Eur Child Adolesc Psychiatry (2014) 23:877–889 DOI 10.1007/s00787-014-0603-2

REVIEW

Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review Larissa Horta Esper • Erikson Felipe Furtado

Received: 1 April 2014 / Accepted: 12 August 2014 / Published online: 28 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract 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

L. H. Esper
E. F. Furtado (&) PAI-PAD Program for Assessment, Intervention and Prevention of Alcohol and Drugs in the Community, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil e-mail: [email protected] E. F. Furtado Section of Child and Adolescent Psychiatry, Department of Neurosciences and Behavior, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil

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. Keywords Fetal alcohol spectrum disorders
Fetal alcohol syndrome
Alcohol drinking
Maternal risk factors
Systematic review
Research quality assessment

Introduction Alcohol abuse during pregnancy is associated with health problems to both mother and fetus. Among possible harms to the fetus caused by alcohol consumption during pregnancy, the Fetal Alcohol Syndrome (FAS) is considered to be the most severe cluster of developmental consequences [1]. While FAS stands for a clinical picture characterized by birth-induced morphological injury and developmental disabilities, the term Fetal Alcohol Spectrum Disorders (FASD) was coined to include other much more frequent conditions either with other birth defects alone or neurodevelopmental or behavioral symptoms without the typical physical abnormalities and facial stigma of FAS. The typical clinical presentation of FAS should include: deficiency in the weight and height growth before and after birth, abnormalities in the neurodevelopment of the nervous central system, and a series of typical facial abnormalities including small palpebral fissures, thin upper lip and smooth philtrum [2]. The prevalence of this syndrome varies according to the population examined. A study verified that this syndrome

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occurs in about 0.02–0.2 % of North American children and in 4–10 % of children born to alcoholic mothers [3]. Developed countries show similar findings. Less is known about FASD/FAS epidemiology in developing countries. The estimated prevalence of FASD in young school children is of 2–5 % in the USA and some Western European countries [4–6]. In South Africa, a prevalence of 40.5–46.4 in 1,000 children at school age was identified. Those numbers are about 18–141 times higher than the ones found in the USA [7]. However, in recent article, the authors argue that studies with in-school design could provide underestimated prevalence due to the screening strategy used (screening for children B10th centile on height, weight and head circumference). Higher prevalence rates were found in Western City Pilot Studies in the USA (a rate of FASD of 16.5 per 1,000 and the rate of FAS was 4.9 per 1,000), however the inclusion criteria used in were more liberal (lower than 24th centile on height, weight and head circumference) [6]. In Brazil, a study of newborns found a FASD prevalence rate of 38.69 per 1,000 live births, while 1.52 per 1,000 live births were identified as FAS cases [8]. A recent published meta-analysis of data concerning the FAS and FASD prevalence in child care settings (e.g., foster care or orphanage) reported a pooled prevalence of 6 and 16.9 %, respectively [9]. The higher prevalence rates found in developing countries and in child care settings pointed out the relevance of social and environmental factors, as for instance the maternal factors and the contributing factors for risky drinking in pregnancy. Since FAS was first documented [10], a series of studies have been conducted to determine the factors related to its development. Alcohol consumption during pregnancy is the core variable associated with the development of FAS. However, it is also the case that other factors, including psychological, environmental, social and biological factors, can influence in the development of this syndrome. Abel and Hannigan [11] propose a theoretical model that discusses the factors associated with the development of FASD. According to these authors, there are two main categories of factors: permissive and provocative. The first category, whenever present, would increase the vulnerability to the teratogenic effects of ethanol (the alcohol molecule present in alcoholic beverages). Use of other psychoactive and addictive drugs (e.g., nicotine or cocaine), stress, low social economic status, and cultural factors are examples of permissive factors. Provocative factors, otherwise, are related to the fetal biological aspects, which would increase the cellular susceptibility to the toxic effects of ethanol. Some provocative factors, for example, are hypoxia, malnutrition and free radicals, which would be related to intrauterine growth retardation and cellular death [11].

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The main objective of this systematic review was to search the literature to identify articles that present results and discuss permissive maternal factors related to FASD such as: demographic characteristics, psychological, and social risk factors and to evaluate the quality of evidence using the Newcastle–Ottawa Quality Assessment Scale criteria [12].

Methods Search strategy Peer-reviewed research articles regarding maternal risk factors associated with FASD were identified through searches in the following electronic databases: PubMed, Web of Knowledge, PsycINFO, SciELO and Lilacs (the last two databases were chosen to include scientific articles from developing countries, such as South Africa and Brazil, not found elsewhere). The bibliographic search engines used different strategies regarding keywords. After a series of previous search attempts with other words in the databases, the most suitable combinations of words related to the proposed objectives were: pregnancy, Fetal Alcohol Syndrome, Fetal Alcohol Spectrum Disorders, characteristics and risk factors. Search limits were also used: only studies with humans and publications in English, Spanish or Portuguese. The searches were conducted to include the period up until January, 2013. The inclusion and exclusion criteria were: articles included in this review should present results on at least one or more demographic, psychological, or social maternal risk factors. Articles with the following characteristics were excluded from this review: studies with animals; case studies; metabolic, nutritional, or genetic maternal assessment; studies about predictors of moderate alcohol consumption during pregnancy; studies that were restricted to specific isolated fetal damage (weight loss, motor or cognitive damage, malformation); articles that did not report primary data; dissertations; letters to editor; and articles not related to the topic. Adding up all the databases, the total of 738 potentially relevant articles were identified. The selection criteria used in each database are presented below. In PubMed, the search was conducted using combinations of the keywords, as follows: pregnancy AND [Fetal Alcohol Syndrome (mesh terms) OR Fetal Alcohol Spectrum Disorders] AND [characteristics OR risk factors (mesh terms)]. In this database, the initial analyses identified 444 potentially relevant references. After applying the search limits and performing a detailed reading of titles and abstracts, 15 articles were selected (see below, Fig. 1).

