maternal nutrition and perinatal survival

Lead Review Article October 200 1 I 3 15-326

Maternal Nutrition and Perinatal Survival David Rush, M.D.

The simple relationship between maternal macro- nutrient status and perinatal survival (increased ma- cronutrient intake -+ increased maternal weight andlor weight gain + increased fetal growth -+ improved survival) that is usually posited is no longer defensible. First, maternal weight and weight gain are remarkably resistant to either dietary advice or supplementation; further, increased birth weight attributable to maternal nutrition does not necessarily increase perinatal survival (because prepregnant weight is positively associated with both birth weight and higher perinatal mortality). Finally, whereas dietary supplements during pregnancy may have a modest effect on birth weight in nonfamine conditions (by contrast with a large effect in famine or near-famine conditions), their impact is not mediated by maternal energy deposition. Rather, the component of maternal weight gain associated with accelerated fetal growth is maternal water (presumably plasma) volume.

Introduction

The initial enthusiasm for maternal food supplementation following World War I1 has since been q~estioned,I-~ but also defended.”’O Such programs have been questioned regarding effectiveness, as well as ~ a f e t y . ~ J ~ J This review aims to add to this dialogue.

Effects of Famine and Dietary Restriction

The 550 g decline in birth weight in Leningrad during World War I1 is the most severe reported depression in birth weight among a population that was previously well nour- ished.13 In the Dutch famine of 1944-1 945, there was an approximate 300 g depression in birth weight.I4J5 In post- war Wuppertal, mean birth weight was depressed by as much as 227 g; but birth weight declined by considerably

Dr. Rush is Professor of Nutrition, Community Health, and Pediatrics (emeritus), Tufts University, Boston MA 021 11, USA. This piece is abstracted from a more detailed review in presse1 that, in part, updates an earlier review on the impact of maternal nutrition on fetal growth!2

less among private patients or when food shortage was intermediate (but with official rations still under 1500 kcall day).16 The declines in birth weight in the Netherlands and in Wuppertal were far greater than the expected 20 g reduction per 1 kg reduction of maternal weight gain.” If maternal weights were lower by approximately 5 or 6 kg, if this algorithm was correct, birth weights would have only been lOCL120 g lower. Perinatal mortality in Leningrad was approximately ten times higher (25%) than in the Nether- lands at the peaks of both famines; nevertheless, the peak rate in the Netherlands was still six times higher than im- mediately before and after the famine.

Intermittent (Seasonal) Severe Deprivation Prentice and Cole1* reviewed the issue of seasonal changes in growth and energy intake (please see details below of their experience in the Gambia). Pebley et al.I9 observed that risk of fetal death was 2.5 times as high for concep- tions in May and June as during the rest of the year in Matlab, Bangladesh. Women who conceived in those months had lower maternal weight at all stages of gestation by approximately one to two kg (2.7 kg weight gain compared with an average of 5 kg for women conceiving during the rest of the year).20 The highest rates of perinatal loss were associated with third trimester food deprivation.

Summary: famine and reproduction. The effects of famine on reproductive health are dramatic: fertility plum- mets, maternal weight gain is depressed, birth weights can fall by 10-1 5%, and perinatal mortality is increased. Under the stress of either acute or seasonal famine, fetal and infant death rates rise. The seasonal fluctuations in diet and anthropometric status among poor women in many developing countries are probably akin to short-term famine, which, if sustained year-round, might not be compat- ible with reproduction. Whereas diet obviously plays a major role in these events, other accompanying forms of privation make it difficult to generalize from famine to nonfamine conditions.

Studies of Iatrogenic Dietary Limitation in Motherwell, Scotland Acute famine is inevitably accompanied by other insults, so that it is impossible to isolate the effects of restricted food intake alone. The quasi-experiments of Dr J.F.K. Grieve

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come close to specifying the effects of decreased energy and increased protein intake. Dr. Grieve began as the ob- stetrician in Motherwell, Scotland in 1938. He developed a program of prenatal care that included avoiding smoking, limiting weight gain, not eating bread or potatoes, limiting milk intake to no more than 10 fluid odday, not eating prunes, plums, bananas, tinned fruits, nuts, or dates, and eating at least onepound (454 g) ofred meat daily throughout gestation.2’.22 Among women under his care, the me- dian weight gain among primigravidae during 1965-1 966 was 0.25 kg/week, only slightly more than half of the 0.46 kg/week gained by women of similar stature and social status in Aberdeen. Mean birth weight in Motherwell was more than 400 g lower than in Aberdeen.23 Apparently, this regimen was not otherwise disadvantageous to the offspring. Perinatal morbidity and mortality were reported to be low, especially among women who successfilly com- plied with the regimen, who had low weight gains, and who surely had infants with low birth weight. Whether the Motherwell children suffered later growth deficit or developmental abnormality, or increased rates of adult diabetes or cardiovascular disease is unknown (given cur- rent theories, children born in Motherwell during this era should now be experiencing an epidemic of diabetes and cardiovascular disease).

