Janet Y. Uriu-Adams

The Plausibility of Micronutrient Deficiencies Being a Significant Contributing Factor to the Occurrence of Pregnancy Complications

Numerous studies support the concept that a major cause of pregnancy complications can be suboptimal embryonic and fetal nutrition. Although the negative effects of diets low in energy on pregnancy outcome are well documented, less clear are the effects of diets that are low in one or more essential micronutrients. However, several observational and intervention studies suggest that diets low in essential vitamins and minerals can pose a significant reproductive risk in diverse human populations. Although maternal nutritional deficiencies typically occur as a result of low dietary intakes of essential nutrients, nutritional deficiencies at the level of the conceptus can arise through multiple mechanisms. Evidence from experimental animals supports the concept that in addition to primary deficiencies, secondary embryonic and fetal nutritional deficiencies can be caused by diverse factors including genetics, maternal disease, toxicant insults and physiological stressors that can trigger a maternal acute phase response. These secondary responses may be significant contributors to the occurrence of birth defects. An implication of the above is that the frequency and severity of pregnancy complications may be reduced through an improvement in the micronutrient status of the mother.

The plausibility of maternal nutritional status being a contributing factor to the risk for fetal alcohol spectrum disorders: The potential influence of zinc status as an example

There is increasing evidence that human pregnancy outcome can be significantly compromised by suboptimal maternal nutritional status. Poor diet results in a maternal–fetal environment in which the teratogenicity of other insults such as alcohol might be amplified. As an example, there is evidence that zinc (Zn) can interact with maternal alcohol exposure to influence the risk for fetal alcohol spectrum disorders (FASD). Studies with experimental animals have shown that the teratogenicity of alcohol is increased under conditions of Zn deficiency, whereas its teratogenicity is lessened when animals are given Zn‐supplemented diets or Zn injections before the alcohol exposure. Alcohol can precipitate an acute‐phase response, resulting in a subsequent increase in maternal liver metallothionein, which can sequester Zn and lead to decreased Zn transfer to the fetus. Importantly, the teratogenicity of acute alcohol exposure is reduced in metallothionein knockout mice, which can have improved Zn transfer to the conceptus relative to wild‐type mice. Consistent with the above, Zn status has been reported to be low in alcoholic women at delivery. Preliminary data from two basic science and clinical nutritional studies that are ongoing as part of the international Collaborative Initiative on Fetal Alcohol Spectrum Disorders support the potential role of Zn, among other nutritional factors, relative to risk for FASD. Importantly, the nutrient levels being examined in these studies are relevant to general clinical populations and represent suboptimal levels rather than severe deficiencies. These data suggest that moderate deficiencies in single nutrients can act as permissive factors for FASD, and that adequate nutritional status or intervention through supplementation may provide protection from some of the adverse effects of prenatal alcohol exposure.

Influence of copper on early development: Prenatal and postnatal considerations

Copper (Cu) is an essential nutrient whose requirement is increased during pregnancy and lactation. These represent times of critical growth and development, and the fetus and neonate are particularly vulnerable to deficiencies of this nutrient. Genetic mutations that predispose the offspring to inadequate stores of Cu can be life threatening as is observed in children with Menkes disease. During the last decade, severe Cu deficiency, once thought to be a rare condition, has been reported in the literature at an increasing frequency. Secondary Cu deficiencies can be induced by a variety of ways such as excessive zinc or iron intake, certain drugs, and bariatric surgery. Premature and low birth weight infants can be born with low Cu stores. A number of mechanisms can contribute to the teratogenicity of Cu including decreased activity of select cuproenzymes, increased oxidative stress, decreased nitric oxide availability, altered iron metabolism, abnormal extracellular matrix protein crosslinking, decreased angiogenesis and altered cell signaling among others. The brain, heart, and vessels as well as tissues such as lung, skin and hair, and systems including the skeletal, immune, and blood systems, are negatively affected by suboptimal Cu during development. Additionally, persistent structural, biochemical, and functional adverse effects in the offspring are noted even when Cu supplementation is initiated after birth, supporting the concept that adequate Cu nutriture during pregnancy and lactation is critical for normal development. Although Cu‐containing IUDs are an effective method for increasing intrauterine Cu concentrations and for reducing the risk of pregnancy, high amounts of dietary Cu are not thought to represent a direct developmental risk.

