A prospective study of maternal fatty acids,micronutrients and homocysteine and their association with birth outcome

Our earlier studies both in animals and in humans have indicated that micronutrients (folic acid, vitamin B12) and long‐chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are interlinked in the one‐carbon cycle, which plays an important role in fetal ‘programming’ of adult diseases. The present study examines the levels of maternal and cord plasma fatty acids, maternal folate, vitamin B12 and homocysteine in healthy mothers at various time points during pregnancy and also examine an association between them. A longitudinal study of 106 normal pregnant women was carried out, and maternal blood was collected at three time points, viz., T1 = 16–20th week, T2 = 26–30th week and T3 = at delivery. Cord blood was collected at delivery. Fatty acids were estimated using a gas chromatograph. Levels of folate, vitamin B12 and homocysteine were estimated by the chemiluminescent microparticle immunoassay (CMIA) technology. Maternal plasma folate (P < 0.05), vitamin B12 (P < 0.01) and DHA (P < 0.05) levels were lowest, while maternal homocysteine levels were highest (P < 0.01) at T3. There was a negative association between maternal DHA and homocysteine at T2 (P < 0.05) and T3 (P < 0.01). There was a positive association between plasma DHA in maternal blood at T3 and cord blood. Furthermore, there was a positive association between maternal folate and vitamin B12 at T3 and baby weight, whereas maternal homocysteine at T1 were inversely associated with baby weight at delivery. Our study provides evidence for the associations of folic acid, vitamin B12, homocysteine with DHA and baby weight, suggesting that a balanced dietary supplementation of folate–vitamin B12–DHA during pregnancy may be beneficial.     

Influence of folic acid on birthweight and growth of the erythroblastotic infant. I. Birthweight.

The birthweights of 100 infants with erythroblastosis were carefully matched as to sex, gestational age, and parity with the birthweights of 200 control infants born during the same period. At all gestational ages the average birthweight of the affected infants was below that of the controls, the average reduction being 227 g. The more severely affected infants tended to be at a lower centile for birthweight than were the mildly affected ones. The relationships between maternal serum folate, cord blood serum folate, and centile for birthweight among affected infants were also studied. There was a strong correlation between low maternal serum folate and the incidence of small-for-dates babies among the affected infants. There was also a strong correlation between maternal and cord blood serum folate values. There was a lack of correlation between maternal serum folate and cord blood haemoglobin. It is concluded that infants with erythroblastosis are lighter than controls and that the reason for this may be a shortage of folic acid available for fetal growth.     

Free erythrocyte protoporphyrin as an index of perinatal iron status

The relationship between free erythrocyte protoporphyrin and conventional indices of iron status was studied in 49 mothers and their infants. Maternal venous blood samples were collected at 34 weeks gestation and at delivery. The corresponding infant blood samples were collected from the umbilical cord and at age 6 weeks. In each case free erythrocyte protoporphyrin, serum iron, total iron binding capacity, and serum ferritin were determined. Cord free erythrocyte protoporphyrin was negatively correlated with maternal ferritin at 34 weeks gestation (p = 0.016) and at delivery (p = 0.014), and with transferrin saturation at delivery (p = 0.026). The infants' haemoglobin concentrations at 6 weeks were significantly negatively related to maternal free erythrocyte protoporphyrin at 34 weeks (p = 0.026) and at delivery (p = 0.026). Cord free erythrocyte protoporphyrin is an index of maternal iron status in the last trimester. Maternal free erythrocyte protoporphyrin in the last trimester predicts the magnitude of physiological anaemia of the infant at age 6 weeks.     

