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1.  A Prospective Cohort Study of the Prevalence of Growth, Facial, and Central Nervous System Abnormalities in Children with Heavy Prenatal Alcohol Exposure 
Background
Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited.
Methods
This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status.
Results
One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome.
Conclusions
After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure.
doi:10.1111/j.1530-0277.2012.01794.x
PMCID: PMC4162305  PMID: 22823161
Alcohol; Pregnancy; Fetal Alcohol Spectrum Disorders; Growth Restriction; Neurodevelopment
2.  Alcohol Consumption at Midlife and Successful Ageing in Women: A Prospective Cohort Analysis in the Nurses' Health Study 
PLoS Medicine  2011;8(9):e1001090.
Using the Nurses' Health Study, Qi Sun and colleagues examine whether moderate alcohol intake is associated with overall health and well-being among women who survive to older age.
Background
Observational studies have documented inverse associations between moderate alcohol consumption and risk of premature death. It is largely unknown whether moderate alcohol intake is also associated with overall health and well-being among populations who have survived to older age. In this study, we prospectively examined alcohol use assessed at midlife in relation to successful ageing in a cohort of US women.
Methods and Findings
Alcohol consumption at midlife was assessed using a validated food frequency questionnaire. Subsequently, successful ageing was defined in 13,894 Nurses' Health Study participants who survived to age 70 or older, and whose health status was continuously updated. “Successful ageing” was considered as being free of 11 major chronic diseases and having no major cognitive impairment, physical impairment, or mental health limitations. Analyses were restricted to the 98.1% of participants who were not heavier drinkers (>45 g/d) at midlife. Of all eligible study participants, 1,491 (10.7%) achieved successful ageing. After multivariable adjustment of potential confounders, light-to-moderate alcohol consumption at midlife was associated with modestly increased odds of successful ageing. The odds ratios (95% confidence interval) were 1.0 (referent) for nondrinkers, 1.11 (0.96–1.29) for ≤5.0 g/d, 1.19 (1.01–1.40) for 5.1–15.0 g/d, 1.28 (1.03–1.58) for 15.1–30.0 g/d, and 1.24 (0.87–1.76) for 30.1–45.0 g/d. Meanwhile, independent of total alcohol intake, participants who drank alcohol at regular patterns throughout the week, rather than on a single occasion, had somewhat better odds of successful ageing; for example, the odds ratios (95% confidence interval) were 1.29 (1.01–1.64) and 1.47 (1.14–1.90) for those drinking 3–4 days and 5–7 days per week in comparison with nondrinkers, respectively, whereas the odds ratio was 1.10 (0.94–1.30) for those drinking only 1–2 days per week.
Conclusions
These data suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health status among women who survive to older ages.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
People have always drunk alcoholic beverages but throughout history there have been arguments about the risks and benefits of beer, wine, and spirits. It is clear that excessive alcohol use—heavy drinking (an average of more than two drinks per day for men or more than one drink per day for women; in the US, a “drink” is defined as 15 g of alcohol or, roughly speaking, a can of beer or a small glass of wine) or binge drinking (five or more drinks on a single occasion for men; 4 or more drinks at one time for women)—is harmful. It causes liver damage and increases the risk of developing some types of cancer. It contributes to depression and violence and interferes with relationships. And it is often implicated in fatal traffic accidents. However, in contrast to these and other harms associated with excessive alcohol use, moderate alcohol consumption seems to reduce the risk of specific diseases such as heart disease, stroke, and cognitive decline (deterioration in learning, reasoning, and perception).
Why Was This Study Done?
Although people who drink moderate amounts of alcohol have a reduced risk of premature death compared to abstainers or heavy drinkers, it is not known whether moderate alcohol consumption is associated with overall health among ageing populations. In many countries, elderly people are an increasingly large part of the population, so it is important to know how moderate alcohol consumption affects their well-being. In this study, the researchers examine the effect of alcohol consumption at midlife on successful ageing among the participants of the Nurses' Health Study. The researchers study the effect of midlife alcohol consumption because the chronic conditions that affect elderly people develop slowly and it is likely that factors in earlier life determine health in later life. Successful ageing is defined as being free of major chronic diseases such as cancer and heart disease, and having no major cognitive impairment, physical impairment, or mental health problems. The Nurses' Health Study enrolled 121,700 female registered nurses in 1976 to investigate the long-term effects of oral contraceptive use but has provided insights into many aspects of health and disease.
What Did the Researchers Do and Find?
The researchers assessed the alcohol consumption of the study participants at midlife (average age 58 years) from food frequency questionnaires completed in 1980 and 1984. Successful ageing for 13,984 participants who survived past 70 years was assessed by analyzing biennial health status questionnaires and cognitive function test results. One tenth of the women achieved successful ageing. After allowing for other factors that might affect their health such as smoking, women who drank light or moderate amounts of alcohol had a modestly increased chance of successful ageing compared to nondrinkers. For example, compared to nondrinkers, women who drank 5–15 g of alcohol per day (between one-third and one drink per day) had about a 20% higher chance of successful ageing. Independent of total alcohol intake, women who drank alcohol regularly had a better chance of successful ageing than occasional drinkers. Thus, compared to nondrinkers, women who drank five to seven days a week had nearly a 50% greater chance of successful ageing whereas women who drank only one or two days a week had a similar likelihood of successful ageing.
What Do These Findings Mean?
These findings suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health among women who survive to older ages. Because this is an observational study, it is possible that the women who drank moderately share other unknown characteristics that are actually responsible for their increased chance of successful ageing. Moreover, because all the study participants were women and most had European ancestry, these findings cannot be applied to men or to other ethnic groups. Nevertheless, these findings provide support for the 2010 US Department of Agriculture dietary guidelines, which state that consumption of up to one alcoholic drink per day for women and up to two alcoholic drinks per day for men may provide health benefits. Importantly, they also suggest that drinking alcohol regularly in moderation rather than occasional heavy drinking may be associated with a greater likelihood of successful ageing.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001090.
The US National Institute on Alcohol Abuse and Alcoholism has detailed information about alcohol and its effects on health, including a fact sheet on women and alcohol and a booklet entitled Alcohol, a woman's health issue
The US Centers for Disease Control and Prevention has a website on alcohol and public health
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including how to calculate consumption
The Nutrition Source, a website maintained by the Department of Nutrition at Harvard School of Public Health, has an article entitled Alcohol: balancing risks and benefits
MedlinePlus provides links to many other resources on alcohol and on seniors' health
Details of the Nurses' Health Study are available
The 2010 US Department of Agriculture dietary guidelines are available
doi:10.1371/journal.pmed.1001090
PMCID: PMC3167795  PMID: 21909248
3.  Exposure to alcohol in utero: Influence on cognitive function and learning in a northern elementary school population 
Paediatrics & Child Health  2000;5(2):93-100.
OBJECTIVES:
To establish the prevalence of fetal alcohol exposure; to compare physical, behavioural and learning patterns of children with significant alcohol exposure in utero with those of a group of children exposed to minimal alcohol; to assess the usefulness of a fetal alcohol syndrome (FAS)/fetal alcohol effect (FAE) score; and to provide feedback to parents, schools and communities.
DESIGN:
Parent questionnaire, complete physical examinations of children, psychometric tests of the children using elements of the Pediatric Early Elementary Examination (PEEX) and the Pediatric Examination of Educational Readiness (PEER), ADD-H comprehensive teachers rating scale (ACTeRS) score, the newly developed FAS/FAE Score, and the Brigance Comprehensive Inventory of Basic Skills to assess language and mathematical achievement. Testers were blinded to the results of the assessments and questionnaires.
SETTING:
Grades 1 to 3 at Sir Alexander MacKenzie School in Inuvik, Northwest Territories.
