Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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then pregnancy entails no appreciable additional

energy (food) cost. It could be argued that the

fetus is remarkably protected from the influence of

maternal malnutrition, and that women exposed

to generations of deprivation have simply adapted

to a limited food supply. Small stature is often

cited (incorrectly) as an example of adaptation.

Studies of the dietary habits of women living in afflu-

ent circumstances, however, have shown that this is

not so.

0009 As long ago as 1953, analyses of the diets of 2300

well-nourished women in Nashville, USA failed

to show any association between maternal food

intake and birthweight. Furthermore, on average, no

increase in food consumption during pregnancy was

apparent (Figure 1). During the second trimester, an

increase of around 251 kJ (60 kcal) per day was

noted, but during the last trimester, when a marked

acceleration in fetal growth occurs, energy intake fell

by 753 kJ (180 kcal) per day. This surprising discov-

ery, ignored for 30 years, has been amply confirmed

by studies in the 1980s in Paris, Cambridge, and

Glasgow.

0010 How, then, is the obvious requirement for increased

nutrition during pregnancy (Table 1) to be reconciled

with the mother’s failure, even under the most favour-

able environmental circumstances, to increase food

intake? Only a small fraction of the fat stored in

the first two trimesters of pregnancy is mobilized

before term, and there exists no ad-hoc store of

minerals and water-soluble vitamins. The answer to

this question is to be found in the complex mechanisms

whereby nutrients are transported from the maternal

circulation to the fetus, and in the adjustments that

occur in the maternal physiology in response to the

gravid state.

Role of the Placenta

0011The role of the placenta is discussed in Pregnancy:

Role of Placenta in Nutrient Transfer. It is primarily

an organ for nutrition of the fetus, but functions also

as an endocrine gland throughout the greater part of

gestation, regulating nutrient utilization by the

mother.

0012Glucose provides the energy for fetal growth, the

fetus being unable to oxidize fatty acids. Transfer of

glucose across the placenta is by ‘facilitated diffu-

sion,‘ and is therefore influenced by the maternal

blood glucose concentration. A prolonged low blood

glucose concentration, as may occur in mothers in the

developing world engaged in hard physical work, or

an abnormally high concentration associated with

gestational diabetes can therefore lead to growth

retardation, or to excessive growth and fat deposition

(macrosomia). From early pregnancy, the fasting

blood glucose concentration is reduced, a change

that may favor transfer to the fetus since the placenta

is particularly effective at extracting nutrients from

low concentrations in the blood. Glucose tolerance

following a glucose load is also progressively relaxed

so that the glucose concentration remains elevated for

a longer period, again facilitating placental uptake.

Whether or not the metabolic response to carbohy-

drate consumed as part of a meal is similarly affected

is unclear. (See Glucose: Maintenance of Blood Glu-

cose Level; Glucose Tolerance and the Glycemic (Gly-

caemic) Index.)

0013Fat-soluble vitamins also cross the placenta by

diffusion, maternal blood levels being maintained

by dietary input and mobilization of tissue stores.

In contrast, amino acids, minerals, and the water-

soluble vitamins are actively transported, the concen-

trations in the fetal circulation being much higher

than in the maternal circulation. Furthermore, there

is evidence that some vitamins are chemically altered

by the placenta to a form that is unable to diffuse

back into the maternal bloodstream, so reinforcing

the one-way transport mechanism. Thus, the fetus

has prior claim on the nutrient supply, much of

which is maintained, by homeostatic regulation,

within narrow concentration limits in the maternal

plasma. In adverse nutritional circumstances, it is the

mother, not the fetus, who is ‘at risk.‘ (See Amino

1600

1700

1800

1900

2000

2100

2200

0.0

1.0

2.0

3.0

816

Stage of pregnancy (weeks)

Weight of fetus (kg)

Maternal energy intake (kcal per day)

24 32 40

fig0001 Figure 1 Diagram showing changes in maternal energy intake

(—) and weight of the fetus (– – –) at different stages of pregnancy.

Reproduced from Pregnancy: Metabolic Adaptations and Nutri-

tional Requirements, Encyclopaedia of Food Science, Food Technol-

ogy and Nutrition, Macrae R, Robinson RK and Sadler MJ (eds),

1993, Academic Press.

PREGNANCY/Metabolic Adaptations and Nutritional Requirements 4725

Acids: Metabolism; Minerals – Dietary Importance;

Vitamins: Overview.)

Metabolic Adjustments in Pregnancy

0014 Under normal circumstances, the integrity of the

tissues is assured by homeostatic regulation of the

absorption, excretion and catabolism of the nutrients.

During reproduction, these control mechanisms are

adjusted, under the influence of hormones secreted by

the placenta, in order to make available an additional

nutrient supply for growth of the conceptus.

Absorption of the Nutrients

0015 The macronutrients, fat, carbohydrate, and protein,

are almost completely digested and absorbed in the

small intestine, so that no appreciable change occurs

in pregnancy. The absorption of minerals, however,

is carefully regulated. Most Western diets provide a

considerable excess of calcium, and no more than

around 30% is normally absorbed. From early in

pregnancy, the blood concentration of the physiolo-

gically active form of vitamin D (1,25-dihydroxy-

cholecalciferol) is elevated, leading to an increased

uptake of calcium from the gut, thus allowing the

mother to satisfy the needs of her developing fetus

without recourse to her own skeletal calcium or the

need to increase her dietary intake. Only when her

customary calcium intake or the biosynthesis of vita-

min D is severely restricted is calcification of the fetal

skeleton compromised. (See Calcium: Physiology;

Cholecalciferol: Physiology.)

0016 As with calcium, the proportional absorption of

iron from a diet providing 12–14 mg per day is very

small (about 10%), but as gestation advances, iron

uptake increases progressively and may exceed 40%.

