You are currently viewing a new version of our website. To view the old version click .
MDPIMDPI
Search all articles
Nutrients
Download PDF
  • Review
  • Open Access

30 June 2023

Nutrient Supplementation during the Prenatal Period in Substance-Using Mothers: A Narrative Review of the Effects on Offspring Development

,
,
and
1
Baby Health Behavior Laboratory, Division of Health Services and Outcomes Research, Children’s Mercy Research Institute, Children’s Mercy Hospital, Kansas City, MO 64108, USA
2
Department of Psychology and the Social Science Research Institute, The Pennsylvania State University, University Park, PA 16801, USA
3
Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO 64110, USA
4
Center for Children’s Healthy Lifestyles and Nutrition, University of Kansas Medical Center, Kansas City, KS 66160, USA
Nutrients2023, 15(13), 2990;https://doi.org/10.3390/nu15132990
This article belongs to the Special Issue Maternal and Infant Nutrition Strategy
Version Notes
Order Reprints

Abstract

Substance use during pregnancy increases the risk for poor developmental outcomes of the offspring, and for substance-dependent mothers, abstaining from substance use during pregnancy is often difficult. Given the addictive nature of many substances, strategies that may mitigate the harmful effects of prenatal substance exposure are important. Prenatal nutrient supplementation is an emerging intervention that may improve developmental outcomes among substance-exposed offspring. We provide a narrative review of the literature on micronutrient and fatty acid supplementation during pregnancies exposed to substance use in relation to offspring developmental outcomes. We first discuss animal models exposed to ethanol during pregnancy with supplementation of choline, zinc, vitamin E, iron, and fatty acids. We follow with human studies of both alcohol- and nicotine-exposed pregnancies with supplementation of choline and vitamin C, respectively. We identified only 26 animal studies on ethanol and 6 human studies on alcohol and nicotine that supplemented nutrients during pregnancy and reported offspring developmental outcomes. There were no studies that examined nutrient supplementation during pregnancies exposed to cannabis, illicit substances, or polysubstance use. Implementations and future directions are discussed.

1. Introduction

Prenatal substance use is a public health concern. There have been significant variations in the prevalence of different substances used during pregnancy across the last three decades [1]. Contemporary data indicate that among pregnant women 18–49 years of age, 13.5% consume alcohol, and 5.2% reported binge drinking, which is defined as having four or more drinks on a single occasion within the last month [2]. Further, 8.4% of pregnant women reported tobacco use, 0.4% used illicit drugs other than cannabis, and 8.0% used cannabis within the last month [3]. There is an extensive body of research indicating an increased risk for mother–infant morbidity and poorer developmental outcomes across time as a function of prenatal substance exposure. For instance, chronic heavy alcohol exposure is associated with an increased risk for compromises in orientation and motor maturity [4], growth deficits [5], facial anomalies [6], reductions in IQ [7], central nervous system malfunction [8], and damage to the hippocampus and corpus collosum [9]. Together, these problems are often referred to as fetal alcohol spectrum disorders (FASDs), which are classified as neurobehavioral disabilities [10]. Meanwhile, prenatal tobacco exposure, in the form of combustible cigarettes, is associated with an increased risk for poor developmental outcomes such as low birthweight [11], reduced brain size [12], and altered brain function [13]. Tobacco exposure is also associated with an increased risk of obesity [14], hypertension [15], asthma [16], and wheezing [17] later in life. Finally, cannabis, which is an increasingly popular drug of choice among pregnant mothers due to its perceived safety and widespread legalization [18], has been linked to reductions in offspring birthweight and birth length [19], learning disabilities, and memory impairments [20,21,22].
Traditionally, healthcare officials called for the abstinence from the aforementioned substances to promote growth and development and to prevent risk to the mother and fetus. However, this approach is problematic for several reasons. First, nearly half (45%) of all pregnancies are unintended [23]; therefore, prenatal substance exposure may occur before women realize they are pregnant. This results in fetal exposure during a critical period of brain development and may increase the risk of negative outcomes across the lifespan of the fetus [24]. Second, although there are dramatic reductions in the amount of use upon pregnancy recognition, pregnant individuals with heavier patterns of use continue to use substances [25]. Given the difficulties associated with quitting or abstaining from substance use for those with heavier use patterns, alternate harm reduction strategies that promote fetal health may be useful. One small prospective study (n = 152) on pregnant women with heavier use patterns revealed that 4% of women who are classified as ‘heavy drinkers’ (i.e., having an average of ≥1.0 oz of absolute alcohol per day or ≥4 or more standard drinks per occasion), 22% of pregnant individuals who use cannabis, 27% of pregnant individuals who snort cocaine, and 68% of individuals who smoke cigarettes on a regular basis continued to engage in these behaviors after learning of their pregnancy [26].
There is an accumulating interest in using prenatal nutrient supplementation as a strategy that may reduce the risk for poorer fetal outcomes after prenatal substance exposure. Vitamins and minerals are vital for optimal fetal development. For instance, choline aids cell division and lipid transport [27]. Zinc, the second most abundant metal in the body, is integral to central nervous system development through myelination and gene expression [28]. Iron is an essential nutrient during pregnancy, and the need for iron increases in order to aid cellular functions in delivering oxygen to support the structural development of fetal organs [29]. Vitamin E regulates embryonic development and placental maturation while also protecting the fetus from oxidative stress [30]. Finally, vitamin C is essential to cognitive development by way of normative hippocampal growth [31]. The supplementation of macronutrients such as omega-3 fatty acids (i.e., docosahexaenoic acid (DHA)) during pregnancy was shown to improve developmental outcomes including better visual acuity and performance on the Mental Development Index in children up to 4 years of age [32]. Accordingly, it is plausible that increased intakes of micronutrients and/or fatty acids amid the prenatal period may help to offset or mitigate the adverse effects of the in utero exposure to substance use on infant development.
For this narrative review, we synthesized the existing literature on nutrient supplementation in pregnant women using substances, focusing on how supplementation influences physical, cognitive, and behavioral development in animals and humans. Upon data extraction, we were unable to locate empirical studies that included substances other than alcohol/ethanol and nicotine. Thus, the following review will be solely focused on nutrient supplementation during the prenatal period in pregnancies with alcohol and nicotine exposure and offspring outcomes.

2. Materials and Methods

2.1. Search Strategy

We conducted a full electronic search within PubMed in January 2023. Search terms encompassed variations of “prenatal substance use”, “maternal nutrition”, “supplementation”, “offspring outcomes”, and “development outcomes” (see Appendix A for full search strategy). Potential papers were screened by title and abstract.

2.2. Eligibility Criteria

Studies were eligible for inclusion if they (1) were published in an academic, peer-reviewed journal and written in English, (2) investigated prenatal nutrient supplementation and substance exposure in animals or humans, and (3) reported on developmental outcomes in the offspring. Studies were excluded if (1) pregnant individuals did not receive nutrient supplements or use substances during the prenatal period, and (2) outcomes reported were unrelated to offspring development. All studies were imported into EndNote 20.0 software for review.

