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

Подождите немного. Документ загружается.

and Nutrition Policy. Reports on Health & Social

Subjects 50: i–xv, 1–101.

Berry RJ, Li Z, Erickson JD et al. (1999) Prevention of

neural-tube defects with folic acid in China. New

England Journal of Medicine 341: 1485–1490.

Botto LD, Moore CA, Khoury MJ and Erickson JD (1999)

Neural-tube defects. New England Journal of Medicine

341: 1509–1519.

Centers for Disease Control and Prevention (1992) Recom-

mendations for the Use of Folic Acid to Reduce the

Number of Cases of Spina Bifida and Other Neural

Tube Defects. MMWR 41 (No. RR-14), pp. 1–7.

Cogswell ME, Perry GS, Schieve LA and Dietz WH (2001)

Obesity in women of childbearing age: risks, prevention,

and treatment. Primary Care Update Ob/Gyns 8:

89–105.

Elwood M, Elwood H and Little J (1992) Diet. In: Elwood

JM, Little J and Elwood JH (eds) Epidemiology and

Control of Neural Tube Defects, pp. 521–603. Oxford:

Oxford University Press.

Institute of Medicine (1998) Dietary Reference Intakes for

Thiamin, Riboflavin, Niacin, Vitamin B

, Folate, Vita-

min B

, Pantothenic Acid, Biotin, and Choline: A

Report of the Standing Committee on the Scientific

Evaluation of Dietary Reference Intakes and its Panel

on Folate, Other B Vitamins, and Choline and Subcom-

mittee on Upper Reference Levels of Nutrients. Wash-

ington, DC: National Academy Press (see http://

www.nap.edu/openbook/ 0309065542/html).

International Centre for Birth Defects and European Regis-

tration of Congenital Anomalies (1998) World Atlas of

Birth Defects, pp. 20–31. Geneva: World Health Organ-

ization.

International Clearinghouse for Birth Defects Monitoring

Systems (1998) Annual Report 1998 with Data for

1996, pp. 100–101. Rome: International Centre for

Birth Defects.

Kirke PN, Molloy AM, Daly LE et al. (1993) Maternal

plasma folate and vitamin B

are independent risk

factors for neural tube defects. Quarterly Journal of

Medicine 86: 703–708.

Mills JL, Scott JM, Kirke PN et al. (1996) Homocysteine

and neural tube defects. Journal of Nutrition 126: 756S–

760S.

Refsum H (2001) Folate, vitamin B

and homocysteine

in relation to birth defects and pregnancy outcome.

British Journal of Nutrition 85 (supplement 2): S109–

S113.

Rosenquist TH and Finnell RH (2001) Genes, folate and

homocysteine in embryonic development. Proceedings

of the Nutrition Society 60: 53–61.

Scott JM, Weir DG and Kirke PN (1995) Folate and neural

tube defects. In: Bailey LB (ed.) Folate in Health and

Disease, pp. 329–361. New York: Marcel Dekker.

Sells CJ and Hall JG (eds) (1998) Neural Tube Defects.-

Mental Retardation and Developmental Disabilities

Research Reviews 4(4). New York: Wiley-Liss.

Wald NJ (1994) Folic acid and neural tube defects: The

current evidence and implications for prevention.

CIBA. Foundation Symposium 181: 192–208.

Preeclampsia and Diet

E Abalos, G Carroli and L Campodo

nico, Centro

Rosarino de Estudios Perinatales, Rosario, Argentina

J Villar, World Health Organization, Geneva,

Switzerland

Background

0001Hypertensive disorders during pregnancy are one

of the main causes of maternal death worldwide,

most of these deaths being attributed to eclampsia.

Hypertensive disorders occur in 6–8% of all

pregnancies, contributing significantly to stillbirths

and neonatal morbidity and mortality. Babies are

also at increased risk of intrauterine growth restric-

tion, low birth weight and preterm delivery. Pregnant

women with hypertension, either newly diagnosed or

pre-existing, are prone to the development of poten-

tially lethal complications, notably abruptio placen-

tae, disseminated intravascular coagulation, cerebral

hemorrhage, pulmonary edema, hepatic failure, and

acute renal failure. The etiology of hypertensive dis-

orders related to pregnancy, particularly preeclamp-

sia, remains unknown. The most important

consideration in the classification of the disease is

differentiating hypertensive disorders that antedate

pregnancy from those that are pregnancy-specific,

from which the more ominous are preeclampsia

and eclampsia. Preeclampsia is a pregnancy-specific

syndrome of reduced organ perfusion secondary to

vasospasm and activation of the coagulation cascade.