This adjustment in absorption, in association with a

reduction in iron loss resulting from the cessation of

menstruation, is sufficient to satisfy the iron cost of

pregnancy. Judged by normal standards, the charac-

teristic fall in hemoglobin concentration that is

noted in pregnancy would indicate a state of anemia.

Blood volume, however, is considerably increased so

that the total amount of hemoglobin in circulation,

and consequently the oxygen-carrying capacity of

the blood, is actually raised. Supplementation of

the diet of women who begin pregnancy in an iron-

sufficient state may therefore be injurious as it has

been shown to increase red cell size and could ad-

versely affect blood flow in the small capillaries. (See

Iron: Physiology.)

0017 Other minerals, such as copper and zinc, may also

show improved absorption. (See Copper: Physiology;

Zinc: Physiology.)

Urinary Excretion of Nutrients

0018The glomerular filtration rate is increased during preg-

nancy. It is suggested that the presence of traces of

glucose in the urine at some stages of pregnancy in

most women merely indicates that more glucose has

been filtered from the plasma than can be reabsorbed

by the kidney tubules at that time. Some women, how-

ever, may lose large amounts of glucose in their urine,

particularly those who develop gestational diabetes.

0019The urinary excretion of most nutrients is altered,

but whether or not this reflects specific modifications

in kidney function is unclear since the picture is ob-

scured by withdrawal of nutrients from circulation by

the placenta, which changes with time. The pattern of

excretion of amino acids is most consistent. In non-

pregnant women, about 1% of total nitrogen excre-

tion is accounted for by free amino acids, but urinary

loss rises in early pregnancy, reaching a plateau in

midpregnancy at a level approximately double that

found in the nongravid state. Most of the increase is

accounted for by the nonessential amino acids, pos-

sibly reflecting selective uptake by the placenta. Since

the plasma amino acid concentrations show little

change, the large increase in urinary excretion cannot

be attributed to kidney overload and is most likely the

result of altered hormonal status affecting kidney

function. The return to normal levels of excretion

during lactation supports this conclusion.

0020One example of altered kidney function that favors

conservation has clearly been identified. The amino

acid taurine, a derivative of the nonessential amino

acid cystine, shows a dramatic and sustained reduc-

tion in excretion from early pregnancy. It has been

suggested that taurine may act as a membrane stabil-

izer, as an inhibitory neurotransmitter or neuro-

modulator, and as a growth modulator in fetal

tissues. Tissue concentrations are particularly high

in the fetus, and the suppression of urinary excretion

of taurine during pregnancy is seen as a means of

satisfying the needs of the developing fetus, which

lacks the ability to synthesize taurine de novo.

Metabolism of Protein

0021The rate of accretion of nitrogen by the fetus and

maternal reproductive tissues is known to rise 10-

fold between the first and last quarters of gestation.

Since, on average, no appreciable change in food

intake, and thus protein intake, occurs in pregnancy,

one would expect to find a positive nitrogen balance,

rising continuously throughout pregnancy. In the few

nitrogen-balance studies carried out on pregnant

women, however, no differences have been found

between the values for nitrogen retention measured

4726 PREGNANCY/Metabolic Adaptations and Nutritional Requirements

at different stages of gestation. This apparent para-

dox was resolved by the study of reproduction in the

rat. (See Protein: Digestion and Absorption of Protein

and Nitrogen Balance.)

0022 During the first 2 weeks of pregnancy, when com-

petition between the dam and her fetuses for nutrients

is minimal, a substantial reserve of protein is built up

in the muscles (the ‘anabolic phase‘). During the final

week, the period of rapid fetal growth, the protein

reserve is broken down, the amino acids released

being taken up by the placenta for growth of the

conceptus. This ‘catabolic phase‘ is not influenced

by the protein content of the maternal diet, and

is controlled by the hormone progesterone. (See

Hormones: Steroid Hormones.)

0023 Evidence for a similar biphasic system of protein

metabolism in women was provided by measurement

of the excretion of the amino acid 3-methylhistidine.

This amino acid is found predominantly in muscle.

Histidine undergoes methylation after its incor-

poration into the peptide chains of the contractile

proteins actin and myosin, and, in the course of muscle

protein turnover, the 3-methylhistidine released is not

reutilized, but is quantitatively excreted in the urine.

In pregnancy, the excretion of 3-methylhistidine rises

sharply during the last trimester, indicating the

hydrolysis of an amount of protein approximating

the estimated protein cost of pregnancy.

0024 Such a redistribution of amino acids from maternal

to fetal tissues would not be detected in measure-

ments of nitrogen balance.

0025 This cyclic course of protein metabolism has im-

portant nutritional implications. The protein cost of

pregnancy is distributed over the whole gestational

period, and the influence of acute or chronic maternal

undernutrition on fetal growth is minimized.

0026 Nitrogen retention occurs when the intake of pro-

tein-nitrogen exceeds nitrogen losses from the body,

largely the products of amino acid catabolism in the

urine (mostly urea) and undigested dietary protein in

the feces along with cells shed from the gut epithe-

lium. If, during pregnancy, the catabolism of amino

acids were in part suppressed, the fraction spared

could be used for fetal protein synthesis. In the case

of a woman existing on 40 g of protein per day, as in

many developing world populations, a reduction of

less than 9% in amino acid oxidation would spare

enough protein to cover the entire estimated require-

ment for pregnancy.

0027 The hypothesis was tested in the rat. The activities

of two rate-limiting enzymes (alanine aminotransfer-

ase and argininosuccinatesynthetase), which regulate

the oxidation of amino acids and the conversion of

amino-nitrogen to urea, were measured in the livers at

different stages of gestation. The activities of both

enzymes were markedly depressed by the end of the

first week, and declined even further (by around

50%) as pregnancy advanced. A parallel change in

plasma urea was also noted.

