Browsing by Author "Letourneau, Nicole Lyn"
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Item Open Access Adverse childhood experiences and HPA axis function in pregnant women(Elsevier, 2018-05-28) Thomas, Jenna C.; Magel, Chantelle; Tomfohr-Madsen, Lianne; Madigan, Sheri L.; Letourneau, Nicole Lyn; Campbell, Tavis S.; Giesbrecht, G. F.; APrON Study TeamItem Open Access Biological embedding of perinatal social relationships in infant stress reactivity(Wiley, 2017-02-21) Thomas, Jenna C.; Letourneau, Nicole Lyn; Bryce, Crystal I.; Campbell, Tavis S.; Giesbrecht, G. F.; APrON Study TeamWhereas significant advances have been made in understanding how exposure to early adversity "gets under the skin" of children to result in long-term changes in developmental outcomes, the processes by which positive social relationships become biologically-embedded remain poorly understood. The aim of this study was to understand the pathways by which maternal and infant social environments become biologically-embedded in infant cortisol reactivity. Two hundred seventy-two pregnant women and their infants were prospectively assessed during pregnancy and at 6 months postpartum. In serial mediation analyses, higher perceived social support from partners during pregnancy was associated with lower infant cortisol reactivity or larger decreases in cortisol in response to a stressor at 6 months of age via lower self-reported prenatal maternal depression and higher mother-infant interaction quality. The findings add to our understanding of how perinatal social relationships become biologically-embedded in child development.Item Open Access Developing an Online Resource to Support Parents’ Search for Apps in The First Year of Parenthood(2020-08-19) Virani, Anila; Duffett-Leger, Linda A.; Letourneau, Nicole Lyn; Stroulia, EleniBackground: Parents’ mobile application (app) use is on the rise due to the affordability of smartphones and the convenience of accessing parenting support 24 hours a day. While apps can assist in parenting, it is hard for parents to find good quality apps that meet their expectations. Therefore, the purpose of this study was to co-create a parenting app directory to supports parents' search for apps in the first year of parenthood and co-design a user interface to feature the directory. Methods: Spinuzzi's (2005) stages of the participatory design methodology guided this study and the project was divided into three phases. Phase one, parenting app review, was conducted to gain insight into the available apps for parents. Phase 2, focus group discussions with 18 first-time Canadian parents (15 mothers, 3 fathers) allowed researchers to understand parents' needs and preferences. Phase three, design sessions were conducted with three parents (two fathers and one mother) to learn about parents' preferred design elements. Results: In phase one, app review, 4,300 apps were identified on the initial search, of which only 16 (0.4%) apps met the quality criteria reflecting the extent of the problem parents face in finding quality parenting apps. The quality apps were further reviewed by parents in phase two, focus group discussions, to finalize the selection of apps and resulted in the co-development of the partnering app directory. The focus group discussions also explored parents’ needs and preferences and the inductive thematic analysis resulted in four themes. Phase three, design sessions, led to the co-creation of a user interface to feature the app directory. Conclusion: Despite the availability of evidence-based apps, parents continue to report difficulties in finding desired quality apps. The app directory is one of the solutions that establishes easy access to quality parenting apps. Initiatives should be taken within the healthcare system to equip front-line nurses and other healthcare professionals with adequate knowledge and training to support contemporary parents’ needs via digital means.Item Open Access How Might We Understand Mothers’ Experiences of the VID-KIDS Intervention? More than Meets the Eye(2021-02-09) Bon Bernard, Jennifer; Letourneau, Nicole Lyn; Tough, Suzanne C.; Moules, Nancy Jean; Tryphonopoulos, Panagiota; McCaffrey, GrahamPostpartum depression (PPD) is a complex public health concern that can disrupt the healthy interaction between a mother and her infant. An impairment in this foundational relationship is perceived by infants to be a toxic stressor, and as a result negative long-term outcomes on growth and development can ensue. Parenting interventions in the early years of an infant’s life that aim to modify this significant stressor are a type of support that can alleviate potential concerns associated with the experience of PPD. Video-Feedback Interaction Guidance for Improving Interactions