Individual nutrient effects on length of gestation and pregnancy outcome

Individual Nutrient Effects on Length of Gestation and Pregnancy Outcome Maureen A. Murtaugh and Julie Weingart

A

Structural and F u n c t i o n a l R o l e s o f Marine Fish Oils

Marine n-3 Fatty Acids

N-3 fatty acids have structural roles in several important human systems. DHA is known to be the predominant fatty acid in retina, brain, and spermatozoa, and is a c o m p o n e n t o f many phospholipid membranes t h r o u g h o u t the body. Depletion of DHA from the membranes of retinal cells results in the decreased efficiency o f the visual process ~ and may be important in retinopathy of prematurity. 4'5 As an important component of cell membranes, n-3 fatty acids influence membrane viscosity and permeability and possibly the enzyme activity of membrane proteins. 6 The functional roles of polyunsaturated fatty acids are equally important to health. Essential fatty acids, including arachidonic acid (20:4, n-6) and EPA (20:5, n-3) are precursors to eicosanoids including prostaglandins, prostacyclins, thromboxane, and leukotrienes, Eicosanoids influence blood pressure, capillary permeability, inflammatory reactions, and blood platelet function, and may provide benefits to those suffering from inflammatory disease and prevent development of atherosclerosis and thromboembolic complications. TM

dequate macronutrient and micronutrient intakes are associated with positive fetal outcome. However, ensuring the adequate micronutrient intakes for both populations and individuals who are pregnant is fraught with difficulties. Appropriate assessment of micronutrient status is challenging. Differences in bioavailability of nutrients between animal and vegetable food sources o f nutrients and between food sources and supplements complicate efforts to accurately predict need or quantify intake. However, nutrient supplementation and altering dietary intake are viewed as relatively safe, inexpensive, and noninvasive interventions. Therefore, the potential for altering fetal outcome or gestation duration via nutrition intervention is o f great interest. This article will review the effects of marine n-3 fatty acids, calcium, folate, and zinc on length of gestation and fetal outcome. Recent interest in these nutrients lies in their potential to alter duration o f gestation or fetal outcome.

Omega-3 fatty acids are manufactured by phytoplankton in water and are consumed and incorporated into the food chain by higher animals. Accordingly, marine foods are the most concentrated sources o f omega-3 fatty acids. Dietary intake varies widely on a geographical basis, with the highest intake r e p o r t e d among Japanese and Eskimo populations (10 g/d). 1 Initially, n-3 fatty acid were considered to be nonessential because humans have the ability to elongate a-linoleic acid (18:3) to eicosapentaenoic (EPA, 20:5) and eventually, docosahexaenoic acid (DHA, 22:6) (Fig 1). Currently, many experts recognize their essentiality, but this role has not been acknowledged by the Food and Nutrition Board. 2 However, the Food and Nutrition Board does foresee the need to reevaluate the evidence and predict the need for an allowance in the future based on their structural and functional roles.

F u n c t i o n o f Marine Fish Oils Related to P r e g n a n c y D u r a t i o n and O u t c o m e In the past 10 years, potential mechanisms for the effects o f polyunsaturated fatty acids on pregnancy and fetal size have been identified. 9'1~ Placental blood flow ~~ seems to be influenced by the effects o f thromboxane and prostaglandin 12 on vasoconstriction or dilation and platelet aggregation potentiation or antagonism a2'~3 (Fig 2). Prostaglandins, specifically, prostaglandin E2 and From the Department of Food and Nutrition Services, Department of Clinical Nutrition, Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, IL. Address reprint requests to Maureen A. Murtaugh, PhD, RD, Department of Clinical Nutrition, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612. Copyright 9 1995 by W.B. Saunders Company O146-0005/95/1903-0003505.00/0

Seminars in Perinatology, Vol 19, No 3 (June), 1995: pp 197-210

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n-3 fatty acid family a-Linolenic

18:3

Octadecietraen~

18:4

A6-desaturase

elongase

A5-desaturase

Eicosaraenoict_et V

20:4

Eicosapent~noic (EPA)

20:5

Docosapentaenoic

22:5

Docosahexaenoic(DHA)

22:6

elongase

A4-desaturase

Figure 1. Metabolic pathways for the desaturation and elongation of n-3 fatty acids. (Adapted and reprinted with permission, from Drevon CA, in Nutrition Reviews 50:38-45, 1992. 6) F2~, are necessary for the onset of labor in humansfl 4 Inhibitors o f prostaglandins, such as aspirin, suppress uterine contractility 15'16 and reduce pregnancy-induced hypertension (preeclampsia) J7 and fetal growth retardation, 18 alt h o u g h the exact mechanisms for these effects are not yet fully understood.

