title: Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study. The effect of docosahexaenoic acid and folic acid supplementation on placental apoptosis and proliferation. Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth: Pune Maternal Nutrition Study. [Deficiency of folates in pregnancy: effect of supplementary folic acid]. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study The relationship between maternal dietary intake and infant birthweight. A prospective study of micronutrient status in adolescent pregnancy. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy
abstract: OBJECTIVE We evaluated the association between mothers ' use of multivitamin supplements and their infants ' risk for omphalocele , a congenital anomaly of the abdominal wall . Omphalocele can occur in certain multiple congenital anomaly patterns with neural tube defects , for which a protective effect of multivitamins with folic acid has been demonstrated . METHODS We used data from a population -based case-control study of infants born from 1968 - 1980 to mothers residing in metropolitan Atlanta . Case-infants with nonsyndromic omphalocele ( n = 72 ) were actively ascertained from multiple sources . Control-infants ( n = 3029 ) , without birth defects , were selected from birth certificates by stratified r and om sampling . RESULTS Compared with no use in the periconceptional period , periconceptional use of multivitamin supplements ( regular use from 3 months before pregnancy through the first trimester of pregnancy ) was associated with an odds ratio for nonsyndromic omphalocele of 0.4 ( 95 % confidence interval [ CI ] : 0.2 - 1.0 ) . For the subset comprising omphalocele alone or with selected midline defects ( neural tube defects , hypospadias , and bladder/cloacal exstrophy ) , the odds ratio was 0.3 ( 95 % CI : 0.1 - 0.9 ) . These estimates were similar when the reference group also included women who began using multivitamins late in pregnancy ( during the second or third month of pregnancy ) . The small number of participants limited the precision of subgroup analyses and translated into wide confidence intervals that included unity . CONCLUSIONS Periconceptional multivitamin use was associated with a 60 % reduction in the risk for nonsyndromic omphalocele . These findings await replication from additional studies to confirm the findings , generate more precise estimates , and detail possible mechanisms of actions The hypothesis was tested that the additional dietary uptake of n-3 fatty acids , in particular of DHA and 5-methyltetrahydrofolate ( 5-MTHF ) , during the second half of pregnancy would influence proliferation and apoptosis in the full-term human placenta . The diets of pregnant women from Spain ( n 55 ) were supplemented with modified fish oil and /or 5-MTHF or placebo , and assigned in a r and om , double-blind manner to one of the four groups . Immunohistochemistry and immunoblotting were used to detect placental proliferation and apoptosis with monoclonal antibodies for key proteins that reflected the extent of both processes : proliferation cell nuclear antigen ( PCNA ) , p53 , cytokeratin 18 neoepitope . The PCNA level in the fish oil/5-MTHF-treated group was higher by 66 % ( P < 0.05 ) than that of the placebo group , whereas the levels of p53 and cytokeratin 18 neoepitope were unaffected by treatment . PCNA expression was altered only in the trophoblast compartment ( placebo 11.1 ( se 0.5 ) % v. combination 21.5 ( se 1.2 ) % ; P < 0.05 ) , whereas the proportion of nuclei stained in endothelial and other stromal cells was similar in the placebo and combined treatment groups . No correlation was found between fish oil or 5-MTHF supplementation and the levels of the proteins . The present data suggest that supplementation with fish oil and /or 5-MTHF had no effect on the parameters reflecting placental proliferation and apoptosis . A defined combination of DHA and 5-MTHF may , however , affect placental proliferation One third of the Indian babies are of low birth weight ( < 2.5 kg ) , and this is attributed to maternal undernutrition . We therefore examined the relationship between maternal nutrition and birth size in a prospect i ve study of 797 rural Indian women , focusing on macronutrient intakes , dietary quality and micronutrient status . Maternal intakes ( 24-h recall and food frequency question naire ) and erythrocyte folate , serum ferritin and vitamin C concentrations were measured at 18 + /- 2 and 28 + /- 2 wk gestation . Mothers were short ( 151.9 + /- 5.1 cm ) and underweight ( 41.7 + /- 5.1 kg ) and had low energy and protein intakes at 18 wk ( 7.4 + /- 2.1 MJ and 45.4 + /- 14.1 g ) and 28 wk ( 7.0 + /- 2.0 MJ and 43.5 + /- 13.5 g ) of gestation . Mean birth weight and length of term babies were also low ( 2665 + /- 358 g and 47.8 + /- 2.0 cm , respectively ) .  