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The importance of β-carotene as a source of vitamin A with special regard to pregnant and breastfeeding women

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Vitamin A is essential for growth and differentiation of a number of cells and tissues. Notably during pregnancy and throughout the breastfeeding period, vitamin A has an important role in the healthy development of the fetus and the newborn, with lung development and maturation being particularly important. The German Nutrition Society (DGE) recommends a 40% increase in vitamin A intake for pregnant women and a 90% increase for breastfeeding women. However, pregnant women or those considering becoming pregnant are generally advised to avoid the intake of vitamin A rich liver and liver foods, based upon unsupported scientific findings. As a result, the provitamin A carotenoid beta-carotene remains their essential source of vitamin A. Basic sources of provitamin A are orange and dark green vegetables, followed by fortified beverages which represent between 20% and 40% of the daily supply. The average intake of beta-carotene in Germany is about 1.5-2 mg a day. Assuming a vitamin A conversion rate for beta-carotene for juices of 4:1, and fruit and vegetables between 12:1 and 26:1; the total vitamin A contribution from beta-carotene intake represents 10-15% of the RDA. The American Pediatrics Association cites vitamin A as one of the most critical vitamins during pregnancy and the breastfeeding period, especially in terms of lung function and maturation. If the vitamin A supply of the mother is inadequate, her supply to the fetus will also be inadequate, as will later be her milk. These inadequacies cannot be compensated by postnatal supplementation. A clinical study in pregnant women with short birth intervals or multiple births showed that almost 1/3 of the women had plasma retinol levels below 1.4 micromol/l corresponding to a borderline deficiency. Despite the fact that vitamin A and beta-carotene rich food is generally available, risk groups for low vitamin A supply exist in the western world. It is therefore highly critical to restrict the beta-carotene supply from diet, particularly from sources of beta-carotene with high consumer acceptance such as fortified juices (e.g. "ACE juices") or dietary supplements (e.g. multivitamins for pregnant women). For the part of the population unable to meet vitamin A requirements according to the DACH recommendations, sufficient intake of beta-carotene may be crucial to help improve and maintain adequate vitamin A status and prevention of developmental disorders. At this time it has to be urgently advised against restricting the beta-carotene supply or putting warning labels on beta-carotene fortified products. It is, however, highly recommended to improve the available data on nutrient intakes in Germany, especially for pregnant and breastfeeding women. For them, recommendations to be aware of potential nutrient intake inadequacies might prove useful.
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CONTENTS
The importance of b-carotene as a
source of vitamin A with special regards
to pregnant and breastfeeding women
Guest Editors:
Prof. Dr. Hans-Konrad Biesalski
University of Hohenheim
Dept. of Biological Chemistry and Nutritional Science
Garbenstraße 30
70593 Stuttgart, Germany
Prof. Dr. Florian J. Schweigert
Lehrstuhl fu
¨
r Physiologie und Pathophysiologie der Erna
¨
hrung
Institut fu
¨
r Erna
¨
hrungswissenschaft
Mathematisch-Naturwissenschaftliche Fakulta
¨
t
Universita
¨
t Potsdam
Arthur-Scheunert-Allee 114-116
14558 Potsdam, Germany
This supplement was sponsored by
Gesellschaft fu
¨
r Angewandte Vitaminforschung (GVF) e.V.
Arthur-Scheunert-Allee 114-116,
14558 Nuthetal, Germany
The guest editors, not the journal’s regular editors, are responsible for the
scientific content of this supplement.
DOI: 10.1007/s00394-007-1002-y
Manuela Strobel
Jana Tinz
Hans-Konrad Biesalski
The importance of b-carotene as a source
of vitamin A with special regard to
pregnant and breastfeeding women
j Summary Vitamin A is essential
for growth and differentiation of a
number of cells and tissues.
Notably during pregnancy and
throughout the breastfeeding per-
iod, vitamin A has an important
role in the healthy development of
the fetus and the newborn, with
lung development and maturation
being particularly important. The
German Nutrition Society (DGE)
recommends a 40% increase in
vitamin A intake for pregnant
women and a 90% increase for
breastfeeding women. However,
pregnant women or those consid-
ering becoming pregnant are gen-
erally advised to avoid the intake
of vitamin A rich liver and liver
foods, based upon unsupported
scientific findings. As a result, the
provitamin A carotenoid b-caro-
tene remains their essential source
of vitamin A. Basic sources of
provitamin A are orange and dark
green vegetables, followed by for-
tified beverages which represent
between 20% and 40% of the daily
supply. The average intake of
b-carotene in Germany is about
1.5–2 mg a day. Assuming a vita-
min A conversion rate for
b-carotene for juices of 4:1, and
fruit and vegetables between 12:1
and 26:1; the total vitamin A
contribution from b-carotene in-
take represents 10–15% of the
RDA. The American Pediatrics
Association cites vitamin A as one
of the most critical vitamins dur-
ing pregnancy and the breastfeed-
ing period, especially in terms of
lung function and maturation. If
the vitamin A supply of the
mother is inadequate, her supply
to the fetus will also be inade-
quate, as will later be her milk.
These inadequacies cannot be
compensated by postnatal supple-
mentation. A clinical study in
pregnant women with short birth
intervals or multiple births
showed that almost 1/3 of the
women had plasma retinol levels
below 1.4 lmol/l corresponding to
a borderline deficiency. Despite
the fact that vitamin A and beta-
carotene rich food is generally
available, risk groups for low
vitamin A supply exist in the
western world. It is therefore
highly critical to restrict the b-
carotene supply from diet, partic-
ularly from sources of b-carotene
with high consumer acceptance
such as fortified juices (e.g. ‘‘ACE
juices’’) or dietary supplements
(e.g. multivitamins for pregnant
women). For the part of the pop-
ulation unable to meet vitamin A
requirements according to the
DACH recommendations, suffi-
cient intake of b-carotene may be
crucial to help improve and
maintain adequate vitamin A sta-
tus and prevention of develop-
mental disorders. At this time it
has to be urgently advised against
restricting the b-carotene supply
or putting warning labels on b-
carotene fortified products. It is,
however, highly recommended to
improve the available data on
nutrient intakes in Germany,
especially for pregnant and
breastfeeding women. For them,
recommendations to be aware of
potential nutrient intake inade-
quacies might prove useful.
j Key words vitamin A
b-carotene pregnancy
breastfeeding bronchopulmo-
nary dysplasia
ORIGINAL CONTRIBUTION
Eur J Nutr (2007) [Suppl 1] 46:I/1–I/20
DOI 10.1007/s00394-007-1101-9
EJN 1101
M. Strobel
Nutrition and Food Security
Gronau, Germany
J. Tinz Æ H.-K. Biesalski (&)
Dept. of Biological Chemistry and
Nutritional Science
University of Hohenheim
Garbenstraße 30
70593 Stuttgart, Germany
Tel.: +49-711/459-24112
Fax: +49-711/459-22283
E-Mail: biesal@uni-hohenheim.de
Introduction
There has been a long-standing discussion to limit
the use of b-carotene in fortified foods and/or food
supplements at European level as well as at National
level in some Member States of the European Union.
Measures discussed include the setting of upper
limits for the use of b-carotene and/or having
warning statements on the product labels. These
discussions were on the one hand driven by results
of the ATBC Trial demonstrating an increased lung
cancer risk in long term heavy smokers upon sup-
plementation with high doses of b-carotene (20 mg/
day) over several years, while in some countries
single entity high dose b-carotene supplements were
marketed, at least seasonally during spring and
summer. On the other hand, in the course of har-
monization of European Law on Food Supplements
and Fortified Foods, the scientific advisory panels to
the European Commission were asked for safety
evaluations of all relevant vitamins and minerals, in
order to establish upper levels of these nutrients,
which can be safely used in food supplements and in
fortified foods.
At the national level, discussions on safe b-car-
otene levels for food supplements and fortified
foods were most intense in those countries in which
b-carotene was popular as ingredient for any of
these food categories, and thus specifically in Ger-
many and partly also in the UK. There, the Expert
Group on Vitamins and Minerals (EVM), a scientific
advisory group to the UK Food Standards Agency
(FSA), set an Upper Safe Level for daily consump-
tion over a lifetime of 7 mg/day of supplemental b-
carotene, for both smokers and non-smokers,
consequently recommending to limit the use of b-
carotene in food supplement to that dose. In
Germany, the German food and food supplement
industry committed in 2001 to voluntarily limit the
use of b-carotene in fortified foods to 2 mg/100 g or
100 ml, and to 4.8 mg/day in food supplements—
4.8 mg being equivalent to one RDA of vitamin A.
Food supplements containing higher doses were to
carry a statement such as should not be taken by
smokers’.
However, these national discussions are now part
of the general discussion at the European level on
setting upper limits for vitamins and minerals in food
supplements, as requested by Article 5 of Directive
2002/46/EC harmonizing the legislation on food sup-
plements in the various European Member States—a
discussion which is linked to the equivalent work to
be done for fortified foods in light of the recently
published European Regulation (EC) No. 1925/2006
for this category of foods.
