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Nutntmn Research. Vol. 20, No. 11, pp.

1645-1687, 2000
Copyright 0 2000 Elsevm Saence Inc.
Printed ,n the USA. All rights reserved
027 I-53 17/00/$-see front matter

ELSEVIER PII: SO271-5317(00)00243-S

ZINC IN HUMAN MILK

Jose G. Dorea, Ph.D.


Department of Nutrition, Universidade de Brasilia
70910.970 Brasilia, DF, Brazil

ABSTRACT

Zinc concentration in breast milk varies within and between mothers. Neither environmental
(zinc intake - either in natural food or supplemented, nutrient interaction. cigarette smoking,
and oral contraceptives) nor constitutional (premature delivery, number of children, teen age
pregnancy, undernutrition, infection, and diabetes) variables consistently affected zinc
concentration or its rate of decrease in breast milk. Stage of lactation is the only variable
associated with important changes in milk zinc concentrations. In the first days of
postpartum, the zinc concentrations in breast-milk fall steeply, and after the first weeks
gradually decreases throughout the following 6 weeks, reaching relatively stable levels by the
3rd month. In spite of increasing volumes of milk consumed by nursing infants the total zinc
intake falls as a function of the rate of decrease in the milk metal concentration. For
postpartum days 1, 7, 15, 30, 60,90, 120, 1.50, and 180 the reported median zinc
concentrations (mg/L) are respectively 8.12, 4.56, 3.36, 2.65, 1.66, 1.35, 1.2, 0.98 and 0.93.
So far, neither maternal controlling mechanisms have been studied, nor any infant benefit is
found in association with such unique pattern. Although human milk is adequate in meeting
infant’s nutrition requirements for growth, zinc deficiency in full term and preterm breast-fed
infants was reported mainly as dermatitis with symptoms appearing circa the 3rd month.
This condition has been reported more frequently in preterm than in term babies. However
breast-milk zinc concentrations were below the median of expected values, and in some cases
milk zinc was abnormaly low for lactation age. Susceptibility of breast-fed infants to develop
zinc responsive dermatitis seems associated with metabolism of their own body zinc reserves.
Experiments with maternal zinc supplementation aimed at enriching breast milk have not
been effective. However, maternal zinc therapy seems to correct abnormalities of zinc
metabolism during gestation and lactation.
0 zwoElsevlrr
sc,ence1°C
KEY WORDS: Zinc, breast milk, lactation, supplementation, breast feeding, deficiency.

1- INTRODUCTION

The nutritional components of human milk are used as paradigm to guide recommendations for
infant’s growth and development. Most minerals, major (1, 2) and trace (3). may show changes in
concentrations during early or prolonged lactation but not to the extent seen for zinc in breast milk.
Such timely changes raise difficulties in choosing reference values, and poses intriguing questions
regarding the maternal regulatory mechanism of zinc secretion in milk and infant physiopathological
consequences.

1645
1646 J.G. DOREA

Values of zinc concentrations used as a reference in human milk studies can sometimes be
misleading. Concentrations (in mgL) of 1.2 (4), 2.2- 2.5 (5), 2.94-3.92 (6, 7) 4 (8), or even 1.7-5.3
(9) can represent milk zinc at early or late lactation (see Table 1). Reference zinc values for breast-
milk used by researchers often do not represent the expected concentration for a given period of
lactation. Such wide variation without complementary information regarding stage of lactation can
be a source of confusion when used as “normal” values for comparative purposes. The need to
identify the range of zinc concentrations for a given age of lactation during exclusive breast-feeding
is apparent from reports of zinc deficiency attributed to “low” zinc concentrations in milk (see
section 11).

Studies of zinc concentrations are reviewed and data are summarized to provide median values of
zinc concentrations as a function of stage of lactation. Infant susceptibility to zinc deficiency during
breast-feeding as well as environmental and constitutional variables thought to affect maternal zinc
metabolism are discussed in regards to zinc concentrations in human milk.

2- ZINC IN BREAST-MILK FRACTIONS

Zinc in breast milk is found in fat globules (IO- 12), high-molecular-weight protein complexes (13-
15), low molecular weight peptides (16). ultrafiltrable substances (17), - like citrate (18), and
picolinate (19) - and amino acids (20). The milk fat fraction carries 10 to 40% of total zinc in milk
(10, 12, 21), and mostly in the outer layer of the fat globule (10, 21, 22). In spite of significant
differences in fat content between fore- and hind-milk (23), zinc concentration in fore- and hind-milk
may (24) or may not (25,26) be significantly different.

Great variability is also reported in the non-fat fractions. In the aqueous fraction zinc is bound to
protein and non-protein compounds. The concentrations of these milk ligands vary depending on the
analytical method of preparation (27, 28). Zinc loading tests with zinc-carrier ligands showed that
the zinc/ligand ratio occurs in the following order: metalothionein >> albumin >>> citrate = casein >
lactoferrin > lysozime (27). Michalke et al (27) reviewed the literature summarizing the percent
composition of these ligands in relation to total protein in the following order: casein, 44 % >
lactoferrin, 29.3 % > lysozyme, 15.6 % > albumin, 4.4 % > metallothionein, 0.1 %.

Using ultracentrifugation techniques, there are reports (10, 22) that zinc m mature milk is 48.4 %
bound to protein, 24.6 % bound to low molecular weight compounds and in casein micelles varying
from 3.3 % to14 % (10, 21). Others (29) using chromatography showed that only 10 % of zinc is
bound to low-molecular-weight fractions. In specific protein fractions, Donangelo et al (15) reported
that sedimentable zinc (presumably casein) in pooled samples varied from 12 to 30 % which agrees
with results of Bates & Tsuchyia (12). Whereas, others (10, 11, 22) reported that zinc was bound to
casein (8-14 %) and serum albumin (28 %). However, Nassi et al (30) reported rather different
results, indicating that zinc was mainly bound to casein, both in colostrum (79.8 %) or mature milk
(83.9 %), while immunoglobulin bind 20.2 % to 16 % respectively (30).

Zinc associated with protein and non-protein compounds indeed shows variability among studies.
Michalke et al (27) summarized the ranges of variation for lactoferrin (0.7 % to 100 %), casein (2 %
to 14 %), albumin (1 % to 5 1 %) and methalothionein (0.5 %). They pointed out that some existing
confusion about zinc distribution in breast-milk fractions may be due to low stability of zinc-organo-
complexes. In colostrum (2-7 d), Michalke et al (27) found that 95.6 % of bound zinc is in the whey
fraction not associated with protein. Others (10, 1 1, 14, 21, 22) showed opposite results indicating
that a large proportion of zinc in whey fraction is protein bound.
ZINC IN HUMAN MILK 1647

TABLE 1

Summary of studies showing range and median of zinc concentration @g/g or pg/rnL) of studies
according to stage of lactation *.
_______________________-_____________________________________________________________________________
Days Minimum Median Maximum References

1 1.32 8.12 12.68 30,37.104.114,116,158,176-180. 196.263,272.285.297.302,308.


2 1.42 7.9 13.2 37.73,176,178,254.263,264.308.
3 2.04 6.4 10.5 39,73.80,111.1 14,160,166,176-179. 263.265-267.272.289.308.
4 0.98 5.3 9.2 41,66,73.154,158,162.176,178,223,263,264. 269.297.302.308.
5 3.33 4.94 8.17 30,73,112,114,163,166,176,177,178,179,283,285,308.
6 4.0 4.9 5.39 73.153.176,271,272.
7 1.13 4.56 9.6 73,85,111,113.116,120.155,161.164,165.172.176,180.196,263,266,
267, 273,290,293,294,300.
15 0.60 3.36 5.7 3O,34.37,64,67.8O,85,89,l12.116,146,154.155,157.158.162,l~,l65.
177-179. 196, 208,275.281,286,294.
30 0.32 2.65 5.61 12,25.29,34,35,42,54.57,71,72.78.85,86.89~92,93,97,102,~12,113,
146.154,155,157. 158, 164,165.169.177-180.196.263.265. 289.274-
277.279-28 1.287.297.300.307.
60 0.16 1.66 5.36 12,25,34,35.42,57.7 l.72.76.86,89.92.93.97,1O2,l12.157.158.164,
166.208.227.265.289.274.275.279.281.283.285.307.
75 0.32 1.66 2.24 34,39.112.146,157,165.280,288,302.
90 0.70 1.35 2.10 12,34.35,42.56,57.65,71.72,85.86,89,92.93,97,102.111,112.119,120,
157.163,169.180.208.264,269,274,275,279,281,286,287,291,
293,294.300.307.
120 0.8 1.2 2.05 12.35.42,54.57.69.71.72.86.89.92.97,1 12.208.265.289.274.275.283,
284.287.
150 0.15 0.98 1.77 12,42,57.71,72,86,89.92.97.112,146.169,180,232.281,286,287,300.
180 0.02 0.93 2.30 12.42.56.57.69,71,72.85.89.97,1 11.112.163.269,277.280.281,283,
285,287.291,293.
210 0.44 0.85 1.36 12,42,57.89,97,281.286.296.
240 0.24 0.83 1.11 12,42,57.89.97,288,296.
270 0.6 0.78 I .32 12,42,57.89.97,280,283.288,293,296.
300 0.4 I 0.75 1.11 42,97,265,267,283,296.
330 0.43 0.54 1.o 42,283,296.
360 0.43 0.50 I .6 42.80.97.263.277.280.283.296.
__________________________________________________________________________________________
* Four weeks or 1 month are grouped as 30 days intervals.