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Using the keyword ‘‘fetal alcohol syndrome’’ for SciELO and Lilacs searches, 10 and 106 articles were identified, respectively; however, those articles did not meet the criteria to be included in this study. In Web of Knowledge 17 articles were identified, from which only two met the criteria to be included. Finally, in PsycINFO, the combination of words ‘‘risk factors AND fetal alcohol syndrome’’ was used and 161 articles were identified. After reading the abstracts, seven articles were selected. The selected articles from Web of Knowledge and PsycINFO had, however, already been found in PubMed. After excluding the repeated articles, the final sample was composed of 15 articles; all articles were published in English (see Table 1 for a list of the articles). The selection procedure used in the systematic review is presented in Fig. 1 as follows. Assessment of the quality of evidence The Newcastle–Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of studies with case– control design [12]. This scale is recommended by the Cochrane Review Group to be used with non-randomized studies [13]. The Newcastle–Ottawa Quality Assessment Scale (NOS) employs three study assessment criteria: comparability, exposure and selection. The first criterion refers to ‘‘comparability’’, i.e., the comparability of the groups based on the case–control study design. The second criterion refers to ‘‘exposure’’ by evaluation of the level of ascertainment of exposure, case–control equal ascertainment of exposure conditions and non-response rate. The third criterion refers to ‘‘selection’’, i.e., the adequate definition and representativeness of cases, and selection method and definition of control groups [12]. Table 1 shows the results of the assessment regarding quality and characteristics of each study. After judgement based on NOS definitions, each criteria receives its own score of ‘‘stars’’. Selection and Exposure criteria have a maximum score of four stars while Comparability has a maximum of two stars (see Table 1).

Results The 15 articles that were selected for inclusion in this review are presented in Table 1 according to the following characteristics: year of publication, country, number of participants, type of methodological design, quality of studies according to the NOS, and a summary of the most relevant findings. In relation to the year of publication, most of the studies were published from 2000 to 2010. Regarding the institutional connection of the first author, it was found that seven

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articles were multi-center studies, published through partnerships of University of New Mexico and researchers from other countries, such as South Africa and Italy; eight articles were carried out by other research centers. In relation to the nationality of the sample of the studies, the samples were composed of Italians, Americans, Australians and South Africans. In summary, most studies were performed with populations outside the US (mainly South Africa). The criteria used to diagnose FAS or FASD in the studies were examined. Seven studies used the criteria proposed by the Institute of Medicine [14]. Two studies used the guidelines published by Sokol and Clarren [15], one study used the 4-digit diagnostic code from Astley and Clarren [16] and in five studies the authors used other criteria or did not describe and explain the criteria used. Regarding the methodological design of the 15 studies, 13 were observational and retrospective and two were descriptive and cross-sectional using medical records as data source [17, 18]. Thirteen studies were classified as case–control. Of these, four studies did analyze data from single or multiple sources of medical reported cases [19–22] and nine used multiple sources, such as surveillance networks and population-based data [3, 4, 7, 23–28]. From the eight case–control studies which used community resources (e.g., schools) as recruitment strategy, six applied the same strategy of sampling selection during the data collection. In these six studies, the first step of sampling selection was conducted in schools where children were screened according to their weight, height and cephalic perimeter. Children identified in the tenth percentile regarding weight and height growth were selected for a second diagnostic screening procedure, in which physical exams and assessment of the characteristics of FAS were conducted. After this assessment, biological mothers of the identified children were invited to provide retrospective information about their alcohol intake during pregnancy [3, 4, 7, 23–27]. From those studies, five conducted a longitudinal assessment of children from the South African region [3, 7, 23, 25, 26], and one applied the same methodology for data collection in a sample of Italian children [4]. Regarding the type of statistical analysis used, the studies applied mainly regression analysis to identify maternal risk factors for the development of children with FAS. In two studies, factors of protection were also identified [18, 23]. Sample sizes ranged from 10 [17] to 976 mothers (221 cases and 755 controls) [24]. According to the NOS criteria, eight studies achieved the maximum score regarding the criteria for quality of selection (definition of suitable cases, representativeness of cases, appropriate selection of control group, definition of control) [3, 4, 7, 21, 23, 25, 26, 28]. Of these eight studies,

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353 (FAS cases)

561 (185 FAS/ FASD cases and 376 controls)

110 (54 FAS cases and 56 controls)

223 (124 FAS cases or partial FAS and 99 controls)

206 (72 FASD cases and 134 controls)

81 (18 FASD cases and 63 controls)

USA

USAa

Australia

South Africa

USAa

USAa

Cannon et al. [28]

May et al. [26]

Coyne et al. [22]

Urban et al. [27]

May et al. [7]

May et al. [4]

Sample

Country

References

123 Controls attending same classes chosen via random-number table

Mothers of control children attending the same school

For each child classified as FAS or partial FAS, a control child was matched for child’s age, sex and ethnicity

Matched controls based on age and month of birth, sex and place of residence. Maternal records reviewed

Mothers of control children attending the same school

Women of reproductive age in the underlying population

Control group

Case– control

Case– control

Institute of Medicine (IOM)

Institute of Medicine (revised IOM criteria)

Institute of Medicine (IOM)

Not informed

Case– control

Case– control

Institute of Medicine (revised IOM criteria)

Center for Disease Control (CDC)