National authorities may provide input to these,
as has recently been done by the German Federal
Institute for Risk Assessment (BfR) in form of a risk
assessment with suggestions for risk management,
i.e. optional measurements to be taken [21]. For
foods supplements, options are to limit the use of b-
carotene to either 2 mg/day, or to 2–4 mg/day,
which is the desirable intake according to the Ger-
man Nutrition Society. For fortified foods, suggested
options are either not to allow b-carotene for food
fortification at all, or limit the use to 2 mg/100 g or
100 ml. For both food categories, the BfR favours
the option of 2 mg/day in supplements and no
fortification, because of safety concerns with the
second options, which, according to the BfR, would
necessitate information statements on product labels
and extensive communication of the detrimental
effects of b-carotene (related to lung cancer) to
consumers.
In the discussion on the safety of (high supple-
mental dosages) of b-carotene in smokers it is often
overlooked that b-carotene is an essential micronu-
trient for the human being due to its function as a
precursor to vitamin A, i.e. as provitamin. It is fre-
quently claimed that the bioavailability of the iso-
lated’ or purified’ b-carotene used in food
supplements and fortified foods is much higher than
the bioavailability of b -carotene naturally occurring
in foods, However, more recent research suggests that
due to conversion factors the contribution of the
provitamin from foods for vitamin A supply is smaller
than previously assumed.
Therefore it is important to investigate the role of
b-carotene in ensuring adequate vitamin A status. On
the basis of those data, risk groups of inadequate
vitamin A supply due to regulatory restrictions can be
identified within the population. In Addition, the
consequences have to be evaluated. The following
report will examine these issues using the situation in
Germany as an example.
Vitamin A/b-carotene requirement and
occurrence
The recommendations of the German Nutrition
Society (DGE) for the daily intake of vitamin A vary
for children between 0.6 mg and 1.1 mg, for adults
between 0.8 mg and 1 mg, for pregnant women. For
breastfeeding women 1.5 mg are recommended [27].
Figure 1 provides an example of the amount of food
required to achieve the daily intake of 0.9 mg of
vitamin A recommended for women.
Figure 1 clearly demonstrates that the only rele-
vant dietary source for vitamin A is liver. All other
I/2 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
foods containing preformed vitamin A need to be
consumed in atypically large amounts in order to
meet the vitamin A requirement. Only 10–15 g of
animal liver is necessary to meet the daily require-
ment, demonstrating that liver is the most important
source of vitamin A for humans. Since vitamin A is
effectively stored in humans, just one portion of liver
(100 g) every 14 days is enough to replenish these
stores. Other foods like meat, butter, eggs and milk
only contribute a small portion (<20%) of dietary
preformed vitamin A. Liver consumption, however,
can essentially be discounted as a significant vitamin
A source in Germany since only 500 g of liver are
consumed per person each year (41 kg of pork, 10 kg
of beef) which is far less than the recommended 100 g
liver every two weeks to reach a sufficient vitamin A
supply. This inadequacy is especially apparent for
young women who are often vegetarians and/or on
low caloric diets.
Provitamin A (b-carotene) found in plant foods
plays an important role for meeting vitamin A
requirements from a diet that excludes the consump-
tion of meat, liver, milk and eggs. According to the
National Consumption Study and the DACH-reference
values, men obtain 25% and women 30% of their vita-
min A intake from the provitamin b-carotene [27, 80].
The German Nutrition Society recommends an
intake of 2–4 mg b-carotene per day [27]. Figure 2
illustrates the amount of foods required to meet the
recommendations, based on a conversion factor of
b-carotene to vitamin A of 6:1.
When assessing b-carotene sources, absorption of
the provitamin b-carotene is strongly dependent on
the source and the manner it is served. For example,
the absorption from raw carrots is virtually non-
existent whereas absorption from carrot juice is up to
60%. For diets lacking fat, the absorption is also
markedly reduced.
Average intake of vitamin A and b-carotene
Mean daily intake data of total vitamin A and carot-
enoids is available from the National Consumption
Study (1985–1988) on food and nutrient intake in
Germany [107]. In Table 1 average intake data for
vitamin A are listed for various age groups. Daily
vitamin A intakes is notably insufficient in children
and adolescents, in particular when recommended
intakes of b-carotene are not being reached.
Similar results were obtained in the DONALD
study, which examined children aged between 2 and
15 years [118]. Boys aged between 13 and 15 years
showed the highest mean intakes of 0.88 mg of vita-
min A per day. However, fortified foods increasingly
contributed to the vitamin A intakes. During the
1996–2000 study period, intake of vitamin A from
fortified food increased significantly whereas total
vitamin A intake from all sources remained un-
changed. Thus, vitamin A intake from conventional
foods, that is foods without fortification, decreased to
only 62% of total vitamin A intake in 2000 (Fig. 3).
Suboptimal supply of carotenoids has clearly been
demonstrated in several other studies. Table 2
describes the results of the National Consumption
Study on carotenoid intake, evaluated by Pelz et al.
(1998), and gives data from the VERA Study, pub-
lished by Schneider et al. (1995), as well as from two
other studies by Mu
¨
ller (1996) and Riedl et al. (1997)
[78, 97, 104, 107]. Since carotenoid intake in the
general population is not normally distributed and
arithmetic means are thus not meaningful, the median
intake has to be used for consideration. Medians are
usually appreciably lower than the arithmetic means.
In Table 2 both medians and arithmetic means are
shown, where available.
According to Mu
¨
ller (1996), the b-carotene intake
of almost half of the population is less than 1 mg
Fig. 2 The amounts of various foods containing the recommended daily
supply of 2 mg of b-carotene
Fig. 1 Different foods each containing the recommended daily supply of
0.9 mg of vitamin A
M. Strobel et al. I/3
Vitamin A in pregnancy and lactation
per day while 64.1% have intakes less than the rec-
ommended intake of 2 mg per day (Fig. 4) [78].
Therefore the b-carotene intake of 75% of the
population is less than 3 mg per day including food
supplements and fortified foods. Considering that
qualified and scientifically justified requirements exist
to increase the b-carotene supply via foods (including
fortified ones), ways of increasing the availability of
foods fortified with b-carotene (possibly with good
bioavailability) should be examined. In addition to
the important role of b-carotene as an antioxidant it
should be remembered that the provitamin is an
important source of vitamin A. Vitamin A intake can
be considered critical in certain population groups,
especially adolescents and young women, for the
reasons discussed above.
Pregnancy and breastfeeding
The need for vitamin A and b-carotene is increased
during pregnancy and the breastfeeding period. On
average, intakes should be one third higher during
pregnancy, and during the breastfeeding period
intake should be 0.7 mg/day higher than that for non-
pregnant or non-breastfeeding women. Due to its
importance for fetal lung development and matura-
tion, adequate vitamin A intake is especially impor-
tant during the second and third trimesters of
pregnancy. The source of vitamin A, which shows the
highest bioavailability is liver. However, depending
on animal feeding practices, liver may contain very
high concentrations of retinol (vitamin A). This has
led the Federal Institute for Consumer Protection and
Veterinary Medicine to advise pregnant women to
avoid consuming liver [14]. Most often this results in
an insufficient supply of vitamin A in pregnant and
Table 1 Results of the National Consumption Study [107] compared to the recommended intake
Age Female persons Male persons
Recommended
intake in mg
Actual intake
in mg
% of recommended
intake
Recommended
intake in mg
Actual intake
in mg
% of recommended
intake
Total vitamin A 4 £ 7 0.7 0.64 91 0.7 0.69 99
7 £ 10 0.8 0.71 89 0.8 0.81 101
10 £ 13 0.9 0.79 88 0.9 0.80 89
13 £ 15 1.0 0.78 78 1.1 0.91 83
15 £ 19 0.9 0.80 89 1.1 0.90 82
19 £ 25 0.8 0.77 96 1.0 0.92 92
25 £ 51 0.8 0.85 106 1.0 0.99 99
51 £ 65 0.8 0.91 114 1.0 1.03 103
65 0.8 0.91 114 1.0 1.04 104
Carotene 4 £ 7 2–4
a
1.15 58 2–4
a
1.14 57
7 £ 10 1.23 62 1.41 71
10 £ 13 1.32 66 1.40 70
13 £ 15 1.32 66 1.32 66
15 £ 19 1.34 67 1.42 71
19 £ 25 1.32 66 1.35 68
25 £ 51 1.48 74 1.45 73
51 £ 65 1.59 80 1.52 76
65 1.54 77 1.62 81
a
estimated value of the recommended intake [27]
Fig. 3 Daily intake based on total vitamin A, shown as % of the recommended
intake [27] and differentiated according to origin (enriched foods versus non-
enriched foods) [118]
Table 2 Average intake of carotenoids in Germany
Median [mg/d] Arithmetic mean [mg/d] Source
1.09 2.53 [78]
1.45 (m) [107]
1.64 (f)
1.81 [97]
1.44 1.84 [104]
I/4 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
breastfeeding women who are therefore reliant on b-
carotene as a source of vitamin A.
