Alcohol-associated liver disease: Epidemiology and management.

Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.

Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models.

BACKGROUND: The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse. METHODS: A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared. RESULTS: Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%). CONCLUSIONS: AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.

Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases.

BACKGROUND: The most common liver diseases are fibrosis, alcoholic liver disease, nonalcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases. OBJECTIVE: To understand the role of interleukins in the assessment and treatment of different types of liver diseases. METHODS: A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov. RESULTS: Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases. CONCLUSION: Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.

The Spectrum of Alcohol Use: Epidemiology, Diagnosis, and Treatment.

In the United States, alcohol is the most common substance used and the spectrum of unhealthy alcohol use is highly prevalent. Complications of unhealthy alcohol use affect nearly every organ system. One of the most frequent and potentially life-threatening of these complications is alcohol withdrawal syndrome for which benzodiazepines remain first-line therapy. Pharmacologic treatment of alcohol use disorder, the most severe form of unhealthy alcohol use, is underutilized despite the availability of multiple effective medications. Although behavioral therapies are an important component of treatment, they are overemphasized at the expense of pharmacotherapy.

Incidence and management patterns of alcohol-related liver disease in Korea: a nationwide standard cohort study.

The recent incidence and management patterns of alcohol-related liver disease (ARLD) are not well defined in Korea. We sought to evaluate the epidemiology of ARLD with regard to disease severity and alcohol cessation management after diagnosis. We performed an observational cohort study of standardized Common Data Model data from the Health Insurance Review and Assessment-National Patient Samples database between 2012 and 2016. The incidence and demographic properties of ARLD were extracted and divided into non-cirrhotic alcoholic liver disease (ALD) and alcoholic liver cirrhosis (ALC). ALC was compared with non-alcoholic cirrhosis by severity at diagnosis. The management patterns were captured by the initiation of pharmaco- and behavioral therapy for alcohol cessation. We analyzed data from 72,556 ALD to 7295 ALC patients. The ALD incidence was stable from 990 to 1025 per 100,000 people. In ALD, the proportion of patients who were ≥ 65 years old, the proportion of female patients, and the comorbidity index increased significantly during the study period (all P values < 0.001). ALC accounted for > 20% of all cirrhosis, with decompensation occurring twice as often as in non-alcoholic cirrhosis. The initiation of alcoholism management was stationary in ARLD, remaining at < 10% for both pharmacotherapy and behavioral therapy, regardless of severity or the site of diagnosis. The incidence of ARLD did not decrease during the study period. Moreover, an increasing trend in the proportion of people vulnerable to drinking was observed. Unfortunately, management for the cessation of alcohol use remains very low. The best way to manage ARLD should be evaluated in further study.

Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action.

Alcohol-associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%-8.6%. In 2017, global prevalence of alcohol-associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol-associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi-faceted and focused on both population and patient-level interventions. Reductions in ALD-related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non-invasive serum and imaging markers, and risk-stratify higher-risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non-healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.

[Diagnosis and Severity Assessment of Alcohol-Related Liver Disease].

A diagnosis of alcohol-related liver disease (ALD) requires information on the history of excessive alcohol consumption (average intake of 40 g or more in men and 20 g or more in women a day). Furthermore, blood tests, such as GGT, AST, ALT, and mean corpuscular volume, and imaging studies, including abdominal ultrasound or transient elastography, are also useful. A liver biopsy can be useful for confirming the diagnosis and has prognostic value. ALD includes alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis, and in most cases, clinical manifestations can overlap. The prognostic scoring systems of ALD are limited mainly to alcoholic hepatitis, and the early mortality and treatment response can be predicted using various scoring systems. This review summarizes how to diagnose and evaluate the severity of ALD in clinical practice.

Epidemiological Realities of Alcoholic Liver Disease: Global Burden, Research Trends, and Therapeutic Promise.

