1.
Circulating levels of maternal vitamin D and risk of ADHD in offspring: results from the Vitamin D Antenatal Asthma Reduction Trial.
Chu, SH, Huang, M, Kelly, RS, Kachroo, P, Litonjua, AA, Weiss, ST, Lasky-Su, J
International journal of epidemiology. 2022;51(3):910-918
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Plain language summary
Acting as both a nutrient and a hormone, vitamin D has been found to play a critical role in neurodevelopment across sensitive periods in utero, infancy and early childhood. Among neurodevelopmental and behavioural disorders in early life, attention-deficit/hyperactivity disorder (ADHD) is the most common among children worldwide. Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent ADHD. The aims of this study were to (i) determine the association between maternal vitamin D levels in the first and third trimesters of pregnancy and the risk of offspring ADHD by age 6 years or later; and (ii) to identify potential sensitive periods in utero during which vitamin D levels might be most important for reducing risk of ADHD. This is an ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART). The VDAART was a randomised, double-blinded, multicentre, clinical trial in which 876 participating mothers were recruited between 10–18 weeks of gestation and assigned to receive either 4400 or 400 IU/day of vitamin D throughout pregnancy. Results show protective associations between maternal 25(OH)D sufficiency in the third trimester and child ADHD, but not at baseline. Furthermore, both at baseline and in the third trimester, there were higher odds of ADHD in male offspring as compared with female offspring with 25(OH)D insufficient mothers (analyses limited by small sample sizes) Authors conclude that higher levels of maternal vitamin D during pregnancy may play a protective role against risk of ADHD in offspring, but further studies are needed to confirm this association and any therapeutic potential therein.
Expert Review
Conflicts of interest:
None
Take Home Message:
Ensure that women in pregnancy, and possibly also those seeking to conceive, have adequate vitamin D status in order to reduce the risk of ADHD in offspring.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
This paper describes a secondary data analysis from an RCT that looked at the effect of prenatal vitamin D supplementation on risk of childhood asthma in offspring. Enrolled women aged 18–39 years with a history of asthma, eczema or allergic rhinitis, or whose partner (biological father of child) had a history of the aforementioned condition, received either 400 IU or 4400 IU vitamin D daily for the duration of their pregnancy. Offspring follow-up is still ongoing.
Aims
The current study aims were twofold: (i) to determine the association between maternal vitamin D levels in trimesters 1 and 3 and the risk of attention deficit/hyperactivity disorder (ADHD) in offspring diagnosed by age 6 years or later; and (ii) to identify potentially sensitive periods during gestation in which vitamin D levels may be especially important for reducing risk of ADHD.
Methods
The analytical sample included 679 mother-child pairs, from the original sample of 876 participating mothers. No sample size calculation was reported, though the sample was considered representative of the overall RCT study population.
Maternal vitamin D (serum 25(OH)D) was classified as follows
- Highly deficient <12 ng/mL
- Deficient 12 ng/mL to 19.9 ng/mL
- Insufficient 20 ng/mL to 29.9 ng/mL
- Sufficient ≥30 ng/mL
ADHD status was assessed through parental reporting between ages 6 and 9 years.
Results
No baseline associations between a vitamin D sufficient status and offspring ADHD in maternal samples collected during trimester 1 were observed (OR 1.06, 95% CI 0.51–2.19; P.0.871), though this association became statistically significant at trimester 3 (OR 0.47, 95% CI 0.26–0.84; P.0.011). This translated to a 53% less chance of having a child with ADHD at age 6 or later among mothers with vitamin D sufficiency compared with children of mothers with vitamin D deficiency. There was also a linear trend in the protective association of vitamin D sufficiency (≥30 ng/mL) on reduced risk of offspring ADHD at age 6 years or later in data from trimester 3. Stratified analyses revealed a protective association for sufficient maternal vitamin D status and offspring ADHD among males (OR 0.47, 95% CI 0.23–0.94).
Conclusions
The authors concluded that vitamin D sufficiency (≥30 ng/mL) in the 3rd trimester of gestation may decrease the risk of ADHD development in offspring.
Notes: The authors reported no relevant conflicts of interest.
Clinical practice applications:
Ensuring a sufficient vitamin D status by the 3rd trimester of pregnancy may help to lessen the risk of ADHD in offspring. Nutritional therapists and other clinicians working with pregnant women or women looking to conceive should consider checking vitamin D status and providing corrective supplementation and lifestyle advice to augment vitamin D levels where indicated.
