evidence-based diagnostic assessment of all fetal alcohol spectrum disorders and optimize supportive measures for the children affected by them.
The deleterious effects of intrauterine exposure to alcohol are collectively referred to as fetal alcohol spectrum disorders (FASD). The spectrum includes:
- Full-blown fetal alcohol syndrome (FAS)
- Partial fetal alcohol syndrome (pFAS)
- Alcohol-related neurodevelopmental disorder (ARND)
- Alcohol-related birth defects (ARBD).
Reports of the prevalence of FAS vary considerably due to the methodological weaknesses of some studies and the heterogeneity of both the samples and the diagnostic criteria. Two population-based cross-sectional studies in Italy estimate prevalence of 7.4 and 8.2 per 1000 live births (1, 2). The number of pregnant women who drink alcohol is much higher than the number who give birth to a child with FAS (3). There is no simple dose–effect relationship, so on the basis of our current knowledge no safe threshold level of alcohol consumption for pregnant women can be defined. Equally, it cannot be stated what proportion of women who consume what quantity of alcohol will have a child with FASD. The studies to date have paid insufficient systematic attention to parameters such as age, ethnicity, nutrition, other pre- and perinatal complications, and genetic factors. Information provided by the mothers is unreliable, and there are no valid means of measuring intrauterine exposure to alcohol throughout the whole pregnancy. The only certain way of avoiding FAS is to abstain from alcohol completely.
The brain injury caused by intrauterine exposure to alcohol is irreversible. The children concerned have functional impairments and problems coping with daily life. They are more likely to drop out of school, and show higher rates of alcohol and drug abuse, abnormal sexual behavior, and delinquency (4). Prompt, adequate diagnosis of FAS is necessary for early support measures, including creation of a protective environment, and can help to avoid problems in future years. A case series showed that diagnosis after the age of 12 years together with absence of a protective environment was associated with considerably increased rates of the above-mentioned problems (odds ratio [OR] 2.25 to 4.16) (4). We know of no randomized controlled studies of the options for treatment and secondary prevention. Research into specific interventions is required. It is plausible, however, that targeted support measures may be beneficial in children with FAS, as has been shown for children with other neurological disorders. Communication of the diagnosis of FAS avoids false conclusions about the cause of the disorder and relieves the pressure on the affected family.
The guideline project was initiated by the German federal government’s commissioner on drug-related issues and conducted by the Society of Neuropediatrics (Gesellschaft für Neuropädiatrie), supported by the Agency for Quality in Medicine (ÄZQ) and the Association of Scientific Medical Societies in Germany (AWMF). The participating professional associations, patient representatives, and experts are listed in eTable 1. The key question was agreed to be: What criteria enable development-based diagnosis of full-blown fetal alcohol syndrome in children and adolescents (age range 0 to 18 years)?
A systematic literature review and evaluation of the evidence was carried out by the ÄZQ (Figure 1).
The literature search embraced all English- and German-language articles in Medline (PubMed) and the Cochrane Library published between 1 January 2001 and 31 October 2011 (for description of the search strategy and the prospectively defined inclusion and exclusion criteria, see eTable 2 and eTable 3), with a manual search for the period before 2001.
The selected full-text articles were systemically assessed with regard to the quality of their methods. The strength of evidence was determined according to the Oxford Centre for Evidence-based Medicine’s classification for diagnostic studies (2009 version; www.cebm.net/index.aspx?o=1025) (eTable 4).
This classification distinguishes three grades of recommendation (A, B, and 0), whose strength is expressed as “we recommend,” “we suggest,” and “may be considered.” As a rule, the strength of recommendation is determined by the quality of the evidence. However, the following parameters were also taken into consideration:
- Benefit versus risk
- The clinical relevance of the study parameters and effect strengths
- The external validity and consistency of the study results
- Ethical considerations.
In the case of diagnostic criteria that were adjudged to be of extreme clinical relevance but for which no sufficient evidence could be found, a guideline recommendation was formulated on the basis of expert consensus. All recommendations were adopted in a formal agreement process (nominal group process with external moderation).
