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Objective: To determine if prenatal alcohol exposure (PAE) affected physical and cognitive/behavioral outcomes in apparently typically developing, first-grade children., Study Design: Three groups were compared: children with fetal alcohol spectrum disorders (FASD); children with PAE without FASD; and children without PAE., Results: The three groups were significantly different on most physical traits and fewer neurodevelopmental traits. Two-group comparisons of exposed and unexposed, non-FASD groups were statistically different on: height, weight, head circumference (OFC), body mass index (BMI), and palpebral fissure length (PFL). Neurobehavioral outcomes were significant in three-group, but not two-group, comparisons. Few sex differences were observed; however, sex ratios indicated fewer male offspring in first grade among women who consumed 6+ drinks per occasion during pregnancy. For weight, OFC, BMI, age, rural residence, and drinking measures, mothers of exposed children without FASD were intermediaries between, and significantly different from, the other maternal groups. Adjusted for socioeconomic covariates, multivariate analysis of covariance (MANCOVA), three-group comparisons were significantly different for cognitive/behavioral variables (p<.001); however, two-group neurobehavior comparisons for children without FASD were not significant (p>.05). Physical trait MANCOVA comparisons of the non-FASD groups were significant only for weight (p<.004) when tested univariately and through stepdown analysis. Socioeconomic-adjusted trend plots were in the expected direction for nonverbal IQ, problem behaviors, attention, height, weight, OFC, vermilion, PFL, and total dysmorphology score., Conclusions: Even when meeting developmental norms, children with PAE exhibited trends of poorer growth and cognitive/behavioral traits than children without PAE. These findings support the notion that abstinence during pregnancy is best., (Copyright © 2024. Published by Elsevier Inc.)

Nutritional status during pregnancy can impact fetal development, yet less is known about how alcohol may interact with nutritional status to influence infant outcomes. Pregnant women (n=196) completed 2, 24-hour dietary recalls and provided a venous blood sample to be analyzed for liver enzymes (GGT -gamma-glutamyl transferase; ALT -alanine transaminase; and AST -aspartate transferase), iron, ferritin, and zinc concentrations. Infants were assessed at 6 weeks of age. Women who consumed alcohol had significantly higher ferritin levels compared to non-drinkers (51.8 vs. 34.2). While 44% of women had ferritin <30 ug/L (an indicator of iron deficiency), and 24% of women were low in serum iron, and 72% were low in serum zinc. All six drinking measures for 1st trimester and previous week were significantly correlated with GGT and AST levels while 4 out of 6 alcohol measures were associated with levels of ALT and ferritin. At six weeks of age, nearly all physical measures differentiated infants with alcohol exposure from infants without exposure. Controlling for six covariates, maternal ferritin was significantly and inversely associated with infant head circumference (OFC) centile among infants with alcohol exposure. GGT was inversely associated with infant height and weight centile among unexposed infants. Seventy-four percent (74%) of mothers who consumed alcohol were found to be low in serum zinc, yet higher maternal zinc was associated with more dysmorphology. This may indicate that higher zinc status is not protecting the fetus from the teratogenic effects of alcohol. Prenatal alcohol exposure, ferritin, and zinc status influence infant growth and neurodevelopment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Maternal risk factors for having a child diagnosed on the fetal alcohol spectrum disorders (FASD) continuum are complex and include not only the quantity, frequency, and timing of alcohol use but also a woman's physical stature, socio-economic status, and pregnancy-related factors. Exposure to trauma may predispose women to a range of physiological and mental disorders. A woman's mental and physical health may in turn influence her probability of having a child with FASD. This study investigated the role of maternal childhood trauma and lifetime traumatic stress on prenatal alcohol consumption and on the risk of having a child with FASD., Methods: A nested, case-control study was conducted for maternal risk assessment. Study participants were mothers of first-grade learners from five rural communities in the Western Cape Province of South Africa who were assessed for FASD. Face-to-face surveys were conducted, which included mental health and trauma assessment questionnaires., Results: In logistic regression analyses, higher maternal childhood trauma scores were associated with an increased likelihood of having a child diagnosed with FASD, although the increase in risk was modest (OR = 1.014, p = 0.015). In addition, structural equation modeling investigated relationships between maternal drinking, childhood trauma, traumatic stress, and a child's FASD diagnosis. Traumatic stress and drinking during pregnancy, but not lifetime alcohol use, were associated with maternal childhood trauma. Lifetime alcohol use influenced drinking during pregnancy, which in turn was significantly associated with having a child diagnosed on the continuum of FASD., Conclusion: No direct influence of maternal childhood trauma on FASD diagnosis could be demonstrated. However, maternal trauma may indirectly contribute to the risk of having a child diagnosed with FASD., (© 2024 The Authors. Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Background: A variety of maternal risk factors for fetal alcohol spectrum disorders (FASD) have been described in the literature. Here, we conducted a multivariate analysis of a large array of potential distal influences on FASD risk., Methods: Interviews were conducted with 2515 mothers of first-grade students whose children were evaluated to assess risk for FASD. Topics included: physical/medical status, childbearing history, demographics, mental health, domestic violence, and trauma. Regression modeling utilized usual level of alcohol consumption by trimester and six selected distal variables (maternal head circumference, body mass index, age at pregnancy, gravidity, marital status, and formal years of education) to differentiate children with FASD from control children., Results: Despite individual variation in distal maternal risk factors among and within the mothers of children with each of the common diagnoses of FASD, patterns emerged that differentiated risk among mothers of children with FASD from mothers whose children were developing typically. Case-control comparisons indicate that mothers of children with FASD were significantly smaller physically, had higher gravidity and parity, and experienced more miscarriages and stillbirths, were less likely to be married, reported later pregnancy recognition, more depression, and lower formal educational achievement. They were also less engaged with a formal religion, were less happy, suffered more childhood trauma and interpersonal violence, were more likely to drink alone or with her partner, and drank to deal with anxiety, tension, and to be part of a group. Regression analysis showed that the predictor variables explain 57.5% of the variance in fetal alcohol syndrome (FAS) diagnoses, 30.1% of partial FAS (PFAS) diagnoses, and 46.4% of alcohol-related neurodevelopmental disorder (ARND) diagnoses in children with FASD compared to controls. While the proximal variables explained most of the diagnostic variance, six distal variables explained 16.7% ( 1 / 6 ) of the variance in FAS diagnoses, 13.9% ( 1 / 7 ) of PFAS, and 12.1% ( 1 / 8 ) of ARND., Conclusions: Differences in distal FASD risks were identified. Complex models to quantify risk for FASD hold promise for guiding prevention/intervention., (© 2023 Research Society on Alcohol.)