Folate,Vitamin B12, Vitamin B6 and homocysteine: impact on pregnancy outcome

Good clinical practice recommends folic acid supplementation 1 month prior to pregnancy and during the first trimester to prevent congenital malformations. However, high rates of fetal growth and development in later pregnancy may increase the demand for folate. Folate and vitamins B12 and B6 are required for DNA synthesis and cell growth, and are involved in homocysteine metabolism. The primary aim of this study was to determine if maternal folate, vitamin B12, vitamin B6 and homocysteine concentrations at 18–20 weeks gestation are associated with subsequent adverse pregnancy outcomes, including pre‐eclampsia and intrauterine growth restriction (IUGR). The secondary aim was to investigate maternal B vitamin concentrations with DNA damage markers in maternal lymphocytes. A prospective observational study was conducted at the Women's and Children's Hospital, Adelaide, South Australia. One hundred and thirty‐seven subjects were identified prior to 20 weeks gestation as at high or low risk for subsequent adverse pregnancy outcome by senior obstetricians. Clinical status, dietary information, circulating micronutrients and genome damage biomarkers were assessed at 18–20 weeks gestation. Women who developed IUGR had reduced red blood cell (RBC) folate (P < 0.001) and increased plasma homocysteine concentrations (P < 0.001) compared with controls. Maternal DNA damage, represented by micronucleus frequency and nucleoplasmic bridges in lymphocytes, was positively correlated with homocysteine (r = 0.179, P = 0.038 and r = 0.171, P = 0.047, respectively). Multivariate regression analysis revealed RBC folate was a strong predictor of IUGR (P = 0.006). This study suggests that low maternal RBC folate and high homocysteine values in mid pregnancy are associated with subsequent reduced fetal growth.     

Transfer of antibodies across the placenta and in breast milk from mothers on intravenous immunoglobulin

We studied the levels of immunoglobulins in colostrum, milk and sera from two common variable immunodeficiency (CVID) mothers (M1 and M2), and in sera from their newborn infants. During pregnancy they continued intravenous immunoglobulin therapy (IVIG). Antibody levels from maternal and cord blood collected at delivery and colostrum and milk, collected on the 3rd and 7th post‐partum days, respectively, were analyzed. Although cord/maternal blood ratios of total immunoglobulins and subclasses, as well as specific antibodies differed between M1 and M2, both showed good placental transfer of anti‐protein and anti‐polysaccharide antibodies, despite lower cord/maternal blood ratios in M2. Anti‐Streptococcus pneumoniae antibody avidity indexes were similar between paired maternal and cord serum. Both mothers’ colostrum and milk samples showed only traces of IgA, and IgM and IgG levels in colostrum were within normal range in M1, whereas M2 presented elevated IgG and low IgM levels, when compared with healthy mothers. The study of colostrum and milk activity showed that they strongly inhibited enteropathogenic Escherichia coli adhesion in vitro. CVID patients must be informed about the relevance of regular IVIG administration during pregnancy, not only for their own health but also for their immune immature offspring. Breast‐feeding should be encouraged as colostra from these CVID patients strongly inhibited E. coli adhesion to human epithelial cells thus providing immunological protection plus nutritional and psychological benefits for the infant.     

Folate and intrauterine growth retardation

The objectives of this case-control study were to compare the levels of folate in cord and maternal blood of 315 mothers who had intrauterine growth-retarded (IUGR) babies and 321 mothers who had appropriate-for-gestational-age (AGA) babies, to evaluate the correlation between cord and maternal folate and to assess the prevalence of folate deficiency. Mothers were recruited from the four largest hospitals in Campinas city, south-east Brazil. The gestational ages of the newborns were evaluated by the Capurro method. They were classified as being IUGR according to the Lubchenco birthweight-for-gestational-age standard. Red blood cell (RBC) folate was measured by radio-immunoassay. Slightly more IUGR (25.7%) than AGA babies (19.9%) had cord folate levels < or = 226.5 nmol/l (100 ng/ml) (p = 0.05) and similar percentages of IUGR (32.1%) and AGA (29.9%) mothers had folate levels < or = 226.5 nmol/l. Mean cord folate levels in IUGR and AGA babies were 10% higher than mean folate levels in the two groups of mothers (p < 0.001). There were weak correlations between maternal and cord folate in IUGR (r = 0.31) and AGA (r = 0.35) (p < 0.001) mother/baby groups. In this population, 35% of mothers were folate-deficient although it was not associated with IUGR. Nevertheless, it would be important to give Brazilian women folate tablets during pregnancy and to investigate the effect on concentrations of homocysteine and on the prevalence of birth defects.     