In Motherwell, profoundly low maternal weight gain and birth weight following dietary manipulation appeared not to be accompanied by increased perinatal mortality.

Studies of Increased Maternal Weight and Weight Gain During Pregnancy*

This subject was reviewed in detail by the Institute of Medicine. I7 Theirs were the standard assumptions noted above. The first of them that we address is the link between maternal diet and weight gain.

To What Extent Can DietaryAdvice or Supplementation Affect Maternal Weight Gain? The prescriptive policy to manipulate weight gain, implicit in weight gain charts, and explicit in the recommendations of the Institute of Medicinei7 and American College of Obstetricians and Gynecologists (ACOG)26 committees, assumes that dietary and nutritional advice can induce women to increase dietary intake during pregnancy, thereby increasing weight gain. The strongest evidence for this assumption is from secular trends in weight gain. Gormican

et al.27 compared total weight gain in one clinic before 197 1, when a policy of weight gain limitation was in place, with subsequent pregnancies after this policy was liberal- ized; the authors found a remarkable increase in mean weight gain: from 15.9 to 24.2 Ib ( P <0.01). There was a concurrent secular increase in the weight of the adult population, and their later subjects were 4.7 pounds heavier when they entered pregnancy ( P <0.01). Flegal et aL2* reported an increase in body mass index (BMI, kg/m2) between 1960 and 1980 in nonpregnant U.S. women 18-34 years of age, from 22.9 to 23.8 in whites and 25.1 to 26.2 in blacks. (One BMI unit is equivalent to 2.56 kg for a woman 1.6 m tall.) Thus, there is strong evidence of an upward secular trend in weight, and reasonable evidence of an upward secular trend in weight gain.

Observational studies of diet and weight gain. Aaronson and M a ~ N e e ~ ~ found no relationship between (a somewhat idiosyncratic index of) diet and weight gain. Observational studies of diet and weight gain have yielded positive30 and negative3’ results and are too imprecise and often confounded to yield dependable results.

Trials of dietary advice and weight gain. The most important evidence to prove that weight could be raised following dietary advice would be from trials of dietary counseling, and this evidence is essentially negative.32 One of the best studies was never fully published,” but the full manuscript was shared for this review.34 Weight gains were nearly identical among 84 women in one prenatal clinic who received intensive counseling aimed to increase weight gain and 147 women in another clinic who did not receive counseling.

Whereas there is a plethora of prescriptions advising increased weight gain during pregnancy, no one has shown that advice to do so will induce women to gain weight, even in highly controlled experimental conditions, let alone in routine practice.

Dietary supplementation and weight gain. After re- lief of starvation, weight gain in pregnant women increases, presumably owing to increased dietary intake, and deprivation of energy intake certainly leads to reduced weight gain. On the other hand, the impact of nutritional supplements in nonfamine conditions to increase weight gain appears to be minimal. In the six supplementation studies reviewed by S ~ s s e r , ~ ~ the weight gains among the supplemented subjects were very small. Kramer3“ reviewed ten trials: in three the supplemented groups gained less than

* This review will not systematically address the relationship of weight gain to duration of gestation for two reasons. The first is that all studies using total weight gain are confounded: duration of gestation and total weight gain are highly correlated, and multivariate adjustment, given the inevitable imprecision of measurement of duration of gestation, cannot fully correct for this confounding. Second, there has been no secular change in the United States in duration of gestation in the face of rising maternal weight and weight gains, even though nutritional intervention can affect duration of gestation.24 In any case, Kramer et aLZ5 found only a spurious relationship of weight gain during pregnancy with spontaneous preterm birth, and no relationship at all with pregravid body mass index (BMI, kg/m2).

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controls; in six the range of increased weight gain among the supplemented was 10-76 &week (only one of which was significant); and in the tenth, an outlier (which Kramer tended to dismiss for methodologic reasons), there was a statistically significant difference of 175 &week (c.l., 104- 246 g/week). The mean gain per week for all studies ex- cluding the outlier was 23.2 g; with it the mean was 38.4 g. This translates into only 302 g and 499 g, respectively, for one trimester of supplementation. Prentice et a1.37,38 and Ceesay et al.39 performed two supplementation trials in the Gambia among women experiencing intermittent, seasonal famine, in which hefty energy supplements led only to small, nonsignificant effects on weight gain in the first trial and small and inconsistent, albeit occasionally significant, effects in the second.