Fish Oils and Pregnancy Duration or Outcome: H u m a n Studies Epidemiological Studies The first association between fish oils and pregnancy duration and birth weight was made by Olsen and Hansen ~~ on the basis of clinical observations. Examination o f data from the Faroe Islands suggested that high intake o f fish, pilot whale meat, and blubber 2~ might be related to the higher birth weights o f infants from the Faroe Islands. 2t Differences in maternal age, parity, marital status were not the cause for increases o f 194 g in weight and 1.5 cm in height between singleton Faroese and Danish infants. Pregnancies were 3.6 days longer, 1~ and more inductions o f labor were p e r f o r m e d in Faroese women, suggesting that about half o f the increase in infant birth weight was related to the duration o f pregnancy. Several methodological concerns need to be identified, including the use of routinely doc-

umented vital statistics by doctors and nurses and estimated gestational age. Although the above findings have not been confirmed by dietary intake assessment in the Faroe Islands as compared with in Denmark, biochemical p r o o f o f increased n-3 fatty acids can be assessed. Erythrocyte phospholipid levels o f n-3 fatty acids seem to be linearly related with the a m o u n t o f n-3 fatty acids ingested several weeks before sampling outside o f pregnancy, z2 Although not yet validated for effects o f gestation and parturition, Olsen et al f o u n d erythrocyte n3 fatty acids 20% greater in Faroese women compared with Danish women 2 days after birth. 2~ Pregnancy duration increased with erythrocyte n-3 fatty acid levels in Danish women, but not in Faroese women, suggesting that there might be a threshold level o f intake above which no increase in gestation could be realized. The authors suggested that Faroese women exceeded the threshold level for n-3 fatty acid intake, whereas Danish women did not. Additional study shows a 234-g increase in birth weight of infants born in the Orkney Islands (with a high consumption o f marine foods) compared with those born in Aberdeen, Scotland. 24 However, most o f the increase (172 g) was attributable to differences in maternal smoking habits, height, weight, and duration o f pregnancy. Because it is not clear what explained the remaining 62-g increase in birth weight, we cannot rule out the possibility o f either a lengthening of gestation or an increase in the rate o f fetal growth related to the intake o f n-3 fatty acids.

Randomized Controlled Studies Only one randomized, controlled trial was identified that adequately tested the n-3 fatty acid effect on duration o f gestation and rate o f fetal growth. 25 Five h u n d r e d thirty-three Danish women were randomized 2/1/1 to receive either fish oil (2.7 g / d n-3 fatty acids) or olive oil (4 g/d), or no supplement at 30 weeks o f gestation. The results suggest either a lengthening effect o f n3 fatty acids or a shortening effect o f olive oil. The mechanisms discussed previously support the f o r m e r hypothesis. Combined effect o f supplement and fish intake at entry to the study allowed identification o f a dose-response effect with a saturation level. The 4-day increase in gestation explained the 107-g increase in birth weight. O f note, there was a trend toward greater blood loss

Nutrient Effects on Pregnancy Outcome

Arachidonic Acid

Clinical Application

Cyclic E idoperoxides

Thromboxane

Prostaglaudin r

e

(TXAp TXA~

P6E)

Prostacyclin (PGI2, PGI3) DECREASE Vasoconstriction Platelet Aggregation Uterine Activity

199

INCREASE Vasoconstriction Platelet Aggregation

Uterine Activity

Figure 2. Pathway for production of hormones affecting uterine blood flow from arachidonic acid. at delivery in the g r o u p receiving fish oil comp a r e d with those receiving olive oil. Evidence f r o m the few observational and intervention studies s u p p o r t a lengthening o f gestation with third trimester n-3 fatty acid supplementation. The evidence is less supportive of an increase in fetal growth with n-3 fatty acid supplementation, although higher doses and earlier supplementation should be investigated. The available data cannot be conclusively interpreted as resulting in a reduction in p r e t e r m or low birth weight delivery, although they Suggest this relationshipf j

Potential Side Effects of Fish Oil Supplementation Few nutrients can be provided supplementally without side effects. The ill effects o f increased n-3 fatty acids can include bleeding, infection, diabetes, lipid peroxidation, and cancer. 6 Several specific concerns relating to pregnancy outcome and birth weight have been raised. The potential for increased bleeding at delivery was evident in the intervention trial and should be investigated further. 25 Likewise, an increase in the need for vitamin E could accompany the increase in n-3 fatty acids; this relationship needs to be clarified. An increase in post-term delivery and intrauterine fetal death also needs to be investigated. 27 Prostaglandin inhibition by n-3 fatty acids could lead to intrauterine closure of the ductus arteriosus, but good evidence to s u p p o r t this effect is lacking. 2s'~9 Last, concern for consumption o f fish f r o m contaminated waters and the resulting risks must not be ignored. 3~

The findings regarding fish oils and length o f gestation must be viewed as works in progress. The results are promising and should lead clinicians to advise consumption o f a wide variety o f foods, including those rich in n-3 fatty acids. However, until further evidence is available, including examination of ill effects and the doseresponse curve, widespread supplements o f fish oils should not be r e c o m m e n d e d .