Arnaud & Favier (17) showed ultrafiltrable zinc to vary from 4 to 56 %. They measured citrate in
human milk (493 mg/L) and found it to carry most of the zinc. In Michalke et al’s (27) summary
there is a range of 19 % to 100 % of the total zinc coming from citrate.

3- STAGE OF LACTATION

The pattern of changes in milk-zinc concentrations is summarized in Table 1. The median values of
reported means show that during the first 7 days there is a 50 % decline that continues throughout
lactation reaching 25 % of the initial value by the 45th day. By the sixth month, when breast-fed
infants have doubled their weight, the relative milk zinc concentrations have fallen to 20 % of the
median concentrations seen in the 15th day.

During the first 10 days postpartum, milk volume increases from 533 mL to 1673 mL (3 1) at a rate
of 6.6 ml/d from day 5 to day 35 (32) while zinc concentration decreases circa 60 % (Table 1). The
downward pattern of zinc in breast-milk is also seen as zinc energy ratio (33, 34). Such decrease in
1648 J.G. DOREA

zinc concentration is not balanced by an increase in milk volume, and in that same period, total zinc
intake by the breast-fed infant can fall 35.3 % (35).

Milk volume and composition evolve from a protein-rich colostrum that is secreted in a small
volume immediatly postpartum to a more homogenous and larger volume of milk by the 15th day of
lactation. The range of total milk protein in the first 3 days (32.9 to 44.6 g/L) decreases
substantially (13.9 to 14.7 g/L) by the second month (36,37). During this time the mammary
secretion of other minerals (Ca, P, Mg, Fe, Cu) is relatively constant (l-3) and it does not seem to be
affected by the increased volume of breast milk, since the total mineral mass also does not show any
substantial change (34). After the third month of lactation total mineral mass decreases only slightly
(34,38-42). Bates and Tsuchyia (12) also showed that breast-milk of British and Gambian mothers
have significant different concentrations of zinc and calcium. but in an opposite trend. Thus
indicating that milk-zmc secretion is specifically regulated and does not depend on the total mineral
mass of milk.

The weaning process, regardless of stage of lactation causes changes in milk composition which
affects zinc concentrations. Dewey et al (43) reported significantly less zinc during weaning in late
lactation. In milk samples of 5 to 6 months of lactation, a slightly higher drop in zinc concentration
was seen during 70 days of the weaning period compared to full lactation (44).

Although total zinc in milk shows correlation with zinc in protein and non-protein fractions, the
overall picture still shows inconsistencies. Bates and Tsuchiya (12) reported a proportional decrease
(70 to 40 %) of zinc in non-sedimentable (whey) fraction while in the sedimentable fraction, from 1
week to 3 months, the proportion of zinc varyed from 12-40 % but was not associated with stage of
lactation. According to Michalke et al (27) lactoferrin and casein, the major zinc-carrier proteins in
milk, represent only 4.9 % of total zinc in milk. None of these fractions per se, however, explain the
pattern of decrease in zinc concentration. Indeed, among major zinc-carrier proteins (lactoferrin,
lactalbumin, casein and lysosime), only lactoferrin shows a pattern of change similar to zinc in the
first 10 days. During the same time the pattern of change in casein concentration was the opposite
(45). Even in mothers secreting abnormally low total zinc, the distribution of zinc in milk fractions
was reported as normal (46).

Lactoferrin will decrease as lactation progresses (15), i.e., from 6.86 mg/mL (1-5 d) to 2.7 1 mg/mL
(61-280 d). Within the first week (4-7 days) total protein in milk decreases rather rapidly from 32.8
g/L to 18.1 g/L (36), with lactoferrin comprising 6-20% of total protein. Hirai et al (36) reported that
a 50% decrease in total protein between colostrum and mature milk was accompanied by a 61%
decrease in lactoferrin concentration. Lonnerdal et al (37) reported a significant decrease in total
protein, lactoferrin, whey protein, and total zinc between day 1 and day 15 (Table 7). Coincidentally,
two independent studies reported that there were higher concentrations of lactoferrin (47) and total
zinc (12) in Gambia mothers compared to UK mothers.

Non-protein zinc studied by ultrafiltration represents 16- 18% of total zinc, also showing a
significant positive correlation with total zinc in milk (17). The decrease in the ultrafiltrable-fraction
observed in the first month of lactation resembles the pattern of decrease in total zinc (17). There is
limited information on the pattern of changes of zinc binding ligands. either citrate (18) or picolinate
(19) during the course of lactation. Morriss et al (48) measured citrate and reported a 3 fold increase
from 2-3 days to 14-21 days.

Studies on zinc localization in milk fractions or compounds have contributed significantly to


understand acrodermatitis enterophatica (I 6) as well as zinc bioavailability (49). However, there is
no explanation for the mechanisms involved in the pattern of zinc decrease in human milk. The
ZINC IN HUMAN MILK 1649

TABLE2

Summary of breast-milk zinc concentrations @g/g or pg/mL) in studies that compared countries.
regions and races.
_________________________________________________________________________________________________________
Reference Group- I Group-2
Stage of lactaction”, Group- 1.
group-2
_________________________________._____________-__________________________________________________________
Bates and Tsuchtya (I 2) 4.1 30 d. Gambia.
3.4 I
3 60 d. Gambta. UK
2.7 2 90 d. Gambta. UK
1.66 0.84 120 d. Gambta. UK
1.64 0.7 I 150 d. Gambta. UK
2.09 0.7 I I80 d. Gambta. UK
I .45 6-9 mo. Gambia
1.13 9-12 mo. Gambta
1.26 12-15 mo. Gambia
I.17 15-I8 mo. Gambia
0.6 210 d, UK
0.24 240 d. UK
0.72 270 d. UK
Belavady (67) I .96 I .62 30-90 d, Indta. USA
Bratter et al (79) 0.03 22 d, Selemferous regtonl
0,02 22 d. Selemferous regton2
0,02 22 d, Selemferous region3
Dang et al (75) 2.1 7.3 NG. India trtbal. urban
Duncan (73) 7.9 7.6 2 d, White, Indian (S. Africa)
7.3 6.4 3 d. White, Indian (S. Africa)
5.1 4.7 4 d, White. Indian (S. Africa)
4.3 5.6 5 d. White. Indian (S. Africa)
5 4 6 d, White, Indian (S. Africa)
5.4 4 7 d, White, Indian (S. Africa)
Fransson et al (66) 5.14 6.06 4-5 d, Sweden, Ethiopta
Karraet al (71) 2.28 2.37 I mo. USA. Egypt
1.41 1.47 2 mo, USA, Egypt
I .26 I. 17 3 mo. USA, Egypt
0.9 0.98 4 mo. USA, Egypt
0.72 0.82 5 mo. USA. Egypt
0.6 0.82 6 m. USA, Egypt
Karmaet al (63) 0.98 0.97 7-9 mo, USA, Egypt
Moser et al (70) I .09 I .20 2-6 mo, USA, Nepal
Palma and Howe1 (68) NC NG l-3 mo, USA, Mexico
Parr et al (65) 2.6 I 3 mo, Guatemala
1.2 3 mo. Hungary
I .68 3 mo, Nigeria
I .98 3 mo, Philippines
0.7 3 mo, Sweden
I.9 3 mo. Zaire
Radzanowski et al (222) 0.86 1-12 mo. Australia
0.88 1-12 mo, Canada
I .94 l-12 mo, Chile
1.28 l-12 mo, China
1.18 l-12 mo, Japan
I .05 1-12 mo, Mexico
I.58 1-12 mo, Phillipines
1.27 l-12 mo, UK
Rajalakshimi & Srikantia (92) 2.00 1.88 l-3 mo. India Urban, Rural
1.33 1.32 4-6 mo, India Urban. Rural
1.12 1.03 7-12 mo, India Urban, Rural

(‘Table continued)
1650 J.G. DOREA

Continued from Table 2


1.16 I .03 > 13 mo. India Urban. Rural
Villalpando et al (69) 1.2 I .5 4 mo. Mexico. USA
I I I. I 6 mo. MCXKZO, USA
Yamamoto et al (74) * 2.5 21-60 d. I7 regtons m Japan

* d= days; mo= months.


’ Mean of all regtons.

timely and specific decrease seen in breast-milk is a result of a net change in zinc carriers. Major
milk fractions such as casein and whey proteins change throughout lactation. The caseimwhey-
protein ratio is lo:90 in early lactation, 40:60 in mature milk and 5050 in late lactation (50).
Individually, milk zinc-ligands do not change at the same rate as total zinc concentrations. During
the first 10 days of lactation, lactoferrin seems to carry a heavier weight on the net change.

4- REGIONAL DIFFERENCES IN ZINC CONCENTRATIONS

It is recognized that sub optimal zinc intake is world wide and affects women, infants and children
(51, 52). There are reports that dietary zinc do not meet maternal recommendations for lactating
mothers in Brazil (53-55) the USA (38. 56. 57), Canada (58), New Zealand (59). Indonesia (60).
Malawi (61,62), Egypt (63) and Spam (64).

Racial and environmental characteristics that may condition natural food-zinc intake due to
geographic and cultural differences are summarized in Table 2. The multicenter study of Parr et al
(65) showed that zinc concentration at 90 days of lactation could vary from 0.7 mg/T-.(Sweden) to
2.61 mg/L (Guatemala) thus demonstrating a wide variation in the six countries studied.
Comparative studies of zinc concentrations between group of mothers from different countries,
reported no significant differences between Ethiopia and Sweden (66), and between the USA and
India (67), Mexico (68, 69), Nepal (70) and Egypt (63, 71).