Summary: dietary advice or supplementation and maternal weight gain. There is thus no consistent or con- vincing evidence that weight gain, other than during overt starvation, is open to much upward shift by dietary advice or supplementation. There has been a secular upward trend in women’s weight and weight gain during pregnancy in the United States. (It is by no means clear that the latter is a result of professional advice or opinion; the former certainly is not.) Whereas there has been a recent secular trend to higher weight gain during pregnancy, no controlled trials of dietary advice to raise weight gain have shown more than minimal effects; a few supplementation studies have reported increased weight gain of small magnitude, and many trials have had no, or hardly any impact. If, under nonfamine conditions, there is an effect of dietary supplementation on weight gain, it seems to be confined to supplementation begun during the first trimester of p r e g n a n ~ y . ~ ~ . ~ ’

Birth Weight and Maternal Weight, Weight Gain, and Body Composition Using sophisticated measures of body composition, Lederman et al.42 found that the component of maternal weight gain correlated with birth weight was not fat, but water (i.e., most likely increased plasma volume). This is consistent with many reports that third trimester reduction in maternal peripheral fat stores is associated with accelerated fetal growth. This is likely at least partly a function of diet. In the longitudinal study of the National WIC (Women, Infants, and Children) Evaluation,4346 supplemented women had significantly thinner triceps and subscapular skinfold thicknesses (adjusted for early pregnancy values; both P <O.OO 1) in late pregnancy compared with comparable women not receiving WIC benefits. Thus, WIC participation led to increased energy and micronutri-

maternal nutrition -+ maternal weight gain --t infant birth weight is not sustained by available evidence except under extreme nutritional deprivation.” He estimated that the threshold at which famine conditions are operative is at energy intakes below 1750 kcal(7.326 MJ)/day. Ofthe other six studies, the pathway from diet to birth weight via weight gain was corroborated in only one, and in that one, only for male ~ffspring.~’ Susser concluded, “In terms of birth weight, maternal diet and nutrition deserve more attention than does maternal weight gain.”

Maternal Weight (and Weight Gain) and Perinatal Death and Congenital Anomaly Higher maternal BMI at conception is strongly associated with higher birth weight, lower rates of intrauterine growth retardation (IUGR), and increased fetal death The relationship between maternal BMI at conception and perinatal mortality is monotonic, i.e., there was no obvious threshold. In addition, Shaw et al.’) and Werler et al.54 found strong relationships of maternal obesity to rates of neural tube defect. Risks for neural tube defect did not rise gradually, but seemed to be confined to very high weights (greater than 80 kg in the women studied by Werler et al. and greater than 100 kg in women studied by Shaw et al.). The same pattern was probably true in an earlier study as

Increased birth weight, presumably owing to maternal nutritional status, cannot be assumed to be an inter- changeable surrogate for better infant health and survival.

Lessons from the Diabetes Literature

Birth weights of infants of women with gestational diabetes mellitus (GDM) are strongly correlated with blood glucose levels.56 Birth weight reflects level of diabetic control. Among women under tightest control (average glucose 437 mg/dL), the rate of IUGR was 20%, 2.5 times higher than infants of other women with GDM, and double that of nondiabetic controls.57 The rate of large-for-gestational-age births among these women with GDM under tightest control was 1.4%, 21 times lower than among women with high blood glucose levels. Thus, the rate of fetal growth appears not to be a hnction of GDM per se, but rather of the level of circulating glucose to which the fetus is exposed. Sermer et al.58 did routine glucose chal- lenge and tolerance tests on 3637 nondiabetic pregnant Toronto women at 26 and 28 weeks of gestation, respectively. Fasting blood sugar was very strongly and significantly associated with the risk for birth weight greater than 4000 g.

Birth Weight and Diet ent intake, only marginal change in weight gain, and lower maternal peripheral fat stores.

Susser3’ reviewed seven sets of studies of nutrition during pregnancy and concluded, “The causal sequence

Birth weight is exponentially related to perinatal sur- and given the difficulty of directly studying nu-

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trition and perinatal survival, birth weight has been used as a surrogate for viability. Observational studies of diet and birth weight have generated uncertain and often con- tradictory results; this review only deals with intervention studies.

Intervention Studies of Dietary Advice and Birth Weight Most studies published before the mid 1980s were previously reviewed in detai1.61*62 Sweeney et al.63 randomly assigned 22 women to counseling by the “Higgins method.” The study group reported eating an average of 2563 kcal and 92 grams of proteidday versus 2373 kcal and 8 1 grams/day for 2 1 controls (not statistically significant but of appreciable magnitude). Maternal weight gain, birth weight, and duration of gestation were said not to differ.

Whereas Bruce and Tchabo@ observed higher total weight gain and birth weight in 57 nutritionally counseled underweight pregnant women compared with 52 controls recruited after those counseled, their results were confounded by the 2-week longer duration of gestation of the counseled women. This suggests that late registrants with early deliveries might have been systematically excluded from the treatment group.

Tharp et al.34 recruited 84 women from two prenatal clinics, who were given intense nutritional advice aimed to raise weight gain, and 147 controls from a third prenatal clinic. There was no overall impact on weight gain; birth length was 0.8 cm shorter (P <0.05), and birth weights were 79 g lower in those counseled (results not significant). However, the rate of breastfeeding was almost three times higher at 4-6 weeks postpartum in subjects (29.8%) versus controls (1 0.9%, P <0.05).

