BREASTFEEDING MEDICINE

Volume 1, Number 3, 2006

© Mary Ann Liebert, Inc.

Vitamin D Status as Related to Race and

Feeding Type in Preterm Infants

SARAH N. TAYLOR, CAROL L. WAGNER, DEANNA FANNING,

LAKEYA QUINONES, and BRUCE W. HOLLIS

ABSTRACT

Background: Despite the higher prevalence of vitamin D deficiency in blacks, the vitamin D
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status of black preterm infants remains unknown. In addition, with the combination of par-
enteral and enteral nutritional support that preterm infants receive, the effect of vitamin D–de-
ficient breast milk on vitamin D status is unknown.
Objective: To evaluate vitamin D status of preterm infants through the first month after de-
livery and compare status by race and feeding type.
Study Design: Thirty-six (36) preterm (
32 weeks gestation) infants (19 black, 17 white) had
assessment of feeding type, vitamin D intake, and serum 25-hydroxyvitamin D [25(OH)D] as
a marker of vitamin D status at three time points in the first month after delivery.
Results: Black infants had a significantly lower mean 25(OH)D level on day 7–8 and day
14–15 evaluations than white infants [14.9
6.6 versus 23.3
9.3 ng/mL (p  0.021) and 18.3

7.3 versus 25.6
10.3 ng/mL (p  0.048), respectively], but the difference was no longer sig-
nificant by day 28–30 evaluation [19.6
7.7 versus 26.2
11.6 ng/mL (p  0.26)]. Vitamin D
status was not significantly lower in infants receiving predominantly breast milk (p  0.6).
Vitamin D intake rose through the month as the amount and caloric density of enteral nu-
trition increased. Six infants had significant decrease in serum 25(OH)D values from day 14–15
to day 28–30 evaluation despite receiving  400 IU/day vitamin D.
Conclusion: Differences in vitamin D status occurred between black and white infants and
were significant through the first 2 weeks after delivery. Infants receiving predominantly
breast milk did not have significantly worse vitamin D status than those receiving formula.
The significant decline in serum 25(OH)D status observed in 28% of the infants was not re-
lated to breast milk intake.

INTRODUCTION mother’s level.2 The authors have previously

studied cord blood 25(OH)D levels stratified by

B LACK PRETERM INFANTS are at risk for low

serum 25(OH)D status because of the high
prevalence of vitamin D deficiency in black
race and found black infants to have signifi-
cantly lower cord blood 25(OH)D levels than
white infants (10.5
6.0 ng/mL versus 19.5

mothers.1 A fetus receives all vitamin D from 9.6 ng/mL, respectively, p  0.0001).3 Over
the mother, and an infant’s serum 25(OH)D 80% of the subjects in this study were full term.
level at birth may be as low as half of the In evaluation of preterm infants over the past

Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.