FAS criteria

Case– control

Case– control

Type of study

H

HHH

HHHH

HH

H

HH

HHH

HHHH

HH

H

HHHH

HHHH

Comparability

Selection

NOS quality of studiesb

H

H

HH

HH

HH

HH

Exposure

Current drinking significantly higher for mothers of cases, but reported rates of overall drinking during pregnancy not significantly different. Dysmorphology related with: drinking in the second and third trimesters, drinks per current drinking day, and current drinks per month. Nonstatistically significant differences between: maternal age, rural/urban residence, church attendance, religious attitude, and employment

Mothers of cases: lower socio-economic status and educational attainment, more rural residents and smoking more cigarettes during pregnancy. Higher birth order of the index child, more gravidity and still birth. Relationship found between child’s dysmorphology and demographic and behavioral maternal risk factors

Mothers of cases were currently smokers, were less likely to have employment or have attended secondary school and had lower body mass index

Mothers of cases were older, of higher parity, smoked more cigarettes, attended fewer antenatal visits and experienced more antenatal and delivery complications

Maternal drinking was the main risk factor of a child’s physical anomalies, followed by maternal demographics, physical characteristics and childbearing variables

FAS Mothers were older, unmarried, unemployed, without prenatal care, smoking during pregnancy, lower educational level, more live born children, another child with suspected alcohol effects, drug use during pregnancy and past history of mental illness

Principal results on maternal risk factors

Table 1 Summary of the major identification characteristics of the selected articles, including quality assessment based on the Newcastle–Ottawa Scale (NOS) for case–control studies and principal study results (n = 15)

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169 (53 FAS cases and 116 controls)

976 (FAS or FASD cases)

USAa

USAa

USA

South Africa

USA

May et al. [25]

May et al. [24]

Kvigne et al. [21]

Viljoen et al. [23]

Astley et al. [16]

80 (FAS cases)

62 (31 FAS cases and 31 controls)

234 (78 FAS cases and 156 controls)

Sample

Country

References

Table 1 continued

–

Matched cases by sex, age, and classroom

Two controls for each case from the same community (one previous birth and the subsequent birth)

Three different samples of mothers of children with FAS or FASD

Mothers of control children attending the same school

Control group

Crosssectional

Clinical guideline by Sokol and Clarren [15] and 4-digit diagnostic code

Institute of Medicine (IOM)

IX International classification of diseases (1981–1992)

Case– control

Case– control

Institute of Medicine (IOM)

Institute of Medicine (IOM)

FAS criteria

Case– control

Case– control

Type of study

HH

HHHH

–

H

HHHH

–

H

H

Comparability

HHH

HHHH

Selection

NOS quality of studiesb

–

H

H

H

H

Exposure

Mothers of cases: often victims of abuse, and with mental health issues (77 % with posttraumatic stress disorder and 44 % simple phobia). High rate of unintended pregnancy, and alcohol exposure pregnancies. Reported using illicit drug at some time their lives (86 %) and use around the time of birth of the index children (40 %)

Mothers of cases: less formal education, less practicing of religion and reporting more heavy drinking among family members;— greater exposure to stress (pregnancy reported as extremely stressful). Control and case group were comparable with respect to age, income, occupation, gravity, parity, miscarriage, number of live births and marital status

Mothers of cases were older, had fewer prenatal visits, more pregnancies, more mental health problems, and more injuries. Drinking prevalence was high in both case and control mothers but case mothers had more alcohol-related medical problems, heavy drinking, binge drinking, and daily drinking

Mothers of cases were older, had high gravidity and parity, frequent binge drinking and heavy drinking in the maternal grandmother. Differences in risk factors comparing US and South African women

Differences found: socioeconomic status, religion, education, gravity, parity, marital relationship. Mothers of cases had more family relatives identified as heavy drinkers and abusers. Control mothers consumed alcohol in smaller amounts or were abstinent. Current and past binge drinking by mothers of cases. No reduction in the use during pregnancy in 87 % of mothers of cases. More tobacco use in the case group

Principal results on maternal risk factors

Eur Child Adolesc Psychiatry (2014) 23:877–889 881

123

123

792 (132 FAS cases and 660 controls)

USA

USA

USA

Bagheri et al. [20]

Miller et al. [19]

Pierog et al. [17]

–

–

Controls were selected from the computerized birth registry and matched by gender, year and month of birth.

Control subject was selected for each case, matched for sex, age, and classroom.

Control group

Crosssectional

Case– control

Case– control

Case– control

Type of study

–

Based on published reports of FAS and consultation of a panel of experts (pediatricians, neonatologists, and geneticists) in Colorado

Clinical guideline by Sokol and Clarren [15] and a diagnostic checklist

Institute of Medicine in the United States (IOM)

FAS criteria

H

H

HH

HH

–

H

HHHH

–

Comparability

Selection

NOS quality of studiesb

b

a

Assessment through the Newcastle–Ottawa Scale

Multi-center studies

S selection criterion, C comparability criterion, E exposure criterion

Maximum score for each criterion: selection HHHH, comparability HH, exposure HHHH. Maximum total score is HHHHHHHHHH

8 (FAS cases)

22 (FAS cases)

76 (35 FAS cases and 41 controls)

USA

May et al. [3]

Sample

Country

References

Table 1 continued

–

H

H

H

Exposure

In this sample was common: no prenatal care during pregnancy, poor obstetric histories (premature infants or abortions) and had another child with suspected alcohol effects

Mothers of cases were more likely to be black, unmarried, unemployed during pregnancy. They were more likely to be ages 30–39, to have given birth to at least five children, to have begun prenatal care in the third trimester and had fewer prenatal consultations. They were also more likely to smoke and drink alcohol during pregnancy

