Direct biomarkers to determine alcohol consumption during pregnancy, which one to use?

Abstract

BackgroundAlcohol consumption during pregnancy, even probably social alcohol consumption, can lead to (severe) fetal damage, such as fetal alcohol syndrome (FAS) or fetal alcohol spectrum disorder (FASD). In order to diagnose a child with FAS or FASD, maternal alcohol consumption during pregnancy needs to be proven. This makes the diagnosis of FAS and FASD a difficult one since self-reported questionnaires underreport the use of alcohol and are therefore biased [1]. Further, research regarding the harmful effects of alcohol during pregnancy is mostly performed with such questionnaires, so results of this kind of research is doubtful. Implementation of a reliable objective marker for alcohol detection would therefore be invaluable. Alcohol markers can be divided into two categories: direct and indirect biomarkers. Indirect biomarkers such as liver enzymes and carbohydrate deficient transferrin, are neither specific nor sensitive enough to be used for detection of alcohol consumption during pregnancy (beyond the scope of this article). Direct biomarkers are chemically derived from ethanol and are way more reliable to detect alcohol consumption during pregnancy. Three biomarkers can be used to detect alcohol in pregnant women: Fatty Acid Ethyl Esters (FAEE), ethyl glucuronide (EtG) / ethyl sulfate (EtS) and phosphatidylethanol (PEth) [2]. Fatty Acid Ethyl Esters (FAEE)FAEE are produced by an enzymatic esterification of ethanol with free endogenous fatty acids, triglycerides, lipoproteins and phospholipids by means of two enzymes, FAEE synthase and acyl-CoA/ethanol O-acyl-transferase (AEAT). The FAEE group has more than 20 different compounds including ethyl laurate (E12), ethyl myristate (E14), ethyl palmitate (E16), ethyl palmitoleate (E16:1), ethyl stearate (E18), ethyl oleate (E18:1), ethyl linoleate (E18:3), ethyl arachidonate (E20:4) and ethyl docosahexanoate (E22:6). All have a lipophilic character. In addition, they are stable at neutral pH. FAEE do not cross the placenta into the fetal circulation, and because they can be detected in fetal matrices, must be produced in the fetus itself from the ethanol which crosses the placenta [2]. FAEE can be measured in blood for 24-44 hours, so it is still, such as ethanol in blood and breathing air, only a snapshot of the alcohol exposition to a child. For chronic exposition hair or meconium can be used. Newborn's hair will cover the last 16 weeks of pregnancy and meconium the last 20-24 weeks of pregnancy, the latter also having a greater ease of collection. Meconium comprises the neonates first several bowel movements, identified most commonly by its dark green-black color and lack of odor. Meconium formation begins at approximately 12 weeks of gestation (i.e. at the end of the first trimester), when fetal swallowing of amniotic fluid is initiated [2]. FAEE can be quantified in meconium by means of gas chromatography coupled with either flame ionization or mass spectrometry (GC-MS). MS allows measurement of lower levels, which makes MS in favor of FID when quantifyi...

Prevalence of alcohol use in late pregnancy

“…However, no post-collection synthesis of PETH occurs in the DBS samples, 22 , 27 and false-positive results are not possible without alcohol use; thus, it can be argued that any concentration above the LOD indicates alcohol use in late pregnancy. 12 , 29 As there is no consensus on what the “ideal” cutoff is for newborns and no reports have identified false-positive PETH results without alcohol consumption, this study used a cutoff of ≥8 ng/ml (0.288 μmol/l) to identify any alcohol exposure 2–4 weeks prior to data collection. 30 …”

Screening for hazardous alcohol use in the Emergency Department: Comparison of phosphatidylethanol with the Alcohol Use Disorders Identification Test and the Timeline Follow‐back

“…It is therefore expected that higher reported intake results in higher PEth values (Viel et al, 2012 ). The lower correlation between the 24‐h TLFB and PEth values can be explained by the fact that PEth is a marker that measures alcohol use over a longer period of time and alcohol intake could have taken place more than 24 h prior to presentation to the ED (Schröck et al, 2017 ; Wassenaar & Koch, 2015 ).…”

“…An important difference with other (indirect) markers is that PEth did not seem to be influenced by patient characteristics such as age, gender, and co‐morbidity (Viel et al, 2012 ). The half‐life is 4–5 days and PEth could be detected up to two or more weeks, which is an advantage compared to, for example, the urinary metabolite ethyl glucuronide (EtG) which reflects alcohol consumption during the last 72 h (Schröck et al, 2017 ; van de Luitgaarden et al, 2019 ; Wassenaar & Koch, 2015 ).…”

“…More than 40 different homologues are discovered. The homologues 16:0/18:1 (PEth 16:0/18:1) and 16:0/18:2 (PEth 16:0/18:2) are the most abundant homologues in human blood (Hahn, Anton, & Javors, 2016 ; Schröck et al, 2017 ; Simon, 2018 ; Wassenaar & Koch, 2015 ). It is suggested to use both these measures to investigate alcohol use (Hill‐Kapturczak et al, 2018 ).…”

Quantitation of phosphatidylethanols in dried blood spots to determine rates of prenatal alcohol exposure in Ontario

“…Fatty acid ethyl esters (FAEEs) form when EtOH conjugates to fatty acids and cannot cross the placenta; therefore, FAEEs detected in the neonate are exclusively from fetal EtOH exposure. FAEEs accumulate in meconium and are an indicator of PAE in the last 20-24 weeks of gestation making it an excellent marker for PAE in the second and third trimesters (Lange et al, 2014;Wassenaar & Koch, 2015).…”