Background: Pregnant women participated in multifaceted case management (MCM) to prevent Fetal Alcohol Spectrum Disorders (FASD)., Methods: Women recruited from antenatal clinics for a longitudinal child development study were screened for alcohol use. Forty-four pregnant women were defined as high-risk drinkers on the Alcohol Use Disorder Identification Test (AUDIT) by an AUDIT score ≥8 and participated in 18 months of MCM to facilitate reduction or cessation of alcohol consumption. Forty-one women completed MCM. Fifty-five equally high-risk women who received standard antenatal care comprised the comparison/control group. Development in offspring was evaluated by a blinded interdisciplinary team of examiners through 5 years of age., Results: At five years of age, more children (34%) of MCM participating women did not meet the criteria for FASD vs. non-MCM offspring (22%). Furthermore, a statistically significant ( p  = .01) lower proportion of MCM offspring (24%) was diagnosed with fetal alcohol syndrome (FAS) compared to controls (49%). Children of MCM participants had significantly ( p  < .05) better physical outcomes: lower total dysmorphology scores, larger head circumferences, longer palpebral fissures, and higher midfacial measurements. Neurodevelopment results showed mixed outcomes. While Bayley developmental scores indicated that MCM offspring were performing significantly worse on most domains through 18 months, group scores equalized and were not significantly different on Kaufman Assessment Battery neurobehavioral measures by five years. Regression analyses indicated that offspring of women who received standard antenatal care were associated with significantly more negative outcomes than MCM offspring: a diagnosis of FAS (OR = 3.2; 95% CI: 1.093-9.081), microcephaly (OR = 5.3; 95% CI: 2.1-13.5), head circumference ≤10th centile (OR = 4.3; 95%CI: 1.8-10.4), and short palpebral fissures (OR = 2.5; 95% CI: 1.0-5.8)., Conclusion: At age five, proportionally fewer children of MCM participants qualified for a diagnosis of FAS, and proportionally more had physical outcomes indicating better prenatal brain development. Neurobehavioral indicators were not significantly different from controls by age five.KEY MESSAGESMultifaceted Case Management (MCM) was designed and employed for 18 months during the prenatal and immediate postpartum period to successfully meet multiple needs of women who had proven to be very high risk for birthing children with fetal alcohol spectrum disorders (FASD).Offspring of the women who participated in MCM were followed up through age five years and were found to have significantly better physical outcomes on multiple variables associated with fetal alcohol syndrome (FAS) and FASD, such as larger head circumferences and fewer minor anomalies, than those children born to equally at-risk women not receiving MCM.Fewer children of women receiving MCM were diagnosed with FASD than the offspring of equally-at-risk controls, and significantly ( p  = .01) fewer MCM offspring had FAS, the most severe FASD diagnosis.

Objective: To explore and analyze the significance of proximal influences of maternal and paternal traits associated with bearing a child with a fetal alcohol spectrum disorder (FASD)., Methods: Aggregated, maternal interview-collected data (N = 2515) concerning alcohol, tobacco, and other drug use were examined to determine risk for FASD from seven cross-sectional samples of mothers of first-grade students who were evaluated for a possible diagnosis of FASD., Results: Mothers of children with fetal alcohol syndrome (FAS) reported the highest alcohol use throughout pregnancy, proportion of binge drinking, drinks per drinking day (DDD), drinking days per week, and total drinks per week. Mothers of children with FAS also consumed significantly more alcohol than mothers of children with partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), or typically developing controls. Mothers of children with PFAS and ARND reported similar drinking patterns, which exposed fetuses to 3-4 times more alcohol than mothers of controls, but the PFAS group was more likely than the ARND group to abstain in latter trimesters. Fathers of all children were predominantly drinkers (70%-85%), but more fathers of children with FASD binged heavily on more days than fathers of controls. Compared to the few mothers of controls who used alcohol during pregnancy, the ARND group binge drank more (3+ DDD) throughout pregnancy and drank more DDD before pregnancy and first trimester. Regression analysis, controlling for tobacco use, indicated that mothers who reported drinking <1 DDD were significantly more likely than abstainers to bear a child with FASD (OR = 2.75) as were those reporting higher levels such as 5-5.9 DDD (OR = 32.99). Exclusive, first-trimester maternal drinking increased risk for FASD five times over that of abstinence (p < 0.001, OR = 5.05, 95% CI: 3.88-6.58), first- and second-trimester drinking by 12.4 times, and drinking all trimesters by 16 times (p < 0.001, OR = 15.69, 95% CI: 11.92-20.64). Paternal drinking during and prior to pregnancy, without adjustment, increased the likelihood of FASD significantly (OR = 1.06 and 1.11, respectively), but the significance of both relationships disappeared when maternal alcohol and tobacco use were controlled., Conclusions: Differences in FASD risk emerged from the examination of multiple proximal variables of maternal alcohol and tobacco use, reflecting increased FASD risk at greater levels of maternal alcohol consumption., (© 2023 Research Society on Alcohol.)