Mothers of cases began prenatal care after the first trimester, had less weight gain during pregnancy, less education, were older, fewer prenatal visits, shorter pregnancy length and unmarried

Mothers of cases: greater current use of alcohol and more drinking before the index pregnancy and during each trimester. Index pregnancy as a time when they had many life problems and drank more heavily. A high percentage of the mothers of control and case alcohol syndrome smoked tobacco during pregnancy

Principal results on maternal risk factors

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six were developed by the same research group [3, 4, 7, 23, 25, 26]. Concerning the criterion of ‘‘comparability’’ (based on the analysis of data or on the methodological design used), four studies were rated with ‘‘two stars’’, the maximum score for this criterion [4, 22, 23, 26]. Finally, for the exposure criterion, which assesses the method for the verification of case and control groups, four studies presented ‘‘two stars’’ from a range of four possible stars [22, 26–28] while the majority reaches just one star. Table 1, below, presents the main results from the 15 selected studies. Demographic factors Low socio-economic status is considered a risk factor associated with the most severe forms of FAS [11, 26]. Low educational level was assessed by nine studies that identified this variable as a maternal risk factor for FAS [4, 18–21, 24, 25, 27, 28]. Eight studies also identified the mothers’ marital status as related to FAS. Five studies indicated being single during the pregnancy of the child with FAS as risk factor [7, 19, 20, 25, 28]. In other three studies, this association was not found [23, 24, 27]. Unemployment [18, 19, 28] and being ‘‘less religious’’ [23, 25] were identified as risk factors in three and two studies, respectively. Interestingly, one study with an Italian sample found that mothers of FASD children were identified as presenting higher scores on religiosity than mothers from the control group [4]. Living in a rural area was also identified as a risk factor in four studies [3, 7, 25, 26], all of them conducted with the same South African sample. The sample was recruited in a region in South Africa known mainly for wine production, and historically, it presents a population with high prevalence of alcohol-related problems. The system known as ‘‘dop’’ was used for decades in this region. It refers to paying rural workers daily with alcohol for their service and is currently forbidden [25, 29]. Earning a lower income was assessed as risk factor by five studies [4, 7, 18, 23, 25]. Of these five studies, two did not confirm lower income as a risk factor [4, 23]. Maternal age at the birth of the child with FAS was examined in 11 studies, and nine of these 11 studies identified older age as risk factor for FAS [7, 17–22, 24, 28]. Average maternal age in the control group was approximately 23–25.7 years; and in relation to the case group, the average maternal age at the birth of the case child was approximately 28–30 years. Additionally, two studies reported that the age of mothers of children with partial FAS was higher than the age of mothers of children with complete FAS [4, 7]. In the remaining two studies, this association was not significant [4, 18].

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Psychiatric and neuropsychological factors Four articles identified a higher prevalence of psychiatric comorbidity among mothers of children with FASD [18, 21, 23, 28]. One study verified that mothers of children with FAS reported more exposure to stress than the control group (pregnancy was reported as having occurred during a very stressful period of their lives). The most common source of stress was a poor relationship with a partner who typically also was an alcohol abuser [23]. One study found that a higher number of stressful events was also identified as a risk factor for alcohol consumption during pregnancy; however, stress did not differ between case and control groups, except for physical aggression, a common experience for mothers of children with FAS or partial FAS [7]. Physical aggression or sexual abuse was identified as risk factor in three studies [7, 18, 21]. One study based on Northern Plains tribes medical records reported 1.66 and 2.29 odds ratio (OR) for suicide attempts in mothers of children with FAS and partial FAS, respectively [21]. The same study found a high proportion of mothers of children with FAS and partial FAS presenting cognitive impairments resembling much of the typical characteristics of FAS. The intergenerational transmission of FAS was strongly suggested through the observation of a 24.00 and 4.98 OR for maternal grandmother alcohol use in mothers of children with FAS and partial FAS, respectively [21].

Family and social factors Some studies indicate that mothers of children with FAS also had family members, with a heavy pattern of alcohol drinking (siblings, father, and mother). This assessment was conducted in five studies [7, 21, 23–25]. Two studies found that maternal grandmothers of children with FAS reported higher levels of alcohol use than the control group [21, 23]. Six studies found that the father of the FAS child also drank alcohol regularly [3, 4, 7, 21, 23, 25]. Another interesting characteristic was the presence of other children with impairments related to maternal alcohol use. The studies identified that those mothers, when assessed, had already given birth to other children with FAS or some other impairment associated with alcohol use during pregnancy [7, 16, 21, 25, 28]. In one study, one in three mothers of children with FAS had other children suspected of having a problem related to maternal alcohol consumption [28].

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884 Fig. 1 Selection procedure used in the systematic review of studies that assessed maternal risk factors associated with FAS

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Total number of studies identified in the data base (N=738) Articles excluded after critical reading of titles and abstracts (n=569) Articles selected for detailed assessment (n=170) Main exclusion factors (n=155): - assessment of characteristics of family members of the child (father, grandmother) with FAS other than the mother; - animal samples; - assessment of moderate alcohol maternal consumption; - development of instruments and methods for assessment of FASD - epidemiology and characteristics of children with FAS in different countries without including maternal risk factors; - preventive strategies and interventions with pregnant women; - analysis of biomarkers in order to verify the use of substances during pregnancy (meconium, mother’s hair); - studies on the prevalence of use of alcohol, tobacco, or other substance during pregnancy; - risk factors for damages for maternal physical health associated with alcohol use during pregnancy; - attitudes and knowledge of mothers about FAS; - studies focused only on metabolic, nutritional, or genetic assessment of the mother. Articles included in the systematic review (n=15)