RESULTS:
Twenty-four per cent of mothers reported frequent or binge drinking, and 76% of mothers reported abstinence or moderate alcohol intake. There were significant ethnic differences; none of the Caucasian mothers reported frequent or binge drinking during pregnancy compared with 40% of Inuvialuit and 33% of Indian mothers. Children with exposure to frequent or binge drinking in utero had smaller palpebral fissures (2.3±0.1 cm versus 2.5±0.3 cm, P<0.01), smaller palpebral fissure to intercanthal distance ratios (0.77±0.05 versus 0.86±0.10, P<0.01) and smaller head circumferences (52.1±1.6 cm versus 53.6±1.6 cm, P<0.01) than those exposed to moderate drinking or abstinence. Children exposed to frequent or binge drinking in utero also demonstrated poorer coordination (P<0.005) and cortical function (P<0.01), attention problems, hyperactivity (ACTeRS), and poorer scholastic achievement in language (P<0.001) and mathematics (P<0.01) than their minimally exposed counterparts. In children in grades 2 and 3, a significant negative correlation was found between FAS/FAE scores and language (r=–0.55, P<0.001) and mathematical achievement (r=–0.28, P=0.20).
CONCLUSIONS:
The prevalence of drinking during pregnancy in the northern population studied was high, and exposure in utero was associated with physical abnormalities, difficulties with coordination and cortical function, and significant delays in language and mathematical achievement. The FAS/FAE score may be useful in predicting success or failure in language development.
PMCID: PMC2817759  PMID: 20177503
Aboriginal health; Alcohol-related birth defects; Alcohol-related neurodevelopmental defects; Attention deficit hyperactivity disorder; Fetal alcohol syndrome; Fetal alcohol effect; Learning difficulties
4.  Prenatal Alcohol Exposure and Interhemispheric Transfer of Tactile Information: Detroit and Cape Town Findings 
Background
Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults.
Methods
In Study 1, the FLT was administered to 40 heavily-exposed and 23 non-exposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation.
Results
In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (≥ 5 standard drinks) during pregnancy than if she drank regularly (M ≥ 1 drink/per day) without binge drinking.
Conclusions
These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.
doi:10.1111/j.1530-0277.2009.00994.x
PMCID: PMC2768060  PMID: 19519722
Fetal alcohol spectrum disorder; interhemispheric transfer; fetal alcohol syndrome; corpus callosum; pregnancy binge drinking; finger localization test
5.  Choline Supplementation Mitigates Trace, but not Delay, Eyeblink Conditioning Deficits in Rats Exposed to Alcohol During Development 
Hippocampus  2011;22(3):619-630.
Children exposed to alcohol prenatally suffer from a range of physical, neuropathological and behavioral alterations, referred to as Fetal Alcohol Spectrum Disorders (FASD). Both the cerebellum and hippocampus are affected by alcohol exposure during development, which may contribute to behavioral and cognitive deficits observed in children with FASD. Despite the known neuropathology associated with prenatal alcohol exposure, many pregnant women continue to drink (heavy drinkers, in particular), creating a need to identify effective treatments for their children who are adversely affected by alcohol. We previously reported that choline supplementation can mitigate alcohol’s effects on cognitive development, specifically on tasks which depend on the functional integrity of the hippocampus. The present study examined whether choline supplementation could differentially mitigate ethanol’s effects on trace eyeblink classical conditioning (a hippocampal-dependent task) and delay eyeblink classical conditioning (a cerebellar-dependent task). Long-Evans rats were exposed to 5.25 g/kg/day alcohol via gastric intubation from postnatal days (PD) 4-9, a period of brain development equivalent to late gestation in humans. A sham-intubated control group was included. From PD 10-30, subjects received subcutaneous injections of 100 mg/kg choline chloride or vehicle. Beginning on PD 32-34, subjects were trained on either delay or trace eyeblink conditioning. Performance of subjects exposed to alcohol was significantly impaired on both tasks, as indicated by significant reductions in percentage and amplitude of conditioned eyeblink responses, an effect that was attenuated by choline supplementation on the trace, but not delay conditioning task. Indeed, ethanol-exposed subjects treated with choline performed at control levels on the trace eyeblink conditioning task. There were no significant main or interactive effects of sex. These data indicate that choline supplementation can significantly reduce the severity of trace eyeblink conditioning deficits associated with early alcohol exposure, even when administered after the alcohol insult is complete. These findings have important implications for the treatment of fetal alcohol spectrum disorders.
doi:10.1002/hipo.20925
PMCID: PMC3754442  PMID: 21542051
fetal alcohol; treatment; ethanol; hippocampus; learning
6.  A Population-Based Study on Alcohol and High-Risk Sexual Behaviors in Botswana 
PLoS Medicine  2006;3(10):e392.
Background
In Botswana, an estimated 24% of adults ages 15–49 years are infected with HIV. While alcohol use is strongly associated with HIV infection in Africa, few population-based studies have characterized the association of alcohol use with specific high-risk sexual behaviors.
Methods and Findings
We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana using a stratified two-stage probability sample design. Multivariate logistic regression was used to assess correlates of heavy alcohol consumption (>14 drinks/week for women, and >21 drinks/week for men) as a dependent variable. We also assessed gender-specific associations between alcohol use as a primary independent variable (categorized as none, moderate, problem and heavy drinking) and several risky sex outcomes including: (a) having unprotected sex with a nonmonogamous partner; (b) having multiple sexual partners; and (c) paying for or selling sex in exchange for money or other resources. Criteria for heavy drinking were met by 31% of men and 17% of women. Adjusted correlates of heavy alcohol use included male gender, intergenerational relationships (age gap ≥10 y), higher education, and living with a sexual partner. Among men, heavy alcohol use was associated with higher odds of all risky sex outcomes examined, including unprotected sex (AOR = 3.48; 95% confidence interval [CI], 1.65 to 7.32), multiple partners (AOR = 3.08; 95% CI, 1.95 to 4.87), and paying for sex (AOR = 3.65; 95% CI, 2.58 to 12.37). Similarly, among women, heavy alcohol consumption was associated with higher odds of unprotected sex (AOR = 3.28; 95% CI, 1.71 to 6.28), multiple partners (AOR = 3.05; 95% CI, 1.83 to 5.07), and selling sex (AOR = 8.50; 95% CI, 3.41 to 21.18). A dose-response relationship was seen between alcohol use and risky sexual behaviors, with moderate drinkers at lower risk than both problem and heavy drinkers.
Conclusions
Alcohol use is associated with multiple risks for HIV transmission among both men and women. The findings of this study underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Alcohol use is associated with multiple risks for HIV transmission in men and women. The findings underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), is most commonly spread through unprotected sex with an infected partner. HIV enters the body through the lining of the sex organs, rectum, or mouth, and destroys immune system cells, leaving the infected person susceptible to other viruses and bacteria. Although HIV education and prevention campaigns emphasize the importance of safe sex in reducing HIV transmission, people continue to become infected by having unprotected sex (that is, not using a condom) with either a nonmonogamous partner or multiple sexual partners, or in situations where they are paying for or selling sex. Research in different populations suggested that heavy alcohol use is associated with risky sexual behaviors. This is because alcohol relaxes the brain and body, reduces inhibitions, and diminishes risk perception. Drinking alcohol may further increase the risk of becoming infected with HIV through its suppressive effects on the immune system.
Why Was This Study Done?
Alcohol abuse is widespread in sub-Saharan Africa where most HIV infections occur and has been associated with risky sexual behaviors. It may therefore be one of the most common, potentially modifiable HIV risk factors in this region. However, research to date has concentrated on the association between alcohol consumption and risky sex in people attending HIV-treatment clinics or recruited at beer halls, and these populations may not be representative of the general population of sub-Saharan Africa. In this study, the researchers have investigated the potential role of alcohol in perpetuating the HIV epidemic by undertaking a population-based study on alcohol use and high-risk sexual behaviors in Botswana. Nearly a quarter of adults are infected with HIV here, and alcohol abuse is also common, particularly in the townships.
