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Alcohol use in Pregnancy ? Under the Radar

Alcohol use in Pregnancy ? Under the Radar. Stefan R Maxwell MD FAAP Director NICU CAMC Women & Children’s Hospital PEDIATRIX MEDICAL GROUP. Disclosures. I am not discussing any commercial products or services I have no financial interests herein

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Alcohol use in Pregnancy ? Under the Radar

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  1. Alcohol use in Pregnancy? Under the Radar Stefan R Maxwell MDFAAP Director NICU CAMC Women & Children’s Hospital PEDIATRIX MEDICAL GROUP

  2. Disclosures I am not discussing any commercial products or services I have no financial interests herein I am in compliance with HIPAA in this presentation

  3. Objectives Fetal alcohol syndrome pFAS, ARND, ARBDs, ND-PAE, FASD Current methods of identification Misdiagnosis and Missed Diagnosis New research, Prevalence in WV Future directions??

  4. Discovery of Fetal Alcohol Syndrome 1968 Paul Lemoine in Nantes, France recognized alcohol effects on the fetus, but was ignored by peers (127 children in 69 families) 1973 David Smith and Kenneth Jonesworking at Univ. of Washington in the area of Dysmorphology became curious….. March of Dimes increased awareness of birth defects caused by teratogens Working together they realized alcoholic mothers had children with developmental delays, microcephaly and growth deficiency Described the Fetal Alcohol Syndrome

  5. Historical evidence of effects of alcohol on developing fetus • Olegaard et al in Sweden: 1/300 babies born with effects of alcohol, 50% with FAS • 10-20% of mental deficiency (IQ 50-80) • 17% of cases of Cerebral Palsy • Studies in Seattle and Northern France show incidence >1/1000

  6. Effects of alcohol on Fetus We now know that ALCOHOL freely crosses the placenta and is a TERATOGEN, causing --brain damage cerebellum, hippocampus, basal ganglia, corpus callosum --fetal alcohol syndrome facial features, SGA, behavioral and cognitive problems

  7. Fetal Effects Increased cellular peroxidase activity Decreased DNA synthesis Disruption of protein synthesis Impaired amino acid transport across placenta Chronic fetal hypoxia from induced hypoglycemia

  8. Effects of Alcohol

  9. DEFINITIONS • FAS : Growth impairment, facial dysmorphology • neurodevelopmental deficits & exposure • pFAS: Exposure, facial features and • neurodevelopmental deficits, but normal growth • ARBD: Exposure, normal growth and neurodevelopmental • functions but major dysmorphology • ARND: Exposure, normal facies and growth • but neurodevelopmental deficits • ND-PAE (will replace ARND) DSM 5th Ed.

  10. Fetal alcohol syndrome Growth restricted Average IQ 63 Motor deficits Tremulousness, irritability, hyperactive Microcephaly,short palpebral fissures, long philtrum, thin upper lip, joint anomalies, small 5th fingernail, VSD/ASD

  11. Fetal Alcohol syndrome There is a narrow window of exposure, so that very few infants have “classic” Fetal Alcohol syndrome Most have “ Alcohol related neurodevelopmental disorder” Other effects are: Esotropia (lazy eye) : frequent ear infections : partial or complete hearing loss : average IQ FAS is 63 ARND with low IQ leads to issues with behavioral regulation, impulsivity, social deficits, poor judgement, class disruption ARND with “normal” IQ has learning disabilities, poor school performance, poor “executive functioning” clumsiness, and poor balance

  12. Effects of Alcohol Fetal alcohol syndrome is most severe effect, but only a small proportion show the facies (1-3/1000) Alcohol related neurodevelopmental disorder (ARND) is much more prevalent (15-30/1000) --exposure early in gestation causes not only features of FAS, but brain anomalies --exposure later does not have gross structural damage, but kills nerve cells, inhibits synapses and myelin formation and biochemical processes Most common non-genetic cause of mental retardation

  13. Effects of alcohol on Brain Timing is important: First Trimester --low set ears, cleft palate and lip, etc due to heavy exposure early in pregnancy Midline structures such as LIMBIC SYSTEM affected --information from sensory inputs processed and sent to prefrontal cortex via Dopamine --damage to hippocampus causes poor memory --damage to corpus callosum causes “ODD” Oppositional defiant disorder

