British Journal of Nutrition (2001), 85, Suppl. 2, S81±S86 DOI: 10.

1049/BJN2000298
q The Author 2001

Immunobiology of gestational zinc deficiency

Nele Wellinghausen
Department of Medical Microbiology and Hygiene, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany

The trace element zinc is an essential micronutrient for the proper functioning of the immune
system. Zinc deficiency leads to impaired function of the unspecific and specific immune
response and consequently to an increased susceptibility to bacterial, viral and fungal infections.
Immunological defects are not only seen in pronounced but even in marginal and moderate zinc
deficiency. Lack of zinc is especially harmful for the development of the immune system, which
stresses the importance of a balanced zinc level during pregnancy. However, gestational zinc
deficiency due to an imbalance between intake and increased requirements is a common
problem world-wide. In animals, gestational zinc deficiency results in reduced thymic and
spleen size and depressed active and passive immunity in the infant. For example, depressed
immunoglobulin levels, altered antibody repertoire, reduced proliferative response of lympho-
cytes and diminished neutrophil functions have been reported. Interestingly, immune defects
caused by prenatal zinc deficiency, such as depressed antibody levels and lymphocyte
proliferation, may even persist in subsequent generations and are not reversible by postnatal
zinc administration. Since gestational zinc deficiency is a common problem throughout all
cultures and socioeconomic levels, it might have immense consequences for the health status of
the population. Based on a summary of the immunobiology of zinc, this article reviews the
significance of zinc deficiency during pregnancy and the effect of gestational zinc deficiency on
passive and active immunity in the infant. It provides a rational basis for both immunological
laboratory investigations and field studies, such as large community-based zinc supplementation
trials in pregnant women.

Zinc deficiency: Pregnancy: Zinc supplementation: Immunology

Introduction zinc deficiency, the significance of zinc deficiency during

pregnancy and the influence of gestational zinc deficiency
The significance of zinc for human nutrition was
on passive and active immunity in the infant.
discovered some decades ago (Prasad, 1991) but only
now are the mechanisms responsible for the pathophysiol-
ogy of zinc deficiency becoming clear. The observed
Zinc requirements
association between increased susceptibility to infectious
diseases and nutritional zinc deficiency led researchers to Zinc deficiency in humans is mainly due to a lack of
hypothesize that the trace element zinc must be important bioavailable zinc in the diet, general malnutrition or
for immunity. The most extreme form of zinc deficiency malabsorption (Good, 1981; Prasad, 1995). Nutritional
can be studied in the zinc-specific malabsorption syndrome zinc requirements are difficult to determine since many
acrodermatitis enteropathica, a rare autosomal recessive dietary factors affect the bioavailability of zinc, and
inheritable disease (Neldner & Hambidge, 1975). The physiological requirements of zinc vary greatly between
immunological significance of zinc, however, also becomes different age groups. However, recommended daily allow-
clear in several more frequent conditions, particularly in ances (RDA by the US National Research Council) of 5 mg
malnutrition. Lack of zinc is especially harmful to the zinc for infants (i.e. children up to one year of age), 10 mg
development of the immune system when it occurs during for children aged 1±14 years, 12 mg for adolescents and
critical periods of ontogeny, which stresses the importance nonpregnant and nonlactating females, and 15 mg for
of a balanced zinc level during pregnancy. However, pregnant and lactating women and male adults appear
gestational zinc deficiency due to imbalances between reasonable to achieve a normal plasma zinc level of
intake and increased requirements is a common problem 11±18 mM (National Research Council, 1989). In a
world-wide. In this article, the significance of zinc recent survey, the Third US National Health and
deficiency for immune function will be reviewed. Special Nutrition Examination Survey, it was shown that these
attention will be drawn to the role of mild and moderate age- and sex-specific RDAs are achieved in the diet of

Corresponding author: Dr Nele Wellinghausen, fax 149 731 502 3473, email [email protected]