Hematological parameters and cobalamin status in infants born to smoking mothers

Hematological parameters, serum cobalamin and folate levels, and the concentrations of the functional markers plasma methylmalonic acid and total homocysteine were determined in 173 newborns and 46 infants at 6 weeks to see whether maternal smoking influences the hematological parameters and the vitamin status of the newborn. At birth, there was a strong inverse correlation between the number of cigarettes smoked per day during pregnancy and red blood cell count (r = -0.56, p = 0.001) and hemoglobin level (r = -0.52, p = 0.003) in the newborns. Neonates born to smoking mothers had lower red blood cell counts and lower hemoglobin and serum cobalamin levels as compared with infants born to nonsmoking mothers. At 6 weeks, maternal smoking significantly predicted the methylmalonic acid and total homocysteine levels, suggesting an influence from smoking on the cobalamin function in these infants.     

The effects of a lipid‐based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron,copper, and zinc in milk from HIV‐infected Malawian mothers and associations with maternal and infant biomarkers

We evaluated effects of antiretroviral (ARV) therapy and lipid‐based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV‐infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post‐partum and blood during pregnancy (≤30 weeks gestation) were collected from 535 mothers/infant‐pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post‐partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80–90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1–19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = ?.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11–.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal α‐1‐acid glycoprotein and C‐reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation.     

母婴因素对脐血CD34+造血干/祖细胞的影响

目的 比较不同母婴因素与脐血有核细胞总数及CD34⁺造血干/祖细胞数量的关系,为脐血库合理选择脐血提供参考。方法 前瞻性收集130例2019年6月至2020年1月期间于大连市妇女儿童医疗中心分娩的新生儿脐血标本,男女比例为1：1。收集围生期相关信息：孕母年龄及血型,有/无妊娠糖尿病、妊娠高血压,妊娠方式、分娩方式、单胎/双胎,新生儿体重、性别、生后Apgar评分,以及胎盘、羊水、脐带情况。结果 根据孕母血型、妊娠糖尿病、妊娠高血压、妊娠方式、分娩方式、单胎/双胎,新生儿性别、生后Apgar评分,胎盘形态、羊水胎粪污染、脐带绕颈等情况进行分组,组间比较脐血有核细胞总数及CD34⁺细胞计数差异均无统计学意义（P > 0.05）。孕母年龄、新生儿体重与脐血有核细胞总数无相关性（P > 0.05）,新生儿体重与CD34⁺细胞计数无相关性（P > 0.05）,孕母年龄与CD34⁺细胞计数呈正相关（P < 0.05）。结论 脐血中CD34⁺细胞数量随孕母年龄增大而增多,故脐血库在筛选脐血时,同等条件下可以选择年龄偏大的孕妇。     

Gene-Environment Interactions and the Risk of Childhood Acute Lymphoblastic Leukemia: Exploring the Role of Maternal Folate Genes and Folic Acid Fortification

Few studies have evaluated the interaction of folic acid fortification and folate metabolic genes on the risk of childhood acute lymphoblastic leukemia (ALL). Because folate status is influenced by both intake and genetic variation, the objective of this study was to explore maternal folate metabolic gene-folic acid fortification interactions and the risk of childhood ALL. The study population consisted of 120 ALL case-parent triads recruited from Texas Children's Cancer Center between 2003 and 2010. For this analysis, we focused on 13 maternal single nucleotide polymorphisms (SNPs) in 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Prefortification was defined as delivery before January 1997 and postfortification as delivery in or after January 1997. We used a two-step approach to evaluate gene-environment interactions. First, a case-only approach was used, as this design provides greater power in the assessment of gene-environment interactions compared to other approaches. Second, we confirmed all statistically significant interactions using a log-linear approach among case-parent triads. Only one of 13 interactions evaluated was confirmed in step 2. Specifically, mothers with the minor allele of MTR rs1804742 and who delivered during the prefortification period were at a greater risk of having a child with ALL (OR = 1.54, 95% CI: 0.82–2.88), compared to those mothers who delivered during the postfortification period (OR = 0.81, 95% CI: 0.22–2.99, P for interaction = .03). In one of the few studies to evaluate maternal folate metabolic genotype-folic acid interactions, we found limited evidence that the maternal MTR rs1804742 appeared to interact with higher folic acid levels to influence childhood ALL risk.     