Although our understanding of this syndrome has

increased, the criteria used to identify the disorder

remain a subject of confusion and controversy. In

chronic hypertension, elevated blood pressure is the

primary pathophysiologic feature, whereas in pree-

clampsia, increased blood pressure is important pri-

marily as a sign of the underlying disorder. As might

be expected, the impact of the two conditions on

mother and fetus is different, as is their management

Table 1.

Classification

0002There are controversies about the definition of

hypertensive disorders during pregnancy, and sev-

eral classifications have been suggested. Recently,

the National High Blood Pressure Education Pro-

gram Working Group on High Blood Pressure in

Pregnancy updated the 1990 report, and classi-

fied the hypertensive disorders during pregnancy

PREGNANCY/Preeclampsia and Diet 4745

as (1) chronic hypertension defined as hypertension

observable before pregnancy, or diagnosed before

the 20th week of gestation; (2) preeclampsia,

which is a pregnancy-specific syndrome usually oc-

curring after 20 weeks’ gestation, determined by

hypertension with proteinuria; (3) preeclampsia

superimposed on chronic hypertension; and (4)

pregnancy-induced hypertension or gestational

hypertension, which is transient hypertension

detected for the first time after midpregnancy if

preeclampsia is not present at the time of delivery

and blood pressure returns to normal by 12 weeks

post partum (a retrospective diagnosis). The system

suggested by the International Society for the Study

of Hypertension in Pregnancy (ISSHP) defines

hypertension as a diastolic blood pressure of

90 mmHg or above on two consecutive occasions

at least 4 h apart, or a single diastolic blood pres-

sure of 110 mmHg or more. The definition of pre-

eclampsia has the same criteria for high blood

pressure, but with the addition of significant protei-

nuria, usually at least 300 mg per 24 h or 1þ on

dipsticks.

Pathophysiology of Preeclampsia

0003Preeclampsia is a syndrome with both fetal and ma-

ternal manifestations. The maternal disease is charac-

terized by vasospasm, activation of the coagulation

system, and perturbations in many humoral and auta-

coid systems related to volume and blood pressure

control. The pathologic changes in this disorder are

primarily ischemic in nature and affect the placenta,

kidney, liver, and brain. Of importance, and distin-

guishing preeclampsia from chronic or gestational

hypertension, is that preeclampsia is more than

hypertension; it is a systemic syndrome, and several

of its ‘nonhypertensive‘ complications can be life-

threatening, even when blood pressure elevations

are quite mild.

0004The cause of preeclampsia is not known. Many

consider the placenta as the pathogenic focus for all

manifestations of preeclampsia because the delivery

of both the baby and the placenta is the only defini-

tive cure of this disease. There is no disease without

the placenta. Thus, research has focused on the

changes in the maternal blood vessels that supply

tbl0001 Table 1 Effectiveness of nutritional interventions in hypertension during pregnancy and preeclampsia

Intervention Hypertension duringpregnancy Preeclampsia

Practice Research Practice Research

Nutritional advice No evidence No effect RR ¼ 0.89

(0.42–1.88)

Balanced protein

(<25%) / energy

No evidence No effect RR ¼ 1.20

(0.77–1.89)

Isocaloric balanced protein

(<25% of total energy)

No evidence No effect RR ¼ 1.00

(0.57–1.75)

Energy/protein restriction for

high PI or high weight gain

No effect RR ¼ 0.97

(0.75–1.26)

No effect RR ¼ 1.13

(0.59–2.18)

Salt restriction No effect RR ¼ 0.97

(0.49–1.94)

No effect RR ¼ 1.11

(0.46–2.66)

Calcium Possibly beneficial for

women at high risk

RR ¼ 0.45 (0.31–0.66) and

with low baseline intake

RR ¼ 0.49 (0.38–0.62)

RCT in progress Possibly beneficial for

women at high risk

RR ¼ 0.21 (0.11–0.39) and

with low baseline intake

RR ¼ 0.32 (0.21–0.49)

RCT in progress

Iron and folate No effect RR ¼ 1.15

(0.41–3.18)

No evidence

Folate No effect RR ¼ 1.26

(0.90–1.76)

No evidence

Magnesium No evidence Needed No effect RR ¼ 0.87

(0.57–1.32)

Needed

Fish oil No effect RR ¼ 0.96

(0.86–1.07)

Possibly beneficial (data

from low quality studies)

RR ¼ 0.70 (0.55–0.90)

Zinc No effect RR ¼ 0.87

(0.65–1.15)

Needed No evidence Needed

Antioxidants No evidence Needed Possibly beneficial for

vitamins C and E (data

from one RCT) RR ¼ 0.46

(0.24–0.91)

Needed

4746 PREGNANCY/Preeclampsia and Diet

blood to the placenta. Failure of the spiral arteries to

remodel is postulated as the morphologic basis for

decreased placental perfusion in preeclampsia,

which ultimately may lead to early placental hypoxia.