Dietary Supplementation Studies During Pregnancy Aimed to Accelerate Fetal Growth Self-selected levels of supplementation: the Guatemalan four-village study. Four villages were randomly allocated to either an energy-dense supplement (Atole), which contained protein, or a sweetened clear liquid without protein (Fresco).65 Women who consumed more than 20,000 kcals during pregnancy from either supplement were compared with those who did not. There was an approximate 1 10 g difference in birth weight favoring those with the higher level of supplementation. Not only was there self-selec- tion of intake level, but the 20,000 kcal criterion leads to a confounding bias in favor ofthose with high intake. Given longer duration of pregnancy, there is greater opportunity to ingest more total calories, and an unknown amount of the observed difference in birth weight was almost surely due, not to dietary intake, but to this confounding.

Another paper from this study related supplementation during two pregnancies and the interpartum period to

birth weight in the second pregnancy.” It offered the hypothesis that feeding during an index pregnancy may not be enough to appreciably affect fetal growth (which was also implicit in the design of a feeding experiment by Chow et al. in T a i ~ a n ) . ~ ’ . ~ ~ The hypothesis that feeding in only one pregnancy is not enough to overcome past malnutrition implies that diet in the first pregnancy should not matter much, and that women who were well supplemented in both the interpregnancy interval and second pregnancy should have done markedly better in the second pregnancy. This is not what happened. Whereas such women who were poorly supplemented in the first pregnancy did have infants who were 249 g heavier in the second, those who were well supplemented throughout had infants who were 89 g lighter in the second pregnancy. This latter finding directly contradicts the investigator’s hypothesis. When the authors tried to compare results by rate of supplementation, rather than with total amount of supplementation (very likely confounded), they lost 42% of their subjects with low intake during the first pregnancy because of unknown duration of gestation. Thus, an analysis of the earlier data from this study unconfounded by duration of gestation is probably impossible because of insufficient data.

Studies in which the decision to supplement was not under the subjects ’ control. Most important studies published by the mid- 1980s have been reviewed in detail else- where.6‘,62

The Montreal Diet Dispensary (the “Higgins Method”) was a large retrospective study using matched controls. The impact of the dietary program of the Montreal Diet Dispensary (MDD), under the direction of the late Agnes Higgins, was evaluated in a retrospective matched- pair cohort study.69 This intensive program of dietary education and (for three-quarters of enrollees) provision of milk, eggs, and oranges, was associated with a statistically significant increase in birth weight of 40 g. Effects were higher in first births, and declined with rising parity. Effects on weight gain, duration of gestation, and perinatal mortality were small and not statistically significant.

Higgins et al.’O compared the outcome of pregnancy among 552 multiparous women enrolled in the MDD with that of one of their prior pregnancies. The overall impact on birth weight (adjusted for parity and sex) in the “effectiveness” (i.e., including all subjects) analysis was estimated as 107 g (P 50.01). The “efficacy” analysis, in which only high compliers were included, was confounded by duration of gestation: women were only included in this analysis if they had a minimum of four sessions with the MDD dietitian, and women delivering prematurely were thus systematically underrepresented by this criterion, as were their low-birth-weight infants. This bias was obvious for program effects on birth weight among women with “stress conditions:” 107 g in the effectiveness analy-

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sis, but almost three times as high, 3 19 g, in the efficacy analysis. The entire effect on perinatal survival was attributable to these women with “stress conditions.” The likely systematic exclusion of shorter durations of gestation in the efficacy analysis dramatically increased apparent program effects. The “effectiveness” analysis is also open to question because of strong possibility of referral bias (higher likelihood of assignment to the MDD if there were problems during the previous pregnancy).

Dubois et al.7’ did another retrospective matched-pair analysis of 1203 adolescent pregnant women served by the MDD between 198 1 and 199 1. The (adjusted) odds ratios for rates of low birth weight, very low birth weight, preterm delivery, and the effect of greatest magnitude- frequency of very preterm delivery-were all significantly in favor of the intervention group. The result for birth weight, a nonsignificant mean difference of 46g (with adjustment this rose to 55 g [P <0.05]) to the advantage of the intervention group was congruent with the earlier matched-control study.69 One of the greatest effects of the program was on the rate of very preterm delivery (2.3% versus 5.1%). This dramatic estimate actually casts doubt on these results because it is more consistent with poor matching than a biologic effect. Kramer,72 in his systematic review of controlled trials of balanced energy and protein supplementation during pregnancy, concluded, “No significant effects were detected on [rate of] preterm birth.” Because women receiving MDD care had to be registered early enough to receive care, and controls did not, it is likely that women registering late for care, or even coming to the hospital in labor, were included in the control group, but could not have received MDD services. As Terris and G l a ~ s e r ~ ~ said, “. . .The relationship of prematurity to initiation of prenatal care.. .was found to be due largely to the fact that early birth prevents the initiation of prenatal care instead of vice versa.” Without adjusting these results for duration of gestation at registration for prenatal care, it is unclear how much of the effect was due to improper matching of controls.