Calcium Dietary Calcium Intake Traditionally, calcium has been linked to bone health. Despite the public awareness campaigns advocating adequate calcium intake to prevent osteoporosis, the average American w o m a n does not consume the r e c o m m e n d e d a m o u n t of dietary calcium. ~2-34 The n u m b e r of w o m e n aged 19 to 50 who consume 800 m g / d calcium is affected by income. Although 57% of the w o m e n with income higher than 300% o f the poverty level sampled in the 1986 Nationwide Food Consumption Survey met or exceeded an intake o f 560 m g / d , only 40% of w o m e n lower than 131% of the poverty level met this level of intake. 3z Similarly, studies of dietary intakes of pregnant w o m e n show that few w o m e n ' s intake meet or exceed the 1,200-mg/d R e c o m m e n d e d Dietary Allowance (RDA) for p r e g n a n t women. The majority o f studies reviewed that measured dietary calcium intake r e p o r t mean intakes close to 600 m g / d , 34-'~6 or 50% of the RDA for p r e g n a n t women. O n e study estimated dietary calcium intake o f p r e g n a n t women at 1,200 m g / d as determined by examination of dietary food patterns and 24-hour recallsY However, meeting or failing to meet RDA levels o f calcium does not constitute calcium sufficiency or deficiency, respectively.

Calcium and Hypertension Interest in calcium supplementation during pregnancy has arisen largely f r o m its association with hypertension. ~s-41 In the n o n p r e g n a n t state, hypertension is characterized by an increase in peripheral resistance caused by increased vascular smooth muscle t o n e . 42'43 Changes in the strength o f contraction must be associated with changes

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in either intracellular calcium levels or cellular response to intracellular calcium l e v e l s . 44'45 Hypertensive patients with elevated serum parathyroid h o r m o n e (PTH) and 1,25(OH)2D and low serum ionized calcium concentration may benefit f r o m calcium supplementation. Resnick hypothesized that calcium regulating h o r m o n e s work in concert with the renin-angiotensin-aldosterone system to monitor mineral homeostasis. 46 Changes in cellular calcium uptake and disposition translate the information about mineral homeostasis at the cellular level. O t h e r possible mechanisms of action for calcium in hypertension include a diuretic e f f e c t , 47'48 effects on calcium binding to vascular smooth muscle cell membranes, and alterations o f calcium as a cellular messenger in response to norepinephrine, epinephrine, and angiotensin. 4:) Preeclampsia complicates 5% to 7% o f all deliveries and contributes significantly to maternal and perinatal morbidity and mortality. 5~ Many alterations in calcium metabolism have been rep o r t e d in patients with preeclampsia. These alterations include decreased calciuria, decreased 1,25 dihydroxyvitamin D, elevated parathyroid h o r m o n e , decreased urinary cyclic adenosine m o n o p h o s p h a t e , increased levels o f intracellular calcium, and reduced levels of ionized calcium. 34''51-56 However, intestinal absorption does not seem to be altered in p r e g n a n t women with preeclampsia. 57 The role o f calcium supplementation during gestation may be similar to its role outside o f gestation. Calcium supplementation causes reductions in parathyroid h o r m o n e levels and in intracellular calcium levels in vascular smooth muscle cells. Smooth muscle cells, in turn, reduce their responsiveness to blood pressure stimuli, thereby reducing blood pressure. 5s

Clinical Trials of Supplemental Calcium to Reduce Hypertensive Disorders in Pregnancy Several clinical studies have been conducted to examine the effect o f calcium supplementation on blood pressure during pregnancy. Preliminary results showed that calcium supplementation can cause reductions in blood pressure in p r e g n a n t w o m e n at the population level. At the individual level, it seems that some individuals may be m o r e responsive to calcium supplementation than others. 35'~'~Thus, clinical trials a m o n g pregnant high-

risk individuals have begun based on the thinking that they may be selectively responsive as well.

Calcium Supplement Trials in Pregnant Women To date, the results o f only one multicenter, double-blind, randomized, controlled trial evaluating the relationship between calcium supplementation (2 g) and hypertensive disorders o f pregnancy has been published. 36 Dietary calcium intake was similar in a s u b g r o u p of 87 w o m e n f r o m the placebo g r o u p and 86 f r o m the supplemental g r o u p (mean + SD, 642 + 448 mg vs 646 + 396 mg, respectively). Supplemental calcium decreased the rate of hypertensive disorders o f pregnancy, even though mean blood pressure values were not different between the groups and the rate of preeclampsia by itself was not decreased substantially (2.6% with calcium, 3.9% without supplement; odds ratio 0.65, 95% CI, 0.35 to 1.25). A low calcium to creatinine excretion ratio at 20 weeks of gestation seemed to be a good predictor of reduction in hypertensive disorders in pregnancy (odds ratio 0.56, 95% CI, 0.29 to 1.09). In a small (n = 50) clinical trial, normotensive and hypertensive women were randomized to receive either 1,000 mg calcium per day or continue their usual dietary habits. 34 T h e r e was a greater reduction in diastolic blood pressure ( - 0 . 9 vs - 0 . 4 m m Hg, P < .05) f r o m 12 to 32 weeks in the s u p p l e m e n t e d hypertensive patients comp a r e d with the hypertensive control subjects. O t h e r studies have failed to detect changes in blood pressure in normotensive subjects supplem e n t e d with only 1 g calcium per day, but have r e p o r t e d differences with 2 g calcium per day. 5s