What Did the Researchers Do and Find?
The researchers recruited a random cross-section of people from the five districts of Botswana with the highest number of HIV-infected individuals and interviewed all 1,268 participants using a questionnaire. This included general questions about the participants (for example, their age and marital status) and questions about alcohol use, sexual behavior, and knowledge of HIV. Overall, 31% of the men in the study and 17% of the women were heavy drinkers—more than 21 drinks/week for men, 14 for women; a drink is half a pint of beer or a glass of wine. Heavy alcohol use was associated with being male, being in an intergenerational relationship (at least 10 years age difference between partners; intergenerational sex facilitates the continued spread of HIV in sub-Saharan Africa), having had more education, and living with a sexual partner. Among men, those who drank heavily were three to four times more likely to have unprotected sex or multiple partners or to pay for sex than nondrinkers. Among women, there was a similar association between heavy drinking and having unprotected sex or multiple partners, and heavy drinkers were eight times as likely to sell sex as nondrinkers. For both men and women, the more they drank, the more likely they were to have risky sex. The study did not address behavior among same-sex partnerships.
What Do These Findings Mean?
This study indicates that heavy alcohol consumption is strongly and consistently associated with sexual risk behaviors in both men and women in Botswana. Because of the study design, it does not prove that heavy alcohol use is the cause of such behaviors but provides strong circumstantial evidence that this is the case. It is possible that these results may not apply to neighboring African countries—Botswana is unique in being relatively wealthy and in its government being strongly committed to tackling HIV. Nevertheless, taken together with the results of other studies, this research strongly argues for the need to deal with alcohol abuse within HIV prevention programs in sub-Saharan Africa. Strategies to do this could include education campaigns that target both alcohol use and HIV in schools and in social venues, including beer halls. But, stress the researchers, any strategy that is used must consider the cultural and social significance of alcohol use (in Botswana, alcohol use is a symbol of masculinity and high socioeconomic status) and must simultaneously tackle not only the overlap between alcohol use and risky sexual behavior but also the overlap between alcohol and other risk behaviors such as intergenerational sex.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030392.
US National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS
US Centers for Disease Control and Prevention information on HIV/AIDS
US National Institute on Alcohol Abuse and Alcoholism patient information on alcohol and HIV/AIDS]
Aidsmap, information on HIV and AIDS provided by the charity NAM,which includes some information on HIV infections and alcohol
AVERT information on HIV and AIDS in Botswana
doi:10.1371/journal.pmed.0030392
PMCID: PMC1592342  PMID: 17032060
7.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
8.  Effects of heavy prenatal alcohol exposure and iron deficiency anemia on child growth and body composition through age 9 years 
BACKGROUND
Prenatal alcohol exposure has been associated with pre- and postnatal growth restriction, but little is known about the natural history of this restriction throughout childhood or the effects of prenatal alcohol on body composition.
OBJECTIVE
To examine the effects of heavy prenatal alcohol exposure on longitudinal growth and body composition.
DESIGN
85 heavy drinking pregnant women (≥ 2 drinks/day or ≥ 4 drinks/occasion) and 63 abstaining and light-drinking controls (< 1 drink/day, no binging) were recruited at initiation of prenatal care in an urban obstetrical clinic in Cape Town, South Africa, and prospectively interviewed during pregnancy about alcohol, smoking, drug use, and demographics. Among their children, length/height, weight, and head circumference were measured at 6.5 and 12 months and at 5 and 9 years. Percent body fat was estimated at age 9 years using bioelectric impedance analysis.
RESULTS
In multiple regression models with repeated measures (adjusted for confounders), heavy alcohol exposure was associated with reductions in weight (0.6 SD), length/height (0.5 SD), and head circumference (0.9 cm) from 6.5 months to 9 years that were largely determined at birth. These effects were exacerbated by iron deficiency in infancy but were not modified by iron deficiency or measures of food security at 5 years. An alcohol-related postnatal delay in weight gain was seen at 12 months. Effects on head circumference were greater at age 9 than at other age points. Although heavy alcohol exposure was not associated with changes in body composition, children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) had lower % body fat than heavy exposed nonsyndromal and control children.
CONCLUSIONS
Heavy prenatal alcohol exposure is related to prenatal growth restriction that persists through age 9 years and an additional delay in weight gain during infancy. FAS and PFAS diagnoses are associated with leaner body composition in later childhood.
doi:10.1111/j.1530-0277.2012.01810.x
PMCID: PMC3697011  PMID: 22897691
fetal alcohol syndrome; intrauterine growth retardation; postnatal growth; body composition; bioelectric impedance analysis; prenatal alcohol exposure; iron deficiency; food security
9.  Living Alone and Alcohol-Related Mortality: A Population-Based Cohort Study from Finland 
PLoS Medicine  2011;8(9):e1001094.
Kimmo Herttua and colleagues showed that living alone is associated with a substantially increased risk of alcohol-related mortality, irrespective of gender, socioeconomic status, or cause of death, and that this effect was exacerbated after a price reduction in alcohol in 2004.
Background
Social isolation and living alone are increasingly common in industrialised countries. However, few studies have investigated the potential public health implications of this trend. We estimated the relative risk of death from alcohol-related causes among individuals living alone and determined whether this risk changed after a large reduction in alcohol prices.
Methods and Findings
We conducted a population-based natural experimental study of a change in the price of alcohol that occurred because of new laws enacted in Finland in January and March of 2004, utilising national registers. The data are based on an 11% sample of the Finnish population aged 15–79 y supplemented with an oversample of deaths. The oversample covered 80% of all deaths during the periods January 1, 2000–December 31, 2003 (the four years immediately before the price reduction of alcohol), and January 1, 2004–December 31, 2007 (the four years immediately after the price reduction). Alcohol-related mortality was defined using both underlying and contributory causes of death. During the 8-y follow-up about 18,200 persons died due to alcohol-related causes. Among married or cohabiting people the increase in alcohol-related mortality was small or non-existing between the periods 2000–2003 and 2004–2007, whereas for those living alone, this increase was substantial, especially in men and women aged 50–69 y. For liver disease in men, the most common fatal alcohol-related disease, the age-adjusted risk ratio associated with living alone was 3.7 (95% confidence interval 3.3, 4.1) before and 4.9 (95% CI 4.4, 5.4) after the price reduction (p<0.001 for difference in risk ratios). In women, the corresponding risk ratios were 1.7 (95% CI 1.4, 2.1) and 2.4 (95% CI 2.0, 2.9), respectively (p ≤ 0.01). Living alone was also associated with other mortality from alcohol-related diseases (range of risk ratios 2.3 to 8.0) as well as deaths from accidents and violence with alcohol as a contributing cause (risk ratios between 2.1 and 4.7), both before and after the price reduction.
Conclusions
Living alone is associated with a substantially increased risk of alcohol-related mortality, irrespective of gender, socioeconomic status, or the specific cause of death. The greater availability of alcohol in Finland after legislation-instituted price reductions in the first three months of 2004 increased in particular the relative excess in fatal liver disease among individuals living alone.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout most of human history, people have lived in tight-knit communities where there was likely to be someone to turn to for help, advice, or company. But the modern way of life in industrialized countries is greatly reducing the quantity and quality of social relationships. Instead of living in extended families, many people now live miles away from their relatives, often living and working alone. Others commute long distances to work, which leaves little time for socializing with friends or relatives. And many delay or forgo getting married and having children. Consequently, loneliness and social isolation are getting more common. In the UK, according to a recent survey by the Mental Health Foundation, 10% of people often feel lonely, a third have a close friend or relative who they think is very lonely, and half think people are getting lonelier in general. Similarly, over the past two decades, there has been a three-fold increase in the number of Americans who say they have no close confidants.