Energy and protein intakes  were not associated with birth size , but higher fat intake at wk 18 was associated with neonatal length ( P < 0.001 ) , birth weight ( P < 0.05 ) and triceps skinfold thickness ( P < 0.05 ) when adjusted for sex , parity and gestation . However , birth size was strongly associated with the consumption of milk at wk 18 ( P < 0.05 ) and of green leafy vegetables ( P < 0.001 ) and fruits ( P < 0.01 ) at wk 28 of gestation even after adjustment for potentially confounding variables . Erythrocyte folate at 28 wk gestation was positively associated with birth weight ( P < 0.001 ) . The lack of association between size at birth and maternal energy and protein intake but strong associations with folate status and with intakes of foods rich in micronutrients suggest that micronutrients may be important limiting factors for fetal growth in this undernourished community Higher folate needs are present during pregnancy , which may lead to tissular deficiency in the mother and to depleted newborn folate reserves . The aim of this work was to assess the prevalence of folate deficiency and to establish the rates of serum and red cell folate in two groups of mothers and newborn infants , one receiving only iron and the other iron and folate during pregnancy .  The rates of serum and red cell folate found at the end of pregnancy were significantly higher in the group which received folate ; however , the percentage of cases with tissular folate deficiency was low in both groups , with no significant difference ( 3.8 % and 1.3 % , respectively ) . These findings , along with the lack of effect of supplemental folate on erythropoiesis , pose some questions on the usefulness of supplemental folate during pregnancy in our country BACKGROUND The risk of recurrent neural-tube defects  is decreased in women who take folic acid or multivitamins containing such during the periconceptional period . The extent to which folic acid supplementation can reduce the first occurrence of defects is not known . METHODS We conducted a r and omized , controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects .  Women planning a pregnancy ( in most cases their first ) were r and omly assigned to receive a single tablet of a vitamin supplement ( containing 12 vitamins , including 0.8 mg of folic acid ; 4 minerals ; and 3 trace elements ) or a trace-element supplement ( containing copper , manganese , zinc , and a very low dose of vitamin C ) daily for at least one month before conception and until the date of the second missed menstrual period or later . RESULTS Pregnancy was confirmed in 4753 women . The outcome of the pregnancy ( whether the fetus or infant had a neural-tube defect or congenital malformation ) was known in 2104 women who received the vitamin supplement and in 2052 who received the trace-element supplement .  Congenital malformations were significantly more prevalent in the group receiving the trace-element supplement than in the vitamin-supplement group ( 22.9 per 1000 vs. 13.3 per 1000 , P = 0.02 ) . There were six cases of neural-tube defects in the group receiving the trace-element supplement , as compared with none in the vitamin-supplement group ( P = 0.029 ) . The prevalence of cleft lip with or without cleft palate was not reduced by periconceptional vitamin supplementation . CONCLUSIONS Periconceptional vitamin use decreases the incidence of a first occurrence of neural-tube defects A r and omised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid ( one of the vitamins in the B group ) or a mixture of seven other vitamins ( A , D , B1,B2,B6,C and nicotinamide ) around the time of conception can prevent neural tube defects ( anencephaly , spina bifida , encephalocele ) . A total of 1817 women at high risk of having a pregnancy with a neural tube defect , because of a previous affected pregnancy , were allocated at r and om to one of four groups -- namely , folic acid , other vitamins , both , or neither .  1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect ; 27 of these had a known neural tube defect , 6 in the folic acid groups and 21 in the two other groups , a 72 % protective effect ( relative risk 0.28 , 95 % confidence interval 0.12 - 0.71 ) . The other vitamins showed no significant protective effect ( relative risk 0.80 , 95 % Cl 0.32 - 1.72 ) . There was no demonstrable harm from the folic acid supplementation , though the ability of the study to detect rare or slight adverse effects was limited . Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy , and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid BACKGROUND Zinc and folate are important for fetal growth . However , the relationship between the dietary intake of these nutrients and pregnancy outcome is not settled . METHODS A prospect i ve study was conducted to ascertain the relationship between  maternal dietary zinc and folate intake  ( n = 1398 ) , serum zinc and folate levels ( n = 289 ) , and infant birthweight .  Twenty-four hour recalls were used to measure energy , zinc , folate and other nutrient intakes at 18 and 30 weeks of gestation . Subjects in the study were offered daily folic acid ( 1.0 mg ) and iron ( 60 mg as ferrous sulfate ) at enrollment . RESULTS Maternal zinc nutriture as assessed by serum and dietary intake was not associated with birthweight or length of gestation . There was a small but significant positive association between maternal folate intake and adjusted infant birthweight ( beta = 0.05 , p = 0.03 ) . The indirect measures of maternal nutritional status including maternal pre-pregnancy weight ( beta = 8.0 , p = 0.0001 ) and weight gain during pregnancy ( beta = 18.1 , p = 0.0001 ) were stronger predictors of adjusted infant birthweight as compared to energy intake and intake of zinc and folate . An increase of 320 , 290 , and 48 g in infant birthweight was associated with the 90th-10th percentile difference for pre-pregnancy weight , weight gain during pregnancy , and folate intake respectively . CONCLUSION These results indicate that pre-pregnancy weight and weight gain during pregnancy are both strong predictors of infant birthweight .  