Differences in maternally inherited and age-related de novo mitochondrial DNA variants between ART and spontaneously conceived individuals associate with low birth weight

BackgroundChildren born using assisted reproductive technologies (ART) have an increased risk of a lower birth weight, the cause of which remains unclear. As a causative factor, we hypothesized that variants in the mitochondrial DNA (mtDNA) that are not associated with disease, may explain changes in birth weight. MethodsWe deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or cycles with ovarian stimulation (OS). The mtDNA genotypes were compared across groups and logistic regression and discriminant analysis were used to study the impact of the different factors on birth weight percentile. ResultsART individuals more frequently carried variants with higher heteroplasmic loads in protein and rRNA-coding regions. These differences in the mitochondrial genome were also predictive of the risk of a lower birth weight percentile, irrespective of the mode of conception but with a sex-dependent culture medium effect. The higher incidence of these variants in ART individuals results both from maternal transmission and de novo mutagenesis, which we found not to be caused by OS but to be associated to maternal ageing. ConclusionsMtDNA variants in protein and rRNA coding regions are associated with a lower birth weight and are more frequently observed in ART children. We propose that these non-disease associated variants can result in a suboptimal mitochondrial function that impacts birth weight. Future research will establish the long-term health consequences of these changes and how these findings will impact the clinical practice and patient counselling in the future.