Therefore a diet rich in including fortified food and
beverages has to be recommended to women at child-
bearing age; especially to women with multiple births,
short birth intervals, low social economic status and
to those who are breastfeeding women. Intake of
dietary b-carotene supplements should be recom-
mended as well since the bioavailability of isolated b-
carotene, which is used in fortified foods and dietary
supplements, is better than from food matrices such
as vegetables.
Vitamin A/b-carotene intake of pregnant and
breastfeeding women: identification of a risk
group
Doyle et al. (2001) examined the diet of women who
gave birth to children with low birth weight [36]. The
group with an adequate diet, compared to the group
with a diet not providing adequate amounts of nutri-
ents, had 20% lower vitamin A intakes. Most likely, the
actual vitamin A intake was even lower because a
conversion factor of 1:6 was used, which overestimates
the contribution of b-carotene to vitamin A supply, as
further discussed below. In addition, the total energy
intake of the inadequately nourished group was only
1633 kcal/d, i.e. below 1800 kcal/d, which are consid-
ered borderline for a diet providing adequate levels of
micronutrients. Doyle’s study (2001) clearly shows
that young, pregnant and breastfeeding women have
to be considered as a group at high risk for low intakes
of micronutrients since those are largely provided by
animal based foods. These groups should be advised to
consume foods fortified with b-carotene or, even
better, with vitamin A plus b-carotene, in order to
avoid nutrition deficits, which should not exist in
industrialized countries.
We conducted a clinical pilot study in pregnant
women with multiple births or short birth intervals
to evaluate the vitamin A and b-carotene supply
during pregnancy and after delivery in this vulner-
able population group [108]. Twenty-nine volunteers
aged between 21 and 36 years were evaluated for
48 h after delivery. During this time frame a food
frequency protocol considering 3 months retrospec-
tive was obtained from all participants. In order to
establish overall supply retinol and b-carotene levels
were determined in maternal plasma, cord blood and
colostrum via HPLC analysis. Regardless of the high
to moderate socio-economic background, 27.6% of
participants showed plasma retinol levels below
1.4 lmol/l. This value is considered as borderline
deficiency. In addition, 46.4% showed retinol intake
<66% of RDA and 50.0% did not consume liver at all
although liver contributes as a main source for
preformed retinol. Despite high total carotenoid in-
take of 6.9 +/) 3.6 mg/d, 20.7% of mothers showed
plasma levels <0.5 lmol/l b-carotene. Retinol and b-
carotene levels were highly significantly correlated
between maternal plasma versus cord blood and
colostrum. In addition, significantly lower levels
were found in cord blood: 31.2 +/) 13.0% of retinol
and 4.1 +/) 1.4% of beta-carotene compared with
maternal plasma. We conclude that despite the fact
that vitamin A and b-carotene rich food is generally
available, risk groups for low vitamin A supply may
exist in Germany and that this may be representative
for the western world.
Relevance of the mother’s vitamin A/b-carotene
intake for the fetal vitamin A status
Several epidemiological studies show that an insuffi-
cient intake of vitamin A poses a risk for fetal
development and also during the newborn period. As
the child is dependent on the mother in terms of its
vitamin A supply during the newborn period, expec-
tant mother’s vitamin A intake during pregnancy is of
critical importance for the later supply to the child. In
addition liver stores of the baby only last for a couple
of days and will be depleted quickly upon sudden
strains or malabsorption states.
When assessing the liver stores in relation to the
birth weight of the child and the intakes of the
mother, Shah et al. (1987) observed a significant dif-
ference between intake groups: Insufficient Vitamin A
intake resulted in low liver stores, low birth weights
and, as discussed above, a higher risk of further
complications [110] (Table 3).
Foetal liver stores increase with increasing gesta-
tional age, but strongly depend on the vitamin A
status of the mother. Supplementation in the second
trimester of pregnancy with physiological doses of
vitamin A may lead to an improvement in fetal vita-
Fig. 4 Frequeny distribution of daily intake of b-carotene [78]
M. Strobel et al. I/5
Vitamin A in pregnancy and lactation
min A liver stores. In addition, supplementation may
also increase retinol levels in the milk, which posi-
tively affects the baby during the postnatal period.
Figure 5 illustrates that there is a direct correlation
between the levels of vitamin A in the mother’s
plasma and the retinol concentration in the umbilical
cord. Research is urgently required to validate the
importance of sufficient vitamin A intakes during
pregnancy and also during the breastfeeding period
for ensuring a sufficient supply to the baby.
Relevance of breastfeeding for the vitamin
A/b-carotene supply of the newborn
Since the fetal liver is only able to store a small
amount of vitamin A during pregnancy, almost all
babies are born with marginal vitamin A deficiency
[12, 23, 130]. This is usually corrected quickly via
the vitamin A supply from the mother’s milk and the
extremely high vitamin A concentrations of the
colostrum (up to 7 lmol/l) [130]. However during
lactation maternal intake of vitamin A and b-caro-
tene strongly affects the amount of these micronu-
trients secreted into breast milk [4]. The average
American newborn has a mean liver vitamin A
content of 5 lmol (assuming that the liver is about
4% of the body’s weight). By comparison, the
breastfed infant obtains approximately 310 lmol
vitamin A from mother’s milk in the first 6 months.
Thus, during the first 6 months, vitamin A intake
from breastfeeding is usually 60 times higher than
the intake that can be attained during the 9 months’
pregnancy [102].
Vitamin A stores in the fetal liver accumulate
during the last trimester of pregnancy but stores are
related to maternal plasma concentrations [83, 84]. In
cases of zinc and vitamin A deficiency during preg-
nancy, daily supplementation with b-carotene
(4.5 mg) and zinc (30 mg) improved vitamin A status
in expectant mothers and in their newborns [33].
Breast milk concentrations of retinol and b-carotene
were higher at 6 months of lactation after supple-
mentation with b-carotene. The authors calculated the
median daily retinol intake from breast milk would be
216 RE (Retinol Equivalents) in the supplemented
and 148 RE in the control group. The UK estimated
average requirement and lower reference nutrient
intake for retinol in this age group are 250 RE and
150 RE respectively [33].
The World Health Organization recommends a
daily minimum intake of 0.63 lmol/l retinol via
breast milk for babies in order to meet basic
requirements [8]. For the development of liver
stores, however, 1.2–1.3 lmol of retinol per day
during the first year and 1.4 lmol/day during the
second and third year are necessary [38]. Assuming
an average milk intake of about 750 ml/day by the
baby, the mother’s milk needs to contain 1.6 lmol
retinol per liter in order to provide the recom-
mended intake requirements of the breastfed baby.
According to data available for Germany, the mean
retinol concentration of mother’s milk is about
2.8 lmol/l, but was less than 1.6 lmol/l in more than
20% of the women, i.e. concentrations, which are
considered critically low for the babies supply.
Insufficient vitamin A intake of the baby may have
serious consequences, especially regarding suscepti-
bility to infections, the development and function of
breathing organs, and the integrity of mucous
membranes.
In a recent randomized controlled trial 150 women
were supplemented with a single dose of retinol
(209 lmol/l) soon after delivery and were advised to
breastfed for 6 months [11]. Pre-supplementation
mean serum retinol was 0.98 lmol and breast milk
retinol 3.85 lmol. Serum and breast milk retinol in-
creased immediately after supplementation compared
to the control group, and breast milk retinol remained
significantly higher for 4 months compared to the
control group (Fig. 6). Further, in the supplemented
group a decreased incidence and duration of various
diseases was observed.
Table 3 Fetal vitamin A concentrations of the liver in relation to the stage of
pregnancy and the mother’s vitamin A intake (mean values with standard
deviation (lg/kg)) [110]
Vitamin A
serum values
of the mother
Vitamin A concentration of the fetal liver mean
values (±SD)
Before the 24th week
of pregnancy
After the 24th week
of pregnancy
<150 lg/l 1.7 ± 0.37 5.2 ± 1.1
150–250 lg/l 6.5 ± 0.74 10.7 ± 1.85
>250 lg/l 10.6 ± 1.42 17.0
Fig. 5 Vitamin A concentration of the umbilical cord compared to the vitamin
A concentration of the mother [117]
I/6 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
Vitamin A and healthy development of the fetus
and newborn
Vitamin A is essentially required for healthy devel-
opment of the fetus and the newborn. A number of
intervention studies indicate that the number of
neural tube defects in children born to women taking
multivitamin supplements compared to women
taking no supplements was significantly lower. In
addition to folic acid, vitamin A supplementation
(4000–6000 IU) was mentioned as important factor
for decreasing such defects [60]. Further, insufficient
micronutrient intakes by pregnant woman influence
the postpartum intake of the child. Several studies
have shown an increased risk of bronchopulmonary
dysplasia (BPD) in preterm infants with insufficient
vitamin A status [7, 25, 61, 132].
Effects of vitamin A on gene expression during
fetal lung development
The vitamin A metabolite retinoic acid (RA) plays an
important role in modulating gene expression during
fetal lung development. RA can inhibit the expression
of the surfactant protein A (SPA), a component of the
surfactant synthesized and secreted in type II alveolar
cells, in a concentration-dependent manner [73, 143].