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 S82 N. Wellinghausen

Table 1. Immunological consequences of zinc deficiency

Effects on specific immunity Effects on innate immunity

Increased involution of the thymus: Decreased natural killer cell activity
X decreased thymocyte count in the thymus
X decreased serum level of thymulin

T-cells: Decreased macrophage functions:

X diminished peripheral T-cell count X phagocytosis
X impaired delayed hypersensitivity X intracellular killing
X decreased proliferative response to PHA
X decreased activity of cytotoxic T-cells
X decreased activity of helper T-cells

B-cells: Decreased neutrophil functions:

X decreased antibody production X chemotaxis
X oxygen burst

approximately 55 % of the US population (Briefel et al. defect (Crea et al. 1990). Furthermore, binding of zinc to
2000). The US National Research Council RDAs are based immunoglobulins with as yet unclear functional relevance
on a dietary availability of zinc of approximately 20 % has been shown (Prasad & Oberleas, 1970). Overall, the
when compared to the recommendations of the World clinical consequence of zinc deficiency is an impaired
Health Organization (National Research Council, 1989; defence against bacterial, viral and fungal infections.
Walsh et al. 1994). If dietary availability of zinc is only
10 %, however, as is the case for many human populations,
especially in developing countries, the nutritional require- Mild and moderate zinc deficiency
ments of zinc might be much higher. Despite our profound Not only severe but even moderate and marginal zinc
knowledge about the zinc intake in the population we still deficiency, which is by far more common than severe
do not know the exact requirements of this micronutrient deficiency, has a profound effect on immune response since
and there is still controversy whether zinc serum level is the the sensitivity of immune cells to an altered zinc level
adequate parameter of zinc status. Nevertheless, due to its varies. For instance, in marginal zinc deficiency in mice
easy accessibility and the existence of a broad range of and humans, thymus size, peripheral blood lymphoid cell
studies determination of zinc serum level as parameter of counts and antibody levels are suppressed (Shankar &
zinc status seems to be appropriately applicable. Prasad, 1998). Interestingly, reduction in thymus size is
seen mainly in the cortex, the zone where the development
of T-cells takes place (Shankar & Prasad, 1998). Therefore,
Immunological significance of zinc
the importance of zinc deficiency for the development of
The immune system is influenced by zinc on various levels. the immune response is obvious. The relevance of
On the one hand, zinc specifically alters immune functions moderate and marginal zinc deficiency is further stressed
and, on the other, the immune system which is a highly by the fact that different functions of a cell are sensitive to
proliferative `organ' is influenced by zinc-dependent zinc deficiency to a variable degree. For instance,
proteins involved in general cellular functions, i.e. replica- intracellular killing by macrophages is much more sensitive
tion, transcription and signal transduction (Valle & to zinc deficiency than interaction with T-cells and
Falchuk, 1993). All cell subsets of the immune response phagocytosis, implying a decreased resistence to intracel-
are affected by zinc (Table 1). Decreased zinc levels impair lular pathogens even in marginal zinc deficiency (Shankar
natural killer cell activity, phagocytosis by macrophages & Prasad, 1998). As a clinical consequence, patients with
and neutrophils, and certain functions like chemotaxis and mild to moderate zinc deficiency may be prone to
the oxidative burst (Keen & Gershwin, 1990). However, infections in which macrophage killing is a central effector,
zinc is important even for the maturation and functioning of such as malaria or tuberculosis.
T-cells, since zinc is an essential cofactor for the thymus
hormone thymulin (Hadden, 1992). This hormone has
Zinc status in pregnancy
intrathymic and peripheral immunoregulatory properties
and is necessary for an intact thymus (Bach, 1981; During pregnancy, zinc requirements are markedly
Wellinghausen et al. 1997a). Zinc deficiency thus leads increased and a meta-analysis of various epidemiological
to thymic atrophy. Zinc also affects mature T-cells. It studies investigating the zinc intake by pregnant women
induces the expression of the high-affinity receptor for estimates an inadequate zinc intake in up to 80 % of cases
interleukin-2 and zinc deficiency is associated with (Caulfield et al. 1998). Although this estimate appears quite
decreased T-cell proliferation after mitogen stimulation high, it is based on a recommended daily allowance of only
(Dowd et al. 1986; Kruse-Jarres, 1989). Antibody produc- 11´5 ^ 1´75 mg zinc per day (Caulfield et al. 1998).
tion of B-cells is also dependent on zinc. Interestingly, Nevertheless, data on zinc intakes are conflicting and a
impaired antibody production can be restored through very recent US National Survey found adequate zinc intake
addition of thymic cells thus suggesting a T-cell dependent in less than 60 % of pregnant women based on a total zinc