Breast milk comparisons made between races (72,73), or regions within the same country also did
not show statistically significant differences (74-77). The exceptions were the studies of Bates and
Tsuchyia (12) between countries and Bratter et al (78,79) between regions of the same country.
Bates and Tsuchiya (12) showed a consistent low zinc concentration in British mothers compared
with Gambian mothers, while Bratter et al (78, 79) showed zinc concentrations to differ between
regions in Venezuela, attributing this to natural maternal selenium intake.

5- MATERNAL ZINC SUPPLEMENTATION

A summary of studies of the effect of maternal zinc supplementation on breast milk is shown in
Table 3. Most experiments with zinc supplementation during lactation did not consistently increase
the metal concentration in milk (4 I, 56, 57, 63, 70, 7 1, 80-87). Even when zinc supplementation
could increase serum zinc up to 30 %, there was no increase in zinc concentration in milk (70.81).
This is in agreement with Fung et al (88) observations that in well nourished women, breast-milk
zinc concentrations are not related to maternal nutritional indexes such as zinc in plasma,
erythrocyte, urine or dietary zinc.

Moser-Villon and Reynolds (85) used zinc and vitamin B-6 to study the effects of nutrient
supplementation on breast-milk enrichment. One of these nutrients (piridoxine) can increase vitamin
B-6 in both maternal serum and breast milk. Their results confirmed that daily doses of 0.5 and 4.0
mg of pyridoxine indeed significantly increased milk pyridoxine concentrations. On the other hand
ZINC IN HUMAN MILK 1651

TABLE 3

Summary of studies comparing the effect of maternal zinc supplementation on breast-milk zinc
concentrations (mg/kg or mg/L).
_________--
_______________________________________________________________________--_______________-

Reference Country Control Zn suppl. Stage of lactaction*, Zn/d


_______________________________________________________________________-_________________________----
Chiertci et al (87) Italy 8.16 s.a9 3 d. 20 mg
3.99 3.36 30 d. 20 mg
2.87 2.63 90 d. 20 mg
Karra et al (7 1) USA 2.28 2.83 I mo.ZSmg-American mothers
1.41 1.81 2 mo. ZSmg-Amertcan mothers
I .26 1.47 3 mo, 25mg-Amertcan mothers
0.9 1.3 4 mo. 25mg-Amertcan mothers
0.72 I .04 5 mo. 25mg-Amertcan mothers
0.6 1.05 6 mo. ZSmg-American mothers
Karra et al (63) USA 0.87 0.78 7-9 mo. l-2 d of 50mg
Egypt 0.7 0.76 7-9 mo. l-2 d of 50mg
Kirksey et al (80) ” USA 4.61 3 d, 28 mg and I1 mg
3.12 14 d. 28 mg and I I mg
2.04 I-3mo.28mgand II mg
0.93 5-7 mo, 28 mg and I I mg
0.45 I yr, 28 mg and I1 mg
Karma and Kirksey (83) USA NG NC I-6 mo, 25mg
Krebs et al (57) USA 2.65 2.83 I mo. 15 mg
I.5 I .55 2 mo, 15 mg
I.1 I .25 3mo. 15mg
1.01 1.13 4 mo, I5 mg
0.83 1.06 5 mo. 15 mg
0.88 0.9 6 mo. I5 mg
0.7 1 0.9 7mo. 15mg
0.53 1.11 am. 15mg
0.67 0.82 9 mo, 15 mg
Krebs et al (89) USA 3.85 3.85 0.5 mo, 15 mg
3.07 3.05 I mo. I5 mg
2.05 2.03 2mo. 15 mg
1.47 I .47 3 mo. 1.5 mg
I .45 I .42 4mo. ISmg
0.85 0.85 5 mo, 15 mg
0.88 0.86 6mo. I5 mg
0.78 0.78 7 mo, 15 mg
Moore et al (126) USA 2.76 5-75 d, before suppl.
2.17 5-75 d, 1 wk 60 mg
Moran et al (81) ** USA I .5 NG, initial value
1.4 NG, after 1 wk 50 mg
I.1 NG, initial value
1.1 NG, after I wk 75 mg
Moser-Villon & Reynolds (85) USA 4.61 4.36 I wk. 25 mg Zn+5 mg B6
3.94 4.26 I wk. 25 mg Zn+4 mg B6
3.62 3.56 2 wk, 25 mg Zn+5 mg B6
2.87 3.22 2 wk. 25 mg Zn+4 mg B6
2.73 2.62 4 wk. 25 mg Zn+5 mg B6
2.71 2.15 4 wk. 25 mg Zn4+mg B6
1.71 1.26 I2 wk. 25 mg Zn+5 mg B6
1.28 1.41 12 wk. 25 mg Zn+4 mg B6
1.37 0.82 24 wk. 25 mg Zn+5 mg B6
0.75 0.75 24 wk. 25 mg Zn+4 mg B6
0.13 0.60 36 wk, 25 mg Zn+5 mg B6
0.64 0.64 36 wk. 25 mg Zn+4 mg B6

(‘Table continued)
1652 J.G. DOREA

Continued from Table 3


Salmenpera et al (82) Finland 4.15 4.94 0 mo. 20 mg
I .4 I I .52 2 mo. 20 mg
0.9 0.95 4 mo. 20 mg
0.67 0.67 6 m. 20 mg
0.61 0.63 7.5 mo. 20 mg
0.6 0.6 9 mo. 20 me
061 0.41 IOmo. 20 mg
0.43 0.5 I I I mo.20 my
0.43 0.46 I2 mo. 20 mg
5.01 0 mo, 40 mg
I 38 2 mo. 40 m_e
I .0x J “IO. 40 mg
0.88 6 mo. 40 mg
0.9 7.5 mo. 40 mg
0.94 9 mo, 40 mg
Sazawal et al (86) ’ India 4 4h I mo. 20 mg
2.10 2 mo. 20 mg
I .5I 3 mo. 20 mg
I .Oh 4 mo. 20 m_e
1.19 5 mo. 20 mS
I .21 0 “10. 20 mg
ShrImpton et al (54) Bran1 2.08 I .x7 30 d. I5 mg
1.33 I .4 I 120d. I5 mg

* d= days; wk=weeks; mo= months.


# Mean for control and supplementation groups
** Same group of mothers.

25 mg of zinc/day, a dosage commonly used in zinc supplementation studies, did not affect zinc
concentration in milk even when maternal intakes of the metal in natural foods were below dietary
recommendations.

Supplemental studies that exceptionally showed an increase in breast-milk zinc concentration were
not consistent. Sazawal et al (86) claimed that supplemental zinc (20 mg/day) could significantly
increase milk zinc in a subgroup of poor mothers only at early lactation. However in Salmenpera et
al (82) only after 6 and 7.5 months with 40 mg Zn/day but not with 20 mg Zn/day there was a
significant increase in milk zinc. The studies of Karra et al (71) and Karra and Kirksey (83), in
which American mothers were supplemented with 2.5 mg Zn/day showed a significant zinc increase
in both milk (83) and maternal serum from 1 to 6 months. In late lactation (7th to 9th month) when
breast-milk zinc concentration is even lower, a subsequent study from the same laboratory reported
that a higher dose of zinc supplementation (50 mg/day) failed to affect significantly breast-milk zinc
concentrations (63).

Although Karra et al (63) showed a greater decrease for the unsuplemented group of American
mothers the zinc supplementation of Egyptian mothers did not affect their milk zinc concentrations
or the percent decrease (same dose and duration). The mean daily intake of total zinc from natural
food was comparable for both American (10.06 mg to 12.16 mg) and Egyptian (8.4 mg to 16.2 mg)
mothers. Inconsistent results were also reported in two studies by Krebs et al (57, 89). In the first
study it was reported that the rate of decrease in milk zinc was less in a group of American women
supplemented with 15 mg zinc/day (Krebs et al (57). However in a subsequent study the same
laboratory showed that milk zinc concentrations were very close in both placebo and zinc
supplemented mothers (89).

Most of the supplementation studies were conducted in well nourished Americans or women from
ZINC IN HUMAN MILK 1653

industrialized nations like Italy and Finland (Table 3). In women of less developed countries, three
studies emerged, one in Brazil among poor mothers of Manaus (54), one in India (86), and another m
Egypt (63). Less privileged mothers in these countries had diets low in zinc, however with some
differences. While Indian and Egyptian diets are high in inhibitors of zinc absorption (63, 86). the
maternal diet m Manaus-Brazil is high in fish (54). In none of these groups of mothers were there
significant differences in milk zinc concentrations due to supplementation. with I5 mg Zn/day (54)
20 mg Zn/day (86) or even 50 mg Zn/day (63). However. both Shrimpton et al, (54) and Sazawal et
al (86) claimed that zinc supplementation could change the rate of decrease in milk zinc
concentration.

Although there are no convincing evidence that maternal zinc supplementation consistently
increases breast-milk zinc concentrations or affects infant growth pattern (82) there are claims of
benefits like increased milk vitamin A and a decrease in respiratory and gastrointestinal disease
episodes in the breast-fed infants (54).