Equally insulin, TGF-b and high concentrations of
glucocorticoids can lead to an inhibition of SPA
mRNA expression [119, 135]. Lower glucocorticoid
concentrations stimulate the expression of this gene
[89]. The SPA mRNA expression is increased in
human fetal lung explants via RA as well as via hy-
peroxia (data from rats) and dexamethasone (human
fetal lung explants) [73, 87, 89, 119, 135]. Thus, the
synthesis of the individual surfactant proteins is
regulated selectively and differently via RA together
with glucocorticoids.
Prostaglandins of the PGE
2
type can increase the
surfactant protein synthesis [59, 67]. Under the
influence of EGF (epidermal growth factor), the for-
mation of prostaglandins and, in particular of PGE
2
,
increases [65, 126]. The expression of the EGF
receptor is increased by RA. EGF increases the pro-
liferation of the lung tissues and leads to an increased
formation of surfactant phospholipids [44, 49, 124].
RA as well as EGF increase (40%, 80%) the PGE
2
secretion in fetal lung cells of the rat in vitro by 40%
and 80%, respectively, while the combination of RA
and EGF increases PGE
2
secretion more than 6-fold
[88]. Therefore RA influences lung development
through its modulating effect on EGF expression and
the resulting PGE
2
induced surfactant synthesis.
Important for the time-dependent regulation of lung
development are a sufficient continuous supply of
retinol (from blood or tissue stores) and a timely
formation of the active metabolite RA.
Vitamin A kinetics during fetal lung
development
Local i.e. extrahepatic stores, of retinyl esters were
demonstrated in fibroblast-like cells located close to
alveolar cells, in type II cells as well as in the respi-
ratory epithelium [15, 90, 144]. The importance of
these retinyl esters as ‘‘acute reserve’’ during lung
development was confirmed in rats: during late pha-
ses of pregnancy, when lung maturation starts, these
retinyl ester stores are quickly depleted [42]. Such
depletion is the result of an increased requirement
during lung development, brought on by the acute’
need for retinoic acid for necessary cellular differen-
tiation (proximalization) and metabolic purposes
(surfactant).
Prenatal lung development is also influenced by
glucocorticoids, both, in parallel and complementary
to vitamin A. This is not surprising since the receptor
for steroids and for retinoids belongs to the same
multi-receptor family. The action of the glucocortic-
oids, however, does not only begin at the level of gene
expression but much earlier in that it seems to reg-
ulate the release of the vitamin. For example, the
administration of dexamethasone leads to increased
levels of the maternal and fetal retinol binding protein
resulting in an improvement in vitamin A supply via
the normal route, i.e. activation of liver stores. Such
increases in vitamin A concentrations in the systemic
circulation however decrease the morbidity and the
mortality of preterm infants due to bronchopulmo-
nary dysplasia [113, 115]. Dexamethasone and
glucocorticoids not only lead to an improved total
vitamin A status by mobilization of liver stores but
also influence the metabolization of the vitamin A
esters stored in the lung [42]. Following administra-
tion of dexamethasone, but also without application
of steroids, the levels of retinyl esters were noticeably
reduced. This may explain the therapeutic successes
Fig. 6 Frequency distribution of vitamin A concentrations in mother’s milk
M. Strobel et al. I/7
Vitamin A in pregnancy and lactation
of steroids but also their failures in the treatment of
lung distress syndrome in preterm infants. If there are
insufficient retinyl ester stores due to insufficient
supply to the fetal lung during the late phases of
pregnancy, the regulating effect of glucocorticoids on
the vitamin A metabolism of the lung cell cannot take
place.
Low vitamin A plasma levels are relatively often
observed in preterm infants, particularly in those with
lung distress syndrome due to the relatively undev-
eloped capacity of the liver to synthesize retinol-
binding protein [111]. The newborn is almost entirely
dependent on its mother for vitamin A supply, i.e., the
retinyl ester stores in its lung will only be replen-
ished–either by direct intake or via synthesis from
circulating retinal–if the mother has had a sufficient
vitamin A supply during pregnancy.
Effects of insufficient vitamin A intake on the
postnatal development of the lung
Preterm infants and particularly newborns are
dependent on a sufficient supply of vitamin A to
ensure regulation of cellular differentiation in the
respiratory and lung epithelia. The more premature
the child, the lower its serum retinol levels are [77].
The plasma levels are critical at birth in terms of lung
development because serum retinol and RBP levels
decrease further following birth.
Several studies consistently show that serum reti-
nol and RBP levels are significantly lower in preterm
infants than in newborns [48, 52, 109]. Compared to
newborns there are also very low retinol levels in the
liver of preterm infants [116]. Plasma values lower
than 20 lg/dl are common and are indicative of a
relative vitamin A deficiency.
Low vitamin A plasma levels in the first months
after birth significantly affect the development of the
baby in general and its susceptibility to infection.
Recurrent infections have often been observed when
retinol plasma levels were low [10, 41, 98]. Such
infections rank among the main complications of
vitamin A deficiencies, which occur in developing
countries, for example. Moreover serum vitamin A
levels decrease further during infections, particularly
of the respiratory tract, because of increased meta-
bolic needs as well as increased renal excretion of
retinol and RBP during acute infections [82, 121].
Bronchopulmonary Dysplasia in preterm infants
Bronchopulmonary dysplasia (BPD) is a chronic dis-
ease of the lung that develops during the neonatal
period (mainly, but not exclusively) in preterm in-
fants. Potential causes are artificial respiration,
barotrauma, respiratory infections, excessive liquid
supply, as well as an insufficient vitamin A status of
the preterm infant. BPD is a syndrome defined by
three characteristics: oxygen dependency, radio-
graphic abnormalities and chronic restriction of lung
function in preterm infants for a time period longer
than 28 days. Today, BPD has become rare in children
with birth weights of more than 1500 g, possibly due
to advances in respiration technology and intensive
care. Since increasing numbers of preterm infants
with very low birth weight survive today, the preva-
lence of BPD has increased again, and it is the most
common chronic lung disease in newborns. For
example, in Tennessee, USA, the incidence of BPD is
seven times higher than that of cystic fibrosis, and 15
times higher than that of chronic interstitial lung
disease or congenital malformations [50]. As BPD is a
multifactorial disease, its therapy is also complex, and
there are no standard recommendations for therapy.
One main cause of BPD may be the vitamin A
status. Some morphological changes are strongly
reminiscent of changes observed in vitamin A defi-
ciency in humans and animals. Specifically, these in-
clude the focal loss of ciliary cells with keratinized
metaplasia, necrosis of the bronchial mucosa as well
as the increase in mucous secreting cells [120, 122].
The effect of vitamin A deficiency in particular on
focal keratinized metaplasias suggests a disturbance
in differentiation at the level of gene expression.
Preterm infants at birth have much lower con-
centrations of vitamin A, vitamin A (retinol) binding
protein (RBP), and of hepatic vitamin A stores com-
pared to full-term infants [20, 56, 76, 81, 111]. Such
relative vitamin A deficiency in preterm infants is
made even more complex because of further
decreases in the vitamin A blood levels, which occur
during intensive care [47, 112, 141]. Furthermore,
preterm infants develop biochemical signs of vitamin
A deficiency at the time point of term delivery [92, 96,
140].
In addition to postnatal treatment (enteral or
parenteral vitamin A), prenatal vitamin A supply of
the developing child is the most important form of
treatment. Postnatal treatment of BPD with vitamin A
does not lead to uniform results (see chapter 6:
Vitamin A therapy of newborns). However a sufficient
prenatal supply of the expectant mother will improve
vitamin A status of the preterm infant.
Vitamin A therapy of newborns
Babies with extremely low birth weights are at obvi-
ous risk of vitamin A deficiencies as they show low
I/8 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
retinol concentrations in plasma during or just after
birth with mean values indicative of marginal
[<0.7 lmol/l (200 lg/l)] or manifest vitamin A defi-
ciency [<0.35 lmol/l (100 lg/l)] [47, 62]. According
to the recommendations of the American Academy of
Pediatrics [145], vitamin A intakes of preterm infants
should be 210–450 lg retinol per kg body weight per
day. However, further data are necessary to establish
if these intake levels shall also apply to babies with
extremely low birth weight. Nevertheless, all children
with birth weights lower than 1500 g who were given
120 lg of retinol per 100 kcal or about 122 lg per kg
body weight for a month still had hyporetinolaemia
[62]. This was particularly evident in children who
were given formula milk, mother’s milk providing
only 100 lg of vitamin A per kg per day, or parenteral
nutrition over a longer period of time without addi-
tional vitamin A supplementation.
The role of vitamin A in epithelial differentiation
has led to studies investigating the effect of high-dose
vitamin A supplementation in children with very low
birth weight, with special regards to the re-epitheli-
zation of the lung tissue after acute damage caused by
barotrauma or hyper oxygenation.