Viegas et a1.74*75 performed two small supplementation trials among women of South Asian origin in Birmingham, England. In the first, the control group had higher mean birth weight than those who received energy supplementation alone (30 g) or those who received protein and energy supplements (40 g).74 In the second, women were stratified by amount of change in triceps skinfold thickness between 20 and 28 weeks of gestation.75 The authors found only one significant difference in outcome: the 14 women who had low prior triceps skinfold thickness gain and received a high protein-energy supplement had infants with mean birth weight of 3340 g compared with 30 10 g for controls and 2950 g for those supplemented with energy alone. The birth weights in the groups with high prior triceps gain were 2980 (energy + protein supplemen-

tation), 3 160 (controls), and 3 1 10 g (only energy supplementation): these results ran counter to their hypothesis that women with high gain should have had bigger babies. This pattern is more consistent with random varia- tion than a coherent treatment effect.

Atton and W a t n e ~ ~ ~ replicated the design of Viegas et al.,75 randomly assigning 62 women with low mean triceps skinfold thickness gain from 18 to 28 weeks pregnancy to a high-energy dietary supplement of moderate protein density from 28 weeks to term. Babies of supplemented women were 90 g lighter than those of unsupplemented control women. Among Asian women, those with high skinfold thickness gain had babies 100 g lighter than supplemented women, and 150 g lighter than unsupplemented women. Low midtrimester triceps gain was associated with higher birth weight (consistent with most other studies; see above), and supplementation did not raise, and might have lowered, birth weight.

The U.S. WIC Program (The Special Supplemental Food Program for Women, Infants, and Children) began in 1973; it supplies food, advice, and coordination of health services to low-income pregnant and postpartum women and preschool children up to the age of 5 who meet one of several criteria of nutritional risk. The program served approximately 7.2 million clients, and was funded with more than four billion dollars in fiscal year 200 1. Approximately one-third ofAmerican pregnant women meet the income- eligibility criterion (<185% of the federally defined pov- erty level). It was estimated that in 1980,40% of income- eligible women were enrolled in the program;26 this number has now risen to approximately 60%. The benefits are substantial: for the pregnant women they come to approximately 800 kcal/day of dairy products, cereals, vitamin C- rich juices, and several miscellaneous items, such as eggs, peanut butter, and lentils. The program is carried out by health professionals, usually nutritionists or dietitians.

In 1978, when the U.S. Congress reauthorized the WIC program, it mandated that a thorough evaluation of the program’s health effects be carried out. The results of that evaluation were presented in a journal ~ u p p l e m e n t . ~ ~ . ~ ~ - 46*77378 One of the four studies in the National WIC Evalua- tion related WIC benefits to perinatal outcome in more than 13 million births in 1322 counties in 19 states during the first decade of the WIC program;24 another was a prospective controlled study of more than 7000 children born to income-eligible women, in 58 randomly selected ar- e a ~ . ~ * ~ ~ In the former, rates of receipt of WIC benefits within counties were related to countywide rates of change in perinatal outcome, specified from linked birth and death certificates, with each county serving as its own control (an “ecologic” level study). With some algebraic manipulation, the authors estimated the effect of WIC service to an average beneficiary and found significant relationships between WIC service and the following outcomes: early

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registration for prenatal care (an increase of 4.1 YO), higher rates of adequate number of prenatal visits (5.0%), increased mean duration of gestation (0.2 weeks), reduction in rates of preterm delivery (0.9%), higher mean birth weight (22.7 g), and perhaps most importantly, reduction in late fetal death rate (from 6.2 1 to 4.09/1000). The magnitude of reduction in neonatal death rate (from 10.59 to 8.30/1000) was comparable with that of fetal death rate, but was not statistically significant.

In order to study outcomes other than those included on birth certificates, a prospective study was done with a large nationwide representative sample of low-income pregnant ~ o m e n . ~ ~ . ~ ~ It found that maternal diets of women enrolled in WIC were increased in energy and in nutrient density, that small deficits in weight gain were made up, and that late pregnancy fat deposition was markedly lowered by WIC participation. Further, whereas birth weight and duration of gestation were not significantly affected by WIC, infant head circumference was (P<O.Ol). As part of the evaluation, some 85 past studies of effects of the WIC program-published and unpublished-were reviewed. Those relevant to this review and published before 1997 were presented in and were later summa- rized.62 One study since is noteworthy. Moss and Carver79 linked birth and death records from the 1988 National Maternal and Infant Health Survey, and found a reduction of between 40% and 50% associated with prenatal WIC benefits in what they called endogenous (i.e., prenatal) causes of infant death, and nearly as great reductions in exogenous (i.e., postnatal) causes of infant death. The nonresponse rate of 38% for the follow-back portion of the infant death cohort (in which the key study data were collected) was high, however, and women answering a questionnaire about an infant who died may have been less motivated or able to specify what services they received during pregnancy than those with a live-born infant.