6- PHYSIOPATHOLOGICAL CONDITIONS THAT ALTER MATERNAL ZINC METABOLISM

6.1 Maternal nutritional status

Significant correlation was found between maternal body mass index and total zinc output in milk
(89). also zinc supplementation during pregnancy in women with body mass index less than 26 had a
significant effect associated with infant’s birth weight and head circumferences (90). Hence the
interest in the effect of maternal nutritional status on zinc concentrations in breast milk. Groups of
mothers from countries with high prevalence of maternal undernutrition were studied and are
summarized in Table 4.

TABLE 4

Summary of studies that reported zinc concentrations (Kg/g or ug/m~) in milk of mothers in social or
nutritional conditions less than ideal.
_________________________~_~~_------------.-~_~_~_____________-.-------_~__._--_---------------.-~--.-~_______________
Reference Country Control Condition Stage of lactaction*,
condition

Dang et al (223) India 6.7 4.3 3-5 d, low income.


2.8 1.3 28-42 d, low income.
Franssonet al (66) Ethiopia 6,66 6.06 4-5 d. non-prtviledged
Moser and Reynolds (56) USA 2.6 I mo, 42 % Zn intake
1.3 2 mo, 42 % Zn intake
1.1 3 mo, 42 % Zn intake
Rajalakshmi and Srikantta (92) India 2.50 2.0 l-3 mo. low income
I .45 1.45 3-6 mo, low income
Ruz et al (93) Chile 2.65 4 wk. undernourished
I .66 1.66 8 wk. undernourished
1.6 0.97 12 wk. undernourished
Van der Elst et al (91) S. Africa 2.57 2.16 19-21 d, thin mothers

* d= days; wk= weeks; mo= months.

Fransson et al (66) found no significant difference in milk zinc concentrations between the
socioeconomic status of Ethiopian mothers. Even when there were significant difference in serum
zinc concentrations, like between Nepalese and American mothers, there was no significant effect
on breast-milk zinc concentration (70). Comparing control mothers with mothers of low body weight
1654 J.G. DOREA

at the 3rd week of lactation. Van der Elst (91) found no statistically significant differences in breast-
milk zinc concentrations.

Contrary to those findings the study of Rajalakshmi and Srikantia (92) in India and Ruz et al (93) in
Chile reported lower milk zinc concentrations in malnourished mothers. Both in India (92) and Chile
(93) mothers showed significant differences in arm skin fold thickness and body mass index
respectively. In the study done in India, the significant difference in milk zmc was seen in pooled
samples of 1 to 3 months of lactation, whereas in Chile, significant differences in zinc concentrations
were observed only at 12 weeks of lactation.

Animal studies showed that nursing mice developed zinc deficiency due to both low milk yield and
zinc concentration of mutant dams (94). In such model, dietary zinc deficiency also caused low milk
yield (95). Although there is an occurrence of low-for-lactation-age milk zinc (see previous section),
we have not yet seen in humans low milk yield due to low maternal zinc intake. A combination of
such conditions, if indeed occurs in humans would affect our present understanding of zinc-nutrition
of the breast-fed infant.

TABLE 5

Summary of studies that reported zinc concentrations (pg/g or pg/mL) in milk of mothers under
conditions that could alter zmc metabolism.

Reference Country Control Condition Stage of lactaction*.


Condition

Arnaud et al (104) Nigena 3.39 3.33 5 d, Fe supplemented


I .37 1.24 90 d. Fe supplemented
0.98 0.84 I80 d. Fe supplemented
Corn et al (76) Italy 3.08 3.45 2 m, rural smokers
3.67 3.87 2 m, urban smokers
Dagnelie et al (98) Netherlands I .90 2.0 60-90 d, macrobiotic
Finley et al (97) * USA 5.61 30 d. vegetarians
3,11 60 d. vegetarians
2,05 90 d. vegetarians
2,05 120 d, vegetarians
I ,77 150 d, vegetarians
I,38 I80 d. vegetarians
I ,36 7mo. vegetarians
I,11 8mo. vegetarians
1.12 9m0, vegetarians
I,1 I IOmo, vegetarians
I.2 I Imo, vegetarians
0.6 I I2mo. vegetarians
Keizer et al (102)” Canada 2.16 28 d, Folic acid (300 mgld)
0.95 56 d. Folic acid (300 mg/d)
I .02 84 d, Folic acid (300 mg/d)
Milnerowicz & Slowinska (109) Poland I .08 1.24 3 d, smokers
Vuori et al (99)’ Finnland I .89 42-56 d. Fe supplemented
0.72 119-154 d. Fe supplemented
Zapata et al (105) Brazil 6.99 7.58 l-2 d, Fe supplemented
2.03 1.67 30-40 d, Fe supplemented
0.9 I 0.98 90-100 d, Fe supplemented
______________________________-______________________________----_________________________
* d= days; mo= months.
” Mean of both groups.
ZINC IN HUMAN MILK 1655

6.2 Dietary composition and nutrient interactions

Diets providing zinc that could meet only 50 % of recommendations had no significant impact on
breast-milk zinc in some studies (56, 85), but in one study (96). it seemed to lower zinc concentration
only in mature mtlk. Also diets that may change the ratio of zinc to other nutrients and/or zinc
broavailability like in vegetariamsm, showed no stgnificant effect on zmc m milk (97. 98). Inversely
at higher dietary zinc intakes there were no significant correlation between dietary zinc and this
element in breast milk (99).

Competitive or inhibitory effects of some nutrients on zinc absorption during pregnancy and
lactation have appeared in the literature. A case report of transient neonatal zinc deficiency was
suspected of being related to maternal mega-vitamin therapy during pregnancy (100). Although
Fransson et al (66) reported that high intakes of iron m natural food, 20 to 30 times that of Swedish
women, had no effect on breast-milk zinc, Fung et al (101) claimed that a 18 mg Fe/day decreased
the efficiency of zinc absortion in lactating women. However, women that took mineral supplements
(iron and zinc) during pregnancy did not show significant difference in milk zinc concentration (41).
Nutrient supplementation and interactions that may affect zinc absorption were also studied during
lactation and no significant effects on zinc concentration were found (Table 5).

TABLE 6

Summary of studies comparing the effect of number of children on zinc concentrations in breast-milk
(~p/g or ng/rW.

Reference Country Control Multi- Teen age Stage of


parous lactaction*

Hussam et al (115) Bangladesh 2.2 1.94 6-36 wk, mormng


1.84 I .64 6-36 wk. midday
2.04 1.64 6-36 wk. afternoon
Jenkryczko et al (114) Poland I 1.79 10.01 Colostrum
9.22 8.77 Id
6.13 6.16 3d
4.98 4.76 5d
Kirsten et al, 1985 (111) S. Afrtca 4.27 7.05 3d
1.17 2.21 -id
0.49 1.37 6w
3.75 5.16 12wk
1.44 2.52 24 wk
0.89 0.96 36 wk
Lipsman et al (72) USA 2.7 2.6 30d
I .7 1.35 60d
1.35 1.6 90d
1 1.3 120d
0.97 0.98 150d
0.96 0.99 180 d
Maedaetal(113) Japan 5.62 5.29 I wk
2.68 2.77 I mo
____________________~~~~~~~~~~~~~~~~~~____~~~~~~~~~_____________________________________
* d= days; wk= weeks; mo= months.

Maternal supplementation with folic acid (55, 102), and iron (55, 99, 103-105) do not seem to
interfere with zinc concentrations in milk, even in cases of teen age mothers (102). Also, long term
supplementation of calcium in lactating Gambian women did not affect indices of zinc nutritional
1656 J.G. DOREA

status (106). The exception was the study of Ortega et al (64) which reported a significant decrease
in zinc in mature milk but not in transitional milk of mothers that had an iron intake greater than
200% of the daily recommendations. Cadmiun released during cigarette smoking can affect zinc
metabolism by “trapping” zinc in the placenta. As a result infants born to smokers had biochemical
indication of marginal zinc deficiency (107). Nevertheless cigarette smoking did not affect zinc
concentrations in milk (76. 108).

6.3 Teen age pregnancy and reproductive experience

The extra nutrient expenditure put on maternal nutrition status due to multiple gestation have studied
in relation to zinc. In regard to milk-carrier proteins Montagne et al (109) showed significant
differences in lactoferrin. immunoglobulin, serum albumin and lactalbumin between breast milk of
primiparous and multiparous. Also Walravens et al (110) observed failure to thrive in infants nursed
by pregnant mothers. Studies dealing with constitutional characteristics that could condition low zinc
stores such as multiparity, or teen age pregnancy are summarized in Table 6. Compared with
controls, neither multiparity nor teen age pregnancy showed statistically significant differences in
milk zinc concentrations (105. 11 l-l 15). Also no significant correlation between breast-nnlk zinc
and parity or lactation experience was found (41).

TABLE 7

Summary of studies that compared health conditions on zinc concentrations in breast milk (pg/g or
Pi?/mL).

Reference Country Control Condition Stage of lactaction*,


condition

Butteetai(118) USA I.1 1.4 73-l 15 d. diabetic mothers


Grekas & Toukantanis (120) Greece 1.13 0.83 i’d, renal transplant
1.03 0.78 90d. renal transplant
Lonnerdal et al (37) Peru 9.95 8.12 I d, ill
8.91 5.47 2 d, ill
3.08 2.89 14 d, 111
Sikorski et al (121) Poland x.3 4 d after C-sectlon
7.0 5 d after C-secuon
7.0 6 d after C-sectron
7.3 7 d after C-sectIon
6.5 8 d after C-section
Zavaleta et al (116) Peru 1.32 1.57 O-6 mo. 1 d ill
1.36 I .45 O-6 mo, 2 d ill
I .43 1.30 O-6 mo, 14 d ill

* d= days; mo= months.

