Risk and protective factors in the origin of conotruncal defects of heart—a population‐based case–control study

Abstract

Congenital heart defect (CHD) cases have been evaluated together as a group in some previous epidemiological studies. However, different CHD entities have different etiologies, and the underlying causes are unclear in the vast majority of patients. Thus the aim of this study was to analyze the possible association of different maternal diseases with the risk of four types of conotruncal defects (CTD), that is, truncus arteriosus, d-transposition of the great arteries, tetralogy of Fallot, and double-outlet right ventricle based on autopsy or surgical report diagnosis. Acute and chronic diseases with related drug treatments and peri-conceptual folic acid or multivitamin supplementations were compared in mothers of 598 CTD cases, of 902 matched controls, and 38,151 population controls without any defects, and with 20,896 malformed controls with other isolated non-cardiac defects in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. Mothers who had medically recorded influenza and the common cold with secondary complications in the prenatal maternity logbook during the second and/or third gestational months were associated with a higher risk of CTD (OR with 95% CI: 2.22, 1.19-3.88). The common denominator of these maternal diseases may be high fever, which could be prevented by antifever therapies. On the other hand, high doses of medically recorded folic acid in early pregnancy were able to reduce the birth prevalence of CTD (OR with 95% CI: 0.54, 0.39-0.73), and this reduction was significant in transposition of the great arteries (0.46, 0.29-0.71) as well. In conclusion, high fever related maternal diseases may have a role in the origin of CTD, while high doses of folic acid in early pregnancy were able to reduce of CTD, particularly transposition of great vessels.

Periconceptional Folic Acid Supplementation and Infant Risk of Congenital Heart Defects inNorway 1999–2009

“…A possible protective effect of folic acid supplements on CHDs is, however, controversial. While some studies have reported reduced risk of CHDs in children whose mothers have taken multivitamins with folic acid or pure folic acid supplements, or after folic acid food fortification, other studies have reported no effect on CHDs of folic acid food fortification …”

“…10 A possible protective effect of folic acid supplements on CHDs is, however, controversial. While some studies have reported reduced risk of CHDs in children whose mothers have taken multivitamins with folic acid 11,12 or pure folic acid supplements, 13,14 or after folic acid food fortification, 6 other studies have reported no effect on CHDs of folic acid food fortification. 15,16 In the Medical Birth Registry of Norway, information on the use of folic acid and multivitamin supplements has been recorded for all women giving birth since 1999.…”

Cardiovascular Management in Pregnancy

“…42,43 All of these modifiable risk factors should be addressed with potential mothers before conception to minimize risk to the fetus.…”

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

“…During embryonic development, the abnormity of outflow tract (OFT) morphogenesis, stemming from altered migration and development of the arterial heart field and second heart field (AHF/SHF), is considered to be responsible to CTDs . The causes of sporadic CTD include multiple cardiac development gene variants, altered genetic buffering pathways, maternal disease, and environmental factors . The genetic basis of CHD, including CTDs, has been partially studied in former studies.…”

“…3,4 The causes of sporadic CTD include multiple cardiac development gene variants, altered genetic buffering pathways, maternal disease, and environmental factors. 5 The genetic basis of CHD, including CTDs, has been partially studied in former studies. CTDs exist among several syndromic diseases along with extracardiac symptoms and 22q11.2 deletion syndrome is a notable one.…”