Substance use and other health characteristics of mothers of FASD children in pregnancy Among the risk factors related to the general health of the pregnant woman, the use of illegal drugs was assessed in five studies [3, 17, 18, 23, 28]. Only one study found no relationship with the use of illegal drugs [3]. Regarding tobacco, seven studies reported higher frequency of tobacco users in the group of mothers of FASD children [3, 7, 19, 22, 23, 25, 28]. There was no difference related to the quantity consumed during pregnancy in case and control groups in three studies [4, 21, 25]. There was no difference in relation to the first use of tobacco or its regular use in one study [7] and there was a negative difference, that is, lower quantity of tobacco used in the group of mothers in the case group in another study [3]. Other factors related to maternal health during pregnancy were: lower number of prenatal doctor appointments [17, 19–22]; lower age during pregnancy and lower weight gain [20]; late prenatal care [19–21]; higher number of children [19, 21, 22, 25, 26, 28]; restriction of uterus growth [20, 22]; premature birth [22]; more pregnancies [7, 21, 24–26]; and higher frequency for complications during pregnancy [19, 28].

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Some studies did not find differences between the case and control groups for: younger age during pregnancy [22], number of children [23], more pregnancies [23] and number of miscarriages [23–25]. Pattern of alcohol consumption The alcohol abuse was another factor frequently assessed in all studies and different measures were used to assess the pattern of alcohol consumption. Mothers of children with FASD presented a distinctive pattern of alcohol consumption. Six studies identified higher levels of intake before pregnancy [3, 22–26]. Of these, three studies reported that mothers of FAS children reported drinking the same amount or substantially more compared to their current level [3, 23, 25], one study reported that South African mothers of children with FAS usually drink 6.7 drinks per occasion before pregnancy [24]; in one study, women self-reported as heavy drinkers before pregnancy ([80 grams per week) [22]; and one study found frequent alcohol use and binge drinking in 3 months before pregnancy and the mean quantity of drinks consumed per typical drinking was 2.4 drinks [26]. A higher level of consumption during pregnancy has been described in studies. As example, in four studies,

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mothers of FAS children reported drinking the same amount or more if compared with their current level [3, 23, 25, 28]; in two studies, the average daily alcohol was 2.3 standards drinks (1.2 oz of absolute alcohol per day) [23, 28]; and in one study, the level of consumption prior to pregnancy was 5.7 drinks per drinking day [25]. In sum, following characteristics of drinking patterns have been identified: higher levels of intake before pregnancy [3, 22–26]; higher levels of consumption during pregnancy [3, 4, 7, 17–28]; no reduction or abstinence during pregnancy [3, 7, 22, 23, 25]; higher levels of current use of alcohol [4, 23, 25]; higher frequency of binge drinking (use of three or more drinks per occasion) during pregnancy [23, 24, 26, 28]; higher number of weekdays with alcohol consumption [4, 23, 28] and early age of regular alcohol consumption after alcohol drinking initiation [23, 25].

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Six studies identified that case mothers had greater gravidity (number of previous pregnancies) than control mothers, a mean of 3.1–3.9 conceptions [7, 23–26] and a mean of 6.0–6.3 in only one study [21]. The mean parity (number of previous births) was also greater in case mothers [7, 21, 23–26], a mean of 2.9–3.5 live births. Evidence of relationship was found for children’s dysmorphia and the following maternal risk factors: higher severity and number of children; lower educational level and income; rural residence; more dosages of alcohol consumed weekly; higher frequency of binge drinking during pregnancy; alcohol intake in all quarters of pregnancy; use of tobacco during pregnancy. Likewise, evidence was also found for associations between the verbal and non-verbal intelligence quotient of the children and behavioral problems and maternal risk factors [7]. A summary of the most important findings is shown in Fig. 2.

FAS and partial FAS mothers Kvigne et al. [21] in their study on mothers of FASD children from Northern Plains tribes compared mothers of children with FAS and mothers of children with any characteristic of FAS on a variety of possible risk factors for FAS. Results of logistic regression analysis yielded no statistic differences in the groups related to most risk factors. However, maternal alcohol consumption, mother’s age, intentional injuries, depression and sexual abuse were strong predictors for FAS. They also reported that mothers of children with FAS presented higher levels of alcohol consumption and addiction than mothers of children with partial FAS [21]. Maternal risk factors and severity of damages to the fetus In a study conducted with a sample of Italian mothers, a relationship between measures of alcohol intake (monthly amount of alcohol in the second and third quarter of pregnancy and daily current dosages) and a higher score of dysmorphia in children with FAS was reported [4]. Weight, height, and body mass index of the neonates were lower in the group of mothers of children with FAS than in the control groups in four studies [7, 20, 25, 26]. The following maternal factors: maternal age, short stature, weight and body mass index were not associated with the non-verbal intelligence quotient (IQ) of the child. Few significant bivariate relationships were found between psychological measures and the child’s development. The only noteworthy exception was the score for lack of attention, significantly associated with all the variables of maternal alcohol consumption, except current daily quantity of alcohol intake [4].