0028Evidence for a similar adjustment in amino acid

catabolism in pregnant women was later obtained in

a metabolic study using urea labeled with a stable

isotope of nitrogen. Measurements made in the last

trimester and in the postpartum postlactational

period showed a reduction of 30% in the rate of

urea synthesis in late pregnancy and a similar fall in

the plasma urea concentration.

0029The mechanism for protein sparing, which oper-

ates progressively throughout pregnancy, combined

with the biphasic system of early storage and later

breakdown of stored protein, ensures a supply of

amino acids commensurate with the demands of the

growing fetus. The suppression of hepatic amino acid

oxidation was also shown to be induced by the

placental hormone progesterone. The fetoplacental

unit thus indirectly controls its supply of amino

acids as well as its energy needs.

Metabolism of Energy

0030As stated earlier, the dietary energy supply is the

major determinant of fetal growth. In healthy preg-

nant women, energy balance becomes positive during

the first trimester, probably in response to the rising

secretion of progesterone. The purpose of the aug-

mented fat reserve, amounting, on average, to some

4 kg of fat, is primarily to subsidize the high energy

cost of lactation, but a small amount is mobilized in

late pregnancy to provide an alternative fuel for use

by the maternal tissues and enhance the availability of

glucose for use by the fetoplacental unit. The human

fetus derives its energy almost exclusively from the

oxidation of glucose. (See Energy: Energy Expend-

iture and Energy Balance.)

0031The discrepancy between the measured energy

intakes of healthy pregnant women and the values

predicted for energy expenditure has yet to be

explained. There is no doubt that some saving is

made in energy expenditure from a reduced level of

physical activity, but this is difficult to quantify.

0032The alterations in carbohydrate metabolism that

are characteristic of pregnancy could also lead to the

sparing of energy. In pregnancy, there is an increased

output of insulin in response to a glucose stimulus,

and reduced glucose uptake by the peripheral tissues

(muscle and adipose tissue). Insulin antagonism has

been attributed to the action of placental lactogen.

Consequently, more of the ingested carbohydrate

is directed to the liver, the organ that maintains the

blood glucose concentration. The conversion of

PREGNANCY/Metabolic Adaptations and Nutritional Requirements 4727

carbohydrate to fat is a very costly process. Approxi-

mately 20% of the energy that is available from the

direct oxidation of glucose is lost as heat if the glucose

is first converted to fat, and the fat is later oxidized to

produce energy. This adjustment in carbohydrate util-

ization, therefore, not only conserves energy for ana-

bolic purposes, but also safeguards the fetal energy

supply. (See Carbohydrates: Digestion, Absorption,

and Metabolism.)

Dietary Recommendations for Pregnancy

0033 Growth of the fetus is little affected by transient or

prolonged moderate undernutrition of the mother.

Relatively small deficits in birthweight may be ac-

counted for by a lower proportion of body fat resulting

from maternal dietary energy restriction in late preg-

nancy, from the diversion of glucose (the fetal fuel) to

the muscles should the mother be engaged in hard

physical work throughout pregnancy, or from mal-

function of the placenta.

0034 The security of the fetus is provided by the pla-

centa, an organ designed not only to ensure a priority

claim on all nutrients present in the maternal circula-

tion, but also, by the secretion of hormones, to modu-

late the homeostatic regulation of nutrient utilization

at all levels – absorption, excretion, and catabolism,

in order to augment the nutrient supplies. No govern-

ment committee responsible for devising dietary

guidelines would be so incautious as to suggest that

women during pregnancy require no more food than

when in the nongravid state, although all evidence

points very clearly to that conclusion. One obvious

a priori condition would be that nutritional status

should be satisfactory before conception and

throughout pregnancy.

0035 Attention has been focused on the latter half of

pregnancy, when fetal growth is most rapid, the

need for nutritional input is at its greatest, and the

effects of maternal food deprivation most apparent.

These considerations led a Joint FAO/WHO (Food

and Agriculture Organization, World Health Organ-

ization) Ad Hoc Expert Committee in 1973 to pro-

pose an additional 628 kJ (150 kcal) per day for the

first trimester, rising to 1464 kJ (350 kcal) per day for

the second and third trimesters, the stage of preg-

nancy when women, unencumbered by professional

advice, would spontaneously reduce their food con-

sumption. In the light of continuing research, how-

ever, estimates of energy and nutrient requirements

are being revised in a downward direction. In 1974,

the US report on Recommended Daily Allowances

proposed an additional daily supplement of 30 g of

protein, 400 mg of calcium and 30–60 mg of iron for

the pregnant woman, acknowledging that such a high

intake of iron could not be met by the iron content of

habitual US diets. The implication was that preg-

nancy was a clinical condition that required thera-

peutic intervention. One decade later, the proposed

increments in energy and calcium were little changed,

but the supplement of iron was reduced to 15 mg, and

the protein allowance was changed to anticipate the

pattern of accretion by the fetus, rising from 1.2 g per

day in the first trimester to 10.7 g in the final trimester

of pregnancy. (See Dietary Requirements of Adults.)

0036The UK dietary recommendations for pregnancy

have consistently been on a less generous scale. Over

a similar period, the daily allowance for energy has

fallen from 1004 kJ (240 kcal) in the second and third

trimesters to 837 kJ (200 kcal) during the third

trimester only. Protein is unchanged at 6 g per day

throughout pregnancy, but the recommendation for

calcium has fallen from 700 mg per day in the third

trimestertozero.Likewise,norecommendationwas

made for an increase in iron intake in the 1991 report

on Dietary Reference Values, compared with the small

increase of 1 mg per day in the earlier 1979 edition.

0037There is no doubt that as scientific opinion changes,

other values will also be reduced, and nutritional

guidelines for pregnancy ultimately will correspond

to the dietary practices of healthy women satisfying

their natural appetites on a well-balanced diet.