2.3. Data Extraction

After duplicate removal, we assessed 36,934 studies. Of these studies, 112 had abstracts that warranted a full text review (Figure 1). Two separate investigators (C.S. and A.K.G.T.) evaluated whether the (1) design, (2) timing and duration of nutrient supplementation, and (3) outcomes reported were relevant to the topic at hand. A third investigator (K.K.) further reviewed these studies in order to find a consensus over which ones met the inclusion criteria for the present study. Following this discussion, we decided to exclude 80 studies because they did not meet inclusion criteria. In total, 32 studies are present in this narrative review, and a full summary of their characteristics, methodology, and findings, organized alphabetically by first author’s last name, can be found in Table 1 and Table 2.
Figure 1. Flow chart of excluded and included studies.
Table 1. Overview of characteristics, methodology, and results from studies evaluating the effects of nutrient supplementation on maternal substance use in outcomes related to offspring development in animals.
Table 2. Overview of characteristics, methodology, and results from studies evaluating the main interaction effects of substance use and nutrient supplementation on outcomes related to offspring development in humans.

3. Results

3.1. General Study Characteristics

Table 1 and Table 2 provide a description of the general study characteristics and findings. We reported on 32 studies investigating the interactive effects of nutrient supplementation and substance use during the prenatal period on developmental outcomes in offspring. Of these studies, 26 were experimental studies in animals (16 were conducted on rats, 7 on mice, 3 on ewes), and 6 were observational studies in humans. In the animal studies, we included rodent studies that supplemented nutrients on postnatal days (PDs) 1–10, because these days are the equivalent to the human third trimester. The rodent gestation is accelerated in comparison to human gestation, with the first trimester equivalent to gestational days (GDs) 1–10, the second trimester equivalent to GDs 11–20, and the third trimester and cognitive brain growth spurt corresponding to PDs 1–10 [68].

3.2. Animal Studies

All animal studies solely investigated the effects of maternal nutrient supplementation on prenatal ethanol exposure. The breakdown of the following outline is based on micro- (i.e., choline, zinc, vitamin E, and iron) and macronutrient supplementation (i.e., fatty acids) under the backdrop of ethanol exposure in animal studies.

3.2.1. Effects of Choline on Maternal Ethanol Consumption and Offspring Developmental Outcomes

Choline was the predominant micronutrient investigated, as it was examined in 18 studies. More than half of these studies (11/18) found varying positive effects of choline on the outcomes of interest [34,36,40,41,43,44,45,47,48,49,50]. From the studies that found positive protective factors from choline supplementation against ethanol, five reported an ameliorating effect of choline on preventing the reduction in body, brain, liver, and heart weights, and the brain-to-liver weight ratio, as well as an increased length of gestation (an indicator of increased fetal body weight) [36,40,44,48,68]. Three studies reported choline’s positive effect on motor coordination and balance [34,36,44], and three more found a positive effect on working memory and learning [47,49,50]. According to two studies, choline contributed to significant reductions in hyperactivity levels [41,47], and another found that choline improved visuospatial discrimination acquisition [45]. Finally, choline had positive effects on craniofacial abnormalities [43] and was found to partially ameliorate anxiety-like behaviors [36]. It is important to note the study conducted by Thomas et al. [49], which investigated the concurrent administration of ethanol with choline during the prenatal period. It found mitigating effects of choline on body weight growth alongside behavioral tasks including spontaneous alteration and spatial working memory. Specifically, the ethanol-exposed subjects who were treated with choline performed at levels that did not significantly differ from the performance levels of the control group that was not exposed to ethanol on the tasks described [49].
In contrast, six of the studies found that choline had no effects on growth [33,35,37,38,39,42], and one found no positive effects of choline on motor coordination [46]. Among the outcomes that did not have any protective effects associated with choline supplementation included whole brain measurements, cognition, and attention [35,39]. Table 1 summarizes these studies.

3.2.2. Effects of Zinc on Maternal Ethanol Consumption and Offspring Developmental Outcomes

Three animal studies by Summers et al. [51,52,53] investigated zinc supplementation against ethanol exposure, and all three reported positive effects. Table 1 displays these findings. These studies used the same condition in which mice were injected with 25% ethanol on gestational day 8 (i.e., first trimester equivalent) or a saline control. Zinc supplementation was administrated on gestational day 8 or throughout both the first and second trimester equivalent (i.e., gestational days 1–18) [52,53]. Summers et al. [51] investigated the cognitive impairments of offspring after maternal ethanol exposure and found that zinc supplementation helped to improve cognitive outcomes. The offspring of mothers who were exposed to ethanol and zinc during pregnancy performed at the same level as the offspring of mothers who were exposed to saline control for the cross-maze water escape task, which measures spatial learning and recall in memory. This work was replicated, and the findings indicated that the offspring of the ethanol plus zinc group performed at the same level as the saline control group on the cross-maze water escape and object recognition memory tasks [52]. Finally, Summers at al. (2009) reported that zinc supplementation protected against incidences of physical abnormalities and postnatal mortality. In the ethanol-exposed group without zinc treatment, the authors observed a 35% occurrence for both physical abnormalities and postnatal mortality. When zinc was supplemented, only 12% of the offspring from mothers who were exposed to ethanol had physical abnormalities. This is a relatively comparable risk to the 10% in the saline group and the 9% in the saline plus zinc group. Similarly, when zinc was supplemented, postnatal mortality was only 12%, which is lower than both the saline group (14%) and saline plus zinc group (18%) [53].

3.2.3. Effects of Vitamin E on Maternal Ethanol Consumption and Offspring Developmental Outcomes

Two animal studies investigated the protective effects of vitamin E against prenatal ethanol administration during the third trimester equivalent in humans (i.e., PD 6 and PDs 4–9), and neither study found protective effects [54,55]. Marino et al. [54] supplemented vitamin E on postnatal days 6–9, prior to ethanol exposure on days 7–9, and did not find any mitigating effects on the reductions in body weight; fetuses born to dams in the ethanol only and ethanol plus vitamin E groups had significantly lower body weights on postnatal days 8 and 9 compared to the control group. Furthermore, the Morris water maze task given to the ethanol-exposed subjects indicated that vitamin E supplementation did not improve impairments in spatial navigation [54]. In the study conducted by Tran et al. [55], vitamin E supplementation occurred concurrently with ethanol exposure on postnatal days 4–9 and failed to protect against deficits in functional learning outcomes, which were measured using eyeblink conditioning [55].

3.2.4. Effects of Fatty Acids on Maternal Ethanol Consumption and Offspring Developmental Outcomes

Two animal studies supplemented gamma-linolenic acid [57] and saturated fats versus polyunsaturated fats [56] against the teratogenic effects of ethanol and reported mixed findings. The first study, conducted by Wainwright et al. [57], investigated the supplementation of gamma-linolenic acid, a long-chain fatty acid, during pregnancy on acute ethanol exposure. The supplementation occurred concurrently with ethanol exposure from gestational days 7 to 17 (i.e., first and second trimester equivalent). They did not find attenuating effects of gamma-linolenic acid on reductions in body weight and brain weight. Additionally, there were no effects on any of the behavioral outcomes of interest, such as a battery of tests measuring reflex response, open field behaviors, and locomotor activity. The second study, conducted by Abel and Reddy [56], investigated the effects of a high saturated fat diet compared to a high polyunsaturated fat diet against teratogenic ethanol exposure on hyperactivity levels in rats, which is a common behavioral characteristic of children born with FASD [10]. The alcohol-exposed offspring who were fed a diet high in saturated fat had lower hyperactivity levels than their pair-fed controls, and these offspring also engaged in less anxiety-like behaviors such as head-dipping. In contrast, the high polyunsaturated fat diet did not significantly improve alcohol’s effects on hyperactivity and anxiety-like behaviors [56].