Between Depressed Mothers and their Infants (VID-KIDS) is an example of a parenting intervention that has been evaluated to improve the quality of mother-infant interactions when mothers are experiencing PPD, improve maternal depression and decrease infants stress levels. To ensure successful uptake of VID-KIDS in public health care settings, it is essential that maternal perspectives are heard and applied accordingly. The goal of this research project was to understand the perspectives of mothers who participated in the VID-KIDS intervention, as this was a gap that required further exploration. Four mothers were interviewed, following the tenets of hermeneutics, to understand the meaning that they attached to this experience. The findings of this study provided encouragement that VID-KIDS makes a positive difference in the lives of mothers and their infants when experiencing PPD.Item Open Access Intergenerational transmission of adverse childhood experiences via maternal depression and anxiety and moderation by child sex(2018-07-23) Letourneau, Nicole Lyn; Dewey, Deborah; Kaplan, Bonnie J.; Ntanda, Henry N.; Novick, Jason; Thomas, Jenna C.; Deane, Andrea J.; Leung, Brenda My; Pon, Kylie; Giesbrecht, G. F.; APrON Study TeamAdverse childhood experiences (ACEs) of parents are associated with a variety of negative health outcomes in offspring. Little is known about the mechanisms by which ACEs are transmitted to the next generation. Given that maternal depression and anxiety are related to ACEs and negatively affect children's behaviour, these exposures may be pathways between maternal ACEs and child psychopathology. Child sex may modify these associations. Our objectives were to determine: (1) the association between ACEs and children's behaviour, (2) whether maternal symptoms of prenatal and postnatal depression and anxiety mediate the relationship between maternal ACEs and children's behaviour, and (3) whether these relationships are moderated by child sex. Pearson correlations and latent path analyses were undertaken using data from 907 children and their mothers enrolled the Alberta Pregnancy Outcomes and Nutrition study. Overall, maternal ACEs were associated with symptoms of anxiety and depression during the perinatal period, and externalizing problems in children. Furthermore, we observed indirect associations between maternal ACEs and children's internalizing and externalizing problems via maternal anxiety and depression. Sex differences were observed, with boys demonstrating greater vulnerability to the indirect effects of maternal ACEs via both anxiety and depression. Findings suggest that maternal mental health may be a mechanism by which maternal early life adversity is transmitted to children, especially boys. Further research is needed to determine if targeted interventions with women who have both high ACEs and mental health problems can prevent or ameliorate the effects of ACEs on children's behavioural psychopathology.Item Open Access Maternal Adverse Childhood Experiences and Infant DNA Methylation: Examining an Epigenetic Biomarker of Intergenerational Risk(2019-04-22) Sekhon, Bikramjit; Letourneau, Nicole Lyn; Kobor, Michael S.; Giesbrecht, Gerald; Madigan, Sheri L.While “nature" and "nurture" are often viewed as opposing influences on human development, epigenetics is one area of study investigating how these influences work together. Until recently, transmission of intergenerational risk to human development has centred on claims of genetic inheritance, or the persistence of poor social environments such as adverse childhood experiences (ACEs), across generations. Stress occurring during gestation, that affects both the fetus and mother, has also been proposed as a method of transmitting intergenerational risk to offspring. New evidence in animal models suggests that “preconception stress” may also predict DNA methylation (DNAm; one component of epigenetics) in offspring, potentially impacting developmental health outcomes. Thus, the purpose of this study was to investigate the association between human mothers’ preconception stress and differential DNAm patterns in their biological infants. A secondary analysis was conducted, utilizing data obtained from the Fetal Programming (FetalPro) cohort study, a sub-set of participants in the Alberta Pregnancy Outcomes and Nutrition (APrON) study. APrON study participants were voluntary, and all pregnant women were over 16-years-old and before 22 weeks of gestation at enrolment. Measures included mothers’ scores on the Adverse Childhood Experiences (ACEs) questionnaire, mental health during pregnancy including the Edinburgh Postnatal Depression Scale and the Symptom Checklist 90 Revised, as well as demographics. Epigenetic data were obtained from buccal epithelial