Developmental Consequences of Trace Mineral Deficiencies in Rodents: Acute and Long-Term Effects

Approximately 3% of infants born have at least one serious congenital malformation. In the U.S., an average of 10 infants per thousand die before 1 y of life; about half of these deaths can be attributed to birth defects, low birth weight or prematurity. Although the causes of developmental abnormalities are clearly multifactorial in nature, we suggest that a common factor contributing to the occurrence of developmental abnormalities is suboptimal mineral nutrition during embryonic and fetal development. Using zinc and copper as examples, evidence is presented that nutritional deficiencies can rapidly affect the developing conceptus and result in gross structural abnormalities. Deficits of zinc or copper can result in rapid changes in cellular redox balance, tissue oxidative stress, inappropriate patterns of cell death, alterations in the migration of neural crest cells and changes in the expression of key patterning genes. In addition to well-recognized malformations, mineral deficiencies during perinatal development can result in behavioral, immunological and biochemical abnormalities that persist into adulthood. Although these persistent defects can in part be attributed to subtle morphological abnormalities, in other cases they may be secondary to epigenetic or developmental changes in DNA methylation patterns. Epigenetic defects combined with subtle morphological abnormalities can influence an individuals risk for certain chronic diseases and thus influence his or her risk for morbidity and mortality later in life.

Copper-Deficient Rat Embryos Are Characterized by Low Superoxide Dismutase Activity and Elevated Superoxide Anions

Abstract The teratogenicity of copper (Cu) deficiency may result from increased oxidative stress and oxidative damage. Dams were fed either control (8.0 μg Cu/g) or Cu-deficient (0.5 μg Cu/g) diets. Embryos were collected on Gestational Day 12 for in vivo studies or on Gestational Day 10 and cultured for 48 h in Cu-deficient or Cu-adequate media for in vitro studies. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR) activities were measured in control and Cu-deficient embryos as markers of the oxidant defense system. Superoxide anions were measured as an index of exposure to reactive oxygen species (ROS). No differences were found in GPX or GR activities among treatment groups. However, SOD activity was lower and superoxide anion concentrations higher in Cu-deficient embryos cultured in Cu-deficient serum compared to control embryos cultured in control serum. Even so, Cu-deficient embryos had similar CuZnSOD protein levels as controls. In the in vitro system, Cu-deficient embryos had a higher frequency of malformations and increased staining for superoxide anions in the forebrain, heart, forelimb, and somites compared to controls. When assessed for lipid and DNA oxidative damage, conjugated diene concentrations were similar among the groups, but a tendency was observed for Cu-deficient embryos to have higher 8-hydroxy-2′-deoxyguanosine concentrations than controls. Thus, Cu deficiency resulted in embryos with malformations and reduced SOD enzyme activity. Increased ROS concentrations in the Cu-deficient embryo may cause oxidative damage and contribute to the occurrence of developmental defects.

Effect of oral magnesium supplementation on measures of airway resistance and subjective assessment of asthma control and quality of life in men and women with mild to moderate asthma: a randomized placebo controlled trial.

Background: Epidemiological data shows low dietary magnesium(Mg) may be related to incidence and progression of asthma. Objective To determine if long term(6.5 month) treatment with oral Mg would improve asthma control and increase serum measures of Mg status in men and women with mild-to-moderate asthma. Subjects: 55 males and females aged 21 to 55 years with mild to moderate asthma according to the 2002 National Heart, Lung, and Blood Institute(NHLBI) and Asthma Education and Prevention Program(NAEPP) guidelines and who used only beta-agonists or inhaled corticosteroids(ICS) as asthma medications were enrolled. Design: Subjects were randomly assigned to consume 340 mg(170 mg twice a day) of Mg or a placebo for 6.5 months. Measurements: Multiple measures of Mg status including serum, erythrocyte, urine, dietary, ionized and IV Mg were measured. Objective: markers of asthma control were: methacholine challenge test(MCCT) and pulmonary function test(PFT) results. Subjective validated questionnaires on asthma quality of life(AQLQ) and control(ACQ) were completed by participants. Markers of inflammation, including c-reactive protein(CRP) and exhaled nitric oxide(eNO) were determined. Results: The concentration of methacholine required to cause a 20% drop in forced expiratory volume in in minute(FEV1) increased significantly from baseline to month 6 within the Mg group. Peak expiratory flow rate(PEFR) showed a 5.8% predicted improvement over time(P = 0.03) in those consuming the Mg. There was significant improvement in AQLQ mean score units(P < 0.01) and in overall ACQ score only in the Mg group(P = 0.05) after 6.5 months of supplementation. Despite these improvements, there were no significant changes in any of the markers of Mg status. Conclusion: Adults who received oral Mg supplements showed improvement in objective measures of bronchial reactivity to methacholine and PEFR and in subjective measures of asthma control and quality of life.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on information processing skills in Ukrainian infants