Why Was This Study Done?
Some experts think that loneliness is bad for human health. They point to studies that show that people with fewer social relationships die earlier on average than people with more social relationships. But does loneliness increase the risk of dying from specific causes? It is important to investigate the relationship between loneliness and cause-specific mortality (death) because, if for example, loneliness increases the risk of dying from alcohol-related causes (heavy drinking causes liver and heart damage, increases the risk of some cancers, contributes to depression, and increases the risk of death by violence or accident), doctors could advise their patients who live alone about safe drinking. But, although loneliness is recognized as both a contributor to and a consequence of alcohol abuse, there have been no large, population-based studies on the association between living alone and alcohol-related mortality. In this population-based study, the researchers estimate the association between living alone (an indicator of a lack of social relationships) and death from alcohol-related causes in Finland for four years before and four years after an alcohol price reduction in 2004 that increased alcohol consumption.
What Did the Researchers Do and Find?
The researchers obtained information on about 80% of all people who died in Finland between 2000 and 2007 from Statistics Finland, which collects official Finnish statistics. During this period, about 18,200 people (two-thirds of whom lived alone) died from underlying alcohol-related causes (for example, liver disease and alcoholic poisoning) or contributory alcohol-related causes (for example, accidents, violence, and cardiovascular disease, with alcohol as a contributing cause). Among married and cohabiting people, the rate of alcohol-related mortality was similar in 2000–2003 and 2004–2007 but for people living alone (particularly those aged 50–69 years) the 2004 alcohol price reduction substantially increased the alcohol-related mortality rate. For liver disease in men, the risk ratio associated with living alone was 3.7 before and 4.9 after the price reduction. That is, between 2000 and 2003, men living alone were 3.7 times more likely to die of liver disease than married or cohabiting men; between 2004 and 2007, they were 4.9 times more likely to die of liver disease. In women, the corresponding risk ratios for liver disease were 1.7 and 2.4, respectively. Living alone was also associated with an increased risk of dying from other alcohol-related diseases and accidents and violence both before and after the price reduction.
What Do These Findings Mean?
These findings indicate that, in Finland, living alone is associated with an increased risk of alcohol-related mortality. Because of the study design, it is impossible to say whether living alone is a cause or a consequence of alcohol abuse, but the greater increase in alcohol-related deaths (particularly fatal liver disease) among people living alone compared to married and cohabiting people after the alcohol price reduction suggests that people living alone are more vulnerable to the adverse effects of increased alcohol availability. Further research in other countries is now needed to identify whether living alone is a cause or effect of alcohol abuse and to extend these findings to cultures where the pattern of alcohol consumption is different. However, the findings of this natural experiment suggest that living alone should be regarded as a potential risk marker for death from alcohol-related causes.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001094.
The Mental Health America Live Your Life Well webpage includes information about how social relationships improve mental and physical health
The Mental Health Foundation (a UK charity) presents the report The Lonely Society?
The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health
The US Centers for Disease Control and Prevention has a website on alcohol and public health that includes information on the health risks of excessive drinking
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including information on the risks of drinking too much, and personal stories about alcohol problems, including stories from people living alone (My drinks diary shock and I used to drink all day)
MedlinePlus provides links to many other resources on alcohol
doi:10.1371/journal.pmed.1001094
PMCID: PMC3176753  PMID: 21949642
10.  Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy 
BMJ : British Medical Journal  1998;317(7157):505-510.
Objective: To examine the effect of alcohol consumption on the probability of conception.
Design: A follow up study over six menstrual cycles or until a clinically recognised pregnancy occurred after discontinuation of contraception.
Subjects: 430 Danish couples aged 20-35 years trying to conceive for the first time.
Main outcome measures: Clinically recognised pregnancy. Fecundability odds ratio: odds of conception among exposed couples divided by odds among those not exposed.
Results: In the six cycles of follow up 64% (179) of women with a weekly alcohol intake of less than five drinks and 55% (75) of women with a higher intake conceived. After adjustment for cycle number, smoking in either partner or smoking exposure in utero, centre of enrolment, diseases in female reproductive organs, woman’s body mass index, sperm concentration, and duration of menstrual cycle, the odds ratio decreased with increasing alcohol intake from 0.61 (95% confidence interval 0.40 to 0.93) among women consuming 1-5 drinks a week to 0.34 (0.22 to 0.52) among women consuming more than 10 drinks a week (P=0.03 for trend) compared with women with no alcohol intake. Among men no dose-response association was found after control for confounders including women’s alcohol intake.
Conclusion: A woman’s alcohol intake is associated with decreased fecundability even among women with a weekly alcohol intake corresponding to five or fewer drinks. This finding needs further corroboration, but it seems reasonable to encourage women to avoid intake of alcohol when they are trying to become pregnant.
Key messages As alcohol consumption is widespread and increasing in many countries, even a minor effect on fertility is of public health interest Some studies have found that women with high alcohol intake take longer to become pregnant, but none have found that moderate intake has an effect The probability of conception in a menstrual cycle decreased with increasing alcohol intake in women, even among those drinking five or fewer drinks a week Women who are trying to conceive should be encouraged to avoid intake of alcohol
PMCID: PMC28642  PMID: 9712595
11.  Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis 
Hormone Research in Pædiatrics  2010;75(3):166-173.
Aims
To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.
Methods
We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.
Results
IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.
Conclusion
Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.
doi:10.1159/000319706
PMCID: PMC3068754  PMID: 20847545
Fetal alcohol syndrome; Pregnancy; Alcohol abuse; Insulin-like growth factor I; Insulin-like growth factor II
12.  The Effectiveness of Community Action in Reducing Risky Alcohol Consumption and Harm: A Cluster Randomised Controlled Trial 
PLoS Medicine  2014;11(3):e1001617.
In a cluster randomized controlled trial, Anthony Shakeshaft and colleagues measure the effectiveness of a multi-component community-based intervention for reducing alcohol-related harm.
Background
The World Health Organization, governments, and communities agree that community action is likely to reduce risky alcohol consumption and harm. Despite this agreement, there is little rigorous evidence that community action is effective: of the six randomised trials of community action published to date, all were US-based and focused on young people (rather than the whole community), and their outcomes were limited to self-report or alcohol purchase attempts. The objective of this study was to conduct the first non-US randomised controlled trial (RCT) of community action to quantify the effectiveness of this approach in reducing risky alcohol consumption and harms measured using both self-report and routinely collected data.
Methods and Findings
We conducted a cluster RCT comprising 20 communities in Australia that had populations of 5,000–20,000, were at least 100 km from an urban centre (population ≥ 100,000), and were not involved in another community alcohol project. Communities were pair-matched, and one member of each pair was randomly allocated to the experimental group. Thirteen interventions were implemented in the experimental communities from 2005 to 2009: community engagement; general practitioner training in alcohol screening and brief intervention (SBI); feedback to key stakeholders; media campaign; workplace policies/practices training; school-based intervention; general practitioner feedback on their prescribing of alcohol medications; community pharmacy-based SBI; web-based SBI; Aboriginal Community Controlled Health Services support for SBI; Good Sports program for sports clubs; identifying and targeting high-risk weekends; and hospital emergency department–based SBI. Primary outcomes based on routinely collected data were alcohol-related crime, traffic crashes, and hospital inpatient admissions. Routinely collected data for the entire study period (2001–2009) were obtained in 2010. Secondary outcomes based on pre- and post-intervention surveys (n = 2,977 and 2,255, respectively) were the following: long-term risky drinking, short-term high-risk drinking, short-term risky drinking, weekly consumption, hazardous/harmful alcohol use, and experience of alcohol harm. At the 5% level of statistical significance, there was insufficient evidence to conclude that the interventions were effective in the experimental, relative to control, communities for alcohol-related crime, traffic crashes, and hospital inpatient admissions, and for rates of risky alcohol consumption and hazardous/harmful alcohol use. Although respondents in the experimental communities reported statistically significantly lower average weekly consumption (1.90 fewer standard drinks per week, 95% CI = −3.37 to −0.43, p = 0.01) and less alcohol-related verbal abuse (odds ratio = 0.58, 95% CI = 0.35 to 0.96, p = 0.04) post-intervention, the low survey response rates (40% and 24% for the pre- and post-intervention surveys, respectively) require conservative interpretation. The main limitations of this study are as follows: (1) that the study may have been under-powered to detect differences in routinely collected data outcomes as statistically significant, and (2) the low survey response rates.
