3 Maternal nutrition and obstetric outcome

3 Maternal nutrition and obstetric outcome R E G I N E P. M. S T E E G E R S - T H E U N I S S E N

During the past few decades, an important reduction has been achieved in perinatal mortality and morbidity. To further reduce these, primary prevention has to be pursued by the identification and consecutive avoidance or elimination of risk factors for abnormal obstetric outcome. The nutritional status of women, themselves being exposed to environmental and genetic factors, is increasingly regarded as being important during reproductive life. Besides the impact on fertility, there is an effect on obstetric outcome. Furthermore, impaired maternal nutrition may be related to the intrauterine fetal 'programming' of disease expressed in adulthood (Barker et al, 1990; Godfrey et al, 1994). More has to be known, however, about the extent and timing of the elevated nutritional needs during (early) pregnancy for the mother, embryo and fetus, which will possibly differ between the various (micro)nutrients. This chapter will, therefore, focus on the physiology of embryonic and fetal nutrition, and some nutritional risk factors will be described. Finally, recommendations are given regarding nutritional intake and supplementation preconceptionally and during pregnancy. EMBRYONIC AND FETAL NUTRITION

The mechanisms involved in the nutrition of the embryo and fetus are poorly understood. The speculation that the primary oocytes may already be exposed to harmful influences of malnutrition before fertilization is legitimate, as these oocytes are formed and remain dormant in the ovaries until menarche. As a follicle matures, the primary oocyte is surrounded by ovarian follicle fluid. During the first days of embryonic development, nutrition of the fertilized oocyte is provided by the yolk granules present in the cytoplasm (Biggers, 1971). Ovarian follicular fluid is formed by a gradual influx of fluid derived from the blood and by compounds synthesized and secreted by the theca intema and granulosa cells. Therefore, one may hypothesize that the composition of follicular fluid could have some impact on the yolk granules of the oocyte (SteegersTheunissen et al, 1993). During the first weeks of embryogenesis, before organogenesis, nutrients reach the embryo mainly by diffusion across the extraembryonic coelom and primary yolk sac, i.e. there is histiotrophic Bailli~re's Clinical Obstetrics and Gynaecology431 Vol. 9, No. 3, September 1995 ISBN 0-7020-1944-5

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nutrition (Reece et al, 1994). Although the function of the extraembryonic coelom is poorly understood, the determination of high levels of protein, albumin, glucose, calcium, phosphate, folate and vitamin B12 suggests the importance of the coelomic cavity in the maternal-fetal exchange of these (micro)nutrients (Campbell et al, 1992, 1993). The primary yolk sac monitors the passage of complex molecules and is engaged in intense protein synthesis early in gestation (Reece et al, 1993). With the first primary yolk sac circulatory system in the embryo, between 3 and 4 weeks, nutrition of the embryo becomes haemotrophic, i.e. from mother to yolk sac and then from yolk sac to embryo. At this early stage of gestation, the haemochorial placenta is immature, so the yolk sac is crucial to normal embryogenesis (Reece et al, 1994). In the second and third trimesters of pregnancy, the requirement for nutrients depends on the increase of matemal and fetal tissue. Because of the bidirectional transport by diffusion and carrier transport of nutrients across the placenta, the fetus will be nourished and its accumulated metabolites released into the maternal circulation (Schneider, 1991). Although placental transport function and fetal nutrition are closely associated, other aspects, such as placental hormone synthesis and metabolization, as well as maternal metabolic, physiological and endocrine changes, affect the supply of nutrients to the fetus (Viteri et al, 1989). The composition and concentrations of nutrients present in amniotic fluid change during pregnancy and reflect the biochemical and nutritional environment of the developing fetus. The fetus is supplied with nutrients such as electrolytes, carbohydrates, lipids and proteins by swallowing amniotic fluid, by which fetal growth is enhanced (Reid et al, 1971). Because amniotic fluid is produced by both the fetus and the mother, the appearance of abnormal levels of nutrients can be due to abnormalities connected with the maternal intake, production, transport or metabolism of these substances or may manifest itself due to abnormalities in the developing fetus. In this respect, the finding of low levels of vitamin B~2 and high carrier protein levels in amniotic fluid from phenotypically normal sibs of individuals with a mid-line lesion, such as spina bifida, omphalocele and gastroschisis, is of interest, suggesting the involvement of a genetic derangement of vitamin B~2 metabolism or transport (Gardiki-Kouidou and Seller, 1988). This is in agreement with the finding of increased homocysteine amniotic fluid levels in the presence of a fetus with a neural tube defect, as vitamin B~2is known to be involved in homocysteine metabolism (Steegers-Theunissen et al, in press). NUTRITIONAL RISK FACTORS

