ArticleLiterature Review

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

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Abstract

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.

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... Nutritional deficiencies, even without the presence of alcohol, can lead to serious abnormalities in physical and central nervous system (CNS) development (Georgieff, 2007;Keen et al., 1998). But the combination of poor prenatal nutrition and alcohol exposure may be even more damaging to the developing fetus (Keen et al., 2010). For example, animal studies have shown that the teratogenic effects of alcohol, including low birth weight (Wiener et al., 1981), physical anomalies (Weinberg et al., 1990), and brain damage (Wainwright and Fritz, 1985), are more severe when consumed with suboptimal nutrition, although blood alcohol levels are often higher among malnourished subjects (Wiener et al., 1981). ...
... Interestingly, both animal and clinical studies have shown that deficiencies in specific nutrients can exacerbate the teratogenic effects of prenatal alcohol exposure. Prenatal zinc deficiency can lower fetal and offspring body weights, increase resorption rates, and increase physical malformations associated with prenatal alcohol exposure (Dreosti and Partick, 1987;Keen et al., 2010;Keppen et al., 1985;Miller et al., 1983;Ruth and Goldsmith, 1981). Similarly, iron deficiency exacerbates neuropathology and behavioral deficits, such as impaired learning, associated with prenatal alcohol exposure (Beard and Connor, 2003;Congdon et al., 2012;Huebner et al., 2016;Huebner et al., 2015;Rufer et al., 2012). ...
... However, it is possible that prenatal alcohol exposure exacerbates the effects of low dietary choline deficiency on choline metabolism. It is also important to recognize that nutrients can interact with one another (Keen et al., 2010;Sandstrom, 2001) and choline deficiency may result in secondary nutritional deficiencies or demands. For example, choline, methionine, and folate metabolism interact at the point that homocysteine is converted to methionine, and perturbing any one of these methyl donors results in compensatory changes (Zeisel et al., 1991). ...
... Alcohol exposure in animal models also allows variables known to be associated with FASD to be tested. These variables include: genetic and epigenetic factors (Kaminen-Ahola et al., 2010;Kleiber et al., 2014), maternal and fetal stress (Glavas, Ellis, Yu, & Weinberg, 2007;Raineki et al., 2014;Uban, Comeau, Ellis, Galea, & Weinberg, 2013), nutritional status (Keen et al., 2010;Weinberg, 1985;Young, Giesbrecht, Eskin, Aliani, & Suh, 2014) (Keen et al., 2010;Weinberg, 1985;Young et al., 2014), and the ability of the mother or the fetus to metabolize alcohol (Ramchandani, Bosron, & Li, 2001;Riley, Infante, & Warren, 2011;Yelin et al., 2007). These variables can be tested in conjunction with alcohol exposure to determine which variables can further exacerbate the alcohol-induced phenotypes and which treatments or manipulations can rescue or prevent the malformations, such as vitamin A, retinoic acid, or folate (Ballard et al., 2012;Marrs et al., 2010;Serrano et al., 2010;Twal & Zile, 1997;Yelin et al., 2005). ...
... Alcohol exposure in animal models also allows variables known to be associated with FASD to be tested. These variables include: genetic and epigenetic factors (Kaminen-Ahola et al., 2010;Kleiber et al., 2014), maternal and fetal stress (Glavas, Ellis, Yu, & Weinberg, 2007;Raineki et al., 2014;Uban, Comeau, Ellis, Galea, & Weinberg, 2013), nutritional status (Keen et al., 2010;Weinberg, 1985;Young, Giesbrecht, Eskin, Aliani, & Suh, 2014) (Keen et al., 2010;Weinberg, 1985;Young et al., 2014), and the ability of the mother or the fetus to metabolize alcohol (Ramchandani, Bosron, & Li, 2001;Riley, Infante, & Warren, 2011;Yelin et al., 2007). These variables can be tested in conjunction with alcohol exposure to determine which variables can further exacerbate the alcohol-induced phenotypes and which treatments or manipulations can rescue or prevent the malformations, such as vitamin A, retinoic acid, or folate (Ballard et al., 2012;Marrs et al., 2010;Serrano et al., 2010;Twal & Zile, 1997;Yelin et al., 2005). ...
Article
Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge, CHARGE, Smith‐Magenis, Matthew‐Wood and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head and craniofacial development will reveal underlying etiologies of these disorders. This article is protected by copyright. All rights reserved.
... A population-based study the Western Cape Province of South Africa showed that mothers with FASD children had major nutritional deficiencies, with significantly lower intake of vitamins A, C, D, E, B 2 , calcium, omega-3 fatty acids and choline compared to nondrinking mothers (May et al. 2014). Another study with pregnant women in Ukraine and Russia showed that the mothers that consumed alcohol during pregnancy had lower levels of plasma zinc that non-drinking mothers (Keen et al. 2010). Some researches tried to treat women with choline, minerals and ...
... antioxidants in order to reverse nutritional deficiencies commonly seen in FAS mothers (Cohen-Kerem and Koren 2003;Keen et al. 2010;Kable et al. 2015). ...
Article
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Ethanol is the most important teratogen agent in humans. Prenatal alcohol exposure can lead to a wide range of adverse effects, which are broadly termed as Foetal Alcohol Spectrum Disorder (FASD). Socioeconomic status, ethnicity, differences in genetic susceptibility related to ethanol metabolism, alcohol consumption patterns, obstetric problems, maternal nutrition, stress, and other co-administered drugs are all factors that may influence FASD manifestations. Recently, much attention has been paid to the role of nutrition as a protective factor against alcohol teratogenicity. There are a great number of papers related to nutritional treatment of nutritional deficits due to several factors associated with maternal consumption of alcohol and with eating and social disorders in FASD children. Although research showed the clinical benefits of nutritional interventions, a minimum number of studies refer to postnatal nutrition treatment of neurodevelopmental deficits. Nutritional supplementation in children with FASD has a dual objective: to overcome nutritional deficiencies and to reverse or improve the cognitive deleterious effects of prenatal alcohol exposure. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of simultaneous multiple-nutrient supplementation.
... Patients with eating disorders show adverse pregnancy outcomes such as miscarriage, preterm delivery, or fetal anomalies as poor fetal growth or malformations. Altered levels of many nutrients (i.e., vitamin B, folic acid, zinc) can increase the risk of developing fetal disorders [134,135]. ...
Article
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Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. Epigenetic mechanisms in pregnancy are a dynamic phenomenon that responds both to maternal–fetal and environmental factors, which can influence and modify the embryo-fetal development during the various gestational phases. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders.
... Some studies have examined nutrition profiles among children with neurodevelopmental disorders. They show that poor nutrition intake (according to the recommended dietary allowance and estimated average requirement guidelines) and multiple, rather than single, nutrient deficiencies are more common among these children and, in some cases, their mothers [14,15]. While not in and of itself proof of interactions among nutrient mixtures, this finding may be consistent with a nutrient mixture's effect on neurodevelopment. ...
Article
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Adequate nutrition is important for neurodevelopment. Although nutrients are ingested in combination, the impact of specific nutrients within the context of a nutrient mixture has not been studied with respect to health, such as neurodevelopment. Therefore, we examined the impact of prenatal and childhood nutrient mixtures on neurodevelopmental outcomes. Participants included mother–child pairs in the Programming Research in Obesity, Growth, Environment, and Social Stress (PROGRESS) prospective birth cohort in Mexico City. We assessed prenatal and child micro- and macronutrient profiles among 65 and 329 children, respectively, via food frequency questionnaires. Neurodevelopmental outcomes of 4–6-year-old children were measured using the McCarthy Scales of Children’s Abilities (MSCA). We conducted weighted quantile sum (WQS) regression analyses to calculate indices reflecting “good” and “poor” prenatal and childhood nutrition. After adjusting for maternal education, socioeconomic status, the Home Observation for Measurement of the Environment (HOME) score, and total caloric intake, the good prenatal and childhood nutrition indices predicted more favorable neurodevelopment, while both poor nutrition indices predicted poorer neurodevelopment. These associations were stronger in prenatal than childhood models. Monounsaturated fats predicted various neurodevelopmental abilities relatively strongly in both models. Prenatal and childhood consumption of combinations of beneficial nutrients may contribute to more favorable neurodevelopment.
... A recent study analysed plasma levels of zinc (Zn) and Copper (Cu) in heavy drinking pregnant women in Ukraine and Russia, showing that mothers who consumed alcohol during pregnancy had lower levels of these minerals than non-drinking mothers [42]. Alcohol decreases serum levels of zinc because it causes a low intake of intestinal absorption and increases urinary excretion. ...
Article
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The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Suitable maternal nutritional status is crucial to maintain the optimal environment for fetal development but if consumption of alcohol or drugs of abuse disrupt the intake of nutrients, the potential teratogenic effects of these substances increase. Despite evidence of the importance of nutrition in addicted pregnant women, there is a lack of information on the effects of alcohol and drugs of abuse on maternal nutritional status; so, the focus of this review was to provide an overview on the nutritional status of addicted mothers and fetuses. Alcohol and drugs consumption can interfere with the absorption of nutrients, impairing the quality and quantity of proper nutrient and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega–3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs of abuse the supply of essential nutrients are not available for the fetus; this can result in fetal abnormalities like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to find a strategy to reduce fetal physical and neurological impairment as a result of prenatal alcohol and drugs of abuse exposure combined with poor maternal nutrition. Prenatal nutrition interventions and target therapy are required that may reverse the development of such abnormalities.
... Значний вплив алкоголю протягом першого триместру пов'язаний з розвитком у плода структурних аномалій, включаючи аномалії головного мозку; вживання алкоголю в другому триместрі підвищує ризик спонтанного аборту; а в третьому триместрі переважно впливає на вагу, довжину і зростання мозку [15]. Доведено, що нер-вові поведінкові ефекти можуть виникати навіть за відсутності лицевих або структурних аномалій головного мозку [7,12,13]. ...
... Populationbased studies propose an association between poor maternal nutrition and increased FASD risk (May et al. 2014;May et al. 2016). Research predominantly in animal models has identified individual nutrients that may interact with PAE, such as zinc, choline, iron, copper, selenium, methionine, folate, and essential fatty acids (Keen et al. 2010;Young et al. 2014;Zeisel 2013). Alcohol abuse may exacerbate nutrient deficiencies because the alcohol calories displace nutrient-dense foods and because alcohol may impair nutrient absorption and utilization, in part by disrupting liver and gut function (Bishehsari et al. 2017), but also by increasing intestinal bleeding and nutrient losses in stool. ...