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 Zinc in pregnancy S83

Table 2. Immunological consequences of gestational zinc deficiency for the

neonate

Consequences for Consequences for

first-generation offspring subsequent generations
(mice and rhesus monkeys) (mice)
Lymphoid organs: ±
X reduction of thymus and spleen size

B-cells: B-cells:
X hypogammaglobulinaemia: X suppressed IgM levels
persistent IgM deficiency
transient IgA and IgG2 deficiency
altered antibody repertoire

T-cells: T-cells:
X impaired proliferative response X impaired proliferative response

Depressed neutrophil function: ±

X chemotaxis
X phagocytosis

intake at or above 77 % of the 1989 RDA (Briefel et al. Effects of gestational zinc deficiency on
2000). Assessment of zinc intake may be complicated for the immunity of the infant
instance by individual, regional and changing food habits.
While severe zinc deficiency, based on a distinctly Zinc deficiency during pregnancy affects not only the
diminished zinc serum level, is relatively rare, mild to mother but it also has immunological consequences for the
moderate zinc deficiency is widespread and not restricted to fetus. Various immune defects have been reported in
women of low socioeconomic status. Physiologically, the animal studies. In mice and rhesus monkeys suffering from
zinc serum level declines during pregnancy, mainly due to prenatal zinc deficiency, a reduction in lymphoid organ
hemodilution and decreased albumin levels (Bedwal & size, like thymus and spleen, leading to cellular immune
Bahuguna, 1994; Jameson, 1993). While 10´5 mM is defects has been found (Beach et al. 1982a). One of the
considered as the lower limit of serum zinc during the earliest and clinically most relevant signs of maternal zinc
first and second trimester, the zinc level physiologically deficiency are low levels of natural immunoglobulins
declines down to 9´5 mM in the third trimester (Jameson, including a persistent defect in IgM and transiently
1993). Insufficient intake further aggravates the physiolo- diminished levels of IgA and IgG2 in the neonate (Table 2;
gical drop of zinc. Furthermore, not only serum zinc but Favier, 1992). Diminished placental transport of immuno-
also zinc content in peripheral blood leucocytes has been globulins has been proposed as a possible explanation
observed to decrease from the second trimester of normal (Shankar & Prasad, 1998). However, not only is the total
pregnancy (Valdes-Ramos, 1992) and correlates with fetus amount of antibodies diminished; even the repertoire of
leucocyte levels (Favier, 1992). Intestinal absorption is not antigens recognized by these antibodies is depressed.
increased during pregnancy and thus the additional zinc Interestingly, this effect is even seen in mild or transient
requirements by fetal and placental tissues have to be zinc deficiency during pregnancy (Shankar & Prasad,
covered from increased intake or from maternal tissues 1998). Certain developmental steps responsible for B-cell
(Favier, 1992). receptor repertoire maturation thus seem to be dependent
Zinc deficiency during pregnancy provokes similar on zinc. Concerning T-cell function, impaired proliferative
symptoms and increased susceptibility to infections as response to mitogen has been observed in the offspring of
does zinc deficiency in non-pregnant adults. However, zinc-deficient animals (Keen & Gershwin, 1990). In mice,
infections might be more prolonged or severe due to prenatal zinc deficiency has led to an inability to form
physiological pregnancy-related metabolic and hormonal rosettes after immunization (Beach et al. 1983). In addition
changes (Favier, 1992). Zinc supplementation at the end of to a negative impact on the specific immune responses,
pregnancy has only a weak effect on mothers' zinc status depression of innate immune mechanisms like chemotaxis
but, if administered during the first trimester, serum zinc and phagocytosis of neutrophils has also been found
increases after supplementation (Favier, 1992). Therefore, (Shankar & Prasad, 1998). Furthermore, prenatal zinc
an early recognition and correction of zinc deficiency deficiency leads to disturbed postnatal metabolism of the
during pregnancy are necessary. In a recent study, Caulfield major intracellular zinc binding protein, metallothionein,
et al. showed, that continuous daily zinc supplementation in which has a profound effect on zinc homoeostasis
pregnant women, started at week 10±24 of gestation and (Vruwink et al. 1988).
continued until 4 weeks after delivery, leads to increased Interestingly, some of the immune defects caused by
serum zinc concentrations in the mother and increased prenatal zinc deficiency may even persist into subsequent
cord zinc concentration in the neonate (Caulfield et al. generations (Table 2). In mice, suppressed IgM concentra-
1999a). tion and impaired lymphocyte proliferation have been

