Low, high maternal folate levels tied to congenital heart disease risk in offspring

Key takeaways:

• Maternal folate levels that were too low or too high were associated with risk of congenital heart disease in offspring.
• Concurrent vitamin B12 deficiency or homocysteine elevation may exacerbate CHD risk.

Women with serum folate levels that were too low or too high during midpregnancy were more likely to have an infant born with congenital heart disease, with maternal vitamin B12 and homocysteine levels modulating risk, researchers reported.

“The study highlights a U-shaped association between maternal serum folate levels during early to midpregnancy and congenital heart disease risk in offspring,” Jie Li, MD, PhD, professor and deputy director of the Global Health Research Center at Guangdong Provincial People's Hospital, China, told Healio. “Both low and high folate levels were linked to an increased risk of CHD, indicating that while folate deficiency poses a risk, excessive levels may also have detrimental effects.”

For the case-control study, researchers analyzed maternal serum levels of folate, vitamin B12 and homocysteine from 129 women who delivered an infant with CHD (cases) and from 516 matched controls. Mean maternal age at pregnancy was 31 years; women self-reported folic acid supplementation during face-to-face interviews. Researchers collected serum samples at the first prenatal visit, which was around 16 weeks’ gestation. The primary outcome was CHD confirmed via echocardiography.

The findings were published in JAMA Network Open.

Within the cohort, 95% of women reported taking periconceptional folic acid supplements and there was no difference in supplementation rates between CHD cases and controls.

Researchers observed a U-shaped association between maternal serum folate levels at early to midpregnancy and CHD risk in offspring (overall P < .001; P for nonlinearity, < .001).

Compared with offspring in the second and third quartiles of maternal folate, those in the lowest quartile (aOR, 3.09; 95% CI, 1.88-5.08) and highest quartile (OR, 1.81; 95% CI, 1.07-3.06) had increased odds for developing CHD.

When compared using normal levels of folate as defined by WHO criteria (5.9-20 ng/mL), both folate deficiency (aOR = 18.97; 95% CI, 3.87-93.11) and elevated folate (aOR = 5.71; 95% CI, 2.71-11.98) were linked to elevated CHD risk in offspring, according to researchers.

Using interaction analyses, researchers observed L-shaped associations between maternal serum levels of vitamin B12 and CHD risk and the amino acid homocysteine and CHD risk, suggesting vitamin B12 deficiency or elevated homocysteine can magnify risk in the setting of low or high folate levels.

“Clinicians should carefully monitor and manage maternal folate levels during pregnancy, aiming for an optimal range,” Li told Healio. “This study underscores the importance of personalized supplementation strategies to avoid both folate deficiency and excess, which could prevent adverse pregnancy outcomes such as CHD.”

Researchers noted global recommendations advise women of childbearing age to take at least 0.4 mg of folic acid daily from 1 month before conception through at least 2 months after pregnancy. Meanwhile, about 60 countries have implemented effective mandatory fortification of folic acid in wheat flour, maize flour or rice.

Li said more research is needed on the interactions between folate, vitamin B12 and homocysteine levels to refine supplementation guidelines.

For more information:

Jie Li, MD, PhD, can be reached at lijie4863@gdph.org.cn.