Homocysteine

​Homocysteine testing is an important marker for assessing methylation and cardiovascular health, particularly during pregnancy when elevated levels can signal nutrient deficiencies or increased risk of complications. This article examines the role of homocysteine testing in pregnancy, reference ranges, and the most common causes of elevated levels to guide better maternal and fetal health management.

Homocysteine Testing

 The Homocysteine test measures the amount of homocysteine in the bloodstream.

Homocysteine is a metabolic intermediate produced by the demethylation of methionine. Homocysteine is commonly found in the blood in three forms: free, bound to albumin, and in a complex with other homocysteine thiols. Homocysteine is then further metabolized in the body through two main pathways: remethylation, which converts homocysteine back to methionine, and transsulfuration, which converts homocysteine to cysteine.

There are two pathways of remethylation and one pathway of transsulfuration.

The remethylation of homocysteine to methionine on the folate side involves a series of enzymatic reactions that require the presence of folate (specifically, 5-methyltetrahydrofolate) and the cofactors riboflavin (vitamin B2) and cobalamin (vitamin B12). Folate is first converted to 5,10-methylenetetrahydrofolate through a reaction catalyzed by the enzyme dihydrofolate reductase (DHFR). Then 5,10 methylenetetrahydrofolate is converted to 5-methyltetrahydrofolate (5-methyl-THF) by the enzyme methylenetetrahydrofolate reductase (MTHFR), which requires riboflavin. This step involves the transfer of a methyl group.

The methyl group carried by 5-methyl-THF is transferred to homocysteine in a reaction catalyzed by the enzyme methionine synthase (also known as cobalamin-dependent methionine synthase). This transfer is facilitated by vitamin B12, which serves as a cofactor for methionine synthase.

​The choline betaine pathway, also known as the alternative or non-folate remethylation pathway, is another mechanism for remethylating homocysteine. In the liver, choline is oxidized to betaine in a reaction catalyzed by the enzyme choline oxidase. Betaine donates a methyl group to homocysteine in a reaction catalyzed by the enzyme betaine-homocysteine methyltransferase (BHMT).

The transsulfuration pathway involves the conversion of homocysteine to glutathione.

Hypohomocysteinemia is medically defined as a homocysteine <6.0μmol/L, while hyperhomocysteinemia is medically defined as a homocysteine >15 μmol/L in nonpregnant adults.

Homocysteine in Pregnancy

Homocysteine levels decrease in normal pregnancies. This drop is attributed to both hemodilution as well as increased use during pregnancy. Homocysteine levels decrease during early pregnancy, reaching the lowest point during the second trimester, and steadily increase during the later third trimester reaching early pregnancy levels.

High Homocysteine in Pregnancy

There is an association between elevated homocysteine levels and pregnancy complications such as early miscarriage, preeclampsia, IUGR, and placental abruption, as well as in certain cases of maternal and fetal mortality.

Preconception homocysteine levels >12.4 μ mol/L increase the prevalence of preterm labor by four times.

A 5 μ mol/L increased change in homocysteine concentration was associated with 63% increased odds of placental mediated complications.

Studies have found that higher homocysteine levels within six weeks postpartum are associated with postpartum depression, regardless of folate and vitamin B12 levels.

Although studies find increased complication risk with higher homocysteine levels, the ranges used in these studies are not consistent, and developing a range based on these studies is not accurate. Generally, studies find that levels >10 μmol/L are associated with increased risks of varying severity.

Most Common Causes of High Homocysteine in Pregnancy

• Nutritional Deficiencies (vitamin B9, vitamin B12, vitamin B2, vitamin B6, choline)
• Hypothyroidism
• Oxidative Stress
• Genetics 

Low Homocysteine in Pregnancy

There is little research on hypohomocysteinemia and none related to pregnancy.

In one study, 41% of patients with idiopathic peripheral neuropathy were found to have low homocysteine levels.18

Most Common Causes of Low Homocysteine in Pregnancy

• Inflammation/Oxidative Stress
• Low Protein Diet
• Overdose of methyl-folate

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Medical Disclaimer:
This content is for educational purposes only and is intended for licensed medical professionals. It is based on current research, subject to change, and not intended to diagnose, treat, or prevent any medical condition. This information does not replace consultation with a qualified healthcare provider. Seek professional medical evaluation and treatment from a licensed provider. Use of this information is at your own risk.​

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