3.2.5. Effects of Iron on Maternal Ethanol Consumption and Offspring Developmental Outcomes

The one remaining animal study supplemented elemental iron [58] against the embryotoxic effects of ethanol and reported one positive finding relating to physical development. Helfrich et al. [58] explored the supplementation of iron during pregnancy on acute ethanol exposure, with concurrent ethanol exposure and iron supplementation occurring from gestational days 13.5 to 19.5 (i.e., second trimester equivalent). They found significant mitigating effects of iron supplementation on absolute brain weight in male pups exposed to ethanol, but not females. There were no other interactive effects of iron supplementation against ethanol exposure for birth weight or liver and heart weights in either male or female pups.

3.3. Human Studies

Studies involving human participants investigated the effects of choline on prenatal alcohol consumption (n = 4 studies) [59,60,61,63] and the effects of vitamin C on nicotine exposure (n = 2 studies) [64,65].

3.3.1. Effects of Choline on Maternal Alcohol Consumption and Offspring Developmental Outcomes

Four studies examined the potential protective effects of choline supplementation against alcohol exposure either alone [60,63] or in combination with a multivitamin [59,61]. The results were mixed. Two studies [60,63] found positive protective effects of choline on alcohol-exposed pregnancies. Jacobson et al. [60] recruited heavy drinkers, which they defined as having an average consumption of at least two standard drinks (1.0 oz absolute alcohol) per day or at least one incident of binge drinking (four or more standard drinks per occasion) over the course of pregnancy. They were randomly assigned to either the placebo group or 2 g choline supplementation group at the 23rd week of gestation. The choline supplementation demonstrated protective effects for physical and cognitive development; the choline-treated infants showed considerable catch-up growth in weight and head circumference at 6.5 and 12 months. These infants were more likely to meet the criterion for eyeblink conditioning and showed greater increases in conditioned responses across the three training sessions. At 12 months, the infants in the choline treatment arm had better visual recognition memory as measured by the Fagan Test of Infant Intelligence in comparison to the controls who were exposed to ethanol but did not receive choline supplementation [60]. Warton et al. [63] recruited heavy drinkers, which they defined as having an average consumption of two standard drinks (1.0 oz absolute alcohol) per day or at least one incident of binge drinking (four or more standard drinks per occasion) during pregnancy, who were enrolled at 23 weeks’ gestation. When 2 g of choline per day was supplemented to the women, the authors observed an improvement in brain structural outcomes of the offspring. Specifically, infants exposed to choline showed larger brain volumes in 6 of the 12 regions. The development of the larger right putamen and corpus callosum regions were associated with higher scores on the Fagan Test of Infant Intelligence [63].
In contrast to the first two studies, the two studies by Coles et al. [59] and Kable et al. [61], and the follow-up findings from the original randomized controlled trial (RCT) by Kable [62], paired choline with a multivitamin and found that this showed no effects on the offspring of heavy drinkers. Coles et al. [59] recruited heavy drinkers, which they defined as (1) having at least weekly binge episodes (5 + drinks), (2) at least five episodes of 3–4 standard drinks, or (3) at least ten episodes of 1–2 standard drinks either in the month around conception or the most recent month of pregnancy. The participants were assigned to one of the following three groups: (1) regular diet with a recommendation to take a multivitamin but were not provided with one, (2) regular diet with a multivitamin provided, or (3) regular diet with a multivitamin and 750 mg of choline supplement provided. Among the offspring of women who were assigned to the multivitamin and choline supplements group, the author did not observe improved scores on the Psychomotor Development Index and Mental Development Index. Additionally, the behavioral rating in the Bayley Scales of Infant Development 2nd Edition did not indicate improvement in areas of orientation/engagement, emotional reactivity, motor quality, or total behavior. Interestingly, the Mental Development Index showed that the multivitamin only group scored significantly higher than the multivitamin plus choline group [59].
In the original RCT reported by Kable et al. [61], heavy drinkers were assigned to one of the following three groups: (1) mother’s regular diet with a recommendation to take a multivitamin supplement that is not provided by the study, (2) mother’s regular diet plus a provided multivitamin supplement, and (3) regular diet plus a provided multivitamin and 750 mg of choline supplement. This study reported no mitigating effects of multivitamin and choline supplements on reductions in birth weight, length, or head circumference in alcohol-exposed infants. Furthermore, choline did not significantly affect cardiac-orienting responses to the auditory stimuli, nor did it significantly affect latency responses in the visual habituation tasks, which are measures of cognitive development. However, the prenatal supplementation of multivitamins and choline resulted in a significantly greater change in the heart rate in the visual habituation task, which is an index of early cognitive functioning, in children between 6–12 months of age in both the ethanol-exposed and control groups [61]. Finally, Kable et al. [62] reported follow-up results from an RCT on the reaction time of 4-year-old preschoolers (mean age 3.96 years). These preschoolers were participants from a previous study conducted in 2015 [61]. The authors reported that although multivitamin supplementation improved the reaction time performance in male preschoolers, it did not have the same effect on female preschoolers. Additionally, choline supplementation improved the reaction time in male preschoolers who were not exposed to alcohol, but not in those who were exposed to alcohol or in female preschoolers [62]. This was the only study in which the pairing of choline supplementation with a multivitamin, which contains a variety of vitamins and minerals, produced positive effects.

3.3.2. Effects of Vitamin C on Maternal Nicotine Consumption and Offspring Developmental Outcomes

Two studies [64,65] and two follow-up studies [66,67] investigated the ameliorating effects of vitamin C against nicotine exposure, and all showed positive effects of vitamin C supplementation on physical development, specifically the pulmonary function of infants, both at the original timepoint, as well as at the follow-up timepoints. Across both studies, current smokers who smoke at least one cigarette per day were randomized to the vitamin C supplementation group or to the placebo pill group at ≤22 weeks’ gestation. In a stand-alone study by McEvoy et al. [64], pulmonary assessments completed at 3 days of age and 12 months of age reported effects in offspring. In addition to the stand-alone study, McEvoy et al. [65] are conducting an ongoing RCT [65], which follows children from 3 months of age at the original timepoint to 12 months of age [66] and 5 years of age [67] in the respective follow-up timepoints. Despite the variance in the assessment age, the results of both studies largely show positive effects of vitamin C supplementation on pulmonary outcomes. In the first stand-alone study, McEvoy et al. [64] reported that vitamin C supplementation had a positive effect on incidences of wheezing. In assessments of infants from three days though one year of age, the infants of women who received vitamin C had significantly decreased incidences of wheezing in comparison to those who received the placebo. The participants in the ongoing RCT [65] with follow-ups through 5 years of age differ from the previously reported 2014 stand-alone study, as they are a part of the report on the use of vitamin C to decrease the effects of smoking in pregnancy on infant lung function (VCSIP) cohort. The study by McEvoy et al. [65] was the first to report VCSIP findings, and it found additional positive effects. Infants whose mothers were randomized to receive vitamin C during pregnancy had an increased forced expiratory flow at 75% of the expired volume during a pulmonary function test as well as a significantly increased forced expiratory flow at 50% of the expired volume at 3 months of age compared with those who were randomized to receive the placebo [65]. In the next report of VCSIP findings, McEvoy et al. [66] reported similar positive results. Forced expiratory flows in the vitamin C-treated group increased from 11.6% to 16.1% in comparison to the placebo group, and vitamin C produced a persistently significant increase in the offspring’s airway function at 3 and 12 months of age [66]. The final VCSIP study, McEvoy et al. [67], is the most recent follow-up study, and it reports that supplemental vitamin C contributes to significantly better airway function and a lower occurrence of wheezing in offspring at 5 years of age.