Conclusions
This RCT provides little evidence that community action significantly reduces risky alcohol consumption and alcohol-related harms, other than potential reductions in self-reported average weekly consumption and experience of alcohol-related verbal abuse. Complementary legislative action may be required to more effectively reduce alcohol harms.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12607000123448
Please see later in the article for the Editors' Summary
Editors' Summary
Background
People have consumed alcoholic beverages throughout history, but alcohol use is now an increasing global public health problem. According to the World Health Organization's 2010 Global Burden of Disease Study, alcohol use is the fifth leading risk factor (after high blood pressure and smoking) for disease and is responsible for 3.9% of the global disease burden. Alcohol use contributes to heart disease, liver disease, depression, some cancers, and many other health conditions. Alcohol also affects the well-being and health of people around those who drink, through alcohol-related crimes and road traffic crashes. The impact of alcohol use on disease and injury depends on the amount of alcohol consumed and the pattern of drinking. Most guidelines define long-term risky drinking as more than four drinks per day on average for men or more than two drinks per day for women (a “drink” is, roughly speaking, a can of beer or a small glass of wine), and short-term risky drinking (also called binge drinking) as seven or more drinks on a single occasion for men or five or more drinks on a single occasion for women. However, recent changes to the Australian guidelines acknowledge that a lower level of alcohol consumption is considered risky (with lifetime risky drinking defined as more than two drinks a day and binge drinking defined as more than four drinks on one occasion).
Why Was This Study Done?
In 2010, the World Health Assembly endorsed a global strategy to reduce the harmful use of alcohol. This strategy emphasizes the importance of community action–a process in which a community defines its own needs and determines the actions that are required to meet these needs. Although community action is highly acceptable to community members, few studies have looked at the effectiveness of community action in reducing risky alcohol consumption and alcohol-related harm. Here, the researchers undertake a cluster randomized controlled trial (the Alcohol Action in Rural Communities [AARC] project) to quantify the effectiveness of community action in reducing risky alcohol consumption and harms in rural communities in Australia. A cluster randomized trial compares outcomes in clusters of people (here, communities) who receive alternative interventions assigned through the play of chance.
What Did the Researchers Do and Find?
The researchers pair-matched 20 rural Australian communities according to the proportion of their population that was Aboriginal (rates of alcohol-related harm are disproportionately higher among Aboriginal individuals than among non-Aboriginal individuals in Australia; they are also higher among young people and males, but the proportions of these two groups across communities was comparable). They randomly assigned one member of each pair to the experimental group and implemented 13 interventions in these communities by negotiating with key individuals in each community to define and implement each intervention. Examples of interventions included general practitioner training in screening for alcohol use disorders and in implementing a brief intervention, and a school-based interactive session designed to reduce alcohol harm among young people. The researchers quantified the effectiveness of the interventions using routinely collected data on alcohol-related crime and road traffic crashes, and on hospital inpatient admissions for alcohol dependence or abuse (which were expected to increase in the experimental group if the intervention was effective because of more people seeking or being referred for treatment). They also examined drinking habits and experiences of alcohol-related harm, such as verbal abuse, among community members using pre- and post-intervention surveys. After implementation of the interventions, the rates of alcohol-related crime, road traffic crashes, and hospital admissions, and of risky and hazardous/harmful alcohol consumption (measured using a validated tool called the Alcohol Use Disorders Identification Test) were not statistically significantly different in the experimental and control communities (a difference in outcomes that is not statistically significantly different can occur by chance). However, the reported average weekly consumption of alcohol was 20% lower in the experimental communities after the intervention than in the control communities (equivalent to 1.9 fewer standard drinks per week per respondent) and there was less alcohol-related verbal abuse post-intervention in the experimental communities than in the control communities.
What Do These Findings Mean?
These findings provide little evidence that community action reduced risky alcohol consumption and alcohol-related harms in rural Australian communities. Although there was some evidence of significant reductions in self-reported weekly alcohol consumption and in experiences of alcohol-related verbal abuse, these findings must be interpreted cautiously because they are based on surveys with very low response rates. A larger or differently designed study might provide statistically significant evidence for the effectiveness of community action in reducing risky alcohol consumption. However, given their findings, the researchers suggest that legislative approaches that are beyond the control of individual communities, such as alcohol taxation and restrictions on alcohol availability, may be required to effectively reduce alcohol harms. In other words, community action alone may not be the most effective way to reduce alcohol-related harm.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001617.
The World Health Organization provides detailed information about alcohol; its fact sheet on alcohol includes information about the global strategy to reduce the harmful use of alcohol; the Global Information System on Alcohol and Health provides further information about alcohol, including information on control policies around the world
The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health
The US Centers for Disease Control and Prevention has a website on alcohol and public health that includes information on the health risks of excessive drinking
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including information on the risks of drinking too much, tools for calculating alcohol consumption, and personal stories about alcohol use problems
MedlinePlus provides links to many other resources on alcohol
More information about the Alcohol Action in Rural Communities project is available
doi:10.1371/journal.pmed.1001617
PMCID: PMC3949675  PMID: 24618831
13.  Neurodevelopment of adopted children exposed in utero to cocaine. 
OBJECTIVE: To assess the neurodevelopment of adopted children who had been exposed in utero to cocaine. DESIGN: A case-control observational study. PARTICIPANTS: Twenty-three children aged 14 months to 6.5 years exposed in utero to cocaine and their adoptive mothers, and 23 age-matched control children not exposed to cocaine and their mothers, matched with the adoptive mothers for IQ and socioeconomic status. SETTING: The Motherisk Programme at The Hospital for Sick Children, Toronto, a consultation service for chemical exposure during pregnancy. MAIN OUTCOME MEASURES: Height, weight and head circumference at birth and at follow-up, and achievement on standard tests of cognitive and language development. RESULTS: Compared with the control group, children exposed in utero to cocaine had an 8-fold increased risk for microcephaly (95% confidence interval 1.5 to 42.3); they also had a lower mean birth weight (p = 0.005) and a lower gestational age (p = 0.002). In follow-up the cocaine-exposed children caught up with the control subjects in weight and stature but not in head circumference (mean 31st percentile v. 63rd percentile) (p = 0.001). Although there were no significant differences between the two groups in global IQ, the cocaine-exposed children had significantly lower scores than the control subjects on the Reynell language test for both verbal comprehension (p = 0.003) and expressive language (p = 0.001). CONCLUSIONS: This is the first study to document that intrauterine exposure to cocaine is associated with measurable and clinically significant toxic neurologic effects, independent of postnatal home and environmental confounders. Because women who use cocaine during pregnancy almost invariably smoke cigarettes and often use alcohol, it is impossible to attribute the measured toxic effects to cocaine alone.
PMCID: PMC1337370  PMID: 7954158
14.  Facial Dysmorphism Across the Fetal Alcohol Spectrum 
Pediatrics  2013;131(3):e779-e788.
