Fetal alcohol spectrum disorders and access to regional center services in San Diego County.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are developmental disabilities that are estimated to occur in 2-5% of elementary school children and that negatively impact a child's ability to function without support. Timely diagnosis-informed interventions are crucial to optimizing the developmental trajectory of children with FASD. The true prevalence of FASD among children receiving services for developmental disabilities is unknown. METHODS: An FASD prevalence study was carried out between 2011 and 2014 among a sample of 5- to 7-year-old children who were receiving services provided by the California State Regional Center for Developmental Disabilities in San Diego County. Children whose parent or caregiver consented were evaluated using the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence study assessment protocol and classification criteria. RESULTS: Among 216 eligible caregiver-child dyads, 44 completed assessments that were sufficient to obtain a classification for FASD, including fetal alcohol syndrome (FAS), partial FAS, alcohol-related neurodevelopmental disorder, or no fetal alcohol spectrum disorder. Fifteen children were classified as meeting the criteria for an FASD. A minimum FASD prevalence rate of 69.4 per 1000 (6.9%) among all eligible children was estimated. None of the children classified as FASD were receiving services because of an FASD diagnosis, and none had previously been diagnosed with FASD. Autism was the most common qualifying diagnosis for which children classified as FASD were receiving services. CONCLUSIONS: The 6.9% prevalence estimate among Regional Center clients was higher than the prevalence estimate of 2.3% in the same community among 5- to 7-year-old children in the general population, though the estimate was based on only 20% of eligible dyads. All children in the sample were receiving Regional Center services for another diagnosis. Barriers to eligibility for services for children with FASD may lead to less than optimum care for these children. Study findings support the facilitation of access to developmental services for children with FASD.

Prenatal alcohol exposure can be determined from baby teeth: Proof of concept.

BACKGROUND: Prenatal alcohol exposure (PAE), leading to fetal alcohol spectrum disorders (FASD), is a serious public health issue in the United States and globally. Diagnosis of FASD is crucial in obtaining appropriate care, but it is not always possible when PAE cannot be documented. METHODS: Deciduous teeth from a child with known PAE and a child with known absence of PAE were analyzed using liquid chromatography-isotope dilution tandem mass spectrometry (LC-IDMS/MS) in a multiple-reaction monitoring mode for direct markers and LC-high resolution MS in positive and negative mode with hydrophilic interaction liquid chromatography and reverse-phase chromatography, respectively, for indirect markers. RESULTS: Direct markers of PAE (ethyl glucuronide and ethyl sulfate) were detected in prenatal and postnatal dentine from a case tooth but not from a control tooth. Indirect biomarker analysis indicated a dysregulation of amino acids and an increase in cholesterol sulfate in the case compared to the control tooth. CONCLUSIONS: This proof-of-concept study demonstrates for the first time that direct biomarkers of PAE are detectable and measurable in deciduous teeth which begin forming in utero and are typically naturally shed between 5 and 12 years of age. Further examination of these novel biomarkers may allow diagnosis of FASD where documentation of PAE is otherwise unavailable. Furthermore, because teeth grow incrementally, defined growth zones can be sampled allowing for identification of gestational timing of PAE to help better understand mechanisms underlying alcohol's disruption of perinatal development.

Preconception interventions to reduce the risk of alcohol-exposed pregnancies: A systematic review.

BACKGROUND: The preconception period provides a unique opportunity to optimize the health of women and children. High rates of alcohol use and unintended pregnancies are common across many Western societies, and alcohol-exposed pregnancies (AEPs) are a possible unintended outcome. The aim of the current study was to evaluate preconception interventions for the prevention of AEPs. METHODS: A systematic search of four electronic databases (PubMed, Embase, CINAHL, and PsycINFO) was undertaken for relevant peer-reviewed articles published from 1970 onward. Studies were included if they enrolled women and/or their support networks during the preconception period. RESULTS: Nineteen studies met the inclusion criteria. The majority of studies (n = 14) evaluated CHOICES-based interventions, which incorporate motivational interviewing approaches to change alcohol and/or contraceptive behavior. The other five interventions included a range of different approaches and modes of delivery. The majority of interventions were successful in reducing AEP risk. Changes in AEP risk were more often driven by changes in contraceptive behavior, although some approaches led to changes in both alcohol and contraceptive behavior. CONCLUSIONS: The review indicated that many interventions were efficacious at reducing AEP risk during the preconception period through preventing unplanned pregnancy. The effectiveness estimated from these clinical trials may be greater than that seen in interventions when implemented in practice where there is a lack of blinding and greater attrition of participants during follow-up. Further research investigating the real-world effectiveness of these intervention approaches implemented across a wide range of clinical settings would be beneficial.

The Prevalence of Fetal Alcohol Spectrum Disorders in An American Indian Community.