Many earlier studies done in developing countries were discussed in detail previously.62 (The small study in three Indian villages of Devadas et aLS0 was not included in the previous review.)

The studies in the Gambia by Prentice and col- l e a g u e ~ ~ ~ - ~ ~ are important for several reasons. First, nutritional supplementation was added to a base of preexistent health services. Lamb et aLS1 found that, after basic health services had been introduced, “almost all the described improvements in mortality pre-date” the initiation of prenatal maternal nutritional supplementation. Second, the studies took place in conditions of seasonal famine, and may therefore be similar to those of wartime famine.

The first study was a comparison of outcome before and after the initiation of nutritional supplementation in one village that was first reported in 1 983,37 and was later extended and r e a n a l y ~ e d . ~ ~ The authors concluded that

supplements had powerful effects on birth weight during the wet (or hunger) season under conditions of heavy physical labor and shortage of food, but were basically irrelevant during the dry season, when these stresses were not so severe. The meaning of these studies is clouded by changing and partially circular definitions of season. In the first paper,37 the definition was, “...the dry season (February-June). . .the wet season (July-January). . .” In the second,38 the authors said, “...long, hot, dry season (November-June) and a discrete wet season (July-Octo- ber).” In the 1997 p ~ b l i c a t i o n , ~ ~ the definition of the wet season was changed again, this time lasting from June to October and the dry season lasting November to May. The authors stated in this last paper, “. . .the hungry season was defined as June to October on the basis of envi- ronmental and nutritional events and because post hoc analysis yielded the greatest discrimination between hungry and harvest season events (emphasis added).” In fact, births during the key month of June, previously in the dry season, contributed approximately 40% of the total effect of supplements on birth weight during the 5- month wet season. Thus, the definition of season is not only different in each of the three published analyses, but it has been adjusted to fit the results of the study.

In the first study, control birth weights were mea- sured for 4 years among all births in one village. In the next 2 years of supplementation, supplemented women had infants of higher birth weight compared with prior years, but only during the wet (hungry) season.37 The investigators interpreted this result to mean that only with the additional stress of greater field work and lower food supplies could any effect of supplementation be detected. The dietary data they presented cast some doubt on this interpretation. During the control years (before supplementation), daily mean energy intake (calculated from their paper) during the wet season was almost identical to that in the dry season (1464 versus 1468 kcal/day) and the incremental intake from supplementation was also the same across seasons (430 kcal/day during the wet season and 433 kcallday during the dry season). Thus, if these data were correct, the only factor that could have varied was physical labor. In addition, their logic predicts that supplementation during the wet season should bring birth weights up to levels already prevailing during the dry season, but not higher. In fact, what was observed was that supplemented women delivering in the wet season had infants with adjusted birth weights considerably higher than during the dry season. The second study was a large controlled trial with randomization of 28 villages.39 Pregnant women received either 4.3 MJ/day (=lo00 kcal) or no prenatal supplements. There were significant effects on maternal weight gain, birth weight, infant length, head circumference, and perinatal and infant survival. The effects w,ere not confined to the “hungry” or wet season. The

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effects? of supplementation on birth weight after adjustment for several possibly confounding variables were 94 g ( P <0.01) during the dry season and 201 g ( P <0.001) during the wet season; head circumference was increased 0.25 cm(P<0.05)inthedryseasonand0.39cm (P<O.OI)in the wet season. Whereas supplementation lowered the odds ratios (OR) for low birth weight significantly, this effect was not different across seasons (OR for both = 0.61 ; P <O.OO I ) . The effect on the OR for risk of stillbirth was dramatic (OR = 0.47, P <0.05); that for neonatal death, although of considerable magnitude (OR = 0.64), was not significant. The only caveat about the validity of the impact on survival might be that, somehow, the presence of the research staff in the test villages might have also improved obstetric services at the time of labor because of the availability of staff, or transport, etc.

Comparison of the results on mortality with those of Lamb et a1.8i 13 years earlier, prior to nutritional intervention, are shown in Table 1. These results suggest that the effects of supplementation were much greater on stillbirth than neonatal mortality rates: the rates in the trial were no lower than those achieved more than a decade earlier by health care alone. Further, it is unlikely that such good results could have been achieved from the nutritional intervention in the absence of adequate health services.82

In a small study in rural Thailand, Tontisirin et al.83 assigned by rotation a total of 43 rural Thai women who were at approximately 28 weeks gestation to one of two dietary supplements, or to a control group. Each of the supplements supplied between 400 and 560 kcal and 16.6 to 20.1 g proteidday. Weight gain and arm circumference were significantly accelerated by both supplements; only one supplemented group had significantly increased triceps skinfold thickness. Birth weight, but not length or head circumference, was significantly greater in both treatment groups than in controls (236 and 25 1 g). The control group’s mean birth weight was suspiciously low for healthy nonsmokers (2853 g), however, especially given the mean maternal heights ( 1 52.1 cm) and mean weight at the onset ofthe experiment (53.9 kg).