4. Discussion

Our review of the literature finds that the implementation of nutrient supplementation to ameliorate child risk for negative outcomes related to prenatal substance exposure is promising. Although preclinical models support the finding that micronutrient zinc improves the developmental outcomes of ethanol-exposed fetuses during pregnancy, this intervention has yet to be examined in studies with human participants. Additional studies in preclinical models provide less evidence, though positive results, for the use of choline, iron, and fatty acids, but none of the studies regarding vitamin E found that supplementation improved offspring developmental outcomes. As for studies involving human participants, only choline and vitamin C supplementation have been investigated regarding alcohol and nicotine exposure, respectively. Similar to the preclinical models, these studies found that the efficacy of choline supplementation after alcohol exposure is mixed, though mostly positive. Other studies, such as those examining vitamin C, suggest that its supplementation improves pulmonary outcomes in fetuses with nicotine exposure. However, the included studies varied greatly regarding the timing of nutrient supplementation and the timing and dose of ethanol exposure, assessed developmental outcomes, study design, and prenatal nutrient of interest. Taken together, ethanol exposure during the prenatal period increases the risk for cognitive, behavioral, and neural changes in the fetus. These alterations vary based on the dosing, duration, and timing of the ethanol exposure. Moreover, substances may alter fetal development through a variety of possible mechanisms; ethanol exposure during pregnancy induces cell and mitochondrial damage, which leads to central nervous system dysfunction [69]. Additionally, fetal ethanol exposure produces alterations in DNA methylation and microRNA expression and function in zebra fish, leading to developmental deficits [70]. Furthermore, nicotine is an addictive substance that readily crosses the placenta, and the fetal concentrations of the compounds are higher than the maternal concentrations alone. This increases the risk for a number of outcomes such as poor regulation of arousal within the first month of life to cognitive deficits, including language comprehension and sensory processing, persisting through 18 years of age [24]. It is plausible that supplementations of nutrients such as zinc, vitamin C, iron, and choline may work to ameliorate these poor developmental outcomes as they play essential roles in growth, DNA synthesis, and neurodevelopment. For instance, possible mechanisms of choline’s effects in FASD include its role in the production of phospholipids that are essential for growth and myelination [71]. Additionally, choline supplementation also affects choline acetyltransferase levels in the hippocampus in animal models, resulting in improved memory [72]. Moreover, vitamin C may reduce ethanol’s effects on oxidative stress because it stops the production of peroxidative stress with the help of vitamin E [73]. Notably, iron is essential to the uptake of oxygen needed by the developing fetal brain, which accounts for 60% of the fetal oxygen consumption rate [74]. Finally, zinc plays an essential role in a variety of complex mechanisms including cell division and replication, gene expression, and hormone regulation [75].
The substances administered (i.e., ethanol in animal studies and alcohol and nicotine in human studies) are also limited, as none of these studies examined substances such as cannabis, prescription pain medications, or illicit opioids, nor did they examine polysubstance use, despite this being a common pattern of use among heavier users or users of illicit substances including opioids. However, half (3/6) of the human samples [60,61,63] included polysubstance use during pregnancy among samples recruited for alcohol or nicotine use. Specifically, Jacobsen et al. [60] reported high levels of cigarette use (1/4 pack/day), and four participants reported the use of methamphetamine later in pregnancy in addition to heavy prenatal alcohol consumption. Moreover, Kable et al. [61] and Warton et al. [63] also reported that women who consumed alcohol while pregnant had significantly higher cigarette use, and Warton et al. [63] observed higher cannabis use in the alcohol-using women as well. As a result, this review summarizes the efficacy of prenatal micronutrient supplementation as a potential protective factor for fetuses on ethanol-/alcohol- and nicotine-exposed pregnancies.
While this review shows promise for the ability of micronutrient and fatty acid supplementation to protect developing fetuses from harmful substances based on animal models, our search of the literature reveals that there are few studies involving human participants. One explanation for the lack of human studies may be due to the general stigma surrounding prenatal substance exposure and the subsequent hesitancy of expectant mothers to report their use accurately and honestly due to the fear of losing custody of their child [76]. Garg et al. [77] reported that substance use during pregnancy is substantially underreported for commonly consumed substances, even among women who regularly participate in urine substance screens [77]. This suggests that the number of pregnant women actively engaging in illicit substance use may be even higher than the current reported rate. Additionally, pregnant individuals with substance use disorder face many relational and structural barriers, including perceived judgmental attitudes of health care providers and a lack of access to treatment for lower income women and women of color [77]. Though not a commonly reported reason, according to a study conducted by Borland and colleagues, women choosing to continue the use of substances during pregnancy could be due to the perceived fear of causing stress and undue harm to the fetus as a result of quitting substance use [78]. For example, exposing the fetus to increased levels of psychological stress as a result of quitting was perceived by some women to be more harmful for the baby than the substance use itself. Thus, nutrient supplementation may play a vital role in providing protection to fetuses of pregnant women who employ harm reduction strategies, rather than abstinence, while pregnant.
As preclinical and translational research continues to unfold, the next step to protect fetuses from substance-use-related harm during pregnancy is to begin implementing these important findings. To achieve this, we suggest the following: first, while outside of the scope of this review, ensuring access to quality prenatal care beginning in the first trimester is essential to improve fetal outcomes for pregnant individuals with substance use disorders. Improved levels of prenatal care are associated with a reduced risk of poor pregnancy outcomes after substance use [79]; however, pregnant individuals with substance use disorders face many barriers to receiving adequate prenatal care [80]. It is pivotal to develop strategies that eliminate these barriers, allowing for this population to have an improved access to prenatal care. Particularly, many prenatal healthcare providers are the sole suppliers of supplements to pregnant individuals who may not possess the resources to obtain these supplements on their own. Therefore, regular visits to a prenatal healthcare provider offers an avenue for free supplementation that can be beneficial to the development of the fetus. Next, the consumption of a diet that is rich in meats (i.e., zinc, choline, saturated fats, iron), eggs (i.e., choline, long-chain fatty acids), fatty fish (i.e., long-chain fatty acids), and fruits and vegetables (i.e., vitamin C, iron) is recommended in order to obtain the nutrients that were shown to protect fetuses from harmful substances. Encouraging eligible women to enroll in programs like the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and the Supplemental Nutrition Assistance Program (SNAP) is a strategy that improves food and nutrition security in households where the access to nutritious food is limited. Last, the consumption of a high-quality prenatal supplement is recommended. This supplement must contain adequate levels of choline and long-chain fatty acids (i.e., DHA), which are two nutrients that are commonly found in inadequate amounts in both prenatal supplements and the typical American diet. Perhaps future policies and procedures can center on improving the intake of high-quality prenatal supplements for pregnant individuals with substance use disorders by making these prenatal supplements accessible through their providers.
There are limitations to this review. First, the literature regarding prenatal supplementation is limited in terms of the quantity and heterogeneity in its methodological designs. Of the studies which investigated prenatal alcohol consumption, none intentionally investigated the mitigating effects of micronutrient supplementation on polysubstance use, despite the recent reports that concurrent substance use is as high as 40% in pregnant women who consume alcohol [81]. Additionally, the small sample size of the included studies is a limitation. Thus, future review papers or meta-analyses on this topic could consider expanding their search terms to encompass a wider range of nutrient supplementation. Furthermore, no study investigated the effects of nutrient supplementation on illicit substance exposure, despite our knowledge that illicit substance use during pregnancy can produce deleterious effects on pregnancy and fetal outcomes. Another limitation is the substantial differences in the methodological approaches across animal studies. For instance, there appeared to be no consensus on the timing of micronutrient supplementation and the administration of ethanol, or there are large variations in ethanol dose during pregnancy. Although a slim majority reported both micronutrient supplementation and ethanol use during the prenatal period, the specific prenatal days in which the nutrient supplementation was provided and the occurrence of ethanol exposure varied greatly. In addition, all animal studies reported the use of ethanol-exposed models without further study of prenatal substance exposure models beyond this area. The lack of human studies serves as a limitation as rodents have an accelerated gestation, and thus, findings in rodent models cannot always be successfully translated to humans. Furthermore, though the zinc supplementation studies reported robust protective effects against ethanol teratogenicity, it should be noted that these studies were conducted by the same authors, making this a notable limitation. Finally, in the few existing human studies and animal models, there are discrepancies regarding the exposure and treatment dosage. Within the preclinical ethanol-exposed animal models, there was a significant variation in the amount of ethanol administered, which could be a factor that affected the variations in outcomes. For the four studies on alcohol consumption, the authors did not have the same consensus or definition of “heavy drinking”. Incongruent definitions of “heavy drinking” does not allow for the cross-study comparison on the relative effects of nutrient supplementation on offspring outcomes. The variability of nutrient dosing across the studies further limits the success of the protective effects of choline. Within the same four studies that examined concurrent multivitamin and choline supplementation, two of the studies did not confer protective effects against ethanol use in children through 12 months of age. This may be a result from an inadequate treatment dosage. More specifically, Coles et al. [59] and Kable et al. [61] supplemented 750 mg of choline paired with a multivitamin and did not find any protective effects through 12 months of age. On the other hand, the two studies [60,63] found ameliorating effects of choline through 12 months of age using the supplementation of choline alone, with a dosage of 2 g of choline per day. This indicates a possible important factor of dosing in choline efficacy.
From these limitations, we identified several future directions for this area of research. First, studies that examine the influence of nutrient supplementation in pregnancies with polysubstance use are needed. Following this is the need for studies designed to identify the optimal timing of nutrient supplementation during pregnancies with substance use. Finally, a majority of studies involve rodent models, and because rodent pregnancy is accelerated in comparison to human pregnancy, the results may not be easily translated to humans. More studies involving human participants are needed, particularly studies that are not limited in the length of assessment. More specifically, there is a need for studies to follow up years after prenatal supplementation has occurred to help elucidate the long-term benefits.