Relation between prenatal maternal blood pressure and infant irritability

Chisholm et al. [4], using samples of Navajo and Malaysian newborns, found a significant positive relation between maternal normotensive blood pressures during the second trimester of pregnancy and at delivery and infant irritability in response to the Brazelton Examination. Measuring spontaneous crying with an electronic activity monitor and using a white middle-class American population, this relation was replicated for mothers with normotensive blood pressures during the third trimester of pregnancy. The combined findings of the 3 studies seem to suggest that maternal blood pressure in the latter part of pregnancy, even when within normal limits, is a factor in how irritable normal newborn infants are.     

Serum amino acid concentrations during pregnancy of women heterozygous for phenylketonuria.

Increased concentrations of phenylalanine were found in blood specimens from pregnant women who were heterozygous for phenylketonuria, but the concentration differences between normal controls, nonpregnant heterozygous, and pregnant heterozygous, and pregnant heterozygous women were small. Phenylalanine concentrations in cord blood were in the same range as in maternal blood at time of delivery. Phenylalanie concentrations in the carrier do not rise sufficiently during pregnancy to harm the infant in utero.     

Fetomaternal therapeutic follow-up of spiramycin during pregnancy

In the preventive treatment of congenital toxoplasmosis it is admitted that spiramycin is concentrated in the placenta and crosses the placental barrier at the end of pregnancy. However, little is known about its entry in the fetal circulation. We studied fetal spiramycin blood levels during the 2nd and 3rd trimesters of pregnancy in women who, having presented with toxoplasmosis during the 1st trimester, had been given spiramycin until delivery. Microbiological titrations of spiramycin were performed--in the maternal blood at the onset of treatment, at the time of fetal blood sampling and during delivery), in the fetal blood at the time of prenatal diagnosis of toxoplasmosis, in cord blood and placenta at birth. We were able to confirm transplacental crossing of spiramycin. Fetal blood levels during the 2nd trimester were about 47% of the maternal ones and there was no correlation between maternal and fetal levels. Levels at birth showed that (1) there was no accumulation in the course of treatment, (2) spiramycin was concentrated in placenta and (3) there was a correlation between fetal and maternal levels during the 3rd trimester.     

Fatty acid compositions of colostrum,cord blood,maternal blood and major infant formulas in Japan

Lipid profiles in colostrum, cord blood, maternal blood and major infant formulas in Japan were analyzed. In the first part of the study, colostrum obtained from 36 normal delivery women and six kinds of infant formulas provided by three major milk companies were analyzed for their fatty acid composition using capillary gas-lipid chromatography. Although enriched with docosahexaenoic acid (DHA), the percent composition of DHA in the six infant formulas (0.15–0.21%) was significantly lower than that in the colostrum (1.1 ± 0.54). Arachidonic acid (AA) and eicosapentaenoic acid (EPA) were present in the colostrum but not detectable in the infant formulas. It is recommended that although the exact amount of specific fatty acids needed in the infant diet was not completely known, to be as close as possible to natural breast milk, the level of DHA, EPA and AA should be raised in the infant formulas. In the second part of the study, 19 pairs of maternal and cord blood were analyzed for their lipid profile. All samples were from normal vaginal delivery. The measurement of cholesterol, triglycerides, phospholipids and free fatty acids was performed with commercially available enzymatic methods on an automated discrete random access analyzer. Total fatty acid was determined as described in the first part of the study. The results were analyzed with Spearman's rank correlation coefficient. No correlation could be found between maternal and fetal concentrations of cholesterol, triglycerides, phospholipids or total fatty acids. Correlation could be found in non-esterified fatty acids, in palmitic acids, and oleic acid levels. It was concluded that the lipid transport and metabolism in the fetal-placenta unit is complex and further delicate investigation is required.     