Globally, alcohol consumption contributes to more than 3 million deaths each year. While much of its ramifications is preventable, a coherent public health discourse on how to limit alcohol-related harm has been overdue. By synthesizing information from national and global databases, we show in this analysis that alcohol consumption level and alcohol-attributable burden of diseases, particularly alcoholic liver disease (ALD), are intimately linked to national income distribution, cultural norms, religion, sex, age, and health status. Prevalence and burden of ALD are positively associated with economic standing in most countries, which necessitate active governmental control via cost-effective policies, such as the best buys proposed by the World Health Organization. To date, a number of critical questions remain unanswered over the molecular mechanisms underlying ALD pathophysiology; the insights gained thereof should provide new opportunities for the advancement of novel diagnostic and management strategies. In comparison with other prevailing liver diseases (e.g., viral hepatitis and nonalcoholic fatty liver disease), governmental support to ALD investigation has been sluggish in most Western countries and China, resulting in a dearth of breakthroughs on both the basic and clinical research fronts in the past decades. Emerging foci of clinical trials for ALD therapy include empirical use of probiotics, antioxidants, growth factors, monoclonal antibodies against key inflammatory mediators, and technology-enhanced behavioral interventions. In this article, we seek to provide a comprehensive analysis on the progress and challenges in tackling ALD as a global health problem, with particular emphasis on global disease burden, socioeconomic influences, research trends, government roles, and future therapies.

Sex and Gender Disparities in Pretransplant Characteristics and Relationships with Postoperative Outcomes in Liver Transplant Recipients with Alcoholic Liver Disease.

OBJECTIVES: Previous studies of liver transplant recipients have reported discrepancies with regard to gender and/or sex differences but have focused on pretransplant outcomes. Female candidates are less likely to receive liver transplant and more likely to die or be delisted than their male counterparts. Here, we examined differences in men versus women with alcoholic liver disease before liver transplant and the effects of these differences on posttransplant survival. MATERIALS AND METHODS: We analyzed the Scientific Registry of Transplant Recipients records of adult, deceased-donor, whole liver transplant recipients with decompensated alcoholic liver disease from 2002 to 2017 to evaluate the effects of gender on survival in 2 alcoholic liver disease cohorts: (a) including and (b) excluding recipients with additional diagnoses. Pretransplant characteristics were compared using chi-square or t tests. Kaplan-Meier and multivariable proportional hazards regression models were used to evaluate the main and covariable-adjusted effects of gender on survival. RESULTS: Of 13781 transplant recipients with decompensated end-stage liver disease, as defined by Model for End-Stage Liver Disease score ≥ 15, 10924 (79%) were men and 2857 (21%) were women. Women had higher Model for End-Stage Liver Disease scores, higher rates of stage 4 and 5 chronic kidney disease, and were more likely to be on dialysis or ventilator support at time of transplant (all P < .05). Among all recipients, and after adjusting for risk factors, men were approximately 9% more likely than women to experience long-term graft loss (hazard ratio = 1.093; 95% confidence interval, 1.00-1.19; P = .043). However, sex difference was not associated with risk of graft loss among those without additional diagnoses (hazard ratio = 1.09; 95% confidence interval, 0.99-1.21; P = .095). CONCLUSIONS: Although women with alcoholic liver disease who undergo liver transplant have higher severity of illness than their male counterparts, long-term outcomes are comparable.

Cost-Effectiveness of Noninvasive Screening for Alcohol-Related Liver Fibrosis.