Discussion This systematic literature review based on the abovementioned search strategies and selection criteria found relatively few empirical studies examining maternal risk factors and their association with FASD. Only 15 studies could be selected, and most of these studies presented descriptive or predictive analysis through group contrasting, with cross-sectional and observational case–control research design. At this moment, the required conditions for a meta-analysis are not present in the scientific literature on maternal factors and their relationship to the occurrence of FASD/FAS. Moreover, concerning the studies that used case–control design, none of them reached the highest possible quality profile, according to the criteria of comparability, exposure and selection on the Newcastle–Ottawa Quality Assessment Scale. About the criteria choosed to diagnose FAS or FASD, the most frequently used FASD diagnose system was the one proposed by the Institute of Medicine (IoM) [14]. Among all studies that choosed the IoM diagnose system, at least two studies used the most recent IoM revised version [30]. The revised IoM criteria of 2005 were developed in an attempt to improve the practical application in a clinical study [31]. The selected studies examined samples from different populations, including samples from Australia [22], USA [16, 17, 19–21, 28], Italy [4] and South Africa [3, 7, 23, 25–27]. Although the populations are different, some maternal risk factors were common among the studies, such as: older age, lower educational level, having other children with FASD, presence of other family members

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who abuse alcohol, and higher number of children and pregnancies. However, some authors indicate differences regarding the risk factors in samples of American women (Northern Plains tribes) and in samples of South African women. Both samples were selected in areas of known high prevalence for FAS. The risk factors changed substantially according to the population studied. For instance, the sample of Native American women presented a higher frequency for binge drinking and alcohol abuse prior to the onset of pregnancy. Nevertheless, during pregnancy, there was a decrease in the alcohol intake and less damage to the fetus in comparison to South African women. Moreover, Native American women presented higher body mass index and were better nourished, a factor that could produce a relative protection for the American group in contrast to the African women, according to the authors [24]. Although the pattern of alcohol consumption is the core variable associated with the development of FAS, there are a series of other factors, including psychological, social and biological factors, which are presented as potential risk factors for the occurence and severity of FAS. Evidence of the influence of social demographic factors was frequent in the selected studies. Those variables were identified as the main permissive factors for FASD [11]. Low social economic status, precarious life conditions and lower educational levels were identified as risk factors in studies conducted in South African women [7, 24, 25]. Older age at the time of birth of the child with FAS was a frequently associated variable, present in 12 studies. A reasonable hypothesis could be that children born later would be more exposed to higher blood level of alcohol in the womb, due to the increasing tolerance to this substance and to the higher severity of chronic maternal health problems caused by alcohol abuse [11]. They would suffer yet from the general risk factors associated with becoming pregnant after 35 years of age [32]. One study also verified that children born to older mothers who used alcohol during pregnancy were more adversely affected, mainly regarding the dysmorphia characteristics for FAS and non-verbal intelligence quotient measures [7]. The presence of another child with some impairment related to alcohol abuse during pregnancy or with FAS was identified in six studies [7, 17, 18, 21, 25, 28]. Two studies suggest that mothers should be the target for intervention to prevent FAS and damages to the next pregnancy [16, 28]. FAS is only one of the severe consequences to the fetus associated with alcohol abuse. Literature indicates that a series of other problems are caused by alcohol use during pregnancy. The number of pregnant women who use alcohol during pregnancy is higher than the number of children who have developed FAS. It is estimated that

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50 % of pregnant women who use alcohol during pregnancy have children with clinical alterations, not necessarily FAS [33]. Currently, the term Fetal Alcohol Spectrum Disorders (FASD) is used to describe several outcomes of prenatal alcohol exposure, including: FAS, Partial Fetal Alcohol Syndrome (pFAS), alcohol-related neurodevelopmental disorders (ARND) and alcohol-related birth defects (ARBD) [30]. There was also a higher presence of psychiatric symptoms among those women [16, 21, 23, 28]. A higher incidence of psychiatric diagnosis, particularly depression, appears to be the more common among pregnant women who abuse or are dependent on alcohol in contrast with women who do not have these diagnoses [34]. In one study conducted with a sample of American Indians of the northern plains, the authors found that mothers of children with FASD had more symptoms’ subscales of somatic anxiety, decreased energy, decreased mood, hostility, anxious, mood panic/phobia, impaired cognition, sleep, disturbance, decreased appetite and overall distress. The analysis revealed that there was a significant difference for total distress among mothers of case and control mothers [35]. The presence of stressful events was identified as a cause for alcohol consumption during the prenatal period in one study [7] especially in the case of physical aggression, a risk factor for FAS also mentioned in two other studies [7, 16, 21]. Women who abuse alcohol during pregnancy seem to have, in their life histories, higher levels of physical and sexual abuse in comparison with women who do not use alcohol [36]. Regarding the pattern of maternal alcohol consumption, some authors indicate that the damage to the fetus caused by alcohol abuse during pregnancy alters considerably according to the QFT. QFT stands for quantity, frequency and timing of alcohol consumption according to the pregnancy stage. The different patterns of consumption would be associated with the severity of the damages caused to the fetus [26]. In relation to quantity and frequency, it was demonstrated that especially binge drinking (3 drinks or 5 drinks per occasion during pregnancy) was significantly associated with many negative measures of cognitive and behavioral performance and increased child dysmorphology. About the timing of drinking, although it is difficult to define the exact number of exposed children who will present some future damages, one study estimates that when a pregnant woman ingests alcohol during all trimesters of gestation, the likelihood of having a child with FASD rises to 65 times [37]. The 15 studies found that mothers of children with FAS present distinctive characteristics with regard to their alcohol consumption. For instance, there was a higher level of alcohol use before pregnancy and an earlier age at first

Eur Child Adolesc Psychiatry (2014) 23:877–889 Fig. 2 Main maternal reported risk factors related with Fetal Alcohol Syndrome

