Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

2019-08-19
PloS one 14(8)
- Barbara Troesch
- Johann Demmelmair
- Martina Gimpfl
- Christina Hecht
- Goran Lakovic
- Robert Roehle
- Ljilja Sipka
- Branka Trisic
- Milica Vusurovic
- Rotraut Schoop
- Sznezana Zdjelar
- Berthold Koletzko

PubMed: 31425504
DOI: 10.1371/journal.pone.0216790

Study Design

Type: Randomized Controlled Trial (RCT)
Sample size: n = 120
Population: Healthy term infants (n=120 intervention, n=120 control, plus a reference group of breastfed infants)
Methods: Randomized, double-blind, parallel, controlled trial; formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 μg/100 ml) or folic acid (10.0 μg/100 ml)
Blinding: Double-blind
Funding: Unclear

Large Human Trial

L-5-methyltetrahydrofolate is the predominant folate form in human milk but is currently not approved as a folate source for infant and follow-on formula. We aimed to assess the suitability of L-5-methyltetrahydrofolate as a folate source for infants. Growth and tolerance in healthy term infants fed formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 μg/ 100 ml, n = 120, intervention group) or folic acid (10.0 μg/ 100 ml, n = 120, control group) was assessed in a randomized, double-blind, parallel, controlled trial. A reference group of breastfed infants was followed. Both formulae were well accepted without differences in tolerance or occurrence of adverse events. The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection. Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d). In line with this, there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g). Equivalence was also shown for gain in head circumference but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters. Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001) and higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095). We conclude that L-5-methyltetrahydrofolate is suitable for use in infant and follow-on formula, and there are no indications of untoward effects. Trial registration: This trial was registered at ClinicalTrials.gov (NCT02437721).

Research Insights

L-Methylfolate→Improved Body Weight Gain
there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g).
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
L-Methylfolate→Improved Head Circumference Gain
Equivalence was also shown for gain in head circumference
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
L-Methylfolate→Improved Recumbent Length Gain
Equivalence was also shown for gain in head circumference but not for recumbent length gain [...] adjusted means at visit 4 were not significantly different
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
L-Methylfolate→Increased Body Weight Gain
Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d).
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
L-Methylfolate→Increased Caloric Intake in Females
but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters.
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Increased Head Circumference
Equivalence was also shown for gain in head circumference
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Increased Recumbent Length
but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters.
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Increased Red Cell Folate Level
higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095)
Effect
Beneficial
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Increased Weight Gain
Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d).
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Reduced Body Weight
there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g).
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml
L-Methylfolate→Reduced Unmetabolized Folic Acid Level
Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001)
Effect
Beneficial
Effect size
Small
Dose
10.4 μg/100 ml
Vitamin B9→Improved Body Weight Gain
there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g).
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
Vitamin B9→Improved Head Circumference Gain
Equivalence was also shown for gain in head circumference
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
Vitamin B9→Improved Recumbent Length Gain
Equivalence was also shown for gain in head circumference but not for recumbent length gain [...] adjusted means at visit 4 were not significantly different
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
Vitamin B9→Increased Body Weight Gain
Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d).
Effect
Neutral
Effect size
Small
Dose
10.0 μg/100 ml
Vitamin B9→Increased Caloric Intake in Females
but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters.
Effect
Neutral
Effect size
Small
Dose
10.4 μg/100 ml

Adverse Events Reported

L-Methylfolate→red cell folate (level)
and higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095)
Finding
No significant difference
Magnitude
intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095
Significant
Yes
L-Methylfolate→unmetabolized folic acid (plasma level)
Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001)
Finding
No significant difference
Magnitude
intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001
Significant
Yes
L-Methylfolate→Overall tolerability
Both formulae were well accepted without differences in tolerance or occurrence of adverse events.
Finding
Reported
Vitamin B9→Overall tolerability
Both formulae were well accepted without differences in tolerance or occurrence of adverse events.
Finding
Reported
Vitamin B9→common cold
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→common cold
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→dry skin
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
Vitamin B9→dry skin
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
Vitamin B9→eczema
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→eczema
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
Vitamin B9→poor weight gain or growth
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→poor weight gain or growth
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
Vitamin B9→rash
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→rash
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
L-Methylfolate→respiratory tract infection
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported
Vitamin B9→respiratory tract infection
The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection.
Finding
Reported