Calcium Supplementation in Pregnancies at Risk for Hypertensive Disorders Sanchez-Ramos et a135 tested the hypothesis that 2 g calcium would reduce the incidence of pregnancy-induced hypertension f r o m 60% to 20% in 53 angiotensin II-sensitive nuUiparous patients. Screening for angiotensin II-sensitivity and randomization to supplementation or placebo occurred between 24 and 28 weeks' gestation. The relative risk (RR) o f preeclampsia was reduced a m o n g w o m e n receiving calcium supplements (RR = 0.37, 95% CI 0.15 to 0.92, P = .01), and the risk o f pregnancy-induced hypertension

Nutrient Effects on Pregnancy Outcome

was reduced f r o m 64.7% to 31% with calcium supplementation (RR = 0.46, 95% CI 0.25 to 0.86, P = .01). Thus, it seems that calcium supplementation is protective against pregnancy-induced hypertension and preeclampsia in individuals who are angiotensin II-sensitive. Studies of calcium supplementation in pregnant and n o n p r e g n a n t subjects have provided some consistencies. Calcium supplementation is m o r e likely to be effective at doses higher than 1 g per day, and the benefit may be greater in hypertensive than normotensive subjects. Hypertensive patients with evidence of altered calcium metabolism such as a low serum ionized calcium, low urinary to creatinine excretion ratio, 3~ or angiotensin II-sensitivity34 may be m o r e likely to benefit f r o m calcium supplementation than other hypertensive patients. Further study is needed to confirm these results and better identify individuals, b o t h p r e g n a n t and nonpregnant, who might benefit f r o m calcium supplementation.

Calcium Supplementation to Reduce Preterm Births In theory, the effects of calcium supplementation would affect intracellular calcium concentrations and thus reduce smooth muscle tone, including that o f uterine muscle. However, clinical trials using supplemental calcium to examine the effects on hypertensive disorders during pregnancy have not found any alteration in gestation or birth weight attributable to calcium supplementation. 34'36 Villar and Repke tested the hypothesis that 2 g daily calcium supplementation might reduce p r e t e r m delivery in an adolescent population in B a l t i m o r e Y This randomized, doubleblind, controlled trial enrolled 189 women, who were 17 years old or younger before their 23rd week o f gestation, with an estimated dietary calcium intake approximately 1,200 nag per day using 24-hour recall. Delivery before 37 weeks o f gestation was reduced in the supplemented group (7.4% v s 21.1%, P = .007). Risk of low birth weight was similarly reduced by calcium supplementation. I f confirmed by further clinical study, s u p p l e m e n t a t i o n with these p h a r m a c o l o g i c a l doses of calcium represents a relatively simple and inexpensive intervention for the reduction o f p r e t e r m birth.

2 01

Side Effects of Calcium Supplementation Few side effects have been r e p o r t e d in the clinical trials providing supplemental calcium to pregnant women. 34-36'58 Supplementation with high doses of calcium may cause constipation 2 and decreased intestinal absorption of iron, zinc, and o t h e r minerals. 6~ Concern for an increase in calcium excretion and the subsequent risk o f renal calcium stones is common. N o n e of these studies have r e p o r t e d any trend toward an increase in renal calcium s t o n e s . 34'36'58 The lack of reports of kidney stones in interventional studies providing calcium supplements and two recent reports in n o n p r e g n a n t subjects lead to questions of the long-held assumption that increased calcium intake could increase risk for calcium kidney stones. A recent prospective study in men reported a decrease in risk of symptomatic kidney stones with high calcium intake. 6j Dietary calcium may act to decrease the risk o f symptomatic calcium stones by binding oxalates in the intestine, reducing their absorption and the subsequent urinary oxalate excretion. In a n o t h e r report, women susceptible to kidney stones received supplemental calcium citrate without an increase in calcium oxalate saturation. 62 Further study is needed to u n d e r s t a n d this relationship between calcium supplements and risk o f calcium stones.