Considerations for future research:
The authors of this study postulated that the statistically significant protective association between vitamin D at trimester 3 and ADHD in offspring was not significant in trimester 1 due to a low observed variability in vitamin D status (>75% of women were vitamin D insufficient), and thus the statistical test being underpowered to see difference between groups with sufficient or insufficient status.
Further research could expand upon this hypothesis to test whether vitamin D status in trimester 1, or preconceptually, may offer a protective association for ADHD and other related neurological conditions that may manifest in early life.
Abstract
BACKGROUND Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD. METHODS Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed. RESULTS No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08). CONCLUSIONS Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings.
2.
Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial.
Lambert, MNT, Thybo, CB, Lykkeboe, S, Rasmussen, LM, Frette, X, Christensen, LP, Jeppesen, PB
The American journal of clinical nutrition. 2017;106(3):909-920
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Oestrogens play a vital role in maintaining bone health. The natural decline in oestrogen during menopause negatively impacts bone mineral density and increases the risk of osteoporosis and fractures. Standard interventions offered include calcium and vitamin D supplementation and hormone replacement therapy. As hormone replacement therapy is associated with increased cancer risk, there is a need to find effective treatments that display a suitable safety profile for long-term use. Isoflavones are compounds found in legume plants, many of which are dietary staples in some cultures. Isoflavones are phytoestrogens, substances that can selectively interact with human oestrogen receptors. Initial research on Isoflavones indicated that it reduces bone breakdown whilst showing protective effects for certain cancers. This randomized, double- blind, placebo-controlled trial compared the effectiveness of an lactic acid fermented, probiotic-rich isoflavone product from Red Clover (RCE) or a placebo, when given in addition to Calcium, Magnesium and Vitamin D (CMD) in postmenopausal women with osteopenia. Participants were monitored using blood tests assessing phytoestrogen activity and oestrogen metabolism, DXA scans to observe changes in bone structure and activity and dietary questionnaires. A total of 78 participants completed the study. The results showed that twice a day 60 mg isoflavones from RCE had a significant physiological impact on preventing bone loss associated with oestrogen deficiency, and was more effective in preserving bone density than CDM alone. The authors concluded that RCE was close to effectiveness to conventional bone-preserving treatments like hormone therapy but stood out due to its better safety profile and minimal side effects. Gut bacteria enhance the effectiveness of these isoflavones, which can be metabolised into compounds called equol. While before the study none of the participants could produce equol, in the end, half of the participants in the RCE group were able to produce equol, suggesting that the probiotic presence in the supplement positively influenced the participants' gut bacteria, creating favourable conditions. Additionally, RCE treatment led to favourable changes in urinary oestrogen metabolites associated with less carcinogenic oestrogen metabolism. In conclusion, the probiotic RCE, enhanced the effectiveness of CMD in preventing bone loss, whilst also increasing the ability to produce equol.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Fermented red clover extract, rich in bioavailable isoflavones with selective oestrogen receptor affinity and probiotics, combined with traditional supplementation (calcium, magnesium and vitamin D) improves bone mineral density and bone turnover compared to placebo in post menopausal women with osteopenia.
- Combining probiotics with isoflavones appears to enhance intestinal isoflavone uptake and isoflavone metabolism.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This was a well-constructed randomised, parallel-design, placebo-controlled, double-blind trial over 12 months. The primary aim was to determine the effectiveness of a novel fermented red clover extract (RCE) containing isoflavones and probiotics combined with traditional calcium/magnesium/vitamin D supplementation, in comparison with traditional calcium/magnesium/vitamin D supplementation alone on bone mineral density (BMD) in postmenopausal women with osteopenia.
Methods
- The trial followed the guidelines of the Declaration of Helsinki and received ethics approval.
- Inclusion criteria: female; >=1 year postmenopause; age 60-85; and bone T score of -1 to -2.25.
- Exclusion criteria: medical treatment for osteopenia or hormone replacement therapy within the past 3 months; diet rich in or supplementation with isoflavones; supplementation with Vitamin K; medical history of stipulated conditions.
- 85 participants were eligible and randomised to either the control or treatment group.
- Treatment group received 95 mL of RCE twice daily, containing 60 mg isoflavone aglycones and probiotics, plus 1040mg calcium, 487mg magnesium and 25μg Vitamin D daily (CMD/d). Control group received masked RCE placebo plus CMD/d.