See also: Anorexia Nervosa; Calcium: Physiology;

Carbohydrates: Digestion, Absorption, and Metabolism;

Dietary Requirements of Adults; Energy: Energy

Expenditure and Energy Balance; Fats: Requirements;

Hormones: Steroid Hormones; Iron: Physiology;

Lactation: Human Milk: Composition and Nutritional

Value; Malnutrition: Malnutrition in Developed Countries;

Minerals – Dietary Importance; Premenstrual

Syndrome: Nutritional Aspects; Protein: Digestion and

Absorption of Protein and Nitrogen Balance; Vitamins:

Overview

Further Reading

Campbell DM and Gilmer DG (eds) (1983) Nutrition in

Pregnancy. London: Royal College of Obstetricians and

Gynaecologists.

Department of Health (1991) Dietary Reference Values for

Food Energy and Nutrients for the United Kingdom.

London: The Stationery Office.

Hytten F and Chamberlain GVP (eds) (1980) Clinical

Physiology in Obstetrics. Oxford: Blackwell Scientific.

Naismith DJ (1983) Maternal nutrition and fetal health. In:

Chiswick ML (ed.) Recent Advances in Perinatal

Medicine, vol. I, pp. 21–39. Edinburgh: Churchill

Livingstone.

National Research Council (1989) Recommended Daily

Allowances 10th edn. Washington, DC: National

Academy Press.

4728 PREGNANCY/Metabolic Adaptations and Nutritional Requirements

Role of Placenta in Nutrient

Transfer

Y Kudo

and C A R Boyd,UniversityofOxford,

Oxford, UK

Introduction

0001 During intrauterine life, the developing fetus effect-

ively receives all of its nutrition across the placenta,

which, in the human, has a chorionic villus structure in

which maternal blood directly superfuses the external

surface, the trophoblast of the placenta. This tropho-

blast forms an unusual epithelium separating the ma-

ternal plasma from the fetal extracellular space of the

villus core through which the fetal capillary circula-

tion flows. For the fetus, the trophoblast is thus

equivalent to the epithelium lining the small intestine

of the newborn, since, from a nutritional perspective,

it must absorb those molecules required for both

growth and maintenance of the organism. The tropho-

blast also has an important role in acting as the lung for

the fetus (since all gas exchange between mother and

baby must occur across this surface), as the fetus’s

kidney (since excretion from the conceptus to the

mother occurs across this structure), as well as being

an important endocrine tissue secreting peptide and

steroid hormones into the mother. The placenta itself

also plays a very substantial role in intermediary me-

tabolism, so that it cannot be assumed that there is no

metabolism of absorbed nutrients during solute move-

ment from mother to fetus.

0002 As an epithelium, the trophoblast has two surfaces,

the one facing the mother and the other facing the

fetus. These surfaces differ structurally; for example,

microvilli are found projecting into the maternal

bloodstream at the apical surface, where they form a

brush border, whereas the basal surface facing the

fetus does not have this surface specialization. From

the functional point of view, it is the differences in

the distribution of transport membrane proteins

(channels, carriers, and pumps) that determine the

overall transport of nutrients from mother to baby,

at least as far as water-soluble molecules are con-

cerned. In the placenta, all transport appears to be

across the trophoblast since, uniquely, the cells that

compose this structure are fused to form a syncytium;

this is in contrast to other epithelia where transport

between adjacent epithelial cells allows a functional

paracellular route to lie in parallel to the route

through the epithelial cells themselves (the transcel-

lular route). The question in the human as to

whether there is a special route available for the

transport of large molecules (MW 5000) is not yet

resolved: certainly, at term, the human placenta does

appear to be able to permit the transport of larger

molecules at a slow rate from baby to mother.

This route is unlikely to be of nutritional significance,

since the rate of transport is low, but it may be

important with regard, for example, to immuno-

logical sensitization.

0003The placenta, together with the growing fetus, has

a very substantial metabolic energy requirement, and

in the human, ATP synthesis appears to be met by the

very substantial rate of glucose delivery from the

mother. The glucose transporter systems that are

found in both the apical and basal surfaces of the

human trophoblast appear to be the type named

GLUT1; in other words, they are sodium-independent

facilitated transporters that are not regulated by insu-

lin. The Michaelis constant (K

) for glucose transport

at both surfaces is relatively high (approximately

30 mM), and the maximal transport rate (V

max

)is

very substantial. The result of this is that glucose

delivery across the brush-border membrane of the

placenta will be in a direction and rate that are

dependent solely on the chemical driving force from

mother to baby (maternal–fetal plasma glucose con-

centration). It seems likely that this fundamental

property is the basis for the macrosomia (‘large-for-

dates‘) found in the babies of mothers with elevated

plasma glucose concentration, as typically found in

diabetes mellitus. Transport of glucose, which is

stereospecific, may be inhibited by glucose analogs

that share the chemical structure of d-glucose at

carbon 1; for example, both 3-0-methylglucose and

2-deoxyglucose are transported, whereas a-methyl-

glucoside (with a methyl group on carbon 1) is not.

The transport of other monosaccharides has been

studied rather little; in the human, fructose is trans-

ported much more slowly than glucose itself (in con-

trast to other nonprimate species). The question of

regulation of carbohydrate delivery across the pla-

centa is not fully resolved since some glucose trans-

porters may be regulated by phosphorylation, and

the gradient for transplacental glucose delivery will

also depend upon factors regulating glucose utiliza-

tion and production by the placenta itself; little is

known of the physiological regulation of either of

these processes. (See Carbohydrates: Digestion,

Absorption, and Metabolism; Glucose: Maintenance

of Blood Glucose Level.)