The prevalence of fetal alcohol spectrum disorders (FASD) differs among populations and is largely unknown among minority populations. Prevalence and characterization of FASD is necessary for prevention efforts and allocation of resources for treatment and support. However, prevalence data are lacking, including among many minority populations. The aim of this study was to obtain an FASD prevalence estimate in a Southern California American Indian community employing active case-ascertainment. In 2016, American Indian children aged 5-7 years and their caregivers were recruited in collaboration with Southern California Tribal Health Clinic. Children were assessed using physical examinations and neurobehavioral testing. Parent or guardian interviews assessed child behavior and prenatal exposures including alcohol. Of 488 children identified as eligible to participate, 119 families consented and 94 completed assessments to allow a classification for FASD. Participating children (n = 94) were an average of 6.61 ± 0.91 years old and half were female. Most interviews were conducted with biological mothers (85.1%). Less than one third (29.8%) of mothers reported consuming any alcohol in pregnancy and 19.1% met study criteria for risky alcohol exposure prior to pregnancy recognition. Overall 20 children met criteria for FASD, resulting in an estimated minimum prevalence of 41.0 per 1000 (4.1%). No cases of fetal alcohol syndrome (FAS) were identified; 14 (70.0%) met criteria for alcohol related neuro- developmental disorder (ARND). Minimum prevalence estimates found in this sample are consistent with those noted in the general population.

Tailoring an Alcohol Intervention for American Indian Alaska Native Women of Childbearing Age: Listening to the Community.

BACKGROUND: Reduction of risky drinking in women of childbearing age is 1 strategy that may be employed to prevent fetal alcohol spectrum disorder, a sequela of prenatal alcohol exposure. Communities differ in risk and protective factors, necessitating culturally informed interventions for maximal efficacy. This article describes the modification of an existing web-based screening, brief intervention, and referral to treatment intervention to reduce risky drinking among American Indian Alaska Native (AIAN) women of childbearing age in Southern California into a peer-to-peer-based intervention using motivational interviewing (MI). METHODS: The modification process was iterative and included various community focus groups, interviews, and a final review. RESULTS: Intervention modification was required for cultural congruence. Components of the peer-to-peer intervention designed by this project included a flip chart used to guide the motivational interviewing, charts of the financial and physical costs of alcohol consumption, revised baseline and follow-up questionnaires, and guidance regarding the application of MI techniques. CONCLUSIONS: This study may inform the modification of future interventions among AIAN communities.

Second-Trimester Ultrasound as a Tool for Early Detection of Fetal Alcohol Spectrum Disorders.

BACKGROUND: Early detection of fetal alcohol spectrum disorders (FASDs) is desirable to allow earlier and more comprehensive interventions to be initiated for the mother and infant. We examined prenatal ultrasound as an early method of detecting markers of the physical features and neurobehavioral deficits characteristic of FASD. METHODS: A longitudinal cohort of pregnant women in Ukraine was recruited as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Women were enrolled into a moderately to heavy-alcohol-exposed group or a low- or no-alcohol exposure group and were followed to pregnancy outcome. In the second trimester, a fetal ultrasound was performed to measure transverse cerebellar diameter, occipital frontal diameter (OFD), caval-calvarial distance, frontothalamic distance (FTD), interorbital distance (IOD), outer orbital diameter, and orbital diameter (OD). Live born infants received a dysmorphological examination and a neurobehavioral evaluation using the Bayley Scales of Infant Development. These data were used to classify infants with respect to FASD. Comparisons were made on the ultrasound measures between those with and without features of FASD, adjusting for gestational age at ultrasound and maternal smoking. RESULTS: A total of 233 mother/child dyads were included. Children classified as FASD had significantly longer IOD and lower FTD/IOD, OFD/IOD, and FTD/OD ratios (p < 0.05). Children with a Bayley score <85 had significantly shorter FTD, longer IOD, lower OFD/IOD, and FTD/IOD ratios (p < 0.05). In general, mean differences were small. Ultrasound variables alone predicted <10% of the variance in the FASD outcome. CONCLUSIONS: Some ultrasound measurements were associated with FASD, selected facial features of the disorder, and lower neurobehavioral scores. However, mean differences were relatively small, making it difficult to predict affected children based solely on these measures. It may be advantageous to combine these easily obtained ultrasound measures with other data to aid in identifying high risk for an FASD outcome.

Fetal alcohol-spectrum disorders: identifying at-risk mothers.