156
 VITAMIN D STATUS IN PRETERM INFANTS 157

30 years, studies of vitamin D status have not gestation; (b) first feeding within the first 7
stratified by skin pigmentation or race, ignor- days after delivery; and (c) absence of major
ing analysis of a population at high risk for de- congenital anomalies. The study was con-
ficiency.4–18 ducted during a 3-year period.
The risk for low 25(OH)D status in preterm
infants also is a result of the difficulty in pro- Study design
viding nutrition to these infants. Preterm in-
This is a prospective study of preterm infants
fants have an immature gastrointestinal (GI)
32 weeks’ gestation who were followed for a
system that necessitates slow advancement of
1-month study period as a part of an overall
enteral feeds. Before achieving sufficient en-
nutritional and gut maturity assessment. A
teral feeds, a preterm infant relies on parenteral
component of the study was to measure the vi-
nutrition support, which is deficient in provid-
tamin D status of this cohort over time as re-
ing vitamin D when an infant weighs 1250
lated to race and infant feeding status.
g.19 Once feedings are initiated, the preferred
feeding for preterm infants is breast milk. How-
Sample size determination
ever, breast milk often is low in vitamin D con-
tent unless the mother is receiving high-dose The sample size was determined for the par-
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vitamin D (4000 IU/day) or has regular sun- ent study of overall nutritional and gut matu-
light exposure.20–23 The single study compar- rity assessment with the primary outcome vari-
ing serum 25(OH)D status between preterm able of gut permeability maturity. The study
breast milk- and formula-fed infants provided was not powered for the evaluation of serum
at least 1000 IU/day vitamin D supplementa- 25(OH)D by race and feeding type. In assess-
tion to all infants; therefore, it does not reflect ment of vitamin D status in a previous study
the standard vitamin D supplementation (200 that was specifically powered to detect differ-
to 400 IU/day) provided to breast milk–fed in- ences in serum 25(OH)D as a function of two
fants in the United States.5 vitamin D doses and race, the power calcula-
With the unstudied vitamin D status of a tion was 16 infants with 8 in each dose group
population at risk of deficiency because of race and further stratification by race.23
or nutritional inadequacies, the authors de-
signed this observational study to evaluate Study protocol
serum 25(OH)D status in the first month after After receiving informed consent, infants who
delivery in a cohort of preterm infants. The au- met criteria were followed for a 1-month study
thors hypothesized that black infants would period. Data were collected using a standardized
have significantly lower serum 25(OH)D early form developed by the investigators to ascertain
on and that infants receiving predominantly information about prenatal history, delivery
breast milk feedings would have significantly characteristics, health status, dose and volume of
lower serum 25(OH)D than infants receiving breast milk received, initiation and duration of
predominantly formula feedings. parenteral nutrition, use of human milk fortifier,
and episodes of feeding intolerance that resulted
in an infant being designated NPO (nothing by
MATERIALS AND METHODS mouth) for at least a 24-hour period. Birth head
circumference was measured in this study be-
Subjects
cause of reports in both preterm and term infants
After receiving approval from the Institu- of association between head circumference and
tional Review Board for Human Subjects at the vitamin D status.12,24
Medical University of South Carolina, parents Each infant had blood samples collected on
whose infants were admitted to the neonatal days 7–8, 14–15, and 28–30 after delivery. In-
intensive care unit were approached for con- fants who had been without enteral feedings
sent for their infant’s participation if their in- for 72 hours before a study day exited the
fant met the following criteria: (a) 32 weeks study, with the intention to collect data on
 158 TAYLOR ET AL.

those premature infants who were without GI authors previously calculated the amount of vi-
compromise. If an infant was without enteral tamin D activity in breast milk by quantitation
feedings for 72 hours on a study day, then of vitamin D2, vitamin D3, 25(OH)D2, and
the infant missed that sample collection but 25(OH)D3 in the milk by competitive protein
continued participation in the study. Blood binding assay.20 Quantitation of these mea-
samples were sent to the General Clinical Re- surements give a range of 20 to 70 IU/L vita-
search Center at MUSC for processing and min D provided by breast milk when the
were stored at 80°C until later analysis. mother is not receiving high-dose vitamin D or
regular sunlight exposure, as previously re-
Assignment of feeding type ported.20–23 In the present study, an approxi-
mation of 50 IU/L was used for calculations.
Feeding type was defined as predominantly
Table 1 shows the vitamin D activity estimated
(80% feeding volume) breast milk, formula,
for breast milk.
or a combination of breast milk and formula.
At each of the three time points, dose and vol-
ume of breast milk and formula over the in-
Human milk fortifier
terim period were recorded.
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Once an infant achieved total feed volume of

Measurement of vitamin D status 120 to 150 cc/kg per day, human milk fortifier
was added to all breast milk at a concentration
Circulating 25-hydroxy vitamin D [25(OH)D]
to provide an additional 4 kcal/oz (3.6 g forti-
was measured as an indicator of vitamin D sta-
fier/100 mL milk). This concentration added
tus25 at day 7–8, day 14–15, and day 28–30 after
120 IU vitamin D to 100 mL milk (see Table 1).27
delivery. The vitamin D metabolite, 25(OH)D,
was assessed using assays developed in the lab-
oratory of Dr. Hollis and have been described in
Parenteral nutrition
detail elsewhere.26 A rapid, direct radioim-
munoassay (RIA) for 25(OH)D was used to test When an infant weighed 2500 g, the
for nutritional vitamin D status. The reagent for amount of multivitamin solution added to par-
the 125I-labeled RIA for 25(OH)D was purchased enteral nutrition was based on weight at a
from the Diasorin Corp. (Stillwater, MN). The concentration of 160 IU/kg.19 An infant who
normal adult circulating levels of the serum weighed 2500 g received 400 IU/day vita-
25(OH)D, in the authors’ laboratory is 32 to 90 min D.
ng/mL. The lower limit of detection of this as-
say is 2 ng/mL.
TABLE 1. VITAMIN D ACTIVITY SUPPLIED
Vitamin D intake calculation BY VARIOUS FEEDING TYPES