0004In contrast to glucose transport, amino acid trans-

port can be powered. The overall gradient of amino

acid between maternal plasma and fetal plasma varies

Deceased.

PREGNANCY/Role of Placenta in Nutrient Transfer 4729

for individual amino acids. Typically, individual

amino acid concentrations are twice as high in fetal

as in maternal plasma. Current understanding of the

mechanisms responsible for this relates to the distri-

bution of the membrane transport proteins between

the two faces of the trophoblast and in particular to

the distribution of sodium-coupled transporters that

are found predominantly (although not exclusively)

in the brush border. Recent work using isolated mem-

branes that reseal to form artificial structures (ves-

icles) has been useful in establishing the numbers and

properties of such transporters. In addition to the

direct effect of sodium ions in moving amino acids

into the trophoblast across the brush-border mem-

brane against a concentration gradient, these trans-

porters are often electrogenic and are thus also driven

physiologically by the membrane potential. One

example of such a process is the transport system

called ‘A,‘ which uses alanine, serine, and proline

as transported substrates and accumulates these

amino acids in the trophoblast against a concentra-

tion gradient. These amino acids then leave the

trophoblast across the basal membrane by a different

transport system. Other amino acids may be trans-

ported via tertiary active transport; for example, leu-

cine is found in higher concentrations in fetal plasma

than in maternal plasma, but it is not itself a substrate

for sodium-coupled transport; rather, it appears to

exchange with amino acids, such as alanine, that

have been accumulated in the trophoblast as just

described.

0005 The cationic and anionic amino acids are unusual

in that, having their own charge, they will be acceler-

ated or retarded by the membrane potential in cross-

ing each of the plasma membrane surfaces of the

trophoblast. For cationic amino acids (lysine, argin-

ine, histidine), entry into the placenta appears to be

largely by system y

(Na

-independent), whereas exit

into the fetus involves an electroneutral system (y

L),

which exchanges the cationic amino acid for a neutral

amino acid (e.g., leucine) and a sodium ion, thus

effectively solving the problem of permitting posi-

tively charged amino acids to exit against an inside-

negative membrane potential. For anionic amino

acids (glutamate and aspartate), very high intratro-

phoblast concentrations are achieved by a transport

system that is coupled to K

efflux as well as Na

entry. Essential amino acid requirements for the fetus

are different from those of adults. However, it is not

clear whether transport of specific amino acids across

the placenta ever becomes rate-limiting for fetal

growth. In the human, intrauterine growth retard-

ation not associated with other disease has been

shown to be associated with reduced placental deliv-

ery of amino acids through specific systems, e.g.,

associated with decreased function of system A. IGF

(insulin-like growth factor) and IGFBP (insulin-like

growth factor binding protein) are now recognized as

having an important role in either normal or abnor-

mal fetal growth via controlling placental amino

acids and glucose transport (e.g., IGF-I (insulin-like

growth factor-1) selectively enhances system A activ-

ity). In certain unusual metabolic disorders (e.g., ma-

ternal phenylketonuria (PKU)) maternal levels of one

particular amino acid may be elevated; this results in

competition between this amino acid and others that

share the same transporters. Some of the abnormal-

ities found in the developing babies of such mothers

may be a consequence of nutritional deprivation of

tyrosine, for example, owing to competition by raised

maternal phenylalanine levels for the delivery of this

amino acid across the placenta. The fact that amino

acid transport across the placenta involves a family

of transport proteins with overlapping substrate

(amino acid) specificities means that the nutritional

consequences for the fetus of changing the level of

one amino acid in the mother will be complex.

This follows because, in contrast to placental glucose

transporters, the K

and V

max

of the amino acid

transporters are relatively low.

0006Lipid transport across the placenta in relation to

human nutrition has been studied less rigorously,

in part because it is likely to be perfusion- rather

than membrane-limited, since the lipid-soluble nature

of such a substrate allows ready transmembrane

transport. Nutritionally, the nervous system of the

developing fetus requires substrate delivery of precur-

sors for myelin synthesis. Studies suggest that placen-

tal binding proteins may provide a pool of essential

fatty acids for fetal utilization. (See Amino Acids:

Metabolism; Fatty Acids: Metabolism.)

0007Transport of the inorganic cations of sodium and

potassium involves both channels and transporters.

Sodium transport into the trophoblast is coupled to

the entry of those solutes (which include both organic

and inorganic molecules) powered by secondary

active transport. The extrusion of sodium across the

basal surface of the trophoblast is likely to be a result

of sodium pumping by Na

ATPase activity. In

contrast, potassium, accumulated in the trophoblast,

as in other epithelia by the sodium pump, requires

channel-mediated release to account for its move-

ments between mother and baby. Potassium channels

have recently been shown to be sensitive to modula-

tion in this tissue (e.g., by G proteins, by arachidonic

acid, and by pH). These regulatory factors may them-

selves be controlled by circulating factors in both

mother and fetus. It is clear that fetal plasma potas-

sium is carefully regulated by control of placental

transport of this cation.

4730 PREGNANCY/Role of Placenta in Nutrient Transfer

0008 The divalent cation of calcium is found in higher

concentrations in fetal than in maternal plasma.

Active transport processes are therefore involved in

placental calcium metabolism, and these are unusual

in that regulation of transport is clearly precisely

controlled. It seems likely that calcium extrusion

across the basal surface of the trophoblast is ATP-

driven and regulated by calmodulin. Entry of calcium

across the brush border is now known to be via ECaC

(epithelial calcium channels) that are regulated: mem-

brane potential hyperpolarization activates, and

intracellular calcium inhibits, these channels. Fetal

parathyroid hormone and vitamin D are likely to

regulate all of these events.