6.4 Maternal health conditions

Although it was suggested by Neville et al (122) that mastitis may be a source of difference in zinc
concentration between breasts, acute (infections) or chronic (diabetes) health conditions found to
affect zinc metabolism did not influence zinc concentrations in milk (Table 7). Acute infections
during lactation that changed serum zinc did not affect breast-milk zinc (37, 116). Milk in women
with insulin dependent diabetes mellitus, had significantly lower lactose, higher total nitrogen and
infants had significantly less milk intake (117). In diabetic mothers, no significant change in breast-
milk zinc concentration was observed (118). Breast-fed infants of high-risk pregnancies that included
ZINC IN HUMAN MILK 1657

diabetes mellitus showed higher weight gam than formula supplemented with zinc (I 19). Thus
supporting that zinc in breast milk was not affected. Even in patients of renal transplant. there were
no effects on zinc concentrations in milk ( 120). In comparison to expected values (Table 1) zinc
concentration in the first week after C-section delivery seems normal ( I2 1).

6.5 Zinc treatment of nwthers nursing zinc-dejicient breast-fed @ants

Zinc deficiency during breast-feedmg IS not a rare condition. like rtckets (1). In cases of zinc
deficiency during breast-feeding (see section I I) some authors believe that a mammary gland defect
may cause an abnormally low secretion of zinc (46). Maternal zinc treatment to correct the low-for-
lactation-age zinc in milk were attempted and results are summarised in Table 8.

TABLE 8

Summary of studies reporting the effects of maternal zinc therapy on zinc concentrations @g/g or
pg/mL) in milk of mothers nursing infants with clinical signs of zinc deficiency.

Reference Daily dose Duration Before R, After R,

Connors et al ( 125) 220 mgi8 h* I week 0.39 NCR


Heinen et al ( 130) 12 Fmol/kg b.w 18 weeks 0.37 0.80
Kuramoto et al (129) 5 mgikg b w IO days 1.6 NCR
Moore et al (I 26) 60 mg 2 weeks 0.35 0.30
Naqw et al (132) 30 mg NC 0.30 0.99
Niemi et al (127) I 9 mg/kg bw NG 0.25 NCR
Parker et al (131) 45 mg 5 days 0.12 0.23
Sharma et al (84) 220 mg* 5 days 0.20 0.20
Weymouth et al (123) 220 mg/X h* I week 0.26 NCR
Weymouth and Czarnecki (128) 220 mg/8 h* I week 0.39 NCR
Zimmerman et al (124) - case I 50- 150 mg 13 weeks 0.33 NCR
- case 2 50mg 8 weeks 0.50 0.40

NCR= No change reported


* Zinc sulfate (ZnS04.7HzO)

During symptomatic zinc deficiency of breast-fed infants, maternal treatment with oral zinc did not
increase breast-milk zinc (84. 123- 129) in most studies. Exceptions were the reports of Heinen et al
(130) Parker et al (131) and Naqvi et al (132). After 18 weeks of oral zinc treatment (3.27 mg Zn/kg
b.w.), Heinen et al (130) reported a substantial increase in zinc concentration from 0.37 mg/L to 0.80
mg/L, while Parker et al ( 13 1) also found that a larger dose (45 mgZn/d) could double the zinc
content of breast milk in a shorter intervention time (five days). Naqvi et al (132) reported a 3 fold
increase (0.30 to 0.99 mg/L) in zinc concentration after maternal zinc therapy (dose and duration not
given). Overall, case reports of zinc therapy of mothers of zinc deficient breast-fed infants are in
agreement with experimental zinc supplementation, that is, milk zinc is not consistently affected.

7- HORMONAL CONTRACEPTIVES

The use of oral contraceptives (OC) appears to affect mineral metabolism (133) and may (134) or
may not (135) affect some indices of maternal zinc nutritional status. There are studies showing
effects of oral contraceptives on lactation and milk composition (136). In spite of 30 % of total body
zinc residing in the adult skeleton (137) and oral contraceptives affecting bone metabolism during
lactation, so far no significant effects of OC were seen on zinc concentrations in milk (Table 9).
1658 J.G. DOREA

Kirksey et al (80) studied the effects of OC taken over long periods of time prior to pregnancy and
lactation and found no significant effects on zinc concentrations in milk. In Australia, Cumming et al
(138) reported that the use of progestin-only (30 l.tg of levonergestrel or 350 l.tg norethisterone/day)
contraceptive during lactation affected zinc concentrations neither in serum nor in milk. These
authors studied only 5 mothers and employed simple mean comparisons. without correcting for
decrease in zinc

TABLE 9

Summary of studies of zinc concentrations (up/g or pg/mL) in milk of mothers using oral
contraceptives (OC).
____________________________________________________________________________________________________
Reference Country Control OC Stage of lactaction*.
condition

Cummlng et al (138) Australia 1.57 8-16 wk. OC users + non users


Doreaetal (141) Brazil 2.1 88 d. Combined pill
I .4 I34 d. Combined pill
1.8 73 d. Minipill
I.5 80 d. Minipdl
1.8 36 d. I.P.
1.4 52 d. I.P.
2 57 d. IUD
I 80 d. IUD
1.5 108 d. Control
1.4 130 d. Control
Kirksey et al (80) ’ USA 4.65 4.55 3d
2.97 3.18 14 d
_________________________________________________________________________~~~~~~-~______________~___~~~
* d= days; wk= weeks.
” OC treatment before pregnancy.

concentrations that occurs naturally. Besides, progestogens are less likely to interfere with lactation
(139) and their effects on mineral metabolism are not as marked as estrogens (140). However,
adjusting for stage of lactation, length of treatment and type of OC. Dorea et al (141) also did not
find significant differences in zinc concentrations in serum or in milk.

The contraceptives used in those studies were combination pills (progestogen plus estrogen), and
progestogen-only types (minipill or injectable progesterone). Over the years, hormonal therapy for
control of fertility underwent considerable changes. Formulas for a combined pill have shown a
decline in both progestogen and estrogen, with substantially more changes in the former.
Progestogens also changed in both minipills and injectable formulas (136). Therefore, it is unlikely
that hormonal treatment of fertility during lactation can affect zinc concentrations in breast milk.

8- MATERNAL HANDLING OF ZINC DURING LACTATION

The amount of maternal zinc retained by the fetus during the last trimester of pregnancy is less than
that secreted in the first three months of lactation. The fetus accumulates 36.7 mg of zinc in the last
three months antenatal (142) and can receive 108 mg in breast milk in the first three months
postnatal (56). The total zinc laid down in fetal tissue, placenta and uterine growth, has been
estimated as 100.7 mg (143). Therefore, maternal zinc expenditure is greater during lactation,
especially in the early weeks. However, the increase in zinc expenditure during lactation may not be
fully compensated by an increased absorption. Indeed, absorption in the second month of lactation
ZINC IN HUMAN MILK

was not significantly different from levels of absorption during pregnancy (88). Also it seems that
no significant difference was observed in urinary zinc (88) although Klein et al (144) claimed the
contrary. Mechanisms not yet understood protect the maternal organism but not its reproductive
outcome (fetus and breast milk).

The maternal organism is susceptible to faltering zinc metabolism with consequences to the fetus
and breast-fed infant. Cavdar et al (145) reported that zinc supplementation helped a mother to carry
a normal pregnancy and to deliver a healthy newborn after two successive deliveries of anancephalic
stillborn infants. Murphy et al (146) also reported that a mother of a zinc-deficient breast-fed infant
could successfully breast feed the child of a second pregnancy after zinc therapy. In view of such
cases, it seems that zinc therapy can benefit both infant and mother.

Maternal tissue reserves are important for fetal and infant development during breast feeding.
Uterine tissue catabolism during post-delivery involution to pre-pregnancy structure could release
zinc to feed the maternal zinc pool and expand the endogenous compartment available for the high
zinc concentrations occurring in colostrum and transition milk during early lactation. In animal
studies there is an increase of 9.7 to 16.7 fold in total zinc content in uterus with a significant
increase in liver zinc (147). In humans the uterine morphological and functional changes during
pregnancy brings a tissue weight increase from 70 g to I 110 g (148). Such tissue mass will approach
pre-pregnancy levels around the 45th day postpartum.

In well nourished mothers hormonal shifts following parturition could mobilize zinc stores
accumulated during pregnancy without compromising zinc nutritional status. Such reserves would
not be sufficient to protect the maternal organism from zinc depletion if levels of 8 mg or higher (as
in colostrum and transition milk) were secreted in volumes of 800 and 1000 mL throughout
lactation. According to Klein et al (144), zinc conservation mechanisms that depresses urinary zinc
represents a savings equivalent to 8 % of daily zinc in milk over a 6 month period. They based their
estimation on a zinc concentration of 1.2 mg/L that is observed only after the 6th month of lactation
and seems to be an overestimation. Fung et al (88) found no significant difference in urinary zinc of
lactating mothers. Instead of kidneys the intestines seems to play an important role in zinc
conservation. According to Jackson et al (149) lactating women adapted to low dietary zinc intake
and absorption of a high proportion from the diet and also by reduction of loss of zinc into the gut.