Maternal weight Women who are underweight, due either to a metabolic disorder or an unbalanced nutrient intake, have, in general, a lower caloric intake and

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reduced body fat stores, showing a delayed menarche, irregular ovulation and amenorrhoea, as can be noticed in anorexia nervosa patients (Brown, 1993). However, after replacement of the body fat stores in normal women, the ovarian activity usually returns. The link between body fat and fertility appears to be alterations in the synthesis of oestrogens, LH, FSH and GRH (Thomas et al, 1989). Pregnant women underweight owing to famine or artificial dieting have an increased risk of having a child with birth defects, low birthweight and obstetric complications (Rush, 1989). Although the precise influence of maternal nutrition on fetal development is as yet not clarified, the quality of maternal nutrition seems to correlate best with birthweight (Wynn et al, 1991). Birthweight is an important measure for pregnancy outcome, because low birthweight coincides with an increased neonatal morbidity and mortality, as revealed from the meta-analysis of Kramer (1987). In this respect, there is research of interest by Lumey (1992), who showed that mothers exposed to famine during their first and second trimesters had offspring with birthweights lower than did mothers not exposed to famine. Birthweights in the offspring of mothers exposed in their third trimester were, however, not reduced. Excessive body fat is associated with infertility and a number of metabolic abnormalities, including abnormal glucose metabolism. Pregnant obese women have an increased risk of obstetric complications, such as hypertension and diabetes, which inversely influences pregnancy outcome (Johnson et al, 1987). Obese women seem to have a poor choice of foods (Hotzel, 1986). Because of this and the association between maternal vitamin deficiencies and birth defects, Waller et al (1994) hypothesized that obesity may be a risk factor for having a child with a birth defect. Their data are supported by Naeye (1990), who also suggested that the offspring of obese women are at an increased risk of having neural tube defects and several other birth defects. However, further research will be necessary before it can be concluded that weight reduction before pregnancy will lower the risk of birth defects among obese women.

Energy, proteins and fat In general, pregnant women should increase their energy intake, because of the requirements of the increased basal maternal metabolism and the synthesis of new maternal and fetal tissues. The accommodation and adaptation to changes in energy intake has been an area of controversy for decades. Van Raaij et al (1987) demonstrated that the energy balance of pregnant women shows an energy deficit, in comparison with the nonpregnant situation. Schoeller and Field (1991) demonstrated, with the doubly-labelled water method, that adaptive changes in energy expenditure of the human organism are relatively small and that most changes in energy expenditure are mediated through changes in body size and physical activity. In this view, the energy deficit in the energy balance of pregnant women might be explained by behavioural adaptations in physical activity and lowering the energy expenditure, especially during the second and third trimesters of pregnancy.

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During pregnancy, additional needs for proteins relate to both mother and fetus. Proteins are stored and synthesized de novo from amino acids. Maternal plasma concentrations of free amino acid nitrogen axe reduced during pregnancy (Hay, 1989). Essential amino acids are modified through metabolic activities within the placenta, followed by active transport through the placenta and into fetal tissues, contributing to the prevention of fetal protein malnutrition when maternal intake is inadequate. The enzymes involved in amino acid synthesis are not developed during early fetal life. Therefore, all amino acids are essential until the time of hepatic maturation. High protein supplementation during pregnancy, however, is unlikely to be beneficial, may even impair fetal growth and may increase the risk of neonatal complications. It is revealed from intervention studies that only balanced maternal energy/protein supplementation results in modest increases in maternal weight and fetal growth (Rush, 1989). These increases do not appear greater in undernourished women, nor do they seem to result in long-term benefits, such as the growth and neurocognitive development of the child. The available evidence is inadequate to reach conclusions concerning the effects on preterm births, fetal and neonatal survival or maternal condition. Especially during the first trimester of pregnancy, maternal fat is stored to ensure adequate fat resources during the last trimester, when endocrine mechanisms favour fat transfer through the placenta to the fetus, and the lactation period. Arachidonic and linoleic acids are essential for fetal growth. Saturated fatty acids are required for membrane synthesis and effective myelinization of the nerves, which starts in the spinal cord during mid-fetal life and in the brain at the end of the pregnancy. A well-balanced maternal fat intake is important because it has been suggested that the production of myelin can be modified if the composition of fatty acids in the maternal diet is altered (Hansen et al, 1970).