BACKGROUND AND AIMS: Alcohol-related liver disease is often undetected until irreversible late-stage decompensated disease manifests. Consequently, there is an unmet need for effective and economically reasonable pathways to screen for advanced alcohol-related fibrosis. APPROACH AND RESULTS: We used real-world data from a large biopsy-controlled study of excessive drinkers recruited from primary and secondary care, to evaluate the cost-effectiveness of four primary care initiated strategies: (1) routine liver function tests with follow-up ultrasonography for test-positives, (2) the enhanced liver fibrosis (ELF) test with hospital liver stiffness measurement (LSM) for positives, (3) a three-tier strategy using the Forns Index to control before strategy 2, and (4) direct referral of all to LSM. We used linked decision trees and Markov models to evaluate outcomes short term (cost-per-accurate diagnosis) and long term (quality-adjusted life-years [QALYs]). For low-prevalence populations, ELF with LSM follow-up was most cost-effective, both short term (accuracy 96%, $196 per patient) and long term (incremental cost-effectiveness ratio [ICER] $5,387-$8,430/QALY), depending on whether diagnostic testing had lasting or temporary effects on abstinence rates. Adding Forns Index decreased costs to $72 per patient and accuracy to 95%. The strategy resulted in fewer QALYs due to more false negatives but an ICER of $3,012, making this strategy suited for areas with restricted access to ELF and transient elastography or lower willingness-to-pay. For high-prevalence populations, direct referral to LSM was highly cost-effective (accuracy 93%, $297 per patient), with ICERs between $490 and $1,037/QALY. CONCLUSIONS: Noninvasive screening for advanced alcohol-related fibrosis is a cost-effective intervention when different referral pathways are used according to the prevalence of advanced fibrosis. Patients in the primary health care sector should be tested with the ELF test followed by LSM if the test was positive, whereas direct referral to LSM is highly cost-effective in high-prevalence cohorts.

Growing burden of alcoholic liver disease in China: A review.

Explosive economic growth and increasing social openness in China over the last 30 years have significantly boosted alcohol consumption, and consequently, the incidence of alcoholic liver disease (ALD) in China has increased. Because the epidemiologic and clinical features of ALD in the Chinese population may differ from those of the Caucasian population, this review describes the epidemiology, pathogenesis, genetic polymorphisms, diagnosis, and treatment of ALD in the Chinese population. This updated knowledge of ALD in China provides information needed for a global understanding of ALD and may help in the development of useful strategies for reducing the global ALD burden.

Years of Life Lost due to Diseases of the Digestive System in Poland in 2000-2014.

BACKGROUND AND AIMS: Diseases of the digestive system substantially contribute to premature mortality of the Polish population. Years of Life Lost (YLLs) are more and more commonly used in order to evaluate social and economic aspects of these deaths. The aim of the study was to analyse YLLs due to diseases of the digestive system in Poland between 2000-2014. METHODS: The study material included a database which contained information gathered from 5,601,568 death certificates of Poles who died between 2000-2014. Data on deaths due to diseases of the digestive system were used for the analysis (i.e. coded as K00-K93 according to International Statistical Classification of Diseases and Related Health Problems, 10th Revision). Standard Expected Years of Life Lost (SEYLL) was used to calculate YLLs. RESULTS: In 2000-2014 diseases of the digestive system contributed to 239,176 deaths of Poles (4.3% of all deaths), which corresponded to 5,470,096.8 YLLs (95.2 years per 10,000 population). Each death due to the above cause was responsible for the average loss of 22.9 years. Diseases of the liver, including alcoholic liver disease and fibrosis and cirrhosis of the liver, contributed to the highest number of YLLs (54.1%). CONCLUSIONS: Of all digestive diseases, the dominant causes of YLLs are alcohol-related liver diseases. In order to minimize this phenomenon, it is important to intensify public health activities, aimed at combating alcohol addiction in Poland.

Changing Trends in Etiology-Based Annual Mortality From Chronic Liver Disease, From 2007 Through 2016.