Oxidative stress and inflammatory-like responses

may also be important in the pathophysiology of

preeclampsia.

0005 Research on how alterations in the immune re-

sponse at the maternal interface might lead to pree-

clampsia addresses the link between placenta and

maternal disease. A nonclassical human leukocyte

antigen (HLA), HLA G, is expressed in normal

placental tissue and may play a role in modulating

the maternal immune response to the immunologic-

ally foreign placenta. Placental tissue from pre-

eclamptic pregnancies may express fewer or different

HLA G proteins, resulting in a breakdown of mater-

nal tolerance to the placenta. Additional evidence

for alterations in immunity in pathogenesis includes

the disease prominence in nulliparous gestations

with subsequent normal pregnancies, a decreased

prevalence after heterologous blood transfusions,

long cohabitation before successful conception,

and observed pathologic changes in the placental

vasculature in preeclampsia that resemble allo-

graft rejection. Finally, there are increased levels

of inflammatory cytokines in the placenta and mater-

nal circulation, as well as evidence of increased

‘natural killer‘ cells and neutrophil activation in

pre-eclampsia.

0006 The mechanisms underlying vasoconstriction and

altered vascular reactivity in preeclampsia remain

obscure. Research has focused on changes in the

ratio of vasodilative and vasoconstrictive prosta-

noids, since there is evidence suggesting decrements

and increments in the production of prostacyclin

and thromboxane, respectively. More recently, inves-

tigators have postulated that the vasoconstrictive

potential of pressor substances (e.g., Angiotensin II

and endothelin) is magnified in preeclampsia as a

consequence of a decreased activity of nitric oxide

(NO) syntheses and decreased production of NO-

dependent or -independent endothelium relaxing

factor (EDRF). Also under investigation is the role

of endothelial cells (the site of prostanoid, endothelin,

and EDRF production), which, in preeclampsia, may

be dysfunctional, owing perhaps to inflammatory

cytokines (e.g., tumor necrosis factor a) and increased

oxidative stress. Other systems postulated to play a

role in pre-eclamptic hypertension are the sympa-

thetic nervous system, calciotrophic hormones,

insulin, and magnesium metabolism.

0007 Finally, some nutritional factor deficiencies

have been postulated as playing a role in the patho-

genesis of preeclampsia. This chapter discusses

their possible role on the hypertensive disorders of

pregnancy.

Possible Role of Nutrition in the

Pathophysiology of Preeclampsia

0008Nutrient supplements in addition to food sources of

nutrients are provided to populations either to in-

crease the intake among those with a deficiency (in

order to prevent or treat functional outcomes related

to such a deficit) or to obtain a pharmacological,

perhaps nonnutritional effect, among individuals

with an adequate intake of the nutrient in question.

0009Epidemiological observations have long suggested

a role for nutritional deficiencies in preeclampsia (i.e.,

calcium, proteins, vitamins, etc.). However, interven-

tion evaluations have failed to confirm such promis-

ing observations. We will describe here the evidence

from randomized-controlled trials that support the

relationship between different nutrients and pree-

clampsia.

Calcium

0010There is considerable evidence linking calcium intake

and hypertension during pregnancy from observa-

tional and experimental studies. However, there is

still no satisfactory explanation for the mechanisms

involved in the calcium-mediated effect on blood

pressure prevention. It was postulated that parathy-

roid hormone could be involved in this relationship.

Demonstrated alterations in extracellular calcium

homeostasis in preeclampsia include hypocalciuria

and decrease serum levels of calcitriol. Increased

parathyroid hormone (PTH) and decreased plasma

ionized calcium concentration have not been con-

sistently observed. Also, consistent abnormalities of

intracellular calcium metabolism have been described

in pre-eclamptic women, such as increased intra-

cellular free calcium concentration in platelets and

lymphocytes. Increases in intracellular free calcium

concentration in circulating cells are hypothesized to

result from fluctuation in hormones or vasoactive

substances that cause similar alteration in vascular

smooth muscle. Pregnancy is a state of high calcium

requirements as a result of fetal demands while

maternal adaptive mechanisms are partially in-

hibited. These phenomena lead to the hyperparathyr-

oid state of pregnancy. An increase in parathyroid

hormone serum levels would involve an increase in

free intracellular calcium. Thus, the concentration of

intracellular free calcium in vascular smooth muscle

cells determines the degree of tension and is the trig-

ger for muscular contraction. So, the vasoconstrictive

effect, with a rise in blood pressure, results from an

increase in vascular smooth muscle tension.