Article
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Alcohol consumption during pregnancy places the fetus at risk for permanent physical, cognitive, and behavioral impairments, collectively termed fetal alcohol spectrum disorders (FASD). However, prenatal alcohol exposure (PAE) outcomes vary widely, and growing evidence suggests that maternal nutrition is a modifying factor. Certain nutrients, such as iron, may modulate FASD outcomes. Untreated gestational iron deficiency (ID) causes persistent neurodevelopmental deficits in the offspring that affect many of the same domains damaged by PAE. Although chronic alcohol consumption enhances iron uptake and elevates liver iron stores in adult alcoholics, alcohol-abusing premenopausal women often have low iron reserves due to menstruation, childbirth, and poor diet. Recent investigations show that low iron reserves in during pregancy are strongly associated with a worsening of several hallmark features in FASD including reduced growth and impaired associative learning. This review discusses recent clinical and animal model findings that maternal ID worsens fetal outcomes in response to PAE. It also discusses underlying mechanisms by which PAE disrupts maternal and fetal iron homeostasis. We suggest that alcohol-exposed, ID pregnancies contribute to the severe end of the FASD spectrum.
... Our results reaffirm that oxidative stress [13,44] is a causal factor for several immunological and neurological impairments [45] observed in FASD. More importantly, these results show that maternal antioxidant status has direct consequences on fetal brain development; therefore, even a minor short-term shift in redox-oxidative balance during gestation increases the possibility of fetotoxicity from ethanol exposure. ...
Article
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Background Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive. Methods Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16–17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes. ResultsWe show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6–24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2). Conclusions Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors.
... The precise risk of an AEP resulting in a child with an FASD is complicated by myriad maternal and fetal factors including the pattern of maternal alcohol consumption, maternal comorbidities and nutritional status, and maternal and fetal genetics (Abel, 2004;Burd et al., 2012;Finegersh et al., 2015;Gareri et al., 2009;Keen et al., 2010;May et al., 2004;Michaelis and Michaelis, 1994;Montag, 2016;Streissguth and Dehaene, 1993). In addition, FASD may be missed as a diagnosis for a variety of reasons, including lack of availability of accurate data on prenatal alcohol exposure. ...
Article
Background: Reduction of risky drinking in women of childbearing age is one strategy that may be employed to prevent fetal alcohol spectrum disorder, a sequela of prenatal alcohol-exposure. Communities differ in risk and protective factors, necessitating culturally informed interventions for maximal efficacy. This manuscript describes the modification of an existing web-based SBIRT intervention to reduce risky drinking among AIAN women of child-bearing age in Southern California into a peer-to-peer based intervention using motivational interviewing. Methods: The modification process was iterative and included various community focus groups, interviews, and a final review. Results: Intervention modification was required for cultural congruence. Components of the peer-to-peer intervention designed by this project included a flip chart used to guide the motivational interviewing, charts of the financial and physical costs of alcohol consumption, revised baseline and follow-up questionnaires, and guidance regarding the application of motivational interviewing techniques. Conclusions: This study may inform the modification of future interventions among AIAN communities. This article is protected by copyright. All rights reserved.
... Others have documented that alcohol consumption was more prevalent in pregnant women who had been diagnosed with HIV than those without this disease (Desmond et al., 2012;Parry et al., 2005). Finally, poor nutrition among pregnant mothers has been postulated as amplifying the teratogenic effects of prenatal alcohol exposure (Carter, Jacobson, Molteno, & Jacobson, 2007;Keen et al., 2010;Shankar, Ronis, & Badger, 2007). This connection seems plausible given food insecurity (i.e., food unavailability, eating less) has been significantly linked with alcohol consumption (Eaton et al., 2014). ...
Article
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Olusanya, O., & Barry, A. (2015). Letter to the Editor: Why do pregnant South African women drink alcohol? A call to action for more qualitative investigations. The International Journal Of Alcohol And Drug Research, 4 (2), 171-174. doi: http://dx.doi.org/10.7895/ijadr.v4i2.213 Even though the adverse effects of alcohol consumption during pregnancy have been well documented, millions of babies each year continue to be affected by fetal alcohol spectrum disorders (FASD). This is concerning given that FASD is completely preventable. FASDs have been documented across a variety of races and geographical regions worldwide, yet the highest known prevalence rates are recorded in Africa. Specifically, for every 1000 children born in the Western Cape Province of South Africa, approximately 59.3 to 91.0 are determined to have fetal alcohol syndrome, the most severe form of FASD. While the risk factors contributing to FASDs have been examined quantitatively among South African women, there is a dearth of qualitative investigations that articulate and contextualize the underling motivations, beliefs, and attitudes that influence these risk factors. Qualitative investigations have been conducted in other geographic regions (e.g., Australia), but are not generalizable to South Africa. Qualitative investigations, which explore the familial, social, cultural, and economic factors that influence maternal drinking, are needed to inform future health promotion programs and interventions aimed at decreasing and ultimately eliminating maternal alcohol consumption among South African women.
... Taking into account the association between maternal zinc deficiency and poor fetal outcome including neural tube defects [47], zinc status in pregnant and especially IVF-pregnant women should be monitored. Moreover, it has been demonstrated that Zn deficiency may contribute to adverse health effects of certain toxic substances including alcohol exposure in fetal alcohol spectrum disorders development [48]. ...
Article
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The objective of the present study was to perform comparative analysis of hair trace element content in women with natural and in vitro fertilization (IVF)-induced pregnancy. Hair trace element content in 33 women with IVF-induced pregnancy and 99 age- and body mass index-matched control pregnant women (natural pregnancy) was assessed using inductively coupled plasma mass spectrometry. The results demonstrated that IVF-pregnant women are characterized by significantly lower hair levels of Cu, Fe, Si, Zn, Ca, Mg, and Ba at p < 0.05 or lower. Comparison of the individual levels with the national reference values demonstrated higher incidence of Fe and Cu deficiency in IVF-pregnant women in comparison to that of the controls. IVF pregnancy was also associated with higher hair As levels (p < 0.05). Multiple regression analysis revealed a significant interrelation between IVF pregnancy and hair Cu, Fe, Si, and As content. Hair Cu levels were also influenced by vitamin/mineral supplementation and the number of pregnancies, whereas hair Zn content was dependent on prepregnancy anthropometric parameters. In turn, planning of pregnancy had a significant impact on Mg levels in scalp hair. Generally, the obtained data demonstrate an elevated risk of copper, iron, zinc, calcium, and magnesium deficiency and arsenic overload in women with IVF-induced pregnancy. The obtained data indicate the necessity of regular monitoring of micronutrient status in IVF-pregnant women in order to prevent potential deleterious effects of altered mineral homeostasis.
... The dietary intake of mothers of children with fetal alcohol spectrum disorder (FASD) compared to mothers of normal controls has been reported to be inadequate for a number of nutrients [18]. It is thought that suboptimal maternal nutritional status plays a role in the expression of certain alcohol-related disorders, including FASD [19]. Rodent studies have shown that offspring of dams fed iron-deficient diets throughout gestation and who were administered alcohol in the early postnatal period have poor neurocognitive outcomes compared to offspring from iron-sufficient dams [20]; maternal choline supplementation during the prenatal period can reduce the severity of FASD effects in the rat offspring [21]. ...
Article
Objective: Heavy alcohol consumption can alter vitamin D status; however, the relationships between alcohol consumption and vitamin D concentrations in pregnant women have not been well studied. The aim of this study was to investigate the vitamin D status in a population of alcohol-exposed (N = 180) and low/unexposed control (N = 179) Ukrainian pregnant women. Methods: Women who attended prenatal care facilities in 2 regions of Ukraine (Rivne and Khmelnytsky) for a routine prenatal visit were screened for the study. At the time of enrollment (20.4 ± 7.0 weeks of gestation), blood samples and alcohol consumption data (during a typical week around conception and the most recent 2 weeks) were collected. Vitamin D status was assessed by 25-hydroxyvitamin D [25(OH)D] concentrations. Results: A high prevalence of suboptimal vitamin D status in pregnant Ukrainian women was observed. Overall, 50.1% and 33.4% of the women were classified as vitamin D deficient [25(OH)D < 20 ng/mL] or insufficient [25(OH)D ≥ 20 ng/mL and ≤30 ng/mL], respectively, based on 2011 Endocrine Society guidelines. Alcohol-exposed women had significantly lower 25(OH)D concentrations than low/unexposed women in Spring (p = 0.006) and Winter (p = 0.022). When vitamin D concentrations were grouped into sunny season (Summer + Fall) compared to not sunny season (Winter + Spring), there was a significant ethanol by season interaction (p = 0.0028), with alcohol-drinking women having lower circulating vitamin D compared to low/unexposed women in seasons of low sun availability. Conclusions: These data suggest that when vitamin D concentrations are generally low (e.g., during seasons of low sun availability), alcohol consumption during pregnancy has a negative impact on vitamin D status.
... To our knowledge, only 2 published studies have documented the effects of choline supplementation in clinical populations with or at risk of FASDs. The first study was published as part of a larger clinical trial that explored micronutrient supplementation in alcohol-consuming pregnant women in the Ukraine (11,12) and showed that choline supplementation improved neurophysiologic encoding and memory in both alcohol-exposed and -unexposed infants (13). The second study was a randomized clinical trial of choline supplementation in preschool-aged children with FASDs and revealed that choline improved memory function in young children between the ages of 2.5 and 5 y (14). ...
Article
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Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design: In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.
... However, different genetic variants may possibly influence fetal vulnerability to alcohol teratogenesis. Research has shown that teratogenic effects of PAE can be influenced by multiple maternal factors, including hormone status (particularly hormones of the HPA axis), nutrition, oxidative stress level, age, parity and years of drinking [117][118][119][120]. Genetic profiles of both mother and fetus may also alter the metabolism of alcohol and risk of physical birth defects, prenatal mortality, learning and other neurobehavioral deficits in the offspring [121][122][123]. ...
Article
Children and adolescents affected by prenatal exposure to alcohol who have brain damage that is manifested in functional impairments of neurocognition, self-regulation, and adaptive functioning may most appropriately be diagnosed with neurobehavioral disorder associated with prenatal exposure. This Special Article outlines clinical implications and guidelines for pediatric medical home clinicians to identify, diagnose, and refer children regarding neurobehavioral disorder associated with prenatal exposure. Emphasis is given to reported or observable behaviors that can be identified as part of care in pediatric medical homes, differential diagnosis, and potential comorbidities. In addition, brief guidance is provided on the management of affected children in the pediatric medical home. Finally, suggestions are given for obtaining prenatal history of in utero exposure to alcohol for the pediatric patient.
