Growth and tolerance of formula with lactoferrin in infants through one year of age: double-blind, randomized, controlled trial


A total of 480 participants were enrolled and randomized (Control: 155; LF-0.6: 165;
LF-1.0: 160). Participants who were randomized but consumed no study formula (Control:
1; LF-0.6: 1; LF-1.0: 2) were not included in subsequent analyses (Fig. 1). No differences in body weight, length, or head circumference were observed by gender
among groups at study enrollment (Table 2). Birth anthropometric measures as well as gender, race, and ethnic distribution,
history of breastfeeding, family history of allergy, and exposure to smoking in the
home were also similar among groups (data not shown). No group differences from 30
to 365 days of age in daycare enrollment and exposure to smoking in the home and/or
daycare were detected (data not shown). A total of 353 infants completed the study
(Control: 110; LF-0.6: 127; LF-1.0: 116).

Fig. 1. Flow of study participants

Table 2. Infant characteristics at study entry


Growth rates were analyzed from 14–365 days of age. As outlined in guidance provided
by the AAP Task Force on Clinical Testing of Infant Formulas, rate of weight gain
(g/day) is used as the most important parameter in clinical evaluation of infant formulas
with differences of 3 g/day over a 3–4 month period considered clinically significant
23]. Consequently, no statistically significant group differences by gender in the primary
outcome, weight growth rate from day 14–120, were detected (Table 3). No statistically significant differences were observed for weight, length, or head
circumference growth rates by gender for any measured age range among study groups
with the exception of lower weight growth rate for females in the LF-1.0 compared
to the Control group from day 14–60 (29.7?±?0.9 vs 32.4?±?1.0 g/day; P??0.05). This small difference within a single measured age range at less than 3
g/day was not considered clinically significant. In addition, no other statistically
significant differences were observed for mean achieved weight, length, or head circumference
at any measured time point up to 365 days of age. Mean achieved weight for males (Fig. 2) and females (Fig. 3) plotted on the WHO weight-for-age standard growth chart 24], 25] fell approximately within the 25
and 75
percentiles at all study time points.

Table 3. Weight, length, and head circumference growth rates from 14 days to 30, 60, 90, 120,
180, 275, and 365 days of age

Fig. 2. Mean achieved weight for male participants with World Health Organization (WHO) reference
percentiles (3
to 97
) through 12 months (14 to 365 days) of age. Control, stars; LF-0.6, circles; LF-1.0,

Fig. 3. Mean achieved weight for female participants with World Health Organization (WHO)
reference percentiles (3
to 97
) through 12 months (14 to 365 days) of age. Control, stars; LF-1.0, circles; LF-0.6,


Parent-reported mean study formula intake (fl oz/day; data not shown) increased from
day 30–120 for all groups by gender, indicating normal intake for LF-0.6 and LF-1.0
groups when compared to the Control for this time period (examples: females at day
30, 25.9–26.9 fl oz/day and day 120, 33.3–34.2 fl oz/day; males at day 30, 28.2–30.0
fl oz/day and day 120, 35.0–35.7 fl oz/day). Intake for female participants by group
was similar at all time points assessed. Statistically significant group differences
in intake were noted among males at days 180 (Control: 36.5 fl oz/day; LF-0.6: 31.9
fl /day; LF-1.0: 33.7 fl oz/day; Control vs LF-0.6, P??0.05) and 275 only. However, by day 180, mean reported study formula intake began
to decline in general for both male and female participants which could be expected
as parents and caregivers likely begin to offer complementary foods to infants at
approximately 4–6 months of age. Parent-reported gassiness and fussiness were similar
among groups at all study time points (data not shown). Using 24-h recall, the amount
of gas most commonly reported was “slight amount” or “moderate amount” up to 180 days
of age and “none at all” or “slight amount” by 275 and 365 days of age. Fussiness
was most often characterized as “slightly fussy” or “not at all fussy” in all groups.
No significant group differences in mean (±SE) stool frequency (number/day) were detected
at any time point assessed (Table 4). No group differences in mean (±SE) stool consistency (with categories corresponding
to 1?=?hard, 2?=?formed, 3?=?soft, 4?=?unformed or seedy, 5?=?watery; Table 4) were detected at baseline. Significant differences in stool consistency were detected
between Control and investigational formula groups from day 30 through 180. By category,
the primary differences at these study time points were more infants with a formed
and fewer infants with an unformed or seedy stool consistency in the Control compared
to LF-0.6 and LF-1.0 groups. The majority of infants in all groups from day 30–365
were reported to have a soft stool consistency. There were no significant differences
among study formula groups by day 275, possibly reflecting the increased amount of
complementary feeding in older children consuming less formula.

Table 4. Stool characteristics at 14, 30, 60, 90, 120, 180, 275, and 365 days of age

In the overall study population (all participants up to 365 days of age) no statistically
significant group differences were detected for study formula discontinuation either
related to study formula (Control: 18, 12 %; LF-0.6: 20, 12 %; LF-1.0: 17, 11 %) or
not related to study formula (Control: 50, 32 %; LF-0.6: 42, 26 %; LF-1.0: 49, 31
%). Of the 55 participants with formula-related discontinuation, formula intolerance
as determined by the study investigator was the most common reason (Control: 13; LF-0.6:
14; LF-1.0: 15) with fussiness (Control: 5; LF-0.6: 8; LF-1.0: 10) and gas (Control:
6; LF-0.6: 3; LF-1.0: 6) as the most common symptoms. Parental decision was the most
common reason for discontinuation not related to study formula (Control: 13; LF-0.6:
7; LF-1.0: 19).

No group difference was detected in the number of participants for whom at least one
medically-confirmed adverse event was reported (Control: 141, 92 %; LF-0.6: 154, 94
%; LF-1.0: 149; 94 %). There were no statistically significant group differences detected
in the overall incidence of adverse events for the following systems: Body as a Whole;
Cardiovascular; Eyes, Ear, Nose and Throat; Endocrine; Gastrointestinal (GI); Metabolic
and Nutrition; Musculoskeletal; Nervous System; Respiratory; and Skin. Significantly
fewer participants in the Control (6, 4 %) and LF-0.6 (7, 4 %) groups versus the LF-1.0
group (17, 11 %; P??0.05) experienced Urogenital system events. Although no significant group differences
were detected for specific adverse events in this system, the incidence of penile
adhesion (Control: 2, 2 %; LF-0.6: 3, 3 %; LF-1.0: 8, 9 %), commonly associated with
circumcision in young male infants, appeared to drive the overall statistical difference.
Within the GI System, the medically-confirmed incidence of diarrhea, constipation,
emesis, or gas was low with no significant group differences; however gastroesophageal
(GE) reflux (Control: 27, 18 %; LF-0.6: 24, 15 %; LF-1.0: 41, 26 %) was significantly
lower in the LF-0.6 versus the LF-1.0 group (P??0.05). Within the Nervous System the incidence of macrocephaly (defined as head
circumference 98
reference percentile; Control: 3, 2 %; LF-0.6: 0; LF-1.0: 0; P??0.05) was low, albeit statistically significant. No associated underlying health
conditions were reported by study investigators for these participants and all completed
the study. No group differences were detected in the incidence of allergy- or infection-related
adverse events; however, this study was not powered to detect likely subtle differences
in this population of healthy term infants. A total of 41 participants (Control: 14,
9 %; LF-0.6: 13, 8 %; LF-1.0: 14, 9 %) experienced serious adverse events (SAEs).
With the exception of one SAE in the Control group in which the participant was diagnosed
with likely cow’s milk protein intolerance, all SAEs were deemed unrelated to study
formulas as assessed by study physicians.