PREGNANCY/Preeclampsia and Diet 4747

Antioxidant Agents

0011 An additional role for nutrition in the genesis of pre-

eclampsia could be nutritional factors that strengthen

oxidative stress, leading to preeclampsia. A nutri-

tional factor could be the deficiency of antioxidant

intake, specifically vitamins C and E. Vitamin C is

central for the neutralization of both water-soluble

and lipid-soluble free radicals. As a water-soluble mol-

ecule, its ability to neutralize free radicals in the aque-

ous compartment is clear. Also, ascorbate is not made

in humans and must come from the diet. Vitamin E, a

potent antioxidant, has been suggested to play a role

in preventing preeclampsia. Vitamin E is not usually

reduced by dietary deficiencies, and reductions are

more likely due to consumption.

Other Nutrients

0012 Nutritional factors other than antioxidants can also

contribute to oxidative stress. Hyperhomocysteine-

mia can be a result of dietary deficiencies. Hyperho-

mocysteinemia is a risk factor for preeclampsia and

atherosclerosis, and endothelial function is said to be

altered, at least in part, by the genesis of oxidative

stress. Vitamins B

and B

and folic acid are involved

at different steps in the metabolic pathway for remov-

ing or recycling homocysteine to methionine. Dietary

deficiencies of any of these micronutrients can

increase circulating homocysteine. Preeclampsia is

characterized by increased triglycerides that favor

the formation of small, dense low-density lipoprotein

(LDL). This lipoprotein variant has increased access

to the subendothelial space, where it is sequestered

from bloodborne antioxidants. The relevant role of

triglycerides in the genesis of preeclampsia is indi-

cated by the fact that they are increased long before

clinically evident disease. Similarly, free fatty acids

are increased in preeclampsia, and this increment

was observed months before the diagnosis. Recent

studies indicate that this effect may be secondary to

altered copper binding by albumin to which large

amounts of free fatty acids are bound. Unbound

copper is a potent stimulator of free radical forma-

tion. Normally, this effect of copper is prevented

by protein binding (quantitatively, primarily to

albumin). However, with fatty acid binding, albumin

binds copper differently. In this configuration,

copper bound to albumin maintains its ability to

participate in redox reactions. Thus, it appears

that increased free fatty acids can also contribute to

oxidative stress.

0013 All of these nutritional alterations may be agreeable

to dietary modification raising the possibility of

nutritional prophylaxis.

Nutritional Interventions and

Hypertensive Disorders of Pregnancy

Prevention

0014The ability to prevent hypertensive disorders of preg-

nancy is limited by a lack of knowledge of its under-

lying etiology. Prevention is focused on identifying

women at higher risk of developing pregnancy-

induced hypertension or preeclampsia during preg-

nancy, followed by close clinical and laboratory

monitoring to recognize the clinical symptoms of the

disease in its early stages. These women and their

pregnancies can then be selected for more intensive

monitoring or delivery. Although these measures do

not prevent the disease, they may be helpful for pre-

venting some adverse maternal and fetal sequelae.

0015As part of many other nonpharmacological inter-

ventions, some dietary interventions were proposed

to prevent the development of pregnancy-induced

hypertension and preeclampsia.

0016Nutritional advice in pregnancy Literature was

reviewed in order to assess the effects of advising

pregnant women to increase their energy and protein

intakes on the outcome of pregnancy, and maternal

and fetal/infant morbidity and mortality. Nutrit-

ional advice appears to be effective in increasing preg-

nant women’s energy and protein intake, but the

implications for fetal, infant, or maternal health

cannot be judged from the available evidence. Pree-

clampsia prevention was assessed only in one small

trial involving 136 women with no beneficial effects

[relative risk (RR): 0.89, 95% confidence intervals

(CI) 0.42–1.88].

0017Protein/energy supplementation The effect of bal-

anced protein/energy supplements for pregnant

women on gestational weight gain and pregnancy

outcomes was assessed on a Cochrane systematic

review. Preeclampsia prevention was evaluated in

three trials involving 516 women, with no significant

beneficial effects (RR: 1.20; 95% CI: 0.77–1.89).

However, these trials had methodological flaws, al-

ternate allocation, and large lost-to-follow-up for the

main outcomes, so results should be taken cautiously.

In another Cochrane systematic review, only one trial

involving 782 women evaluated preeclampsia pre-

vention when isocaloric balanced protein/energy

supplements were given to underweight pregnant

women, showing no effect (RR: 1.00; 95% CI:

0.57–1.75).

0018Energy/protein restriction for obese pregnant

women Excessive weight gain during pregnancy

4748 PREGNANCY/Preeclampsia and Diet

has long been recognized as a clinical sign of edema

and impending preeclampsia. Epidemiological studies

suggest that a high maternal weight is positively asso-

ciated with the risk of preeclampsia.