The mammary-gland regulatory mechanisms controlling the timely changes in milk zinc
concentration are not fully understood. Apparently the initial high zinc concentrations in milk are not
modulated by exogenous zinc sources. Endogenous zinc, partly originated from compartment
changes as a consequence of hormonal shifts after delivery will be passed to milk through specific
zinc carriers. As part of the characteristic components of human milk, these organo-metallic
complexes will change throughout lactation (see Sections 3 and 6). Therefore maternal zinc
compartment changes such as those occurring during illnesses, or hormonal influence, per se can not
influence zinc concentrations in milk because they are not capable of modulating the milk synthesis
of zinc carriers.
9- PREMATURITY

The interest in the suitability of breast milk to compensate increased requirements due to fast
growth of preterm babies led to research into the milk composition of mothers delivering preterm.
Some (150, 15 1) proposed that preterm milk is better than term milk for supporting weight gain of
preterm infants. Indeed significant differences were found in relation to immunological components
of term and preterm milk (45, 109). Some of these immunoprotective factors, like lactoferrin, are
zinc carrier proteins. However, differences between term and pretemr milk were not consistent.
While Velona et al (45) showed a higher concentration of lactoferrin in term milk only at early
1660 J.G. DOREA

TABLE IO

Summary of studies comparlng zinc concentrations (pg/g or pg/mL) in term and preterm breast-
milk.

Reference Country Term Preterm Stage of lactactlon

Alkanam et a (161) Canada 4.34 4.87 7 days


Aquilio et al (162) Italy 2.2 2.1 2-6 days
2.3 2.1 12-16 days
2.3 2.2 21 days
Atkinson et al (46) l Canada 3.9 6 days
3.0 21 days
2.9 25 days
2.7 21 days
2.2 35 days
2.2 36 days
I .o I35 days
Attnmo & Omololu (I 66) Nlgerla 5.98 7.14 I weeks
5.49 5.91 2 weeks
3.93 5 36 8 weeks
Butte et al (156) USA 3.4 4.1 2 weeks
2.9 3.2 4 weeks
2.1 2.7 6 weeks
1.9 2.9 8 weeks
1.8 2 IO weeks
I .4 I .6 I2 weeks
Ehrenkranz et al (158) ’ USA 9.09 I days
7.15 4-5 days
4.67 14-15 days
3.7 28 days
2.6 56-70 days
Ehrenkranz et al (190) USA 4.99 NG
F&l et al ( 164) Canada 4.58 5.31 I week
3.99 3.68 2 weeks
3.54 2.88 3 weeks
3.37 2.85 4 weeks
2.5 2.25 5 weeks
2.32 2.09 6 weeks
I .89 I .74 7 weeks
I .56 I .77 8 weeks
1.14 1.17 12 weeks
Garza et al ( 152) USA NC NC NC
Gupta et al (157) India 2.22 2.13 2-5 days
L.83 1.73 6-10 days
I .62 I .62 I l-30 days
Hemalatha et al ( 163) 2.26 2.95 Colostrum
2.19 2.34 Transition
I .90 2.28 l-3 months
I .50 I .67 4-6 months
1.15 1.47 7-12 months
Hurgoiu and Caseanu (276) Rumama 2.8 7-15 days
3.72 16-23 days
2.5 24-30 days
Itabashi et al (165) ’ Japan 6.9 I days
5.7 14 days
4.2 21 days
3.6 28 days
2.3 35-42 days
ZINC IN HUMAN MILK 1661

Continued from Table IO


1.x 49-56 days
I .4 63-84 days
Jtraptnyo et al (159) Thadand 1.91 I .9s 7-28 days
Mend&on et a (154) Canada s 3s 53 3-S days
4.1 4 7s X-IO days
3.37 4.31 IS-17 days
2.6 3 92 28-30 days
Mend&on et al (224) Canada s 3s 7 days
4.07 14 days
3.43 28 days
Moran et al (155) # USA 5.07 7 days
3.87 I4 days
3 21 days
2.24 28 daya
2.24 35 days
1.56 42 days
I s7 49 days
Perrone et al (167) ** Italy 36.4 26.4 1 days
24.6 24.1 I4 days
2X.6 22 21 days
21.7 14.1 21-121 days
Sann et al (I 53) France 3.87 5.07 6 days
2.24 3 7-14 days
I .s7 I .S6 >I5 days
Trugo et al (160) Bran1 7 26 5.52 I-5 days
2.19 2.32 6-36 days

y-G= Not given; . Calculated from linear regression equatton. *Mean of term and preterm groups.
Dry wetght basis.

lactation, Montagne et al (109) reported higher concentrations of immune proteins and lower
concentrations of “nutritive” proteins.

In regards to total zinc in milk, a summary of studies presented in Table IO does not show
statistically significant differences between term and preterm breast-milk (152- 165). Claims of
significant differences in zinc concentrations at specific intervals, like first week of lactation,
showed an inverse trend by Atinmo & Omolulu (166) and Perrone et al (167). Most studies did not
show significant differences. Indeed comparisons of the rate of zinc decrease between term and
preterm milk were not statistically significant (124, 156).

Considering the high metabolic demands of catch-up growth and development, preterm breast-milk
alone may not be able to provide the zinc needed by infants during catch-up growth period. Ziegler
et al, (168) estimated that during the first month a premature infant gain weight (18.3 gmIkg/d) at
higher rates than term infants (9.5 gm/Kg/day).

Therefore the preponderance of zinc deficiency in preterm infants reported during breast-feeding
(Table 11) may indicate that there are no maternal physiological mechanism operating to suit preterm
breast milk with adequate supply of zinc to meet infant needs. Additionally it is worth mentioning
that “defective mammary gland secretion of zinc” was reported in preterm breast-milk (46). As
noticed by Dauncey et al (142), the diminished body reserves due to immaturity can pose a risk of
zinc deficiency to the pre-term infant. Coupled with that, differences in zinc metabolism between
term and preterm infants, have consistently showed a negative zinc balance lasting longer in preterm
(169) which is reflected in higher meconium (endogenous) zinc (164).
J.G. DOREA

IO- ROLE OF ZINC IN COLOSTRUM DURING THE PERINATAL PERIOD

The relatively high concentrations of zinc in colostrum and the high fecal-zinc loss in the neonatal
period are related to physiological events or are merely pathophysiological coincidence ?

Concentrations of metals in colostrum and meconium should reflect metabolic events during the
transitional days from fetal to neonatal life at the perinatal period. The occurrence of zinc per se, or
in association with iron, and copper in colostrum and mecontum seems to fulfill important
physiological functions. Chemical composition studies of meconium and colostrum in late
intrauterine or early extrauterine life show that zinc is higher than copper and iron, leavmg (with
meconium) or entering (with breast milk) the intestines.

It is expected that during growth there should be positive balance of nutrients, or that total milk
nutrient intake should be proportional to somatic growth and metabolic functions. In the early days
of lactation the sharp decrease in both milk zinc concentration and infant total-zinc intake also
coincide with a negative zinc balance. Indeed negative zinc balances are reported in breast-fed term-
infants (169, 170). In spite of colostrum and transitional milk having relatively high concentrations
of zinc, the infant’s body-zinc reserves are an important complementary source to attend to the
decreased intake of zinc and provide this element for the exchangeable zinc pool in order to meet the
infant’s high demands for fast organ maturation and biochemical functions. Indeed, Hambidge et al
(171) showed a relatively higher exchangeable zinc pool in infants compared to adults.

The Zn:Fe molar ratio (3:7) favors zinc in meconium (172-175). The zinc to copper ratio (3.5:4) in
meconium also favors zinc ( 172-175). The ratios of zinc to copper and zinc to iron in colostrum are
even higher than in meconium. Zinc to iron ratio in one-day colostrum is found as 8.26 to 15.4
(37,176), while zinc to copper ranges from 7.14 to 41 (177-180).

The immediate post-natal period is characterized by profound changes related to organ growth,
morphologic changes and functional maturation that are associated with colostrum ingestion (18 1).
During a short postpartum period, there is an emergence of antioxydant enzymes that is fundamental
to protect the new-born against free radicals (182). Also, protection against oxidant injury can be
accomplished by the antioxidant effect of iron depletion (183).

Colostt-um born trophic factors modulates gastrointestinal development in newborns. Although


these trophic factors may or may not be organo-zinc substances, the role of zinc in mitogenic
enzymes, and specially in DNA systhesis reflect an immediate increased requirement (readily
available colostrum zinc) and intense zinc metabolism (meconium and fecal zinc losses). Colostrum
is also important in the gut colonization, promoting an increase in fecal microbial diversity. In
breast-milk-fed infants, the total number of bacterial species increased significantly with time as did
quantitative bacterial counts (184). Castillo et al (185) suggested that the lack of intraluminal
nutrients resulted in the blunting of the striking increases in cellular proliferation exhibited by the
intestinal mucosa.

One of the properties of human milk is the protective effect it provides to the infant. Considering
that iron withholding is an important defense against pathogenic microorganisms, a high Zn:Fe molar
ratio can confer bacteriostatic effect, protecting the fragile infant during the perinatal transition from
intra- to extra- uterine life. Evidence for the role of zinc enhancing the bacteriostatic effect of iron-
witholding mechanisms can be derived from studies of zinc-modulation of lactoferrin. In vitro
studies demonstrated that zinc enhances the iron binding capacity of lactoferrin (13). Recently,
Marchetti et al (186) showed that zinc-lactoferrin compared to other milk proteins, like alpha- and
beta-lactoglobulin, was the sole compound capable of inhibiting a phase of infection of polivirus
ZINC IN HUMAN MILK 1663

type 1 internalization into host cells. Saturation of the iron binding capacity of the milk with iron
leads to loss of its bacteriostatic properties ( 187). Weinberg (188) has heeded pediatricians for
potentially hazardous amounts of iron in infant formulas.

