Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder

May combine two claims.

The highest quintile of maternal iron intake during the index period was associated with reduced autism spectrum disorder risk compared with the lowest quintile (adjusted odds ratio 0.49, 95% confidence interval 0.29-0.82), with the association especially pronounced during breastfeeding.

“The highest quintile of iron intake during the index period was associated with reduced ASD risk compared with the lowest (adjusted odds ratio = 0.49, 95% confidence interval: 0.29, 0.82), especially during breastfeeding.”

May combine two claims.

For the ASD-iron intake link, adjusted odds ratios by quintile varied somewhat by child's birth year, but not for the highest quintile compared with the lowest, for which odds ratios were consistently below the null.

“Finally, adjusted odds ratios for the association between quintile of iron intake and ASD differed somewhat by the child ' s birth year, but not for the highest quintile of iron intake compared with the lowest, for which odds ratios were consistently below the null (Web Table 7, Web Figure 3).”

May combine two claims.

A significant multiplicative interaction (P = 0.002) linked low maternal iron intake with older maternal age at delivery; mothers aged 35 or older in the lowest iron quintile had over 5 times the ASD risk of younger mothers in the highest quintile (OR = 5.01, 95% CI: 1.98, 12.69).

“A signi fi cant multiplicative interaction ( P = 0.002) was found between low maternal iron intake and older maternal age at delivery, with more than a 5-fold increased risk of ASD for mothers aged 35 years or older with iron intake in the lowest quintile as compared with younger mothers with iron intake in the highest quintile (OR = 5.01, 95% CI: 1.98, 12.69) (Table 5).”

May combine two claims.

In the CHARGE Study, adjusted odds ratios for the link between ASD and reported iron supplement use were below the null throughout the index period, but they were not statistically significant except during breastfeeding among mothers who breastfed.

“Adjusted odds ratios for associations between ASD and reported use of iron supplements were consistently below the null across the index period but were nonsigni fi cant except during breastfeeding (among those who breastfed)”

May combine two claims.

Low maternal iron intake carried a much higher ASD risk when the mother was also older at delivery and/or had metabolic conditions in pregnancy.

“Further, ASD risk associated with low maternal iron intake was much greater when the mother also was older at the time of the child ' s birth and/or had metabolic conditions during pregnancy.”

May combine two claims.

Maternal iron intake showed no significant interactions with child sex, child or maternal race/ethnicity, or interpregnancy interval.

“No signi fi cant interactions were observed between maternal iron intake and child sex, child or maternal race/ethnicity, or interpregnancy interval.”

The quote only partly states this claim.

Mean iron intake from multivitamins during the index period was higher among mothers of children with ASD than among mothers of children with typical development.

“while maternal intake of iron from multivitamins was higher (Table 3).”

May combine two claims.

In both groups, average iron intake from cereals and supplements across pregnancy exceeded the Tolerable Upper Intake Limit for iron, yet matched national supplement-intake estimates for pregnant women (48 mg/day) and women of childbearing age (18 mg/day).

“Average iron intake from cereals and supplements throughout pregnancy for both groups in this study was above the Tolerable Upper Intake Limit for iron (40) but was in line with national estimates of intake from supplements for pregnant women (48 mg/day) (41) and women of childbearing age (18 mg/day) (42).”

• cites [40] Food and Nutrition Board, Institute of Medicine, 2001Not checked yet

  Not checked in the free run.

• cites [41] 2013, Dietary supplement use and folate status during pregnancy in the United States, J Nutr sourceNot checked yet

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• cites [42] 2005, Iron supplement use and iron status among US adults: results from the third National Health and Nutrition Examination Survey, Am J Clin Nutr sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Total iron intake peaked in the second half of pregnancy in both groups.

“Mean total iron intake was highest in the second half of pregnancy for both groups (Figure 3).”

May combine two claims.

A significant multiplicative interaction (P = 0.01) showed higher ASD risk when mothers had metabolic conditions and were in the lowest iron quintile (OR = 4.72, 95% CI: 1.69, 13.15); this exceeded by over twofold what additive (OR = 2.07) or multiplicative (OR = 2.36) models predicted.

“There was also a signi fi cant multiplicative interaction ( P = 0.01), with higher ASD risk being associated with the combination of mothers having metabolic conditions and iron intake in the lowest quintile (OR = 4.72, 95% CI: 1.69, 13.15), which was over twice that expected from adding (OR = 2.07) or multiplying (OR = 2.36) their independent associations (Table 6).”