Maternal dietary intake is likely a contributing factor to fetal alcohol spectrum disorders (FASD). Two, 24-hour dietary recalls were completed by pregnant women (n = 196) in South African communities with high rates of FASD. More than 50% of all women in this study were below the Estimated Average Requirement (EAR) for pregnancy for vitamins A, C, D, E, riboflavin, vitamin B6, folate, calcium, magnesium, iron, and zinc. More than 90% of mothers were below the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for pregnancy on vitamin A, K, D, E, choline, calcium, magnesium, zinc, and potassium. More than 80% were below RDA/AI for pantothenic acid, vitamin B6, and folate. Women who consumed alcohol reported significantly lower intake of calcium and three saturated fatty acids and significantly higher intake of two monounsaturated fatty acids. On average, infants were < 40th centile on length, weight, and head circumference at 6 weeks old, regardless of alcohol exposure. Twenty nutrients correlated with at least one measure of 1st trimester drinking (drinks per drinking day, number of drinking days per week, and/or total drinks per week). Nutrients included four saturated fatty acids, eight amino acids, calcium, B-complex vitamins, choline, and betaine. Calcium correlated with all three drinking measures. Further analyses revealed seven nutrients were associated with infant length, weight, and/or head circumference among unexposed infants, and 12 nutrients were associated among infants with prenatal alcohol exposure. Inadequate maternal dietary intake, with alcohol exposure, may increase risk for poor infant growth and likelihood of FASD in this population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: This early intervention study investigated the effectiveness of a relationship-based, developmental enhancement process for children who were prenatally exposed to alcohol in the South African context., Methods: Groups were created according to the child's level of risk for alcohol-related developmental issues based on each mother's alcohol use during pregnancy as assessed using the Alcohol Use Disorders Identification Test (AUDIT). Primary caregiver/child dyads were the focus of the intervention and child development was monitored by the Ages and Stages Questionnaire (ASQ). Eighteen caregiver/child dyads were in the heavily alcohol-exposed group, and 20 caregiver/child dyads were in the no or light alcohol-exposure group. The Home Observation Measurement of the Environment (HOME) was measured pre and post intervention., Results: The results indicated significant improvements in the home environment (p < .001) post-intervention for the entire cohort. For the total HOME score, there was a statistically significant main effect for time (pre- vs post-test), F(1, 36)= 65.205, p < .001, partial η 2 = .64. with 99% confidence limits from .35 to .78. The offspring and parents from both the heavy alcohol exposure group and the no/low alcohol exposure group benefitted from the intervention over the duration of the intervention. Of the HOME domains affected, responsivity was the most improved in the households. The children's scores on the ASQ varied substantially over the months of the intervention, and the offspring of the heavy exposure group often performed significantly worse than the no/low exposure group. Nevertheless, further analysis revealed that children with the lowest performance at baseline improved their performance on most ASQ domains throughout the intervention and performed significantly better on all ASQ domains over time and at completion of the intervention., Conclusions: This relationship-based, early intervention program for children resulted in benefits to all of the children over time., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the literature on alcohol use biomarkers, there has been debate as to what a valid and/or utilitarian cut off level should be for various research applications. In this manuscript, we assessed the sensitivity and specificity of multiple cutoff values for phosphatidylethanol (PEth) from bloodspots relative to self-report, the Alcohol Use Disorder Identification Test (AUDIT) scores, and another alcohol use biomarker ethyl glucuronide (EtG) from fingernails in a sample of 222 pregnant women in the Western Cape Province of South Africa. Receiver operating characteristic (ROC) curves were used to assess the area under the curve (AUC) and assess PEth cutoff values of ≥2, ≥4, ≥8, ≥14, and ≥20 nanograms per milliliter (ng/ml). The highest AUC value was attained when PEth was compared to an AUDIT score of 1 or more. Depending on the cutoff used to determine alcohol consumption, PEth identified 47%-70% of the individuals as alcohol-consuming while 62.6%-75.2% were identified by self-reported measures, and 35.6% were identified by EtG. In this sample, sensitivity and accuracy were highest at less stringent PEth cutoffs when compared to self-report, AUDIT score of 1 or more, 5 or more, 8 or more, and EtG ≥ 8 picograms per milligram (pg/mg). For research purposes, less stringent cutoffs, such as PEth ≥ 8 ng/ml, may be considered a valid, positive cutoff for identifying women who consume alcohol during pregnancy in this population. A cutoff of PEth ≥ 20 ng/ml may miss individuals who reported consuming alcohol (false negatives)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Prenatal alcohol exposure can produce offspring growth deficits and is a leading cause of neurodevelopmental disability. We used untargeted metabolomics to generate mechanistic insight into how alcohol impairs fetal development. In the Western Cape Province of South Africa, 52 women between gestational weeks 5-36 (mean 18.5 ± 6.5) were recruited, and they provided a finger-prick fasting bloodspot that underwent mass spectrometry. Metabolomic data were analyzed using partial least squares-discriminant analyses (PLS-DA) to identify metabolites that correlated with alcohol exposure and infant birth outcomes. Women who consumed alcohol in the past seven days were distinguished by a metabolite profile that included reduced sphingomyelins, cholesterol, and pregnenolones, and elevated fatty acids, acyl and amino acyl carnitines, and androsterones. Using PLS-DA, 25 of the top 30 metabolites differentiating maternal groups were reduced by alcohol with medium-chain free fatty acids and oxidized sugar derivatives having the greatest influence. A separate ortho -PLS-DA analysis identified a common set of 13 metabolites that were associated with infant length, weight, and head circumference. These included monoacylglycerols, glycerol-3-phosphate, and unidentified metabolites, and most of their associations were negative, implying they represent processes having adverse consequences for fetal development.

Background: This study is the ninth cross-sectional community study of fetal alcohol spectrum disorders (FASD) conducted by the multidisciplinary Fetal Alcohol Syndrome Epidemiology Research team in the Western Cape Province of South Africa. It is the third comprehensive study of FASD in a rural, agricultural region of South Africa., Methods: Population-based, active case ascertainment methods were employed among a school-based cohort to assess child physical and neurobehavioral traits, and maternal risk factor interviews were conducted to identify all children with FASD to determine its prevalence., Results: Consent was obtained for 76.7% of 1158 children attending first grade in the region's public schools. Case-control results are presented for 95 with fetal alcohol syndrome (FAS), 64 with partial fetal alcohol syndrome (PFAS), 77 with alcohol-related neurodevelopmental disorder (ARND), 2 with alcohol-related birth defects (ARBD), and 213 randomly-selected controls. Four techniques estimating FASD prevalence from in-person examinations and testing yielded a range of total FASD prevalence of 206-366 per 1000. The final weighted, estimated prevalence of FAS was 104.5 per 1000, PFAS was 77.7 per 1000, ARND was 125.2 per 1000, and total FASD prevalence was 310 per 1000 (95% CI = 283.4-336.7). Expressed as a percentage, 31% had FASD. Although the rate of total FASD remained steady over 9 years, the proportion of children within the FASD group has changed significantly: FAS trended down and ARND trended up. A detailed evaluation is presented of the specific child physical and neurobehavioral traits integral to assessing the full continuum of FASD. The diagnosis of a child with FASD was significantly associated with maternal proximal risk factors such as: co-morbid prenatal use of alcohol and tobacco (OR = 19.1); maternal drinking of two (OR = 5.9), three (OR = 5.9), four (OR = 38.3), or more alcoholic drinks per drinking day; and drinking in the first trimester (OR = 8.4), first and second trimesters (OR = 17.7), or throughout pregnancy (OR = 18.6). Distal maternal risk factors included the following: slight or small physical status (height, weight, and head circumference), lower BMI, less formal education, late recognition of pregnancy, and higher gravidity, parity, and older age during the index pregnancy., Conclusion: The prevalence of FASD remained a significant problem in this region, but the severity of physical traits and anomalies within the continuum of FASD is trending downwards., (© 2022 Research Society on Alcoholism.)