New England Maternal PKU Project: prospective study of untreated and treated pregnancies and their outcomes

Four women with classic phenylketonuria (blood phenylalanine greater than 1200 mumol/L) were given a phenylalanine-restricted diet; three also received L-tyrosine supplements. Biochemical measures of nutrition were normal except for iron deficiency anemia, and in one woman folate deficiency. One pregnancy in which treatment began before conception and another treated from 8 weeks gestation, both with blood phenylalanine levels maintained at 120 to 730 mumol/L, resulted in normal newborn infants whose postnatal growth and development have also been normal. A third pregnancy, treated from 6 gestational weeks, was marked by poor dietary compliance until the middle of the second trimester; fetal microcephaly was identified by ultrasonography at 28 weeks but not at 21 weeks. The child has microcephaly and motor delay. The fourth pregnancy, not treated until the third trimester, produced a child with microcephaly, mental retardation, hyperactivity, and neurologic deficits. It is likely that fetal damage from maternal phenylketonuria can be largely and perhaps entirely prevented by dietary therapy, but therapy must begin before conception for the best chance of a normal infant.     

Decrease in birth weight in relation to maternal bone-lead burden

OBJECTIVES: Birth weight predicts infant survival, growth, and development. Previous research suggests that low levels of fetal lead exposure, as estimated by umbilical cord blood-lead levels at birth, may have an adverse effect on birth weight. This report examines the relationship of lead levels in cord blood and maternal bone to birth weight. METHODS: Umbilical cord and maternal venous blood samples and anthropometric and sociodemographic data were obtained at delivery and 1-month postpartum. Blood-lead levels were analyzed by atomic absorption spectrophotometry. Maternal tibia and patella lead levels were determined at 1-month postpartum with use of a spot-source 109Cd K-X-ray fluorescence instrument. The relationship between birth weight and lead burden was evaluated by multiple regression with control of known determinants of size at birth. RESULTS: Data on all variables of interest were obtained for 272 mother-infant pairs. After adjustment for other determinants of birth weight, tibia lead was the only lead biomarker clearly related to birth weight. The decline in birth weight associated to increments in tibia lead was nonlinear and accelerated at the highest tibia lead quartile. In the upper quartile, neonates were on average, 156 grams lighter than those in the lowest quartile. Other significant birth weight predictors included maternal nutritional status, parity, education, gestational age, and smoking during pregnancy. CONCLUSIONS: Our results indicate that bone-lead burden is inversely related to birth weight. Taken together with other research indicating that lead can mobilize from bone into plasma without detectable changes in whole blood lead, these findings suggest that bone lead might be a better biomarker than blood lead. Because lead remains in bone for years to decades, mobilization of bone lead during pregnancy may pose a significant fetal exposure with health consequences, long after maternal external lead exposure has declined.     

Fetal iron status in maternal anemia

Hemoglobin, serum iron, transferrin saturation and ferritin were measured on paired maternal and cord blood samples in 54 anemic (hemoglobin < 110 g/L) and 22 non-anemic (hemoglobin ≥ 110 g/L) pregnant women at term gestation. The levels of hemoglobin, serum iron, transferrin saturation and ferritin were significantly low in the cord blood of anemic women, suggesting that iron supply to the fetus was reduced in maternal anemia. The linear relationships of these parameters with both maternal hemoglobin and maternal serum ferritin indicated that the fetus extracted iron in amounts proportional to the levels available in the mother. Infants of mothers with moderate and severe anemia had significantly lower cord serum ferritin levels and hence poor iron stores at birth. It is concluded that iron deficiency anemia during pregnancy adversely affects the iron endowment of the infant at birth.     