0019 Energy/protein restriction for high weight-for-

height or weight gain during pregnancy was assessed

in a Cochrane systematic review. Preeclampsia was

evaluated in two trials (284 women) showing no

reduction in the risk of occurrence (RR: 1.13; 95%

CI: 0.59–2.18), and the same as for pregnancy-

induced hypertension (three trials, 384 women; RR:

0.97; 95% CI: 0.75–1.26). The limited evidence

available suggests that protein/energy restriction of

pregnant women who are overweight or show a

high weight gain is unlikely to be beneficial and may

be harmful to the developing fetus. Although weight

reduction may be helpful in reducing or preventing

high blood pressure in nonpregnant women, it is not

recommended during pregnancy, because there is no

effect on preventing preeclampsia, even in obese

women. Clinicians frequently ask pregnant women

to restrict their food intake in an attempt to prevent

preeclampsia, despite the absence of evidence that

such advice is beneficial.

0020 Salt restriction Even in an early phase of pregnancy,

marked hemodynamic changes occur, including a fall

in vascular resistance and blood pressure and a rise

in cardiac output. To compensate for the increased

intravascular capacity, the kidney retains more

sodium and water. Apparently, the set point of

sodium homeostasis shifts to a higher level at the

expense of an expansion of extracellular volume. In

nonpregnant women, a strong positive association of

sodium intake with blood pressure has been estab-

lished, but the relationship between sodium intake

and blood pressure in human pregnancy remains

obscure up to date. For decades, a low salt diet has

been often recommended as treatment for edema,

with the idea that restricting salt intake would

treat, and also prevent, preeclampsia. Recently, this

practice was questioned, and even a high sodium

intake was proposed for preeclampsia treatment and

prevention.

0021 Concerns about the effect of a low sodium diet

during pregnancy on maternal nutritional status led

researchers to investigate whether such changes

could alter other nutrient intakes. It was shown that

the reduction in sodium intake also caused a signifi-

cant reduction in the intake of energy, protein, carbo-

hydrates, fat, calcium, zinc, magnesium, iron, and

cholesterol. Even though women are no longer ad-

vised by many clinicians to alter their salt intake

during pregnancy, this is still current practice in

many other settings around the world.

0022A recently published Cochrane systematic review

evaluates the effect of the advice about low dietary

salt intake during pregnancy. The review includes

two trials with data reported for 603 women. Both

compared nutritional advice to restrict dietary salt

with advice to continue a normal diet. Women with

established preeclampsia were not enrolled, so this

review provides no information about the effects

of advice to restrict salt intake for the treatment of

preeclampsia. No effect was found in preventing pre--

eclampsia (RR: 1.11; 95% CI: 0.46–2.66) or preg-

nancy-induced hypertension (RR: 0.97; 95% CI:

0.49–1.94). Women’s preferences were not reported,

but authors presumed that a low-salt diet was not

very palatable and was therefore difficult to follow.

0023Calcium supplementation A role for altered calcium

metabolism in the pathogenesis of preeclampsia is

suggested by epidemiological evidence linking low

dietary levels of calcium with increased incidence of

the disease. In agreement with these observations,

several modifications in calcium metabolism have

been observed in pre-eclamptic women and in cal-

cium-supplemented mothers.

0024A Cochrane systematic review of calcium supple-

mentation during pregnancy has been published.

Authors pre-specified comparison groups taking into

account women’s risk of hypertensive disorders

of pregnancy (low versus increased) and women’s

baseline dietary calcium intake (low, < 900 mg per

day, versus adequate, 900 mg per day).

0025High blood pressure with or without proteinuria

was evaluated in nine trials, involving 6604 women.

Overall, there is less high blood pressure with calcium

supplementation (RR 0.81; 95% CI: 0.74–0.89), but

there is a variation in the magnitude of the effect

across the subgroups. The effect was considerably

greater in women at high risk of developing hyperten-

sion (four trials, 327 women: RR: 0.45; 95% CI:

0.31–0.66) than in those at low risk (11 trials, 6894

women: RR: 0.68; 95% CI: 0.57–0.81). Taking into

account women’s calcium intake, the effect was also

greater in those with low baseline dietary calcium

(five trials, 1582 women: RR: 0.49; 95% CI:

0.38–0.62) than in those with adequate calcium

intake (four trials, 5022 women: RR: 0.90; 95% CI:

0.81–0.99).