In a trial of two forms of supplements among poor women in Santiago, Mardones-Santander et aLS4 observed

what was, in effect, a strong confirmation of the toxicity of high-density protein supplements during pregnancy. They alternately assigned 1 135 poor underweight Chilean women registering for prenatal care before the 20th week of gestation to either a powdered milk formula that supplied 498 kcal/day, 22.4% of which was derived from protein, or a commercial formula that supplied 470 kcal/day, 12.3% as protein calories (final n = 391 in both groups). Both maternal weight gains (0.98 kg; P<0.05) and birth weights (73 g; P <0.05) were significantly lower in the high-protein group. Perinatal survival was not mentioned.

Kusin and colleagues performed a randomized trial of dietary supplementation in three, then two, villages in rural East Java.85 The final analysis included 272 third trimester pregnant women who received an high-energy supplement (HE), which provided 465 kcal/day and 7.1 g ofprotein, 265 (or 266) women who received 52 kcal/day and 6.2 g of protein (low energy, LE), and 205 (or 204) noncompliers, who were drawn from both treatment groups. The LE supplement contained 6.2 g/day of protein, which supplied 48% of its 52 kcal. The authors based their central analyses of the effect of supplementation on birth weight on the number of days of supplementation. This measure is confounded by duration of gestation (if a woman had a longer duration of pregnancy, independent of any treatment effect, she also had greater opportunity to ingest more days of supplement, and would have had a bigger baby, totally independent of nutrition).

A 1980 publication reported that high-density protein supplements (more than approximately 20% of calories as protein) in pregnancy were to xi^;^'',^' This then turned out not to be an isolated finding: in a review published 2 years later,62.86 this was found to have been true, but not com- mented upon, in all past trials. Kusin et al.’s LE supplement had the highest protein density (48%) of that in any reported trial. Whereas it only contained 52 kcal/day, in most supplementation trials the mean estimated increment in energy intake was typically about 100 kcal/day, and an increment of 52 kcal/day was probably not trivial. The outcomes of this trial suggested protein toxicity. It was the highest compliers in the LE group that had the lowest maternal weight gains and birth weights, the opposite of

Table 1. Stillbirth and Neonatal Mortality Rates (per 1000 Births) After Initiation of Health Services, and with the Addition of Prenatal Nutritional Supplementation

From earlier reporfsl (health services alone)

From later trial3’ (plus nutritional supplementation)

1974-1975 1976-1977 1978-1979 1980-1981 1982-1983 Control Supplemented Stillbirth 57.5 47.1 46.3 24.5 28.7 24 11 Neonatal 83.7 60.4 48.5 20.1 24.5 40 25

It is not clear whether the multistage analytic model took so-called “design effects” into account, the reduction in statistical power associated with randomization by group rather than by individual.

Nutrition Reviews”, Vol. 59, No. 10 32 1

the expected trend that might be due to confounding by duration of gestation. Therefore, the actual extent of protein toxicity was likely to have been greater than it appears: in spite of the fact that the birth weight results are biased toward a spurious “effect” of higher birth weight with more days of supplementation, in the LE group the high users (90+ daily packets) had infants with lower birth weight than low users by 45 g, and intermediate users (45-89 packets), by 56 g. Further, in the authors’ regression analyses, protein intake, holding energy constant, was associated with significantly lower birth weight. Whereas the units of the regression coefficients were not given, assuming that the unit for protein was gramdday, and for energy, kcal/day, the relationships were +0.24 g birth weight for an increase of one kcal/day, but -0.87 g birth weight for every kcal/day derived from protein. The high users of the LE supplement also had depressed third trimester weight gain (-0.6 kg) compared with low users.

Using unconfounded measures, the project had no significant effect on either maternal weight gain or on birth weight: the HE group had infants with mean birth weight of 2908 g, 40 g less than both the LE group mean and the noncompliers. (No results by “intention to treat” were presented.) No data on the effect of supplementation on perinatal mortality were presented. The authors did not test whether women with low prepregnant BMI responded to the nutritional supplements more vigorously than others, despite strongly advising that supplements should be tar- geted to women with low BMI.

Summary: nutritional supplementation and perinatal outcome. The conclusion of an earlier review62 stated, “attempts at nutritional supplementation, while well-in- tentioned, have not always had the desired effect. First, it is clear that high-density protein supplements are consistently associated with depression, rather than increase, of mean birth weight. Second, although consistent increments (on average = 30-50 g) in mean birth weight have been found in association with programs of aggressive nutritional counseling and/or supplementation with prepara- tions of lower protein density, the magnitude of these increments is nevertheless lower than had been hoped.

“The magnitude of effect was not influenced by whether the entire family was supplemented (as in Bogota4’ and G ~ a t e m a l a ~ ~ ) or only the pregnant woman was supplemented, nor whether supplementation was fit- ted to the individual needs of the recipient (as in MontreaP9 or in the WIC program) or was identical for all those treated. Moreover, effects were remarkably similar in developed and developing societies, with few exceptions that suggested greater effect among the most impover- ished women in developing countries.