Application Pregnant w o m e n do not, on the average, consume adequate dietary calcium. R e c o m m e n d i n g consumption of dairy products and other foods to increase dietary calcium intake is consistent with r e c o m m e n d a t i o n s a p p r o p r i a t e for all pregnant women. Calcium supplementation (Table 1) to meet the RDA when dietary intake is low is also a reasonable a p p r o a c h to meeting the needs T a b l e 1. Calcium S u p p l e m e n t s : P e r c e n t Calcium and Approximate Absorption

Supplement Type

Calcium (%)

Dose (mg)

Approximate Absorption (%)

Calcimn carbonate Tricalcium phosphate Calcium citrate Calcium gluconate

40 38 21 9

250-500 200-300 200-300 10-500

26 25 35 34

Adapted and reprinted with pernfission, from Levenson DI, Bockman RS. Nutr Rev 52:221-232, 1994.

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o f pregnant women. Decisions regarding specific individuals who might benefit from calcium supplementation should be made by the individual's physician and dietitian.

Zinc Zinc is a necessary component o f enzymes in most major metabolic pathways 2 and is essential for growth. Whole organism symptoms have failed to implicate any single zinc-dependent enzyme function responsible for the rapid onset o f symptoms o f zinc deficiency. It is believed that as a c o m p o n e n t o f zinc finger proteins, the largest class of DNA-binding proteins and the zinc finger protein control o f gene expression in which zinc is important to development and growth. 6"~ Regardless, p o o r zinc status has been implicated in a n u m b e r o f p o o r outcomes of pregnancy.

Assessment of Zinc Status Clinical assessment of zinc nutriture is particularly difficult. Serum zinc levels are a p o o r reflection of zinc nutriture in individuals. ~'6466 Gestational alterations in plasma and serum zinc levels only complicate assessment o f zinc status during pregnancy. 67 Leukocyte zinc levels may be more useful in determining zinc status o f individuals, but the methodology is more difficult and not generally available in the clinical setting. To date, no method meeting accuracy, sensitivity, and availability criteria is available for inclusion as a part o f routine prenatal c a r e . 66 Difficulty in accurately assessing zinc nutriture makes defining the association between zinc status and pregnancy o u t c o m e even more difficult.

Dietary Zinc Intake A m o n g American women, dietary zinc intake is often below the RDA level of 1 5 m g / d . ~ Animal products, particularly meat, may be the largest source of zinc in the United States. 68 Therefore, the lower bioavailability o f zinc from foods high in phytates compared with animal sources is not a primary concern in the United States. 69 The estimated daily dietary zinc intake a m o n g pregnant women is between 8.8 + 3.5 mg and 14.4 • 1 . 5 mg. 7~ The small stores of available zinc in humans combined with intake at or below estimated need make marginal zinc status and its effect on pregnancy outcome in the United States

a valid concern. Scholl et al are a m o n g the few researchers who have measured dietary zinc and the effect on pregnancy o u t c o m e . 72 In a recent study by Scholl et al,22 average zinc intake of the 818 women was 11. l m g / d , and was linearly related to total calorie (r = 0.66) and protein (r = 0.57) intake. Zinc intakes below 6 m g / d were associated with a twofold increased risk of low birth weight and preterm delivery. However, this study established an association only between zinc intake and low birth weight, because zinc was highly correlated to both energy and protein intakes, and energy intake c o n f o u n d e d the relationship between zinc and preterm delivery. These results also did not distinguish low birth weight versus size for gestational age.

Zinc Nutriture and Pregnancy Outcome: Animal Models Animal models have provided strong support for the relationship between zinc status and pregnancy outcome, with effects at all phases of reproduction. In animals, zinc deficiency during the estrous cycle can cause infertility. 73 During embryogenesis, it can cause skeletal and central nervous system defects. 74 Growth retardation has been found in primate and rat offspring in response to zinc deprivation during gestation. 75 Zinc-deficient diets fed to rhesus monkeys during pregnancy resulted in an increased incidence o f stillbirths, spontaneous abortion, neonatal death, and delivery complications as compared with controls. 7~-79O t h e r perinatal effects include prolonged labor and atonic bleeding, s~ Postnatal effects include behavioral abnormalities in rats and monkeys. 81 The strong animal basis for a role o f zinc in fetal outcome has led to examination of the relationship between zinc and pregnancy outcome in humans despite the difficulties in assessing zinc status.

Zinc Nutriture and Pregnancy Outcome: Human Study Relationship of Maternal Zinc Status to Fetal Anomalies. Although animal models support a terato-

genic effect of zinc deficiency, h u m a n studies have failed to detect a consistent relationship between neural tube defects (NTD) or other congenital anomalies and maternal serum zinc levels. Both negative s2's~ and positive results 84-87 have been reported in observational studies o f preg-