5. Conclusions

The effects of nutrient supplementation on substance-exposed pregnancies are promising, especially regarding choline, zinc, iron, and vitamin C. Still, there is a lack of studies, and there is no consensus amongst these studies on the dosing of substance exposure and the timing of nutrient supplementation during gestation to elucidate any clear conclusions. Furthermore, thoughtfully designed human and animal studies are needed to investigate the effects of micronutrient supplementation on polysubstance use. The continuation and augmentation of this work might lead to the development of new clinical interventions that can improve fetal outcomes in the context of prenatal substance exposure, leading to potential long-term developmental benefits.

Author Contributions

Conceptualization, C.A.S. and K.L.K.; methodology, C.A.S.; software, C.A.S.; validation, C.A.S., A.K.G.-T., R.D.E. and K.L.K.; formal analysis, C.A.S. and A.K.G.-T.; investigation, C.A.S.; resources, K.L.K.; data curation, C.A.S.; writing—original draft preparation, C.A.S.; writing—review and editing, A.K.G.-T., R.D.E. and K.L.K.; visualization, C.A.S.; supervision, K.L.K.; project administration, K.L.K.; funding acquisition, K.L.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Institute on Child Health and Human Development of the National Institutes of Health; Grant ID: R01 HD087082-01.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created. The full search strategy is found in the appendix, and any questions or concerns may be sent to the corresponding authors.

Acknowledgments

The authors would like to acknowledge Brenda Burgess for her work in the early stages of this project.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Full Search Strategy:
(Prenatal Substance Use) AND (Maternal Nutrient Intakes OR Maternal Supplements OR Supplement Use OR Supplementation OR Vitamins and Minerals OR Antioxidants OR Iron OR Choline OR Maternal Nutrition OR Supplement Intake OR Maternal Supplements) AND (Fetal Outcomes OR Offspring Outcomes OR Cognitive Development Outcomes).