Background: Mothers of children with fetal alcohol spectrum disorders tend to have lower weight compared to other mothers. Yet how alcohol and maternal weight may predispose infants to poorer physical growth and neurodevelopmental trajectories is relatively unexplained., Methods: South African mothers ( n  = 406) were recruited prenatally and their offspring were provided standardized dysmorphology and neurodevelopment examinations at 6 weeks and 9 months of age. Maternal weight was obtained postpartum, and linear mixed modeling determined whether postpartum maternal weight and prenatal alcohol exposure significantly influenced infant growth, dysmorphology, and neurodevelopment within the first year of life., Results: Postpartum maternal weight was positively associated with birth length, weight, and head circumference centile, but the rate of growth from birth to nine months was similar among all infants. Maternal weight was inversely associated with dysmorphology. Many infants in this population were performing within the borderline or extremely low range. Higher maternal weight was associated with significantly better cognitive and motor performance at 6 weeks; however, the rate of developmental growth was similar among all infants, regardless of postpartum maternal weight., Conclusion: Higher postpartum maternal weight may be a protective factor but does not eliminate the adverse effects of alcohol on infant growth and dysmorphology. Regardless of maternal weight, alcohol remains a powerful teratogen and moderate to high use prenatally can result in adverse infant physical and neurocognitive development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: To investigate gestational age and growth at birth as predictors of fetal alcohol spectrum disorders (FASD)., Methods: The sample analyzed here comprises 737 randomly selected children who were assessed for growth, dysmorphology, and neurobehavior at 7 years of age. Maternal interviews were conducted to ascertain prenatal alcohol exposure and other maternal risk factors. Birth data originated from clinic records and the data at 7 years of age originated from population-based, in-school studies. Binary linear regression assessed the relationship between preterm birth, small for gestational age (SGA), and their combination on the odds of a specific FASD diagnosis or any FASD., Results: Among children diagnosed with FASD at 7 years of age (n = 255), a review of birth records indicated that 18.4% were born preterm, 51.4% were SGA, and 5.9% were both preterm and SGA. When compared to non-FASD controls (n = 482), the birth percentages born preterm, SGA, and both preterm and SGA were respectively 12.0%, 27.7%, and 0.5%. Mothers of children with FASD reported more drinking during all trimesters, higher gravidity, lower educational attainment, and older age at pregnancy. After controlling for usual drinks per drinking day in the first trimester, number of trimesters of drinking, maternal education, tobacco use, and maternal age, the odds ratio of an FASD diagnosis by age 7 was significantly associated with SGA (OR = 2.16, 95% CI: 1.35 to 3.45). SGA was also significantly associated with each of the 3 most common specific diagnoses within the FASD continuum: fetal alcohol syndrome (FAS; OR = 3.1), partial FAS (OR = 2.1), and alcohol-related neurodevelopmental disorder (OR = 2.0)., Conclusion: SGA is a robust early indicator for FASD in this random sample of children assessed at 7 years of age., (© 2021 by the Research Society on Alcoholism.)

Background: Prevalence and characteristics of fetal alcohol spectrum disorders (FASD) have been described previously in this community., Methods: Active case ascertainment methods were employed in a new cross-sectional study with Revised Institute of Medicine criteria among first grade students (n = 735) via dysmorphology examinations and neurobehavioral assessments. Their mothers were interviewed regarding risk factors. Final diagnoses were assigned via structured case conferences., Results: Children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and alcohol related-neurodevelopmental disorder (ARND) were significantly different from controls on all cardinal variables, multiple dysmorphology traits and neurobehavioral performance. Mothers of children with FASD reported significantly more drinking before and during pregnancy (mothers of children with FAS reported 7.8 (±6.1) drinks per drinking day (DDD) prior to pregnancy and 5.1 (±5.9) after pregnancy recognition). Distal risk variables for a diagnosis on the continuum of FASD were: lower maternal height, weight, and body mass index; higher gravidity; lower education and household income; and later pregnancy recognition. Alcohol and tobacco remain the only commonly used drugs. Women reporting first trimester drinking of two DDD were 13 times more likely (95 % CI:1.3-133.4) to have a child with FASD than non-drinkers; and those who reported drinking throughout pregnancy were 19.4 times more likely (95 % CI:8.2-46.0) to have a child with FASD., Conclusion: Seventeen years after the first study in this community, FASD prevalence remains high at 16 %-31 %. The FAS rate may have declined somewhat, but rates of PFAS and ARND seemed to plateau, at a high rate., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objectives: Fetal alcohol spectrum disorders (FASD) comprise the continuum of disabilities associated with prenatal alcohol exposure. Although infancy remains the most effective time for initiation of intervention services, current diagnostic schemes demonstrate the greatest confidence, accuracy, and reliability in school-aged children. Our aims for the current study were to identify growth, dysmorphology, and neurodevelopmental features in infants that were most predictive of FASD at age 5, thereby improving the timeliness of diagnoses., Methods: A cohort of pregnant South African women attending primary health care clinics or giving birth in provincial hospitals was enrolled in the project. Children were followed longitudinally from birth to 60 months to determine their physical and developmental trajectories ( N = 155). Standardized protocols were used to assess growth, dysmorphology, and development at 6 weeks and at 9, 18, 42, and 60 months. A structured maternal interview, including estimation of prenatal alcohol intake, was administered at 42 or 60 months., Results: Growth restriction and total dysmorphology scores differentiated among children with and without FASD as early as 9 months (area under the receiver operating characteristic curve = 0.777; P < .001; 95% confidence interval: 0.705-0.849), although children who were severely affected could be identified earlier. Assessment of developmental milestones revealed significant developmental differences emerging among children with and without FASD between 18 and 42 months. Mothers of children with FASD were significantly smaller, with lower BMIs and higher alcohol intake during pregnancy, than mothers of children without FASD., Conclusions: Assessment of a combination of growth, dysmorphology, and neurobehavioral characteristics allows for accurate identification of most children with FASD as early as 9 to 18 months., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objective: Determine the prevalence of Dop, a system of labor payment via alcoholic beverages, in a South African province, and its influence on maternal drinking and fetal alcohol spectrum disorders (FASD). Methods: Data from studies of FASD epidemiology were analyzed. Results: Forty-two percent to 67% of mothers reported drinking. In 1999, 5% of women reported Dop allocations in their lifetime: 14% of mothers of FASD children and 1% of controls. In 2010, 1.1% of mothers reported lifetime Dop: 1.6% of FASD mothers and 0.7% of controls. Commercial alcohol sales have replaced the Dop system. Total FASD rates remained high in rural areas in 2010 and rose in urban settings. Urban rates of total FASD surpassed rural area rates in 2010. Correlation analysis did not reveal a strong or significant, direct relationship between Dop experience and heavy drinking ( r = 0.123, p < 0.001, r 2 = 0.015), or the diagnosis of FASD in children ( OR = 0.003, p = 0.183). Conclusion: Dop, as a systematic practice, is dead and does not have a direct influence on alcohol availability, heavy maternal drinking, or the probability of an FASD diagnosis. Nevertheless, today's problematic drinking patterns were heavily influenced (shaped) by Dop and have negatively impacted the prevalence and severity of FASD.