... The identification of the neurobehavioral consequences of prenatal alcohol exposure (PAE) has proven to be multi-faceted and complex. Although considerable research has been done documenting a variety of neurocognitive and behavioral outcomes (see reviews (Senturias, 2014;Riley et al., 2011)), a consistent diagnostic formulation of these symptoms is complicated by the variability in the consumption patterns of women who drink in pregnancy (Halmesmaki et al., 1987;Iversen et al., 2015;Fortin et al., 2016), maternal nutrition (Keen et al., 2010), the metabolism of the mother (Church et al., 1990), the genetics and epigenetics of the mother and child (Mead and Sarkar, 2014;Sulik, 2014;Gilliam and Irtenkauf, 1990;Israel et al., 2006), and the impact of the postnatal environment on these outcomes (May and Gossage, 2011). Various diagnostic systems for fetal alcohol spectrum disorders ( (Astley, 2013;Hoyme et al., 2005;Stratton et al., 1996;Astley, 2006) have attempted to formulate methods of identifying alcohol-affected individuals for appropriate diagnosis and to facilitate their access to treatment services but there is a lack of consistency across these systems (Astley, 2006;Coles. ...
Article
Neurobehavioral Disorder associated with Prenatal Alcohol Exposure (ND-PAE) was proposed as a diagnostic formulation intended to capture the range of mental health problems occurring in alcohol-affected individuals with a history of prenatal alcohol exposure. The proposed criteria for the disorder are reviewed as well as various factors considered in the development of the disorder and its associated criteria. The taxonomic research related to the disorder is reviewed with preliminary analyses indicating that clinicians are readily able to agree when applying the diagnostic criteria but that the adaptive functioning criteria may need to be modified to expand its coverage of alcohol-affected individuals and to aid in discriminating these individuals from others not alcohol-affected. Finally, the challenges with translating the diagnosis into European medical and mental healthcare systems are discussed and recommendations for facilitating implementation are made.
... This relationship is consistent with a belief held by some women that low-level consumption of alcohol is associated with low risk, particularly in the context of an otherwise healthy lifestyle (30) . While there is some research evidence to support the idea that good maternal nutrition can ameliorate some of the effects of fetal exposure to alcohol (31)(32)(33) , current medical advice recommends abstinence during pregnancy as the safest policy. ...
Article
Objective: To examine overall micronutrient intake periconceptionally and throughout pregnancy in a population-based cohort of Australian women. Design: In a prospective cohort study, micronutrient dosages were extracted from self-reported maternal supplement use, recorded pre-conception, and for each trimester of pregnancy. A food frequency scale (DQESv2) captured usual maternal diet for gestational weeks 14-26. The influence of sociodemographic and lifestyle factors associated with supplement use was examined using logistic regression, and changes in micronutrient intakes prior to and throughout pregnancy were assessed using repeated-measures ANOVA analyses. Setting: Metropolitan hospital sites in Melbourne, Australia. Subjects: Women with a viable singleton pregnancy were recruited at less than 19 weeks' gestation (n 2146). Results: Compared with non-users, women using supplements during pregnancy were more likely to have planned their pregnancy, be >25 years old, primiparous, Caucasian, non-smokers, have a tertiary education and be consuming a folate-rich diet. Intakes of folate, Fe and Zn were significantly lower in the periconceptional period, compared with other periods (P<0·001). Intakes below Recommended Daily Intake levels were common both periconceptionally and throughout pregnancy, with 19-46 % of women not meeting the Recommended Daily Intake for folate, 68-82 % for Fe and 17-36 % for Zn. Conversely, 15-19 % of women consumed beyond the recommended Upper Limit for folate and 11-24 % for Fe. Conclusions: The study highlights the need for improved public health education on nutritional needs during pregnancy, especially among women with lower educational achievements and income.
... Even though alcohol consumption by itself does not correlate with the socioeconomic status of pregnant women, women with lower socioeconomic status are more likely to have poor nutrition and non-ideal living conditions as well. Many studies have highlighted decreased intake of micronutrients such as zinc, copper and folate following al- cohol exposure [41]. Conversely, choline supplementation has been shown to ameliorate several behavioural deficits in rats exposed to alcohol [42]. ...
Article
Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects and neurodevelopmental deficits referred to as "Fetal Alcohol Spectrum Disorders (FASD)". The more visible phenotypes caused by PAE include growth retardation, and characteristic craniofacial abnormalities associated with functional and structural damage to the central nervous system. Ethanol is a teratogenic agent itself; but it can also alter gene expression. These changes may contribute to the spectrum of effects and different phenotypes that are dependent on alcohol metabolism, as well as the timing and duration of alcohol exposure. Evidence from both human patients and animal models show that genetic factors and epigenetic mechanisms such as DNA methylation, histone post-translational modifications and noncoding RNAs, contribute to the gene expression changes caused by ethanol. Not all embryos that are exposed to alcohol during development exhibit FASD symptoms after birth. FASD patients may present severe birth defects, while others are normal in physical appearance but present a variety of cognitive and behavioral difficulties. It has been hypothesized that maternal and paternal genetic factors may contribute to the sensitivity, resistance or vulnerability of the fetus to alcohol. Moreover, the epigenome is highly sensitive to a multitude of environmental insults including PAE. Studies also show 'transgenerational' effects of alcohol. In such cases, maternal or paternal preconception alcohol consumption could lead to FASD-like phenotypes in the newborn. Thus, the phenotypes in FASD can be modified by interplay between maternal/paternal genetic factors and epigenetic mechanisms. This current review summarizes the contribution of genetic and epigenetic mechanisms in FASD pathobiology, and how this information could be utilized for prevention, early diagnosis and potentially treatment of the affected individuals.
... The Adverse effects of prenatal alcohol exposure can be modified by numerous factors, including genetics, developmental timing and pattern of alcohol exposure, postnatal environment, and nutrition (Abel and Hannigan, 1995;Gemma et al., 2007;May et al., 2013). Both clinical and preclinical studies indicate that nutritional deficiencies may exacerbate ethanol's teratogenic effects, whereas nutritional supplements may reduce fetal risk to alcohol's damaging consequences (Guerrini et al., 2007;Keen et al., 2010;Rufer et al., 2012;Summers et al., 2008;Wang et al., 2009). Although it is not surprising that prenatal nutrition can alter alcohol's effects on the developing fetus, less is known of how the postnatal nutritional intake of an individual with fetal alcohol spectrum disorders (FASD) influences postnatal brain and behavioral development. ...
Article
Background: Children exposed to alcohol prenatally may suffer from behavioral and cognitive alterations that adversely affect their quality of life. Animal studies have shown that perinatal supplementation with the nutrient choline can attenuate ethanol's adverse effects on development; however, it is not clear how late in development choline can be administered and still effectively reduce the consequences of prenatal alcohol exposure. Using a rodent model, this study examined whether choline supplementation is effective in mitigating alcohol's teratogenic effects when administered during adolescence/young adulthood. Methods: Sprague-Dawley rats were exposed to alcohol (5.25 g/kg/d) during the third trimester equivalent brain growth spurt, which occurs from postnatal day (PD) 4 to 9, via oral intubation. Sham-intubated and nontreated controls were included. Subjects were treated with 100 mg/kg/d choline chloride or vehicle from PD 40 to 60, a period equivalent to young adulthood in the rat. After the choline treatment had ceased, subjects were tested on a series of behavioral tasks: open field activity (PD 61 to 64), Morris water maze spatial learning (PD 65 to 73), and spatial working memory (PD 87 to 91). Results: Ethanol-exposed subjects were overactive in the activity chambers and impaired on both the spatial and the working memory versions of the Morris water maze. Choline treatment failed to attenuate alcohol-related overactivity in the open field and deficits in Morris water maze performance. In contrast, choline supplementation significantly mitigated alcohol-related deficits in working memory, which may suggest that choline administration at this later developmental time affects functioning of the prefrontal cortex. Conclusions: The results indicate that adolescent choline supplementation can attenuate some, but not all, of the behavioral deficits associated with early developmental alcohol exposure. The results of this study indicate that dietary intervention may reduce some fetal alcohol effects, even when administered later in life, findings with important implications for adolescents and young adults with fetal alcohol spectrum disorders.
... However, the onset of mental disorders can be influenced by moderator and mediator factors, which overlap with independent risk factors [12]. The complex interaction of genetic, metabolic, and nutritional factors [13,14] have generated uncertainties about the exact role of prenatal risk factors in the onset of mental disorders in childhood [15]. ...
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The objective of the study was to investigate the association between alcohol use during pregnancy and mental disorders in childhood, controlling for confounding risk factors by a longitudinal study of pregnant women and their offspring. The initial cohort comprised pregnant women attending an obstetric service. From the initial sample of 449 pregnant women, 81 mother–child pairs agreed to participate. After 12 years, mother–child pairs were assessed through self-administered questionnaires and semi-structured interviews. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) was used to assess the presence of any mental disorders in the children. The mothers were assessed by the Self-Reporting Questionnaire (SRQ) and the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, data on the mother’s alcohol use collected during pregnancy were analysed. A logistic regression tested the influence of alcohol consumption in all trimesters and binge drinking on the occurrence of attention-deficit/hyperactivity disorder (ADHD), controlling for covariates. Binge drinking at any time during pregnancy or low–moderate alcohol consumption in all trimesters of pregnancy was associated with a fivefold increased odds of child ADHD. The combination of both patterns of alcohol use added an increase of 19% in the variance of ADHD’s occurrence. The episodic use of at least four drinks or the regular use of low–moderate alcohol doses during pregnancy was associated with significantly increased odds of subsequent child ADHD. Reducing binge drinking and regular alcohol use of pregnant women may lead to a significant decrease in their children developing ADHD.
... In a follow-up study, with a different sample of women in the same South African community, these investigators found that mothers of children with FASD consumed more nutrients than non-drinking mothers but alcohol diminished any potential beneficial effects of additional nutrients (May et al., 2015). Furthermore, an investigation of the nutritional status of pregnant women in Russia and the Ukraine revealed that alcohol-consuming mothers have significantly lower levels of plasma zinc and copper when compared to nondrinking mothers attending the same prenatal clinics (Keen et al., 2010). Such nutritional deficiencies pose a severe threat to healthy fetal development, and evidence from animal models clearly demonstrates that undernutrition increases alcohol-related fetal toxicity (Weinberg et al., 1990, Wiener et al., 1981, Shankar et al., 2006, Shankar et al., 2007, Keppen et al., 1985, Huebner et al., 2015. ...