0026There is a reduction in the risk of preeclampsia,

evaluated on 10 trials involving 6864 women (RR:

0.70; 95% CI: 0.58–0.83). When predefined sub-

groups are considered, there is a significant reduction

in women with low baseline dietary calcium intake (six

trials, 1842 women: RR: 0.32; 95% CI: 0.21–0.49),

but not in those with adequate calcium intake (four

trials, 5022 women: RR: 0.86; 95% CI: 0.71–1.05).

PREGNANCY/Preeclampsia and Diet 4749

Preeclampsia was considerably reduced in women at

high risk of hypertension (four trials, 557 women: RR:

0.22; 95% CI: 0.11–0.43), and less consistently in

those at low risk of hypertension (six trials, 6307

women: RR: 0.79; 95% CI: 0.65–0.94).

0027 The results from the largest trial conducted by

NIH, which studied low-risk women with adequate

baseline calcium diet, and in whom all women in both

groups received low-dose calcium supplementation

as part of their routine antenatal care, showed no

significant effect on hypertension and preeclampsia.

Based on this, authorities from developed countries

where adequate dietary calcium intake is common

discourage the use of routine calcium supplementa-

tion during pregnancy. Evidence from this review

supports the idea that calcium supplementation

might benefit women at high risk of gestational

hypertension and women with a low dietary calcium

intake at risk of developing preeclampsia. However,

further methodologically sound randomized con-

trolled trials with adequate sample size are needed

to confirm or reject this hypothesis.

0028 Iron and folate supplementation Numerous trials

involving various populations of pregnant women

with normal hemoglobin levels have evaluated the

effects of iron and/or folate supplementation on sev-

eral outcomes, some of them including hypertensive

disorders of pregnancy. A Cochrane systematic review

of two trials involving 87 women with normal

hemoglobin levels, in which iron and folic acid were

compared with no treatment, showed no effect on the

occurrence of gestational hypertension (RR: 1.15;

95% CI: 0.41–3.18). Preeclampsia was not evaluated.

Another Cochrane review that included two trials

involving 696 pregnant women already receiving

iron, in which women were allocated to receive folic

acid or no treatment/placebo, showed no effect on

prevention of gestational hypertension either (RR:

1.26; 95% CI: 0.90–1.76).

0029 Although evidence shows that iron and folate sup-

plementation is not effective in preventing hyper-

tensive disorders during pregnancy, they should be

prescribed for other established beneficial effects on

pregnancy such as prevention of anemia.

0030 Magnesium supplementation Magnesium is one of

the essential minerals needed by humans in relatively

large amounts. Magnesium works with many

enzymes in regulating body temperature and synthe-

sizing proteins as well as maintaining electrical poten-

tials in nerves and muscle membranes. Magnesium

occurs widely in many foods; dairy products, breads

and cereals, vegetables, and meats are all good

sources. It is therefore not surprising that genuine

clinical magnesium deficiency has never been reported

to occur in healthy individuals who eat standard diets.

However, dietary intake studies during pregnancy

consistently demonstrate that many women, espe-

cially those from disadvantaged backgrounds, have

intakes of magnesium below recommended levels.

Observational studies based on medical records have

reported that magnesium supplementation during

pregnancy was associated with a reduced risk of

fetal growth retardation and preeclampsia, and that

magnesium intake was associated with increased

birth weight. Stimulated by these encouraging epi-

demiological studies, randomized clinical trials have

been undertaken to evaluate the potential benefits of

magnesium supplementation during pregnancy on

pregnancy and neonatal outcomes.

0031A Cochrane systematic review of these random-

ized-controlled trials was carried out in order to

assess the effects of magnesium supplementation

during normal or high-risk pregnancies on maternal,

neonatal, and pediatric outcomes. Results from two

trials (474 women) showed no apparent effect of

magnesium treatment on prevention of preeclampsia

(RR: 0.87; 95% CI: 0.57–1.32). However, these

results may have been confounded by the fact that

in the largest trial all women (both magnesium-

supplemented and placebo groups) received a multi-

vitamin and mineral preparation containing low

doses of magnesium. Trials also have a poor method-

ological quality, especially related to concealment of

allocation, which could give biased results. Authors

conclude that dietary magnesium supplementation of

pregnant women cannot be recommended for routine

clinical practice because of the poor methodological

quality of the current evidence.

0032Fish oil supplementation Studies of nonpregnant

subjects suggest that fish oil, rich in long-chain n-3

fatty acids, has a moderate effect on blood pressure in

normotensive as well as hypertensive individuals. A

meta-analysis of controlled clinical trials of the effect

of fish oil on blood pressure has demonstrated a

significant reduction in systolic and diastolic blood

pressure in untreated hypertensive nonpregnant indi-

viduals, but found no other significant effect on nor-

motensives. Fish oil has been shown to interfere with

prostaglandin metabolism, and its effect on blood

pressure has often been assumed to be due to such

interference. Epidemiological studies suggested that

marine diets could have a preventive effect on early

delivery and hypertensive disorders of pregnancy.