Nutrient Effects on Pregnancy Outcome

nancies. A report of 6 pregnancies with NTD and 16 with raised plasma alpha-fetoprotein but no evident fetal malformations did find significantly lower leukocyte zinc and selenium levels when c o m p a r e d with n o n p r e g n a n t w o m e n and pregn a n t w o m e n who had normal pregnancy outcomes, as T h e r e are several possible interpretations for these findings. First, it is possible that reduced zinc a n d / o r selenium levels resulted f r o m the a b n o r m a l pregnancy rather than causing the abnormality. Alternatively, these findings could have been a result o f p o o r tissue zinc a n d / or selenium stores before neural tube closure in the NTD-affected pregnancies and after NTD closure in the pregnancies with raised alpha-fetoprotein. Although this finding is supportive of zinc deficiency as a cause o f NTD, further study on larger samples are needed. Acrodermatitis Enteropathica. Acrodermatitis enteropathica (AE) is a hereditary disorder characterized by impaired zinc absorption. W o m e n with AE have provided a natural model for the study o f zinc deficiency in humans. Seven pregnancies in three w o m e n with AE resulted in two m a j o r malformations and one spontaneous abortion, s8 A subsequent r e p o r t o f two pregnancies in one w o m a n showed good pregnancy outcomes with zinc supplementation. 89 These cases d e m o n s t r a t e the high risk of p o o r o u t c o m e with zinc deficiency. Maternal Zinc Status and Fetal Growth. Studies examining the relationship between maternal zinc status and infant birth weight provide conflicting results. Both positive 9~ and negative results 71'92''~:~have been reported. Differences in timing o f measures, the measures themselves, and gestational d e p e n d e n c e o f zinc measures make interpretation o f this relationship difficult. The p o o r correlation between some o f the measures, such as serum zinc and maternal whole body zinc status and active placental transfer o f zinc to the fetus, probably contribute to the difficulty in demonstrating a consistent relationship. Several randomized, controlled, interventional studies have b e e n conduected to examine the relationship between zinc nutriture and fetal weight. In a G e r m a n study, supplementation with 20 mg zinc was associated with a nonsignificant increase in birth weight o f 84 g.94 In the US, a longitudinal study following 46 middle-class women, 10 of w h o m received 15 mg supplemental zinc, did not find any difference in birth

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weights. 67 The interpretation o f these studies is h a m p e r e d by inadequate sample sizes and study methodology. No definitive conclusions can be drawn f r o m these data. Zinc and Maternal Morbidity. The effects of supplemental zinc on maternal morbidities such as pregnancy-induced hypertension, prolonged labor, and extended gestation have been examined in a few randomized-blinded, controlled trials. Supplements o f 45 mg daily were provided to 133 w o m e n with serum zinc concentrations less than 9.9 # m o l / L early in pregnancy, s4 Reduction in p o s t t e r m pregnancy and p r o l o n g e d labor was n o t e d in the s u p p l e m e n t e d g r o u p as c o m p a r e d with the control groups. Hispanic adults 95 and teenagers 92 were provided with supplemental zinc. Serum zinc levels were associated with pregnancy-induced hypertension in both groups, with a reduction in incidence in adults 95 but not in the teenagers, 92 although serum levels were lower in those teenagers with pregnancy-induced hypertension than those without. No effect o f supplemental zinc on pregnancy-induced hypertension was detected in a sample o f black teenagers, p6 although an association between low plasma zinc and pregnancy-induced hypertension was r e p o r t e d earlier in the same population. 97 Thus far, zinc supplementation has not b e e n successful in consistently reducing maternal morbidity incidence.

Application There is little evidence to suggest that widespread zinc supplementation would be beneficial in the US. However, interactions between zinc, iron, and c o p p e r are o f particular concern a m o n g pregnant women in the US because supplemental iron is commonly prescribed to p r e g n a n t w o m e n even in the absence o f d o c u m e n t e d iron deftciency. 9s It is also interesting to note that several foods commonly e n c o u r a g e d as high iron foods are also high in zinc (Table 2). Perhaps it is the ratio of zinc to other minerals that is important. Further evidence suggests an interaction between iron and zinc, particularly when iron is provided in doses higher than 25 rag. 99"1~ The Food and Nutrition Board currently r e c o m m e n d s that p r e g n a n t women receive a supplement o f 30 m g of elemental iron after the first trimester. 66 In contrast, however, the US Preventive Services Task Force 9s failed to find sufficient evidence to r e c o m m e n d such routine iron supplementation.

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Table 2. Selected High Zinc:Iron Ratio Foods*

Food Beef Roasted chicken Oysters Beef liver Pork chop Scrambled egg

Iron (rag) Zinc (mg) 0.525 0.47 3.8 1.91 0.26 0.34

1.037 0.611 51.7 1.72 0.829 0.28

Protein (g) 5.1 7.6 4.0 6.9 7.9 3.1

* Per 1 oz portion. Values from Nutritionist IV, N-squared Computing, The Hearst Corporation, San Bruno, CA, 1994.