OBJECTIVE:
Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics.
METHODS:
Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior.
RESULTS:
Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97–1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics.
CONCLUSIONS:
Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment.
doi:10.1542/peds.2012-1371
PMCID: PMC3581841  PMID: 23439907
facial dysmorphism; fetal alcohol spectrum disorders; fetal alcohol syndrome; dense surface modeling; signature graphs; prenatal alcohol exposure; alcohol-related neurodevelopmental disorder
15.  Alcohol use in pregnancy, craniofacial features, and fetal growth. 
STUDY OBJECTIVE--The aim was to study the relationship between the level of alcohol consumption in pregnancy and craniofacial characteristics of the neonate. DESIGN--This was a prospective survey of a sample of pregnant women, stratified on prepregnancy level of alcohol consumption. SETTING--The study was carried out at the public antenatal clinic of Roubaix maternity hospital. PARTICIPANTS--During an eight month period, 684 women (89% of those eligible) were interviewed in a standardised way at their first antenatal clinic visit. Of these, all who were suspected of being alcoholic or heavy drinkers (at least 21 drinks per week) were selected for follow up, as was a subsample of light (0-6 drinks per week) and moderate (7-20 drinks per week) drinkers. Of 347 women selected in this way, 202 had their infants assessed by a standardised morphological examination. MEASUREMENTS AND AND MAIN RESULTS--Suggestive craniofacial characteristics of the infants, present either in isolation or in association with growth retardation ("fetal alcohol effects"), were compared in relation to maternal alcohol consumption (alcoholic 12%; heavy drinking 24%; moderate drinking 28%; light drinking 36%). No differences were found between light and moderate drinkers. Infants born to alcoholics had a greater number of craniofacial characteristics and the proportion with features compatible with fetal alcohol effects was higher. There was a similar trend for infants of heavy drinkers. Infants of heavy drinkers who had decreased their alcohol consumption during pregnancy had fewer craniofacial features. Infants of heavy smokers were also found to have increased numbers of craniofacial characteristics. CONCLUSIONS--Craniofacial morphology could be a sensitive indicator of alcohol exposure in utero. Altered morphology is usually considered specific for alcohol exposure, but the relation observed with smoking needs further exploration.
PMCID: PMC1060674  PMID: 2277252
16.  Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats 
BACKGROUND
Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD). Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol’s teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development.
METHODS
Pregnant Sprague-Dawley rats were intubated with 6 g/kg/day ethanol in a binge-like manner from gestational days 5–20; pair-fed and ad lib chow controls were included. During treatment, subjects from each group were intubated with either 250 mg/kg/day choline chloride or vehicle. Spontaneous alternation, parallel bar motor coordination, Morris water maze, and spatial working memory were assessed in male and female offspring.
RESULTS
Subjects prenatally exposed to alcohol exhibited delayed development of spontaneous alternation behavior and deficits on the working memory version of the Morris water maze during adulthood, effects that were mitigated with prenatal choline supplementation. Neither alcohol nor choline influenced performance on the motor coordination task.
CONCLUSIONS
These data indicate that choline supplementation during prenatal alcohol exposure may reduce the severity of fetal alcohol effects, particularly on alterations in tasks that require behavioral flexibility. These findings have important implications for children of women who drink alcohol during pregnancy.
doi:10.1002/bdra.20713
PMCID: PMC3677823  PMID: 20706995
fetal alcohol spectrum disorders; treatment; nutrition; ethanol; fetal alcohol syndrome
17.  Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders 
Psychiatry research  2010;181(2):101.
Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), which includes the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this region’s role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8–16) with histories of heavy prenatal alcohol exposure (n = 21) and demographically-matched comparison subjects (n = 10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes, compared to controls. After adjusting for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.
doi:10.1016/j.pscychresns.2009.10.004
PMCID: PMC2815126  PMID: 20080394
Prenatal alcohol exposure; Fetal alcohol syndrome; MRI; White matter; Cognitive control; Attention deficits
18.  Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats 
Neurotoxicology and teratology  2009;31(5):303-311.
Prenatal alcohol exposure can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Variability in outcome observed among children with FASD is likely related to various pre- and postnatal factors, including nutritional variables. Choline is an essential nutrient that influences brain and behavioral development. Recent animal research indicates that prenatal choline supplementation leads to long-lasting cognitive enhancement, as well as changes in brain morphology, electrophysiology and neurochemistry. The present study examined whether choline supplementation during ethanol exposure effectively reduces fetal alcohol effects. Pregnant dams were exposed to 6.0 g/kg/day ethanol via intubation from gestational day (GD) 5-20; pair-fed and lab chow controls were included. During treatment, subjects from each group received choline chloride (250 mg/kg/day) or vehicle. Physical development and behavioral development (righting reflex, geotactic reflex, cliff avoidance, reflex suspension and hindlimb coordination) were examined. Subjects prenatally exposed to alcohol exhibited reduced birth weight and brain weight, delays in eye opening and incisor emergence, and alterations in the development of all behaviors. Choline supplementation significantly attenuated ethanol’s effects on birth and brain weight, incisor emergence, and most behavioral measures. In fact, behavioral performance of ethanol-exposed subjects treated with choline did not differ from that of controls. Importantly, choline supplementation did not influence peak blood alcohol level or metabolism, indicating that choline’s effects were not due to differential alcohol exposure. These data indicate early dietary supplements may reduce the severity of some fetal alcohol effects, findings with important implications for children of women who drink alcohol during pregnancy.
doi:10.1016/j.ntt.2009.07.002
PMCID: PMC2952280  PMID: 19616089
fetal alcohol spectrum disorders; ethanol; physical development; reflex development; treatment
19.  Comparison of Adaptive Behavior in Children With Heavy Prenatal Alcohol Exposure or Attention-Deficit/Hyperactivity Disorder 
Background
Adaptive behavior, the ability to respond successfully to everyday demands, may be especially sensitive to the effects of heavy prenatal alcohol exposure. Similar adaptive dysfunction is common in other developmental disorders including attention-deficit/hyperactivity disorder (ADHD). ADHD is frequently present in alcohol-exposed children and this overlap in clinical presentation makes identification of alcohol-exposed children difficult. Direct comparison of children with prenatal alcohol exposure and ADHD may yield distinct patterns of cognitive and behavioral performance and add to growing knowledge of the neuropsychological and behavioral profile of prenatal alcohol exposure. Therefore, the aim of the current study was to compare adaptive behavior in children with histories of heavy prenatal alcohol exposure (ALC), nonexposed children with ADHD (ADHD), and typically developing controls (CON).
Methods
Sixty-five children (ALC = 22, ADHD = 23, CON = 20) were selected from a larger ongoing study of the behavioral teratogenicity of alcohol. Alcohol-exposed and control participants were selected to match the ADHD subjects on age, sex, socioeconomic status, and race/ethnicity. Caregivers were administered the Vineland Adaptive Behavior Scales, a semi-structured interview, and were asked to rate their child’s behavior on 3 domains of adaptive function. Data were analyzed using regression techniques.
Results
Relative to controls, children in both the ALC and ADHD groups showed adaptive behavior deficits on all 3 domains and children in the ALC group were significantly more impaired than the ADHD group on the daily living skills domain. Within the ALC group, socialization standard scores were lower at older ages. This negative relationship between age and standard scores in the ALC group was also observed on the communication domain, a finding not previously reported.