The systematic review of PubMed and the Cochrane Library identified 1363 and 20 publications respectively. After inspection of the abstracts, 326 publications were selected for full-text assessment. According to prospectively established criteria 178 publications were included in the study (Figure 1). We know of no studies published in the period November 2011 to June 2013 whose findings would lead to modification of the diagnostic criteria.
The formal agreement process resulted in seven key recommendations (R 1 to R 7) (Table). Furthermore, clarifying recommendations on diagnosis were formulated.
All recommendations (exception: cut-off values for head-circumference percentile) were adopted with “strong agreement” (endorsed by more than 95% of the participants of the guideline consensus group) or with “agreement” (endorsed by more than 75% of the participants).
Clarifying recommendations on diagnostic procedures
R 1: Diagnostic categories
Multimodal and interdisciplinary assessment is recommended in any child suspected to have FAS (expert consensus).
R 2: Growth abnormalities
Klug et al. (5) retrospectively evaluated a consecutive cohort of 322 children who attended outpatient consultations. The percentiles for weight at birth and body weight at the time of examination were significantly lower in children with FAS (mean percentile 18.2/31.5) than in children without FAS (mean percentile 39.6/56.5; p<0.001). The percentiles for body length at birth and time of examination were also significantly lower in children with FAS (mean percentile 33.5/30.5 versus 58.6/51.1; p<0.001). Moreover, 22% of the children with FAS (26/120) had a body mass index below the 3rd percentile, compared with 3% of those without FAS (2/70) (level of evidence [LoE] 2b-). Day et al. (cohort study, n = 580) (6) found that 14-year-old children whose mothers had drunk alcohol in the first and second trimesters of pregnancy showed reduced body weight, and maternal alcohol consumption in the first trimester led to smaller body length (LoE 2b).
Explanation of the growth disturbance purely by other causes has to be excluded (expert consensus). These potential causes include:
- Familial microsomia
- Constitutional developmental retardation
- Prenatal deficiency states
- Skeletal dysplasia
- Hormonal disorders
- Genetic syndromes
- Chronic diseases
R 3: Facial anomalies
In 1976, Jones et al. (case series, n = 48) (7) described characteristic abnormalities of the facial features in children with intrauterine exposure to alcohol. This was confirmed in a case–control study (LoE 4) by Clarren et al. in 1987 (severe [n = 21] versus negligible [n = 21] exposure to alcohol) (8). On the basis of a validation cohort study (FAS n = 39, no FAS n = 155; LoE 1b-) published in 1995, Astley and Clarren described a combination of facial characteristics specific to FAS (9). Regardless of ethnicity and sex, the most powerful discriminating characteristics for FAS proved to be smoothing of the philtrum, a thin upper lip, and short palpebral fissure length. These facial screening criteria for FAS showed sensitivity of 100% and acceptable specificity of 89.4%.
To aid quantitative assessment of upper lip thickness and philtrum smoothness, Astley and Clarren (10, 11) developed a lip–philtrum guide with five photographs comparable to a five-point Likert scale. Upper lip and philtrum scores of 4 or 5 on this scale are considered pathological in the context of suspected FAS (Figure 2).
The length of the palpebral fissure can be measured using a transparent ruler, either directly or on a photograph furnished with a circle of diameter corresponding to 1 cm on the patient’s forehead for reference (Figure 3).
In 2010, Clarren et al. (12) developed percentile curves for palpebral fissure length based on measurements in 2097 healthy Canadian girls and boys ranging in age from 6 to 16 years (explorative cohort study, LoE 2b). In a population from the USA, Astley et al. (13) showed that the mean palpebral fissure lengths of children with FAS (n = 22) were at least two standard deviations lower than the corresponding values in healthy Canadian children (statistical validation study, LoE 2b-), while those of healthy children (n = 90) were within the normal range. There are no recent data on percentile curves for palpebral fissure length in children under 6 years of age (14–16).
R 4: Abnormalities of the CNS
Early injury of the brain by alcohol toxicity may be primarily manifested by pathological restriction of growth (microcephaly). The severe functional abnormalities shown by affected children and adolescents in their daily lives represent behavioral phenotypes of toxic damage to brain structures.