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Risk factors Social and demographic Older age at the birth of the child with FAS (>28 years) Lower educational level Marital status: single during pregnancy Unemployment during pregnancy Less religious women Rural residence Lower income Psychiatric and neuropsychological factors Psychiatric morbidity Cognitive impairments typical in FAS (memory, judgment, learning, abstraction and reasoning) Suicide attempts Stress Physical aggression or sexual abuse Family Other children with FAS or with any impairment associated with alcohol abuse during pregnancy Other family members with alcohol abuse (siblings, maternal father and/or mother) Partner or father of the child with FAS with alcohol abuse Substance use and health Use of tobacco during pregnancy Use of illegal drugs Lower weight, height and body mass index Pregnancy Less prenatal appointments Younger age during pregnancy Late prenatal care Restriction of uterus growth Complications during pregnancy and miscarriages Gravity >3 Parity > 3 Pattern of alcohol consumption Higher consumption before and during pregnancy Non-reduction of consumption during pregnancy Higher current alcohol use More binge drinking during pregnancy More weekdays of alcohol consumption Early age when first drank alcohol and began drinking regularly

alcohol use. Regarding the pregnancy period, those women who present a higher level of alcohol intake during pregnancy do not seem to reduce their typical drinking pattern and amount consumed and have more episodes of binge drinking. In sum, the distinctive characteristics about alcohol consumption were: higher consumption before and during pregnancy, non-reduction of consumption during

pregnancy, higher current alcohol use, more binge drinking during pregnancy, more weekdays of alcohol consumption, precocious age for starting drinking. Finally, three studies conducted the assessment of maternal risk factors and severity of damages to the fetus. Verbal IQ, behavioral problems and dysmorphia characteristics for FAS were associated mainly with social

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demographic factors and factors related to the pattern of alcohol consumption [7, 26]. Measures for maternal alcohol consumption were the strongest predictors of physical abnormalities in children, either with full FAS or partial FAS [26].

Conclusion The aim of this study was to identify maternal factors associated with the development of FAS. A review of the published literature yielded 15 studies which indicated that mothers of children with FAS present multiple distinctive characteristics. These characteristics include: older age, lower educational level, family relatives who abuse alcohol, little prenatal care and a more severe pattern of alcohol consumption in general and particularly in pregnancy. In conclusion, mothers of children with FAS experience serious social, economic, and behavioral disadvantages which suggest that preventive interventions on FAS risk reduction necessarily have to be targeted at such groups. It is important to emphasize that the risk factors discussed here should not be considered as isolated causes. As indicated in the present review, FAS is a multifactorial condition, and it is potentiated by complex relationships among several factors, social and biological. Few studies were identified that assessed the interactions of maternal risk factors. Studies with this type of design are important because they allow researchers to approach better the relationships between those factors. Moreover, studies that are aimed to identify the associations between multiple maternal risk factors before and during pregnancy and factors related to fetal development could provide important information regarding the pathological mechanisms of maternal factors on child’s development. Finally, to reduce the incidence of FASD, it is necessary to identify and characterize the population of women at the risk of having children with FASD, and develop specific and effective intervention strategies for this population. In addition to more high-quality epidemiological studies, more clinical epidemiological comparative studies are needed. Such studies should be primarily performed on well-defined high-risk groups and controls and focused on the identification of maternal factors that can potentiate FAS as well the development of evidence-based preventive interventions. Acknowledgments CAPES Foundation (Brazilian Coordination for the Improvement of Higher Education Personnel, Ministry of Education) provided a PhD grant for Larissa Horta Esper. The authors greatly acknowledge Prof. Hendree E. Jones, University of North Carolina at Chapel Hill, for her contribution with many suggestions for the improvement of the manuscript.

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Eur Child Adolesc Psychiatry (2014) 23:877–889 Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

References 1. Memo L, Gnoato E, Caminiti S, Pichini S, Tarani L (2013) Fetal Alcohol Spectrum Disorders and fetal alcohol syndrome: the state of the art and new diagnostic tools. Early Hum Dev. 89(Suppl 1):S40–S43 2. Landgraf MN, Nothacker M, Heinen F (2013) Diagnosis of fetal alcohol syndrome (FAS): german guideline version 2013. Eur J Paediatr Neurol. 17(5):437–446 3. May PA, Brooke L, Gossage JP, Croxford J, Adnams C, Jones KL et al (2000) Epidemiology of fetal alcohol syndrome in a South African community in the Western Cape Province. Am J Public Health 90(12):1905–1912 4. May PA, Fiorentino D, Phillip Gossage J, Kalberg WO, Eugene Hoyme H, Robinson LK et al (2006) Epidemiology of FASD in a province in Italy: prevalence and characteristics of children in a random sample of schools. Alcohol Clin Exp Res 30:1562–1575 (United States) 5. May PA, Gossage JP (2001) Estimating the prevalence of fetal alcohol syndrome. A summary. Alcohol Res Health. 25(3): 159–167 6. May PA, May PA, Gossage JP, Kalberg WO, Robinson LK, Buckley D, Manning M, Hoyme HE (2009) The prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on in-school studies. Dev Disabil Res Rev 15(3):176–192 7. May PA, Gossage JP, Marais AS, Hendricks LS, Snell CL, Tabachnick BG et al (2008) Maternal risk factors for fetal alcohol syndrome and partial fetal alcohol syndrome in South Africa: a third study. Alcohol Clin Exp Res 32:738–753 (England) 8. Mesquita MDA, Segre CADM (2009) Frequ¨eˆncia dos efeitos do a´lcool no feto e padra˜o de consumo de bebidas alcoo´licas pelas gestantes de maternidade pu´blica da cidade de sa˜o paulo. Revista Brasileira de Crescimento e Desenvolvimento Humano, pp 63–77 9. Lange S, Shield K, Rehm J, Popova S (2013) Prevalence of Fetal Alcohol Spectrum Disorders in child care settings: a meta-analysis. Pediatrics 132(4):980–995 10. Jones KL, Smith DW, Ulleland CN, Streissguth AP (1973) Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 301:1267–1271 11. Abel EL, Hannigan JH (1995) Maternal risk factors in fetal alcohol syndrome: provocative and permissive influences. Neurotoxicol Teratol 17:445–462 (United States) 12. 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_epidemiol ogy/oxford.htm 13. Lundh A, Gotzsche PC (2008) Recommendations by Cochrane Review Groups for assessment of the risk of bias in studies. BMC Med Res Methodol 8:22 (England) 14. Stratton KR, Howe CJ, Battaglia FC (1996) Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. National Academy Press, Washington, DC 15. Sokol RL, Clarren SK (1989) Guidelines for use of terminology describing the impact of prenatal alcohol on the offspring. Alcoholism 13:597–598 16. Astley SJ, Clarren SK (2000) Diagnosing the full spectrum of fetal alcohol-exposed individuals: introducing the 4-digit diagnostic code. Alcohol Alcohol 35(4):400–410