Vitamins Vitamins are organic substances essential to ensure normal growth, development and maintenance of the human organism but can potentially be harmful in excess. They must be consumed through the diet, with the exception of vitamin D, which is synthesized in the skin after exposure to sunlight, and biotin and pantothenate, which are manufactured by intestinal bacteria. Vitamins can be divided into the fat-soluble vitamins A, D, E and K and the water-soluble vitamins B and C. Vitamins B~ (thiamin), B2 (riboflavin) and B 3 (niacin) support the conversion of calories into energy. Although the requirement for these vitamins will be mildly enhanced during pregnancy, a deficiency is very unlikely to develop. Information on the effect of an excess of these vitamins on pregnancy is lacking. Vitamin A, mainly present as retinol, is needed for the visual process, reproduction, bone and tooth growth, and the maintenance and differentiation of epithelial tissues. Because this vitamin is stored in, especially, the liver, a deficiency is very rare in civilized countries but is common in many third world countries. An excessive intake can cause liver damage and

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other toxicity problems. During pregnancy, the vitamin A requirement is increased. Although less information is available about embryonic exposure to large doses of vitamin A (in particular that of all trans- and 13cis-retinoic acids by transfer from the maternal plasma into the coelomic cavity and yolk sac), humans are considered to be the species most sensitive for hypervitaminosis A (Howard and Willhite, 1986). In the first trimester of pregnancy, structural malformations, such as skeletal, cardiac and central nervous system malformations, may develop, and in the second and third trimesters of pregnancy, functional defects are described (Hathcock et al, 1990). Because of the strong accumulation of vitamin A, it is possible that an excessive intake during the period before conception can also be a risk factor. Teratogenicity from dietary sources, with the exception of liver and liver products, is very unlikely. However, the use of vitamin preparations, drugs derived from vitamin A (isotretinoin) and cosmetics containing large amounts of retinol can be dangerous during pregnancy and should be discouraged. Vitamin D 3 is the main derivative of vitamin D, which is essential in calcium and phosphate homeostasis. Pregnancy induces enormous shifts in calcium, which is in part regulated by vitamin D (Bouillon and Van Assche, 1982). It is actively transferred by the placenta to the fetus, where it is necessary for the mineralization of bones. Vitamin D3 requirements during pregnancy are increased. Although no specific pathology has been related to a maternal vitamin D deficiency, this may be a risk factor for neonatal hypocalcaemia in premature babies (Wills et al, 1982). In vulnerable communities, vitamin D supplementation of pregnant women reduces the risk of neonatal hypocalcaemia. The most common and active form of vitamin E is alpha-tocopherol, which is a fat-soluble antioxidant and plays an important role in the metabolism of selenium. Vitamin E and selenium are involved in the maintenance of the functional integrity of subcellular membranes. Less information is available about the consequences of decreased and increased vitamin E intake during pregnancy. The maternal levels of vitamin E seem to rise, especially during the second and third trimesters (Takahashi et al, 1978). Decreased levels of vitamin E have been reported in patients with abruptio placentae (Sharma et al, 1986). Vitamin K is essential in bone metabolism and in the synthesis of prothrombin, which is important in the blood clotting proces. About 50% of vitamin K is synthesized by intestinal bacteria, because of which the occurrence of vitamin K deficiency is very rare. Less information is available on the requirement and metabolism of vitamin K in pregnant women. Those who suffer from fat malabsorption and kidney disorders may need extra vitamin K. Some newborns may be susceptible to vitamin K deficiency because they lack the intestinal bacteria needed during the first few days of life (von Kries et al, 1988). Pregnant women using the enzymeinducing antiepileptic drugs carbamazepine, phenytoin and phenobarbital during pregnancy are rarely vitamin K deficient. However, the incidence of vitamin K deficiency is increased in their infants. Because of the relationship between vitamin K deficiency and haemorrhagic disease of the