Common goal of these studies was to prevent the
development of BPD. They were evaluated according
to the criteria of the Cochrane Reviews by Darlow and
Graham (1999) [28]. Overall, the studies examined the
effect of vitamin A supplementation on vitamin A
plasma levels as well as on decreasing mortality and
morbidity in children with a birth weight between
700 g and 1500 g. Morbidity was defined as chronic
lung disease, BPD and retinopathy of the newborn.
Five out of ten studies met the selection criteria of the
Cochrane Reviews. All studies were randomized or
‘‘quasi-randomized’’ and tested a high dose of vitamin
A (intramuscular or oral administration) against
placebo or no treatment.
The meta-analysis included 149 children who were
given vitamin A, and 141 untreated children. Four of
the studies used water-soluble retinyl palmitate (600–
1200 lg vitamin A every second day or three times a
week) given intramuscularly for 28 days [13, 28, 93,
95]. In the fifth study approximately 750 lg (2500 IU)
were administered daily intravenously using a lipid
emulsion [136]. During the examination period, no or
nearly no prenatal and postnatal steroids and sur-
factant proteins were given.
One result of the meta-analysis of Darlow and
Graham (1999) was that high-dose vitamin A did not
influence the mortality of one-month-old children but
showed a clear tendency for decreased dependency on
oxygen therapy [28]. There was a significant effect of
high-dose vitamin A when mortality and oxygen
therapy were evaluated together. Further, retinopathy
in preterm infants tended to be lower.
In a multicenter study published after the meta-
analysis, 807 children with a birth weight lower than
1 kg were given 1500 lg (5000 IU) of vitamin A
intramuscularly in the form of retinyl palmitate for
three times per week for 4 weeks [128]. There was a
small but significant decrease (62% compared to 55%
for non-treated controls) of the mortality rate or in
the incidence of chronic lung diseases at the age of
36 weeks. However, the treatment did not achieve
plasma retinol levels above the level indicative of
biochemical deficiency (0.7 lmol/l) in all children.
The multicenter study showed that a 1500 lg
(5000 IU) dose of vitamin A administered three times
a week is necessary to maintain normal biochemical
vitamin A status [128]. An expert panel of the Life
Sciences Research Office (LSRO) of the American
Society for Nutritional Sciences (ASNS) has recom-
mended, however that preterm infants be given at least
204 lg of RE (retinol equivalents)/100 kcal (680 IU/
100 kcal) and at most 380 lg of RE (1267 IU)/100 kcal
for preterm infants [60].
In conclusion, high-dose vitamin A seems to play a
role in the prevention of BPD. Further studies are
needed to support the effects of high-dose vitamin A
applied in conjunction with steroid therapy, as is
commonly done today in clinical practice. When gi-
ven to children with extremely low birth weights,
steroids and in particular dexamethasone, induce
temporary increases in plasma retinol and RBP pre-
sumably by stimulating their release from the liver
and from stores in the lungs [43, 114]. The results of
the meta-analysis demonstrate that compensating for
vitamin A deficiencies of preterm infants and new-
borns is only partially successful. Much more
important is ensuring sufficient vitamin A stores of
the child. This occurs mainly during the last 90 days
of pregnancy and can only be ensured by a diet
supplying considerable amounts of b-carotene-rich
fruit and vegetables or preformed vitamin A (for
example 50–100 g of liver/week).
Weekly supplementation of women in Nepal with
vitamin A (7 mg) or b-carotene (42 mg) reduced
mortality during pregnancy by 40% and 49% [138].
The apparent reason for reduced mortality risk was
less susceptibility to infection.
General considerations on b-carotene as a source
of vitamin A
j Bioavailability and bioequivalence
Bioavailability is defined as the fraction of a substance
(e.g. carotenoids), which is available for normal
physiological functions or for storage. Bioconversion
M. Strobel et al. I/9
Vitamin A in pregnancy and lactation
refers to the amount of a carotenoid converted to
retinol in the body.
Carotenoids are lipophilic substances absorbed
from the small intestine along with other lipids and
reappearing in the lipoprotein fractions of the plasma,
as well as in erythrocytes and leucocytes [68, 71, 94].
The largest portion of the carotenoids in lipoproteins
is found in LDL (75–80%) followed by HDL with 10–
25% and in VLDL with 5–10% [72]. Increases in
plasma concentration after carotenoid intake are
subject to large inter-individual variation [34].
Typical serum levels of the most common carotenoid
b-carotene range from 0.2–0.5 lmol/l [16]. Non-ab-
sorbed b-carotene is exclusively found in the feces
while apocarotenals and not identified fragments have
also been found in urine [46, 69].
Factors determining bioavailability and biocon-
version are grouped under the mnemonic ‘‘SLAM-
ENGHI’’ (Species of carotenoid, molecular Linkage,
Amount of carotenoids consumed in a meal, Matrix in
which the carotenoid is incorporated, Effectors of
absorption and bioconversion, Nutrient status of the
host, Genetic factors, Host-related factors and math-
ematical Interactions) [137]. The type and amount of
carotenoids in plasma reflect those contained in the
diet.
The bioavailability of carotenoids is influenced by
the form in which they are present in the food matrix,
especially if they are in crystalline form, esterified
and/or emulsified in fat. Depending on the fat content
of the meal, absorption from plant foods ranges be-
tween 30% and 60% and is subject to large inter-
individual variation [35, 101]. The following Fig. 7
summarizes these effects using a number of examples.
Intake of b-carotene from supplements results in a
larger plasma level increase compared to intakes of
corresponding amounts from vegetables. Studies
conducted by Micozzi et al. (1992) demonstrated that
supplementation with a low dose of b-carotene
(12 mg per day) leads to significantly greater
increases in plasma concentrations (from 0.3 to
3.9 lmol/l) than can achieved by intake from foods
[75]. These results were corroborated by findings
from Le Marchand et al. (1994), who showed that
doubling fruit and vegetable intake only increased the
b-carotene plasma level by 40% [64].
In addition to fat, a number of other nutrients can
impact carotenoids absorption, metabolism and bio-
conversion if consumed in conjunction with carote-
noids. Proteins help to stabilize the fat emulsion in
the small intestine and along with lecithin support
micelle formation. The stomach pH can also consid-
erably influence the absorption of carotenoids: After
administrating a single dose of 120 mg b-carotene, its
absorption at a pH value of 6.4 was only half as much
at normal stomach pH (at about 2) [127]. Genetic
factors that influence carotenoid absorption might be
linked to fat absorption. Dividing a daily carotenoid
dose into three single doses can improve absorption,
as well as the presence of bile acids [91, 100].
The greatest absorption rate is achieved by carot-
enoids dissolved in oil, so that 3.3 lgofb-carotene
can be converted into 1 lg of retinol [53]. Bioavail-
ability of carotenoids from most other foods is much
lower than from those prepared with oil. Therefore in
1967, ‘‘6’’ was established as the mean conversion
factor for calculating retinol equivalents (RE) from
carotenoids [37]. However, more recent studies
showed that the bioavailability of b-carotene from
vegetables is much lower than previously assumed,
and that the so far accepted conversion factor most
probably overestimates the contribution of carote-
noids to the dietary vitamin A supply [29, 30]. De Pee
(1995, 1998) now recommends a conversion factor of
12 for b-carotene from fruits and 26 for b-carotene
from vegetables, instead of the current 6 [29, 30]. The
following table shows the various conversion factors
for different foods and the corresponding literature
sources.
When evaluating studies that examined the bio-
availability from foods versus dietary supplements, it is
obvious how much bioavailability can vary, and how
important b-carotene sources with high bioavailability
and thus bioconversion, such as food supplements, can
be to ensure sufficient vitamin A intakes.
Table 5 lists the most important studies regarding
bioavailability. As shown in the table, subjects received
either food supplements or a specific diet for a period of
three to nine weeks. Following the supplementation
period, plasma b-carotene levels were determined. The
bioavailability and bioconversion of a given food and
thus a food group can be estimated from the increases
in plasma b-carotene concentrations upon supple-
mentation or the specific diet. Thus, a conversion factor
may be established to determine the amount of b-car-
otene required from a specific food source in order to
Fig. 7 Influences of the matrix on the bioavailability of beta-carotene [32]
I/10 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
provide 1 lg of RE. A pre-requisite for deriving this
conversion factor from dietary supplementation stud-
ies, however, is that the bioefficacy of b-carotene dis-
solved in oil needs is known.
The efficacy of purified b-carotene dispersed in oil
was first established in 1949 in a study involving two
subjects with overt vitamin A deficiency [51]. After
18- and 22-month depletion the subjects were given b-
carotene in oil for six months and five weeks. The
impaired vision (reduced dark adaptation) that had
occurred due to depletion was reversed by adminis-
tering a dose of 2500 IU of b-carotene in oil or
1300 IU of vitamin A. Therefore an effect ratio of 2:1
was defined.
The basis of these data from 1949, however, is now
regarded as highly questionable: Today, it is known
that the correction of dark adaptation via b-carotene
occurs through via the action of the enzyme 15, 15¢-
dioxygenase that is found in the pigment epithelium,
but not, as was assumed at that time, only by for-
mation of vitamin A from b-carotene in the intestine.
Therefore, even low amounts of b-carotene may
produce that effect.