References

  1. Tran, E.L.; England, L.J.; Park, Y.; Denny, C.H.; Kim, S.Y. Systematic Review: Polysubstance Prevalence Estimates Reported during Pregnancy, US, 2009–2020. Matern. Child Health J. 2023, 27, 426–458. [Google Scholar] [CrossRef] [PubMed]
  2. Gosdin, L.K.; Deputy, N.P.; Kim, S.Y.; Dang, E.P.; Denny, C.H. Alcohol Consumption and Binge Drinking during Pregnancy among Adults Aged 18–49 Years—United States, 2018–2020. MMWR Morb. Mortal. Wkly. Rep. 2022, 71, 10–13. [Google Scholar] [CrossRef] [PubMed]
  3. Substance Abuse and Mental Health Services Administration. 2020 NSDUH Detailed Tables. National Survey on Drug Use and Health. 2022. Available online: https://www.samhsa.gov/data/report/2020-nsduh-detailed-tables (accessed on 30 March 2023).
  4. Schneider, M.L.; Moore, C.F.; Adkins, M.M. The effects of prenatal alcohol exposure on behavior: Rodent and primate studies. Neuropsychol. Rev. 2011, 21, 186–203. [Google Scholar] [CrossRef] [PubMed]
  5. Larkby, C.; Day, N. The effects of prenatal alcohol exposure. Alcohol. Health Res. World 1997, 21, 192–198. [Google Scholar]
  6. Streissguth, A.P.; Aase, J.M.; Clarren, S.K.; Randels, S.P.; LaDue, R.A.; Smith, D.F. Fetal Alcohol Syndrome in Adolescents and Adults. JAMA 1991, 265, 1961–1967. [Google Scholar] [CrossRef]
  7. Day, N.L. Research on the effects of prenatal alcohol exposure—A new direction. Am. J. Public Health 1995, 85, 1614–1615. [Google Scholar] [CrossRef]
  8. Riley, E.P.; Mattson, S.N.; Sowell, E.R.; Jernigan, T.L.; Sobel, D.F.; Jones, K.L. Abnormalities of the corpus callosum in children prenatally exposed to alcohol. Alcohol. Clin. Exp. Res. 1995, 19, 1198–1202. [Google Scholar] [CrossRef]
  9. Berman, R.F.; Hannigan, J.H. Effects of prenatal alcohol exposure on the hippocampus: Spatial behavior, electrophysiology, and neuroanatomy. Hippocampus 2000, 10, 94–110. [Google Scholar] [CrossRef]
  10. Denny, L.; Coles, S.; Blitz, R. Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorders. Am. Fam. Physician 2017, 96, 515–522. [Google Scholar]
  11. Banderali, G.; Martelli, A.; Landi, M.; Moretti, F.; Betti, F.; Radaelli, G.; Lassandro, C.; Verduci, E. Short and long term health effects of parental tobacco smoking during pregnancy and lactation: A descriptive review. J. Transl. Med. 2015, 13, 327. [Google Scholar] [CrossRef]
  12. Ko, T.J.; Tsai, L.Y.; Chu, L.C.; Yeh, S.J.; Leung, C.; Chen, C.Y.; Chou, H.C.; Tsao, P.N.; Chen, P.C.; Hsieh, W.S. Parental smoking during pregnancy and its association with low birth weight, small for gestational age, and preterm birth offspring: A birth cohort study. Pediatr. Neonatol. 2014, 55, 20–27. [Google Scholar] [CrossRef]
  13. Ekblad, M.; Korkeila, J.; Lehtonen, L. Smoking during pregnancy affects foetal brain development. Acta Paediatr. 2015, 104, 12–18. [Google Scholar] [CrossRef]
  14. Ino, T. Maternal smoking during pregnancy and offspring obesity: Meta-analysis. Pediatr. Int. 2010, 52, 94–99. [Google Scholar] [CrossRef]
  15. Bruin, J.E.; Gerstein, H.C.; Holloway, A.C. Long-term consequences of fetal and neonatal nicotine exposure: A critical review. Toxicol. Sci. 2010, 116, 364–374. [Google Scholar] [CrossRef]
  16. Oken, E.; Huh, S.Y.; Taveras, E.M.; Rich-Edwards, J.W.; Gillman, M.W. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes. Res. 2005, 13, 2021–2028. [Google Scholar] [CrossRef]
  17. Cheraghi, M.; Salvi, S. Environmental tobacco smoke (ETS) and respiratory health in children. Eur. J. Pediatr. 2009, 168, 897–905. [Google Scholar] [CrossRef]
  18. Chang, J.C.; Tarr, J.A.; Holland, C.L.; De Genna, N.M.; Richardson, G.A.; Rodriguez, K.L.; Sheeder, J.; Kraemer, K.L.; Day, N.L.; Rubio, D.; et al. Beliefs and attitudes regarding prenatal marijuana use: Perspectives of pregnant women who report use. Drug Alcohol. Depend. 2019, 196, 14–20. [Google Scholar] [CrossRef]
  19. Gunn, J.K.; Rosales, C.B.; Center, K.E.; Nuñez, A.; Gibson, S.J.; Christ, C.; Ehiri, J.E. Prenatal exposure to cannabis and maternal and child health outcomes: A systematic review and meta-analysis. BMJ Open 2016, 6, e009986. [Google Scholar] [CrossRef]
  20. Wu, C.S.; Jew, C.P.; Lu, H.C. Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol. 2011, 6, 459–480. [Google Scholar] [CrossRef]
  21. Fried, P.A.; Watkinson, B.; Gray, R. Neurocognitive consequences of marihuana—A comparison with pre-drug performance. Neurotoxicol. Teratol. 2005, 27, 231–239. [Google Scholar] [CrossRef] [PubMed]
  22. Noland, J.S.; Singer, L.T.; Short, E.J.; Minnes, S.; Arendt, R.E.; Kirchner, H.L.; Bearer, C. Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol. Teratol. 2005, 27, 429–438. [Google Scholar] [CrossRef]
  23. Finer, L.B.; Zolna, M.R. Declines in Unintended Pregnancy in the United States, 2008–2011. N. Engl. J. Med. 2016, 374, 843–852. [Google Scholar] [CrossRef] [PubMed]
  24. Ross, E.J.; Graham, D.L.; Money, K.M.; Stanwood, G.D. Developmental consequences of fetal exposure to drugs: What we know and what we still must learn. Neuropsychopharmacology 2015, 40, 61–87. [Google Scholar] [CrossRef]
  25. Eiden, R.D.; Homish, G.G.; Colder, C.R.; Schuetze, P.; Gray, T.R.; Huestis, M.A. Changes in smoking patterns during pregnancy. Subst. Use Misuse 2013, 48, 513–522. [Google Scholar] [CrossRef] [PubMed]
  26. Forray, A.; Merry, B.; Lin, H.; Ruger, J.P.; Yonkers, K.A. Perinatal substance use: A prospective evaluation of abstinence and relapse. Drug Alcohol. Depend. 2015, 150, 147–155. [Google Scholar] [CrossRef]
  27. Radziejewska, A.; Chmurzynska, A. Folate and choline absorption and uptake: Their role in fetal development. Biochimie 2019, 158, 10–19. [Google Scholar] [CrossRef]
  28. Gower-Winter, S.D.; Levenson, C.W. Zinc in the central nervous system: From molecules to behavior. Biofactors 2012, 38, 186–193. [Google Scholar] [CrossRef]
  29. Georgieff, M.K. Iron deficiency in pregnancy. Am. J. Obstet. Gynecol. 2020, 223, 516–524. [Google Scholar] [CrossRef]
  30. Mahmood, N.; Hameed, A.; Hussain, T. Vitamin E and Selenium Treatment Alleviates Saline Environment-Induced Oxidative Stress through Enhanced Antioxidants and Growth Performance in Suckling Kids of Beetal Goats. Oxidative Med. Cell. Longev. 2020, 2020, 4960507. [Google Scholar] [CrossRef]
  31. Tveden-Nyborg, P.; Johansen, L.K.; Raida, Z.; Villumsen, C.K.; Larsen, J.O.; Lykkesfeldt, J. Vitamin C deficiency in early postnatal life impairs spatial memory and reduces the number of hippocampal neurons in guinea pigs. Am. J. Clin. Nutr. 2009, 90, 540–546. [Google Scholar] [CrossRef]