  14. Anomalies of corpus callosum Begins at 39th day after conception Adult morphology by 115th day Damage early in 1st trimester Partial or total agenesis Poor motor coordination Delayed milestones Cognitive disabilities Social difficulties

  15. Stages of brain development

  16. Effects of Alcohol on Brain Third trimester exposure prevents MIGRATION and MYELINATION which causes LISSENCEPHALY

  17. Effects of alcohol Severityof exposure Greater exposure causes worse effects --episodic binge drinking worse than same amounts consumed steadily Chronicityof exposure: --older mothers drinking for years cause higher risk for affected baby --maybe they have reduced ability to metabolize alcohol

  18. Prenatal alcohol exposure In animals.. -- some interventions shown to ameliorate effects --motor-training, physically and socially stimulating environment may improve outcomes (brain plasticity) -- better to protect from the insult than try to correct after the exposure

  19. The developing brain Animal studies: Rats reared in a complex environment had more synaptic connections, larger dendritic fields, more dendritic spines and more supportive glial tissue than those raised in barren cages. Both early and late exposure were effective, but the sooner the exposure, the better.

  20. Evaluating FASD using Zebrafish models

  21. Zebrafish research • Daniorerio is a tropical fish from Ganges river and a great model • Easily raised (hundreds of eggs/week) • External fertilization so can observe development • Have nearly all organs of humans (except lungs, prostate, mammary glands • Have 84% of genes known to cause human disease • Can be easily exposed to ethanol during development and can look at key features of the human syndrome FASD

  22. Zebrafish research in FASD • Exposing zebrafish embryos to ethanol can cause: • Increases in ubiquitinated proteins (mark proteins for degradation using the proteasome) • Upregulation of proteasome components • Specific inhibition of degradation of damaged or unnecessary proteins by the proteasome • May contribute to teratogenic effects this way

  23. Zebrafish research in FASD

  24. FASD research using Zebrafish • Can be used to model one of the alcohol-induced social deficits, which is a devastating symptom of FASD • Also work with cannabinoids has shown they are teratogenic early in pregnancy and can exacerbate the effects of alcohol • Studies show impairment of Sonic Hedgehog (Shh) signaling pathways and effects on craniofacial and brain development

  25. Human Brain Development Language Sensing Pathways (vision, hearing) Higher Cognitive Function Conception -6 -3 0 3 6 9 1 4 8 12 16 Months Years AGE

  26. Alcohol effects :Can we salvage the babies? Primary goal of US DHHS is prevention Central goal is to identify affected babies early and place in Early Intervention May ameliorate effects on language and emotional dysregulation May prevent academic, legal and psychiatric problems

  27. EARLY DIAGNOSIS IS IMPORTANT! • Children with primary FAS/PAE have secondary disabilities later which are potentially preventable • -- disrupted school experiences • -- mental health problems • -- inappropriate sexual behaviors • -- alcohol and drug abuse • -- incarceration and retention in the justice system • High prevalence of persistent psychiatric problems that persist into adulthood DIAGNOSIS BEFORE SIX YEARS OF AGE IS IDEAL

  28. Challenges of Diagnosis • Maternal history is unreliable due to social stigmas • Different screening tools used : • AUDIT, CAGE, TWEAK, T-ACE, MAST, TLFB • Need screeners that are adequately trained to use these • Urine screening is inaccurate and therefore unreliable • Lack of clear physical findings in babies or children • Surveys of pediatricians reveal they feel incompetent • in making the diagnosis. Usually diagnose as ADHD • PHARMACOLOGIC INTERVENTIONS ARE DISASTROUS

  29. Misdiagnosis and Missed Diagnosis Chasnoff et al. Pediatrics vol.35#2Feb2015 Sample of 547 children :comprehensive multi-disciplinary and diagnostic evaluation 156 kids met criteria within fetal alcohol spectrum: 125 never diagnosed! (80.1% missed diagnosis rate) 31 kids diagnosed as FAS..10 had diagnosis changed: (6.4% misdiagnosis rate) 21 kids remained with accurate diagnosis

  30. Misdiagnosis and Missed Diagnosis Chasnoff: In this clinical sample, 86.5% of youth with FASD had never been diagnosed or were misdiagnosed Clearly these high rates of inaccuracy have significant implications for intervention and therapeutic services.

  31. WV Umbilical CordStudy, 2009 Source: Stitley, Michael, MD, et.al. “Prevalence of Drug Use in Pregnant West Virginia Patients,” West Virginia Medical Journal, Voll. 106, No. 4, 2010.