Conclusions
This study suggests that both children with prenatal alcohol exposure and children with ADHD show impairments in adaptive function relative to controls, but that the pattern of impairment differs between these clinical groups. Adaptive ability in children with prenatal alcohol exposure is characterized by an arrest in development, as evidenced by a lack of improvement with age in socialization and communication scores. In contrast, children with ADHD exhibit a developmental delay in adaptive ability as their scores continued to improve with age, albeit not to the level of control children. Continued research focused on elucidating the patterns of deficits that exist in alcohol-exposed children ultimately will lead to improved differential diagnosis and effective interventions.
doi:10.1111/j.1530-0277.2009.01040.x
PMCID: PMC3442782  PMID: 19719794
Fetal Alcohol Spectrum Disorders; Fetal Alcohol Syndrome; Adaptive Behavior; ADHD; Differential Diagnosis; Neurobehavioral Profile
20.  Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya 
PLoS Medicine  2009;6(7):e1000116.
In a prospective cohort study of newborns residing in a malaria holoendemic area of Kenya, Christopher King and colleagues find a subset of children born to malaria-infected women who acquire a tolerant phenotype, which persists into childhood and is associated with increased susceptibility to malarial infection and anemia.
Background
Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections.
Methods and Findings
We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNγ, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNγ, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf−, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10–2.43; p = 0.024) and 1.34 (95% CI 0.95–1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97–2.07, p = 0.074) and 1.39 (95%CI 0.99–2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNγ and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage–specific IgG antibody levels were similar among the three groups.
Conclusions
These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Each year, Plasmodium falciparum, a mosquito-borne parasite, causes about 500 million cases of malaria and about one million people die as a result. Most of these deaths occur in young children in sub-Saharan Africa. Indeed, malaria accounts for a fifth of all childhood deaths in Africa, which makes it one of the most important childhood infectious diseases in this region. Very young children—those up to 6 months old—are relatively resistant to high-density parasitaemia and to clinical malaria, but children between 6 and 36 months old have an increased susceptibility to parasitaemia and to clinical malaria. Parasitaemia is the presence of P. falciparum parasites in the blood; a high density of blood-stage parasites causes the symptoms of clinical malaria (including high fever) and life-threatening organ damage and anemia (a lack of red blood cells).
Why Was This Study Done?
The age-dependent pattern of susceptibility to malaria suggests that young babies are protected by antibodies provided by their mothers, but that by 6 months old, when these antibodies have largely disappeared, babies have not yet fully developed their own anti-malaria immunity. However, little is known about the acquisition of anti-malaria immunity in infants, a process that needs to be understood in order to design effective vaccines for this age group. In particular, it is unclear how maternal malaria infection affects the acquisition of anti-malaria immunity. Malaria in pregnancy may expose the unborn child to malaria-infected red blood cells and to soluble malaria antigens (molecules that the immune system recognizes as foreign). This exposure could increase or decrease the child's immune responses to blood-stage malaria antigens and thus affect his/her ability to fight off malaria. In this study, the researchers investigated how prenatal malaria exposure affects anti-malaria immunity in young children and their susceptibility to subsequent malaria infections.
What Did the Researchers Do and Find?
The researchers determined which of 586 newborn babies enrolled into their study in an area of Kenya where malaria is very common had been exposed to P. falciparum before birth by looking for parasites in their mother's blood at delivery. They looked for malaria-specific immune responses in T cells (a type of immune system cell) in the newborn babies' cord blood by measuring the production of cytokines (molecules that either activate or inhibit the immune system) by these cells after exposure to malaria antigens. Finally, they examined the infants twice yearly for 3 years for malaria infection, malaria-specific immune responses, and anemia. The researchers classified the babies into three groups; cord blood cells of “sensitized” babies made activating cytokines in response to malaria antigens; cord blood cells of “exposed, not-sensitized” babies did not make activating cytokines but made an inhibitory cytokine (IL-10); and “not-exposed” babies were born to mothers with no P. falciparum infection at delivery. In their first 3 years of life, the exposed, not-sensitized group had a 60% greater risk of malaria infection (measured by counting parasites in their blood) than the unexposed group and a slightly higher risk of malaria infection than the sensitized group. They also had lower hemoglobulin levels (a sign of anemia) than the other babies. At age 6 months, the T cells of exposed, not-sensitized children were less likely to make activating cytokines in response to malaria antigens but made more IL-10 than the T cells of the other children; malaria-specific antibody levels were similar in the three groups.
What Do These Findings Mean?
These findings suggest that some children who are exposed to malaria before birth become “tolerant” to blood-stage malaria antigens. Exposure to malaria antigens before birth “tricks” their T cells into recognizing these antigens as self antigens. This immune tolerance, which persists into childhood, reduces the ability of the immune system to attack and destroy parasites and increases the susceptibility of these tolerant children to malaria infection. Why some children who are exposed to malaria before birth become tolerant while exposure to malaria antigens “primes” the immune system of other children to respond efficiently to these antigens is not clear. However, these findings could have important implications for the design of malaria vaccines for use in areas where children are often exposed to malaria before birth and for the design of strategies for the prevention of malaria during pregnancy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000116.
This study is further discussed in a PLoS Medicine Perspective by Lars Hviid
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy and on children and malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000116
PMCID: PMC2707618  PMID: 19636353
21.  Can prenatal ultrasound detect the effects of in-utero alcohol exposure? A pilot study 
Objectives
The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions.
Methods
We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner.
Results
From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval–calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05).
Conclusions
Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD.
doi:10.1002/uog.6379
PMCID: PMC3746738  PMID: 19444822
brain measurement; frontothalamic distance; prenatal alcohol exposure; ultrasound
22.  Alcohol Sales and Risk of Serious Assault 
PLoS Medicine  2008;5(5):e104.
Background
Alcohol is a contributing cause of unintentional injuries, such as motor vehicle crashes. Prior research on the association between alcohol use and violent injury was limited to survey-based data, and the inclusion of cases from a single trauma centre, without adequate controls. Beyond these limitations was the inability of prior researchers to comprehensively capture most alcohol sales. In Ontario, most alcohol is sold through retail outlets run by the provincial government, and hospitals are financed under a provincial health care system. We assessed the risk of being hospitalized due to assault in association with retail alcohol sales across Ontario.
Methods and Findings
We performed a population-based case-crossover analysis of all persons aged 13 years and older hospitalized for assault in Ontario from 1 April 2002 to 1 December 2004. On the day prior to each assault case's hospitalization, the volume of alcohol sold at the store in closest proximity to the victim's home was compared to the volume of alcohol sold at the same store 7 d earlier. Conditional logistic regression analysis was used to determine the associated relative risk (RR) of assault per 1,000 l higher daily sales of alcohol. Of the 3,212 persons admitted to hospital for assault, nearly 25% were between the ages of 13 and 20 y, and 83% were male. A total of 1,150 assaults (36%) involved the use of a sharp or blunt weapon, and 1,532 (48%) arose during an unarmed brawl or fight. For every 1,000 l more of alcohol sold per store per day, the relative risk of being hospitalized for assault was 1.13 (95% confidence interval [CI] 1.02–1.26). The risk was accentuated for males (1.18, 95% CI 1.05–1.33), youth aged 13 to 20 y (1.21, 95% CI 0.99–1.46), and those in urban areas (1.19, 95% CI 1.06–1.35).
Conclusions
The risk of being a victim of serious assault increases with alcohol sales, especially among young urban men. Akin to reducing the risk of driving while impaired, consideration should be given to novel methods of preventing alcohol-related violence.
In a population-based case-crossover analysis, Joel Ray and colleagues find that the risk of being a victim of serious assault increases with retail alcohol sales, especially among young urban men.
Editors' Summary
Background.