Background: Alcohol use is reported accurately among pregnant women in some populations., Methods: Self-reported alcohol use via the AUDIT and 90-day recall for 193 women from antenatal clinics was compared to biomarker results: phosphatidylethanol (PEth) from bloodspots and ethyl glucuronide (EtG) in fingernails., Results: AUDIT was positive for 67.9% of respondents, and 65.3% directly reported drinking. Individual biomarkers detected less drinking (PEth = 57.0%, EtG = 38.9%) than self-report. But 64.8% had drinking-positive values (>8 ng) on one or both biomarkers, which was not significantly different from self-report. Biomarkers indicated that 3.1% -6.8% of drinkers denied drinking. Combined biomarker sensitivity was 95% -80% and specificity 49% -76% for drinking in the previous 7-90 days. Combined biomarker results have their best yield (89.6%) and accuracy (78.8%) when measuring 90 day drinking., Conclusions: Women reported their alcohol use accurately, and the combined use of PEth and EtG is supported., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To examine outcomes among boys and girls that are associated with prenatal alcohol exposure., Methods: Boys and girls with fetal alcohol spectrum disorders (FASD) and randomly-selected controls were compared on a variety of physical and neurobehavioral traits., Results: Sex ratios indicated that heavy maternal binge drinking may have significantly diminished viability to birth and survival of boys postpartum more than girls by age seven. Case control comparisons of a variety of physical and neurobehavioral traits at age seven indicate that both sexes were affected similarly for a majority of variables. However, alcohol-exposed girls had significantly more dysmorphology overall than boys and performed significantly worse on non-verbal IQ tests than males. A three-step sequential regression analysis, controlling for multiple covariates, further indicated that dysmorphology among girls was significantly more associated with five maternal drinking variables and three distal maternal risk factors. However, the overall model, which included five associated neurobehavioral measures at step three, was not significant (p=0.09, two-tailed test). A separate sequential logistic regression analysis of predictors of a FASD diagnosis, however, indicated significantly more negative outcomes overall for girls than boys (Nagelkerke R 2 =0.42 for boys and 0.54 for girls, z=-2.9, p=0.004)., Conclusion: Boys and girls had mostly similar outcomes when prenatal alcohol exposure was linked to poor physical and neurocognitive development. Nevertheless, sex ratios implicate lower viability and survival of males by first grade, and girls have more dysmorphology and neurocognitive impairment than boys resulting in a higher probability of a FASD diagnosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background : Prevalence and characteristics of fetal alcohol syndrome (FAS) and total fetal alcohol spectrum disorders (FASD) were studied in a second sample of three South African rural communities to assess change. Methods : Active case ascertainment focused on children with height, weight and/or head circumference ≤25th centile and randomly-selected children. Final diagnoses were based on dysmorphology, neurobehavioral scores, and maternal risk interviews. Results : Cardinal facial features, head circumference, and total dysmorphology scores differentiated specific FASD diagnostic categories in a somewhat linear fashion but all FASD traits were significantly worse than those of randomly-selected controls. Neurodevelopmental delays were significantly worse for children with FASD than controls. Binge alcohol use was clearly documented as the proximal maternal risk factor for FASD, and significant distal risk factors were: low body mass, education, and income; high gravidity, parity, and age at birth of the index child. FAS rates continue to extremely high in these communities at 9-129 per 1000 children. Total FASD affect 196-276 per 1000 or 20-28% of the children in these communities. Conclusions : Very high rates of FASD persist in these general populations where regular, heavy drinking, often in a binge fashion, co-occurs with low socioeconomic conditions.

Background: The prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in a fifth sample in a South African community., Methods: An active case ascertainment approach was employed among all first grade learners in this community (n=862). Following individual examination by clinical geneticists/dysmorphologists, cognitive/behavioral testing, and maternal interviews, final diagnoses were made in multidisciplinary case conferences., Results: Physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories in a consistent, linear fashion, from severe to mild. Neurodevelopmental delays and behavioral problems were significantly worse for each of the FASD diagnostic categories, although not as consistently linear across diagnostic groups. Alcohol use was documented by direct report from the mother in 71% to 100% of cases in specific diagnostic groups. Significant distal maternal risk factors in this population are: advanced maternal age at pregnancy; low height, weight, and body mass index (BMI); small head circumference; low education; low income; and rural residence. Even when controlling for socioeconomic status, prenatal drinking correlates significantly with total dysmorphology score, head circumference, and five cognitive and behavioral measures. In this community, FAS occurs in 59-79 per 1,000 children, and total FASD in 170-233 per 1,000 children, or 17% to 23%., Conclusions: Very high rates of FASD continue in this community where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development in a significant portion of the population., Competing Interests: Conflict of interests None of the authors have any conflicts of interest to declare., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol., (Copyright © 2016 by the American Academy of Pediatrics.)

Objective: Determine any effects that maternal alcohol consumption during the breastfeeding period has on child outcomes., Methods: Population-based samples of children with fetal alcohol spectrum disorders (FASD), normally-developing children, and their mothers were analyzed for differences in child outcomes., Results: Ninety percent (90%) of mothers breastfed for an average of 19.9 months. Of mothers who drank postpartum and breastfed (MDPB), 47% breastfed for 12 months or more. In case control analyses, children of MDPB were significantly lighter, had lower verbal IQ scores, and more anomalies in comparisons controlling for prenatal alcohol exposure and final FASD diagnosis. Utilizing a stepwise logistic regression model adjusting for nine confounders of prenatal drinking and other maternal risks, MDPB were 6.4 times more likely to have a child with FASD than breastfeeding mothers who abstained from alcohol while breastfeeding., Conclusions: Alcohol use during the period of breastfeeding was found to significantly compromise a child's development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in previously unstudied rural, agricultural, lower socioeconomic populations in South Africa (ZA)., Methods: Using an active case ascertainment approach among first grade learners, 1354 (72.6%) were consented into the study via: height, weight, and/or head circumference ≤ 25th centile and/or random selection as normal control candidates. Final diagnoses were made following: examination by pediatric dysmorphologists/geneticists, cognitive/behavioral testing, and maternal risk factor interviews., Results: FASD children were significantly growth deficient and dysmorphic: physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories from severe to mild to normal in a consistent, linear fashion. Neurodevelopmental delays were also significantly worse for each of the FASD diagnostic categories, although not as consistently linear across groups. Alcohol use is well documented as the proximal maternal risk factor for each diagnostic group. Significant distal maternal risk factors in this population are: low body weight, body mass, education, and income; and high gravidity, parity, and age at birth of the index child. In this low SES, highly rural region, FAS occurs in 93-128 per 1000 children, PFAS in 58-86, and, ARND in 32-46 per 1000. Total FASD affect 182-259 per 1000 children or 18-26%., Conclusions: Very high rates of FASD exist in these rural areas and isolated towns where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Compare nutritional status of 57 South African mothers of children with fetal alcohol spectrum disorders (FASD) with 148 mothers of controls., Methods: Dietary data were analyzed for macronutrients, micronutrients, and fats via estimated average requirements (EAR) and adequate intakes (AI) for pregnant women., Results: Virtually all mothers were likely deficient on most micronutrients by either EAR (<50%) or AI values. Mothers of FASD children consumed more of 13 of 25 micronutrients. For percentage below EAR, only vitamin D was significantly higher for FASD mothers. Despite no difference in total food intake, control mothers had a higher mean body mass index (BMI) than FASD mothers. Maternal BMI is more significant for positive child outcomes than any individual nutrient., Conclusions: Most mothers have inadequate dietary intake. Minor advantages in nutrient intake are overpowered by teratogenic effects of alcohol. Further study is needed of the interaction of alcohol, maternal nutrition, and metabolism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In the Western Cape Province of South Africa (ZA) a subculture of binge drinking produces the highest global documented prevalence of fetal alcohol spectrum disorders (FASD). FASD prevention research activities in ZA use the Comprehensive Prevention approach from the United States Institute of Medicine. Case management (CM) was delivered as a method of indicated prevention to empower heavy drinking pregnant women to achieve cessation or a reduction in drinking. CM activities incorporated life management, Motivational Interviewing (MI) techniques and the Community Reinforcement Approach (CRA). Data were collected at baseline, 6, 12 and 18 months. Mean drinking decreases 6 months into CM; but overall alcohol consumption rose significantly over time to levels higher than baseline at 12 and 18 months. Alcohol consumption drops significantly from before pregnancy to the second and third trimesters. AUDIT scores indicate that problematic drinking decreases significantly even after the vulnerable fetus/baby was born. CM significantly increases client happiness, which correlates with reduced weekend drinking. CM was successful for women with high-risk drinking behaviour, and was effective in helping women stop drinking, or drink less, while pregnant, reducing the risk of FASD.

