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USDTL Research

Overcoming Obstacles in Identifying Prenatal Alcohol Exposure

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Originally published in NeoTox, Winter/Spring 2016.
Determining the prevalence of maternal alcohol consumption is difficult, but studies show the future of prenatal alcohol screening is promising.

by Stefan Maxwell, MB.,BS., FAAP

Infants whose mothers consume alcohol during pregnancy can have a range of neurobehavioral and developmental disabilities that are collectively referred to as fetal alcohol spectrum disorders (FASD).  The extent of damage is dependent on the duration and magnitude of alcohol exposure and developmental timing.1,2 The most severe cases from chronic exposure to high levels of alcohol are diagnosed with fetal alcohol syndrome (FAS), a disorder defined by growth deficiencies and specific facial and nervous system malformations.  

Determining the prevalence of FASD in populations is challenging, as identifying children affected by prenatal alcohol exposure is a difficult task that results in under diagnosis of FASD. Historically, prevalence rates of FAS and FASD have utilized surveillance systems, medical and other records, or special referral clinics and have likely underestimated the actual prevalence rates.3,4 The Centers for Disease Control and Prevention (CDC) has estimated that FAS occurs at a rate of 0.2 to 1.5 per 1000 children5,6 and the Institute of Medicine (IOM) estimates 0.5 to 3 infants with FAS per 1000 children.7 More current estimates in the United States range from 0.2 to 7 infants with FAS per 1000 children and up to 2% to 5% of school age children with an extended diagnosis of FASD.8,9  

There are several barriers to the early recognition and accurate diagnosis of children and adolescents with FASD. There is frequently a lack of clear physical findings in children affected by alcohol exposure, confusing language and diagnostic terminologies applied to these children, and the stigmata associated with alcohol use in pregnancy, which leads to inaccurate history-taking in prenatal visits. In a recent study by Chasnoff et al. (2015) a comprehensive evaluation was completed on 547 children that had been referred to their children’s mental health clinic to assess the rate of missed diagnoses and misdiagnosis of FASD. They found that among the children that met criteria for a diagnosis of FASD, 80.1% had a missed diagnosis for FASD and a misdiagnosis within the spectrum of FASD in 6.4% of the children.10 In that study, attention deficit/hyperactivity disorder (ADHD) was the most common referral diagnosis for children who were ultimately diagnosed with FASD. 

One important factor leading to misdiagnosis and missed diagnoses of FAS and FASD is that there is no medical test available to document alcohol exposure during pregnancy. A majority of infants exposed to alcohol during pregnancy have no clear physical features of FAS at birth, and consequently are not diagnosed with FASD until much later in childhood. The availability of a reliable marker to ascertain alcohol exposure in early postnatal life could assist in the diagnosis of these children much sooner. These children could then be targeted for early intervention and developmental assessments much earlier in life, particularly helping children from birth to 3 years of age take advantage of early neuroplasticity and reduce the long-term adverse effects of fetal alcohol exposure.

Confirmation of exposure to alcohol during pregnancy has typically relied on maternal history documentation, including approved screening instruments (AUDIT-C, T-ACE, 4 Ps Plus, TWEAK, TQDH), or detection of ethanol or ethanol metabolites in urine, hair, or nails. These methods can be unreliable if pregnant women do not give an accurate drinking history due to recall bias or fear of stigmatization and embarrassment, and urine testing can only detect alcohol consumption for up to 36 hours. In the infant, there are also biological markers of alcohol exposure that can be detected in urine, meconium, umbilical cord tissue or more recently, from the heel stick blood spot that is collected from every newborn for routine genetic screening tests. 

A new assay that has become available recently is for detecting Phosphatidylethanol (PEth) in dried blood spot cards. PEth can form in red blood cells as a component of the cellular membrane only when ethanol is present, and is therefore a direct alcohol biomarker. This assay is a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the extraction and detection of PEth from dried blood spots on filter paper.11 Detection of PEth can indicate alcohol consumption for up to a 3-week period after moderate to heavy drinking. There are a growing number of published studies that suggest screening newborn dried blood cards for detection of PEth could also be a feasible and effective method to detect prenatal alcohol exposure. Studies have demonstrated that the dried blood cards that are used to collect newborn blood samples for genomic screening can stabilize PEth at room temperature for six to nine months and even longer when stored at lower temperatures.12,13,14 Ongoing studies by Bakhireva et al. (2014) have demonstrated that PEth screening of newborn dried blood cards is a feasible and highly specific method for detecting prenatal alcohol exposure and is also more sensitive than other currently used newborn alcohol biomarkers.15 Further research studies by USDTL and outside research groups that have partnered with USDTL to utilize PEth screening are aiming to establish the evidentiary utility of PEth as a biological screening test for prenatal alcohol exposure and the predictive ability of PEth to determine level of risk for the development of disabilities related to FASD.  