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Background: Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. Methods: Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall (ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children (What We Eat in America, NHANES 2007-2008). Results: Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. Conclusions: The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted.
... In lowand middle-income countries (LMICs), such as South Africa, the estimated prevalence of FASDs is as high as 111.1 per 1000 children in some communities (Olivier et al., 2016). The majority of previous studies exploring the impact of PAE on child development in the context of psychobiological and psychosocial factors have been performed in high-income countries, even though higher rates of PAE, poverty, post-traumatic stress disorder (PTSD) and depression exist in LMICs (May et al., 2008;Keen et al., 2010;Flak et al., 2014). The research taking into account contextual factors such as those cited above underscores the importance of examining the adverse effects of PAE in young children (May et al., 2008;Flak et al., 2014), within the broader context of psychosocial and environmental risk factors that may additionally influence not only early neurodevelopmental outcomes but also lifelong health trajectories. ...
Article
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Objective To investigate the association of prenatal alcohol exposure (PAE) and early neurodevelopment in the first 2 years of life, adjusting for maternal sociodemographic and psychosocial factors, in the Drakenstein Child Health Study (DCHS), a South African birth cohort study. Methods The DCHS comprises a population-based birth cohort of 1143 children, of which, a subsample completed the Bayley Scales of Infant Development-III (BSID-III) at 6 (n = 260) and 24 months of age (n = 734). A subset of alcohol exposed, and unexposed children was included in this analysis at age 6 months (n = 52 exposed; n = 104 unexposed) and 24 months (n = 92 exposed; n=184 unexposed). Multiple hierarchical regression was used to explore the associations of PAE with motor and language development. Results PAE was significantly associated with decreased gross motor (OR = 0.16, 95%CI 0.06-0.44, p = 0.001) or fine motor (OR = 0.16, 95%CI 0.06-0.46, p = 0.001) functioning after adjusting for maternal sociodemographic and psychosocial factors at 6 months of age only. No significant effects were found in either receptive or expressive communication and cognitive outcomes at either time point. Conclusion PAE has potentially important consequences for motor development in the first 2 years of life, a period during which the most rapid growth and maturation occurs. These findings highlight the importance of identifying high-risk families in order to provide preventive interventions, particularly in antenatal clinics and early intervention services.
... Fetal alcohol spectrum disorders (FASD) encompass all alcohol-related birth defects including fetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Since alcohol consumption can aggravate nutrient deficiencies, it has been suggested that maternal nutritional status plays a role in the risk for FASD (3)(4)(5). In addition, rates of cigarette smoking during pregnancy are often higher among women who consume alcohol creating additional consequences to nutritional status, as well as increasing odd ratios for preterm birth, low birth weight, and growth restriction beyond either alcohol or cigarette use alone (6)(7)(8)(9)(10)(11). ...
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Objective: Polyunsaturated fatty acids are vital for optimal fetal neuronal development. The relationship between maternal alcohol consumption and smoking with third trimester plasma fatty acids were examined and their association with Fetal Alcohol Spectrum Disorders (FASD). Methods: Moderate to heavy alcohol-using and low/unexposed comparison women were recruited during mid-pregnancy from two prenatal clinics in Ukraine. The participants’ infants underwent physical and neurobehavioral exams prior to one-year of age and classified as having FASD by maternal alcohol consumption and neurobehavioral scores. A subset of mother-child pairs was selected representing three groups of cases and controls: Alcohol-Exposed with FASD (AE-FASD, n = 30), Alcohol-Exposed Normally Developing (AE-ND, n = 33), or Controls (n = 46). Third trimester maternal plasma samples were analyzed for fatty acids and levels were compared across groups. Results: The percent of C18:0 (p < 0.001), arachidonic acid (AA, C20:4n-6, p = 0.017) and C22:5n-6 (p = 0.001) were significantly higher in AE-FASD women than controls or AE-ND women. Alcohol-exposed women who smoked had lower C22:5n-3 (p = 0.029) and docosahexaenoic acid (DHA, C22:6n-3, p = 0.005) and higher C22:5n-6 (p = 0.013) than women consuming alcohol alone or abstainers. Conclusion: Alterations in fatty acid profiles were observed in moderate to heavy alcohol-consuming mothers with infants classified with FASD compared to alcohol-exposed normally developing infants or controls.
... Research studies show that many other risk factors can also influence development of FASD, which include a smaller body profile of mother (height, weight, and body mass index [BMI]), maternal age, low socioeconomic status and smoking [52], a poor nutritional status (deficit of riboflavin, calcium, and zinc; [70], genetic polymorphisms [71,72], and paternal alcohol consumption [73]. ...
Article
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Background: Alcohol is a teratogen and prenatal exposure may adversely impact the developing fetus, increasing risk for negative outcomes, including Fetal Alcohol Spectrum Disorder (FASD). Global trends of increasing alcohol use among women of childbearing age due to economic development, changing gender roles, increased availability of alcohol, peer pressure and social acceptability of women's alcohol use may put an increasing number of pregnancies at risk for prenatal alcohol exposure (PAE). This risk has been exacerbated by the ongoing COVID-19 pandemic in some countries. Method: This literature review presents an overview on the epidemiology of alcohol use among childbearing age and pregnant women and FASD by World Health Organization regions; impact of PAE on fetal health, including FASD; associated comorbidities; and social outcomes. Results/conclusion: The impact of alcohol on fetal health and social outcomes later in life is enormous, placing a huge economic burden on countries. Prevention of prenatal alcohol exposure and early identification of affected individuals should be a global public health priority.
... Zinc is essential for proper immune system function of the fetus, and like smoking itself, zinc deficiency during pregnancy is linked to impaired fetal growth and development (Wellinghausen, 2001;Suzuki et al., 2014). Lack of zinc has also been linked to teratogenicity and neurodevelopmental abnormalities (Kuhnert et al., 1988;Chowanadisai et al., 2013) and in animal models, increasing the zinc supply to the fetus has thus been shown to ameliorate neurotoxicological effects such as the ones caused by prenatal alcohol exposures (Keen et al., 2010). ...
Article
Study question: Does maternal smoking in early pregnancy affect metallothionein 1 and 2 (MT1 and MT2) mRNA and protein expression in first trimester placenta or embryonic/fetal liver? Summary answer: In the first trimester, MT protein expression is seen only in liver, where smoking is associated with a significantly reduced expression. What is known already: Zinc homeostasis is altered by smoking. Smoking induces MT in the blood of smokers properly as a result of the cadmium binding capacities of MT. In term placenta MT is present and smoking induces gene and protein expression (MT2 in particular), but the MT presence and response to smoking have never been examined in first trimester placenta or embryonic/fetal tissues. Study design, size, duration: Cross sectional study where the presence of MT mRNA and protein was examined at the time of the abortion. The material was collected with informed consent after surgical intervention and frozen immediately. For protein expression analysis, liver tissue originating from smoking exposed n = 10 and unexposed n = 12 pregnancies was used. For mRNA expression analyses, placental tissue originating from smokers n = 19 and non-smokers n = 23 and fetal liver tissue from smoking exposed n = 16 and smoking unexposed pregnancies n = 13, respectively, were used. Participants/materials, setting, methods: Tissues were obtained from women who voluntarily and legally chose to terminate their pregnancy between gestational week 6 and 12. Western blot was used to determine the protein expression of MT, and real-time PCR was used to quantify the mRNA expression of MT2A and eight MT1 genes alongside the expression of key placental zinc transporters: zinc transporter protein-1 (ZNT1), Zrt-, Irt-related protein-8 and -14 (ZIP8 and ZIP14). Main results and the role of chance: A significant reduction in the protein expression of MT1/2 in liver tissue (P = 0.023) was found by western blot using antibodies detecting both MT forms. Overall, a similar tendency was observed on the mRNA level although not statistically significant. Protein expression was not present in placenta, but the mRNA regulation suggested a down regulation of MT as well. A suggested mechanism based on the known role of MT in zinc homeostasis could be that the findings reflect reduced levels of easily accessible zinc in the blood of pregnant smokers and hence a reduced MT response in smoking exposed fetal/embryonic tissues. Limitations and reasons for caution: Smoking was based on self-reports; however, our previous studies have shown high consistency regarding cotinine residues and smoking status. Passive smoking could interfere but was found mainly among smokers. The number of fetuses was limited, and other factors such as medication and alcohol might affect the findings. Information on alcohol was not consistently obtained, and we cannot exclude that it was more readily obtained from non-users. In the study, alcohol consumption was reported by a limited number (less than 1 out of 5) of women but with more smokers consuming alcohol. However, the alcohol consumption reported was typically limited to one or few times low doses. The interaction between alcohol and smoking is discussed in the paper. Notably we would have liked to measure zinc status to test our hypothesis, but maternal blood samples were not available. Wider implications of the findings: Zinc deficiency-in particular severe zinc deficiency-can affect pregnancy outcome and growth. Our findings indicate that zinc homeostasis is also affected in early pregnancy of smokers, and we know from pilot studies that even among women who want to keep their babies, the zinc status is low. Our findings support that zinc supplements should be considered in particular to women who smoke. Study funding/competing interest(s): We thank the Department of Biomedicine for providing laboratory facilities and laboratory technicians and the Lundbeck Foundation and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Legat for financial support. The authors have no competing interests to declare. Trial registration number: N/A.
... There are both hyperglutamatergic (MacMaster et al. 2003) and hypoglutamatergic (Carlsson 2000(Carlsson , 2001O'Neill et al. 2013) models of ADHD which link the condition to cell energy metabolism (Russell et al. 2006;Todd and Botteron 2001), but it is not established whether putative glutamatergic abnormalities prevail in both ADHD+PAE and ADHD-PAE etiologies. Recent rodent (Ryan et al. 2008;Schneider and Thomas 2016;Thomas et al. 2000Thomas et al. , 2004Thomas et al. , 2007Thomas et al. , 2009Thomas et al. , 2012 and human (Coles et al. 2015;Kable et al. 2015;Keen et al. 2010;Nguyen et al. 2016;Wozniak et al. 2020) trials of prospective cholinotherapies for FASD have rekindled interest in choline. In a pilot study (O'Neill et al. 2019), we found lower choline in the anterior corona radiata in ADHD+PAE than ADHD-PAE. ...