BACKGROUND & AIMS: Although treatment of hepatitis C virus (HCV) infection has improved, the prevalence of alcoholic liver disease (ALD) has been increasing, so we need an updated estimate of the burden and etiology-specific mortality of chronic liver diseases. We studied trends in age-standardized mortality of chronic liver diseases in adults at least 20 years old in the United States from 2007 through 2016. METHODS: We collected data from the US Census and National Center for Health Statistics mortality records and identified individuals with HCV infection, ALD, nonalcoholic fatty liver disease, or hepatitis B virus infection using ICD-10 codes. We obtained temporal mortality rate patterns using joinpoint trend analysis with estimates of annual percentage change (APC). RESULTS: Age-standardized HCV-related mortality increased from 7.17 per 100,000 persons in 2007 to 8.14 per 100,000 persons in 2013, followed by a marked decrease in the time period at which patients began receiving treatment with direct-acting antiviral agents (from 8.09 per 100,000 persons in 2014 to 7.15 per 100,000 persons in 2016). The APC in HCV mortality increased 2.0%/year from 2007 through 2014 but decreased 6.4%/year from 2014 through 2016. In contrast, age-standardized mortality increased for ALD (APC 2.3% from 2007 through 2013 and APC 5.5% from 2013 through 2016) and nonalcoholic fatty liver disease (APC 6.1% from 2007 through 2013 and APC 11.3% from 2013 through 2016). Mortality related to hepatitis B virus decreased steadily from 2007 through 2016, with an average APC of -2.1% (95% CI -3.0 to -1.2). Etiology-based mortality in minority populations was higher. HCV-related mortality (per 100,000 persons) was highest in non-Hispanic blacks (10.28) and whites (6.92), followed by Hispanics (5.94), and lowest in non-Hispanic Asians (2.33). Non-Hispanic Asians had higher mortality for hepatitis B virus infection (2.82 per 100,000 vs 1.02 for non-Hispanic blacks and 0.47 for non-Hispanic whites). CONCLUSION: In our population-based analysis of chronic liver disease mortality in the United States, the decrease in HCV-related mortality coincided with the introduction of direct-acting antiviral therapies, whereas mortality from ALD and nonalcoholic fatty liver disease increased during the same period. Minorities in the United States have disproportionately higher mortality related to chronic liver disease.

Trends in the management and burden of alcoholic liver disease.

Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe and is the leading cause of death among adults with excessive alcohol consumption. There is a dose-response relationship between the amount of alcohol consumed and the risk of ALD. The relative risk of cirrhosis increases in subjects who consume more than 25 g/day. The burden of alcohol-attributable liver cirrhosis and liver cancer is high and is entirely preventable. Health agencies should develop population-based policies to reduce the prevalence of harmful and/or hazardous alcohol consumption and foster research in this field to provide new diagnostic and therapeutic tools. Disease progression of patients with ALD is heavily influenced by both genetic and environmental factors. Non-invasive methods for the diagnosis of fibrosis have opened new perspectives in the early detection of advanced ALD in asymptomatic patients. Alcoholic hepatitis, the most severe form of ALD, carries a high short-term mortality (around 30-50% at 3 months). Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis but duration of therapy should be adapted to early response. Liver transplantation is the best option for patients with severe liver dysfunction. However, alcohol relapse after transplantation remains a critical issue and drinking habits of transplanted patients need to be routinely screened.

[Diagnostic accuracy for alcoholic liver disease with controlled Attenuation Parameter (CAP) measured by transient elastography for the non-invasive assessment of liver steatosis].

Along with the development of interferon and therapeutic medication, the incidence of viral hepatitis constituting the largest part of liver disease decreased, and the main target in the field of liver disease is now shifting from viral hepatitis to alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) as metabolic liver disease. Although these diseases tend.to. be gathered as non-viral liver disease because the similar specific liver tissue, the natural history and etiology are considerably different between them. We need to distinguish both of them to do appropriate treatment intervention. Questioning of amount of drinking is needed, but we experience some difficult cases to understand drinking history because of a too little declaration of amount of drinking. A new ultrasonic image analyses using propagation speed in the organization of the pulse vibration wave was developed as Fibroscan by Echosens company in recent years. Fibroscan is a non-invasive test to quantify liver fibrosis as Liver Stiffness Measurement (LSM). It also detects and quantifies steatosis simultaneously using the Controlled Attenuation Parameter (CAP). CAP is a measurement of the ultrasound attenuation. We measured liver steatosis of patients using Fibroscan, and other blood tests. 63 cases of ALD, 177 cases of NAFLD, 57 cases of Virus and 271 cases of Normal were enrolled. CAP value were significantly lower in the ALD group compared with NAFLD group. (P < 0.0053, ALD 268 dB/m : NAFLD 290 dB/m) We elucidate the diagnostic accuracy of CAP using Fibroscan for ALD patients, comparing the results of them to those of virus patients and NAFLD patients.