To calculate the bioefficacy of individual foods in
the following Table 5, the conversion factor defined
by the International Union of Pure and Applied
Chemistry (IUPAC) in 1959, was used: 3.3 lgofb-
carotene in oil correspond to 1 lg of retinol [53].
In 2001 the Food and Nutrition Board (FNB)
published a new conversion factor in the USA, in
addition to new recommendations for vitamin A
intakes [31]. The long used unit for vitamin A intake
(Retinol Equivalent, RE) was replaced by a new unit
named the retinol activity equivalent (RAE). Accord-
ing to this new unit, the vitamin A activity of carot-
enoids absorbed from foods as provitamin is now half
its former value. The RAE of b-carotene was defined
as 12 lg of carotenoids per 1 lg of retinol [31].
Therefore, the new values show a provitamin activity
of b-carotene from fruit and vegetables, which is only
half of the previous RDAs (Recommended Dietary
Allowances) [103].
The application of a conversion factor of 12, instead
of 6, to VERA data would result in a more than 15%
reduction of the total vitamin A intakes in Germany.
The percentage of people achieving just 50% of the
recommended intakes would increase considerably.
Previously, an average of 87% of the total vitamin A
requirement was met by children and adolescents
(females, 4 £ 19 years). Using the conversion factor of
12 instead, the requirements are met by on average less
than 70% in these population subgroups.
Daily carotene intake of women was calculated as
1.64 mg a day by Schneider et al. (1995), which is only
82% of the recommended intake considering a rec-
ommended daily intake of 2 mg [107]. According to
data from the VERA study, 52% of these come from
fresh vegetables and about 10% from juices and non-
alcoholic drinks (Fig. 8).
These calculations, however, are purely based on
consumption data and do not account for differences
in bioavailability from different foods. Taking into
account differences in bioavailabilty using conversion
factors as stated in Tables 4 and 5, weighing of the
food groups shifts in favor of juices and non-alcoholic
drinks. Figure 9 shows the intake of b-carotene in RE
calculated using conversion factors proposed by
De Pee et al. (1998) (fresh vegetables: 26:1, vegetarian
products and fruits: 12:1 and other foods: 6:1) in
comparison with a calculation using the conversion
factors as recommended by the FNB; naturally
occurring b-carotene: 12:1) [30, 31]. Juices and non-
alcoholic drinks are considered in both cases with the
factor 4:1 because b-carotene is more readily bio-
available from juices and juices and non-alcoholic
drinks are frequently fortified with b-carotene.
Using the conversion factors proposed by De Pee
et al. (1998) results in higher intakes in terms of RE
from juices and non-alcoholic drinks compared with
intakes from fresh vegetables [30]. If fortification of
juices and non-alcoholic drinks with b-carotene is
reduced, or consumption of such products is
decreased, consumers lose an important source of
vitamin A, and certain risk groups, will have insuffi-
cient intakes.
Even when using the conversion factor of the FNB
(12), beverages remain an important source of
b-carotene that should not to be ignored.
Plasma and tissue concentrations in the German
population
Mean b-carotene plasma levels in Germany are 0.3–
0.6 lmol/l. Studies from other countries indicate
differences in b-carotene levels of 20–100% between
men and women [5, 6, 19, 26, 55, 85]. Additional
factors that can influence carotenoid status are age,
disease and/or diet. Even short-term supplementation
of physiological amounts of b-carotene results in
considerable changes in plasma concentrations. As
Table 4 Conversion factors for b-carotene according to the food matrix
Matrix Conversion factor Source
Oil 3.3 [53]
Mixed food beta-carotene supply <1 mg: 4 [37]
beta-carotene supply 1–4 mg: 6
beta-carotene supply >4 mg: 10
Fruit 12 [30]
Vegetables 26
Fruit and vegetables (1:4) 21
M. Strobel et al. I/11
Vitamin A in pregnancy and lactation
Johnson et al. (1995) observed a short-term increase
of 127% (0.54 ± 0.11 lmol/l) occurred after a single
b-carotene administration of 120 mg [58].
Long-term supplementation of carotenoids leads to
sustained increases in serum concentration with a
plateau being reached after 4 weeks on average, and
plateau concentrations varying from individual to
individual [57, 70, 134].
Which plasma and tissue concentrations may be
related to good health, or may be critical, and the
means of achieving these are the subject of numerous
discussions. The Consensus Conference on antioxi-
dants concluded that a plasma level greater than
0.4 lmol/l, as achieved from a daily intake of 2–4 mg
of b-carotene, can be regarded as desirable regarding
disease prevention [17]. However, based on the find-
ings of two intervention studies (ATBC, CARET), a
value for plasma levels must be determined corre-
sponding to a limit value for a tolerable upper intake
level (UL). Because the Food and Nutrition Board
(FNB) did not define a tolerable upper intake level
(UL) for b-carotene, the plasma levels achievable from
supplementation need to be taken as the limit value to
assess safety. A key question to address is whether a
critical plasma level will be exceeded by a defined b-
carotene dosage. According to the definition given by
the Consensus Conference on Antioxidants, the
‘‘critical plasma level’’ is a level greater than 3 lmol/l
[17]. Thus, it must be determined whether a specific
amount of b-carotene consumed for a certain period
of time will result in plasma levels exceeding this
‘‘critical plasma level’’, taking into account individual
variability. Unfortunately, there is very few scientific
data to answer this question, and the data available is
of very variable quality due to the large number and
not standardized methods of measurement used, but
it also reflects the high degree of variability of indi-
vidual b-carotene plasma levels.
Inter-individual variability
The plasma levels of b-carotene are on average higher
in women than in men with differences of between 20
Table 5 Bioavailability and bioconversion of b-carotene from diet and dietary supplements
Ref. Group of test persons Design of study Dosage Result Resultant conversion
factors
[75] 30 men,
20–45 years,
USA
Diet/supplementation,
6 weeks
Dietary supplement:
30 mg/d
Carrots: 30 mg/d
Broccoli: 6 mg/d
Increase in the beta-carotene plasma
values via carrots corresponded to
18% of the increase via the dietary
supplement
For carrots: 18.3
For broccoli: 27.5
Increase via broccoli corresponded
to 12% of the increase via the
dietary supplement
[29] 173 children,
7–11 years,
Indonesia
Diet, 9 weeks Vegetables: 3.5 mg/d
Fruit: 2.3 mg/d
Increase in the beta-carotene plasma
values was 5–6 times higher in the
case of a diet with fruit compared to
a diet with fruit compared to a diet
with vegetables
[129] 42 women,
20–53 years,
Finland
Diet/supplementation,
6 weeks
Diet with small amount
of carotenoids
Increase in the beta-carotene plasma
values via raw carrots corresponded
to 26% of the increase via dietary
supplements
For carrots: 12.7
[30] 188 anemic pupils,
7–11 years,
Indonesia
Diet, 9 weeks + raw carrots: 12 mg/d
+ dietary supplement
Fruit: 509 lg/d
Dark green leafy vegetables
+carrots: 684 lg/d
Diet with small amount of
total vitamin A
Increase in the beta-carotene plasma
values was 3.5 times higher in the
case of the diet with fruit compared
to the diet with green leafy
vegetables (+carrots)
Recommended factors
a
For vegetables: 26
For fruit: 12
[22] 72 men and women,
18–58 years,
Netherlands
Diet/supplementation,
3 weeks
Control diet: 0.5 mg/d
Dietary supplement:
9.8 mg/d
Spinach: 10.4 mg/d
Increase in the beta-carotene plasma
values via spinach corresponded
to 5% of the increase via dietary
supplements
For spinach: 66
[131] 55 men and women,
18–45 years,
Netherlands
Diet/supplementation,
4 weeks
Dietary supplement:
7.2 mg/d
Mixed vegetables: 5.1 mg/d
Increase in the beta-carotene plasma
values via vegetables corresponded
to 14% of the increase via dietary
supplements
For vegetables: 23.6
a
factors recommended by the authors
The calculation of the conversion factor is based on the assumption that 3.3 lg of beta-carotene in oil correspond to 1 lg of retinol [53]
The factors shown in parentheses are calculated based on the assumption that 2 lg of beta-carotene in oil correspond to 1 lg of retinol [31]
I/12 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
and 100%, depending on the study [5, 6, 19, 26, 55,
85]. Markedly reduced plasma levels of b-carotene are
observed in smokers and alcoholics [1, 24, 54, 63, 66,
105, 123, 129]. Even low daily alcohol consumption
(0.5 g/kg body weight/day) can lead to clear reduc-
tions in b-carotene plasma levels [125]. Further fac-
tors affecting plasma levels are age, illness and/or the
type of diet. In addition to these more obvious
parameters, there are others requiring more study
such as responder type and interaction with other
micronutrients (tocopherols, retinol, other carote-
noids) [74]. These interrelationships are often unclear
and even partly contradictory [3, 45].
