Study Reveals Link Between Maternal Folate Levels and Increased Risk of Congenital Heart Disease in Offspring

"The findings indicate that, alongside preventing folate deficiency, it is crucial to recognize the potentially harmful effects of excess folate on the risk of congenital heart disease in offspring," the researchers wrote.

Maternal serum folate levels during pregnancy are crucial for fetal development. However, the association of folate supplementation with CHD prevention is controversial. In this context, Yanji Qu, Southern Medical University, Guangzhou, Guangdong, China, and colleagues investigate the relationship between maternal serum folate levels during early to mid-pregnancy and the risk of congenital heart disease in offspring.

For this purpose, the researchers conducted a case-control study at one of China’s largest cardiac referral centers between 2015 and 2018. They recruited participants by matching congenital heart disease (CHD) cases with non-CHD controls based on maternal age at a ratio of 1:4. Data analysis took place from May to August 2023.

Around 16 weeks of gestation, maternal serum levels of folate, vitamin B12, and homocysteine were measured. The primary outcome was CHD, confirmed through echocardiography. The study measured the relationship between maternal folate levels and the risk of CHD in offspring using adjusted odds ratios (aORs) in conditional logistic regression analyses. Additionally, the researchers assessed interactions between folate, vitamin B12, and homocysteine regarding CHD risk on a multiplicative scale.

Based on the study, the researchers reported the following findings:

• The study included 129 cases of congenital heart disease (CHD), with ventricular septal defect being the most common type, and 516 matched controls. The average maternal age during pregnancy was 31.6 years.
• There was a U-shaped relationship between maternal serum folate levels during early to mid-pregnancy and CHD risk in offspring.
• Compared to children whose mothers had folate levels in the second and third quartiles, those in the lowest quartile had significantly higher odds of CHD (aOR, 3.09), as did those in the highest quartile (OR, 1.81).
• The odds ratios increased when applying the World Health Organization criteria for normal serum folate levels.
• Interaction analyses indicated that the negative effects of low and high maternal folate on CHD risk might be worsened by vitamin B12 deficiency or elevated homocysteine levels.

The study found that low maternal serum folate levels during early to mid-pregnancy are linked to a higher risk of congenital heart disease in offspring. Interestingly, it also suggested that very high folate levels could increase this risk. Furthermore, these associations may be influenced by vitamin B12 and homocysteine levels, although the exact mechanisms remain to be explored. These findings highlight the importance of a tailored folic acid supplementation strategy for pregnant women.

"Further research is necessary to establish causal links for the observed associations and to clarify the underlying mechanisms," the researchers concluded.

Reference:

Qu Y, Liu X, Lin S, et al. Maternal Serum Folate During Pregnancy and Congenital Heart Disease in Offspring. JAMA Netw Open. 2024;7(10):e2438747. doi:10.1001/jamanetworkopen.2024.38747