Fetal alcohol spectrum disorder in twin pregnancies

Motherisk Int J 2020;1:18

 

Gideon Koren MD, FRCPC, FACMT and Rana Cohen BSc Pharm, MBA

Adelson School of Medicine, Ariel University and Motherisk Israel Program

 

Question:

If a heavily drinking mother has twins, are both affected by FASD?

Answer: Not necessarily. Studies in humans and experiments in laboratory animals reveal full concordance in FASD occurrence between monozygotic twins, but only partial concordance between dizygotic twins. This highlights both genetic sources of variability, as well as the role of the placenta in processing ethanol, as dizygotic twins do not share the same placenta in most cases.

 

Excessive alcohol exposure is the cause of fetal alcohol spectrum disorder (FASD), inflicting up to 1-5% American children in some areas (1). At present, mediators of susceptibility to alcohol-related fetal toxicity are relatively unknown. The placenta is naturally a source of variability to be considered when it comes to the fetal environment. Meconium is a matrix unique to the developing fetus and our previous work has shown that accumulation of fatty acid ethyl esters (FAEE), a group of non - oxidative metabolites of ethanol, is a potent biomarker of fetal exposure to maternal drinking (2). In large epidemiological studies we and other have shown that meconium FAEE levels above a cut-off of 2nmol/L have high sensitivity and specificity for heavy maternal drinking (3-4).

Animal experiments: In a study of guinea pig littermates, after the dams received chronically 4g/kg/d ethanol, FAEE concentrations differed substantially within and among litters.  For example: Litter 1 had mean FAEE concentration of 0.996 nmol/L, Litter 2=5.17 nmol/L, Litter 3= 5.16, Litter 4= 18.57 and litter 5 = 0.00 nmoL/L (5). Hence identical maternal ethanol exposure produced substantially differing levels of fetal exposure.

Human fetal variability: A meconium sample was collected from a pair of dizygotic twins suspected of heavy maternal drinking. The twins yielded very different levels of FAEE: In the girl we measured a positive meconium level (>2.00 nmol /L) at 2.21 nmol /L. In contrast, her male twin brother had no measurable levels of meconium FAEE(5).

In our FASD diagnostic clinic we have recently encountered a pair of dizygotic twins exposed in utero to heavy maternal drinking. The female twin exhibited pathognomonic facia changes associated with FASD ( flat philtrum and a thin upper lip) but relatively mild behavioral changes. In contrast, her twin brother did not exhibit facial changes, but suffered from much more severe adverse cognitive and behavioral effects.

In 2019, Astley Hemingway and colleagues in Seattle reported on a large cohort of twins derived from their Fetal Alcohol Syndrome Diagnosis and Prevention Network clinical database (6). They had 9 monozygotic and 39 dizygotic pairs of twins, 27 full sibling and 9 half sibling pairs. The prevalence of pairwise discordance in FASD diagnosis was 0% for the monozygotic twins, 44% for the dizygotic, 59% for the full- sibling and 78% for the half sibling pairs. Despite virtually identical level of exposure to maternal alcohol, 4 pairs of dizygotic twins had FASD diagnosis at opposite ends of the fetal alcohol spectrum.  Astley Hemingway et al concluded, similar to our FAEE study shown above, that despite virtually identical alcohol exposure levels, twin fetuses may be affected very differently.

These data indicate that the placenta may have an important role in mediating ethanol- induced fetal injury.

References:

  1. May PA, Chambers CD, Kalberg WO et al. Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities. JAMA. 2018;319(5):474-48
  2. Koren G, Cohen R. Meconium Fatty Acid Ethyl Esters (FAEE);A Biomarker for Quantifying Fetal Alcohol Exposure. Motherisk Int J 2020;1:2
  3. Delano K, Koren G, Zack M et al. Prevalence of Fetal Alcohol Exposure by Analysis of Meconium Fatty Acid Ethyl Esters; A National Canadian Study.  Sci Rep. 2019; 9: 2298. doi: 10.1038/s41598-019-38856-5
  4. Lange S, Shield K, Koren G et al. A comparison of the prevalence of prenatal alcohol exposure obtained via maternal self-reports versus meconium testing: a systematic literature review and meta-analysis. BMC Pregnancy and Childbirth 2014;14: 127
  5. Gareri J, Brien J, Reynolds J et al. Potential role of the placenta in fetal alcohol spectrum disorder. Ped Drugs 2990; 11: 26-29
  6. Astley Hemingway SJ, Bledsoe JM, Davies JK et al. Twin study confirms virtually identical prenatal alcohol exposures can lead to markedly different fetal alcohol spectrum disorder outcomes-fetal genetics influences fetal vulnerability. Adv Pediatr Res2019;5:23