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newborn, these women are advised to use an oral dose of 10 mg vitamin K per day from the 36th or 37th week of gestation until delivery (Cornelissen et al, 1993). Vitamin C (ascorbic acid) is involved in the synthesis of collagen, the protection against oxidation of the vitamins A, E and fatty acids and the metabolism of amino acids, steroids, catecholamines and folic acid, and it stimulates the absorption of inorganic iron. Although, during pregnancy, vitamin C requirement is enhanced, there is no consensus on the effect of vitamin C deficiency on the pregnant woman and her child. It has been suggested that patients with a low vitamin C level show a higher prevalence of abruptio placentae, intrauterine growth retardation and premature rupture of membranes (Schorah et al, 1978; Sharma et al, 1986; Casanueva et al, 1991). The maternal intake of megadoses of vitamin C is not advised during pregnancy, because it can cause diarrhoea, nutritional imbalances and tissue deprivation of oxygen and may cause depositions of oxalate in the kidneys. Vitamin B 6 (pyridoxine) is especially involved in amino acid, carbohydrate and lipid metabolism and in the production of red cells. Most pregnant women receive adequate amounts of B 6 t h r o u g h their diets. Although various reports concerning vitamin B6-related pathology in pregnancy have been published, the data are as yet inconclusive (van den Berg and Bruinse, 1988). The coenzyme vitamin B12 is involved in the synthesis of DNA and fatty acids and the myelinization of the nerves. A deficiency results in severe megaloblastic anaemia. Although pregnancy is not a predisposing factor for the development of vitamin B12 deficiency, it is associated with a steady and physiological fall of serum vitamin B12, owing to the transfer to the fetus, haemodilution, hormonal influences and changes in vitamin B12 binding (Shojania, 1984). In particular, pregnant vegetarians, and those who are not able to absorb vitamin Bn properly from food, have an increased risk of developing a vitamin B12 deficiency. Especially during the last 10 years, more research has been focused on the role of vitamin B12 in pregnancy. Schorah et al (1980) suggested an association between a maternal vitamin B12 deficiency and the occurrence of birth defects. This has been supported by case reports in which infants with a neural tube defect were born to obese women with gastric bypass operations resulting in subnormal vitamin B12 levels and borderline folate concentrations (Haddow et al, 1986). In addition, it has been suggested that vitamin B12 production or transport is deranged owing to a defect in the genes responsible for the production of transcobalamins, the cartier proteins for vitamin B12, in mothers carrying a fetus with a midline defect (Gardiki-Kouidou and Seller, 1988). More research has to be conducted regarding the impact of vitamin B12 status on obstetric outcome. Vitamin B , (folic acid or folate) interacts with vitamin Bn in the synthesis of DNA and, therefore, in the production of all cells. Folate is an important methyl donor involved in nucleic acid synthesis, purine-pyrimidine metabolism and protein synthesis. Megaloblastic anaerma is a consequence of folate deficiency and is a common finding in pregnant