  32. Birch, E.E.; Garfield, S.; Castañeda, Y.; Hughbanks-Wheaton, D.; Uauy, R.; Hoffman, D. Visual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Early Hum. Dev. 2007, 83, 279–284. [Google Scholar] [CrossRef] [PubMed]
  33. Balaraman, S.; Idrus, N.M.; Miranda, R.C.; Thomas, J.D. Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure. Alcohol 2017, 60, 159–167. [Google Scholar] [CrossRef] [PubMed]
  34. Bearer, C.F.; Wellmann, K.A.; Tang, N.; He, M.; Mooney, S.M. Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure. Cerebellum 2015, 14, 413–420. [Google Scholar] [CrossRef] [PubMed]
  35. Birch, S.M.; Lenox, M.W.; Kornegay, J.N.; Paniagua, B.; Styner, M.A.; Goodlett, C.R.; Cudd, T.A.; Washburn, S.E. Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs. Alcohol 2016, 55, 1–8. [Google Scholar] [CrossRef] [PubMed]
  36. Bottom, R.T.; Abbott, C.W., 3rd; Huffman, K.J. Rescue of ethanol-induced FASD-like phenotypes via prenatal co-administration of choline. Neuropharmacology 2020, 168, 107990. [Google Scholar] [CrossRef]
  37. Carugati, M.; Goodlett, C.R.; Cudd, T.A.; Washburn, S.E. The effects of gestational choline supplementation on cerebellar Purkinje cell number in the sheep model of binge alcohol exposure during the first trimester-equivalent. Alcohol 2022, 100, 11–21. [Google Scholar] [CrossRef]
  38. Goeke, C.M.; Roberts, M.L.; Hashimoto, J.G.; Finn, D.A.; Guizzetti, M. Neonatal Ethanol and Choline Treatments Alter the Morphology of Developing Rat Hippocampal Pyramidal Neurons in Opposite Directions. Neuroscience 2018, 374, 13–24. [Google Scholar] [CrossRef]
  39. Hunt, P.S.; Jacobson, S.E.; Kim, S. Supplemental choline does not attenuate the effects of neonatal ethanol administration on habituation of the heart rate orienting response in rats. Neurotoxicol. Teratol. 2014, 44, 121–125. [Google Scholar] [CrossRef]
  40. Kwan, S.T.C.; Ricketts, D.K.; Presswood, B.H.; Smith, S.M.; Mooney, S.M. Prenatal choline supplementation during mouse pregnancy has differential effects in alcohol-exposed fetal organs. Alcohol. Clin. Exp. Res. 2021, 45, 2471–2484. [Google Scholar] [CrossRef]
  41. Monk, B.R.; Leslie, F.M.; Thomas, J.D. The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt. Hippocampus 2012, 22, 1750–1757. [Google Scholar] [CrossRef]
  42. Otero, N.K.; Thomas, J.D.; Saski, C.A.; Xia, X.; Kelly, S.J. Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. Alcohol. Clin. Exp. Res. 2012, 36, 1701–1709. [Google Scholar] [CrossRef]
  43. Sawant, O.B.; Birch, S.M.; Goodlett, C.R.; Cudd, T.A.; Washburn, S.E. Maternal choline supplementation mitigates alcohol-induced fetal cranio-facial abnormalities detected using an ultrasonographic examination in a sheep model. Alcohol 2019, 81, 31–38. [Google Scholar] [CrossRef]
  44. Steane, S.E.; Fielding, A.M.; Kent, N.L.; Andersen, I.; Browne, D.J.; Tejo, E.N.; Gardebjer, E.M.; Kalisch-Smith, J.I.; Sullivan, M.A.; Moritz, K.M.; et al. Maternal choline supplementation in a rat model of periconceptional alcohol exposure: Impacts on the fetus and placenta. Alcohol. Clin. Exp. Res. 2021, 45, 2130–2146. [Google Scholar] [CrossRef]
  45. Thomas, J.D.; La Fiette, M.H.; Quinn, V.R.; Riley, E.P. Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats. Neurotoxicol. Teratol. 2000, 22, 703–711. [Google Scholar] [CrossRef]
  46. Thomas, J.D.; O'Neill, T.M.; Dominguez, H.D. Perinatal choline supplementation does not mitigate motor coordination deficits associated with neonatal alcohol exposure in rats. Neurotoxicol. Teratol. 2004, 26, 223–229. [Google Scholar] [CrossRef]
  47. Thomas, J.D.; Garrison, M.; O’Neill, T.M. Perinatal choline supplementation attenuates behavioral alterations associated with neonatal alcohol exposure in rats. Neurotoxicol. Teratol. 2004, 26, 35–45. [Google Scholar] [CrossRef]
  48. Thomas, J.D.; Abou, E.J.; Dominguez, H.D. Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats. Neurotoxicol. Teratol. 2009, 31, 303–311. [Google Scholar] [CrossRef]
  49. Thomas, J.D.; Idrus, N.M.; Monk, B.R.; Dominguez, H.D. Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats. Birth Defects Res. A Clin. Mol. Teratol. 2010, 88, 827–837. [Google Scholar] [CrossRef]
  50. Wagner, A.F.; Hunt, P.S. Impaired trace fear conditioning following neonatal ethanol: Reversal by choline. Behav. Neurosci. 2006, 120, 482–487. [Google Scholar] [CrossRef] [PubMed]
  51. Summers, B.L.; Rofe, A.M.; Coyle, P. Prenatal zinc treatment at the time of acute ethanol exposure limits spatial memory impairments in mouse offspring. Pediatr. Res. 2006, 59, 66–71. [Google Scholar] [CrossRef]
  52. Summers, B.L.; Henry, C.M.; Rofe, A.M.; Coyle, P. Dietary zinc supplementation during pregnancy prevents spatial and object recognition memory impairments caused by early prenatal ethanol exposure. Behav. Brain Res. 2008, 186, 230–238. [Google Scholar] [CrossRef] [PubMed]
  53. Summers, B.L.; Rofe, A.M.; Coyle, P. Dietary zinc supplementation throughout pregnancy protects against fetal dysmorphology and improves postnatal survival after prenatal ethanol exposure in mice. Alcohol. Clin. Exp. Res. 2009, 33, 591–600. [Google Scholar] [CrossRef]
  54. Marino, M.D.; Aksenov, M.Y.; Kelly, S.J. Vitamin E protects against alcohol-induced cell loss and oxidative stress in the neonatal rat hippocampus. Int. J. Dev. Neurosci. 2004, 22, 363–377. [Google Scholar] [CrossRef] [PubMed]
  55. Tran, T.D.; Jackson, H.D.; Horn, K.H.; Goodlett, C.R. Vitamin E does not protect against neonatal ethanol-induced cerebellar damage or deficits in eyeblink classical conditioning in rats. Alcohol. Clin. Exp. Res. 2005, 29, 117–129. [Google Scholar] [CrossRef]
  56. Abel, E.L.; Reddy, P.P. Prenatal high saturated fat diet modifies behavioral effects of prenatal alcohol exposure in rats. Alcohol 1997, 14, 25–29. [Google Scholar] [CrossRef]
  57. Wainwright, P.; Ward, G.R.; Molnar, J.D. gamma-Linolenic acid fails to prevent the effects of prenatal ethanol exposure on brain and behavioral development in B6D2F2 mice. Alcohol. Clin. Exp. Res. 1985, 9, 377–383. [Google Scholar] [CrossRef]
  58. Helfrich, K.K.; Saini, N.; Kwan, S.T.C.; Rivera, O.C.; Hodges, R.; Smith, S.M. Gestational Iron Supplementation Improves Fetal Outcomes in a Rat Model of Prenatal Alcohol Exposure. Nutrients 2022, 14, 1653. [Google Scholar] [CrossRef] [PubMed]