Fetal alcohol-spectrum disorders (FASDs) are a collection of physical and neurobehavioral disabilities caused by prenatal exposure to alcohol. To prevent or mitigate the costly effects of FASD, we must identify mothers at risk for having a child with FASD, so that we may reach them with interventions. Identifying mothers at risk is beneficial at all time points, whether prior to pregnancy, during pregnancy, or following the birth of the child. In this review, three approaches to identifying mothers at risk are explored: using characteristics of the mother and her pregnancy, using laboratory biomarkers, and using self-report assessment of alcohol-consumption risk. At present, all approaches have serious limitations. Research is needed to improve the sensitivity and specificity of biomarkers and screening instruments, and to link them to outcomes as opposed to exposure. Universal self-report screening of all women of childbearing potential should ideally be incorporated into routine obstetric and gynecologic care, followed by brief interventions, including education and personalized feedback for all who consume alcohol, and referral to treatment as indicated. Effective biomarkers or combinations of biomarkers may be used during pregnancy and at birth to determine maternal and fetal alcohol exposure. The combination of self-report and biomarker screening may help identify a greater proportion of women at risk for having a child with FASD, allowing them to access information and treatment, and empowering them to make decisions that benefit their children.

Effect of Depression on Risky Drinking and Response to a Screening, Brief Intervention, and Referral to Treatment Intervention.

We assessed alcohol consumption and depression in 234 American Indian/Alaska Native women (aged 18-45 years) in Southern California. Women were randomized to intervention or assessment alone and followed for 6 months (2011-2013). Depression was associated with risk factors for alcohol-exposed pregnancy (AEP). Both treatment groups reduced drinking (P < .001). Depressed, but not nondepressed, women reduced drinking in response to SBIRT above the reduction in response to assessment alone. Screening for depression may assist in allocating women to specific AEP prevention interventions.

Preventing alcohol-exposed pregnancy among an American Indian/Alaska Native population: effect of a screening, brief intervention, and referral to treatment intervention.

BACKGROUND: Fetal alcohol spectrum disorders are the result of alcohol-exposed pregnancies (AEP) and believed to be the leading known cause of developmental disabilities in the United States. Our objective was to determine whether a culturally targeted Screening, Brief Intervention, and Referral to Treatment (SBIRT) intervention may reduce risky drinking and vulnerability to AEP among American Indian/Alaska Native (AIAN) women in Southern California. METHODS: Southern California AIAN women of childbearing age who completed a survey including questions regarding alcohol consumption and contraceptive use were randomized into intervention or treatment as usual groups where the former group completed an online SBIRT intervention, and were followed up at 1, 3, and 6 months postintervention. RESULTS: Of 263 women recruited and 247 with follow-up data, one-third were at high risk of having an AEP at baseline. Both treatment groups decreased self-reported risky drinking behavior (drinks per week, p < 0.001; frequency of heavy episodic [binge] drinking episodes per 2 weeks, p = 0.017 and risk of AEP p < 0.001 at 6 months postintervention) in the follow-up period. There was no difference between treatment groups. Baseline factors associated with decreased risk of an AEP at follow-up included the perception that other women in their peer group consumed a greater number of drinks per week, having reported a greater number of binge episodes in the past 2 weeks, and depression/impaired functionality. CONCLUSIONS: Participation in assessment alone may have been sufficient to encourage behavioral change even without the web-based SBIRT intervention. Randomization to the SBIRT did not result in a significantly different change in risky drinking behaviors. The importance of perception of other women's drinking and one's own depression/functionality may have implications for future interventions.

A review of evidence-based approaches for reduction of alcohol consumption in Native women who are pregnant or of reproductive age.

BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are the leading preventable cause of developmental disabilities in the United States and likely throughout the world. FASDs can be prevented by avoiding alcohol use during pregnancy; however, efforts to prevent risky alcohol consumption in women of childbearing potential have not been universally successful. OBJECTIVES: Data suggest that successful interventions may require tailoring methods to meet the needs of specific populations and cultures. Key findings of interventions previously tested among American Indian and Alaskan Native (AI/AN) women who are or may become pregnant, data gaps, and promising ongoing interventions are reviewed. METHODS: A systematic review of the current literature on empirically based interventions among AI/AN women was conducted. Selected alternative approaches currently being tested in AI/AN settings are also described. RESULTS: Similar to findings among other populations of women in the United States, a number of interventions have been implemented; however, only a small number have measured results. Approaches have included standard interventions involving hospitalization, inpatient, or outpatient care; wellness education; traditional approaches; and case management for high-risk women. An ongoing Screening, Brief Intervention, and Referral to Treatment (SBIRT) protocol comparing the effectiveness of a web-based culturally adapted tool, or a peer health educator model to standard clinical practice is described. CONCLUSION: Translation of successful interventions from other settings to AI/AN populations holds promise. SCIENTIFIC SIGNIFICANCE: FASDs represent a significant health issue with high personal and societal costs. Improvement of interventions to prevent prenatal alcohol consumption in specific populations, including AI/AN women, is a critical public health need.

Indian Student Involvement in Tribal Community-Based Research: Underage Drinking Prevention among Rural Native Californians.