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women because of their increased folate needs for the growing fetal and maternal tissues (Shojania, 1984). Other factors that might affect folate availability in pregnancy include a dietary lack, the physiological haemodilution of pregnancy, increased plasma clearance and genetic disorders affecting the production, transport and metabolism of folate. Folate has been identified as an important factor in the prevention of neural tube defects. The reduction of neural tube defects by folate supplementation has been demonstrated in a number of studies (MRC Vitamin Study Research Group, 1991; Czeizel and Dud~ts, 1992). Women taking antiepileptic drugs have an increased risk of birth defects and spontaneous abortion (Steegers-Theunissen et al, 1994). Although some of these drugs inhibit the intestinal absorption or increase the turnover of folate by the stimulation of liver enzymes, the exact teratogenic mechanism is not yet clear. It is possible that a genetic predisposition to birth defects may be activated by reduced folate levels. This is supported by the demonstration of a relationship between antiepileptic drugs, folate levels and abnormal obstetric outcome (Dansky et al, 1987). The possible reduction of the prevalence of birth defects in these women by folate supplementation needs to be investigated further (Biale and Lewenthal, 1984). The vitamins folic acid and B~2 are involved in the metabolism of the essential amino acid methionine. The relationship between these vitamins and homocysteine metabolism is shown in Figure 1. Methionine is converted to S-adenosylmethionine, which is the ultimate methyl donor in the body. After methyl transfer, S-adenosylhomocysteine is formed and reversibly hydrolysed to homocysteine and adenosine. Homocysteine is either remethylated to methionine or irreversibly trans-sulphurated to cystathionine and cysteine (Mudd et al, 1989). The remethylation pathway of homocysteine into methionine is dependent on folate as 5-methyltetrahydrofolate and vitamin B~2 as methylcobalamin. A relative or absolute lack of folate, vitamin B~2 or remethylation enzymes might increase homocysteine and decrease methionine blood levels. The teratogenicity of homocysteinaemia is largely unknown. Mudd et al (1985) reported a fetal loss rate of almost 50% in untreated hyperhomocysteinaemic women. In vitro studies in the rat have also shown that a shortage of methionine in the culture medium could be related to a disturbance in the morphogenesis of the embryo, and the development of neural tube defects in particular (Coelho et al, 1987; Coelho and Klein, 1990). It has been shown that about 25% of women who previously had an infant with a neural tube defect, and those who suffered from recurrent spontaneous abortion or abruptio placentae, had mildly to severely elevated homocysteine blood levels (Steegers-Theunissen et al, 1991, 1992). This is suggested to be due to a defect in folate or vitamin B~2 metabolism and/or a lack of remethylation enzymes, which can be partially compensated for by treatment with folic acid, vitamin B~2 or pyridoxine. In this respect, also of interest is the study of Bunin et al (1993), who suggested that a high maternal folate intake and the early use of multivitamins may prevent the occurrence of primitive neuroectodermal tumours in the young child.

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HOOC-!-CHt-CH=-S-CH3 NH2 [ METHIONINE J S-aden°sylm~,,Hhi°nine

IHOUOCVSTEINEI pyridoxa hosphate

H! OH ! HOOC-C-CH=-CH= I~IH= HOMOSERINE

(t-KETOBUTYRATE ~L-CoA METHYLMALONYL-CoA adenosyl- cobalamin

HOOC-Cl-CH=-CI'II-S-CHi"C-COOH Nil= NH= CYSTATHIONINE ~ l . I:~/rtd~d phosphate

.-S-C..-C,-COOH NH=

1. cystathioninesynthase 2. betaine homocysteine methyltransferase 3. NS-methyltetrahydro folate homocysteine methyitranslerase 4. 5. lO-methylenetetrahydrofolate reductase

%

ho~rmcysteine

8UCCINYL-CoA CO= Figure 1. Relationship between vitamins and homocysteine metabolism. Reproduced from SteegersTheunissen et al (1994, Metabolism 43: 1475-1480) with permission.

Trace elements During pregnancy, iron requirement is increased, owing to the needs of both the fetus and the mother. Iron deficiency often occurs simultaneously with folate deficiency during pregnancy (O'Connor, 1991) and remains a very common problem, still related to an increased maternal and fetal mortality (Gadowsky et al, 1992). Fetal problems develop when the oxygen-carrying capacity of the blood becomes insufficient. As a result, birthweight will be reduced and perinatal mortality will increase (Scholl et al, 1992). Therefore, iron supplementation during pregnancy is useful to treat iron deficiency. However, it remains doubtful whether routine supplementation of iron during pregnancy is useful. Iodine deficiency is recognized as a major international public health problem and influences all stages of human development. During pregnancy, iodine requirement is slightly increased, and a deficiency may result in spontaneous abortion, stillbirth and birth defects. Hetzel and Mano