  59. Coles, C.D.; Kable, J.A.; Keen, C.L.; Jones, K.L.; Wertelecki, W.; Granovska, I.V.; Pashtepa, A.O.; Chambers, C.B.; CIFSAD. Dose and Timing of Prenatal Alcohol Exposure and Maternal Nutritional Supplements: Developmental Effects on 6-Month-Old Infants. Matern. Child Health J. 2015, 19, 2605–2614. [Google Scholar] [CrossRef]
  60. Jacobson, S.W.; Carter, R.C.; Molteno, C.D.; Stanton, M.E.; Herbert, J.S.; Lindinger, N.M.; Lewis, C.E.; Dodge, N.C.; Hoyme, H.E.; Zeisel, S.H.; et al. Efficacy of Maternal Choline Supplementation during Pregnancy in Mitigating Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Alcohol. Clin. Exp. Res. 2018, 42, 1327–1341. [Google Scholar] [CrossRef]
  61. Kable, J.A.; Coles, C.D.; Keen, C.L.; Uriu-Adams, J.Y.; Jones, K.L.; Yevtushok, L.; Kulikovsky, Y.; Wertelecki, W.; Pederson, T.L.; Chambers, C.D.; et al. The impact of micronutrient supplementation in alcohol-exposed pregnancies on information processing skills in Ukrainian infants. Alcohol 2015, 49, 647–656. [Google Scholar] [CrossRef]
  62. Kable, J.A.; Coles, C.D.; Keen, C.L.; Uriu-Adams, J.Y.; Jones, K.L.; Yevtushok, L.; Zymak-Zakutnya, N.; Dubchak, I.; Akhmedzhanova, D.; Wertelecki, W.; et al. The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine. Alcohol 2022, 99, 49–58. [Google Scholar] [CrossRef]
  63. Warton, F.L.; Molteno, C.D.; Warton, C.M.R.; Wintermark, P.; Lindinger, N.M.; Dodge, N.C.; Zollei, L.; van der Kouwe, A.J.W.; Carter, R.C.; Jacobson, J.L.; et al. Maternal choline supplementation mitigates alcohol exposure effects on neonatal brain volumes. Alcohol. Clin. Exp. Res. 2021, 45, 1762–1774. [Google Scholar] [CrossRef]
  64. McEvoy, C.T.; Schilling, D.; Clay, N.; Jackson, K.; Go, M.D.; Spitale, P.; Bunten, C.; Leiva, M.; Gonzales, D.; Hollister-Smith, J.; et al. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: A randomized clinical trial. JAMA 2014, 311, 2074–2082. [Google Scholar] [CrossRef]
  65. McEvoy, C.T.; Shorey-Kendrick, L.E.; Milner, K.; Schilling, D.; Tiller, C.; Vuylsteke, B.; Scherman, A.; Jackson, K.; Haas, D.M.; Harris, J.; et al. Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial. Am. J. Respir. Crit. Care Med. 2019, 199, 1139–1147. [Google Scholar] [CrossRef]
  66. McEvoy, C.T.; Shorey-Kendrick, L.E.; Milner, K.; Schilling, D.; Tiller, C.; Vuylsteke, B.; Scherman, A.; Jackson, K.; Haas, D.M.; Harris, J.; et al. Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12 Months of Age: A Randomised Trial. Eur. Respir. J. 2020, 56, 1902208. [Google Scholar] [CrossRef]
  67. McEvoy, C.T.; Shorey-Kendrick, L.E.; Milner, K.; Harris, J.; Vuylsteke, B.; Cunningham, M.; Tiller, C.; Stewart, J.; Schilling, D.; Brownsberger, J.; et al. Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial. JAMA Pediatr. 2023, 177, 16–24. [Google Scholar] [CrossRef]
  68. Patten, A.R.; Fontaine, C.J.; Christie, B.R. A comparison of the different animal models of fetal alcohol spectrum disorders and their use in studying complex behaviors. Front. Pediatr. 2014, 2, 93. [Google Scholar] [CrossRef]
  69. Gupta, K.K.; Gupta, V.K.; Shirasaka, T. An Update on Fetal Alcohol Syndrome-Pathogenesis, Risks, and Treatment. Alcohol. Clin. Exp. Res. 2016, 40, 1594–1602. [Google Scholar] [CrossRef]
  70. Pappalardo-Carter, D.L.; Balaraman, S.; Sathyan, P.; Carter, E.S.; Chen, W.J.; Miranda, R.C. Suppression and epigenetic regulation of MiR-9 contributes to ethanol teratology: Evidence from zebrafish and murine fetal neural stem cell models. Alcohol. Clin. Exp. Res. 2013, 37, 1657–1667. [Google Scholar] [CrossRef]
  71. Wozniak, J.R.; Fuglestad, A.J.; Eckerle, J.K.; Kroupina, M.G.; Miller, N.C.; Boys, C.J.; Brearley, A.M.; Fink, B.A.; Hoecker, H.L.; Zeisel, S.H.; et al. Choline supplementation in children with fetal alcohol spectrum disorders has high feasibility and tolerability. Nutr. Res. 2013, 33, 897–904. [Google Scholar] [CrossRef]
  72. Meck, W.H.; Smith, R.A.; Williams, C.L. Organizational changes in cholinergic activity and enhanced visuospatial memory as a function of choline administered prenatally or postnatally or both. Behav. Neurosci. 1989, 103, 1234–1241. [Google Scholar] [CrossRef] [PubMed]
  73. Kawashima, A.; Sekizawa, A.; Koide, K.; Hasegawa, J.; Satoh, K.; Arakaki, T.; Takenaka, S.; Matsuoka, R. Vitamin C Induces the Reduction of Oxidative Stress and Paradoxically Stimulates the Apoptotic Gene Expression in Extravillous Trophoblasts Derived from First-Trimester Tissue. Reprod. Sci. 2015, 22, 783–790. [Google Scholar] [CrossRef] [PubMed]
  74. Kuzawa, C.W. Adipose tissue in human infancy and childhood: An evolutionary perspective. Am. J. Phys. Anthropol. 1998, 27, 177–209. [Google Scholar] [CrossRef]
  75. Donangelo, C.M.; King, J.C. Maternal zinc intakes and homeostatic adjustments during pregnancy and lactation. Nutrients 2012, 4, 782–798. [Google Scholar] [CrossRef] [PubMed]
  76. Barnett, E.R.; Knight, E.; Herman, R.J.; Amarakaran, K.; Jankowski, M.K. Difficult binds: A systematic review of facilitators and barriers to treatment among mothers with substance use disorders. J. Subst. Abuse Treat. 2021, 126, 108341. [Google Scholar] [CrossRef]
  77. Garg, M.; Garrison, L.; Leeman, L.; Hamidovic, A.; Borrego, M.; Rayburn, W.F. Validity of Self-Reported Drug Use Information among Pregnant Women. Matern. Child Health J. 2016, 20, 41–47. [Google Scholar] [CrossRef]
  78. Borland, T.; Babayan, A.; Irfan, S.; Schwartz, R. Exploring the adequacy of smoking cessation support for pregnant and postpartum women. BMC Public Health 2013, 13, 472. [Google Scholar] [CrossRef]
  79. El-Mohandes, A.; Herman, A.A.; Nabil El-Khorazaty, M.; Katta, P.S.; White, D.; Grylack, L. Prenatal care reduces the impact of illicit drug use on perinatal outcomes. J. Perinatol. 2003, 23, 354–360. [Google Scholar] [CrossRef]
  80. Roberts, S.C.; Pies, C. Complex calculations: How drug use during pregnancy becomes a barrier to prenatal care. Matern. Child Health J. 2011, 15, 333–341. [Google Scholar] [CrossRef]
  81. England, L.J.; Bennett, C.; Denny, C.H.; Honein, M.A.; Gilboa, S.M.; Kim, S.Y.; Guy, G.P., Jr.; Tran, E.L.; Rose, C.E.; Bohm, M.K.; et al. Alcohol Use and Co-Use of Other Substances among Pregnant Females Aged 12–44 Years—United States, 2015–2018. MMWR Morb. Mortal. Wkly. Rep. 2020, 69, 1009–1014. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Download PDF
Can Nutrition Contribute to a Reduction in Sarcopenia, Frailty, and Comorbidities in a Super-Aged Society?
Previous
Dietary Energy and Nutrient Intake of Healthy Pre-School Children in Hungary
Next