Critique 151: “Fetal alcohol syndromes” result from multiple maternal factors during pregnancy — 20 November 2014
Esper LH, Furtado EF. Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review. Eur Child Adolesc Psychiatry (2014) 23:877–889; DOI 10.1007/s00787-014-0603-2.
To identify the demographic, psychological, and social maternal risk factors associated with the development of Fetal Alcohol Spectrum Disorders (FASD). A bibliographic search was conducted in PubMed, SciELO, Lilacs, Web of Knowledge, and PsycINFO. The Newcastle–Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the studies with case–control design. Articles were selected based on their relevance and presentation of data related to statistical comparisons of at least one or more demographic, psychological, or social maternal risk factors for FASD. 738 references were identified, of which 15 met the criteria to be included in the present review.
Mothers of FASD children tend to: be older at the time of birth of the affected child, present lower educational level, have other family relatives with alcohol abuse, have other children with FASD, present a pattern of little prenatal care and a distinguishing pattern of alcohol consumption (alcohol use before and during pregnancy, failure to reduce alcohol use during pregnancy, and frequent episodes of binge drinking). Application of the NOS scale of methodological quality indicated that 8 studies (53 %) met the criterion for selection, 4 (27 %) were suitable for the criterion for comparability and only 4 studies were suitable for the exposition criterion.
Mothers of FASD children have a distinctive pattern of drinking and accumulate several social risk factors. Maternal age at birth of the child seems to accentuate the risk. There are, however, few controlled studies that are adequate according to the NOS requirements for methodological quality. Fewer are based on the verification of a theoretical model. Clinicians should be aware of the relevance of preventive assessment of FASD risk mothers.
Excessive maternal alcohol consumption during pregnancy (especially among women with alcohol dependency) is known to markedly increase the risk of the fetus showing a group of developmental disorders defined as fetal alcohol spectrum syndrome (FASD) (Memo et al). The most serious form of this syndrome is fetal alcohol syndrome (FAS), which can consist of a large number of debilitating morphological and developmental abnormalities (Landgraf et al). While occasional or light use of alcohol during pregnancy has not been found to be associated with FAS, the lack of the ability to identify a clear threshold of effect of alcohol has led many to advise that women abstain from all alcohol consumption during pregnancy.
The authors of the present paper quote a theoretical model proposed by Abel and Hannigan to identify two main categories of factors: permissive and provocative. Conditions from the first category increase the vulnerability to the teratogenic effects of alcohol; this category includes use of other psychoactive and addictive drugs (e.g., nicotine and cocaine), stress, low socio-economic status and cultural factors. The latter, provocative factors, relate to fetal biological aspects, which would increase the cellular susceptibility to toxic effects of ethanol These, for example, are hypoxia, malnutrition, and free radicals which could be related to intrauterine growth retardation and cellular death.
In this paper, the authors attempted to identify maternal risk factors for FASD and FAS, combining data from 15 studies on the topic. They discovered that there were not enough data to carry out a formal meta-analysis, but describe important maternal risk factors that have been reported in the literature to relate to these syndromes. The more frequent maternal conditions related to the risk of FASD or FAS include older age of mother, lower educational level, family relatives who abuse alcohol, little prenatal care, and a more severe pattern of alcohol consumption in general and particularly during pregnancy. They emphasize that “FAS is a multifactorial condition, and it is potentiated by complex relationships among several factors, social and biological.”
Specific comments on study by Forum members: Given the permanent nature of many of the defects found in FASD and FAS, and limited therapeutic options, it is important that the focus should be on the prevention of these syndromes. The present analysis includes data on a variety of maternal factors that could be useful in identifying women who may be at particular risk of producing a child with FAS or FASD. Their findings could lead to enhanced efforts by the medical community to intervene on high-risk women prior to and during pregnancy to prevent these disease states. However, as the authors point out, there are few studies providing adequate information to permit a formal meta-analysis seeking more specific data on the key determinants of FASD and FAS.
Reviewer Ellison thought that the analytic approaches were done well, but pointed out that there is always the underlying problem of the diagnosis of FAS and FASD: the main difficulty is that something that is a risk factor (alcohol consumption) is also a necessary component of the outcome diagnosis. In other words, particularly for FASD, many of the abnormalities in infants and children found could be due to alcohol exposure or to other factors, and finding a history of alcohol consumption during pregnancy is a prerequisite for making the diagnosis of a FASD. For the more rare FAS, there are more distinctive features that tend to support the diagnosis of an alcohol-related condition, although even here there may be cases in which there is no evidence of alcohol intake during pregnancy.
The authors have used a good instrument, the Newcastle-Ottawa Quality Assessment Scale (NOS) (Wells et al) to evaluate how each study reached a diagnosis, but even here one of the ‘exposures,’ a history of alcohol consumption during pregnancy, is required for the diagnosis. Forum member Thelle stated: “It is as you state a (logical) problem that the suggested causal factor is used as a prerequisite for a syndrome labeled by the factor. But this kind of seemingly circular arguments is often encountered in disease classification.” Reviewer Finkel remarked “This is a most complex and emotionally charged subject. A question does occur to me: What do we call FASD if it occurs without alcohol exposure?”