Still, it is clear that when supplements in excess o f 30 mg elemental iron are prescribed, supplemental zinc (15 mg) should accompany it. 66 Folate Folate is a generic name for a wide range of compounds that have nutritional properties and chemical structures similar to folic acid (pteroylglutamic acid [PGA]). Folate is i m p o r t a n t in the maintenance o f normal metabolism, tissue turnover, and growth. Its main function is as a coenzyme for one-carbon transfer reactions and is essential for n u m e r o u s metabolic reactions, including DNA synthesis and amino acids interconversions. J02 During rapid growth periods, folate requirements are larger due to increased cell division and metabolism. For p r e g n a n t women, folate is additionally important in organogenesis. nr~-~~ Studies have shown that p r e g n a n t w o m e n without adequate stores of folate are at a greater risk o f having children with congenital anomalies, such as neural tube defects (NTD) and fetal growth retardation.~~ This article's section will discuss folate supplementation, incident and r e c u r r e n t NTD, and suggest methods to ensure an adequate dietary intake o f folate. Approximately 400,000 children worldwide are affected by NTD, or a b o u t 2% to 3% o f all births.l~ Inadequate folate stores may play a role in the development of NTDs (eg, spina bifida, anencephaly, and encephalocele). Because of women's 10-fold increased risk o f having another NTD-affected baby, those who have already had a NTD-affected baby and those on antiepileptic drug therapy are considered at "high risk". 104'105'10s Low-risk pregnancies or p r e g n a n t w o m e n who have not previously given birth to a NTD-affected baby account for approximately 95% of the NTDaffected births, l~

The mechanism whereby folic acid prevents defects in the closing o f the neural tube are not well understood for a n u m b e r o f reasons. Animal models have s u p p o r t e d a defect in methionine metabolism.l ~0-114 Considering the link between methionine, folate, and B12 in the p r o d u c t i o n of purines and pyrimidines for DNA synthesis, alteration in methionine metabolism seems a plausible cause for some NTDs in humans (Fig 3). Supporting this theory is a recent study in which a methionine-loading test was given to 21 w o m e n who had a previous NTD-affected pregnancy and 15 control subjects in the Netherlands. 115 This small trial showed that 5 o f the w o m e n who had a NTD-affected pregnancy had an elevated response to the methionine load with normal folate, B]2 , and pyridoxine levels. This finding caused concern that these w o m e n may be heterozygous carriers of homocystinuria, which can be corrected by high doses o f folic acid, B12, o r pyridoxine.116.117 Further investigation into b o t h homocysteinemia and NTDs and prevention by vitamin supplements is indicated. Study o f R e c u r r e n c e o f N T D s Many studies have been conducted evaluating the effect of folate supplementation on the pregnancy o u t c o m e o f high-risk patients. Smithells et al 1~ p e r f o r m e d a n o n r a n d o m i z e d study on 550 p r e g n a n t w o m e n (with a previous NTD-affected pregnancy) who were fully, partially, or not supp l e m e n t e d with a multivitamin (MVI) containing 0.36 m g / d o f folate. The s u p p l e m e n t e d w o m e n had a significantly lower rate of NTD-affected babies (P < .01). Laurence et al 1~ evaluated the use o f MVI (with 4 mg folate) in a double-blinded, randomized study o f 111 p r e g n a n t w o m e n with a history o f a NTD-affected pregnancy. T h e r e was a significantly lower risk for the supplem e n t e d women to give birth to a NTD-affected

MethylYransferase /~

Figure 3. Folate, B12 , and methionine relationship in cell metabolism. THF, tetrahydrofolate.

Nutrient Effects on Pregnancy Outcome

baby by a one-sided test (P < .04), but not twosided test (P = .08), probably due to the small sample size. More convincing are the results o f the Medical Research Council Study.~~ The MRC study compared the use o f MVI, folate (4 mg), and a placebo in 1,195 pregnant women with a history of a NTD-affected pregnancy in a randomized, double-blinded study. The risk of having a NTDaffected pregnancy was significantly lower among the folate-supplemented g r o u p compared with the unsupplemented g r o u p (P < .0001). Alt h o u g h diet and compliance to supplement use were not directly measured, the results of this study are supportive o f a protective role of folate supplementation on the recurrence of NTD. However, further study is needed to determine whether a smaller dose may also be effective.

Improvement of Dietary Intake and Recurrent NTD Only one study was identified that examined the relationship between changes in dietary folate intake and the incidence of N T D s ] is Laurence et al ~s p e r f o r m e d a prospective case-control study of 180 pregnant women with previous NTD births to examine the effects of dietary quality during the first trimester on NTD-affected births. Diets were rated according to variety o f intake rather than quantitative assessment. All of the NTD recurrences (n = 8 of 186) were in women with " p o o r " diets. Although the authors suggest a protective effect o f "adequate diets," no differences in nutrient intake or nutritional status were measured.