This study describes alcohol consumption in five Western Cape Province communities. Cross-sectional data from a community household sample (n = 591) describe the alcohol use patterns of adult males and females, and farm workers vs. others. Data reveal that men were more likely to be current drinkers than women, 75.1% vs. 65.8% (p = 0.033); farm laborers were more likely to be current drinkers than individuals in other occupations 83.1% vs. 66.8% (p = 0.004). Group, binge drinking on weekends was the norm; men were more likely to be binge drinkers in the past week than women 59.8% vs. 48.8% (p = 0.086); farm workers were more likely to binge than others 75.0% vs. 47.5% (p < 0.001). The legacy of "Dop" contributes to current risky drinking behaviors. Farm owners or managers were interviewed on 11 farms, they described working conditions on their farms and how the legacy of "Dop" is reflected in the current use of alcohol by their workers. "Dop" was given to farm workers in the past on six of the 11 farms, but was discontinued for different reasons. There is zero tolerance for coming to work intoxicated; farm owners encourage responsible use of alcohol and assist farm workers in getting help for alcohol problems when necessary. The farm owners report some positive initiatives, were ahead of the movement to provide meaningful wages, and provide other important amenities. Further research is needed to assess whether progressive practices on some farms will reduce harmful alcohol use.

In this study, we describe the nutritional status of women from a South African community with very high rates of fetal alcohol spectrum disorders (FASD). Nutrient intake (24-h recall) of mothers of children with FASD was compared to mothers of normal controls. Nutrient adequacy was assessed using Dietary Reference Intakes (DRIs). More than 50% of all mothers were below the Estimated Average Requirement (EAR) for vitamins A, D, E, and C, thiamin, riboflavin, vitamin B6, folate, calcium, magnesium, iron, and zinc. Mean intakes were below the Adequate Intake (AI) for vitamin K, potassium, and choline. Mothers of children with FASD reported significantly lower intake of calcium, docosapentaenoic acid (DPA), riboflavin, and choline than controls. Lower intake of multiple key nutrients correlates significantly with heavy drinking. Poor diet quality and multiple nutritional inadequacies coupled with prenatal alcohol exposure may increase the risk for FASD in this population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Concise, accurate measures of maternal prenatal alcohol use are needed to better understand fetal alcohol spectrum disorders (FASD)., Methods: Measures of drinking by mothers of children with specific FASD diagnoses and mothers of randomly-selected controls are compared and also correlated with physical and cognitive/behavioral outcomes., Results: Measures of maternal alcohol use can differentiate maternal drinking associated with FASD from that of controls and some from mothers of alcohol-exposed normals. Six variables that combine quantity and frequency concepts distinguish mothers of FASD children from normal controls. Alcohol use variables, when applied to each trimester and three months prior to pregnancy, provide insight on critical timing of exposure as well. Measures of drinking, especially bingeing, correlate significantly with increased child dysmorphology and negative cognitive/behavioral outcomes in children, especially low non-verbal IQ, poor attention, and behavioral problems. Logistic regression links (p<.001) first trimester drinking (vs. no drinking) with FASD, elevating FASD likelihood 12 times; first and second trimester drinking increases FASD outcomes 61 times; and drinking in all trimesters 65 times. Conversely, a similar regression (p=.008) indicates that drinking only in the first trimester makes the birth of a child with an FASD 5 times less likely than drinking in all trimesters., Conclusions: There is significant variation in alcohol consumption both within and between diagnostic groupings of mothers bearing children diagnosed within the FASD continuum. Drinking measures are empirically identified and correlated with specific child outcomes. Alcohol use, especially heavy use, should be avoided throughout pregnancy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To provide an analysis of multiple predictors of cognitive and behavioral traits for children with fetal alcohol spectrum disorders (FASDs)., Method: Multivariate correlation techniques were used with maternal and child data from epidemiologic studies in a community in South Africa. Data on 561 first-grade children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and not FASD and their mothers were analyzed by grouping 19 maternal variables into categories (physical, demographic, childbearing, and drinking) and used in structural equation models (SEMs) to assess correlates of child intelligence (verbal and nonverbal) and behavior., Results: A first SEM using only 7 maternal alcohol use variables to predict cognitive/behavioral traits was statistically significant (B = 3.10, p < .05) but explained only 17.3% of the variance. The second model incorporated multiple maternal variables and was statistically significant explaining 55.3% of the variance. Significantly correlated with low intelligence and problem behavior were demographic (B = 3.83, p < .05) (low maternal education, low socioeconomic status [SES], and rural residence) and maternal physical characteristics (B = 2.70, p < .05) (short stature, small head circumference, and low weight). Childbearing history and alcohol use composites were not statistically significant in the final complex model and were overpowered by SES and maternal physical traits., Conclusions: Although other analytic techniques have amply demonstrated the negative effects of maternal drinking on intelligence and behavior, this highly controlled analysis of multiple maternal influences reveals that maternal demographics and physical traits make a significant enabling or disabling contribution to child functioning in FASD.

Aim: Estimate the efficacy of Case Management (CM) for women at high risk for bearing a child with Fetal Alcohol Spectrum Disorders (FASD)., Design: Women were recruited from antenatal clinics and engaged in 18 months of CM., Setting: A South African community with a subculture of heavy, regular, weekend, recreational drinking and high documented rates of FASD., Participants: Forty-one women who were high risk for bearing a child with FASD., Measures: Statistical analysis of trends in drinking and other risk factors., Findings: At intake 87.8% were pregnant, most had previous alcohol-exposed pregnancies, most/all of their friends drink alcohol (67.5%), and 50.0% had stressful lives. CM was particularly valuable for pregnant women, as statistically significant reductions in alcohol risk were obtained for them in multiple variables: total drinks on weekends after six months of CM ( p = .026) and estimated peak blood alcohol concentration (BAC) at six ( p < .001) and 18 months ( p < .001). For participants completing 18 months of CM, AUDIT scores improved significantly by 6-month follow-up (from 19.8 to 9.7, p = .000), and even though rising at 12 and 18 months, AUDIT scores indicate that problematic drinking remained statistically significantly lower than baseline throughout CM. Happiness scale scores correlated significantly with reduced drinking in most time periods., Conclusions: An enduring change in drinking behavior is difficult in this social setting. Yet, CM provided by skilled and empathic case managers reduced maternal drinking at critical times, and therefore, alcohol exposure levels to the fetus.