0033Fish oil supplementation during pregnancy was

evaluated in a systematic review of two trials (5135

women), showing no effect on pregnancy-induced

hypertension (two trials, 5135 women; RR: 0.96;

4750 PREGNANCY/Preeclampsia and Diet

95% CI: 0.86–1.07). There was a statistically signifi-

cant, but modest, reduction in the rate of preeclamp-

sia (RR: 0.70; 95% CI: 0.55–0.90). However, this

reduction is strongly influenced by a large nonrando-

mized trial conducted in 1942, in which vitamins and

minerals were given to women in addition to fish oil.

Another seven trials of fish oil supplementation in-

volving more than 2000 women have been published

recently, none of which demonstrates any differences

in the incidence of hypertension and preeclampsia

between groups. Based on current evidence, fish oil

supplementation is not recommended during preg-

nancy.

0034 Zinc supplementation Zinc is thought to play an

important role in many biological functions, includ-

ing protein synthesis and nucleic acid metabolism.

There are controversies in the literature in demon-

strating the relationship between low serum zinc

levels with abnormalities on pregnancy outcomes

such as pregnancy-induced hypertension, prolonged

labor, post partum hemorrhage, preterm or postterm

pregnancies, small-for-gestational-age babies, or poor

perinatal outcomes.

0035 The role of routine zinc supplementation during

pregnancy on outcomes for both mother and new-

born was assessed in a Cochrane systematic review.

Routine zinc supplementation in pregnancy had no

detectable effect on gestational hypertension (four

trials, 1962 women; RR: 0.87; 95% CI: 0.65–1.15).

However, there appears to be inconsistency between

trials regarding the effects from other pregnancy out-

comes. This may be related to varied population

characteristics of women recruited in the various

trials, as some included normal pregnant women

with no systemic illness, other studies specifically

selected women at high risk of low zinc status, and

in one study, participants were selected on the basis of

proven low plasma zinc levels. There is at present no

evidence of overall benefit from routine as opposed to

selective zinc supplementation in pregnancy on preg-

nancy-induced hypertension or preeclampsia.

0036 Vitamin supplementation In terms of vitamins A, E,

and C, an oxidant/antioxidant imbalance has been

suggested among the pathogenic factors involved in

preeclampsia. As vitamin E is one of the most import-

ant antioxidants in body components, its levels and

their relation with circulating levels of lipids perox-

ides on pre-eclamptic women have been intensively

studied in recent years. As with other antioxidants,

several studies found decreased vitamin E levels in

serum from women with gestational hypertension

and preeclampsia compared with controls. However,

these findings could not be demonstrated in other

studies. Increased ascorbate radical formation and

ascorbate depletion were also found in plasma from

women with preeclampsia. Recently, a randomized-

controlled trial involving 283 women at high risk of

developing preeclampsia was conducted. Women

were randomly assigned to vitamin E and vitamin C

supplements, or placebo at 16–22 weeks of gestation.

Authors found a significant reduction in the risk of

developing preeclampsia in the vitamin-supple-

mented group compared with controls (RR: 0.46;

95% CI: 0.24–0.91). The authors concluded that

supplementation with vitamins C and E may be bene-

ficial for preventing preeclampsia in women at in-

creased risk of the disease. However, these findings

need to be evaluated further in different settings and

populations, as well as in low-risk women.

0037The role of vitamin A in pregnancy-induced hyper-

tension and preeclampsia is a subject of controversy.

It was proposed as a chain-breaking antioxidant on

free radical cascade. Some studies found significantly

reduced serum vitamin A levels in pre-eclamptic and

eclamptic women when compared with those found

in healthy women in the third trimester. To date, no

trials have been published that assess the effect of

vitamin A supplementation on pregnancy-induced

hypertension or preeclampsia. A double-blind, cluster

randomized trial of low dose supplementation with

vitamin A or b-carotene carried out in Nepal in 44 646

married women showed a 40% reduction in maternal

mortality related to pregnancy in vitamin A-supple-

mented women. However, differences in cause of

deaths, including preeclampsia/eclampsia, could not

be reliably distinguished between supplemented and

placebo groups. The future prospect of giving vitamin

A supplements for the prophylaxis/management of

pregnancy-induced hypertension and preeclampsia

needs to be evaluated further before it is recom-

mended.