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Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8–13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.
... These associations may be due to latent factors such as tendencies towards healthy or unhealthy lifestyle behaviours (depicted as the 'risky behaviour' node in the DAG). Among children with PAE, lower calorific intake has been found to increase the risk of FASD, while evidence from animal studies suggests that specific nutrients (including vitamin A, docosahexaenoic acid, folate, zinc, choline, vitamin E, selenium, riboflavin, calcium, docosapentaenoic acid, zinc, B-vitamins, iron and protein) may reduce the risk of FASD-relevant outcomes including physical malformations, growth deficiency, behavioural regulation and memory [98,99,[103][104][105][106]. During pregnancy, mothers of children with FASD report a lower intake of key nutrients and report being hungry more often than controls [59,107]. ...
Article
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Foetal alcohol spectrum disorders (FASDs) are a leading cause of developmental disability. Prenatal alcohol use is the sole necessary cause of FASD, but it is not always sufficient. Multiple factors influence a child’s susceptibility to FASD following prenatal alcohol exposure. Much of the FASD risk factor literature has been limited to discussions of association, rather than causation. While knowledge of predictor variables is important for identifying who is most at risk of FASD and for targeting interventions, causal knowledge is important for identifying effective mechanisms for prevention and intervention programmes. We conducted a systematic search and narrative synthesis of the evidence and used this to create a causal diagram (directed acyclic graph; DAG) to describe the causal pathways to FASD. Our results show that the aetiology of FASD is multifaceted and complex. FASD risk is determined by a range of lifestyle, sociodemographic, maternal, social, gestational, and genetic factors. The causal diagram that we present in this review provides a comprehensive summary of causal risk factors for FASD and can be used as a tool to inform data collection and statistical modelling strategies to minimise bias in future studies of FASD.
... Given that PTP1B dephosphorylates both JAK2 and STAT3 [40][41][42], this phosphatase emerges as a potential target for the adverse consequences of Zn deficiency on astrogliogenesis. In fact, indirect findings showed a possible connection between PTP1B and alcohol-associated Zn deficiency during pregnancy [43]. While prenatal alcohol exposure induces Zn deficiency and impairs Zn utilization by the offspring [44][45][46], PTP1B activity increased in the brain of rats exposed to alcohol during gestation [47]. ...
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We previously showed that zinc (Zn) deficiency affects the STAT3 signaling pathway in part through redox-regulated mechanisms. Given that STAT3 is central to the process of astrogliogenesis, this study investigated the consequences of maternal marginal Zn deficiency on the developmental timing and key mechanisms of STAT3 activation, and its consequences on astrogliogenesis in the offspring. This work characterized the temporal profile of cortical STAT3 activation from the mid embryonic stage up to young adulthood in the offspring from dams fed a marginal Zn deficient diet (MZD) throughout gestation and until postnatal day (P) 2. All rats were fed a Zn sufficient diet (control) from P2 until P56. Maternal zinc deficiency disrupted cortical STAT3 activation at E19 and P2. This was accompanied by altered activation of JAK2 kinase due to changes in PTP1B phosphatase activity. The underlying mechanisms mediating the adverse impact of a decreased Zn availability on STAT3 activation in the offspring brain include: (i) impaired PTP1B degradation via the ubiquitin/proteasome pathway; (ii) tubulin oxidation, associated decreased interactions with STAT3 and consequent impaired nuclear translocation; and (iii) decreased nuclear STAT3 acetylation. Zn deficiency-associated decreased STAT3 activation adversely impacted astrogliogenesis, leading to a lower astrocyte number in the early postnatal and adult brain cortex. Thus, a decreased availability of Zn during early development can have a major and irreversible adverse effect on astrogliogenesis, in part via multistep alterations in the STAT3 pathway.
... Some individuals with PAE have no readily observable impact of their exposure as indicated by the presence of alcohol-related dysmorphia, growth deficits, and alcohol-related neurodevelopmental deficits (Day and Richardson, 1991). The variability in impact may be linked to maternal and fetal genetics (Dodge et al., 2014;Fish et al., 2017), timing of exposure (Sulik, 2014), dosage and patterning of the exposure (Bandoli et al., 2019;Feldman et al., 2012), and various other co-occurring factors that may contribute to adverse fetal development (i.e., nutritional factors (Keen et al., 2010)). A biomarker is needed to identify those for whom intervention may be most beneficial, particularly during infancy when the brain is still going through rapid development (Fox et al., 2010). ...
Article
Background Prenatal alcohol exposure (PAE) has been identified as one of the leading preventable causes of developmental disabilities but early identification of those impacted has been challenging. This study evaluated the use of infant cardiac orienting responses (CORs), which assess neurophysiological encoding of environmental events and are sensitive to the impact of PAE, to predict later Fetal Alcohol Spectrum Disorder (FASD) status. Methods Mother‐infant dyads from Ukraine were recruited during pregnancy based on the mother’s use of alcohol. Participants (n = 120) were then seen at 6 and 12 months when CORs were collected and in the preschool period when they were categorized as having (1) fetal alcohol syndrome (FAS), (2) partial FAS (pFAS), (3) alcohol‐related neurodevelopmental disorder (ARND), (4) PAE and no diagnosis, or (5) no PAE and no diagnosis. To assess CORs, stimuli (auditory tones and pictures) were presented using a fixed‐trial habituation/dishabituation paradigm. Heart rate (HR) responses were aggregated across the first 3 habituation and dishabituation trials and converted to z‐scores relative to the sample’s mean response at each second by stimuli. Z‐scores greater than 1 were then counted by condition (habituation or dishabituation) to compute a total risk index. Results Significant group differences were found on total deviation scores of the CORs elicited from visual but not auditory stimuli. Those categorized as pFAS/FAS had significantly higher total deviation scores than did those categorized as ARND or as having no alcohol‐related diagnosis with or without a history of PAE. Receiver operating characteristic curve analysis of the visual response yielded an area under the curve value of .765 for predicting to pFAS/FAS status. Conclusions A score reflecting total deviation from typical HR during CORs elicited using visual stimuli in infancy may be useful in identifying individuals who need early intervention as a result of their PAE.
... In developing countries, over half-a-million deaths of infants and small children are caused by a deficiency of zinc [9]. Special attention is paid to the influence of alcohol during pregnancy, which changes the metabolism of zinc and causes serious consequences for the foetus [10]. ...
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Introduction. Interactions occur between concentrations of metals in the human body and the environment in various geographic locations, which can be of importance for both the proper development and the course of pregnancy. Objective. The aim of the study was to assess the concentrations of Zn, Cu and Cd and Zn:Cu and Zn:Cd molar ratios in the placenta, umbilical cord and in the foetal membrane, and to examine the relationship between concentrations of these elements and the place of residence. Materials and method. The research material was obtained from 99 healthy women from north-western and central Poland. Data for the study were collected from the medical history and documents of admission to the ward and documents confirming the birth of the newborn. Concentrations of zinc (Zn), copper (Cu) and cadmium (Cd) were determined using the ICP–AES method (spectrophotometry of atomic absorption) in inductively coupled argon plasma. Results. The average concentration of Zn, Cu and Cd in afterbirths was ~ 0.01 mg/kg of dry weight (dw). In central Poland, the results revealed a significant increase in zinc in the membrane (OR=1.098, p=0.002), cadmium in the placenta (OR=1.324, p=0.006), Zn:Cu in the membrane (OR=1.012, p<0.001). In north-western Poland, an increase in copper in the membrane (OR=1.239, p=0.025) was revealed. Conclusions. The use biological materials, such as the placenta, foetal membrane and umbilical cord to assess exposure to heavy metals and necessary elements is justified.
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Neurobehavioral disorder associated with prenatal alcohol exposure (ND_PAE) was proposed to capture the full range of mental health problems found in individuals who have been adversely impacted by their prenatal alcohol exposure (PAE). The disorder can be used with individuals who both have and do not have the physical symptoms of PAE. Specific symptoms of the disorder are described and the psychometric characteristics of the disorder are reviewed. Although there is substantial evidence to support the validity of the symptoms in individuals with a history of PAE, the unique formulation of these symptoms as currently proposed in the American Psychiatric Diagnostic and Statistical Manual, fifth edition (DSM-5), may need modification.
Article
Background: We previously reported that maternal alcohol use significantly increases the risk of sepsis in premature and term newborns. In the mouse, fetal ethanol exposure results in an immunosuppressed phenotype for the alveolar macrophage (AM) and decreases bacterial phagocytosis. In pregnant mice, ethanol decreased AM zinc homeostasis, which contributed to immunosuppression and impaired AM phagocytosis. In this study, we explored whether ethanol-induced zinc insufficiency extended to the pup AMs and contributed to immunosuppression and exacerbated viral lung infections. Methods: C57BL/6 female mice were fed a liquid diet with 25% ethanol-derived calories or pair-fed a control diet with 25% of calories as maltose-dextrin. Some pup AMs were treated in vitro with zinc acetate before measuring zinc pools or transporter expression and bacteria phagocytosis. Some dams were fed additional zinc supplements in the ethanol or control diets, and then we assessed pup AM zinc pools, zinc transporters, and the immunosuppressant TGFβ1. On postnatal day 10, some pups were given intranasal saline or respiratory syncytial virus (RSV), and then AM RSV phagocytosis and the RSV burden in the airway lining fluid were assessed. Results: Fetal ethanol exposure decreased pup AM zinc pools, zinc transporter expression, and bacterial clearance, but in vitro zinc treatments reversed these alterations. In addition, the expected ethanol-induced increase in TGFβ1 and immunosuppression were associated with decreased RSV phagocytosis and exacerbated RSV infections. However, additional maternal zinc supplements blocked the ethanol-induced perturbations in the pup AM zinc homeostasis and TGFβ1 immunosuppression, thereby improving RSV phagocytosis and attenuating the RSV burden in the lung. Conclusion: These studies suggest that, despite normal maternal dietary zinc intake, in utero alcohol exposure results in zinc insufficiency, which contributes to compromised neonatal AM immune functions, thereby increasing the risk of bacterial and viral infections.