cell (BEC) samples collected from mothers’ 3-month-old infants. Cellular DNA were processed with the Illumina Infinium HumanMethylation450 Bead Chip to investigate DNAm. Relationships were investigated using regression modelling with the Limma function in R-package. Results showed a strong relationship between mothers’ total ACE score and differential DNAm patterning in their infants at eight epigenetic sites out of over 450,000 sites investigated. These findings have implications for the study of DNAm patterning as a biomarker for the transfer of preconception stress in humans and suggest a role for epigenetics in the transfer of intergenerational trauma.Item Open Access Maternal Prenatal Anxiety, Attachment and Children’s Externalizing and Internalizing Behavioral Problems(2020-09-09) Ali, Elena; Letourneau, Nicole Lyn; Giesbrecht, Gerald F.; Benzies, Karen MariePerinatal anxiety is common, and affects up to 15-20% of women during perinatal period (Abrar, Fairbrother, Smith, Skoll, & Albert, 2020). Regarded as a prenatal programming factor (Madigan et al., 2018), prenatal anxiety (PA) is associated with biological, cognitive, and behavioral development in offspring, increasing risk for later externalizing and internalizing problems and adult psychopathology (Finsaas et al., 2018; Vogel, Jackson, Barch, Tillman, & Luby, 2019). Child behavioral development is also influenced by the postpartum anxiety (Madigan et al., 2018; Vogel et al., 2019). Externalizing behaviors are more often observed in boys and internalizing behaviors are more often observed in girls (Martel, 2013). Maternal-child attachment is defined as an affectionate, mutually satisfying relationship between a child and a caregiver that is involved in making the child feel safe, secure, and protected (Bowlby, 1958). Maternal-child attachment may moderate the association between PA and externalizing and internalizing behavioral problems, and function differently for boys and girls. The first manuscript provides a review of women’s experiences with postpartum anxiety, showing that postpartum anxiety is common, and can have serious implications for the maternal-child relationship. The second manuscript consists of a concept analysis of parent-child attachment to advance the application of this concept in nursing practice. The third manuscript presents the results of testing associations between PA and children's behavioral problems, and the role of maternal-child attachment and child sex as moderators of this association. Maternal-child attachment security moderated the association between prenatal anxiety and children’s behavioral problems; however, the sex of the child did not. The final paper describes the sample from which the third paper was derived, the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort, highlighting findings on maternal and paternal mental health from pregnancy to three years postpartum. The dissertation concludes with recommendations for nursing research, policy, education and practice.Item Open Access Maternal sensitivity and social support protect against childhood atopic dermatitis(Springer Nature, 2017-05-26) Letourneau, Nicole Lyn; Kozyrskyj, Anita L.; Cosic, Nela; Ntanda, Henry N.; Anis, Lubna; Hart, Martha J.; Campbell, Tavis S.; Giesbrecht, G. F.; APrON Study TeamBackground: Many studies have identified associations between qualities of maternal–child relationships and childhood asthma, but few have examined associations with childhood atopic dermatitis (AD), a common precursor to asthma. Moreover, maternal psychological distress, including prenatal and postnatal depression, anxiety and stress, may increase risk, while social support from partners may reduce risk for childhood AD. We sought to uncover the association between maternal–infant relationship qualities (maternal sensitivity towards infant behavioral signals, controlling behavior, and unresponsiveness) and child AD after accounting for risk (i.e., prenatal and postnatal maternal depression, anxiety and stress) and protective (i.e., social support) factors. Methods: We conducted a secondary analysis of data collected on a sub-sample of 242 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition cohort study. Inclusion criteria required mothers to be >16 years of age, English speaking and <22 weeks gestational age at enrolment. Data on depression, anxiety and stress in the prenatal and postnatal periods and physician diagnosis of childhood AD at 18 months were gathered via maternal report. Maternal sensitivity, unresponsiveness and controlling behaviours were assessed via videotaped observations using the Child-Adult Relationship Experimental (CARE)-Index at 6 months of infant age. Results: Higher maternal sensitivity, or the inability of the mother to appropriately