Results
- The change in BMD (p=0.043) and T score (p=0.045) showed a statistically significant greater decrease in the lumbar spine, femoral neck and hip of the control group than the RCE treatment group after 12 months of treatment.
- A statistically significant reduction in one bone resorption marker was found in the RCE group compared to control (p=0.045). All other bone biomarkers failed to reach significance.
- Plasma isoflavone concentration was elevated in the RCE treatment group compared to control (p=0.0094).
- The concentration ratios of urinary oestrogen metabolites 2-OH:16αOH was significantly increased in the RCE group compared to control (p=0.026).
Conclusion
Fermented RCE with CMD/d slowed oestrogen-deficient BMD loss and improved one marker of bone turnover in postmenopausal osteopenic women. Combining RCE with CMD/d was found to be more effective in preserving bone density than CMD/d alone in this target group. Probiotics in the fermented RCE appear to enhance intestinal isoflavone uptake, metabolism, and therapeutic effect.
Clinical practice applications:
- Healthcare practitioners working with women in post-menopause with osteopenia could consider the addition of fermented RCE with CMD/d for improved bone mineral density and bone turnover over 12 months.
- Given the positive impact of RCE intake over 12 months on 2-OH:16αOH oestrogen metabolite ratios, healthcare practitioners could consider fermented RCE when HRT is not an available option in relation to cancer risk.
- Based on these results, Nutritional Therapists working with post-menopausal women with osteopenia can focus on dietary isoflavone intake and pre and probiotic foods to support BMD, alongside supplementary options.
Considerations for future research:
- Given the length of time taken in bone remodelling cycles, a clinical trial of more than 2 years would strengthen the evidence provided by DXA scan.
- All trial participants were normotensive and healthy weight. Future studies could include women with hypertension and obesity to determine effects of RCE on bone and blood pressure/lipid markers in this group.
- Controlled feeding studies to determine the dietary effects of isoflavones and pre and probiotic foods would provide additional information in this area.
- Other fermented RCE products should be trialled to replicate findings.
Abstract
Background: Female age-related estrogen deficiency increases the risk of osteoporosis, which can be effectively treated with the use of hormone replacement therapy. However, hormone replacement therapy is demonstrated to increase cancer risk. Bioavailable isoflavones with selective estrogen receptor affinity show potential to prevent and treat osteoporosis while minimizing or eliminating carcinogenic side effects.Objective: In this study, we sought to determine the beneficial effects of a bioavailable isoflavone and probiotic treatment against postmenopausal osteopenia.Design: We used a novel red clover extract (RCE) rich in isoflavone aglycones and probiotics to concomitantly promote uptake and a favorable intestinal bacterial profile to enhance isoflavone bioavailability. This was a 12-mo, double-blind, parallel design, placebo-controlled, randomized controlled trial of 78 postmenopausal osteopenic women supplemented with calcium (1200 mg/d), magnesium (550 mg/d), and calcitriol (25 μg/d) given either RCE (60 mg isoflavone aglycones/d and probiotics) or a masked placebo [control (CON)].Results: RCE significantly attenuated bone mineral density (BMD) loss at the L2-L4 lumbar spine vertebra (P < 0.05), femoral neck (P < 0.01), and trochanter (P < 0.01) compared with CON (-0.99% and -2.2%; -1.04% and -3.05%; and -0.67% and -2.79, respectively). Plasma concentrations of collagen type 1 cross-linked C-telopeptide was significantly decreased in the RCE group (P < 0.05) compared with CON (-9.40% and -6.76%, respectively). RCE significantly elevated the plasma isoflavone concentration (P < 0.05), the urinary 2-hydroxyestrone (2-OH) to 16α-hydroxyestrone (16α-OH) ratio (P < 0.05), and equol-producer status (P < 0.05) compared with CON. RCE had no significant effect on other bone turnover biomarkers. Self-reported diet and physical activity were consistent and differences were nonsignificant between groups throughout the study. RCE was well tolerated with no adverse events.Conclusions: Twice daily RCE intake over 1 y potently attenuated BMD loss caused by estrogen deficiency, improved bone turnover, promoted a favorable estrogen metabolite profile (2-OH:16α-OH), and stimulated equol production in postmenopausal women with osteopenia. RCE intake combined with supplementation (calcium, magnesium, and calcitriol) was more effective than supplementation alone. This trial was registered at clinicaltrials.gov as NCT02174666.