The critical need for increased numbers of American Indian/Alaska Native scientists and health professionals motivated the development of the California Native American Research Center for Health (CA-NARCH) initiative. One strategy of the initiative has been to encourage opportunities for applied research experiences for American Indian/Alaska Native students. Placement of CA-NARCH students in funded research assistant positions for a research project "Preventing Underage Drinking by Southwest California Indians: Building Capacity" based at the Southern California Tribal Health Clinic, Inc., in a rural part of Southern California, provides a model in which both American Indian//Alaska Native students and research investigators have benefitted. Six students received training in research ethics, data collection methods and data management and analysis. The students' participation in project activities has resulted in positive experiences for themselves, a productive research staff for the project and positive responses from community members to this sensitive research project.

Delivery of high levels of anti-proliferative nucleoside triphosphates to CYP3A-expressing cells as a potential treatment for hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is a life-threatening condition with only one drug treatment regimen approved for use. Oncolytic nucleosides are minimally effective against HCC putatively because of their inability to achieve cytotoxic levels of the active metabolite [nucleoside triphosphate (NTP)] in tumor cells at doses that are well tolerated. The aim of our studies was to explore the utility of CYP3A-activated prodrugs of cytarabine and fludarabine monophosphate for the treatment of HCC. METHODS: Prodrugs of cytarabine and fludarabine monophosphates were evaluated for their ability to safely achieve NTP levels in the liver of normal mice that are cytotoxic to hepatoma cells. RESULTS: While therapeutic levels of NTPs are achieved in the livers of normal rodents after administration of the prodrugs, only MB07133 achieved these levels without exhibiting signs of liver toxicity or myelosuppression. CONCLUSIONS: As the levels of araCTP achieved in the liver at therapeutic doses are only toxic to proliferating cells (such as those in HCC tumors), but not the non-proliferative adjacent tissue, MB07133 treatment has the potential to be both efficacious and well tolerated in HCC patients.

Liver-targeted drug delivery using HepDirect prodrugs.

Targeting drugs to specific organs, tissues, or cells is an attractive strategy for enhancing drug efficacy and reducing side effects. Drug carriers such as antibodies, natural and manmade polymers, and labeled liposomes are capable of targeting drugs to blood vessels of individual tissues but often fail to deliver drugs to extravascular sites. An alternative strategy is to use low molecular weight prodrugs that distribute throughout the body but cleave intracellularly to the active drug by an organ-specific enzyme. Here we show that a series of phosphate and phosphonate prodrugs, called HepDirect prodrugs, results in liver-targeted drug delivery following a cytochrome P450-catalyzed oxidative cleavage reaction inside hepatocytes. Liver targeting was demonstrated in rodents for MB06866 [(2R,4S)-9-[2-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxyethyl]adenine (remofovir)], a Hep-Direct prodrug of the nucleotide analog adefovir (PMEA), and MB07133 [(2R,4S)-4-amino-1-[5-O-[2-oxo-4-(4-pyridyl)-1,3,2-dioxaphosphorinan-2-yl]-beta-d-arabinofuranosyl]-2(1H)-pyrimidinone], a HepDirect prodrug of cytarabine (araC) 5'-monophosphate. Liver targeting led to higher levels of the biologically active form of PMEA and araC in the liver and to lower levels in the most toxicologically sensitive organs. Liver targeting also confined production of the prodrug byproduct, an aryl vinyl ketone, to hepatocytes. Glutathione within the hepatocytes rapidly reacted with the byproduct to form a glutathione conjugate. No byproduct-related toxicity was observed in hepatocytes or animals treated with HepDirect prodrugs. A 5-day safety study in mice demonstrated the toxicological benefits of liver targeting. These findings suggest that HepDirect prodrugs represent a potential strategy for targeting drugs to the liver and achieving more effective therapies against chronic liver diseases such as hepatitis B, hepatitis C, and hepatocellular carcinoma.

Modulation of cardiac remodeling by adenosine: in vitro and in vivo effects.

The increasing incidence of congestive heart failure has stimulated efforts to develop pharmacologic strategies to prevent or reverse the associated process of adverse cardiac remodeling. The possibility of utilizing endogenously generated factors that are capable of inhibiting this process is beginning to be explored. Adenosine, has been described as a retaliatory autacoid with homeostatic activities in the regulation of myocardial blood flow, catecholamine release, and reduction of injury resulting from periods of ischemia. Adenosine exerts a variety of actions that are consistent with the concept that it can reduce or inhibit the process of cardiac remodeling. In this manuscript, the basics of adenosine metabolism, its cell surface receptors and beneficial actions on the cardiovascular system are reviewed. In addition new, in vitro and in vivo data will be presented supporting the concept that adenosine exerts actions that may ameliorate adverse cardiac remodeling.