R 5: Functional abnormalities of the CNS
Most of the published studies on functional regions of the CNS in which children with full-blown FAS typically show below-average performance (17–24) are exploratory case–control studies (exceptions: the cohort studies by Nash et al. , LoE 2b-, and Coles et al. , LoE3b-), corresponding to evidence level 4. On this basis no specific neuropsychological profile of children with FAS can currently be defined. The consensus-based recommendation in a child suspected to have FAS is therefore as follows: Functional abnormalities of the CNS should be evaluated by means of standardized neuropsychological tests together with behavioral assessment by a psychologist or physician (expert consensus).
Because alcohol affects the brain globally or multifocally, abnormalities in at least three aspects of the CNS are necessary for the diagnosis of FAS (expert consensus).
In a cohort composed of patients from two FAS centers (27), Bell et al. found that 5.9% of children and adults with FASD (FAS/pFAS n = 85, ARND n = 340) showed epilepsy (ecological study/registry study, LoE 2c). This is much higher than the 0.6% prevalence of epilepsy found in the normal population (National Survey of Children’s Health, n = 91 605, Russ et al. ). In the presence of epilepsy, FAS can therefore be diagnosed when only two or more functional regions of the CNS are affected (expert consensus).
R 6: Structural abnormalities of the CNS
Day et al. (cohort study, n = 580) (6) showed that the head circumference of children whose mothers had not stopped drinking alcohol during pregnancy (n = 375 in first trimester, n = 185 in third trimester) was lower than that of those without intrauterine exposure to alcohol (absolute difference 6.6 mm, LoE 2b). On prenatal sonography Handmaker et al. (29) found no absolute negative difference in head circumference among fetuses of mothers who continued to drink alcohol after finding out they were pregnant, but the head circumference of these fetuses was smaller in relation to abdominal circumference (cohort study; n = 51 versus alcohol abstinence n = 46) (LoE 2b).
There is no agreement in the literature of the past 10 years regarding a recorded cut-off value for microcephaly in children with FAS. The guideline group was unable to achieve consensus on this criterion. Thus, head circumference ≤ 3rd percentile and head circumference ≤ 10th percentile are both adjudged to fulfill the criteria for the diagnostic category “structural abnormalities of the CNS”.
Owing to the limited evidence on structural abnormalities of the CNS such as volume reduction of the cerebellum and thickening of the cortex (30–35), the guideline group agreed that structural CNS abnormalities other than microcephaly cannot currently be used as criteria for the diagnosis of FAS.
R 7: Importance of the confirmation of maternal alcohol consumption for diagnosis
Burd et al. (36) investigated the importance of confirmation of alcohol consumption of the mother during pregnancy for the certainty of the diagnosis of FAS (retrospective cohort study: FAS n = 152, pFAS n = 151, no FAS n = 87; LoE 3b). In cases where maternal alcohol consumption could not be confirmed, sensitivity for the diagnosis FAS was higher (unconfirmed 89%, confirmed 85%), while specificity was lower (71.1% versus 82.4%). In other words, more children with FAS actually have FAS diagnosed when alcohol consumption by their mother is not confirmed. Given the existence of estimates that a large proportion of children with FAS in Germany do not have their disorder diagnosed, the guideline group accepted the low specificity of the diagnostic criterion “unconfirmed intrauterine alcohol exposure” (LoE 3b, recommendation grade A).
The experience of experts and affected patients alike shows that many people with FAS in Germany go undiagnosed, although they display the typical signs, and thus fail to receive appropriate help. Many physicians and psychologists receive too little information about FAS during their education and advanced training and therefore do not give sufficient consideration to the possibility of FAS when assessing children with developmental disorders or adults with cognitive deficits or psychiatric disorders.
The primary goal of the German guideline group was to identify the best diagnostic criteria for children and adolescents with full-blown FAS as laid out in this article. The long and short versions of the guideline are available in German at www.awmf.org.
It remains difficult to conduct high-quality studies on FAS diagnosis:
- The diagnosis of FAS often rests on information from the mother about her alcohol consumption or abstinence during pregnancy. “Social desirability bias” is to be expected, as is “recall bias” for pregnancies a long time in the past.
- The validation of diagnostic criteria for FAS is often tested on children who have already been diagnosed with FAS. There is thus no independent reference standard (“incorporation bias”).