0009 Iron is also transported from mother to fetus in a

regulated fashion, and again, there is a greater con-

centration of iron in the fetal circulation. In some

species, transport of iron has been shown to be active

in that it is inhibited by anoxia. The role of the

transferrin receptor found in the human placental

microvillus membrane is now known to be related

to the mechanisms of iron entry into the cytosol.

From this compartment, iron has to leave, but the

mechanisms responsible for this are not fully under-

stood. (See Calcium: Physiology; Hormones: Thyroid

Hormones; Iron: Physiology; Potassium: Physiology;

Sodium: Physiology.)

0010 Anion entry into the placenta has been studied

using isolated membrane preparations. These studies

show that for monovalent ions (chloride and other

halides), two routes are available, an exchange

and a conductive route, the latter likely to be via

channels. The anion exchange system appears to

be functionally linked to the transport of organic

anions (bicarbonate, lactate) from placenta into the

maternal circulation. Phosphate transport is also

regulated and appears to involve a sodium-dependent

cotransporter at the maternal-facing surface and an

efflux mechanism (possibly driven by the membrane

potential) at the basal surface of the tissue. As for

calcium transport, phosphate delivery is regulated

by parathyroid hormone concentration in the fetus.

0011 Trace-element delivery across the placenta also in-

volves specific placental binding proteins analogous

to those found in adult liver; however, membrane

transport is also required to allow such ions to gain

access to and from the trophoblast. The nature of

such transporters varies greatly, although the role

of the divalent cation transporter (DCT-1) in the

placenta may be more generally important. For

zinc, there is evidence that the histidine amino

acid transporter is responsible for delivery of a histi-

dine–zinc complex, whereas for transition-metal

oxides, it appears that anion exchange is important.

The transport of iodide across the human placenta is

also likely to be by anion exchange since SCN can

inhibit it, but the mechanisms responsible for the

concentration of this element in the fetal compart-

ment are not clear. Selenate appears to share a path-

way with sulfate for entry across the brush border,

and the transport of both of these ions is inhibited by

blockers of anion exchange. This pathway appears to

be shared with those available for transport of the

trace elements chromium and molybdenum as chro-

mate and molybdate. (See Trace Elements.)

0012Vitamin transport also is highly specific for indi-

vidual substrates; thus, for ascorbic acid, a sodium-

independent transporter for the reduced from of this

nutrient has been described in the brush-border mem-

brane; this transporter appears to be functionally

coupled to a placental system that maintains ascor-

bate in this chemical form. The Na

-dependent

multivitamin transporter that transports panto-

thenate, biotin, and lipoate is expressed in human

placenta.

See also: Amino Acids: Metabolism; Calcium:

Physiology; Carbohydrates: Digestion, Absorption, and

Metabolism; Fatty Acids: Metabolism; Glucose:

Maintenance of Blood Glucose Level; Hormones: Thyroid

Hormones; Iron: Physiology; Potassium: Physiology;

Sodium: Physiology; Trace Elements

Further Reading

Bain MD, Copas DK, Taylor A et al. (1990) Permeability of

human placenta in vivo to four non-electrolytes. Journal

of Physiology 431: 505–513.

Boyd CAR and Kudo Y (1990) Placental amino acid trans-

port. Biochimica et Biophysica Acta 121: 169–174.

Hoenderop JGJ, van der Kemp AW, Hartog A et al. (1999)

Molecular identification of the apical Ca

2þ

channel in

1,25-dihydroxyvitamin D

-responsive epithelia. Journal

of Biological Chemistry 274: 8375–8378.

Kudo Y and Boyd CAR (1996) Placental tyrosine transport

and maternal phenylketonuria. Acta Paediatrica 85:

109–110.

Parkkila S, Waheed A, Britton RS et al. (1997) Association

of the transferrin receptor in human placenta with HFE,

the protein defective in hereditary hemochromatosis.

Proceedings of the National Academy of Sciences, USA

94: 13198–13202.

Shennan DB and Boyd CAR (1988) Trace element transport

in placenta. Placenta 9: 333–343.

Sibley CP, Birdsey TJ, Brownbill P et al. (1998) Mechan-

isms of maternofetal exchange across the human pla-

centa. Biochemical Society Transactions 26: 86–91.

Wang H, Huang W, Fei YJ et al. (1999) Human placental

-dependent multivitamin transporter. Journal of

Biological Chemistry 274: 14875–14883.

PREGNANCY/Role of Placenta in Nutrient Transfer 4731

Safe Diet

R B Fraser and F A Ford, University of Sheffield,

Sheffield, UK

Introduction

0001 Would-be pregnant and pregnant women have

heightened concerns about their diet, which can be

summarized by the common question, ‘Will it harm

my baby?‘ Because the question is so common, many

sources of advice are available in the lay press, not all

as scrupulously researched and scientifically based as

they might be. Another source of potentially mislead-

ing advice is the food industry and written media, the

agents of which possess a lack of objectivity that may

not be obvious to the casual reader. Articles prolifer-

ate with titles such as ‘How to have a beautiful baby‘

and ‘How to have a perfect baby‘. These tend to

contain a mixture of dietary and lifestyle advice

with the implication that, if followed, the undesirable

outcomes of pregnancy such as miscarriage, congeni-

tal malformation, and fetal death are avoidable. Pro-

fessionals in the field of nutrition must be aware of

this for the following reason. If a woman learns

of such advice only after her pregnancy has failed in

some way there is a potential for a lifelong burden of

guilt. For this reason purveyors of advice should re-

strict themselves to that which has been demonstrated

in scientifically valid experiments. In particular, they

should be guarded in their extrapolations from obser-

vational studies and animal experiments.

0002 This article highlights the principal areas in which

women have dietary concerns. Some of these are

dealt with in more detail elsewhere and are cross-

referenced.

Periconceptional Nutrition

0003 In an ideal world, pregnancies would be planned but

in the real world a high proportion are not. It is

important to remember that many women who have

not planned their pregnancies and have not subse-

quently followed the advice outlined below may

need reassuring that they have probably not caused

harm to their baby.

