March 1, 2024

Research team discovers genetic cause of low birth weight among children conceived after fertility treatment

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Low birth weight individuals conceived spontaneously and ART exposed to Vitrolife culture medium have a higher incidence of non-synonymous and rRNA variants. The, B Prevalence of haplogroups and subhaplogroups, respectively, among SC and ART individuals exposed to Vitrolife culture medium, categorized according to birth weight percentile. Two-sided Fisher’s exact test, no significant differences were found after Bonferroni correction (P values ​​≤ 0.007 were considered significant). w Percentage of SC and ART individuals exposed to Vitrolife culture medium carrying homoplasmic variants in different regions and categorized according to birth weight percentile. Homoplasmies in the tRNA regions were found more frequently in children with birth weight p = 0.006 (P values ​​≤ 0.00625 were considered significant)). d Number of SC and ART individuals exposed to Vitrolife culture medium, stratified by birth weight percentile below or above P10 or P25, carrying non-synonymous variants at protein coding or rRNA loci. Children born with birth weight p = 0.015). It is Number of SC and ART individuals exposed to Vitrolife culture medium, stratified by birth weight percentile below or above P10 or P25, carrying non-synonymous protein coding and/or rRNA loci variants. 52.9% of P10: 31.3%, two-sided Fisher’s exact test, P= 0.106, >P25: 28.6%, Fisher’s exact test, **P = 0.002). f Sum of loads of SC and ART individuals exposed to Vitrolife culture medium below or above P10 and P25 containing non-synonymous protein coding and rRNA variants. p = 0.077 and **P = 0.003, respectively). n < P10 = 17 individuals, n> P10 = 265 individuals, n < P25 = 48 individuals, n> P25 = 234 individuals. The horizontal bars in the panels represent the average of the values ​​in the scatterplot, each point represents a sample. # meaningful P -value after Bonferroni correction, +P< 0.2, included in backward conditional binary logistic regression. Credit: Nature Communications(2024). DOI: 10.1038/s41467-024-45446-1

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Low birth weight individuals conceived spontaneously and ART exposed to Vitrolife culture medium have a higher incidence of non-synonymous and rRNA variants. The, B Prevalence of haplogroups and subhaplogroups, respectively, among SC and ART individuals exposed to Vitrolife culture medium, categorized according to birth weight percentile. Two-sided Fisher’s exact test, no significant differences were found after Bonferroni correction (Pvalues ​​≤ 0.007 were considered significant). w Percentage of SC and ART individuals exposed to Vitrolife culture medium carrying homoplasmic variants in different regions and categorized according to birth weight percentile. Homoplasmies in the tRNA regions were found more frequently in children with birth weight p = 0.006 (Pvalues ​​≤ 0.00625 were considered significant)). d Number of SC and ART individuals exposed to Vitrolife culture medium, stratified by birth weight percentile below or above P10 or P25, carrying non-synonymous variants at protein coding or rRNA loci. Children born with birth weight p = 0.015). It is Number of SC and ART individuals exposed to Vitrolife culture medium, stratified by birth weight percentile below or above P10 or P25, carrying non-synonymous protein coding and/or rRNA loci variants. 52.9% of P10: 31.3%, two-sided Fisher’s exact test, P= 0.106, >P25: 28.6%, Fisher’s exact test, **P= 0.002). f Sum of loads of SC and ART individuals exposed to Vitrolife culture medium below or above P10 and P25 containing non-synonymous protein coding and rRNA variants. p = 0.077 and **P= 0.003, respectively). n< P10 = 17 individuals, n> P10 = 265 individuals, n< P25 = 48 individuals, n> P25 = 234 individuals. The horizontal bars in the panels represent the average of the values ​​in the scatterplot, each point represents a sample. # meaningful P-value after Bonferroni correction, +P< 0.2, included in backward conditional binary logistic regression. Credit: Nature Communications(2024). DOI: 10.1038/s41467-024-45446-1

VUB professor Claudia Spits from the Reproduction and Genetics research group at Vrije Universiteit Brussel has identified a genetic cause for the increased risk of low birth weight in babies born after assisted reproductive technologies such as in vitro fertilization.

“Previous studies have identified treatment-related causes of low birth weight, but this is the first time we have been able to identify an underlying genetic factor,” says Professor Spits. She organized a large-scale study with the Brussels IVF (center for reproductive medicine at UZ Brussel), the center for medical genetics (CMG) at UZ Brussels and the Maastricht University Medical Center (UMC).

The article is published in Nature Communications.

Initially, she studied the DNA of babies born from spontaneous pregnancies and after fertility treatment. She found that in both groups, a higher risk of low birth weight was associated with certain mutations in mitochondrial DNA, and that these mutations were slightly more common in children born after fertility treatment.

Mitochondria are the “energy factories” of the cell that are inherited from the mother. If they don’t work properly, as they develop, they can cause a variety of health problems, such as cardiovascular disease and diabetes.

To determine whether these mutations are passed from mother to child, the researchers also studied the mothers’ DNA. The analysis showed that children born after fertility treatment have more new, untransmitted mutations than babies conceived without assistance.

As a final step, the group studied oocytes obtained through hormonal stimulation and the natural cycle to determine whether hormonal stimulation was harmful. The mitochondrial mutations did not necessarily appear to be caused by hormonal stimulation. “In particular, a combination of age-related factors in conjunction with hormonal stimulation may lead to an increased risk of abnormal oocytes,” says Spits.

“The risk of mutations in oocyte mitochondrial DNA increases with age. During a normal cycle, mechanisms exist to remove mutated oocytes and select only healthy cells. However, with hormonal stimulation to increase oocyte production, this mechanism is turned off and the mutated oocytes are released.”

Spits’ team will conduct additional studies, but these insights can be immediately implemented into assisted reproductive technology (ART) treatments to limit the risk of oocytes with mutagenic mitochondria.

“It seems that the greater the number of oocytes obtained after hormonal stimulation, the greater the chance of mutations. In the future, we can pay more attention to achieving an appropriate balance between adequate oocyte production and minimizing the risk of mutations,” Spits concludes.

More information:
Joke Mertens et al, Children born after assisted reproduction most commonly carry a mitochondrial genotype associated with low birth weight, Nature Communications(2024). DOI: 10.1038/s41467-024-45446-1

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