Antiepileptic Drugs W o m e n taking antiepileptic drugs are also at an increased risk for having a pregnancy with p o o r outcome, t1.~with one o f the manifestations being NTD.12~ Long-term use of antiepileptic drugs and valproic acid (VPA) depresses serum and red cell levels o f folate] 1'~'12:~Results of studies examining the association between antiepileptic drugs, folate status, and fetal outcome have not been conclusive. ~19.124-127Differences in the positive and negative associations might be attributable to variation in methodology, measurement o f only serum folate concentrations, and poorly timed measurements. However, the finding o f more frequent p o o r outcomes a m o n g pregnan-

~05

cies treated with antiepileptic drugs and having low serum folate 1~9implicates folate in the genesis of p o o r outcome. Clinical guidelines 12s exist for the management o f women treated with antiepileptic drugs before and during pregnancy, but studies evaluating whether folate can prevent NTDs in women treated for epilepsy are needed.

Incidence of NTDs Folate supplementation in "low-risk" pregnant women has reduced the incidence of NTDs in the majority of the studies performed. In contrast, Mills et al~29 f o u n d no association between MVI (with folate) use and the occurrence of NTD births in 1,143 pregnant women. These findings are probably due to the fact that NTD births were less than average in the area studied and the response rate was poor. In observational studies p e r f o r m e d by Mulinere et a113~and Milunsky et al, TM folic acid provided a protective effect and showed an association between folate supplementation and risk of NTD-affected birth. Czeizel et al ~~ randomized 4,753 pregnant women to receive MVI with 0.8 mg folate or placebo in a double-blind study. Dietary folate intake was similar between groups, but risk for NTD-affected births was reduced in the supplemented g r o u p versus placebo groups (22.0 per 1,000 vs 13.3 per 1,000; P = .02). The balance of evidence supports a preventive effect o f folate supplementation in doses of 0.4 to 0.8 m g / d on incident NTD cases.

Recommendations for Folate Intake Both the US Public Health Service and the Food and Nutrition Board r e c o m m e n d that women o f child-bearing age consume at least 0.4 m g / d o f folate. 2'1~ Not only is the p r o p e r amount of folate important, but timing is critical as well. Adequate folate intake seems to be most important before and during embryonic neural tube closure, or about 6 weeks after conception. Because many American pregnancies are unplanned, the only way to ensure adequate folate intake for all pregnancies is to r e c o m m e n d that all women o f child-bearing potential receive adequate dietary folate.

Obtaining Adequate Dietary Folate Unfortunately, the average American consumes about 0.2 mg folate daily, less than the recom-

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mendation for p r e g n a n t women. 66 W o m e n who smoke, consmne excessive alcohol, are p r e g n a n t with multiples, are taking antiepileptic drugs, and who have had a previous NTD-affected pregnancy all have an increased r e q u i r e m e n t for folate. 10~ T h r e e potential approaches to increasing folate in the diet are the following: supplementation, alteration in diet, and food fortification. Although most MVI contain 0.4 to 0.8 mg o f folate, not all w o m e n of child-bearing potential will take MVI. Additionally, caution must be used when taking supplements because of proven teratogenic effects o f high doses o f other vitamins such as vitamin A.~:~2 Fortunately, supplementation is not the only choice for women. By following the US dietary pyramid, women will most likely consume m o r e than 1.4 mg folate daily, ~ which surpasses the RDA. Especially rich f o o d sources o f folate include raw green leafy vegetables (eg, spinach, turnips, mustard greens), citrus fruits (oranges), and fortified cereals and whole grains.13'~ The method of food preparation must be considered, because 50% to 90% o f folate can be lost during cooking. Finally, fortification o f folate in o u r f o o d supply has been a topic o f m u c h debate. The potential advantages include reduction in NTD-affected births, increase in fetal growth, prevention o f p r e c a n c e r o u s lesions in the lung and cervix, reduction in homocysteinemia (which has been associated with coronary artery disease), and prevention o f overdoses o f MVI. T M ~37 Unfortunately, there are also severe disadvantages to folate fortification, including masking o f B12 deficiency and decreased effectiveness o f antiepileptic drugs. ~~ T h e r e is clear evidence of a link between the consumption o f folate and NTD-affected births. Further studies need to be conducted to determine the ideal intake for p r e g n a n t women, as well as to define how folate supplementation decreases incidence of NTDs. Presently, all women o f child-bearing age should increase their folate intake to at least 0.4 mg, but not exceed 1 m g / d, by following the dietary pyramid and consuming foods high in folate. Persons unable to consume adequate dietary sources should ensure adequate intake by use of a MVI which contains 0.4 mg folate.

Conclusion Although in nature, individual nutrients do not act in isolation, and there is a move toward mul-

tifactorial, nutritional interventions, 1~8 supplementation with individual nutrients can provide desirable effects. Clearly, p r e g n a n t w o m e n should consume a diet based on a wide variety o f foods to provide adequate dietary intake o f all nutrients. Supplementation with multivitamins in doses at or less than the RDA to provide nutrients not available from dietary intake on an individual basis is a reasonable practice. Research regarding supplemental nutrients provided at p h a r m a c o logical doses (ie, folate for prevention o f NTD recurrence, or calcium for hypertensive disorders of pregnancy) should continue. Further research should determine minimum doses needed for their positive effects, with particular attention to identifying individuals who will benefit.

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