No attempt was made to control vitamin D Feeding type 20 kcal/oz* 24 kcal/oz*

intake. Calculation of the daily vitamin D in- Breast milk 50 IU/L** 1201 IU/L**
take was an average of the vitamin D provided (breast milk
daily for the 7 days before the serum 25(OH)D fortifier added)†
measurements on day 7–8 and day 14–15. The Formula 1† 1013 IU/L 1220 IU/L
Formula 2‡ 1600 IU/L 1905 IU/L
daily vitamin D provided for the 14 days be-
fore the measurement on day 28–30 was aver- *For this study, the caloric density of breast milk was
aged and recorded. Calculated vitamin D approximated to 20 kcal/oz without additives and 24
kcal/oz with breast milk fortifier concentrated to add 4
amounts were from formula, parenteral nutri- kcal/oz to breast milk.
tion, and/or vitamin D supplements. **Vitamin D activity in breast milk ranges from 20 to
70 IU/L. An approximation of 50 IU/L was used for un-
supplemented breast milk.
Breast milk †Ross Products Handbook. Abbott Park, IL, Abbott Lab-

oratories, 2004.
The vitamin D supplied in breast milk was ‡Mead Johnson Nutritional Products Handbook. Evansville,

not measured but estimated in this study. The IN, Mead Johnson and Company, 2004.
 VITAMIN D STATUS IN PRETERM INFANTS 159

Formula nience sample. Clinical characteristics are given

in Table 2. No significant differences existed be-
The vitamin D content of the two formulas
tween black and white infants in sociodemo-
given at the institution during the study time
graphic and clinical parameters.
period is shown in Table 1. For the purpose of
Three infants (1 black and 2 white) did not
this study, 20 kcal/oz is considered nonforti-
have serum results at the first study visit on day
fied formula and 24 kcal/oz is considered for-
7–8. On day 14–15, 16 black and 12 white infants
tified formula. Formula feeds were fortified
had serum laboratory measurements per-
when an infant achieved total feed volume of
formed. On day 28–30, 10 black and 11 white in-
120 to 150 cc/kg per day.
fants had laboratory measurements. One infant
did not have laboratory measurements on day
Statistical analyses
28–30 because of discontinuation of feeds when
Statistical analyses were performed using necrotizing enterocolitis developed after day
SAS software (SAS Institute, Cary, NC) and in- 14–15. The other infants exited the study because
cluded two-tailed student’s t-test, chi-square, of discharge from the hospital.
ANOVA, and MANOVA. Significance was set Table 3 presents the serum 25(OH)D levels
at p  0.05 a priori. measured at each of the three time points dur-
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ing the first month after delivery with com-

parison between the black and white infants.
RESULTS The black infants had a significantly lower
mean 25(OH)D level at both of the first two
During the 3-year study period, 783 infants evaluations: day 7–8 (p  0.021) and day 14–15
were born at 32 weeks gestation and were re- (p  0.048). By day 28–30, the difference was no
ceiving enteral feeds before 7 days after deliv- longer significant (p  0.26) (Fig. 1).
ery. Thirty-six (36) infants, 19 black and 17 Eleven infants (6 black and 5 white), who re-
white, were enrolled in the study as a conve- ceived 80% of enteral nutrition as breast milk,

TABLE 2. SUBJECT DEMOGRAPHICS AND NUTRITIONAL SUPPORT CHARACTERISTICS

All infants Black infants White infants

Characteristics (n  36) (n  19) (n  17) p value

% male 31 (n  11) 26 (n  5) 35 (n  6) 0.56

% receiving 80% BM feeds 31 (n  11) 32 (n  6 29 (n  5) 0.57
Birth weight (g)
mean ± S.D. 1275
300 1251
266 1302
340 0.57
median 1228 1230 1225
Birth head circumference (cm)
mean
S.D. 27.0
1.8 27.1
1.7 26.8
2.0 0.83
median 27.5 27.5 27.5
Gestational age (wks)
mean
S.D. 29.2
1.6 29.4
1.6 29.1
1.7 0.83
median 29.1 29.1 29.5
Days receiving parenteral nutrition
mean
S.D. 13.1
6.2 16.0
6.0 12.3
7.1 0.72
median 10.5 11 10
Age at first enteral feed (days)
mean
S.D. 3.8
1.5 3.6
1.3 4.0
1.7 0.41
median 4 3.5 4
Age when full enteral feeds achieved (days)
mean
S.D. 14.7
6.7 14.0
7.3 15.5
6.2 0.61
median 12 12 13
Age when feeds fortified (days)
mean
S.D. 16.0
6.2 15.3
6.9 16.6
5.6 0.49
median 14 13 14

n  number of infants. P values compare black and white infants.