The rise in plasma concentrations, which can be
achieved through a specific dose, cannot be clearly
predicted on the basis of the studies conducted during
the previous 12 years (Fig. 10). The average plasma
levels of healthy humans vary between 0.2 and
0.6 lmol/l, taking into account the variations dis-
cussed above. With daily dosages ranging from 12 to
about 15 mg, plasma levels between 3 and 4 lmol/l
are reached, often even after just a few (4–6) weeks of
supplementation. With a few exceptions, markedly
greater increases were observed only with signifi-
cantly higher doses (100–580 mg/day). Here plasma
levels of 7 to higher than 12 lmol/l were reached.
Lower dosages (20 mg) can lead to higher levels
(7 lmol/l) if daily supplementation is continued over
a number of years [2]. Such high dosages cannot be
considered as ‘‘normal’’ supplementation level for the
general population, but may well be of importance in
specific circumstances.
Very little is known about the time-dependent
course of plasma b-carotene during a dietary sup-
plementation regimen because most studies have only
determined an end value. According to Prince and
Frisoli (1993) the half-life of b-carotene in plasma is
independent on the daily dosage and is approximately
9–10 days. In their study, the steady state was reached
after about 30 days (Fig. 11), and was depended on
the daily dose [100]. Once supplementation was
stopped, plasma concentrations dropped exponen-
tially (half-life about 10 days). Comparable results
had already been presented previously by Ringer et al.
(1991) [106]. At daily doses of b-carotene between
15 mg and 180 mg a plateau was reached in all groups
after 2–4 weeks, with the plateau concentrations
depending on the given dose. However, it is unclear if
and how plateau concentrations can be modified by
other parameters. According to animal experiments,
the activity of 15,15¢-dioxygenase, the enzyme that
cleaves b-carotene to form vitamin A in the intestinal
mucosa, depends upon the retinol status of the animal
[133]. Therefore, in the case of suppressed dioxy-
genase activity (for example during simultaneous in-
take of vitamin A), the bioavailability of b-carotene
may be increased.
Despite of the importance to answer such ques-
tions, interactions with other nutrients in humans
have only been investigated in few studies. The results
were often contradictory, for example with regard to
vitamin E. While some researchers observed a de-
crease in vitamin E plasma levels upon b-carotene
supplementation others found no such decrease or
even observed a slight increase [3, 18, 45, 79, 86, 139,
142]. Provided that there is no deficiency retinol
plasma levels are not affected by b-carotene supple-
mentation as has been reported consistently [3, 99,
139]. Synergistic effects of simultaneous administra-
tion of b-carotene and vitamin A have not been
investigated yet. However, data from animals suggest
that such an interaction may occur, modulated via
regulation of the 15, 15¢-dioxygenase activity.
In conclusion, b-carotene plasma levels are subject
to strong inter-individual variations, which are partly
due to factors such as gender, age, diet, nicotine and
Fig. 9 Percentage of different food groups of total retinol intake compared
with recommended intake in % (women with a mean supply of 0.8 mg/day).
Blue line: Recommended intake in % (cumulative) [29, 30]
Fig. 8 Percentage of different food groups of total intake of b-carotene in
comparison with recommended intake in % (women with a mean intake of
1.64 mg/day) [107]
M. Strobel et al. I/13
Vitamin A in pregnancy and lactation
alcohol consumption. Supplementation of b-carotene
leads to a marked increase in plasma levels, on
average by factor 10. After about 4 weeks, a plateau is
reached. The plateau level achieved is not only
dependent on the daily dose but also on the food (or
supplement) matrix, daily dose frequency, simulta-
neous intake of fat, as well as the baseline levels of the
individual. Once supplementation is discontinued,
plasma concentrations return to baseline levels within
a few weeks. It is not yet well understood if and to
what extent interactions with other micronutrients
affect the absorption of b-carotene.
Conclusions
b-carotene is a substance widely distributed in nat-
ure and found in foods of plant origin. b-carotene
concentrations in these foods are, however, subject
to considerable variation. b-Carotene is an important
nutrient due to the many functions in the human
body, depending on its metabolization: b-carotene
acts as antioxidant, by quenching singlet oxygen and
scavenging peroxyl radicals. Further, the apocarote-
nals obtained from eccentric cleavage may exert
their own effects, as is currently addressed in many
studies.
Long before the importance of b-carotene as anti-
oxidant was established, b-carotene was known as
provitamin A and thus as a precursor for an essential
nutrient. This function became a ‘‘side issue’’ during
the period of high interest in the antioxidant effects of
b-carotene, and was re-considered recently when
studies re-examined if and how much b-carotene is
needed to meet the vitamin A requirements of hu-
mans by b-carotene alone. This was especially
important for regions of the world where the provi-
tamin represented the major source of vitamin A, as
diets lack preformed vitamin A. A pre-requisite for b-
carotene being used as precursor for vitamin A is that
the provitamin present in foods is bioavailable and
converted to vitamin A. Established b-carotene con-
version factors vary between 4:1 (fortified juices) and
26:1 (fresh spinach) depending on the individual
food. The conversion of b-carotene dispersed in oil,
the form found in food supplements, is assumed to be
3.3 while for fortified juices the conversion rate is 4:1–
6:1, for fruit 12:1 and for vegetables 26:1. The Food
and Nutrition Board of the USA 31 cited 12:1 as the
general conversion factor for typical plant based
foods, i.e., 12 mg of b-carotene needs to be consumed
in order to produce 1 mg of vitamin A; the daily
recommended dose. The b-carotene intake in
Germany is approximately 2 mg per day, and usually
Fig. 10 b-carotene plasma values from supplementation of different daily
doses (the numbers in the graphic show the individual daily doses of
b-carotene in mg)
4
3
2
1
0
010
20
30 40
010
20
30 40
Time (days)
Time (days)
17 mg tid
Serum Carotenoids (mg/L)
Serum Carotenoids (mg/L)
8
6
4
2
0
102 mg tid
1
5
2
4
3
Yellow
Stool
Yellow
Skin
1
2
3
4
5
β-carotene
Retinol (ave.)
Lycopene (ave.)
Fig. 11 Temporary course of the plasma concentrations during a supplemen-
tation of two different daily doses (source [100])
I/14 European Journal of Nutrition Vol. 46, Supplement 1 (2007)
Steinkopff Verlag 2007
lower, according to the four studies available so far.
This means that b-carotene from food sources con-
tributes at the most to 10–15% of the recommended
vitamin A intakes. For calculating the vitamin A in-
take, which amounts to on average about 1 mg/day in
Germany and thus meets the current recommenda-
tions (1 mg), the contribution of b-carotene is in-
cluded in the calculation using a conversion factor of
6. This means, unfortunately, that the actual contri-
bution of b -carotene to the vitamin A intake is
overestimated, due to the poorer conversation rates of
b-carotene known today. Children and adolescents,
for example, hardly meet the recommended vitamin A
intakes for their age groups. Even more critical, for
pregnant and breastfeeding women it is nearly
impossible to meet the higher intakes recommended
for their special situation. If the more recent, now
accepted conversion factors were applied, the vitamin
A intakes of these risk groups would be even worse.
Adolescents would only consume about 70% of the
recommendations for vitamin A intakes, and preg-
nant and breastfeeding women even less, especially if
they do not consume liver. NHANES III showed that
16–33% of all children examined (mainly from lower
income families) aged between 4 and 8 years had
critically low vitamin A blood levels [9]. This is a
serious condition as retinol levels only decrease if the
liver stores are almost depleted. According to the
third nutrition report of the FASEB, too low vitamin A
intakes have to be considered a frequent and serious
health problem [39].
Considering the improved bioavailability of
b-carotene from food supplements (conversion rate
3.3:1) and the fortification of beverages and other
foods, specifically those with a lipid matrix, fortified
foods and food supplements potentially play an
important role in supplying vitamin A to the popu-
lation. Studies conducted in Germany show that
b-carotene accounts for up 25–30% of vitamin A
intakes. Considering a conversion factor of 12:1, 30%
of the total b-carotene intake is derived from fortified
juices and the so-called ‘‘ACE drinks’’, implying that
about 10% of the total vitamin A supply comes from
juices and other beverages. This is especially impor-
tant for young women who are known to avoid meat
and innards. A restriction of, or a warning label on
such fortified foods or food supplements, cautioning
against b-carotene, would cause young women,
especially those considering pregnancy, to avoid those
foods completely. This may create a difficult situation,
as indicated already by a number of recent studies:
insufficient vitamin A intakes in spite of ample pos-
sibilities to ensure adequate intakes.