- In the studies published to date, various diagnostic instruments (e.g., the Institute of Medicine criteria and the 4-Digit Diagnostic Code) have been used to identify patients with FAS. These instruments feature various diagnostic criteria and cut-offs (e.g., head circumference percentile, number of facial characteristics, consideration of functional CNS abnormalities) and thus display no consistent diagnostic discrimination.
In light of these methodological difficulties, the systematically evaluated diagnostic recommendations for FAS presented here are based on the evidence-rated literature and on formal consensus of the representative multidisciplinary guideline group.
The diagnosis of FAS is complex:
- Documentation of maternal alcohol intake is difficult. On the one hand many mothers are not questioned about their alcohol consumption during pregnancy because the physicians or midwives caring for them are worried about loss of trust or even a complete breakdown of the relationship. On the other, mothers frequently give inaccurate answers for reasons of social acceptability. Many children with FAS in Germany live in adoptive and foster families, so the information that can be obtained about the biological parents is often rudimentary. No adequately validated, objective measures for alcohol consumption during the entire pregnancy have yet been identified.
- A further problem in diagnosis is that the characteristic abnormalities in children with FAS change with age (37). Typically, the facial abnormalities and growth deficiencies are obvious in childhood but less distinct in adolescence and adulthood. In contrast, while very young children with FAS often show little in the way of functional abnormalities of the CNS, adolescents almost always exhibit disorders of behavior, attention, and executive functions (higher cognitive adaptive processes). In early infancy the diagnosis of FAS frequently depends on detailed assessment by an experienced developmental neurologist. In later childhood and adolescence an indispensable role is played by complex psychological evaluation, because knowledge of the impairments in functional regions of the CNS is essential not only for diagnosing FAS but also in providing appropriate individual support, improving functional performance in daily life, and raising the quality of life of the affected adolescents and their families.
The neuropsychological tests proposed in the guideline provide a practical means of assessing the functional regions of the CNS that are typically affected in FAS.
The second aim was to promote awareness among professionals of the existence of a professional support system and to increase knowledge of the typical characteristics of children and adolescents with FAS. Only with the assistance of specifically trained, experienced helpers in the health and social system can there be adequate education of society regarding the life-altering consequences of maternal alcohol consumption during pregnancy.
An “FAS Pocket Guide” has been compiled to provide practical orientation for physicians and institutions (eSupplement). A simple algorithm depicts the diagnostic procedure in the case of suspicion of FAS. Differential diagnoses are listed for each diagnostic category. Links are given to websites providing further information on prevention of alcohol consumption in pregnancy and support services for people with FAS and their families.
Because of the limited evidence available from the research carried out to date, this guideline had to be restricted to full-blown FAS in children and adolescents. The guideline group is fully aware of the importance of fetal alcohol spectrum disorders—whose prevalence is estimated by experts to be several times higher than that of FAS alone. FASD is harder to diagnose owing to the patients’ inconspicuous appearance, yet the problems they face in daily life are just as great as in FAS (6). This leaves a gap that can only be filled by initiatives in research and in the care of people affected by FAS and FASD.
We are grateful to all participants in this guideline project for their constructive and efficient support and cooperation (eTable 1). Special thanks are due to Dipl.-Psych. Penelope Thomas and Dipl.-Psych. Jessica Wagner for their help in evaluating the quality criteria of the neuropsychological tests and to the staff of both the Agency for Quality in Medicine and the AWMF Institute for Management of Medical Knowledge for advice and support in conducting the study.
The study received financial support from the Federal Ministry of Health (BMG), the Society of Neuropediatrics (GNP), and the Association of Scientific Medical Societies in Germany (AWMF).
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 21 May 2013, revised version accepted on 15 July 2013.
Translated from the original German by David Roseveare.
Dr. med. Dipl.-Psych. Mirjam N. Landgraf
Dr. von Haunersches Kinderspital
80337 Munich, Germany
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. MEDLINE
Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF), Institute of Medical Knowledge Management, Marburg: Dr. med. Nothacker, MPH; Prof. Dr. med. Kopp
German Society of Pediatrics and Adolescent Medicine (DGKJ), Society for Neuropediatrics (GNP):
Prof. Dr. med. Heinen
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