 160 TAYLOR ET AL.

TABLE 3. 25(OH)D LEVELS AT THREE TIME POINTS IN THE FIRST MONTH AFTER DELIVERY

25(OH)D ng/mL All infants Black infants White infants p value

Day 7–8
Mean
S.D. 18.6
8.8 14.9
6.6 23.3
9.3 0.021*
Median 16.2 13.7 24.3
Range 7.6–37.8 7.6–33.2 9.1–37.8
Number of subjects 33 18 15
Day 14–15
Mean
S.D. 21.5
9.3 18.3
7.3 25.6
10.3 0.048*
Median 19.4 16.0 24.9
Range 8.5–40.2 9.5–40.2 8.5–39.9
Number of subjects 28 16 12
Day 28–30
Mean
S.D. 23.6
10.5 19.6
7.7 26.2
11.6 0.258
Median 21.6 17.6 23.4
Range 9.5–50.2 12.3–31.5 9.5–50.2
Number of subjects 21 10 11

P values compare black and white infants.

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*Demonstrates significance. Test is ANOVA.

did not have statistically lower 25(OH)D levels shows the variation for each race and feeding
than infants receiving 80% breast milk or all type over the month. No significant difference
formula at 28 to 30 days after delivery (22.1
was found in vitamin D intake between black
11.5 ng/mL versus 23.7
10.4 ng/mL). Vita- and white infants at any time point or between
min D supplementation was not evaluated as infants receiving predominantly breast milk
a function of feeding type before the day 28–30 (80%) and those receiving either 80% of feed
time point because of the presence of parenteral volume as breast milk (formula received instead
nutrition. of breast milk) or formula with no breast milk
When evaluating the average daily amount when compared at the end of the month.
of vitamin D intake in this cohort, the mean Six infants (three black and three white) had
daily intake in the first week after delivery was significantly decreased serum 25(OH)D levels
195
53 IU. The mean daily intake increased from day 14–15 to day 28–30 despite improved
over the month as infants received more enteral vitamin D intake over the month, including
nutrition and fortification of feeds. Table 4 400 IU/day vitamin D in the last 14 days of
the month, as shown in Table 5. Their gesta-
30
tional ages ranged from 25 to 32 weeks, and
Circulating 25(OH)D (ng/mL)

**
their birth weights ranged from 1035 to 1746 g.
25 * None of the six patients received predomi-
20 nantly breast milk. Two of the six received no
** Black parenteral nutrition and four received par-
15 White
*
enteral nutrition for 8 to 19 days. Their average
10
days for feeding initiation, full feed achieve-
5 ment, and feed fortification were similar to the
0 other study patients. These infants account for
Day 7–8 25(OH)D

Day 14–15 25(OH)D

Day 28–30 25(OH)D

28% of those with serum 25(OH)D evaluation

at the day 28–30 time point.

DISCUSSION

FIG. 1. Mean circulating 25(OH)D during first postna- In this preterm infant population, the black
tal month as a function of race. *p  0.021 and **p  0.048. infants had significantly lower 25(OH)D levels
 VITAMIN D STATUS IN PRETERM INFANTS 161

TABLE 4. DAILY VITAMIN D INTAKE

Vitamin D intake
(IU/day) Day 7–8 Day 14–15 Day 28–30

All infants 195
53 (n  33) 223
97 (n  28) 507
223 (n  21)

Black 195
50 (n  18) 227
81 (n  16) 467
222 (n  10)
White 196
58 (n  15) 239
113 (n  12) 544
223 (n  11)
All infants receiving 165
49 (n  11) 177
49 (n  8) 435
279 (n  6)
80% of feed as BM

