A recent study reveals a U-shaped association between maternal serum folate levels during early to mid-pregnancy and the risk of congenital heart disease (CHD) in offspring. Both low and high folate levels have been linked to an increased risk of CHD, with deficiencies in vitamin B12 and elevated homocysteine levels exacerbating this risk.
Methodology
The research was conducted as a case-control study at the Guangdong Provincial People’s Hospital in China, involving 129 participants diagnosed with CHD and 516 matched control participants. Data was collected between 2015 and 2018, with maternal serum levels of folate, vitamin B12, and homocysteine measured at approximately 16 weeks of gestation using a chemiluminescence microparticle immunoassay.
The confirmation of CHD was achieved through echocardiography, and participants were matched by maternal age at a 1:4 ratio. The study accounted for several covariates, including:
Periconceptional folic acid supplementation
Maternal education and occupation
Parity and abortion history
Pregnancy complications
Genetic polymorphisms related to folate metabolism
Conditional logistic regression was utilized to assess the associations, adjusting for various covariates and conducting sensitivity analyses that excluded participants with missing genetic data.
Key Findings
The study demonstrated a significant U-shaped association between maternal serum folate levels and the risk of CHD in offspring (P < .001). Specific findings include:
Low maternal folate levels were associated with an adjusted odds ratio (aOR) of 3.09 (95% CI, 1.88-5.08) for the risk of CHD.
High maternal folate levels were linked to an aOR of 1.81 (95% CI, 1.07-3.06).
According to World Health Organization criteria, folate deficiency (defined as < 5.9 ng/mL) had an aOR of 18.97 (95% CI, 3.87-93.11).
Elevated folate levels (> 20 ng/mL) had an aOR of 5.71 (95% CI, 2.72-11.98) for CHD risk.
Additionally, the risk associated with both low and high maternal folate levels was further compounded by vitamin B12 deficiency and elevated homocysteine levels.
Clinical Implications
The authors noted that insufficient levels of folate and vitamin B12 could lead to increased homocysteine levels, which is detrimental to cardiovascular health. They proposed that homocysteine might serve as a central mediator in the relationship between deficiencies in folate and vitamin B12 and the risk of CHD. Moreover, they highlighted that folate plays a role beyond just mediating homocysteine levels, contributing independently to processes such as placental implantation and vascular remodeling.
Source
The study, led by Yanji Qu, PhD, and Jie Li, PhD, from the Global Health Research Center at Guangdong Provincial People’s Hospital, was published online on October 10 in JAMA Network Open.
Limitations
The study does have certain limitations:
Maternal serum folate levels were measured at a single time point, which may not accurately reflect levels during the preconception and early postconception periods.
The findings may not be generalizable to other populations, as participants were recruited from a single cardiac referral center in Southern China.
The absence of dietary intake data limited the capacity to account for related biases.
While the sample size is relatively large for CHD research, it may lack sufficient power for more nuanced stratified analyses.
Disclosures
Michael S. Bloom, PhD, disclosed receiving personal fees from the Guangdong Cardiovascular Institute unrelated to this work. Additional disclosures are available in the original article.
Conclusion
This study underscores the critical role of maternal serum folate levels during pregnancy in influencing the risk of congenital heart disease in offspring. Both low and high folate levels present significant risks, and the interplay between folate, vitamin B12, and homocysteine warrants further investigation to improve maternal and fetal health outcomes.
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