Folic Acid, Neural Tube Defects, and Congenital Coronary heart Defects


Neural tube defects (NTDs) are among the many most typical main malformations in the USA. Each day folic acid supplementation within the periconceptional interval considerably reduces the danger of neural tube defects.  Nevertheless, most girls don’t obtain the advisable every day consumption of folate from weight loss program alone; thus, it is suggested that every one girls of childbearing age ought to take supplemental folic acid.

Since half of all pregnancies within the US are unplanned, the US Preventive Companies TAsk Power recommends that every one girls who’re able to getting pregnant ought to take a every day complement or multivitamin containing 0.Four to 0.Eight mg (400 to 800 mcg) of folic acid.  When it comes to stopping neural tube defects, the important interval for supplementation begins no less than 1 month earlier than conception and continues by means of the primary 2 to three months of being pregnant.

Folic Acid and Congenital Coronary heart Defects

Whereas the preliminary impetus to fortify grains with folic acid and to suggest folic acid supplementation throughout being pregnant was pushed by a want to decrease danger for neural tube defects, there’s growing proof to point that periconceptual use of folic acid could produce other advantages.

For instance, periconceptual use of folic acid has been proven to lower danger for congenital coronary heart defects (CHDs).  There’s appreciable variation within the magnitude of the impact throughout research, with some research suggesting a higher than 50% discount in danger (Obeid et al, 2019); nevertheless, a current meta-analysis estimated that periconceptual folate supplementation was related to an roughly 20% discount in danger of CHDs (Cheng et al, 2022).  Much like what has been noticed for NTDs, the discount in danger is most evident when folic acid supplementation is initiated earlier than conception.

 RBC Folate Ranges Predict Threat for Neural Tube Defects

The focus of folate in crimson blood cells (RBC) is regarded as a extra correct measurement of folate standing than serum folate ranges.  Whereas RBC folate ranges do fluctuate in keeping with weight loss program and folate supplementation, RBC folate ranges are a greater indicator of tissue shops of folate over the earlier Three to Four months and will due to this fact be much less vulnerable to day-to-day adjustments in folate consumption than serum folate ranges.

Solely two research have examined the affiliation between maternal RBC folate concentrations throughout being pregnant and danger for NTD danger.  Each research noticed that greater RBC folate concentrations in early being pregnant have been related to a decrease NTD danger.  Whereas there is no such thing as a established cut-off worth for RBC folate concentrations, Crider and colleagues noticed that with a RBC folate focus of 500 nmol/L the estimated danger of a neural tube defect was 25.4 (20.Eight to 31.2) per 10,000, whereas at a RBC folate focus of 1200 nmol/L, the estimated danger was greater than fourfold decrease at 5.8 (4.6 to 7.1) per 10,000.

This examine concluded {that a} RBC folate focus of roughly 1000-1300 nmol/L would possibly obtain optimum prevention of folate delicate neural tube defects, with an estimated 87.9% discount within the danger for NTD.

The World Health Organization (WHO) recommends that ed blood cell folate concentrations ought to be above 400 ng/ml (or 906 nmol/L) in girls of reproductive age to attain the best discount of NTDs.  Present suggestions indicatie supplementation with 400 mcg to 800 mcg of folate; nevertheless, we usually we don’t assess serum or RBC folate ranges proximate to the time of conception to substantiate enough supplementation.

Extra Folic Acid Could Be Required to Cut back Threat for CHDs    

Proof for the prevention of CHDs utilizing prenatal folate supplementation shouldn’t be as robust as that noticed for the prevention of NTDs.  One doable clarification is {that a} greater dose of folic acid could also be required to scale back danger of CHDs than for NTDs.   A current examine from China seemed susceptible to congenital coronary heart defects and folate standing, utilizing RBC folate concentrations as a extra correct measurement of folate standing (Chen et al, 2022).  

On this nested case management examine, 197 moms with offspring with a CHD have been in comparison with 788 individually matched moms of unaffected offspring from the SPCC (Shanghai Preconception Cohort).  Maternal RBC folate was measured earlier than or throughout the early levels of being pregnant. 

Moms who had a toddler with a congenital coronary heart defect had decrease maternal RBC folate concentrations than the controls (moms of youngsters with out CHD).  Imply maternal folate ranges have been 714 nmol/L [interquartile range, 482 to 1008 nmol/L] within the circumstances versus 788 nmol/L [557 to 1094 nmol/L]) within the unaffected controls. 