0004 The work of Frisch in the USA identified the link

between body composition and ovulation in the

human female. She suggested that fat must comprise

at least 22% of body weight for the maintenance of

ovulatory cycles and also observed that in normal

postpuberty women fat is about 28% of body weight.

It is well recognized that the relationship is to the fat

content of the body rather than absolute body weight,

as trained athletes of average or above-average body

weight may have very low body fat content and may

be oligo- or amenorrheic. Frisch observed that

amongst trained athletes who became fit after a

normal menarche, 60% continued regular cycles,

but 40% had irregular cycles and presumably associ-

ated subfertility. Other causes of secondary amenor-

rhea leading to infertility include psychological stress,

thyrotoxicosis, and the various malabsorption syn-

dromes. Eating disorders such as anorexia nervosa

and bulimia nervosa which may have been under-

diagnosed in the past are now been seen as contrib-

uting to the problem. Particularly for bulimics, a

remission in the disorder may allow the body fat to

build up to a stage where ovulation and conception

can take place, but the disorder may relapse during

the pregnancy, leading to serious nutritional deficien-

cies for the mother and possibly for the fetus.

0005The Nurses Health Study in the USA has also pro-

duced some interesting information about the relative

risk of menstrual cycle irregularity, not only in under-

weight but also in overweight women. For women

with a body mass index (BMI) below 20, at the age of

18 years, ovulatory infertility was found with a rela-

tive risk of about 1.2 compared to women with a BMI

between 20 and 25. Interestingly, however, the rela-

tive risk of ovulatory infertility was 1.5 in those with

a BMI of 28 and more than 2 in the obese group with

a BMI above 30. About half of the risk is associated

with polycystic ovarian syndrome (PCOS) in which

ovulatory infertility and obesity coexist but there is

still a doubling in relative risk of ovulatory infertility

in women with a BMI above 30 who do not have

ultrasonically detectable polycystic ovaries.

Vitamin Intakes and Congenital

Malformations

Folic Acid

0006In 1991, the Medical Research Council (MRC) vita-

min trial reported that a significant reduction in the

recurrence of neural tube defects (NTD) had been

obtained by a daily dietary supplement of 4 mg of

folic acid in women who were at high risk. Women

at risk of a recurrence of NTD should be advised to

take a folic acid supplement of 5 mg (5000 mg) per day

when planning a pregnancy and continue with it until

12 weeks’ gestation. A later study reported that first

occurrence of NTD could also be prevented by daily

supplements containing 800 mg of folic acid. In the

UK, in line with many other nations, women are

advised to take a prepregnancy supplement of

0.4 mg (400 mg) of folic acid as a daily medicinal

supplement from when they begin trying to conceive

4732 PREGNANCY/Safe Diet

until 12 weeks’ gestation, in addition to eating a

folate-rich diet and breads and breakfast cereals

fortified with folic acid.

0007 The mechanism for the effect of folic acid in redu-

cing the risk of NTD is not clear. The most likely

explanation is that it overcomes genetically deter-

mined defects in folate metabolism that interfere

with normal neural tube development. One other

hypothesis is that it might decrease the likelihood of

an affected pregnancy surviving, and there is some

concern that folic acid supplementation could be

associated with a higher risk of fetal death. How-

ever, the generally accepted explanation for this is

that folic acid might initially permit the survival of

affected or nonviable pregnancies to a point where

they are recognized as spontaneous abortions.

0008 Educational campaigns conducted since 1995 have

had a substantial effect in increasing the number of

women in the UK who are aware of the link between

folic acid and NTD. However, such education can

only have a limited effect because it is estimated that

only 50% of all pregnancies are planned. NTD arise

very early in gestation and by the time a woman

realizes that she is pregnant it is usually too late to

prevent an NTD by taking supplements. For this

reason it has been suggested that the most effective

way of reducing NTD in the UK would be to fortify

the food supply with folic acid so that even women

with unplanned pregnancies would be less likely

than at present to have offspring with NTD. The

Department of Health Committee on Medical

Aspects of Food and Nutrition Policy (COMA) has

recently recommended universal fortification of flour

at 240 mg 100 g

1

, which would reduce the risk of

NTD by 41% without resulting in unacceptably

high intakes in any group of the population.

Retinol

0009 It has been known for a long time from animal studies

that high levels of vitamin A in the form of retinol

are teratogenic in the periconceptional period. This

led to the Department of Health in 1990 advising

women to avoid food sources containing high levels

of the retinal form of vitamin A in the periconcep-

tional period and indeed during pregnancy. The

Department of Health advises that very high intakes

of retinol, i.e., more than 10 times the recommended

dietary allowance either in liver/liver products or

vitamin/fish liver oil supplements, can damage the

developing embryo. This advice remains current and

all women of child-bearing age should avoid liver and

its products and should not take supplements con-

taining more than four times the recommended daily

amount of retinol.

0010The same risks do not seem to be present for vita-

min A derived from b-carotene. Manufacturers of

multivitamin supplements recommended for preg-

nancy have generally recognized this and switched

the source of vitamin A to b-carotene.

Nutritional Management of Common

Symptoms in Pregnancy

Heartburn

0011Heartburn is thought to be caused by gastroesopha-

geal reflux. Although occasionally experienced in the

first trimester, it is generally more common in the last

trimester and occurs in 30–50% of women.

0012Small, frequent meals or snacks are usually toler-

ated better than large, well-spaced meals. Common

foods cited as causing heartburn as spicy and fatty

foods, fizzy drinks, citrus fruits, fruit juices, and

cucumber. Milk and milk products can help to relieve

symptoms but antacids are frequently used.