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) was explored in a clinical trial conducted in Ukraine. Cardiac orienting responses (ORs) during a habituation/dishabituation learning paradigm were obtained from 6 to 12 month-olds to assess neurophysiological encoding and memory. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to a group (No study-provided supplements, multivitamin/mineral supplement, or multivitamin/mineral supplement plus choline supplement). Heart rate was collected for 30 s prior to stimulus onset and 12 s post-stimulus onset. Difference values (∆HR) for the first 3 trials of each condition were aggregated for analysis. Gestational blood samples were collected to assess maternal nutritional status and changes as a function of the intervention. Choline supplementation resulted in a greater ∆HR on the visual habituation trials for all infants and for the infants with no PAE on the dishabituation trials. The latency of the response was reduced in both conditions for all infants whose mothers received choline supplementation. Change in gestational choline level was positively related to ∆HR during habituation trials and levels of one choline metabolite, dimethylglycine (DMG), predicted ∆HR during habituation trials and latency of responses. A trend was found between DMG and ∆HR on the dishabituation trials and latency of the response. Supplementation did not affect ORs to auditory stimuli. Choline supplementation when administered together with routinely recommended multivitamin/mineral prenatal supplements during pregnancy may provide a beneficial impact to basic learning mechanisms involved in encoding and memory of environmental events in alcohol-exposed pregnancies as well as non- or low alcohol-exposed pregnancies. Changes in maternal nutrient status suggested that one mechanism by which choline supplementation may positively impact brain development is through prevention of fetal alcohol-related depletion of DMG, a metabolic nutrient that can protect against overproduction of glycine, during critical periods of neurogenesis.

Effect of butyl benzyl phthalate on reproduction and zinc metabolism.

Butyl benzyl phthalate (BBP) has been shown to be teratogenic. One mechanism contributing to the teratogenicity of several developmental toxicants, is chemical-induced changes in maternal zinc (Zn) metabolism which result in an increased synthesis of maternal liver metallothionein (Mt), and a subsequent reduction in Zn delivery to the conceptus. We investigated the effects of maternal BBP exposure on maternal-fetal Zn metabolism in Wistar rats. In study I, dams were gavaged with BBP (0,250,1000,1500 or 2000 mg/kg) on gestation days (GD) 11 through 13, and killed on GD 20. Maternal toxicity was evident in the three highest dose groups. Embryo/fetal death and small pup weights and lengths were noted in the 2000 mg BBP/kg group. Fetuses in the 1500 and 2000 mg/kg groups were characterized by poor skeletal ossification, and a high frequency of cleft palate. Rib anomalies were observed in the three highest dose groups. Maternal liver Mt concentrations were only slightly elevated in the 1500 and 2000 mg/kg groups. In study II, dams treated as above, were gavaged with 65Zn and killed 18 h later. While the 2000 mg/kg group had high percentages of 65Zn in some maternal tissues, sequestration of 65Zn in maternal liver was not evident. Thus, BBP is not a strong inducer of Mt, and the teratogenicity of BBP does not appear to be due to alterations in maternal and/or embryonic Zn metabolism.

Vitamin D and maternal and child health: Overview and implications for dietary requirements

The essentiality of vitamin D for normal growth and development has been recognized for over 80 years, and vitamin D fortification programs have been in place in the United States for more than 70 years. Despite the above, vitamin D deficiency continues to be a common finding in certain population groups. Vitamin D deficiency has been suggested as a potential risk factor for the development of preeclampsia, and vitamin D deficiency during infancy and early childhood is associated with an increased risk for numerous skeletal disorders, as well as immunological and vascular abnormalities. Vitamin D deficiency can occur through multiple mechanisms including the consumption of diets low in this vitamin and inadequate exposure to environmental ultraviolet B rays. The potential value of vitamin D supplementation in high-risk pregnancies and during infancy and early childhood is discussed. Currently, there is vigorous debate concerning what constitutes appropriate vitamin D intakes during early development as exemplified by differing recommendations from the Institute of Medicine Dietary Reference Intake report and recent recommendations by the Endocrine Society. As is discussed, a major issue that needs to be resolved is what key biological endpoint should be used when making vitamin D recommendations for the pregnant woman and her offspring.

Multiple Measures of Magnesium Status Are Comparable in Mild Asthma and Control Subjects

Magnesium (Mg) may be a significant factor in asthma management. There is debate about how to best assess Mg status. We evaluated multiple indices of Mg status and lung function in 52 people with mild to moderate asthma and 47 controls. Mg measures included serum total, ionized and erythrocyte Mg, intravenous Mg load retention and dietary recall. Methacholine challenge and pulmonary function tests were used to assess diagnosis and severity of asthma. Mg status was similar in asthma and controls, and was not correlated to lung function. Total serum Mg closely reflected ionized Mg and offers a useful clinical diagnostic monitor.