May combine two claims.

Case mothers reported lower average iron intake than control mothers, particularly before pregnancy and in early pregnancy.

“Mean intake reported by case mothers was lower than that reported by control mothers, especially for the months before pregnancy and during early pregnancy (Figure 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Prenatal vitamins were the main source of iron for mothers in both the ASD and typical development groups during the index period.

“Prenatal vitamins were the greatest source of iron for mothers in both diagnostic groups during the index period (Table 3).”

May combine two claims.

Case mothers reported lower intake of iron from sources other than iron-specific supplements (breakfast cereal), which would not have been as likely to increase in response to an anemia diagnosis.

“However, case mothers reported lower intake of iron from sources other than iron-speci fi c supplements (breakfast cereal) that would not have been as likely to increase in response to an anemia diagnosis.”

May combine two claims.

During breastfeeding, the association with iron-specific supplements, which was not correlated with folic acid, was consistently below the null and significant.

“In addition, the association with iron-speci fi c supplements, which was not correlated with folic acid, was consistently below the null and signi fi cant during breastfeeding.”

May combine two claims.

Iron is critical for early neurodevelopment, and its deficiency may affect pathways dysregulated in autism spectrum disorder.

“Iron is critical for early neurodevelopmental processes that are dysregulated in autism spectrum disorder (ASD).”

• Also stated in: § Rebecca J. Schmidt * , Daniel J. Tancredi, Paula Krakowiak, Robin L. Hansen, and Sally Ozonoff · p. 2 · plain

  “Iron is crucial to early neurodevelopment. In the brain, iron contributes to neurotransmitter production, myelination, and immune function (14); dysregulation of all 3 of these pathways has been associated with ASD.”

• cites [14] 2000, Effectiveness and strategies of iron supplementation during pregnancy, Am J Clin NutrNot checked yet

  Not checked in the free run.

May combine two claims.

Early-life iron deficiency impairs cognition, motor development, social orientation and engagement, and language development, with improvements observed upon iron supplementation.

“Iron de fi ciency early in life has been shown to impair cognition, motor development, social orientation and engagement, and language development, with improvements being observed upon iron supplementation (15 -19).”

• cites [15] 2005, Effect of iron supplementation on mental and motor development in children: systematic review of randomized controlled trials, Public Health Nutr sourceNot checked yet

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• cites [16] 2004, Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants, Am J Clin Nutr sourceNot checked yet

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• cites [17] 2004, Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers, Pediatr Res sourceNot checked yet

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• cites [18] 2001, Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study, BMJ sourceNot checked yet

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• cites [19] 1991, Long-term developmental outcome of infants with iron deficiency, N Engl J Med sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Iron deficiency is common during pregnancy, affecting 40%-50% of women and their infants.

“Iron de fi ciency, with its resultant anemia, is the most commonly measured nutrient de fi ciency, and it is especially common during pregnancy, affecting 40% -50% of women and their infants (8 -10).”

• cites [8] 2001, Defining iron-deficiency anemia in public health terms: a time for reflection, J Nutr sourceNot checked yet

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• cites [9] 2003, Maternal iron status influences iron transfer to the fetus during the third trimester of pregnancy, Am J Clin Nutr sourceNot checked yet

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• cites [10] World Health Organization, 2001Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder were less likely to have eaten cereal during the index period than mothers of typically developing children.

“and less likely to have eaten cereal during the index period.”

Classified as probably not a substantial claim.

Survey research methods with inverse participation probability weights were used to fit logistic regression models.

“To ensure that the results represented the study base, we used survey research methods to fi t the logistic regression models, with participants being assigned weights equal to the inverse of the estimated participation probability in strata de fi ned by the entry case group and demographic factors (38).”

• cites [38] 2007, Survey research methods in evaluation and case-control studies, Stat Med sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Confounders were selected by backward elimination, retaining variables that changed exposure estimates by at least 10%; maternal folic acid intake, home ownership, and child's birth year were the only variables meeting the criteria.

“Variables were then excluded using backward selection, retaining in the model any variables that caused at least a 10% change in the exposure parameter estimates. Maternal folic acid intake, home ownership, and child ' s birth year were the only variables meeting the confounder criteria.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder tended to be older than mothers of typically developing children.

“Their mothers also tended to be older”

Classified as probably not a substantial claim.

Evidence supports an influence of gestational nutrition.

“and an in fl uence of gestational nutrition (6, 7).”