Background: The prevalence and characteristics of fetal alcohol spectrum disorders (FASD) were determined in this fourth study of first-grade children in a South African community., Methods: Active case ascertainment methods were employed among 747 first-grade pupils. The detailed characteristics of children within the continuum of FASD are contrasted with randomly selected, normal controls on (i) physical growth and dysmorphology; (ii) cognitive/behavioral characteristics; and (iii) maternal risk factors., Results: The rates of specific diagnoses within the FASD spectrum continue to be among the highest reported in any community in the world. The prevalence (per 1,000) is as follows: fetal alcohol syndrome (FAS)-59.3 to 91.0; partial fetal alcohol syndrome (PFAS)-45.3 to 69.6; and alcohol-related neurodevelopmental disorder (ARND)-30.5 to 46.8. The overall rate of FASD is therefore 135.1 to 207.5 per 1,000 (or 13.6 to 20.9%). Clinical profiles of the physical and cognitive/behavioral traits of children with a specific FASD diagnosis and controls are provided for understanding the full spectrum of FASD in a community. The spectral effect is evident in the characteristics of the diagnostic groups and summarized by the total (mean) dysmorphology scores of the children: FAS = 18.9; PFAS = 14.3; ARND = 12.2; and normal controls, alcohol exposed = 8.2 and unexposed = 7.1. Documented drinking during pregnancy is significantly correlated with verbal (r = -0.253) and nonverbal ability (r = -0.265), negative behaviors (r = 0.203), and total dysmorphology score (r = 0.431). Other measures of drinking during pregnancy are significantly associated with FASD, including binge drinking as low as 3 drinks per episode on 2 days of the week., Conclusions: High rates of specific diagnoses within FASD were well documented in this new cohort of children. FASD persists in this community. The data reflect an increased ability to provide accurate and discriminating diagnoses throughout the continuum of FASD., (Copyright © 2012 by the Research Society on Alcoholism.)

Foetal Alcohol Syndrome (FAS) has been identified as among the most serious consequences associated with hazardous and harmful drinking in the Western Cape province, South Africa. Community surveys were conducted in two wine growing regions in this province to assess drinking behaviour, guide interventions and serve as a baseline for assessing the impact of population-level interventions. As part of a cross-sectional comparative study interviews were conducted with 384 and 209 randomly selected adults in the prevention (PC) and comparison communities (CC) respectively. Over 80% of respondents resided in urban areas, except in the CC, where 61% of males resided on farms. Symptoms of hazardous or harmful drinking were reported by 16.0% of females and 32.5% of males in the PC, while 19.3% of females and 56.2% of males in the CC reported such drinking. Over two-thirds of respondents indicated that it was equally harmful for a woman to drink during any of the trimesters of pregnancy, but more than 30% of the women interviewed had never had a health worker speak to them about the effects of drinking during pregnancy. Over 10% had never heard of fetal alcohol syndrome. The findings reinforce the need for interventions to address hazardous/harmful use of alcohol in both communities and also to address gaps in knowledge regarding the effects of drinking during pregnancy.

Background: Previous research in South Africa revealed very high rates of fetal alcohol syndrome (FAS), of 46-89 per 1000 among young children. Maternal and child data from studies in this community summarize the multiple predictors of FAS and partial fetal alcohol syndrome (PFAS)., Method: Sequential regression was employed to examine influences on child physical characteristics and dysmorphology from four categories of maternal traits: physical, demographic, childbearing, and drinking. Then, a structural equation model (SEM) was constructed to predict influences on child physical characteristics., Results: Individual sequential regressions revealed that maternal drinking measures were the most powerful predictors of a child's physical anomalies (R² = .30, p < .001), followed by maternal demographics (R² = .24, p < .001), maternal physical characteristics (R²=.15, p < .001), and childbearing variables (R² = .06, p < .001). The SEM utilized both individual variables and the four composite categories of maternal traits to predict a set of child physical characteristics, including a total dysmorphology score. As predicted, drinking behavior is a relatively strong predictor of child physical characteristics (β = 0.61, p < .001), even when all other maternal risk variables are included; higher levels of drinking predict child physical anomalies., Conclusions: Overall, the SEM model explains 62% of the variance in child physical anomalies. As expected, drinking variables explain the most variance. But this highly controlled estimation of multiple effects also reveals a significant contribution played by maternal demographics and, to a lesser degree, maternal physical and childbearing variables., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder with ectopic mineralization in the skin, eyes and cardiovascular system. PXE is caused by mutations in ABCC6., Objective: To examine 54 unrelated South African PXE patients for ABCC6 PXE causing mutations., Methods: Patients were screened for mutations in ABCC6 using two strategies. The first involved a comprehensive screening of all the ABCC6 exons and flanking regions by dHPLC or sequencing whereas the second involved screening patients only for the common PXE mutations. The ABCC6 gene was screened in ten white and ten black healthy unrelated South Africans in order to examine the level of common non-PXE associated variation., Results: The Afrikaner founder mutation, R1339C, was present in 0.41 of white ABCC6 PXE alleles, confirming the founder effect and its presence in both Afrikaans- (34/63 PXE alleles) and English-speakers (4/28). Eleven mutations were detected in the white patients (of European origin), including two nonsense mutations, 6 missense mutations, two frameshift mutations and a large deletion mutation. The five "Coloured" patients (of mixed Khoisan, Malay, European and African origin) included three compound heterozygotes with R1339C as one of the mutations. The three black patients (sub-Saharan African origin) were all apparent homozygotes for the R1314W mutation. Blacks showed a trend towards a higher degree of neurtral variation (18 variants) when compared to whites (12 variants)., Conclusion: Delineation of the ABCC6 mutation profile in South African PXE patients will be used as a guide for molecular genetic testing in a clinical setting and for genetic counselling.