  32. Results of Umbilical Cord Tissue Study, 2009

  33. Detection of alcohol rates in pregnancy Stitely ML. et al WV Med J 2010,106:48-52 --Cord study ( anonymous) 39/759 = 5.1% --Birth cert/WV Birth score: 13/1079=1.2% Detection rates at W&C Hosp, and WMC --Cord study (anonymous) : 11/133 = 8.3% --Birth cert/WV Birth score :2/283 =0.7% Urine screens (3/1/12-1/31/13): 6/545 =1.1%

  34. Detection of Prenatal Alcohol Exposure Biological Markers of Alcohol Exposure in the Newborn: Ethyl Glucuronide in Umbilical Cord Tissue Fatty Acid Ethyl Esters in Meconium Phosphatidylethanol in Blood

  35. Ethyl Glucuronide • Ethanol is metabolized in the liver to produce EtG only when ethanol is present • EtG has been detected in urine, blood, sweat, hair and fingernails in adults and in newborn meconium and umbilical cord

  36. Fatty Acid Ethyl Esters (FAEEs) Fatty acid ethyl esters (FAEEs) are nonoxidative metabolites that are formed when alcohol conjugates to free fatty acids and fatty acyl-CoA. FAEEs have been detected in the umbilical cord tissue, blood, hair, and meconium of newborns.

  37. Phosphatidylethanol (PEth) Phosphatidylethanols (PEth) are a group of phospholipids with a common phosphoethanol head group onto which 2 fatty acid chains are attached. Phosphoethanol head group Fatty acid chains

  38. PEth can form in red blood cells as a component of the cellular membrane. • PEth is a direct alcohol biomarker, meaning that ethanol is incorporated into the final product.

  39. When Ethanol is not Present Phosphatidylcholine (PC) PC Phospholipase D (H2O) Phosphatidic acid and choline

  40. When Ethanol is Present Phosphatidylcholine (PC) PC PEth Phospholipase D (Ethanol) Phosphatidylethanol (PEth) - Ethanol

  41. Detection of PEth in dried blood spots US Drug testing Lab developed and validated a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) system for the extraction and detection of PEth from dried blood spots. Filter paper cards lyse and fix red blood cells completely and prevent further PEth synthesis or the filter paper stabilizes PEth, minimizing sample degradation.

  42. Validity of using DBS for detection of PEth Baldwin et al (International Journal of Alcohol and Drug Research. 2015, 4(2), 131-137) “Detection of PEth from newborn DBS cards can identify PAE and be used for retrospective surveillance of alcohol consumption during the last 3-4 weeks of pregnancy. Storage of cards at room temperature for three months had a 96.3% initial concentration detectable after 30 days” Bakhireva et al (Alcohol ClinExp Res Vol 41, No 5 2017 pp1004-1011) Systematically estimated the prevalence of PAE in Texas by measuring PEth in 1000 infant residual dried blood spots from the Texas Newborn Screening Repository

  43. Study 1a: Compare alcohol use in pregnancy rates based on self-report methods and analysis of urine ethanol screening and detection of alcohol biomarkers. Maternal Biomarker Studies

  44. Results: Study 1a; maternal screening 314 patients screened for urine ethanol, self-report and PEth at the Charleston Area Medical Center

  45. Improving screening for alcohol consumption during pregnancy with phosphatidylethanol (Bracero et al) Reproductive Toxicology 74(2017) 104-107 • Compared rates of alcohol use between urine ethanol testing and self-reporting (Method 1) and PEth dried blood spot testing and self-reporting (Method 2) • Method 2 identified more alcohol users than Method 1. • Combining both methods resulted in a detection rate of 10.2% in the first trimester or at first antenatal visit

  46. Purpose of Study 1b To compare the ability of two alcohol biomarkers in identifying maternal alcohol consumption at the time of delivery. Umbilical cord tissue Ethyl Glucuronide (EtG) vs. Umbilical cord blood Phosphatidylethanol (PEth) To determine the early neonatal outcomes associated with 3rd trimester maternal alcohol consumption during pregnancy by comparing umbilical cord PEth + vs. PEth - pregnancies

  47. METHODS Observational study of infants born to women who received prenatal care at WMC during 1/2013-8/2014 We compared the detection rate of umbilical cord blood PEth to the currently used Cordstat EtOH test (Ethyl Glucuronide Etg)

  48. RESULTS

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