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(1989) pointed, in their review, to the impact of iodine deficiency on both fetal survival and brain development. Iodine deficiency is the major preventable cause of mental defects in the human. The children of mothers from iodine-deficient communities who were treated with iodine prior to the second trimester of pregnancy had better neuromotor function than did controls (Fierro-Benftez et al, 1989). Zinc regulates the major metabolic processes in the body and is essential for proper cell growth. The enzyme y-glutamyl hydrolase is zinc dependent and converts folate as polyglutamate to monoglutamate, which is an important step in the absorption of folate (Canton and Cremin, 1990). Therefore, zinc deficiency will decrease folate absorption. It has also been suggested that excessive folate intake may adversely affect zinc metabolism, owing to the formation of complexes (Milne et al, 1984). During pregnancy, the amount of zinc in maternal tissue increases, and a part of the zinc amount is stored by the fetus. A marginal zinc status is possibly not uncommon in civilized countries, because the zinc concentration in the average diet is frequently below the recommended daily allowances (Sandstead, 1985). This may be important, as dietary zinc deficiency and a relative shortage of maternal zinc has been associated with neural tube defects in human (Cavdar et al, 1988; Milunsky et al, 1992). In addition, Neggers et al (1991) showed that serum zinc concentrations measured at approximately 16 and 32 weeks of gestation were both found to be significant predictors of birthweight. The results of this study suggest a threshold for maternal serum zinc below which the prevalence of low birthweight increases rapidly. P R A C T I C A L IMPLICATIONS With the limited current knowledge about the effects of nutrition on obstetric outcome, only a few main preventive nutritional recommendations can be made. For all (pre)pregnant women, a balanced diet is advised, containing a large variety of foods, in particular meat, eggs and milk, green vegetables and fruits, with a relatively low consumption of confectionery and soft drinks. This will provide a generous intake of most essential (micro)nutrients. However, the general nutritional status of pregnant women in civilized countries may still be at risk for some nutrients. Because of a marginal intake of some nutrients and the increased needs during pregnancy, a deficiency of, for example, iron, folate and zinc can easily occur. Adequate monitoring of the iron status and the consequent treatment of iron deficiency with iron-containing supplements is beneficial. Current evidence stresses the importance of an adequate folate intake during the periconceptional period to prevent the occurrence and recurrence of offspring with a neural tube defect (MRC Vitamin Study Research Group, 1991; Czeizel and Dudhs, 1992). This has resulted in the recommendation for women with a normal risk of having offspring with a neural tube defect that they should take 400 ~tg folic acid per day from puberty through to the menopause. Women who have had a child with such a birth defect are advised to use 4000 ~tg folic acid per day, after excluding a

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vitamin Bl2 deficiency. Similar supplementation is appropriate for women with recognized nutritional deficiencies, malabsorption states and gastric bypass operations, if they are pregnant or planning to become pregnant. The same is true for women taking folate-antagonist drugs and possibly for those taking antiepileptic drugs. Many countries are now reviewing the recommended daily intake of folic acid, and these reviews could lead to fortification of staple foods. Although proper figures about the zinc status of fertile women are lacking, it has been suggested that because of a relative low daily intake, and owing to the recommendations launched for folate supplementation, the (pre)pregnant zinc status may be deficient in general maternal nutritional status in civilized countries. However, no data are available about a possible beneficial effect of zinc supplementation on obstetric outcome. Women using the antiepileptic drugs carbamazepine, phenytoin or phenobarbital are advised to use a daily oral dose of vitamin K (10 mg) during the last month of pregnancy to prevent neonatal haemorrhagic diseases. In general, the use of supplements containing pharmacological doses of vitamins can be regarded as controversial or even contra-indicated, especially during pregnancy. If vitamin supplements are indicated, they should be provided in physiological doses. An excessive intake of vitamin A should be avoided, as retinoic acid embryopathy has been reported as a side-effect of the use of vitamin A supplements, liver or vitamin A-related drugs. SUMMARY In general, maternal nutritional status in civilized countries is not at risk. However, even a marginal malnutritional state for some (micro)nutrients for the pregnant women can adversely affect obstetrical outcome. From the data available so far, only folic acid supplementation is advised. However, the importance of an adequate iron and zinc status has to be stressed. In addition, women should be warned preconceptionally about excessive intake of vitamins, especially of those products containing large amounts of vitamin A. REFERENCES Barker DIP, Bull AR, Osmond C & Simmonds SJ (1990) Fetal and placental size and risk of hypertension in adult life. British Medical Journal 301: 259-262. Biale Y & Lewenthal H (1984) Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. EuropeanJournal of Obstetrics, Gynecology, and Reproductive Biology 18: 211-216. Biggers JD (1971) New observations on the nutrition of the mammalian oocyte and the preimplantation embryo. In Blandau RJ (ed.) The Biology of the Blastocyst, pp 173-198. Chicago: University of Chicago Press. Bouillon R & van Assche FA (1982) Perinatal vitamin D metabolism. DevelopmentalPharmacology and Therapeutics 4(1): 38-44.