Mean
standard deviation is given. P value 0.1 in comparison of vitamin D intake between black and white in-
fants at all time points and comparison of vitamin D intake between infants receiving 80% of feed as BM and all
other infants.

than the white infants at 7 to 8 days and 14 to D activity in this study is not responsible for
15 days after delivery, with this trend still ev- this result. A linear relationship between vita-
ident at 28 to 30 days after delivery. The dif- min D intake and serum 25(OH)D measure-
ference seen in the first 2 weeks was most likely ments has been shown in adults.29 If a similar
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caused by lower levels in the black mothers and relationship exists in children, this decrease in
the consequential effect on vitamin D status in serum 25(OH)D may demonstrate poor intesti-
the newborn infant. Although the disappear- nal absorption of the vitamin D in formula by
ance of a significant difference between the these preterm infants.
races by 28 to 30 days after delivery may re- No significant difference was observed in vi-
flect the similar vitamin D intake received by tamin D intake by feeding type. The infants re-
the infants during the month, it also may re- ceiving predominantly breast milk had lower
flect a Type 2 error given the small sample vitamin D intake than those who received more
number at that time period. With mean vita- formula or formula alone, but this difference
min D supplementation at approximately 200 was not significant. The lack of significant dif-
IU/day in the first week after delivery and in- ference in vitamin D intakes between breast
creasing to over 400 IU/day by the end of the milk and formula-fed infants is most likely due
first month, most infants of both races had im- to intake of breast milk fortifier by the major-
provement in vitamin D status. ity of the breast fed infants by 16 days.
The six infants who had significantly de- This study demonstrates that black preterm
creased serum 25(OH)D values, despite receiv- infants are at risk for lower serum 25(OH)D sta-
ing 400 IU/day vitamin D by 3 weeks after tus than white infants. It also raises the ques-
delivery, generate consideration of the ade- tion of whether the recommendations of 200 to
quacy of 200 IU/day or even 400 IU/day as the 400 IU/day vitamin D are adequate to main-
recommended intake for all infants.6,28 As none tain stable vitamin D status in all preterm in-
of these infants received predominantly breast fants. These results are limited by lack of un-
milk, the approximation of breast milk vitamin derstanding sufficient serum 25(OH)D status in

TABLE 5. VITAMIN D STATUS AND INTAKE OF THE SIX INFANTS WITH

INCREASING INTAKE AND DECREASING SERUM 25(OH)D

Parameters Day 7–8 Day 14–15 Day 28–30

25(OH)D, ng/mL 21.4
7.7* 28.3
9.4** 17.0
4.8**

(10.6–29) (19–40) (12.3–24.4)
Vitamin D intake, IU/d 207
26 224
85** 598
164*
(169–243) (102–245) (425–857)

Mean
standard deviation and range shown. Vitamin D intake is the average daily intake for the 7 days before
day 7–8 and day 14–15 and the 14 days before day 28–30 study days.
*Only four of the six infants had serum 25(OH)D values for day 7.
**In comparison with day 14–15 and day 28–30 serum 25(OH)D values, p is significant at 0.02.
 162 TAYLOR ET AL.

infants. Historically, vitamin D deficiency in after delivery despite receiving an average of

children is defined by the serum 25(OH)D level 425 to 857 IU/day. Improved understanding of
measured when rickets is clinically apparent. vitamin D sufficiency in this population is
This level ranges from 5 to 11 ng/mL.30 Al- needed to define the true requirements for vi-
though the study population did not demon- tamin D intake.
strate this magnitude of vitamin D deficiency,
studies in adults have shown that a serum
25(OH)D level in the range of 15 to 32 ng/mL ACKNOWLEDGMENT
is required to promote optimal calcium ab-
sorption, bone mineral density, and normal This work was funded in part by a grant from
parathyroid function, which are essential for the University Research Committee, the Gen-
maintaining normal bone health.31–33 Until vi- eral Clinical Research Center, Medical Univer-
tamin D sufficiency is defined for the preterm sity of South Carolina, Charleston, SC, NIH
infant population, the authors do not know if #RR01070 and NIH 3 M01 RR01070-24S2.
the drop in serum 25(OH)D seen in 28% of in-
fants with evaluation at the end of the month,
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P.O. Box 250917
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a 125I-labeled tracer. Clin Chem 1993;39:529–533. Charleston, SC 29425
27. Ross Products Handbook. 2004 Abbott Laboratories.
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