Objectives: This is a third exploration of risk factors for the two most severe forms of fetal alcohol spectrum disorders (FASD), fetal alcohol syndrome (FAS) and Partial FAS (PFAS), in a South African community with the highest reported prevalence of FAS in the world., Methods: In a case control design, interview and collateral data concerning mothers of 72 first grade children with FAS or PFAS are compared with 134 randomly selected maternal controls of children from the same schools., Results: Significant differences were found between the mothers of FASD children and controls in socio-economic status, educational attainment, and a higher prevalence of FASD among rural residents. The birth order of the index children, gravidity, and still birth were significantly higher among mothers of FASD children. Mothers of children with a FASD are less likely to be married and more likely to have a male partner who drank during the index pregnancy. Current and gestational alcohol use by mothers of FASD children is bingeing on weekends, with no reduction in drinking reported in any trimester in 75 to 90% of the pregnancies that resulted in an FAS child or during 50 to 87% of PFAS-producing pregnancies. There was significantly less drinking among the controls in the second and third trimesters (11 to 14%). Estimated peak blood alcohol concentrations (BAC)s of the mothers of PFAS children range from 0.155 in the first trimester to 0.102 in the third, and for mothers of FAS children the range is from 0.197 to 0.200 to 0.191 in the first, second, and third. Smoking percentage during pregnancy was significantly higher for mothers of FASD children (82 to 84%) than controls (35%); but average quantity smoked is low in the 3 groups at 30 to 41 cigarettes per week. A relatively young average age of the mother at the time of FAS and PFAS births (28.8 and 24.8 years respectively) is not explained by early onset of regular drinking (mean = 20.3 to 20.5 years of age). But the mean years of alcohol consumption is different between groups, 16.3, 10.7, and 12.1 years respectively for mothers of FAS, FASD, and drinking controls. Mothers of FAS and PFAS children were significantly smaller in height and weight than controls at time of interview. The child's total dysmorphology score correlates significantly with mother's weight (-0.46) and BMI (-0.39). Bivariate correlations are significant between the child's dysmorphology and known independent demographic and behavioral maternal risk factors for FASD: higher gravidity and parity; lower education and income; rural residence; drinks consumed daily, weekly, and bingeing during pregnancy; drinking in all trimesters; partner's alcohol consumption during pregnancy; and use of tobacco during pregnancy. Similar significant correlations were also found for most of the above independent maternal risk variables and the child's verbal IQ, non-verbal IQ and behavioral problems., Conclusions: Maternal data in this population are generally consistent with a spectrum of effects exhibited in the children. Variation within the spectrum links greater alcohol doses with a greater severity of effects among children of older and smaller mothers of lower socio economic status in their later pregnancies. Prevention is needed to address known maternal risk factors for FASD in this population.

Background: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6)., Objective: To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations., Methods: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed., Results: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease., Conclusions: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.

Objectives: The prevalence and characteristics of fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (PFAS) were determined in a third primary school cohort in a community in South Africa (SA)., Methods: An active case ascertainment, two-tier screening methodology, and the revised Institute of Medicine diagnostic criteria were employed among 818 first grade pupils. Characteristics of children with FAS and PFAS are contrasted with a randomly selected control group. Data were collected and analyzed for children in the study regarding: (1) physical growth and development, including dysmorphology, (2) intelligence and behavioral characteristics, and (3) their mother's social, behavioral, and physical characteristics., Results: The rate of FAS and PFAS in this area continues as the highest reported in any overall community and is much higher than rates elsewhere. In this cohort it is 68.0-89.2 per 1000. Severe episodic drinking on weekends among mothers of children with FAS and PFAS accounts for 96% of all alcohol consumed. Various measures of maternal drinking are significantly correlated with negative outcomes of children in the areas of non-verbal intelligence (-0.26), verbal intelligence (-0.28), problem behavior (0.31), and overall dysmorphology score (0.59). Significantly more FAS and PFAS exists among children of rural residents (OR=3.79)., Conclusions: A high rate of FAS and PFAS was again documented in this community, and it has increased. Given population similarities, we suspect that other communities in the Western Cape Province of South Africa also have high rates. Programs for prevention are needed.

Objective: The aim of the study was to determine the prevalence and characteristics of fetal alcohol syndrome (FAS) in a second primary school cohort in a community in South Africa., Method: Active case ascertainment, two-tier screening, and Institute of Medicine assessment methodology were employed among 857 first grade pupils, most born in 1993. Characteristics of children with FAS were contrasted with characteristics of a randomly selected control group from the same classrooms. Physical growth and development, dysmorphology and psychological characteristics of the children and measures of maternal alcohol use and smoking were analyzed., Results: The rate of FAS found in this study is the highest yet reported in any overall community in the world, 65.2-74.2 per 1,000 children in the first grade population. These rates are 33-148 times greater than U.S. estimates and higher than in a previous cohort study in this same community (40.5-46.4 per 1,000). Detailed documentation of physical features indicates that FAS children in South Africa have characteristics similar to those elsewhere: poor growth and development, facial and limb dysmorphology, and lower intellectual functioning. Frequent, severe episodic drinking of beer and wine is common among mothers and fathers of FAS children. Their lives are characterized by serious familial, social and economic challenges, compared with controls. Heavy episodic maternal drinking is significantly associated with negative outcomes of children in the area of nonverbal intelligence but even more so in verbal intelligence, behavior and overall dysmorphology (physical anomalies). Significantly more FAS exists among children of women who were rural residents (odds ratio: 7.36, 95% confidence interval: 3.31-16.52), usually among workers on local farms., Conclusion: A high rate of FAS was documented in this community. Given social and economic similarities and racial admixture, we suspect that other communities in the Western Cape have rates that also are quite high.

Objectives: We defined risk factors for fetal alcohol syndrome (FAS) in a region with the highest documented prevalence of FAS in the world., Methods: We compared mothers of 53 first-grade students with FAS (cases) with 116 randomly selected mothers of first-grade students without FAS (controls)., Results: Differences between case and control mothers in our study population existed regarding socioeconomic status, religiosity, education, gravidity, parity, and marital status. Mothers of children with FAS came from alcohol-abusing families in which heavy drinking was almost universal; control mothers drank little to no alcohol. Current and past alcohol use by case mothers was characterized by heavy binge drinking on weekends, with no reduction of use during pregnancy in 87% of the mothers. Twenty percent of control mothers drank during pregnancy, a rate that declined to 12.7% by the third trimester. The percentage who smoked during pregnancy was higher for case mothers than for control mothers (75.5% vs 30.3%), but the number of cigarettes smoked was low among case mothers. The incidence of FAS in offspring of relatively young women (28 years) was not explained by early drinking onset or years of drinking (mean, 7.6 years among case mothers). In addition to traditional FAS risk factors, case mothers were smaller in height, weight, head circumference, and body mass index, all anthropomorphic measures that indicate poor nutrition and second-generation fetal alcohol exposure., Conclusions: Preventive interventions are needed to address maternal risk factors for FAS.

Objective: To test the sensitivity and specificity of fatty acid ethyl esters (FAEEs) extracted from meconium to identify alcohol-using pregnant women with a sensitive and specific methodology, gas chromatography-tandem mass spectroscopy (GC/MS/MS). Study design Twenty-seven samples of meconium were obtained from infants from the mixed race community in Cape Town, South Africa, who were enrolled in a longitudinal neurobehavioral study. Maternal alcohol use was reported prospectively during pregnancy. FAEEs were isolated from meconium and quantitated by GC/MS/MS., Results: Ethyl oleate was the FAEE that correlated most strongly with maternal self-reported drinking, especially with the average ounces of absolute alcohol ingested per drinking day. Ethyl oleate was most strongly related to drinking in the second and third trimesters (Pearson r=.55 and.40, respectively). At a threshold of 1.5 average ounces of absolute alcohol ingested per drinking day, the area under the receiving operator characteristic curve was.92 (95% confidence interval, 0.74-0.97). Using a cut-off value of 32 ng/g, sensitivity was 84.2% and specificity was 83.3%., Conclusions: Ethyl oleate concentration in meconium assayed by GC/MS/MS provides a highly sensitive and specific indicator of maternal alcohol use during pregnancy.

Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.