Alcohol has been produced and consumed around the world since prehistoric times. In the Western world it is now the most commonly consumed psychoactive drug (a substance that changes mood, behavior, and thought processes). The World Health Organization reports that there are 76.3 million persons with alcohol use disorders worldwide. Alcohol consumption is an important factor in unintentional injuries, such as motor vehicle crashes, and in violent criminal behavior. In the United Kingdom, for example, a higher proportion of heavy drinkers than light drinkers cause violent criminal offenses. Other figures suggest that people (in particular, young men) have an increased risk of committing a criminally violent offense within 24 h of drinking alcohol. There is also some evidence that suggests that the victims as well as the perpetrators of assaults have often been drinking recently, possibly because alcohol impairs the victim's ability to judge potentially explosive situations.
Why Was This Study Done?
The researchers wanted to know more about the relationship between alcohol and intentional violence. The recognition of a clear link between driving when impaired by alcohol and motor vehicle crashes has led many countries to introduce public awareness programs that stigmatize drunk driving. If a clear link between alcohol consumption by the people involved in violent crime could also be established, similar programs might reduce alcohol-related assaults. The researchers tested the hypothesis that the risk of being hospitalized due to a violent assault increases when there are increased alcohol sales in the immediate vicinity of the victim's place of residence.
What Did the Researchers Do and Find?
The researchers did their study in Ontario, Canada for three reasons. First, Ontario is Canada's largest province. Second, the province keeps detailed computerized medical records, including records of people hospitalized from being violently assaulted. Third, most alcohol is sold in government-run shops, and the district has the infrastructure to allow daily alcohol sales to be tracked. The researchers identified more than 3,000 people over the age of 13 y who were hospitalized in the province because of a serious assault during a 32-mo period. They compared the volume of alcohol sold at the liquor store nearest to the victim's home the day before the assault with the volume sold at the same store a week earlier (this type of study is called a “case-crossover” study). For every extra 1,000 l of alcohol sold per store per day (a doubling of alcohol sales), the overall risk of being hospitalized for assault increased by 13%. The risk was highest in three subgroups of people: men (18% increased risk), youths aged 13 to 20 y (21% increased risk), and those living in urban areas (19% increased risk). At peak times of alcohol sales, the risk of assault was 41% higher than at times when alcohol sales were lowest.
What Do These Findings Mean?
These findings indicate that the risk of being seriously assaulted increases with the amount of alcohol sold locally the day before the assault and show that the individuals most at risk are young men living in urban areas. Because the study considers only serious assaults and alcohol sold in shops (i.e., not including alcohol sold in bars), it probably underestimates the association between alcohol and assault. It also does not indicate whether the victim or perpetrator of the assault (or both) had been drinking, and its findings may not apply to countries with different drinking habits. Nevertheless, these findings support the idea that the consumption of alcohol contributes to the occurrence of medical injuries from intentional violence. Increasing the price of alcohol or making alcohol harder to obtain might help to reduce the occurrence of alcohol-related assaults. The researchers suggest that a particularly effective approach may be to stigmatize alcohol-related brawling, analogous to the way that driving under the influence of alcohol has been made socially unacceptable.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050104.
This study is further discussed in a PLoS Medicine Perspective by Bennetts and Seabrook
The US National Institute on Alcohol Abuse and Alcoholism provides information on all aspects of alcohol abuse, including an article on alcohol use and violence among young adults
Alcohol-related assault is examined in the British Crime Survey
Alcohol Concern, the UK national agency on alcohol misuse, provides fact sheets on the health impacts of alcohol, young people's drinking, and alcohol and crime
The Canadian Centre for Addiction and Mental Health in Toronto provides information about alcohol addiction (in English and French)
doi:10.1371/journal.pmed.0050104
PMCID: PMC2375945  PMID: 18479181
23.  Alcohol Induced Facial Dysmorphology in C57BL/6 Mouse Models of Fetal Alcohol Spectrum Disorder 
Alcohol (Fayetteville, N.Y.)  2010;44(7-8):659-671.
Alcohol consumption during pregnancy causes Fetal Alcohol Spectrum Disorder (FASD), which includes a range of developmental deficits. Fetal alcohol syndrome (FAS) is the most severe form of FASD and can be diagnosed with pathognomonic facial features (smooth philtrum, short palpebral fissure, and thin upper vermilion). However, many children with developmental damage due to prenatal alcohol exposure exhibit no, or only a subset, of the above features, making diagnosis difficult. This study explored novel analyses to quantify the effect of a known dose of alcohol on specific facial measurements in sub-strains C57BL/B6J (B6J) and C57BL/6NHsd (B6N) mice. Mouse dams were provided alcohol (Alc) consisting of 4.8% (v/v) alcohol in a liquid diet for 16 days pre-pregnancy, chow and water diet during mating, and the alcohol liquid diet reinstated on gestational days 7(E7) to E17. Treatment controls included a pair-fed (PF) group given matched volumes of an alcohol-free liquid diet made isocalorically, and a group given ad lib access to lab chow and water (Chow). Maternal diet intake (Alc and PF), blood alcohol concentrations (BACs), embryo weights, and 15 morphometric facial measurements for E17 embryos were analyzed. B6N dams drank more alcohol during pregnancy and generated higher BAC than B6J dams. Both the Alc and PF treatments induced significant reductions in embryo weights relative to Chow in both sub-strains. Alcohol treatments produced significant changes, relative to controls, in four of the 15 facial measures for the B6N sub-strain, but only in two measures for the B6J sub-strain. Discriminant analysis demonstrated successful classification of the B6N alcohol-exposed versus non-alcohol exposed embryos with high sensitivity (86%), and specificity (80%), and overall classification (total correct 83%), while, B6J mice yielded sensitivity of 80%, specificity 78%, and overall correct classification in 79%. In addition, B6N mice showed significantly more effects of pair feeding on these facial measures than did B6J, suggesting that the B6N sub-strain may be more vulnerable to nutritional stress during pregnancy. Overall, these data indicate that B6N and B6J mice were both vulnerable to alcohol but show differences in the severity and location of alcohol-induced dysmorphic facial features and may parallel findings from human studies comparing different ethnic groups. Furthermore these findings suggest that discriminant analysis may be useful in predicting alcohol exposure in either mouse sub-strain.
doi:10.1016/j.alcohol.2010.04.002
PMCID: PMC2955190  PMID: 20570474
facial development; genetic variance; morphometrics; anthropometry; diagnosis; craniofacial; translational study
24.  Prospective study of children exposed to variable amounts of alcohol in utero. 
Archives of Disease in Childhood  1985;60(4):316-321.
Forty children exposed to variable amounts of alcohol in utero and 40 control children were studied. All mothers had been enrolled in an antenatal programme aiming to identify and reduce alcohol use and abuse during pregnancy. Follow up was at the median age of 22 (18 to 27) months. A significant reduction in intrauterine growth was seen in children born to alcoholic mothers. Three of six children continuously exposed to high amounts of alcohol throughout fetal life showed growth retardation and physical abnormalities characteristic of fetal alcohol exposure, while infants whose mothers had stopped drinking did not suffer these effects. Psychological or behavioural disturbances were found in all but one of 13 children born to alcoholic mothers. The home environment during the first two years did not compensate for the effects of fetal alcohol exposure. Mothers classified as excessive drinkers but not abusers all reduced their alcohol consumption after the first trimester. Their children did not differ from controls with regard to physical development or behaviour but many were retarded in speech and, in addition had a more unstable family background.
PMCID: PMC1777236  PMID: 2408587
25.  Moderators of Naltrexone's Effects on Drinking, Urge and Alcohol Effects in Non-Treatment-Seeking Heavy Drinkers in the Natural Environment 
Background:
Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the μ-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects.
Methods:
After a one-week placebo lead-in period, heavy drinkers (n = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption.
Results:
NTX reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects.
Conclusions:
These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.
doi:10.1111/j.1530-0277.2007.00545.x
PMCID: PMC2743136  PMID: 18028530
naltrexone; family history; genetics; treatment; pharmacology

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