understand and respond to infant needs based on behavioral signals, predicted reduced odds of AD independent of and in combination with low prenatal and postnatal anxiety and high paternal support. After adjustment, higher maternal controlling behaviours and unresponsiveness also predicted greater odds of AD. Conclusions: Low maternal sensitivity is a risk factor for childhood AD, independently and in combination with perinatal anxiety and low social support. Thus, interventions that improve maternal–infant relationship quality, especially sensitivity, reduce anxiety and improve social support from partners could reduce odds of childhood AD.Item Open Access Neuropsychological Outcomes of Prenatal Exposure to Phenols and Phthalates in Young Children(2019-09-20) Ejaredar, Maede; Dewey, Deborah; Giesbrecht, Gerald; Letourneau, Nicole Lyn; Martin, Jonathan W.; Patten, Scott B.Background: Bisphenols and phthalates are endocrine disrupting chemicals (EDCs). The primary route of exposure to these chemicals is through diet. Prenatal maternal exposure is a significant concern as these EDCs cross the blood-brain barrier and placenta. In children, some studies have reported that prenatal exposure to maternal bisphenol A (BPA) has been associated with a broad range of behavioral and cognitive outcomes including higher levels of aggression, hyperactivity, anxiety, depression, poorer emotional control and lower IQ. No previous studies have examined the prenatal effects of maternal exposure to bisphenol S (BPS), a chemical alternative to BPA, on children’s neurodevelopment. Additionally, some studies suggest that prenatal maternal exposure to phthalates has been associated with social impairments, lower IQ, poorer language and motor skills, and poorer psychomotor and mental development in children. In addition, some studies report that the associations between prenatal exposure to maternal BPA and phthalates are more pronounced in girls, whereas others report greater effects in boys. The primary objective for this dissertation was to examine the effects of prenatal maternal bisphenol (BPA, BPS) and phthalate exposure on neurodevelopmental outcomes of children who were three to four years of age. The secondary objective was to examine the possible modifying role of child sex. We hypothesize that higher levels of prenatal exposure to bisphenols and phthalates would be associated with lower performance on measures of behavior, cognition and motor function at three to four years of age. Methods: Two systematic reviews were undertaken to characterize current knowledge and gaps related to the associations between prenatal and childhood exposure to urinary BPA or phthalates, and neurodevelopmental outcomes. Subsequently, mother-child pairs were recruited from the Alberta Pregnancy Outcomes and Nutrition cohort study (APrON). Maternal BPA, BPS and levels for 14 phthalate metabolites were quantified using single spot maternal urine samples that were collected between 14 and 26 weeks of pregnancy in 410 maternal-child pairs who participated in the studies reported here. Children’s neurodevelopment was assessed at three to four years using standardized measures of behavior (i.e., Child Behavioral Checklist (CBCL)), cognition (i.e., Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition (WPPSI-IV)), and motor function (i.e., Movement Assessment Battery for Children – Second Edition (MABC-2)). Sex-stratified analysis and multivariate linear regression were used to assess relationships between prenatal maternal BPA, BPS or phthalate concentrations and neurodevelopmental outcomes. We adjusted for multiple confounding variables including urinary creatinine, maternal age, education and child sex. We also used the Benjamini-Hochberg procedure to correct for multiple statistical comparisons. Results: The two systematic reviews of the literature suggested inconsistent findings, with studies reporting positive, negative or no association between prenatal maternal BPA or phthalates exposure and neurodevelopmental outcomes. Both reviews also suggested inconsistent sex-specific effects. Further, many of the studies that examined the effects of prenatal maternal exposure to phthalates had investigated a limited number of phthalate metabolites. The systematic reviews supported the need for well-designed prospective cohort studies to investigate these gaps. Findings from our prospective cohort study suggested that prior to correction for multiple comparison, higher maternal urinary BPA concentrations were not associated with neurodevelopmental problems and n No associations were found between prenatal maternal bisphenols levels and motor and cognitive development. After correcting for multiple comparisons, only the association between higher BPS and attention