Prevalence of alcoholic liver disease and its association with socioeconomic status in north-eastern China.

BACKGROUND: Alcohol consumption has substantially increased in China during the last 3 decades. Socioeconomic status (SES) most likely influences the development of alcoholic liver disease (ALD) in Chinese people who excessively consume alcohol. At the present time, however, little information is available in this field. The objectives of this study were to investigate the population-based prevalence of ALD and to identify the correlation of socioeconomics with the development of ALD. METHODS: A cross-sectional survey was conducted in 8,186 individuals who resided in Shandong Province and were over 18 years old in 2011 using a randomized multistage clustered sampling approach. Among these subjects, 7,295 (89.12%) were interviewed. Questionnaires covered demographic characteristic, medical history, current medication, and health-relevant behavior, particularly alcohol consumption, dietary habit, and physical activity. Anthropometric measurements, biochemical tests, and abdominal ultrasonography were also performed. RESULTS: Among the 7,295 subjects, 624 (8.55%) were diagnosed with ALD. The prevalence rate was significantly higher in males than in females (15.76% in males vs. 1.42% in females, p < 0.05). In this population, the risk of ALD was highest in the 40- to 49-year-old group. The incidence of ALD was highest in individuals who had a high level of occupation. Individuals who had received a low level of education had the highest incidence of ALD. Subjects with a low family income were more likely to have ALD than did those with an abundant family income. Currently, unmarried individuals had a higher incidence of ALD in the overall population. CONCLUSIONS: ALD is prevalent in north-eastern China. SES correlates with the development of ALD. Socioeconomic risk factors for ALD in north-eastern China include male gender, middle age, currently unmarried, low level of education, low family income, and high level of occupation.

[Prognosis assessment of alcoholic liver disease: how and why?]. / Évaluation pronostique de la maladie alcoolique du foie : comment et pourquoi ?

Alcoholic liver disease (ALD) causes more than 5000 deaths per year in France. Most of those deaths could be prevented by an early diagnosis, which would give the patients the opportunity to modify their alcohol consumption while liver lesions are still reversible. Hepatic histology is the main parameter that predicts morbidity and mortality in patients with ALD. Non-invasive methods such as biomarker tests (e.g. FibroTest(®) or FibroMetre A(®)) or hepatic elastography (FibroScan(®)) may allow diagnosing alcohol-induced liver lesion without systematic biopsy. Despite promising preliminary results, those methods are not validated yet in ALD. A validation of non-invasive methods for ALD could allow a large screening of the severe forms of this pathology.

Mothers with alcoholic liver disease and the risk for preterm and small-for-gestational-age birth.

AIMS: To study pregnancy outcome in women with alcoholic liver disease (ALD). METHODS: Using the Swedish nation-wide Patient and Medical Birth Registers, we investigated risk of adverse pregnancy outcome in 720 women diagnosed with ALD before and 1720 diagnosed after birth and compared them with 24 460 population-based control births. RESULTS: Women with ALD diagnosed before or after birth were generally of higher age and body mass index, more likely to smoke cigarettes during pregnancy and to have a low socio-economic status compared with controls. Women diagnosed with ALD before birth had an increased risk of moderately and very preterm birth, adjusted odd ratio (OR) = 1.53 (95% confidence interval (CI): 1.37-1.72 and 1.15-2.06 95%), respectively. Infants of mothers with ALD before birth were more often small-for-gestational age, adjusted OR = 1.22 (95% CI: 1.05-1.43), and were at increased risk for low Apgar scores (<7) at 5 min, adjusted OR = 1.49 (95% CI: 1.15-1.92) compared with controls. Similar associations with slightly lower-risk estimates were found among women diagnosed with ALD after birth. CONCLUSIONS: ALD is associated with adverse-birth outcomes, highlighting the importance of screening women for alcohol dependence in antenatal care.