There are two main causes for that: Young women
and those considering pregnancy have been repeat-
edly advised to avoid the consumption of liver be-
cause of the claimed risk for very high vitamin A
levels in liver [14]. However, a risk for too high
vitamin A intake in form of preformed vitamin A
exists, if at all, only during the first 4 weeks of preg-
nancy, but not later. Furthermore, assuming an
absorption rate of 40%, it is hardly possible to con-
sume critical amounts of vitamin A from 100 g of
liver. In addition, the actual teratogenic substance is
not vitamin A (retinol), but its metabolite retinoic
acid, which does not occur in foods, but will only be
synthesized from retinol in the body. Since the syn-
thesis of retinoic acid from retinol is strictly con-
trolled, even excessive retinol intakes will not result in
supra-physiological levels of retinoic acid. Thus, the
warning against liver consumption is not based on
scientific evidence, and may have caused the low
consumption of liver to decrease even further, espe-
cially among young women. The amount of liver
consumed in Germany is approximately 500 g/capita/
year and has probably ceased completely for young
women, as confirmed by data from Austria and the
UK [40].
b-carotene in plant foods as previously discussed,
is only a limited vitamin A source. Nevertheless, it
may be an important vitamin A source if provided in
sufficient amounts. In Germany the recommendations
are just about reached even though food supplements
and fortified food have already been considered. Not
only the health of the mother may be at risk if vitamin
A intakes are insufficient, but also and even more so
the development of the child. Studies from the UK
demonstrated that decreasing energy intakes
(<1800 kcal) results in reduced intakes of various
micronutrients, particularly folic acid, iron and vita-
min A, and is associated with low birth weight. The
overall development of the baby, and especially lung
development and maturation of the embryo, is
essentially depending on a sufficient vitamin A sup-
ply. If vitamin A supply is low, vitamin A stores in the
lung especially of preterm babies are low. Vitamin A
stores are, however, necessary to ensure proper lung
development, including expression of surfactant
proteins and a number of factors for growths and
differentiation. In preterm infants the vitamin A
blood levels are usually too low because the liver
cannot yet produce sufficient retinol binding protein
in order to secrete vitamin A. Therefore it is critical to
develop sufficient vitamin A stores in the lung, which
happens in the third trimester of pregnancy. If not,
these children will be at increased risk for broncho-
pulmonary dysplasia (BPD), one of the most frequent
and threatening respiratory diseases in preterm in-
fants. Postnatal treatment with vitamin A was only
moderately successful so far, strongly suggesting that
maternal vitamin A supply in the third trimester of
pregnancy is essential for the development of suffi-
M. Strobel et al. I/15
Vitamin A in pregnancy and lactation
cient vitamin A stores for proper lung development.
The same applies to babies, which are breastfed and
thus get their vitamin A via their mother’s milk. If the
vitamin A status of the mother is low, an adequate
supply to the baby cannot be ensured, which has been
associated with increased sensitivity to respiratory
diseases caused by the respiratory syncytial virus
(RSV). A significant relation between RSV-associated
lung disease and previous BPD has been demon-
strated.
A further scientifically not justified restriction of
vitamin A sources initiated by authorities places the
safe and adequate vitamin A supply at risk. Due to
better bioavailablity particularly b-carotene fortified
foods contribute significantly to vitamin A intakes.
Restrictions, which are largely relevant to smokers
should be considered very carefully: The application
of warning labels or other measures on products may
avoid those who depend on such products (e.g. young
women considering pregnancy) consuming them.
Scientific evidence on the risks of an insufficient
vitamin A status for lung maturation and develop-
ment of the fetus and the baby are much more con-
vincing and accepted by the scientific community
than the evidence for developing lung cancer upon
high b-carotene intakes. Furthermore, the dosages
used in the studies on lung cancer can not be achieved
in Germany from foods, even if fortified foods are
included, even less so on a long term basis. Until the
contribution of b-carotene containing food supple-
ments and fortified foods to vitamin A intakes has
been fully clarified, any restrictive limitations should
be avoided. This does not mean that label indications
specific for smokers might not be useful, or that
higher b-carotene dosages (>5 mg per day) might be
refined to licensed medicines. The main focus should
however be on diet and health education measures,
which communicate the risk for micronutrient defi-
ciencies especially in young women, and offer strat-
egies for avoiding such risks.
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Though considered an agricultural country, the Philippines is the world’s largest importer of rice. The persistent problem of insufficient rice supply, however, has been exacerbated by economic crises and natural calamities. Yet, for the Higaonon tribe in Bukidnon Province, the Philippines, the rich agrobiodiversity and wild edible plants are vital for food security and resilience since the mountainous terrain in this province presents a challenge for rice cultivation. To gain insight from the indigenous edible plant knowledge of the Higaonon tribe, we conducted an ethnobotanical research to document the diversity, utilization, and biocultural refugia of both cultivated and wild edible plants. A total of 76 edible plant species belonging to 62 genera and 36 botanical families were documented. The most represented botanical families included the Fabaceae, Solanaceae, and Zingiberaceae. In terms of dietary usage, 3 species were categorized as cereals; 8 species were white roots, tubers, and plantains; 3 species were vitamin A-rich vegetables and tubers; 16 species were green leafy vegetables; 12 species were categorized as other vegetables; 2 species were vitamin A-rich fruits; 27 species were classified as other fruits; 7 species were legumes, nuts, and seeds; and 8 species were used as spices, condiments, and beverages. Using the statistical software R with ethnobotanyR package, we further calculated the ethnobotanical indices (use-report (UR), use-value (UV), number of use (NU), and fidelity level (FL)) from 1254 URs in all 9 food use-categories. The species with the highest UV and UR were from a variety of nutrient-rich edible plants such as Ipomoea batatas (L.) Lam., Musa species, Colocasia esculenta (L.) Schott, Zea mays L., and Manihot esculenta Crantz. The extensive utilization of root and tuber crops along with corn and plantain that contain a higher amount of energy and protein, carbohydrates, minerals, and vitamins were shown to be an important nutrient-rich alternatives to rice. Whilst males appeared to be more knowledgeable of edible plant species collected from the forests and communal areas, there were no significant differences between males and females in terms of knowledge of edible plants collected from homegardens, riverbanks, and farms. The various food collection sites of the Higaonon tribe may be considered as food biocultural refugia given their socio-ecological function in food security, biodiversity conservation, and preservation of indigenous knowledge.
... Vitamin A is involved in several functions, such as normal immune and visual system function, epithelial integrity and red blood cell production [17,23,24], especially during pregnancy. Vitamin A affects the antibody response to T-cell-dependent antigens, which is also directly modulated by retinoic acid [25]. ...
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Numerous approaches demonstrate how nutritional intake can be sufficient to ensure the necessary supply of vitamins. However, it is evident that not all vitamins are contained in all foods, so it is necessary either to combine different food groups or to use a vitamin supplement to be well-fed. During pregnancy, deficiencies are often exacerbated due to increased energy and nutritional demands, causing adverse outcomes in mother and child. Micronutrient supplementation could lead to optimal pregnancy outcomes being essential for proper metabolic activities that are involved in tissue growth and functioning in the developing fetus. In order to establish adequate vitamin supplementation, various conditions should be considered, such as metabolism, nutrition and genetic elements. This review accurately evaluated vitamin requirements and possible toxic effects during pregnancy. Much attention was given to investigate the mechanisms of cell response and risk assessment of practical applications to improve quality of life. Importantly, genetic studies suggest that common allelic variants and polymorphisms may play an important role in vitamin metabolism during pregnancy. Changes in gene expression of different proteins involved in micronutrients’ metabolism may influence the physiological needs of the pregnant woman.
... Only one study assessed plasma retinol simultaneously for women during pregnancy and postpartum [12], and reported that retinol decreased from mid-to late pregnancy, increased after delivery, and then returned to the level before conception by 6-wk postpartum. These results suggested that women are becoming more vulnerable to vitamin A depletion as pregnancy progress, warranting that women particularly during late pregnancy when adequate plasma vitamin A is crucial for foetal lung maturation [36], need to be concerned. Additionally, trimester-specific cutoffs of plasma retinol concentrations for defining vitamin A deficiency in pregnant women are warranted to be studied. ...
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PurposeTo examine plasma retinol status and its determinants in Chinese pregnant or lactating women.MethodsA cross-sectional study involving 1211 healthy women in mid-pregnancy, late pregnancy, or lactation was conducted in northern, central, and southern China. Plasma retinol concentration was determined by high-performance liquid chromatography. Multivariate quantile regression or modified Poisson regression was used to estimate adjusted medians, or to examine the associations of suboptimal retinol concentration (< 1.05 µmol/L) with various factors.ResultsThe overall median (interquartile range) retinol concentration was 1.25 (1.06–1.46) µmol/L. The adjusted concentration was higher in women at lactation (1.39 [1.20–1.63] µmol/L) and mid-pregnancy (1.26 [1.10–1.44] µmol/L) than late pregnancy (1.07 [0.92–1.28] µmol/L), and higher in women in the central area (1.34 [1.18–1.49] µmol/L) and the north (1.26 [1.10–1.43] µmol/L) than the south (1.19 [1.07–1.31] µmol/L). The retinol concentration was more likely to be low in women with lower pre-pregnancy BMI, younger age, less education, and in lactating women who had a caesarean birth or were breastfeeding exclusively. A total of 290 (24.0%) women had a suboptimal retinol concentration, and the prevalence was higher in women at late pregnancy, residing in the south, with younger age, and having underweight pre-pregnancy.Conclusion About one-fourth of pregnant or lactating women in China had suboptimal retinol concentrations that varied with phases of pregnancy and lactation, region of residence, and socio-demographic characteristics, indicating a need for population-specific public health strategies to optimize vitamin A status.