• cites [6] 2011, Closely spaced pregnancies are associated with increased odds of autism in California sibling births, Pediatrics sourceNot checked yet

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• cites [7] 2011, Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism, Epidemiology sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder were more likely to have been born outside the United States than mothers of typically developing children.

“were more likely to have been born outside of the United States”

May combine two claims.

Poor iron status in children with autism spectrum disorder does not necessarily correlate with low iron intake, suggesting less efficient absorption or metabolism of iron.

“Poor iron status is more prevalent in children with ASD (20 -24) and does not necessarily correlate with low iron intake (22), suggesting that these children could absorb and/or metabolize iron less ef fi ciently.”

• cites [22] 2012, Iron status in children with autism spectrum disorder, PediatricsNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder were more likely to have some college education but no bachelor's or higher degree than mothers of typically developing children.

“their mothers were signi fi cantly more likely to have some college education but no bachelor ' s or higher degree”

Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder were more likely to have smoked cigarettes than mothers of typically developing children.

“to have smoked cigarettes”

Classified as probably not a substantial claim. May combine two claims.

Data completeness was high: 510 (98%) ASD participants and 341 (99%) TD participants had information on maternal iron supplement use, and 454 (87%) ASD and 307 (89%) TD participants had information on total average maternal iron intake.

“Of the 520 ASD and 346 TD CHARGE participants eligible for these analyses, 510 (98%) ASD participants and 341 (99%) TD participants had information on maternal use of iron supplements during the index period, and 454 (87%) ASD participants and 307 (89%) TD participants had information on total average maternal iron intake from all sources.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Children with autism spectrum disorder were more likely to have been born earlier than typically developing children.

“Children with ASD were more likely to have been born earlier than”

Probably not a substantial claim: may not pass S3 (load-bearing).

Missing data were assessed using multiple imputation via the Markov chain Monte Carlo algorithm.

“In sensitivity analyses, we assessed the impact of missing data using multiple imputation via the Markov chain Monte Carlo algorithm (37).”

• cites [37] 1997Not checked yet

  Not checked in the free run.

May combine two claims.

The findings of reduced ASD risk with higher maternal iron intake persisted after imputation of missing values and when survey weights were used.

“These fi ndings remained after imputation of missing values and when using survey weights (Table 4).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Parents of children with autism spectrum disorder were less likely to own their homes than parents of typically developing children.

“Parents of children with ASD were significantly less likely to own their homes.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Mothers of children with autism spectrum disorder were less likely to have private medical insurance than mothers of typically developing children.

“and were less likely to have private medical insurance.”

May combine two claims.

During the study years, data were not collected on other dietary sources of iron, so information was not available to completely assess dietary iron intake.

“In addition, during these study years data were not collected on other dietary sources of iron, so information was not available with which to completely assess dietary iron intake.”

Classified as probably not a substantial claim. May combine two claims.

High iron intake from supplements or fortified products is known to be toxic, has been linked to negative health effects such as adverse neurodevelopmental outcomes, and may be particularly harmful for some genetically susceptible people.

“very high iron intake in supplemental or forti fi ed forms is known to be toxic and has been associated with negative health impacts, including adverse neurodevelopmental outcomes, and could be especially harmful for certain genetically susceptible individuals (42, 45).”

• cites [42] 2005, Iron supplement use and iron status among US adults: results from the third National Health and Nutrition Examination Survey, Am J Clin Nutr sourceNot checked yet

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• cites [45] 2002, Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age, J Pediatr sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Periconceptional folic acid is associated with reduced risk of autism spectrum disorder.

“as expected given that periconceptional folic acid is associated with reduced ASD risk (35, 69)”

• cites [35] 2012, Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study, Am J Clin Nutr sourceNot checked yet

  Not checked in the free run.

• cites [69] 2013, Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children, JAMA sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A randomized, double-blind trial found that 40 mg/day of supplemental iron in pregnancy prevented iron deficiency in most women and that doses up to 80 mg/day were well tolerated.

“A randomized, double-blind trial demonstrated that during pregnancy, 40 mg/day of supplemental iron was needed to prevent iron de fi ciency in the majority of women and that up to 80 mg/ day was well-tolerated (43).”

• cites [43] 2005, Iron prophylaxis during pregnancy—how much iron is needed? A randomized dose-response study of 20–80 mg ferrous iron daily in pregnant women, Acta Obstet Gynecol Scand sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Genetic differences were not considered in this study.