Folic acid supplementation in low birth weight infants.

Low birth weight infants (246) entered a trial to folic acid supplementation from 3 weeks to 12 months of age. The folic acid group had significantly higher mean hemoglobin levels at 6 and 9 months of age but the differences were only about 0.5 gm/dl, there was no significant difference in hematocrit, and in both groups of infants the mean hemoglobin levels were higher than those of normal birth weight infants. The differences in hemoglobin, although statistically significant, are of uncertain clinical significance. Median red cell folate levels remained within the normal adult range in both groups of infants. A minority of infants in the untreated group had low red cell folate levels but this was usually temporary, corrected by dietary folate, and not associated with low hemoglobin. Weight gain was not affected by folic acid supplementation. The infants in this trial were fed with a milk preparation containing 3.5 microgram/100 ml of folic acid which is a similar concentration to that of human milk and we recommend that the folate content of milks fed to low birth weight infants should not fall below this level. We do not have sufficient grounds to recommend routine folic acid supplements for all low birth weight infants throughout the first year of life but there is a possibility that their folate intake may sometimes be suboptimal.     

Prenatal maternal stress programs infant stress regulation

Objective: Prenatal exposure to inappropriate levels of glucocorticoids (GCs) and maternal stress are putative mechanisms for the fetal programming of later health outcomes. The current investigation examined the influence of prenatal maternal cortisol and maternal psychosocial stress on infant physiological and behavioral responses to stress. Methods: The study sample comprised 116 women and their full term infants. Maternal plasma cortisol and report of stress, anxiety and depression were assessed at 15, 19, 25, 31 and 36 + weeks’ gestational age. Infant cortisol and behavioral responses to the painful stress of a heel‐stick blood draw were evaluated at 24 hours after birth. The association between prenatal maternal measures and infant cortisol and behavioral stress responses was examined using hierarchical linear growth curve modeling. Results: A larger infant cortisol response to the heel‐stick procedure was associated with exposure to elevated concentrations of maternal cortisol during the late second and third trimesters. Additionally, a slower rate of behavioral recovery from the painful stress of a heel‐stick blood draw was predicted by elevated levels of maternal cortisol early in pregnancy as well as prenatal maternal psychosocial stress throughout gestation. These associations could not be explained by mode of delivery, prenatal medical history, socioeconomic status or child race, sex or birth order. Conclusions: These data suggest that exposure to maternal cortisol and psychosocial stress exerts programming influences on the developing fetus with consequences for infant stress regulation.     

Folate of pregnant women after a nationwide folic acid supplementation in China

Folate insufficiency during the periconceptional period increases the risk of neural tube defects (NTDs) in offspring, and folic acid supplementation substantially reduces the risk. Widespread large‐scale folic acid supplementation (0.4‐mg folic acid tablet) has been adopted as a main strategy to prevent NTDs in China since 2009. We examined folate concentrations in plasma and red blood cells (RBCs) of pregnant women and the factors associated with blood folate concentrations in a population with a high prevalence of NTDs in northern China. A cross‐sectional survey was conducted in 2014, and 1,107 pregnant women were recruited from 11 county or city maternal and child health centres across Shanxi province. Microbiological assays were used to determine folate concentrations. Factors associated with blood folate insufficiency were identified. The median (25th and 75th percentiles) folate concentrations were 28.4 (17.6, 45.2) nmol L^?1 and 1,001.2 (658.7, 1,402.5) nmol L^?1 in plasma and RBCs, respectively. According to the proposed RBC (906 nmol L^?1) concentrations for optimal NTD prevention, 42.4% participants had RBC folate insufficiency. Rural women had a higher proportion of folate insufficiency than urban women. Folic acid supplementation was the only factor associated with RBC folate insufficiency. A large proportion of women had RBC folate concentrations that are not optimal for the prevention of NTDs despite free access to folic acid supplements. Actions that aim to improve folic acid supplementation compliance are needed to reach the full potential of the nationwide folic acid supplementation programme in terms of NTD prevention.