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 S84 N. Wellinghausen

observed in second and third generation offspring (Beach development, greater fetal birth weight and reduced
et al. 1982b). The mechanisms responsible for this preterm delivery and placental abruption have been
persistency are still unknown but changes in methylation described (Merialdi et al. 1999; Goldenberg et al. 1995;
patterns of immunoregulatory genes and other putative Jameson, 1993) whereas, on the other hand, studies
epigenetic effects have been proposed (Keen & Gershwin, showing no beneficial effect on, for example, birth size
1990). It should be noted that the immune defects are also available (Caulfield et al. 1999b). Surprisingly,
mentioned above have also been observed in the offsprings studies investigating immunological effects of a zinc
of only marginally zinc deficient mice. However, there supplementation on pregnant women are very limited.
definitely arises a need for further studies to determine the There has been reported a lowered rate of spontaneous
significance of these observations in humans since data abortions after gestational zinc supplementation (Jameson
about the consequences of gestational zinc deficiency for 1993; Caulfield et al. 1998) but studies directly addressing
the immune response of the newborn are still completely immunological mechanisms are completely lacking.
lacking. Prenatal zinc deficiency might have an important Despite the potential advantages of zinc substitution, the
effect on child immunity as observed in animal studies. administration of zinc should optimally be assessed on the
Hypogammaglobulinaemia together with altered antibody individual's particular requirements and controlled by
repertoire and decreased T-cell proliferation in response to plasma zinc level because depressed immune function has
T-cell dependent antigens may lead to impaired success of been reported with high dose zinc therapy. Of course, such
vaccination in the infant which again may have important an individually adapted supplementation approach is
consequences for the health status of the population. In neither possible nor even desirable in the interest of public
humans, immunological defects might possibly also be seen health but may be applicable in individual cases. At zinc
in subsequent generations as suggested by animal studies dosages of 100±300 mg/day, i.e. ten times the daily
and may be irreversible (Beach et al. 1983). requirements, diminished lymphocyte proliferation, neu-
trophil chemotaxis and phagocytosis have been reported in
humans (Chandra, 1984). Interestingly, monocytes and
Immunoregulatory effects of zinc
T-cells show a different susceptibility to high zinc dosages.
Zinc supplementation in humans has been shown to reverse While monocytes are stimulated by and can tolerate quite
nearly all the defects as seen in zinc deficiency. Reversal of high zinc concentrations, T-cell function is impaired at
thymic involution, most probably caused by inhibition of much lower zinc levels which can be achieved by zinc
apoptosis, and, as a consequence, increased thymulin levels supplementation (Wellinghausen et al. 1997b). This
have been observed (Mocchegiani et al. 1995). This explains why immunosuppression by high zinc dosages
facilitates normal T-cell development and helper cell mainly affects T-cell function. However, even at dosages
function. Impaired functions of macrophages, neutrophils, below 100 mg/day effects on the homoeostasis of other
NK cells, and B-cells are also restored. Interestingly, zinc micronutrients, such as a depressed copper level and an