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Annika C Montag Department of Pediatrics, Division of Dysmorphology and Teratology, University of California San Diego, San Diego, CA, USA Abstract: Fetal alcohol-spectrum disorders (FASDs) are a collection of physical and neuro­behavioral disabilities caused by prenatal exposure to alcohol. To prevent or mitigate the costly effects of FASD, we must identify mothers at risk for having a child with FASD, so that we may reach them with interventions. Identifying mothers at risk is beneficial at all time points, whether prior to pregnancy, during pregnancy, or following the birth of the child. In this review, three approaches to identifying mothers at risk are explored: using characteristics of the mother and her pregnancy, using laboratory biomarkers, and using self-report assessment of alcohol-consumption risk. At present, all approaches have serious limitations. Research is needed to improve the sensitivity and specificity of biomarkers and screening instruments, and to link them to outcomes as opposed to exposure. Universal self-report screening of all women of childbearing potential should ideally be incorporated into routine obstetric and gynecologic care, followed by brief interventions, including education and personalized feedback for all who consume alcohol, and referral to treatment as indicated. Effective biomarkers or combinations of biomarkers may be used during pregnancy and at birth to determine maternal and fetal alcohol exposure. The combination of self-report and biomarker screening may help identify a greater proportion of women at risk for having a child with FASD, allowing them to access information and treatment, and empowering them to make decisions that benefit their children. Keywords: fetal alcohol-spectrum disorder (FASD), alcohol, pregnancy, screening, biomarkers, SBIRT
Article
Alcohol is a well-established teratogen that can cause variable physical and behavioral effects on the fetus. The most severe condition in this spectrum of diseases is known as fetal alcohol syndrome (FAS). The differences in maternal and fetal enzymes, in terms of abundance and efficiency, in addition to reduced elimination, allow for alcohol to have a prolonged effect on the fetus. This can act as a teratogen through numerous methods including reactive oxygen species (generated as by products of CYP2E1), decreased endogenous antioxidant levels, mitochondrial damage, lipid peroxidation, disrupted neuronal cell-cell adhesion, placental vasoconstriction, and inhibition of cofactors required for fetal growth and development. More recently, alcohol has also been shown to have epigenetic effects. Increased fetal exposure to alcohol and sustained alcohol intake during any trimester of pregnancy is associated with an increased risk of FAS. Other risk factors include genetic influences, maternal characteristics, for example, lower socioeconomic statuses and smoking, and paternal chronic alcohol use. The treatment options for FAS have recently started to be explored although none are currently approved clinically. These include prenatal antioxidant administration food supplements, folic acid, choline, neuroactive peptides, and neurotrophic growth factors. Tackling the wider impacts of FAS, such as comorbidities, and the family system have been shown to improve the quality of life of FAS patients. This review aimed to focus on the pathogenesis, especially mechanisms of alcohol teratogenicity, and risks of developing FAS. Recent developments in potential management strategies, including prenatal interventions, are discussed.
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Alcohol-related diseases, including those of the brain, liver, pancreas, and the lung, result both from the direct toxic effects of alcohol and the indirect effects of nutritional deficiencies associated with drinking. Individuals who consume significant amount of alcohol (ethanol) derive most of their caloric intake from the alcoholic beverages and foods rich in unhealthy fats and added sugars. When alcohol intake replaces food, there can be numerous nutritional deficiencies caused by the lack of adequate nutrients intake [1–3]. Excessive alcohol consumption can induce deficiencies of vitamins and minerals such as riboflavin, B12, vitamin A, folate, possibly retinoic acid, Zn, and calcium. From the many studies published to date, it is evident that, in addition to the independent effects of heavy drinking, various dietary factors play a vital role in the development and progression of various diseases attributed to alcohol abuse [1, 4].
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Some historical clues suggest an ancient understanding that alcohol should be avoided during pregnancy, but these may have been overstated. Further evidence appears during times of widespread alcohol use in the middle ages, but the current understanding of prenatal alcohol exposure and FASD has its source in the latter half of the 20th century. This chapter describes the history of FASD, from Aristotle and the Old Testament up to modern neuroscience and genetics. After bringing the reader back to the present day, there follows a review of the mechanisms of alcohol-related harm to the foetus, and factors that mediate that harm.
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Maternal alcohol use and abuse can have devastating consequences to fetal development and outcomes. Although there is widespread societal pressure, particularly within developed countries, against the ingestion of any alcohol during pregnancy, many women may drink heavily before they recognize they are pregnant or may continue to do so despite their awareness. Much of the focus among healthcare professionals and biomedical investigators has been on the fetal alcohol syndrome (FAS), more commonly now referred to as the fetal alcohol spectrum disorder (FASD), which in its most advanced form is manifested by craniofacial abnormalities and severe neurocognitive deficits. However, FAS and FASD are disorders in term infants, and it is now being recognized that maternal alcohol ingestion appears to impact the risk for both premature delivery as well as medical complications associated with neonatal prematurity. In particular, experimental and clinical evidence is beginning to elucidate the mechanisms by which maternal alcohol ingestion can increase the already significant oxidative stress within the neonatal lung and impair host immune functions. As a consequence, the premature neonate with significant exposure to alcohol in utero appears to be at an even greater risk of developing serious infectious complications. Further, experimental models suggest that maternal alcohol ingestion can impair prenatal lung development and, if these findings translate to the human condition, could thereby render the premature infant at increased risk for adverse complications including bronchopulmonary dysplasia and late-onset sepsis. This chapter provides a brief overview of the epidemiology of maternal alcohol use during pregnancy and highlights some of the experimental and clinical evidence that show that such use can have devastating effects on neonatal outcomes.
Article
Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in quail embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.
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Pregnant women are at risk of developing trace elements deficiency. This is attributed to deficient dietary sources, physiological changes during pregnancy, and genetic factors. Adequate trace elements are essential for the health of the mother and her fetus. Many deleterious effects are associated with trace elements deficiency, which can be extended even after delivery and contribute to maternal and fetal morbidity and mortality. Trace elements deficiency can lead to congenital malformations, e.g., neural tube defects, aortic aneurysm, and valvular lesions. Clinical trials demonstrated that supplementation of trace elements has beneficial effects. This chapter highlights the molecular mechanism by which select trace elements are implicated in the pathogenicity of selected clinical conditions such as gestational diabetes, preeclampsia, low birth weight, and teratogenicity.
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Exposure to alcohol during pregnancy is associated with an increased risk of spontaneous abortion, growth retardation, congenital malformations and central nervous system dysfunction [1, 2]. These negative birth outcomes, which are collectively referred to as fetal alcohol spectrum disorder (FASD), range in severity from full fetal alcohol syndrome (FAS) through milder although clinically significant forms which can affect physical and behavioural outcomes (i.e. alcohol-related birth defects (ARBD) and alcohol-related neurodevelopmental disorders (ARND)). These outcomes are associated not only with chronic consumption of alcohol at high intakes and frequency but also with a single episode of alcohol intake, which is commonly called ‘binge drinking’ (>4 drinks/occasion). Although abstinence from alcohol during pregnancy would prevent these disorders, the motivation for self-restraint from drinking alcohol is not uniformly accepted among women [3–6]. Moreover, up to two-thirds of pregnancies are reported to be unplanned, indicating that many women may be unaware of their pregnancy when consuming alcohol [3, 5, 6]. Thus, the consumption of alcohol during pregnancy will continue to negatively impact on birth outcomes well into the future.
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Background: Large general population surveys show that heavy regular and episodic alcohol consumption are associated with lower intakes of fruits and vegetables, and higher intakes of processed and fried meat. This is of particular concern regarding pregnant women, as both alcohol intake and inadequate maternal nutrition are independently associated with adverse fetal outcomes. The current study aimed to determine associations between maternal dietary patterns and alcohol consumption during pregnancy. Methods: Women were participating in the Avon Longitudinal Study of Parents and Children, and provided details of alcohol consumption at 18 weeks' gestation and diet at 32 weeks' gestation (n = 9,839). Dietary patterns were derived from the food frequency questionnaire data using principal components analysis. Associations between alcohol consumption and dietary patterns were determined using multiple linear regression, adjusted for various sociodemographic and lifestyle factors. Results: After adjustment, drinking ≥1 unit/d during the first trimester (β = 0.23 [95% CI: 0.08, 0.38]; p = 0.002) and binge drinking (≥4 units in 1 day) during the first half of pregnancy (β = 0.14 [95% CI: 0.07, 0.21]; p < 0.0001) were associated with greater adherence to the "Processed" dietary pattern (high intakes of processed meat and low intakes of fruit and vegetables). Light-to-moderate alcohol consumption (≤1 drink/d) during the first trimester was associated with greater adherence to the "Health conscious" dietary pattern (high intakes of fruit, vegetables, whole grains, and fish) (β = 0.09 [95% CI: 0.04, 0.14]; p < 0.0001). Conclusions: Two important components of health behavior during pregnancy appear to be related: greater consumption of processed foods associated with heavier alcohol consumption, and healthier dietary choices associated with light-to-moderate alcohol intake. Potential synergistic effects of these behaviors may have implications for maternal and fetal health and warrant further investigation. A more holistic approach to addressing health behaviors in women of reproductive age is required.
Article
Compute population prevalence rates of neural tube defects and microcephaly as well as levels of incorporated Cs137 by pregnant women in two areas of the Rivne Province of Ukraine, a northern half (Polissia) polluted by Chornobyl radiation and not‐Polissia areas. Monitoring of congenital malformations was conducted with adherence to methods adopted by a European surveillance network (EUROCAT). Incorporated Cs137 (Bq/kg) by pregnant women residing in the Polissia and not‐Polissia areas were obtained concurrently with prenatal ultrasound examinations. In Polissia, the incorporated Cs137 levels by pregnant women as well as the prevalence rates of neural tube defects and microcephaly are significantly higher than in not‐Polissia. In Polissia, the prevalence rates of neural tube defects and microcephaly are among the highest in Europe. The debate concerning the teratogenic impact of chronic exposures to low levels of ionizing radiation was re‐ignited by our 2010 report. Health agencies uphold the notion that exposure to Chornobyl radiation levels are too low to be teratogenic, which is inconsistent with our observations. Further investigations in Rivne by international teams can, we believe, contribute facts to the ongoing debate. Our monitoring system, experience and data can facilitate concurrent investigations of teratogenic risks from exposures to other sources of ionizing radiation, alcohol, folate and zinc deficiencies, among other risk factors. Study of genomic impacts can likewise be undertaken. This article is protected by copyright. All rights reserved.