Maternal RBC folate concentrations have been inversely related to danger for offspring CHD. The adjusted odds ratio (OR) for moms with periconception RBC folate concentrations of 906 nmol/L or extra (vs. <906 nmol/L) was 0.61. Moreover, every 100-nmol improve in maternal RBC folate focus was related to an additional discount in offspring danger for CHD.

Ought to We Measure RBC Folate Ranges Previous to Conception?

That is the primary examine to have a look at RBC folate concentrations and danger of congenital coronary heart defects. The discovering that greater periconceptual folate ranges are related to decreased danger of CHDs is per earlier research analyzing danger of neural tube defects the place RBC folate ranges of 906 nmol/L or extra have been related to an 87.9% discount within the inhabitants danger for NTD (0.Eight vs. 6.6 circumstances per 1000). 

The present examine discovered a 51.3% discount within the estimated inhabitants danger for CHD when girls attained RBC folate ranges between 906 and 1132 nmol/L (vs. <226 nmol/L: 6.6 vs. 13.5 per 1000 births), with a further 4.7% discount in danger with RBC ranges of 1360 nmol/L or extra. The impact of RBC folate ranges appeared to flatten out at greater ranges, suggesting an approximate threshold with regard to offspring CHD danger. This discovering is per RBC folate concentrations and danger for NTDs, the place RBC folate ranges above 1300 to 1500 nmol/L offered little extra profit.

Increasing on the proof base for suggestions and pointers about main prevention of beginning defects, the authors suggest that greater goal RBC folate ranges than at present advisable is likely to be advisable for periconception girls to attain the impact of main CHD prevention. Nevertheless, they word that earlier than any adjustments to observe pointers may be applied, we should have a greater understanding of the adversarial results of extreme folate ranges or unabsorbed or unmetabolized folic acid on the mom and the creating fetus.  

Regardless of the unequivocal advantages of folic acid supplementation and proposals urging all girls of reproductive age to take folic acid dietary supplements, preconceptual use of folic acid has not elevated considerably.  The authors word that in a earlier cross-sectional examine in Chinese language girls, solely 42.6% of ladies took the advisable 400 mcg of folic acid every day earlier than being pregnant.  On this examine, imply RBC folate ranges have been suboptimal in 90.1% of ladies planning for being pregnant.  In the USA, Tinker and colleagues noticed that  22.8% of reproductive aged girls had suboptimal RBC folate concentrations. 

As a part of preconception counseling, the American College of Obstetricians and Gynecologists recommends that clinicians talk about weight loss program and the significance of folic acid supplementation previous to being pregnant.  On the first prenatal go to, blood testing features a full blood cell depend and screening for rubella immunity, hepatitis B, syphilis and HIV.

In our space of New England, many pregnant girls will obtain blood exams for thyroid illness and vitamin D ranges.  Screening for thyroid illness is advisable in high-risk sufferers; nevertheless, universal screening shouldn’t be normal of care.  Whereas research point out that vitamin D supplementation may decrease risk for some adverse outcomes in pregnancy, checking vitamin D ranges shouldn’t be universally advisable.

Whereas the above findings could counsel that it will even be helpful to measure RBC folate focus and this might result in decreased danger for NTDs and coronary heart defects, it might be troublesome to institute routine screening of folate standing.  Extra particularly, the primary prenatal go to usually happens between 6 and 12 weeks of gestation.  At this level, the neural tube and coronary heart have already fashioned, and supplementing with folic acid at this level wouldn’t have any impression on the danger of malformation.

Ruta Nonacs, MD PhD


Chen H, Zhang Y, Wang D, Chen X, Li M, Huang X, Jiang Y, Dou Y, Wang Y, Ma X, Sheng W, Jia B, Yan W, Huang G; SPCC (Shanghai Preconception Cohort) Group. Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease : Nested Case-Control and Mendelian Randomization Studies. Ann Intern Med. 2022 Aug 23. 

Cheng Z, Gu R, Lian Z, Gu HF. Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis. Nutr J. 2022 Mar 26;21(1):20. 

Obeid R, Holzgreve W, Pietrzik Okay. Folate supplementation for prevention of congenital heart defects and low birth weight: an update. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S424-S433. 

Tinker SC, Hamner HC, Qi YP, et al. 2015. U.S. girls of childbearing age who’re at doable elevated danger of a neural tube defect-affected being pregnant as a result of suboptimal crimson blood cell folate concentrations, Nationwide Well being and Diet Examination Survey 2007 to 2012. Beginning Defects Res. A Clin. Mol. Teratol. 103: 517–526.

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