An excess of zinc to copper could benefit the immature organism m the prenatal or neonatal stages.
Excess dietary zinc slows down intestinal copper absorption. This approach has been successfully
employed in the management of diseases of copper metabolism in adults (189). Ehrenkrantz et al
(190) found that in premature infants supplementing breast milk with zinc and copper to increase its
concentration to 8 mg/L and 0.4 mg/L (Zn to Cu ratio of 20). comparable concentrations found in the
upper limits of colostrum. showed a significant higher excretion of copper. Also a substantial
decrease in both percent net absorption and retention of copper were observed (190). Therefore it
seems that the chemical composition of colostrum can help infant gut-development and colonization.
Also, that a metabolic role designed to protect the transitional immaturity of the young infant from
harmful pathogens or chemical insults could explain the peculiar pattern of zinc, in relation to
copper, and iron in human milk.

1 l- INFANT ZINC DEFICIENCY DURING BREAST-FEEDING

Although biochemical indices of zinc status are better in breast-fed infants compared to formula-fed
infants (163, 191). clinical signs of zinc deficiency in breast-fed infants have been reported more
frequently than other trace elements. like iron and copper (3). Table 11 summarizes zinc
concentrations in case studies of zinc deficiency during breast-feeding. Most of the reported cases
(75 %) were seen in preterms, however the age range (2-6 months) in which symptoms appeared are
comparable in both term and preterm. Indeed, one study reported zinc deficiency in a preterm
consuming breast milk with zinc concentrations at levels comparable to a zinc-deficient term-baby
15 days older (192).

In the zinc-deficient breast-fed infants skin rashes or dermatitis are the main symptoms, failure to
thrive and irritability are often seen and at least in one case edema and hypoproteinemia (193) were
also reported. In most cases, biochemical indices consist of low serum zinc and alkaline
phosphatase. Additionally, in an otherwise normal group of infants, zinc deficiency (as skin rash)
may have an important prevalence. Collip et al (194) studied diaper rash in “normal” infants and
noticed that a significant association between reduction in hair zinc concentration, with hair loss and
diaper rash. In his study 10 % of infants were exclusively breast-fed. All these symptoms are
corrected with infant’s zinc supplementation. Zinc concentrations in breast milk were reported to be
“low” and suspected of being the precipitating factor. Almost all studies showed zinc
concentrations below median values (Tables 1 and 11). Indeed some studies do
show zinc concentrations below the minimum values for respective lactation age. However, zinc
deficiency symptoms with breast-milk zinc concentration above median values (195) may suggest
infant associated causes.

The concept that infant zinc deficiency during breast-feeding could be caused by low-for-lactation-
age zinc concentration deserves consideration. Indeed studies that compared milk from mothers
nursing symptomatic infants with controls (Table 11) matched for lactation age, showed a reduced
zinc concentration (130, 146, 196, 197). Although most milk zinc values were in the lower range
when compared to reported means in Table 1, some were even below the lower limit of respective
age of lactation (46, 84, 13 1, 146. 197).

Atkinson et al (46) described several cases of low-for-lactation-age zinc concentrations. However,


among the studied cases, only one infant developed zinc deficiency. Maternal zinc therapy to correct
low-for-lactation-age milk-zinc was discussed in Section 6.5 and results summarized in Table 8.
1664 J.G. DOREA

TABLE 1I

Summary of studies reporting zinc concentrations @g/g or pg/mL), and percent of reference values
(calculated from table I) in milk of mothers breast-feeding infants with clinical signs of zinc
deficiency.

Reference Country Zn % of median Stage of lactation,


(Table I ) days

Abitan et al ( 225) France 0.36 30.5 210


Agget et al (198) UK 0.58 68 119
Ahmed and Blair (226) UK NG 180
Ando et al (227) Japan 0.16 9.6 63
Atkinson et al (46) Canada 0.29 27.6 135
Bilinski et al (195) USA 6.4 80.6
3.92 150.7 28
I.91 I I9 56
2.2 258 196
I 122 280
Blom et al (228) Sweden 0.26 24.7 140
0.39 17 I40
Buehning and Goltz (229) USA 0.02 2.1 180
Bye et al (230) UK 0.27 25.7 140
Connors et al (125) Australia 0.39 30 98
Glover and Atherton (196) UK 2.64 32.2
I .37 32
0.3 1 9.4 14
0.26 21.6 112
Heinen et al (130) Germany 0.37 35.2 140. before Zn R,
0.80 106 294, after Zn R,
0.75 71.4 140, control
0.49 65.3 294, control
Husnoo et al (231) UK 0.34 28.3 105
Inoue et al (232) 0.15 14.3 150
Khoshoo et al (233) USA 0.13 15.3 210
Komulainen and Reitano (234) Finnland 0.28 29.2 168
Kuramoto et al ( 129) Japan 0.18 IO 70. stster- I
0.14 4.8 70. sister-2 before Zn R,
0.16 12.3 After IOd/S mg/bw
Lee et al (197) Korea 0.02 I .9 140-154
0.58 45.2 140-154, control
Leigh et al (235) UK NG 75
Mancini and Tunnesssen (236) USA NG 70
Moore et al ( 126) USA 0.35 13.3 I50
0,30 31.3 164, after Zn R,
Munro et al (237) UK 0,15 14.3 147
0.20 16.7 105
Murphy et al (146) UK 0.60 18 I4
0,32 12.3 28
0.32 17.8 70
0.26 24.8 140
Naqvi et al (132) USA 0.3 25 126, before Zn R,
0.99 NG, after Zn R,
Niemt et al ( 127) Sweden 0.64 60.1 150, case 1
0.25 23.8 150, case 2
Obladen et al (238) Germany 2 46.9 36
t,1 65.9 65
0.82 63.1 99
0.48 40 129
ZINC IN HUMAN MILK 1665

Continued from Table I I


Parkeret al (131) USA 0.09 9.4 180.9 d after Zn R,
Paupe et al (239) France 2.0 166.7 Ill
Phuvichit et al (262) Thaliand NC NG 120
Piela et al (240) USA 1.6 152.4 150, case I
0.32 26.7 120. case 2
Roberts et al (241) USA 0.27 II.8 225
0.03 2.8 150
Sahn et al (242)* USA NG 75
Sharma et al (84) India 0.20 15.4 90
Shinwell and Gorodtscher (243) Israel NG NG
Singh and Sinha (244) India 0.6 50 120
Stapleton et al (245) Australia 0.46 43.8 140
Stevens and Lubitz (192) Austraha 0.30 25 105. case 2
0.29 22.3 90. case I
Walravens et al (110) USA 0.49 51 180. minimum
0.64 66.7 180, maximum
Weismann and At-roe (246) Dennmark 0.33 NG
Weymouth et al (123) Australia 0.26 24.8 150
0.13 15.8 273
Weymouth Czerneki (128) Australia 0.26 21.7 120
0.39 32.5 120
Zimmerman et al (124) USA 3.5 81.9
0.85 70.8 105. case I
0.55 64.7 210, case 2
0.37 30.8 105. case 3

NG= Not given; * Acrodermatitis enteropathica

Low-for-lactation-age zinc concentrations were studied in the same women during two consecutive
pregnancies and lactations ( 124, 129, 146, 196). Maternal zinc therapy in two of these rare studies
(124, 129) contributed to avoid zinc deficiency in the nursing infant conceived in the second
pregnancy.

In the study done by Kuramoto et al (129) maternal zinc therapy corrected plasma zinc but did not
affect zinc in breast milk. Also, in Zimmerman et al (124), maternal therapy increased zinc in urinary
but did not increase in milk. In the cases studied by Murphy et al (146), there were remarkable
differences in zinc concentration between first and second lactation even without maternal zinc
intervention. The second lactation showed normal milk-zinc levels and the second nursing child did
not develop zinc deficiency. However, the first child which nursed on breast milk with low zinc
developed zinc deficiency (Murphy et al (146). Murphy et al (146) attributed these differences to a
probable “immaturity” of the milk. In the Glover and Atherton (196) study, both children developed
zinc deficiency as a result of breast-feeding on milk with “low” zinc concentration. At 16-20 weeks
of lactation, milk zinc concentrations in both lactations of the same woman were similar and below
matched controls (Table 11).

Walravens et al (110) reported zinc deficiency in infants fed breast milk with zinc concentrations
“in normal range for stage of lactation” (range: 0.49-0.64 l.tg/mL). Compared with data in Table 1,
zinc was in the lower range. In two of the infants failure to thrive coincided with concurrent maternal
pregnancy.

Some aspects of fetal and neonatal zinc metabolism are not well understood and regulatory and
biochemical functions beyond growth may be unappreciated (Section 11). The high amounts of zinc
in the intestinal milieu of the newborn ensues an obligatory zinc loss which is reflected as a negative
zinc balance seen in term and preterm infants (142). Even while sustaining symptoms of zinc
1666 J.G. DOREA

deficiency, preterm babies showed negative zinc balances (46, 198). At a time of high metabolic
demands the intestinal losses of zinc have been explained as “inadequate dietary intake, defective
zinc absorption or excessive intestinal losses” (198) or immature gastrointestinal tract (199). The
study of Higashi et al (169), clearly indicates that infant metabolic events related to post-conceptual
age modulates endogenous zinc losses. The turn point from negative to positive zinc balance seems
to occur 36 weeks postconceptually.