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Objective To investigate associations between alcohol consumption patterns and diet quality, nutrient intakes and biochemical profile of women of childbearing age. Design Nutrient intake data from 24 h diet recalls, alcohol consumption data and diet quality from the Dietary Habits Questionnaire, and biochemical analyses from the cross-sectional 2008/09 Adult Nutrition Survey in New Zealand. Setting New Zealand households. Participants New Zealand women aged 18–45 years ( n 1124). Results All analyses were completed using Stata and survey weights were used to allow for the complex survey design to produce population estimates. Multinomial logistic regression models were used to examine the associations between drinking patterns and the variables of interest, with ‘infrequent moderate/light’ drinkers being the reference category. The findings indicate that alcohol-consuming women of childbearing age tend to replace food energy with alcohol energy ( P = 0·022). ‘More frequent heavy’ and ‘more frequent moderate/light’ drinkers had higher intakes of total, mono- and polyunsaturated fats with the latter group also consuming higher levels of saturated fats ( P < 0·05). Women who were ‘infrequent moderate/light’ drinkers had relatively better diet quality, nutrient intakes and adequate biochemical status in comparison to other drinkers and abstainers. ‘Infrequent heavy’ drinkers, who were predominantly younger in age, had lower serum vitamin B 12 levels ( P = 0·01) with a higher proportion of women in this category having below-recommended levels of serum folate ( P < 0·05). Conclusions Alcohol consumption, especially heavy drinking patterns, may compromise nutritional status of women of childbearing age.
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Objective: To review data on the role of ethanol-induced alteration of Zn homeostasis in mediation of adverse effects of alcohol abuse. Methods: The scholarly published articles on the association between Zn metabolism and alcohol-associated disorders (liver, brain, lung, gut dysfunction, and fetal alcohol syndrome) have been reviewed. Results: It is demonstrated that alcohol-induced modulation of zinc transporters results in decreased Zn levels in lungs, liver, gut, and brain. Zn deficiency in the gut results in increased gut permeability, ultimately leading to endotoxemia and systemic inflammation. Similarly, Zn deficiency in lung epithelia and alveolar macrophages decreases lung barrier function resulting in respiratory distress syndrome. In turn, increased endotoxemia significantly contributes to proinflammatory state in alcoholic liver disease. Finally, impaired gut and liver functions may play a significant role in alcoholic brain damage, being associated with both increased proinflammatory signaling and accumulation of neurotoxic metabolites. It is also hypothesized that ethanol-induced Zn deficiency may interfere with neurotransmission. Similar changes may take place in the fetus as a result of impaired placental zinc transfer, maternal zinc deficiency, or maternal Zn sequestration, resulting in fetal alcoholic syndrome. Therefore, alcoholic Zn deficiency not only mediates the adverse effects of ethanol exposure, but also provides an additional link between different alcohol-induced disorders. Conclusions: Generally, current findings suggest that assessment of Zn status could be used as a diagnostic marker of metabolic disturbances in alcohol abuse, whereas modulation of Zn metabolism may be a potential tool in the treatment of alcohol-associated disorders.
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Human infertility has become a serious medical and social issue worldwide, especially in developed countries. Numerous assisted reproductive technologies (ARTs) (e.g., artificial insemination [AI], in vitro fertilization [IVF], and intracytoplasmic sperm injection [ICSI]) are widely used to treat infertility, but when embryos produced using these techniques are transferred, the pregnancy outcome is only approx. 20–50%, necessitating further improvement in ARTs. Many factors (including zinc) affect successful fertilization, further embryonic development, and the establishment and maintenance of pregnancy. Zinc signaling has many physiological functions in various types of cells, and it is thus speculated that zinc signaling has an important role in the abovementioned reproductive events, even in germ cells and reproductive tissues. Prior studies demonstrated that zinc deficiency results in a number of anomalies in the formation and maturation of spermatozoa, ovulation, and fertilization. During pregnancy, zinc deficiency causes spontaneous abortion, pregnancy-related toxemia, extended pregnancy or preterm birth, malformations, and retarded growth. The molecular mechanisms underlying zinc signaling in reproduction are not yet clear. In this chapter, we summarize the current knowledge about zinc signaling in reproduction—mainly in mammals—and we discuss recent advances in this field.
Article
The potential impact of prenatal alcohol exposure (PAE) varies considerably among exposed individuals, with some displaying serious alcohol-related effects and others showing few or even no overt signs of a fetal alcohol spectrum disorder (FASD). In animal models variables such as nutrition, genetic background, health, other drugs, and stress, as well as dosage, duration and gestational timing of alcohol exposure can all be controlled in a way not possible in a clinical situation. In this review we examine mouse PAE models and focus on those with demonstrated craniofacial malformations, abnormal brain development, or behavioural phenotypes that may be considered FASD-like outcomes. Analysis of these data should provide a valuable tool for researchers wishing to choose the PAE model best-suited to their research questions or to investigate established PAE models for FASD comorbidities. It should also allow recognition of patterns linking gestational timing, dosage and duration of PAE with FASD-like outcomes. The latter could be particularly insightful and lead to a better understanding of the molecular mechanisms underlying FASD.
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Objective Reducing alcohol use during pregnancy is a pressing public health priority in Sub-Saharan Africa, but insight into the factors that influence prenatal drinking practices is lacking. This study investigated perceptions of, and motivations for, alcohol consumption during pregnancy and associated practices in a rural district of Lesotho. Methods A combination of purposive and snowball sampling methods were used to identify pregnant women and mothers with young children from the general community, as well as from alcohol-serving venues. Between September 2016 and March 2017, a trained data collector conducted in-depth interviews with 40 women on reasons why pregnant women drink, what they know about the risk of drinking alcohol during pregnancy, and perceptions of women who drink during pregnancy. Results Sixty-five percent of women (n = 26) reported that they consumed alcohol during pregnancy. Findings were clustered into four themes: 1) alcohol use in daily and cultural life; 2) alcohol as relief from stress and hunger; 3) alcohol's effect on the baby; and 4) access to information about alcohol consumption. Our data suggest that alcohol use was a prominent feature of daily life and a key part of traditional events and ceremonies. Other than potentially harming the baby through falling on their stomachs while inebriated, women did not mention other risks associated with prenatal alcohol use. Rather, there were prominent beliefs that drinking alcohol – home-brewed alcohol in particular – had cleansing or protective benefits for the baby. Experiences of food insecurity were prominent, and women reported that alcohol helped curb their hunger and allowed them to save food to give to their children. Conclusions Within this context of chronic poverty and food insecurity, alcohol use during pregnancy will continue to represent a valid, though tragic choice if the structural conditions and current social arrangements that facilitate prenatal alcohol use remain unchanged.
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In utero alcohol exposure can disrupt the development of the fetal brain and result in a wide‐range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). This paper provides a comprehensive review of the cognitive and behavioral outcomes of prenatal alcohol exposure, including domains of general intelligence, executive functioning, language development, learning and memory, adaptive functioning, academic performance, and concurrent psychopathology. In addition, the current status of the neurobehavioral profile of FASD and its potential as a diagnostic tool will be discussed. This article is protected by copyright. All rights reserved.
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The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Optimal maternal nutritional status is of great importance for proper fetal development, yet is often altered with alcohol or drugs consumption. There is a lack of information on the effects of alcohol and drugs on maternal nutritional status, so the focus of this review was to provide an overview on nutrional status of mother and fetus in abusers pregnant women. Alcohol and drugs consumption can adversely affect the quality and quantity of proper nutrient supply and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega-3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs essential nutrients are not available for the fetus, this can result in suboptimal outcomes like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to determine a means to resolve and reduce the physical and neurological malformations that develop in the fetus as a result of prenatal alcohol and drugs exposure combined with poor maternal nutrition. Prenatal nutrition interventions are required that may prevent or alleviate the development of such abnormalities.
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Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, beta-carotene, ascorbic acid, and alpha-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At approximately 14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% CI were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy-adjusted intakes of vegetable protein, fiber, beta-carotene, ascorbic acid, alpha-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC.
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The insulin-like growth factor (IGF) axis, a key regulator of embryonic growth and development, is exquisitely sensitive to the nutrient status of the animal. In addition to macronutrient deficiencies, zinc deficiency can impact the IGF axis. Gestational zinc deficiency is teratogenic, resulting in intrauterine growth retardation and structural abnormalities. The aim of this study was to investigate the effects of gestational zinc deficiency on the fetal IGF axis in a rat model. From gestation day (GD) 0.5, dams consumed zinc-deficient (ZD, 0.3 mg zinc/kg) or control (25 mg zinc/kg) diet ad libitum, while a third group of dams consumed the control diet in amounts equivalent to the food intake of the ZD dams (Paired group). On GD 19.5 fetal tissue, blood and amniotic fluid were collected. Fetal growth was significantly reduced by zinc deficiency compared with the Paired and Control groups. Fetuses from the Paired group were smaller compared with the Control, but only ZD fetuses had structural malformations. Amniotic fluid IGF-1 concentrations were significantly lower in the Paired group than in the ZD and Control groups. Plasma of ZD fetuses contained lower levels of IGF binding protein-1 when compared with fetuses in the Paired and Control groups. Fetal liver IGF-1 mRNA levels were lower in the ZD fetuses than in the Paired and Control fetuses. These observations suggest that differences in the fetal IGF axis between ZD and Paired groups contribute to the poor pregnancy outcome and enhanced fetal growth retardation observed with zinc deficiency.
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Early life nutritional exposures, combined with changes in lifestyle in adult life, can result in increased risk of chronic diseases. Although much of the focus on the developmental origins of disease has been on birth size and growth in postnatal life and the availability of energy and protein during these critical developmental periods, micronutrient deficiencies may also play an important role in fetal growth and development. Micronutrient status in fetal and early life may alter metabolism, vasculature, and organ growth and function, leading to increased risk of cardiometabolic disorders, adiposity, altered kidney function, and, ultimately, to type 2 diabetes and cardiovascular diseases. This review elucidates pathways through which micronutrient deficiencies lead to developmental impairment and describes the research to date on the evidence that micronutrient deficiencies in utero influence the development of chronic disease risk. Animal studies, observational human studies examining maternal diet or micronutrient status, and limited data from intervention studies are reviewed. Where data are lacking, plausible mechanisms and pathways of action have been derived from the existing animal and in vitro models. This review fills a critical gap in the literature related to the seminal role of micronutrients in early life and extends the discussion on the developmental origins of health and disease beyond birth size and energy and protein deficiency.