  1. Spagnolo A. Teratogenesis of alcohol. Annali dell’Istituto superiore di sanita. 1993;29(1):89-96. Epub 1993/01/01. PubMed PMID: 8129276
  2. May PA, Blankenship J, Marais AS, Gossage JP, Kalberg WO, Joubert B, et al. Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): Quantity, frequency, and timing of drinking. Drug and alcohol dependence. 2013. Epub 2013/08/13. doi: 10.1016/j.drugalcdep.2013.07.013. PubMed PMID: 23932841.
  3. Jones KL, Smith DW Recognition of the fetal alcohol syndrome in early infancy. Lancet. 1973, 302(7836): 999-1001.
  4. May PA, Baete A, Russo J et al. Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics. 2014, 134 (5) 855-866.
  5. Centers for Disease Control and Prevention (CDC) Surveillance for fetal alcohol syndrome using multiple sources—Atlanta GA, 1981-1989. MMWR Morb Mortal Wkly Rep. 1997;46(47):1118-1120.
  6. Centers for Disease Control and Prevention (CDC) Update trends in fetal alcohol syndrome—United States, 1979-1993. MMWR Morb Mortal Wkly Rep. 1995; 44(13): 249-251.
  7. Stratton KR, Howe CJ, et al. Fetal Alcohol Syndrome Diagnosis, Epidemiology, Prevention and Treatment. Washington DC National Academy Press. 1996.
  8. May PA, Gossage JP, et al. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev. Disabil Res Rev. 2009;15(3):176-192.
  9. Sampson PD, Streissguth AP, et al. Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology. 1997;56(5):317-326.
  10. Chasnoff IJ, Wells AM, King L. Misdiagnosis and Missed diagnoses in Foster and Adopted Children with Prenatal Alcohol Exposure. Pediatrics. 2015;135(2):264-270.
  11. Jones JJ, M.;  Plate, C.;  Lewis, D. The detection of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol in human dried blood spots. Analytical Methods. 2011;3(5):1101-6.
  12. Faller A, Richter B, Kluge M, Koenig P, Seitz HK, Skopp G. Stability of phosphatidylethanol species in spiked and authentic whole blood and matching dried blood spots. Int J Legal Med. 2012.
  13. Bakhireva LN, Shrestha S, Gutierrez HL, Berry M, Schmitt C, Sarangarm D. Stability of Phosphatidylethanol in Dry Blood Spot Cards. Alcohol. 2015. Epub 2015/11/01. doi: 10.1093/alcalc/agv120. PubMed PMID: 26519350
  14. Baldwin AE, Plate C , Shu I, Jones J, Lewis D.  Retrospective Assessment of Prenatal Alcohol Exposure by Detection of Phosphatidylethanol in Stored Dried Blood Spot Cards; an Objective Method for Determining Prevalence Rates of Alcohol Consumption During Pregnancy. International Journal of Alcohol and Drug Research. 2015, 4(2), 131-137.
  15. Bakhireva LN, Leeman L, Savich RD, Cano S, Gutierrez H, Savage DD, et al. The validity of phosphatidylethanol in dried blood spots of newborns for the identification of prenatal alcohol exposure. Alcohol Clin Exp Res. 2014;38(4):1078-85. Epub 2014/02/12. doi: 10.1111/acer.12349. PubMed PMID: 24511895.

Dr. Stefan Maxwell has served the mothers and babies at CAMC Women and Children’s Hospital in Charleston, West Virginia, as Chief of Pediatrics and Medical Director of the NICU for over 25 years. He is a founding member of PEDIATRIX Medical Group and has served on the West Virginia Perinatal Partnership Central Advisory Council since 2006, providing leadership as Chair of the Central Advisory Council since 2013 and as Chair of the Committee on Substance Use During Pregnancy for over 9 years. In addition, Stefan is a Clinical Associate Professor of Pediatrics at West Virginia University School of Medicine.

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