Eur Child Adolesc Psychiatry (2014) 23:877–889 17. Pierog S, Chandavasu O, Wexler I (1979) The fetal alcohol syndrome: some maternal characteristics. Int J Gynaecol Obstet 16(5):412–415 18. Astley SJ, Bailey D, Talbot C, Clarren SK (2000) Fetal alcohol syndrome (FAS) primary prevention through fas diagnosis: II. A comprehensive profile of 80 birth mothers of children with FAS. Alcohol Alcohol 35(5):509–519 19. Miller LA, Shaikh T, Stanton C, Montgomery A, Rickard R, Keefer S et al (1995) Surveillance for fetal alcohol syndrome in Colorado. Public Health Rep 110(6):690–697 20. Bagheri MM, Burd L, Martsolf JT, Klug MG (1998) Fetal alcohol syndrome: maternal and neonatal characteristics. J Perinat Med 26(4):263–269 21. Kvigne VL, Leonardson GR, Borzelleca J, Brock E, Neff-Smith M, Welty TK (2003) Characteristics of mothers who have children with fetal alcohol syndrome or some characteristics of fetal alcohol syndrome. J Am Board Fam Pract 16:296–303 (United States) 22. Coyne KL, de Costa CM, Heazlewood RJ, Newman HC (2008) Pregnancy characteristics of women giving birth to children with fetal alcohol syndrome in Far North Queensland. Aust N Z J Obstet Gynaecol 48:240–247 (Australia) 23. Viljoen D, Croxford J, Gossage JP, Kodituwakku PW, May PA (2002) Characteristics of mothers of children with fetal alcohol syndrome in the Western Cape Province of South Africa: a case control study. J Stud Alcohol 63(1):6–17 24. May PA, Gossage JP, White-Country M, Goodhart K, Decoteau S, Trujillo PM et al (2004) Alcohol consumption and other maternal risk factors for fetal alcohol syndrome among three distinct samples of women before, during, and after pregnancy: the risk is relative. Am J Med Genet C Semin Med Genet. 127C(1):10–20 25. May PA, Gossage JP, Brooke LE, Snell CL, Marais AS, Hendricks LS et al (2005) Maternal risk factors for fetal alcohol syndrome in the Western cape province of South Africa: a population-based study. Am J Public Health 95:1190–1199 (United States) 26. May PA, Tabachnick BG, Gossage JP, Kalberg WO, Marais AS, Robinson LK et al (2011) Maternal risk factors predicting child physical characteristics and dysmorphology in fetal alcohol syndrome and partial fetal alcohol syndrome. Drug Alcohol Depend 119:18–27

889 27. Urban M, Chersich MF, Fourie LA, Chetty C, Olivier L, Viljoen D (2008) Fetal alcohol syndrome among grade 1 schoolchildren in Northern Cape Province: prevalence and risk factors. S Afr Med J 98(11):877–882 28. Cannon MJ, Dominique Y, O’Leary LA, Sniezek JE, Floyd RL (2012) Characteristics and behaviors of mothers who have a child with fetal alcohol syndrome. Neurotoxicol Teratol 34:90–95 29. London L (2000) Alcohol consumption amongst South African farm workers: a challenge for post-apartheid health sector transformation. Drug Alcohol Depend 59:199–206 30. Hoyme HE, May PA, Kalberg WO, Kodituwakku P, Gossage JP, Trujillo PM, Buckley DG, Miller JH, Aragon AS, Khaole N, Viljoen DL, Jones KL, Robinson LK (2005) A practical clinical approach to diagnosis of Fetal Alcohol Spectrum Disorders: clarification of the 1996 institute of medicine criteria. Pediatrics 115:39–47 31. British medical association board of science (2007) Fetal Alcohol Spectrum Disorders: a Guide for Healthcare Professionals. British Medical Association, London 32. Jolly M, Sebire N, Harris J, Robinson S, Regan L (2000) The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 15(11):2433–2437 33. Chudley AE, Conry J, Cook JL, Loock C, Rosales T, LeBlanc N et al (2005) Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis. CMAJ 172(5 Suppl):S1–S21 34. Pinheiro SN, Laprega MR, Furtado EF (2005) Psychiatric morbidity and alcohol use by pregnant women in a public obstetric service. Rev Saude Publica 39:593–598 (Brazil) 35. Lewis PT, Shipman VC, May PA (2010) socioeconomic status, psychological distress, and other maternal risk factors for FASD among American Indians of the Northern Plains. Am Indian Alsk Nativ Res 17(2):1–21 36. Simpson TL, Miller WR (2002) Concomitance between childhood sexual and physical abuse and substance use problems. A review. Clin Psychol Rev. 22(1):27–77 37. May PA et al (2013) Maternal alcohol consumption producing Fetal Alcohol Spectrum Disorders (FASD): quantity, frequency, and timing of drinking. Drug Alcohol Depend 133(2):502–512

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