Results
General characteristics, lifestyle, biomarkers as folate, homocysteine
and vitamin concentrations and foetal outcomes, of case mothers and
control mothers were summarized in Table 1 . The interval after
index pregnancy, BMI, maternal COD incidence, ethnicity, use of alcohol,
smoking and folic acid supplement use were comparable between both
groups. Case mothers had a significantly higher age (p=0.009) with a
mean age of 31,8 years in case mothers and 30,9 years in control
mothers. A positive family history for COD was more common in case
mothers. A significant difference was found in education level between
cases and controls, where a low and high education level was more common
in the case mothers. Homocysteine and folate concentrations were
comparable between the groups. Birth weight of offspring was
significantly lower in the group of case mothers compared to control
mothers. Preterm birth was significantly more common in case mothers.
The COD phenotypes of case children (n = 306) comprised aortic valve
stenosis (n = 7), atrioventricular septal defect (n = 29),
perimembranous ventricular septal defect (n = 84), pulmonary valve
stenosis (n=42), coarctation of the aorta (n = 33), hypoplastic left
heart syndrome (n = 12), transposition of the great arteries (n = 50),
tetralogy of Fallot (n = 38) and others (n = 11). Two hundred thirty
four of the 306 cases were defined as isolated COD cases. Seventy three
cases were non-isolated and had another major structural congenital
anomaly besides COD. Forty two of the 72 non-isolated cases had a
genetic syndrome, i.e. trisomy (n = 27), deletion 22q11 (n=5), Noonan
syndrome (n=4), Beckwith-Wiedemann syndrome (n=1), CHARGE syndrome
(n=1), Saethre-Chotzen syndrome (n=1), Alagille syndrome (n=1),
Kartagener syndrome (n=1) and Turner syndrome (n=1). The distribution of
maternal TL (T/S ratio) among the controls, COD cases and VSD cases were
depicted in Figure 2. Maternal age revealed a significantly
inverse correlation with TL (R = -0.13; p=<0.001).
There was no correlation between the homocysteine concentrations in
plasma and TL (R = 0.037; p=0.32) (Figure S1 ). A
positive family history for COD was not significantly associated with
TL. A multivariable logistic model was used to determine the independent
association of maternal TL with COD risk in offspring (Table
2A ). Model 1 and model 2 showed no significant associations between
shorter maternal TL, per decrease in standard deviation of TL, and the
risk of COD offspring (crude OR 1.10 (95%CI 0.95-1.27), p= 0.22). Model
1: adjOR 1.07 (95%CI 0.92-1.24), p=0.37 and Model 2: adjOR 1.07 (95%CI
0.92-1.24), p=0,40. The syndromal and non-syndromal COD group showed
also a comparable non-significant association, crude OR 1.15 (95%CI
0.84-1.58), p=0.36 and crude OR 1.09 (95%CI 0.93-1.27), p=0.28,
respectively.
In addition, we analysed the association between TL and VSD (n = 113),
and demonstrated that a shorter maternal TL is associated with a
significantly increased risk of VSD in their offspring (crude OR 1.29
(95% CI 1.04-1.61), p=0.02, per standard deviation TL decrease). In
Model 1 the association remained significant (adjOR 1.25 (95% CI
1.01-1.55), p=0.04)(Table 2B ). In Model 2 the association
slightly attenuated (adjOR 1.24 (95% CI 1.00-1.55). After
stratification, the syndromal VSD group showed no association between
shorter maternal TL and the risk of VSD in offspring (crude OR 1.28
(95% CI 0.88-1.89), p=0.20). Whereas, the non-syndromal VSD group
showed a significant association between shorter maternal TL and the
risk of VSD in offspring (crude OR 1.29 (95% CI 1.02-1.66), p=0.04). In
model 1 and model 2 this association remained, albeit not significant
(adjOR 1.26 (95% CI 0.99-1.62), p= 0.06 and adjOR 1.28 (95% CI 1.00
-1.64), respectively)(Table 2B ).
Adjustment of the associations for homocysteine concentrations did not
substantially affect the association between TL and the risk of COD and
VSD offspring.