remained statistically significant. Prior to correction for multiple comparisons, adjusted models revealed that higher maternal prenatal Mono-benzyl phthalate (MBzP) and more externalizing and aggressive behaviors on the CBCL. On the WPPSI-IV, we found that higher exposure to maternal phthalates (i.e. High Molecular Weight (HMW), (Mono-isobutyl phthalate (MiBP), Mono-carboxyoctyl phthalate (MCOP), and MBzP) during the second trimester in pregnancy were associated with improved cognitive performance (FSIQ, visual spatial and working memory skills). For motor outcomes, we found that higher exposure to Di-ethylhexyl phthalates (DEHP), were associated with poor performance in MABC-2. Correction for multiple comparisons attenuated most of these associations such that they became non-significant. Only the association between DEHP metabolites and lower Balance scores remained significant after corrections. We found sex-specific effects, such that adverse behavioral outcomes were only observed in boys. Lower Verbal Comprehension was found in boys while better Visual Spatial scores were found in girls. Poor overall motor function was found among boys while balance problems was observed among girls. Conclusions: Maternal BPS concentrations during pregnancy may be associated with more attention problems, as measured by CBCL, in children at three to four years of age. The current study is the first child neurodevelopmental study to suggest that BPS may not be a safe alternative for BPA. Also, higher prenatal maternal DEHP concentrations were associated with more balance problems on CBCL. However, we do not have sufficient evidence to support that prenatal maternal exposure to BPA and other phthalate metabolites during the second trimester of pregnancy is associated with adverse neurodevelopmental outcomes in children at three to four years of age. Future research in prospective cohorts who are similar in terms of levels of exposure and sociodemographic and cultural background are needed to corroborate these findings.Item Open Access Pregnancy-Specific Anxiety and Maternal Social Support: Relationships with Offspring Attention and Executive Function Through Epigenetic Age(2023-08) Lowe, Catherine T.; Climie, Emma Alison; Ross, Kharah MacKenzie; Climie, Emma A.; Ross, Kharah MacKenzie; Letourneau, Nicole Lyn; Murias, Kara RochelePrenatal exposure to maternal distress, such as pregnancy-specific anxiety, is associated with diminished child attention and executive functioning, commonly experienced with attention deficit/hyperactivity disorder (ADHD). Maternal social support is related to better child outcomes. In utero experiences can affect genetic expression by fine-tuning child phenotypes, potentially through child epigenetic age differences relative to chronological age through DNA methylation (DNAm), but whether this relates to child attention or executive function or mediates protective factors such as social support is unknown. Pregnant women (n = 96) reported pregnancy-specific anxiety and social support, and their 3-month-old infant buccal epithelial and buffy coat cell tissue samples were collected and assayed for DNAm, indicating epigenetic age differences identified through the Horvath Pan-Tissue clock. Children’s executive function and attention were assessed using the Behavior Assessment System for Children (2nd Ed) at 5 years of age. Multiple regression and structural equation mediation path analysis examined associations and indirect pathways between pregnancy-specific anxiety and social support on child attention and executive functioning through epigenetic age difference. Neither pregnancy-specific anxiety nor social support showed direct or indirect associations with children’s attention. However, pregnancy-specific anxiety and social support independently indirectly predicted better child executive functioning, mediated through increased, or biologically older, epigenetic age differences. Small to moderate amounts of pregnancy-specific anxiety is a normative and non-pathological experience, differentiated from maternal distress broadly. Both pregnancy-specific anxiety and social support are related to child DNAm, suggesting a possible impact on phenotype expression with implications for future research directions and potential targeted psychosocial interventions to preserve child executive functioning.Item Open Access Prenatal bisphenol a exposure and dysregulation of infant hypothalamic-pituitary-adrenal axis function: findings from the APrON cohort study(Springer Nature, 2017-05-19) Giesbrecht, G. F.; Ejaredar, Maede; Liu, Jiaying; Thomas, Jenna C.; Letourneau, Nicole Lyn; Campbell, Tavis S.; Martin, Jonathan W.; Dewey, Deborah; APrON Study TeamBackground: Animal models show that prenatal bisphenol A (BPA) exposure