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Although iron and zinc deficiencies are known to occur together and also appear to be high in Ghana, a few supplementation studies addressed this concurrently in pregnancy. In a double-blind, randomized controlled trial, 600 pregnant women in Ghana were randomly assigned to receive either a combined supplement of 40 mg of zinc as zinc gluconate and 40 mg of iron as ferrous sulphate or 40 mg of elemental iron as ferrous sulphate. Overall, there was no detectable difference in the mean birthweight between the study groups, although the effect of iron-zinc supplementation on the mean birthweight was masked by a strong interaction between the type of supplement and the iron status of participants [F (1,179) = 5.614, p = 0.019]. Prenatal iron-zinc supplementation was effective in increasing the mean birthweight among anaemic and iron-deficient women but not among women with elevated iron stores in early pregnancy.
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Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G0/G1 phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis.
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"Barker's hypothesis" emerged almost 25 years ago from epidemiological studies of birth and death records that revealed a high geographic correlation between rates of infant mortality and certain classes of later adult deaths as well as an association between birthweight and rates of adult death from ischemic heart disease. These observations led to a theory that undernutrition during gestation was an important early origin of adult cardiac and metabolic disorders due to fetal programming that permanently shaped the body's structure, function, and metabolism and contributed to adult disease. This theory stimulated interest in the fetal origins of adult disorders, which expanded and coalesced approximately 5 years ago with the formation of an international society for developmental origins of health and disease (DOHaD). Here we review a few examples of the many emergent themes of the DOHaD approach, including theoretical advances related to predictive adaptive responses of the fetus to a broad range of environmental cues, empirical observations of effects of overnutrition and stress during pregnancy on outcomes in childhood and adulthood, and potential epigenetic mechanisms that may underlie these observations and theory. Next, we discuss the relevance of the DOHaD approach to reproductive medicine. Finally, we consider the next steps that might be taken to apply, evaluate, and extend the DOHaD approach.
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Deprivation is associated with poor pregnancy outcome but the role of nutrition as a mediating factor is not well understood. We carried out a prospective cohort study of 1461 singleton pregnancies in Aberdeen, UK during 2000-6. We measured nutrient intake and supplement use, B vitamin and homocysteine status, birth weight, gestational age, neonatal treatment and socio-economic deprivation status. Women in the most deprived deciles were approximately 6 years younger and half as likely to take folic acid supplements periconceptually as the least deprived mothers. Deprivation was associated with low blood folate, high homocysteine and diets low in protein, fibre and many of the vitamins and minerals. The diets of the more deprived women were also characterised by low intakes of fruit, vegetables and oily fish and higher intakes of processed meat, fried potatoes, crisps and snacks. Deprivation was related to preterm birth (OR 1.14 (95 % CI 1.03, 1.25); P = 0.009) and whether the baby required neonatal treatment (OR 1.07 (95 % CI 1.01, 1.14); P = 0.028). Low birth weight was more common in women consuming diets low in vitamin C (OR 0.79 (95 % CI 0.64, 0.97); P = 0.028), riboflavin (OR 0.77 (95 % CI 0.63, 0.93); P = 0.008), pantothenic acid (OR 0.79 (95 % CI 0.65, 0.97); P = 0.023) and sugars (OR 0.78 (95 % CI 0.64, 0.96); P = 0.017) even after adjustment for deprivation index, smoking, marital status and parity. Deprivation in pregnancy is associated with diets poor in specific nutrients and poor diet appears to contribute to inequalities in pregnancy outcome. Improving the nutrient intake of disadvantaged women of childbearing age may potentially improve pregnancy outcome.
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The aim of this study was to assess the effect of high dose zinc (Zn) supplement during pregnancy in pregnancy outcome in healthy pregnant women with a previous preterm delivery in Isfahan, Iran. A double-blind placebo-controlled randomized clinical trial was conducted between January 2007 and June 2008. Eighty-four pregnant women with a previous preterm delivery age 19 to 35 years were randomly allocated to receive either 50 mg/day Zn as Zn sulfate or placebo from 12 to 16 weeks of gestation till delivery. Pregnancy outcome was assessed in term of incidence of intrauterine growth retardation (IUGR), birth weight, crown-heel length, head circumference, Apgar score, and gestational age at delivery. The mean birth head circumference was higher in Zn supplemented group than in the placebo group (35.0 cm vs. 33.7 cm, P < 0.05). Although gestational age at delivery (37.1 week vs. 36.7 week) and birth weight (2960.6 g vs. 2819.0 g) of babies born in Zn supplemented group was slightly higher than placebo group, it was not statistically significant. No significant differences were seen for infant length, Apgar score, and IUGR. Adding Zn supplementation during pregnancy to routine care of women with a previous preterm delivery had no significant effect on the gestational age at delivery and birth weight but increased the birth head circumference.
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Previous studies have shown a high rate of neural tube defects (NTD) in Gorgan, northern (tub efcs (NTD) in Gorgan, northern Islamic Republic of Iran. This case-control study during 2003-04 compared serum zinc levels and other variables in 23 mothers of neonates affected with NTD and 36 mothers with normal healthy neonates in Dezyani hospital in Gorgan. Mean serum zinc levels in the case and control groups were 13.43 micromol/L (SD 6.3) and 11.41 micromol/L (SD 6.3) respectively. Zinc deficiency was found in 13 (36.5%) of the cases and 7 (19.4%) of the controls. Logistic regression analysis showed an association between the presence of NTD and zinc deficiency (OR 5.06; 95% CI: 1.51-16.94).
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Zinc deficiency increases the risk and severity of a variety of infections, restricts physical growth, and affects specific outcomes of pregnancy. Global recognition of the importance of zinc nutrition in public health has expanded dramatically in recent years, and more experience has accumulated on the design and implementation of zinc intervention programs. Therefore, the Steering Committee of the International Zinc Nutrition Consultative Group (IZiNCG) completed a second IZiNCG technical document that reexamines the latest information on the intervention strategies that have been developed to enhance zinc nutrition and control zinc deficiency. In particular, the document reviews the current evidence regarding preventive zinc supplementation and the role of zinc as adjunctive therapy for selected infections, zinc fortification, and dietary diversification or modification strategies, including the promotion and protection of breastfeeding and biofortification. The purposes of this introductory paper are to summarize new guidelines on the assessment of population zinc status, as recommended by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the International Atomic Energy Agency (IAEA), and IZiNCG, and to provide an overview on several new advances in zinc metabolism. The following papers will then review the intervention strategies individually.
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Adolescents are more likely than adults to consume energy-dense, micronutrient-poor diets and to experience adverse pregnancy outcomes. The objectives were to assess micronutrient intake and blood biomarkers prospectively in pregnant adolescents recruited to the About Teenage Eating (ATE) Study and to determine associations with pregnancy outcome. Pregnant adolescents (n = 500) were recruited from 2 UK inner city populations. 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. 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). Poor micronutrient intake and status increase the risk of SGA births in pregnant adolescents.
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Chronic alcohol abuse impairs both alveolar epithelial and macrophage function, and renders individuals susceptible to acute lung injury, pneumonia, and other serious lung diseases. Zinc deficiency, which is known to impact both epithelial and immune cell functions, is also associated with alcohol abuse. In this study, chronic alcohol ingestion (6 wk) in rats altered expression of key zinc transporters and storage proteins in the small intestine and the lung, and decreased zinc levels in the alveolar compartment. Zinc supplementation of alveolar epithelial monolayers derived from alcohol-fed rats in vitro, or of the diets of alcohol-fed rats in vivo, restored alveolar epithelial barrier function, and these improvements were associated with salutary changes in tight junction protein expression and membrane localization. In parallel, dietary zinc supplementation increased intracellular zinc levels, GM-CSF receptor expression, and bacterial phagocytic capacity in the alveolar macrophages of alcohol-fed rats. Together, these studies implicate zinc deficiency as a novel mechanism mediating alcohol-induced alveolar epithelial and macrophage dysfunction. Importantly, these findings argue that dietary supplementation can overcome alcohol-induced zinc deficiency and restore alveolar epithelial and macrophage function, and therefore could be an effective treatment for the susceptible alcoholic lung phenotype.
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Nutrient requirements increase during periods of growth and development such as pregnancy and lactation. In response, many clinicians recommend dietary supplements during these important periods of the life cycle. Although there exist some recommendations concerning the need for a limited number of nutrients in supplemental form (eg, iron, folic acid, and iodine), there is a relative paucity of data concerning the use of dietary supplements during pregnancy and lactation. Limited data suggest, however, that usage is dependent on demographic, sociologic, and economic factors. Thus, it is possible that the nation's most at-risk populations may be those who are least likely to comply with these recommendations. As researchers continue to study what is meant by "optimal nutrition" during pregnancy and lactation, it is likely that additional recommendations concerning dietary supplements will emerge. For example, it is possible that increased consumption of some of the long-chain polyunsaturated fatty acids during pregnancy or lactation may impart a benefit to infant health. Understanding better the population dynamics related to supplement use during these periods will be critical in implementation of campaigns designed to encourage appropriate use--and discourage inappropriate use--of dietary supplements during these important phases of human reproduction. The purpose of this article is to briefly review what is known about the use of dietary supplements in North America and, more specifically, in pregnant and lactating women. In addition, information concerning barriers to supplement use is discussed as are current recommendations for dietary supplement consumption during these periods of the life cycle.
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During development, the fetus is entirely dependent on the mother for its nutrient requirements. Subsequently, it is a period when both are vulnerable to changes in dietary supply, especially of those nutrients that are marginal under normal circumstances. In developed countries, this applies mainly to micronutrients. Even now, iron deficiency is a common disorder, especially in pregnancy. Similarly, copper intake in the U.K. population is rarely above adequate levels. It is now becoming clear that nutrient deficiencies during pregnancy can result in problems for the offspring, in both the short- and long-term. Early studies showed that lambs born to mothers on copper-deficient pastures developed 'swayback', with neurological and muscular symptoms that could not be reversed by postnatal supplementation. Our own findings have shown that prenatal iron deficiency results in increased postnatal blood pressure, even though the offspring have normal dietary iron levels from birth. These observations emphasize the importance of iron and copper in growth and development. Complicating the situation further is the fact that copper and iron are known to interact with each other in many ways, including absorption and intracellular transport. However, their interactions during the pregnancy appear to be more complex than during the non-pregnant state. In the present review, we examine the importance of these metals and their interactions, the consequences, both short- and long-term, of deficiency and consider some possible mechanisms whereby these effects may be generated.
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