Folate intake , although significantly associated with birthweight , was a weak predictor while maternal intake of zinc and other nutrients was not associated with birthweight BACKGROUND Adolescents are more likely than adults to consume energy-dense , micronutrient-poor diets and to experience adverse pregnancy outcomes . OBJECTIVES The objectives were to assess micronutrient intake  and  blood biomarkers  prospect ively in pregnant adolescents recruited to the About Teenage Eating ( ATE ) Study and to determine associations with pregnancy outcome . DESIGN Pregnant adolescents ( n = 500 ) were recruited from 2 UK inner city population s.  Dietary intake was assessed with three 24-h dietary recalls , and micronutrient status was assessed by measurement of third trimester blood biomarkers . Pregnancy outcomes included small-for-gestational age ( SGA ) birth and preterm delivery . RESULTS Median iron and folate intakes were lower than UK and US recommended amounts . Folate and vitamin B-12 status were lower in smokers , despite no differences in dietary intake . Serum folate was < 7.0 nmol/L in 12 % of subjects , and serum total homocysteine ( tHcy ) was elevated ( > 10 micromol/L ) in 20 % of subjects . Fifty-two percent of the subjects had iron deficiency anemia , and 30 % had serum 25-hydroxyvitamin D concentrations < 25 nmol/L. The incidence of SGA birth was higher in subjects with poorer folate status ( red blood cell folate , P = 0.003 ; serum folate , P = 0.02 ; tHcy , P = 0.01 ; simple regression ) and those with low folate intakes , regardless of the inclusion ( P = 0.021 ) or exclusion ( P = 0.049 ) of intake from supplements ( simple regression ) . Adjustment for confounding variables confirmed the independence of these associations . The risk of SGA birth was also higher in subjects with low food iron intake ( P = 0.049 ) , but not when intake included iron from supplements ( P = 0.21 ) . The risk of SGA birth was lower in subjects with iron deficiency anemia ( P = 0.002 ) . CONCLUSION Poor micronutrient intake and status increase the risk of SGA births in pregnant adolescents We investigated whether a woman 's periconceptional use of a multivitamin containing folic acid was associated with a reduced risk for delivering offspring with a conotruncal heart defect or a limb deficiency .  Data were derived from a population -based case-control study of fetuses and liveborn infants with conotruncal or limb defects among a 1987 - 88 cohort of births in California .  Telephone interviews were conducted with mothers of 207 ( 87.0 % of eligible ) conotruncal cases , 178 ( 82.0 % ) limb defect cases , and of 481 ( 76.2 % ) r and omly selected liveborn nonmalformed control infants . Reduced risks were observed for maternal use of multivitamins containing folic acid from one month before until two months after conception . Odds ratios and 95 % confidence intervals for any compared to no multivitamin use were 0.70 ( 0.46 - 1.1 ) for conotruncal defects and 0.64 ( 0.41 - 1.0 ) for limb defects . Controlling for maternal race/ethnicity , age , education , gravidity , alcohol use , and cigarette use result ed in a further reduction to the odds ratio for conotruncal defects , 0.53 ( 0.34 - 0.85 ) , but not for limb defects . Among non-vitamin using women , consumption of cereal containing folic acid was also associated with reduced risk for both defects . Women who take multivitamins have 30 - 35 % lower risk of delivering offspring with either conotruncal or limb defects . This association may not be attributable to folic acid specifically , but may be a consequence of other multivitamin components , or some unknown behaviors that highly correlate with regular use of a multivitamin . However , should the association prove causal , it offers an important opportunity for preventing thous and s of serious birth defects Folic acid administered to pregnant Bantu , whose diet is low in folate , was associated with a significant reduction in the incidence of prematurity . No such effect could be demonstrated in White patients subsisting on an average Western diet . This suggests that folate deficiency may contribute to the “ pregnancy wastage ” in population s whose dietary folate intake is low , and is a further indication for folic acid supplementation during pregnancy in these groups
target: In contrast , we did not find any beneficial effect of  folate supplementation on placental weight or on length of gestation .
  There is a paucity of well-conducted RCTs investigating the effect of  folate supplementation on health outcomes in pregnancy .
background: The beneficial effect of folic acid supplementation before and shortly after conception is well recognized , whereas the effect of supplementation during the second and third trimesters is controversial and poorly documented .
  Our aims were to systematic ally review r and omized controlled trials ( RCTs ) investigating the effect of folate supplementation on birth weight , placental weight and length of gestation and to assess the dose – response relationship between folate intake ( folic acid plus dietary folate ) and health outcomes .