Nausea and Vomiting

0013Psychological factors, changing hormone levels,

hunger, altered carbohydrate metabolism, and vita-

min deficiencies have all been proposed as possible

causes for nausea and vomiting, but none has been

confirmed.

0014Symptoms may start before the woman knows she

is pregnant or in later pregnancy but commonly they

are worst between weeks 6 and 10, and subside by

about 13 weeks. Nausea is experienced at any time of

day or night and can be either slight or severe. It often

becomes worse when the stomach is empty, and

eating small, frequent meals based on starchy carbo-

hydrates may relieve it. Morning sickness is common

and consuming dry biscuits or toast before getting up

can relieve this.

0015Nausea can also be triggered by traveling, fried and

spicy foods, and smells such as coffee, perfume, and

cigarette smoke.

0016Some women just feel nauseated while others actu-

ally vomit as well; this may cause minor weight loss

but rarely causes nutrient deficiency. Women need

reassurance that not eating proper cooked meals or

losing some weight and their taste alterations will

cause no problems for their developing fetus. The

more severe cases of pregnancy vomiting (hyper-

emesis gravidarum) require hospital admission, intra-

venous fluids and, sometimes, parenteral nutrition.

Constipation

0017Constipation is common at all stages of pregnancy. It

may be related to a general reduction in motility in

the gastrointestinal tract, with prolonged transit

PREGNANCY/Safe Diet 4733

times and increased water resorption from the stool.

General advice about constipation is also suitable for

pregnancy, i.e., increased intake of fiber, particularly

cereal fiber, and increased fluid intake.

0018 Constipation may be aggravated by the consump-

tion of iron tablets; if it is not appropriate to reduce or

stop them, bulking agents may be prescribed.

Qualitative Aspects of Diet

0019 The following section refers to common questions of

dietary safety; some arise because of suspicion of

harm when items are included in the diet, others for

the paradoxical reason that their omission from the

diet might be dangerous.

Alcohol

0020 As far as alcohol is concerned, the picture is confus-

ing. There is no doubt that a heavy intake of alcohol

can damage the unborn baby and cause miscarriage.

Many women choose to give up alcohol and this

seems to be a sensible practice but there is no evidence

of harm from occasional drinking or the consumption

of less than 2 units per day (Table 1). Despite this,

many women do give up alcohol when trying to con-

ceive or whilst pregnant, and this seems a sensible but

not mandatory practice. (One unit is 15 g of absolute

alcohol, e.g., 0.28 l of beer, one glass of wine, or one

measure of spirits.)

0021 A well-defined group of anomalies referred to as

the fetal alcohol syndrome is now recognized. The

major defects of affected infants are weight and

length below the 10th centile for gestational age,

and microcephaly. Microcephaly is a condition of

small head size associated with an underdeveloped

brain. Such children are likely to be mentally retarded

and their physical growth is stunted. The syndrome

has been reported in up to 40% of the infants of

women drinking more than 6 units of alcohol per day.

0022 Definite harm has been recorded to the offspring of

women drinking between two and six units of alcohol

per day and long-term growth retardation and mental

retardation to offspring of those drinking more than 6

units a day (fetal alcohol syndrome).

0023A recent study showed that a woman’s alcohol

intake is associated with decreased fertility, even

among women with a weekly alcohol intake corres-

ponding to five or fewer drinks. This finding needs

further corroboration, but it seems reasonable for the

moment to encourage women to avoid alcohol if they

are having trouble conceiving.

Caffeine

0024Concern about the detrimental effects of caffeine

during pregnancy is not new but to some extent the

literature is conflicting. Caffeine is present in tea,

coffee, cola drinks, and many over-the-counter

remedies for colds and allergic symptoms. Animal ex-

periments with high doses have shown that some

congenital malformations may be induced but there is

no evidence of harm in humans. Current recommenda-

tions are that pregnant and breast-feeding women

should limit their caffeine intake to 300 mg day

1

which is equivalent to 4 cups ordinary-strength coffee

per day (or 6 cups of tea or 7 cans of cola). A recent

review from the UK Committee on Toxicity of Chem-

icals in Food, Consumer Products and the Environment

(DoH 2001) issued a statement on the reproductive

effects of caffeine in October 2001. A meta-analysis

of studies of maternal caffeine intake during pregnancy

and the risk of spontaneous abortion or low birth

weight, compared maternal caffeine intakes during

pregnancy of more than 150 mg/day with less than

150 mg/day. Calculated odds ratios were significantly

increased for spontaneous abortion (miscarriage) (odds

ratio ¼1.36; 95% confidence interval, 1.29–1.45) and

low birth weight (odds ratio ¼1.51; 95% confidence

interval, 1.39–1.63), for low birth weight (< 2.5 kg).

0025Two studies, which examined the links between

caffeine intake and pregnancy in SIDS, received a

huge amount of publicity and caused a lot of worry

for women. However, the results were conflicting.

Peanuts

0026Peanut allergy is increasing in children, although the

cause is unclear. The use of peanuts and peanut oil in

the British diet has increased rapidly over the last few

years and it is thought that being exposed to peanuts

at a young age may cause the allergy. However, it is

not known if this can happen as a result of a mother

eating peanuts when she is pregnant or breast-

feeding. Current advice is that women, their partners,

and existing children who have a family history of

atopic disease should avoid peanuts.

Over-the-Counter Remedies

0027As a general rule, self-prescribing in pregnancy

should be kept to a minimum. Those drugs that

tbl0001 Table 1 Congenital malformation rates and maternal alcohol

consumption

DrinksperdayMalformationrates(per1000)

None 78

Less than one 77

One to two 83

No statistically significant difference.

From Mills JL and Graubard BI (1987) Is moderate drinking during

pregnancy associated with an increased risk for malformations? Pediatrics

80: 309–314.

4734 PREGNANCY/Safe Diet