Treatment

0038The objectives of treatment for established pree-

clampsia, or pregnancy-induced hypertension are to

prevent eclampsia as well as other severe maternal

complications. Close maternal evaluation is aimed

at observing the progression of the condition, both

to prevent maternal complications and to determine

whether fetal well-being can be assessed. As this

disorder is often completely reversible and usually

begins to abate with delivery, an imbalance between

the mother’s condition and the chance of the fetus

surviving without any significant neonatal complica-

tions in utero or in the nursery must be continuously

evaluated. Even though the only definitive treatment

of preeclampsia is delivery, several nonpharmacolo-

gical approaches were proposed as part of an overall

PREGNANCY/Preeclampsia and Diet 4751

strategy of management of the disease to achieve

these goals.

0039 Unfortunately, there is no information from

randomized controlled trials related to dietary

approaches on the management of the disease in its

mild to moderate stage, when conservative manage-

ment is decided on.

Pre-existing (Chronic) Hypertension

0040 Mild and uncomplicated chronic hypertension during

pregnancy has a better prognosis than preeclampsia.

However, there is an increased risk of superimposed

preeclampsia and possible complications if pre-

existing renal disease or systemic illness is present.

The primary aim of therapy, if necessary, is to prevent

cerebrovascular complications and to avoid the pro-

gression to superimposed preeclampsia with worse

prognosis. Nonpharmacological management of this

condition during pregnancy remains controversial.

0041 In a published review of management of mild-

chronic hypertension during pregnancy, no trials

were found that compared non-pharmacological

interventions with either pharmacological agents or

no intervention in pregnant women. This comprehen-

sive search identified 50 randomized controlled trials,

but they involved either normotensive women or

women with a history of preeclampsia. For the man-

agement of established chronic hypertension during

pregnancy, no relevant evidence could be located to

assess the effects of non-pharmacological interven-

tions, such as limiting activity, diet modifications or

stress reduction.

0042 Weight reduction during pregnancy, even in obese

women, is generally not recommended to improve

pregnancy outcomes. As weight reduction may be

helpful in reducing blood pressure in nonpregnant

women, for obese hypertensive women planning a

pregnancy, weight reduction before conception is ad-

visable. Even though obesity may be a risk factor for

superimposed preeclampsia, there is no evidence that

limiting weight gain during pregnancy reduces its

occurrence.

0043 Pregnant women with hypertension have a lower

plasma volume than do normotensive women, and

some studies suggest that the severity of hypertension

correlates with the degree of plasma volume concen-

tration. For this reason, sodium restriction is gener-

ally not recommended during pregnancy for the

reduction of blood pressure. In addition, an increase

in plasma volume concentration is a risk factor for

intrauterine growth restriction. If, however, a preg-

nant woman with chronic hypertension is known to

have salt-sensitive hypertension and has been treated

successfully with low salt diet before pregnancy, it is

reasonable to continue some sodium restriction for

blood pressure control during pregnancy, but not for

preventing superimposed preeclampsia.

0044High alcohol intake is related to hypertension in

nonpregnant women but is not associated with an

increased risk for gestational hypertension, pree-

clampsia, or eclampsia. There is no conclusive

evidence of adverse effects on pregnancy outcomes,

including fetal growth, at levels of consumption

below 120 g of alcohol per week. However, there are

suggestions that excessive consumption of alcohol

can cause or aggravate maternal hypertension.

0045There is no reliable information from well-

designed, randomized controlled trials assessing

the best dietary approach for the management of

pre-existing hypertension during pregnancy. Recom-

mendations come from experts’ consensus and au-

thorities’ statements. It seems that mild-to-moderate

pre-existing (chronic, essential) hypertension without

any risk factor should be managed in the same way

as in the nonpregnant state. However, additional

concerns include effects on fetal well-being (mainly

intrauterine growth restriction) and worsening of

hypertension, particularly as a result of superimposed

pre-eclampsia.

Conclusions

0046In short, based on the available data from systematic

reviews (presented in the Appendix), we can conclude

that there is some evidence that calcium supplemen-

tation in populations with a low calcium intake and/

or at risk of developing pregnancy-induced hyperten-

sion could be beneficial. Antioxidants (particularly

vitamins E and C) are promising, but there is a need

for adequately sized and designed randomized con-

trolled trials to confirm these findings before any

widespread recommendation. Although pregnant

women living in developing countries could be

exposed to several other nutrient deficiencies, no evi-

dence precludes recommending other nutrient supple-

mentations as part of their routine antenatal care in

order to prevent the occurrence of pregnancy-induced

hypertension or preeclampsia.

See also: Antioxidants: Natural Antioxidants; Calcium:

Properties and Determination; Copper: Properties and

Determination; Hypertension: Physiology; Obesity:

Etiology and Diagnosis; Pregnancy: Metabolic

Adaptations and Nutritional Requirements; Vitamins:

Overview