New Forum member Van Den Bree pointed out that “the effects of alcohol on the developing fetus can also depend on genes influencing alcohol metabolism in the mother as well as in the child.” She particularly noted papers by Gemma et al and McCarver.
The authors of this paper describe huge variations in the overall risk of an infant being diagnosed with one of these syndromes, related primarily to the rates of underlying alcohol abuse in the population studied. Many studies are carried out among groups such as native Americans or poor populations in South Africa, groups in which the prevalence of known risk factors is much higher than in the general population. The fact that these syndromes are so uncommon in the general population makes it somewhat difficult to evaluate risk factors (other than heavy alcohol drinking) for these disorders among pregnant women in cultures with a more typical pattern of light-to-moderate alcohol intake.
Reviewer Van Velden stated: “I sent this article to Professor Hein Odendaal, a colleague of mine who is doing research on FAS as part of an international FAS research project; their analyses are based on data from 12,000 participants, and the results will be published shortly.” Professor Odendaal stated that the findings from his study are in agreement with the present article. He added: “It is still unclear what is the pathophysiological basis for higher motherly age as a risk factor for FAS. The use of alcohol should NOT be part of the diagnosis.” Prof Odendaal’s group has demonstrated that there are children with “FAS” who did not have maternal alcohol intake as an exposure. Van Velden concluded: “In short, we agree with other Forum members’ comments; this is a well-balanced view on FAS, which is a major problem in South Africa.”
Forum member Skovenberg tended to agree with the comments of other reviewers, and added: “My feeling is that the subject is inflamed by the impossibility of arguing against the just to be safe warning of zero consumption. A modest hope would be to have the naked scientific facts delivered to pregnant women together with the zero advice.” Stated reviewer Lanzmann-Petithory, “I agree that this paper is done correctly and is well-balanced. All of the conclusions seem to me obvious, including the necessity of a targeting preventive efforts toward certain pregnant women.”
References from Forum review
Abel EL, Hannigan JH. Maternal risk factors in fetal alcohol syndrome: provocative and permissive influences. Neurotoxicol Teratol 1995;17:445–462 (United States)
Gemma S, Vichi S, Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. Neurosci Biobehav Rev 2007;31:221-229.
Landgraf MN, Nothacker M, Heinen F. Diagnosis of fetal alcohol syndrome (FAS): german guideline version 2013. Eur J Paediatr Neurol 2013;17:437–446.
McCarver DG. ADH2 and CYP2E1 genetic polymorphisms: Risk factors for alcohol-related birth defects. Drug Metab Dispos 2001;29:562-565.
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–S43.
Wells GA, Shea B, O’Connell D et al (2000). The Newcastle–Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
Excessive maternal alcohol consumption during pregnancy (especially among women with alcohol dependency) is known to markedly increase the risk of the fetus showing a group of developmental disorders defined as fetal alcohol spectrum syndrome (FASD), with the most serious form being fetal alcohol syndrome (FAS). The present paper attempts to identify maternal risk factors for FASD and FAS, but the authors report that there were not enough data to carry out a formal meta-analysis. They do, however, describe important maternal risk factors that have been reported in the literature to relate to these syndromes. The more frequent maternal conditions related to the risk of FASD or FAS include older age of mother, lower educational level, family relatives who abuse alcohol, little prenatal care, and a more severe pattern of alcohol consumption in general and particularly during pregnancy. They emphasize that “FAS is a multifactorial condition, and it is potentiated by complex relationships among several factors, social and biological.”
Forum reviewers considered this to be a well-done analysis presenting important and balanced information on these syndromes. Forum members agreed that many genetic and environmental factors, in addition to heavy alcohol consumption, may contribute to the development of these syndromes (e.g., certain genetic polymorphisms, inadequate pre-natal care, poverty, low education, familial alcoholism, use of illicit drugs, etc.).
Given the permanent nature of many of the defects found in FASD and FAS, and limited therapeutic options, it is important that the focus should be on the prevention of these syndromes. If they are to be prevented, it will be necessary to intervene among high-risk women, either prior to or early during pregnancy. Better knowledge of all the factors involved will help facilitate interventions that may help prevent these serious conditions.
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Comments on this paper have been provided by the following members of the International Scientific Forum on Alcohol Research:
Marianne van den Bree, PhD; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Dag S. Thelle, MD, PhD, Senior Professor of Cardiovascular Epidemiology and Prevention, University of Gothenburg, Sweden; Senior Professor of Quantitative Medicine at the University of Oslo, Norway
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
With additional invited comments from Professor Hein Odendaal, former Head, Department of Obstetrics and Gynaecology, Stellenbosch University, South Africa