administration can not only reverse impaired immune altered metabolism of vitamin A, may be observed (Fischer
function but it can even enhance normal immune response et al. 1984; Vallee & Falchuk, 1993; Christian & West,
(Crea et al. 1990; Wellinghausen et al. 1997a). In fact, zinc 1998).
is the simplest mitogen known, being able to stimulate As mentioned earlier, it is very difficult to determine a
peripheral blood mononuclear cells. Zinc can directly safe upper limit of zinc administration. The WHO
induce cytokines like interleukin 1 and 6 and tumor established safe upper limits of daily zinc intake, i.e. up
necrosis factor alpha in human monocytes. Zinc-stimulated to 13 mg for infants up to one year, 23 mg for children
monocytes can then stimulate T-cells (Kirchner & RuÈhl, aged 1±6 years, 32±34 mg for adolescents, and up to
1970; Salas & Kirchner, 1987; Driessen et al. 1994). Zinc 50 mg for adults (Walsh et al. 1994). However, these
is, it seems, involved in nearly all levels of the immune recommendations are based mainly on short-term trials and
response. may not take into account the possible negative effects of
long-term zinc supplementation. Some of the authors agree
in considering a daily dosage of 50 mg zinc as safe (Favier
Zinc supplementation in humans
& Favier, 1990) Fischer et al. observed depression of
In the recent past, several large community-based supple- copper-zinc superoxide dismutase in normal adults after
mentation trials involving groups at an increased risk of only 6 weeks of 50 mg daily zinc supplementation (Fischer
zinc deficiency have been conducted. For instance, in et al. 1984). Others recommend a total intake of only
double-blind, randomized controlled trials, zinc supple- 20 mg zinc daily (Mertz, 1995). In his toxicity assessment
mentation has led to a reduction in the incidence and of zinc supplementation, which considered possible
prevalence of diarrheal disease and respiratory tract negative interactions between zinc and other trace elements
infections in children of low socioeconomic status as well as risks of long-term supplementation, Sandstead
(Sazawal et al. 1995; Black, 1998). Zinc supplementation calculated a daily intake of only 9 mg zinc for 60-kg adults
has not only been evaluated as a therapeutical measure but as the upper limit without negative side-effects (Sandstead,
it has also proven useful to prevent diarrhea and malaria 1995).
morbidity when administered prophylactically (Black, In the light of the problematic nature of an adequate zinc
1998). Supplementation trials on pregnant women, a dosage the 1989 RDA committee noted that chronic
population at great risk of zinc deficiency, are controver- ingestion of zinc supplements at a level exceeding 15 mg
sial. On the one hand, improved fetal neurobehavioral per day is not recommended without medical supervision

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 Zinc in pregnancy S85

(National Research Council, 1989). However, according to Beach RS, Gershwin ME & Hurley LS (1982b) Gestational zinc
the Third National Health and Nutrition Examination deprivation in mice: persistence of immunodeficiency for three
Survey about 40 % of pregnant and lactating females in generations. Science 218, 469±471.
the US take daily zinc supplements of .15 mg (Briefel Beach RS, Gershwin ME & Hurley LS (1983) Persistent
immunological consequences of gestational zinc deprivation.
et al. 2000). It is possible that the current RDA of 15 mg
American Journal of Clinical Nutrition 38, 579±590.
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