“Because the increase in mean birth weight associated with nutritional counseling and supplementation has been relatively small, further trials of these interventions

must concentrate on the subsets of women in which a beneficial effect is most likely to be demonstrated. This notion is supported by the fact that in our New York study, nutritional intervention matched our expectations only among those women who were heavy smokers. Women who are likely to benefit most from dietary supplementation might be identified in a number of ways. Reliance on dietary history alone has been unrewarding.” These conclusions remain valid. What is new is that during intermittent famine, dietary supplements probably do confer appreciable benefit, and that we must abandon birth weight as a surrogate for such benefit.

Conclusions

Maternal Nutrition, Weight, and Weight Gain Except in famine conditions, maternal weight gain during pregnancy has not been demonstrated to increase much when women are given advice to do so, and maternal weight has been shown to be only minimally affected by dietary supplements.

The component of maternal weight gain associated with increased fetal growth is not stored energy, (i.e., fat) but rather water (likely plasma volume).

Decreasing third trimester maternal fat stores are associated with accelerated fetal growth, and improved maternal diets have been shown to lead to decreased maternal fat stores.

Maternal Nutrition, Birth Weight, and Perinatal Mortality Birth weight is strongly associated with maternal nutritional status. Unfortunately, one important index of such nutritional status, weight at conception, although strongly associated with birth weight, is also consistently associated with increased perinatal mortality. Thus, the assumption that any and all nutritional strategies to increase birth weight are beneficial is not true, and birth weight alone is an insufficient index of perinatal well-being.

Further, increases in mean birth weight associated with nutritional counseling andor supplementation with balanced protein-energy supplements in nonfamine conditions have been relatively small, and further trials of these interventions might best concentrate on the subsets of women in which a beneficial effect is most likely to be demonstrated.

Further research should not only pay attention to whether the observed range of increments in birth weight are consistently associated with decreased perinatal morbidity and mortality, but also with improved long-term growth and development of the infant and child. Much larger populations are required to study effects on mortality and careful longitudinal research is essential to under- stand long-term development. Whereas there is obvious

322 Nutrition Reviews”, Vol. 59, No. 10

need of further research into the best means of promoting optimal nutrition in pregnancy, this should not condemn hungry women to wait for the results of more research. They should have access both to adequate amounts of food and to informed, sympathetic care.

We can now define a subset of vulnerable women who are likely to respond to supplementation, and we know with some certainty that birth weight is an incomplete and possibly deceptive index of improved perinatal survival. The evidence for a strategy of feeding before or between pregnancies is fragmentary and relatively unconvincing.

Among poor women worldwide, in both industrial- ized and developing countries, energy supplements during pregnancy that are of low and moderate protein density can raise birth weights. Unlike times of famine, supplementation seems not to be optimal unless started before the beginning of the third trimester. The major negative studies (in East Java, for instancea5) did not start supple- menting until the third trimester.

In the larger and more sophisticated trials, the observed increments in birth weight have been considerably smaller than had been hoped when these studies were first conceived. The typical increments are in the range of 20-50 g, other than in conditions that approximate famine, such as the seasonal deprivation in the Gambia,37-39 during which birth weights may have been raised by as much as 200 g as a result of supplementation. There is urgent need to replicate these results among other populations of poor women in developing countries.

There is repeated and consistent evidence that high- density protein supplements (those in which protein supplies much more than 20% of energy) are toxic: birth weights are consistently lower than those of unsupplemented women. These results may be mediated by the anorectic effect of high-density protein supplements because maternal weight gains are typically also lowered.$

Whereas few studies have been large enough to address the impact of balanced energy and other nutrient supplementation on fetal survival, there does seem to be a consistent pattern of benefit. There is every reason to be skeptical, however, that the effects of dietary supplementation on fetal mortality are mediated entirely by increased birth weight. Other than during famine, there is ethical and scientific need to demonstrate some benefit to macronu- trient supplementation during pregnancy beyond increased birth weight. This is because increased birth weight associated with increased maternal weight at conception is associated with higher perinatal mortality, and nutritionally induced low birth weight not associated with famine seems to not have much demonstrable impact, at least on short-term morbidity or mortality.

The state of research in this field remains discourag-

ingly weak. Further observational studies relating diet to fetal growth should only be undertaken in unusual cir- cumstances where especially warranted. Confounding of the effect of feeding by not correctly dealing with duration of gestation, either in design or analysis, has happened repeatedly, and has led to false claims of impact when none has been proven.

Acknowledgment. This work was supported (in part) by a grant from USAID’s OMNI Research Program through the Human Nutrition Institute of the International Life Sci- ences Institute (ILSI). The opinions expressed herein are those of the author(s) and do not necessarily represent the views of ILSI.

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