leads to sexually-dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3-month-old infants. Methods: Mother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010–2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure. Results: Higher maternal BPA was associated with increases in baseline cortisol among females (β = 0.13 log μg/dL; 95% CI: 0.01, 0.26), but decreases among males (β = −0.22 log μg/dL; 95% CI: -0.39, −0.05). In contrast, higher BPA was associated with increased reactivity in males (β = .30 log μg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (β = −0.15 log μg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results. Conclusions: Prenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children’s behaviour following prenatal BPA exposure are mediated by sexually-dimorphic changes in HPA axis function. Keywords: Bisphenol-A, Fetal exposure, Cortisol, Hypothalamic-pituitary-adrenal axis, Infant stress reactivityItem Open Access Social buffering of the maternal and infant HPA axes: Mediation and moderation in the intergenerational transmission of adverse childhood experiences(Cambridge University Press, 2018-08-02) Thomas, Jenna C.; Letourneau, Nicole Lyn; Campbell, Tavis S.; Giesbrecht, G. F.; APrON Study TeamSupportive social relationships can reduce both psychological and physiological responses to stressful experiences. Recently, studies have also assessed the potential for social relationships to buffer the intergenerational transmission of stress. The majority of these studies, however, have focussed on social learning as a mechanism responsible for the intergenerational transmission of stress. Evidence of biological mechanisms is lacking. The objective of the current study was, therefore, to determine whether the association between maternal adverse childhood experiences (ACEs) and infant hypothalamic-pituitary-adrenal (HPA) axis function is mediated by maternal HPA axis function during pregnancy and moderated by social support. Data were from 243 mother-infant dyads enrolled in a prospective longitudinal cohort (the Alberta Pregnancy Outcomes and Nutrition Study). Maternal history of ACEs was retrospectively assessed while maternal perceived social support and salivary cortisol were assessed prospectively at 6-22 weeks gestation (Time 1) and 27-37 weeks gestation (Time 2), and infant cortisol reactivity to a laboratory stressor and maternal perceived social support were assessed at 5-10 months postnatal (Time 3). Results revealed that maternal HPA axis function during pregnancy mediated the effects of maternal ACEs on infant HPA axis reactivity, suggesting that the maternal HPA axis is a mechanism by which maternal early life stress is transmitted to offspring. Furthermore, social support in the prenatal and postnatal periods moderated the cascade from maternal ACEs to infant HPA axis reactivity. Specifically, prenatal social support moderated the association between ACEs and maternal HPA axis function during pregnancy, and postnatal social support moderated the association between maternal HPA axis function and infant cortisol reactivity. These findings highlight the social sensitivity of the HPA axis and suggest the utility of social relationships as an intervention target to reduce the effects of maternal early life stress on infant outcomes.Item Open Access Vitamin D Deficiency and Antenatal and Postpartum Depression: A Systematic Review(MDPI, 2018-04-12) Aghajafari, Fariba; Letourneau, Nicole Lyn; Mahinpey, Newsha; Cosic, Nela; Giesbrecht, G. F.Vitamin D has been implicated in antenatal depression (AD) and postpartum depression (PPD) in many studies; however, results have been inconsistent due to the complexity of this association. We searched the MEDLINE, Embase, PsycINFO, and Maternity and Infant Care databases for literature addressing associations between vitamin D and AD and PPD. Two independent authors reviewed titles and abstracts of the search results and selected studies for full review. Data were extracted, and a quality rating was done using the Newcastle–Ottawa Scale (NOS) on the selected studies. A total of 239 studies were identified; 14 were included in the review. The quality assessment of the included studies ranged from moderate to high. Of the studies on PPD, five of nine (55%) showed a significant association between vitamin D and PPD. Five of seven (71%) studies on AD showed a significant association with vitamin D status. As the included studies used different effect estimates and statistical analyses to report the association, it was not possible to transform the existing data into one single effect measure to employ meta-analytic techniques. While results of this systematic review vary, they indicate a significant association between vitamin D status and AD and PD.