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Brown JE (1993) Preconceptional nutrition and reproductive outcome. Annals of the New York Academy of Sciences 678: 286-292. Bunin GR, Kuijten RR, Buckley JD et al (1993) Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young children. New England Journal of Medicine 329: 536-541. Campbell J, Wathen N, Macintosh M, Cass Pet al (1992) Biochemical composition of amniotic fluid and extraembryonic coelomic fluid in the first trimester of pregnancy. British Journal of Obstetrics and Gynaecology 99: 563-565. Campbell J, Wathen J, Perry Get al (1993) The coelomic cavity: an important site of materuo-fetal nutrient exchange in the first trimester of pregnancy. British Journal of Obstetrics and Gynaecology 100: 765-767. Canton MC & Cremin FM (1990) The effect of dietary zinc depletion and repletion on rats: concentration in various tissues and activity of pancreatic gamma-glutamyl hydrolase (EC 3.4.22.12) as indices of Zn status. British Journal of Nutrition 64: 201-209. Casanueva E, Magana L, Pfeffer F & Baez A (1991) Incidence of premature rupture of membranes in pregnant women with low leukocyte levels of vitamin C. European Journal of Clinical Nutrition 45: 401-405. Cavdar AO, Bahceci M, Akar N e t al (1988) Zinc status in pregnancy and the occurrence of anencephaly in Turkey. Journal of Trace Elements, Electrolytes, in Health and Disease 2- 9-14. Coelho CND & Klein NW (1990) Methionine and neural tube closure in cultured rat embryos: morphological and biochemical analyses. Teratology 42" 437-451. Coelho CND, Weber JA, Klein NW et al (1987) Whole rat embryos require methionine for neural tube closure when cultured on cow serum. Journal of Nutrition 119: 1716-1725. Cornelissen M, Steegers-Theunissen R, Kollee L e t al (1993) Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. American Journal of Obstetrics and Gynecology 168: 884-888. Czeizel AE & Dud~s 1 (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. New England Journal of Medicine 327: 1832-1835. Dansky LV, Andermann E, Rosenblatt D et al (1987) Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Annals of Neurology 21- 176-182. Fierro-Benftez R, Cazar R, Sandoval H et al (1989) Early correction of iodine deficiency and late effects on psychomotor capabilities and migration. In DeLong GR, Robbins J & Condliffe PG (eds) Iodine and the Brain, pp 289-302. New York: Plenum Press. Gadowsky SL, Wolfe S, Jory Jet al (1992) Laboratory folate and iron indices of pregnant adolescents accessed through the public health system in Southern Ontario. FASEB Journal 6:A1959. Gardiki-Kouidou P & Seller MJ (1988) Amniotic fluid folate, vitamin Biz and transcobalamins in neural tube defects. Clinical Genetics 33" 441-448. Godfrey KM, Forrester T, Barker DJP et al (1994) Maternal nutritional status in pregnancy and blood pressure in childhood. British Journal of Obstetrics and Gynaecology 101: 398--403. Haddow JE, Hill LE, Kloza EM & Thanhauser D (1986) Neural tube defects after gastric bypass. Lancet 1:1330 (letter). Hansen IB, Clausen J, Somers K & Patel AK (1970) The fatty acid composition of serum breastmilk and foetal brain in two different environments. Acta Neurologica Scandinavia 46: 301-312. Hathcock JN, Hattan DG, Jenkins MY et al (1990) Evaluation of vitamin A toxicity. American Journal of Clinical Nutrition 52" 183-202. Hay WW (1989) Placental control of fetal metabolism. In Sharp F, Fraser RB & Milner RDG (eds) Fetal Growth, pp 33-42. Heidelberg: Springer. Hetzel BS & Mano MT (1989) A review of experimental studies of iodine deficiency during fetal development. Journal of Nutrition 119: 145-151. Hotzel D (1986) Suboptimal nutritional status in obesity. Bibliotheca Nutritio et Dieta 37: 36-41. Howard WB & Willhite CC (1986) Toxicity of retinoids in humans and animals. Journal of Toxicology Review 5: 55-94. Johnson SR, Kolberg BH, Varner MW & Railsback LD (1987) Maternal obesity and pregnancy. Surgery, Gynecology and Obstetrics 164:431-437. Kramer MS (1987) Determinants of low birthweight: methodological assessment and meta-analysis. Bulletin of the Worm Health Organization 65: 663-729. von Kries R, Shearer MJ & Gobel U (1988) Vitamin K in infancy. European Journal of Pediatrics 147: 106-112.

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