Although the zinc supplied by breast milk is important and commonly associated with cases of zinc
deficiency, the role of infant’s zinc reserves is difficult to be assessed. Animal studies have shown
that zinc depletion is fast and appetite-disturbance symptoms may appear within 5 days in rats (200).
Therefore, it is believed that zinc stores are low (201). Studies in animals and humans indicate that
hepatic zinc-metalothionein may be a fetal reserve of zinc (202). Indeed metalothionein and hepatic
zinc concentrations in the neonate declines to constant levels at about 4 months (203). The infant is
born with body reserves of zinc (204) that can compensate for a higher demand of early human
development not met by the diminished zinc intake during exclusive breast-feeding. At time of birth,
a quarter of total zinc in the body is found in the liver (205). Autopsy studies indicate a difference of
33 % in zinc concentration in liver from birth to 16 weeks (204). Therefore emphasizing the role of
the body-zinc reserves on zinc metabolism during early development. Wastney et al (206) found that
premature infants retaining zinc at rates less than rn uterus grew satisfactorily, thus suggestmg the
importance of endogenous reserves.

The wide variation of zinc reserves seen in infant’s liver (204) could compromise the buffering
capacity of liver to supply zinc for the exchangeable zinc pool. Furthermore the variation in age of
appearance of zinc-deficiency symptoms is indicative of the variability of infant’s endogenous
sources as a modulator of zinc metabolism.

12- HUMAN MILK AND INFANT SUSCEPTIBILITY TO ZINC DEFICIENCY

Studies that estimated infant’s breast-milk intake reported a decline in total zinc intake in spite of
some compensating increase in breast-milk volume (12. 33, 112, 207). The decrease in total zinc
intake by the breast-fed infant is best illustrated when expressed as a function of body weight.
Sievers et al (208) showed that the median intake (0.6 mg Zn/kg body weight/day) at 17 days
dropped (0.15 mg Zn/kg body weight/day) at I 13 days. These values coincide with the study of
Butte et al (35) in which total zinc intake at one month (0.36 mg/kg b.w./d) fell 2/3 at 4 months (0.12
mg/kg b.w./d). Also, studies showing zinc intakes of breast-fed infants below recommended levels
may convey the concept of a potential risk of zinc deficiency or at least a less than ideal nutrition
environment during breast-feeding.

Whether due to insufficient zinc intake, low zinc reserves, high intestinal zinc losses, per se or in
combination, the breast-fed infant can develop zinc deficiency as early as two months (Section 10).
At this time high demands for growth depends on drawn reserves not compensated by diminished
zinc intake from breast milk (209). thus turning the infant more vulnerable to the limitation of milk
zinc (210). Indeed asymptomatic breast-fed infants were found to benefit from zinc supplementation
after the third month (21 l), and zinc adequacy through complementary foods for children 9-l 1
months still breast feeding has been recommended at levels close to 100 % of zinc requirements
(212).

Banking of human milk is a common practice in many developing countries. In most maternity
wards the exchange of breast milk among mothers is encouraged. In more organized services, a
collection system of recruiting milk donors at various stages of lactation and after proper treatment,
the milk is then redistributed, especially among preterm or infants whose mother may have lactation
ZINC IN HUMAN MILK 1667

TABLE 12

Summary of studies reporting zinc concentrations (@g or ug/mL) in pooled samples of breast milk.
------________________________________________________________-___._______________---__________________
References Country Zn Stage of
Lactatton

Abrams et al (247) USA I 5-7 months


Bhatia and Rasstn (248) USA 3 14-28 days
Arpadjan and Stoianova (295 ) Bulgaria 13.8 NG
Bikgokt al (249) France 2 NG
Dauncey et al (142) UK 3.36 NG
2.75 NG
Dorea et al (34) Braztl I.15 15-90 d
Durrand and Ward (250) UK 0.39 Minimum, NG
7.18 Maximum, NG
Fransson and Lonnerdal (2 1) USA I .45 0.5- I2 months
Gross et al (60) Indonesia 1.7 0- I50 days
Higashi et al (25 1) Japan 2.1 7-128 days
Johnson and Evans (252) USA 1.8 2 months- I year
Knudsen et al (253) Denmark 4.77 NG
Krachler et al (254) Austrta 0.47 97-293 days
Krebs et al (298) USA 1.62 2-5 months
Lin et al (255) Taiwan 1.41 30-90 days
0.77 90- 180 days
0.55 6-12 months
Mandic et al (256) Croatia I .93 > 60 days
Mbofung and Atinmo (301) Nigerta 5.83 NG. Colostrum
Murthy and Rhea (257) USA 0.08 NG
Nyazema et al (258) Zimbabwe 0.38 NG. mature
Ohtake and Tamura (259) Japan 1.76 15-84 days
0.76 85-201 days
Picciano and Guthrie (282) USA I .63 42-84 days
Richmond et al (299 ) UK 0.92 17-61 weeks
Rossipal and Krachler (303) Austria 0.76 42-60 days
Rydzewsja and Krol(304) Poland 7.48 NG, transition
Sachde and Bundt (305) Germany 1.4 NG
Sandstrom et al (292) USA 2.9 NG. Banked
Schramel et al (268) Germany 1.7 NG. mature
Sharda et al (270) India 2.01 30- 180 days
Shaw (306) UK I .90 60-90 days
Shen et al (309) Belgium 0.60 NC
Silva et al (260) Brazil 1.75 NG
Tripathi et al (261) India 1.77 NG

problems. It is difficult to find studies that explored differences in milk composition due to stage of
lactation of donors and its nutrient adequacy regarding age of receptors. So far the only practical
caution regarding milk composition in banked milk has been issued for drip breast-milk that contains
low fat concentrations (213, 214). While no practical consequences may exist for other nutrients,
zinc may be a cause of concern. In view of differences in zinc concentration due to stage of
lactation, depending on the duration of human-milk feeding, there should be some matching between
donors and receptors especially during early lactation. Freezing and thawing commonly practiced in
milk banks had no effect on zinc concentration of milk fractions (215). In spite of that Hibberd et al
(177) studied the shortcomings of human milk either pooled or provided by milk banks in relation to
pre-term infant requirements. They concluded that the observed variation in zinc concentrations
(1.02 to 7.77 mg/L) could not meet zinc requirements (177).
J.G. DOREA

It is expected a wide variation in zinc concentrations when breast-milk samples are pooled or
collected without the proper concern for stage of lactation. Reported mean concentrations for such
cases are summarized in Table 12. Even within narrow interval of stages of lactation (Table 1)
recommended nutrient intakes for preterm infants can only be met before one month of lactation
(216). Therefore, guidelines of zinc concentrations in milk such as 1.2 mg/L provided by the
American Academy of Pediatrics (217) should be used with caution, specially when the stage of
lactation is unspecified.

Growth faltering, an important outcome of zinc deficiency in infants, has been observed during
exclusive breast-feeding (2 18). Children with growth faltering between three and eight months had
no significant difference in the volume of breast milk ingested. This reinforces the concept of zinc
being the first limiting nutrient in breast milk (210). Due to its high bioavailability (219) so far
evidence points to higher zinc retention and hair zinc indices in infants fed mother’s milk, either term
(191,220) orpreterm (221).

13- CONCLUSIONS

Zinc is the trace element showing the most Intriguing pattern of concentration changes in breast-
milk during the course of lactation. High zinc concentrations during the first week postpartum, fall
consistently as lactation progresses. Even the initial increase in milk volume is not enough to
compensate for the fall in total zinc intake by the nursing infant, and as a consequence can become
the first limiting nutrient in breast milk. Furthermore, in early life at times of high metabolic needs,
zinc balance is negative and lasts longer in preterm babies. The variations of zinc concentrations in
breastmilk are neither affected by dietary composition nor by maternal metabolism. Unlike other
mammals, concentrations of zinc in human milk do not seem to be affected by dietary zinc intake.
Localization of zinc in milk fractions or ligands can not explain per se the decrease of zinc
concentrations with stage of lactation. Unknown maternal physiological mechanism modulate the
decrease in zinc especially during initial lactation.

In circumstances not yet identified, women can secrete low-for-lactation-age zinc in milk. In spite
of no consistent increase in breast-milk zinc after maternal zinc supplementation, some case reports
of low-for-gestational-age zinc may be corrected with maternal zinc therapy. Furthermore, there are
indications that pregnant. lactating women and breast-fed infants can benefit from maternal zinc
supplementation.

Due to causes related to infant metabolism, zinc deficiency can occur in the breast-fed (term or
preterm) infant as early as the second month of life. The luminal chemical environment of late
intrauterine life will provide a high ratio of zinc to both iron and copper in meconium, that is
matched by colostrum in early extrauterine life. Such ratios create an intestinal environment that is
fundamental for organ growth and maturation while it is also protective agent against growth of
pathogenic germs and chemical oxidative stress by iron and copper. Therefore, differences in milk
composition due to lactation stage of donors in pooled or banked human milk, should be of concern
for pre-term infants. On a physiological basis, infant’s zinc provision should match the pattern of
breast-milk composition for the specific infant’s age when on human milk other than own mother.

Summing up, secretion of elevated levels of milk zinc for a relatively short period will not pose a
zinc deficiency risk to the well nourished mother. Nevertheless, it will attend infant’s immediate
post-natal needs for organ growth and maturation while high ratios of zinc to iron and zinc to copper
will enhance the infant’s protection against pathogens and chemical stress.
ZINC IN HUMAN MILK 1669

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Accepted for publication May 23, 2000.