Main findings
This is the first study showing that shortening of maternal TL per
standard deviation decrease is associated with an almost 30% increased
risk of VSD in offspring that attenuated to 25% after adjustment for
maternal age (adjOR 1.25 (95% CI 1.01-1.55), p= 0.04). Moreover, we
demonstrated a significant association between shorter maternal TL and
the non-syndromal VSD group (crude OR 1.29 (95% CI 1.02-1.66), p=0.04),
where after adjustment the association remained, but lost significance.
Strengths and limitationsOne of the main methodological strengths of this study is the use of the
standardized samples taken approximately 1 year after the periconception
period of the index pregnancy, which minimizes recall bias. Moreover, we
prevented misclassification of cases and controls, given that most CODs
are diagnosed during the first year of life. Another strength is the
detailed description of the neural crest-related COD phenotypes and the
ethnic homogeneity of case and control families. Another strength is the
stratification in syndromes. As COD as part of a syndrome is more likely
to be due to chromosomal abnormalities. A limitation of our study could
be the measurement of TL in blood, which may not be representative for
TL in the maternal oocytes or embryonic cardiac cells. However, it has
been shown that leukocyte TL is highly correlated with TL of other
somatic tissues from the same individual such as muscle, fat, skin and
synovial tissue. This indicates that a clear intra-individual
synchronization in TL exists in adults,(19) suggesting blood cell TL to
be a valid measurement. Mean TL is measured, while cell senescence seems
to be related to the shortest TL per cell.(20)
A limitation of our study is that there are more typical COD types such
as arterial trunk and double outlet right ventricle. The representation
of these group were low in our study population and we were most
interested in the VSD group as this was our largestgroup ofthe HAVEN
study and most common phenotype of COD.
Interpretation
Our data support our hypothesis of using TL as biomarker for multiple
exposures of oxidative stress and inflammation to assess the risk of COD
offspring in the future. However, maternal age is the strongest
determinant in this association. Thereby, the intricacy of TL translates
in a high inter-individual variability, when comparing same-aged
people.(21). This may be an explanation for the non-significant
association found between TL and the risk of COD in general. Therefore,
in future studies larger sample sizes are needed.
Previous studies in mice showed that, embryonic mice deficient in the
telomerase gene show shorter TL and failure of closure of the neural
tube as the main defect, suggesting that this developmental process is
sensitive to telomere loss and chromosomal instability.(13, 22) These
results support our findings, considering the similar risk factors
neural tube defects and COD share.
A hypothetical role of TL in neural tube defects (NTD) and COD is
illustrated by the epidemiological and biological evidence of the
association between hyperhomocysteinemia and increased risk of NTD and
COD in offspring. (6, 13, 23). Hyperhomocysteinemia is a sensitive
biomarker of oxidative stress and as such may reduce the synthesis or
increase the damage of DNA, including the telomeres. The underlying
mechanism could be impairment of the programming due to global or gene
specific hypomethylation of telomerase. (24) In our study homocysteine
was comparable between the groups, however homocysteine levels tended to
be higher in cases. In our study population no correlation between
homocysteine and TL was found. Thereby, adjusting for homocysteine
concentrations had no significant influence on the association between
TL and the risk of COD and or VSD offspring.
Entringer et all. proposed that the effect of suboptimal intrauterine
conditions on initial setting of TL and telomerase activity, is mediated
by the programming actions of stress-related maternal-placental-foetal
oxidative and metabolic pathways, in a way that accelerate cellular
dysfunction, ageing and disease over the lifespan.(25) Embryogenesis in
early pregnancy is sensitive to excessive oxidative stressors in the
environment, resulting in structural and functional changes in cells,
tissues and organ systems. Changes in TL of cells in the foetal heart
may also play a role in normal cardiac development during embryogenesis
and supports the association between TL and increased risk of VSD
offspring.(26)
The process of foetal programming of telomeres may reflect an effect
shown across generations, that influences the health and well-being of
not only individuals but also their offspring. Thereby, mother-offspring
correlation in TL appears to be stronger than the father-offspring
correlation, regardless of the gender of offspring.(27, 28) These
finding emphasize the importance of efforts for early prediction and
prevention.
Other associations between TL and obstetric outcomes have also been
reported. Telomerase activity is decreased or absent in placentas of
foetal growth restricted newborns.(29) In this way, foetal growth
restriction is a common occurrence during COD pregnancies.(30)