“These genetic differences were not considered here, and they deserve further evaluation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Other unmeasured confounding factors associated with taking supplements could have played a role in the findings.

“Still, other unmeasured confounding factors associated with taking supplements could have played a role in our fi ndings.”

Probably not a substantial claim: may not pass S3 (load-bearing).

On the basis of genetic differences, the efficiency of iron uptake and metabolism differs vastly between individuals.

“The ef fi ciency of iron uptake and metabolism differs vastly between individuals on the basis of genetic differences (46).”

• cites [46] 2004, Iron, zinc, and copper concentrations in breast milk are independent of maternal mineral status, Am J Clin Nutr sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Genetically determined metabolic efficiency could likely modify the need for and the effects of iron supplementation.

“It is likely that genetically determined metabolic ef fi ciency could modify the need for and the effects of iron supplementation.”

May combine two claims.

Prevention of iron deficiency might be key for protecting against adverse neurodevelopmental outcomes, and early developmental periods are critical.

“Long-term effects are observed in adulthood, long after iron repletion, in hippocampal structure and function, monoamine metabolism, and myelination (55 -60), indicating that early developmental periods are critical and that prevention of iron de fi ciency might be key for protecting against adverse neurodevelopmental outcomes.”

• cites [55] 2006, Long-lasting neural and behavioral effects of iron deficiency in infancy, Nutr Rev sourceNot checked yet

  Not checked in the free run.

• cites [56] 2003, Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats, Dev Neurosci sourceNot checked yet

  Not checked in the free run.

• cites [57] 2007, Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [58] 2006, Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain, J Neural Transm SupplNot checked yet

  Not checked in the free run.

• cites [59] 2005, Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [60] 2003, Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons, Dev Neurosci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In adulthood, long after iron repletion, long-term effects are observed in hippocampal structure and function, monoamine metabolism, and myelination.

“Long-term effects are observed in adulthood, long after iron repletion, in hippocampal structure and function, monoamine metabolism, and myelination (55 -60), indicating that early developmental periods are critical and that prevention of iron de fi ciency might be key for protecting against adverse neurodevelopmental outcomes.”

• cites [55] 2006, Long-lasting neural and behavioral effects of iron deficiency in infancy, Nutr Rev sourceNot checked yet

  Not checked in the free run.

• cites [56] 2003, Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats, Dev Neurosci sourceNot checked yet

  Not checked in the free run.

• cites [57] 2007, Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [58] 2006, Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain, J Neural Transm SupplNot checked yet

  Not checked in the free run.

• cites [59] 2005, Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [60] 2003, Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons, Dev Neurosci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

During brain development, maternal iron intake can influence both the mother's iron status and her child's status.

“Maternal circulation constitutes the only source of iron for the developing fetus (11), and maternal iron intake can in fl uence both the mother ' s iron status and her child ' s status (47) during brain development.”

• cites [47] 2000, Iron supplementation in pregnancy, Cochrane Database Syst Rev.Not checked yet

  Not checked in the free run.

May combine two claims.

A 1.7-fold increased risk of autism spectrum disorder and nearly a 2-fold risk of developmental delays are independently associated with metabolic conditions.

“Notably, metabolic conditions are independently associated with a 1.7-fold increased risk of ASD and nearly a 2-fold risk of developmental delays (36).”

• cites [36] 2012, Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders, Pediatrics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Prenatal inflammation can cause a cytokine-mediated reduction of circulating nonheme iron, or hypoferremia, which can disrupt fetal brain development and lead to persistent structural and functional brain defects.

“Prenatal in fl ammation can produce a cytokine-mediated reduction of circulating nonheme iron, or hypoferremia (48), that can disrupt fetal brain development and lead to persistent structural and functional brain defects (55 -60).”

• cites [48] 2010, Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia, PLoS One sourceNot checked yet

  Not checked in the free run.

• cites [55] 2006, Long-lasting neural and behavioral effects of iron deficiency in infancy, Nutr Rev sourceNot checked yet

  Not checked in the free run.

• cites [56] 2003, Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats, Dev Neurosci sourceNot checked yet

  Not checked in the free run.

• cites [57] 2007, Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [58] 2006, Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain, J Neural Transm SupplNot checked yet

  Not checked in the free run.

• cites [59] 2005, Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus, Hippocampus sourceNot checked yet

  Not checked in the free run.

• cites [60] 2003, Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons, Dev Neurosci sourceNot checked yet

  Not checked in the free run.