Abstract
Most persons with fetal alcohol spectrum disorders (FASDs) remain undiagnosed or are diagnosed in later life. To address the need for earlier diagnosis, we previously assessed miRNAs in the blood plasma of pregnant women who were classified as unexposed to alcohol (UE), heavily exposed with affected infants (HEa), or heavily exposed with apparently unaffected infants (HEua). We reported that maternal miRNAs predicted FASD-related growth and psychomotor deficits in infants. Here, we assessed whether fetal sex influenced alterations in maternal circulating miRNAs following prenatal alcohol exposure (PAE). To overcome the loss of statistical power due to disaggregating maternal samples by fetal sex, we adapted a strategy of iterative bootstrap resampling with replacement to assess the stability of statistical parameter estimates. Bootstrap estimates of parametric and effect size tests identified male and female fetal sex-associated maternal miRNA responses to PAE that were not observed in the aggregated sample. Additionally, we observed, in HEa mothers of female, but not male fetuses, a network of co-secreted miRNAs whose expression was linked to miRNAs encoded on the X-chromosome. Interestingly, the number of significant miRNA correlations for the HEua group mothers with female fetuses was intermediate between HEa and UE mothers at mid-pregnancy, but more similar to UE mothers by the end of pregnancy. Collectively, these data show that fetal sex predicts maternal circulating miRNA adaptations, a critical consideration when adopting maternal miRNAs as diagnostic biomarkers. Moreover, a maternal co-secretion network, predominantly in pregnancies with female fetuses, emerged as an index of risk for adverse birth outcomes due to PAE.
Highlights
In a prospective cohort of pregnant women in Ukraine [5], we identified maternal miRNAs that could be used to classify heavy alcohol-exposed pregnancies that resulted in the birth of infants with neurodevelopmental and growth deficits (HEa) as distinct from unexposed pregnancies (UE) or heavy alcohol-exposed pregnancies where the infants were apparently unaffected at birth (HEua)
We employed a statistical strategy of iterative bootstrap resampling with replacement [11] to simulate characteristics of the population of Prenatal alcohol exposure (PAE)-exposed pregnancies disaggregated by fetal sex
To identify maternal miRNAs that likely show a fetal sex-dependent response to PAE, we identified the miRNAs which were classified as significant (ANOVA, p < 0.05) in more than 50% of the resampling iterations following bootstrap analyses
Summary
In a recent state-wide study in Texas, we found that 8.4% of assessed newborn infants were positive for a blood alcohol metabolite, indicative of at least 3rd trimester PAE [3]. Fetal alcohol spectrum disorders (FASDs), a cluster of physical and neurobehavioral anomalies that can result from PAE [52], are common [35]. In the USA, a recent prospective case ascertainment study showed that between 1.1 and 9% of school-aged children met the diagnostic criteria for FASD [41]. The inadequacy of diagnosis results in missed opportunities for early intervention to minimize the effects of PAE and, increases the risk for secondary scholastic and other disabilities [45]
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